You are on page 1of 79

Solutions Manual to the Third Edition of Organic Synthesis

This book contains answers to most of the end-of-the-chapter problems found in Organic Synthesis, 3rd edition. The vast majority of problems and answers are taken from the literature, and the appropriate citation is given for each answer. For reactions, only the product is shown, along with the literature reference. For discussion type problems and for mechanistic questions, a brief explanation is usually offered, again with the literature citation. The only exception is chapter 10, where answers are not provided. In a few cases, literature citations are given where a synthesis can be found. In most cases, however, I believe that solutions to synthesis problems are best discussed with your instructor because there is no one correct answer. If there are errors, corrections, and suggestions, please let me know by EMail or normal post. Any errors will be posted. Thank you again. I hope this new solutions manual is useful to you in your studies using Organic Synthesis . Michael B. Smith, April, 2010 Storrs, Connecticut 06269-3060

University of Connecticut, Department of Chemistry, 55 N. Eagleville Road, Storrs, Connecticut EMail: michael.smith@uconn.edu fax: 860-486-2981 homepage: http://orgchem.chem.uconn.edu/home/mbs-home.html

Table of Contents
Answers to Chapter 1 Problems Answers to Chapter 2 Problems Answers to Chapter 3 Problems Answers to Chapter 4 Problems Answers to Chapter 5 Problems Answers to Chapter 6 Problems Answers to Chapter 7 Problems Answers to Chapter 8 Problems Answers to Chapter 9 Problems Answers to Chapter 10 Problems Answers to Chapter 11 Problems Answers to Chapter 12 Problems Answers to Chapter 13 Problems 3 13 26 37 52 60 66 77 96 117 119 133 143

Organic Synthesis Solutions Manual

CHAPTER 1
1. The calculations are shown for each molecule using values from Table 1.5 in Chapter 1.
CHMe2 Me2 HC C C-CH3 NH 2 C  CMe A NH2 Me2 HC B

NH2 C CMe

(a) HA = ACHR2 + AC = 2.1 + 0.2 = 2.3 kcal mol-1 HB = ANHR + GC + GCHR2 = 1.3 + 0 + 0.8 = 2.1 kcal mol-1 H = HB HA = 2.1 2.3 = 0.2 kcal mol-1 At 150C, 2.303RT = 2.303(1.987)(423)* = 1.936 kcal mol-1 [* T is in Kelvin = C + 273] therefore  G = 0.2 = 1.936 log Keq -0.2 log Keq = -1.936 = +0.103 Keq = 100.103 = 1.27 1.27 = B(2.27) 1.27 2.27 = B = 0.56 Therefore, 56% of B and 100-56 = 44% of A.

If A + B = 1 then, A = 1-B B B Keq = A = 1-B Keq(1-B) = B Keq and B = 1+K , via


eq

1.27(1-B) = B 1.27 - 1.27B = B 1.27 = B+1.27B

Since A has two axial groups and B has only one, an initial glance suggests that B will be lower in energy and be the greatest contributor to the chair population. Conformation A has one axial group (CHMe2) on the top and one axial group (CCMe) on the bottom so ACHR2 and AC are used from Table 1.5. In B there is only one axial group (NH2) so AOR is used. The two equatorial groups in B (CHMe2 and CCMe) are on adjacent carbons, so there are two G terms, GC and GCHR2 .

Chapter 4

Cl H 3C MeO O MeO

CH3 Cl Cl A O H3 C B OMe

(b)

HA = 4 (ACH2R + ACl) = 0.1.8 + 0.4 = 1.65 kcal mol-1


3 3 4

If A + B = 1 then, A = 1-B B B Keq = A = 1-B Keq(1-B) = B Keq and B = 1+K 0.526 1.526 = B = 0.345
eq

HB = 4 (AOR + GCH2 R + GCl) =

(1.8 + 0.4 + 0.5) = 2.03 kcal mol-1

H = HB HA = 2.03 1.65 = 0.38 kcal mol-1 at 25C,  G = 0.38 = -1.364 log Keq log Keq = -1.364 = -0.279 Keq = 10-0.279 = 0.526 Therefore, 34.5% of B and 100-34.5 = 65.5% of A.
0.38

Although B has two axial groups, it is actually lower in energy because the axial chlorine has a lower interaction that the combined G value interactions in B. It accounts for only 35% of the population of chair conformers. Conformation B has two adjacent and diequatorial groups, so GCH2R and GCl are used from Table 1.5. Since B has one axial methoxy group, AOR is used.
Cl MeO OMe Me OMe MeO

OMe Me OMe Cl MeO

OMe OMe Me B

Cl A

(c)

(c) HA = AOR + ACl + GCH2R + GOR = 0.8 + 1.8 + 0.4 + 0.2 = 3.2 kcal mol-1 HB = UOR + UOR + ACH2 R + GCl + GOR = 0.8 + 0.8 + 1.8 + 0.5 + 0.2 = 4.1 kcal mol-1 H = HB HA = 4.1 3.2 = 0.9 kcal mol-1 at 25C,  G = 0.9 = 1.364 log Keq 0.9 log Keq = -1.364 = 0.66 Keq = 10-0.66 = 0.22 Therefore, 18% of B and 100-18 = 82% of A.

If A + B = 1 then, A = 1-B

B B Keq = A = 1-B Keq(1-B) = B Keq and B = 1+K


eq

0.22 1.22 = B = 0.18

Organic Synthesis Solutions Manual

The three axial groups in B, along with the two G-interactions make it much more sterically demanding than the two axial groups and the two G-interactions in A. Therefore, A accounts for the greater percentage of chair conformations.
Ph Me3C Ph Me3C Ph A CMe3 B

(e)

HA = no interactions = 0 kcal mol-1

If A + B = 1 then, A = 1-B B B Keq = A = 1-B Keq(1-B) = B Keq and B = 1+K


eq

HB = Aaryl + ACR3 = 3.0 + 6.0 = 9.0 kcal mol-1 H = HB HA = 9.0 0 = 9.0 kcal mol-1 at 25C,  G = 9.0 = 1.364 log Keq 9.0 log Keq = -1.364 = -6.598 Keq = 10-6.598 = 3x10-7 Therefore, 0.00003% of B and 100-0.00003 = 99.99997% of A.

3x10-7 -7 1.00 = B =3x10

Since A has two large equatorial groups and B have two large axial group, the equilibrium is pushed in the direction of A, in essentially 100%. 2. The absolute configuration for each chiral center in the following molecules is shown beside the appropriate chiral center.

OH HO (a) H H O O HH H HH O O (+)-absinthin see J. Am. Chem. Soc., 2005, 127, 18 H (b)

H O O O O H biepiasterolide see J. Org. Chem., 2004, 69, 9100 H OAc (+)-laurencin see Org. Lett., 2005, 7, 75 O H (c) H Br

3.

Chapter 4

O (a) O O O O O (b) O O (c) OH OH N MeO2C

ON

amphidinolide X see J. Am. Chem. Soc., 2004, 126, 15970

(+)-lapidilectine B see J. Org. Chem., 2004, 69, 9109 O OH OH

O mycolactone C see Org. Lett. 2004, 6, 4901

4. After donor and acceptor sites for disconnect fragments 22 and 23, fragment B represents an umpolung reagent (acyl anion equivalent - see Chap. 8, Sec. 8.6.B), F. Fragment A is simply the alkyl halide,

22

O 23

a A

d O

B AND C

a O

Br

S S

CuLi Cl 2 O G H

E. The other d/a combination is C (which is the equivalent of organocuprate, G) and D (which is the equivalent of acid chloride H). Both are viable processes but we not will choose the reaction of E and F since alkylation of dithiane reagents can be sluggish (see Chap. 8, Sec. 8.6.B.ii) and because an extra step is required to convert the dithiane back to the carbonyl (see Chap. 7, Sec. 7.3.B.ii). Acid chloride H contains

Cl O H

HO O I OH J

the four carbons of the starting material, and it is obviously derived from isobutyric acid (I), available from Aldrich (2000-2001), $25.50/L. Assume it must be made from 2-methylpropene, however. Accord-ing to Figure 1.1, one route to an acid is by oxidation of an alcohol (see Chap. 3, Sec. 3.2.A). The alcohol (J) can be prepared from the alkene by hydroboration (see Chap. 5, Sec. 5.4.A). Once acid chloride H is available, it is reacted with

Organic Synthesis Solutions Manual

organocuprate G, derived from bromide E. In this analysis, E is not formally prepared from 2-methylpropene (although a synthesis could be designed if desired), and G is considered to be a reagent in this synthesis (an 'off the shelf' compound that is reacted with the molecules derived from the retrosynthesis, just like B2H6 or CrO3 in the sequence shown). If the reagents provided in this synthesis are not familiar, careful reading of the remainder of this book and the literature will explain these choices. 5. There is more than one "correct" answer. One possible solution is shown for each transformation. The letters (a), (f), etc., beside each reagent refer to the lettered transformations from Figure 1.1 in Chapter 1. (a)
1. B2 H6 2. NaOH/H2 O2 OH (w)

(b)

RCO3 H (v)

O 2. hydrolysis (c) C N

1. NaCN , THF

OH

dilute NaOH Br

(c)

OH CHO (a) (c) The first reaction is a poor one since elimination will be a major process. Limiting the choices to those in Figure 1.1 is a problem since there are other ways to do this.

CrO3 , H+

OH

PBr3 (d)

KOH , EtOH Br (f)

1. O3 2. H2 O2 2. SOCl2 ; MeOH
Me OH

CO2 Me CO2 Me

(d) (e)

(x) & no reactions for conversion to acid derivatives


1. O 3 2. Me 2 S (x) O MeMgBr (3b) see Table 1.1

1. H3 O+

(f)

CN

2. SOCl2 3. NH3

CONH2

No reagents are provided in Figure 1.1 they are part of the conversion to acid derivatives

6. There are potentially many examples for each part (but not always; see the last sentence for this answer). This is a literature searching question, and there are no correct or incorrect answers. The appropriate sections and pages from Vol. 11of the Compendium are indicated for each category.

Chapter 4

(a) Acids from Nitriles. Section 28. Volume 11: p. 15 (0 examples). (b) Aldehydes from Nitriles. Section 58. Volume 11: p. 103 (0 examples). (c) Amines from Halides. Section 100. Volume 11: pp. 289-294 (28 examples). (d) Amides from Nitriles. Section 88. Volume 11: p. 257 (5 examples). (e) Ethers from Halides. Section 130. Volume 11: pp. 347-348 (6 examples). (f) Halides from Amines. Section 142. Volume 11: p. 369 (0 examples) (g) Ketones from Olefins. Section 179. Volume 11: p. 409 (3 examples). (h) Olefins from Aldehydes. Section 199. Volume 11: pp. 440-443 (17 examples). The real lesson from this exercise, apart from learning to use this literature resource, is that some functional group exchange reactions are well studied and there are many variations. this case, further literature searching in the older literature is a necessity. 7. The bicyclo[2.2.1]heptane unit (A) is very rigid and greatly influences the stereochemistry for the molecule. Others yield only a handful of possibilities. Despite the request for three examples in the question, noexamples were found for (a), (b) or (f). In

The appended six-membered ring B assumes a conformation that is close to a twist-boat, and it cannot 'ring flip' easily due to the conformationally immobile bicycloheptane unit. This constraint forces the methyl group (Me2) into a pseudo-axial position. The other methyl group (Me1) is at a bridgehead position of the bicycloheptane and is effectively perpendicular to that ring, as shown. The hydroxyl group is formally in a pseudo-axial position relative to ring B.
Me HO B A A Me
1 2

Me2 H A

Me

8. For each molecule, a representative model from the indicatied perspective using Spartan is shown.

Organic Synthesis Solutions Manual

1 2 O

O 4 AcO

(plus 'top' [above page] and 'bottom [below page] views)

(+)-mycoepoxydiene 3 see J. Org. Chem., 2004, 69, 8789

top view

bottom view

2H (b) N

O OH

halochlorine see J. Org. Chem., 2004, 69, 7928

1 Cl (plus 'top' [above page] and 'bottom [below page] views)

top

3
bottom

Chapter 4

The purpose of this drawing exercise is to cast yourself in the role of a reagent approaching a molecule. Different angles of approach means the reagent "sees" a different set of groups and atoms for each portion of the molecule, which will have an important effect on the reactivity of the incoming reagent. By drawing the molecule from several perspectives, the goal is to see how angle of approach and topography may influence reactivity in a given molecule. Also, it emphasizes that the two-dimensional drawings we usually use often have little meaning in terms of the real structure of a molecule and determining its reactivity. 9. The R or S configuration for the chiral axis of each molecule that has a chiral axis rather, as well as that of stereogenic centers chiral center, is shown for (a) - (e).
OMe Cl (a) Br C H (b) CH 2CH2 Cl OH NH2 H (c) NH Me Me 2 HC CMe3 HOH2 C OH (d) Cl Et CH2 Cl H O (e) CHMe 2

For (a), Cl is 1 and H is 2; Br is 3 and CH2 CH2Cl is 4. For (b), OH is 1 and Caryl is 2; NH2 is 3 and Caryl is 4. For (c), Cl is 1 and Et is 2; Me is 3 and H is 4. For (d), CH2 Cl is 1 and Et is 2; CMe3 is 3 and CHMe2 is 4. For (e) the epoxy O is 1 and MHMe2 is 2; OH is 3 and CH2OH is 4.
Et H Me Me Me O Me H (a) Me Me (b) P R Me R P Ph Ar Ph3 P (c) OC Cp Fe EtO2 C O (d) Ph O Me EtO O OiPr

Me Me O Mg Br

10.

11. When the hydroxy-acid cyclizes to form the lactone (see A) the two methyl groups are 1,3-diaxial, with the tertbutyl group equatorial. In the presence of acid, the hydroxyl group can be protonated and eliminate water and form a cation. In the presence of water, the alcohol is re-formed, but both epimers are generated since reaction with water leads

10

Organic Synthesis Solutions Manual

to the methyl group being axial or equatorial in the lactone. Under equilibration conditions, the lactone with one axial methyl and one equatorial methyl will be lower in energy due to diminished A-strain, and the equilibrium will shift to favor that lactone (net epimerization of the alcohol-bearing carbon in the hydroxy-acid). Acid catalyzed opening of the lactone gives, of course, the hydroxy-acid.
Me t-Bu H Me O Me H t-Bu H O A O O B Me O H O H

12. The diaxial conformation allows hydrogen bonding (see B ). Such hydrogen bonding counterbalances the energy difference of the diaxial (which has U-strain) vs. diequatorial conformations. The net result is that although the diaxial conformation has U-strain, the hydrogen bonding makes it the dominant species.
a O c b re c si b H b (b)a re OH c a c (c) b Ph N a N-H Ph si

(a)

13.

14. The correlation is Taken from Eur. J. Org. Chem. 2004, 2398
OH
2 1 3 4 6 5 6 5 7

4 3

A
7

Br OH
2 3 4

Br

Br

Cl

2 S, 3 R, 5R
6 5

ery th ro and
2 1 3 4 5 6

s yn

A
7

Br
threo

Cl
an d

Br

Br

an ti

15. 16.

2S, 3S, 5 S

(a) diastereoselective

(b) enantiospecific

(c) regiospecific and diastereoselective.

Chapter 4

11

17. Cyclodecane has a relatively small internal cavity where transannular interactions are maximized. This transannular interaction disappears in cyclooctadecane where the additional carbons make the internal cavity large enough for the "internal" hydrogens to have little interaction. Compare 182B and 184 on page ??? in the text. Inspection of Figure 1.13 of the text can answer the second part of this question. Cyclohexadecane is an evenmembered ring and, as such, will fit better on the diamond lattice. Since cyclopentadecane has an odd-membered ring, there is a "twist" in the ring when attempting to "lay it on the diamond lattice". This "twist" makes the energy of the ring slightly higher.

H H H H

18.

See J. Am. Chem. Soc., 1994, 116, 10306.

12

Organic Synthesis Solutions Manual

CHAPTER 2

1. This solvolysis reaction proceeds with loss of the leaving group to generate a cation. The aromatic ring will stabilize that cation either by -donation from the ring or by formal resonance participation via a non-classical ion. In either case, an electron-donating substituent on the aromatic ring will stabilize the charge and, thereby, stabilize the intermediate cation. This stability will be reflected in the relative rate of the solvolysis reaction. Both OMe and Me are electron donating and therefore enhance the rate. Since OMe is a more powerful electron donating group, the effect is large. The Cl substituent is mildly electron withdrawing and, therefore, slows the relative rate by slightly destabilizing the intermediate cation. This problem is taken from J. Org. Chem., 1985, 50, 821. 2. Since the OH group in 3-pentanol is an extremely poor leaving group and iodide is a nucleophile, an SN2 reaction is not facile. Despite the presence of the water, solvolysis of the alcohol moiety to generate a cation is somewhat slow. If an acid catalyst is added, however, protonation of the OH occurs and loss of water generates the cation. The cation is then trapped under SN1 conditions by iodide to give 3-iodopentane.

H+ OH H

- H 2O O H

+ I I

3. This bromide is in fact a neopentyl-like molecule [R3 C-CH(R')X] and, therefore, very sterically hindered to nucleophilic displacement (see Sec. 2.6.A.i). Neopentyl halides react much slower with nucleophiles under SN2 conditions than do tertiary halides (see Table 2.11 on page 105 in the text). The use of KOH in DMF promotes substitution, and the DMF does not allow facile ionization to give an SN1 displacement. Elimination with the basic KOH dominates if the substitution reaction is too slow to compete. 4. (a) Since the phenyl ring is somewhat electron-withdrawing, the three phenoxides are less basic than the cyclohexanol anion. The OMe group is electron releasing, and this makes the availability of electron density on Ogreater than on phenoxide. Similarly, the nitro group is electron withdrawing, making the electron density on O less than in phenoxide. (b) When comparing formic acid and acetic acid, the electron releasing methyl group in acetic acid diminishes the positive character of the acidic hydrogen. It is therefore less acidic. In addition, once ionized to the carboxylate, the presence of the electron releasing methyl group slightly diminishes the adjacent positive character

Chapter 4

13

of the carboxyl carbon, destabilizing the anion relative to the formate anion. The smaller formate anion is probably better solvated than the acetate anion, which also contributes to enhanced acidity. ortho -Methoxyphenol is more acidic than para-methoxyphenol due to the "ortho effect." The proximity of the OMe in the ortho derivative allows internal hydrogen bonding with the O-H moiety, making that bond more polarized and more acidic. Such internal hydrogen bonding is not possible in the para derivative, although intermolecular hydrogen bonding may occur. Acetic acid is more acidic in water, although THF is a stronger base. Ionization is much easier in water than in THF, and water can better stabilize the ionic products. This makes the ionization (loss of H+) easier, enhancing acidity relative to THF where ionization is less efficient.
N(CH2 Ph)2 O (a) (b) Et O Cl OMe O H N SiMe3 O (c) MeO O see Tetrahedron Lett., 2000, 41, 733 O OMe

Et see J. Org. Chem., 1999, 64, 7586 see J. Org. Chem., 1999, 64, 4980 OMe O O (d) Cl NHi-Pr (e) MeO NEt2 (f)

Me (CH2 )9 O

H N Me

Ph

OMe see Tetrahedron Lett., 2000, 41, 1975 see J. Am. Chem. Soc., 1994, 116, 9921 see J. Org. Chem., 1999, 64, 2450 O (g) N O O (h) H O MeO O N O O

5.

see J. Org. Chem., 1999, 64, 3736

see J. Am. Chem. Soc., 1994, 116, 9921

6. Taken from Stock, L.M., Aromatic Substitution Reactions, Prentice-Hall, Englewood Cliffs, N.J., 1968, p. 91. This reaction proceeds via a benzyne intermediate (X). Addition of NH2 to either carbon of the triple bond leads to the two products shown and the 14C label on both carbons relative to the ipso carbon bearing the amine unit.

14

Organic Synthesis Solutions Manual

Cl *

H2 N

* H 2O

NH2 *

NH2 + *

* =

14

7.

This cyclohexane derivative exists in two chair forms, A and B. An E2 reaction cannot occur from A because A trans-diaxial relationship between the bromine and any -hydrogen(s) is a

the bromine is equatorial.

requirement. Only when the bromine is axial in conformation B is one -hydrogen is axial. This means that the E2 reaction can give only one alkene with the double bond toward the methyl group rather than the ethyl group. The stereochemistry in the halide makes this a regiospecific elimination.
Me Br Et Me Et Me A Me H Br Me H B Et Br Me H Et Me Me

8. See Tetrahedron Lett., 2000 , 41, 3411. The tertiary allylic alcohol reacts with the acidic resin (H+) to give the oxonium ion. There are two pathways. An SN2' displacement of water by the primary alcohol unit leads to the product directly. This is the mechanism presented by the authors of this paper. An alternative mechanism would be ionization to an allylic tertiary cation followed by cyclization and loss of a proton, as shown in the diagram.

HO OH

+ H+

H 2O OH

S N2' H2 O O

H2 O H+ vinylogous S N1-like OH H O Tetrahedron Lett., 2000, 41, 3411

9. This reaction proceeds via a mercury-stabilized secondary cation. In this paper, a detergent (sodium dodecyl sulfate) was added and it had an important effect. The cation formed in the reaction can react with water (from the aqueous solvent) to give an alcohol after reductive cleavage of the C-Hg bond with sodium borohydride. The ether is formed by attack of octanol on the cation. There is a large excess of water, however, so the alcohol is the major product. Increasing the proportion of octanol leads to increased amounts of ether. Even when 10 equivalents of

Chapter 4

15

octanol are used, water is present in a large excess. In fact, water and octanol are close in nucleophilic strength. The detergent leads to enhanced local concentrations of octanol that can overcome the bulk concentration effects of the excess water, leading to more ether product. Taken from J. Org. Chem., 1987, 52 , 5039. 10. This problem was taken from J. Org. Chem., 1987, 52, 260; 1984, 47, 4855.

(a) Product A is the usual product of reaction of an alkene with chlorine. Formation of chloronium ion X was followed by addition of chloride ion to give A, as shown. Product B arises by a cationic mechanism that involves participation of the aromatic ring. If chloronium ion X opens to form cation Y, the benzene ring attacks the positive charge to form the bridged cation Z. If chloride ion attacks the three-membered ring, as shown, B results.
MeO MeO MeO Cl

ClCl X MeO

Cl Y Cl MeO

MeO Cl Cl Z

Cl

Cl A Cl B

Cl

(b) If the OMe group, which is electron-releasing, is replaced with Cl, which is electron-withdrawing, product B should be more difficult to form. Cation Z is stabilized by the electron releasing OMe group, but an electron withdrawing Cl would destabilize this intermediate, making formation of Z more difficult and, thereby, formation of B. 11. See Tetrahedron Lett., 1997, 38, 3469. When drawn in a form that approximates the three-dimensional shape it is clear that the cyclobutanone unit flattens the tricyclic system. Protonation of the glycol unit is followed by acidcatalyzed addition of methanol to the ketone. A Grob-like fragmentation leads to formation of the methyl ester unit and a cation. This cation traps water and with proton transfers loses ethylene glycol to form the ketone unit found in the final product.

16

Organic Synthesis Solutions Manual

O H O O MeOH , 1N HCl RT O H CO2 Me H O O O O H H + H+ H H O O O H H H + MeOH; H+ transfer H O O OMe HO H H


+

O OMe HO H O H OH OMe HO H H+;+H+ H O H O O OMe HO + H2 O H O OH2 OMe HO ethylene glycol H+

12. See Tetrahedron Lett., 2000, 41, 403. This reaction proceeds by protonation of the alcohol and loss of water from A to form a carbocation 1. There are two potential sites for rearrangement to a tertiary cation, to 2 or to 3. To form cation 3 requires that the sp2 carbon be flattened to a trigonal planar shape. This would subject the tricyclic system to a great deal of strain, and the result is that cation 2 is formed preferentially. Loss of a proton via an E1 mechanism leads to the alkene product, B.
OH p-TsOH , benzene H A H + H+ ; H2 O lower in energy H H 2 high energy due to flattening the tricyclic ring systemless favorable reflux 70% H+ B H H

H 1

H 3

13. This reaction is taken from Org. Lett., 2003, 4, 59. Initial deprotonation of the alcohol leads to the alkoxide

Chapter 4

17

shown. As the carbonyl of the aldehyde is formed, the four-membered ring is formed by transannular displacement of the bride, which is properly positioned for reaction.
O Br H OH KH O O Br H CHO

14. Initial attack of hydroxide leads to opening of the oxazolone ring, and the nitrogen attacks the epoxide, forming the indolizidine ring and generating an alkoxide. Protonation to give the alcohol is followed by a second attack of hydroxide on the carbonate ester. Carbonic acid is formed as the alkoxide is released in an acyl substitution reaction. The carbonic acid decomposes to water and carbon dioxide and protonation by ethanol gives the final product.
O OBn N O O OH OBn O O HO H EtOH N OBn OH OH see J. Org. Chem., 2000, 65, 9129 HO H N N O O OH OH OBn O OH O OH H N OBn H N O EtOH OBn O O HO HO OH OBn O

OH

H N

HO O

15. (a) This is the Hofmann elimination reaction (Sec. 2.9.C.i) and demands a syn transition state (an eclipsed conformation for reaction). Because of the requirement for an eclipsed conformation (where the leaving group on the -carbon and the "base" can be in close enough contact) the lowest energy eclipsed conformation will lead to the major product. In this case, the lowest energy transition state is A rather than B, and ethene is the major alkene product, not 4-methyl-2-pentene. The i-PrMe interaction in B destabilizes that conformation relative to the

18

Organic Synthesis Solutions Manual

HH interactions in A. In both A and B, the NR3H interactions are about the same.
H HH A NEt2 C4 H9 H H H Me Me B NEt3 H H

(b) Taken from J. Org. Chem., 2004, 69, 7616. The strongly electronegative fluorine atoms withdraw electron density, making the C=C unit very electrophilic. This inductive effective make the alkene carbon more susceptible to attack than the epoxide carbon, despite the fact that there is modest steric hindrance. Such attack drives the SN2' reaction to the allylic alcohol shown, as a mixture of E and Z isomers.
F F Li O Ph F Bu F OH Ph 2nd step of workup included E+Z

(c) This is an SN2 reaction, and inspection of the Walden inversion transition state shows that these two neutral reactants produce a charged transition state where a positive charge builds on the nitrogen (not on carbon) and a negative charge builds on iodine (see A). Separation of these two charges (water promotes separation
+ Et3 N H C 3H 9  C I H A  X R B R +  C I R

of charges) favors formation of the final products since the carbon is transferred to the positive nitrogen, with iodide as the counter-ion. This contrasts with transition state B, the "normal" Walden inversion that arises when a charged nucleophile attacks a neutral substrate. Water as a solvent will separate charges and promote ionization. Separation of charges in B will slow the reaction since the incoming charged nucleophile is separated from the developing charge on the central carbon. In A, however, separation of positive and negative charges favors product formation. For this reason, the reaction of an amine and a halide to give an ammonium halide is faster in aqueous media than in non-aqueous media (which cannot separate charges). (d) The proximity of the ammonium group to the carboxyl carbon is the key to this answer. The aminopropanoic acid has the amino group two carbons away, whereas the amino group is four carbons away in aminopentanoic acid. Both inductive effects and field effects are strongest when the ammonium groups are close. For this reason, amino propanoic acid is more acidic than amine pentanoic acid. (e) The nitro group in 4-nitrophenol is electron withdrawing and, therefore, stabilizes the charge in the phenoxide product. No such stabilization is possible with phenol. The electronic effects also weaken the OH bond, enhancing acidity.

Chapter 4

19

16. 3-Bromo-4-methylhexane reacts with hydroxide (a base for an E2 reaction) by removing Ha. The orientation of the molecule does not matter because the important feature is the anti-relationship of the Br and Ha. When Ha is removed, the transition state for the E2 reaction will retain the stereochemical relationship of the groups. Since the two ethyl groups are on the same side in the anti-orientation, they will be on the same side in the transition state, and this will lead to cis-3-hexene as the major product, with the two ethyl groups sill on the same side. If this reaction were carried out under E1 conditions, ionization of the bromine would lead to planar carbocation C, and removal of Ha could occur from either face since the bond to the carbon bearing Ha is free to rotate. This leads to scrambling of the stereochemistry and a mixture of cis- and trans-alkenes.
Me H Ha H OH Me rotation about this bond leads to a mixture of cis- and trans-alkenes

Br 3 H 1 1 2 H 3 Br 2

Me 4 A Ha Ha

4 Me B

17. See J. Org. Chem., 1997, 62, 641. 18. See Synthesis, 1996, 219. Since NBS is a source of bromine, reaction with the alkene unit generates a bromonium ion. The oxygen of the alcohol is fixed on the bottom of the molecule relative to the Br, and properly positioned to open the bromonium ion to form the ether unit. This places the bromine on the top of the molecule.

H OH Br Br 2 from NBS HO H

NBS , CH 2Cl2 25C  RT Br H O H

Br O H+

19. This sequence is taken from Org. Lett., 2003, 5, 3361. The alkene unit reacts with iodine to give the diiodide in situ, and the proximal iodide is displaced by the amine in an internal SN2 reaction to give the bicyclic amine. A

20

Organic Synthesis Solutions Manual

second internal SN2 reaction displaces the remaining iodide to form an aziridinium iodide. the nucleophilic iodide ion attacks the methyl group of the ester, displacing the carboxylate group, and the electron flow is such that the oxygen opens the aziridinium ion to form the lactone unit in the product.
t-BuMe2 SiO t-BuMe2 SiO t-BuMe2 SiO I 2 , CH2 Cl2 /ether CO2 Me NH rt , 2 d t-BuMe2 SiO CO2 Me NH I I

Me

Me

Me

Me

t-BuMe2 SiO t-BuMe2 SiO t- BuMe 2SiO Me H N I Me CO2 Me t-BuMe 2 SiO

Me H N I O H3 C O Me

t-BuMe2 SiO t-BuMe 2 SiO

Me H Me H O O

20.
Et C 3 H7 N Et

MeCH 2O Me

OSiMe 2t- Bu OPMB HO O O OH note inversion of configuration at the site of ether formation see Eur. J. Org. Chem., 2000, 1889

via OH  Br followed by internal SN 2 by nitrogen J. Org. Chem., 2003, 68, 4371 (a)

(b)

J. Org. Chem., 2003, 68, 8129

(c)

Chapter 4

21

O N HO H H N PhH2 CO Me NH O N CH2 OMe O CH2 OMe

HO N Et N H

OCH2 Ph

OCH2 Ph

NHCH2 Ph

(d)

J. Am. Chem. Soc., 2002, 124, 3939

(e)

J. Am.Chem. Soc., 2002, 124, 4628

(f)

J. Am. Chem. Soc., 2002, 124, 8584

Br

THPO

BnO

N CO2 t-Bu

C 12 H25 OH

OCH 2OCH 2CH2 OMe

(g)

J. Org. Chem., 2003, 68, 6905

(h)

J. Org. Chem., 2003, 68, 6279

(i)

J. Am. Chem. Soc., 2004, 126, 36

O O
OCH 2OMe NC

Bu

OH O

O
O O J. Nat. Prod., 2002, 65, 909

(j)

Org. Lett. 2002, 4, 937

(k)

J. Org. Chem., 2003, 68, 4039

(l)

PhH2 CO
H Br O H

CO2 Me CN O

O O N Me

HO
OH J. Org. Chem., 2004, 69, 1744 (m)

OMe

HO

(n)

J. Org. Chem.,2003, 68, 7422

(o)

J. Org. Chem., 2004, 69, 2191

22

Organic Synthesis Solutions Manual

MeO

HO
H N Et Me

OMe O N3 OAc

O Me 3 SiO

AcO AcO

J. Chem. Soc., Perkin Trans. 1, 2001, 2398 (p)

(q)

Org. Lett. 2001, 3, 3353

(r)

Org. Lett., 2004 6, 2961

Me 2 N O HN

N H

H I

OH O CO 2Me MeO2 C

HO O H I OH Br Tetrahedron Lett.,

HN

(s) J. Org. Chem., 2002, 67, 7147 (t)

Org. Lett. 2003, 5 , 4385

(u) 2000, 41, 2573

Me MeO
I

Me

Me OH Me

Me

t-BuO2 C

(v) see Tetrahedron Lett., 2000, 41, 1151 (w) see J. Org. Chem., 1993, 58, 2186
O MeO MeO N

(x)

J. Org. Chem., 2002, 67, 6181

TBSO BnO

SiMe3

MeO2 C

CO 2Me

H H NH HN O O Chem. Commun., 2004 , 2404 (aa)

(y)

J. Am. Chem. Soc., 2001, 123, 3214

(z)

J. Am. Chem. Soc., 2005, 127, 5596

p- Tol

O S Ph

NH

OH

O CH3

(bb)

Org. Lett., 2003, 5, 3855

21. (a) The transition state is shown in brackets. Hydroxide removes the -hydrogen only when that hydrogen is in

Chapter 4

23

a conformation that places it anti to the leaving group (here, bromine). In this transition state, the relative position of the groups are fixed and this is translated to the alkene, where a single product is formed. The reaction is, therefore, stereospecific.
Me Et Br Me Ph H Ph H Me Br H Et Br H Ph

rotate Me Et H Ph H Br H

Et HBr H

Me Et Ph

OH

(b) The major product is trans-1,2-diphenyl-1-propene. (c) This is an E2 reaction.


O (a) (b) MeO (c) CO 2H NC

OAc

Me Ph Ph (d) (e) HO

Me

22.

HO

(a) The most acidic hydrogen is the phenolic hydrogen (pKa  10) vs. pKa  17 for the primary alcohol. Deprotonation gives the phenoxide, which reacts with iodomethane to give the anisole derivative shown. (b) Two equivalents of base deprotonate both the carboxyl first (most acidic) and the alcohol second (least acidic). Of the two anions, the carboxyl anion is resonance stabilized and less nucleophilic than the alkoxide, where the charge resides almost entirely on oxygen. Since the alkoxide oxygen is more nucleophilic, it will react

preferentially with one equivalent of allyl bromide to give the ether shown. (c) There are two leaving groups in this molecule that can be displaced by the nucleophilic cyanide in an SN2 reaction. The mesylate group is a much better leaving group than acetate. For this reason, one expects the cyanoacetate product shown to predominate rather than the alternative cyanomesylate. (d) The dianion shown has a carbon nucleophile and an oxygen nucleophile. The carbon nucleophile is more nucleophilic, despite the fact that it is resonance stabilized by the adjacent phenyls. The product will therefore be the methylated derivative shown. Since the nucleophilic strength of the carbanion is diminished by resonance, some alkoxide may be formed. (e) In this case, the primary iodide is treated with base. Normally, primary iodides undergo elimination slowly, and substitution predominates when a nucleophilic base is used. In this case, however, DBU is a non-nucleophilic base, and reaction will give the alkene shown as the major product. (f) The product is that shown. Initial formation of the enolate anion and quenching with PhSecl generated the phenylselenide. Oxidation with hydrogen peroxide gave the selenoxide in situ, which eliminated spontaneously to

24

Organic Synthesis Solutions Manual

give the alkene unit in the conjugated lactam product.


O N CO2 t-Bu

OSiPh2 t-Bu J. Am. Chem. Soc. 2002, 124, 14826

23. The product is the less substituted alkene (4,6-dimethylhept-2-ene, C) via syn elimination of an intermediate sulfoxide. The syn elimination demands an eclipsed transition state, and the two pertinent eclipsed conformations where a -hydrogen can be removed are A and B. From these Newman projections, A (for removal of Ha) is less sterically hindered due to decreased torsion strain than is B (for removal of Hb). For this reason, A will have a higher population at a lower energy and will account for the major product, C. Note that C is shown as a mixture of cis and trans isomers, despite the fact that the starting iodide contained a stereogenic center. Removal of the two Ha's in A will lead to the isomeric mixture of alkenes, C.

O Ha Hb O S H Ph H Ha

Ha Ph S A

Hb Ph S B Hb C

Me CHb (Me)C 5H 11 H C5 H11

Me CHHa Me

24. (a) The Fischer projection for the starting material represents a chiral, non-racemic bromide. Once the bromine and -hydrogen are in the proper anti conformation, the base removes the hydrogen and expels the bromine. The other groups are fixed in this transition state, leading to trans-2-phenyl-3-methyl-pent-2-ene.
Br CHO a Br b C CMe (a) CBr 4 , PPh3 (b) BuLi (c) H2 O

(b) This cyclohexane derivative exists as an equilibrium mixture of A and B. For an E2 reaction, the bromine and a -hydrogen must be trans and diaxial. In A, the bromine is equatorial, so there is no chance for elimination. In B, the axial bromine is axial to two axial hydrogens. Elimination will therefore lead to a mixture of two

Chapter 4

25

regioisomeric products, C and D.


Br Et Me Et Me Br A Br Et H B Me H C D Et Me Et Me

(c) In this example, the cyclohexane bromide also exists as A and B, and A cannot react via an E2 reaction because the bromine is equatorial. In B, however, only the hydrogen attached to the methyl-bearing carbon is trans and diaxial with the bromine, so there is but one product, C.
Br Me Br A H B H Et C

Br Me Et Et

Me

Me

Et

Br

Br b C CMe (a) CBr4 , PPh3 (b) BuLi (c) H2 O

(a)

CHO

25.
NO2 b Cl NH2 f Cl SO3 H SO 3H Cl c Cl (a) HNO3 /H2 SO4 (b) Cl2 /AlCl3 , heat (c) H2 , Pd/C (see chap. 4, sec. 4.8.D) (d) Ac2 O (e) SO3 /H2 SO 4 (f) aq acid NH 2 d

NO2 a

NHAc

NHAc e

(b)
Cl

NO2 a b Cl c

NH 2 d

OH

(c)
+ ortho Cl Cl Cl (separate) (a) Cl2 , AlCl3 (b) HNO 3 , H2 SO 4 (c) H2 , Pt (d) NaNO2 , HCl ; H2 O (reflux)

26

Organic Synthesis Solutions Manual

OH

Br a b

CN c

OH d

NEt2

(d)

(a) PBr3

(b) NaCN , DMF

(c) 6N HCl , heat

(d) 1. SOCl2 2. Et2 NH

NO2 b

NO2 c Br

NH2 d Br

OH

(e)
Br (a) HNO3 , H2 SO 4 (b) Br 2 , AlCl3 (c) H2 , Ni (d) NaNO2 , HCl ; H2 O (reflux)

(f)

OH CN

OH CN 2. saponify

(a) 1. NaCN , THF 2. aq acid

(b) 1. PhCO 2Na , PPh3 , DEAD

(g)

OH

OEt (a) aq H2 SO4 (b) 1. NaH , THF 2. EtI

(h)

OH

Et (a) 1. NaH 2. CS2 3. MeI 4. 200C

OH a d

Br

CN

CO2H

O NMe 2

(i)
(a) POCl3 , pyridine (b) HBr , h (c) NaCN , DMF (d) H3O+ , heat

(e) i. SOCl2 i.. HNMe2

Chapter 4

27

CHAPTER 3

1. The product is the aldehyde, and the mechanism is analogous to the DMSO-based oxidations discussed in Section 3.2.C. A reasonable mechanism is shown. Pyridine N-oxide attacks the bromomethyl moiety via an SN2 mechanism. Upon heating, pyridine N-oxide (or eventually the pyridine by-product) removes the hydrogen, as shown, with displacement of pyridine (the leaving group) to generate the aldehyde. This is related to DMSO oxidations of alcohols in that a leaving group is attached to the oxygen in A, making the -hydrogen susceptible to removal by a base. See J. Org. Chem., 1999, 64, 3778.
base H R Br R = C 5 H11 OTHP R O N N H R O

Br

ON

2. These reagents are used for the Sharpless asymmetric epoxidation. Using the Sharpless model shown, ()-DET will deliver the epoxide oxygen from the front of the (R)-enantiomer of the racemic alcohol to give the epoxide shown. Since the (S)-enantiomer is mismatched for this chiral additive, it will react much slower so it is possible to convert the (R)-enantiomer to the epoxide while the (S )-enantiomer does not react. Therefore, the authors in the cited paper isolated the unreacted enantiopure alcohol for use in their synthesis. This process is called kinetic resolution.
OH OBn Ti(OiPr)4 , D-()-DET t-BuOOH , MS 4 20C , 4 d MOMO OBn

OH A MOMO

OBn + MOMO

OH

OMOM

see Synthesis, 1993, 615 via

"O" D-()-DET

OH H OBn

3. (a) This reaction is taken from J. Am. Chem. Soc., 2002, 124, 9199. The epoxidation must take place from the top face, as the molecule is drawn, to give the proper stereochemistry of the alcohol unit. The alcohol is formed by removal of the ketone a-hydrogen with the base (DBU - sec. 2.9.A), formation of the C=C unit and opening the epoxide ring. The stereochemistry of epoxidation is discerned from the model (C=C alkene carbons A and B are marked. It is not completely obvious from the model that the top face is less hindered because of the methyl group,

28

Organic Synthesis Solutions Manual

but the fused five-membered rings are somewhat puckered, and this blocks approach of the bulky metachloroperoxybenzoic acid from the bottom. remember that the transition state for this epoxidation is rather bulky (sec. 3.4.C).
B

A O

H H OH OH H H 1. mcpba , CH2 Cl2

H O

H H A OH B

2. DBU PhH

O OH

(b) This is a Baeyer-Villiger rearrangement, and the carbon best able to bear a positive charge is the one that migrates. The tertiary bridgehead carbon therefore migrates in preference to the primary carbon. (c) Oxidation of phenol with Fremy's salt shows a preference for the para quinone. The reason is formation of the intermediate Ar-ON(SO3 K)2 . This rather bulky substituent shows less steric hindrance with the oxygen in the para position than it does in the ortho position. Relief of steric hindrance therefore drives this reaction to give the para intermediate and, thereby, the para quinone. (d) In general, alkenes bearing electron withdrawing groups react slower than simple alkenes. There is also a steric effect that may lay a role, since dihydroxylation usually occurs at the less sterically hindered site. See J. Am. Chem. Soc., 1999, 121, 7582 4. (a) In this reaction, the active reagent is the hydroperoxide anion (HOO). Conjugate addition to the ,unsaturated carbonyl occurs from the face of the molecule opposite the methyl groups in order to minimize steric hindrance. The resulting enolate anion attacks the electrophilic oxygen to generate an epoxide, with loss of hydroxyl. Steric hindrance with the methyl groups dictates delivery of HOO from the bottom face of the molecule, and the reaction proceeds with high diastereoselectivity for the product shown.

Chapter 4

29

too hindered

Me Me

O H

OOH

OH H O

(b) The reagents will induce cis hydroxylation of the alkene. As drawn, the reagent will be delivered from the less sterically hindered exo face to give the major product. The primary source of this steric hindrance is the hydrogen bridging ether unit on the bottom side of the ring, which interacts with any reagent approaching from that face. In a simple bicyclo[2.2.1]heptene, about 20-30% delivery of regent from the endo face is common, but here the bridging ether effectively prevents this.
Br O H cat OsO4 , NMO , aq THF 10C  RT see Synthesis, 1996, 219 O Br H OH OH

(c) The major product described in J. Am. Chem. Soc., 2002, 124, 9726 is the diol shown. There may be a neighboring group effect involving the allylic alcohol unit to direct the dihydroxylation via path 1. Inspection of the model suggests that the top face is less hindered, and that approach to carbons A/B (path 1) may be somewhat less hindered than approach to carbons C/D (path 2). It is likely that the regioselectivity arises from a combination path 1 being less hindered and the neighboring group assistance provided by the allylic OH.

2 O C D B A OH OsO4 69% HO HO OH O C D B A

(d) In this reaction, the presence of the hydroxyl group might be expected to provide a neighboring group effect, placing the epoxy-oxygen syn to the OH. A quick look at the 3D model, however, shows that the conformation of the 8-membered ring places the OH more or less at right angles to the -bond so one face is not

30

Organic Synthesis Solutions Manual

favored over the other via coordination. This reaction is dominated by a steric effect, and the top face (A) is less hindered, leading to the stereochemistry shown.

2 1 N OH MCPBA , CH2 Cl2 O 74%

O OH N O O

1 2 O

see J. Org. Chem., 2000, 65, 9129

(e) In the first reaction, the mild Dess-Martin procedure converts the allylic alcohol unit to a conjugated ketone. In the second step, the AD-mix- delivers dihydroxylation from the top face to give the diol shown, with high diastereoselectivity and enantioselectivity. Using the Sharpless model, AD-mix- should deliver the hydroxyls from the bottom but in that model, bottom is relative to the methyl groups at the allylic position. Therefore, delivery opposite the methyl groups leads to the stereochemistry shown. This sequence is take from Lee's synthesis of amphidinolide B1 (see reference).
OPMB a OH OSiiPr3 OSiMe2 t-Bu HO OSiMe2 t-Bu b O OSiiPr3 OSiMe2 t-Bu OH ?b OPMB

OSiMe 2 t- Bu

OSiMe 2t- Bu O OSiiPr3 OSiMe2 t-Bu

OPMB

?a

(a) Dess-Martin periodinane , pyridine, CH2 Cl2 (b) AD-mix-  , MeSO2 NH 2 , aq t-BuOH see Tetrahedron Lett., 2000, 41, 2573

5. These three reactions involve Sharpless asymmetric epoxidation. The model in Figure 3.2 is used to predict delivery of the reagent from the re or si face.

OH

t- BuOOH , ()-DET Ti(O i- Pr)4 , CH2 Cl2

OH

see J. Org. Chem., 2000, 65, 1738

Chapter 4

31

(a) When oriented according to Figure 3.2, () tartrate delivers O from the bottom face to give the epoxide with the stereochemistry shown. (b) Using the same model from Figure 3.2, the allylic alcohol is aligned as shown, and ()-tartrate should approach from the back for best selectivity. This would lead to the stereochemistry shown with the epoxy unit to the rear and the methyl projected to the front. Notice that the allylic acetate unit was not epoxidized under these conditions, only the allylic alcohol unit.

OAc t- BuOOH , ()-DET Ti(OiPr)4 , CH2 Cl2 OH see Tetrahedron Lett., 2000, 41, 2181 O OH

OAc

OH

OAc ()-tartrate

(c) Using the model from Figure 3.2, the orientation of the allylic alcohol using ()-DIPT delivers the oxygen from the bottom, as shown. The smaller ethyl group is on that face, and the epoxide shown is generated with good stereoselectivity.

H OH ()-tartrate O H OH

6. The major products of each reaction are shown in the following sequence.

32

Organic Synthesis Solutions Manual

O O a OSiMe2 t-Bu

O O b OSiMe2 t-Bu O

OH OH OSiMe 2 t-Bu ?b Ph (b) MeOH, H+

OMe OH

OMe O O O ?a Ph

OMe O

c OMe O O Ph ?c OSiMe 2 t- Bu (a) benzoyl chloride

(c) NaIO4

J. Am. Chem. Soc., 1999, 121, 5589

(a)
OH

OMe

b O

OMe

c O

OH OMe

?a (a) BuLi , ether-DMSO ; MeI

?b (b) O 3 ; PPh3 (c) PDC , DMF

?c

(b)

J. Org. Chem., 2000, 65, 3738

7. This sequence is taken from J. Am. Chem. Soc., 2002, 124, 9060. Swern oxidation (3.2.C.i) gives the ketone, which eliminates the tosyl group in the presence of triethylamine (via removal of the acidic -hydrogen with concomitant loss f the tosyl) to give the conjugated ketone. An internal conjugate addition of the pyrrole unit (also see 9.7.A) leads to the observed product.

Chapter 4

33

OH

O NH

O2 N Me N NO 2 NEt3 DMSO , (COCl) 2 H TolO 2S H N

O NH N O

O2 N Me N NO2

TolO 2S H N

N O

67%

O Ts N H N

O NH

O2 N Me N NO2

O H+ N N O

O NH

O2 N Me N

NO 2

8. The initial reaction is the expected oxidation of the benzylic alcohol to the aldehyde. This is susceptible to attack by the pendant OH unit, to form a protonated hemiacetal, and loss of the proton gives the hemi-acetal. If the OH unit is oxidized further with MnO2 that is still present, the observed lactone is obtained.
OH O H OH O MnO2 MnO2 OH OH MnO 2 , CH2 Cl2 OH O CHO + O

H H+

O OH

see Heterocycles, 1996, 42, 589

2%

98%

34

Organic Synthesis Solutions Manual

HO O

H H OSiMe 2 t- Bu O OPMB A H H

O O H OSiMe2 t-Bu O OPMB B H

9. (a)

Ac

OH O O

(b)

MeO N Me H O

(c) ( i-Pr)3 SiO

(d) HO

Org. Lett. 2002, 4, 443

J. Org. Chem., 2003, 68, 4215

O J. Org. Chem., 2002, 67, 2566

O O MeO OMe

O H OSiMe2 t-Bu

(e)

(f)
J. Org. Chem., 2003, 68, 1030

(g)
OPMB PMB - p-methoxybenzoyl J. Am. Chem. Soc., 2002, 124, 5654

Org. Lett., 2002, 4, 19

SiMe3

(h)

NH

(i)

NHCO2 t-Bu N O H see J. Am. Chem. Soc., 1999, 121, 9574

CHO CHO

(j)

Cl OH OH

J. Org. Chem., 2003, 68, 1242

see J. Chem. Soc., Perkin Trans 1, 1993, 1095

HO

HO Me

CHO O O

OHC O

O2N
O

Br

(k)

(l)

(m)

HO OH

M Me e see J. Am. Chem. Soc., 1979, 101, 4400

J. Org. Chem., 2003, 68, 7428

Tetrahedron,2003, 59, 9239

Chapter 4

35

Me H O N OH OH O

PMBO

(n)

(o)
O O O OH

(p)
O

Me O Et O

OBn Me

O OCH2 Ph PMB = p-methoxybenzyl J. Org. Chem., 2003, 68, 7818

see J. Org. Chem., 2000, 65, 9129

see J. Am. Chem. Soc., 1987, 109, 5878

(q)
O O

OSiMe 2t- Bu

(r)
O O C12 H25 OAc J. Org. Chem., 2003, 68, 7548

(s)

CHO see J. Org. Chem., 2000, 65, 3432

see p 137 (Cope elimination)

t- BuMe 2 SiO
Me

HO HO

OH N CO 2t- Bu O 2C(4-NO2 -C 6 H4 )

O
Me HO Me O

HO O O

(v) (u)
AcO J. Am. Chem. Soc., 2004, 126, 2194

(t)

see J. Am. Chem. Soc., 1999, 121, 5087

see J. Org. Chem., 2002, 67, 7774

OHC
OHC
MeO OAc

N CO t-Bu 2 N O

CO2 Me OAc Me Me

(w)
H O Org. Lett. 2003, 5, 3931

(x)

(y) HN
Si(i- Pr) 3 Angew. Chem. Int. Ed., 2003, 42, 694

t-BuPh2 SiO Org. Lett. 2002, 4, 1543

OMe
CHO
O

OH
CO2 t-Bu Me

(z)
O see Chem. Commun., 2000, 837

(aa)

(ab)
OMe Org. Lett. 2002, 4, 909

see Synthesis, 1998, 479

36

Organic Synthesis Solutions Manual

t-BuMe2 SiO CHO


O

Me CO2 Et Me

HO Me N MeO2 C

OH

OSiMe2 t-Bu

(ac) J. Am. Chem. Soc., 2002, 124, 11102

O OMe see Org. Lett., 2000 , 2 , 3177 see Org. Lett., 2000 , 2 , 3039 (ad) (ae)

10. In each case one example of a suitable synthesis is shown. In many, perhaps most, cases there are other synthetic approaches that are reasonable. (a) The shortest approach is to use the appropriate Grignard reagent with the aldehyde derived from oxidative cleavage of a diol, derived from hydrolysis of the starting epoxide. The Grignard reaction is discussed in Section 8.4.C.

OH OH

CHO

OH Ph

O Ph

(a) aq. H+

(b) OsO4 , NaIO4

(c) PhCH2 CH2 MgBr ; H 2O

(d) PCC

(b) See the actual synthesis in Chem. Lett., 1979, 1245. This pertinent reactions are outlined below.
Me O HO2 C H Me H Me MeO2 C e H Me a H Me H Me CHO H Me (a) O 3 ; H2 O2 (b) SOCl2 ; MeOH (c) NaBH4 ; H3 O+ (d) POCl3, pyridine (e) O3 ; Me2 S b MeO2 C H Me H Me O MeO2 C c H Me H Me HO MeO2 C d H Me H Me

(c) It is very possible that the hydroxy acid will spontaneously cyclize to the lactone. The acid catalysis in step d is added as a formalism since six-membered ring lactones are somewhat harder to form than five-membered ring lactones, which spontaneously form from hydroxy acids in virtually all cases. Step c is a reduction and the functional group reaction wheel in Chapter 1 (Figure 1.1) provides several possible reagents, including sodium

Chapter 4

37

borohydride, which will be discussed in Section 4..4.A.


Me d O O

Me Br

a Me

b O HO 2C

Me

c HO 2C

Me OH

(a) KOH , EtOH (b) O3 ; H2 O2 (c) NaBH 4 ; H3 O+ (d) H +

(d) This reaction uses a Baeyer-Villiger rearrangement (Sec. 3.6.A) to set the oxygen on the cyclohexane ring. Eventual oxidation leads to the ketone that can be converted to its dioxolane ketal.
O a O O (a) MCPBA (b) i. aq KOH ii. aq H+ (c) PCC (d) 1,2-ethanediol, cat H+ b OH c O d O O

(e) The conversion of the alcohol to the alkene involves a Chugaev elimination (see Sec. 2.9.C.iv). Other syn elimination methods could be used if the alcohol were converted to another functional group.

Ph a

Ph O

Ph OH

Ph

Ph

(a) O 3 ; Me 2S (b) NaBH 4 ; H3 O+ (c) i. CS2 ii. MeI iii. 200C (d) MCPBA

(f) An E2 reaction gives the alkene, allowing a selenium dioxide oxidation to the allylic alcohol. Oxidation to the acid with PDC in DMF is followed by conversion to the acid chloride and quenching with ammonia to give the amide.
O OH c (a) KOH , EtOH (b) SeO2 (c) PDC , DMF d (d) i. oxalyl chloride ii. NH3 O NH2

a Br

OH

(g) An E2 reaction gives cyclohexene and epoxidation followed by an acid-catalyzed ring opening in the presence of methanol gives 2-methoxy cyclohexanol. Oxidation gives the ketone and Swern oxidation was used here, although most of the milder conditions in this chapter would suffice.

38

Organic Synthesis Solutions Manual

Br a

OH OMe

O OMe

(a) KOH , EtOH (b) MCPBA (c) MeOH , cat H+

(d) Swern oxidation

(a)

(b)

OH CN

(c)

OMe CN

(d)

OMe CO 2H

(h) (i)
OH

(a) MCPBA
a

(b) NaCN , DMF ; hydrolysis


b

(c) i. NaH ii. MeI


CO 2H c

(d) i. aq NaOH ii. H 3O +


O NMe2

(a) POCl3 , pyridine (b) O3 ; H2 O2 (c) i. SOCl2 ii. HNMe2

(j) Oxidation of the secondary alcohol in the presence of the tertiary alcohol requires a mild oxidizing agent. Several reagents are available, including tetrapropylperruthenate and the Dess-Martin reagent shown.

a HO OH

HO O

(a) OsO4 , NMO

(b) Dess-Martin periodinane

(k) Elimination of the alcohol with POCl3 (Sec. 2.8.A) and pyridine gives the alkene, and ozonolysis leads to the methyl ketone. The final step is a Baeyer-Villiger rearrangement.

a OH

O Me

OAc

(a) POCl3 , pyridine

(b) O3 , Me 2S

(c) MCPBA

O a

OAc b

OH c d

OH e N3

(l)

(a) MCPBA

(b) i. aq KOH ii. aq H+ (c) POCl3 , pyridine (d) MCPBA (e) NaN3 , THF

(m) This diol to ketone rearrangement is the pinacol rearrangement (see Sec. 12.3.A).

Chapter 4

39

HO OH

O (a) OsO 4 ; NMO (b) H+

40

Organic Synthesis Solutions Manual

CHAPTER 4

1. In each case, the Cram model is shown first and then the Felkin-Ahn model, both in Newman projection. The diastereomer that is predicted to be the major product is also shown. (a)
O n- C3 H 7 OH O n-C 3 H 7 H HO n-C 3 H 7 H H OH

H n-C H HO 3 7

H H

C RAM

FELKIN-AHN

(b)
O O Me Me Na phth C R AM HO H Me Me Na phth H H Me Na phth OH Me Na phth Me H Na phth Me HO Me H H Me Na phth OH

FELKIN-AHN

(c) In this case, reduction does not generate a chiral center, so the model used is irrelevant. Nonetheless, the models are shown.

Me OH 2 C O H H CR AM Ph

C H 2 OM e HO H H H Ph H OH Ph

O H H C H 2 OM e Ph

HO H

H H C H 2 OM e

H Ph MeO

OH H

FELKIN-AHN

(d)

Chapter 4
O N O H Me CRAM Et H N HO Me Et H N O O Me H OH Et O H Me N O H H Et Me OH N O N O

41

Me H OH

FELKIN-AHN

2.

(a) The conformation of this molecule is shown in the usual half-chair of a cyclohexenone derivative. Since Therefore, approach is from the top to give the

cerium borohydride will give selective 1,2-reduction, the main issue is stereochemistry. The bulky siloxymethyl group on the bottom blocks approach from that face. stereochemistry shown for the alcohol product.

Ts O EtO N Ts NaBH 4CeCl3 EtO OSiPh2 t- Bu N Ts OH via OSiPh2 t-Bu H EtO B N

A O H OSiPh2 t-Bu

see Synthesis, 1999, 1889

(b) To predict the stereochemistry of this reduction, we can examine a 3D model of the ketone. The gemdimethyl unit as well as the other bridgehead methyl sterically block path A, but path B is relatively open and predicts the major product. Alternatively, a LUMO map of the ketone shows a more intense blue color exposed to face B, so delivery of hydride will be from that face.
Me Me Me H O see J. Org. Chem., 2000, 65, 7865 H OBn LiAlH4 , THF 0C A Me Me Me H H OH OBn

Me

Me

42

Organic Synthesis Solutions Manual

(c) Coordination of the alcohol moiety with zinc borohydride modifies the conformation, as shown, to deliver hydride from behind. The result is the diastereomeric trans diol shown.
Me H OH HO

Me H H O O Zn H4 B BH 4

Me OH H

OH

(d) The ethyl group effectively blocks one face of the azabicyclooctane ring. Delivery of hydride from the direction of the arrow leads to the diastereomeric alcohol shown.
O Et H Naphth
Me O CO2 H

HO Et

H Naphth

NaBH 4 , CeCl3

Me

3.

see J. Org. Chem., 1998, 63, 1259

Cerium borohydride gives selective 1,2-reduction of the conjugated ketone, delivering hydride from the bottom face to give the alcohol. This alcohol unit then reacts with the free carboxyl to form the lactone. Examination of the 3D figure clearly suggests that attack from the top face (A) is blocked by both the methyl group and the CH2COOH group. The bottom face (B) is unencumbered, leading to the stereochemistry indicated for reduction of the ketone to the alcohol and shown in the lactone. The LUMO map shows that attack from the bottom face, to give the alcohol precursor required to give the lactone product, is slightly preferred.

Chapter 4

43

top B bottom

4.

The first step is to look at the actual conformation of the steroid. Using the usual model for conjugated ketones This

with R being the steroid ring, predictions can be made for reduction of the carbonyl. Diisobutylaluminum hydride will coordinate to the carbonyl oxygen, restricting the angle from which hydride will be delivered. coordination leads to delivery of hydride via a complex that gives anti-Cram selectivity and generates the diastereomer labeled . Selectride, however, does not coordinate, and delivery will be from the less sterically hindered pathway (Cram selectivity), as shown, to give the -diastereomer. see Tetrahedron Lett., 1985, 26, 69.
H Me H Me O Me THPO H H H H R Me H H Me Al O Me i-Bu i-Bu

Selectride
Selectride Me H R H HO H R  H Me H H OH Me H H R 

Me O iBu iBu Al

Me

Me H

5. The first step of this reaction is reduction of the ketone unit to give an alcohol. Treatment with the basic reagent tert-butoxide leads to an alkoxide product, as shown. With the tosylate unit properly positioned, a Grob-like fragmentation is possible, leads to the aldehyde and the alkene units in the final product.

44

Organic Synthesis Solutions Manual

see J. Org. Chem., 1999, 64, 4304 OTs O TsO LiBEt3 H H Ph N OH TsO KOt-Bu H CO2 Et H Ph O CHO H CO2 Et N CO2 t- Bu H Ph N H CO2 Et

H Ph

CO2 Et N CO2 t-Bu

CO2 t- Bu

CO2 t-Bu

6. The reaction products shown are taken from the cited reference. The first step is epoxidation of the C=C unit with meta-chloroperoxybenzoic acid. The Spartan model shown can be interpreted in several way: the methyl group on the adjacent allylic carbon can provide steric hindrance, or the bridgehead methyl on the lower face could block the reaction. In fact, the lower face is more hindered, and epoxidation occurs from the top face, in 81% yield. Lithium borohydride opens the epoxide, this time from the lower face, and regioselectively at the less sterically hindered carbon (see model) to give the alcohol shown.

OSiMe2 Thex mCPBA O H O see J. Org. Chem., 2003, 68, 3831 LiBEt3H , THF Na2 CO3

OSiMe2 Thex

O O H O OSiMe 2 Thex

OH O H O

7. Inspection of the 3D model shows that path A is blocked by the methyl group, so reduction with LiAlH4 occurs by attack via path B, which gives the stereochemistry shown for the allylic alcohol. Both 1,2- and 1,4-addition are possible, so LiAlH4 is used in ether at low temperature to maximize 1,2-addition. The second reaction is simply a Mitsunobu reaction with the alcohol, first forming the benzoate ester with inversion of configuration, and the

Chapter 4

45

treatment with methanolic KOH to give the requisite alcohol.


A
OH

LiAlH 4 , ether 20C O

PPh3 , DEAD , PhCOOH then KOH/MeOH OH

see Synthesis, 1998, 495

8.

(a) Aluminum hydride coordinates effectively to the oxygen of the carbonyl. 1,4-Reduction demands

delivery of hydride to carbon via path B, whereas 1,2-reduction demands delivery via path A. Once bound to oxygen, the distance between H and the terminal C of the C=C unit via path B is rather long, making delivery difficult. Delivery via path A is facile due to the relatively short distance between the carbonyl C and H. Coordination to oxygen therefore inhibits 1,4-addition and promotes 1,2-addition.
B H H H H O A H H Al H

(b) L-Selectride is much more bulky than sodium borohydride. On approach to the carbonyl carbon, this steric bulk will maximize steric interactions with the indane ring system and lead to greater selectivity relative to NaBH4. Using the Cram model, the diastereomer shown is predicted to be the major product.

H H H H

O H

H H

OH H

(c) In this reaction, sodium transfers an electron to benzene to generate radical anion A. The proximity of the single electron and the negative charge (2 electrons localized on that carbon) destabilize A due to electrostatic

46

Organic Synthesis Solutions Manual

repulsion. The resonance form (B) diminishes electrostatic interactions and is energetically favored. Transfer of hydrogens to B leads to the final product, 1,4-cyclohexadiene.

(d) Transfer of an electron from sodium to anisole can generate two different regioisomeric radical anions, A and B. The proximity of the negative charge to the electron donating OMe group destabilizes A, making B energetically more favorable. This leads to the product shown. Similar reaction with benzoic acid leads to C and D as the possible radical anions. In this case, the electron withdrawing carboxylate group stabilizes the adjacent negative change in C, making it more stable than D where the charge is distal to the carboxylate group. For this reason, C leads to the major product shown.
OMe OMe A CO 2H CO 2 C B CO 2 CO2 H OMe

OMe

(e) Lithium aluminum hydride is a powerful reducing agent due to the charge distribution and polarity of the AlH moiety. It will reduce ester groups, acid groups, and carboxylate anion groups. Since LiAlH4 will reduce both the ester and the acid, the product is a diol. Borane coordinates with the acid but not with the ester. It will therefore transfer hydride only to the acid and not to the ester, and the acid is reduced and the ester is not. The product is a hydroxy-ester. (f) This reduction occurs via a six-centered transition state, as shown.
R R H H N N

When the alkene is symmetrical and not polarized, electron density is readily transferred to hydrogen, leading eventually to expulsion of N2, which drives the reaction. When the alkene is conjugated to a carbonyl, the electron donating ability of the alkene is diminished, slowing the reaction by destabilizing the requisite six-centered transition state. See J. Am. Chem. Soc., 1961, 83, 4302.

Chapter 4

47

(g) In A there is a neighboring group effect where the OH group coordinates with zinc borohydride and delivers hydride from the same face as the hydroxyl group. OSiR3 group. (h) This transformation is taken from J. Am. Chem. Soc., 2002, 124, 12416. Birch reduction of the naphthalene unit containing the electron releasing OMe groups is expected to give the reduced product shown. Aqueous hydrolysis converts the vinyl ether to the ketone, but the C=C unit in the ketone-bearing ring will move into the other ring to form the aromatic ring, rather than into conjugated with the carbonyl. aromatization is the driving force leading to the major product.
OMe Na , EtOH , reflux MeO OMe A MeO OMe B OMe OMe aq HCl reflux O MeO OMe O

When the OH is blocked as the silyl derivative, zinc

borohydride cannot coordinate, and the usual steric effects lead to delivery of hydride from the face opposite the

MeO

9. The first transformation can be effected with Sn/HCl (Stephen reduction) or with LiAlH(Ot-Bu)3. The second transformation can be effected with LiAlH4 or with LiBHEt3. 10.
O O
Me (CH 2) 4O Piv OPM B O M eO Me O OPM B O PM B J. Am. Chem. Soc., 2003 , 125 , 12844 O TIPS

(a) (b)
H OH Org. Lett., 2003, 5, 4741

(c)
HO

CHO

PMB = p-methoxybenzyl Piv = pivaloyl

OMe

(d)

MeO MeO

CO2 H NH2

(e) MeO2 C

CO2 Me N CO2 t- Bu

(f)

MeO

Br

Eur. J. Org. Chem., 2003, 1231

J. Org. Chem., 2002. 67, 8284

Org. Lett., 2003, 5, 999

NHPMB MeO PMB - p- methoxybenzyl

48

Organic Synthesis Solutions Manual

O O

H N
Br

N Me N HO J. Org. Chem.,2004, 69, 1283 H

(g)
t-BuMe 2 SiO OH Org. Lett., 2002, 4, 1451

(h)

N Ph MeO CO2 t- Bu Org. Lett. 2003, 5, 1927

(i)

CO2 Me NHCO 2t- Bu


Me Me

(j)
N H J. Am. Chem. Soc., 2003, 125, 5628

(k) t- BuMe SiO 2


OH see J. Org. Chem., 1999, 64, 4477

(l)

HO

CO2 Me N H CO t-Bu 2 Org. Lett., 2003, 5, 447

PhMe 2Si

CH2 OH

OH H

(m)
N H

N H

(n)

O O OH

(o)
N CH3 Me

J. Org. Chem. 2003, 68, 4523

J. Org. Chem., 2003 68, 2572

see J. Org. Chem., 1999, 64, 2184

(p)

O C 15 H31

(q)
CN
N O

H OSiMe 2 t- Bu

(r)

OSiPh2t- Bu CHO J. Am. Chem. Soc., 2002, 124, 4257

see Tetrahedron Lett., 2000, 41, 3467

Org. Lett. 2002, 4, 177

O HO OO O OH O

I H OH O

O Me

(s)
Org. Lett. 2003, 5, 3357

(t)

(u)

see J. Am. Chem. Soc., 1999, 121, 5176

H Me see J. Chem. Soc., Perkin Trans. 1 2000, 2645

Chapter 4

49

OMe
Me3 Si Ph OH OH

MeO

Br OMe NO2
OHC

CHO

(v)

J. Am. Chem. Soc., 2004, 126, 2194

(w) J. Org. Chem. 2003, 68, 8162

(x) J. Org. Chem., 2004, 69, 1598

O
OSiMe 2 t- Bu C 13 H27 OH

TBSO O O

see Can. J. Chem., (y) 1997, 75, 621

NHAc see Tetrahedron Lett., 2000, 41, 2765 (z)

(aa)

O see J. Org. Chem., 2002, 67, 4127

CH2 OH N Cl CH3
Ph Ph (ab) see Synlett, 1999, 182

N CO2 Et

t-BuMe2 SiO t-BuMe2 SiO

OH

OH

J. Am. Chem. Soc., 2002, 124, 9476 (ac)

(ad)

J. Am. Chem. Soc., 2002, 124, 12806

11. In each case a synthesis is shown. These are not necessarily the only approaches. It is very likely there are many approaches for several of these questions. (a) The acid hydrolysis of the vinyl ether to the ketone may also convert the methyl ester to the acid. If this occurs, an esterification step (thionyl chloride; methanol) would be required. Mild acid hydrolysis of the vinyl ether should be possible, however.
Me a MeO MeO CO2 Me CO2 Me Me (a) Na , NH3 , EtOH (b) aq H+ (c) O3 ; H2 O2 CO2 Me

Me b O

Me c O CO2 Me

(b) The first step requires a chain extension and converting the alcohol to its tosylate introduces the requisite leaving group, allowing a subsequent reaction with NaCN to give the corresponding nitrile. DIBAL-H reduction of the nitrile gives the aldehyde.

50

Organic Synthesis Solutions Manual

OPMB a HO

OPMB b NC

OPMB

(a) 1. TsCl , pyridine (b) DIBAL-H , THF

2. NaCN , DMSO

OHC

see Tetrahedron Lett., 2000, 41, 33

(c) All steps in this synthesis are taken from Org. Lett., 2002, 4, 1379. Bromination of the allylic alcohol (2.8) and SN2 displacement with cyanide gives the nitrile (2.6.A.i). Basic hydrolysis to the carboxylic acid, and esterification with diazomethane (2.5.C; 13.9.C), was followed by selenium dioxide oxidation to the aldehyde (3.8.A). Reduction of both the ester and aldehyde with LiAlH4 gave the diol (4.2.B), and selective chlorination of the allylic alcohol with N-chlorosuccinimide (2.8) gave the final target.
OH a Br b CN c CO2 H d

CO 2Me e OHC

CO2 Me f

OH g

OH

OH

Cl

(a) PBr3 t- BuOMe (b) KCN , DMSO (c) 25% KOH , MeOH (d) CH 2N 2 , ether (e) SeO 2 , t-BuOOH , CH 2Cl2 (f) LiAlH4 , THF (g) NCS , Me 2 S , CHCl2

(d) The Wittig olefination step is discussed in chapter 8.


OMe d OHC OMe e O f OH (a) NaH ; MeI (b) Na , NH3 , EtOH (c) H2 , Pd (d) O3 ; Me 2 S (e) Ph3 P=CH2 (f) LiAlH 4 O

OH a

OMe b

OMe c

OMe

(e) All reagents are taken from the cited reference. The first reaction reduces the ester unit to an alcohol. This is followed by conversion to a tosylate that allows Super-Hydride reduction to give the methyl group. The O-SiR3

Chapter 4

51

unit is cleaved with aqueous acid to give the corresponding alcohol (see chap. 7, sec. 7.3.A.i). The primary alcohol is then converted to the aldehyde by a Swern oxidation (see chap. 3, sec. 3.2.C.i).
a OSiMe 2 t- Bu CO2 Me c OSiMe2 t-Bu CH2 OTS e H O Me CH3 CH2 OH d OSiMe 2 t- Bu OH CH3 OSiMe2 t-Bu

see Tetrahedron Lett., 2000, 41, 403


(a) DIBAL-H , toluene , 78C (b) TsCl , DMAP , NEt 3 (d) AcOH , aq THF (e) DMSO , (COCl)2 , NEt 3 (c) LiEt 3 BH , THF

(f) All reagents are taken from the cited reference. Initial reduction of the acid to the alcohol was followed by treatment with tosic acid. This led to an internal transesterification to the lactone, and conversion of the dioxolone to the alcohol. Treatment with the dimethyl acetal of formaldehyde led to the ether shown (a MOM group - see. chap. 7, sec. 7.3.A.i), and DIBAL-H reduction converts the lactone to a lactol.
O O O CO2 H a O O OH HO O O O O O b

HO

(a) BH3 , THF ; H3 O+

(b) p-TsOH , CHCl3

(c) CH2 (OMe)2 , P2 O5

(d) DIBAL-H , CH2 Cl2

see J. Org. Chem, 2000, 65, 9129

(g) All reagents are taken from the cited reference. Initial reduction of the ester unit (using DIBAL-H) gives the allylic alcohol. To insert the proper stereochemistry for the new alcohol unit, Sharpless asymmetric epoxidation using (-)-DIPT (see Sec. 3.4.D.i) gives the epoxide and selective reduction of the less sterically hindered carbon of the epoxide with Red-Al gives the final product.

52

Organic Synthesis Solutions Manual

SiMe 3 CO2 Et O a O

SiMe 3 OH b

O O

SiMe3 OH

SiMe3 OH OH

see Tetrahedron Lett., 2000, 41, 2821 (a) DIBAL-H , CH2 Cl2 , 78C (b) ()-DIPT , t- BuOOH , Ti(OiPr)4 (c) Red-Al , THF

(h) A Friedel-Crafts acylation inserts the ketone moiety, and the Wolff-Kishner reduction removes the carbonyl. Catalytic hydrogenation reduces not only the benzene ring but also the nitro group in a single step.
n-C 3 H7 d

O a Section 12.4.D p 1090

n-C 3 H7 b

n-C 3H 7 c

n-C 3 H7

NO 2

NH 2

(a) butanoyl chloride , AlCl3 (b) N2 H4 , KOH (c) HNO 3 , H2 SO 4 ; separate ortho product(d) excess H2 , Ni(R)

(i) All reagents were taken from Eur. J. Org. Chem., 2003, 4445. Reduction of the acid with borane (4.6.A) was followed by bromination with carbon tetrabromide and triphenylphosphine (2.8.A).
HO a Cl N OMe Cl N OMe b (a) BH3 SMe 2 , B(Me) 3 , THF Cl N OMe (b) CBr4 , PPh3 , benzene Br

CO2 H

(j) All reagents are taken from the cited reference. The first problem is how to remove the OH group. If the OH is first converted to a tosylate, Finkelstein exchange (chap. 2) generates an iodide which can be reduced with tin hydride. The ester is reduced to an alcohol with LiBH4, and aqueous acid converts the dioxolane unit (a ketal) to the carbonyl (see chap. 7, sec. 7.3.B.i). The final step is an oxidation. Several methods can be used from chap. 3, sec. 3.2, but the Dess-Martin periodinane reagent was used in this citation.

Chapter 4

53

O EtO2 C N O

O a EtO2 C

O b EtO2 C

O HOH2 C

N OH O OTs

N O

N O

OMe O HOH2 C d N O

OMe O OHC e N O

OMe

OMe see J. Am. Chem. Soc., 1999, 121 , 7778

(a) TsCl , DMAP (b) 1. NaI , acetone 2. Bu3 SnH , AIBN (c) LiBH4 , THF (d) HCl , aq. AcOH (e) Dess-Martin

OMe

OMe

(k) Hydrogenation with a Lindlar catalyst sets the cis alkene geometry.
a b c

Bu

Bu

Bu

Bu

Bu

(a) NaNH2 ; n-C 4H 9-I (b) NaNH2 ; n- C4 H9 -I (c) H2 , PdCO3 , quinoline

12. In each case a synthetic solution is shown. There are other approaches based on other disconnections. The Aldrich catalog (2000-2001) was used as a source for the starting material for convenience. There are, obviously, other sources of chemicals. (a) An attractive starting material is the commercially available benzylacetone at $95.40/Kg, but it has more than the required five carbons. One more disconnection leads to acetone, which can be converted to benzylacetone via enolate alkylation (see Sec. 9.3.A). Acetone is available from Aldrich ($18.30/L) and has less than five carbons. The Wittig olefination step(a) is discussed in Section 8.8.A.

54

Organic Synthesis Solutions Manual

Br Me Br O Me Me a Me O Me Ph b Ph Me Me

Ph

O Me benzylacetone Ph c

Ph

Me

Me acetone Br Me Br Me Ph

Me

Me (a) LiN(iPr) 2 ; BnBr (b) Ph3 P=CHMe (b) Br2 , CCl4

(b) The starting material is 3-methyl-2-butanol at $43.10/100 mL. Initial conversion to a mesylate allows an SN2 reaction with the anion of 1-propyne. The alcohol could also be converted to a bromide using PBr3 or a similar reagent. Lindlar reduction of the alkyne leads to the cis-alkene.

OH

OH

OMs

(a) MeSO2 Cl , NEt3

(b) MeC C Na + , DMF

(c) H2 , Pd-BaCO 3-quinoline (Lindlar)

(c) The requirement that the starting material be five carbons or less makes this a very cumbersome synthesis. The point of this exercise is first to give practice for various reactions but also to show that setting arbitrary starting material requirements can have profound consequences. A shorter approach, for example, would use phenetole (ethoxy benzene) and Birch reduction. In the synthesis shown, 2-ethoxy-propanoic acid was not found to be commercially available (someone probably sells it if sufficient time was taken to find a source), but the expensive -propiolactone at $76.20/5 mL can be opened with ethanol (transesterification) to give the requisite alcohol-ester. Wittig olefination (see Sec. 8.8.A) can be done with a carboxyl substituent.
O EtO 2C O EtO2 C CHO EtO2 C NHBu EtO2 C O OH O CO2 H EtO2 C O

CO2 H

Chapter 4

55

O O d

a EtO 2C EtO2 C

OH

b EtO2 C e EtO2 C CHO

c O EtO2 C

CO2 H

CO 2H O

(a) EtOH , H+ (b) PDC , CH2 Cl2 (c) Ph3 P=CHCH 2CO2 Na+

NHBu O (d) MCPBA (e) BuNH2 , DCC

(d) This synthesis begins with benzene at $31.00/L and bromination followed by reaction with cuprous cyanide gives benzonitrile. Rosenmund reduction gives benzaldehyde (remember that we had to begin with material containing only 6 carbons). A Wittig olefination (see Sec. 8.8.A) gives styrene and a radical HBr addition gives the primary bromide. An SN2 displacement with cyanide allows selective reduction to the aldehyde.
CHO a Br b

Ph

Ph PhBr (a) Br2 , FeBr3

PhCHO c (c) Sn , HCl f Ph CN g

PhH

PhH

PhCN

PhCHO

(b) CuCN , heat Ph Br

PhCHO

d Ph

e d) Ph3 P=CH2

Ph (g) LiAlH(O t- Bu) 3

CHO

(e) HBr , ROOR

(f) NaCN , DMF

13. (a) NaBH4 reagent

(b) Na , NH3 , EtOH

(c) LiAlH(Ot-Bu)3 - some diol will also be formed with virtually any

(d) NaBH3 CN , pH 7

(e) The first step requires reduction of the ketone to an alcohol, and the mild reagent NaBH4 was used. The second step uses NBS to form a bromonium ion, which is opened by the proximal alcohol unit to give the bromo-ether shown. Both reagents used here were taken from the cited reference.
O N CO2 Bn

1. NaBH4 , MeOH 2. NBS , MeCN see Synthesis, 1999, 1814

Br

O N CO2 Bn

(f) LiAlH4 will reduce the ester to the alcohol, the azide to the amide, and the lactam to the cyclic amine. See J. Org. Chem., 1996, 61, 4572.

56

Organic Synthesis Solutions Manual

CHAPTER 5

1. Boranes are fundamentally Lewis acids and, as such, have a limited range of reactivity. Once the Lewis acid reacts with a Lewis base, however, an ate complete is formed. The wide variety of Lewis bases makes possible a range of ate complexes. Ate complexes can react with a wider variety of reagents and undergo rearrangement, displacement, cleavage, and elimination reactions. complex to facilitate further transformations. 2. When drawn so that the conformation of the molecule is more representative, as in A, it is clear that borane can be delivered to the alkene from only one direction. The final product is diastereomer B. The bridgehead methyl group effectively blocks formation of the other diastereomer. This reaction is, therefore, diastereo-specific or at least highly diastereoselective. The alkene is symmetrical, so addition of boron to the two identical alkene carbons generates opposite antipodes. The reaction therefore exhibits no enantioselectivity or regioselectivity. For this reason, boranes are usually converted to the ate

Me H Me H A Me

OH H H

Me

H B

OH

3. The products are


Me B A B Me NH2 C Me D D Me OH E Me I F O

All reactions are straightforward except for E and F. The iodine/hydroxide reagent converts vinylboranes to vinyl iodides. It is not clear the same reaction occurs with A, and product E could generate D or it could form an alkene product. The reaction labeled (v) usually gives ketones with trialkylboranes. In this case, 9-BBN was used, and the most reasonable product is bicyclic ketone F.
Me H Me B H Et H Me Et H Me B Et H Et H

Me (a)

Et

Et HO (b) H Et

Me

Et HO H Et Et

4.

Chapter 6

57

Me (c)

Et Me

H B Me

Et Me Me Me

Et H OH

Et

5. Three examples are shown. There are several other possibilities and a variety of possible alkene and polyene substrates.
1. B 2H 6 2. NaCN 3. (CF 3CO) 2O 4. NaOH , H2 O2

Ph

1. B 2H 6 2. CO (70 atm) 150C ethylene glycol 3. NaOH , H2O2

Ph

OH

Ph Me Me

Ph

1. B 2H 6 2. acrolein , aq THF

CHO

6. In this process, borane adds to the alkene, and the initially formed alkylborane reverts back to the alkene and borane at this elevated temperature. When borane adds again, it can add to one of two alkene carbons. When borane is lost, two possible alkenes are formed. Under these thermodynamic conditions, loss of borane to form the alkene and re-addition to form a new borane will eventually accumulate the more stable borane, which has the borane at the terminal carbon. A reasonable representation of this process is shown.
+ BH3 BH2 - BH 3 + BH3 BH3 BH2

+ BH3 BH3 + BH3 BH3

BH 2

+ BH3 BH 3 + BH 3 BH3

7.

This reaction can be explained by initial addition of borane to the less hindered face of the molecule.

58

Organic Synthesis Solutions Manual

Examination of the 3D model shows that path B is blocked by the isopropyl group, leaving path A less sterically encumbered. Delivery of borane from face A leads to 1 as the is the borane product of this addition. The borane is now situated to coordinate with the oxygen of the proximal carbonyl group as in 2, and transfer of hydrogen intramolecularly from the top face reduces the carbonyl to give the alcohol with the stereo-chemistry shown.
O O H O BH3 O H O 1 O 2 O H see J. Am. Chem. Soc., 1997, 119, 4130 O H B Me H H O B Me H OH Me O H B A

Me

1. BH 3SMe 2 2. H2 O2 , NaOH

OH

8.

(a) In this case, a hydroboration route would generate the anti-Markovnikov alcohol which would have to be

converted to a halide. The radical addition of HBr generates that bromide directly.
a b OH c

Br

CHO

(a) HBr , t- BuOOt-Bu (b) 1. Mg , THF 2. CH2 O (c) PCC

(b) Without hydroboration this is a difficult synthesis. The alkyne coupling reaction is called a Glaser reaction (see Sec. 13.8.C). Two sequential Lindlar hydrogenations (Sec. 4.8.B) set the cis geometry of the alkenes. The problem with this approach is that the first hydrogenation may be difficult to control in terms of reacting with only one alkyne. In the second hydrogenation, over-reduction could be a problem, although this is usually not significant with Lindlar hydrogenation.
a H c n-C 3 H7 H b

n-C 3 H7 n-C 3H 7

H d

n- C3 H7 n-C 3 H7

n-C 3 H7 (a) NaNH 2 ; n- C3 H7 I (b) CuCl2 , NH4 OH (c) H2 , Lindlar (d) H 2 , Lindlar

n-C 3 H7

(c) The major problem here is stereoselectivity. Most approaches would incorporate a halide or alcohol moiety and then displace it with ammonia or an amine surrogate such as the phthalimide anion. Methods to incorporate

Chapter 6

59

halides generally involve cation intermediates and will give the wrong stereochemical halide. Reaction with HBr and peroxides will give the correct regiochemistry, but as a mixture of diastereomers which must be separated (if possible). Reaction with potassium phthalimide inserts the nitrogen moiety, and treatment with hydrazine unmasks the amine.
Me O c Br N d

Me a

Me b Br

Me

Me NH2

O (a) HBr , t-BuOO t- Bu (b) chromatography (c) K phthalimide (d) NH 2NH2

(d) The following sequence is offered as a possible alternative synthesis. It is cumbersome and not particularly attractive. To incorporate the additional carbon atom, a Grignard reaction with formaldehyde is used (see Sec. 8.4.C.i). Incorporation of the bromine via reaction with HBr will generate two regioisomeric bromides which must be separated chromatographically (not an easy task). Epoxidation and conversion of the alcohol to a halide is followed by an internal Grignard ring opening (see Sec. 8.4.E). First, generating the Grignard reagent without serious side reactions will not be easy. Second, the organometallic can attack the epoxide to form a five-membered ring which will probably be the major product. Removal of the alkene and alcohol moieties via reduction give the alkane. Radical bromination will be rather selective for the tertiary bromide, and elimination to the alkene is followed by oxy-mercuration-demercuration to give the requisite alcohol. Without question, hydroboration

transforms the hideous approach shown here into a very straight-forward synthesis. It is noted that choosing a different starting material might allow a non-hydroboration syntheses with fewer potential problems. It is also noted that the triene starting material must be independently synthesized. With an alternative starting material to the targeted alcohol, an alternative synthesis may be attractive. Using disconnection techniques (see Sec. 10.5), a useful exercise is to devise a synthesis of the alcohol and then look up the synthesis of the triene used in the hydroboration sequence. Compare and contrast the two.

OH a Br b c

Br d

O e f Br g h OH

OH

(a) HBr - separate isomers (b) Mg ; HCHO (c) i. PBr 3 ii. MCPBA (d) Mg - separate isomers (e) H 2 , Pd ; PBr 3 ; LiAlH 4 (f) Br2 , h (g) KOH , EtOH (h) Hg(OAc)2 , H2 O ; NaBH4

60

Organic Synthesis Solutions Manual

9. As shown in the cited reference, the product of the reaction is that shown (isolated in 7%% yield). Inspection of the model suggests that top-face (1) is much more sterically hindered than the bottom-face (2). The conformation of the two rings, along with the substituents effectively block the top face. Delivery of borane, and hence the OH unit, from the bottom is predicted. In addition, examination of the tow alkene carbons (B,C) shown that carbon C is less hindered, leading to high regioselectivity for hydroboration at that less crowded carbon atom.

CO2 Me N
A

1. BH3 THF 2. 3N NaOH , 30% H2 O2

CO2 Me N
C A

(1)

B C

SEMO

OBn

SEMO OH

OBn

see J. Org. Chem., 2003, 68, 5274

( 2)

10.
H O
Ph O O Ph Me Me O O OH

O MeO P MeO OH

(a)

H see Indian J. Chem., 1975, 13, 764

(b)
OSiMe2 t-Bu H J. Am. Chem. Soc., 2003, 125, 11893

(c)

J. Org. Chem., 2003, 68, 9502

OH H

MeOH2 CO

(d)
see J. Am. Chem. Soc., 1967, 89, 567

(e)
N Me H

(f)
N CO2 t-Bu

OH

Org. Lett., 2002, 4, 4681

Org. lett., 2003, 5, 27

TBSO Me

OH

(g)

OH OSi(i-Pr) 3 Org. Lett., 2002, 4, 2043

(h)
O see Org. Lett., 2000, 2, 2695

(i)

Ph

OH

Ph see Org. Lett., 2000, 2, 1455

(j)

n-Bu

n-Bu n-Bu

(k)

Et

(l)
Ph

n-C 5H 11 Ph see J. Organomet. Chem., 1981, 213, C53

see Tetrahedron Lett., 1986, 27, 977

see J. Chem. Soc., Chem. Commun., 1973, 606

Chapter 6

61

(m)
Ph

OH

(n)
n- C6 H13

OH n- C6 H13 n-C 6 H13

see J. Org. Chem., 1977, 42, 579

see J. Am. Chem. Soc., 1967, 89, 2737, 5478

11. (a) The alkene moiety of the cyclohexene ring is effectively blocked from the bottom face, as it is drawn, by the bicyclohexane moiety (also see the model). Borane will be delivered from the top face, accounting for the stereoselectivity. The less sterically hindered carbon (not bearing the isopropyl group) will be the major site for delivery of the boron, accounting for the regioselectivity.
BH3 H Me BH3 Me H H H OH

MeO2 C

H MeO2 C

(b) Taken from J. Med. Chem., 2003, 46, 1886. Regioselectivity for the less substituted position predicts the product, and analysis of the model clearly shows that delivery from the bottom face is preferred.
OCH2 Ph a b PhH 2CO 1. catecholborane LiBH4 , THF 2. NaOH , H2 O2 PhH2 CO HO

OCH 2Ph

a b

less hindered preferred

12. A synthesis is shown for each sequence. Other synthetic sequences are possible.

62

Organic Synthesis Solutions Manual

n-Bu H c n-Bu Br (a) NaNH 2 ; n- Bu-I (b) i. HBBr 2 SMe2 ii. BBr 3 (c) I 2 , AcOH (d) t-BuLi ; MeOH see pp 461-462 - text and Tetrahedron Lett., 1986, 27, 977 (a) H a b n- Bu n-Bu H d Br n- Bu n-Bu B Br n- Bu

Me a Br

Me b

O c NH2 d N H Ph

(b) (a) KOH , EtOH (b) B 2 H6 , 165C , 1-hexadecene (c) 9-BBN ; NH2 SO3 H (d) benzoyl chloride

(c) This was included because it does not require a hydroboration step. The final step (c to d) may occur spontaneously once the hydroxy-acid is formed. Step d is added as a formalism since sometimes six-membered rings do not form spontaneously.
Me a Br b Me HO2 C O Me c HO2 C Me OH d O O Me

(a) KOH , EtOH (b) O3 ; H2 O2 (c) NaBH4 ; H3 O+ (d) H+

(d)
OMe O O t- BuMe 2 SiO t-BuMe2 SiO OHC c O OAc t- BuMe 2 SiO (a) Hg(OAc) 2 , MeOH ; NaBH3 CN/THF (d) O3 , CH2 Cl2 ; PPh3 (e) t-BuMe2 SiO d HO O OAc t-BuMe2 SiO (c) TMSOTf ,
SiMe 3

OMe b O t-BuMe2 SiO O OAc

O OAc

(b) LiAlH(Ot0Bu) 3 ; Ac 2 O . NaOAc ; NaBO 3

B(Ipc) 2

see Tetrahedron Lett., 2000, 41, 3801

(e) This sequence is taken precisely from the paper. Hydroboration with HBCl2 generates an intermediate that can

Chapter 6

63

react with methyl azide to give the corresponding N-methylamine. Subsequent treatment with NaOH allows an intramolecular SN2 reaction to give the bicyclic amine product.

a Br (a) HBCl2 (b) MeN3 ; MeOH BCl2

Br b

Br NHMe c N Me

(c) NaOH

see Bull. Soc. Chim. Fr., 1995, 1003

64

Organic Synthesis Solutions Manual

CHAPTER 6

1. In some cases, the ring size exceeds those proposed by Baldwin's rules. In those cases, the rules are simply extended to include that ring. In (a), the internal aldol condensation is discussed in Section 9.4.A. In (b), the thermodynamic conditions (see Sec. 9.2.E) favors the enolate at the more substituted carbon, but cyclization would generate a higher-energy four-membered ring. Under equilibrium conditions, the enolate at the less substituted carbon is also formed, and it cyclizes as shown. Reaction (c) is an internal William's ether synthesis, (Sec. 2.6.A.i) with displacement of the bromide. In reaction (d) HBr reacts with the alcohol moiety, with loss of water, to form a carbon cation. This cation is then attacked by the alkyne to form a vinyl cation, which reacts with bromide. The flow of electrons does not formally fit Baldwin's rules, but the positive charge ends up exo to the newly formed ring and the classification exo-dig is used. Reaction (e) is 7-exo-trig because the electron flow is out of the newly formed ring, even if it is within a second ring. Reaction (f) is another internal William's ether synthesis. In reaction (g), the alcohol essentially attack an activated carbonyl, making it an exo-trig reaction.
H N

(a)
6-exo-dig NH

SPh

SPh O

(b)
O 6-exo-tet

(c)

7-exo-trig

(d)
O 5-exo-tet

(e)
O

OH 7-enolendo-exo-trig see p. 608 - text

(f)

OH 6-enolexo-exo-trig see p.608 - text

(g)

O O 13-exo-trig

2. The reaction with PCC oxidizes the secondary alcohol to a ketone. The concave shape of the molecule, due to the cis-oxazolidinone ring, leads to delivery of the bulky hydride reagent from the side opposite the oxazolidinone ring to give the diastereomer shown. This is seen by comparing path A, which is blocked by the oxazolidone ring, with path B. Clearly, path B is relativity unhindered, and delivery of hydride along path B leads to the product. . see J. Org. Chem., 1948, 49, 5072.
O O H H B N H O A

3. The first reaction reduces the ketone to an alcohol. Treatment with acid induces elimination of water to form the conjugated alkene. Epoxidation is followed by a second treatment with acid. When the epoxide is protonated, the

Chapter 6

65

ring opens to give the more stable cation (conjugated to the aromatic ring), and elimination gives an enol, which tautomerizes to the ketone shown. For related reactions, see (a) Advanced Organic Chemistry, L.F. Fieser; M. Fieser, Reinhold, New York, 1961, pp 897-898; (b) Technol. Repts. Osaka Univ., 1958, 8, 455 [Chem. Abstr., 1959, 53: 18920i].
Me O NaBH4 MeO MeO MeO MeO

Me

OH

Me

Me

O H+

Me

H O MeO

Me OH + H MeO

Me OH MeO

Me O

MeO

4. Treatment with base gives an alkoxide, which attacks the epoxide to give an ether. The epoxide can be attacked via a 7-endo mode (see A) to form a seven-membered ring, and the transition state for that reaction will assume a conformation close to that of a seven-membered ring (a chair - although the boat conformation is close in energy see Section 1.5.B). Alternatively, attack via a 6-exo mode (see B) will give a six-membered ring, and the transition state will assume a conformation analogous to that of a six-membered ring (a chair). Generally, forming the sixmembered ring is lower in energy than forming a seven-membered ring, and the exo-attack mode in B should require less distortion than the endo mode in A. For these two reasons, the predicts product is C, via B.

O H O A H O H B OH O O C

5. Saponification gives a hydroxy-acid in both cases. Under acidic conditions, formation of a five-membered ring is energetically very easy, and the equilibrium in this acid-base reaction favors closure to the five-membered ring. In this case, the energy demands on the ring are low (little torsion strain or Baeyer strain). In the second case, once opened, ring closure would regenerate an eleven-membered ring. Eleven-membered rings are inherently high in transannular strain, and the transition state leading to ring closure would assume the conformation of the elevenmembered ring. The strain for regeneration of the eleven-membered ring would therefore be very high, inhibiting its formation.

66

Organic Synthesis Solutions Manual

6. Treatment with potassium carbonate leads to the enolate, which is planar as shown. This enolate reacts with methanol, with delivery of the proton from the less sterically hindered endo face. This generates the diastereomeric exo-acid. Under these conditions, the ester can be converted to the carboxylic acid, requiring a second step of thionyl chloride and ethanol to give the ethyl ester.
CO2 t-Bu N CO2 Et CO2 t-Bu O N C OH

1. K2 CO3 , MeOH , 80C 2. SOCl2 , EtOH 95% CO2 t-Bu N CO2 H

CO2 t-Bu N CO2 Et

7. To obtain the stereochemistry shown, the butyl group must be delivered from the endo face of the bicyclic system, in an SN2 '-like fashion. This will lead to migration of the double bond and formation of the alkoxide. Protonation gives the alcohol. Exo attack is inhibited by the lone electron pairs on oxygen. There is a plane of symmetry bisecting the ether oxygen and the carbonyl group, so attack at either carbon of the double bond will give the same product and a racemic keto-alcohol will result. see J. Org. Chem., 1990, 55, 5305.
O H Bu BuCu(CN)Li2 O H

O H

Bu OH

8. The reaction that gives A is the Sharpless asymmetric epoxidation (see Sec. 3.4.D.i), and the reaction that gives B is the Mitsunobu reaction (see Sec. 2.6.A.ii). see J. Org. Chem., 1990, 55, 5324.
Me3 S i O Me 3 Si R H O R H

HO A

ArCO2 B

Chapter 6

67

9. The product is the less substituted alkene when the E2 conditions are supposed to give the more substituted alkene. In this case, formation of the more substituted alkene would generate the double bond at the bridgehead carbon of a small ring compound. This would generate an anti-Bredt alkene, which is very difficult to form. Due to the high energy required to form this alkene, the elimination reaction can only give the less substituted alkene shown.

10. The Mukaiyama reagent simply activates the carbonyl to a greater extent than the Corey-Nicolaou reagent. The Mukaiyama reagent reacts with the alkoxy oxygen of the carbonyl group displacing the ortho chloro group. The ammonium salt coordinates the hydroxyl, and formation of the lactone generates a pyridone. The equilibrium favoring formation of the pyridone is better than that favoring formation of the thiopyridone product produced by the Corey-Nicolaou reagent. In addition, the Corey-Nicolaou reagent depends upon protonation, whereas the Mukaiyama reagent is an ammonium salt that does not require external protonation. 11. Both reactions are macrocyclizations that generate a macrocyclic lactone. The free hydroxyl that is circled reacts with the carboxylic acid unit to form a lactone using the Yamaguchi protocol for (a) and (b).
Me Me

BnO HO (a) Me S N Me Me TBSO

O Me Me CO2 H 1. Cl

Cl Cl

O Cl

TBSO O O Me S N Me

O OBn

Me

Me

NEt3 ,THF , 0C 2. DMAP , toluene , RT

see Org. Lett., 2000, 2, 2575

68

Organic Synthesis Solutions Manual

(b) O

O HO2 C 2,4,6-trichlorobenzoyl chloride DMAP , NEt3

OMe

O O O

KOH MeOH MeO

O O O see J. Am. Chem. Soc., 2002, 124, 1664 OH

O (c) OH Me

OMe OMe OH Me

OMe OMe

O Me

1. TPAP , NMO , CH2 Cl2 2. NaBH4 , AcOH , THF Org. Lett. 2002, 4, 367 OH

O Me

OH

12. (a) The first reaction is the Mitsunobu reaction that inverts the stereochemistry of the hydroxyl group. The methoxymethyl ether protecting group in the last step is discussed in Section 7.3.A.i
OH a OBz b OH c OMOM

(a) PhCO2 Na , DEAD , PPh3 (b) i. aq KOH ii. aq H + (c) NaH ; MeOCH 2Cl

(b) This is also a Mitsunobu reaction, with azide. Hydrogenation leads to the amine.
OH a N3 NH2

(a) NaN3 , DEAD , PPh3 (b) H2 , Pd

(c) A Mitsunobu reaction is used to invert the hydroxyl group, but the hydroxy-acid is first cyclized to the lactone to facilitate the transesterification reaction with sodium benzoate.

CO2 H OH

a O O

b OBz (a) H
+

CO2 H c

CO2 H OH

(b) PhCO2 Na , DEAD, PPh3 (c) i. aq. KOH ii. aq. H +

(d) In step (f), two regioisomeric alkenes are formed. They are separated, and the desired alkene is ozonized. The use of the MOM protecting group is discussed in Section 7.3.A.i.

Chapter 6

69

a O e

HO Me OMOM

c AcO Me OMOM Me Me g

d AcO Me CO2 H OMOM h O AcO Me

OH Me

AcO Me Me

CO2 H OH

Me Me Me Me + (a) LiAlH 4 (b) MeCO2 Cl , NEt3 (c) MCPBA (d) MeMgBr ; H 3O (e) NaH ; MeOCH2 Cl (f) i. aq H+ ii. POCl3 , pyridine (g) O3 ; H2 O2 (h) BF 3

(e)
OH (CH2 )10 d CH2 (CH2 )10 OMOM e a (CH2 )10 OMOM b OH OMOM OH (CH2 )10 CO2 H OMOM g OMOM c (CH2 )10 O O (CH2 )10 O OMOM

f (CH2 )10 (CH2 )10 (a) NaH ; MeOCH2 Cl (b) 9-BBN ; H 2O 2 , NaOH (c) PDC (d) Ph3 P=CH 2 (e) 9-BBN ; H 2O 2 , NaOH (f) CrO3 , H + (g) i. BF 3 ii. Mukaiyama reagent

(f)
Me a OH Me b Me Cl c Me d Me n-C 3 H7

C  Cn- C3 H7

(a) 9-BBN ; NaOH , H2 O2 (b) SOCl2 (c) NaC C n-C 3 H7 (d) H2 , Lindlar

70

Organic Synthesis Solutions Manual

CHAPTER 7

1. (a) Reducing an aldehyde in the presence of a ketone is very difficult. Although the aldehyde is more reactive, the difference in reactivity is so small that finding a reagent to selectively reduce one in the presence of the other is difficult. The use of mono-hydride reagents such as DIBAL-H or lithium trimethoxyaluminum hydride at low temperature offers the best solution. This system is, however, a candidate for protection. A similar argument applies to catalytic hydrogenation and reaction with Grignard reagents. Since the ketone is unlikely to be affected by Jones oxidation or the use of PCC, protection is unnecessary. (b) In this example, it is possible that oxidation with Jones reagent can cleave the ketone moiety, but this option requires very stringent conditions and will be ignored. Since vigorous oxidation is not an issue here, the focus will be on reduction and Grignard reactions. Cerium borohydride, zinc borohydride, and aluminum hydride (see Secs. 4.3, 4.4.B) are reagents that will react with conjugated ketones to give 1,2-reduction. These reagents also react with non-conjugated ketones, and protection may be necessary. The use of palladium catalysts should allow hydrogenation of the alkene moiety in the presence of ketone moieties, and platinum catalysts can be used to maximize reduction of carbonyl moieties. There will be a mixture of products, however, and the highest yields of selective reduction will be realized by using protecting groups. Similar arguments apply to Grignard reagents, although addition of cuprous salts to the Grignard reagent will give predominately Michael addition to the conjugated ketone. (c) Only the ketone reacts with hydrides, or with hydrogenation and a catalyst. If the resulting alcohol is to be differentiated from the existing alcohol, then protection of that alcohol moiety will be required. The alcohol can easily be oxidized in the presence of the ketone, but if that new ketone is to be differentiated from the original ketone, then the original ketone must be protected. The use of excess Grignard reagent will allow the ketone to react normally. This is not a problem with methylmagnesium bromide, but this is not as attractive with an expensive Grignard reagent, and protection of the alcohol will give better results. (d) Hydride reduction of the aldehyde with sodium borohydride or any of the other selective hydride reagents discussed in Sections 4.3 & 4.4.B will selectively reduce the aldehyde. If the resulting secondary alcohol is to be differentiated from the primary alcohol, best results are obtained if the primary alcohol is protected. Borane might selectively reduce the carboxyl group in the presence of the aldehyde, but protection of the aldehyde is probably necessary. Protection of the existing primary alcohol is required if it is to be differentiated from the primary alcohol product. Carboxylic acids resist catalytic hydrogenation, so hydrogenation of the aldehyde is quite easy, without protection. The comments concerning formation of the new alcohol made previously also apply. Oxidation of the primary alcohol with PCC in the presence of the aldehyde is facile, but if the resulting aldehyde is to be differentiated from the existing aldehyde, the latter must be protected. Oxidation with Jones reagent will likely convert the aldehyde to an acid, and protection of the aldehyde is required. Both the alcohol and the acid will react with a Grignard reagent, and excess Grignard reagent is required (although a dianion will likely have

Chapter 6

71

solubility problems) or protection of those groups. 2. The sequence of the events depicted in this mechanism can be called into question, in that the OMOM may come off first. Nonetheless, transfer of a proton (from the acidic Dowex) to the dioxolane oxygen and ring opening leads to an O-stabilized cation, which reacts with water (water is present in the Dowex resin) to give an oxonium ion. Loss of a proton and transfer to the other oxygen allows loss of protonated acetone to give the diol. The oxygen of the MOM group is then protonated and loss of the CH2=OMe]+ unit leads to the triol, B. In the second step, methanolic potassium carbonate contains some methoxide (MeO-), which attacks the amide carbonyl and acyl substitution leads to methyl trifluoroacetate and the amide anion, which is quickly protonated by methanol. This amine is now positioned to react with the carbonyl of the lactone (see crude conformational drawing). One again, acyl substitution leads to the amide and an alkoxide. The alkoxide is protonated by methanol to give the final product, C.
OMOM O O O O O O A O O OMOM O H + H+ HN O H + H+ O O O O O OH OH O O OH OH OH NH2 O O OH OH O O NH2 O CF 3 CO 2Me MeOH O O O O O HN CF3 O O MeO B OH OH OH HN CF 3 OMe O HN O CH2 =OMe O HN CF 3 H+ O O O O OMOM O O O O O CF 3 O O O OH OH OH CF3 HN H OH HN CF 3 O O + H2 O O O O OMOM O O CF 3 H OH2 HN O O OMOM O OMOM O O O O CF3

O H OH O HN CF 3

O O

O - Me2 C=OH O O O OH OH

O O O

HN

CF3

OHO O

72

Organic Synthesis Solutions Manual

OH OH OH OH OHO O NH O NH O O OH MeOH O OH O C O NH OH HO OH

O see J. Org. Chem., 1999, 64, 4465

3. One mechanistic rationale is presented here, based on the cited reference.


H O Me see J. Org. Chem., 1999, 64 7067 Me H O O
+

Me

O Me

+ H+

Me

Me O Me Me HO C 12 H25 O O -MeOH

Me O Me Me Me H O OMe

Me O Me

Me O

OMe +H O O Me

Me
+Me

OMe

O C 12 H25 O O H

C12 H25 Me +MeOH Me O C 12 H25 Me Me O C 12 H25 O O H O OMe Me

C12 H25

Me O H O H

Me OMe O

H+

C 12H 25 Me

Me O O H

Me O +H+

OMe

C12 H25

O H

Me O O H Me

OMe

Me O H

H+

Me O

OMe

Me O

Me +H+

H Me O Me O O O H

Me O

Me O MeOH C 12 H25 O O H

Me O

C12 H25 H CO 2Me

O O H H+

C 12 H25 O C 12 H25 O

O C 12H 25

CO 2Me

4.
H
OAc

O
OAc

(a)
O

(b)

N H H

(c)
S MeO2 C

CO 2Me S S

see J. Am. Chem. Soc., 1999, 121, 5653

I Angew. Chem. Int. Ed., 2002, 41, 4316

see Synthesis, 1996, 71

Chapter 6

73

OH O
HO

H2 N

HOMe2 CH2 CH 2C

H N O'

(d)

O Br J. Org. Chem., 2002, 567, 9248

(e)

N Boc see J. Org. Chem., 2000, 65, 1738

(f)
see J. Org. Chem., 1999, 64, 3736

OAc BzO OAc OAc NH

(g)
MeO2 C

O CO2 Me

(h)

O O

(i)

O NBoc

OH J. Org. Chem., 2002, 67, 4200

OH O Org. Lett. 2002, 4, 1343

J. Org. Chem., 2003, 68, 3838

O
O

OH
OBz O O

(j)

Ph

O Ph

O
OH OSiPh2 t-Bu

(k)
Eur. J. Org. Chem., 2004, 499

OH

Angew. Chem. Int. Ed., 2003, 42, 4779

(l)

J. Am. Chem. Soc., 2003, 125, 8238

HO

H CHO N
OSEM CHO

Ph H N O

N H Me

H Me

(m)

Org. Lett. 2002, 4, 687

(n)

see Tetrahedron Lett., 2000, 41, 2821

(o)

J. Org. Chem., 2002, 67, 4337

5. (a) Step b may cause problems due to the poor nucleophilicity of acetate, but the allylic bromide moiety is rather reactive. Protection is definitely required to set the proper stereochemistry of the product.
Br a b c OH (a) NBS , h (b) NaOAc , DMF ; H3 O
+

HO

t-BuMe2 SiO OH d

HO OH OH

(c) 1. Me 2t- BuSiCl , DMAP 2. OsO4 , NMO (d) TBAF

If the alcohol moiety is not protected, osmylation will proceed with a neighboring group effect giving primarily the all-cis product. When protected with the bulky silyl group, osmylation occurs from the opposite face to give the desired cis-trans triol as the major product. The silyl group was also chosen because it is removed under mild conditions that should not effect the diol moiety of the triol product.

74

Organic Synthesis Solutions Manual

(b) Protection of the alcohol is not necessary since the neighboring group effect of the OH is required to set the stereochemistry. Sharpless asymmetric epoxidation is probably preferable to give enantiopure material. Reduction of the epoxide proceeds without the need of a protecting group. Oxidation of the secondary alcohol in the presence of a tertiary alcohol also does not require a protecting group.
OH a Me b Me Me O OH (a) MCPBA (b) LiAlH4 (c) PDC , CH 2Cl2 OH c Me OH O

OH

(c) Incorporation of the tertiary alcohol via oxy-mercuration does not require that the first alcohol be protected. Although this reaction is done under aqueous conditions with a Lewis acid, loss of a primary OH under these conditions is unlikely. The oxidation step is also straightforward, without protection, since the tertiary alcohol will not react.

a CO2 H

OH

HO b

OH

HO c CHO

(a) LiAlH 4 (b) Hg(OAc)2 , H2 O ; NaBH 4 (c) PDC , CH2 Cl2

(d) Since an aldehyde and a ketone moiety are involved in the sequence, they must be incorporated at diff-erent times. For this reason, ozonolysis used an oxidative workup to give the ketone-acid. This allowed pro-tection of the ketone moiety and then selective reduction of the acid to the aldehyde, via a methyl ester. The aldehyde reacted with the alkyne anion and the ketone was unmasked, allowing reduction to the targeted diol.

O CO2 H O

O CO2 H

CHO f

OH

Et

OH
+

Et

OH

Et
+

OH

(a) O 3 ; H2 O2 (b) ethylene glycol , H

(c) i. CH2 N2 ii. DIBAL-H , -78C (d) EtC C Na (e) aq H+ (f) NaBH4

(e) Conversion to the alkynyl alcohol is straightforward. The next step involves hydroboration and requires protection of the tertiary alcohol. The TIPS group was chosen for ease and mildness of removal in the final step.

Chapter 6

75

Me a

Me O

Me b

Me

Me d
n-Bu

n-Bu

c OSi(iPr)3 OH OH Cl + (a) 1. 9-BBN ; NaOH,H 2O 2 2. PCC (b) HC C Na (c) NaH , iPr3 SiCl (d) 1. B H NaOMe ; AcOH , reflux 2. TBAF

6. In each case a synthesis is provided. These are not the only possible syntheses, however. In many cases there are several other possible routes. (a)
O OH OH O OH OSiMe 2 t- Bu O CHO OSiMe2 t-Bu g O d O a O OBz OH I OSiMe2 t-Bu OH OSiMe 2t- Bu h e O b O OBz OSiMe 2t- Bu CN f see J. Org. Chem., 1999, 64, 4798 c

OSiMe 2t- Bu O OH OH

(a) PhCOCl , NEt3 , DMAP (b) t- BuMe 2SiCl , imidazole (c) NaOMe , MeOH (d) I2 , imidazole , PPh3 (e) KCN , DMSO (f) DIBAL-H (g) NaBH4 (h) TBAF , THF

This sequence is taken directly from the cited paper. Other protecting groups can be used of course, but the idea is to take advantage of the grater reactivity of the primary alcohol to protect it first with a short term group. This allows the secondary alcohol to be blocked with a longer term group. The primary alcohol is then liberated and chain extended. Steps a-g are taken directly form the paper in the order in which they were done. Step h is added and simply deprotects the OTBS group with tetrabutylammonium fluoride. (b) Since the last step is a Grignard reaction (Sec. 8.4.C), the alcohol in the starting material must be oxidized to a ketone. That ketone must then be protected, with a group impervious to aqueous acid, allowing Birch reduction of the aromatic ring (Sec. 4.9.E) and conversion of the vinyl ether to a conjugated ketone. Selective reduction of the carbonyl and protection allows unmasking of the ketone and Grignard reaction. The Lewis acid used to unmask the dithiane could affect the silane, although this is probably not a significantly problem. Sulfur compounds such as the dithiane can be reduced by sodium in ammonia. If this is a problem, then the ketone moiety may have to be protected as an imine. Alternatively, the original alcohol may have to be protected, unmasked after the allylic alcohol is protected and then oxidized before reaction with crotyl magnesium bromide. The procedure shown here is more straightforward, however, and should produce the targeted diol.

76

Organic Synthesis Solutions Manual

MeO

OH a

MeO

MeO

S S

MeO c

S S t- BuMe 2SiO f d

S S O g HO

t- BuMe 2SiO e OH

S S

(a) PDC (b) 1,3-propanedithiol , BF 3 (c) Na , NH3 , EtOH (d) aq H + (e) 1. Zn(BH4 )2 2. t-BuMe2 SiCl , imidazole (f) HgCl2 , aq THF , BF3 (g) crotyl MgBr ; H3 O+

(c) The aldehyde unit was incorporated by conversion of the alcohol to a tosylate and displacement with NaCN. The authors of this paper used the allyl borane shown in order to add to the aldehyde, and the reaction proceeded with high stereoselectivity (not indicated in the answer shown here). The final step is a protection of the alcohol using a variation of the ethoxyethyl ether group.

HO

O O

OMe a TsO OPMB e OPMB EtO

b NC OPMB

c OHC OPMB

HO

OPMB

(a) TsCl , pyridine (b) NaCN , DMSO (c) DIBAL-H , THF , -78C (d) Ipc2 BCH2 CH=CH2 , ether , 100C (e) CH2 =CHCH(OEt)2 , p-TsOH

see Tetrahedron Lett., 2000, 41, 33

(d) These reagents are taken form the cited reference. Short term protection of the alcohol as the tetrahydro-pyran derivative allowed LiAlH4 reduction of the lactone to give the diol (see chap. 4, sec. 4.2.B). The OTHP group is removed to give the triol, and two hydroxy groups are protected as the dioxane by treatment with benzaldehyde. This allowed oxidation of the hydroxymethyl unit to the aldehyde with pyridinium dichromate (see Sec. 3.2.B.iii).
OH O O OH OH OH a O d O O OTHP O OH e O Ph (c) TsOH , MeOH O b OH CHO see Synthesis, 1993, 137 OTHP OH c

Ph (a) dihydropyran , TsOH , CH2 Cl2 (b) LiAlH4 , ether (d) PhCHO , TsOH (e) PDC , CH2 Cl2

Chapter 6

77

(e) This sequence is taken from J. Am. Chem. Soc., 2003, 125, 1567. Protection of the ketone unit as the dioxolane (7.3.B.i) was followed by hydroboration to give the alcohol (5.4.A). Protection of the alcohol as the benzyl ether (7.3.A.i), and deprotection of the ketone unit gave the target.
O a O O O b HO (a) (MeO)3 CH , MeOH , TsOH O c O O d BnO

BnO

(b) 1. BH3 THF 2. NaOH , H2 O2 (c) KH , BnBr , Nu4 NI (d) TsOH , aq acetone

(f) This sequence is taken from J. Org. Chem., 2004, 69, 3857. Protection of the free hydroxyl unit as the acetate was followed by deprotection of the ketone, by treatment of the dithiolane with aqueous N-bromosuccinimide. Saponification of the acetate group was followed by oxidation to the aldehyde with pyridinium chlorochromate (3.2.B.ii)
OH OTBS OBn Ac2 O , DMAP NEt3 OH OTBS NaOMe MeOH O O OBn PCC H OAc OTBS OBn NBS , aq acetone S S O O OTBS OBn

OAc OTBS OBn

(g) All steps are taken directly from the cited reference. Reduction of the ester unit with DIBAL-H gave the alcohol (Sec. 4.6.C), and Mitsunobu reaction with phthalimide converts the OH unit to phthalimidoyl (Sec. 2.6.A.ii). Epoxidation with MCPBA (Sec. 3.4.C) was followed by deprotection of the phthalimide by reaction with hydrazine (the Gabriel synthesis, see Sec. 2.6.A.ii.) to give the amine, which opened the epoxide intramolecularly to give the pyrrolidine derivative. The amine was protected as the Boc derivative, and the trityl group removed by catalytic hydrogenation. This is possible because the Ph3CO group is benzylic and subject to hydrogenolysis (Sec. 4.8.E). The primary alcohol is selectively converted to a mesylate and deprotection of the N-Boc unit allows cyclization to give the pyrrolizidine product. The OMOM group is sensitive to acid, and it is removed during the deprotection-cyclization sequence, accounting for the final product.

78

Organic Synthesis Solutions Manual

OMOM CO2 Et a

OMOM OH b

OMOM NPhth c O

OMOM NPhth d

Ph3 CO OMOM

TrO

TrO OMOM

TrO OMOM e HO H N Boc f HO H N Boc OMOM

NH2 HO O TrO HO g MsO Boc TrO H N

H N H

TrO OMOM h

HO OH

HO H N

see Synthesis, 1993, 615

(a) DIBAL-H , THF (b) phthalimide, DEAD , PPh3 (c) MCPBA , NaHCO3 , CH 2Cl2 (d) N2 H4 , EtOH (e) Boc2 O , THF , i-Pr2 NH (f) H2 , Pd-C , MeOH , cat. HCl (g) MeSO2 Cl , Py , CH2 Cl2 (h) CF 3 COOH, MeOH

(h) The reagents used are taken form the reference. Reduction of the carboxylic acid with borane (Sec. 4.6.A) was followed by protection of the amine as the Boc derivative. This allowed Swern oxidation to give the aldehyde (Sec. 3.2.C.i).

a N H CO 2H N H CH2 OH

b N CH2 OH Boc

c N O CHO O t- Bu

(a) BH3 THF ; aq NaOH

(b) Boc2 O

(c) (COCl) 2 , DMSO

ssee J. Am. Chem. Soc., 1999, 121, 700

(i) These reagents are taken from J. Org. Chem., 2003, 58, 2790. In this particular synthesis, Wittig olefination of the aldehyde unit (Sec. 8.8.A.i) was followed by treatment with acid to convert the dioxolane to the diol shown. Protection of the primary alcohol unit as the t-butyldimethylsilyl ether was followed by protection of the secondary alcohol unit as the methoxymethyl ether. Subsequent treatment with tetrabutylammonium fluoride deprotected the silyl ether to give the free primary alcohol, and oxidation to the acid was accomplished with PDC in DMF (Sec. 3.2.B.iii).

Chapter 6

79

O O

CHO

O O d C 14H 29 HO MOMO

HO HO e C 14 H29

TBDMSO HO C 14H 29

C14 H29

HOOC

C14 H29 OMOM

(a) C 15H 31 PPh3 Br , BuLi , 78C (b) H+ , rt (c) TBDMSCl , NEt3 , cat DMAP , CH2 Cl2 (d) 1. MOMCl , i- Pr 2NEt , CH2 Cl2 2. Bu4 NF , THF (e) PDC , DMF , 40-50C

(j) All steps are taken from Angew. Chem. Int. Ed., 2002, 41, 1062. Deprotection of the diol (7.3.B.i) was followed by conversion of the primary alcohol unit to the pivaloyl ester (7.3.A.ii). The diol unit that remains was then converted to a new acetonide. (7.3.B.i)

O O OH Me 3Si a HO

HO OH b

OPiv

OH OH c

OPiv

O O

Me3 S i (a) 3N HCl , MeOH

Me3 Si

Me 3Si (c) p-TsOH , 10 eq Me2 C(OMe)2 , DMF , 70C

(b) pivaloyl chloride , Py , 23C

(k) The reagents are taken from the cited reference. The first step is to deprotect the benzyloxy group and DDQ was chosen as the reagent. This allowed the protecting group to be changed to TBDPS and methanolic potassium carbonate deprotected the acetate groups to give the final diol.

OAc a O OAc HO O

OAc

b O

OAc

c O

OH OH

BnO (a) DDQ , CH 2Cl2

OAc TBDPSO

OAc TBDPSO

(b) t- BuPh2 SiCl , imidazole , THF

(c) K2 CO3 , MeOH

see J. Am. Chem. Soc., 1999, 121, 5653

(l) All reagents are taken from the cited reference. Protection of the free hydroxyl as a MOM is followed by dihydroxylation of the alkene with OsO4 (Sec. 3.5.B). Protection of the diol as an acetonide allows the alcohol to be converted to a mesylate. Methanesulfonic anhydride was used, but based on information provided in most undergraduate courses, methanesulfonyl chloride would probably have been chosen. Reaction with potassium t-butoxide leads to elimination and formation of the diene. Deprotection of the diol with aqueous acetic acid allows oxidative cleavage with sodium periodate to give the aldehyde. (m)