Learn more about Swern Oxidation
Bioactive Natural Products (Part I)
Byung H. Lee, in Studies in Natural Products Chemistry, 2003
Synthesis of 14β-hydroxy-MFA (31) and 14β-methyl-14α-hydroxy-MFA (32)
Because of the enhanced biological activity of 14α-hydroxy-MFA (23),
the synthesis of its antipode was carried out as shown in Fig. (8).
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Fig. (8). Synthesis of 14β-hydroxy-MFA and 32
Swern oxidation (oxalyl chloride, DMSO, NEt3, -78 °C, 1 h)
of 23provided 14-oxo-MFA (30, 74%). Reduction of 30 with NaBH4 (6
equiv/THF, 0 °C, 1 h) gave 14β-hydroxy-MFA 31, 50%) and 14α-
hydroxy-MFA (23, 3%). Compound 31 was inactive, thus
demonstrating the need for correct stereochemistry of
the hydroxylgroup at C14. To assess the effect of the C14 methyl
group on biological activity, 30 was reacted with
methylmagnesium bromide to yield 32 (50% based on recovered
starting material), the six membered homologue of PHA. The related
a-methyl epimer was present only in trace amounts. Compound 32 iss
the first MFA analog with nematocidal activity comparable to that of
PHA.
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Five- and Six-membered Fused Systems with Bridgehead
(Ring Junction) Heteroatoms concluded: 6-6 Bicyclic with
One or Two N or Other Heteroatoms; Polycyclic;
Spirocyclic
I. Hermecz, L. Vasvári-Debreczy, in Comprehensive Heterocyclic
Chemistry III, 2008
[Link].3 Oxidation, dehydrogenation
Swern oxidation of perhydropyrido[2,1-c][1,4]oxazin-1-oles using
(COCl)2 <1997SL799, 1998EJO2461, 1998T10309, 2000JOC4435,
2000SC2565, 2001EJO2385> or COCl2 <1999SL1094,
2002JMC2424> gave perhydropyrido[2,1-c]oxazin-1-ones. Swern
oxidation of 7-[(4-fluorophenyl)hydroxymethyl]-2-substituted 2-
pyrimidyl)perhydropyrido[1,2-a]pyrazines <1996WO96/010570,
1996WO96/010571, 2001EPP1074257> and of 7-hydroxyethyl-2-(2-
pyrimidinyl)perhydropyrido[1,2-a]pyrazines <1999WO99/020622,
2001EPP1074257> yielded 7-(4-fluorobenzoyl) derivatives and 7-
formyl derivatives, respectively.
A mixture of epimers of sulfoxides and sulfones were obtained
from 288 (X = S, R = R1 = H) by oxidation with 1 or 2 equiv of MCPBA,
respectively <1995TL5159>. Oxidation of 7-(4-
fluorophenylthio)methyl-2-(2-pyrimidinyl)perhydropyrido[1,2-a]pyrazine
with MCPBA gave the 7-(4-fluorophenylsulfonyl)
derivative <1996WO96/010571>. Treatment of 10-methylthio-9-fluoro-
3-methyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-
carboxylate with oxone at 0 °C afforded 10-methylsulfonyl
derivative <1999H(51)1563>. The methylthio group in a 7-(4-
methylthiophenyl)-5-oxo-2,3-dihydro-5H-pyrido[1,2,3-de]-1,4-
benzoxazine-3-carboxamide was oxidized to a sulfoxide and
a sulfonegroup <2000WO00/013682>. Oxidation of 7-hydroxy- and 7-
aryl-5-oxo-2,3-dihydro-5H-pyrido[1,2,3-de]-1,4-benzothiazine-6-
carboxylates and -6-carboxamides with m-
chloroperbenzoic acid(MCPBA) yielded sulfoxides and sulfones,
depending on the molar ratio of the substrate and oxidizing
agent <2000WO00/006580>. A sulfoxide was prepared by the
oxidation of (3S)-3-methyl-10-(10-(2,6-dimethyl-4-pyridyl)-7-oxo-2,3-
dihydro-7H-pyrido[1,2,3-de]-1,4-benzothiazine-6-
carboxylate <2000WO00/046223>. A sulfoxide was obtained from 8-
[(4-trifluoromethylthiophenyl)methoxy]-2-cyclopentyl-1,2,3,4,11,11a-
hexahydro-6H-pyrazino[1,2-b]isoquinoline-1,4-dione with 36% H2O2 in
AcOH <1998WO98/016526>, and from 1-[2-(4-thiomorpholin-1-
yl)acetyl]-7-(3-methoxyphenyl)-N-methyl-N-{[3,5-
bis(trifluoromethyl)phenyl}-5-oxo-1,2,3,5-tetrahydropyrido[1,2,3-
de]quinoxaline-6-carboxamide with MCPBA <2001WO01/085732>. A
7-[(4-fluorophenylsulfonyl)methyl] derivative was obtained from a 7-
[(4-fluorophenylsulfanyl)methyl]perhydropyrido[1,2-a]pyrazine
derivative with MCPBA <2001EPP1074257>. Treatment of an
epimeric mixture of 1-hydroxy-8-methylene-4-phenyl-
perhydropyrido[2,1-c][1,4]oxazines with OsO4 in the presence of
NaIO4 gave an epimeric mixture of 1-hydroxyl-8-oxo
derivatives <2000JOC4435, 2001EJO2385>. Oxidation of 8-
hydroxyperhydropyrido[1,2-a]pyrazines with SO3–pyridine complex at
0 °C in the presence of NEt3 afforded 8-oxo
derivatives <2000JAK00/86659>. Oxidation of a 1-epimeric mixture of
7-formyl-2-benzyloxycarbonyl-1-hydroxy-4-oxoperhydropyrido[1,2-
a]pyrazine-6-carboxylates with aqueous NaClO2 and NaH2PO4 in the
presence of 2-methylbut-2-ene in tert-BuOH afforded 7-
carboxylic acids<2004EJO1527, 2005TL4373>. Treatment of 2-
substituted 8,9-dihydroxy-1,2,3,4-tetrahydro-6H-pyrido[1,2-a]pyrazine-
1,6-diones with NaH (60% oil dispersion) in DMSO yielded 1,2-dihydro
derivatives <2004WO04/024078>. 7-Formyl-8-[(4-
cyanophenyl)methoxy]-2-cyclopentyl-1,2,3,4,11,11a-hexahydro-6H-
pyrazino[1,2-b]isoquinoline-1,4-dione was prepared by oxidation of the
7-ethenyl derivative with OsO4 in the presence of
NaIO4<1998WO98/016526>. Biomimetic oxidation
of praziquantelcatalyzed by metalloporphyrins was
investigated <2005JMO23>. 7,9a-cis-H-7-Hydroxymethyl-2-tert-
butoxycarbonylperhydropyrido[1,2-a]pyrazine was converted to the
7,9a-trans-H derivative by oxidation of the hydroxymethyl group with
SO3 in pyridine to a formyl groupfollowed by equilibration to the
thermodynamically favored trans-isomer, and by reduction of the
formyl group with NaBH4<1998BML725, 1999WO99/052907>.
Oxidation of a 7-hydroxymethylperhydropyrido[1,2-a]pyrazine with
Pr4NRuO4 in the presence of N-methylmorpholine-N-oxide yielded a 7-
formyl derivative <1996WO96/010571, 2001EPP1074257>.
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Seven-membered Heterocyclic Rings and their Fused
Derivatives
L.I. Belen’kii, in Comprehensive Heterocyclic Chemistry III, 2008
[Link].1 By formation of seven- from three-membered rings
The Swern oxidation of isopropenyl-substituted cyclopropylcarbinols
(Scheme 26) results in ring expansion to respective
methyldihydrooxepines <1997BCJ2215>. The experimental
parameters of the hetero-Cope rearrangement of
vinylcyclopropanecarbaldehyde, as a model molecule, are well
reproduced by MP2/6-31G* ab initio and B3LYP/6-31G*
DFT quantum-chemical calculations, the aldehyde and oxepin being
nearly isoenergetic while the activation energy is
∼25 kcal mol−1<1997LA2443>.
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Scheme 26.
Condensation of β-(hydroxyalkyl)cyclopropanols with aldehydes,
followed by rearrangement of acetals formed (Scheme 27), is
proposed as simple and convenient method for the synthesis of cis-
2,7-disubstituted oxepan-4-ones <2005OL515>. Though the
intermediate acetal could be isolated in some cases, the reaction is
usually carried out as one-pot procedure with sequential addition of
two Lewis acids, Al(OTf)2 and TiCl4. The overall yields range from 50%
to 70%.
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Scheme 27.
The 2-(alken-1-yl)cyclopropanecarbaldehyde–1,4-dihydrooxepine
equilibrium (Scheme 28) was found to be shifted to the right when
alken-1-yl is not vinyl, and this fact was used for the preparation
of oxepines from properly substituted cyclopropanes under Dess–
Martin oxidation conditions <1993JOC1295>.
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Scheme 28.
Cyclopropyl carbinols bearing a (tert-butyldiphenylsilyl)methyl
substituent undergo silicon-assisted regioselective ring cleavage to
generate γ-methylene oxacycles without cleavage of the silanemoiety.
In particular, the ring opening of 2-(tert-butyldiphenylsilyl)methyl-1-
hydroxymethyl-1-(3-hydroxypropyl)cyclopropane gives 2-(tert-
butyldiphenylsilyl)methyl-5-methyleneoxepanes
regioselectively <2002CC514>.
Treatment of 1,2-cyclopropane-annulated carbohydrate derivatives
with Lewis acid (Scheme 29) is a convenient route to 2-substituted-
2,3,6,7-tetrahydrooxepines <1995TL6831, 1997JOC6615>.
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Scheme 29.
The ring opening of an annulated cyclopropane fragment proceeds
through a seven-membered oxonium ion. In galactal-based
oxonium ions like 70, due to their stereochemistry, the ‘upper’ face is
hindered and the direct attack of a nucleophile from ‘below’ proceeds
in contrast to glucal derivatives, for example, 71 (Scheme 30). This
fact provides much higher diastereoselectivity of the ring expansion of
cyclopropanated galactal <2003TL9043>.
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Scheme 30.
Tandem intermolecular Paterno–Büchi reaction
of benzophenonewith trimethylsilyl vinylcyclopropyl ether 72 (Scheme
31) leads in its first step to the formation of seven-membered 73 rather
than to four-membered heterocycle while its second step proceeds in
a normal fashion. With aromatic aldehydes, only tetrahydrooxepine
derivatives 74 are formed <1998J(P1)2363>.
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Scheme 31.
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Oxidations and Reductions
Kenneth A. Savin, in Writing Reaction Mechanisms in Organic
Chemistry (Third Edition), 2014
Swern Oxidation
The initial step in the Swern oxidation creates activated
chlorodimethyl sulfonium chloride 7-44 by the reaction
of dimethyl sulfoxide with oxalyl chloride. The process generates one
equivalent each of CO2, CO (it is often possible to see the
mixture bubble as the fast decomposition ensues), and chloride ion.
The chloride ion attacks the sulfur (7-45) to form the sulfonium
chloride.
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In the second step of the process, the alcohol displaces the chloride
(7-46) to deliver alkoxy sulfonium intermediate 7-47. The hydrogens
on the carbon adjacent to the sulfonium sulfur are relatively acidic,
due to stabilization afforded by the sulfonium salt (pKa
∼18.9,comparable to an enolizable proton adjacent to a carbonyl,
see appendix C).∗ The triethylamine deprotonates 7-47 to form the
sulfur ylide (7-48). In a cyclic transformation, the anionic carbon
abstracts a proton and the alcohol is oxidized to the carbonyl, as the
sulfur–oxygen bond is broken and dialkyl sulfide is released.
The sources are Corey and Kim, (1972); Mancuso and Swern, (1981);
Marx and Tidwell, (1984); Tidwell, (1990a); Tidwell, (1990b);
McConnell et al., (2008).
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Four-membered Heterocycles together with all Fused
Systems containing a Four-membered Heterocyclic Ring
L.K. Mehta, J. Parrick, in Comprehensive Heterocyclic Chemistry III,
2008
[Link] From a 3,4-Disubstituted Four-Membered Ring
Banfi and Guanti have used Swern oxidation of
the alcohol 277(R = CH2OH) to the aldehyde 277 (R = CHO) as a step
on the way to the bicyclics 71 and 72. Ring closure was obtained by
the intramolecular version of the Nozaki–Hiyama–Kishi coupling using
a mixture of chromium(ii) chloride and nickel(ii) chloride
as reagentwhich gave 71 and 72 in good yield and in a ratio of 55:45.
Success in the coupling reaction depended upon the aldehyde being
freshly chromatographed through silica gel and azeotropically dried
immediately prior to use. The two bicyclic isomers were easily
separated by silica gel chromatography and no evidence was found
of epimerization at the ring junction <1995AGE2393, 1997T3249>.
The same general approach to the cyclization of the enediyne chain
on to the β-lactam has been successfully applied in the preparation of
more highly substituted and more usefully protected
bicyclic enediynes 278 <2002EJO3745, 2002TL7427>.
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It is interesting to note that only one isomer of the bicyclic product was
detected in the last case. A likely explanation is that
the stereoselectivity in the cyclization step is controlled by the steric
size of the substituents. Cyclization on to the ‘outside’ carbonyl
group in 279 favors formation of 280 and the cyclization with the
‘inside’ carbonyl group of 281 yields 282 (Equations 28 and 29). The
bulky N-protecting group on the aldehyde precursor of 278 favors the
formation of the ‘outside’ configuration of the carbonyl group.
However, the evidence adduced supports the view that the steric size
of R2 in 279 is much more important than R1 in determining the
configuration of the aldehyde <1997T3249, 2002TL7427>.
(28)
(29)
The same group of workers has developed a method for the closure of
the 3,4-bis(but-2-ynal)azetidinone 283 using Pedersenvanadium(ii)-
mediated pinacol coupling to give the vic-diol 284 from which it was
possible to get the bicyclic enediyne in two steps and 63% overall
yield from the diol <2000EJO939> (see Section [Link]).
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Another example of the exploitation of the effectiveness of inorganic
or organometallic reagents is in bringing about ring closure
of 285 to 286 through a coupling reaction. The intramolecular Stille
reactionrequires the use of bis(dibenzylidene)acetone palladium,
Pd2(DBA)3, and triphenylarsine (Equation 30) <2001TL1251>.
(30)
Stereocontrolled access to bicyclic β-lactams has been achieved by
application of the Heck reaction to bromoalkenes. Cyclization of the
3,4-disubstituted azetidinone 287 (R = H) was achieved using
palladium(ii) acetate, triphenylphosphine, and potassium carbonatein
DMF but two products 288 (R = H) and 289 were obtained in 21% and
27% yield, respectively. When the allyloxy group had a
methoxycarbonyl substituent in 287 (R = CO2Me) only one
product 288 (R = CO2Me) was produced in 47%
yield <2005JOC2713>.
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RCM reactions have been little used with 3,4-
disubstituted azetidinesor azetidinones, in contrast to their
enthusiastic use with the corresponding 1,4-disubstituted compounds
(see Section [Link]). However, the 3,4-disubstituted β-
lactam 290 has been converted to the bicyclic β-lactam 291 in 93%
yield with>95% de by the action of
the ruthenium carbene (Equation 31) <2003T3253>.
(31)
The primary amine in derivative 292 (R = H) reacts with
the lactonefunction in the presence of triethylamine trihydrofluoride in
THF to give the bicyclic 205 in 86% overall yield from the protected
amine 292 (R = BOC) <2005JA15386>.
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In the presence of triethylamine, the sulfur atom in 293 displaces the
acetoxy function to afford the bicyclic 294 in 98% yield <2000S289>.
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When a mixture of stereoisomers of the disulfide 295 was kept at
room temperature under argon at pH 9, the bicyclic
azetidinone 296was obtained in 76% yield <1999CCC190>.
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Additional Problems
Kenneth A. Savin, in Writing Reaction Mechanisms in Organic
Chemistry (Third Edition), 2014
Problem 8.21
This is a sequence of two Swern or “activated sulfoxide” oxidations. In
the first step, the dimethyl sulfoxide is mixed with
trifluoroacetic anhydride to generate the activated sulfoxide species.
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The substrate, a diol, is then added and the primary and secondary
alcohols are oxidized to the corresponding aldehyde and ketone
through the process shown below.
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With the aid of the amidine base DBU (1,8 Diazabicyclo [5.4.0]undec-
7-ene), the ketoaldehyde intermediate 8-88 cyclizes through an aldol
condensation to provide the β-hydroxy ketone 8-89.
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Step 2
The β-hydroxy ketone 8-89 was treated with more of the
hexafluoroacetic anhydride to form the trifluoroacetate. The
trifluoroacetate is a good leaving group and is eliminated as shown
below to provide the product enone 8-90.
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Ring Systems with at least Two Fused Heterocyclic Five-
or Six-membered Rings with no Bridgehead Heteroatom
A. Krutošóková, T. Gracza, in Comprehensive Heterocyclic Chemistry
III, 2008
10.01.11 Synthesis of Particular Classes of Compounds
Bailey et al. <1999TL4593> studied the Swern
oxidation <1981S165>of various indolic substrates. They found that
when the Swern oxidation of N-
acetyl tryptophan methyl ester 501 was carried out at low temperature
(−78 °C), 502 was formed, but when the reaction was allowed to warm
up to room temperature, before recooling and adding NEt3, the
desired cyclization was always accompanied by the introduction of the
CH2SMe group at C-4, that is, 503 was formed (Scheme 64). The
introduction of the CH2SMe group at C-4 indole position via an
unprecedented rearrangement of the Swern intermediate was
discussed <1999TL4593>.
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Scheme 64.
A structurally novel series of substituted 10H-benzo[4,5]furo[3,2-
b]indole-1-carboxylic acids 504–507 was prepared and shown to
possess potent, bladder-selective smooth muscle relaxant properties
and thus is potentially useful for the treatment of urge urinary
incontinence. Electrophysiological studies using rat detrusor myocytes
have demonstrated that prototype compound 8 produces a significant
increase in hyperpolarizing current, which is iberiotoxin(IbTx)-
reversed, thus consistent with activation of the large-conductance
Ca2+-activated potassium channel (BKCa) <2001BML2093>.
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The fully saturated 5:5 fused heterocyclic systems appear in a number
of interesting natural products and are versatile precursors for
synthesis. A very powerful process for the construction of
stereochemically defined bicycles is palladium(ii)-promoted
bicyclization of unsaturated polyols and amino alcohols <1991S1108,
1997S634>. Alkene polyols and amino alcohols undergo Wacker-type
intramolecular oxygen-cyclization, and CO-insertion to form
corresponding bicyclic skeletons with high regioselectivity and
excellent cis-stereoselectivity (Scheme 65). The saturated furo[3,2-
b]furans 508 (X = O) were used as chirons for synthesis of (+)-
erythroskyrine 509 <1999J(P1)839>, plakortones A–D 510–
513<1999OL1905, 2000TL3567>, Hagen-
Gland lactones 514 and 515<1997TL3479>, (−)-trans-
kumausyne 516 <1998JOC916>, (+)-
goniothalesdiol 517 <2002TL6983, 2005T2471>, and (−)-
panacene <2006OL3597)>.
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Scheme 65.
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Three-membered Heterocycles, together with all Fused
Systems containing a Three-membered Heterocyclic Ring
A. Padwa, in Comprehensive Heterocyclic Chemistry III, 2008
[Link] Elimination from N-Sulfinylaziridines
3-Alkyl-2H-aziridine-2-carboxylates 867 have been oxidized with
the Swern reagent to afford 2H-azirine-2-carboxylates <1995TL4665>.
Oxidation of either the (Z)- or the (E)- isomers of 867 provides the
same 2H-azirine-2-carboxylate 868, where the integrity of the
stereogenic center at C-2 is retained. This regioselectivity results from
the unexpected removal of the apparently less acidic C-3 protonduring
the base-induced syn-elimination of the N-dimethylsulfonium
intermediate (Scheme 217).
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Scheme 217.
The closely related 2H-azirine-2-carboxylate esters 871 have been
prepared in enantiomerically pure form via the base-
induced elimination of sulfenic acid from nonracemic N-
sulfinylaziridine 2-carboxylate esters 869 <1997JOC3796,
1999JOC8929>. For steric reasons, the N-sulfinylaziridine invertomers
likely adopt structure 870 in which the bulky p-toluenesulfinyl group
is anti to the aziridinering substituents (Scheme 218). This syn-
periplanar arrangement of leaving groups results in a syn-elimination
of sulfenic acid to afford 2H-azirine 871.
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Scheme 218.
Finally, chemoenzymatic synthesis has been used for the preparation
of entiomerically pure 2H-azirines. Thus, (S)-(+)-phenyl-2H-azirine-2-
methanol 873 and its (R)-(−)-acetate 874 were prepared by a lipase-
catalyzed kinetic resolution of the racemic 2H-azirinemethanol 872.
The reaction was carried out at very low temperature (−40 °C) and
therefore enhanced the enantioselectivity (Scheme
219) <1997JOC4906>.
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Scheme 219.
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TAKAI Zn CO Olefination to TSUJI–TROST Allylation
A. Hassner, I. Namboothiri, in Organic Syntheses Based on Name
Reactions (Third Edition), 2012
TAYLOR–IRELAND One-Pot Alcohol Olefination
One-pot oxidation–olefination of primary alcohols, a Wittig reaction
circumventing isolation of aldehydes. Oxidation can be carried out
by Swern,1 Dess-Martin,12 TPAP,4 PCC, MnO2 for allylic or benzylic
alcohols,2,5 Ba(MnO4)2,6 IBX,3 TEMPO/BAIB conditions in the presence
of stable P-ylides (Wittig); also Cu catalyzed aerial
oxidation.11 Resulting olefins are often mainly E. Compare
with Grieco alcohol olefination.
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E,E,E-triene (5).2 To 123 mg (0.5 mmol) of 2-buten-1,4-diol (4)and
(carboethoxymethylene) triphenyl phosphorane 2 (418 mg, 1.2 mmol)
in 25 mL DCM was added activated MnO2 (0.87 g, 10 mmol) and the
mixture was stirred at r.t. for 15 h. After filtrationand washing with
DCM the organic layers were evaporated to 1–2
mL. Chromatography (PE-ether, 7:1) afforded 160 mg of 5 (84%), mp
145–147 °C.
