Benzyne

The Adventures of a
Reactive Intermediate
Pamela Tadross
Stoltz Group Literature Presentation
Noyes 147
8 PM, May 15, 2006

Overview
History and Structure

Methods of Generation
+N
2

TMS

-O C
2

OTf

NH2

Cl

NH2

NaNH2

Cl

NH3 (l)

Nearly 1:1 ratio!

Polar Reactions

Pericyclic Reactions

Nu
Nu-

E
E+

PhN3

N
N
N
Ph

Applications to Natural Product Synthesis

Unusual Rearrangements of Substituted Benzenes

Gilman, Wittig, and Roberts observed strange behavior in reactions of halobenzenes in
the 1940s and 1950s
Cl

NH2

OCH3

OCH3
Cl

NaNH2
NH3 (l), -38 C

LiNEt2
NH3 (l), -38 C

F. W. Bergstrom, C. H. Horning, J. Org. Chem. 1946, 11, 334.

H. Gilman, S. Avakian, J. Am. Chem. Soc. 1945, 67, 349.

C6H5Li
THF, -78 C

Li

G. Wittig, Naturwissenschafter 1942, 30, 696.

Cl

LiNEt2
NH3 (l), -38 C

NEt2

NEt2
+
NEt2

J. D. Roberts, H. E. Simmons Jr., L. A. Carlsmith, C. W. Vaughan, J. Am. Chem. Soc. 1953, 75, 3290.

Wittig's Explanation
Close but no cigar...

F
C6H5Li
THF, -78 C

C6H5Li

- LiF
Li

Li
zwitterionic intermediate

G. Wittig, Naturwissenschafter 1942, 30, 696.

John D. Roberts: The Right Place at the Right Time

Reactions are very rapid even at -38 C
The entering amino group is never more than one carbon away from the position occupied by the
leaving halogen
Cl

NEt2

LiNEt2

NH3 (l), -38 C

NEt2

no p-aminotoluene formed
The starting halides and the resulting anilines are not isomerized under reaction conditions

Cl

Cl

NH3 (l), -38 C

NEt2

NH3 (l), -38 C

No reaction occurs when there is no hydrogen adjacent to the leaving halogen

Br
LiNEt2

No Reaction

NH3 (l), -38 C

J. D. Roberts, H. E. Simmons Jr., L. A. Carlsmith, C. W. Vaughan, J. Am. Chem. Soc. 1953, 75, 3290.

NEt2

Further Mechanistic Evidence...

NH2

product

NH2
substrate

NH2

45

55

none

40

52

none

62

38

Cl

Cl

Cl

J. D. Roberts, C. W. Vaughan, L. A. Carlsmith, D. A. Semenow, J. Am. Chem. Soc. 1956, 78, 611-14.

The Classic 14C Labeling Experiment

The Hypothesis: If one started with chlorobenzene-1-14C, equal amounts of aminobenzenes with the 14C
at C-1 and C-2 would be formed.

Cl

NH2
NH2

NaNH2

NH3 (l)

Nearly 1:1 ratio!

Roberts' Proposed Intermediate:

BENZYNE!
"These facts as well as the orientation data for various substituents can be accomodated by an elimination-addition
mechanism involving at least transitory existence of an electrically neutral "benzyne" intermediate."
J. D. Roberts, H. E. Simmons Jr., L. A. Carlsmith, C. W. Vaughan, J. Am. Chem. Soc. 1953, 75, 3290.

Further Support from Wittig and Huisgen

Wittig finds that benzyne can participate in Diels-Alder reactions as a dienophile:

G. Wittig, L. Pohmer, Angew. Chem. 1955, 67(13), 348.

Huisgen reports that arynes generated from different precursors have identical reactivity:
F
O
Li

O
k1

F
MgBr

k1/k2 = constant

N2+
CO2k2

N
N
S
O2

R. Huisgen, R. Knorr, Tetrahedron Lett. 1963, 1017.

Overview
History and Structure

Methods of Generation
+N
2

-O

TMS

2C

OTf

NH2

Cl

NH2

NaNH2

Cl

NH3 (l)

Nearly 1:1 ratio!

Polar Reactions

Pericyclic Reactions

Nu
Nu-

E
E+

PhN3

N
N
N
Ph

Applications to Natural Product Synthesis

Generation of Benzyne
Earlier basic and harsh methods give way to recent neutral and mild methods of aryne generation
N2+
N

F
CO2-

N
S
O2

MgBr
0 C

F
Li

heat

0 C

-20 C

Pb(OAc)2

strong base

Bu4NF

X
Mg or
RMgX

NH2

TMS

Bu4NF
n-BuLi

X1
X2

OTf
Ph
I

OTf
TMS

OTf

Iodonium Triflate: T. Kitamura, M. Yamane, J. Chem. Soc., Chem. Commun. 1995, 983. Silyl Triflate: Y. Himeshima, T. Sonoda, H. Kobayashi, Chem. Lett.
1983, 1211. Benztriazole: C. D. Campbell, C. W. Rees, J. Chem. Soc. (C) 1969, 742. Halo Triflate: T. Matsumoto, T. Hosoya, M. Katsuki, K. Suzuki, Tet. Lett.
1991, 32, 6735. Diazonium Carboxylate: L. Friedman, F. M. Logullo, J. Am. Chem. Soc. 1963, 85, 1792. Fluoro Magnesium and Fluoro Lithium: R. W.
Hoffmann, Dehydrobenzene and Cycloalkanes, Academic Press, New York, 1967. Benzothiadiazol-1,1-dioxide: G. Wittig, R. W. Hoffmann, Org. Synth., Coll. Vol.
V, 60, 1971.

Overview
History and Structure

Methods of Generation
+N
2

-O

TMS

2C

OTf

NH2

Cl

NH2

NaNH2

Cl

NH3 (l)

Nearly 1:1 ratio!

Polar Reactions

Pericyclic Reactions

Nu
Nu-

E
E+

PhN3

N
N
N
Ph

Applications to Natural Product Synthesis

Polar Reactions of Benzyne

Benzyne reacts as both nucleophile and electrophile
Nu

Nu

E
+

Nu- +

E+

Nu

Nu
E+

Nu- +

Regiochemistry of Nucleophilic Additions to Benzyne

EWG

EWG

Nu-

Nu

EDG

EDG
+

Nu
+

Nu-

Harold Hart; in Chemistry of Triple Bonded Functional Groups; Saul Patai, Ed.; The Chemistry of Functional Groups, Supplement C2;
Wiley: Chichester, UK, 1994, 1017-1134.

Additions of Carbon Nucleophiles

Grignard reagents:

E+

MgBr

E = H, CHO, CO2H, RX
E

MgBr

H. Hart, A. Saednya, Synth. Commun. 1988, 18, 749.

Organolithium reagents:

RLi

O
Li

HO

E+
R

Copper-lithium reagents:

N
1. R2CuLi
2.

HO
E

H+

H+

R
E
E = H, CHO, CO2H, RX

O
E
E = H, CHO, CO2H, RX

E+
R

P. D. Pansegrau, W. F. Rieker, A. I. Meyers, J. Am. Chem. Soc. 1988, 110, 7178.

M. E. Jung, G. T. Lowen, Tetrahedron Lett. 1986, 27, 5319.

Synthesis of Substituted Indoles

E
Br

tBuLi, THF, -110 C

F
N

E+

Li
N

R = Me, allyl
E

E
DIBAL
[NiCl2(dppp)]
PhMe, 20 C

R
Me
Me
allyl
Me

N
H

E+
H2O
PhCHO
Bu3SnCl
Bu3SnCl

E
H
PhC(H)OH
SnBu3
SnBu3

N
Br

Yield
75%
69%
52%
67%

tBuLi, THF, -110 C

pTsOH, PhMe

E+

110 C
N

E = Br: 59%
E = CO2Et: 65%

J. Barluenga, F. J. Fananas, R. Sanz, Y. Fernandez, Chem. Eur. J. 2002, 8(9), 2034.

Stabilized Carbon Nucleophiles

R1

R3

Br
+

R3

CN

R1

NaNH2

OMe

R2

R2

R3
CN

R1

H3O+

OMe

R2

O
O

S. P. Khanapure, E. R. Biehl, J. Org. Chem. 1990, 55, 1471.

Alternative Pathway: C-C Insertion

R

Cl

CN

CN

N Li

Li
Li

CN

CN
H+

J. H. Waggenspack, L. Tran, S. Taylor, L. K. Leung, M. Morgan,

A. Deshmukh, S. P. Khanapure, E. R. Biehl, Synthesis, 1992,
765.

Li
R

R
R = Ph: 40%
R = 3-FC6H4: 80%
R = 3-MeOC6H4: 70%

More Stabilized Carbanions

Anthraquinone Synthesis:
OMe

OMe
R

NC

CO2Et

OMe
Li

LDA

Br

OEt

Li+
OOEt

CN

CN
OMe O
R

OMe

OMe OH
R

OEt

OMe

Li
CN

R = H: 36%
R = OMe: 38%

CN

B. M. Bahwal, S. P. Khanapure, H. Zhang, E. R. Biehl, J. Org. Chem. 1991, 56, 2846.

Basic Skeleton of Ergot and Aristolactam Alkaloids:

O

Br

CN

NH

LDA

+
R

CO2H

CN

CO2H

S
R

A. Wang, E. R. Biehl, J. Chem. Soc., Perkin Trans. 1 1998, 1461.

R = OMe: 77%
R = Me: 57%

Reactions of Enolates with Arynes

Facile access to strained aromatic polycyclic compounds

Br

O
+

HO O

t-BuONa

AcO

NaNH2

O
Li

M. A. Zouaoui, A. Mouaddib, B. Jamart-Gregoire, S. Ianelli, M.

Nardelli, P. Caubere J. Org. Chem. 1991, 56, 4078.

NH3
83%
Br
O

LiTMP

+
NHAr

Li

O-Li+

O-Li+

+
NAr

O-Li+
NAr

NAr

+
NHAr

O
NHAr

69:9
A. R. Deshmukh, T. Long, E. R. Biehl, J. Org. Chem. 1992, 57, 667.
A. R. Deshmukh, H. Zhang, T. L. Duc, E. R. Biehl, J. Org. Chem. 1992, 57, 2485.

Total Synthesis of Dynemicin A

OMOM
Br

OMOM

Li
MeO2C

OMOM

MOMO

CO2Me

CO2Me

CO2Me

OMe

OMOM

CO2Me

MOMO

Li
THF, -78 C

MOMO

OMOM

OMOM

CO2Me
CO2Me

MOMO

steps

CO2Me

O OMe

OMOM

HN

CO2H
O
OMe
H

OH

71%

CO2Me
CO2Me
OMOM

Me

H
OH

H+

OH
dynemicin A

M. D. Shair, T. Y. Yoon, K. K. Mosny, T. C. Chou, S. J.

Danishefsky, J. Am. Chem. Soc. 1996, 118, 9509.
K. C. Nicolaou, S. A. Snyder, Dynemicin A. Classics in Total
Synthesis II; Wiley-VCH: Weinheim, 2003; 75-108.

Total Synthesis of Fredericamycin A

OMe

OMe

OMe

Br

Li

MeO

MeO
OMe

MeO2C

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

MeO

OMe

OMe
steps

steps
OMe OMe

OMe O
O
58%

MeO

O
MeO

OMe O

O
OMe OMe

OMe

HO

OMe OMe
O

steps

HO O

OH

MeO

HN

OMe O

fredericamycin A
Y. Kita, K. Higuchi, Y. Yoshida, K. Iio, S. Kitagaki, K. Ueda, S. Akai, H. Fujioka, J. Am. Chem. Soc. 2001, 123, 3214.

C-C -Bond Insertion Reactions

O
O

TMS
+

MeCN (0.2 M)
80 C, 1.5 h

EtO

OTf

CsF (2.5 equiv)

O
+

EtO
Ph

H+

OEt

H+
Cs+ O

Cs+

EtO
O

EtO2C

OEt

U. K. Tambar, B. M. Stoltz, J. Am. Chem. Soc. 2005, 127, 5340.

O
TMS

KF (3 equiv)
18-crown-6 (3 equiv)

+
OTf

THF, room temp.

O

H. Yoshida, M. Watanabe, J. Ohshita, A. Kunai, Chem. Commun. 2005, 3292.

R = OEt: 71%
R = Ph: 68%
R = Me: 56%
R, R = O(CH2)8O: 61%

Averufin
OR

OR

OR

O
+

Br

LiTMP

RO

OR

O
RO

R = CH2OCH3
OR

OH

OR

OH

steps

O
RO

HO

O
O

averufin

35%

C. A. Townsend, S. G. Davis, S. B. Christensen, J. C. Link, C. P. Lewis, J. Am. Chem. Soc. 1981, 103, 6885.

Cephalotaxine
O
N

O
O

KCPh3

OMe

O
OMe
16%

O
H

M. F. SemmeIhack, B. P. Chong, L. D. Jones, J. Am. Chem. Soc.

1972, 94, 8629.

HO

OMe

DIBAL
PhH, 25 C

H
O

DME, 50 C

Cl

OMe

cephalotaxine

Additions of Nitrogen Nucleophiles

Preparation of alkylated anilines:
Cl

NH2

Li
NH3

F. W. Bergstrom, C. H. Horning, J. Org. Chem. 1946, 11, 334.

Ph

Ph

Ph
+

H
N

14%
A. G. Giumanini, J. Org. Chem. 1971, 37, 513.

Preparation of indoles:
Ph H

Ph

N
+

Ph
H

Ph

Ph

Ph
Ph
N
H

50%

V. Nair, K. H. Kim, J. Org. Chem. 1975, 40, 3784.

H
N

Ph

Ph

Preparation of Acridones
O
OMe
N

CO2Me
+

Li

M. Watanabe, A. Kurosaki, S. Furukawa, Chem. Pharm. Bull. 1984, 32, 1264.

OMe
CO2Me
N

Br
LiICA

Li

acronycine, 41%
LiICA =

N
Li

M. Watanabe, A. Kurosaki, S. Furukawa, Chem. Pharm. Bull. 1984, 32, 1264.

Total Synthesis of -Licorane

Two benzyne cyclization reactions complete the skeleton...

NH2

MeO

NH2

MeO

Cl

N
O

N
H

MeO

Li

O
Br

O
N

O
O

O
O

40%
O

O
O

-licorane
H. Ilda, S. Aoyagi, C. Kibayashi, J. Chem. Soc. Perkin Trans. 1, 1975, 2502.
N. Ueda, T. Tokuyama, T. Sakan, Bull. Chem. Soc. Japan, 1966, 39, 2012.

Competitive Cyclization Reactions

HO

OR

RO

RO

RO
N
Br

NaH
DMSO

N
RO

RO

RO
OR

OR

CH2SOMe
RO
N

HO

OR

RO
HO

RO
N

CH2SOMe
OR
N

RO
OR
20%

ortho cyclization
aporphine

30%

amine cyclization
dibenzindolizine

OR
HO
OR
2%

para cyclization
morphinandienone

S. V. Kessar, S. Batra, S. S. Ghandi, Indian J. Chem. 1970, 8, 468. S. V. Kessar, R. Randhawa, S. S. Ghandi, Tetrahedron Lett. 1973, 2923. S. V. Kessar, S.
Batra, U. K. Nadir, S. S. Ghandi, Indian J. Chem. 1975, 13, 1109.
T. Kametani, S. Shibuya, K. Kigasawa, M. Hiiragi, O. Kusama, J. Chem. Soc. C 1971, 2712. T. Kametani, K. Fukumoto, T. Nakano, Tetrahedron 1972, 28, 4667.
M. S. Gibson, G. W. Prenton, J. M. Walthew, J. Chem. Soc. C 1970, 2234. I. Ahmad, M. S. Gibson, Can. J. Chem. 1975, 53, 3660.

Ortho Cyclizations of Imines and Anilines

Synthesis of Benzophenanthridine Alkaloids

Cl

NH2

N
NH2

N
NH2

> 90%

S. V. Kessar, D. Pal, M. Singh, Tetrahedron 1973, 29, 177.

S. V. Kessar, Acc. Chem. Res. 1978, 11, 283.

O
OH
O

MeO

OMe

MeO

MeO

OMe

chlerythrine

fagaronine

S. V. Kessar, M. Singh, P. Balakrishnan, Indian J. Chem. 1974, 12, 323.

Cl

HN

NH2

J. P. Gillespie, L. G. Amros, F. R. Stermitz, J. Org. Chem. 1974, 39, 3239

S. V. Kessar, Acc. Chem. Res. 1978, 11, 283.

NH

Overview
History and Structure

Methods of Generation
+N
2

-O

TMS

2C

OTf

NH2

Cl

NH2

NaNH2

Cl

NH3 (l)

Nearly 1:1 ratio!

Polar Reactions

Pericyclic Reactions

Nu
Nu-

E
E+

PhN3

N
N
N
Ph

Applications to Natural Product Synthesis

Diels-Alder Reactions of Arynes

O
O
+

88%
G. Wittig, L. Pohmer, Angew. Chem. 1955, 67, 348.

-CO2

Ph

G. Wittig, R. W. Hoffmann, Chem. Ber.

1962, 95, 2718.

Ph
+

Ph

Ph

36%

Ph
Ph

Ph Ph
+
-CO

R = H, CH3, CO2Me, NO2,

CH2Cl, CH2OH, CH(OMe)2,
CN, etc.

Ph
Ph
C. D. Campbell, C. W. Rees, Proc. Chem.
Soc. 1964, 296.

Yields 6-75%
Ph
Ph
95%

E. C. Kornfeld, P. Barney, J.
Blankley, W. Faul, J. Med. Chem.
1965, 8, 342.

Total Synthesis of the Gilvocarcins

OBn

OMe OBn

I
OBn
Me

H
TfO

O
+

OBn
O

OMe

n-BuLi
THF, -78 C
10 min

OBn
O

OBn

OBn

OMe OH

OMe OBn
H
OH

OMe

OBn
Me

OBn
O

OH
Me

gilvocarcin M: R = Me
gilvocarcin V: R = vinyl
gilvocarcin E: R = Et

OH
O

88%

OH

OBn

Head-to-head Product
OMe

OBn
Me

OR

Head-to-tail Product

OMe OR

OR

OH

O
OH

OMe

T. Matsumoto, T. Hosoya, K. Suzuki, J. Am. Chem. Soc, 1992, 114, 3568.

T. Hosoya, E. Takashiro, T. Matsumoto, K. Suzuki, J. Am. Chem. Soc. 1994, 116, 1004.

OMe

OR

Application to the Synthesis of Aporphinoid Natural Products

O
MeO

MeO
N

MeO

O
N

MeO

O
N

O
O
MeO

lysicamine

duguenaine

OMe

pontevedrine

MeO
O
MeO

MeO

MeO

N
MeO

NH

MeO

alkaloid PO-3

norcepharadione B

cepharadione B

N. Atanes, L. Castedo, E. Guitian, C. Saa, J. M. Saa, R. Suau, J. Org. Chem. 1991, 56, 2984.
H. Guinaudeau, M. Lebouef, A. Cave, J. Nat. Prod. 1983, 46, 761.
M. Shamma, The Isoquinoline Alkaloids; Academic Press: New York, 1972.

Norcepharadione B, Cepharadione B, and Pontevedrine

O
O

MeO

MeO

R1

O
+
NR3

MeO

O
NR3

MeO
R2

R1
R2

O
MeO

O
O
NR3

MeO

R1

MeO
aromatization

O
NR3

MeO

Yields 20% - 68%

R1
R2

R2
R1 = R2 = R3 = H: norcepharadione B
R1 = R2 = OMe, R3 = Me: pontevedrine
R1 = R2 = H, R3 = Me: cepharadione B

N. Atanes, L. Castedo, E. Guitian, C. Saa, J. M. Saa, R. Suau, J. Org. Chem. 1991, 56, 2984.

Total Syntheses of Nitidine and Fagaronine

CO2R4

CO2R4

O
R1
R5O

O
N

R5O

R5O

R2
R3

R5O

R1
R2

-CO2

R3

CO2R4
R1
R5O

R2
N

R5O

R3

R1
MeO
MeO

R2
N

O
40%

D. Perez, E. Guitian, L. Castedo, J. Org. Chem. 1992, 57, 5911.

R1 = OH, R2 = OMe:
fagaronine
R1 + R2 = -OCH2O-:
nitidine

Total Synthesis of Protoberberines: Corydaline

MeO
OMe

MeO

OMe

MeO

MeO

O +

OMe

O
OMe

MeO
MeO
MeO

MeO

O
-CO
O

MeO

MeO
OMe

OMe

N
H

OMe

H
OMe

OMe
32%
single regioisomer

C. Saa, E. Guitian, L. Castedo, R. Suau, J. M. Saa, J. Org. Chem. 1986, 51, 2781.
A. Cobas, E. Guitian, L. Castedo, J. Org. Chem. 1992, 57, 6765.

OMe

corydaline

Total Synthesis of the Lycorines:

Intramolecular Aryne Diels-Alder Reactions
LDA

Br
H
N

N
OLi

N
O

OH

Yields 61% - 91%

OH
HO
H

O
N

OH

lycorine

hippadine

O
N
Cl

anhydrolycorinium chloride

kalbretorine
OH

N
Cl

ungeremine

C. Gonzalez, D. Perez, E. Guitian, L. Castedo, J. Org. Chem. 1995, 60, 6318.

Intramolecular Diels-Alder: Lysergic Acid

HOOC

HOOC

OOC

HOOC

LDA
O

-30 C
O

N
H

N
H

Br

N
H

lysergic acid

30%
B. Gomez, E. Guitian, L. Castedo, Synlett, 1992, 903.

Pseudopterosin A and E Aglycon

Me

OMe

OH
OH

OMe

OMe

O
OMe

Br
O

Me

Me

Me

58

Me

H
Me

O
+
OMe

71%

Me

Me

pseudopterosin A and E aglycon

OMe
O
O
Me

Me

42

K. R. Buszek, D. L. Bixby, Tetrahedron Lett. 1995, 36, 9129.

Mansonone I and F
Me

Br
MeO

Br

MeO

n-BuLi

Me
O

O
MeO

O
Me

Me

Me

O
Me

O
61%

Me

Me

O
H2SO4
EtOH

Me
O

OH

Me
O

Me

mansonone I

Me

mansonone F

W. Best, D. Wege, Aust. J. Chem. 1986, 39, 647.

[2 + 2] Cycloadditions of Arynes
In the absence of a reactive partner:
N2+
CO2apparent [2 + 2] cycloaddition product
biphenylene also seen as side product in most aryne reactions!

With other olefins:

R

R
R

R
R

Problem: [2 + 2] cycloadditions are not allowed thermally!

Proposed Mechanism
R

R R

R
R

R
R

R
R
stepwise addition

Best yields and regiochemical control with R = electron-donating groups

Facile Access to Benzocyclobutenes

R1

R1

R2

MeO

OMe

R2

NaNH2

OMe
OMe

Br
R1
H
OMe
OMe
H
Cl

R2
H
H
OMe
OMe
H

Yield
63%
76%
68%
56% (+8% other regioisomer)
76%

Hydrolysis to benzocyclobutenones:
R1
R2

R1

OMe

H3O+

OMe

R2

Rationalizing Regiochemistry
OMe
MeO

OMe
MeO

OMe
+

MeO

OMe
OMe

MeO

OMe

R. V. Stevens, G. S. Bisacci, J. Org. Chem. 1982, 47, 2393.

L. S. Liebeskind, L. J. Lescosky, C. M. McSwain Jr., J. Org. Chem. 1989, 54, 1435.

OMe
OMe

Total Synthesis of Taxodione

OMe

OMe
MeO

MeO

OMe

MeO

1. NaNH2
2.

Li

H3O+

Br

OMe
OH

HO

OMe

OMe
OMe

t-BuOK
t-BuOH
O
H

taxodione
R. V. Stevens, G. S. Bisacchi, J. Org. Chem. 1982, 47, 2396.

Xylopinine
CO2-

OAc
+

MeO

OAc

MeO

N2+

OMe
OMe

MeO
N

MeO

MeO

MeO
N

MeO

OMe
MeO
OMe

OMe
OMe

OMe
OMe

xylopinine
T. Kametani, T. Kato, K. Fukumoto, Tetrahedron 1974, 30, 1043.

[2 + 2] Aryne Cycloadditions in Steroid Synthesis

O
OMe

OMe

K2CO3, Me2CO
> 93%

O
MeO2C

MeO2C

MeO2C

H
MeO2C

> 85%
O
O H

O
O

MeO2C

Steroids obtained in 5 steps from 1,3-butadiene in overall

yields of 27-33%

H
H

single diastereomer

P. Y. Michellys, P. Maurin, L. Toupet, H. Pellissier, M. Santelli, J. Org. Chem. 2001, 66, 115.

1,3-Dipolar Cycloadditions of Arynes

Some early examples...

O
F. Minisci, A. Quilico, Chimica e
Industria 1964, 46, 428

O N

nitrile oxides
N

55%

N
G. A. Reynolds, J. Org. Chem. 1964,
29, 3733.
G. Wittig, R. W. Hoffmann, Chem.
Ber. 1962, 95, 2718.

N
N N

azides

88%

N
O

R. Huisgen, R. Knorr, Naturwiss.

1961, 48, 716.

nitrones
O

92%
EtO2C

O
N
N

diazoalkanes

R. Huisgen, R. Knorr, Naturwiss.

1961, 48, 716.

N
N

Regiochemical Control
or the lack thereof...
R1

t-Bu

OTf

N
Ph

R2

R1

R1

Ph

n-BuLi

THF

N
R2

R2

Br

t-Bu

Ph

A
R1
OMOM
Me
t-Bu
TMS
TBS

EWG

EDG

B
R2
H
H
H
Me
Me

%A
91
23
76
5
12

%B
0
63
14
89
82

Regiochemical rationale:
R

R = EWG

R
+

O
Ph

Ph
O

t-Bu

Ph
N

t-Bu

t-Bu

t-Bu
R = EDG

R
O
+

t-Bu

Ph
Ph

Steric effects also influence the regiochemistry!

T. Matsumoto, T. Sohma, S. Hatazaki, K. Suzuki, Synlett, 1993, 843.

t-Bu

Food for Thought...

Arynes are highly reactive intermediates that can participate in a wide variety of polar and pericyclic
reactions

There is a need for better understanding and control of aryne reactivity pathways (e.g. [2 + 2] vs. ene
vs. Diels-Alder)

There is a need for better control of regiochemistry in aryne reactions

Since their discovery in 1953, the synthetic power of arynes has barely been explored - there is an
immense amount of uncharted territory!
C-C (and maybe even C-H) -bond insertions seem to hold the most potential
Insertion into strained ring systems (e.g. -lactams, -oxonitriles)
Transition metal catalyzed reactions of arynes (especially Pd and Ni) have only recently been
investigated - opportunity to control aryne reactivity
M. A. Bennett, E. Wenger, Chem. Ber. 1997, 130, 1029.
D. Pena, S. Escudero, D. Perez, E. Guitian, L. Castedo, Angew. Chem. Int. Ed. Engl. 1998, 37, 2659.
D. Pena, D. Perez, E. Guitian, L. Castedo, Org. Lett. 1999, 1, 1555.
K. V. Radhakrishnan, E. Yoshikawa, Y. Yamamoto, Tetrahedron Lett. 1999, 121, 5827.
D. Pena, D. Perez, E. Guitian, L. Castedo, J. Org. Chem. 2000, 65, 6944.
D. Pena, D. Perez, E. Guitian, L. Castedo, Synlett 2000, 7, 1061.
E. Yoshikawa, Y. Yamamoto, Angew. Chem. Int. Ed. Engl. 2000, 39, 173.
E. Yoshikawa, K. V. Radhakrishnan, Y. Yamamoto, Tetrahedron Lett. 2000, 41, 729.

Handy Reviews and Books

Books:
R. W. Hoffmann; Dehydrobenzene and Cycloalkynes; Academic Press: New York, 1967.
J. D. Roberts; The Right Place at the Right Time; J. I. Seeman, Ed.; Profiles, Pathways, and Dreams Series; American
Chemical Society: Washington, DC, 1990.

Review Articles:
T. L. Gilchrist; Arynes. In The Chemistry of Triple-bonded Functional Groups, Supplement C; S. Patai and Z. Rappoport,
Eds.; The Chemistry of Functional Groups Series; John Wiley and Sons: New York, 1983; Volume 1, pp. 383-419.
H. Hart; Arynes and Heteroarynes. In The Chemistry of Triple-bonded Functional Groups, Supplement C; S. Patai, Ed.;
The Chemistry of Functional Groups Series; John Wiley and Sons: New York, 1983; Volume 2, pp. 1017-1134.
L. Castedo; E. Guitian; Synthesis of Natural Products via Arynes. In Studies in Natural Products Chemistry; Atta-urRahman, Ed.; Stereoselective Synthesis (Part B) Series; Elsevier: Amsterdam,1989; Volume 3, pp. 417-454.
M. Winkler; H. H. Wenk; W. Sander; Arynes. In Reactive Intermediate Chemistry; R. A. Moss, M. S. Platz, M. Jones Jr.,
Eds.; Wiley-Interscience: New York, 2004; pp. 741-794.
H. Pellissier, M. Santelli; The Use of Arynes in Organic Synthesis, Tetrahedron 2003, 59, 710-730.