Benzyne

The Adventures of a Reactive Intermediate

Pamela Tadross Stoltz Group Literature Presentation Noyes 147 8 PM, May 15, 2006

Overview
History and Structure
+N 2

Methods of Generation
TMS OTf

-O C 2

Cl NaNH2 NH3 (l)

NH2 NH2 +

Cl

Nearly 1:1 ratio!

Polar Reactions
Nu Nu-

Pericyclic Reactions
+

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 NaNH2 NH3 (l), -38 C
F. W. Bergstrom, C. H. Horning, J. Org. Chem. 1946, 11, 334.

NH2

OCH3 Cl LiNEt2 NH3 (l), -38 C

OCH3

NEt2

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

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

F - LiF Li Li zwitterionic intermediate C6H5Li

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 LiNEt2 NH3 (l), -38 C NEt2 + NEt2

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

Cl

NH3 (l), -38 C

Cl

NEt2

NH3 (l), -38 C

NEt2

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

Br LiNEt2 NH3 (l), -38 C No Reaction

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

Further Mechanistic Evidence...

product

NH2 NH2

substrate

NH2

%
Cl

% 55

% none

45

40
Cl

52

none
Cl

62

38

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 NaNH2 NH3 (l)

NH2 NH2 +

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 F MgBr N2+ CO2N N S O2
R. Huisgen, R. Knorr, Tetrahedron Lett. 1963, 1017.

O k1

k1/k2 = constant

k2

Overview
History and Structure
+N 2

Methods of Generation
TMS OTf

-O

2C

Cl NaNH2 NH3 (l)

NH2 NH2 +

Cl

Nearly 1:1 ratio!

Polar Reactions
Nu Nu-

Pericyclic Reactions
+

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+ F CO2MgBr F Li -20 C 0 C heat 0 C Pb(OAc)2 N N S O2 N N N NH2

strong base X Mg or RMgX X1 X2 X OTf

Bu4NF

TMS OTf Ph I OTf TMS

Bu4NF n-BuLi

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
+N 2

Methods of Generation
TMS OTf

-O

2C

Cl NaNH2 NH3 (l)

NH2 NH2 +

Cl

Nearly 1:1 ratio!

Polar Reactions
Nu Nu-

Pericyclic Reactions

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- + Nu + E+ E E

Nu Nu- + E+

Nu E

Regiochemistry of Nucleophilic Additions to Benzyne

EWG + + NuNu EWG

EDG + + Nu-

EDG 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:

MgBr MgBr

E+ E

E = H, CHO, CO2H, RX

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

Organolithium reagents:

N RLi

O Li R E+

N R E H+

HO

O R E

Copper-lithium reagents:

E = H, CHO, CO2H, RX

N 1. R2CuLi 2. E+

N E R H+

HO

O E E = H, CHO, CO2H, RX 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 N R F tBuLi, THF, -110 C R N R Li N R E+ N

R = Me, allyl E DIBAL [NiCl2(dppp)] PhMe, 20 C H E R Me Me allyl Me E+ H2O PhCHO Bu3SnCl Bu3SnCl E H PhC(H)OH SnBu3 SnBu3 Yield 75% 69% 52% 67%

N R

F N Br tBuLi, THF, -110 C E+

E pTsOH, PhMe 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 R2 Br + OMe R2 R3 CN NaNH2 R3 R1 CN OMe H3O+ R1 R2 O R3 O

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

Alternative Pathway: C-C Insertion

Cl + Li Li R R R CN CN N Li

CN H+ Li R

CN
J. H. Waggenspack, L. Tran, S. Taylor, L. K. Leung, M. Morgan, A. Deshmukh, S. P. Khanapure, E. R. Biehl, Synthesis, 1992, 765.

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

More Stabilized Carbanions

Anthraquinone Synthesis:
OMe R Br NC CO2Et LDA CN OMe O R OEt Li CN CN OMe R R OMe OH OMe R R = H: 36% R = OMe: 38% R OMe Li OEt O R OMe Li+ OOEt 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 CO2H + Br R S R CN LDA S R S CO2H CN NH

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 O O NaNH2 t-BuONa

O HO O O O

AcO

O Li NH3 83%

O
M. A. Zouaoui, A. Mouaddib, B. Jamart-Gregoire, S. Ianelli, M. Nardelli, P. Caubere J. Org. Chem. 1991, 56, 4078.

Br O + NHAr LiTMP O-Li+ + NAr Li O-Li+ NAr

O-Li+ NAr

O NHAr

+ 69:9

O NHAr

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 MeO2C Li CO2Me OMOM CO2Me CO2Me OMOM N Li THF, -78 C OMOM MOMO MOMO CO2Me O OMe

MOMO CO2Me

OMOM CO2Me O OMe CO2Me OMOM H+ 71%

OMOM CO2Me CO2Me OMOM

MOMO

steps

H OH O HN O

Me CO2H OMe H
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.

OH

OH dynemicin A

Total Synthesis of Fredericamycin A

OMe Br MeO OMe MeO2C CO2Me N Li MeO OMe steps OMe OMe O MeO OMe O O OMe OMe O MeO OMe O O HN O steps O HO HO O O 58% MeO OMe OMe OMe O OH O CO2Me + CO2Me MeO OMe steps OMe O O OMe OMe CO2Me CO2Me

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 TMS + OTf EtO O O CsF (2.5 equiv) MeCN (0.2 M) 80 C, 1.5 h EtO Ph O OEt O O +

H+ Cs+

H+ Cs+ O

O EtO

EtO2C

OEt

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

O TMS + OTf R R O O KF (3 equiv) 18-crown-6 (3 equiv) THF, room temp. O R R R = OEt: 71% R = Ph: 68% R = Me: 56% R, R = O(CH2)8O: 61%

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

Averufin
OR O O RO R = CH2OCH3 OR O OR steps O RO O 35% O HO O O OH O OH O + Br O OR O LiTMP RO OR O O O OR O

averufin

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

Cephalotaxine
O O O Cl O O H DIBAL PhH, 25 C O HO N
M. F. SemmeIhack, B. P. Chong, L. D. Jones, J. Am. Chem. Soc. 1972, 94, 8629.

KCPh3 DME, 50 C OMe

O O

N O OMe O O

OMe 16%

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 + N N H N

Ph H N Ph

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

Preparation of indoles:
Ph H N + Ph Ph H N Ph Ph H N Ph

Ph Ph N H 50%
V. Nair, K. H. Kim, J. Org. Chem. 1975, 40, 3784.

Preparation of Acridones
O OMe N Li + N N CO2Me O

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

OMe CO2Me N Li + O Br LiICA

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...

MeO Cl

NH2 MeO

NH2

MeO

N H

N O Br N

Li O N O O

N 40%

O O

O O

H O O

H N

-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

RO HO N Br NaH DMSO RO RO O N OR

N RO OR RO OR RO O

CH2SOMe RO HO N RO HO RO OR 20% 30% OR HO OR 2% N OR N RO CH2SOMe OR

ortho cyclization aporphine

amine cyclization dibenzindolizine

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

S. V. Kessar, D. Pal, M. Singh, Tetrahedron 1973, 29, 177. S. V. Kessar, Acc. Chem. Res. 1978, 11, 283.

> 90%

O OH O MeO OMe N MeO N MeO OMe

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

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

Cl

HN

NH2

NH

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

Overview
History and Structure
+N 2

Methods of Generation
TMS OTf

-O

2C

Cl NaNH2 NH3 (l)

NH2 NH2 +

Cl

Nearly 1:1 ratio!

Polar Reactions
Nu Nu-

Pericyclic Reactions
+

E E+ PhN3

N N N Ph

Applications to Natural Product Synthesis

Diels-Alder Reactions of Arynes

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

-CO2

Ph Ph + Ph Ph O Ph

O Ph

G. Wittig, R. W. Hoffmann, Chem. Ber. 1962, 95, 2718.

36% R + -CO R = H, CH3, CO2Me, NO2, CH2Cl, CH2OH, CH(OMe)2, CN, etc. Yields 6-75% Ph Ph 95% R
E. C. Kornfeld, P. Barney, J. Blankley, W. Faul, J. Med. Chem. 1965, 8, 342.

Ph Ph

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

Total Synthesis of the Gilvocarcins

OBn I H TfO OBn O OBn Me + O OMe O n-BuLi THF, -78 C 10 min H OBn O OBn Me OMe OBn

OBn

OBn

OMe OBn H OH 88% OBn O OBn Me OMe

OMe OH H O O OBn OH OH O OH Me

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

Head-to-head Product
OMe O OH OR OMe OR O OMe

Head-to-tail Product
OR OH OR

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.

Application to the Synthesis of Aporphinoid Natural Products

O MeO MeO N O MeO MeO MeO N O O O N O

lysicamine

OMe

duguenaine

pontevedrine
O MeO O MeO N MeO O NH MeO N O MeO O O

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 O + NR3 R2 R1 MeO MeO O NR3

R1 R2

O MeO MeO O NR3 aromatization MeO MeO

O O NR3 Yields 20% - 68%

R1 R2

R1 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 O R1 R5O R5O O N O R3 + R2 R5O O R5O

CO2R4

R1 R2 -CO2

O N R3

CO2R4 R1 R5O R5O O 40% N R3 R2 MeO MeO N R1 R2 R1 = OH, R2 = OMe: fagaronine R1 + R2 = -OCH2O-: nitidine

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

Total Synthesis of Protoberberines: Corydaline

MeO MeO MeO N O + O OMe OMe OMe O OMe MeO N O

MeO MeO MeO N O -CO O OMe OMe 32% single regioisomer MeO N O OMe OMe MeO N H H OMe OMe MeO

corydaline

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.

Total Synthesis of the Lycorines: Intramolecular Aryne Diels-Alder Reactions

Br H N O LDA N OLi N OH O Yields 61% - 91% OH HO H O O N H O O O N O O OH O N N

lycorine

hippadine
OH

kalbretorine

O O N Cl

O O N Cl

anhydrolycorinium chloride

ungeremine

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

Intramolecular Diels-Alder: Lysergic Acid

HOOC N LDA O N H Br -30 C O O N 30%
B. Gomez, E. Guitian, L. Castedo, Synlett, 1992, 903.

HOOC OOC N

HOOC

N H

N H

lysergic acid

Pseudopterosin A and E Aglycon

OMe OMe Me 58 H Me 71% OMe O O Me O Me 42 Me Me Me OH OH Me

OMe OMe Br O Me Me

O O + OMe

pseudopterosin A and E aglycon

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

Mansonone I and F
Br MeO Br O Me O Me O O Me MeO O O Me n-BuLi O MeO O O O 61% Me Me O O

O O

Me O H2SO4 EtOH Me

Me

Me O OH Me

Me

mansonone I

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 R R R

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

Proposed Mechanism
R + R R R R stepwise addition Best yields and regiochemical control with R = electron-donating groups R R R R R R R

Facile Access to Benzocyclobutenes

R1 R2 Br R1 H OMe OMe H Cl R2 H H OMe OMe H Yield 63% 76% 68% 56% (+8% other regioisomer) 76% + MeO OMe NaNH2 R2 R1 OMe OMe

Hydrolysis to benzocyclobutenones:
R1 R2 OMe OMe R1 H3O+ R2 O

Rationalizing Regiochemistry
OMe MeO + MeO OMe + MeO OMe OMe OMe MeO OMe OMe 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.

Total Synthesis of Taxodione

OMe MeO Br OMe OH OMe OMe t-BuOK t-BuOH O H
R. V. Stevens, G. S. Bisacchi, J. Org. Chem. 1982, 47, 2396.

OMe + MeO OMe 1. NaNH2 2. H3O+ O OMe HO O MeO Li

taxodione

Xylopinine
CO2+ N2+ MeO N MeO OMe MeO OMe OMe
T. Kametani, T. Kato, K. Fukumoto, Tetrahedron 1974, 30, 1043.

OAc

OAc

MeO MeO N OMe OMe MeO N MeO N

MeO

OMe OMe

OMe

xylopinine

[2 + 2] Aryne Cycloadditions in Steroid Synthesis

O OMe OMe I + MeO2C O K2CO3, Me2CO > 93%

O MeO2C O

O O H MeO2C O O H

> 85%

MeO2C

O MeO2C H H H O

Steroids obtained in 5 steps from 1,3-butadiene in overall yields of 27-33%

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 N N

55%

N N N

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

azides

88%

N O O
R. Huisgen, R. Knorr, Naturwiss. 1961, 48, 716.

nitrones
O O N N EtO2C N N
R. Huisgen, R. Knorr, Naturwiss. 1961, 48, 716.

92%

diazoalkanes

Regiochemical Control
or the lack thereof...
R1 OTf R2 Br + Ph N O t-Bu R1 n-BuLi THF R2 O N t-Bu R1 Ph + R2 Ph O N t-Bu

A
R1 OMOM Me t-Bu TMS TBS R2 H H H Me Me %A 91 23 76 5 12

B
%B 0 63 14 89 82

EWG

EDG

Regiochemical rationale:
R R + O Ph N t-Bu R = EDG R O + Ph Ph N t-Bu R O N t-Bu R = EWG + Ph O N t-Bu R Ph N O t-Bu

Steric effects also influence the regiochemistry!

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

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.