Iodine ate complexes and N-lithiobenzocyclobutenamine intermediates in the reactions of α-lithionitriles with benzyne

Article abstract of DOI:10.1016/S0040-4039(00)01493-3

α-Lithionitriles add to benzynes to give N-lithiobenzocyclobutenamines in a two-step process. The intermediate aryllithiums can be trapped prior to cyclization with iodobenzene or 2,6-dimethoxyiodobenzene to form iodine-ate complex intermediates which fragment preferentially to 2-(α-cyanobenzyl)-iodobenzenes. The N-lithiobenzocyclobutenamines undergo ring opening to yield either 2-substituted benzonitriles or α-substituted benzylcyanides depending on the substitution pattern on the aryl and cyclobutene rings. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01493-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8401–8405
Iodine ate complexes and N-lithiobenzocyclobutenamine
intermediates in the reactions of a-lithionitriles with benzyne
Sasmita Tripathy, Helmi Hussain and Tony Durst*
Department of Chemistry, University of Ottawa, Ottawa, Canada KIN 6N5
Received 20 June 2000; revised 28 August 2000; accepted 5 September 2000
Abstract
a-Lithionitriles add to benzynes to give N-lithiobenzocyclobutenamines in a two-step process. The
intermediate aryllithiums can be trapped prior to cyclization with iodobenzene or 2,6-dimethoxyiodo-
benzene to form iodine-ate complex intermediates which fragment preferentially to 2-(a-cyanobenzyl)-
iodobenzenes. The N-lithiobenzocyclobutenamines undergo ring opening to yield either 2-substituted
benzonitriles or a-substituted benzylcyanides depending on the substitution pattern on the aryl and
cyclobutene rings. © 2000 Published by Elsevier Science Ltd.
We have recently reported that addition of a range of nucleophiles to benzynes in the presence
of iodobenzene results in the formation of both mono and disubstituted benzenes, 2 and 3.1
These products are most readily explained by assuming that iodine-ate complexes are generated
as intermediates. Evidence for such species has recently been reviewed by Wiberg, Sklenak and
Bailey (Scheme 1).2
Scheme 1.
The reaction of a-lithionitriles with arynes has been studied to a considerable extent mainly
by Biehl and co-workers,3 but also by others.4,5 We have reinvestigated the aryne–lithionitrile
reaction armed with a knowledge that the iodine-ate complexes are formed rapidly if a suitable
nucleophile is added to the benzyne in the presence of excess of iodobenzene.1 This study has
* Corresponding author. E-mail: tdurst@science.uottawa.ca
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01493-3

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enabled us to address not only some remaining mechanistic ambiguities concerning the reaction
of a-lithionitriles with benzyne, but also broadens the scope of the products accessible from this
reaction. In particular, we report that 2-iodo-benzylcyanides, 4, are the major product if the
reaction of benzyne with a-lithionitrile is carried out in the presence of iodobenzene or
2,6-dimethoxyiodobenzene, 7.
In the absence of the iodinating species, 2-cyanobenzylnitriles 5 and the monosubstituted
aromatics 6 are obtained typically when a-lithiophenylacetonitriles and a-lithioalkylnitriles,
respectively, are reacted with benzynes.
The products 5 result from the intermediacy of the N-lithiobenzocyclobutenamines 8, fol-
lowed by fragmentation to yield the relatively stable diarylmethane anions 9.3f Meyers has
proposed similar intermediates to explain the products obtained from reaction of a-lithioalkyl-
nitriles to 3-oxazolidinyl substituted benzyne.5 Alternate explanations not involving the four-
membered intermediate 8b have been proposed by Biehl and co-workers3e,f to account for the
formation of 6. Two mechanistic issues remain. (i) Are the N-lithiobenzocyclobutenamines 8
formed by a concerted 2+2 cycloaddition between the benzyne and the lithiated nitrile,6,7 or via
a two-step process involving the lithiated benzene derivative 10, followed by cyclization? (ii) Are
the N-lithiobenzocyclobutenamines 8 intermediates irrespective of the substitution on the
lithiated nitrile? Both the questions are addressed below (Scheme 2).
Scheme 2.
Reaction of bromobenzene with LTMP in THF at −40°C containing LiCH(CN)Ph for 2 h
followed by warming to 0°C gave the expected major products, 2-benzylbenzonitrile, 11,8 and
9-amino-10-phenylanthracene, 12,8 in 35 and 12% yield, respectively. When bromobenzene was
replaced by iodobenzene, a small amount, 5%, of the 2-iodophenyl derivative 138 was also
isolated. Addition of an equivalent of 7, a better positive iodine species than iodobenzene, to the
bromobenzene reaction, increased the amount of 13 to 37% while 11 and 12 were formed in 8
and 7% yield, respectively. These results are consistent with the mechanism in Scheme 2 which
shows a two-step sequence for the formation of 8a. The positive iodine sources, iodobenzene
and 7 are capable of intercepting the aryllithium 10 (R=Ph) rather than the diarylmethyllithium
9. The results indicate that the rate of cyclization of 10 to 8a is somewhat faster than its rate of
reaction with iodobenzene to form the ate complex 1 since about 7 times more product is
derived from the cyclization compared to the ate complex pathway. When one equivalent of the
more reactive positive iodine donor 7 is used, 37% of the product is derived from ate complex

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formation and only 15% via the lithiobenzocyclobutenamine, 8a. Results of reaction of
LiCH(CN)Ph with other arynes such as 3,5-dimethoxybenzyne, 3-methoxybenzyne and 3-pyri-
dyne mirror the above experiments; all give the 2-iodinated benzylic cyanides as the major
product when 7 is added as a positive iodine source (Scheme 3, Table 1).
Scheme 3.
Table 1
Benzyne
Iodine source
Product (% isolated)
2-Benzyl cyanide Aryl iodide
3,5-Dimethoxybenzyne
3,5-Dimethoxybenzyne
3-Methoxybenzyne
3-Pyridyne
None
33a
5
–
–
7
7
7
42
47
61b
–
a 18% of (3,5-dimethoxyphenyl)-phenylacetonitrile was also isolated.
b A 3:2 mixture of 3-iodo-4-a-cyanobenzyl- and 4-iodo-3-a-cyanobenzylpyridine.
In contrast, reaction of iodobenzene with LTMP and the lithio derivatives of alkylnitriles
gives only 2-(2-iodophenyl)-alkanonitriles.8 For example, benzyne generated from iodobenzene
and LTMP in the presence of LiCH(CN)CH3 afforded 14 in 52% yield. Similarly, when
3-methoxybenzyne was generated in the presence of LiCH(CN)C5H11 and 7, the aryl iodide 15
was obtained in 38% yield. Under the same reaction conditions, 3-pyridyne was trapped to give
47% of a 4:5 mixture of 16 and 17 (Scheme 4). No rearrangement product corresponding to 5
or monosubstitution products, 6, were observed. The products 14–17 arise via iodination and ate
complex formation of the aryllithium 10, or analogs. We propose that 10 is trapped either
directly after its formation from the addition of the lithiated alkylnitriles to the appropriate
benzyne, or after cyclization and re-opening of the N-lithio-2-alkylbenzocyclobutenamine, 8b,
Scheme 2.
Scheme 4.

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The direction of ring opening of the N-lithiobenzocyclobutenamines is governed by the
relative stability of the anions generated in the two possible processes. It can be influenced by
both the substituent at C2 of the cyclobutene ring and on the aryl ring. For example, reaction
of 3,5-dimethoxybenzyne with lithiophenylacetonitrile at −40°C afforded the benzonitrile 18 and
benzyl cyanide 19 in 18 and 33% yield, respectively. The presence of the methoxy group which
stabilizes an ortho lithio substituent, allows ring opening of the N-lithiobenzocyclobutenamine
20 to the aryllithium 22 [path (b)] to compete with the alternate process yielding 21 [path (a)]
(Scheme 5).
Scheme 5.
In agreement with this explanation is the isolation of 2-methylthiophenylbenzonitrile, 23, and
9-amino-10-thiophenylanthracene, 24, upon generation of benzyne in the presence of
LiCH(CN)SPh. These products require the intermediacy of an N-lithiobenzocyclobutenamine 25
which opens preferentially to the lithioderivative of 23. The latter reacts with additional benzyne
to yield 24 (Scheme 6).3b Therefore, contrary to the earlier suggestion of Biehl,3f we propose that
all a-lithionitriles react with benzynes according to Scheme 2.
Scheme 6.
The variation in the direction of ring opening of the N-lithiobenzocyclobutenamines parallels
that observed for benzocyclobutenones in the presence of NaOH.9 Here too, the ratio of the
pathway (a) to (b) is influenced by structural features on both aryl and cyclobutene rings
(Scheme 7).
Scheme 7.
When reactive halides, such as methyl iodide, allylic, and benzylic bromides, are added to the
reaction mixture which produced 15 and 16, alkylated compounds, for example 26 and 27, were
obtained in 30–40% yield (Scheme 8).

8405
Scheme 8.
Acknowledgements
The financial support of NSERC (Canada) is gratefully acknowledged.
References
1. Tripaphy, S.; LeBlanc, R.; Durst, T. Org. Lett. 1999, 1, 1973.
2. For a recent discussion on ate complexes, see: Wiberg, K.; Sklenak, W. S.; Bailey, W. F. J. Org. Chem. 2000, 65,
2014 and references cited therein.
3. (a) Khanapure, S. P.; Crenshaw, L.; Reddy, R. T.; Biehl, E. R. J. Org. Chem. 1988, 53, 4915; (b) Dutt, M.; Fravel,
B.; Ford, G. P.; Biehl, E. R. J. Org. Chem. 1994, 59, 497; (c) Wang, A.; Biehl, E. J. Chem. Soc., Perkin Trans.
1 1998, 1461; (d) Tandel, S.; Zhang, H.; Qadri, N.; Ford, G. P.; Biehl, E. R. J. Chem Soc, Perkin Trans. 1 2000,
587; (e) Self, J. L.; Khanapure, S. P.; Biehl, E. R. Heterocycles 1991, 32, 311; (f) For an earlier review on the
addition of nucleophiles to benzyne, see: Biehl, E. R.; Khanapure, S. P. Acc. Chem. Res. 1989, 22, 275; (g) Hart,
H. In The Chemistry of Functional Groups, Suppl. C2: The Chemistry of Triplebonded Functional Groups; Potai, S.,
Ed.; Wiley: Chichester, 1994; pp. 1017–1134.
4. Jamart-Gregoire, B.; Leger, C.; Caubere, P. Tetrahedron Lett. 1990, 31, 7599.
5. Meyers, A. I.; Pansegrau, P. D. Tetrahedron Lett. 1984, 25, 2941.
6. (a) Benzynes undergo many known 2+2 cycloadditions, including those with ketene acetals: Hosaya, T.; Hasegawa,
T.; Kuriyama, Y.; Sujuki, K. Tetrahedron Lett. 1995, 36, 3377; (b) Hosaya, T.; Hasegawa, T.; Kuriyama, Y.;
Matsumoto, T.; Sujuki, K. Synlett 1995, 177.
7. The a-phenylacetonitrile anion structure has been carefully investigated. It was concluded that PhCꢀCꢀNLi best
represented the structure: (a) Strzalko, T.; Seyden-Penne, J.; Wartski, L.; Corset, J.; Castella-Ventura, M.;
Froment, F. J. Org. Chem. 1998, 63, 3287; (b) Strzalko, T.; Seyden-Penne, J.; Wartski, L.; Corset, J.;
Castella-Ventura, M.; Froment, F. J. Org. Chem. 1998, 63, 3295.
1
8. All new products reported in this paper were fully characterized via H and 13C and HRMS spectra. Yields refer
to chromatographically and spectroscopically pure fractions.
9. Bradley, J.-C.; Durst, T. Can. J. Chem. 1995, 73, 1660 and references cited therein.
.