Formation of 2-substituted Iodobenzenes from Iodobenzene via Benzyne and Ate Complex Intermediates

Article abstract of DOI:10.1021/ol991129k

(Matrix Presented) The generation of benzyne from iodobenzene with lithium tetramethylpiperidide in THF at -40 °C in the presence of lithium amides and ester enolates leads to mixtures in which 2-substituted iodobenzenes are often the major products. These products are obtained by iodine transfer from iodobenzene to the intermediate 2-lithioaromatics. The transfer of iodine occurs via a hypervalent iodine (ate) complex.

Full text of DOI:10.1021/ol991129k

ORGANIC
LETTERS
1999
Vol. 1, No. 12
1973-1975
Formation of 2-Substituted
Iodobenzenes from Iodobenzene via
Benzyne and Ate Complex Intermediates
Sasmita Tripathy, Richard LeBlanc, and Tony Durst*
Department of Chemistry, UniVersity of Ottawa, Ottawa, Canada K1N 6N5
tdurst@science.uottawa.ca
Received October 7, 1999
ABSTRACT
The generation of benzyne from iodobenzene with lithium tetramethylpiperidide in THF at −40 °C in the presence of lithium amides and ester
enolates leads to mixtures in which 2-substituted iodobenzenes are often the major products. These products are obtained by iodine transfer
from iodobenzene to the intermediate 2-lithioaromatics. The transfer of iodine occurs via a hypervalent iodine (ate) complex.
In 1973, Dougherty and Olofson reported that lithium
tetramethylpiperidide (LTMP) constituted an excellent re-
agent for the generation of benzyne from chlorobenzene.
When carried out in the presence of phenylacetilide or
PhS-Li+, excellent yields of the trapping products diphenyl-
acetylene and diphenyl disulfide were obtained.1 These and
further results from the Olofson laboratory were interpreted
as indicating that LTMP was an extremely poor trap for
benzyne.2
As part of a study aimed at the synthesis of benzocyclo-
butenones via the trapping of benzynes with ester or amide
enolates,3 we examined the generation of benzyne from
iodobenzene with LTMP in THF at -40 °C. To our surprise,
the major product isolated in 81% yield was N-(2-iodo-
phenyl)-2,2,6,6-tetramethylpiperidine (1);4 a lesser amount
(9%) of N-phenyl-2,2,6,6-tetramethylpiperidine (2)5 was also
isolated (eq 1). Not only is LTMP an efficient trap for
excellent source of electrophilic iodine and transfers its iodine
to another aryllithium. Replacement of iodobenzene by
bromobenzene resulted in the formation of the bromo
analogue of 1 and 2 in a 1:3 ratio in 85% total yield.
The formation of 1 is rationalized in Scheme 1. The lithio
derivative 3, formed by the trapping of benzyne with LTMP,
Scheme 1
(1)
benzyne, at least in the absence of other nuceophiles, but
even more surprisingly iodobenzene can function as an
combines rapidly with unreacted iodobenzene to give the
ate complex 4. Related complexes have been shown to form
quantitatively when PhI is added to PhLi in THF/HMPA at
-80 °C.6 The ate complexes are unreactive toward typical
(1) Dougherty, C. M.; Olofson, R. A. J. Am. Chem. Soc. 1973, 95, 581.
(2) Fitzgerald, J. J.; Drysdale, N. E.; Olofson. R. A. J. Org. Chem. 1992,
57, 7122.
10.1021/ol991129k CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/16/1999

electrophiles but are in equilibrium with their components.6
In the case of Ph2I-Li+, reversal regenerates the starting
materials.
lithio derivative 9 is much less reactive toward tetramethyl-
piperidine than is PhLi and thus the fragmentation of 4 occurs
irreversibly toward 1 (Scheme 2).
The unsymmetrical ate complex 4 fragments preferentially
to 1 and PhLi rather than PhI and the ortho-lithiated amine
3. The lithio derivatives formed in these fragmentations
presumably react further with tetramethylpiperidine to yield
benzene, 2, and LTMP.
Scheme 2
When iodobenzene was reacted with excess LDA in THF
at -40 °C, the ratio of the products, 2-iodo-N,N-diisopropyl-
aniline, 5, to N,N-diisopropylaniline, 6, was 2:3. In contrast,
when benzyne was generated from iodobenzene in the
presence of N-lithiopiperidine or N-lithiopyrrolidine, only
N-phenylpiperidine, 7, and N-phenylpyrrolidine, 8, could be
isolated. No evidence of the 2-iodo derivatives of these
compounds could be detected (Table 1).
Table 1. Trapping of Benzyne with Various Nitrogen
Nucleophilesa
When benzyne was generated in the presence of the ester
and amide enolates 12a,b, the 2-iododerivatives 15a,b
respectively were obtained in 69% and 88% isolated yields
along with minor quantities of the monosubstituted ester and
amide 17a,b.7
No evidence for the formation of the desired benzocyclo-
butanone 16 was found. We also anticipated that the lithio
derivatives 13a,b might be quenched rapidly by the acidic
hydrogens which are both benzylic and R to the ester
carbonyl group. The results indicate that ate complex
formation is very facile and faster than these processes. Once
formed, the ate complexes 14a,b were expected to revert
preferentially to 13a,b and PhI, rather than 15a,b and PhLi,
due to the strong internal coordination available in 13a,b.
Since this is not the case, an alternate explanation for the
formation of the ortho iodo derivatives 15 must be sought
(Scheme 3).
a Yields are based on 2 mol of iodobenzene and 1 mol of product.
Scheme 3
The preferred direction of the fragmentation of unsym-
metrical ate complexes such as 4 and 10 appears to be
governed by steric effects. Internal coordination of lithium
to nitrogen should be less favorable in 9 than in 11.
Additionally, the sterically less hindered lithiated benzenes
in each equilibrium may be favored by the formation of more
stable dimers.6 It is also possible that the highly hindered
(3) LeBlanc, R. M.Sc. Thesis, University of Ottawa, 1999.
(4) 1H NMR (CDCl3, 500 MHz): δ 7.92 (dd, 1 H, J ) 7.9, 1.5 Hz),
7.41 (dd, 1 H, J ) 7.9, 1.6 Hz), 7.27 (dt, 1 H, J ) 7.8, 1.5 Hz), 6.87 (dt,
1 H, J ) 7.9, 1.6 Hz), 1.89 (m, 1 H), 1.80 (broad dt, 2 H, J ) 12.1, 2.5
Hz), 1.63 (m, 1 H), 1.56 (m, 2 H), 1.28 (s, 6 H), 0.91 (s, 6 H). 13C NMR
(CDCl3, 125 MHz): δ 148.9, 139.7, 131.8, 127.9, 127.2, 114.3, 56.1, 41.3,
31.6, 25.6, 18.5. HRMS: calcd for C15H22N 343.0798, found 343.0788.
The observation that the methyl groups in 1 occur as two singlets (1:1 ratio)
indicates a significant barrier to rotations around the N-aryl bond. Molecular
mechanics calculations show that the barrier to ring flipping/nitrogen
inversion is approximately 41 kcal/mol. In compound 2, a single peak is
observed for the four methyl groups.
Addition of an equimolar mixture of 3-bromoanisole (18)
and iodobenzene to a solution of THF containing the enolate
1974
Org. Lett., Vol. 1, No. 12, 1999

12a and LTMP yielded the iodoester 21 as the major product
(36%) along with minor amounts of monosubstituted 22. This
further substantiates that the product 218 is formed by
addition of ester enolate 12a to 3-methoxybenzyne with
iodine being transferred to the lithio derivative 19 via the
ate complex 20 (Scheme 4).
Scheme 5
Scheme 4
the first examples of iodobenzene serving as a source of
positive iodine in a synthetically useful manner. The transfer
of bromine from bromobenzene to an aryllithium via an ate
complex has also been observed.
The iodo derivative 21 was also formed in 15% yield when
2-iodoanisole was added to a solution of LTMP containing
12a. A 30% yield of the â-ketoester 23a was also obtained.
We have observed that benzyne formation from 2-iodoanisole
is relatively slow and requires somewhat higher tempertures
than -40 °C. Thus some of the enolate 12a can generate
ketene and combine with remaining 12a to give the dianion
24a. This species reacts with 3-methoxybenzyne and iodo-
benzene to give 23a via an ate complex analogous to 20
(Scheme 5). A similar reaction was found when 2-iodoanisole
was added to a mixture of the enolate of ethyl acetate and
LTMP in THF at -40 to 0 °C. The 2-iodoester 21c (R )
OEt) and the iodo â-ketoester 23c were obtained in 18%
and 28% isolated yields, respectively.9
Acknowledgment. The support of NSERC (Canada) is
gratefully acknowledged.
OL991129K
(6) Reich, H. J.; Green, D. P.; Phillips, N. H. J. Am. Chem. Soc. 1989,
111, 3444. Reich, H. J.; Reich, I. L.; Phillips, N. H. J. Am, Chem. Soc.
1985, 107, 4101.
(7) The structures of all the compounds are characterized by the
1
combination of HRMS and H and 13C NMR data.
(8) For compound 21. 1H NMR (CDCl3, 200 MHz): δ 7.28 (t, 1 H, J )
7.6 Hz), 6.85 (d, 1 H, J ) 7.6 Hz), 6.68 (d, 1 H, J ) 7.6 Hz), 3.89 (s, 1 H,
OMe), 3.76 (s, 2 H), 1.45 (s, 9 H). 13C NMR (CDCl3, 50 MHz): δ 170.5,
158.9, 140.9, 129.6, 123.8, 109.9, 94.1, 81.7, 57.1, 48.5, 28.7. HRMS: calcd
for C13H17OI 348.0226, found 348.0223.
To the best of our knowledge, these results, especially the
formation of the iodo derivatives 15, 21, and 23 represent
1
(9) For compound 23c. H NMR (CDCl3, 500 MHz): δ 7.25 (t, 1 H, J
) 8.6 Hz), 6.82 (d, 1 H, J ) 8.6 Hz), 4.18 (q, 2 H), 4.05 (s, 2 H), 3.85 (s,
3 H, OMe), 3.51 (s, 2 H), 1.25 (t, 3 H, J ) 6.8 Hz). 13C NMR (CDCl3, 125
MHz): δ 199.2, 166.9, 158.5, 139.4, 129.2, 123.4, 109.6, 90.6, 61.3, 56.4,
54.8, 46.2, 14.1. HRMS: calcd for C13H15O4I 362.0015, found 362.0027.
(5) 1H NMR (CDCl3, 200 MHz): δ 7.25 (m, 5 H), 1.62-1.59 (m, 6 H),
1.05 (s, 12 H). 13C NMR (CDCl3, 50 MHz): δ 147.3, 134.8, 128.2, 126.1,
54.6, 42.9, 30.4, 19.1. HRMS: calcd for C15H23N 217.1831, found 217.1816.
Org. Lett., Vol. 1, No. 12, 1999
1975