Benzannulated bicycles by three-component aryne reactions

Article abstract of DOI:10.1002/anie.201100911

Triple crown: A pair of three-component coupling reactions between arynes, isocyanides, and either activated alkynes or phenyl esters generates unusual iminoindenones or phenoxy iminoisobenzofurans (see scheme), the latter of which may be advanced to o-ke

Full text of DOI:10.1002/anie.201100911

Communications
DOI: 10.1002/anie.201100911
Multicomponent Reactions
Benzannulated Bicycles by Three-Component Aryne Reactions**
Kevin M. Allan, Christopher D. Gilmore, and Brian M. Stoltz*
Benzyne has been an integral tool for the discovery of new
multicomponent reactions for over 70 years.[1] In particular,
the ability to function as a relay species between a nucleophile
and an electrophile makes this reactive intermediate well
suited to the rapid preparation of 1,2-disubstituted arene
scaffolds.[2] In designing an approach toward new multi-
component aryne reactions, we began by considering reac-
tivity patterns of classic transformations. In the Passerini
synthesis of a-acyloxyamides (e.g., 6),[3] an aldehyde compo-
nent (1) acts as both an electrophile and a latent nucleophile
(i.e., 1!6)[4] during the course of the reaction (Scheme 1a).
protonation at the aryl anion. In order to avoid this outcome,
we envisioned that the third component be replaced with an
ester (9), which would instead undergo nucleophilic attack.
Subsequent expulsion of the alkoxide (ꢀOR4) to generate the
benzylic ketone and recombination with the nitrilium cation
would ultimately generate o-ketobenzimidate 10. Further
access to the corresponding o-ketobenzamide (11) could then
be gained through hydrolysis.
Our initial attempt to accomplish this three-component
transformation employed ethyl acetate with 2-(trimethylsi-
lyl)phenyl triflate (12a) and tert-butyl isocyanide (2a) in the
presence of tetra-N-butylammonium difluorotriphenylsilicate
(TBAT) (Scheme 2a). Unfortunately, this ester failed to
Scheme 1. a) Passerini reaction. b) Aryne analogue of the Passerini
reaction.
We postulated that this rudimentary mechanism could be
adapted to the synthesis of o-ketobenzamides (11) by replac-
ing the aldehyde component with an aryne (Scheme 1b). In
analogy to the formation of zwitterion 3, nucleophilic
addition of the isocyanide to benzyne (7) has been shown to
form aryl nitrilium 8.[5] In the presence of a carboxylic acid,
however, this intermediate would be expected to undergo
Scheme 2. a) Attempted three-component coupling using ethyl acetate.
b) Phenoxy iminoisobenzofuran synthesis by three-component cou-
pling of benzyne, tert-butyl isocyanide, and phenyl acetate.
provide the desired o-ketobenzimidate, instead producing
trace quantities of N-tert-butylbenzamide (13) through hydra-
tion of zwitterion 8 (R1 = tBu).[5] Reasoning that a more
electrophilic ester would display greater reactivity toward the
aryl anion, we decided to employ phenyl acetate (9a).
However, under the same conditions, we were surprised to
find that instead of the expected benzimidate, phenoxy
iminoisobenzofuran 14a was isolated in 60% yield. Presum-
ably, this heterocycle is formed through intramolecular attack
of the tetrahedral alkoxide on the nitrilium cation (15) and
results in formation of a formal dipolar cycloaddition product
(Scheme 2b),[6] akin to reactivity previously observed by
Yoshida and Kunai et al. using aldehydes[7] and aldimines.[8,9]
To our knowledge, this method represents the first prepara-
tion of a stable phenoxy-substituted iminoisobenzofuran.[10,11]
Intrigued by this new three-component coupling reaction
and the unusual heterocyclic scaffold observed in the product,
we examined the scope of the reaction. By altering the
stoichiometry of the reagents involved, optimized conditions
[*] K. M. Allan, C. D. Gilmore, Prof. B. M. Stoltz
The Warren and Katharine Schlinger Laboratory for Chemistry and
Chemical Engineering, Division of Chemistry and Chemical Engi-
neering, California Institute of Technology
1200 E. California Boulevard, MC 101-20, Pasadena, CA 91125
(USA)
Fax: (+1)626-395-8436
E-mail: stoltz@caltech.edu
[**] The authors thank Abbott, Amgen, Boehringer Ingelheim, Bristol-
Myers Squibb, Merck, Sigma–Aldrich, Teva, and Caltech for financial
support. Lawrence Henling and Dr. Michael Day are gratefully
acknowledged for X-ray crystallographic structural determination.
The Bruker KAPPA APEX II X-ray diffractometer was purchased
through an NSF CRIF:MU award to the California Institute of
Technology, CHE-0639094. Dr. Scott C. Virgil is acknowledged for
helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100911.
4488
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 4488 –4491

were found wherein a THF solution containing a limiting
amount of the ester (9) and two equivalents each of the silyl
aryl triflate (12), isocyanide (2), and TBAT is heated to 408C
for 8–12 h. By employing these reaction conditions, we found
the scope to be reasonably broad with respect to all three
components.
We initially examined a number of substituted phenyl
esters prepared directly from the corresponding carboxylic
acids (Table 1). Esters bearing linear (14b), branched (14c),
nide, reported by Kobayashi et al.,[12] which produced the
desired iminoisobenzofuran (14q) in 58% yield.
Finally, we performed the three-component coupling with
a series of heteroatom-functionalized aryne precursors to
generate aryl-substituted adducts 14r–v. Importantly, when
unsymmetrical arynes were employed, the reaction pro-
ceeded regioselectively to provide phenoxy iminoisobenzo-
furans 14r and 14s as single isomers.[13,14]
Although we had yet to prepare an o-ketobenzamide
using our multicomponent approach, we recognized that the
phenoxy iminoisobenzofurans had only to undergo hydrolysis
in order to produce this originally targeted structure. We
therefore examined conditions under which the three-com-
ponent coupling adducts could be hydrolyzed to generate o-
ketobenzamides (i.e., 16) in a single sequence (Table 2). A
Table 1: Synthesis of phenoxy iminoisobenzofurans.[a]
Table 2: One-pot synthesis of o-ketobenzamides.[a]
[a] Yield of isolated product. [b] Three-component coupling reaction
performed at 608C.
thorough evaluation of various protic acids led to the
identification of oxalic acid as the optimal catalyst for
phenoxy iminoisobenzofuran hydrolysis (i.e., 14!16). Upon
completion of the three-component coupling, the addition of
a saturated aqueous solution of oxalic acid to the cooled
reaction mixture resulted in hydrolytic production of o-
ketobenzamides 16a–g. In this way, we are able to generate
di- (16b, d, and e), tri- (16c), and tetrasubstituted (16a, f, and
g) o-ketobenzamides in good yield from readily available o-
silyl aryl triflates (12), isocyanides (2), and phenyl esters (9) as
starting materials.
In order to demonstrate the synthetic utility of the o-
ketobenzamides, we carried out an intramolecular cyclization
of bromobenzamides 16e–g to generate caprolactams
(Scheme 3). By heating the substrates in the presence of
copper(I) iodide and potassium carbonate in DMF, dibenzo-
ketocaprolactams 17a–c are formed in 61–85% yield. The
structural similarity that these polycycles share with bioactive
natural products such as the antifungal agent, silvaticamide
(18),[15] suggests the enabling role this method could play in
total synthesis.
[a] Yield of isolated product. [b] Reaction performed at 608C.
and cyclic aliphatic substituents (14d) performed well under
the established reaction conditions, as did benzoic esters
(14e–j). Not surprisingly, we found that electron-withdrawing
substituents (14g–j) promoted greater reactivity than elec-
tron-donating substituents (14 f). Despite concerns that an a-
haloester would react unfavorably with tert-butyl isocyanide,
phenyl chloroacetate produced the expected three-compo-
nent adduct in comparable yield (14k). Notably, even
dihydrocoumarin and phenyl carbonate gave rise to interest-
ing spirocyclic (14l) and masked orthoester products (14m),
respectively.
Next, we evaluated the isocyanide component, replacing
tert-butyl isocyanide with 4-methoxyphenyl isocyanide, lead-
ing to N-arylated products 14n and 14o. Additionally, 2-
benzyloxyethyl isocyanide furnished imidate 14p. Moreover,
we tested the unusual o-(b-dimethoxyethyl)phenyl isocya-
Angew. Chem. Int. Ed. 2011, 50, 4488 –4491
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 4489

Communications
Table 3: Synthesis of iminoindenones.[a]
Scheme 3. Dibenzoketocaprolactam synthesis.
Recognizing that the ester constituent of our three-
component coupling reaction was essentially a dipolarophile
in a [3+2] cycloaddition, we investigated additional substrates
capable of reacting in a similar ambiphilic manner. We
reasoned that a conjugate acceptor (e.g., 19a) could poten-
tially fill this role, and thus examined a series of a,b-
unsaturated carbonyl compounds with the aim of generating
carbocyclic adducts (e.g., 20a). Ultimately, methyl propiolate
(19a) was found to react with 2-(trimethylsilyl)phenyl triflate
(12a) and tert-butyl isocyanide (2a) to produce iminoinde-
none 20a in 88% yield (Scheme 4).[16]
[a] Yield of isolated product.
partners, giving rise to a wide array of heterocyclic adducts. In
combination with a subsequent hydrolysis step, this method-
ology enables the rapid, one-pot synthesis of o-ketobenza-
mides (i.e., 16), useful synthetic building blocks that can be
advanced to functionalized dibenzoketocaprolactams (e.g.,
17a–c). Furthermore, we have translated the observed
reactivity of this three-component coupling to the formation
of carbocyclic iminoindenones (i.e., 20) by employing elec-
tron-deficient alkynes in place of the ester component.
Current efforts are directed toward the discovery of addi-
tional relay species and the application of these method-
ologies within the realm of natural product total synthesis.
Scheme 4. Iminoindenone synthesis by three-component coupling of
benzyne, tert-butyl isocyanide, and methyl propiolate.
Received: February 5, 2011
Published online: April 11, 2011
Keywords: arynes · heterocycles · isocyanides ·
multicomponent reactions · polycycles
With this initial result in hand, we evaluated the scope of
this new three-component coupling reaction and again found
it to be tolerant of changes to all three pieces. Dimethyl
acetylenedicarboxylate was found to be an equally competent
substrate, providing access to a 2,3-disubstituted iminoinde-
none (20b). Interestingly, replacing the conjugate acceptor
with phenyl acetylene furnished a 2-phenyliminoindenone
(20c) in 51% yield.[17] As in the previous multicomponent
coupling, this reaction proved amenable to the incorporation
of a number of substituted aryne motifs. Both symmetrical
and unsymmetrical heteroatom-functionalized arynes formed
the expected three-component adducts in good yields (20d–h)
as single isomers (i.e., 20d and 20e). Additionally, Kobaya-
shiꢀs isocyanide[12] could be employed to efficiently generate
20i and 20j (Table 3).
.
[1] For early examples of multicomponent aryne reactions, see:
a) G. Wittig, G. Pieper, G. Fuhrmann, Ber. Dtsch. Chem. Ges.
1940, 73, 1193 – 1197; b) G. Wittig, G. Fuhrmann, Ber. Dtsch.
Chem. Ges. 1940, 73, 1197 – 1218; c) G. Wittig, Naturwissen-
schaften 1942, 30, 696 – 703; d) A. I. Meyers, P. D. Pansegrau,
Tetrahedron Lett. 1983, 24, 4935 – 4938; e) A. I. Meyers, P. D.
Pansegrau, J. Chem. Soc. Chem. Commun. 1985, 690 – 691.
[2] For select examples of multicomponent aryne methodologies to
generate 1,2-disubstituted arene scaffolds, see: a) J. Pawlas, M.
Begtrup, Org. Lett. 2002, 4, 2687 – 2690; b) H. Yoshida, M.
Watanabe, H. Fukushima, J. Ohshita, A. Kunai, Org. Lett. 2004,
6, 4049 – 4051; c) I. Larrosa, M. I. Da Silva, P. M. Gꢁmez, P.
Hannen, E. Ko, S. R. Lenger, S. R. Linke, A. J. P. White, D.
Wilton, A. G. M. Barrett, J. Am. Chem. Soc. 2006, 128, 14042 –
14043; d) H. Yoshida, H. Fukushima, J. Ohshita, A. Kunai, J.
Am. Chem. Soc. 2006, 128, 11040 – 11041; e) X. Huang, J. Xue, J.
Org. Chem. 2007, 72, 3965 – 3968; f) C. Xie, Y. Zhang, Org. Lett.
2007, 9, 781 – 784; g) H. Yoshida, T. Morishita, H. Fukushima, J.
Ohshita, A. Kunai, Org. Lett. 2007, 9, 3367 – 3370; h) T.
In summary, during the course of our efforts to develop an
aryne-intercepted version of the Passerini reaction, we
discovered a novel three-component coupling of arynes,
isocyanides, and phenyl esters that furnishes unusual phenoxy
iminoisobenzofuran motifs (i.e., 14). This reaction is tolerant
of considerable substitution on each of the three reaction
4490 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 4488 –4491

Morishita, H. Fukushima, H. Yoshida, J. Ohshita, A. Kunai, J.
Org. Chem. 2008, 73, 5452 – 5457; i) D. Soorukram, T. Qu,
A. G. M. Barrett, Org. Lett. 2008, 10, 3833 – 3835; j) C. Xie, Y.
Zhang, P. Xu, Synlett 2008, 3115 – 3120; k) H. Yoshida, T.
Morishita, J. Ohshita, Org. Lett. 2008, 10, 3845 – 3847; l) X.
Huang, T. Zhang, Tetrahedron Lett. 2009, 50, 208 – 211; m) F.
Sha, X. Huang, Angew. Chem. 2009, 121, 3510 – 3513; Angew.
Chem. Int. Ed. 2009, 48, 3458 – 3461.
Senzaki, T. Goto, M. Saito, Bull. Chem. Soc. Jpn. 1988, 61, 2481 –
2485.
[12] C. B. Gilley, M. J. Buller, Y. Kobayashi, Org. Lett. 2007, 9, 3631 –
3634.
[13] For results highlighting regioselective additions to unsymmet-
rical arynes, see: a) R. Huisgen, W. Mack, M. L. Mꢂbius,
Tetrahedron 1960, 9, 29 – 39; b) R. Huisgen, J. Sauer, Angew.
Chem. 1960, 72, 91 – 108; c) J. F. Bunnett, D. A. R. Happer, M.
Patsch, C. Pyun, H. Takayama, J. Am. Chem. Soc. 1966, 88,
5250 – 5254; d) E. R. Biehl, E. Nieh, K. C. Hsu, J. Org. Chem.
1969, 34, 3595 – 3599; e) M. S. Newman, R. Kannan, J. Org.
Chem. 1976, 41, 3356 – 3359; f) H. Y. Xin, E. R. Biehl, J. Org.
Chem. 1983, 48, 4397 – 4399; g) Y. X. Han, M. V. Jovanovic, E. R.
Biehl, J. Org. Chem. 1985, 50, 1334 – 1337; h) E. R. Biehl, A.
Razzuk, M. V. Jovanovic, S. P. Khanapure, J. Org. Chem. 1986,
51, 5157 – 5160; i) M. Tielemans, V. Areschka, J. Colomer, R.
Promel, W. Langenaeker, P. Geerlings, Tetrahedron 1992, 48,
10575 – 10586; j) P. M. Tadross, C. D. Gilmore, P. Bugga, S. C.
Virgil, B. M. Stoltz, Org. Lett. 2010, 12, 1224 – 1227.
[14] For computational studies of aryne electronic properties, see:
a) A. Hinchliffe, H. J. S. Machado, J. Mol. Struct.: THEOCHEM
1994, 313, 265 – 273; b) W. Langenaeker, F. De Proft, P. Geerl-
ings, J. Phys. Chem. A 1998, 102, 5944 – 5950; c) W. T. G.
Johnson, C. J. Cramer, J. Am. Chem. Soc. 2001, 123, 923 – 928;
d) W. T. G. Johnson, C. J. Cramer, J. Phys. Org. Chem. 2001, 14,
597 – 603; e) P. H.-Y. Cheong, R. S. Paton, S. M. Bronner, G.-Y. J.
Im, N. K. Garg, K. N. Houk, J. Am. Chem. Soc. 2010, 132, 1267 –
1269.
[3] M. Passerini, Gazz. Chim. Ital. 1921, 51, 181 – 189.
[4] a) R. H. Baker, D. Stanonis, J. Am. Chem. Soc. 1951, 73, 699 –
702; b) I. Ugi, R. Meyr, Chem. Ber. 1961, 94, 2229 – 2233; c) T.
Saegusa, N. Taka-ishi, H. Fujii, Tetrahedron 1968, 24, 3795 –
3798; d) P. Hoffmann, D. Marquarding, H. Kliimann, I. Ugi in
The Chemistry of the Cyano Group (Ed.: Z. Rappoport), Wiley,
New York, 1970, pp. 853 – 883.
[5] J. H. Rigby, S. Laurent, J. Org. Chem. 1998, 63, 6742 – 6744.
[6] a) R. Huisgen, Angew. Chem. 1963, 75, 603 – 637; Angew. Chem.
Int. Ed. Eng. 1963, 2, 565 – 598; b) R. Huisgen, J. Org. Chem.
1976, 41, 403 – 419; c) R. Huisgen in 1,3-Dipolar Cycloaddition
Chemistry, Vol. 1 (Ed.: A. Padwa), Wiley, New York, 1984,
pp. 1 – 176; d) R. Huisgen, Helv. Chim. Acta 1967, 50, 2427 –
2439; e) H.-J. Hansen, H. Heimgartner in 1,3-Dipolar Cyclo-
addition Chemistry, Vol. 1 (Ed.: A. Padwa), Wiley, New York,
1984, pp. 177 – 290.
[7] H. Yoshida, H. Fukushima, J. Ohshita, A. Kunai, Angew. Chem.
2004, 116, 4025 – 4028; Angew. Chem. Int. Ed. 2004, 43, 3935 –
3938.
[8] H. Yoshida, H. Fukushima, J. Ohshita, A. Kunai, Tetrahedron
Lett. 2004, 45, 8659 – 8662.
[15] a) M. Yamazaki, H. Fujimoto, Y. Ohta, Y. Iitaka, A. Itai,
Heterocycles 1981, 15, 889 – 893; b) Y. Maebayashi, M. Yama-
zaki, Chem. Pharm. Bull. 1985, 33, 4296 – 4298.
[9] H. Yoshida, H. Fukushima, T. Morishita, J. Ohshita, A. Kunai,
Tetrahedron 2007, 63, 4793 – 4805.
[10] The phenoxy iminoisobenzofuran framework was unambigu-
ously confirmed by obtaining the X-ray crystal structure of
phenoxy iminoisobenzofuran 14r (Table 1). See Supporting
Information for details.
[11] The closest related structures include an iminium perchlorate
reported by Boyd and a series of cyclic imidates reported by Sato
et al. However, these structures are shown to be unstable in the
presence of water. See: a) G. V. Boyd, Tetrahedron Lett. 1972, 13,
2711 – 2714; b) G. V. Boyd, J. Chem. Soc. Perkin Trans. 1 1973,
1731 – 1737; c) R. Sato, M. Ohmori, F. Kaitani, A. Kurosawa, T.
[16] Attempts were made to carry out similar transformations using
methyl acrylate, methyl methacrylate, 2-cyclopentenone, and 2-
cyclohexenone in place of methyl propiolate (19a). However,
each failed to generate the corresponding iminoindanone under
the reaction conditions.
[17] Efforts to employ additional alkynes lacking conjugate acceptors
(e.g., cyclohexylacetylene, ethoxyacetylene, and diphenylacety-
lene) failed to generate the corresponding three-component
adducts.
Angew. Chem. Int. Ed. 2011, 50, 4488 –4491
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4491