Enamide-benzyne-[2 + 2] cycloaddition: Stereoselective tandem [2 + 2]-pericyclic ring-opening-intramolecular N-tethered [4 + 2] cycloadditions

Article abstract of DOI:10.1021/ol901434g

Image Presented Benzyne-[2 + 2] cycloadditions with enamides are described. This effort led to the development of a highly stereoselective tandem [2 + 2] cycloaddition-pericyclic ring-opening-intramolecular-N-tethered-[4 + 2] cycloaddition for rapid assembly of nitrogen heterocycles.

Full text of DOI:10.1021/ol901434g

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3666-3669
Enamide-Benzyne-[2 + 2] Cycloaddition:
Stereoselective Tandem [2 + 2]-Pericyclic
Ring-Opening-Intramolecular
N-Tethered [4 + 2] Cycloadditions
John B. Feltenberger, Ryuji Hayashi, Yu Tang, Eric S. C. Babiash,
and Richard P. Hsung*
Department of Chemistry and DiVision of Pharmaceutical Sciences, UniVersity of
Wisconsin, Madison, Wisconsin 53705
rhsung@wisc.edu
Received June 24, 2009
ABSTRACT
Benzyne-[2 + 2] cycloadditions with enamides are described. This effort led to the development of a highly stereoselective tandem [2 + 2]
cycloaddition-pericyclic ring-opening-intramolecular-N-tethered-[4 + 2] cycloaddition for rapid assembly of nitrogen heterocycles.
Chemistry of benzynes1 has reemerged, as evident by an elegant
array of work that has appeared in the recent literature covering
a number of different synthetic transformations.2-4 As Larock4
pointed out, this new surge is in part related to the usage of
Kobayashi’s5 mild fluoride-based conditions for generating
benzynes in situ from o-(trimethylsilyl)aryl triflates. In
particular, Stoltz’s6 beautiful studies on annulations of
enamides with benzynes en route to indolines and iso-
quinolines provoked us to envision another transformation
also involving enamides but through a [2 + 2] cycload-
dition as shown in Scheme 1. While benzyne-[2 + 2]
cycloaddition is well-known,1,7 there are very few examples
(1) For recent reviews on aryne chemistry, see: (a) Pen˜a, D.; Pe´rez, D.;
Guitia´n, E. Angew. Chem., Int. Ed. 2006, 45, 3579. (b) Pellissier, H.; Santelli,
M. Tetrahedron 2003, 59, 701. (c) Kessar, S. V. ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991;
Vol. 4, pp 483-515. (d) Heaney, H. Chem. ReV. 1962, 62, 81.
(2) For leading examples of nucleophilic additions, see: (a) Liu, Z.;
Larock, R. C. Org. Lett. 2004, 6, 99. (b) Jeganmohn, M.; Chen, C.-H. Org.
Lett. 2004, 6, 2821. (c) Jeganmohan, M.; Cheng, C.-H. Synthesis 2005,
1693. (d) Bhuvaneswari, S.; Jeganmohan, M.; Yang, M.-C.; Cheng, C.-H.
Chem. Commun. 2008, 2158. (e) Xie, C.; Liu, L.; Zhang, Y.; Xu, P. Org.
Lett. 2008, 10, 2393. (f) Sha, F.; Huang, X. Angew. Chem., Int. Ed. 2009,
(4) For recent examples on annulations and cycloadditions, see: (a) Liu,
Z.; Larock, R. C. Tetrahedron 2007, 63, 347. (b) Liu, Z.; Shi, F.; Martinez,
P. D. G.; Raminelli, C.; Larock, R. C. J. Org. Chem. 2008, 73, 219. (c)
Shi, F.; Waldo, J. P.; Chen, Y.; Larock, R. C. Org. Lett. 2008, 10, 2409.
(d) Worlikar, S. A.; Larock, R. C. Org. Lett. 2009, 11, 2413. (e) Also see
ref 6.
38, 3458
.
(3) For examples of interesting insertion-type processes, see: (a) Liu,
Z.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 13112. (b) Tambar, U. K.;
Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340. (c) Tambar, U. K.; Ebner,
D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 127, 11752. (d) Pi, S.-F.;
Tang, B.-X.; Li, J.-H.; Liu, Y.-L.; Liang, Y. Org. Lett. 2009, 11, 2309. (e)
Also see ref 1a.
(5) For a mild and general preparation of arynes using o-(trimethylsi-
lyl)aryl triflates, see: Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem.
Lett. 1983, 1211.
(6) (a) Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 17270.
(b) Gilmore, C. D.; Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008,
130, 1558.
10.1021/ol901434g CCC: $40.75
Published on Web 07/22/2009
 2009 American Chemical Society

amido-o-quinonedimethides 2 (or a 1-amidodiene)17,18 through
pericyclic ring-opening,1,19 but also the possibility of a
tandem sequence consisting of benzyne-[2 + 2] cycloaddi-
tion-ring-opening-N-tethered intramolecular [4 + 2] cy-
cloaddition.1,19,20 This tandem process should be useful for
rapid assembly of complex nitrogen heterocycles [(benzyne+
enamide) f 1a f 2a f 3]. We communicate here our
success in this endeavor.
Scheme 1. Tandem Benzyne-Enamide-[2 + 2]-Diels-Alder
Feasibility of the enamide-benzyne [2 + 2] cycloaddition
was established using benzyne precursor 4 and enamide 5
in the presence of a fluoride source (Table 1). The first
Table 1. Fluoride Sources and Solvents for Benzyne Formation
involving enamines,8 with no systematic examinations of
enamides in this capacity.1,9,10 While conceptually simple,
this endeavor is timely and significant because enamides
represent an increasingly more accessible substrate11-14 and
a useful functional group in modern organic synthesis.15,16
More importantly, we recognized that the union of
benzynes and enamides would lead to not only amido-
benzocyclobutanes 1, which are excellent precursors to
yield [%]
entry 4 [equiv] FQ [equiv]a solventb time [h] NMR isolated
1
2.0
2.0
2.0
2.0
4.0
2.0
4.0
3.0
3.0
3.0
TBAT [2.0] THF
6
22
22
22
12
22
12
22
22
22
14
2
TBAT [2.0] CH3CN
TBAT [2.0] toluene
TBAT [2.0] ClCH2CH2Cl
TBAT [4.0] DME
3
29
(7) For some examples of aryne-[2 + 2] cycloaddition, see: (a)
4
´
Barluenga, J.; Calleja, J.; Anto´n, M. J.; Alvarez-Rodrigo, L.; Rodr´ıguez,
5
51
41
71
F.; Fan˜ana´s, F. J. Org. Lett. 2008, 10, 4469. (b) Hamura, T.; Arisawa, T.;
Matsumoto, T.; Suzuki, K. Angew. Chem., Int. Ed. 2006, 45, 6842.
(8) For [2 + 2] cycloadditions of arynes with enamines, see: (a) Gingrich,
H. L.; Huang, Q.; Morales, A. L.; Jones, M. J. Org. Chem. 1992, 57, 3803.
(b) Heaney, H.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 1974, 2693. (c)
Crews, P.; Beard, J. J. Org. Chem. 1973, 38, 522. (d) Kametani, T.;
Kigasawa, K.; Hiiragi, M.; Hayasaka, T.; Kusama, O. J. Chem. Soc. C 1971,
1051.
6
TBAT [2.0] dioxane
TBAT [4.0] dioxane
HF-pyridine dioxane
TBAF [4.0] dioxane
7
83
87
8
9
10
CsF [4.0]
dioxane
a TBAT: tetra-n-butyl-ammonium triphenyldifluorosilicate. b DME:
dimethoxyethane; dioxane: 1,4-dioxane.
(9) For reports on amido-benzocyclobutane formation as side products
through enamide-benzyne-[2 + 2] cycloaddition, see: (a) Castedo, L.;
Guitian, E.; Saa´, C.; Suau, R.; Saa´, J. M. Tetrahedron Lett. 1983, 24, 2107.
(b) Blackburn, T.; Ramtohul, Y. K. Synlett 2008, 1159. For an example of
using vinylogous amides which led to only addition reaction and not
benzocyclobutane formation, see: (c) Ramtohul, Y. K.; Chartrand, A. Org.
fluoride anion source employed was TBAT (tetra-n-Bu-
ammonium triphenyldifluorosilicate). After screening through
a variety of solvents, 1,4-dioxane proves to be the optimal
solvent (entries 6 and 7), leading to amido-benzocyclobutane
621 in 83% yield. Intriguingly, THF, the commonly used
Lett. 2007, 9, 1029
.
(10) For a leading example of [2 + 2] cycloadditions of chiral enamides
that does not involve arynes, see: (a) Hegedus, L. S.; Bates, R. W.;
Soderberg, B. C. J. Am. Chem. Soc. 1991, 113, 923. (b) For a review, see
:Hegedus, L. S. Tetrahedron 1997, 53, 4105
.
(11) For reviews on Cu-mediated C-N and C-O bond formations, see:
(a) Evano, G.; Blanchard, N.; Toumi, M. Chem. ReV. 2008, 108, 3054. (b)
Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun. 2005, 973. (c) Ley, S. V.;
Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (d) Lindley, J.
Tetrahedron 1984, 40, 1433. For reviews on Pd-catalyzed N-arylations of
amines and amides, see: (e) Hartwig, J. F. Angew. Chem., Int. Ed. 1998,
37, 2046. (f) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. Acc.
(16) For recent examples, see: (a) Ylioja, P. M.; Mosley, A. D.; Charlot,
C. E.; Carbery, D. R. Tetrahedron Lett. 2008, 49, 1111. (b) Lu, T.; Song,
Z.; Hsung, R. P. Org. Lett. 2008, 10, 541. (c) Nguyen, T. B.; Martel, A.;
Dhal, R.; Dujardin, G. J. Org. Chem. 2008, 73, 2621. (d) Gohier, F.;
Bouhadjera, K.; Faye, D.; Gaulon, C.; Maisonneuve, V.; Dujardin, G.; Dhal,
R. Org. Lett. 2007, 9, 211. (e) Song, Z.; Lu, T.; Hsung, R. P.; Al-Rashid,
Z. F.; Ko, C.; Tang, Y. Angew. Chem., Int. Ed. 2007, 46, 4069. (f) Martin,
R.; Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 5221. (g) Ko, C.; Hsung,
R. P.; Al-Rashid, Z. F.; Feltenberger, J. B.; Lu, T.; Wei, Y.; Yang, J.;
Zificsak, C. A. Org. Lett. 2007, 9, 4459. (h) Barbazanges, M.; Meyer, C.;
Chem. Res. 1998, 31, 805
.
(12) For a general review on the synthesis of enamides, see: Tracey,
M. R.; Hsung, R. P.; Antoline, J.; Kurtz, K. C. M.; Shen, L.; Slafer, B. W.;
Zhang, Y. In Science of Synthesis, Houben-Weyl Methods of Molecular
Transformations; Weinreb, S. M., Ed.; Georg Thieme Verlag KG: Stuttgart,
2005; Chapter 21.4.
Cossy, J. Org. Lett. 2007, 9, 3245
.
(17) For reviews on chemistry of dienamides, see: (a) Overman, L. E.
Acc. Chem. Res. 1980, 13, 218. (b) Petrzilka, M. Synthesis 1981, 753. (c)
Campbell, A. L.; Lenz, G. R. Synthesis 1987, 421.
(13) For leading examples of enamide syntheses, see: (a) Chechik-
Lankin, H.; Livshin, S.; Marek, I. Synlett 2005, 2098. (b) Han, C.; Shen,
R.; Su, S.; Porco, J. A., Jr., Org. Lett. 2004, 6, 27. (c) Pan, X.; Cai, Q.; Ma,
D. Org. Lett. 2004, 6, 1809. (d) Brice, J. L.; Meerdink, J. E.; Stahl, S. S.
Org. Lett. 2004, 6, 1845. (e) Langner, M.; Bolm, C. Angew. Chem., Int.
Ed. 2004, 43, 5984. (f) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L.
Org. Lett. 2003, 5, 3667. (g) Shen, R.; Lin, C. T.; Porco, J. A., Jr. J. Am.
(18) For recent examples 1-amido-diene-[4 + 2] cycloadditions, see:
(a) Smith, A. B., III; Wexler, B. A.; Tu, C.-Y.; Konopelski, J. P. J. Am.
Chem. Soc. 1985, 107, 1308. (b) Schlessinger, R. H.; Pettus, T. R. R.;
Springer, J. P.; Hoogsteen, K. J. Org. Chem. 1994, 59, 3246. (c) Kozmin,
S. A.; Rawal, V. H. J. Am. Chem. Soc. 1997, 119, 7165. (d) Huang, Y.;
Iwama, T.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 5950. (e) Robiette,
R.; Cheboub-Benchaba, K.; Peeters, D.; Marchand-Brynaert, J. J. Org.
Chem. Soc. 2002, 124, 5650
.
(14) For a synthesis of Z-enamides, see: Zhang, X.; Zhang, Y.; Huang,
Chem. 2003, 68, 9809
.
J.; Hsung, R. P.; Kurtz, K. C. M.; Oppenheimer, J.; Petersen, M. E.;
(19) For a leading review, see: Sadana, A. K.; Saini, R. K.; Billups,
Sagamanova, I. K.; Tracey, M. R. J. Org. Chem. 2006, 71, 4170
.
W. E. Chem. ReV. 2003, 103, 1539.
(15) For a leading review on recent chemistry of enamides, see: (a)
Carbery, D. R. Org. Biomol. Chem. 2008, 9, 3455. Also see: (b) Rappoport,
Z. The Chemistry of Enamines in The Chemistry of Functional Groups;
(20) For a pioneering example of benzocyclobutene ring-opening-
dienamide Diels-Alder sequences, see: Oppolzer, W. J. Am. Chem. Soc.
1971, 93, 3834
.
John Wiley and Sons: New York, 1994
.
(21) See Supporting Information.
Org. Lett., Vol. 11, No. 16, 2009
3667

solvent for benzyne reactions, afforded the desired product in
only 14% isolated yield (entry 1) with the formation of a
significant side product.22 Increasing the loading of silylaryl
triflate 4 and fluoride ion afforded higher yields (entry 6 versus
7). When examining other fluoride sources (entries 8-10), none
was effective except CsF, which was ultimately determined to
be the best fluoride source for ease of operation (entry 10).
Having established these conditions, a variety of enamides
were found to undergo the benzyne-[2 + 2] cycloaddition (Table
2). Electronically, cycloadditions of both N-acyl and N-sulfonyl
with ratios of 1:1 to 2:1, to control this diastereoselectivity
is not essential because the major application of these
amido-benzocyclobutanes pertains to a pericyclic ring-
opening, which would lose the stereochemical information
en route to amido-o-quinonedimethides. In accord with
this understanding, we recognized that while these new
amido-benzocyclobutanes are synthetically useful, the
most attractive feature here is to employ enamide-benzyne-
[2 + 2] cycloaddition in tandem with the ring-opening to
o-quinonedimethide for the ensuing [4 + 2] cycloaddition.
As shown in Scheme 2, this concept was readily achieved
using enamide 15 tethered with an olefin to give aza-tricycle
19 in 95% yield as a single diastereomer (assigned via NOE
Table 2. General Benzyne-Enamide-[2 + 2] Cycloaddition
Scheme 2. Tandem Benzyne-Enamide-[2 + 2]-[4 + 2]
a Unless otherwise noted, all reactions were carried out in 1,4-dioxane
at 110 °C with CsF (4.0 equiv) and 4 (3.0 equiv) being employed. b Isolated
yields. c dr ratio is 2:1 as determined by 1H NMR; major isomer unassigned.
experiments). Aza-tricycle 22 could also be obtained from the
respective enamide 20. The formation of 19 (or 22) would
constitute a four-bond formation through benzocyclobutane
synthesis (2 red bonds), a torquoselective pericyclic ring-opening
in favor of the amido group rotating outwardly,24,25 and an
N-tethered intramolecular [4 + 2] cycloaddition. The latter
two reactions in tandem already represents a highly useful
synthetic strategy, as evident from elegant work by Op-
polzer,20 thereby further accentuating the potential signifi-
cance of developing an enamide-benzyne-[2 + 2] cycload-
dition manifold.
d
1
dr ratio is 1:1 as determined by H NMR.
enamides 7 and 9 proceeded well (entries 1 and 2). Cyclic
enamides 11a and 11b were also excellent substrates, affording
unique aza-tricycles 12a and 12b, respectively, in nearly
quantitative yields (entries 3 and 4). In addition, achiral
oxazolidinone substituted enamide 13a was viable for the
cycloaddition, leading to amido-benzocyclobutane 14a in 62%
yield (entry 5), while chiral enamides 13b-e were equally
efficient (entries 7-11). It is noteworthy that amido-benzocy-
clobutane product 14e provides an access to free amino-
benzocyclobutane via reductive ring-opening of the chiral
oxazolidinone motif through hydrogenolysis.23
The synthetic scope of this tandem process can be
illustrated in two facets. First, as shown in Scheme 3,
(23) Song, Z.; Lu, T.; Hsung, R. P.; Al-Rashid, Z. F.; Ko, C.; Tang, Y.
Although amido-benzocyclobutane products 14b-e
were isolated as an inseparable mixture of diastereomers
Angew. Chem., Int. Ed. 2007, 46, 4069
.
(24) (a) Kirmse, W.; Rondan, N. G.; Houk, K. N. J. Am. Chem. Soc.
1984, 106, 7989. (b) Kallel, E. A.; Wang, Y.; Spellmeyer, D. C.; Houk,
K. N. J. Am. Chem. Soc. 1990, 112, 6759. (c) Dolbier, W. R., Jr.; Koroniak,
H.; Houk, K. N.; Sheu, C. Acc. Chem. Res. 1996, 29, 471. (d) Lee, P. S.;
(22) We found THF had reacted with benzyne at 110 °C, leading to the
formation of cyclic ether ii, thereby constituting a stepwise C-O insertion
process through oxonium intermediate i.
Zhang, X.; Houk, K. N. J. Am. Chem. Soc. 2003, 125, 5072
.
(25) Also see: (a) Murakami, M.; Miyamoto, Y.; Ito, Y. Angew. Chem.,
Int. Ed. 2001, 40, 189. (b) Murakami, M.; Miyamoto, Y.; Ito, Y. J. Am.
Chem. Soc. 2001, 123, 6441. (c) Murakami, M.; Hasegawa, M.; Igawa, H.
J. Org. Chem. 2004, 69, 587. (d) Hasegawa, M.; Murakami, M. J. Org.
Chem. 2007, 72, 3674
.
3668
Org. Lett., Vol. 11, No. 16, 2009

Scheme 3
.
Substituted Olefins for [4 + 2] Cycloaddition
Scheme 4. Asymmetric Tandem [2 + 2]-[4 + 2]
cycloadditions of enamides 23a and 23b tethered to a cis-
olefin gave respective cycloadducts 26a and 26b in good
yields as a single isomer with all-cis relative stereochemistry
at CR, Cꢀ, and Cγ as assigned through NOE experiments.
The cis relative stereochemistry at Cꢀ and Cγ suggests the
concerted nature in the [4 + 2] cycloaddition, as the integrity
of the olefin geometry is preserved.1,19 In addition, enamide
27 with a trisubstituted olefin was also feasible for the tandem
sequence, although the yield for the desired aza-tetracycle
28 is lower. We note here that even with the more electron-
rich di- and trisubstituted olefins, the benzyne-[2 + 2]
cycloaddition still favored the enamide motif.
through the current state of art in their preparations. In
addition, the robustness of enamides allows one to carry them
through multiple organic transformations as a functional
group while assembling greater complexity.
We have described here an enamide-benzyne-[2 + 2]
cycloaddition. This work led to the development of a highly
stereoselective tandem [2 + 2] cycloaddition-pericyclic ring-
opening-intramolecular [4 + 2] cycloaddition that should
be useful for the rapid construction of nitrogen heterocycles.
Efforts in applying this tandem process to alkaloid synthesis
are currently underway.
The second facet features an asymmetric variant of this
tandem sequence (Scheme 4). Chiral enamide 29, derived
from (S)-aspartic acid, could be transformed into enamide
31 tethered to a trans-acrylate motif through Swern oxidation
and Wittig olefination. Subjecting 31 to the tandem benzyne-
[2 + 2]-ring-opening-intramolecular [4 + 2] process
afforded aza-tetracycle 34 in a highly stereoselective manner.
This exercise underscores the timeliness and significance of
this strategy because chiral enamides are readily accessible
Acknowledgment. The authors thank the NIH (GM066055)
for funding.
Supporting Information Available: Experimental pro-
cedures as well as NMR spectra and characterizations. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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