An ionic O → α- and β-vinyl carbamoyl translocation of 2-(O-carbamoyl) stilbenes

Article abstract of DOI:10.1021/ol049740t

(Equation Presented) New anionic oxygen to α- and β-vinyl carbamoyl migration reactions, 17a and 26a-c → 18 and 30a-c, proceed under LDA-mediated conditions leading stereoselectively to highly substituted stilbenes bearing electron-donating and -withdrawing substituants. Compounds 17a and 26a-c are prepared by combination of efficient, directed ortho metalation, Sonogashira, and Suzuki-Miyaura cross-coupling procedures.

Full text of DOI:10.1021/ol049740t

ORGANIC
LETTERS
2004
Vol. 6, No. 14
2297-2300
Anionic O f r- and â-Vinyl Carbamoyl
Translocation of 2-(O-Carbamoyl)
Stilbenes†
Mark A. Reed, Michelle T. Chang, and Victor Snieckus*
Department of Chemistry, Queen’s UniVersity, Kingston, ON, K7L 3N6, Canada
snieckus@chem.queensu.ca
Received February 13, 2004 (Revised Manuscript Received April 8, 2004)
ABSTRACT
New anionic oxygen to r- and â-vinyl carbamoyl migration reactions, 17a and 26a−c f 18 and 30a−c, proceed under LDA-mediated conditions
leading stereoselectively to highly substituted stilbenes bearing electron-donating and -withdrawing substituents. Compounds 17a and 26a−c
are prepared by combination of efficient, directed ortho metalation, Sonogashira, and Suzuki−Miyaura cross-coupling procedures.
In continuation of efforts (Figure 1, 1-6) to devise useful
carbanion-based methodology for the synthesis of aromatics
Scheme 1
of 2-O-carbamoyl stilbenes (Scheme 1). With the obligatory
prevention of the anionic Fries rearrangement1a (8 f 7) by
silicon protection (8, X ) TMS), migration to both R- (8 f
9) and â-vinyl (8 f 10) positions may be induced, depending
(1) (a) Anionic ortho-Fries: Sibi, M. P.; Snieckus, V. J. Org. Chem.
1983, 48, 1935-1937. (b) Vinylogous anionic ortho-Fries: Kalinin, A. V.;
Miah, M. A. J.; Chattopadhyay, S.; Tsukazaki, M.; Wicki, M.; Nguen, T.;
Coelho, A. L.; Kerr, M.; Snieckus, V. Synlett 1997, 7, 839-841. (c) 1,5-
Of O CONEt2 translocation: Chauder, B. A.; Kalinin, A. V.; Taylor, N.
J.; Snieckus, V. Angew. Chem., Int. Ed. 1999, 38, 1435-1438. (d) Remote
anionic Fries: Wang, W.; Snieckus, V. J. Org. Chem. 1992, 57, 424-426.
(e) 1,2 Wittig Versus 1,5-Of O CONEt2 translocation: Zhang, P.; Gawley,
R. E. J. Org. Chem. 1993, 12, 3222-3223. (f) Carbamoyl Baker-
Venkatarman reaction: Kalinin, A. V.; da Silva, A. J. M.; Lopes, C. C.;
Lopes, R. S. C.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4995-4998.
Figure 1.
and heteroaromatics,1 we have uncovered a stereoselective
LDA-mediated O f ortho-vinyl carbamoyl rearrangement
† This paper is dedicated with respect and appreciation to Al Meyers
who pointed the way to ortho metalation and provides a rich lore of synthetic
organolithium chemistry.
10.1021/ol049740t CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/18/2004

on the open site, and thereby provides new heterocycles. In
particular, our method allows the synthesis of 3-arylcoumarin
and 3,4-diaryl coumarin approaches to diversely substituted
stilbenes and, from these, benzofurananone2 19 and cou-
marin3 31, which, in the context of current studies, may be
of future biological interest.4,5 Although mechanistically
somewhat ambiguous (vide infra), the carbamoyl migrations
are, to the best of our knowledge, unprecedented in aromatic
carbanionic chemistry6 and may be conceptualized to be
driven by the complex-induced proximity effect (CIPE).7
The requisite test substrate 8, X ) TMS for the O-
carbamoyl f R-vinyl migration was prepared by first
constructing the intermediate styryl borolane 13 using a two-
pronged approach (Scheme 2). Thus, in a five-step synthetic
available 2-O-carbamoyl acetophenone 119 with diethyl
chlorophosphonate at -78 °C followed by LDA (4 equiv)
and TMSCl (3 equiv) gave the bis-silylated aryl acetylene
12 in high yield. Selective desilylation followed by hydrobo-
ration with i(isopropylprenyl)borane (iPP2BH)10 gave the
vinyl borolane 13.11
In the alternative route, subjection of the O-phenyl
carbamate 14 to a sequential, one-pot double-directed ortho
metalation (DoM)-TMSCl and iodine quench procedure
afforded the contiguously substituted iodide 15 (77% yield)
which, upon Sonogashira coupling with TMS acetylene
furnished the bis-silylated derivative 12 in 81% yield. In view
of the high cost of TMS acetylene and the difficulties of
scaling-up this route, the procedure starting from 11 was
preferred. Suzuki-Miyaura cross coupling of 13 with
bromobenzene under standard conditions delivered the
requisite 2-O-carbamoyl stilbene 17a in 83% yield (Scheme
3).12 As expected from general observation,1a treatment of
Scheme 2
Scheme 3
operation in one pot and following, in part, the interesting
Negishi protocol,8 treatment of the enolate of the readily
(2) For naturally occurring benzofuranones (isoaurones) with topomerase
inhibitory effects, see: (a) Suzuki, K.; Yahara, S.; Maehata, K.; Uyeda, M.
J. Nat. Prod. 2001, 64, 204-207. For recent synthetic work, see: (b) Burke,
A. J.; O’Sullivan, W. I. Tetrahedron 1997, 35, 2539-2543.
(3) For naturally occurring coumarins, some of which exhibit diverse
(proapoptotic, antitumor, transcriptional suppression of HIV promoter)
bioactivity, see: Bailly, C.; Bal, C.; Barbier, P.; Combes, S.; Finet, J.-P.;
Hildebrand, M.-P.; Peyrot, V.; Wattez, N. J. Med. Chem. 2003, 46, 5437-
5444 and references therein.
(4) (a) Guilet, D.; He´lesbeux, J-J.; Se´raphin, D.; Se´venet, T.; Richomme,
P.; Bruneton, J. J. Nat. Prod. 2001, 64, 563-568. (b) Murray, R. D. H.;
Me´ndez, J.; Brown, S. A. The Natural Coumarins: Occurrence, Chemistry
and Biochemistry; J. Wiley: New York, 1982.
(5) ,4-Diarylcoumarins may be considered as restricted tamoxifen
derivatives, the latter being an FDA approved drug widely used for treatment
of estrogen-dependent breast cancer. For key references and recent synthetic
work, see: Yu, D. D.; Forman, B. M. J. Org. Chem. 2003, 68, 9489-9491.
Yus, M.; Ramo´n, D. J.; Go´mez, I. Tetrahedron 2003, 59, 3219-3225.
(6) Stilbene undergoes reductive dilithiation in the presenece of Li metal
as discovered by Schlenk in his prognostic contributions to organolithium
chemistry: (a) Schlenk, W.; Bergmann, E. Annalen 1928, 483, 106; Houben-
Weyl 13/1, 162 ff. Monolithio and 1,1- or 1,2-dilithio stilbene species have
been generated mainly by metal-halogen exchange or Li addition to
diphenylacetylene: (b) Maercker, A.; Kemmer, M.; Wang, H. C.; Dong,
D.-H.; Szwarc, M. Angew Chem., Int. Ed. 1998, 37, 2136-2138. (c) Boche,
G. Top. Curr. Chem. 1988, 146, 3-56. Their configurational stability and
proton-transfer reactions are highly dependent on solvent and temperature,
see: (d) Houben-Weyl, 1952, 13/1, p 133 and 1989E, 19d, pp 176, 483,
498. (e) Maercker, A. In Sapse, A. M., Schleyer, P. von R. Lithium
Chemistry. A Theoretical and Experimental OVerView, Wiley: New York,
1995; p 477.
17b (Scheme 3), derived by selective desilylation (TBAF/
rt) of 17a, with LDA (3 equiv) resulted in quantitative
conversion to the anionic ortho-Fries rearrangement product
16. On the other hand, the TMS-protected derivative 17a,
upon treatment with LDA (2.5 equiv) between -10 and 0
°C led smoothly to the formation of the carbamoyl-migrated
product 18 in 94% yield. To ensure the position of amide
translocation, 18 was cyclized to the known benzofuranone
19 (1:1 E:Z mixture).13 A single-crystal X-ray structure
analysis of 1814 established stereochemical conservation of
(E)-stilbene in the transformation. Generalization of the
(8) Negishi, E.-i.; King, A. O.; Klima, W. L. J. Org. Chem. 1980, 2,
193-196.
(9) Prepared in 93% yield from 2-hydroxyacetophenone using NaH,
ClCONEt2/DMF.
(10) For the general utility of this new hydroboration reagent, see:
Kalinin, A.; Scherer, S.; Snieckus, V. Angew. Chem., Int. Ed. 2003, 42,
3399-3404.
(11) For purification purposes, the intermediate boronic acid was first
converted into its crystalline diethanolamine adduct, which was subjected
to treatment with pinacol in 50% citric acid/hexane mixture to give
analytically pure 13.
(12) Kalinin, A. V.; Reed, M. A.; Norman, B. H.; Snieckus, V. J. Org.
Chem. 2003, 68, 5992-5999.
(13) Msaddek, M.; Rammah, M.; Ciamala, K.; Vebrel, J.; Laude, B.
Synthesis 1997, 1495-1498.
(7) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem.,
Int. Ed. 2004, 43, 2206.
2298
Org. Lett., Vol. 6, No. 14, 2004

yield (entry 5). The N-Boc stilbenoid 20f, upon treatment
under the standard excess LDA conditions, led to recovered
starting material. Suspecting the possible deactivation effect
of the incipient N-anion, we subjected compound 20f to
LDA/TMSCl (1.1:1.1 equiv) followed by LDA (3 equiv) and
workup to give the desired product 21f in modest yield (entry
6). The aldehydic stilbenoid 20g required initial in situ
protection with LiNEt2 (1 equiv)15 followed by application
of the standard LDA conditions to afford 21g (entry 7).
Turning attention to substrates bearing electron-withdrawing
groups, both tertiary sulfonamide and tert-butyl ester systems,
20h and 20i, showed good behavior to furnish products 21h
and 21i, respectively (entries 8 and 9), while cyano- and
chloro-substituted derivatives 20j and 20k showed instability
in the presence of LDA even at low temperatures and did
not lead to the rearranged products 21j and 21k, respectively
(entries 10 and 11). For these two cases, attack at the CN
function16 and benzyne formation17 may be the complicating
factors. In accord with previous experience on similar
systems,18 and consistent with pKa considerations, benzo-
thiophene 20l required prior in situ 2-TMS protection in order
to achieve reasonably effective formation of the R-carbamoyl
migration product 21l. Reaction of CF3-substituted aryl,
2-furanyl, 2-thienyl, and 3- and 4-pyridinyl substituted
systems led only to overall decomposition. Treatment of 23
(Scheme 4) under the LDA conditions yielded 24, perhaps
Table 1. Synthetic 2(O-Carbamoyl)stilbene Translocation
Reactions 20 into 21
a (Z)-Stilbene derivative. b In addition, 12 and 15% yields of R-meth-
ylsilyl amides 22a and 22b, respectively, were obtained. c Corresponding
TES derivative of 21e was used. d Substrate 20f was first treated with
TMSCl (1.1 equiv)/LDA (1.1 equiv) at -78 °C, warmed to 0 °C, and
recooled to -78 °C. e Treated with LiNEt2 at -78 °C and stirred for 30
min, and then the conditions shown were followed. f Substrate was
sequentially treated with TMSCl (1.5 equiv) and LDA (5 equiv).
Scheme 4
not a surprising result of carbamoyl migration followed by
Michael addition or vice versa, which may be viewed as a
product of a first step of an intramolecular Baylis-Hillman
reaction.19 To test the O-carbamoyl-â-vinyl translocation
(Scheme 1, 8 f 10), the R-phenyl stilbenes 26a-c were
prepared (Scheme 5). Thus, Suzuki-Miyaura cross coupling
of the (Z)-stilbene borolane, 25a,10 with the previously
prepared iodide 15 afforded compound 26a, while analogous
couplings of 2720 with 28 gave 29 and then, with 4-Me-
OC6H4B(OH)2, the corresponding 26c. Disilylated stilbene
26b was obtained by the corresponding coupling of 25b with
15. All coupling reactions proceeded with complete stereo-
selectivity.21 Treatment with LDA at room temperature led
to the â-vinyl migration products 30a-c, respectively, in
carbamoyl translocation reaction (20 f 21, Table 1) deserves
comment. Starting substrates were prepared according to the
method described (Schemes 2 and 3) using aryl bromides
and aryl iodides as coupling partners (See Supporting
Information). Interestingly, the (Z)-stilbene derivative cor-
responding to the (E)-isomer 17a, underwent comparatively
faster rearrangement to give isomeric carbamoyl-migrated
product 21a in high yield (entry 1). Stilbenes bearing
electron-donating OMe groups, 20b-e, provided the ex-
pected products 21b-e (entries 2-5) but also, in two cases
(entries 2 and 5), minor amounts of R-methylsilyl amides
22a and 22b, presumably due, in balance, to an R-vinyl C-H
deacidifying effect of the OMe groups. Following our
established circumvention of such byproducts in O-biaryl
carbamate remote anionic Fries rearrangement,1d the ortho-
triethylsilyl (TES) derivative corresponding to 20e was
prepared and subjected to the LDA conditions to afford
cleanly the R-vinyl carbamoyl-migrated product 21e in 88%
(15) Roschangar, F.; Brown, J. C.; Cooley, B. E.; Sharp, M. J.; Matsuoka,
R. T. Tetrahedron 2002, 58, 1657-1666.
(16) Krizan, T. D.; Martin, J. C. J. Am. Chem. Soc. 1983, 105, 6155-
6157.
(17) Gohier, F.; Castanet, A.-S.; Mortier, J. Org. Lett. 2003, 5, 1919-
1922.
(14) CCDC 235465 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge via the Internet at
www.ccdc.cam.ac.uk/data_request/cif,byemailingdata_request@ccdc.cam.ac.uk,
or by contacting The Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge CB2 1EZ, UK, fax: +44 1223 336033.
(18) James, C. Ph.D. Thesis, University of Waterloo, Waterloo, Canada,
1998.
(19) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003, 103,
811-892.
(20) Prepared by the method in: Shen, W. Synlett 2000, 737-739.
Org. Lett., Vol. 6, No. 14, 2004
2299

mechanistic interpretations of the results.23 Furthermore, the
conservation of stereochemistry of the incipient lithio species
derived from both 17a and 26 suggests O-carbamate coor-
dinative stabilization, which is unavailable for ortho-unfunc-
tionalized lithiostilbene species and hence may contribute
to their configurational instability.6d,f Although the conversion
of 17b f 16 implies higher aromaticity over vinyl C-H
acidity, comparative pKa data are not available.24 A contribu-
tion of the CIPE7 via the O-carbamate may also be suggested
for the observed anionic rearrangements.
Scheme 5
In summary, stereoselective and moderately general oxy-
gen to R- and â-vinyl carbamoyl migration reactions 20 f
21 (Table 1) and 26 f 30 have been demonstrated, which
may be of mechanistic interest and which provide new routes
to benzofuranones 19 and 3-aryl 31d and 3,4-diaryl 31b and
31f coumarins of current biological interest.4 Of potential
added synthetic value may be the methodologies devised for
the efficient construction of precursor aromatics 12 and
stilbenes 1725 whose contiguous substitution patterns are the
trademarks of directed ortho metalation-mediated synthetic
strategies. Several aspects of these observations are under
further study.
Acknowledgment. We are grateful to NSERC Canada
for support of our synthetic programs. Dr. Ruiyao Wang
provided expert X-ray crystallographic analysis. M.T.C.
thanks Pfizer Global Research and Development for a 2004
Pfizer Summer Undergraduate Research Award. Sheldon
Lyn, 2003 NSERC Undergraduate Summer Research Award-
ee, reproduced a number of experiments in this research with
great enthusiasm. Frontier Scientific graciously provided a
number of boronic acids.
high yields. The disappearance of the vinyl C-H signal in
the H NMR discounted the alternative path of remote
1
anionic Fries rearrangement1a into the R-phenyl ring. Struc-
tural integrity and synthetic utility was shown by conversion,
under glacial acetic acid conditions, into compounds 31a,
31c, and 31e, which underwent smooth desilylation to afford
the 3-aryl and 3,4-diaryl coumarins 31b, 31d, and 31f,
respectively.22 To obtain evidence for the intermediacy of
the R-vinyllithium species in the O-carbamoyl migration,
compound 29, prepared from 28, was subjected to typical
metal-halogen exchange conditions (n-BuLi/-78 f -30
°C/THF), which led to the formation of product 18, shown
to be identical with that obtained from the LDA-mediated
reaction of 17a. Although not unequivocal, this result coupled
with the observation of â-vinyl migration (26a-c f 30a-
c) supports the R- and â-vinyl anionic pathways as reasonable
Supporting Information Available: Full spectral data
and experimental procedures for the synthesis of compounds
12, 13, 15, 16, 17a, 17b, 18, 20e, 21e, 20i, 21i, 23, 24, 26a,
and 30a and X-ray crystallographic data for compound 18.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL049740T
(23) Michael addition of LDA followed by carbamoyl transfer and LDA
elimination, envisaged only for the R-vinyl rearrangement result; a type of
an intramolecular Baylis-Hillman reaction (ref 19) is an alternate, less
likely, explanation.
(24) For O-aryl carbamate, pKa ) 37.2, see: Fraser, R. R.; Bresse, M.;
Mansour, T. S. J. Am. Chem. Soc. 1983, 105, 7790-7791.
(25) Stereoselective construction of stilbene is of interest in context of
natural product, bioactive molecule, and material science substance
synthesis; see inter alia: Rathore, R.; Deselinicu, M. I.; Burns, C. L. J.
Am. Chem. Soc. 2002, 124, 14832-14833. Jeffery, T.; Ferber, B. Tetera-
hedron Lett. 2003, 44, 193-197. Kabalka, G. W.; Wu, Z.; Ju, Y.
Tetrahedron Lett. 2001, 42, 4759-4760.
(21) Stereoselective trans coupling of 1,2-dibromostilbenes is prece-
dented; see ref 20 and: Gaukroger, K.; Hadfield, J. A.; Hepworth, L. A.;
Lawrence, N. J.; McGown, A. T. J. Org. Chem. 2001, 66, 8135-8138.
(22) 27d: Yoneda, E.; Sugioka, T.; Hirao, K.; Zhang, S.-W.; Takahashi,
S. J. Chem. Soc, Perkin Trans. 1 1998, 3, 477-483. 27b: see ref 3d. 27f:
see Supporting Information.
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