Rhodium-catalyzed annulation of ynamides with bifunctional arylboron reagents

Article abstract of DOI:10.1021/ol100769p

Annulation of ynamides with arylboronic acids or esters containing an electrophilic functional group at the ortho-position proceeds under the action of rhodium catalysis to generate 2-amidoindenols or 2-amidoindenes, usually with good regioselectivity.

Full text of DOI:10.1021/ol100769p

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2554-2557
Rhodium-Catalyzed Annulation of
Ynamides with Bifunctional Arylboron
Reagents
Benoit Gourdet, Mairi E. Rudkin, and Hon Wai Lam*
School of Chemistry, UniVersity of Edinburgh, The King’s Buildings, West Mains
Road, Edinburgh EH9 3JJ, U.K.
h.lam@ed.ac.uk
Received April 2, 2010
ABSTRACT
Annulation of ynamides with arylboronic acids or esters containing an electrophilic functional group at the ortho-position proceeds under the
action of rhodium catalysis to generate 2-amidoindenols or 2-amidoindenes, usually with good regioselectivity.
Ynamides1,2 have recently been demonstrated to be valuable
substrates in carbometalation reactions3 with various orga-
nometallic reagents.4,5 We recently became interested in
rhodium-catalyzed6 ynamide carbometalations with orga-
noboron reagents, and in particular, arylboron compounds 2
containing an electrophilic functional group at the ortho-
position to trap the alkenylrhodium intermediates 3 generated
upon initial carborhodation of the ynamide 1 (Scheme 1).7
The annulation of ortho-functionalized arylboron reagents
has previously been accomplished using alkynes8 and
alkenes,8d,e,9 and these processes10-12 benefit from mild
reaction conditions and broad tolerance of functional groups.
To our knowledge, the annulation of ynamides in analogous
reactions has not been described previously, and we viewed
(1) For general reviews of ynamide chemistry, see: (a) Evano, G.; Coste,
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S. K. Heterocycles 2004, 63, 1455–1475
.
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Y. J. Org. Chem. 2009, 74, 4630–4633. (h) Alayrac, C.; Schollmeyer, D.;
Witulski, B. Chem. Commun. 2009, 1464–1466. (i) Garcia, P.; Moulin, S.;
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36, 32–33. (d) Yasui, H.; Yorimitsu, H.; Oshima, K. Bull. Chem. Soc. Jpn.
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see: (a) Gourdet, B.; Lam, H. W. J. Am. Chem. Soc. 2009, 131, 3802–
3803. (b) Gourdet, B.; Rudkin, M. E.; Watts, C. A.; Lam, H. W. J. Org.
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Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim,
1998; pp 514-522.
(6) For a review of rhodium-catalyzed carbon-carbon bond-forming
reactions of organometallic compounds, see: Fagnou, K.; Lautens, M. Chem.
ReV. 2003, 103, 169–196.
(7) The carbometalation of ynamides 1 with arylboron reagents lacking
an electrophilic functional group at the ortho-position will be the subject
of a separate report from our laboratories.
10.1021/ol100769p  2010 American Chemical Society
Published on Web 05/06/2010

Because of their efficacy in previous rhodium-catalyzed
carbozincations,5 ynamides 1a-1f containing oxazolidin-2-
one or imidazolin-2-one rings were chosen for this study
(Figure 1). Acyclic ynamide 5 was also studied for com-
Scheme 1
.
Proposed Rh-Catalyzed Annulation of Ynamides
with Bifunctional Arylboron Reagents
Figure 1. Ynamides employed in this study.
parison purposes. Regarding the bifunctional arylboron
reagent, commercially available 2-acylphenylboronic acids
6a and 6b were examined first (Figure 2). An initial survey
the formation of 2-amidoindenes 4 in such a process to be
attractive for a number of reasons. First, the indene ring
system is present in biologically active compounds13 and
functional materials.14 Second, it was of fundamental interest
to ascertain whether the directing effect15 of the carbonyl or
sulfonyl group of ynamides as proposed in previous ynamide
carbometalations4,5 would also be operative here, to provide
indenes with high regioselectivities. Third, the enamide
moiety present within the products 4 could potentially serve
as a useful handle for further manipulations.16 In this Letter,
the successful execution of this strategy is reported.
(8) Using rhodium catalysis: (a) Lautens, M.; Marquardt, T. J. Org.
Chem. 2004, 69, 4607–4614. (b) Shintani, R.; Okamoto, K.; Hayashi, T.
Chem. Lett. 2005, 34, 1294–1295. (c) Matsuda, T.; Makano, M.; Murakami,
M. Chem. Lett. 2005, 34, 1416–1417. (d) Miura, T.; Murakami, M. Org.
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(f) Miyamoto, M.; Harada, Y.; Tobisu, M.; Chatani, N. Org. Lett. 2008,
10, 2975–2978. (g) Tobisu, M.; Onoe, M.; Kita, Y.; Chatani, N. J. Am.
Chem. Soc. 2009, 131, 7506–7507. Using palladium catalysis: (h) Yang,
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Tetrahedron: Asymmetry 2008, 19, 1778–1783. (e) Tseng, N.-W.; Lautens,
M. J. Org. Chem. 2009, 74, 1809–1811.
(10) For related reactions involving dienylboronate esters, see: (a) Tseng,
N.-W.; Mancuso, J.; Lautens, M. J. Am. Chem. Soc. 2006, 128, 5338–5339.
(b) Tseng, N.-W.; Lautens, M. J. Org. Chem. 2009, 74, 2521–2526.
(11) For reviews of rhodium-catalyzed domino reactions using orga-
noboron reagents, see: (a) Miura, T.; Murakami, M. Chem. Commun. 2007,
217–224. (b) Youn, S. W. Eur. J. Org. Chem. 2009, 2597–2605.
(12) For related reactions involving o-haloaromatic aldehydes and
ketones, see: (a) Quan, L. G.; Gevorgyan, V.; Yamamoto, Y. J. Am. Chem.
Soc. 1999, 121, 3545–3546. (b) Gevorgyan, V.; Quan, L. G.; Yamamoto,
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Figure 2. Rhodium-catalyzed annulation of ynamides with
2-acylphenylboronic acids. rr ) Regioisomeric ratio as determined
1
by H NMR analysis of the unpurified reaction mixtures. Unless
stated otherwise, cited yields are of isolated major regioisomers.
Notes: (a) Isolated as a 9:1 inseparable mixture of regioisomers.
(b) Products were accompanied by ca. 5-7% of unidentified
inseparable impurities.
(13) For examples, see: (a) Ishiguro, Y.; Okamoto, K.; Ojima, F.;
Sonoda, Y. Chem. Lett. 1993, 22, 1139–1140. (b) Karaguni, I.-M.;
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Chem., Int. Ed. 2004, 43, 450–454.
of reaction conditions revealed that reaction of ynamides 1
with 2-formylphenylboronic acid (6a) in the presence of
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Chem. 2008, 6, 3455–3460. (b) Matsubara, R.; Kobayashi, S. Acc. Chem.
Res. 2008, 41, 292–301. (c) Larock, R. C. ComprehensiVe Organic
Transformations: A Guide to Functional Group Preparations; Wiley-VCH:
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K. C. M.; Shen, L.; Slafer, B. W.; Zhang, Y. In Science of Synthesis,
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Georg Thieme Verlag KG: New York, 1999; Chapter 21.4.
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Cava, M. P. J. Org. Chem. 2000, 65, 6739–6742.
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Org. Lett., Vol. 12, No. 11, 2010
2555

[Rh(cod)Cl]2 (4 mol %) and KOH (0.3 equiv) in 20:1 THF/
H2O was successful to provide a range of 2-amidoindenols
7a-7e with generally high regioselectivities17 and good
yields. Aliphatic or aromatic substituents on the ynamide
were tolerated. 2-Acetylphenylboronic acid (6b) was also a
competent reaction partner under these conditions, providing
tertiary-alcohol-containing 2-amidoindenols 7f-7i with high
regioselectivities. Perhaps unsurprisingly, however, the lower
electrophilicity of the ketone in 6b compared with the
aldehyde in 6a was manifested in decreased reaction rates18
and isolated yields. In addition, small quantities of unidenti-
fied side products were observed in these cases. Consistent
with previous reports of rhodium-catalyzed ynamide carbo-
metalations,5 annulation of acyclic ynamide 5 with 6a
proceeded successfully but with low regioselectivity.19
Next, the reactions of ynamides 1 with 2-alkenylphenyl-
boronic esters 8 were evaluated under similar reaction
conditions, and 2-amidoindenes 9 were formed in generally
good yields (Figure 3). Arylboron reagents containing R,ꢀ-
unsaturated aldehydes (8a), ketones (8b and 8c), or esters
(8d) were effective coupling partners, whereas R,ꢀ-unsatur-
ated nitrile 8e did not lead to any indene, even after
prolonged heating at 50 °C. The lack of reactivity of 8e has
been documented previously.20 With ynamides 1a-1d
containing aliphatic substituents, the regioselectivities were
high (products 9a-9c, 9e, and 9g), but phenyl-substituted
ynamides 1e and 1f resulted in lower selectivities (products
9d, 9fa, and 9h).21 Once again, acyclic ynamide 5 was not
an effective substrate with boronic esters 8, resulting in
inseparable mixtures of indene regioisomers with low se-
lectivities.22 Interestingly, reaction of ynamide 1a with
dienone-substituted phenylboronic ester 7f provided a com-
plex mixture from which 2-amidoindene 10 containing a ꢀ,γ-
unsaturated ketone was isolated in 47% yield (eq 1).
Figure 3. Rhodium-catalyzed annulation of ynamides with 2-alk-
enylphenylboronic esters. rr ) Regioisomeric ratio as determined
1
by H NMR analysis of the unpurified reaction mixtures. Unless
stated otherwise, cited yields are of isolated major regioisomers.
Notes: (a) Product was isolated as an 11:1 inseparable mixture of
regioisomers. (b) Product was isolated as a >10:1 inseparable
mixture of regioisomers. (c) The minor regioisomer 9fb (not shown)
was isolated in 28% yield.
Further reactions of the 2-amidoindene products are
illustrated in eqs 2 and 3. When treated with Et3N, 2-ami-
(17) The regioselectivity of annulation of ynamide 1c with arylboronic
acid 6a was established through X-ray crystallography of a derivative of
the resulting indene 7b. See Supporting Information for details.
(18) Reactions employing 6a were complete within 3 h, whereas
reactions employing 6b required overnight stirring for completion.
(19) This experiment produced a 1.7:1 inseparable mixture of indenols
7ja and 7jb, accompanied by small quantities of unidentified impurities.
See Supporting Information for details.
(20) Catalyst deactivation through coordination of multiple nitrile groups
to rhodium was cited as a possible explanation for the unreactive nature of
8e. See ref 9b.
(21) Single X-ray crystallography of indene 9h allowed confirmation
of the regiochemical outcome.
doindenol 7e underwent a facile formal 1,3-hydrogen rear-
rangement reaction23 to provide indanone 11 as a 4:1
inseparable mixture of diastereomers in 77% yield (eq 2).24
(23) This reaction most likely proceeds via a series of base-induced [1,5]
hydrogen shifts; see: (a) Clark, W. M.; Tickner-Eldridge, A. M.; Huang,
G. K.; Pridgen, L. N.; Olsen, M. A.; Mills, R. J.; Lantos, I.; Baine, N. H.
J. Am. Chem. Soc. 1998, 120, 4550–4551. See also: (b) Hedberg, C.;
Andersson, P. G. AdV. Synth. Catal. 2005, 347, 662–666. (c) Gevorgyan,
V.; Quan, L. G.; Yamamoto, Y. Tetrahedron Lett. 1999, 40, 4089–4092.
(24) Stirring indanone 11 (4:1 dr) in CD2Cl2 with DBU (1.0 equiv)
increased the diastereomeric ratio to 7:1 after 5 h, after which time
decomposition started to occur.
(22) For example, annulation of 5 with 8d provided a 2:1 inseparable
mixture of indenes 9ia and 9ib in 95% yield. See Supporting Information
for details.
2556
Org. Lett., Vol. 12, No. 11, 2010

Hydrogenation of 2-amidoindene 9c produced indane 12 as
a 3:1 inseparable mixture of diastereomers with concomitant
deprotection of the silyl group (eq 3).25
a ketone, or an electron-deficient alkene at the ortho-position
have been developed. The reactions proceed under mild
conditions to provide a range of functionalized 2-amidoin-
denes with generally good levels of regioselectivity. The
development of enantioselective variants of these reactions
will be the subject of future reports.
Acknowledgment. This work was supported by the
European Commission (Project No. MEST-CT-2005-020744),
GlaxoSmithKline, the ESPRC, and the University of Edin-
burgh. We thank Dr. Fraser J. White at the School of
Chemistry, University of Edinburgh for assistance with X-ray
crystallography. We also thank the EPSRC National Mass
Spectrometry Service Centre at the University of Wales,
Swansea, for providing high resolution mass spectra.
Supporting Information Available: Experimental pro-
cedures, full spectroscopic data for all new compounds, and
crystallographic data in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
In summary, rhodium-catalyzed annulation reactions of
ynamides with arylboron compounds containing an aldehyde,
(25) The diastereochemical outcome of this reaction was established
through NOESY 1H NMR spectra. See Supporting Information for
details.
OL100769P
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