Rhodium-catalyzed [2 + 2] cycloaddition of ynamides with nitroalkenes

Article abstract of DOI:10.1021/ol302259v

In the presence of a diene-ligated rhodium complex, ynamides and nitroalkenes undergo catalytic [2 + 2] cycloadditions to provide cyclobutenamides. The presence of sodium tetraphenylborate was found to be crucial for the reactions to proceed efficiently.

Full text of DOI:10.1021/ol302259v

ORGANIC
LETTERS
2
012
Vol. 14, No. 18
934–4937
Rhodium-Catalyzed [2 þ 2] Cycloaddition
4
of Ynamides with Nitroalkenes
†
Donna L. Smith, Suresh Reddy Chidipudi, William R. Goundry, and Hon Wai Lam*
†
‡
,†
EaStCHEM, School of Chemistry, University of Edinburgh, Joseph Black Building,
The King’s Buildings, West Mains Road, Edinburgh, EH9 3JJ, United Kingdom, and
AstraZeneca Process Research and Development, Charter Way, Silk Road Business
Park, Macclesfield, Cheshire, SK10 2NA, United Kingdom
h.lam@ed.ac.uk
Received August 14, 2012
ABSTRACT
In the presence of a diene-ligated rhodium complex, ynamides and nitroalkenes undergo catalytic [2 þ 2] cycloadditions to provide
cyclobutenamides. The presence of sodium tetraphenylborate was found to be crucial for the reactions to proceed efficiently.
The Ficini reaction is the stepwise [2 þ 2] cycloaddition
means that ynamines are often difficult to prepare, handle,
and store due to their sensitivity toward hydrolysis. In
1
of ynamines with cyclic electron-deficient alkenes to form
2ꢀ4
1bꢀd,5,6
cyclobutenamines. Key to the success of these reactions
is the high reactivity of ynamines. However, this reactivity
contrast, ynamides
possess increased stability due
to delocalization of the nitrogen lone pair into the carbo-
nyl/sulfonyl group, thus diminishing electron donation
into the alkyne. Despite their greater stability, ynamides
retain sufficient levels of reactivity to participate in a range
†
University of Edinburgh
‡
AstraZeneca.
1) For selected reviews of ynamine chemistry, see: (a) Ficini, J.
(
Tetrahedron 1976, 32, 1449–1486. (b) Zificsak, C. A.; Mulder, J. A.;
Hsung, R. P.; Rameshkumar, C.; Wei, L. L. Tetrahedron 2001, 57, 7575–
(6) For selected recent examples of ynamides in synthesis, see: (a)
Fadel, A.; Legrand, F.; Evano, G.; Rabasso, N. Adv. Synth. Catal. 2011,
7606. (c) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett 2003,
1379–1390. (d) Katritzky, A. R.; Jiang, R.; Singh, S. K. Heterocycles
2004, 63, 1455–1475.
3
53, 263–267. (b) Mak, X. Y.; Crombie, A. L.; Danheiser, R. L. J. Org.
Chem. 2011, 76, 1852–1873. (c) Kramer, S.; Friis, S. D.; Xin, Z.;
Odabachian, Y.; Skrydstrup, T. Org. Lett. 2011, 13, 1750–1753. (d)
Saito, N.; Saito, K.; Shiro, M.; Sato, Y. Org. Lett. 2011, 13, 2718–2721.
(e) DeKorver, K. A.; Johnson, W. L.; Zhang, Y.; Hsung, R. P.; Dai, H.;
Deng, J.; Lohse, A. G.; Zhang, Y.-S. J. Org. Chem. 2011, 76, 5092–5103.
(f) Lu, Z.; Kong, W.; Yuan, Z.; Zhao, X.; Zhu, G. J. Org. Chem. 2011,
76, 8524–8529. (g) Greenaway, R. L.; Campbell, C. D.; Holton, O. T.;
Russell, C. A.; Anderson, E. A. Chem.;Eur. J. 2011, 17, 14366–14370.
(h) Jouvin, K.; Heimburger, J.; Evano, G. Chem. Sci. 2012, 3, 756–760.
(i) Smith, D. L.; Goundry, W. R. F.; Lam, H. W. Chem. Commun. 2012,
48, 1505–1507. (j) Dateer, R. B.; Shaibu, B. S.; Liu, R.-S. Angew. Chem.,
Int. Ed. 2012, 51, 113–117. (k) Compain, G.; Jouvin, K.; Martin-Mingot,
A.; Evano, G.; Marrot, J.; Thibaudeau, S. Chem. Commun. 2012, 48,
5196–5198. (l) Saito, N.; Ichimaru, T.; Sato, Y. Org. Lett. 2012, 14,
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Song, W.-Z.; Wang, X.-N.; Walton, M. C. Org. Lett. 2012, 14, 3214–
3217. (o) Gati, W.; Rammah, M. M.; Rammah, M. B.; Couty, F.; Evano,
G. J. Am. Chem. Soc. 2012, 134, 9078–9081. (p) Karad, S. N.; Bhunia, S.;
Liu, R.-S. Angew. Chem., Int. Ed. 2012, 51, 8722–8726.
(
2) The seminal reference: Ficini, J.; Krief, A. Tetrahedron Lett. 1969,
431–1434.
3) (a) Ficini, J.; Poulique, J. Tetrahedron Lett. 1972, 1135–1138. (b)
1
(
Ficini, J.; Touzin, A. M. Tetrahedron Lett. 1972, 2093–2096. (c) Ficini,
J.; Touzin, A. M. Bull. Soc. Chim. Fr. 1972, 2385–2387. (d) Ficini, J.;
Touzin, A. M. Tetrahedron Lett. 1972, 2097–2100. (e) Ficini, J.; Touzin,
A. M. Tetrahedron Lett. 1974, 1447–1450. (f) Ficini, J.; Dangelo, J.;
Eman, A.; Touzin, A. M. Tetrahedron Lett. 1976, 683–686. (g) Ficini, J.;
Eman, A.; Touzin, A. M. Tetrahedron Lett. 1976, 679–682. (h) Ficini, J.;
Krief, A.; Guingant, A.; Desmaele, D. Tetrahedron Lett. 1981, 22, 725–
728. (i) Ficini, J.; Desmaele, D.; Touzin, A. M. Tetrahedron Lett. 1983,
24, 1025–1026. (j) Ficini, J.; Guingant, A.; Dangelo, J.; Stork, G.
Tetrahedron Lett. 1983, 24, 907–910.
(
4) For [2 þ 2] cycloadditions of ynamines with vinylidene chromium
carbonyl complexes, see: Fischer, H.; Podschadly, O.; Roth, G.;
Herminghaus, S.; Klewitz, S.; Heck, J.; Houbrechts, S.; Meyer, T.
J. Organomet. Chem. 1997, 541, 321–332.
(
5) For reviews of ynamides, see: (a) DeKorver, K. A.; Li, H.; Lohse,
A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010,
10, 5064–5106. (b) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem., Int.
Ed. 2010, 49, 2840–2859. See also refs 1bꢀ1d.
(7) (a) Riddell, N.; Villeneuve, K.; Tam, W. Org. Lett. 2005, 7, 3681–
3684. (b) Villeneuve, K.; Riddell, N.; Tam, W. Tetrahedron 2006, 62,
3823–3836.
1
1
0.1021/ol302259v r 2012 American Chemical Society
Published on Web 09/06/2012

of [2 þ 2] cycloaddition reactions with strained bicyclic
The closest precedent to this process is the work of the
Reinhoudt group describing the uncatalyzed reactions of
ynamines with nitroalkenes which, in addition to cyclo-
butenamines, gave, in most cases, four-membered cyclic
7
8
9
10
alkenes, ketenes, carbonyl compounds, and imines.
However, it was not until recently that Ficini [2 þ 2] cyclo-
1
1
additions of ynamides with cyclic enones were reported.
Hsung and co-workers described a racemic Cu-catalyzed
1
3
nitrones (representative example in eq 2).
1
1a
variant that also proceeds with certain acyclic enones,
while the Mezzetti group reported an enantioselective Ru-
11bꢀd
catalyzed variant with cyclic unsaturated β-ketoesters.
Although this progess is highly encouraging, expansion of the
substrate scope of ynamide [2 þ 2] cycloadditions to encom-
pass other types of alkene reaction partners would be highly
valuable. Here, we describe the discovery and develop-
ment of Rh-catalyzed [2 þ 2] cycloadditions of ynamides
with nitroalkenes.
The [2 þ 2] cycloaddition of 1a with 2a to give 4a does
These investigations were initiated by a serendipitous
discovery; in an attempt to induce a domino reaction
1
not appeartobea simple Lewis-acid-catalyzedprocess as
1
1
1a
1
2
evidenced by the complete failure of CuCl
/AgSbF ,
2 6
sequence consisting of Rh-catalyzed ynamide arylation
followed by conjugate addition of the resulting alkenylr-
hodium species to an electron-deficient alkene, nitroalkene
InBr , and Sn(OTf) to promote the reaction. Further-
3
2
more, control experiments conducted in the absence of
either [Rh(cod)Cl] or NaBPh established that both com-
ponents are crucial for the reaction to proceed.
2
4
1
and catalytic [Rh(cod)Cl] in 10:1 THF/MeOH at room
a and ynamide 2a were treated with NaBPh (1.1 equiv)
4
2
temperature. Instead ofobtaining the hoped-for product 3,
cyclobutenes 4a and 5a were obtained in 43% and 15%
yield, respectively (eq 1).
a
Table 1. Optimization of Reaction Conditions
(
8) (a) Kohnen, A. L.; Mak, X. Y.; Lam, T. Y.; Dunetz, J. R.;
b
b
Danheiser, R. L. Tetrahedron 2006, 62, 3815–3822. (b) Wang, Y. P.;
Danheiser, R. L. Tetrahedron Lett. 2011, 52, 2111–2114.
(
ketones, followed by electrocyclic ring-opening, see: (a) Hsung,
R. P.; Zificsak, C. A.; Wei, L.-L.; Douglas, C. J.; Xiong, H.; Mulder,
J. A. Org. Lett. 1999, 1, 1237–1240. (b) Kurtz, K. C. M.; Hsung, R. P.;
Zhang, Y. Org. Lett. 2005, 8, 231–234. (c) You, L.; Al-Rashid, Z. F.;
Figueroa, R.; Ghosh, S. K.; Li, G.; Lu, T.; Hsung, R. P. Synlett 2007,
entry [Rh] (5 mol %)
ligand additive conv (%)
4a/5a
1
2
3
4
[Rh(cod)Cl]
[Rh(cod)Cl]
2
2
;
;
Et
Et
Et
66
66
67:33
82:18
84:16
87:13
9) For [2 þ 2] cycloadditions of ynamides with aldehydes or
c
c
c
;
3
3
3
N
N
N
[Rh(C
[Rh(C
2
H
H
4
)
)
2
Cl]
Cl]
2
L1
60
2
4
2
2
rac-L2
>90
a
b
Reactions were conducted using 0.30 mmol of 2a. Determined by
H NMR analysis of the unpurified reaction mixtures. Reaction
conducted in a 20:2:1 THF/MeOH/Et N mixture.
1
656–1662.
1
c
(10) For [2 þ 2] cycloadditions of ynamides with imines, followed by
electrocyclic ring-opening, see: Shindoh, N.; Takemoto, Y.; Takasu, K.
3
Chem.;Eur. J. 2009, 15, 7026–7030.
(11) (a) Li, H. Y.; Hsung, R. P.; DeKorver, K. A.; Wei, Y. G. Org.
Lett. 2010, 12, 3780–3783. (b) Schotes, C.; Mezzetti, A. Angew. Chem.,
Int. Ed. 2011, 50, 3072–3074. (c) Schotes, C.; Althaus, M.; Aardoom, R.;
Mezzetti, A. J. Am. Chem. Soc. 2012, 134, 1331–1343. (d) Schotes, C.;
Bigler, R.; Mezzetti, A. Synthesis 2012, 513–526.
Additional experiments were then performed in an
attempt to increase the efficiency of the reaction presented
in eq 1 (Table 1). First, we found that appreciable quan-
tities of the products 4a and 5a (66% conversion) were still
(
12) Gourdet, B.; Smith, D. L.; Lam, H. W. Tetrahedron 2010, 66,
026–6031.
13) (a) Reinhoudt, D. N.; Kouwenhoven, C. G. Recl. Trav. Chim.
6
obtained when the loading of NaBPh was decreased
4
(
Pays-Bas 1976, 95, 67–73. (b) Dewit, A. D.; Pennings, M. L. M.;
Trompenaars, W. P.; Reinhoudt, D. N.; Harkema, S.; Nevestveit, O.
J. Chem. Soc., Chem. Commun. 1979, 993–995. (c) Pennings, M. L. M.;
Reinhoudt, D. N. J. Org. Chem. 1982, 47, 1816–1823. (d) van Eijk, P. J.
S. S.; Overkempe, C.; Trompenaars, W. P.; Reinhoudt, D. N.; Harkema,
S. Recl. Trav. Chim. Pays-Bas 1988, 107, 40–51. (e) Verboom, W.; Van
Eijk, P. J. S. S.; Conti, P. O. M.; Reinhoudt, D. N. Tetrahedron 1989, 45,
to 10 mol % (entry 1). Second, conducting the reaction
in a 20:2:1 THF/MeOH/Et N mixture improved the ratio
of 4a/5a by base-promoted equilibration toward the
3
(14) Stirring the pure cis-isomer 5a in 20:2:1 THF/MeOH/Et
2 h provided an 81:19 mixture of 4a/5a.
3
N for
3131–3138.
Org. Lett., Vol. 14, No. 18, 2012
4935

1
thermodynamic mixture (entry 2). While an attempt to
4
render the reaction enantioselective by use of R-phellan-
1
5
drene-derived chiral diene L1 in combination with
Rh(C H ) Cl] as the precatalyst afforded only racemic
[
2
4 2
2
products (entry 3), the related racemic chiral diene L2
gave increased conversion (entry 4). Ligand L2 was there-
fore selected for further exploration of the scope of this
process. It should be noted that the use of rhodiumꢀ
diene complexes was optimal; when various rhodiumꢀ
bisphosphine complexes were employed, the conversion
decreased dramatically.
Figure 1. Ynamides employed in this study.
With effective conditions in hand, a range of ynamides
2
aꢀ2j (Figure 1) were evaluated in the reaction with
1
6
nitroalkene 1a (Figure 2). Oxazolidinone-based yna-
mides 2aꢀ2g containing various aryl or aliphatic groups
on the alkyne were found to be effective substrates, result-
ing in cyclobutenamides 4aꢀ4g along with their corre-
sponding diastereomers 5aꢀ5g. With ynamide 2g, a
reaction temperature of 40 °C was required to ensure
reasonable conversion. With aryl-substituted ynamides,
the two diastereomers of the corresponding products could
in many cases be separated by column chromatography.
With aliphatic-substituted ynamides, however, the pro-
ducts were isolated as inseparable diastereomeric mixtures.
The overall yields of these reactions were mostly good,
except when ynamide 2d containing a 3-nitrophenyl group
was employed (products 4d and 5d isolated in 48% com-
bined yield). Imidazolinone- and pyrrolidinone-based yna-
mides 2hꢀ2j were also competent reaction partners when
the reaction was conducted at 40 °C, though ynamide 2j
provided a mixture of 4j and 5j in only 41% yield.
Figure 2. Rh-catalyzed [2 þ 2] cycloaddition of ynamides with
nitroalkene 1a. Reactions were conducted using 0.30 mmol of 2.
Yields are of isolated material. Diastereomeric ratios were deter-
1
mined by H NMR spectroscopy of the unpurified reaction
mixtures. Inseparable mixture of diastereomers. Ratio of 4d/
a
b
c
5
d in isolated product was 83:17. Reaction conducted at 40 °C.
d
e
Reaction time of 6 h. Ratio of 4j/5j in isolated product was 90:10.
The relative stereochemistry of the products was estab-
lished by X-ray crystallographic analysis of 4b, which
confirmed the trans-relationship of the nitro and phenyl
groups in the major isomers (Figure 3).
Figure 4 presents a brief investigation of the scope of the
nitroalkene in reactions with ynamide 2a. A range of aryl
substituentson the nitroalkene weretolerated inthesereac-
tions, including 1-naphthyl (products9a/10a), 4-fluorophe-
nyl (products 9b/10b), 4-bromophenyl (products 9c/10c),and
(
15) Okamoto, K.; Hayashi, T.; Rawal, V. H. Chem. Commun. 2009,
815–4817.
16) The following ynamides, in which the nitrogen atom is not part
Figure 3. X-ray structure of product 4b.
4
(
of a cyclic system, were poor substrates in these reactions, generally
providing very low conversions.
4-nitrophenyl (products 9d/10d). Aliphatic nitroalkenes
were unreactive in these cycloadditions.
A tentative catalytic cycle for these reactions, using
nitroalkene 1a for illustrative purposes, is depicted in
Scheme 1. We assume that an as-yet-unidentified Rh(I)
4
936
Org. Lett., Vol. 14, No. 18, 2012

Scheme 1. Tentative Catalytic Cycle for These Reactions
(eq 3), but whether this is the active catalytic species itself,
or whether it is converted into the active catalyst by some
1
9
other means in the reaction, is unclear at present.
In conclusion, we have reported the first metal-
catalyzed [2 þ 2] cycloadditions of ynamides with
nitroalkenes. The reactions are promoted by sub-
stoichiometric quantities of a racemic chiral dieneꢀ
Figure 4. Rh-catalyzed [2 þ 2] cycloaddition of ynamide 2a with
nitroalkenes 1bꢀ1e. Reactions were conducted using 0.30 mmol
of 2. Yields are of isolated material. Diastereomeric ratios were
1
determined by H NMR spectroscopy of the unpurified reaction
rhodium complex in conjunction with NaBPh , result-
a
b
4
mixtures. Reaction was conducted at 40 °C for 6 h. Ratio of
d/10d in isolated product was 81:19.
ing in a range of cyclobutenamide products. Further
work is aimed at elucidation of the mechanism of these
reactions, which may guide the development of related
rhodium-catalyzed cycloadditions.
9
complex 11 formed in the reaction mixture can coordinate
to the ynamide 2 and nitroalkene 1a to form 12, which then
undergoes oxidative cyclization to form a rhodacycle. This
rhodacycle can interconvert between the trans isomer 13
Acknowledgment. This work was supported by the
EPRSC, AstraZeneca, and the European Commission
(Marie Curie International Incoming Fellowship to S.R.C.,
Project No. PIIF-GA-2009-252561). We thank Dr. Gary S.
Nichol (University of Edinburgh) for X-ray crystallography
and the EPSRC National Mass Spectrometry Service Centre
at Swansea University for providing high-resolution mass
spectra.
1
7
and the cis isomer 15 via 14. Reductive elimination of this
rhodacycle thenreleases the product 4/5 while regenerating
1
and the important role of NaBPh in these reactions are not
1. However, the nature of the active catalytic species 11
4
18
clear at the current time. On the basis of literature precedent,
it appears likely that [Rh(C H ) Cl] , rac-L2, and NaBPh
4
2
4 2
2
6
would react initially to form Rh(L2)(η -C H )BPh (16)
6
5
3
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data for all new compounds,
and crystallographic data in cif format. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(
17) For an example of a similar oxidative cyclization involving an
alkyne, an alkene, and Ni(0), see: Hratchian, H. P.; Chowdhury, S. K.;
Gutierrez-Garcia, V. M.; Amarasinghe, K. K. D.; Heeg, M. J.; Schlegel,
H. B.; Montgomery, J. Organometallics 2004, 23, 4636–4646.
(18) (a) Nolte, M. J.; Gafner, G.; Haines, L. M. J. Chem. Soc. D 1969,
1406–1407. (b) Schrock, R. R.; Osborn, J. A. Inorg. Chem. 1970, 9, 2339–
2343. (c) Oro, L. A.; Pinilla, E.; Tenajas, M. L. J. Organomet. Chem.
1978, 148, 81–84. (d) Garralda, M. A.; Ibarlucea, L. Polyhedron 1982, 1,
339–341. (e) Shintani, R.; Tsutsumi, Y.; Nagaosa, M.; Nishimura, T.;
(19) ArepeatofthereactioninTable1, entry4ona0.10mmolscaleusing
BPh (10 mol %) in place of NaBPh , provided 4a/5a in 36% conversion.
3
4
Hayashi, T. J. Am. Chem. Soc. 2009, 131, 13588–13589.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 18, 2012
4937