Atom-efficient synthesis of α-alkylidene-N-furylimines via catalytic vinylcarbene-transfer reactions to carbonyl-ene-nitrile compounds

Article abstract of DOI:10.1039/b924752a

The reaction of carbonyl-ene-nitrile compounds with propargyl carboxylates in the presence of a catalytic amount of PtCl₂ afforded the α-alkylidene-N-furylimines with high stereoselectivities.

Full text of DOI:10.1039/b924752a

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Atom-efficient synthesis of a-alkylidene-N-furylimines via catalytic
vinylcarbene-transfer reactions to carbonyl-ene-nitrile compoundsw
Masahito Murai, Shotaro Yoshida, Koji Miki and Kouichi Ohe*
Received (in Cambridge, UK) 24th November 2009, Accepted 25th February 2010
First published as an Advance Article on the web 23rd March 2010
DOI: 10.1039/b924752a
The reaction of carbonyl-ene-nitrile compounds with propargyl
carboxylates in the presence of catalytic amount of
When the reaction of 1-phenyl-2-propynyl acetate 1a as a
carbene precursor with carbonyl-ene-nitrile compound 2a
was carried out in the presence of a catalytic amount
of [RuCl2(CO)3]2 (5 mol%) in ClCH2CH2Cl at 70 1C,
a-alkylidene-N-furylimine 3a was obtained in 16% yield as a
single stereoisomer (eqn (3)).
a
PtCl2 afforded the a-alkylidene-N-furylimines with high stereo-
selectivities.
Catalytic carbene-transfer reactions have been well investigated,
aimed at developing facile and efficient access to structurally
complex molecules.1 Among them, addition reactions of
rhodium–carbene complexes generated from a-diazocarbonyl
compounds to nitriles provides a straightforward method
for the synthesis of 1,3-oxazoles.2 Recently, this method
has been expanded to the rhodium-catalyzed synthesis of
imidazopyridines3 and imidazoles.4 However, to the best of
our knowledge, the reported examples have been limited to the
reactions between nitriles and carbene species having nucleo-
philic carbonyl or imino groups a to the carbenoid carbons
(eqn (1)).5 These facts prompted us to investigate the reactions
of nitriles which possess nucleophilic moieties in close
proximity to the carbon–nitrogen triple bonds (eqn (2)).
ð3Þ
This unusual reaction of a nitrile encouraged us to optimize
the reaction conditions. First, reactions of 1a and 2a in the
presence of several transition metal catalysts were examined.
The results are summarized in Table 1. Among the catalysts
screened, we found that PtCl2 was superior to [RuCl2(CO)3]2,
giving 3a in 27% yield (entry 1). Although other platinum
catalysts, such as PtCl2(PPh3)2 and PtCl4, exhibited marginal
catalytic activity (entries 4 and 5), [Rh(OAc)2]2, GaCl3, AuCl3,
AuCl(PPh3), [RuCl2(p-cymene)]2, and PdCl2(CH3CN)2 were
almost ineffective for the present reaction, 2a being recovered
intact (entries 6–8). This reaction was strongly influenced by
the solvent used. Among the solvents examined, toluene was
superior to ClCH2CH2Cl and THF, and 3a was obtained in
52% yield (entry 3). In all cases, 2a was not completely
converted to the product even with extended reaction time.10
Next, we examined the substrate scope of the reaction using
a variety of 1-aryl-2-propynyl carboxylates 1 as carbene
precursors in the presence of PtCl2 (Table 2). Reactions of
propargyl pivalate 1b and benzoate 1c with 2a (entries 1 and 2)
gave a-alkylidene-N-furylimines 3b and 3c, respectively, with
slightly lower yields in comparison with propargyl acetate 1a.
The reaction was sensitive to the electronic features of the aryl
group of 1. Propargyl acetates 1d, 1e, and 1f, which possess
electron-withdrawing groups, reacted with 2a to give the
corresponding a-alkylidene-N-furylimines 3d, 3e, and 3f,
respectively, in good yields (entries 3–5). On the other hand,
propargyl acetates 1g and 1h having electron-donating groups
at the para-position of the aryl group produced a-alkylidene-
N-furylimines in lower yields (entries 6 and 7). These results
ð1Þ
ð2Þ
Recently, the reaction between propargyl carboxylates and
transition metals has received considerable attention as a
diazoalkane-free atom-efficient generation method of vinyl-
carbene complexes.6 We developed a wide range of catalytic
vinylcarbene-transfer reactions using propargyl carboxylates.7
Thus, we set out our investigation using propargyl carboxylates
as carbene precursors and nitriles as carbene acceptors to seek
for new reactions as depicted in eqn (2). Herein, we wish to
report atom-efficient synthesis of a-alkylidene-N-furylimines
via catalytic vinylcarbene-transfer reactions to carbonyl-ene-
nitrile compounds 2 (Scheme 1).8,9
Department of Energy and Hydrocarbon Chemistry, Graduate School
of Engineering, Kyoto University, Kyoto 615-8510, Japan.
E-mail: ohe@scl. kyoto-u.ac.jp; Fax: (+81) 75-383-2499;
Tel: (+81) 75-383-2495
w Electronic supplementary information (ESI) available: Experimental
details and analytical data are provided. CCDC 755818. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/b924752a
Scheme
1
Transition metal-catalyzed reactions of propargyl
carboxylates 1 with carbonyl-ene-nitrile compounds 2.
ꢀc
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Table 1 Optimization of reaction conditionsa
2b with propargyl acetate 1a gave the corresponding
a-alkylidene-N-furylimine 3j in 48% yield. Interestingly, a
cyano group and an ester group as an R1 in 2c and 2d can
be tolerated under these reaction conditions, the corresponding
a-alkylidene-N-furyl-imines 3k and 3l being obtained in good
yields. Moreover, cyclohexene-fused carbonyl-ene-nitrile
compounds 2e and 2f reacted with 1a to give 3m and 3n in
66% and 72% yields, respectively.
Entry
[M]
Solvent
Conv. of 2a
Yieldb
1
2
3
4
5
6c
7
8
PtCl2
PtCl2
PtCl2
PtCl2(PPh3)2
PtCl4
[Rh(OAc)2]2
GaCl3
AuCl3
ClCH2CH2Cl
THF
Toluene
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
32%
8%
66%
3%
28%
0%
0%
27%
3%
52%
1%
21%
0%
0%
The most plausible mechanism for the present reaction is
illustrated in Scheme 2. First, platinum-vinylcarbene complex
A is formed via the 1,2-migration of the acetate to an internal
carbon atom of the alkyne.7 Platinum-vinylcarbene complex A
then reacts with 2 through two possible pathways (path A or
B). In path A, nucleophilic attack of a cyano moiety of 2 on
the carbenoid carbon would afford metal-containing nitrile
ylide intermediate B, which then converts to a-alkylidene-
N-furylimine via intramolecular cyclization followed by
regeneration of the catalyst. In path B, [2+2] cycloaddition
between A and 2 followed by ring cleavage generates
iminocarbene complex D,12 which undergoes insertion of a
carbonyl group to give the a-alkylidene-N-furylimine 3 along
with regeneration of the catalyst.
0%
0%
a
Reaction conditions: 1a (0.90 mmol), 2a (0.30 mmol), [M]
c
b
(0.030 mmol) in solvent (1.2 mL). Isolated yields. [Rh(OAc)2]2
(5 mol%).
Table 2 Pt-catalyzed reactions of carbonyl-ene-nitrile compound 2a
with 1-aryl-2-propynyl carboxylates 1a
Because a-alkylidene-N-furylimines were obtained from the
one-pot reaction, we next demonstrated the synthetic application
of them to N-furyl substituted nitrogen-containing heterocycles.
Entry
R1
R2
R3
Product
Yieldb
Table 3 Pt-catalyzed reactions of carbonyl-ene-nitrile compounds 2
with 1-phenyl-2-propynyl acetate 1aa
1
2
3
4
5
6
7
Ph
Ph
H
H
H
H
H
H
H
Piv
Bz
1b
1c
1d
1e
1f
3b
3c
3d
3e
3f
47%
57%
64%
66%
74%
38%
24%
4-BrC6H4
4-CF3C6H4
C6F5
4-CH3C6H4
4-Anisyl
Ac
Ac
Ac
Ac
Ac
1g
1h
3g
3h
Entry
R1
R2
R3
Product
Yield
8
Ac
1i
3i
80%
1
2
3
4
5
4-Tol
CN
CO2Et
–(CH2)4–
–(CH2)4–
H
H
H
Ph
Ph
Ph
Ph
2b
2c
2d
2e
2f
3j
3k
3l
3m
3n
48%
68%
58%
66%
72%
a
Reaction conditions:
(0.030 mmol) in solvent (1.2 mL). Isolated yields.
1 (0.90 mmol), 2a (0.30 mmol), PtCl2
b
4-CF3C6H4
a
Reaction conditions: 1a (0.90 mmol),
b
2
(0.030 mmol) in solvent (1.2 mL). Isolated yields.
(0.30 mmol), PtCl2
can be explained by assuming the resonance structures of
vinylcarbene complex intermediates (Fig. 1).7 The substrate
scope could be expanded to tert-propargyl acetates. The
reaction of 1i7e with 2a gave a-fluoren-9-ylidene-N-furylimine
3i in 80% yield (entry 8). The formation of Z- and anti-
stereoregulated products reflects the intervention of Z-vinyl-
carbene complexes (Fig. 1).
The structure of the product was confirmed by X-ray
crystallographic analysis.11 An ORTEP drawing of 3f
unambiguously shows the anti configuration of the imine
and Z-geometry of the alkenyl moiety (Fig. S1 in ESIw).
N-Furylimines were produced by reactions with various
carbonyl-ene-nitrile compounds 2 (Table 3). The reaction of
Fig. 1 Proposed structures of Pt-vinylcarbenoids.
Scheme 2 Plausible reaction mechanism.
ꢀc
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1979, 44, 1717; (b) A. S. Kende, P. Hebeisen, P. J. Sanfilippo and
B. H. Toder, J. Am. Chem. Soc., 1982, 104, 4244; (c) N. J. Turro,
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M. Tomas, N. J. Turro, Y. Cha and I. R. Gould, J. Am. Chem.
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6 For recent reviews, see: (a) B. Crone and S. F. Kirsch, Angew.
Chem. Int. Ed., 2008, 14, 3514; (b) Z. Li, C. Brouwer and C. He,
Chem. Rev., 2008, 108, 3239; (c) K. Ohe and K. Miki, J. Synth.
Org. Chem, Jpn., 2009, 67, 1161.
7 (a) K. Miki, K. Ohe and S. Uemura, Tetrahedron Lett., 2003, 44,
2019; (b) K. Miki, K. Ohe and S. Uemura, J. Org. Chem., 2003, 68,
8505; (c) K. Miki, M. Fujita, S. Uemura and K. Ohe, Org. Lett.,
2006, 8, 1741; (d) K. Ohe, M. Fujita, H. Matsumoto, Y. Tai and
K. Miki, J. Am. Chem. Soc., 2006, 128, 9270; (e) K. Miki,
Y. Senda, T. Kowada and K. Ohe, Synlett, 2009, 1937.
8 (Z)-Carbonyl-ene-nitrile compounds 2 are ring-opened isomers of
(2-furyl)nitrenes. Ring-opening of its analogous, (2-pyrazolyl)-
nitrenes and (1,2,3-triazolyl)nitrenes to acyclic conjugated nitriles
have been investigated. See: (a) P. A. S. Smith, W. Resemann and
L. O. Krbechek, J. Am. Chem. Soc., 1964, 86, 2025; (b) P. A.
S. Smith and H. Founchis, J. Org. Chem., 1973, 38, 2958;
Scheme 3 Synthetic application.
When the reduction of 3a with LiAlH4 was performed,
N-(2-furyl)-a-amino ketone 4 was obtained in 88% yield.13
The subsequent annulation with ethyl acetoacetate afforded
N-(2-furyl)pyrrole 5 in 74% yield (Scheme 3).14
In conclusion, we have demonstrated catalytic carbene
transfer reactions to carbonyl-ene-nitrile compounds on the
basis of the in situ generation of vinylcarbene complexes from
propargyl carboxylates leading to a-alkylidene-N-furylimine
derivatives. The reaction proceeds in a complete atom-
economical fashion and provides straightforward access to
a-alkylidene-N-furylimines, which can be employed as
building blocks for the synthesis of nitrogen-containing
heterocycles. a-Alkylidene-N-furylimines can be considered
as coupling products of vinylcarbenes and 2-furylnitrenes.8,15
Further investigations of the scope and reaction mechanisms,
as well as synthetic applications, are currently in progress in
our laboratory.
(c) D. Suarez and T. L. Sordo, J. Am. Chem. Soc., 1997, 119,
´
10291; (d) N. Svenstrup, K. B. Simonsen, N. Thorup, J. Brodersen,
W. Dehaen and J. Becher, J. Org. Chem., 1999, 64, 2814.
9 For synthetic applications to N-heterocycles, see: (a) M. Murai,
S. Kawai, K. Miki and K. Ohe, J. Organomet. Chem., 2007, 692,
579; (b) M. Murai, K. Miki and K. Ohe, J. Org. Chem., 2008, 73,
9174.
10 No reaction of substrate 2a occurred in the absence of 1a, and 2a
being recovered intact.
This work is financially supported by a Grant-in-Aid for
Scientific Research on Priority Areas ‘‘Synergistic Effects for
Creation of Functional Molecules’’ (Area 459, No. 20036031)
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan. M. M. thanks the JSPS Research
Fellowships for Young Scientists. We would like to thank
Dr Tetsuaki Fujihara for his help with the X-ray crystallo-
graphic analysis.
11 See supplementary information for the detail of X-ray crystal
analysis data. CCDC 755818 contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_ request/cif.
12 For stoichiometric reactions of group 6 Fischer carbene complexes
with nitriles leading to iminocarbene complexes, see: (a) H. Fischer
and S. Zeuner, J. Organomet. Chem., 1987, 327, 63; (b) D. C. Yang,
V. Dragisich, W. D. Wulff and J. C. Huffman, J. Am. Chem. Soc.,
1988, 110, 307. The azametallacyclobutene intermediates like C
were reported by Gevorgyan et al. See ref. 3 and 4.
Notes and references
13 Reduction of vinylcarboxylates into corresponding ketones with
LiAlH4 has been reported. See: P. Mauleon, J. L. Krinsky and
F. D. Toste, J. Am. Chem. Soc., 2009, 131, 4513.
1 (a) F. Z. Dorwald, in Metal Carbenes in Organic Synthesis,
¨
Wiley-VCH, Weinheim, 1999; (b) H. M. L. Davies and R. E.
¨
J. Beckwith, Chem. Rev., 2003, 103, 2861; (c) K. H. Dotz, Metal
14 N-(2-furyl)pyrroles are of biological interest as inhibitor of
xanthine oxidase, antagonist on thromboxane A2, and prostaglandin
D2 receptors. See: (a) T. Honma, Y. Hiramatsu and A. Arimura,
PCT Int. Appl, WO 2000053573, 2000 [Chem. Abstr. 2000, 133,
222579]; (b) T. Yagami, T. Honma and G. Katsuura, PCT Int.
Appl, WO2000030683, 2000 [Chem. Abstr. 2000, 133, 12765];
(c) N. Tanimoto and A. Arimura, PCT Int. Appl, WO
2001094309, 2001 [Chem. Abstr. 2001, 136, 37614];
(d) K. Shimizu, Y. Takigawa, H. Fujikura, M. IIzuka,
M. Hiratochi and N. Kikuchi, PCT Int. Appl, WO 2008126899,
2008 [Chem. Abstr. 2008, 149, 493522].
Carbenes in Organic Synthesis, Springer-Verlag, Berlin, 2004;
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2 For recent reviews, see: (a) A. Padwa and S. F. Hornbuckle, Chem.
Rev., 1991, 91, 263; (b) C. Escolano, M. D. Duque and A Va
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3 S. Chuprakov, F. W. Hwang and V. Gevorgyan, Angew. Chem.,
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4 T. Horneff, S. Chuprakov, N. Chernyak, V. Gevorgyan and
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5 Non-catalytic 1,3-dipolar cycloadditions of nitrile ylides, which are
formed by reactions of nitriles with carbenes generated from
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special interest. See: (a) W. A. Sheppard, G. W. Gokel,
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15 Recently, cross-coupling of vinylcarbenes generated from propargyl
carboxylates with diazoalkane has been reported. See: C. Vovard-Le
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Bray, S. Derien and P. H. Dixneuf, Angew. Chem., Int. Ed., 2009, 48,
1439.
ꢀc
This journal is The Royal Society of Chemistry 2010
3368 | Chem. Commun., 2010, 46, 3366–3368