Discrimination of diazo compounds toward carbenoids: Copper(I)catalyzed synthesis of substituted cyclobutenes

Full text of DOI:10.1002/anie.200903902

Angewandte
Chemie
DOI: 10.1002/anie.200903902
Copper Catalysis
Discrimination of Diazo Compounds Toward Carbenoids: Copper(I)-
Catalyzed Synthesis of Substituted Cyclobutenes**
Josꢀ Barluenga,* Lorena Riesgo, Luis A. Lꢁpez, Eduardo Rubio, and Miguel Tomꢂs
In the last few years the role of diazo compounds in organic
synthesis, particularly in cyclization reactions via metal
carbenoids (metal: ruthenium, copper, rhodium, etc.) has
been prominent.[1] By taking advantage of the ease with which
these metal carbenes collapse into the corresponding sym-
metrical alkenes (homocoupling), we and others have been
able to access nonsymmetrical alkenes by the selective
heterocoupling of diazoacetate esters with copper(I)[2] and
ruthenium(II)[3] carbene complexes [Eq. (1)]. Interestingly,
the metal-catalyzed selective cross-coupling reaction between
two different diazo substrates has been reported recently
[Eq. (2)].[4]
This initial result seems to encompass, among others, two
relevant features: 1) it represents a novel [3+1] coupling
À
between diazo compounds, wherein two C C bonds rather
=
than one C C bond are formed, and 2) it might provide direct
access to a relevant, uncommon structure. Therefore, herein
we report our preliminary studies on the synthesis of cyclo-
butene structures by copper(I)-catalyzed cyclization of vinyl-
diazoacetate esters and diazo compounds (Table 1).
Table 1: Copper(I)-catalyzed synthesis of cyclobutene derivatives 3 and 4
from vinyldiazoacetates 1 and diazo compounds 2.
Entry R1
1
R2
R3
2
3 (yield [%])/4 (yield [%])[a]
At this point, we became intrigued as to whether
discrimination between appropriately selected diazo com-
pounds, for instance simple diazo and vinyldiazo systems,
could be attained. Firstly, we found that [Cu(MeCN)4]BF4
catalyzes the reaction between ethyl vinyldiazoacetate and
ethyl diazoacetate at room temperature. Surprisingly, the
expected cross-coupling conjugated diene was not formed,
but diethyl 2-methylcyclobutene-1,3-dicarboxylate was
obtained in moderate yield as the sole heterocoupling product
[Eq. (3)].
1
2
3
4
5
Me 1a CO2Et
Me 1a CO2tBu
Me 1a CO2Et
Me 1a CO2tBu Ph
Me 1a COMe
H
H
Ph
2a 3aa (33)
2b 3ab (45)
2c 3ac (56)
2d 3ad (79)
2e 3ae (66)
Ph
6
7
8
9
H
H
H
1b CO2Et
1b CO2tBu Ph
1b COMe
Ph
2c 3bc (44)/4bc (11)
2d 3bd (46)/4bd (15)
2e 3be (51)/4be (13)
2 f 3af + 4af (52)[b]
Ph
H
Me 1a Ph
10
11
12
Me 1a CO2Et
PMP[c] 2g 4ag (63)
PMP[c] 2g 4bg (66)
H
1b CO2Et
[*] Prof. J. Barluenga, L. Riesgo, Dr. L. A. Lꢀpez, Dr. E. Rubio,
Prof. M. Tomꢁs
Me 1a Ph
Ph
2h 4ah (57)
[a] Yield of isolated products after column chromatography. [b] Isolated
as a nonseparable 60:40 mixture of regioisomers. [c] PMP=4-MeOC6H4.
Instituto Universitario de Quꢂmica Organometꢁlica “Enrique
Moles”, Unidad Asociada al CSIC, Universidad de Oviedo
Juliꢁn Claverꢂa 8, 33071 Oviedo (Spain)
Fax: (+34)985-103-450
First, [Cu(MeCN)4]BF4 (5 mol%) was added to a solution
of ethyl 2-diazo-3-methylbut-3-enoate 1a (R1 = Me) and ethyl
diazoacetate 2a (R2 = CO2Et, R3 = H) in CH2Cl2 at room
temperature. After stirring the reaction mixture for two hours
the solvent was removed and the resulting mixture was
subjected to column chromatography, affording the cyclo-
butene 3aa in 33% yield along with ethyl maleate and ethyl
fumarate (entry 1). The yield could be increased to 45% using
tert-butyl diazoacetate 2b (entry 2). The cyclization of 1a with
E-mail: barluenga@uniovi.es
[**] We are grateful to the Ministerio de Educaciꢀn of Spain (Grant CTQ-
2007-61048) and the Principado de Asturias (Grant IB 08-088). L.R.
thanks the Ministerio de Educaciꢀn and the European Union
(Fondo Social Europeo) for a predoctoral fellowship. We are also
grateful to Dr. I. Merino (Servicios Cientꢂfico Tꢃcnicos, Universidad
de Oviedo) for her assistance in the collection of the 2D NMR data.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903902.
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phenyl-substituted diazoacetates 2c,d and diazoketone 2e
(R3 = Ph) produced the expected cycloadducts 3ac–ae in
higher yields (56–79%) (entries 3–5). On the contrary,
mixtures of regioisomers were in general obtained in the
case of unsubstituted vinyldiazo substrate 1b (R1 = H)
(entries 6–8). Therefore, the copper(I)-catalyzed reaction of
1b and 2c–e afforded a mixture of separable isomers 3bc–
3be/4bc–be (ratio 3/4 = 3.0–4.0) in moderate combined yields
(55–64%). In the same way, phenyldiazomethane 2 f (R2 =
Ph; R3 = H) and ethyl propenyldiazoacetate 1a provided a
nonseparable 3:2 mixture of 3af/4af in 52% yield (entry 9).
Interestingly, complete reversal of the regioselectivity was
encountered in the case of PMP-substituted diazo compounds
2 (PMP = 4-methoxyphenyl; entries 10 and 11). Thus, ethyl
2-diazo-2-(4-methoxyphenyl)acetate 2g yielded exclusively
the cycloadducts 4ag and 4bg (63–66% yield) upon reaction
with both vinyldiazo esters 1a and 1b, respectively. Following
the same regioselectivity pattern, diphenyldiazomethane 2h
reacted with vinyldiazo ester 1a giving rise, selectively, to 4ah
(entry 12).
Scheme 1. Proposed mechanism for the copper(I)-catalyzed synthesis
of cyclobutene derivatives 3 and 4 from vinyldiazoacetates 1 and diazo
compounds 2.
From Table 1 various points worth attention: 1) the yields
are moderate to acceptable and can be notably increased in
going from ethyl to tert-butyl diazoacetate esters; 2) the
regioselectivity is dictated by the presence of either an
electron-rich aryl group (R3 = PMP) or two phenyl groups
(R2 = R3 = Ph) in component 2 in favor of regioisomer 4
(entries 10–12); 3) the presence of a methyl group (R1 = Me)
in component 1 strongly favors regioisomer 3 (entries 1–5).
When the silyloxy-substituted vinyl diazoacetate 1c (R1 =
OSiMe2tBu) was employed, the cyclobutene derivative 3ce
could not be isolated, but the 4H-pyran-4-one derivative 5
was obtained in 61% yield after chromatographic purification
[Eq. (4)]. The formation of 5 from 3ce would involve
torquoselective 4p-electron ring-opening and subsequent
6p-electron ring-closing, chromatographic hydrolysis, and
air-oxidation.[5]
stabilizing the partial positive charge developed on C2 (PMP
or two Ph groups). In the absence of such charge-stabilizing
effect it seems that the less sterically hindered cyclobutene 3
À
(C1 C3 cleavage) is preferentially formed. This mechanistic
proposal is in good agreement with a recent communication
on the rearrangement of cyclopropyl metal carbenes to
cyclobutenes reported by Tang and co-workers.[8a]
At this point we thought to additionally exploit the
multifaceted nature of the copper catalyst by designing a
longer cascade sequence. We recently reported the copper(I)-
catalyzed cycloisomerization/furan formation sequence of
bis(propargylic) esters 6, which was assumed to involve a furyl
carbene of copper(I).[9] Accordingly, we subjected an equi-
molecular mixture of vinyldiazoacetate esters 1a,b
and propargylic esters
6 in CH2Cl2 to the action of
[Cu(MeCN)4]BF4 (5 mol%). After stirring the reaction
mixture at room temperature for four hours, removal of the
solvent, and chromatographic purification, the furyl-substi-
tuted cyclobutenes 7 were isolated as the sole isomer in 48–
73% yield. With regard to the substrate 6, different sub-
stitution patterns proved to work satisfactorily (R2 = alkyl,
cycloalkyl, phenyl; R3 = alkyl, vinyl).
Compounds 7 (Scheme 2) are proposed to result from a
cascade process wherein all steps involve a copper(I) species
(Scheme 3). The initial isomerization of the propargylic
substrate 6 to the (E)-Knoevenagel intermediate IV then
undergoes a 5-exo-dig cyclization to generate the putative
2-furyl copper(I) carbene species V, as already reported.[9]
Now, the carbenoid nature of V is strongly supported as it
cyclopropanates substrate 1 leading to the cyclopropyldiazo
intermediate VI, which in turn undergoes the metal-catalyzed
ring expansion to the final cyclobutene 7. As in the case of the
PMP-substituted diazo substrates 2 (Table 1 and Scheme 1),
the furyl substituent in VI perfectly controls the regioselec-
tivity affording a single cyclobutene.
A tentative reaction pathway based on the manifold
participation of the copper catalyst is depicted in Scheme 1.
The preferential formation of copper carbenoid I from diazo
substrate 2[6] would be then undergo cyclopropanation of the
[7]
=
activated C C functionality of 1. The newly formed cyclo-
propyldiazoacetate ester II would then lead to the cyclo-
butene structures 3,4 by copper-catalyzed decomposition to
copper–cyclopropylcarbene III and rearrangement by cleav-
1
2
3
À
À
age of the bond between either C1 C2 (CR CR R ) or
1
[8]
À
À
C1 C3 (CR CH2). Apparently, both electronic and steric
effects control the regiochemistry of the latter rearrangement.
In conclusion, we have demonstrated that copper(I) is
able to discriminate between simple and vinyldiazo systems
À
Thus, the formation of regioisomer 4 (C1 C2 cleavage) would
=
be a consequence of the presence of group(s) capable of
towards carbenoid formation. The presumed C C bond
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Experimental Section
Typical procedure for the copper(I)-catalyzed synthesis of cyclo-
butene derivatives 3 and 4: [Cu(MeCN)4]BF4 (5 mol%) was added to
a solution of vinyldiazoacetate esters 1 (0.5 mmol) and diazomethane
derivatives 2 or bis(propargylic) esters 6 (0.5 mmol) in CH2Cl2
(5 mL). The reaction mixture was stirred at room temperature until
disappearance of the starting diazo compounds (checked by TLC;
2–4 h). The solvent was removed under reduced pressure and the
residue was purified by flash chromatography (SiO2, 10:1 hexanes/
ethyl acetate) to give the corresponding cyclobutene derivatives 3 or
4.
Full experimental details and characterization data are given in
the Supporting Information.
Received: July 16, 2009
Published online: September 8, 2009
Keywords: carbenes · copper · cyclobutenes · diazo compounds ·
.
homogeneous catalysis
[1] a) M. P. Doyle, M. A. McKevery, Y. Ye, Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds, Wiley,
New York, 1998; Selected reviews; b) H. Lebel, J.-F. Marcoux, C.
Molinaro, A. B. Charette, Chem. Rev. 2003, 103, 977; c) H. M. L.
Davies, J. R. Manning, Nature 2008, 451, 417.
[2] J. Barluenga, L. A. Lꢀpez, O. Lꢁber, M. Tomꢂs, S. Garcꢃa-
Granda, C. ꢄlvarez-Rffla, J. Borge, Angew. Chem. 2001, 113,
3495; Angew. Chem. Int. Ed. 2001, 40, 3392.
Scheme 2. Copper(I)-catalyzed synthesis of furyl-substituted cyclobu-
tenes 7 from vinyldiazoacetates 1 and propargylic esters 6. The
reported yields are those of the products isolated after column
chromatography.
[3] C. Vovard-Le Bray, S. DØrien, P. Dixneuf, Angew. Chem. 2009,
121, 1467; Angew. Chem. Int. Ed. 2009, 48, 1439.
[4] For examples of metal-catalyzed heterocoupling of diazocom-
pounds, see: a) A. D. Zotto, W. Baratta, G. Verardo, P. Rigo, Eur.
J. Org. Chem. 2000, 2795; b) D. M. Hodgson, D. Angrish, J. Mol.
Catal. A 2006, 254, 93; c) D. M. Hodgson, D. Angrish, Chem.
Eur. J. 2007, 13, 3470.
[5] The preference for the inward rotation for electron-accepting
groups at the 3-position in the ring-opening of cyclobutenes is
well documented. For example, see: N. G. Rondan, K. N. Houk,
J. Am. Chem. Soc. 1985, 107, 2099.
[6] Actually we experienced that the copper(I)-catalyzed dimeriza-
tion of ethyl diazoacetate is faster than that of a,b-unsaturated
diazoacetate esters, which is likely a consequence of the faster
formation of the carbenoid of the former.
[7] A related cyclopropanation reaction has been proposed by
Davies et al in the rhodium(II)-catalyzed dimerization and
trimerization of some vinyldiazoacetate esters: H. M. L. Davies,
L. M. Hodges, J. J. Matasi, T. Hansen, D. G. Stafford, Tetrahe-
dron Lett. 1998, 39, 4417.
Scheme 3. Proposed intermediates in the copper(I)-catalyzed synthesis
of furyl-substituted cyclobutene derivatives 7 from propargylic esters 6
and vinyldiazoacetates 1.
[8] a) H. Xu, W. Zhang, D. Shu, J. B. Werness, W. Tang, Angew.
Chem. 2008, 120, 9065; Angew. Chem. Int. Ed. 2008, 47, 8933;
b) The rearrangement of metal-free cyclopropyl carbenes has
been also reported: R. A. Moss, W. Liu, K. Krogh-Jespersen, J.
Phys. Chem. 1993, 97, 13413.
coupling reaction does not occur, but both species nicely
collapse through cyclopropanation and subsequent ring
enlargement to produce cyclobutenes, a class of interesting
compounds whose synthesis currently represents a challeng-
ing task.[10,11] The procedure depicted herein provides differ-
ent substituted cyclobutenes yet in moderate yield in a
straightforward, atom-economic, and simple manner. It is also
proved that this concept can be integrated into more complex
synthetic sequences that involve metal carbene species, a fact
that demonstrates the great capability of copper(I) to
sequentially catalyze various reactions of different nature.
[9] J. Barluenga, L. Riesgo, R. Vicente, L. A. Lꢀpez, M. Tomꢂs, J.
Am. Chem. Soc. 2008, 130, 13528.
[10] a) For a review on the versatility of substituted cyclobutenes in
synthesis, see: N. Gauvry, C. Lescop, F. Huet, Eur. J. Org. Chem.
2006, 5207; b) For a recent application of cyclobutene esters in
polymer science, see: A. Song, K. A. Parker, N. S. Sampson, J.
Am. Chem. Soc. 2009, 131, 3444.
[11] For the synthesis of cyclobutenes by metal-catalyzed rerrange-
ment of methylenecyclopropanes, see: a) A. Fürstner, C. Aïsa, J.
Am. Chem. Soc. 2006, 128, 6306; b) M. Shi, L.-P. Liu, J. Tang, J.
Am. Chem. Soc. 2006, 128, 7430. For a selection of recent
syntheses of cyclobutenes involving transition metal catalyzed
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Communications
cycloisomerization of 1,n-enynes, see: c) Y. Odabachian, F.
Chem. Soc. 2005, 127, 8244. For more specific syntheses of
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Kawachi, Org. Lett. 2006, 8, 1343; i) H. M. Sheldrake, T. W.
Wallace, C. P. Wilson, Org. Lett. 2005, 7, 4233; j) Y. Liu, M. Liu,
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Takasu, M. Ihara, J. Am. Chem. Soc. 2005, 127, 3668; l) K.
Villeneuve, W. Tang, Angew. Chem. 2004, 116, 620; Angew.
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Campagne, J. Am. Chem. Soc. 2008, 130, 1562; e) C. Nieto-
Oberhuber, S. Lꢀpez, E. JimØnez-Nfflæez, A. M. Echavarren,
Chem. Eur. J. 2006, 12, 5916; f) C. Nieto-Oberhuber, S. Lꢀpez,
M. P. Muæoz, D. J. Cꢂrdenas, E. Buæuel, C. Nevado, A.
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