Zinc-catalyzed synthesis of 2-alkenylfurans via cross-coupling of enynones and diazo compounds

Article abstract of DOI:10.1039/c4cc03960b

Inexpensive, less-toxic ZnCl₂ serves as the catalyst for selective cross-coupling of enynones and diazo compounds, an unprecedented reaction pathway for zinc carbenoids. A cascade sequence comprising formal cyclization/cross-coupling leads to a variety of 2-alkenylfurans. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc03960b

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COMMUNICATION
Zinc-catalyzed synthesis of 2-alkenylfurans
via cross-coupling of enynones and diazo
compounds†
Cite this: Chem. Commun., 2014,
50, 8536
Received 23rd May 2014,
Accepted 10th June 2014
Jesus Gonzalez, Luis A. Lopez* and Ruben Vicente*
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DOI: 10.1039/c4cc03960b
www.rsc.org/chemcomm
Inexpensive, less-toxic ZnCl2 serves as the catalyst for selective cross-
coupling of enynones and diazo compounds, an unprecedented reaction
pathway for zinc carbenoids. A cascade sequence comprising formal
cyclization/cross-coupling leads to a variety of 2-alkenylfurans.
The replacement of precious metals with catalysts based on more
abundant and less-toxic metals is gaining relevance due to economic
and environmental reasons, both in industry and academia.1 As a
result, elegant transformations based on the use of iron, copper or
cobalt catalysts, among others, have appeared in recent years.2 Whilst
the utility of zinc in synthetic organic chemistry has been known for
more than a century, zinc-catalyzed transformations remain less
developed.3,4 For instance, the well-known Simmons–Smith cyclopro-
panation is typically accomplished with over-stoichiometric amounts
Scheme 1 Reactivity of in situ generated 2-furyl zinc carbenoids.
of zinc (moisture and oxygen sensitive Et2Zn).5 With the aim of suitable carbon-nucleophilic reagent bearing a leaving group.
overcoming this limitation, we became interested in exploring the Thus, the formation of a new C–C bond by nucleophilic attack
feasibility to generate zinc carbenoids in a catalytic manner and to should set the stage for an elimination process delivering the
exploit their reactivities for the synthesis of relevant compounds. Thus, desired target and allowing catalyst turnover (Scheme 1b).
we recently reported the use of enynones 1 as carbene precursors Herein, we disclosed our findings regarding the unprecedented
using simple ZnCl2 as the catalyst (Scheme 1a).6,7 The cyclization reactivity of zinc carbenoids.
of 1 generates a 2-furyl zinc carbenoid intermediate I,8 which can
The evaluation of the initial hypothesis was carried out using
be further trapped with alkenes or silanes to yield valuable readily available enynone 1a as the benchmark reagent and ZnCl2 as
2-cyclopropyl- or 2-alkylsilylfurans, respectively. Computational the catalyst. As coupling reagents, we selected stabilized ylides 2–4a
studies provided support for the proposed 2-furyl zinc Fischer- (Scheme 2a) which meet the requirements to achieve the desired
type carbenoid intermediate.6 This approach provides a catalytic transformation since they are good nucleophiles and contain a
alternative to previously established zinc-mediated cyclopropana- leaving group. Unfortunately, only phosphorous ylide 2a led to the
tion5b or Si–H insertions.9
formation of the desired 2-alkenylfuran, albeit in unpractical low
In order to further explore the synthetic potential of the yield (o10%). Then, we turned our attention to stabilized diazo
postulated 2-furyl zinc–carbenoid intermediate I, we wondered compounds. In contrast to other transition metals, in general,
whether the reactivity could be expanded beyond its classically stabilized diazo compounds do not decompose to carbenoids in
known reactivity patterns. According to the predicted electrophilicity the presence of zinc salts,11 yet they are good carbon nucleophiles
of the putative zinc carbenoid, we envisioned a route to relevant and have an excellent leaving group such as N2.12 Indeed, using ethyl
2-alkenylfuran derivatives10 by trapping the carbenoid with a diazoacetate (EDA, 5a) under reaction conditions similar to those
previously reported for related transformations (10.0 mol% ZnCl2,
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Departamento de Quımica Organica e Inorganica e Instituto Universitario de
6.0 equiv. of 5a, 25 1C, CH2Cl2, 1 h),6a we isolated 2-alkenylfuran
6a in good yield and selectivity (89%, Z : E = 8.5 : 1) (Scheme 2b).
A further optimization demonstrated that 5.0 mol% of ZnCl2 and only
a slight excess of 5a (1.2 equiv., CH2Cl2, 25 1C, 1 h) gave rise to
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Quımica Organometalica ‘‘Enrique Moles’’, Universidad de Oviedo. c/ Julian
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Claverıa 8, 33007, Oviedo, Spain. E-mail: lalg@uniovi.es, vicenteruben@uniovi.es
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data and NMR spectra. See DOI: 10.1039/c4cc03960b
8536 | Chem. Commun., 2014, 50, 8536--8538
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was examined. Thus, reactions with aryl substituted enynones
proceeded smoothly to afford compounds 6a–d, and those with
both electron-rich and electron-deficient aryl groups gave the
expected products in good yields and variable stereoselectivity.
Even an ortho-substituent in the aryl group is well tolerated,
though a slight decrease of the yield was observed.16 An alkenyl
substituent at the alkyne terminus was also suitable giving rise
to compound 6e (63%, Z : E = 4.6 : 1). Interestingly, alkyl sub-
stituents on the alkyne, both primary and secondary, afforded
efficiently the corresponding 2-alkenylfurans 6f–6j with high
Z-selectivity.17 Notably, the presence of a protected alcohol in the
substrate was compatible with this protocol affording the furan
derivative 6h in reasonable yield (67%) and high Z-selectivity. Further
modifications of the substituents R1 and R2 in the enynone led to
compounds 6k–m. Then, we evaluated the diazo compound compo-
nent. Various carboxylic esters as well as ketones as stabilizing groups
of the diazo compound proved to be suitable substituents, yielding
furans 6n–q in respectable yields (77–89%). In contrast, this procedure
could not be applied to phenyl-, trimethylsilyl diazomethane or ethyl
2-diazo-2-phenylacetate, which gave rise to complex reaction mixtures,
under various similar reaction conditions tested, while dimethyl
2-diazomalonate proved to be unreactive.
Scheme 2 Zinc-catalyzed preparation of 2-alkenylfuran 6a: initial find-
ings and optimized reaction conditions.
comparable results (87%, Z:E = 6.5:1).13 Additionally, to check the
practicality of the protocol, the test reaction was carried out on a larger
scale (10 mmol) with almost the same efficiency (2.56 g of 6a, 86%,
Z:E = 5.8 : 1). The formation of compound 6a validates our initial
hypothesis as it represents an unprecedented reaction pathway for zinc
carbenoids. Besides, the overall transformation comprises a rather
unusual example of formal selective hetero-coupling of two different
carbenoid precursors.14 Notably, ZnCl2 showed better efficiency and
selectivity when compared to other representative metal catalysts
known to be capable of generating carbenoids from enynones.15
With the optimized reaction conditions in hand, we next
explored the scope of the transformation (Table 1). First, the
reaction of EDA (5a) with an array of easily available enynones 1
Interestingly, we found that other enynones such as com-
pound 1n proved to be applicable to this coupling. Indeed,
treatment of 1n with EDA (5a) in the presence of 10 mol% of
Zn(OTf)2 resulted in the formation of tetrasubstituted furan 6r
in moderate yield (49%) after stirring in 1,2-dichloroethane at
50 1C for 12 h (Scheme 3).
The preparation of chemicals bearing a trifluoromethyl group
has recently attracted great interest. Since trifluoromethyl diazo-
methane can be conveniently generated in situ,18 we checked the
feasibility of accessing the corresponding alkenyl–CF3 furyl deriva-
tives as a complementary approach towards the relevant moiety.19
Indeed, the reaction of various representative enynones 1 with an
excess of trifluoromethyl diazomethane (5e, B20 equiv.) generated
from trifluoromethylamine hydrochloride and NaNO2, in the
presence of ZnCl2 allowed us to obtain CF3-substituted alkenes
6s–v in synthetically useful yields (Scheme 4).20
Table 1 Zinc-catalyzed synthesis of 2-alkenylfurans 6: scopea
As depicted in Scheme 1(b), the formation of 2-alkenylfurans
6 can be explained through the initial 5-exo-dig cyclization of
enynones 1 to generate the 2-furyl zinc carbenoid species I.
Subsequent nucleophilic attack of the diazo compound 5 likely
affords intermediate II.12 Favoured extrusion of N2 with a
concomitant release of the zinc catalyst leads to furans 6 and
allows catalyst turnover.21,22
In summary, we have herein reported a new zinc-catalyzed
formal selective hetero-coupling of two carbenoid precursors
such as enynones 1 and diazo compounds 5. The observed
reactivity constitutes an unprecedented reactivity pattern for
a
Reaction conditions:
1 (0.2–0.3 mmol), 5 (1.2 equiv.), ZnCl2
(5.0 mol%), CH2Cl2 (0.1 M), RT. Yields correspond to isolated products.
b
c
d
Z/E selectivity was determined by NMR. See ref. 16. At 0 1C. o5%
of an unidentified isomer was detected.
Scheme 3 Zinc-catalyzed preparation of 2-alkenylfuran 6r from enynone 1n.
Chem. Commun., 2014, 50, 8536--8538 | 8537
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(b) K. Miki, F. Nishino, K. Ohe and S. Uemura, J. Am. Chem. Soc.,
2002, 124, 5260.
9 (a) J. Nishimura, J. Furukawa and N. Kawabata, J. Organomet. Chem.,
1971, 29, 237; (b) H. Kondo, Y. Yamanoi and H. Nishihara, Chem.
Commun., 2011, 47, 6671.
10 Selected references on relevant compounds containing the
2-alkenylfuran scaffold: (a) P. A. Roethle and D. Trauner, Nat. Prod.
Rep., 2008, 25, 298; (b) C. H. Woo, P. M. Beaujuge, T. W. Holcombe,
´
O. P. Lee and J. M. J. Frechet, J. Am. Chem. Soc., 2010, 132, 15547;
(c) O. Tsuge, S. Kanamasa and H. Suga, Bull. Chem. Soc. Jpn., 1988,
61, 2133; (d) J. A. Pfefferkorn, M. L. Greene, R. A. Nungent,
R. J. Gross, M. A. Mitchell, B. C. Finzel, M. S. Harris, P. A. Wells,
J. A. Shelly, R. A. Anstadt, R. E. Kilkuskie, L. A. Kopta and F. J.
Schwende, Bioorg. Med. Chem. Lett., 2005, 15, 2481; (e) J. T. Lin,
P.-C. Chen, Y.-S. Yen, Y.-C. Hsu, H.-H. Chou and M.-C. P. Yeh, Org.
Lett., 2009, 11, 97; ( f ) X. Cui, X. Xu, L. Wojtas, M. M. Kim and
X. P. Zhang, J. Am. Chem. Soc., 2012, 134, 19981.
Scheme 4 Zinc-catalyzed synthesis of CF3-substituted 2-alkenylfurans
6s–v. Yields correspond to isolated products. Z/E selectivity was deter-
mined by NMR. ZnCl2 100 mol%. At 0 1C. ZnCl2 20 mol%.
a
b
c
11 For zinc-promoted decomposition of diazomethane or diaryldiazo-
methane, see: (a) G. Wittig and K. Schwarzenbach, Angew. Chem.,
1959, 71, 652; (b) S. H. Goh, L. E. Closs and G. L. Closs, J. Org. Chem.,
1969, 34, 25; (c) L. J. Altman, R. C. Kowerski and D. R. Laungani,
J. Am. Chem. Soc., 1978, 100, 6174.
12 For a review on the reactivity of diazo compounds as nucleophiles,
see: Y. Zhang and J. Wang, Chem. Commun., 2009, 5350.
zinc carbenoids. This transformation has enabled the preparation
of valuable 2-alkenylfuran derivatives 6 with a remarkable scope.10
The overall process comprises cyclization of the enynone 1 followed
by coupling with the diazo compound and leads to the formation of
new C–O and CQC bonds. Relevant CF3-substituted 2-vinylfuran
analogues can also be accessed by this methodology using in situ
generated trifluoromethyl diazomethane. The use of an inexpensive
and less-toxic ZnCl2 as the catalyst is remarkable within the context
of the new avenues of chemistry regarding the development of
sustainable transformations.
13 See ESI† for additional details.
14 For selected examples of carbenoid hetero-cross-coupling reactions,
´
see: (a) C. Vovard-Le Bray, S. Derien and P. H. Dixneaf, Angew.
Chem., Int. Ed., 2009, 48, 1439; (b) J. Barluenga, L. Riesgo,
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L. A. Lopez, E. Rubio and M. Tomas, Angew. Chem., Int. Ed., 2009,
48, 7569; (c) J. H. Hansen, B. T. Parr, P. Pelphrey, Q. Jin,
J. Autschbach and H. M. L. Davies, Angew. Chem., Int. Ed., 2011,
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50, 2544; (d) S. Moulin, H. Zhang, S. Raju, C. Bruneau and S. Derien,
Chem. – Eur. J., 2013, 19, 3292; (e) Y. Xia, Z. Liu, Q. Xiao, P. Qu, R. Ge,
Y. Zhang and J. Wang, Angew. Chem., Int. Ed., 2012, 51, 5714.
15 Experiments were carried out using CuBr and [(IPr)Au(NTf2)] under
otherwise identical reaction conditions: CuBr (6a, 43%, Z/E = 1.4 : 1,
CH2Cl2, 25 1C, 24 h); [(IPr)Au(NTf2)] (6a, 71%, Z/E = 1.7 : 1, CH2Cl2,
25 1C, 24 h).
Financial support from MINECO of Spain (Grant CTQ2012-
20517-C02-01 and predoctoral grant for J. G.) is gratefully
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acknowledged. R. V. is a Ramon y Cajal fellow. We thank
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Prof. Dr J. M. Gonzalez for his support and Dr J. Gonzalez for
his assistance in theoretical studies.
16 Enynone 1c bearing the o-MeO-C6H4 group led to the formation of
compound 6c0 (11%) as byproduct. The use of a larger excess of ethyl
diazoacetate (5a) did not improve the yield of 6c0.
Notes and references
1 Selected reviews: (a) Catalysis without precious metals, ed. R. B. Bullock,
Wiley-VCH Weinheim, 2010; (b) M. S. Holzwarth and B. Plietker,
ChemSusChem, 2013, 5, 1650.
2 (a) S. Enthaler, K. Junge and M. Beller, Angew. Chem., Int. Ed., 2008,
47, 3317; (b) S. E. Allen, R. R. Walvoord, R. Padilla-Salinas and
M. C. Kozlowski, Chem. Rev., 2013, 113, 6234; (c) G. Cahiez and
A. Moyeux, Chem. Rev., 2010, 110, 1435.
17 An enynone bearing a bulky R3 group such as tert-butyl proved to be
unreactive towards 4a under several reaction conditions.
3 Recent reviews on zinc catalysis: (a) S. Enthaler, ACS Catal., 2013,
3, 150; (b) X.-F. Wu, Chem. – Asian J., 2012, 7, 2502; (c) X.-F. Wu and 18 (a) Z. Li, Z. Cui and Z.-Q. Liu, Org. Lett., 2013, 15, 406; (b) Y. Yasu,
H. Neumann, Adv. Synth. Catal., 2012, 254, 3141.
4 Selected examples on zinc-catalysis: (a) A. Sniday, A. Durham,
M. S. Morreale, K. A. Wheeler and R. Dembinsky, Org. Lett., 2007,
T. Koike and M. Akita, Chem. Commun., 2013, 49, 2037; (c) X. Wang,
Y. Xu, Y. Deng, Y. Zhou, J. Feng, G. Ji, Y. Zhang and J. Wang,
Chem. – Eur. J., 2014, 20, 961.
9, 1175; (b) K. Alex, A. Tillack, N. Schwarz and M. Beller, Angew. 19 (a) B. L. Dyatkin and E. P. Mochalina, Izv. Akad. Nauk SSSR, Ser.
Chem., Int. Ed., 2008, 47, 2304; (c) S. Yamazaki, Chem. – Eur. J., 2008,
14, 6026; (d) T. Sugiishi and H. Nakamura, J. Am. Chem. Soc., 2012,
134, 2504; (e) Y. Nagashima, R. Takita, K. Yoshida, K. Hirano and
M. Uchiyama, J. Am. Chem. Soc., 2013, 135, 18730.
Khim., 1964, 7, 1225; (b) B. Morandi and E. M. Carreira, Angew.
Chem., Int. Ed., 2011, 50, 9085; (c) B. Morandi and E. M. Carreira,
Science, 2012, 335, 1471.
20 See ESI† for specific conditions for the generation of 4e and the
reaction conditions for the formation of 6s–v.
5 (a) J. Furukawa, N. Kawabata and J. Nishimura, Tetrahedron Lett.,
1966, 7, 3353; (b) H. Lebel, J.-F. Marcoux, C. Molinaro and 21 Preliminary computational studies indicate that (E)-6 are the most
A. B. Charette, Chem. Rev., 2003, 103, 977.
stable isomers. Thus, without further additional evidence, we
believe that Z/E selectivities likely originate from kinetic control.
See the ESI† for computational details.
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6 (a) R. Vicente, J. Gonzalez, L. Riesgo, J. Gonzalez and L. A. Lopez,
Angew. Chem., Int. Ed., 2012, 51, 8063. See also: (b) J. Gonzalez,
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J. Gonzalez, C. Perez-Calleja, L. A. Lopez and R. Vicente, Angew. 22 At this stage, the following pathway cannot be ruled out: (i) activa-
Chem., Int. Ed., 2013, 52, 5853.
7 For zinc-catalyzed cyclopropanations using phenyldiazomethane as
the carbene source, see: (a) S. R. Goudreau and A. B. Charette, J. Am.
Chem. Soc., 2009, 131, 15633; (b) E. Levesque, S. R. Goudreau and
A. B. Charette, Org. Lett., 2014, 16, 1490.
8 Selected examples of metal furylcarbenoids, see: (a) Y. Xia, S. Qu,
Q. Xiao, Z.-X. Wang, P. Qu, L. Chen, Z. Liu, L. Tian, Z. Huang,
Y. Zhang and J. Wang, J. Am. Chem. Soc., 2013, 135, 13502;
tion of the substrate by coordination of zinc to the carbonyl
group(s); (ii) conjugate attack of the diazo compound on the triple
bond; (iii) cyclization with elimination of N2. However, other
common Lewis acids tested (BF3ꢀEt2O, AlCl3, TiCl4, and MgCl2,
under catalytic or stoichiometric conditions) did not give rise to
the expected 2-alkenylfuran derivatives 6. In contrast, other metals
are known to activate alkynes to generate carbenoids as Cu or Au
showed the same reactivity, see ref. 15.
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8538 | Chem. Commun., 2014, 50, 8536--8538
This journal is ©The Royal Society of Chemistry 2014