Nickel-catalysed cyclopropanation of electron-deficient alkenes with diiodomethane and diethylzinc

Article abstract of DOI:10.1039/c5cc10296k

In the presence of a nickel catalyst, the cyclopropanation of electron-deficient alkenes with diiodomethane and diethylzinc is drastically accelerated. A wide range of cyclopropyl ketones, esters and amides can be accessed under these conditions.

Full text of DOI:10.1039/c5cc10296k

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DOI: 10.1039/C5CC10296K
An inexpensive nickel catalyst enables cyclopropanation of electron-deficient olefins under a modified
Furukawa’s procedure in moderate to good yields.

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DOI: 10.1039/C5CC10296K
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COMMUNICATION
Nickel-Catalysed Cyclopropanation of Electron-Deficient Alkenes
with Diiodomethane and Diethylzinc
Jin Xu, Nazurah Binte Samsuri, Hung A. Duong*
ssReceived 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
In the presence of a nickel catalyst, the cyclopropanation of Smith type reagents.6 In an interesting report, Kanai et al.
electron-deficient alkenes with diiodomethane and diethylzinc is showed that nickel(0) catalyst can facilitate the
drastically accelerated. A wide range of cyclopropyl ketones, cyclopropanation of methyl vinyl ketone (MVK), methyl
a
esters and amides can be accessed under these conditions.
acrylate (MA) and acrylonitrile (AN) with CH2Br2/Zn (Scheme
1a).7 Notably, CH2I2 was less effective than CH2Br2. The scope
of this reaction, however, could not be extended to substrates
bearing additional substituent(s). Recently, Sugimura et al.
Cyclopropane is a structural element found in a wide range of
natural and unnatural compounds that display important
biological activities.1 Due to its unique ring strain,
cyclopropane can also serve as a versatile synthetic handle.2
Simmons-Smith cyclopropanation is amongst the most widely
used methods to access this valuable moiety from alkenes due
to its excellent chemoselectivity and stereospecificity.3,4 In this
reaction, an iodomethylzinc species (IZnCH2I) is generated in
situ from a combination of CH2I2 and a Zn/Cu couple. To
overcome the cumbersome preparation of Zn/Cu couple, a
number of methods have been introduced, for instance, the
Furukawa’s procedure to replace activated Zn with Et2Zn,
discovered a Cu(OTf)2-catalysed cyclopropanation of 
-
unsaturated ketones with CH2I2/Et2Zn (Scheme 1b).8 We report
herein a nickel-catalysed cyclopropanation with CH2I2/Et2Zn
that allows access to a broad range of cyclopropyl ketones,
esters and amides (Scheme 1c). Our conditions comprise a
simple modification of the widely used Furukawa’s procedure
with the aid of an inexpensive nickel catalyst, and offer an
alternative to other cyclopropanation methods for Michael
acceptors (i.e. Corey-Chaykovsky reaction and metal-catalysed
decomposition of diazomethane).
resulting in
a
more reactive reagent and better
We initially investigated the cyclopropanation of chalcone
reproducibility.5
Table 1. Cyclopropanation of chalcone 1a.a
Entry Ni catalyst
CH2I2
Et2Zn
T
Conv. Yield of
(equiv) (equiv) (oC)
(%)b
79
2a (%)b
58
Scheme 1. Cyclopropanation of electron-deficient alkenes with Simmons-Smith
type reagents.
1
20 mol% NiCl2
4
4
4
4
4
4
4
2
4
4
4
2
2
2
2
2
2
1.2
2
2
0
0
rt
2
None
25
7
3
4
20 mol% NiCl2
20 mol% NiCl2
20% Ni(COD)2
20 mol% NiCl2
20 mol% NiCl2
20 mol% NiCl2
10 mol% NiCl2
2 mol% NiCl2
None
84
71
Simmons-Smith reaction of electron-deficient alkenes is
rather sluggish due to the electrophilic nature of zinc
carbenoid species.3 Methods addressing this reactivity issue
could considerably enhance the synthetic utilities of Simmons-
40
40
40
40
40
40
40
40
>99
67
100
56
91
94
96
41
5
6c
7
0 (98)d
38
8
9
10
11
71 (9)d
94
2
2
98
96
a.Institute of Chemical and Engineering Sciences (ICES)
Agency for Science,
,
30
7
Technology and Research (A*STAR), 8, Biomedical Grove, Neuros, #07-01,
Singapore 138665. Fax: +65 6464 2102; Tel: +65 6799 8519; Emails:
duong_hung@ices.a-star.edu.sg.
Electronic Supplementary Information (ESI) available: Full experimental
procedures, compound characterisation and copies of NMR spectra. See
a
A solution of Et2Zn in hexane was added slowly to a mixture of 1a, CH2I2 and Ni
b
catalyst in CH2Cl2. Determined by GC analysis using dodecane as an internal
†
standard. c CH2Br2 was used instead of CH2I2. d Yield of 2a’.
DOI: 10.1039/x0xx00000x
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1a with CH2I2/Et2Zn under nickel catalysis. To minimize the less activated systems, including chalcone 1e and enones
View Article1Ofn-l1inje,
potential competitive conjugate addition of Et2Zn to 1a 9
,
a
due to decomposition of starting mateDriOaIl:s1.0.1A03n9/iCn5cCrCea10s2e96inK
solution of Et2Zn (2 equiv.) in hexane was added slowly to a NiCl2 could help improve the reaction yield of 1e from 57% (2
mixture of 1a, NiCl2 (20 mol%) and CH2I2 (4 equiv.) in CH2Cl2 at mol% NiCl2) to 74% (20 mol% NiCl2). Similarly, 61% of 2f could
0
oC. 58% of 2a was formed as determined by GC analysis be obtained at 10 mol% catalyst loading. Cyclohexenone 1k
(Table 1, entry 1). No change in the conversion and yield could also underwent the cyclopropanation in 44% isolated yield.
be observed beyond 1h. Only 7% of 2a was obtained in the Reactions of tri-substituted olefins 1l-1n were sluggish. Even
absence of the nickel catalyst (entry 2). An increase in the under forcing conditions (20 mol% NiCl2, 70 oC), the reaction of
reaction temperature to 40oC led to 96% yield of 2a (entries 3 1l only led to 21% of 2l as determined by GC analysis, together
and 4). The reaction was completed within 10 min after the with 30% of the starting material remaining. Reactions of 1m
addition of Et2Zn. Other nickel halides exhibited reactivity and 1n also gave poor yields of the desired products.
similar to NiCl2 (see ESI† for more details) while Ni(COD)2 only
led to 41% of the product (entry 5). Reaction with CH2Br2 methyl cinnamate 3a
We further probed the possibility to cyclopropanate
under nickel catalysis (Table 3). ZnCl2 (1

instead of CH2I2 resulted in exclusive formation of 2a’ (entry 6). equiv.) additive was found to considerably improve the
While attempts to reduce the amount of CH2I2 or Et2Zn was reaction yield to give 90% of 4a (entries 1-3). In this case, only
detrimental to the reaction yields (entries 7 and 8), the 2 equiv. of CH2I2 was needed as the nickel-catalysed conjugate
catalyst loading could be lowered to 2 mol% (entries 9-11).
addition of Et2Zn to 3a was no long competitive. No addition
product was observed in the reaction of 3a with Et2Zn in the
presence of NiCl2 (entry 4).
Table 2. Ni-catalysed cyclopropanation of -unsaturated ketones.
Table 3. Cyclopropanation of methyl cinnamate 3a.
NiCl2
(mol%)
20
20
20
20
20
20
20
20
20
0
Additive
(mol%)
none
CH2I2
(equiv)
Et2Zn
Conv.
4a
Entry
(equiv) (%)a
(%)a
64
1
2
3
4
5
6
7
8
2
2
2
0
2
2
2
2
2
2
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
2
2
91
96
99
7
ZnCl2 (50)
ZnCl2 (100)
ZnCl2 (100)
ZnBr2 (100)
ZnI2 (100)
Zn(OTf)2 (100)
AlCl3 (100)
Sc(OTf)3 (100)
ZnCl2 (100)
ZnCl2 (100)
ZnCl2 (100)
ZnCl2 (100)
ZnCl2 (100)
83
90
0 (0)b
76
94
97
76
89
41
20
79
89
98
99
88
50
63
17
10
62
80
89
9
10
11
12
13
14
20
20
5
2
90
a
b
Determined by GC analysis using dodecane as an internal standard. Yield of
4a’.
The addition of zinc bromide or iodide was also
advantageous to the reaction yields (entries 5 and 6). While
zinc halides may serve as a Lewis acid to activate the electron-
deficient alkene,10 Zn(OTf)2, AlCl3 and Sc(OTf)3 were not as
effective (entries 7-9). In the absence of a nickel catalyst, ZnCl2
alone led to only 10% of the cyclopropane (entry 10). Attempts
to reduce the amounts of CH2I2 or Et2Zn led to reductions in
yields (entries 11-12). The catalyst loading could be reduced to
2 mol% without affecting the reaction outcome to any
noticeable extent (entries 13-14).
The conditions developed were applicable to the synthesis
of a range of cyclopropyl esters (Table 4). 4a was isolated in
90% yield from the reaction of 3a. Cyclopropanation of
cinnamate 3b with a fluorine substituent on the phenyl ring
a Isolated yields. b Reaction was run with 3 equiv. of Et2Zn. c Reaction was run with
20 mol% of NiCl2. d Reaction was run with 10 mol% of NiCl2. e Reaction was run
with 20 mol% NiCl2 in DCE at 70 oC. f Determined by GC analysis using dodecane
as an internal standard.
With the optimized conditions in hand, we explored the
scope of the nickel-catalysed reaction (Table 2). Chalcones 1a
-
1d were cyclopropanated in good yields. The reaction of 1b
required 3 equiv. of Et2Zn to achieve full conversion due to
deactivation of the substrate by a strongly electron-donating
methoxy group. Lower yields were obtained in the reactions of
2 | J. Name., 2012, 00, 1-3
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gave 76% yield of the desired product whereas a lower
COMMUNICATION
The nickel-catalysed cyclopropanation is compatible with a
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reactivity was observed with 3c featuring a methoxy group. As wide range of functional groups, incluDdOinI:g10k.1e0t3o9n/Ce5sC, Ce1s0t2e9r6sK,
expected, benzyl cinammate 3d underwent cyclopropanation amides, ethers and aryl bromides (Tables 2 and 4).
in 82% yield. The reaction of benzyl crotonate 3e was sluggish
due to deactivation of the olefin by a methyl substituent. Even
running the reaction in DCE at 70 oC only resulted in 37% of 4e
.
For the more reactive terminal alkene 3f, a good yield (76%) of
the cyclopropane could be obtained with only 1 equiv. of CH2I2
and 1.1 equiv. of Et2Zn.11
a Isolated yield. b Determined by GCMS and 1H NMR analysis.
Scheme 2. Cyclopropanation of Z-olefins.
Table 4. Ni-catalysed cyclopropanation of -unsaturated esters and amides.
For reactions of 1a-1h, 3a-3e and 3h-3j, the trans-products
were obtained exclusively. We further investigated the
cyclopropanation of ketones Z-1f, Z-1o, Z-1p and ester Z-3a
(Scheme 2). Reaction of Z-1f led to exclusive formation of
trans-2f in 52% isolated yield. Both the E- and Z-olefins could
1
be observed by H NMR in the reaction mixtures of Z-1f, Z-1o
and Z-3a, suggestive of isomerization of the starting material
to the trans-isomer during the course of the reaction. The
reaction mixtures of Z-1o and of Z-3a were rather complex,
indicating extensive side reactions occurring. Cyclopropanation
of Z-1p resulted in a 1:2 mixture of the cis- and trans-products
1
as determined by H NMR analysis. Overall, it was not possible
to obtain cis-cyclopropanes selectively from (Z)-
-
unsaturated carbonyls.
a
Isolated yields. b Reaction was run in DCE at 70 oC. c 1 equiv. of CH2I2 and 1.1
d
e
equiv. of Et2Zn were employed. 20 mol% of NiCl2. 10 mol% of NiCl2 was
employed.
Remarkably, the nickel catalyst can reverse the
chemoselectivity normally observed in Simmons-Smith
reaction. A 2:1 ratio of the mono- and bis-cyclopropanation
products was obtained in the reaction of diene 3g, favouring
cyclopropanation at the electron-deficient alkene. An increase
in the catalyst loading to 20 mol% helped improve the
selectivity to 7:1, and 68% of the mono-cyclopropanation
product was isolated.
Scheme 3. Plausible pathways for the nickel-catalysed cyclopropanation with
CH2I2/Et2Zn.
Two plausible pathways for the nickel-catalysed
cyclopropanation could be considered. The first proceeds via a
Michael-initiated ring closure process whereby a nickel-
catalysed conjugate addition of an iodomethylzinc species to
an -unsaturated carbonyl is followed by an intramolecular
cyclisation (Scheme 3, pathway a).9 Alternatively, a mechanism
similar to that proposed by Kanai et al. could involve a reaction
of a nickel-carbene with an electron-deficient olefin to form a
-unsaturated amides can also be cyclopropanated
under nickel catalysis, albeit requiring more forcing conditions
o
to achieve reasonable conversions (10 mol% of NiCl2, 70 C)
nickelacyclobutane
C
(Scheme 3, pathway b).7b Milstein et al.
(Table 4). The reactions of cinnamoylamides 3h and 3j
afforded the corresponding cyclopropanes in 60% and 72%
yields, respectively, while cyclopropanation of crotonamide 3i
produced 4i in 36% yield.12
13
previously showed that Zn(CH2I)2 can serve as an effective
reagent for the formation of ruthenium and iridium
carbenes.14 Thus, it is possible that
a nickel-carbene
intermediate could be generated from the reaction of Ni(0)
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with an iodomethylzinc species.15 Reactions of metal-carbenes
and electron-deficient olefins are known to afford
cyclopropanes.16 Furthermore, Grubbs et al. and by Hillhouse
et al. showed that isolated nickelacyclobutanes can undergo
reductive elimination.17 The intermediacy of nickel-carbene in
cyclopropanation has also been invoked in some cases.7b,18
While further studies are needed to evaluate these
possibilities, some initial observations deserve attention. Ester
3a failed to undergo conjugate addition with Et2Zn under
nickel catalysis, and yet, can be cyclopropanated efficiently
(Table 3). The result seems to cast doubt on pathway a.
Notably, Ni(COD)2 was not as effective as nickel halides in the
cyclopropanation of 1a with CH2I2/Et2Zn (Table 1, entry 5). The
difference in the catalytic efficiencies of Ni(0) and Ni(II) salts in
reactions involving dialkylzinc is well-documented.15,19
Interestingly, Ni(COD)2 catalysed the cyclopropanation of 1a
with pre-formed Zn(CH2I)2 in 79% yield (Scheme 4) whereas
the corresponding reaction employing NiCl2 afforded 30% of
2a. Compared to Zn(CH2I)2, other iodomethylzinc (i.e. EtZnCH2I
and IZnCH2I), which could also be present in the reaction
mixture,10 resulted in lower yields of 2a under similar
conditions. While these experiments do not provide a direct
evidence for a nickel-carbene mechanism, they indicate that a
Ni(0)-catalysed pathway could be possible.
and A. B. Charette, Angew. Chem., Int. Ed., 2010, 49, 486; (e)
M.-N. Roy, V. N. G. Lindsay and A. B. DCOhaI:r1e0t.t1e03,V9iien/wCS5ACcrtiiCcel1ne0cO2en9l6ionKef
Synthesis, Stereoselective Synthesis, ed. J. G. de Vries,
Thieme, 2011, vol. 1, ch. 14, pp. 731–817.
(a) H. W. Simmons and R. D. Smith, J. Am. Chem. Soc., 1958,
80, 5323; (b) H. W. Simmons and R. D. Smith, J. Am. Chem.
Soc., 1959, 81, 4256.
3
4
For reviews, see: (a) H. E. Simmons, T.L. Cairns, S. A.
Vladuchick and C. M. Hoiness, Org. React., 1973, 20, 1-131;
(b) A. B. Charette and A. Beauchemin, Org.React., 2001, 58
,
1-415. (c) H. Lebel, J.-F. Marcoux, C. Molinaro and A. B.
Charette, Chem Rev., 2003, 103, 977-1050.
5
6
(a) J. Furukawa, N. Kawabata and J. Nishimura, Tetrahedron
Lett., 1966,
7, 3353; (b) J. Furukawa, N. Kawabata and J.
Nishimura, Tetrahedron, 1968, 24, 53. For some recent
developments on Simmon-Smith reagents, see: (c) A. B.
Charette, A. Beauchemin and S. Francoeur, J. Am. Chem.
Soc., 2001, 123, 8139; (d) R. G. Cornwall, O. A. Wong, H. Du,
T. A. Ramirez and Y. Shi, Org. Biomol. Chem., 2012, 10, 5498.
For reports on directed cyclopropanation of -unsaturated
amides and carboxylic acids with samarium- and chromium-
based carbenoids, see: (a) J. M. Concellón, H. Rodríguez –
Solla and C. Gómez, Angew. Chem. Int. Ed. 2002, 41, 1917;
(b) J. M. Concellón, H. Rodríguez –Solla and C. Simal, Org.
Lett. 2007,
9
, 2685; (c) J. M. Concellón, H. Rodríguez -Solla, C.
, 2981; (d) J. M.
Méjica and E. G. Blanco, Org. Lett. 2007,
9
Concellón, H. Rodríguez -Solla, C. Concellón and V. del Amo,
Chem. Soc. Rev. 2010, 39, 4103.
(a) H. Kanai and N. Hiraki, Chem. Lett., 1979, 761; (b) H.
7
Kanai, N. Hiraki and S. Iida, Bull. Chem. Soc. Jpn. 1983, 56
1025.
,
8
9
F. Kanami, M. Tomonori and T. Sugimura, Chem. Lett., 2014,
43, 634.
For examples on nickel-catalysed 1,4-addition of alkylzinc
reagents, see: (a) A. E. Greene, J.-P. Lansard, J.-L. Luche and
C. Petrier, J. Org. Chem., 1984, 49, 931; (b) K. Soai, S.
Yokoyama, T. Hayasaka and K. Ebihara, J. Org. Chem., 1988,
Scheme 4. Ni(COD)2-catalysed cyclopropanation of 1a with iodomethylzinc.
53, 4148; (c) C. Bolm, Tetrahedron: Asymm., 1991,
(d) J. F. G. A. Jansen and B. L. Feringa, Tetrahedron: Aymm.,
1992, , 581.
2, 701;
Conclusions
3
In conclusion, a nickel-catalysed cyclopropanation of 
-
10 Zinc halides may also help attenuate the equilibrium
between zinc carbenoids intermediates (i.e. EtZnCH2I,
Zn(CH2I)2 and IZnCH2I) towards more favourable conditions
for cyclopropanation, see: (a) A. B. Charette and J. F.
Marcoux, J. Am. Chem. Soc., 1996, 118, 4539; (b) S. E.
Denmark and S. P. Oconnor, J. Org. Chem., 1997, 62, 3390.
11 Reaction of 3a with 1 equiv. CH2I2 and 1.1 equiv. Et2Zn
resulted in only 59% of 4a together with 41% of unreacted
unsaturated carbonyls with CH2I2/Et2Zn has been developed.
Under our conditions, a variety of cyclopropyl ketones, esters
and amides can be prepared in moderate to good yields.
Further studies are needed to gain a better understanding of
the reaction mechanism.
3a
12 Reaction of 3j with CH2I2/Et2Zn under nickel-free conditions
only gave 13% of 4j
.
Acknowledgements
The financial support for this work was provided by the
Institute of Chemical and Engineering Sciences (ICES), Agency
for Science, Technology and Research (A*STAR), Singapore.
.
13 (a) G. Wittig and F. Wingler, Chem. Ber., 1964, 97, 2146; (b)
S. E. Denmark and J. P. Edwards, J. Org. Chem., 1991, 56,
6974.
14 E. Poverenova and D. Milstein, Chem. Commun., 2007, 43
,
3189.
15 For references on reduction of Ni(II) to Ni(0) by dialkylzinc,
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DOI: 10.1039/C5CC10296K
19 The instability of Ni(COD)2 in the presence of dihalomethane
may also explain its lower efficiency in reaction with
CH2I2/Et2Zn, see reference 7b and: J. S. Miller and K. I.
Pokhodnya, J. Mater. Chem., 2007, 17, 3585.
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