Ni-catalyzed carbocyclization of 1,6-enynes mediated by dialkylzinc reagents: Me2Zn or Et2Zn makes a difference

Article abstract of DOI:10.1055/s-0029-1217368

Unactivated 1,6-enynes were firstly found to undergo different cyclization process under the catalysis of Ni⁰ species in situ generated from Ni^II complexes and dialkylzinc reagents. When stoichiometric Me2Zn was used as the reducing

Full text of DOI:10.1055/s-0029-1217368

LETTER
1785
Ni-Catalyzed Carbocyclization of 1,6-Enynes Mediated by Dialkylzinc
Reagents: Me2Zn or Et2Zn Makes a Difference
N
i-CatalyzedC
h
arbocyclizati
u
on of 1,6-E
n
o
ynes Chai, Hai-Feng Wang, Gang Zhao*
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Lu, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: zhaog@mail.sioc.ac.cn
Received 4 March 2009
a combination of Ni(acac)2/i-Pr2Zn.7 However, an excess
Abstract: Unactivated 1,6-enynes were firstly found to undergo
of i-Pr2Zn (3.0 equiv) and a relatively long reaction time
were required to obtain good results, and the reaction sub-
strates were restricted to N- or O-tethered 1,6-enynes.
different cyclization process under the catalysis of Ni0 species in
situ generated from NiII complexes and dialkylzinc reagents. When
stoichiometric Me2Zn was used as the reducing agent, only the
dimerization products {[2+2+2+2] or [2+2+2]} were obtained. On Thus, an efficient protocol with a broad substrate scope
the other hand, reductive cyclization products were obtained solely
using relatively inexpensive organozinc reagents as the
when 0.6 equivalents of Et2Zn were employed as the reductant un-
reductant under mild conditions would be desirable. We
der otherwise the same reaction conditions. In the former case, up
have previously studied the Pauson–Khand reaction of
to 1:7 selectivity in favor of the [2+2+2] products was also achieved
these substrates with a combination of Cp2TiCl2/Mg.8
with NiCl2(PPh3)2/Me2Zn.
Herein, we report an unprecedented finding that the
Key words: organozinc reagents, enynes, cyclizations, nickel
choice of Me2Zn or Et2Zn has dramatic influence on the
reaction of 1,6-enynes with the NiII/R2Zn (R = Me or Et)
combination. Using a combination of different NiII com-
Nickel-catalyzed reductive coupling and cyclization reac-
tions play an important role in modern organic chemistry
due to its good atom economy and high efficiency for the
construction of complex structures from widely available
plexes and Me2Zn, we unexpectedly found that the
[2+2+2+2]-type products 2 or the [2+2+2]-type products
3 were selectively obtained in good to excellent yields,
while the reductive cyclization products 4 were exclusive-
reaction components and the easy availability and rela-
ly formed when only 0.6 equivalents of Et2Zn were used
tively low costs of Ni-based catalysts.1 Common in most
as the reductant.
of these nickel-catalyzed reactions is the intermediacy of
Initially, the C-tethered 1,6-enyne 1a was selected as the
probe substrate. With 4 mol% of Ni(acac)2 and 1 equiva-
a Ni0 species. One approach to access the desired reactive
Ni0 species is the direct use of Ni0 complexes [most com-
lent of Me2Zn in THF at room temperature, the reaction
monly Ni(cod)2], and this strategy has found successful
could proceed smoothly to provide two dimerization
applications in cycloadditions1,2 and inter- or intramolec-
products of 1a, namely the [2+2+2+2]-type product 2a
ular couplings of alkynes or dienes with various part-
and the [2+2+2]-type product 3a, in 89% total yield with
approximately 1:1 ratio within 1 hour (Table 1, entry 1).
ners.1,3 The other approach relies on the in situ generation
of the reactive Ni0 species from air-stable and inexpensive
The absence of the reductive cyclization product similar
NiII complexes with various reductants.4 This method
to that in Lei’s work may be attributed to the inability of
could circumvent the great inconvenience involved in the
Me2Zn to provide b-hydrogen atom, and it may also imply
that the corresponding reductive cyclization process in-
volving methyl shift is much slower than the dimerization
process.9 To the best of our knowledge, there have been
no reported examples on the Ni0-catalyzed homocoupling
of unactivated 1,6-enynes.10 Although Wender and co-
workers have reported the use of Ni complexes as the cat-
alyst for [2+2+2+2] cycloaddition, this reaction was con-
fined to terminal diynes with a large catalytic amount of
the Ni catalyst.11 Then the reaction temperature, solvents,
the amount of Ni(acac)2, and several other nickel com-
plexes were all examined in order to improve the product
ratio. Interestingly, the use of NiCl2(PCy3)2 as the nickel
source could furnish the two products with good selectiv-
ity (3a/2a = 6:1) at an elevated reaction temperature
(Table 1, entry 13) while the separate use of Cy3P (5
mol%) with Ni(acac)2 allowed the reaction to proceed at
room temperature but led to much poorer selectivity (78%
yield, 3a/2a = 1.5:1).12 The better selectivity observed
manipulation of the extremely air-sensitive Ni0 complexes
utilized in the first one and also enable the discovery of
some new organic transformations. Important applica-
tions of this approach include the coupling of carbonyl
with dienes to form homoallylic alcohols,5 and the reduc-
tive aldol cyclization of substrates containing an a,b-un-
saturated carbonyl moiety tethered to a ketone to form b-
hydroxylactams or b-hydroxylactones.6
Nevertheless, most of the above Ni-catalyzed cyclizations
were restricted to substrates having an electrophilic dou-
ble bond, and rare studies have dealt with the application
of Ni catalysis to convert electronically unactivated 1,6-
enynes. Until very recently, Lei et al. reported the reduc-
tive cyclization reaction of these compounds mediated by
SYNLETT 2009, No. 11, pp 1785–1790
x
x
.x
x
.2
0
0
9
Advanced online publication: 12.06.2009
DOI: 10.1055/s-0029-1217368; Art ID: W02909ST
© Georg Thieme Verlag Stuttgart · New York

1786
Z. Chai et al.
LETTER
with NiCl2(PCy3)2 than NiCl2(PPh3)2 indicated that the Subsequently, a series of 1,6-enynes was selected to ex-
more sterically demanding tricyclohexyl phosphine plore the substrate scope of both the Ni(acac)2/Me2Zn and
ligand favored the [2+2+2] process (Table 1, entries 12 NiCl2(PCy3)2/Me2Zn combinations (Table 2). For C-teth-
and 13). It is worth mentioning that excellent regioselec- ered enynes 1a–g containing aryl substituents at R, high
tivity could be obtained in the formation of 3a with the total yields of the two products were obtained with the
two phenyl groups at meta positions, which was con- Ni(acac)2/Me2Zn combination irrespective of the elec-
firmed by X-ray crystallographic analysis.13 Regretably, tronic nature of the substituents on the phenyl ring, albeit
the use of solvents with weaker coordinating ability, the with poor selectivity (approximately 1:1, Table 2, entries
employment of other Ni salts or the adoption of a larger 1–5). Accordingly, when the NiCl2(PCy3)2/Me2Zn combi-
catalyst loading [20 mol% of Ni(acac)2]14 all failed to pro- nation was used, these substrates invariably favored the
mote the formation of the [2+2+2+2]-type product 2a formation of the [2+2+2] products 3 in moderate yields
(Table 1, entries 4–11). Notably, although mechanistical- with ratios ranging from 4:1 to 7:1 (Table 2, entries 11–
ly a catalytic amount of Me2Zn should be enough to effect 15). However, when the substrate 1f with a terminal
the reaction, the reaction failed to proceed when less than alkyne (R = H) moiety was used, a mixture of many prod-
1 equivalent of Me2Zn was used.15 In addition, the reac- ucts was obtained in the presence of both catalytic sys-
tion was also completely inhibited when performed under tems (Table 2, entries 6 and 16). In addition, when R was
an atmosphere of carbon monoxide (Table 1, entry 4).16
an alkyl substituent (R = n-Bu), no reaction was observed
(Table 2, entries 7 and 17). Surprisingly, only the cyclo-
Table 1 Dimerization of 1a with NiX2/Me2Zn under Various Conditionsa
MeO2C
CO2Me
MeO2C
Ph
CO2Me
Ph
MeO2C
NiII (4 mol%)
MeO2C
MeO2C
Ph
Ph
+
MeO2C
1a
Me2Zn (1 equiv)
THF, 1 h
Ph
3a
MeO2C
CO2Me
2a
Entry
1
Catalyst
Temp
r.t.
Solvent
THF
Yield (%)b
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
NiCl2
89
79
70
0
2
reflux
0 °C
r.t.
THF
3
THF
4c
5d
6
THF
r.t.
THF
70
81
85
81
73
71
0
r.t.
toluene
CH2Cl2
Et2O
THF
7
r.t.
8
r.t.
9
r.t.
10
11
12e
13f
14
(dme)NiCl2
Ni(OAc)2
NiCl2(PPh3)2
NiCl2(PCy3)2
Ni(dppe)Cl2
r.t.
THF
r.t.
THF
reflux
reflux
r.t.
THF
88
75
78
THF
THF
a All reactions were run at a substrate concentration of 0.1 M on a 0.3 mmol scale.
b Total yield of the isolated products 2a + 3a, the ratio of these two compounds was estimated by 1H NMR analysis of the crude product to be
approximately 1:1 unless otherwise noted.
c The reaction was run under an atmosphere of carbon monoxide.
d The amount of 20 mol% of Ni(acac)2 used.
e Ratio of 3a/2a = 3:1.
f Ratio of 3a/2a = 6:1, yield referred to the isolated pure 3a.
Synlett 2009, No. 11, 1785–1790 © Thieme Stuttgart · New York

LETTER
Ni-Catalyzed Carbocyclization of 1,6-Enynes
1787
octadiene product 2h17 was obtained for both the two and 1j. In the case of N-tosylated enyne 1i, only some un-
combinations in the case of the O-tethered enyne 1h in a identifiable polymeric products were obtained which may
lower yield which may be attributed to the cleavage of the be due to the oligomerization of the substrate,19 and a
allyl ether in the presence of Ni0 species (Table 2, entries complex reaction mixture was obtained for the N-benzyl
8 and 18).18 More striking difference between the two enyne 1j when the Ni(acac)2/Me2Zn combination was em-
combinations was found for the N-tethered substrates 1i ployed (Table 2, entries 9 and 10). However, the corre-
Table 2 Substrate Scope Study with NiX2/Me2Zna,22
R
R
R
NiII (4 mol%)
X
X
X
X
+
X
Me2Zn (1 equiv)
THF, 1 h
R
r.t. or reflux
3
1
R
2
Entry
Catalyst
Substrate
X
R
Yield (%)b
2
3
1
2
Ni(acac)2
1a
1b
1c
1d
1e
1f
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
O
Ph
46 (2a)
45 (2b)
41 (2c)
42 (2d)
38 (2e)
complex
43 (3a)
43 (3b)
42 (3c)
43 (3d)
42 (3e)
Ni(acac)2
4-FC6H4
4-F3CC6H4
4-MeC6H4
4-PhC6H4
H
3
Ni(acac)2
4
Ni(acac)2
5
Ni(acac)2
6
Ni(acac)2
c
7
Ni(acac)2
1g
1h
1i
n-Bu
–
d
8
Ni(acac)2
Ph
25 (2h)
–
e
9
Ni(acac)2
NTs
Ph
–
10
11
12
13
14
15
16
17
18
19
20
Ni(acac)2
1j
NBn
Ph
complex
d
NiCl2(PCy3)2
NiCl2(PCy3)2
NiCl2(PCy3)2
NiCl2(PCy3)2
NiCl2(PCy3)2
NiCl2(PCy3)2
NiCl2(PCy3)2
NiCl2(PCy3)2
NiCl2(PCy3)2
NiCl2(PCy3)2
1a
1b
1c
1d
1e
1f
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
O
Ph
–
75 (3a)f
68 (3b)g
65 (3c)h
73 (3d)i
70 (3e)j
d
4-FC6H4
4-F3CC6H4
4-MeC6H4
4-PhC6H4
H
–
d
–
d
–
d
–
complex
c
1g
1h
1i
n-Bu
–
d
Ph
23 (2h)
–
d
NTs
Ph
–
75 (3i)k
69 (3j)k
d
1j
NBn
Ph
–
a All reactions were run at a substrate concentration of 0.1 M on a 0.3 mmol scale; r.t. for Ni(acac)2/Me2Zn and refluxing temperature for
NiCl2(PCy3)2/Me2Zn.
b Yield of the isolated product after column chromatography, the ratio of these two compounds was estimated by 1H NMR analysis of the crude
product.
c Starting material was recovered.
d Not isolated.
e Unidentifiable polymeric product was obtained.
f Ratio of 3a/2a = 6:1.
g Ratio of 3b/2b = 7:1.
h Ratio of 3c/2c = 5:1.
i Ratio of 3d/2d = 6:1.
j Ratio of 3e/2e = 4:1.
k Single-product formation was observed by 1H NMR analysis.
Synlett 2009, No. 11, 1785–1790 © Thieme Stuttgart · New York

1788
Z. Chai et al.
LETTER
sponding [2+2+2]-type products 3i and 3j could be Table 3 Substrate Scope Study with Ni(acac)2/Et2Zna
obtained solely in 75% and 69% yields, respectively, for
R
the NiCl2(PCy3)2/Me2Zn combination (Table 2, entries 19
and 20).
R
Ni(acac)2 (4 mol%)
X
X
Et2Zn (0.6 equiv)
THF, r.t., 1 h
In contrast, when Et2Zn was used instead of Me2Zn under
the same reaction conditions described above, only the re-
ductive cyclization products 4 were obtained for all the
substrates examined (Table 3).20 In general, the substrate
scope in this case is broader than that of the Me2Zn sys-
tem. It was found that the use of 0.6 equivalents of Et2Zn
could deliver the desired product in comparable yield to
that when 1.2 equivalents of Et2Zn were employed, which
may indicate that both the two ethyl groups in Et2Zn could
serve as the hydride source in the reaction (Table 3, en-
tries 1 and 2). Of all the C-tethered enynes 1a–n, the cor-
responding cyclopentane products could be obtained in
moderate to good yields with excellent Z-selectivity for
the newly formed alkene while no ethylated cyclization
products were observed (Table 3, entries 1–9). Notably,
the unsuccessful substrates 1f and 1g in the dimerization
reaction could participate in the reaction to provide the de-
sired products in moderate yields (Table 3, entries 6 and
7). In addition, enynes 1m and 1n with substituted alkene
groups also provide the desired products in good yields
(Table 3, entries 8 and 9). However, when the O-tethered
enyne 1h was used, both the normal product 4ha and the
ethylated cyclization product 4hb were obtained in low
yields and poor selectivity (Table 3, entry 10). Further op-
timization of this reaction revealed that lowering the reac-
tion to –30 °C and using 2 equivalents of Et2Zn could
improve the selectivity to 1:5 (4ha/4hb) in 58% total
yield.21 Under the standard reaction conditions, no desired
reductive cyclization product for the N-tosylated enyne 1i
could be obtained, which may also be caused by the sub-
strate oligomerization similar to that when Me2Zn was
employed. It seemed that an excess of Et2Zn and elevated
reaction temperature favored the reductive cyclization
process, and the desired product could be obtained in 56%
yield upon optimization (Table 3, entry 11).
1
4
Entry Substrate X
R
Product
Yield
(%)b
1
1a
C(CO2Me)2 Ph
C(CO2Me)2 Ph
4a
4a
75
78
80
83
81
60
73
2c 1a
3
4
5
6
7
1c
1d
1l
C(CO2Me)2 4-F3CC6H4 4c
C(CO2Me)2 4-MeC6H4 4d
C(CO2Me)2 4-ClC6H4
C(CO2Me)2
4l
1f
H
4f
4g
1g
C(CO2Me)2 n-Bu
CO2Me
8
9
1m
1n
4m
4n
85
88
CO2Me
Ph
MeO2C
MeO2C
Ph
Ph
29
23
10
1h
O
Ph
O
R
4ha R = H
4hb R = Et
4i
11d 1i
NTs
Ph
Ph
Ph
56
12
13
1j
NBn
NBoc
complex
complex
32
1k
4k
a All reactions were run at a substrate concentration of 0.1 M on a 0.3
mmol scale.
b Yield of the isolated product after column chromatography.
c The amount of 1.2 equiv of Et2Zn was used.
d The amount of 2.2 equiv of Et2Zn was used, and the reaction was run
at 60 °C.
In summary, we have firstly disclosed the distinct effects
of different dialkylzinc reagents on the Ni0-catalyzed car-
bocyclizations of unactivated 1,6-enynes. The finding of
the homodimerization of these substrates under the catal-
ysis of Ni0 species is unprecedented. This research also af-
fords an easy way to construct cyclooctadienes or bicyclic
diene compounds as well as five-membered rings.
References and Notes
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Acknowledgment
Generous financial support from the National Natural Science
Foundation of China, QT Program and Shanghai Natural Science
Council is gratefully acknowledged.
Synlett 2009, No. 11, 1785–1790 © Thieme Stuttgart · New York

LETTER
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(15) When 50 mol% or 20 mol% of Me2Zn were used, the
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(19) In ref. 7, the authors also proposed that oligomerization may
be the possible reason for the decreased yield with 1j.
(20) For selected examples for the reductive cyclization of
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(9) For examples of Ni-catalyzed reductive cyclization pro-
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references cited therein.
(10) For a example of Rh-catalyzed homodimerization of 1,6-
enynes, see: (a) Evans, P. A.; Robinson, J. E.; Baum, E. W.;
Fazal, A. N. J. Am. Chem. Soc. 2002, 124, 8782. For
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metallocyclopentadienes in the homodimerization of
1,3-perfluoroalkylenynes, see: (d) Saito, S.; Tanaka, T.;
Koizumi, T.; Tsuboya, N.; Itagaki, H.; Kawasaki, T.; Endo,
S.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 1810.
(e) Saito, S.; Kawasaki, T.; Tsuboya, N.; Yamamoto, Y.
J. Org. Chem. 2001, 66, 796.
(21) The addition of 5 mol% of Ph3P, PCy3 or (R)-BINAP did not
improve the product selectivity significantly.
(22) Typical Procedure for the Dimerization of 1 with NiII/
Me2Zn Combination
Under an atmosphere of argon, 3.2 mg (0.012 mmol) of
Ni(acac)2 were added to a Schlenk tube, and the system was
purged with argon three times. Then enyne 1a (86 mg, 0.3
mmol) in 3.0 mL of freshly distilled THF was added via a
syringe followed by the addition of Me2Zn 0.3 mmol (1.2 M
in toluene) in one portion [in the case of NiCl2(PCy3), Me2Zn
was added at reflux]. The reaction mixture was stirred for 1
h at r.t. before being quenched with sat. aq NH4Cl soln.
Then, the mixture was extracted with CH2Cl2 (3 × 3 mL),
dried with anhyd Na2SO4. After removal of the solvent in
vacuum, the residue was purified by column
(11) Wender, P. A.; Christy, J. P. J. Am. Chem. Soc. 2007, 129,
13402.
(12) The combined use of 6 mol% of Cy3P and 5 mol% of
Ni(acac)2 only led to a ratio of 1.5:1 favoring the [2+2+2]
product 3a. Attempts to interject the reaction intermediate
with a third alkyne (3 equiv) resulted in a complex mixture
(when ethyl 3-phenylpropiolate was used) or the recovery of
most of the starting 1,6-enyne 1a (when phenylacetylene or
1-hexyne were used), however, similar strategy was
successful with Rh-catalyzed reactions of unactivated 1,6-
enynes: (a) Baik, M.-H.; Baum, E. W.; Burland, M. C.;
Evans, P. A. J. Am. Chem. Soc. 2005, 127, 1602. (b) Evans,
P. A.; Lai, K. W.; Sawyer, J. R. J. Am. Chem. Soc. 2005, 127,
12466. (c) Evans, P. A.; Sawyer, J. R.; Lai, K. W.; Huffman,
J. C. Chem. Commun. 2005, 63. (d) Evans, P. A.; Baum,
chromatography (silica gel, PE–Et2O = 4:1) to provide the
desired products 2a and 3a.
(5E,10E)-Tetramethyl-5,10-diphenyl-3a,4,8a,9-
tetrahydropyrene-2,2,7,7(1H,3H,6H,8H)-tetracarboxy-
late (2a)
Colorless crystal; mp 193–194 °C (hexane–Et2O). 1H NMR
(300 MHz, CDCl3): d = 7.36–7.17 (m, 10 H), 3.67 (s, 6 H),
3.63 (s, 6 H), 3.05–2.70 (m, 10 H), 2.24 (d, J = 10.6 Hz, 2 H),
1.95–1.89 (dd, J = 13.1, 6.8 Hz, 2 H) ppm. 13C NMR (75
MHz, CDCl3): d = 172.0, 171.7, 145.2, 144.2, 136.1, 128.3,
127.7, 126.3, 59.4, 52.60, 52.59, 46.2, 43.9, 43.0, 40.4 ppm.
IR (KBr): 2952, 1734, 1434, 1250, 1205, 1070, 703 cm–1.
MS (EI): m/z = 572 [M+], 167(base). HRMS (EI): m/z calcd
Synlett 2009, No. 11, 1785–1790 © Thieme Stuttgart · New York

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Z. Chai et al.
LETTER
for C34H36O8: 572.2410; found: 572.2413.
1.95 (dd, J = 13.2, 8.8 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): d = 172.2, 171.9, 171.1, 142.1, 141.4, 139.2, 133.7,
133.1, 130.1, 129.8, 129.6, 128.4, 128.0, 127.8, 127.0,
126.6, 117.7, 60.2, 59.0, 52.9, 52.7, 52.0, 39.6, 39.1, 38.5,
38.4, 37.8, 30.5 ppm. IR (KBr): 2953, 1732, 1491, 1435,
1380, 763, 735, 703 cm–1. MS (EI): m/z = 572 [M+],
279(base). HRMS (EI): m/z calcd for C34H36O8Na+:
595.2316 0.002; found: 595.2302.
Dimethyl 6-[2,2-Bis(methoxycarbonyl)pent-4-enyl]-5,7-
diphenyl-3a,4-dihydro-1H-indene-2,2(3H)-dicarboxy-
late (3a)
Colorless crystal;13 mp 87–89 °C (hexane–Et2O). 1H NMR
(300 MHz, CDCl3): d = 7.39–7.18 (m, 10 H), 4.86–4.74 (m,
1 H), 4.58–4.68 (m, 2 H), 3.77 (s, 3 H), 3.64 (s, 3 H), 3.46 (s,
3 H), 3.36 (s, 3 H), 3.32–3.22 (m, 1 H), 2.97–2.57 (m, 5 H),
2.28 (d, J = 6.9 Hz, 2 H), 2.14 (t, J = 17.4 Hz, 1 H), 2.02–
Synlett 2009, No. 11, 1785–1790 © Thieme Stuttgart · New York