Ni-catalyzed reductive allylation of unactivated alkyl halides with allylic carbonates

Article abstract of DOI:10.1002/chem.201102984

Game of two electrophiles: Two partially positively charged sp³ carbon atoms can be connected by using a catalytic Ni species in the presence of an environmentally benign Zn reductant, delivering allylated alkanes (see scheme). This unprecedent

Full text of DOI:10.1002/chem.201102984

DOI: 10.1002/chem.201102984
Ni-Catalyzed Reductive Allylation of Unactivated Alkyl Halides with Allylic
Carbonates
Yijing Dai, Fan Wu, Zhenhua Zang, Hengzhi You, and Hegui Gong*[a]
Allylation of alkyl substrates represents a very important
reaction type in modern synthetic organic chemistry. Numer-
ous elegant approaches to allylated alkanes have been de-
veloped, primarily based on the transition-metal-catalyzed
addition of alkyl nucleophiles to allylic electrophiles.[1–3] This
includes the recent Ni-catalyzed asymmetric Negishi cou-
pling of primary alkylzinc reagents with allylic chlorides de-
veloped by Fu and co-workers.[2] There are also a few exam-
ples focusing on the catalytic coupling of allylic Grignard re-
agents with alkyl electrophiles.[3] On the other hand, the
direct coupling of alkyl halides with allylic electrophiles, de-
spite appearing to be a more convenient strategy because
alkyl halides are, in general, more accessible and easier to
use than alkyl nucleophiles, has not been well addressed. In
addition to the Cu-catalyzed allylation of in situ alkyl
Grignard reagents, radical allylation of alkyl halides has also
been documented.[4–7] However, these methods are subject
to either narrow substrate scope or regioselectivity issues. In
particular, the classical radical addition and fragmentation
process often requires toxic radical initiators or light ir-
pling approaches that use unactivated alkyl halides with
other electrophiles, we recently discovered a direct coupling
reaction of two different unactivated alkyl halides under Ni-
catalyzed reductive conditions, for which the catalyst dis-
plays intriguing features in differentiating the alkyl sub-
strates and subduing the competitive homocoupling side re-
actions.[10a] Extension of this strategy to the reductive cou-
pling of unactivated alkyl halides with allylic electrophiles is
therefore appealing because the allylic electrophiles can be
viewed as activated alkyl species that possess very different
reactivities from the unactivated alkyl halides.
In addition, recent studies on the Ni-catalyzed Negishi
coupling of alkyl halides have suggested that the oxidative
addition of alkyl halides to a NiI intermediate involves the
generation of an alkyl radical and a NiII species prior to the
formation of NiIII.[11–13] This further prompted us to deter-
mine the feasibility of the Ni-catalyzed allylation of alkyl
halides with allylic electrophiles in the presence of a termi-
nal reductant, such as Zn. We reasoned that alkyl radi-
cal[10a,14] and allyl–NiII intermediates can be generated under
these conditions, which may lead to allylated alkanes.
Herein, we disclose the Ni-catalyzed allylation of various
functionalized alkyl halides with substituted allylic carbo-
nates by using environmentally benign Zn powder as the re-
ductant to provide E-alkenes in good to excellent yields and
excellent regioselectivities. Our preliminary mechanistic
studies also suggest that a catalytic redox process may be in-
volved in this method.
ACHTUNGTRENNUNGradiation, and suffers from poor E/Z selectivity. Therefore,
development of a highly efficient reductive coupling be-
tween alkyl halides and allylic electrophiles is still widely
sought. Very recently, a cobalt-catalyzed reductive coupling
of alkyl halides with allylic acetate or carbonates was dis-
closed, for which moderate regioselectivity was observed for
more hindered alkyl and allylic substrates.[8]
The catalytic reductive coupling of alkyl and/or aryl elec-
trophiles has advanced rapidly since 2009.[8–10] In general,
these coupling processes can be classified into two types,
namely, in situ formation of organometallic nucleophiles
and redox processes. Whereas the first category comprises
Co-, Fe-, and Pd-catalyzed reductive couplings of alkyl and
aryl halides,[9] the second reaction type has been demon-
strated in the Co- and Ni-catalyzed reductive coupling of
alkyl halides.[8,10] As part of an effort to develop cross-cou-
We initially examined the reaction of 4-iodo-1-tosylpiperi-
dine (1a) with allyl methylcarbonate (2a) by employing [Ni-
AHCTUNGRTEG(NNUN cod)2] (10 mol%; cod=1,5-cyclooctadiene)/iPr-PyBox 4a
(15 mol%), Zn as the reductant,[15] and N,N-dimethylaceta-
mide (DMA) as the solvent. Gratifyingly, the allylated prod-
uct 3a was obtained in a 67% yield (Table 1, entry 1). Addi-
tion of CuI (20 mol%) further enhanced the yield to 82%
(Table 1, entry 2). The reactions went to completion after
six hours either with or without CuI. The excess 2a under-
went slow homocoupling, and a substantial amount of 2a
was recovered after 12 h. The byproducts arising from 1a in
both cases were determined to be a 2:1 ratio of the hydro-
dehalogenation and b-hydride elimination products, along
with a trace amount of the homocoupling product of 1a.
Therefore, CuI appears to inhibit the side reactions.[16] Rais-
ing the CuI loading or the temperature did not yield better
results (Table 1, entries 3 and 4). Other ligands, such as 4b,
also did not generate better yields (Table 1, entry 5). Allylic
[a] Y. Dai, F. Wu, Z. Zang, H. You, Prof. Dr. H. Gong
Department of Chemistry
Shanghai University
Shang-Da Road, E-327 (P.R. China)
Fax : (+)86-21-66134594
E-mail: Hegui_gong@shu.edu.cn
Homepage: http://www.chem.shu.edu.cn/Portals/287/Gonghegui/
Gonghegui/
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102984.
808
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 808 – 812

COMMUNICATION
Table 1. Optimization of the coupling reaction of 1 with allyl carbonate 2a.[a]
hydro-dehalogenation (ꢀ10%), b-hydride elimina-
tion (ꢀ10%), and homocoupling (ꢀ10%). The
side reactions, however, could be significantly sup-
pressed by employing a stoichiometric amount of
MgCl2 as the sole additive (Table 1, entries 16–19).
A
combination of 1 equivalent of MgCl2 and
15 mol% of 6 gave the highest yield (91%). The
amount of 6 could be further reduced to 10 mol%
without diminishing the yield by utilizing 1.5 equiv-
alents of MgCl2 (Table 1, entry 19).
By using the optimized conditions for 2a
(Table 1, entries 4 and 19), a diverse set of substitut-
ed allylic carbonates 2b–2m were examined for the
coupling reaction with 1a and 1b (Table 2). For the
3-alkyl-substituted allyl substrates 2b (trans) and 2c
(cis), moderate to good yields were obtained with
1a (Table 2, entries 1 and 3), whereas excellent
yields were observed with 1b (Table 2, entries 2 and
4). It should be noted that only the trans-product
3c was isolated for the reaction of cis-3-ethyl car-
bonate 2c (Table 2, entries 3 and 4). For trans-3-
phenyl carbonate 2d, both 1a and 1b delivered the
allylated product 3d in high yields, despite the fact
that 1b appears to be more efficient (Table 2, en-
tries 5 and 6). The allylic carbonates bearing 2-
methyl groups, as in 2e and 2 f, generally displayed
much lower reactivity, giving poor results for both
1a and 1b (Table 2, entries 7–10). The 2-phenyl car-
bonate 2g, however, behaved differently from the
2-alkyl-substituted analogues, providing moderate
and excellent yields for 1a and 1b, respectively
(Table 2, entries 11 and 12). The coupling reactions
of 1a and 1b with 1-alkyl-substituted allyl sub-
strates 2h–2k were generally highly efficient
X
Ligand
([mol%])
R
Y
Additive
([mol%])
T
[8C]
t
Yield
[%][b]
G
E
[h]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
I
I
I
I
4a (15)
4a (15)
4a (15)
4a (15)
4b (15)
4a (15)
4a (15)
4a (15)
4b (15)
4c (15)
4d (15)
4e (15)
5 (15)
iPr
iPr
iPr
iPr
H
iPr
iPr
iPr
H
Me
sBu
tBu
–
iPr
–
H
H
H
H
H
H
H
H
H
H
H
H
–
none
CuI (20)
CuI (50)
CuI (30)
CuI (20)
none
none
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
25
25
25
35
25
25
80
80
80
80
80
80
80
80
80
80
80
80
80
12
12
6
67
82
82
82
5
6
I
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
n.d.[c]
7
45
10
20
40
n.d.[c]
35
CuI (20)
4a (15)
6 (15)
4a (15)
4 f (15)
6 (15)
H
–
H
OMe
–
CuI (20)/MgCl2 (1:1)
CuI (20)/MgCl2 (1:1)
MgCl2 (100)
MgCl2 (100)
MgCl2 (100)
MgCl2 (150)
65
65
76
68
91
91
iPr
iPr
–
6 (10)
–
–
[a] Reaction conditions: 1 (100 mol%, 0.15m in DMA), 2 (200 mol%), [NiACTHNUTRGNE(UNG cod)2]
(10 mol%), Zn (300 mol%), DMA (1 mL). Ligand, additive, temperature, and reac-
tion time are variables. [b] Isolated yields. [c] n.d.=not detected.
substrates bearing leaving groups, such as acetate and tBu-
carbonates, resulted in low yields; no products were ob-
tained for allyl bromide and phenyl sulfonate reagents.
When 4-bromo-1-tosylpiperidine (1b) was subjected to
(Table 2, entries 13–20). Poor results were delivered for 1-
phenyl allylic carbonate 2l due to extensive homocoupling
(Table 2, entries 21–22). Finally, the sterically more congest-
ed 1,3-diethyl compound 2m provided 3m in poor yields
(Table 2, entries 23 and 24).
the [NiACHTUNGTRENNUNG(cod)2]/4a/Zn/DMA conditions at 258C, only hydro-
dehalogenation and b-hydride elimination of 1b were ob-
served (Table 1, entry 6). Raising the temperature produced
3a in a highest yield of only 7% at 808C (Table 1, entry 7
and Table S1 in the Supporting Information).[17] The addi-
tion of CuI (20 mol%) boosted the yield to 45% (Table 1,
entry 8 and Table S2 in the Supporting Information).[17] Ex-
tensive examination of ligands (Table 1, entries 9–13) and
solvents (Table S3 in the Supporting Information) did not
result in any further improvements.[17] However, the addition
of anhydrous MgCl2 (20 mol%) promoted the yield to 65%
by using 4a as the ligand (Table 1, entry 14),[18] which is
comparable to the yield found when using tBu-Terpy (6;
Table 1, entry 15) as the ligand. Further screening of differ-
ent Ni sources and reductants did not provide better results
(Tables S4 and S5 in the Supporting Information). Under
the improved reaction conditions (Table 1, entry 14), 1b was
consumed after 8 h, whereas a substantial amount of 2a was
recovered; the byproducts derived from 1b were from
Interestingly, extensive screening of other ligands for the
example reactions in Table 2 indicated that the coupling effi-
ciency for 1a with 3-alkyl and 2-aryl allylic carbonates, and
1b with 2-alkyl and 3,3’-dimethyl allylic carbonates could be
drastically improved by using ligand 4g (Table 3). The gen-
erality of these scenarios was evident for 2b, 2c, and 2n
(Table 3, entries 1–3), 2e, 2 f, and 2o (Table 3, entries 4–6),
and 2g and 2p (Table 3, entries 7 and 8).
Notably, all reactions examined in Tables 2 and 3 gave E-
alkenes only. The excellent regioselectivities (>20:1) for un-
symmetrical allylic substrates were derived from the addi-
tion of the alkyl group to the sterically less hindered allylic
terminus. In general, sterically more encumbered allylic sub-
strates, such as 2m, led to lower yields. When the allylation
was less efficient, hydro-dehalogenation and homocoupling
of 1a or 1b were usually the major factors accounting for
poor results, with the latter being the main side reaction.
Chem. Eur. J. 2012, 18, 808 – 812
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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809

H. Gong et al.
Table 2. Coupling of 1 with substituted allylic carbonates.[a]
Table 3. Use of 4g for the coupling of 1 and allylic substrates with cer-
tain substitution patterns.[a]
À
R X Allylic Substrates
Product
Yield
[%][b]
1
2
3
4
5
6
7
8
1a
1b
1a
1b
1a
1b
1a
1b
65
82
40
89
75
91
trace
35
2b
2c
2d
3b
3c
3d
À
R X
Allylic Substrates
Product
Yield
[%][b]
1
2
3
1a
1a
1a
2b
2c
2n
3b
3c
3n
70
74
75
2e
3e
9
1a
trace
37
2 f
2g
3 f
3g
4
1b
2e
3e
90
10 1b
11 1a
12 1b
49
85
5
6
1b
1b
2 f
3 f
78
83
13 1a
14 1b
88
90
2h 3h=3b
2o
3o
15 1a
16 1b
85
90
2i
2j
3i=3c
7
8
1a
1b
Ar=Ph
Ar=4-MeO-C6H4
2g
2p
3g
3p
75
70
17 1a
18 1b
82
91
3j
[a] Reaction conditions: 1 (100 mol%, 0.15m in DMA), 2 (200 mol%),
[Ni(cod)2] (10 mol%), Zn (300 mol%), DMA (1 mL). For X=I, meth-
19 1a
20 1b
80
70
2k 3k=3e
AHCTUNGTRENNUNG
od A: 4g (15 mol%), CuI (30 mol%) at 358C, 6 h; for X=Br, method B:
6 (10 mol%), MgCl2 (150 mol%) at 808C, 12 h. [b] Isolated yields.
21 1a
22 1b
trace
14
2l
3l=3d
23 1a
24 1b
trace
17
2m
3l
[a] Reaction conditions: 1 (100 mol%, 0.15m in DMA), 2 (200 mol%),
[Ni(cod)2] (10 mol%), Zn (300 mol%), DMA (1 mL). For X=I, meth-
od A: 4a (15 mol%), CuI (30 mol%) at 358C, 6 h; for X=Br, method B:
6 (10 mol%), MgCl2 (150 mol%) at 808C, 12 h. [b] Isolated yields.
entry 16), for which a combination of 4a, CuI, and MgCl2
was determined to be the optimal reaction mixture.
ACHTUNGTRENNUNG
To obtain insight into the reaction mechanism, we first ex-
amined whether the in situ formation of alkylzinc reagents
was a possible reaction route,[20] by attempting the coupling
of cyclohexylzinc halides with 2g under the optimized reac-
tion conditions in the absence of Zn. However, this reaction
only produced trace amounts of 8g at 35 or 808C
(Scheme 1). This provides direct evidence that the allylation
Extension of the allylation approach to other alkyl halides
7a–7n was also pursued (Table 4). The reaction tolerated a
wide array of functional groups, including amide, aryl
halide, ketal, ether, nitrile, ester, and even alcohol groups.
Excellent regioselectivities (>
20:1) were also observed, with
addition of the alkyl group to
the less hindered allylic carbon
terminus (Table 4, entries 1–7,
12 and 16). In general, secon-
dary cyclic alkyl halides 7a–7k
Scheme 1. Coupling of an organozinc reagent with 2g.
provided the allylated alkanes
8a–8k in good to excellent
yields (Table 4, entries 1–13), with the exception of only a
53% yield of 8j due to substantial homocoupling of 7j (X=
I, Table 4, entry 12). Of special note is the high yield ob-
tained for 8k, containing a free hydroxyl group. The open
chain secondary alkyl halides were also compatible with the
optimized reaction conditions, offering 8l and 8m in good to
excellent yields (Table 4, entries 14 and 15). No enantiose-
lectivity was observed for 8l (Table 4, entry 14, see the Sup-
porting Information).[19] Finally, primary alkyl halide 7n also
produced the allylated product 8n in a 62% yield (Table 4,
process is unlikely to proceed through an in situ alkylzinc/
Negishi pathway.[2,21]
Additionally, under the allylation conditions, compound 9
underwent intramolecular cyclization followed by allylation
with 2g to give 10 in high endo diastereoselectivity, indicat-
ing that a radical intermediate was probably involved in the
oxidative-addition step (Scheme 2).[13c,22] A mechanism im-
plicating radical addition to allyl carbonate, followed by
fragmentation to generate the allylated product, can be
ruled out based on previous studies.[23]
810
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 808 – 812

Ni-Catalyzed Reductive Allylation
COMMUNICATION
Table 4. Scope and limitation of alkyl halides.[a]
X
Ligand
2
Product
Yield
[%][b]
1
2
3
4
5
6
I
I
I
Br
Br
Br
4a
4a
4a
6
6
6
2h
2h
2h
2h
2h
2b
8b, R=F
8b, R=Cl 94
8c, R=Br 67
8a, R=F
8b, R=Cl 90
8d, R=CN 62
90
91
Scheme 3. Proposed reaction mechanism for the allylic alkylation.
allyl–NiI intermediate,[24] which enables one-electron reduc-
tion of alkyl halides to give an alkyl radical and a second
allyl–NiII complex. This hypothesis is in agreement with the
stoichiometric allylic coupling of allylnickel(I) complexes
with alkyl halides through a possible electron-transfer radi-
cal chain process.[25] Combination of the alkyl radical and
7
Br 4a
2e
8e
80
8
9
Br
Br
6
6
6
2g
2g
2g
8 f
8g
8h
85
72
II
III
À
the Ni intermediates generates an R Ni –allyl species. Re-
ductive elimination delivers the allylated alkane, along with
a second NiI intermediate that is reduced to Ni0 by Zn, al-
lowing for the catalytic cycle to proceed. Although not di-
rectly relevant, NiI/NiIII catalytic transformations have also
been suggested in the Ni-catalyzed reductive coupling of
aryl and alkyl halides.[10,11c,26]
10 Br
11 Br
56[c]
6
2g
2h
8i
8j
75[c]
53[d]
12
I
4a
An alternative pathway involving reductive transmetala-
tion of allyl–NiII to allyl–Zn followed by a Negishi transfor-
mation is possible.[27] However, this notion seems to contra-
dict the failure of the coupling of allylzinc bromide with 1a
and 1b under the optimized reaction conditions in the ab-
13 Br
6
2a
8k
82[c]
À
sence of 2a and zinc, for which the reduction of the C X
bonds accounted for the major product.
14
I
4a
6
2a
2g
8l
64[e]
85
In conclusion, an efficient Ni-catalyzed method for the al-
lylation of alkyl halides has been developed. Allylic sub-
strates with various substitution patterns, and alkyl halides
decorated with different functional groups are tolerated. Al-
kylation of unsymmetrical allylic carbonates provides exclu-
sively E-alkenyl products. For less congested allylic carbo-
nates, this method displays excellent regioselectivities by ad-
dition of alkyl groups to the less hindered allylic carbon
atom. In addition, although more evidence is required, this
unprecedented Ni-catalyzed allylation process appears to be
mechanistically in agreement with a NiI/NiIII redox process
that has been proposed for the stoichiometric coupling of
allyl-NiI with alkyl halides.[25] Future work will focus on de-
tailed mechanistic studies, including reaction kinetics, as
well as extending this protocol to sterically more encum-
bered reactants.
15 Br
8m
16 Br 4a
2b
8n
62[f]
[a] Reaction conditions: 1 (100 mol%, 0.15m in DMA), 2 (200 mol%),
[Ni(cod)2] (10 mol%), Zn (300 mol%), DMA (1 mL). For X=I, meth-
ACHTUNGTRENNUNG
od A: 4a (15 mol%), CuI (30 mol%) at 358C, 6 h; for X=Br, method B:
4g or 6 (10 mol%), MgCl2 (150 mol%) at 808C, 12 h. [b] Isolated yields.
[c]>20:1 diastereoselectivity. [d] 208C. [e] No enantioselectivity was ob-
tained. [f] Use of 4a (15 mol%)/CuI (20 mol%)/MgCl2 (20 mol%) at
808C.
Although more experiments are required to further un-
derstand the allylation mechanism, we propose that the re-
action is likely to proceed first by oxidative addition of Ni0
to allyl carbonate to produce
a
p-allyl–NiII species
(Scheme 3). Single-electron reduction by Zn leads to an
Acknowledgements
Prof. Gagnꢁ (UNC) is thanked for ini-
tial advice on this work. Prof. Xile Hu
(EPEL) is acknowledged for helpful
suggestions. Dr. Hongmei Deng is
thanked for helping with the use of
the NMR facility at Shanghai Univer-
sity. Financial support was provided by
Scheme 2. Coupling of compound 9 with 2g.
Chem. Eur. J. 2012, 18, 808 – 812
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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811

H. Gong et al.
the Chinese NSF (Nos. 2097209 and 21172140), the Program for Profes-
sor of Special Appointment at Shanghai Institutions of Higher Learning
Shanghai Education Committee and Shanghai Leading Academic Disci-
pline Project (No. S30107).
48, 154–156; b) J. Zhou, G. C. Fu, J. Am. Chem. Soc. 2003, 125,
14726–14727; c) H. Gong, M. R. Gagnꢁ, J. Am. Chem. Soc. 2008,
130, 12177–12183; d) R. Giovannini, P. Knochel, J. Am. Chem. Soc.
1998, 120, 11186–11187.
[13] For mechanistic discussions on Ni-catalyzed Negishi reactions, see:
a) X. Lin, J. Sun, Y. Xi, D. Lin, Organometallics 2011, 30, 3284–
3292; b) X. Lin, D. L. Phillips, J. Org. Chem. 2008, 73, 3680–3688;
c) V. B. Phapale, E. BuÇuel, M. Garcꢂa-Iglesias, D. J. Cꢃrdenas,
Angew. Chem. 2007, 119, 8946–8951; Angew. Chem. Int. Ed. 2007,
46, 8790–8795; d) G. D. Jones, J. L. Martin, C. McFarland, O. R.
Allen, R. E. Hall, A. D. Haley, R. J. Brandon, T. Konovalova, P. J.
Desrochers, P. Pulay, D. A. Vicic, J. Am. Chem. Soc. 2006, 128,
13175–13813.
[14] H. Gong, R. S. Andrews, J. L. Zuccarello, S. J. Lee, M. R. Gagnꢁ,
Org. Lett. 2009, 11, 879–882.b) R. Shrestha, D. J. Weix, Org. Lett.
2011, 13, 2766–2769.
[15] Zn powder activated with HCl (2n) was crucial for reproducibility.
[16] CuI has been used to mediate the Barbier alkylation of aldehydes,
involving the formation of alkyl radicals, see: Z.-L. Shen, Y.-L. Yeo,
T.-P. Loh, J. Org. Chem. 2008, 73, 3922–3924.
Keywords: alkyl halides · allylation · allylic compounds ·
nickel · reductive coupling
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[17] See the Supporting Information for Tables S1–S5.
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˘
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Received: September 22, 2011
Published online: December 14, 2011
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