Nickel-Catalyzed reductive cross-Coupling of unactivated alkyl halides

Article abstract of DOI:10.1021/ol200617f

A Ni-catalyzed reductive approach to the cross-coupling of two unactivated alkyl halides has been successfully developed. The reaction works efficiently for primary and secondary halides, with at least one being bromide. The mild reaction conditions allow for excellent functional group tolerance and provide the C(sp³)-C(sp³) coupling products in moderate to excellent yields.

Full text of DOI:10.1021/ol200617f

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2138–2141
Nickel-Catalyzed Reductive Cross-
Coupling of Unactivated Alkyl Halides
Xiaolong Yu, Tao Yang, Shulin Wang, Hailiang Xu, and Hegui Gong*
Department of Chemistry, Shanghai University, 99 Shang-Da Road, Shanghai 200444,
China
hegui_gong@shu.edu.cn
Received March 8, 2011
ABSTRACT
A Ni-catalyzed reductive approach to the cross-coupling of two unactivated alkyl halides has been successfully developed. The reaction works
efficiently for primary and secondary halides, with at least one being bromide. The mild reaction conditions allow for excellent functional group
tolerance and provide the C(sp3)ꢀC(sp3) coupling products in moderate to excellent yields.
The transition-metal-catalyzed cross-coupling reactions of
alkyl halides and organometallic reagents developed by Fu
and many others represent elegant advances toward CꢀC
bond formation on sp3 carbons.1ꢀ3 On the other hand, the
development of catalytic reductive coupling approaches
directly between two organohalides has emerged to be a
powerful strategy to CꢀC bond formation,4ꢀ6 which has led
to an efficient synthesis of arylꢀalkyl cross-coupling5 and
alkylꢀalkyl homocoupling products.6 To the best of our
knowledge, a direct catalytic cross-coupling of two unacti-
vated alkyl halides to form C(sp3)ꢀC(sp3) bonds has yet to
be explored.
(1) For selected reviews, see: (a) Rudolph, A.; Lautens, M. Angew.
Chem., Int. Ed. 2009, 48, 2656–2670. (b) Frisch, A. C.; Beller, M. Angew.
Chem., Int. Ed. 2005, 44, 674–688.
(2) For recent examples on Ni-Catalyzed asymmetrical cross-cou-
plings of alkyl halides, see: (a) Lou, S.; Fu, G. C. J. Am. Chem. Soc. 2010,
132, 1264–1266. (b) Lou, S.; Fu, G. C. J. Am. Chem. Soc. 2010, 132,
5010–5011. (c) Owston, N. A.; Fu, G. C. J. Am. Chem. Soc. 2010, 132,
11908–11909.
(3) For recent examples of Pd-, Cu-, and Fe-catalyzed cross-cou-
plings on alkyl electrophiles, see: (a) He, A.; Falck, J. R. J. Am. Chem.
Soc. 2010, 132, 2524–2525. (b) Terao, J.; Todo, H.; Begum, S. A.;
Kuniyasu, H.; Kambe, N. Angew. Chem., Int. Ed. 2007, 46, 2086–
2089. (c) Hatakeyama, T.; Hashimoto, T.; Kondo, Y.; Fujiwara, Y.;
Seike, H.; Takaya, H.; Tamada, Y.; Ono, T.; Nakamura, M. J. Am.
In contrast to the conventional coupling approaches utiliz-
ing alkyl metallic nucleophiles to generate alkylꢀalkyl bonds,
the development of a catalytic reductive coupling method
between two alkyl halides is advantageous, considering that
alkyl halides are generally more accessible and easier to
handle than alkyl nucleophiles. However, the challenges are
noticeable. First, alkyl halides are in general considered as
poor coupling partners in the transition metal-catalyzed
coupling reactions.1b Second, it is of great difficulty to
identify a catalytic system that can effectively disfavor the
highly competitive homocoupling side reactions for the
two alkyl halide partners with similar structures. Herein,
we report an unprecedented mild Ni-catalyzed reductive
cross-coupling reaction of two unactivated alkyl halides that
provides efficient synthesis of alkylꢀalkyl CꢀC bonds.
To begin with, we chose the coupling of 4-bromo-1-
tosylpiperidine 1 with n-C3H7I and n-C4H7Br as the model
reactions (Table 1). After considerable effort, we determined
€
Chem. Soc. 2010, 132, 10674–10676. (d) Furstner, A.; Martin, R.;
Krause, H.; Seidel, G.; Goddard, R.; Lehmann, C. W. J. Am. Chem.
Soc. 2008, 130, 8773–8787.
(4) For recent examples of catalytic coupling of ArꢀAr halides, see:
(a) Lee, K.; Lee, P. H. Tetrahedron Lett. 2008, 49, 4302–4305. (b) Wang,
L.; Zhang, Y.; Liu, L.; Wang, Y. J. Org. Chem. 2006, 71, 1284–1287. (c)
Gosmini, C.; Bassene-Ernst, C.; Durandetti, M. Tetrahedron 2009, 65,
6141–6146. (d) Wang, L.; Lu, W. Org. Lett. 2009, 11, 1079–1082. (e)
Amatore, M.; Gosmini, C. Angew. Chem., Int. Ed. 2008, 47, 2089–2092.
(5) For the coupling of alkyl with aryl or alkenyl halides, see: (a)
Czaplik, W. M.; Mayer, M.; Grupe, S.; von Wangelin, A. J. Pure Appl.
Chem. 2010, 82, 1545–1553. (b) Everson, D. A.; Shrestha, R.; Weix, D. J.
J. Am. Chem. Soc. 2010, 132, 920–921. (c) Krasovskiy, A.; Duplais, C.;
Lipshutz, B. H. J. Am. Chem. Soc. 2009, 131, 15592–15593. (d) Czaplik,
W. M.; Mayer, M.; von Wangelin, A. J. Angew. Chem., Int. Ed. 2009, 48,
607–610. (e) Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. Org. Lett.
2010, 12, 4742–4744.
(6) For catalytic homocoupling of two alkyl electrophiles, see: (a)
Prinsell, M. R.; Everson, D. A.; Weix, D. J. Chem. Commun. 2010, 5743–
5745. and references cited therein(b) Goldup, S. M.; Leigh, D. A.;
McBurney, R. T.; McGonigal, P. R.; Plant, A. Chem Sci 2010, 1, 383–386.
r
10.1021/ol200617f
Published on Web 03/24/2011
2011 American Chemical Society

that Ni(COD)2 (10 mol %), (S)-sBu-Pybox 3a (8 mol %),7,8
and Zn (300 mol %) in DMA (N,N-dimethylacetamide)9 at
25 °C were optimal for n-propyl iodide (300 mol %),
providing the coupling product 2a in a 67% yield (entry 1)
after 12 h (Tables S1ꢀS7, Supporting Information).10 The
side reactions arising from 1 consisted of homocoupling
(∼26%), hydro-dehalogenation of the CꢀBr bond (<5%),
and β-H elimination (trace).11 Interestingly, use of 2 equiv of
n-C3H7I provided 2a in a 59% yield as opposed to 49%
employing 5 equiv of n-C3H7I, indicating that the cross-
coupling should not be simply attributed to a statistically
controlled process (Table S6, Supporting Information).10
Other Ni sources (Table S3, Supporting Information), li-
gands including 3bꢀ3j, tBu-Terpy, and bathophenanthroline
(entries 2ꢀ12), solvents (Table S4, Supporting Information),
reductants (Table S5, Supporting Information) and tempera-
tures (Table S1, Supporting Information) were either ineffec-
tive or less effective.10 Notably, excess (S)-sBu-Pybox 3a
(>10%) led to a decrease in yield (Table S2, Supporting
Information). For n-BuBr (entries 1ꢀ4, 10ꢀ17), the optimal
ligand was identified as (4-Cl)-H-Pybox 3n (entry 16);
(4-Me)- 3k and (4-Ph)-H-Pybox 3l were comparable
(entries 13 and 14). The profile of the byproducts derived
from 1 after 16 h was similar to that with n-PrI. In compar-
ison, under the optimized conditions, 4-iodo-1-tosylpiperi-
dine was much less effective due to homocoupling, generating
2a in 37% with n-C3H7I and a trace amount of 2b with
n-C4H9Br, respectively. It should be noted when the less
effective Pybox ligands were employed in Table 1, 1 was
consumed and majorly converted to the homocoupling
byproduct. Therefore, tuning the structures of Pybox ligands
appeared to be crucial to suppress the homocoupling side
reactions whiling promote the cross-coupling efficiency.
Using the optimized procedure, cross-coupling of a range
of alkyl halides with 1 was examined, furnishing the coupling
products 2cꢀp (Table 2). The elongated n-heptyl chain
slightly diminished the yields (entries 1 and 2). The bypro-
ducts derived from n-heptyl iodide and bromide comprised
the homocoupling (∼70% based on n-C7H15X) (Table S9,
Supporting Information),10 the hydro-dehalogenation of the
CꢀI bond (10%) or CꢀBr bond (<5%), and the β-H
elimination (trace). A small quantity (<5%) of n-heptyl
bromide was also recovered after the reaction was run for 16
Table 1. Optimization for the Coupling of 1 and n-CnH2nþ1-Xa
yieldb (%)
entry
ligand
n = 3, X = I n = 4, X = Br
1
2
(S)-sBu-Pybox (3a)
(S)-Me-Pybox (3b)
(S)-iPr-Pybox (3c)
67
64
47
35
3
35
24
4
(S)-Ph-Pybox (3d)
56
36
5
(S)-tBu-Pybox (3e)
<5
60
NAc
NA
NA
NA
NA
25
6
(4-Me)-(S)-sBu-Pybox (3f)
(4-Ph)-(S)-sBu-Pybox (3g)
(4-MeO)-(S)-sBu-Pybox (3h)
(4-Cl)-(S)-sBu-Pybox (3i)
tBu-Terpy
7
40
8
52
9
50
10
11
12
13
14
15
16
17
18
bathophenanthroline
(4-H)-H-Pybox (3j)
<5
43
15
51
(4-Me)-H-Pybox (3k)
(4-Ph)-H-Pybox (3l)
(4-MeO)-H-Pybox (3m)
(4-Cl)-H-Pybox (3n)
(4-(4-F-Ph))-H-Pybox (3o)
NA
NA
NA
NA
NA
65
65
40
67
55
a Reaction conditions: 1 (100 mol %, 0.16 M in DMA), n-CnH2nþ1-X
(300 mol %), Ni(COD)2 (10 mol %), ligand (8 mol %), Zn (300 mol %),
25 °C, 12 h for X = I, 16 h for X = Br. b Isolated yields. c Not available.
h. In both cases, the major side reactions for 1 were homo-
coupling. For benzyloxy- and phenyl-tethered alkyl halides,
the bromides appeared to be more efficient than the iodide
analogues (entries 3ꢀ7). The length of the alkyl chain in
benzyloxylated bromides did not seem to affect the reactivity
(entries 3 and 4). Other functionalities compatible with the
reaction conditions included imide, ester, alkene, acetal, and
even alcohol (entries 8ꢀ14). The secondary bromides also
provided 2mꢀpin moderate to fairly good yields, except for a
poor result for cyclopropyl bromide (entries 15ꢀ19).
(7) The Ni(COD)2/(S)-sBu-Pybox 3a catalytic system has proven to
be highly efficient for the Negishi coupling of unactivated alkyl halides
with primary alkylzincs: Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
14726–14727.
(8) For other selected examples of Ni/Pybox-catalyzed Negishi cou-
plings, see: (a) Lundin, P. M.; Esquivias, J.; Fu, G. C. Angew. Chem., Int.
ꢀ
Ed. 2009, 48, 154–156. (b) Gong, H.; Sinisi, R.; Gagne, M. R. J. Am.
Chem. Soc. 2007, 129, 1908–1909.
(9) DMA of extra dry (Acros), extra pure (99.5%, Acros), and AR
grade (Aladdin Co., China, $8/1 L) qualities gave similar yields. The
details of the effects of water and acids are provided in Table S7
(Supporting Information).
In order to gain insight into this coupling method, we
carefully monitored the reaction progress using the examples
illustrated in Table 2. Interestingly, examination of n-C7H15I
(entry 1) and benzoyloxypentyl iodide (entry 12) demon-
strated that higher cross-coupling yields were obtained when
slower rates of homocoupling of the primary alkyl iodides
took place. n-Heptyl and benzoyloxypentyl iodides were
consumed within 2 and 1 h, respectively, by majorly
(10) See the Supporting Information for details.
(11) In addition to refs 2aꢀ2c, other non-Pybox ligands have also
been used in the Ni-catalyzed cross-coupling of alkyl halides to avoid
β-H elimination: (a) Breitenfeld, J.; Vechorkin, O.; Corminboeuf, C.;
Scopelliti, R.; Hu, X. Organometallics 2010, 29, 3686–3689. (b) Smith,
S. W.; Fu, G. C. Angew. Chem., Int. Ed. 2008, 47, 9334–9336. (c) Gong,
ꢀ
H.; Gagne, M. R. J. Am. Chem. Soc. 2008, 130, 12177–12183. (d) Powell,
D. A.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 7788–7789.
Org. Lett., Vol. 13, No. 8, 2011
2139

5-bromopentyl benzoate under the optimized reaction con-
ditions gave recovered primary alkyl bromide (>60%), 2i
(∼30%) and homocoupling of 1 (>60%) after 4 h, suggest-
ing that 1 possesses higher reactivity than the primary
bromide. This may explain why excess primary alkyl bro-
mides are required to achieve good cross-coupling yields,
probably due to enhanced chance for the catalyst or catalytic
intermediate to find the less reactive primary bromides. Use
of 5 equiv of 5-bromopentyl benzoate, however, did not yield
better results than that with 3 equiv.
Table 2. Coupling of 1 (Limiting Reagent) with Various Alkyl
Halidesa
The scope of primary and secondary bromides as the
limiting reagents is illustrated in Table 3. The coupling of
cyclic secondary alkyl bromides with primary alkyl halides
provided the products 4bꢀ13b in moderate to good yields
(entries 1ꢀ11). The poor solubility of dodecyl bromide in
DMA had little effect on the coupling efficiency (entry 3).
No Barbier alkylation of ketone was observed when
bromocyclohexanone was used (entries 6ꢀ7). The 2-bro-
mo-2,3-dihydro-1H-indene bearing active benzylic pro-
tons also provided 11b with a moderate result (entry 9).
Notably, substrates containing the β-hydroxyl group also
afforded the coupling products 12bꢀ13b in good yields
(entries 10 and 11). No enantioselectivities were observed
for 12b and 13b when (S)-sBu-Pybox 3a was used. More-
over, the open chain secondary and primary bromides
underwent efficient coupling with iPr-Br, n-C4H9X (X =
I, Br) and 1-butenyl bromide, affording 14bꢀ18b in mod-
erate to excellent yields (entries 12ꢀ18).
Since this method displays extraordinary similarity to Fu’s
Ni/Pybox catalytic Negishi system, it is therefore important
to understand whether an in situ organozinc/Negishi process
is involved.7,8 When 1, (bromomethyl)cyclopropane, and
5-bromopentyl benzoate (up to 1 M in DMA) were indepen-
dently treated with Zn (up to 3 equiv), no or trace quantities
of organozincs formed in the presence or absence of I2 (up to
10%),13 (4-Cl)-H-Pybox 3n (8%), or Ni(COD)2 (10%) after
16 h at 25 °C, respectively. Next, treatment of 5-iodopentyl
benzoate (up to 1 M in DMA) with Zn (1.5 equiv) produced
trace amounts of benzoyloxypentylzinc iodide after 16 h at 25
°C. With the addition of 10% Ni(COD)2, 45% of the starting
5-iodopentyl benzoate (0.47 M in DMA) was converted to
organozinc iodide after 1 h,14 implying possible organozinc/
Negishi pathways for alkyl iodides. However, a mixture of 1,
5-iodopentyl benzoate, and its organozinc reagent in a ratio
of 1:1:1.5 in the presence of Ni(COD)2/3a delivered large
amount of unreacted 1 (95%) and 5-iodopentyl benzoate
(44%) after 1 h. This suggests that a non-Negishi process may
be operative and kinetically favored considering 5-iodopentyl
benzoate was consumed under our coupling conditions
(Table S12, Supporting Information).10 Moreover, the cou-
pling of 1with 3-iodo- and -bromopropanol (entries 9 and 10,
Table 2) provided the desired products in 17% and 60%
yields, respectively. In both cases, homocoupling of 1 and
3-halopropanol was the major side reaction. Formation of
a As in Table 1, footnote a. b Isolated yields. c The yield was estimated by
NMR analysis of an inseparable mixture (see the Supporting Information).
converting to the homocoupling byproducts, suggesting that
the terminal substituents on the primary alkyl iodides play
important roles in affecting the rates of homocoupling. The
corresponding yields of the desired products were 60%
and 30%, respectively (Tables S8 and S9, Supporting
Information).10 Meanwhile, substantial quantities of 1 were
recovered in both cases, indicating that the primary alkyl
iodides were more reactive than 1. For phthalimidyl propyl
(entry 8), n-heptyl (entry 2), and benzoyloxypentyl (entry 11)
bromides, complete consumption of 1 occurred within 4 h. In
the case of 1-butenyl bromide (entry 13), it took approxi-
mately 4.5 h to digest 1. A possible Niꢀalkene coordination
may be responsible for the high yield for 2j (entry 13).12 In all
these cases, homocoupling accounted for the major side
reactions for both coupling partners, though hydro-dehalo-
genation (<5%) and β-hydride elimination (trace) were also
observed. Interestingly, substantial amounts of the starting
primary alkyl bromides (∼30%, i.e. ∼1 equiv of alkyl bro-
mides) were recovered, suggesting that the amount of excess
alkyl bromides may be reduced to 2 equiv. In fact, use of 2
equiv of n-C4H9Br led to a 63% yield. Re-examination of the
examples in Table 2 using 2 equiv of primary alkyl bromides
generally only caused ∼5% loss of yields as compared to
those using 3 equiv. Finally, an equimolar mixture of 1 and
(13) Huo, S. Org. Lett. 2003, 5, 423–425.
(14) With the use of 5% and 10% I2 or 8% 3a as activation reagents,
the percent conversion of the starting 5-iodopentyl benzoate (0.47 M in
DMA) to the organozinc reagent was 0.22, 68, and 45 after 3 h,
respectively.
(12) Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79–85.
2140
Org. Lett., Vol. 13, No. 8, 2011

necessary for this cross-coupling event, although the par-
ticipation of such a process cannot be unambiguously
excluded for primary alkyl iodides.
Table 3. Scope of Alkyl Bromides (As the Limiting Reagents)a
Finally, the coupling of alkyl bromide bearing pendant
olefin 19a with (bromomethyl)cyclopropane gave a cycliza-
tion/cross-coupling sequence along with ring-opening of
cyclopropane product 19b (eq 1), wherein excellent
diastereoselectivity (>20:1 endo/exo) was observed; this
indicates that the two alkyl halides went through radical
intermediates during the course of coupling.16a Therefore,
oxidative addition of low-valent Ni-intermediates to both
R1-X and R2-X involving formation of alkyl radicals ap-
pears to be plausible in the catalytic process.16 Moreover,
this coupling event may involve a key R1-Ni(III)-R2 inter-
mediate through oxidative addition of a R1-Ni(I) species to
R2-X prior to the product formation. Though not directly
relevant, a similar hypothesis has been suggested in the
coupling of arylꢀaryl17 and arylꢀalkyl halides,5b dimeriza-
tion of alkyl halides,6b as well as Negishi reactions.18
In conclusion, we have established the first effective cross-
coupling of two alkyl halides via a Ni-catalyzed reductive
process. The mild, easy-to-handle method allows excellent
functional group tolerance and provides alkylꢀalkyl cou-
pling products in moderate to excellent yields. The catalyst
also displays intriguing features in differentiating the alkyl
coupling partners, and inhibiting the homocoupling side
reactions that may be further improved by tuning the ligand
structures. Whereas alkyl bromides are unlikely to involve an
in situ organozinc/Negishi process, such pathways cannot be
unambiguously ruled out for primary alkyl iodides, although
a non-Negishi process appears to be kinetically more favored.
Further improvement of the coupling efficiency as well as
understanding the reaction mechanism will be the focus of
our future investigations.
a As in Table 1, footnote a. b Isolated yields. c >20:1 diastereoselec-
tivity (dr). d The yield was estimated by NMR analysis of an inseparable
mixture (see the Supporting Information). e 4:1 dr. f No enantioselec-
tivity using (S)-sBu-Pybox 3a. g 6:1 dr.
3-hydroxypropylzinc halides can be excluded because of
intramolecular proton quenching.15a Since 1 did not con-
vert to the organozinc reagent even with 10% Ni(COD)2
(vide supra), an in situ organozinc/Negishi mechanism
would be highly implausible in both cases. Additionally,
the coupling of 1 with n-C3H7I in the presence of more
acidic 4-bromophenol (3 equiv) gave 2a in a 48% yield.
A Negishi mechanism should not be operative due to
instant hydrolysis of organozinc.15 The collective studies
support that the organozinc/Negishi pathways are not
Acknowledgment. The reviewers are acknowledged for
helpful comments. Prof. Feng Shi (Henan University) is
thanked for helpful suggestions. Financial support was
provided by the Chinese NSF (No. 2097209), the Program
for Professor of Special Appointment (Eastern Scholar)
at Shanghai Institutions of Higher Learning, Shanghai Edu-
cation Committee (No. 10YZ04), and Shanghai Leading
Academic Discipline Project (No. S30107).
(15) (a) Knochel has demonstrated that 73% of OctZnBr LiCl is
3
protonated after 5 min with 1 equiv of iPr-OH, and using phenol as the
proton source led to an instant complete hydrolysis of octylzinc bromide
after 30 s: Manolikakes, G.; Hernandez, C. M.; Matthias, A.; Schade,
M. A.; Metzger, A.; Knochel, P. J. Org. Chem. 2008, 73, 8422–8436. (b)
Under Ni-catalyzed Negishi conditions, a 1:3:3 mixture of 1, benzoylox-
ypentyl zinc bromide, and 4-Br-phenol only gave recovered 1.
Supporting Information Available. Spectral data of new
compounds and experimental details. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
ꢀ
(16) (a) Gonzalez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128,
5360–5361. (b) Gong, H.; Andrews, R. S.; Zuccarello, J. L.; Lee, S. J.;
(18) For mechanistic studies that implicate NiI and NiIII intermedi-
ates in Ni-catalyzed Negishi reactions, see: (a) Lin, X.; Phillips, D. L. J.
ꢀ
Gagne, M. R. Org. Lett. 2009, 11, 879–882.
(17) For mechanistic discussions on the Ni-catalyzed reductive coupling
of arylꢀaryl halides involving NiI and NiIII intermediates, see: (a) Tsou, T. T.;
Kochi, J. K. J. Am. Chem. Soc. 1979, 101, 7547–7560. (b) Colon, I.; Kelsey,
D. R. J. Org. Chem. 1986, 51, 2627–2637. (c) Amatore, C.; Jutand, A.
Organometallics 1988, 7, 2203–2214. (d) Klein, A.; Budnikova, Y. H.;
Sinyashin, O. G. J. Organomet. Chem. 2007, 692, 3156–3166.
~
Org. Chem. 2008, 73, 3680–3688. (b) Phapale, V. B.; Bunuel, E.; Garcıa-
´
ꢀ
Iglesias, M.; Cardenas, D. J. Angew. Chem., Int. Ed. 2007, 46, 8790–
8795. (c) Jones, G. D.; Martin, J. L.; McFarland, C.; Allen, O. R.; Hall,
R. E.; Haley, A. D.; Brandon, R. J.; Konovalova, T.; Desrochers, P. J.;
Pulay, P.; Vicic, D. A. J. Am. Chem. Soc. 2006, 128, 13175–13813.
Org. Lett., Vol. 13, No. 8, 2011
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