Nickel-Catalyzed Reductive Coupling of Aryl Bromides with Tertiary Alkyl Halides

Article abstract of DOI:10.1021/jacs.5b06255

A mild Ni-catalyzed reductive arylation of tertiary alkyl halides with aryl bromides has been developed that delivers products bearing all-carbon quaternary centers in moderate to excellent yields with excellent functional group tolerance. Electron-deficient arenes are generally more effective in inhibiting alkyl isomerization. The reactions proceed successfully with pyridine or 4-(dimethylamino)pyridine, while imidazolium salts slightly enhance the coupling efficiency.

Full text of DOI:10.1021/jacs.5b06255

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Communication
Nickel-Catalyzed Reductive Coupling of
Aryl Bromides with Tertiary Alkyl Halides
Xuan Wang, Shulin Wang, Weichao Xue, and Hegui Gong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b06255 • Publication Date (Web): 01 Sep 2015
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Nickel-Catalyzed Reductive Coupling of Aryl Bromides with Tertiary
Alkyl Halides
Xuan Wang,† ,‡ Shulin Wang,‡ Weichao Xue‡ and Hegui Gong*,† ,‡
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† School of Materials Science and Engineering and ‡ Department of Chemistry, Shanghai University, 99 Shang-Da Road, Shanghai
200444, China
Supporting Information Placeholder
thesis of aryl-substituted all-carbon quaternary centers via Ni-
catalyzed reductive coupling of tertiary alkyl halides with aryl
ABSTRACT: A mild Ni-catalyzed reductive arylation of ter-
tiary alkyl halides with aryl halides has been developed, which
delivers products bearing all-carbon quaternary centers in
halides, wherein DMAP or pyridine proves to be crucial for
the catalytic process; moderate to high coupling efficiency is
moderate to excellent yields with excellent functional group
observed which may generally be promoted by imidazolium
tolerance. Electron-deficient arenes are generally more effec-
tive in inhibiting alkyl isomerization. The reactions proceed
successfully with pyridine or DMAP, while the imidazolium
salts slightly enhance the coupling efficiency.
salts at minor extent.
Scheme 1. Ni-catalyzed methods to t-Ralkyl‒Ar com-
pounds.4,5
The catalytic formation of all-carbon quaternary centers re-
mains a challenge in the current nucleophile/electrophile
cross-coupling methods.1‒7 This is particular true for the con-
struction of tertiary alkyl—aryl C(sp3)—C(sp2) bonds. 1d–e,2,4‒5
For instance, the strategies based on the Cu- and Co-catalyzed
coupling of tertiary alkyl nucleophiles with organo electro-
philes though have achieved important progress,1‒4 arylation of
tertiary alkyl–M (M = Mg, Zn) only succeeds for certain aza-
heteroaromatic halides.1d-e,2 In contrast, the Ni/carbene-
catalyzed Kumada protocol recently revealed by Glorius and
Biscoe, permits a wide range of aryl electrophiles to couple
with tertiary alkyl–Mg (Scheme 1).4 Of note is Biscoe’s ap-
proach that is much more efficient by virtue of broader sub-
strate scope and excellent control of isomerization of tertiary
developed for secondary alkyl halides proved to be ineffective
alkyl groups. Using a different strategy, Fu has demonstrated
To begin with, the reaction of tBuBr (limiting reagent) with
2 equiv of methyl 4-bromobenzoate was tested. The pyridine-
derived bidentate and tridentate ligands that are previously
albeit with numerous efforts (e.g., Table 1, entries 1‒2). In the
presence of
that tertiary alkyl halides are competent for the coupling with
1 equiv of pyridine, a combination of
aryl-9-BBN under Ni-catalyzed Suzuki conditions.5 Of the
very limited examples emphasizing unactivated tertiary alkyl
halides as the coupling partners, Fu’s method significantly
expands the scope of nucleophiles that are previously re-
strained to special allyl– and benzyl–Zn, Mg reagents.6 It also
displays excellent functional group compatibility as opposed
to the protocols using tertiary alkyl Grignard reagents. Alt-
hough only phenyl- and arylborons bearing certain meta-
substituted groups are viable, the Suzuki method represents
the first use of Ni catalyst for manipulating unactivated ter-
tiary halides.5
Ni(acac)2/Zn/MgCl2 in DMA with the readily accessible car-
bene precursor 4a gave product 1 (retaining the quaternary
center) and the isomerization product 1’ in an overall 61%
yield with a 8:1 retention/isomerization (R/I) ratio (entry 3).
Replacing pyridine with DMAP boosted the R/I ratio to 20:1
(entry 4). By switching the ratio of tBuBr to the ArBr (x/y)
from 1:2 to 2:1, the overall yield for 1 and 1’ was enhanced to
81% with a R/I ratio of 40:1 (entry 5). Under equivalent con-
ditions, pyridine was not effective (entry 6). While 4b did not
generate a better yield (entry 7), the more hindered tBuIm-HCl
salt 4c gave a similar overall yield to that with 4a but with
enhanced isomerization (entry 8). Other carbene precursors
5‒7 did not improve the coupling yields, nor the R/I ratios
(entries 9‒13 and Table S1).15 A control experiment in the
absence of 4a remarkably afforded 1 and 1’ in a 75% overall
yield and a 20:1 R/I ratio (entry 14), suggesting that the car-
bene precursors may not serve as ligands, but additives. A
screen of other pyridine derivatives e.g., 8 did not result in
better results (entry 15 and Table S1).15 Both DMAP and
MgCl2 were found to be indispensable (entries 16–17). While
Recently, we and others have demonstrated that Ni-
catalyzed reductive approaches enable effective coupling of
alkyl halides with other elelctrophiles.8‒13 These include direct
coupling of aryl halides with secondary alkyl bromides that
effectively affords alkyl—aryl compounds.13 We have also
disclosed that tertiary alkyl halides can be employed to form
ketones when coupled with in situ activated acids.14 It would
therefore be interesting to extend the reductive coupling pro-
tocol to generate tertiary alkyl—aryl products, which unfortu-
nately remains very challenging. Herein, we present the syn-
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the former may function as a labile ligand,16 the latter may
erated 18 in a poor yield, albeit high R/I ratio. Use of pyridine
accelerate the reduction of Ni species.14
1
2
3
4
5
6
7
8
in lieu of DMAP again promoted the overall coupling yield to
72%, but the R/I ratio decreased to 4:1. Likewise, under the
DMAP conditions, less electron-donating groups including
benzoyloxy and phthalimidyl on the para and meta-positions
resulted in 19‒21 in trace amounts, wherein majority of the
aryl halides were recovered. The yields arising from these less
reactive arene derivatives particularly for 20 were boosted
significantly by replacing DMAP with pyridine, although low
R/I ratios were produced. At this time, the reason why pyri-
dine and DMAP exhibit profound impacts on the reactivities
of substrates and the isomerization side paths remains unclear.
Table 1. Optimization for the formation of 1.a,b
entry
x/y
ligand or additive
DMAP or Py
yield% (1:1’)
1
2
1/2
1/2
1/2
1/2
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2
Py
12 c
9
3
Py
trace
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12
13
14
15
16
17
18
19
20
21
22
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60
3
4a
Py
61 (8:1)
60 (20:1)
81 (40:1)d
45 (5:1)
68 (45:1)
82 (15:1)
78 (25:1)
63 (13:1)
79 (32:1)
78 (25:1)
61 (6:1)c
75 (20:1)
62 (18:1)
trace
With the standard method A, sterically more hindered 2-
bromo-2-methylhexane only resulted in 22 in 39% yield with a
15:1 R/I ratio. In contrast, 3-bromo-3-methylbutyl benzoate
generated 23 in a good yield and a good R/I ratio, possibly due
to the pendent OBz group enhanced the reactivity of the C‒Br
bond, albeit two carbons away from the reactive carbon cen-
ter.17
4
4a
DMAP
DMAP
Py
5
4a
6
4a
7
4b
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
8a
8
4c
9
5a
10
11
12
13
14
15
16
17
5b
6a
Table 2. Scope of alkyl and aryl bromides using method
A.a,b,c
7a
7b
none
none
4a, w/o MgCl2
DMAP
none
4a
6 %
a Reaction Conditions: tBuBr or ArBr as the limiting reagent (0.3
mmol), Ni(acac)2 (10 mol %), 2‒3 (10 mol %) or 4‒7 (30 mol %),
MgCl2 (150 mol %), pyridine or DMAP (100 mol %) was used, Zn
b
(200 mol %), DMA (1 mL). Yield for 1 and 1’, and 1/1’ ratio
1
were determined from a mixture containing other impurities by H
NMR using 2,5-dimethylfuran as the internal reference after a quick
d
flash column chromatography. c 30 mol % of TBAB was added.
Isolated yield: 82% (R/I = 40:1).
Next, a range of aryl bromides was subjected to the opti-
mized conditions (method A, Table 1, entry 5) as shown in
Table 2. It was disclosed that electron-withdrawing groups
generally furnished good to excellent yields when coupled
with tBuBr as evident in 9–14 (Table 2). Good yield and R/I
ratio were even obtained for 11 allowing installation of tBu to
the ortho-position of an ester group, although 2 more equiva-
lents of tBuBr was necessary to drive the arylbromide to com-
pletion. The meta- and ortho-substitution patterns seemingly
resulted in lower coupling yields than the para-modes. Unpro-
tected 4-bromobenzaldehyde only revealed a trace amount of
product 15 along with substantial unreacted aryl bromide.
However, when pyridine was a surrogate for DMAP, a good
yield as well as a good R/I ratio was obtained. With an elec-
tron-withdrawing group on the para position, arylbromides
bearing additional meta-substituents including ester and meth-
oxy gave good yields as evident in 16 and 17. By comparison,
4-methoxyphenylbromide containing m-ester substituent gen-
b
a Reaction Conditions: as in Table 1, entry 5. Isolated yields for a
c
mixture of product and isomer. R/I ratios in the parenthesis were
determined by H NMR after purification. d 4a (30%). 4a (0%).
1
e
f
g
Additional 2 equivalents of tBuBr were loaded after 8 h. Pyridine
h
was used instead of DMAP. NMR yield using 2,5-dimethylfuran as
the internal reference due to contamination with inseparable hy-
drodehalogenated arene.
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To gain more details about the impact of imidazolium salts, partner, method B proved to be effective for a wide set of oth-
1
2
3
4
5
6
7
8
er sterically more bulky alkyl halides (with respect to tBuBr)
as evident in 23‒32 (Table 3). The R/I ratios were generally
high. Phthalimidyl-pendent alkyl bromide required pyridine as
the additive due to cleavage of the amide bonds by DMAP,
which resulted in a moderate R/I ratio for 26, but high for 27.
In both cases the isomerization products can be partially sepa-
rated out (Table 3). This agrees with that more electron-
deficient aryl bromides produced good R/I ratios even when
pyridine was utilized, as supported in 15 (Table 1). However,
more sterically bulky 3-bromo-3-ethylpentane (Et3CBr) was
less satisfactory wherein a poor yield for 33 with a low R/I
ratio was disclosed, indicating one limitation of this method.
The compatibility of aryl halides bearing electron-deficient
substituents was examined for 34‒43, wherein good yields and
R/I ratios were effectively delivered. Of note is a good result
for 43 albeit containing an ortho-methyl group. In the absence
of 4c, the coupling yields and R/I ratios again diminished
slightly for most of the examples in Table 3, which reinforces
the notion that carbene precursors are not essential for the
coupling event.
equivalent reaction conditions without 4a was conducted for
9‒21. It was generally found that the yields and R/I ratios de-
creased slightly as compared to those with 4a (Table 2). This
observation consistently supports that DMAP or pyridine was
crucial for the coupling process, although the imidazolium
salts may play some minor roles.16
Table 3. Coupling of alkyl halides and electron-deficient
aryl bromidesa,b,c
9
10
11
12
13
14
15
16
17
18
19
20
21
22
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In general, the side reactions for alkyl halides arose from
hydrodehalogenation and β-H elimination, whereas dimeriza-
tion and hydrodehalogenation of aryl halides accounted for the
major mass balance for the aryl partners. Tracking the cou-
pling process for 23 with both methods A and B revealed that
the alkyl bromide consumed more rapidly than the aryl bro-
mide in both cases.15 In addition, substitution of Zn with Mn
also provided 1 in >40% yield,15 suggesting a Negishi mecha-
nism is unlikely.13b
Similar to the previously disclosed Ni-catalyzed reductive
cyclization/coupling of alkyl halides,9a-c coupling of 44 with
methyl 4-bromobenzoate using method B and pyridine as the
additive provided the desired cyclization/arylation product 45
in 50% yield with a R/I ratio of 10:1 or 8:1 without 4c (eq 1).
This result indicates possible participation of in situ generated
tertiary alkyl radical, which is consistent with the observations
for a variety of Ni-catalyzed coupling on alkyl halides.14,18‒19 It
is unclear whether the present method follows Weix’s radical
chain mechanism.18b
Finally, this reductive coupling strategy enabled facile syn-
thesis of cylcotryptamine analogs, which have attracted wide-
spread synthetic interest over the past decades.20 Using method
B without 4c, the tertiary benzyl chlorides were efficiently
converted into 48‒50 in good to excellent yields when coupled
with the electron-deficient aryl bromides (Scheme 2). Pyridine
appeared to be much more effective than DMAP (Scheme
S1).15 Notably, no isomerization byproducts were detected,
demonstrating potential applications of this work to the con-
struction of complex molecules. This method differs from the
Friedel–Crafts synthesis that is suited for electron-rich aryl
compounds.21
a Reaction Conditions: tert-RBr (0.3 mmol, 100 mol %, 0.15 M in
DMA), Ni(acac)2 (10 mol %), 4c (30 mol %), MgCl2 (100 mol %), Zn
(200 mol %), DMA (1 mL), DMAP was used unless otherwise noted.
b R/I ratios in the parenthesis were determined by 1H NMR after puri-
c
fication.
Isolated yields for a mixture of product and isomer. d 4a
(30%). e 4a (0%). f NMR yield using 2,5-dimethylfuran as the internal
standard. g Pyridine was used instead of DMAP. h The initial R/I ratios
for 26 and 27 prior to purification were determined to be 4:1 and 9:1 ,
respectively.
When n-Bu(Me)2CBr was set as the limiting reagent, its cou-
pling with 2 equiv of methyl 4-bromobenzoate using DMAP
and 4c as the additives (method B) improved the yield for 22
to 52% as opposed to 37% with method A (Table 2). The
amount of DMAP and MgCl2 can be lowered to 30% and
100%, respectively. It should be noted that method B is less
effective for tBuBr, which generated 1 in 69% yield with a
15:1 R/I ratio. Using methyl 4-bromobenzoate as the coupling
Scheme 2. Synthesis of cyclotryptamine analogs.
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(4) Coupling of tertiary R-MgX catalyzed by Ni: (a) Lohre, C.;
Dröge, T.; Wang, C.; Glorius, F. Chem.–Eur. J. 2011, 17, 6052. (b)
Joshi-Pangu, A.; Wang, C.‒Y.; Biscoe, M. R. J. Am. Chem. Soc.
2011, 133, 8478.
(5) Coupling of tert-alkyl halides with Ar-9BBN: Zultanski, S. L.; Fu,
G. C. J. Am. Chem. Soc. 2013, 135, 624.
1
2
3
4
5
6
7
8
(6) Coupling of Ar-MgX with only admantanyl chloride is known: (a)
Ghorai, S. K.; Jin, M.; Hatakeyama, T.; Nakamura, M. Org. Lett.
2012, 14, 1066. Coupling of tertiary alkyl halides with allylic and
benzylic metallics: (b) Someya, H.; Ohmiya, H.; Yorimitsu, H.;
Oshima, K. Org. Lett. 2008, 10, 969. (c) Mitamura, Y.; Asada, Y.;
Murakami, K.; Someya, H.; Yorimitsu, H.; Oshima, K. Chem.‒Asian
J. 2010, 5, 1487. (d) Tsuji, T.; Yorimitsu, H.; Oshima, K. Angew.
Chem., Int. Ed. 2002, 41, 4137.
(7) (a) Direct coupling of Ar2Zn with tertiary bromides including tBu-
and admantanyl-Br, see: Dunsford, J. J.; Ewan R.; Clark, E. R.; Ingle-
son, M. J. Angew. Chem., Int. Ed. 2015, 54, 5688. (b) Coupling of
styrenyl aziridines with organozincs to give all quaternary carbon
In summary, this easy-to-operate method features direct cou-
pling of a wide range of readily accessible tertiary alkyl and
aryl halides under mild Ni-catalyzed conditions. While pyri-
dine and DMAP proved to be pivotal for the feasibility of this
coupling event, the imidazolium salts only slightly promoted
the efficiency. The present reductive protocol exhibits excel-
lent functional group compatibility, which generally enables
the electron-deficient aryl halides to deliver arylated quater-
nary products in good to excellent yields with low isomeriza-
tion/retention ratios. In contrast, electron-rich aryl halides are
less effective. The practicability of this reductive coupling
approach is further manifested in the synthesis of cyclotrypta-
mine analogs. Finally, although the insight into the reaction
mechanism is still under investigation, the possible involve-
ment of a radical process is in line with the general profiles for
Ni-catalyzed reductive coupling of alkyl halides.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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43
44
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48
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products,
see:
J. Am. Chem. Soc. 2015, 137, 5638.
Huang,
C.-Y.;
Doyle,
A.
G.
(8) For recent reviews on reductive coupling of two electrophiles, see:
(a) Knappke, C. E. I.; Grupe, S.; Gärtner, D.; Corpet, M.; Gosmini, C.;
von Wangelin, A. J. Chem. ‒Eur. J. 2014, 20, 6828. (b) Everson, D.
A.; Weix, D. J. J. Org. Chem. 2014, 79, 4793. (c) Moragas, T.; Cor-
rea, A.; Martin, R. Chem. ‒Eur. J. 2014, 20, 8242. (d) Weix, D. J.
Acc. Res. Chem. 2015, 48, 1767.
(9) For catalytic C(sp3)–C(sp3) bond formation via cross-coupling of
alkyl electrophiles, see: (a) Yu, X.; Yang, T.; Wang, S.; Xu, H.;
Gong, H. Org. Lett. 2011, 13, 2138. (b) Xu, H.; Zhao, C.; Qian, Q.;
Deng, W.; Gong, H. Chem. Sci. 2013, 4, 4022. (c) Dai, Y.; Wu, F.;
Zang, Z.; You, H.; Gong, H. Chem. Eur. J. 2012, 16, 808. (d) Anka-
Lufford, L. L.; Prinsell, M. R.; Weix, D. J. J. Org. Chem. 2012, 77,
9989. (e) Qian, X.; Auffrant, A.; Felouat, A.; Gosmini, C. Angew.
Chem., Int. Ed. 2011, 50, 10402. (f) Peng, Y.; Luo, L.; Yan, C.‒S.;
Zhang, J.‒J.; Wang, Y.‒W. J. Org. Chem. 2013, 78, 10960.
(10) For selected examples of Ni-catalyzed C(sp3)–C(sp2) coupling,
producing ketones: (a) Wu, F.; Lu, W.; Qian, Q.; Ren, Q.; Gong, H.
Org. Lett. 2012, 14, 3044. (b) Yin, H.; Zhao, C.; You, H.; Lin, Q.;
Gong, H. Chem. Commun. 2012, 48, 7034. (c) Wotal, A. C.; Weix, D.
J. Org. Lett. 2012, 14, 1476.
(11) For CO2 trapping with alkyl halides and allylic acetates, see: (a)
Liu, Y.; Cornella, J.; Martin, R. J. Am. Chem. Soc.2014, 136, 11212.
(b) Moragas, T.; Cornella, J.; Martin, R. J. Am. Chem. Soc.2014, 136,
17702. (c) Correa, A.; León, T.; Martin, R. J. Am. Chem. Soc. 2014,
136, 1062. (d) Wang, X.; Liu, Y.; Martin R. J. Am. Chem. Soc. 2015,
137, 6476.
(12) For Ni-catalyzed asymmetric vinylation and acylation of benylic
halides, see: (a) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. J.
Am. Chem. Soc. 2013, 135, 7442. (b) Alan H. Cherney, A. H.; Reis-
man, S. E. J. Am. Chem. Soc.2014, 136, 14365.
ASSOCIATED CONTENT
Supporting Information. Detailed experimental procedures, charac-
terization of new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
hegui_gong@shu.edu.cn
ACKNOWLEDGMENT
Financial support was provided by the Chinese NSF (Nos.
21172140 and 21372151), the Program for Professor of Special
Appointment (Dongfang Scholarship) at Shanghai Education
Committee. Prof. Yu Peng (Lanzhou Univ.) and Dr. Hongmei
Deng (Shanghai Univ.) are thanked for helpful discussions and
helping use of the NMR facility, respectively. Mr. Xiao Jia was
acknowledged for providing compound 47 and repeating the op-
timized reaction conditions for 1. The reviewers are recognized
for insightful comments.
(13) (a) Wang, S.; Qian, Q.; Gong, H. Org. Lett. 2012, 14, 3352. (b)
Everson, D. A.; Shrestha, R.; Weix, D. J. J. Am. Chem. Soc. 2010,
132, 920. (c) Yan, C.-S.; Peng, Y.; Xu, X.-B.; Wang, Y.-W. Chem.–
Eur. J. 2012, 18, 6039. (d) Everson, D. A.; Jones, B. A.; Weix, D. J.
J. Am. Chem. Soc. 2012, 134, 6146. (e) Molander, G. A.; Kaitlin M.;
Traister, K. M.; O’Neill, B. T. J. Org. Chem. 2015, 80, 2907.
(14) Zhao, C.; Jia, X.; Wang, X.; Gong, H. J. Am. Chem. Soc. 2014,
136, 17645.
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(16) Pyridine as the sole ligand/additive in a Ni-catalyzed electro-
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