Ni-catalyzed reductive coupling of alkyl acids with unactivated tertiary alkyl and glycosyl halides

Article abstract of DOI:10.1021/ja510653n

This work highlights Ni-catalyzed reductive coupling of alkyl acids with alkyl halides, particularly sterically hindered unactivated tertiary alkyl bromides for the production of all carbon quaternary ketones. The reductive strategy is applicable to α-selective synthesis of saturated, fully oxygenated C-acyl glycosides through easy manipulations of the readily available sugar bromides and alkyl acids, avoiding otherwise difficult multistep conversions. Initial mechanistic studies suggest that a radical chain mechanism (cycle B, Scheme 1) may be plausible, wherein MgCl₂ promotes the reduction of Ni^II complexes.

Full text of DOI:10.1021/ja510653n

Article
pubs.acs.org/JACS
Ni-Catalyzed Reductive Coupling of Alkyl Acids with Unactivated
Tertiary Alkyl and Glycosyl Halides
Chenglong Zhao,† Xiao Jia,† Xuan Wang, and Hegui Gong*
Department of Chemistry, Shanghai University, 99 Shang-Da Road, Shanghai 200444, China
S
* Supporting Information
ABSTRACT: This work highlights Ni-catalyzed reductive coupling of
alkyl acids with alkyl halides, particularly sterically hindered unactivated
tertiary alkyl bromides for the production of all carbon quaternary
ketones. The reductive strategy is applicable to α-selective synthesis of
saturated, fully oxygenated C-acyl glycosides through easy manipulations
of the readily available sugar bromides and alkyl acids, avoiding
otherwise difficult multistep conversions. Initial mechanistic studies
suggest that a radical chain mechanism (cycle B, Scheme 1) may be
plausible, wherein MgCl2 promotes the reduction of NiII complexes.
1. INTRODUCTION
In catalytic coupling reactions, tertiary alkyl−metallic re-
agents1,2 or tertiary alkyl electrophiles3,4 generally display
pronounced difference and challenges as compared to their
primary and secondary alkyl analogs, which require special and
independent attentions. For instance, the recent development
of catalytic coupling of unactivated secondary alkyl zinc reagents
with aryl halides5,6 has only been extended to adamantylzinc
reagents.7 Moreover, although catalytic formation of ketones
involving alkyl nucleophiles has been widely explored,8−11 the
employment of tertiary alkyl−metallic reagents is very rare.7,12
The challenge for the coupling of tertiary alkyl halides can be
manifested in Oshima and Fu’s recent construction of
quaternary carbon centers through Kumada coupling of
allyl-/benzyl-Mg and Suzuki coupling of aryl-9-BBN, respec-
Figure 1. Ni-catalyzed ketone formation via alkyl halides.
tively. While the former is limited to special organometallics,
the latter is very sensitive to the electronic nature of aryl
moieties.3,4
and alkyl glycosides,19−21 are generally not applicable to C-acyl
glycosides. The challenges are apparent; glycosyl C1 (sp3) and
acyl nucleophiles are notoriously difficult to prepare and
participate in coupling reactions.22,23 Thus, far, benzoyl β-C-
glucoside has been the sole example documented in a Pd-
catalyzed acylation of 1-glycosyl-Sn method.24 As a result, much
less efficient multistep conversions from 1-glycosyl acids,
cyanides, alkyne and allenes dominate the current synthesis
of C-acyl glycosides.25,26 The development of a general and
straightforward method to C-acyl glycosides particularly the α-
anomers is therefore highly needed.
Therefore, it is not surprising to notice that although recent
Ni-catalyzed reductive coupling of primary and secondary alkyl
halides with other electrophiles including acid derivatives
effectively generates C(sp3)−C(sp3) and C(sp3)−C(sp2)
products (Figure 1),13−16 tertiary alkyl halides are not
competent. Moreover, although we have extended the reductive
protocol to ketone formation through the coupling of alkyl
halides with in situ activated aryl acids, four equiv of aryl acids
are necessary to ensure low to moderate coupling efficiency,
and only alkyl iodides are compatible with limited aryl acids;
alkyl acids prove to be ineffective.16a Hence, development of
reductive ketone synthesis that allows for tertiary alkyl halides
and alkyl acids is important.
We herein report an efficient Ni-catalyzed alkyl−alkyl ketone
formation method with emphasis on the coupling of tertiary
alkyl and glycosyl halides with alkyl acids using Zn as the
reductant (Figure 1). To the best of our knowledge, this work
In addition, although C-glycosides including C-acyl glyco-
sides are believed to be important bioactive candidates,17,18
their preparation has not been achieved by reductive coupling
of two electrophiles. The conventional transition-metal-
catalyzed coupling methods, though have succeeded in C-aryl
Received: October 16, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja510653n | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
demonstrates the first construction of all carbon quaternary centers
via the reductive coupling of unactivated tertiary alkyl halides with
a second electrophile other than Barbier-type radical addition to
carbonyl or activated alkenes.27,28 It also represents the first
reductive synthesis of C-glycosides via readily available
electrophiles featuring α-selectivities. Finally, the initial
mechanistic studies seem to support a radical chain mechanism,
wherein MgCl2 accelerates the reduction of the NiII complexes
by Zn.
(entries 8 vs 13), the yield was boosted to 65% from 19% when
ligand 4b was employed (entries 9 vs 14). Decrease of iPr2NEt
from 1.5 to 0.85 equiv further enhanced the yield to 79%
(entries 15). Raising the temperature from 25 to 30 °C resulted
in a slight increase of the yield to 82% (entry 16). With these
conditions (method A), ligand 4a turned out to be much less
efficient (entry 17).
With the optimized conditions (method A, Table 1, entry 16)
in hand, a wide set of acids were able to generate good to
excellent yields when coupling with tBu-Br as evident in 2a−f,
except that a low yield was obtained for 2g using a secondary
acid. The excellent compatibility of sterically more hindered
tert-alkyl bromides was illustrated in 7−15 (Table 2). Notably,
compound 14 was obtained in high trans-diaseteromeric
selectivity (trans-4-acyl/phenyl) from its cis-bromo precursor
(cis-4-bromo/phenyl).29
2. RESULTS AND DISSCUSIONS
2.1. Coupling of Tertiary Alkyl Halides with Alkyl
Acids. To identify whether alkyl acids and tertiary alkyl halides
are competent, the coupling of tBuBr (1a) with 1.7 equiv of 3-
phenylpropanoic acid was intensively surveyed in the presence
of Boc2O/Zn and 1.5 equiv of MgCl2 (Table 1).29 With
Table 1. Optimization for the Reaction of tBuBr (1a) with 3-
Phenylpropanoic Acid
Table 2. Coupling of Unactivated tert-Alkyl Bromides with
Acids
a
a
iPr2NEt MgCl2
yield
b
entry ligand
solvent
(%)
(%)
°C
(%)
1
3a
3b
4a
4a
4a
4a
4a
4a
4b
4c
5a
6a
4a
4b
4b
4b
4a
THF
THF
THF
0
0
150
150
150
150
150
150
150
150
150
150
150
150
100
100
100
100
100
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
30
30
16
7
2
3
0
24
25
34
44
36
47
19
46
<10
<10
39
65
79
82
39
4
DMSO
0
5
DME
0
6
DMSO/DME = 8:2
DMSO/DME = 2:8
DMSO/DME = 2:8
DMSO/DME = 2:8
DMSO/DME = 2:8
DMSO/DME = 2:8
DMSO/DME = 2:8
DMSO/DME = 2:8
DMSO/DME = 2:8
DMSO/DME = 2:8
DMSO/DME = 2:8
DMSO/DME = 2:8
0
7
0
8
150
150
150
150
150
150
150
85
85
85
9
10
11
12
13
14
15
16
17
a
Reaction Conditions (method A): tert-RBr (0.3 mmol, 100 mol %),
acid (170 mol %), Ni(acac)2 (10 mol %), 4b (12 mol %), MgCl2 (100
a
Reaction Conditions: tBuBr (0.3 mmol, 100 mol %), acid (170 mol
mol %), iPr2NEt (85 mol %), Boc2O (200 mol %), Zn (300 mol %),
b
%), Ni(acac)2 (10 mol %), ligand (12 mol %), Boc2O (200 mol %), Zn
(300 mol %), MgCl2 (100 mol %), solvent (1 mL). GC yields using
dodecane as the internal standard (calibrated).
DMSO/DME (0.2:0.8, v/v, 1 mL). Isolated yield after treatment of
b
an inseparable mixture of product and t-butyl alkanoate (arising from
c
d
Boc2O) with TFA. Isolated yield. 15 mol % of Ni(acac)2 and 15 mol
e
% of 4b were used. The dr for isolated 14 was determined by GC-MS
analysis which is different from the crude reaction mixture (dr = 19:1);
the relative stereochemistry of 14 was determined by single crystal X-
ray diffraction analysis (see Supporting Information).
Ni(acac)2 being the precatalyst, ligand 4a gave the ketone 2a in
24% yield in THF, which is superior than 3a and 3b (Table 1,
entries 1−3). The effects of solvents were next carefully
examined. With 4a as the ligand, DME was slightly better than
DMSO (entries 4−5). While a mixture of DMSO/DME in a
ratio of 8/2 (v/v) worked better than that of 2/8 (entries 6 and
7), addition of 1.5 equiv of iPr2NEt to the latter conditions
increased the yield to 47% (entry 8). Other ligands, e.g., 4b−c,
5a, and 6a did not yield better results (entries 9−12).
Interestingly, whereas reduction of the amount of MgCl2
from 1.5 to 1 equiv diminished the yield using ligand 4a
2.2. Coupling of Tertiary Alkyl Halides with Aryl Acids.
With method A (Table 1, entry 16), coupling of benzoic acid
(1.7 equiv) with (3-bromo-3-methylbutyl)benzene 1b did not
generate ketone 11c, nor did benzoic acid anhydride; the
majority of the tertiary halide remains unreacted, while benzoic
acid and its anhydride were converted into tert-butyl benzoate
or decomposed. A control experiment by exposure of
equimolar mixture of 3-phenylpropanoic (0.85 equiv) and
benzoic acids to 1b gave ketones 11a in 60% yield, while 11c
was not detected (eq 1). In addition, reaction of equimolar
mixture of 1b and 4-bromo-1-tosylpiperidine (16a) with
B
dx.doi.org/10.1021/ja510653n | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
and 17f) but can be activated by addition of Bu4NI as evident
in 29a. Alkyl halides bearing neighboring groups that are more
sterically demanding (e.g., 26a−27a) or vulnerable to β-
elimination as in 26a−28a, and acids bearing Boc and
conjugate double bond were compatible.
2.4. Application to the Synthesis of C-Glycosides. To
showcase the applicability of this work, we extend the reaction
conditions to the synthesis of C-acyl glycosides which are an
important class of bioactive products or their intermedi-
ates.18,25,26 To our delight, the coupling of glucosyl bromides
32 with propionic acid and its anhydride (Table 4) using the
benzoic acid only generated 10% yield of the acylation product
from the secondary halide, wherein most of 1b was recovered
and 16a underwent hydrodehalogenation (eq 2). These results
suggest that alkyl acids are more efficient than aryl acids for
tertiary alkyl halides in the catalytic ketone formation, and
secondary alkyl halides appear to be more reactive than the
tertiary ones when reacting with benzoic acid.
Table 4. Coupling of Glycosyl Bromides with Propionic Acid
and Anhydride
2.3. Coupling of Primary and Secondary Alkyl Halides
with Alkyl Acids. Extension of the conditions for tertiary alkyl
bromides (method A) to secondary halides proved to be
ineffective or not general.29,30 Optimization for the reaction of
4-iodo-1-tosylpiperidine (16b) with 1.5 equiv of 3-phenyl-
propanoic acid in the presence of Boc2O/MgCl2/Zn indicated
that a combination of Ni(acac)2/3a in CH3CN/THF (v/v =
4:6) at 25 °C gave ketone 17a in an optimal 95% yield (Table
3, method B). Likewise, the bromo-analogue 16a gave 17a in a
a
b
entry
sugar
RCOOR′
method
yield% (α:β)
c
1
glucose
glucose
glucose
glucose
glucose
glucose
glucose
mannose
galactose
galactose
(EtCO)2O(2 equiv)
(EtCO)2O (2 equiv)
(EtCO)2O (2 equiv)
EtCO2H (1.5 equiv)
EtCO2H (1.5 equiv)
EtCO2H (1.5 equiv)
EtCO2H (1.5 equiv)
EtCO2H (1.5 equiv)
EtCO2H (1.5 equiv)
EtCO2H (1.5 equiv)
A
not detected
95 (2:1)
c
2
B
c
d
3
C
90 (3:1)
4
B
97 (2.2:1)
82 (2.6:1)
99 (2.9:1)
not detected
87 (α)
a,b,c
Table 3. Formation of Ketones from Alkyl Halides
5
C
e
6
7
C1
A
B
B
8
9
90 (7.5:1)
90 (8.7:1)
e
10
C1
a
Method A as in Table 2, Method B as in Table 3, Method C as in
b
1
Table 3. Isolated yields (α/β ratio was determined by H NMR).
c
d
e
With no Boc2O. This result suffers from poor reproducibility. Same
as method C except DMF/CH3CN = 1:4.
optimized methods B, C and C1 (same as method C except
DMF/CH3CN = 1:4) produced the desired C-acyl glucoside 35
in up to 99% yield with moderate α selectivity (α:β ratio up to
3:1). Method A proved to be ineffective (entries 1−7). With
method B and C1, high yields were obtained for mannosyl and
galactosyl bromides 33 and 34, giving 36 in pure α-form and 37
in high α selectivity (α:β = 8.7:1), respectively (entries 8−10).
The generality of the reductive method to C-acyl glycosides
was exemplified in Table 5. A variety of alkyl acids were
compatible when method C1 (for glucosyl and galactosyl
bromides) and B (for mannosyl bromide) were used,
generating the corresponding ketones 38−46 in good to high
yields, while retaining similar α/β ratios to those observed in
Table 4.
2.5. Radical Chain versus Double Oxidative Addition
Mechanism. 2.5.1. Proposed Catalytic Cycles. A control
experiment indicated that 3-phenylpropanoic anhydride worked
equally well as acid/Boc2O when it couples with 2-bromo-2-
methylbutane. We reasoned that in situ formation of acid
anhydride31 followed by oxidative addition to Ni0 giving
R1C(O)−NiII−OC(O)R1 (I) may constitute the first steps of
the catalytic process.32 Intermediate I may be reduced to
R1C(O)−NiI (II) which undergoes oxidative addition of alkyl
halide leading to a RC(O)NiIII−Ralkyl (IV), possibly involving
rapid combination of an alkyl radical and a NiII intermediate
(III) that was generated by reduction of an alkyl halide with NiI
(II) (Scheme 1, cycle A).33,34 An alternative radical chain
a
b
Isolated yields. Method B: Alkyl iodides (0.15 mmol, 100 mol %),
acid (150%), Ni(acac)2 (10 mol %), 3a (12 mol %), Boc2O (200 mol
%), Zn (300 mol %), MgCl2 (150 mol %), CH3CN/THF (v/v = 4:6, 1
mL), 25 °C. Method C: same as method B except alkyl bromides, 4a
and DMF/THF (v/v = 2:3, 0.5 mL) at 20 °C. 0.5 mL of solvents
were used. dr > 20:1. Bu4NI (50 mol %) was added, and the reaction
was run at 30 °C. Benzylic chlorides were used.
c
d
e
f
g
highest 90% yield using ligand 4a in DMF/THF (v/v = 2:3) at
20 °C, with the initial concentration of 16a being doubled
(Table 3, method C).29 The optimized conditions for 16b was
not applicable to 16a, and vice versa (Supporting Information
Table S3, entries 10 and 14).29,30
With methods B and C, a variety of secondary and primary
halides as well as benzylic chlorides were examined and proved
to be competent, giving ketones 17b−31 in good to excellent
yields (Table 3). The primary bromides were inert (e.g., 22b
C
dx.doi.org/10.1021/ja510653n | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Table 5. Examples of C-Acyl Glycosides Using Methods B
a
and C1
1
Figure 2. H NMR spectra of I-a in DMF without (top) and with
MgCl2, and I-c without and with (bottom) MgCl2.
a
b
1
Isolated yields (α/β ratio was determined by H NMR). Method
c
C1: Same as method C except DMF/CH3CN = 1:4. Method B.
(eq 5),32,37 which are stable in DMF and DMSO, respectively.
Without Zn and MgCl2, tracking the equimolar reaction of
Scheme 1. Double Oxidative Addition (Cycle A) And
Radical Chain Mechanism (Cycle B)
tBuBr with I-b in DMSO/DME indicated that the reaction
went to completion within 180 min, giving 2h in 46% yield
(Supporting Information Figure S7). With 5 equiv of tBuBr, the
reaction completed much faster, delivering 2h in 50% yield after
65 min.29 Similar results were also detected for the reactions of
I-a with 16a (see Supporting Information Table S4), albeit
much slower. The observations that Zn was not needed for the
stoichiometric reactions of I with Ralkyl−X seem to be better
explained by a radical chain mechanism (cycle B, Scheme 1),
which involves addition of Ralkyl radical to I.35b Cycle A is less
likely as it would require reduction of I by Zn to be a key step.
When Zn was introduced, the equimolar reactions of I-b with
tBuBr went to completion faster than those without Zn (eq 5).
If cycle B operates (Scheme 1), Zn would be unnecessary for
the stoichiometric reaction of I-b with tBuBr except reduction
of NiII complex (IV′) to NiI or Ni0. Generation of Ralkyl radicals
by these low-valence Ni species is possible, which may in turn
accelerate the reaction.36c
Addition of MgCl2 to the stoichiometric reactions of I-b with
tBuBr without Zn did not seem to affect the yields and
completion time as much as those with Zn (eq 5). In contrast,
MgCl2 appears to be indispensable for the catalytic conditions
as evident in the coupling of (3-bromo-3-methylbutyl)benzene
(1b) with Ph(CH2)2CO2H, without which no 11a formed. One
of its key roles seems to be to significantly accelerate the
reduction rate of the Ni(II) complexes. Without MgCl2, most
of I-a remained untouched after 3 h in the presence of excess
Zn in DMF (Supporting Information Figure S2).29 With it,
∼80% and ∼100% of I-a were consumed in DMF and DMF/
THF (2:3, v/v) after 1 h, respectively (Supporting Information
Figures S3 and S4).29 1H NMR studies indicated that a different
complex may form upon addition of MgCl2 to I-a in DMF
(Figure 2).29,38 This may involve Cl−/[iPr C(O)O]− anion
metathesis and interaction of the resultant iPrC(O)−Ni(Ln)Cl
process is possible via combination of an alkyl radical with
intermediate I, similar to the recent Hu’s Ni-catalyzed alkyl
Kumada, Weix’s reductive arylation and Fu’s Negishi
mechanisms (Scheme 1, cycle B).35 The alkyl radical can be
generated by reaction of alkyl halide with the NiI (III′) to give
the NiII (IV′). Initial generation of intermediate III′ may arise
from halide abstraction of R−X with complex I to give
R1C(O)−NiIII(OC(O)R)−X (V′), followed by reductive
elimination of acyl-X.
2.5.2. Radical Process. The radical nature of the reaction
was verified in the reductive cyclization/coupling of 47-D with
3-phenylpropanoic acid giving endo-48-D with a 1:1 ratio of
syn/anti for Ha/Hb (eq 3), as well as the ring opening/coupling
of (bromomethyl)cyclopropane with 3-phenylpropanic acid (eq
4).36
2.5.3. Radical Chain versus Double Oxidative Addition
Mechanism. Treatment of Ni(COD)2 with 4a and (iPrCO)2O
or (nPrCO) O in Et2O gave isolatable I-a (Figure 2) and I-b
2
D
dx.doi.org/10.1021/ja510653n | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(I-c) intermediate29,39 with Mg2+, since addition of MgCl2 to I-
c prepared from oxidative addition of iPrCOCl to Ln-Ni(0)
resulted in identical H NMR spectra as that of I-a/MgCl2
3. CONCLUSIONS
In summary, alkyl−alkyl ketones can be efficiently synthesized
via Ni-catalyzed reductive coupling of alkyl halides with acids
under mild conditions. The reactions accommodate various
functional groups. A wide range of acids and alkyl halides are
competent, particularly tertiary alkyl bromides. The easy-to-
operate procedure avoids prepreparation of organometallic
reagents and preactivation of acids, rendering it practical for
ketone synthesis. The α-selective synthesis of potentially
bioactive C-acyl glycosides is particularly intriguing, as it
would otherwise be difficult to achieve using the conventional
methods. The indispensable role of MgCl2 in the catalytic
process is evidenced by formation of a new complex with acyl−
NiII (e.g., I-a), which appears to accelerate the reduction of NiII
by Zn. The collective mechanistic studies seem to support a
radical chain process proposed in cycle B, although more
evidence are required for understanding the details.
1
(Figure 2).37,40 It should be noted that reduction of I-c is much
faster than I-a in the absence of MgCl2 (Supporting
Information Figure S5), indicating anion metathesis plays an
important role in reduction of I-a/MgCl2. However, the role of
Mg2+ cannot be eliminated, as we also observed that MgCl2 can
markedly enhance the rate of reduction of Ln-NiBr2 (Ln = 4a)
by Zn. Without MgCl2, most of Ln-NiBr2 remained intact after
3 h (Supporting Information Figure S6).29,40
The effect of Zn2+ which is an in situ generated byproduct
was also examined. By addition 1 equiv of ZnCl2 to the catalytic
reaction of tBuBr with 3-phenylpropanoic acid, the yield of 2a
was comparable to the optimized one (Table 1). Equimolar
mixture of ZnCl2 with I-b in DMSO showed that I-b
decomposed within 1 h; however, addition of 1.5 equiv of
MgCl2 significantly suppresses the decomposition,29 suggesting
that the effect of Zn2+ on the catalytic reactions is not
important.
To further differentiate the proposed cycles A and B, a radical
clock 6-iodohex-1-ene was examined for the coupling with 3-
phenylpropanoic acid by varying the catalyst loading. According
to Hu and Weix’s studies on the Ni-catalyzed Kumada and
reductive coupling proceses,35a,b a radical-cage-rebound process
in cycle A (namely, rapid combination of alkyl radical with III)
is accepted if the ratio of 49/50 remains constant, while a
radical chain mechanism (namely, addition of alkyl radical to I)
should give a linear dependence of the ratio of 49/50 on the
catalyst loading. Figure 3 showed that by changing the loading
of Ni(acac)2 from 2.5% to 15%, the ratio of 49/50 increased
linearly, which supports the radical chain mechanism in cycle B.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures, characterization 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
■
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The reviewers and Dr. Martin (ICIQ, Spain) are acknowledged
for helpful comments. Dr. Hongmei Deng (Instrumental
Analysis and Research Center of Shanghai University) is
thanked for use of the NMR facility. Financial support was
provided by the Chinese NSF (Nos. 21172140 and 21372151),
the Program for Professor of Special Appointment at Shanghai
Institutions of Higher Learning (Dongfang Scholar) Shanghai
Education Committee.
REFERENCES
■
(1) Coupling of tertiary R−MgX catalyzed by Cu: (a) Terao, J.;
Todo, H.; Begum, S. A.; Kuniyasu, H.; Kambe, N. Angew. Chem., Int.
Ed. 2007, 46, 2086. (b) Ren, P.; Stern, L. A.; Hu, X. L. Angew. Chem.,
Int. Ed. 2012, 51, 9110. (c) Yang, C.-T.; Zhang, Z.-Q.; Liang, J.; Liu, J.-
H.; Lu, X.-Y.; Chen, H.-H.; Liu, L. J. Am. Chem. Soc. 2012, 134, 11124.
Co: (d) Iwasaki, T.; Takagawa, H.; Singh, S. P.; Kuniyasu, H.; Kambe,
N. J. Am. Chem. Soc. 2013, 135, 9604.
(2) Coupling of tertiary R−MgX catalyzed by Ni: (a) Lohre, C.;
Figure 3. Dependence of the ratio of (49/50) on catalyst loading using
a radical clock. Each ratio is averaged based on 4 independent runs.
Droge, 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.
(3) Coupling of tertiary alkyl halides with allylic and benzylic
metallics: (a) Ghorai, S. K.; Jin, M.; Hatakeyama, T.; Nakamura, M.
Org. Lett. 2012, 14, 1066. (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.
The collective studies appear to favor the catalytic cycle B,
although the details of the reaction mechanism require more
evidence. For instance, the observation that Zn accelerates the
stoichiometric reaction should not be simply attributed to
reduction of complex IV′ to Ni0 which is significantly enhanced
by MgCl2. Participation of Zn on promoting the formation of
alkyl radicals cannot be excluded.38
(4) Coupling of tert-alkyl halides with Ar-9BBN: Zultanski, S. L.; Fu,
G. C. J. Am. Chem. Soc. 2013, 135, 624.
E
dx.doi.org/10.1021/ja510653n | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(5) (a) Smith, S. C.; Fu, G. C. Angew. Chem., Int. Ed. 2008, 47, 9334.
(b) Han, C.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 7532.
(c) Thaler, T.; Haag, B.; Gavryushin, A.; Schober, K.; Hartmann, E.;
Gschwind, R. M.; Zipse, H.; Mayer, P.; Knochel, P. Nat. Chem. 2010,
2, 125. (d) Joshi-Pangu, A.; Ganesh, M.; Biscoe, M. R. Org. Lett. 2011,
13, 1218. (e) Li, L.; Wang, C.−Y.; Huang, R.; Biscoe, M. R. Nat. Chem.
2013, 5, 607. (f) Liu, Z.; Dong, N.; Xu, M.; Sun, Z.; Tu, T. J. Org.
Chem. 2013, 78, 7436.
(18) Naturally occurring C-acyl -glycosides: (a) Wu, Q.; Cho, J.-G.;
Lee, D.-S.; Lee, D.-Y.; Song, N.-Y.; Kim, Y.-C.; Lee, K.-T.; Chung, H.-
G.; Choi, M.-S.; Jeong, T.-S.; Ahn, E.-M.; Kim, G.-S.; Baek, N.-I.
Carbohydr. Res. 2013, 372, 9. (b) Disadee, W.; Mahidol, C.;
Sahakitpichan, P.; Sitthimonchai, S.; Ruchirawat, S.; Kanchanapoom,
T. Phytochemistry 2012, 74, 115.
(19) For Ni-catalyzed cross-coupling of glycosyl halides, see:
(a) Gong, H.; Sinisi, R.; Gagne,
1908. (b) Gong, H.; Gagne, M. R. J. Am. Chem. Soc. 2008, 130, 12177.
(c) Gong, H.; Andrews, R. S.; Zuccarello, J. L.; Lee, S. J.; Gagne, M. R.
Org. Lett. 2009, 11, 879.
́
M. R. J. Am. Chem. Soc. 2007, 129,
́
(6) For a review on alkyl-organometallics, see: Jana, R.; Pathak, T. P.;
Sigman, M. S. Chem. Rev. 2011, 111, 1417.
́
(7) Samann, C.; Dhayalan, V.; Schreiner, P. R.; Knochel, P. Org. Lett.
̈
(20) Recent α-selective C-glycoside synthesis, Co-catalyzed: Nicolas,
L.; Angibaud, P.; Stansfield, I.; Bonnet, P.; Meerpoel, L.; Reymond, S.;
Cossy, J. Angew. Chem., Int. Ed. 2012, 51, 11101.
2014, 16, 2418.
(8) For leading reviews on catalytic ketone synthesis, see:
(a) Johnson, J. B.; Rovis, T. Acc. Chem. Res. 2008, 41, 327. (b) Dieter,
R. K. Tetrahedron 1999, 55, 4177.
(9) For selected examples with alkyl-Zn: (a) Tamaru, Y.; Ochiai, H.;
Nakamura, T.; Yoshida, Z. Angew. Chem., Int. Ed. Engl. 1987, 26, 1157.
(b) Reddy, C. K.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1996, 35,
1700. Alkyl-Sn: (c) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc.
1988, 110, 1557. Alkyl-B: (d) Yu, Y.; Liebeskind, L. S. J. Org. Chem.
(21) Ar2Mg to glucosyl bromide: Lemaire, S.; Houpis, I. N.; Xiao, T.;
Li, J.; Digard, E.; Gozlan, C.; Liu, R.; Gavryushin, A.; Dien
̀
e, C.; Wang,
Y.; Farina, V.; Knochel, P. Org. Lett. 2012, 14, 1480.
(22) For a review, see: (a) Somsak, L. Chem. Rev. 2001, 101, 81. The
following glycosyl-metallics are known, but none is involved in
catalytic coupling reactions. Glycosyl-Mn: (b) Deshong, P.; Slough, G.
A.; Elango, V.; Trainor, G. L. J. Am. Chem. Soc. 1985, 107, 7788.
Glycosyl-Pd: (c) Munro-Leighton, C.; Adduci, L. L.; Becker, J. J.;
2004, 69, 3554. Alkyl-Mg: (e) Sherry, B. D.; Furstner, A. Acc. Chem.
̈
Res. 2008, 41, 1500. Alkyl-Zr: (f) Coia, N.; Mokhtari, N.; Vasse, J.-L.;
Szymoniak, J. Org. Lett. 2011, 13, 6292.
Gagne,
A.; Wenger, W.; Rajamannar, T. Chem. Commun. 1999, 2215.
Glycosyl-Si: (e) Pedretti, V.; Veyrieres, A.; Sinay, P. Tetrahedron
1990, 46, 77.
́
M. R. Organometallics 2011, 30, 2646. Glycosyl-B: (d) Vasella,
(10) (a) Johnson, J. B.; Bercot, E. A.; Rowley, J. M.; Coates, G. W.;
Rovis, T. J. Am. Chem. Soc. 2007, 129, 2718. (b) Bercot, E. A.; Rovis,
T. J. Am. Chem. Soc. 2002, 124, 174. (c) Bercot, E. A.; Rovis, T. J. Am.
Chem. Soc. 2005, 127, 247. (d) Zhang, Y.; Rovis, T. J. Am. Chem. Soc.
2004, 126, 15964. (e) Johnson, J. B.; Yu, R. T.; Fink, P.; Bercot, E. A.;
Rovis, T. Org. Lett. 2006, 8, 4307. (f) Kozuch, S.; Lee, S. E.; Shaik, S.
Organometallics. 2009, 28, 1303.
(11) For selected examples of carbonylative coupling of alkyl-
nucleophiles: (a) Ishiyama, T.; Miyaura, N.; Suzuki, A. Bull. Chem. Soc.
Jpn. 1991, 64, 1999. (b) Lee, S. W.; Lee, K.; Seomoon, D.; Kim, S.;
Kim, H.; Kim, H.; Shim, E.; Lee, M.; Lee, S.; Kim, M.; Lee, P. H. J.
Org. Chem. 2004, 69, 4852. (c) Gøgsig, T. M.; Taaning, R. H.;
Lindhardt, A. T.; Skrydstrup, T. Angew. Chem., Int. Ed. 2012, 51, 798.
(12) Rieke, R. D.; Hanson, M. V.; Brown, J. D. J. Org. Chem. 1996,
61, 2726.
̀
̈
(23) For selected examples of acyl nucleophiles: (a) Obora, Y.;
Ogawa, Y.; Imai, Y.; Kawamura, T.; Tsuji, Y. J. Am. Chem. Soc. 2001,
123, 10489. (b) DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2012, 134,
8094.
(24) Pd-catalyzed coupling of sugar-Sn with PhCOCl: Belosludtsev,
Y. Y.; Bhatt, R. K.; Falck, J. R. Tetrahedron Lett. 1995, 36, 5881.
(25) Synthesis of β-acyl C-glycosides, from: sugar benzothiazoles
(a) Dondoni, A.; Catozzi, N.; Marra, A. J. Org. Chem. 2005, 70, 9257.
Sugar CN: (b) Knapp, S.; Shieh, W.−C.; Jaramillo, C.; Trilles, R. V.;
Nandan, S. R. J. Org. Chem. 1994, 59, 946. Sugar acids: (c) Wolfgang
Weiser, W.; Lehmann, J.; Brewer, C. F.; Hehre, E. J. Carbohydr. Res.
1988, 183, 287.
́
(26) Synthesis of α-acyl C-glycosides from: sugar alkyne: (a) Alvarez-
(13) For seminal examples and leading reviews on the Ni-catalyzed
coupling of alkyl halides, see: (a) Rudolph, A.; Lautens, M. Angew.
Chem., Int. Ed. 2009, 48, 2656. (b) Frisch, A. C.; Beller, M. Angew.
Chem., Int. Ed. 2005, 44, 674. (c) Hu, X. Chem. Sci. 2011, 2, 1867.
(d) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726.
Dorta, D.; Leon, E. I.; Kennedy, A. R.; Riesco-Fagundo, C.; Suarez, E.
́
́
Angew. Chem., Int. Ed. 2008, 47, 8917. Sugar allene: (b) Geng, Y.;
Kumar, A.; Faidallah, H. M.; Albar, H. A.; Mhkalid, I. A.; Schmidt, R.
R. Bioorg. Med. Chem. 2013, 21, 4793. Sugar acyl oxazoline:
(c) Jensen, C. M.; Lindsay, K. B.; Taaning, R. H.; Karaffa, J.; Mette
Hansen, A.; Skrydstrup, T. J. Am. Chem. Soc. 2005, 127, 6544. Sugar
alkene to α-C-glycosyl acid: (d) Wong, C.-H.; Moris-Varas, F.; Hung,
S.-C.; Marron, T.-G.; Lin, C.-C.; Gong, K. W.; Weitz-Schmidt, G. J.
Am. Chem. Soc. 1997, 119, 8152.
(e) Devasagayaraj, A.; Studemann, T.; Knochel, P. Angew. Chem., Int.
̈
Ed. Engl. 1995, 34, 2723. For Ni-catalyzed alkyl halides with CO2:
(f) Liu, Y.; Cornella, J.; Martin, R. J. Am. Chem. Soc. 2014, 136, 11212.
(14) For recent reviews on reductive coupling of two electrophiles,
see: (a) Knappke, C. E. I.; Grupe, S.; Gartner, D.; Corpet, M.;
̈
(27) Dimerization of activated tertiary alkyl halides is known:
(a) Peng, Y.; Luo, L.; Yan, C.-S.; Zhang, J.-J.; Wang, Y.-W. J. Org.
Chem. 2013, 78, 10960. (b) Wada, M.; Murata, T.; Oikawa, H.; Oguri,
H. Org. Biomol. Chem. 2014, 12, 298.
(28) (a) Shukla, P.; Hsu, Y.-C.; Cheng, C.-H. J. Org. Chem. 2006, 71,
655. (b) Keh, C. C. K.; Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003, 125,
4062.
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.; Correa, A.; Martin, R. Chem.Eur. J. 2014, 20, 8242.
(15) (a) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. J. Am. Chem.
Soc. 2013, 135, 7442. (b) Wotal, A. C.; Weix, D. J. Org. Lett. 2012, 14,
1476. (c) Amatore, C.; Jutand, A.; Per
Chem. 2000, 131, 1293. (d) d’Incan, E.; Sibille, S.; Per
́
ichon, J.; Rollin, Y. Monatsh.
ichon, J.;
́
(29) See the Supporting Information for details.
Moingeon, M.−O.; Chaussard, J. Tetrahedron Lett. 1986, 27, 4175.
(e) Onaka, M.; Matsuoka, Y.; Mukaiyama, T. Chem. Lett. 1981, 10,
531.
(30) Method A proved to be ineffective for 16b giving only hydro-
dehalogenation product. Although 16a generated 17a in 90% yield, the
yields for other alkyl bromides in Table 3 were generally moderate
(see Table S5 in the Supporting Information). Also, extension of
methods B and C to t-BuBr was not successful. Method B only resulted
in a trace amount of 2a. Method C though provided 2a in 50% yield; 2-
bromo-2-methylhexane did not result in 8.
(16) (a) Yin, H.; Zhao, C.; You, H.; Lin, Q.; Gong, H. Chem.
Commun. 2012, 48, 7034. (b) Wu, F.; Lu, W.; Qian, Q.; Ren, Q.;
Gong, H. Org. Lett. 2012, 14, 3044. (c) Lu, W.; Liang, Z.; Zhang, Y.;
Wu, F.; Qian, Q.; Gong, H. Synthesis 2013, 45, 2234.
(17) For recent reviews in C-glycoside biology and biosynthesis, see:
(a) Bililign, T.; Griffith, B. R.; Thorson, J. S. Nat. Prod. Rep. 2005, 22,
742. (b) Hultin, P. G. Curr. Top. Med. Chem. 2005, 5, 1299. (c) Zou,
W. Curr. Top. Med. Chem. 2005, 5, 1363. (d) Compain, P.; Martin, O.
R. Bioorg. Med. Chem. 2001, 9, 3077. (e) Nicotra, F. Top. Curr. Chem.
1997, 187, 55.
(31) (a) Formation of acid anhydrides via reactions of acids and
(Boc)2O can be promoted by MgCl2: Bartoli, G.; Bosco, M. Synthesis
2007, 22, 3489. (b) Suzuki: Gooßen, L. J.; Ghosh, K. Angew. Chem.,
Int. Ed. 2001, 40, 3458.
(32) Oxidative addition of alkyl acid anhydride to bipyridine-Ni0 is
known, but with no characterization data. (a) Uhlig, E.; Bernd, N. Z.
F
dx.doi.org/10.1021/ja510653n | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Chem. 1981, 21, 451. (b) Fischer, R.; Walther, D.; Kempe, R.; Sieler,
J.; Schonecker, B. J. Organomet. Chem. 1993, 447, 131.
(33) BnCONi(I) is evidenced in the electrochemical reduction
process (ref 15c).
(34) Oxidative addition of alkyl halides to NiI resulting in NiIII is
́
possible: (a) Phapale, V. B.; Bunuel, E.; García-Iglesias, M.; Cardenas,
̃
D. J. Angew. Chem., Int. Ed. 2007, 46, 8790. (b) 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.
(35) (a) Breitenfeld, J.; Ruiz, J.; Wodrich, M. D.; Hu, X. J. Am. Chem.
Soc. 2013, 135, 12004. (b) Biswas, S.; Weix, D. J. J. Am. Chem. Soc.
2013, 135, 16192. (c) Zhao, Y.; Weix, D. J. J. Am. Chem. Soc. 2014,
136, 48. (d) Tellis, J. C.; Primer, D. N.; Molander, G. A. Science 2014,
345, 433. (e) Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle,
A. G.; MacMillan, D. W. C. Science 2014, 345, 437. See also:
(f) Schley, N. D.; Fu, G. C. J. Am. Chem. Soc. 2014, 136, 16588−
16593.
́
(36) (a) Gonzalez-Bobes, R.; Fu, G. C. J. Am. Chem. Soc. 2006, 128,
5360. (b) Powell, D. A.; Maki, T.; Fu, G. C. J. Am. Chem. Soc. 2005,
127, 510. (c) Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H. Org. Lett.
2011, 13, 2138. (d) Xu, H.; Zhao, C.; Qian, Q.; Deng, W.; Gong, H.
Chem. Sci. 2013, 4, 4022. (e) Creutz, S. E.; Lotito, K. J.; Fu, G. C.;
Peters, J. C. Science 2012, 338, 647.
(37) Although a single crystal X-ray structure is not available, the
1
formation of I-a (or [I-a]n) was evidenced by H, 13C NMR and ICP
studies (see the Supporting Information for details).
(38) Complexation of MgCl2 with organometallic reagents, e.g.,
PhZnCl, is known to accelerate an oxidative coupling process: Jin, L.;
Liu, C.; Liu, J.; Hu, F.; Lan, Y.; Batsanov, A. S.; Howard, J. A. K.;
Marder, T. B.; Lei, A. J. Am. Chem. Soc. 2009, 131, 16656.
(39) Very recently, Weix reported a similar synthesis of an alkyl acyl-
Ni(II)−Cl complex in a THF solution with similar observation that Zn
is not necessary but may enhance the reaction rate, see: Wotal, A. C.;
Ribson, R. D.; Weix, D. J. Organometallics 2014, 33, 5874.
(40) MgCl2 may also enhance the solvent dielectric: McCann, L. C.;
Organ, M. G. Angew. Chem., Int. Ed. 2014, 53, 4386.
G
dx.doi.org/10.1021/ja510653n | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX