Ni-Catalyzed Reductive Coupling of Electron-Rich Aryl Iodides with Tertiary Alkyl Halides

Article abstract of DOI:10.1021/jacs.8b09473

This work illustrates the reductive coupling of electron-rich aryl halides with tertiary alkyl halides under Ni-catalyzed cross-electrophile coupling conditions, which offers an efficient protocol for the construction of all carbon quaternary stereogenic centers. The mild and easy-to-operate reaction tolerates a wide range of functional groups. The utility of this method is manifested by the preparation of cyclotryptamine derivatives, wherein successful incorporation of 7-indolyl moieties is of particular interest as numerous naturally occurring products are composed of these key scaffolds. DFT calculations have been carried out to investigate the proposed radical chain and double oxidative addition pathways, which provide useful mechanistic insights into the part of the reaction that takes place in solution.

Full text of DOI:10.1021/jacs.8b09473

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Article
Ni-Catalyzed Reductive Coupling of Electron-
Rich Aryl Iodides with Tertiary Alkyl Halides
Xuan Wang, Guobin Ma, Yu Peng, Chloe E. Pitsch, Brenda J. Moll, Thu D. Ly, Xiaotai Wang, and Hegui Gong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b09473 • Publication Date (Web): 08 Oct 2018
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Journal of the American Chemical Society
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Ni-Catalyzed Reductive Coupling of Electron-Rich Aryl Iodides with
Tertiary Alkyl Halides
†
§
‡
‡
‡
Xuan Wang,† Guobin Ma, Yu Peng, Chloe E. Pitsch, Brenda J. Moll, Thu D. Ly, Xiaotai
‖
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Wang*‡¶ and Hegui Gong*†
†School of Materials Science and Engineering, Center for Supramolecular Chemistry and Catalysis and Department
of Chemistry, Shanghai University, 99 Shang-Da Road, Shanghai 200444, China
‡Department of Chemistry, University of Colorado Denver, Campus Box 194, P.O. Box 173364, Denver, Colorado
80217-3364, United States
¶Institute of Molecular Science, Shanxi University, Taiyuan, Shanxi 030006, China
§State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou 730000, China
Nickel, tert-Alkyl Halides, Aryl iodides, Quaternary carbon
ABSTRACT: This work illustrates the reductive coupling of electron-rich aryl halides with tertiary alkyl halides under Ni-
catalyzed cross-electrophile coupling conditions, which offers an efficient protocol for the construction of all carbon qua-
ternary stereogenic centers. The mild and easy-to-operate reaction tolerates a wide range of functional groups. The utility
of this method is manifested by the preparation of cyclotryptamine derivatives, wherein successful incorporation of 7-
indolyl moieties is of particular interest as numerous naturally-occurring products are composed of these key scaffolds.
DFT calculations have been carried out to investigate the proposed radical chain and double oxidative addition pathways,
which provide useful mechanistic insights into the part of the reaction that takes place in solution.
1. INTRODUCTION
As such, Fu reported a Ni-catalyzed Suzuki method
wherein aryl-9-BBN decorated with electron-donating or -
neutral groups at the meta-positions were coupled with a
broad range of unactivated tertiary alkyl bromides; low
yields were observed for ortho- or para-substituted
arenes.6 Here we report the use of 3-fluoropyrinde (3-F–
Py) as the additive/ligand that allows an efficient coupling
of electron-rich aryl halides with tertiary alkyl halides.
The present strategy is in line with our recent interest in
the creation of arylated carbon quaternary stereogenic
centers through cross-electrophile coupling regimes.8-13
All-carbon quaternary stereocenters containing tertiary
alkyl–aryl bonds are widespread in biologically active nat-
ural products and pharmaceutical compounds.1 Electron-
rich arenes are particular prevalent in this class of struc-
tural motifs. Notable examples include the (+)-asperazine,
(-)-viridicatumotxin B, and (-)-mesembrine families (Fig-
ure 1).2 Numerous cross-coupling protocols have been
implemented to access such highly congested quaternary
carbon centers; nearly without exception, these have re-
lied on the creation of C(sp3)–C(sp2) bonds.3-7 For in-
stance, Biscoe developed a Ni-catalyzed strategy that in-
volves the coupling of a tertiary alkyl–MgX reagent with
aryl halides (Scheme 1).4 The reaction accommodates a
wide array of electron-rich and -poor arenes with high
retention to isomerization ratios (R:I) of the alkyl moie-
ties, although functional group compatibility and the
scope of alkyl substrates may be restricted because alkyl
Grignard reagents are utilized. Recently, a photore-
dox/Ni-catalyzed Suzuki reaction was reported by Mo-
lander, which allows effective coupling of tertiary alkyl
trifluoroborates with electron-deficient aryl bromides
(Scheme 1).5 Alternatively, the coupling of tertiary alkyl
electrophiles with aryl nucleophiles has been advanced.6–7
Figure 1. Examples of the bioactive natural products
We have previously shown that the use of Ni/pyridine
or 4-dimethylaminopyridine (DMAP) catalytic conditions
enables an effective coupling of tertiary bromides with a
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diverse set of electron-deficient aryl bromides (Scheme
50% 3-F pyridine
54%
52%
trace
44%
58%
46%
50%
60%
52%
22%
50%
50%
7
8
9
10
11
12
13
14
15
16
17
18
11:1
10:1
NA
10:1
10:1
10:1
>10:1
10:1
9:1
1).13 Electron-rich aryl halides are incompetent due to low
coupling efficiency and severe isomerization of the alkyl
groups. This method thus fell short of addressing the
challenge needed to create the key aryl–tertiary alkyl
bond present in many natural products, such as those
shown in Figure 1. As detailed below, we have now devel-
oped a Ni/3-F–Py-catalyzed method that allows direct
coupling of tertiary alkyl halides and electron rich io-
doarenes. The practicability of our method is illustrated
by the facile joining of C3(sp3) of cyclotryptophan with
C8’(sp2) indole derivatives. This represents a potentially
complementary solution to the long-standing bottleneck
in the synthesis of (+)-asperazine and its analogs.2b,14
1
2
3
4
5
6
7
8
Mn instead
L2 instead of L1
L3 instead of L1
L4 instead of L1
L5 instead of L1
L6 instead of L1
L7 instead of L1
L8 instead of L1
L9 instead of L1
L10 instead of L1
L11 instead of L1
>20:1
6:1
20:1
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a Reaction Conditions: tertiary bromide 1 (0.3 mmol, 100 mol %), 4-
iodoanisole (200 mol %), Ni(acac)2 (5 mol %), pyridine derivative
(100 mol %), Zn (200 mol %), MgCl2 (100 mol %), LiCl (300 mol %),
b
solvent (1 mL). NMR yield using 2,5-dimethylfuran as the internal
Scheme 1. Creation of Quaternary Carbon Centers
through Ni-Catalyzed Aryl–Alkyl Bond Formation
c
standard. The ratio of retention to isomerization (R:I) of alkyl
1
groups was determined by H NMR analysis of a mixture containing
2a and 2a’ and other impurities that was obtained after passing the
R1
R2
R2
R3
reaction mixture through a short silica column. d Isolated yield.
previous work
X
R1
Ni (cat.)
R3
R
M
R
Me
Ar
Me
Ni(acac)2 (5%)
3-F-pyridine (100%)
MgCl2 (100%)
LiCl (300%)
Me
Me
Br
2
Biscoe (2011)
Glorius (2011)
M = MgX
X = Br, OTf
X = Br
R = EDG, H, EWG
R = EWG
BzO
BzO
retention product
Me
Molander
(2017)
with Ir (cat.) & h
M = BF3K
1
(0.3 mmol)
Zn (200%)
DMA (1 mL)
25 oC, 12 h
Ar
R1
R
R2
Ar-I (2 equiv)
2'
BzO
R2
R1
Br
9-BBN
R
Ni (cat.)
isomerization product
R3
Fu (2013)
R3
Me
R
R = EDG, Ph, H
I
R
Me
I
R2
R1
R2
Gong (2015)
2b
2c
, R = H: 68% (12:1)
, R = Ph: 51% (15:1)
I
Br
R1
Ni (cat.)/Zn
2f
, 4-Me: 67% (10:1)
2g, 2-Me: 50% (15:1)
2h
2i
, R= Me: 60% (8:1)
, R= OMe: 65% (9:1)
not suitable
for electron-
rich arenes
R3
R
R
MgCl2
pyridine or DMAP
2d, R = tBu: 60% (10:1)
2e
X
R3
R
, R = F: 66% (12:1)
X = halides
R = EWG
OMe
OMe
R2
OMe
R1
R2
this work
I
OR
I
R1
Ni (cat.)/Zn
I
suitable for
electron-rich
arenes
R3
MgCl2, LiCl
3-F-pyridine
I
OMe
X
2l
, 2-OMe: 43% (10:1)
2m
R3
2j
, R = Ac: 66% (10:1)
R
2n, 63% (10:1)
, 3-OMe: 66% (10:1)
2k
, R = Ts: 57% (11:1)
X = halides
R = EDG, H
O
NHBoc
2. RESULTS AND DISSCUSIONS
I
N
O
NHR
I
I
2.1. Optimization and Substrate Scope
2p
2q
, R = Ac: 60% (10:1)
, R = Boc: 75% (8:1)
2o
, 60% (>20:1)
2r
, 56% (11:1)
I
Table 1. Optimization for the Reaction of 1 with 4-
iodoanisole a
H2N
O
O
I
N
I
Ph
2s
2t
2u
, 78% (10:1)
, 38% (>20:1)
, 50% (20:1)
I
N
H
N
I
Ac
I
2v
2x
, 63% (20:1)
, 52% (20:1)
2w
: 71% (10:1)
Figure 2. Coupling of 1 with aryl iodides. Reaction conditions are
same as in Table 1, entry 1. Isolated yields each refer to a mixture of
the quaternary product and its isomer. Shown in parenthesis are
ratios of retention to isomerization (R:I) of alkyl groups determined
by 1H NMR analysis after purification.
Entrya
1
Variation from the stand-
ard conditions
R:Ic
10:1
Yieldb
no changes
65%
(71%)d
trace
trace
trace
18%
In our previous studies, the coupling of tertiary alkyl
bromide 1 with 4-bromoanisole using pyridine or DMAP
as the additives/ligands gave rise to the cross-coupling
product 2a in less than 5% yield, with most of the 4-
bromoanisole remaining intact.15 To enhance the reactivi-
ty of the aryl partner, 4-iodoanisole was chosen, but this
w/o Ni
w/o Zn
2
3
4
5
6
NA
NA
NA
50:1
12:1
w/o 3-F pyridine
w/o MgCl2
w/o LiCl
30%
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only increased the yield to 8% with a 2:1 ratio of 2a/2a’.15
1
Efforts to optimize the reaction conditions were then un-
2
3
4
5
6
7
8
9
dertaken (Table 1). It was found that when Ni(acac)2 was
used as the Ni(II) source, DMA (dimethylacetamide) as
the solvent, and 3-F-pyridine as the putative ligand, a 71%
isolated yield was obtained for a mixture of retention
product 2a and its isomer 2a’ in a 10:1 ratio (R:I) in the
presence of LiCl, Zn, and MgCl2. Control experiments
showed the indispensable role of Ni(II), Zn, and 3-F-
pyridine
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O
Me
Me
O
Me
Me
Me
Me
Me
R
Me
O
N
TsO
OMe
5, R = Ac: 50% (>50:1)
, R = Ph: 65% (5:1)
R
OMe
OMe
N
O
3, R = OMe: 70% (10:1)
4, R = CF3: 60% (10:1)
Ph
6
8: 57% (>20:1)
9: 62% (>20:1)
7, R = BzOCH2CH2: 56% (5:1)
NHBoc
OMe
NHBoc
NHBoc
NHBoc
Me
BzO
BzO
O
Me
OBz
N
BocN
Et
O
Cbz
14: 15%a,b
H
OMe
H
10: 42%
11: 68% (3:1)
12: 50%
13: 42%
OMe
15: 73%a,b,c
MeO
MeO
R
Ar
16a, R = AcO: 70%c
16b, R = TsO: 55%c
16c, R = BocNH: 75%c
16d, R = TMS: 70%b,c
S
NBoc
Ar =
N
O
N
H
Boc
16e: 70%c
16f: 75%c
16h: 41%b,c
16g:
80%b,c
16m, R = Ph:76%c,d
Ph
16n, R = 3,4-di-OMe-C6H4: 80%c,d
16o, R = 4-Me-C6H4: 79%c,d
16p, R = 2-naphthyl: 51%c,d
R
N
N
N
Ac
N
Ac
Boc
16q: 61%c,d
16i: 55%b,c
16j: 52%c
16k: 65%c
16l: 82%b,c
MeO
MeO2C
NH
NH
NH
CO2Me
NBoc
CO2Me
CO2Me
NBoc
NBoc
MeO
NBoc
NBoc
NBoc
N
H
N
H
N
N H
Boc
MeO
Boc
19: 40%a,b,c
Boc
17a: 60%b,c
MeO2C
Boc
17b: 57%c,d,e
18: 75%c,f
20: 60%a,b,c
MeO2C
MeO2C
NHBoc
NHBoc
NHBoc
OMe
O
MeO
MeO
NAc
NH
NH
NH
O
O
O
CO2Me
CO2Me
NH
Bn
NH
Bn
NH
Bn
N
NBoc
NBoc
N
N
N
H
H
N
H
N
N
H
N
H
O
Cbz
O
Boc
22: 52%a,b,c
Boc
21: 30%a,b,c
Cbz
Cbz
23:13%a,b,c
24: 40%a,b,c
25: 40%a,b,c
Figure 3. Examination of substrate scope. Unless otherwise indicated the standard reaction conditions same as Table 1, entry 1 were used, and
isolated yields for a mixture of the quaternary product and its isomers (if applicable) were obtained. The R:I ratios shown in parenthesis were
determined by 1H NMR after purification. a 20 mol % of Ni(acac)2 was used. b DMF was used as the solvent. c Alkyl chloride was used. d The ratio
of tertiary alkyl halide to vinyl halide was 1.5:1, and NiI2 (10 mol %) and DMSO were used. e DMAP was used to replace 3-F-pyridine. f 5 μL of H2O
was added via a syringe.
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(Table 1, entries 2–4). The yields were reduced dramatical- DMA) enhanced the coupling yields by inhibiting unde-
1
2
3
4
5
6
7
8
ly in the absence of MgCl2 or LiCl (entries 5–6). Reducing
the amount of 3-F–Py also lowered the yield (entry 7). The
use of Mn instead of Zn resulted in a comparable isomeri-
zation ratio, albeit in a lower overall yield (entry 8). Other
pyridine ligands proved less effective (entries 9-18), alt-
hough the presence of electron-withdrawing groups on
the pyridine ring seemed to be beneficial (e.g. L11 vs L9).
It should be noted that bipyridine and terpyridine ligands
only furnished a trace amount of the coupling products.
Monitoring of the reaction revealed that it proceeded to
completion within one hour (Figure S15).16
sired ring-opening side reactions. This practice is quite
general for low yielding arylation of chlorocyclotrypata-
mine substrates (Figure 3).
To explore further the utility of this coupling strategy,
an effort was made to construct cyclotrypatamine ana-
logs.16 This was done by coupling their chloro-precursors
with a number of aryl and vinyl halides. The bromo-
precursors were incompatible with the reaction condi-
tions, under which they would undergo facile ring-
opening side reactions. In addition to obtaining 16a–e
from the corresponding electron-rich iodobenzenes, it
was found that heteroaromatic iodides could be coupled
effectively to yield 16f–l and 17a. Included in the latter
studies were substrates wherein the iodide was present on
the carbon atoms of 3-thiophene, 5-benzofuran, 6- and 7-
quinoline, as well as 3-, 5-, 6- and 7-indoles. A slight mod-
ification in the reaction conditions enabled the incorpora-
tion of vinyl and dienyl groups into the cyclotrypatamine
scaffolds, as confirmed by the preparation of 16m–q and
17b. Note that vinyl bromides were used in excess because
they were more prone to dimerization as compared with
aryl iodides.10a Similar to our previous observation that
electron-deficient aryl halides generally require DMAP as
the ligand,13 DMAP was necessary for the conversion into
17b of the styrenyl bromide that contains an electron-
withdrawing ester group.
9
10
11
12
13
14
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Next, a variety of aryl iodides were investigated as cou-
pling partners for 1.16 Iodobenzene and its para-
substituted derivatives provided the products 2b–2f in
good yields with good control of isomerization ratios
(Figure 2). Both para- and ortho-methyl iodobenzenes
were compatible with the reaction conditions, with the
former being more effective. Mono-, di- and tri-
substituted methyl and/or methoxy aryl iodides generally
furnished the coupling products 2g–2n in good yields and
high R:I ratios. However, a moderate result was obtained
for 2-methoxy iodobenzene, presumably due to increased
steric hindrance. The reaction conditions were also appli-
cable to arenes bearing amino groups. It was found that
meta- and para-substituted acetyl and Boc-protected
amino and phthalimidyl groups were coupled effectively,
as illustrated by the preparation of 2o–2r. By contrast, a
corresponding substrate bearing a Boc-protected amino
group in the ortho-position failed to give Boc-protected 2s
in an appreciable yield. 2-Iodoaniline itself gave 2s in 38%
yield with a high R:I ratio. Iodobenzene bearing para-
acetal furnished 2t in 50% yield. On other hand, the pre-
sent coupling approach proved compatible with 3-iodo-9-
phenyl-9H-carbazole and 1-iodonaphthalene as evident by
the effective preparation of 2u and 2v. Finally 5- and 7-
iodoindoles were tolerated, with no protecting group
proving necessary for the production of 2x.
As a further extension of the present method, chlorocy-
clotryptamines derived from L-tryptophan encompassing
both the endo and exo-esters were subjected to the cou-
pling conditions. Whereas the exo-ester precursor was
highly effective for the coupling with para- methoxyben-
zene (giving 18), the reaction with 7-iodoindole only fur-
nished product 19 in 40% yield when DMF was used as
solvent and the catalyst loading was increased to 20
mol%. In this case, the majority of the chloro substrate
was converted into its L-tryptophan precursor via a
dechlorination/decyclization process. The addition of a
trace amount of water appears to be essential for the
preparation of 18, which possibly helps remove salts on Zn
surface. By comparison, the endo-ester analog was more
effective; it provided 20 in 60% yield. Since 20 can be
viewed as the key scaffold of the natural product (+)-
asperazine and (+)-pestalazine, the coupling of 7-
iodotrptophan was pursued. This gave products 21 and 22
in 30% and 52% yields, respectively. Arylation of a C3-
chloro tetracycle derived from Trp-Phe dipeptide with 7-
iodotrptophan generated 23 in 13% yield. The major side
reaction arose from dechlorination/decyclization of the
chloro substrate to yield an indolic diketopiperazine.
However, its assembly with 6-indolyl and 3,4,5-
trimethoxyphenyl groups successfully furnished 24 and 25
in synthetically useful yields. It is worth noting that the
joining of 7-indolyl derivatives with tertiary (Csp3)–
carbons is a recognized challenge as evidenced by Movas-
saghi’s synthesis of asperazine and relevant analogs.2b,17
The Friedel−Crafts methods employed by the authors may
encounter a regioselective issue; only a 6% yield was ob-
served for the key intermediate 23.2b Finally, according to
The coupling protocol also displayed good compatibil-
ity across a range of tertiary alkyl electrophiles.16 For in-
stance, a variety of 2-bromo-2-methyl alkanes bearing
benzoyl esters, ketone, benzyl, and tosylate groups gave
products 3–9 in good yields and with good control of R:I
ratios. The more sterically hindered 2-bromo-2-
ethylbutanol protected with benzoyl furnished 10 in 42%
yield without detectable isomerization byproducts. Cyclic
alkyl bromides were also examined. 4-Bromotetrahydro-
2H-pyran resulted in 11 and its isomer in an overall 68%
yield with a R:I ratio of 3:1. (1-Bromocyclohexyl)methyl
benzoate and its five-membered ring analog gave rise to
12 and 13 in 50% and 42% yields with no detectable isom-
erization products. Heterocyclic halides are also compe-
tent for this quaternary carbon-generating method. A low
yield was obtained for 14, due to a highly competitive
dechlorination/decyclization reaction of the tertiary bro-
mide to form Cbz-proteted 2-(cyclopent-1-en-1-yl)ethan-1-
amine. Arylation at the benzylic carbon of tetrahydrofu-
ro[2,3]indole resulted in 15 in 73% yield. In both cases of
14 and 15, the use of 20 mol% of Ni and DMF (instead of
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Journal of the American Chemical Society
singlet in the 1H NMR spectrum.16 Coupling of the deuter-
Overman’s studies, 22 should serve as a strong candidate
for the construction of (+)-asperazine and its analogs.14
Thus, saponificiation of 22 followed by assembly with L-
phenylalanine provided 26, which can be readily cyclized
to form (+)-asperazine.14
ated analog 27-D with methyl 4-bromobenzoate under
the previously reported protocol for electron-withdrawing
groups produced 29-D with a syn/anti ratio of 1:1 (eq 1).13
These results suggest that an alkyl radical was involved in
the coupling process.18
1
2
3
4
5
Scheme 2. Formal Synthesis of (+)-Asperazine
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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2.2.3. Preparation of (Py)nNiAr Complex
The use of pyridine or its derivatives is crucial for this
quaternary carbon-forming process. To gain insight into
the catalytically active species, we treated Ni(COD)2 with
methyl 4-bromobenzoate in the presence of excess DMAP
in THF. A yellow precipitate was isolated and identified as
a diamagnetic [(DMAP)3NiAr]+Br– complex (30-Br).16,19-21
It should be noted that in solution, formation of a mixture
containing low-coordinate pyridine-Ni complexes is also
possible.20b
2.2. Mechanistic Investigations
We have carried out mechanistic studies on the present
quaternary carbon-forming method, using a combination
of experiments and DFT calculations.
2.2.1. Possible Reaction Pathways
Exposure of 30-Br to excess tertiary butyl bromide gave
the quaternary product 31 in 40% yield (eq 2). This result
was consistent with Weix’s observation of a radical chain
mechanism for the arylation of secondary alkyl halides
with aryl halides.22
Two pathways were considered, as shown in Scheme 3.
The reaction may occur by a radical chain mechanism,21
wherein oxidative addition of aryl halide to LnNi0 leads to
(Ln)NiIIAr(X) that intercepts t-Bu radical to give
(Ln)NiIIIAr(t-Bu)X. Reductive elimination results in the t-
Bu–Ar product and (Ln)NiIX. The latter abstracts bromide
from t-BuBr and furnishes (Ln)NiIIX(Br) and t-Bu radical.
While the radical diffuses to the bulk solution and com-
bines with(Ln)NiIIAr(X), (Ln)NiIIX(Br) is reduced to (Ln)Ni0
by Zn, allowing the catalytic cycle to continue. An alter-
native double oxidative addition mechanism may also
operate, which involves reduction of (Ln)NiIIAr(X) to
(Ln)NiIAr by Zn. The Ni(I) species abstracts bromide from
t-BuBr, thereby generating t-Bu radical and (Ln)NiII(Ar)Br,
which combine rapidly to give (Ln)NiIII(Ar)(t-Bu)(Br).25
Subsequent reductive elimination generates the product
and (Ln)NiIBr which is converted into (Ln)Ni0 by Zn re-
duction.
2.2.4 Effects of Salts
Treatment of [(DMAP)3NiIIAr]+X– (30-X; X = I, Br, Cl)
with excess MgCl2 , LiCl, or (nBu)4NCl (TBAC) revealed
complete conversion into a possible (DMAP)2NiII(Cl)Ar
(32) species within 10 min, as confirmed by 1H NMR stud-
ies (eq 3).16,23 In eq 2, it was revealed that the reaction of
30-I with t-BuBr did not give the quaternary product 31
unless MgCl2 or (nBu)4NCl was added. These results sug-
gest that complex 32 is most likely the intermediate inter-
cepting the t-Bu radical and introducing reductive elimi-
nation of the product, wherein Mg2+ and Li+ do not partic-
ipate. By monitoring the reaction of 30-Br with t-BuBr, we
observed significant rate acceleration in the presence of
MgCl2 or TBAC (Figure S8), suggesting that formation of
32 is important for speeding up the reaction.
Scheme 3. Proposed radical chain (left cycle) and double
oxidative addition (right cycle) mechanisms
2.2.2. Involvement of Radicals
Under the standard reaction conditions, a bromotetra-
furan tethered with allyl ether 27-H was effectively cou-
pled with 4-iodoanisole giving 28-H in 50% yield. Howev-
er, the germinal methyl peaks of 28-H coincided as one
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The important roles of MgCl2 and LiCl in the catalytic
Page 6 of 10
process were further identified as follows.16 First, the con-
trol experiments indicated that Mg2+/Cl– or Li+/Cl– ion
pairs cooperatively determine the catalytic transformation
efficiency (Table S2).16 Without MgCl2 and LiCl, with
(nBu)4NCl, or with Mg(OTf)2 and LiOTf, no coupling reac-
tion occurred (Table S2).16 Second, both MgCl2 and LiCl
were able to activate Zn. Treatment of the mixture of ter-
tiary alkyl bromide (1) and 4-iodoanisole with Zn/3-F-Py
in DMA only resulted in recovered halides after 2 h. Hov-
erer, addition of MgCl2 (1 equiv) or LiCl (3 equiv) resulted
in substantial amounts of hydrodebromination and al-
kene products derived from 1 in both cases (Table S3).16
Since Li+/Cl- ions are known to cooperatively solubilize
the organozinc reagents formed on the surface of Zn,24 the
two salts in the present study may well function in a simi-
lar way by activating Zn. Third, MgCl2 was found to react
with a Ni(acac)2/DMAP mixture and the pre-formed
(DMAP)2Ni(acac)2 complex in DMSO-d6 to afford more
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soluble Ni species, as confirmed by H NMR studies. By
contrast, LiCl was much less effective and (nBu)4NCl did
not lead to detectable Ni complex signals at all (Tables
S3–S4 and Figures S9–S12). This was attributed to stronger
interaction of Mg2+ with acac anion.16 Finally, reduction of
the insoluble (DMAP)2 Ni(acac)2 complex in DMSO-d6 to
Ni(0) by Zn was not successful unless MgCl2 was added
(Table S5).16
2.2.5. DFT Computational Study
In view of the experimental findings above, we have
employed DFT calculations in a bid to elucidate the two
possible mechanisms shown in Scheme 3, using Ni0Py2 as
the catalyst (1cat) and iodobenzene and t-BuBr as the
substrates. Note that the formation of (Py)2Ni0 is more
favorable than that of (Py)3Ni0 or (Py)4Ni0 (Figure S19).
Oxidative addition of iodobenzene to (Py)2Ni0proceeds
via the concerted transition state TS1 to form the square
planar Ni(II) complex IM2 (Figure 4). This step has a
readily attainable free energy of activation (7.8 kcal/mol)
and large thermodynamic driving force (44.2 kcal/mol).
IM2 further coordinates with excess pyridine in the sys-
tem to give IM3. The Ni–I bond distance in IM3 suggests
that it should be an ion pair with the iodide outside the
coordination sphere. IM3 dissociates to the cation IM4
which
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Figure 4. Free energy profile for the oxidative addition of PhI to (Py)2Ni0 and subsequent reactions. Selected bond dis-
1
tances are given in Å (the same below).
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III
Figure 5. Free energy profile for the radical chain pathway with a NiII Ni redox manifold following the oxidative addi-
→
tion. Upper left superscripts indicate the spin states of open-shell, paramagnetic structures (the same below). The num-
bers shown in black fonts on selected atoms in 2IM10, 2TS4, and 3IM11 denote spin densities.
Figure 6. Free energy profile for the double oxidative addition pathway with a Ni Ni NiIII redox manifold.
II
I→ →
combines with chloride ion from the salt additives to
form another ion pair, IM5.This ion exchange sets the
stage for the ensuing substitution of chloride for pyridine,
which would yield the trans complex IM6 as the most
stable intermediate in this phase of reaction. It is im-
portant to note that IM3/IM4 and IM6 correspond to the
NMR-observed diamagnetic species described above as
30-X and 32. Thus, the calculations show good experi-
mental–theoretical synergy.
coupling product t-BuPh and generate the linear Ni(I)
complex 2IM9. Reductive elimination via three-coordinate
2
2IM8 and TS3 is more favorable than that through four-
2
2
coordinate IM7 and TS2 because of steric effects. Re-
duced steric hindrance with decreasing coordination
number stabilizes TS3 relative to TS2 more than it does
2
2
2IM8 relative to IM7 (2TS2 – TS3 = 4.3 kcal/mol, IM7 –
2IM8 = 1.5 kcal/mol). This is apparently because the tran-
sition states, wherein the t-Bu and aryl groups need to
move closer, are more sensitive to changes in steric hin-
drance than are their precursor complexes.
2
2
2
We considered that IM6 could convert to the tetrahe-
dral triplet26 3IM6 by a Berry pseudorotation-type mecha-
nism to facilitate the uptake of t-Bu radical by single elec-
tron transfer (SET) (Figure 5). 3IM6 has two unpaired
electrons on the Ni(II) center, so it could readily utilize
one of them to bond with the t-Bu radical to form the
Ni(III) complex 2IM7. Reductive elimination of t-BuPh
from 2IM7 would meet the barrier 2TS2 that is 13.5
kcal/mol relative to 2IM7. The alternative and more favor-
able pathway is by the dissociation of one pyridine ligand
2
Complex IM9 binds t-BuBr through the bromine do-
2
nor atom to form IM10, which then undergoes a facile
intramolecular nickel-to-bromine SET via TS4 (∆G≠ = 4.2
2
2
kcal/mol relative to IM9). This SET step leads to the tri-
plet complex 3IM11 and regenerates the t-Bu radical,
which is supported by spin analysis. As shown in Figure 5,
the spin densities on the selected atoms in TS4 suggest
that TS4 contains an emerging t-Bu radical with a spin
density of 0.55 on the tertiary carbon, as well as an emerg-
ing triplet Ni(II) complex with a spin density of 1.36 on
2
2
2
2
from IM7 to form IM8, which then passes through the
2
lower barrier TS3 (∆G≠ = 10.7 kcal/mol) to release the
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the nickel center. The two spins apparently are antiferro-
tive in that it affords an efficient means of creating qua-
magnetically coupled, making a net doublet of 2TS4.
3IM11 combines with excess pyridine to form the more
ternary carbon centers. The mild Ni-catalyzed reductive
conditions associated with this procedure accommodate a
wide variety of functional groups, thereby allowing a
broad substrate scope. The compatibility of heteroaro-
matic iodides, particularly 7-iodoindoles, may provide
facile access to a number of structurally-relevant natural-
ly-occurring products whose preparation could otherwise
prove challenging using conventional coupling methods.
The DFT computations give the free energy profiles of
two possible reaction coordinates: the radical chain and
the double oxidative addition pathways. The choice of the
pyridine ligand appears to be pivotal in that it plays a cru-
cial role in controlling the dissociation and recombination
of various Ni-containing intermediates. (Py)2Ni complexes
are key for oxidative addition of aryl halides to Ni0,
whereas (Py)2Ni(Ar)Cl complexes are key for radical in-
terception. Although the DFT computations have given
mechanistic insights into the part of the reaction that
takes place in solution, the overall rate and time of this
coupling reaction could be governed by the heterogene-
ous process that generates the active catalyst.27 We be-
lieve that the present study is not only of operational in-
terest in terms of forming otherwise challenging-to-
prepare C–C bonds, but it also provides mechanistic in-
sights for other relevant nickel-mediated coupling reac-
tions.
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3
stable four-coordinate tetrahedral complex IM12, which
is then reduced by zinc to regenerate the catalyst (Py)2Ni0
(1cat). We can rule out the singlets of IM11 and IM12 on
the basis of their much higher energies (Figure 5).
It should be noted that our computational results con-
stitute a complex yet well-defined redox manifold
throughout the reaction pathway from 1cat to 3IM12:
9
II
I
II
0→ → III→ →
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Ni Ni Ni Ni Ni . This is consistent with the fact that
nickel as a 3d metal tends to engage in both one- and
two-electron redox processes. Furthermore, in the com-
plete reaction pathway, the reductive elimination via 2TS3
has the largest ∆G≠ (10.7 kcal/mol) and is also irreversible,
and as such, it is the rate-limiting step for the part of the
reaction that takes place in solution. This readily attaina-
ble activation energy, coupled with the enormous overall
thermodynamic driving force (–91.6 kcal/mol), explains
the high activity of the catalyst system. We also investi-
gated the electronic effects of the pyridine-type ligands
on the activation energies of the reductive elimination
(Figure S21).
Alternatively, the double oxidative addition mechanism
suggests that aryl–NiI complexes could involve in the
coupling with alkyl halides (Scheme 3). Thus, we consid-
ered the possible reduction of the Ni(II) complex IM6 or
3IM6 by zinc to form Ni(I) complexes, which might fur-
nish redox cycles different than what has been described
above. Along these lines of thought, we computed the
(Py)NiIPh complexes 2IM13 and 2IM14 (Figure 6). For their
oxidative addition reactions with t-BuBr, only the SN2-
ASSOCIATED CONTENT
Supporting Information. Methods, experimental procedures,
characterizations of new compounds, and additional computa-
tional results. This material is available free of charge via the
Internet at http://pubs.acs.org.
2
type TS5 was located, and no concerted transition states
2
AUTHOR INFORMATION
were found. The pathway via TS5 is disfavored because it
would require a much higher activation energy than the
Corresponding Authors
2
2
pathway via TS3 (Figure 5). IM14 could undertake an
SET reaction with t-BuBr, similar to the SET reaction in-
volving 2IM9, which proceeds through 2IM15, peaks at
hegui_gong@shu.edu.cn, xiaotai.wang@ucdenver.edu
Author Contributions
‖These authors contributed equally.
3
3
2TS6, and produces the Ni(II) complex IM16. IM16 con-
tinues on another SET reaction with the t-Bu radical to
form the Ni(III) complex 2IM17 with the alkyl ligand,
which undergoes reductive elimination to give the cou-
pling product t-BuPh and revert to the NiI oxidation state
ACKNOWLEDGMENT
We acknowledge support for this work by the NSF of China
(Nos. 21572140 and 21372151), the One Hundred-Talent Pro-
gram of Shanxi Province, and the University of Colorado
Denver. We thank Jiawang Wang and Changzhou Cheng for
purifying the compounds in Figure 3, and Dr. Xiaolong Wan
(SIOC, China) for purifying compound 32. We thank Prof.
Jonathan Sessler (Univ. of Texas) for manuscript proof-
reading. We also thank Profs. Tom Cundari (North Texas
Univ.), Michael Hall (Texas A&M Univ.), Keith Woo (Iowa
State Univ.), and Yanfeng Dang (Tianjin Univ.) and Mr. Xi
Deng for helpful discussions.
2
2
in IM18. IM18 is then reduced by Zn to regenerate 1cat.
This double oxidative addition pathway would contain a
NiI→NiII→NiIII manifold and have the rate-limiting barri-
2
2
2
er TS6 (∆G≠ = 11.4 kcal/mol relative to IM13). TS6 is
2
relatively 0.7 kcal/mol (11.4 – 10.7) higher than TS3, the
rate-limiting barrier in the radical chain pathway (Figure
5), but because this energy gap is rather small, we cannot
rule out either mechanism.
3. CONCLUSIONS
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(19) Although an X-ray single crystal structure of 30-Br was not
1
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(27) In an analogous study by Weix (ref 12b), the overall rate for
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heterogeneous nature of the present catalytic process, the
reaction rate can be affected by various factors, including the
complex functions of the Ni precatalyst, MgCl2/LiCl additives,
and Zn reductant (see the section of Mechanistic Investigations
in the Supporting Information for details).
(12) Selected examples of arylation of primary and secondary
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Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. J. Am. Chem. Soc.
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(14) The seminal work reported by Overman et al. required over
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from (R)-serine. References: (a) Goverk, S. P.; Overman, L. E. J.
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(15) The reaction conditions were described in Ref. 13, which
involved Ni(acac)2 (10%), DMAP (30%), and MgCl2 (150%).
(16) See the Supporting Information (SI) for details.
(17) For additional natural products containing C8’-indole deriv-
atives such as (-)-hodgkinsine, (-)-calycosidine, (-)-quadrigemine
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