Ni-Catalyzed Enantioselective C-Acylation of α-Substituted Lactams

Article abstract of DOI:10.1021/jacs.6b02120

A new strategy for catalytic enantioselective C-acylation to generate α-quaternary-substituted lactams is reported. Ni-catalyzed three-component coupling of lactam enolates, benzonitriles, and aryl halides produces β-imino lactams that then afford β-keto lactams by acid hydrolysis. Use of a readily available Mandyphos-type ligand and addition of LiBr enable the construction of quaternary stereocenters on α-substituted lactams to form β-keto lactams in up to 94% ee.

Full text of DOI:10.1021/jacs.6b02120

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Communication
Ni-Catalyzed Enantioselective C-Acylation of #-Substituted Lactams
Masaki Hayashi, Shoshana Bachman, Satoshi Hashimoto, Chad C. Eichman, and Brian M. Stoltz
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b02120 • Publication Date (Web): 03 Jul 2016
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Ni-Catalyzed Enantioselective C-Acylation of α-Substituted Lactams
Masaki Hayashi1, Shoshana Bachman1, Satoshi Hashimoto1, Chad C. Eichman1,2, and Brian M. Stoltz1*
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1The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and
Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States
2Department of Chemistry and Biochemistry, Loyola University Chicago, Chicago, Illinois 60660, United States
Supporting Information Placeholder
acylated product (4a) is produced by the reaction of the
lithium enolate derived from lactam 1a in the presence of
benzonitrile (2a), chlorobenzene (3a), and a Ni(0) precata-
lyst (Table 1, entry 1).10 Initially, we imagined that 4a
could be formed by direct nucleophilic addition of the
lithium enolate of lactam 1a to benzonitrile 2a followed
by hydrolysis of the resulting imine. Therefore, we con-
ducted a series of control experiments to confirm the reac-
tion pathway. Contrary to our expectations, in the ab-
sence of Ni(COD)2 and BINAP the reaction did not pro-
duce the product 4a, and only trace amount of product
was obtained from the reaction in the absence of ligand
(entries 2 and 3). Most interestingly, the reaction did not
proceed without aryl chloride 3a (entry 4). Notably, Pd(0)
and Ni(II) did not promote the reaction (entries 5 and 6).
Finally, as we observed product 4a when substituting
chlorotoluene for chlorobenzene in the reaction, we eluci-
dated that the source of the α-benzoyl group present in the
product is indeed benzonitrile (2a) and not the corre-
ABSTRACT: A new strategy for the catalytic enantiose-
lective C-acylation to generate α-quaternary substituted
lactams is reported. Ni-catalyzed three-component cou-
pling of lactam enolates, benzonitriles, and aryl halides
produce β-imino lactams that then afford β-keto lactams
by acid hydrolysis. Use of a readily available Man-
dyphos-type ligand and the addition of LiBr enables the
construction of quaternary stereocenters on α-substituted
lactams to form β-keto lactams in up to 94% ee.
The catalytic enantioselective construction of quater-
nary stereocenters remains a challenging problem in syn-
,
thetic chemistry.1 2 Catalytic enantioselective reactions of
enolates with electrophiles are among the most useful
processes to construct quaternary stereocenters.3 In this
area, remarkable success has been achieved in the context
of reactions such as enantioselective alkylations, conju-
gate additions, arylations, and aldol reactions.1b,c,d By
contrast, there remains a paucity of enantioselective C-
acylation reactions of enolates that enable access to β-keto
carbonyl compounds. Recently, intramolecular acyl trans-
fer strategies such as asymmetric Steglich and Black rear-
11
sponding chloroarene.
Table 1. Discovery of a Ni-catalyzed enolate acylationa
"standard conditions"
BINAP (12 mol %)
Ni(COD)2 (5 mol %)
LHMDS (1.1 equiv)
O
O
,
O
rangements have been developed.4 5 However, limited
PhCN
PhCl
+
+
PMP
Ph
PMP
N
N
toluene-THF (5:1), 23 °C, 20 h
then 1M HCl aq
examples are reported for intermolecular enantioselective
C-acylation of enolates or enol ethers.6,7,8 A challenging
issue for C-acylation is competitive O-acylation, leading
to mixtures of C- and O-acylated products.9 Fu has re-
ported an excellent strategy for C-acylation of silyl ketene
acetals utilizing planar-chiral 4-(pyrrolidino)pyridine
(PPY) catalysts, which allows access to cyclic and acyclic
β-keto esters with excellent enantioselectivity.6 Alterna-
tive strategies involve isothiourea or thiourea catalyzed C-
acylation of silyl ketene acetals as reported by Smith and
Jacobsen.7,8 To the best of our knowledge, there have
been no reports of intermolecular enantioselective C-
acylation reactions of carbonyl derivatives other than silyl
ketene acetals. Herein, we report a new strategy for cata-
lytic enantioselective C-acylation that enables the prepara-
tion of lactams bearing α-quaternary stereocenters.
1a
2a
3a
4a
entry
deviation from standard conditions
yield (%)
1
2
3
4
5
6
7
none
31
0
no Ni(COD)2 or (R)-BINAP
no (R)-BINAP
3b
0
no PhCl
Pd(dba)2 instead of Ni(COD)2
NiCl2 instead of Ni(COD)2
p-tolylCl instead of PhCl
0
0
41
aConditions: lactam (1 equiv), PhCN (2 equiv), aryl chloride (2 equiv),
LHMDS (1.1 equiv), Ni(COD)2 (10 mol %), ligand (12 mol %), in 5:1 tolu-
ene-THF (0.2 M) at 23 °C for 20 h, then 1 M HCl aq at 23 °C for 0.5 h.
bHPLC conversion.
With a reasonable handle on the reaction pathway, we
turned our attention toward optimization of the reaction
conditions, with an emphasis on enantioselective cataly-
sis. We examined the C-acylation of lactam 1a using a
variety of chiral ligands (12 mol %) with Ni(COD)2 (10
mol %) and LHMDS (1.1 equiv) in a range of solvents at
23 °C (Table 2).12 As a result of this study, Mandyphos-
type ligands (e.g., L2 and L3) emerged as promising can-
We have reported several strategies for the transition-
metal-catalyzed enantioselective construction of quater-
nary stereocenters.2 In the course of our investigations on
enolate functionalizations, we discovered that an α-
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didates, displaying good enantioselectivity and reactivity. product 4b was produced in moderate yield at ambient
1
2
3
4
5
6
7
8
Further examination revealed that a Josiphos-type ligand
(i.e., L4) in TBME promotes the reaction with greater
enantioselectivity (–60% ee) and conversion (74%).
temperature. Gratifyingly, reaction at 4 °C led to im-
proved yield of lactam 4b. Derivatives 1c and 1d had
similar enantioselectivity as the parent PMP-lactam 1a. In
general, a fair amount of substitution around the N-aryl
group is tolerated in the reaction process affording acylat-
ed lactams in good yields and with high ee. It should be
noted that we observed optimal conversion and ee using a
2:1 lactam:PhCN ratio, which are the conditions we used
for our substrate scope (see Supporting Information).
However, in order to increase the synthetic practicality of
the reaction we were able to lower the ratio to 1.2:1 lac-
tam:nitrile to give comparable results (89% conversion,
87% ee). On a gram-scale with reduced equivalents of
lactam (1.3 equiv), 1a underwent acylation smoothly to
furnish 1.1 g of 4a in 69% yield and 90% ee. Finally, we
attempted reactions with δ-valerolactams, but achieved
low product formation with good ee (13% yield, 77% ee)
under these conditions.
Further studies aimed toward optimization of bases, aryl
halides, and additives are summarized in Table 3. No en-
antioselectivity was observed in reactions using NaHMDS
or KHMDS instead of LHMDS (entries 2–4), which was
attributed to the formation of aryne intermediates under
9
13
these conditions. Bromobenzene (3b) exhibited superior
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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42
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44
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enantioselectivity and reactivity compared to chloroben-
zene (3a, cf. entries 2 and 5), iodobenzene (3c, cf. entries
6 and 5), and phenyl triflate (3d, cf. entries 7 and 5). En-
couraged by these results, we examined lithium salt addi-
tives. To our delight, reactivity and enantioselectivity
were improved dramatically by adding LiBr, especially
,
14 15
using the Mandyphos-type ligands (entries 9 and 10).
Table 2. Ligand and solvent optimization
ligand (12 mol %)
Ni(COD)2 (10 mol %)
LHMDS (1.1 equiv)
O
O
O
Table 4. Scope of the N-protecting groupa
PhCN
PhCl
+
+
PMP
Ph
PMP
N
N
PhCN (2a), PhBr (3b)
L2 (12 mol %)
Ni(COD)2 (10 mol %)
solvent, 23 °C, 20 h
then 1M HCl aq
O
O
O
1a
2a
3a
4a
R
R
Ph
N
N
solvent (conversion / ee)
LHMDS (1.2 equiv)
LiBr (5 equiv)
ligand
THF
–
toluene
dioxane
TBME
DME
–
toluene–THF (5:1)
toluene–THF (10:1), 23 °C, 48 h
then 1 M HCl aq
1a–d
4a–d
L1
L2
L3
L4
31% / –7% ee
70% / 59% ee
71% / 62% ee
–
–
–
MeO
32% /15% ee
29% /13% ee
52% / 47% ee
42% / 47% ee
72% / 51% ee
42% / 31% ee
53% / 25% ee
47% / 21% ee
53% / 52% ee
45% / 53% ee
MeO
R
79% / –30% ee 26% / –2% ee 52% / –30% ee 74% / –60% ee 37% / –6% ee 54% / –41% ee
OMe
OiPr
MeO
1c→4c
80%, 85% eec
Ph
PPh2
R2P
R2P
Fe
1a→4a
86%, 88% eeb
1b→4b
1d→4d
69%, 86% eec
Fe
PPh2
PPh2
NMe2
61%, 92% eeb
81%, 92% eec
yield, ee
Me2N
PR2
aConditions: lactam (2 equiv), PhCN (1 equiv), PhBr (1.5 equiv),
LHMDS (1.2 equiv), LiBr (5 equiv), Ni(COD)2 (10 mol %), ligand (12 mol
%), in toluene–THF (10:1, 0.09 M), then 1 M HCl aq. bReactions were
conducted at 23 °C for 24 h. cReactions were conducted at 4 °C for 48 h.
Ph
L4: SL-J006-1
(R = 3,5-(CF3)2Ph)
L2: SL-M004-1 (R = 4-MeO-3,5-Me2Ph)
L3: SL-M009-1 (R = 3,5-Me2Ph)
L1: (R)-BINAP
aConditions: lactam (1 equiv), PhCN (2 equiv), PhCl (2 equiv), LHMDS
(1.1 equiv), Ni(COD)2 (10 mol %), ligand (12 mol %), in solvent (0.2 M) at
23 °C for 20 h, then 1 M HCl (aq) at 23 °C for 0.5 h.
With the optimized conditions in hand, we explored the
substrate scope of this enantioselective C-acylation reac-
tion (Tables 5 and 6). Generally, the process is tolerant of
a wide range of substituents and functionality on both the
aryl nitrile and the parent lactam substrate. Aryl nitriles
having both electron-donating and electron-withdrawing
substituents at the para position can be successfully ap-
plied, leading to products with excellent enantioselectivi-
ties (e.g., Table 5, 6, 9–12). Despite the uniformly high
ee, electron-withdrawing substituents on the nitrile furnish
Table 3. Optimization of the reaction conditions
O
O
O
ligand (12 mol %)
Ni(COD)2 (10 mol %)
base
PMP
PMP
Ph
N
N
PhCN
PhX
+
+
solvent, 23 °C, 20 h
then 1M HCl aq
1a
2a
3
4a
base
PhX
entry
ligand
solvent
additive
conversion (%) ee (%)
1a
2a
TBME
TBME
0
0
–
tBuOLi
LHMDS
NaHMDS
KHMDS
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
PhCl 3a
PhCl 3a
PhCl 3a
PhCl 3a
PhBr 3b
PhI 3c
L4
L4
L4
L4
L4
L4
L4
L2
L2
L3
L4
–54
74
–
3a
TBME
42
0
–
4a
TBME
51
0
–
5a
TBME
–61
83
–
6a
TBME
–55
65
–
16
7a
TBME
–28
73
–
products in significantly diminished yields (e.g., 11, 12).
PhOTf 3d
PhBr 3b
PhBr 3b
PhBr 3b
PhBr 3b
8b
toluene–THF (10:1)
toluene–THF (10:1)
toluene–THF (10:1)
toluene–THF (10:1)
68
55
–
The reaction is also not impacted to a large degree when
the nitrile is substituted at either the meta or ortho posi-
tion (e.g., 7, 8). Lastly, we unfortunately observed no re-
activity when alkyl nitriles were assayed.
9b
89
98
LiBr (5 equiv)
LiBr (5 equiv)
LiBr (5 equiv)
10b
11b
89
92
–46
28
aConditions: lactam (1 equiv), PhCN (2 equiv), PhX (2 equiv), base (1.1
equiv), Ni(COD)2 (10 mol %), ligand (12 mol %), in solvent (0.2 M) at 23
°C for 20 h, then 1 M HCl aq at 23 °C for 0.5 h. bConditions: lactam (2
equiv), PhCN (1 equiv), PhX (1 equiv), base (1.2 equiv), Ni(COD)2 (10
mol %), ligand (12 mol %), in solvent (0.2 M) at 23 °C for 20 h, then 1 M
HCl aq. 0.5 h at 23 °C.
We then examined the effect of substituents on the N-
aryl fragment of the lactam substrate. Several lactams
(1a–d) were prepared and subjected to the optimized ac-
ylation conditions (Table 4). Lactam 1b displayed slight-
ly superior enantioselectivity to 1a, although acylated
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Table 5. Enantioselective C-acylation of lactams; Scope of
To demonstrate the synthetic utility of our enantioselec-
the nitrilea
1
2
3
4
5
6
7
8
tive lactams acylation, we carried out transformations on
the enantioenriched lactam products generated in this
study (Scheme 1). The o-methoxy protecting group of
lactam 4e was easily removed by CAN oxidation to form
lactam 28 (Scheme 1A).17 Reduction of ketone 4e with
Et3SiH proceeded with perfect diastereoselectively and
afforded alcohol 29 as a single isomer in excellent yield
(Scheme 1B). The relative stereochemistry of lactam 29
was determined by single crystal X-ray diffraction (see
Supporting Information). Lactam 4a could be converted
to α-benzoyloxy lactam 30 by Baeyer–Villiger oxidation,
without loss of enantiopurity (Scheme 1C). Alternatively,
Baeyer–Villiger oxidation of lactam 10 gave α-
aryloxycarbonyl lactam 31 (Scheme 1D). The PMP ke-
tone directs the regioselectivity of the Baeyer–Villiger
oxidation and allows for the asymmetric synthesis of α-
carboxy lactam derivatives.18 To determine the absolute
stereochemistry, 31 was converted to known lactam de-
rivative 33 by ester exchange followed by deprotection of
the o-methoxyphenyl group. The specific optical rotation
of carboxylactam 33 corresponded to the reported value
for (R)-33.19 The absolute configurations of all acylated
lactam products in this manuscript are presented by anal-
ogy to this finding.
PhBr (3b)
L2 (12 mol %)
Ni(COD)2 (10 mol %)
O
O
O
Ar
ArCN
+
N
N
LHMDS, LiBr
toluene–THF (10:1)
4 °C, 48 h
OMe
OMe
1b
then 1 M HCl aq
products
O
O
O
O
O
O
OMP
OMP
OMP
N
N
N
9
4b
81% yield, 92% ee
6
7
92% yield, 91% ee
91% yield, 93% ee
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
O
O
O
OMP
OMP
OMP
N
N
N
tBu
OMe
8
9
10
69% yield, 94% ee
89% yield, 92% ee
85% yield, 89% ee
O
O
O
O
O
O
OMP
OMP
OMP
N
N
N
F
CF3
11
36% yield, 93% ee
12
13
23% yield, 87% eeb
66% yield, 91% ee
aConditions: lactam (2 equiv), ArCN (0.2 mmol, 1 equiv), PhBr (1.5
equiv), base (1.2 equiv), Ni(COD)2 (10 mol %), ligand (12 mol %), in tolu-
ene–THF (10:1, 0.09 M) at 4 °C for 48 h, then 1 M HCl aq. bThe reaction
was carried out at 23 °C for 24 h.
The scope of substitution at the lactam α-carbon is il-
lustrated in Table 6. Although the enantioselectivity tends
to decrease with larger α-substituents, examples having
ethyl, benzyl, substituted-benzyl and substituted-allyl
groups all furnished the C-acylated products with good
enantioselectivities (74–88% ee). Crotyl- and cinnamyl-
substituted lactams were particularly effective in the acyl-
ation, providing interesting lactam products in high ee
(e.g., 21–25).
Scheme 1. Derivatization of C-acylated products and
determination of absolute stereochemistry
A
O
O
O
O
CAN
Ph
Ph
N
HN
MeCN–H2O
75 °C, 20 h
OMe
OMe
75% yield
28
Table 6. Enantioselective C-acylation of lactams; scope of
the lactam α-substiuenta
4e
B
O
OH
O
O
1. Et3SiH, TFA
PhBr (3b
)
Ph
O
Ph
N
N
L2 (12 mol %)
Ni(COD)2 (10 mol %)
O
2. NaOH (aq), CH2Cl2
90% yield
O
O
NC
OMe
29 (X-Ray)
+
R'
OMP
OMP
4e
N
N
LHMDS, LiBr
toluene/THF (10:1)
4 °C, 48 h
R
C
m-CPBA
NaHCO3
O
O
MeO
MeO
OBz
then 1 M HCl aq
Ph
N
N
CH2Cl2
23 °C, 20 h
productsa
O
O
O
O
O
O
4a
(88% ee)
30
(88% ee)
53% yield
OMP
N
OMP
OMP
N
N
D
OMP
O
O
O
O
CF3
m-CPBA
OPMP
OMP
14
50% yield, 78% ee
18
58% yield, 71% ee
N
N
CH2Cl2
OMe
O
R
32% yield
O
10
31
15 (R = H): 61% yield, 81% ee
16 (R = OMe): 77% yield, 81% ee
17 (R = F): 76% yield, 74% ee
O
O
O
O
K2CO3
CAN
OEt
O
O
OEt
OMP
OMP
N
N
HN
O
O
EtOH
MeCN–H2O
16% yield
OMP
N
73% yield
32
(R)-33
OMP
N
OBn
19
67% yield, 60% ee
To clarify the reaction pathway, we attempted to isolate
the putative imine intermediate.11 Fortuitously, by avoid-
ing an acidic aqueous work-up and carefully chromato-
graphing of the crude reaction mixture, we were indeed
able to isolate imine 34, which was obtained as a 60:40
E/Z mixture from the reaction of lactam 1a with o-
tolunitrile 2b and bromobenzene 3b (Scheme 2A). Addi-
tionally, we were able to prepare amine 36 as a 63:37 dia-
stereomeric mixture by in situ reduction of imine interme-
diate 35 (Scheme 2B). These experiments provide further
evidence that an N-arylated imine (e.g., 5a, 34, and 35) is
likely the direct product of the catalytic reaction.
21
70% yield, 86% ee
O
O
20
71% yield, 76% ee
OMP
N
O
O
O
O
OMP
N
OMP
N
R
22 (R = H ): 50% yield, 86% ee
23 (R = Me): 85% yield, 88% ee
24 (R = OMe): 68% yield, 88% ee
25 (R = F): 62% yield, 83% ee
Ph
S
26
76% yield, 83% ee
27
35% yield, 84% ee
aConditions: lactam (2 equiv), p-tolunitrile (0.2 mmol, 1 equiv), PhBr
(1.5 equiv), base (1.2 equiv), Ni(COD)2 (10 mol %), ligand (12 mol %), in
toluene–THF (10:1, 0.09 M) at 4 °C for 48 h, then 1 M HCl aq.
3
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Supporting Information. Experimental procedures, charac-
terization data, single crystal X-ray analysis. This material is
available free of charge via the Internet at http://pubs.acs.org.
Scheme 2. Isolation and reduction of imine intermedi-
ate
1
2
3
4
5
6
7
8
A
Ph
PhBr (3b)
L2 (12 mol %)
Ni(COD)2 (10 mol %)
N
O
O
CN
PMP
+
AUTHOR INFORMATION
Corresponding Author
*stoltz@caltech.edu
PMP
N
N
LHMDS (1 equiv)
LiBr (5 equiv)
toluene–THF
(10:1, 0.09 M)
4 °C, 48 h
1a
2b
34
77% yield
(60:40 E / Z )
B
PhCN (2a, 1.0 equiv)
PhBr (3b, 1.5 equiv)
L2 (12 mol %)
ACKNOWLEDGMENT
Ph
Ph
Ph
O
HN
N
O
O
The authors wish to thank NIH-NIGMS (R01GM080269),
Daiichi-Sankyo Co., Ltd. (M. H.), JSPS (S. H.), MEXT (S.
H.), the Caltech 3CS, and Caltech for financial support.
C.C.E. also thanks Loyola University Chicago for financial
support. Mr. Hashiru Negishi (Caltech), Mr. Larry Henling
(Caltech), and Dr. Scott Virgil (Caltech) are acknowledged
for helpful discussions, instrumentation, and experimental
assistance.
9
NaBH4
OMP
Ni(COD)2 (10 mol %)
Ph
N
OMP
N
OMP
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
LHMDS (1 equiv)
LiBr (5 equiv)
toluene–THF
(10:1, 0.09 M)
4 °C, 48 h
MeOH
23 °C
1b
35
36
70% yield
(67:33 dr)
(2 equiv)
Taking these results into consideration, we illustrate a
possible reaction mechanism for our C-acylation reaction
in Figure 1. We envision that the reaction proceeds by a
Ni0/NiII redox catalytic cycle. Oxidative addition of the
aryl bromide to a Ni0 complex (i.e., A) produces a NiII
arene species (B). Ligand substitution and insertion of the
benzonitrile and lactam enolate is envisioned to be ste-
reodetermining and to produce NiII-imino complex C.
Reductive elimination from C leads to the primary imine
product and regenerates Ni0 complex A. The C-acylated
product is ultimately furnished by hydrolysis of the imine
in aqueous acid.
REFERENCES
(1) For recent reviews on construction of quaternary stereocenters,
see: (a) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U. S. A.
2004, 101, 5363. (b) Trost, B. M. Synthesis 2006, 369. (c) Das, J. P.;
Marek, I. Chem. Commun. 2011, 47, 4593. (d) Quasdorf, K. W.; Over-
man, L. E. Nature 2014, 516, 181.
(2) Liu, Y.; Han, S. J.; Liu, W. B.; Stoltz, B. M. Acc. Chem. Res.
2015, 48, 740.
(3) Stoltz, B. M.; Bennett, N. B.; Duquette, D. C.; Goldberg, A. F.
G.; Liu, Y.; Loewinger, M. B.; Reeves, C. M. Alkylations of Enols and
Enolates. In Comprehensive Organic Synthesis II, 2nd ed.; Knochel, P.,
Ed.; Elsevier: Amsterdam, 2014; pp 1–55.
OLi
P
PG
R
= chiral ligand
N
*
P
(4) (a) Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532.
(b) Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125,
13368. (c) Seitzberg, J. G.; Dissing, C.; Søtofte, I.; Norrby, P.-O.; Jo-
hannsen, M. J. Org. Chem. 2005, 70, 8332. (d) Shaw, S. A.; Aleman, P.;
Christy, J.; Kampf, J. W.; Va, P.; Vedejs, E. J. Am. Chem. Soc. 2006,
128, 925. (e) Nguyen, H. V.; Butler, D. C. D.; Richards, C. J. Org. Lett.
2006, 8, 769. (f) Busto, E.; Gotor-Fernández, V.; Gotor, V. Adv. Synth.
Catal. 2006, 348, 2626. (g) Dietz, F. R.; Gröger, H. Synlett 2008, 663.
(h) Dietz, F. R.; Gröger, H. Synthesis 2009, 4208. (i) Uraguchi, D.;
Koshimoto, K.; Miyake, S.; Ooi, T. Angew. Chem. Int. Ed. 2010, 49,
5567. (j) Zhang, Z.; Xie, F.; Jia, J.; Zhang, W. J. Am. Chem. Soc. 2010,
132, 15939. (k) Campbell, C. D.; Concellón, C.; Smith, A. D. Tetrahe-
dron Asymmetry 2011, 22, 797. (l) De, C. K.; Mittal, N.; Seidel, D. J.
Am. Chem. Soc. 2011, 133, 16802. (m) Viswambharan, B.; Okimura, T.;
Suzuki, S.; Okamoto, S. J. Org. Chem. 2011, 76, 6678. (n) Joannesse,
C.; Johnston, C. P.; Morrill, L. C.; Woods, P. A.; Kieffer, M.; Nigst, T.
A.; Mayr, H.; Lebl, T.; Philp, D.; Bragg, R. A.; Smith, A. D. Chem.
Eur. J. 2012, 18, 2398. (o) Mandai, H.; Fujiwara, T.; Noda, K.; Fujii,
K.; Mitsudo, K.; Korenaga, T.; Suga, S. Org. Lett. 2015, 17, 4436.
(5) Hills, I. D.; Fu, G. C. Angew. Chem. Int. Ed. 2003, 42, 3921. (b)
Ismail, M.; Nguyen, H. V.; Ilyashenko, G.; Motevalli, M.; Richards, C.
J. Tetrahedron Lett. 2009, 50, 6332. (c) Duffey, T. A.; Shaw, S. A.;
Vedejs, E. J. Am. Chem. Soc. 2009, 131, 14. (d) Wang, M.; Zhang, Z.;
Liu, S.; Xie, F.; Zhang, W. Chem. Commun. 2014, 50, 1227.
(6)(a) Mermerian, A. H.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
4050. (b) Mermerian, A. H.; Fu, G. C. J. Am. Chem. Soc. 2005, 127,
5604.
ArCN
ligand
substitution
and
LiBr
P
Ar
P
Ph
O
insertion
N
Ni
*
Br
P
Ni
*
R
N
PG
P
B
Ph
C
reductive
elimination
oxidative
addition
Ph
Ar
P
N
O
O
O
HCl
aq
NiLn
P
*
PhBr
PG
PG
N
Ar
N
R
R
A
Figure 1. Plausible reaction mechanism of enantioselective
C-acylation.
In summary, we have developed the first intermolecular
enantioselective C-acylation of lactams by applying a chi-
ral Ni catalyst. The process is nominally a three-
component coupling reaction involving a lithium enolate,
a benzonitrile, and an aryl halide. Critical to the success
of this new reaction is the implementation of a readily
available Mandyphos-type ligand and the addition of ex-
cess lithium bromide, the combination of which afforded
high enantioselectivity and yield in the acylation. Future
work will focus on expanding the scope of the reaction,
elucidating the stereochemical course and mechanistic
details of the process, and implementation of this new
chemistry in the context of multistep synthesis.
(7) (a) Woods, P. A.; Morrill, L. C.; Lebl, T.; Slawin, A. M. Z.;
Bragg, R. A.; Smith, A. D. Org. Lett., 2010, 12 , 2660. (b) Woods, P.
A.; Morrill, L. C.; Bragg, R. A.; Smith, A. D. Chem. Eur. J. 2011, 17,
11060.
(8) (a) Birrell, J. A.; Desrosiers, J.-N.; Jacobsen, E. N. J. Am. Chem.
Soc. 2011, 133, 13872.
(9) (a) Fleming, I.; Iqbal, J.; Krebs, E.-P. Tetrahedron 1983, 39, 841.
(b) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425. (c)
Crabtree, S. R.; Chu, W. L. A.; Mander, L. N. Synlett 1990, 169. (d) Le
Roux, C.; Mandrou, S.; Dubac, J. J. Org. Chem. 1996, 61, 3885. (e)
ASSOCIATED CONTENT
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Page 5 of 5
Journal of the American Chemical Society
Wiles, C.; Watts, P.; Haswell, S. J.; Pombo-Villar E. Tetrahedron Lett.
2002, 43, 2945.
1
2
3
4
5
(10) For examples of nitrile additives to improve the reactivity in Ni-
based systems, see: (a) Ge, S.; Hartwig, J. F. J. Am. Chem. Soc. 2011,
133, 16330. (b) Park, N. H.; Teverovskiy, G.; Buchwald, S. L. Org.
Lett. 2014, 16, 220. (c) Ge, S.; Green, R. A.; Hartwig, J. F. J. Am.
Chem. Soc. 2014, 136, 1617. (d) Ge, S.; Green, R. A.; Hartwig, J. F.
Angew. Chem. Int. Ed. 2015, 54, 3768.
6
7
8
(11) We have observed N-phenyl imine intermediate 5a by mass
spectrometric analysis of the crude reaction mixture.
NPh
O
9
PMP
Ph
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5a
(12) For a full listing of ligands evaluated, see Supporting Infor-
mation.
(13) Under similar conditions, we have observed that NaHMDS and
KHMDS in the presence of a substituted aryl halide result in two consti-
tutional isomers of cross-coupled product, which we hypothesize arise
from aryne intermediacy.
(14) For a more detailed study of additive effects, see Supporting In-
formation.
(15) The beneficial effect of LiBr may be due to increasing the ionic
strength of the reaction medium or altering the speciation of lithium
enolate aggregates. For related references, see (a) Juaristi, E.; Beck, A.
K.; Hansen, J.; Mukhopadhyay, T.; Simson, M.; Seebach, D. Synthesis,
1993, 12, 1271. (b) Fagnou, K.; Lautens, M. Angew. Chem. Int. Ed.
2002, 41, 26. (c) Zuo, Z.; Cong, H.; Li, W.; Choi, J.; Fu, G. C.; Mac-
Millan, D. W. C. J. Am. Chem. Soc. 2016, 138, 1832. (d) Liang, Y.; Fu,
G. C. Angew. Chem. Int. Ed. 2015, 54, 9047. (e) Son, S. Fu, G. C. J.
Am. Chem. Soc. 2008, 130, 2756.
(16) Reaction using 2-fluorobenzonitrile and 3-fluorobenzonitrile
provided low yields (38% and 34% yield, respectively).
(17) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem.
1982, 47, 2765.
(18) (a) Lindsay, V. N. G.; Nicolas, C.; Charette, A. B. J. Am. Chem.
Soc. 2011, 133, 8972. (b) Qian, D.; Hu, H.; Liu, F.; Tang, B.; Ye, W.;
Wang, Y.; Zhang, J. Angew. Chem. Int. Ed. 2014, 53, 13751.
(19) Banerjee, S.; Smith, J.; Smith, J.; Faulkner, C.; Masterson, D. S.
J. Org. Chem. 2012, 77, 10925. See supporting information for specific
optical rotation data.
TOC Graphic
SL-M004-1 (12 mol %)
Ni(COD)2 (10 mol %)
LHMDS, LiBr
Ph
Ar
O
O
O
HCl aq
O
N
ArCN
PhBr
R1
+
+
R2
R1
Ar
R2
R1
N
N
toluene/THF
N
R2
up to 92% yield
up to 94% ee
Ph
R32P
R1 = p-methoxyphenyl, o-methoxyphenyl
R2 = alkyl, alkenyl
Fe
NMe2
PR3
Ph
2
NMe2
SL-M004-1 (R = 4-MeO-3,5-Me2Ph)
5
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