Palladium-Catalyzed Asymmetric α-Arylation of Alkylnitriles

Article abstract of DOI:10.1021/jacs.6b11610

Asymmetric arylation of alkylnitriles forms quaternary stereocenters in good enantiocontrol for the first time. A lithium heterodimer consisting of an alkylnitrile anion and a disilylamide ion is the actual species responsible for the stereodetermining transmetalation in the catalytic cycle.

Full text of DOI:10.1021/jacs.6b11610

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Palladium-Catalyzed Asymmetric #-Arylation of Alkylnitriles
Zhiwei Jiao, Kwok Wei Chee, and Jianrong (Steve) Zhou
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b11610 • Publication Date (Web): 07 Dec 2016
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Palladium-Catalyzed Asymmetric α-Arylation of Alkylnitriles
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Zhiwei Jiao, Kwok Wei Chee and Jianrong (Steve) Zhou*
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Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological Uni-
versity, 21 Nanyang Link, Singapore 637371
Supporting Information Placeholder
ABSTRACT: Asymmetric arylation of alkylnitriles forms quater-
nary stereocenters in good enantiocontrol for the first time. A
lithium heterodimer consisting of an alkylnitrile anion and a dis-
ilylamide ion is the actual species responsible for the stereode-
termining transmetalation in the catalytic cycle.
In the past two decades, significant progress has been gained
in the transition metal-catalyzed asymmetric couplings of car-
bonyl compounds.1,2 Intermolecular coupling processes offered
α−arylation and vinylation products in good enantiometric ex-
cess (ee) and efficiently formed quaternary stereocenters α to
carbonyl groups such as cyclic ketones, oxindoles, and lactones
(eq 1 in Fig 1).3 The enantioselective C-C coupling has also been
extended to intramolecular arylation and vinylation of aldehydes
and amides, and ketones.4 Asymmetric intermolecular coupling
of acyclic enolates is more challenging to achieve, due to the
need of E/Z control of the enolates. To this end, we5 and other
groups6 have reported metal-catalyzed asymmetric arylation
using geometrically defined soft enolates of esters (eq 2), cyclic
ketones and lactones, which produced base-sensitive tertiary α-
stereocenters.
Alkylnitriles are present in drugs such as an verapamil (anti-
arrhythmic) and anastrozole (advanced breast cancer).7 Moreo-
Figure 1. Examples of asymmetric arylation of enolates and
arylation of alkyl nitriles
ver, the nitriles are readily transformed to many useful groups in
organic synthesis, for example, after hydrolysis,8 hydrogenation,9
addition of hydride and organometallic reagents,10 dipolar cy-
Herein, we report the first example of Pd-catalyzed asymmet-
cloaddition,11 and other processes.12 Previously, Hartwig13 and
ric coupling of aryl halides and alkylnitriles that generated qua-
others14 disclosed Pd-catalyzed procedures for non-
ternary centers in good ee (eq 5). In a test case of α-isopropyl
stereoselective arylation, which led to achiral or racemic prod-
ucts via in situ deprotonation of alkylnitriles or decarboxylation
processes.15 Most of the conditions employed strongly donating
monophosphines as ancillary ligands to achieve good catalytic
activity. However, a catalytic enantioselective arylation of alkylni-
triles remained elusive. The challenge is associated with the diffi-
culty in catalyst differentiation of three groups on the α carbon.
At present, catalytic C-C bond forming processes to prepare
enantioenriched α-arylated alkylnitriles remain under-
developed,16 examples including nickel-catalyzed coupling of α-
bromonitriles and diarylzinc reagents (eq 3),17 and reductive
coupling of α-chloronitriles and heteroaryl iodides (eq 4).18 In
both cases, the nitriles were introduced as electrophiles to pro-
duce new tertiary stereocenters, and the structures of products
that afforded good ee values remained quite restricted. Moreo-
ver, in 2016, Stahl and Liu et al. also reported a copper-catalyzed
asymmetric cyanation of benzylic C-H bonds to form new tertiary
stereocenters.19
benzylnitrile and 2-naphthyl bromide, a combination of a palladi-
um complex and a phosphoramidite ligand L delivered the de-
sired product in 70% yield and 90% ee. The absolute configura-
tion of the coupling product was determined to be 2R, based on
single-crystal X-ray diffractional analysis. A strong base, lithium
hexamethyldisilylamide (LiHMDS) was used for in situ deprotona-
tion of the alkylnitrile. The reaction also produced a byproduct,
naphthalene via β hydrogen elimination from α-cyanoalkyl group
on Pd, which accounted for material balance.
During our catalyst optimization of the model reaction, we ini-
tially detected only <10% ee, in the presence of chelating
bisphosphines such as binap, difluorphos and segphos. The result
was consistent with previous observations of others on the al-
kylnitrile coupling. After many trials, we were gratified to discov-
er that a Feringa′s ligand20 delivered a significant level of stere-
oinduction, 84% ee (Scheme 1). We also tested a diastereomeric
form of Feringa′s ligand and it led to the same enantiomeric
product as the major one (87% ee). Thus, the binaphthyl back-
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bone is the main determinant in setting the absolute configura-
TMEDA gave low yields (<40%) of the coupling products and in
1
2
3
4
5
6
7
8
tion of the product, while the amine fragment had little influence.
To further improve the stereoselctivity of the coupling reac-
tion, we tested phosphoramidite (Sa,S,S)-L on a partially hydro-
genated binaphthyl skeleton.21 To our satisfaction, it led to the
coupling product in 90% ee. Furthermore, other modification of
aryl rings of the amine fragment didn’t lead to further enhance-
ment of the ee, while a small dimethylamine fragment in the
phosphorus ligand resulted in a much less active and less selec-
tive Pd catalyst (19% ee). We observed that Qi-Lin Zhou′s phos-
phoramidite on a spiro diindanyl scaffold afforded a very low
level of stereoinduction (9% ee).22
<80% ee’s. The main side reactions were identified to be the
reduction of the C-Br bonds to PhNMe2 (35-55%) and bimolecular
condensation of alkylnitrile anions to another molecule of the
nitrile (around 10% for isomers of β-ketoalkylnitriles). When
TMEDA was replaced by HMPA,23 the two reactions gave reason-
able yields of desired products (>50%) along with PhNMe2 by-
product (25-35%), while the condensation of alkylnitriles was
prevented. Unfortunately though, benzylnitriles bearing other α
groups (e.g., methyl, ethyl and cyclohexyl) led to low yields.
9
PdCl2(TMEDA) 5 mol%
ligand L 7.5 mol%
Me
Me
Me
Me
Br
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Y
LiHMDS (1.8 x)
Ph
Ph
CN
CN
3a-3q
additive (1.2 x)
toluene, 50 oC, 24 h
1a
Me
Me
(1.5 x)
PdCl2(TMEDA) 5 mol%
ligand 7.5 mol%
i-Pr
Br
Ph
NC
Ph
CN
LiHMDS (1.8 x)
TMEDA (1.2 x)
toluene, 50 oC, 24 h
1a
(1.5 x)
2a
3a
Y
OMe
Ph
3a
3b
3e
model reaction
90% ee, 67% yield
3c Y = Me 91% ee, 62% yield
3d Y = t-Bu 90% ee, 69% yield
89% ee, 65% yield
86% ee, 76% yield
Ph
O
Ph
Ph
Me
Me
Me
Me
Me
O
O
R
N
O
O
O
O
P
N
O
3j
P
N
P
N
OMe
F
Me
3g
Me
3f
Ph
Ph
S ,R,R)-Feringa ligand
a
Ph
92% ee, 57% yield
3h R= Me 83% ee, 56% yield
3i R= Ts 94% ee, 39% yield
93% ee, 53% yield
90% ee, 50% yield
(S ,S,S)-L
a
(
S ,S,S)-Feringa ligand
a
(
Me
90% ee, 70% yield
84% ee, 57% yield
87% ee, 76% yield
Me
CF3
OPh
N
Me
Ph
O
Me
Me
Ph
3n
Ph
O
3l
3m
3k
Me
Me
P
N
Me
O
O
93% ee, 71% yield
92% ee, 60% yield
95% ee, 56% yield
O
90% ee, 70% yield
P
N
P
N
O
2-Naph
F
(
R ,R,R)
a
(
R ,R,R)
a
R
N
R
(
R ,R,R)
a
Ph
3o
R = OMe - 86% ee, 61% yield
R = CF3 - 87% ee, 50% yield
- 84% ee, 58% yied
- 84% ee, 79% yield
3p R= Me 88% ee, 61% yield
3q R= Ts 89% ee, 42% yield
92% ee, 56% yield
Ph
Me
Me
N
O
O
OMe
PPh2
O
N
P
P
Scheme 2. Examples of aryl bromides in asymmetric cou-
pling with α-isopropylbenzylnitrile
O
Me
Me
Ph
(
R ,S,S)
s
(
R
)
(
R)-MOP
R1
R
R1
R
PdCl2(TMEDA) 5 mol%
ligand L 7.5 mol%
- 19% ee, 14% yield
33% ee, 46% yield
9% ee, 46% yield
Br
CN
B
A
B
A
LiHMDS (1.8 x)
TMEDA ( 1.2 x)
toluene, 50 oC, 24 h
CN
4a-4o
1b-1m
(1.5 x)
Scheme 1. The influence of phosphoramidite ligands in a
model arylation reaction
i-Pr
i-Pr
Me
Me
i-Pr
i-Pr
Me
MeO
MeO
During condition optimization of the model reaction, an inter-
esting effect of additives emerged (see the supporting infor-
mation). In the presence of tetramethylethylene-1,2-diamine
(TMEDA), the ee value of the product increased from 60% to 90%.
In comparison, adding (-)-sparteine to the reaction resulted in 75%
ee, while the additives of N,N'-dimethylpropyleneurea (DMPU) or
hexamethylphosphoric triamide (HMPA) provided ee’s slightly
below 90%.
CN
CN
CN
4b
CN
MeO
Me
4c
4a
4d
91% ee, 65% yield
91% ee, 66% yield
87% ee, 63% yield
88% ee, 72% yield
i-Pr
Me
i-Pr
i-Pr
Me
Me
CN
N
CN
4e
CN
F
4g
4f
Me
91% ee, 45% yield
87% ee, 67% yield
85% ee, 41% yield
Ph
Ph
Ph
Cy
Me
NMe2
NMe2
The combination of palladium source and (Sa,S,S)-L was suc-
cessfully applied to asymmetric coupling of other aryl bromides
with the model benzylnitrile (Scheme 2). Not only electron-
deficient but also electron-rich aryl halides reacted smoothly.
Two indolyl bromides were also coupled in good ee values. How-
ever, other bromides such as 3-bromobenzothiophene and 3-
bromoindole, 2-bromothiophene led to low yields of the prod-
ucts. The reactions of aryl iodides led to low yields. The strong
base also caused fast hydrolysis of most aryl triflates.
CN
F
CN
CN
4j
CN
4i
4k
4h
81% ee, 64% yield
81% ee, 62% yield
Me
86% ee, 50% yield
80% ee, 51% yield
(Cy=cyclohexyl)
NPh2
OBn
Me
(
)
4
NMe2
(
)
( )
4
NMe2
NMe2
( )
4
10
NMe2
CN
CN
4l
CN
CN
4o
4n
4m
85% ee, 66% yield
84% ee, 51% yield
81% ee, 53% yield
85% ee, 66% yield
with HMPA (1.2 x)
with HMPA (1.2 x)
with HMPA (1.2 x)
with HMPA (1.2 x)
The ee value of catalytic processes is diagnostic of the stereo-
determining step. Therefore, to probe the transmetalating spe-
cies, we prepared a dimeric complex [Ph(i-Pr)C=C=NLi(TMEDA)]2
A containing a core of Li2N2, using a Boche’s procedure (eq 6 in
Fig 2).24 The iminyl carbon has distinct 13C signals at 154.7 ppm
for C2 and 50.4 ppm for C3, indicative of significant negative
charge localizing on C3 and a Li-bound nitrile group at the nitro-
We also examined the scope of alkylnitriles in couplings with
aryl bromides (Scheme 3). Both electron-donating and withdraw-
ing groups were tolerated on α-aryl rings of nitriles. Furthermore,
the nitriles can have linear alkyl chains containing both ben-
zylether and aniline groups, and enantiomeric ratio of products
was generally >9:1. Notably, the last two cases in the presence of
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gen instead of α carbon, in reference to chemical shifts of related
conclude that the transmetalation of B to cis-(L)2Pd(aryl)Br sets
compounds in the literature.25
the configuration in the coupling product (eq 9). Two cis-ligands L
formed a C2-symmetrical pocket around the palladium center.
After the transmetalation, the chiral α-cyanoalkyl ligand in com-
plex C undergoes very slow epimerization and C-C reductive elim-
ination is relatively fast.
1
2
3
4
5
6
7
8
Scheme 3. Examples of alkylnitriles in asymmetric couplings
of aryl bromides
Me
Me
C2
C
Me
Me
N
N
N
N
N
N
Li
Li
Me
Ph
Me
CN
C3
i-Pr
Ph
(6)
C
n-BuLi
TMEDA
i-Pr
Ph
The result of 2-naphthyl triflate provides additional support for
the stereo-determining nature of the transmetalation process.
The reaction afforded 64% ee in the absence of LiBr (eq 10). We
suggest that the disilylamide occupies the fourth coordination
site on the palladium center. In comparison, the ee increased to
82% in the presence of LiBr (1 equiv). This is probably due to
partial conversion of the disilylamide complex to a bromide com-
plex, the latter being more stereoselective towards transmeta-
lation with B.
hexanes, rt
73%
Me
Me
Me
Me
homodimer
A
13C signal: δ 154.7 ppm for C2;
9
50.4 ppm for C3
PdCl2(TMEDA) 5 mol%
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11
12
13
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i-Pr
Br
ligand L
7.5 mol%
(7)
A
2-Naph
Ph
additive (equiv of Li)
toluene, 50 oC, 24 h
CN
( 2 Li per dimer)
(1 equiv of Li)
Entry
Additives
Product (%)
Ee (%) Naphthalene (%)
1
2
3
No additve
15
41
37
75
71
89
18
31
33
LiHMDS (1x)
LiHMDS (1x)
+TMEDA (1x)
The nitrile groups in the arylation products are readily con-
verted to other functionalities (Scheme 4), for example, an amide
after basic hydrolysis, a ketone via Grignard addition, an alcohol
via DIBAL-H reduction, an N-acetyl protected amine after hydride
reduction. In two cases (b and c), the ee value slightly increased
after flash chromatography, probably due to accidental partial
separation of dimers or oligomers on silica.28
4
5
6
TMEDA (1x)
HMDS (1x)
LiBr (1x)
7
12
15
76
77
78
16
22
19
2-naphthyl bromide
Me
Me
Me
N
N
N
N
Me
Li
Li
PdCl2(TMEDA) 5 mol%
i-Pr
LiHMDS + TMEDA
C7D8
i-Pr
SiMe3
ligand L
7.5 mol%
C
N
N
(8)
A
2-Naph
+ naphthalene
34% yield
Ph
SiMe3
Me
Me
Ph
CN
Me
Me
C7D8, 50 oC, 24 h
3a
89% ee
31% yield
Me
Me
Me
Me
Me
Me
Me
Me
heterodimer
B
(a)
KOH
(b)
MeMgBr;
Ph
NC
Ph
NC
3a
2-Naph
Ph
2-Naph
Ph
MeOC
OMe
t-AmOH
2N HCl
OMe
L
L
CONH2
L
L
NC
L
L
i-Pr
Pd
- PdL2
i-Pr
Pd
+
3f
92% ee
Pd
5a
5b
Br
Ar
(9)
Ar
B
Ar
Ar
Ph
90% ee
Ph
90% ee, 63% yield
Ph
fast reductive
elimination
94% ee, 71% yield
R
CN
3a
L=phosphoramidite
Ar=2-naphthyl
CN
(major)
i-Pr
epi-C (minor)
major isomer
C
R
R
R
slow equilibration of 2 isomers
(c)
DIBAL-H;
(d)
NMe2
NMe2
NMe2
NMe2
i-Pr
LiAlH4
;
no LiBr
Ph
NC
Ph
NC
Ph
Ph
L
L
Ar
NaBH4
(R=n-decyl)
Ph
Pd
AcHN
Ac2O, Et3
N
PdCl2(TMEDA) 5 mol%
ligand L 7.5 mol%
HO
CN
3a
Me
Ar
Me
5d
4n
(Me3Si)2
N
5c
4n
TfO
(R=n-decyl)
(10)
Ph
64% ee
81% ee
81% ee, 88% yield
85% ee, 67% yield
81% ee
26% yield
LiHMDS (1.8 x)
TMEDA (1.2 x)
toluene, 50 oC, 24 h
LiBr (0 or 2x)
CN
(1.2x)
(1x)
L
L
3a
Scheme 4. Transformation of nitrile groups
Pd
LiBr
Br
Ar
82% ee
22% yield
In conclusion, the first examples of enantioselective arylation
of benzylnitriles produce quaternary stereocenters in good ee
values. To our surprise, heterodimer B of a lithium keteneimide,
rather than homodimer A, is responsible for the stereoselective
transmetalation.
Figure 2. Mechanistic study
When complex A was used in the model catalytic reaction of 2-
naphthyl bromide, it only gave 75% ee surprisingly (eq 7, entry 1).
The value is significantly lower than 90% ee observed under in
situ deprotonation conditions (eq 5). Next, we added LiHMDS to
the coupling conditions, but the ee remained almost unchanged
(entry 2). Interestingly, we found that when both LiHMDS and
TMEDA were added, the ee was enhanced to 89% (entry 3). It is
almost identical to the value from in situ deprotonation (90% ee).
Additionally, TMEDA, LiBr or HN(SiMe3)2 alone had little effect on
the streoselectivity of the model reaction (entries 4-6).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental procedures, spectra for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
We then allowed complex A and LiHMDS and TMEDA in an
equimolar ratio (per Li) to stand in d8-toluene overnight, which
gave a clean sample of complex B (eq 8).26 The isopropyl methine
has a distinct heptet at 2.79 ppm, which is shifted upfield from
2.83 ppm of A. When the solution of B was used in the catalytic
reaction, it indeed gave the product in 89% ee (31% yield).
Therefore, we concluded that the active transmetalating species
is heterodimer B instead of homodimer A in the model catalytic
reaction.
*E-mail: jrzhou@ntu.edu.sg
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Singapore Ministry of Education Academic Research
Fund (MOE2013-T2-2-057 and MOE2014-T1-001-021) for finan-
cial support.
Recently, Gschwind et al. revealed that cis-(L)2PdCl2 complexes
of Feringa-type phosphoramidite are stabilized by extensive CH-π
and π-π interactions between two ligands of L, when compared
with the trans isomer.27 Putting all the information together, we
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Angew. Chem. Int. Ed. 2012, 51, 3826-3831. (e) Humbert, N.; Larionov,
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(5) Examples: (a) Huang, Z.; Liu, Z.; Zhou, J. J. Am. Chem. Soc. 2011, 133,
15882-15885. (b) Huang, Z.; Chen, Z.; Lim, L. H.; Quang, G. C. P.; Hirao,
H.; Zhou, J. Angew. Chem. Int. Ed. 2013, 52, 5807-5812. (c) Huang, Z.;
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W. C. J. Am. Chem. Soc. 2009, 131, 11640-11641. (b) Allen, A. E.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133, 4260. (c) Bigot, A.;
Williamson, A. E.; Gaunt, M. J. J. Am. Chem. Soc. 2011, 133, 13778-13781.
(d) Harvey, J. S.; Simonovich, S. P.; Jamison, C. R.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2011, 133, 13782-13785. (e) Skucas, E.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2012, 134, 9090-9093. (f) Zhu, S.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2012, 134, 10815-10818.
(13) (a) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 9330-
9331. (b) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 9330-
9331. (c) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234-245.
(d) Wu, L.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15824-15832.
(14) Examples: (a) You, J.; Verkade, J. G. Angew. Chem. Int. Ed. 2003, 42,
5051-5053. (b) Duez, S.; Bernhardt, S.; Heppekausen, J.; Fleming, F. F.;
Knochel, P. Org. Lett. 2011, 13, 1690-1693. (c) Todorovic, N.; Awuah, E.;
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(15) Examples: (a) Shang, R.; Ji, D.-S.; Chu, L.; Fu, Y.; Liu, L. Angew. Chem.
Int. Ed. 2011, 50, 4470-4474. (b) Velcicky, J.; Soicke, A.; Steiner, R.;
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(16) He, A.; Falck, J. R. J. Am. Chem. Soc. 2010, 132, 2524-2525.
(17) Choi, J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 9102-9105.
(18) Kadunce, N. T.; Reisman, S. E. J. Am. Chem. Soc. 2015, 137, 10480-
10483.
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(19) Zhang, W.; Wang, F.; McCann, S. D.; Wang, D.; Chen, P.; Stahl, S. S.;
Liu, G. Science 2016, 353, 1014-1018.
(20) Reviews: (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-353. (b)
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(7) Novel processes for preparing substantially pure anastrozole:
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