Palladium-catalyzed regioselective arylation of 1,1,3-triaryl-2-azaallyl anions with aryl chlorides

Article abstract of DOI:10.1021/ol502043j

A regioselective arylation of 1,1,3-triaryl-2-azaallyl anions with aryl chlorides is described. The palladium-NIXANTPHOS-based catalyst affords diarylmethylamine derivatives in good yield and without product isomerization. A gram scale sequential one-pot ketimine synthesis/arylation protocol was also developed.

Full text of DOI:10.1021/ol502043j

Letter
pubs.acs.org/OrgLett
Open Access on 08/05/2015
Palladium-Catalyzed Regioselective Arylation of 1,1,3-Triaryl-2-
azaallyl Anions with Aryl Chlorides
Minyan Li, Simon Berritt, and Patrick J. Walsh*
Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry,
University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: A regioselective arylation of 1,1,3-triaryl-2-azaallyl anions
with aryl chlorides is described. The palladium-NIXANTPHOS-based
catalyst affords diarylmethylamine derivatives in good yield and without
product isomerization. A gram scale sequential one-pot ketimine synthesis/
arylation protocol was also developed.
iarylmethylamines are important structural motifs in
with aryl halides at room temperature (Scheme 1c). Although
Dmedicinal chemistry and are present in several medi- the reaction worked very well for aryl bromides, chlorobenzene
cations.1 Their synthesis has, therefore, attracted much
underwent coupling in only 38% yield. Very recently, we
described the in situ generation and regioselective arylation of
1,1,3-triaryl-2-azaallyl anions, from ketimine and aldimine
precursors (Scheme 2), with aryl bromides.2d In this study
attention. One strategy for the synthesis of diarylmethylamines,
and related amines, relies on generation and reactions of 2-
azaallyl anions. 2-Azaallyl anions have been shown to be viable
substrates for palladium-catalyzed cross-coupling reactions with
aryl halides (Scheme 1), although only limited success has been
reported with more readily available aryl chloride coupling
partners.2
Scheme 2. Arylation of 2-Azaallyl Anions Using a
Pd(NIXANTPHOS)-Based Catalyst
Scheme 1. Previous Reports of Arylation of 2-Azaallyl
Anions with Aryl Halides and Triflates
we identified that a palladium complex3 of van Leeuwen’s
bidentate NIXANTPHOS,4 together with a hindered base
[NaN(SiMe3)2], facilitated arylation under mild conditions and
eliminated product isomerization.
In our initial report, we avoided aryl chloride substrates,
because it is well-known that oxidative addition of aryl chlorides
to palladium complexes with bidentate phosphines requires
temperatures of ∼100 °C, at which temperature isomerization
of the type observed by Oshima (Scheme 1a,b) would likely be
problematic. However, we subsequently discovered that the
Pd(NIXANTPHOS)-based catalyst will oxidatively add aryl
chlorides at room temperature (Scheme 3).5 Room temper-
ature oxidative addition of aryl chlorides by palladium generally
occurs with bulky monodentate phosphine complexes (PCy3,
In 2008 and 2009, Oshima and co-workers2a,b reported
pioneering studies on coupling aryl chlorides with N-benzyl
ketimine derivatives via in situ deprotonation with CsOH at
140 °C. Unfortunately, the high reaction temperature caused
isomerization of the product in every case (Scheme 1a and b).
Earlier this year, Buchwald and Zhu2c reported an elegant
enantioselective arylation of 9-aminofluorene-derived aldimines
Received: July 12, 2014
Published: August 5, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
but in contrast to the reactions with aryl bromides where
NaN(SiMe3)2 was optimal.2d Raising the temperature to 60 °C
resulted in an increase in the yield with shorter reaction times
(Table 1, entries 8 and 9). Reducing the catalyst loading from
10 to 5 mol % at 60 °C resulted in a slight drop in the yield
from 92% to 86% (Table 1, entry 10). Optimization of the
arylation at 23 °C led to generation of 3ab in 81% yield with 10
mol % NIXANTPHOS precatalyst 5 in 14 h (Table 1, entry
11).
Scheme 3. Oxidative Addition Using NIXANTPHOS
Precatalysts 4 and 5 at 23 °C
The scope of the aryl chloride−ketamine cross-coupling was
determined (Table 2) at 60 °C (5 mol % cat.). Chlorobenzene
PtBu3, Q-Phos, Buchwald’s phosphines, etc.),6 because the
mechanism proceeds via a Pd−L1 intermediate.7
The discovery that our NIXANTPHOS-based palladium
catalyst oxidatively adds to aryl chlorides5 at rt inspired us to
revisit the arylation of 2-azaallyl anions with more abundant
and economical aryl chlorides. Herein, we report the first highly
regioselective arylation of 1,1,3-triaryl-2-azaallyl anions with aryl
chlorides.
Based on our previous reported arylation with bromoar-
enes,2d we initiated our studies with a 2:1 ratio of ketimine 1a
and aryl chloride 2b, 3 equiv of LiN(SiMe3)2, 5 mol %
Buchwald’s μ-OMs dimer 4,3 and 10 mol % NIXANTPHOS.
The addition of base was done portionwise to minimize the
concentration of the azaallyl anion, which reacts with the imine
to give byproducts.2d We tested five solvents [CPME
(cyclopentyl methyl ether), THF, toluene, DME (dimethoxy-
ethane), and DCE (1,2-dichloroethane)] at 23 °C (Table 1,
entries 1−5). THF was the best of these with a 68% assay yield
(Table 1, entry 2). With THF as solvent, a screen of bases
MN(SiMe3)2 (M = Na K, Li, entries 6−8) indicated that the
reaction with LiN(SiMe3)2 outperformed the others. This result
was consistent with our oxidative addition studies (Scheme 3),5
Table 2. Scope of Aryl Chlorides in the Arylation of
a b
,
Ketimine 1a
entry
Ar
product Pd (mol %) temp (°C) yield (%)
1
Ph
3aa
3ab
3ac
3ad
3ae
3af
5
60
60
60
60
60
60
60
60
23
23
23
23
90
86
77
60
77
87
91
61
83
81
71
85
2
4-tBu-C6H4
3-Me-C6H4
4-OMe-C6H4
4-F-C6H4
5
3
5
4
10
5
5
6
4-CF3-C6H4
3-NC-C6H4
3-Me2N-C6H4
Ph
5
c
7
3ag
3ah
3aa
3ab
3ae
3af
10
10
10
10
10
10
8
d
d
d
d
9
10
11
12
4-tBu-C6H4
4-F-C6H4
4-CF3-C6H4
a
Reactions conducted on a 0.1 mmol scale using 2 equiv of 1a, 3 equiv
of LiN(SiMe3)2, and 1 equiv of ArCl at 0.1 M. Base was added
b
portionwise with speed 0.05 mL/30 min. Isolated yield after
Table 1. Optimization of Arylation of Ketimine 1a with Aryl
Chloride 2b
c
d
a b
,
chromatographic purification. DME as solvent. NIXANTPHOS
precatalyst 5, base was added portionwise with speed 0.1 mL/30 min,
14 h.
gave 3aa in 90% yield. Aryl chlorides bearing alkyl groups
(4-tBu 2b, 3-Me, 2c) provided products 3ab and 3ac in 86%
and 77% yield, respectively. Electron-rich 4-chloroanisole (2d)
was coupled with 1a in 60% yield at a 10 mol % catalyst
loading. Aryl chlorides with electron-withdrawing 4-F, 4-CF3,
and 3-CN groups were also well tolerated, providing products
in 77% (3ae), 87% (3af), and 91% (3ag) yield, respectively. It
is notable that the base-sensitive nitrile-bearing substrate gave
an excellent yield. 3-Chloro-N,N-dimethylaniline reacted with
1a in 61% yield (3ah) at a 10 mol % catalyst loading. With little
drop in the yields, coupling at 23 °C with a 10 mol % palladium
loading (under conditions of Table 1, entry 11) was also
successfully employed, affording electronically diverse products
3aa, 3ab, 3ae, 3af in 71%−85% yield (entries 9−12).
Encouraged by the results of the ketimine arylation with aryl
chlorides, we next investigated translation of the optimized
conditions from Table 1 to the arylation of aldimines (Table 3).
Aldimine substrates have the advantage that there are many
commercially available aldehyde precursors. Coupling reactions
at 60 °C with a 5 mol % catalyst loading and 4-tert-butyl chloro
benzene (2b) gave 3ab in 91% yield (Table 3, entry 1).
Chlorobenzene (2a) and alkyl substituted 4-methyl chlor-
obenzene (2i) gave product 3aa and 3ai in 95% and 86% yield,
respectively (entries 2−3). Coupling of 1a′ with 4-trifluor-
4/L
temp
time
(h)
yield
(%)
entry (mol %)
base
solv
(°C)
1
5/10
5/10
5/10
5/10
5/10
5/10
5/10
5/10
5/10
2.5/5
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
NaN(SiMe3)2
KN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
CPME
THF
Tol.
23
23
23
23
23
23
23
60
60
60
23
12
12
12
12
12
12
12
12
6
N.R.
2
68
3
N.R.
62
4
DME
DCE
THF
THF
THF
THF
THF
THF
5
N.R.
50
6
7
37
8
92
9
92
10
11
6
86
c
d
10
14
83(81)
a
Reactions conducted on a 0.1 mmol scale using 2 equiv of ketimine, 3
equiv of LiN(SiMe3)2, and 1 equiv of ArCl at 0.1 M. Base was added
portionwise with speed 0.05 mL/30 min. N.R. is no reaction. Yield
determined by H NMR spectroscopy of the crude reaction mixture
on a 0.1 mmol scale. NIXANTPHOS precatalyst 5, base was added
portionwise with speed 0.1 mL/30 min. Isolated yield after
chromatographic purification.
b
1
c
d
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Letter
Synthesis of bis-heterocyclic diarylmethylamine derivatives
via coupling of 4-pyridyl ketimine and aldimine with
heterocyclic aryl chlorides was next investigated. Good-to-
excellent yields were observed with ketimine and aldimine
isomers. At a 10 mol % catalyst loading, electron-rich 5-chloro-
2-methoxypyridine (2k) exhibited good reactivity with 3ek
generated in 71% yield from ketimine 1e and 70% yield from
aldimine 1e′ (Table 5, entries 1−2). Employing 3-chloropyr-
Table 3. Scope of Aryl Chlorides in the Arylation of
Aldimine 1a′
a b
,
entry
Ar
prod
Pd (mol %)
temp (°C)
yield (%)
1
2
4-tBu-C6H4
3ab
3aa
3ai
3af
3ae
3aj
3ab
3aa
3ai
3af
5
60
60
60
60
60
60
23
23
23
23
91
95
86
85
84
81
a b
,
Ph
5
Table 5. Bis-heterocyclic Diarylmethylamine Derivative
3
4-Me-C6H4
4-CF-C6H4
4-F-C6H4
3,5-F2-C6H3
4-tBu-C6H4
Ph
5
4
5
5
5
6
10
10
10
10
10
c
7
85
c
8
84
c
9
4-Me-C6H4
4-CF3-C6H4
86
c
10
89
a
Reactions conducted on a 0.1 mmol scale using 2 equiv of 1a′, 3
equiv of LiN(SiMe3)2, and 1 equiv of ArCl at 0.1 M. Base was added
portionwise with speed 0.05 mL/30 min. Isolated yield after
chromatographic purification. NIXANTPHOS precatalyst 5, base
b
entry
imine
ArHetero−Cl
prod.
Pd (mol %)
yield (%)
c
1
2
3
4
5
6
1e
2k
2k
2l
3ek
3ek
3el
10
10
10
10
5
70
71
78
82
90
90
was added portionwise with speed 0.1 mL/30 min, 14 h.
1e′
1e
omethyl chlorobenzene 2f provided 3af in 85% yield (entry 4).
4-Fluoro chlorobenzene reacted smoothly with aldimine 1a′ to
give the product 3ae in 84% yield (entry 5). 1-Chloro-3,5-
difluorobenzene (2j, entry 6) coupled in 81% yield at a 10 mol
% catalyst loading. Coupling of aldimine 1a′ with 4-tert-butyl
chlorobenzene (2b) at 23 °C gave 3ab in 85% yield at a 10 mol
% catalyst loading, which is similar to the ketimine isomer
(Table 2, entry 10, 81% yield). In a similar fashion, syntheses of
3aa, 3ai, and 3af were also conducted at 23 °C in 84%, 86%,
and 89% yield (entries 8−10), respectively.
1e′
1e
2l
3el
2m
2m
3em
3em
1e′
5
a
Reactions conducted on a 0.1 mmol scale using 2 equiv of imine, 3
equiv of LiN(SiMe3)2, and 1 equiv of ArCl at 0.1 M. Base was added
portionwise with speed 0.1 mL/30 min. Isolated yield after
chromatographic purification.
b
idine (2l) led to a 78% yield with ketamine 1e and an 82% yield
with aldimine 1e′ (Table 5, entries 3−4). Excellent yields were
achieved with 6-chloroquinoline (2m) at a 5 mol % catalyst
loading. Product 3em was obtained in 90% yield from both
couplings with 1e and 1e′ (Table 5, entries 5−6).
The substrate scope of ketimines with different substituents
on the N-benzyl group was then studied (Table 4). The
a
Table 4. Scope of Ketimine in Arylation of Chlorobenzene
The arylation is also amenable to a sequential one-pot imine
synthesis/arylation protocol (Scheme 4), which streamlines the
generation of diarylmethylamine derivatives. Thus, we con-
ducted a 3 mmol scale sequential one-pot synthesis of 4-pyridyl
ketimine 1e, followed by arylation with 6-chloroquinoline 2m
entry
Ar
product
yield (%)
1
2
3
4
5
4-Me-C6H4
3,5-F2-C6H3
3-Py
3ai
3aj
3da
3ea
3fa
86
88
60
91
61
Scheme 4. Gram Scale Sequential One-Pot Ketimine
Synthesis/Arylation Protocol
4-Py
2-furyl
a
Reactions conducted on a 0.1 mmol scale using 2 equiv of ketimines,
3 equiv of LiN(SiMe3)2, and 1 equiv of PhCl at 0.1 M. Base was added
portionwise with speed 0.05 mL/30 min.
reaction of the 4-methyl benzyl ketimine derivative (1b)
proceeded efficiently under a 10 mol % loading in 86% yield
(entry 1). Coupling of the 3,5-difluoro benzyl ketimine
derivative (1c) furnished the product in excellent yield (88%,
entry 3) at a 5 mol % catalyst loading. Heterocyclic 3-pyridyl
and 4-pyridyl ketimine derivatives coupled with chlorobenzene
(2a) in 60% (3da) and 91% (3ea) yield. The 2-furyl ketimine
derivative led to a satisfactory yield of product 3fa (61% yield).
It is noteworthy that no substrate in Tables 2−4 exhibited
product isomerization.
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Organic Letters
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at a 2.5 mol % catalyst loading. The bis-heterocylic product 3el
was isolated in 85% yield (1.02 g).
In conclusion, we have developed the first synthetically useful
arylation of 2-azaallyl anions with aryl chlorides. The key to the
success of this transformation is use of the Pd-NIXANTPHOS
precatalyst that efficiently generates catalytically active species
and facilitates the coupling with aryl chlorides. The reaction can
be used with either ketimine or aldimine substrates, has good
generality, and can be applied to a telescoped ketimine
synthesis/arylation reaction on gram scale.
ASSOCIATED CONTENT
■
S
* Supporting Information
Procedures, characterization data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pwalsh@sas.upenn.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CHE-1152488)
and National Institutes of Health (NIGMS 104349) for
financial support. We thank Tiezheng Jia, Dr. Jiadi Zhang,
and Dr. Sonia Montel of UPenn for helpful discussions.
REFERENCES
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