Copper-catalyzed electrophilic amination of functionalized diarylzinc reagents

Article abstract of DOI:10.1021/jo048168g

(Chemical Equation Presented). The copper-catalyzed electrophilic amination of functionalized diarylzinc reagents with O-acyl hydroxylamines allows for the preparation of functionalized tertiary arylamines in high yields, and is noteworthy for the mild re

Full text of DOI:10.1021/jo048168g

Copper-Catalyzed Electrophilic Amination
of Functionalized Diarylzinc Reagents
with these earlier efforts; however, these methods are
typically limited to the preparation of aniline derivatives
lacking sensitive functionality.6
,7
We have recently disclosed a copper-catalyzed electro-
philic amination of diorganozinc reagents with O-acyl
hydroxylamines, allowing for the preparation of tertiary
Ashley M. Berman and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599-3290
8
amines under mild reaction conditions (eq 1).
jsj@unc.edu
Received October 16, 2004
This reaction shows considerable latitude in the nu-
2
cleophilic component, with both sp (aryl, heteroaryl)- and
3
sp (alkyl, benzyl)-hybridized carbanions undergoing
coupling in uniformly high yields. The O-acyl hydroxyl-
amines employed are noteworthy in terms of both ease
of preparation and stability, and represent a convenient
3
source of sp -hybridized nitrogen electrophile for the
9
The copper-catalyzed electrophilic amination of functional-
ized diarylzinc reagents with O-acyl hydroxylamines allows
for the preparation of functionalized tertiary arylamines in
high yields, and is noteworthy for the mild reaction condi-
tions employed. The functionalized diarylzinc reagents were
prepared via an iodine/magnesium exchange of the corre-
sponding aryl iodide followed by transmetalation of the
resultant Grignard species with ZnCl2.
direct delivery of R N(+) synthons. In our previous
2
communication, the preparation of functionalized tertiary
2
amines was not possible since many of the R′ Zn nucleo-
philes were derived from organolithium reagents. As a
new variant of this methodology, we now report the
copper-catalyzed electrophilic amination of functionalized
diarylzinc reagents, prepared via the I/Mg exchange of
aryl iodides, as a general and mild route to functionalized
tertiary arylamines.
The development of methodology for the expeditious
preparation of amines continues to be an active area of
research. Arylamines are particularly attractive targets,
owing to the prominence of this structural motif in
Nature, and many methods have been developed for the
Knochel and co-workers have recently described the
I/Mg exchange reaction as an extremely useful route to
functionalized aryl Grignard reagents.10 Treatment of an
electron -deficient aryl iodide with RMgX (typically
i
PrMgBr) at low temperatures results in rapid I/Mg
1
preparation of such compounds. The Buchwald-Hartwig
exchange. Electron-rich aryl iodides can also be accom-
modated when elevated reaction temperatures (room
temperature) are employed. The resultant Grignard
reagents may be trapped with a number of electrophiles.
Particularly topical examples involve reactions with aryl
azosulfonates or nitroarenes to effect net delivery of a
coupling has in particular gained increasing importance
as a convenient route to functionally dense arylated
amines and is the benchmark in catalyzed nucleophilic
2
,3
amination. Electrophilic amination of nonstabilized
carbanions represents an alternative approach, and is
noteworthy in its use of the umpolung strategy for C-N
1
1,12
protected ArNH(+) synthon to the organometallic.
The Grignard reagents derived from I/Mg exchange
may also undergo transmetalation with 0.5 equiv of ZnCl
4
bond construction. Electrophilic amination of aryl car-
banions has been successfully applied to arylamine
synthesis, but with some exceptions (vide infra) harsh
conditions (RMgX or RLi as the carbon donor) are needed
2
to give access to functionalized diarylzinc reagents. We
envisaged employing these reagents in our copper-
catalyzed electrophilic amination protocol, giving expedi-
tious access to functionalized arylamine products (Scheme
1).
5
and/or modest yields result. Transition metal-catalyzed
methods have recently been developed by Erdik and
Narasaka that alleviate some of the problems associated
(
1) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
400-5449.
2) (a) Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L.
(6) (a) Erdik, E.; Ay, M. Synth. React. Inorg. Met. Org. Chem. 1989,
19, 663-668. (b) Erdik, E.; Daskapan, T. J. Chem. Soc., Perkin Trans.
1 1999, 3139-3142. (c) Erdik, E.; Daskapan, T. Synth. Commun. 1999,
29, 3989-3997.
5
(
J. Org. Chem. 2004, 69, 5578-5587. (b) Muci, A. R.; Buchwald, S. L.
Top. Curr. Chem. 2002, 219, 131-209. (c) Wolfe, J. P.; Wagaw, S.;
Marcoux, J. F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805-818.
(7) (a) Tsutsui, H.; Hayashi, Y.; Narasaka, K. Chem. Lett. 1997,
317-318. (b) Tsutsui, H.; Ichikawa, T.; Narasaka, K. Bull. Chem. Soc.
Jpn. 1999, 72, 1869-1878.
(
3) (a) Hartwig, J. F. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E.-i., Ed.; Wiley: New York, 2002; Vol.
(8) Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126,
5680-5681.
(9) Biloski, A. J.; Ganem, B. Synthesis 1983, 537-538.
(10) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003,
42, 4302-4320.
(11) Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
897-900.
(12) Sapountzis, I.; Knochel, P. J. Am. Chem. Soc. 2002, 124, 9390-
9391.
1
8
, pp 1051-1096. (b) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852-
60.
(
4) (a) Dembech, P.; Seconi, G.; Ricci, A. Chem. Eur. J. 2000, 6,
1
281-1286. (b) Greck, C.; Gen eˆ t, J. P. Synlett 1997, 741-748. (c) Erdik,
E.; Ay, M. Chem. Rev. 1989, 89, 1947-1980.
(
5) For instructive early examples, see: (a) Boche, G.; Mayer, N.;
Bernheim, M.; Wagner, K. Angew. Chem., Int. Ed. Engl. 1978, 17, 687-
88. (b) Beak, P.; Kokko, B. J. J. Org. Chem. 1982, 47, 2822-2823.
For a more thorough treatment of strategies employed, see ref 4.
6
10.1021/jo048168g CCC: $30.25 © 2005 American Chemical Society
364
J. Org. Chem. 2005, 70, 364-366
Published on Web 11/26/2004

SCHEME 1. Strategy for the Preparation of
Functionalized Tertiary Arylamines
TABLE 1. Scope of the Copper-Catalyzed Electrophilic
a
Amination of Functionalized Diarylzinc Reagents
entry
1
R2N-OC(O)Ph
Ar
% yieldd
76
p-NCC6H4
2
3
4
5
6
7
8
9
p-EtO2CC6H4
p-ClC6H4
77
93
71
74
76
95
81
79
83
59
49
90
p-FC6H4
m-F3CC6H4
p-AcOC6H4
p-TfOC6H4
b
p-MeOC6H4
b
p-Me(OCH2CH2O)CC6H4
c
1
1
0
1
o-O2NC6H4
Employing Knochel’s protocol for the preparation of
c
2,4-(O2N)2C6H3
2
functionalized Ar Zn reagents, we proceeded to test our
12
13
2-pyridyl
1-naphthyl
b
hypothesis with a series of diverse aryl substrates. The
requisite aryl iodides were either commercially available
or easily prepared from the corresponding aryl bromides
1
4
p-NCC6H4
p-EtO2CC6H4
95
1
1
5
6
99
88
87
97
1
3
by the method of Buchwald. The amination reaction
showed broad functional group tolerance in the aryl
component (Table 1). Various functional groups, including
nitrile, ester, halide, triflate, and nitro, are tolerated
under the reaction conditions. Those functional groups
requiring prior protection were a phenol (as the derived
acetate ester, entry 6) and a ketone (as the derived ketal,
entry 9). Interestingly, the reaction proceeds equally well
for both electron-deficient (entry 5) and electron-rich
p-ClC6H4
p-MeOC H b
17
18
6
4
c
o-O2NC6H4
a
1
.1 equiv of diarylzinc were employed. Ar2Zn reagents were
prepared from the corresponding ArI as follows: (1) iPrMgBr, -35
b
°C, 1 h, (2) ZnCl2, -35 °C, 10 min. Ar2Zn prepared from the
i
corresponding ArI as follows: (1) PrMgBr, rt, 1 h, (2) ZnCl2, rt,
c
1
(
0 min. Ar2Zn prepared from the corresponding ArI as follows:
d
1) PhMgBr, -35 °C, 10 min, (2) ZnCl2, -35 °C, 10 min. Isolated
1
yield of product of g95% purity as judged by H NMR spectroscopy
and GLC analysis (average of at least two experiments). Yield is
based on the starting R2N-OC(O)Ph.
(
2
entry 8) Ar Zn reagents. Heteroaromatic coupling is also
accommodated under this general protocol (entry 12),
albeit with somewhat diminished yields.
While most reactions were performed with CuOTf as
catalyst, the use of other catalytic sources of copper is
TABLE 2. Copper-Catalyzed Electrophilic Amination of
Functionalized Diarylzinc Reagentsa
also feasible. Both CuI and CuCl
the reaction with equal facility (eq 2; cf. Table 1, entry
).
2
were found to catalyze
6
entry
Ar
% yieldc
1
2
3
4
p-NCC6H4
p-FC6H4
p-TfOC6H4
p-MeOC6H4
74
74
83
71
b
a
0
.6 equiv of diarylzinc were employed. Ar2Zn reagents were
i
prepared from the corresponding ArI as follows: (1) PrMgBr, -35
b
°
C, 1 h, (2) ZnCl2, -35 °C, 10 min. Ar2Zn prepared from the
Catalytic delivery of both aryl groups from the Ar
reagent is also possible (Table 2). While optimized
conditions employ 1.1 equiv of the Ar Zn, the use of 0.6
2
Zn
i
corresponding ArI as follows: (1) PrMgBr, rt, 1 h, (2) ZnCl2, rt,
c
1
0 min. Isolated yield of product of g95% purity as judged by
1
2
H NMR spectroscopy and GLC analysis (average of at least two
equiv resulted in nearly identical (entries 1 and 2; cf.
Table 1, entries 1 and 4) to slightly diminished yields
experiments). Yield is based on the starting R2N-OC(O)Ph.
(
entries 3 and 4; cf. Table 1, entries 7 and 8) of product
tive workup is suitable in most instances to obtain
analytically pure material. The reaction is noteworthy
in its use of Knochel’s I/Mg exchange protocol to generate
functionalized diarylzinc reagents from the corresponding
aryl iodides in situ, thus obviating the need for isolation
in the cases studied.
In summary, we have developed an efficient protocol
for the expeditious preparation of functionalized tertiary
arylamines under mild conditions. The reactions are
conducted at room temperature and are complete in 1 h
or less for all substrates tested. Simple acid/base extrac-
2
and/or purification of Ar Zn. The O-acyl hydroxylamines
employed are easily prepared by the method of Ganem
and show excellent long-term stability. We are currently
examining ways to extend the scope and utility of this
(13) Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
1
4844-14845.
J. Org. Chem, Vol. 70, No. 1, 2005 365

electrophilic amination protocol. Results from these stud-
ies will be the topic of future publications.
were combined and the solvent was removed under reduced
pressure. The resulting residue was taken up in diethyl ether
(
10 mL) and washed with a 1 M hydrochloric acid solution (2 ×
1
0 mL), and the aqueous layer was basified with a 10% sodium
Experimental Section
hydroxide solution and extracted with dichloromethane (2 × 10
mL). The organic extracts were combined and dried over sodium
sulfate, and the solvent was removed under reduced pressure
to yield 4-(morpholin-4-yl)benzonitrile (0.0370 g, 0.20 mmol, 79%
4-(Morpholin-4-yl)benzonitrile (Table 1, entry 1): Rep-
resentative Procedure for the Copper-Catalyzed Amina-
tion of Functionalized Diarylzinc Reagents. An oven-dried
round-bottom flask equipped with a magnetic stir bar was
charged with 4-iodobenzonitrile (0.1258 g, 0.55 mmol) and
anhydrous tetrahydrofuran (3.0 mL); the solution was cooled to
1
yield) as a white solid of g95% purity as judged by H NMR
1
spectroscopy and GLC analysis. The H NMR spectrum was
1
4
consistent with that reported in the literature.
-
35 °C. A tetrahydrofuran solution of isopropylmagnesium
Acknowledgment. Funding for this work was pro-
vided by Johnson and Johnson (Focused Giving Award)
and a UNC Junior Faculty Development award. J.S.J.
is an Eli Lilly Grantee and a 3M Nontenured Faculty
Awardee.
bromide (0.60 mL, 1.0 M) was slowly added along the edges of
the flask and the reaction mixture was stirred at -35 °C for 1
h. A tetrahydrofuran solution of zinc(II) chloride (1.0 mL, 0.28
M) was slowly added along the edges of the flask and the reaction
mixture was stirred at -35 °C for 10 min. A second oven-dried
round-bottom flask equipped with a magnetic stir bar was
charged with 4-(benzoyloxy)morpholine (0.0520 g, 0.25 mmol),
Supporting Information Available: Experimental pro-
cedures for electrophilic amination reactions and spectral data
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
copper(I) trifluoromethanesulfonate benzene complex ([CuOTf]
, 0.0016 g, 0.0031 mmol), and anhydrous tetrahydrofuran
2.0 mL). The contents of the first flask were added to this second
2
‚
6 6
C H
(
flask and the reaction mixture was stirred at room temperature
for 1 h. The reaction mixture was diluted with diethyl ether (10
mL), the organic layer was washed with a saturated sodium
bicarbonate solution (2 × 10 mL), and the aqueous layer was
extracted with dichloromethane (2 × 10 mL). The organic layers
JO048168G
(14) Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
6054-6058.
366 J. Org. Chem., Vol. 70, No. 1, 2005