Nickel-catalyzed electrophilic amination of organozinc halides

Article abstract of DOI:10.1055/s-2005-871567

The nickel-catalyzed electrophilic amination of organozinc halides with O-benzoyl N,N-dialkyl hydroxylamines allows for the preparation of a variety of aryl and alkyl tertiary amines in good yield. The reaction is noteworthy for the mild reaction conditions employed (room temperature) and the ease of product purification (acid/base extractive work up). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-871567

CLUSTER
1799
Nickel-Catalyzed Electrophilic Amination of Organozinc Halides
N
i-CatalyzedElec
s
trophilic
A
h
mination ley M. Berman, Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, USA
Fax +1(919)9622388; E-mail: jsj@unc.edu
Received 29 March 2005
Electrophilic amination of nonstabilized carbanions re-
presents an alternative approach to amine synthesis, and is
noteworthy for its use of the umpolung strategy for C–N
bond construction.9–11 Early examples have focused on
Abstract: The nickel-catalyzed electrophilic amination of orga-
nozinc halides with O-benzoyl N,N-dialkyl hydroxylamines allows
for the preparation of a variety of aryl and alkyl tertiary amines in
good yield. The reaction is noteworthy for the mild reaction condi-
tions employed (room temperature) and the ease of product purifi- the amination of highly reactive carbon donors (R¢Li and
cation (acid/base extractive work up).
R¢MgX), and have generally been hampered by modest
yields and/or harsh reaction conditions. Reports by Erdik
and Narasaka on the metal-catalyzed amination of non-
stabilized carbanions employing O-sulfonyl oximes as
H2N(+) synthons represent an improvement on previous
methodology, but have as yet been limited to the pre-
paration of non-functionalized aniline derivatives.12,13
Rieke’s observation that organozinc halide reagents un-
dergo amination with azodicarboxylates is also germane
to the present investigation.14
Key words: amination, organometallic reagents, nickel, catalysis,
umpolung
The dichotomous behavior of diorganozinc and organo-
zinc halide reagents is common in the application of these
compounds in organic synthesis.1 The divergence is man-
ifested, sometimes dramatically, in different activity of
nominally similar compounds. We recently had occasion
to note significant disparities in reaction efficiency of
R¢ZnX and R¢2Zn reagents in the context of copper-cata-
lyzed electrophilic aminations, with the latter providing
results far superior to the former.2 In this paper we docu-
ment our efforts to bridge this gap through the discovery
that nickel complexes successfully catalyze the electro-
philic amination of organozinc halides (Equation 1).
In the course of our initial screen of potential catalysts and
reagents for the union of weak organic nucleophiles with
R2N(+) synthons, nickel arose as a candidate metal for the
reaction of R¢ZnX with O-benzoyl hydroxylamines.2
Efforts to build upon this preliminary finding focused on
the identity of the nickel complex. Ni(COD)2 was chosen
as a readily available source of Ni(0) and was evaluated
for catalytic competence in the presence of a number of
neutral ligands (Table 1).
R'2Zn
CuCl2 (2.5 mol %)
THF, r.t.
Table 1 Effect of Ligation on the Nickel-Catalyzed Electrophilic
Amination of Phenylzinc Bromidea
R
R'
R
O
Ph
N
R
N
R
Ni(COD)2 (2.5 mol%),
O
Ph
Ph
ligand
O
N
N
PhZnBr
O
O
O
THF, r.t.
R'ZnCl
Ni(PPh3)2Cl2 (2.5 mol %)
Entry
Ligand
None
Time (h)
Yield (%)d
THF, r.t.
1
2
3
4
5
6
7
24
15
24
56
24
56
53
40
65
71
Equation 1
1,10-Phenanthrolineb
BINAPb
This study was initiated as part of a broader effort to
develop new methods for C–N bond formation.3 Of the
modern methods currently available, the Buchwald–
Hartwig cross coupling reaction has gained prominence as
a general protocol for the preparation of aryl amines, re-
presenting the state of the art in metal-catalyzed nucleo-
philic amination.4,5 While typically performed under
palladium catalysis, other transition metals have proven to
be competent catalysts as well. Of particular interest are
reports by Buchwald and others on nickel-catalyzed
nucleophilic amination.6–8
Imes-HClc
0.25
c
PCy3
0.25
0.25
0.25
c
P(OPh)3
c
PPh3
a 1.1 Equiv of PhZnBr was employed. PhZnBr was prepared from
PhMgBr via transmetallation with 1.0 equiv ZnBr2.
b 2.5 mol% ligand employed.
c 5.0 mol% ligand employed.
d Isolated yield of product. Yield based on starting R2N-OC(O)Ph.
SYNLETT 2005, No. 11, pp 1799–1801
0
7
.0
7
.2
0
0
5
Advanced online publication: 27.06.2005
DOI: 10.1055/s-2005-871567; Art ID: Y00505ST
© Georg Thieme Verlag Stuttgart · New York

1800
A. M. Berman, J. S. Johnson
CLUSTER
Table 2 Scope of the Nickel-Catalyzed Electrophilic Amination of
In the absence of ligand, amination proceeds slowly and
only in modest yields (entry 1). When a chelating diamine
(entry 2) or (bis)phosphine (entry 3) is employed, the re-
action rate is once again severely hampered and modest
yields obtained. We observed a dramatic acceleration in
rate when monodentate ligands were employed (15 min
vs. 15 h), along with a more subtle electronic and/or ster-
ic effect on yield (entries 4–7). When an electron-rich and
sterically hindered N-heterocyclic carbene or trialkyl-
phosphine is employed, modest yields of product are ob-
tained (entries 4 and 5). With the electron-poor and
sterically neutral triphenylphosphite, an improvement in
yield is observed (entry 6). Our best results were obtained
with the electronically and sterically neutral triphenyl-
phosphine ligand (entry 7), affording 71% yield of desired
product under unoptimized conditions. The air stable and
commercially available Ni(PPh)2Cl2 complex was also
found to be a competent catalyst for this reaction, and was
employed in all subsequent studies.
Organozinc Halidesa
(Ph3P)2NiCl2
(2.5 mol%)
R
O
Ph
R
R'
N
R
R'ZnCl
N
R
O
THF, r.t.
10 min – 3 h
Entry
1
R2N-OC(O)Ph
R¢ZnCl
Yield (%)b
89
Ph
O
Ph
N
O
O
1a
2
3
4
5
6
1a
o-MePh
p-MeOPh
Bn
73
89
85
58
77
1a
1a
1a
n-octyl
Ph
O
Ph
N
O
1b
With a convenient nickel catalyst in hand, we next set out
to study the scope of the reaction. The R¢ZnX reagents
employed in this study were generated in situ from the
corresponding R¢MgX via transmetalation with 5.0 equiv-
alents of ZnCl2, and were used without isolation and/or
purification.15 The O-benzoyl hydroxylamines were pre-
pared as previously described. As illustrated in Table 2, a
variety of aryl fragments undergo amination in good
yields (entries 1–3, 6, 7, 9, 10). Alkyl (primary) and ben-
zyl fragments likewise undergo transfer to the R2N(+)
electrophile in acceptable yields (entries 4, 5, 8). Attempt-
ed amination of secondary and tertiary alkyl R¢ZnCl failed
to yield the desired product, instead giving complex
reaction mixtures in all cases.
7
8
9
1b
1b
Et
p-MeOPh
Bn
92
68
71
Ph
O
Ph
N
Et
O
1c
10
1c
p-MeOPh
92
a 1.1 Equiv of the R¢ZnCl was employed. The R¢ZnCl was prepared
from the corresponding R¢MgX via transmetallation with 5.0 equiv
ZnCl2.
b Isolated yield of product of ≥ 95% purity as judged by 1H NMR
spectroscopy and GLC analysis (average of at least two experiments).
Yield based on starting R2N-OC(O)Ph.
This is in contrast to the aforementioned copper system, in
which the amination of secondary and tertiary alkyl
fragments occurs readily. Unfortunately, use of R¢ZnX
reagents prepared from direct insertion of Zn(0) into the
corresponding R¢–X electrophile has to date resulted in
significantly depressed yields.
Table 3 Nickel-Catalyzed Electrophilic Amination of Functional-
ized Organozinc Halidesa
(Ph3P)2NiCl2
(2.5 mol%)
R
O
Ph
R
Ar
N
R
ArZnCl
N
R
O
THF, r.t.
1–6 h
The preparation of functionalized tertiary aryl amines was
also explored.16,17 The requisite functionalized ArZnCl
reagents were generated in situ from the corresponding
aryl iodide (ArI) via I–Mg exchange, transmetalation
sequence (5.0 equiv ZnCl2) as previously described.18,19
As illustrated in Table 3, nitrile, ester, and halide func-
tionalities are all accommodated employing the nickel
catalyst system. Amination with functionalized ArZnCl
nucleophiles proved to be markedly sluggish, with ex-
tended reaction times and/or incomplete consumption of
starting material observed in several instances.
Entry
1
R2N-OC(O)Ph
ArZnCl
yield (%)b
56
O
Ph
p-NCPh
N
O
O
1a
1a
2
3
4
p-EtO2CPh
p-ClPh
59
84
82
1a
1a
m-F3CPh
a 1.1 Equiv of the ArZnCl was employed. The ArZnCl was prepared
from the corresponding ArI as follows: 1) i-PrMgBr, –35 °C, 1 h; 2)
ZnCl2 (5.0 equiv), –35 °C, 20 min.
In conclusion, we have developed a nickel-catalyzed elec-
trophilic amination of organozinc halides that comple-
ments our previously reported copper-catalyzed system
for the amination of R¢2Zn reagents. As in the copper sys-
tem, the present protocol is noteworthy for the mild reac-
tion conditions employed (r.t.) and the ease of product
purification (acid/base extractive work up) to obtain
b Isolated yield of product of ≥ 95% purity as judged by 1H NMR
spectroscopy and GLC analysis (average of at least two experiments).
Yield based on starting R2N-OC(O)Ph.
Synlett 2005, No. 11, 1799–1801 © Thieme Stuttgart · New York

CLUSTER
Ni-Catalyzed Electrophilic Amination
1801
analytically pure material. The R¢ZnCl reagents employed
were prepared via transmetalation from the corresponding
R¢MgX and used without prior isolation and/or purifica-
tion. While the nickel system currently lacks the general-
ity of the copper system, the present report nonetheless
expands upon the repertoire of experimental conditions
that may be employed in such processes and documents a
new metal center that is competent for the catalysis of
electrophilic amination. We have a continuing interest in
the development and improvement of this and other meth-
odology for the catalytic delivery of R2N(+) to carbon do-
nors and will report our findings in future publications.
Acknowledgment
The authors gratefully acknowledge a Johnson and Johnson Focu-
sed Giving Grant for support of this work. A.M.B. is the recipient
of a Burroughs-Wellcome fellowship. J.S.J. is an Eli Lilly Grantee
and a 3M Nontenured Faculty Awardee.
References
(1) Knochel, P.; Millot, N.; Rodriguez, A. L.; Tucker, C. E. Org.
React. 2001, 58, 417.
(2) Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126,
5680.
(3) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42,
5400.
(4) Hartwig, J. F. In Handbook of Organopalladium Chemistry
for Organic Synthesis, Vol. 1; Negishi, E.-i., Ed.; Wiley:
New York, 2002, 1051–1096.
Experimental Section
4-Phenylmorpholine (Table 2, Entry 1).
An oven-dried 25 mL, one-necked, round-bottomed flask equipped
with a Teflon-coated magnetic stirbar is maintained under an inert
atmosphere of argon and charged with zinc chloride [0.3748 g, 2.75
mmol, dried 12 h (<1 mm Hg, 150 °C)] and anhyd THF (5.0 mL).
The solution is stirred at r.t. and a 1.0 M ethereal solution of phenyl-
magnesium bromide (0.55 mL, 0.55 mmol) is added via syringe in
one portion. The resulting suspension is stirred at r.t. for 15 min pri-
or to use (vide infra). An oven-dried 25 mL, one-necked, round-bot-
tomed flask equipped with a Teflon-coated magnetic stirbar is
maintained under an inert atmosphere of argon and charged with 4-
benzoyloxy-morpholine (0.1035 g, 0.50 mmol), bis(triphenylphos-
phine)nickel(II) chloride (0.0082 g, 0.0125 mmol), and anhyd THF
(5.0 mL). The suspension is stirred at r.t. and the previously gener-
ated organozinc halide suspension (vide supra) is added via cannula
in one portion. The resulting suspension is stirred at r.t. for 10 min.
Then, Et2O (15 mL) is added and the reaction mixture is transferred
to a 125 mL separatory funnel. The reaction mixture is washed with
three 10 mL portions of sat. aq NaHCO3 solution, the aqueous layer
is extracted with three 10 mL portions of CH2Cl2, and the organic
fractions are combined and concentrated by rotary evaporation. The
resulting residue is dissolved in Et2O (10 mL) and extracted with
three 10 mL portions of 10% aq HCl solution The aqueous extracts
are basified with 40 mL of 10% aq NaOH solution, and extracted
with three 10 mL portions of CH2Cl2. The organic fraction is
washed with 15 mL of brine, dried over Na2SO4, and concentrated
by rotary evaporation, to yield 0.0708 g (87%) of 4-phenylmor-
(5) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219,
131.
(6) Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
6054.
(7) Tasler, S.; Lipshutz, B. H. J. Org. Chem. 2002, 68, 1190.
(8) Desmarets, C.; Schneider, R.; Fort, Y. J. Org. Chem. 2002,
67, 3029.
(9) Erdik, E.; Ay, M. Chem. Rev. 1989, 89, 1947.
(10) Greck, C.; Genêt, J. P. Synlett 1997, 741.
(11) Dembech, P.; Seconi, G.; Ricci, A. Chem.–Eur. J. 2000, 6,
1281.
(12) Erdik, E.; Daskapan, T. J. Chem. Soc., Perkin Trans. 1 1999,
3139.
(13) Narasaka, K. Pure Appl. Chem. 2002, 74, 143.
(14) Velarde-Ortiz, R.; Guijarro, A.; Rieke, R. D. Tetrahedron
Lett. 1998, 39, 9157.
(15) Higher yields were obtained with this protocol relative to
that using 1 equiv of ZnCl2 (or ZnBr2).
(16) Sapountzis, I.; Knochel, P. J. Am. Chem. Soc. 2002, 124,
9390.
(17) Sapountzis, I.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43,
897.
(18) 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.
1
(19) Berman, A. M.; Johnson, J. S. J. Org. Chem. 2005, 70, 364.
pholine as a white solid of ≥ 95% purity as judged by H NMR
spectroscopy and GLC analysis.
Synlett 2005, No. 11, 1799–1801 © Thieme Stuttgart · New York