Zinc trimethylsilylamide as a mild ammonia equivalent and base for the amination of aryl halides and triflates

Article abstract of DOI:10.1021/ol050141b

(Chemical Equation Presented) We report that Zn[N(SiMe₃) ₂]₂ is a mild ammonia equivalent and base for the palladium-catalyzed amination of aryl halides and triflates. In contrast to LiN(SiMe₃)₂, the combination of Zn[N(SiMe ₃)₂]₂ and LiCl coupled with aryl halides and triflates containing base-sensitive functionality in high yields. In addition, aryl bromides coupled with aryl and alkylamines with the combination of Zn[N(SiMe₃)₂]₂ and LiCl as base. These aminations occurred without racemization of the enolizable stereocenter of an optically active ester.

Full text of DOI:10.1021/ol050141b

ORGANIC
LETTERS
2005
Vol. 7, No. 6
1169-1172
Zinc Trimethylsilylamide as a Mild
Ammonia Equivalent and Base for the
Amination of Aryl Halides and Triflates
Dae-Yon Lee and John F. Hartwig*
Department of Chemistry, Yale UniVersity, P.O. Box 208107,
New HaVen, Connecticut 6520-8107
john.hartwig@yale.edu
Received January 21, 2005
ABSTRACT
We report that Zn[N(SiMe3)2]2 is a mild ammonia equivalent and base for the palladium-catalyzed amination of aryl halides and triflates. In
contrast to LiN(SiMe3)2, the combination of Zn[N(SiMe3)2]2 and LiCl coupled with aryl halides and triflates containing base-sensitive functionality
in high yields. In addition, aryl bromides coupled with aryl and alkylamines with the combination of Zn[N(SiMe3)2]2 and LiCl as base. These
aminations occurred without racemization of the enolizable stereocenter of an optically active ester.
Palladium-catalyzed C-N bond formation has developed into
a general and efficient way to prepare arylamines from aryl
halides.1-5 While a variety of amines and other nitrogen
nucleophiles undergo this reaction in the presence of base,
ammonia does not form primary arylamines. Thus, reactions
have been conducted with ammonia surrogates, such as
allylamine6 or benzophenone imine.7,8 Recently, we reported
the synthesis of primary arylamines catalyzed by Pd(dba)2
and P(t-Bu)3 with lithium bis(trimethylsilyl)amide (LiN-
(SiMe3)2) as an ammonia equivalent. This reagent is inex-
pensive, and the aryl silylamine is easily deprotected.9
Buchwald reported a similar coupling with catalysts contain-
ing 2-phosphinobiphenyl ligands.10 While LiN(SiMe3)2 coupled
with a range of aryl halides under mild conditions with low
catalyst loading, the strong basicity of the reagent prevented
reactions with aryl halides bearing base-sensitive functional
groups or enolizable hydrogens.9,10
Recently, we developed conditions for the coupling of zinc
enolates with aryl halides.11 The functional group compat-
ability of the R-arylation of carbonyl compounds with zinc
enolates was greater than that with alkali metal enolates.12
With this result in mind, we sought conditions to use zinc
(1) (a) Hartwig, J. F. Handbook of Organopalladium Chemistry for
Organic Synthesis 2002, 1, 1051. (b) Hartwig, J. F. In Modern Arene
Chemistry; Austruc, C., Ed.; Wiley-VCH: Weinheim, 2002; pp 107-168.
(c) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131. (d)
Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
(2) (a) Stauffer, S. R.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 6977.
(b) Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem. 2003,
68, 2861. (c) Kuwano, R.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem.
2002, 67, 6479. (d) Stambuli, J. P.; Kuwano, R.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2002, 41, 4746. (e) Kataoka, N.; Shelby, Q.; Stambuli, J.
P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553. (f) Stauffer, S. R.; Lee, S.;
Stambuli, J. P.; Hauck, S. I.; Hartwig, J. F. Org. Lett. 2000, 2, 1423.
(3) (a) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653. (b) Zim, D.; Buchwald,
S. L. Org. Lett. 2003, 5, 2413. (c) Strieter, E. R.; Blackmond, D. G.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 13978. (d) Ali, M. H.;
Buchwald, S. L. J. Org. Chem. 2001, 66, 2560.
(4) (a) Viciu, M. S.; Kelly, R. A., III; Stevens, E. D.; Naud, F.; Studer,
M.; Nolan, S. P. Org. Lett. 2003, 5, 1479. (b) Viciu, M. S.; Germaneau, R.
F.; Navarro-Fernandez, O.; Stevens, E. D.; Nolan, S. P. Organometallics
2002, 21, 5470. (c) Viciu, M. S.; Kissling, R. M.; Stevens, E. D.; Nolan, S.
P. Org. Lett. 2002, 4, 2229.
(5) (a) Rataboul, F.; Zapf, A.; Jackstell, R.; Harkal, S.; Riermeier, T.;
Monsees, A.; Dingerdissen, U.; Beller, M. Chem. Eur. J. 2004, 10, 2983.
(b) Loones, K. T. J.; Maes, B. U. W.; Dommisse, R. A.; Lemiere, G. L. F.
Chem. Commun. 2004, 2466. (c) Smith, C. J.; Early, T. R.; Holmes, A. B.;
Shute, R. E. Chem. Commun. 2004, 1976. (d) Urgaonkar, S.; Xu, J.-H.;
Verkade, J. G. J. Org. Chem. 2003, 68, 8416.
(6) Jaime-Figueroa, S.; Liu, Y.; Muchowski, J. M.; Putman, D. G.
Tetrahedron Lett. 1998, 39, 1313.
(7) Mann, G.; Hartwig, J. F.; Driver, M. S.; Fernandez-Rivas, C. J. Am.
Chem. Soc. 1998, 120, 827.
(8) (a) Wolfe, J. P.; Ahman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald,
S. L. Tetrahedron Lett. 1997, 38, 6367. (b) Cioffi, C. L.; Berlin, M. L.;
Herr, R. J. Synlett 2004, 841.
(9) Lee, S.; Jorgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3, 2729.
(10) Huang, X.; Buchwald, S. L. Org. Lett. 2001, 3, 3417.
(11) Hama, T.; Liu, X.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc.
2003, 125, 11176.
10.1021/ol050141b CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/24/2005

Scheme 1
Table 1. Coupling of Aryl Halides and LiN(SiMe3)2 in the
Presence of ZnCl2
entry
R
X
T (°C) time (h) isolated yield (%)
1
2b
3
4
5
6
7
8
9
4-NO2
Br
rta
50
rt
rt
rt
2
8
2
1
3
2
4
12
18
95
90
91
90
90
91
92
80
(71)c
3-NO2
4-CN
4-CO2Et
Br
Br
Br
bis(trimethylsilyl)amides and perhaps zinc aryl and alkyl-
amides to improve the tolerance of the coupling to form C-N
bonds to sensitive functionality. We report the development
of conditions to conduct the coupling of aryl halides and
triflates with zinc silylamide as reagent and the coupling of
aryl and alkylamines with zinc silylamide as base. These
conditions increase the scope of the synthesis of primary
arylamines and help alleviate racemization of enolizable
stereocenters during coupling of alkyl and arylamines.
4-CO2Me Br
rt
4-NO2
4-CN
4-Me
Cl
50
50
rt
Br
a 25 °C. b The amount of Pd(dba)2 was 2 mol %. c Conversion.
We first investigated the potential of zinc bis(hexameth-
yldisilazide) as a reagent for the synthesis of primary
arylamines. To do so, we conducted reactions with a series
of ligands in different media (see the Supporting Informa-
tion). In the presence of Pd(dba)2 and P(t-Bu)3 as catalyst,
the reaction of Zn[N(SiMe3)2]2 with aryl bromides in DMF
formed the corresponding silylamine derivatives upon mild
heating. The primary arylamines were isolated after hydroly-
sis with acid (Scheme 1). Under these conditions, the reaction
proceeded with aryl halides possessing functionality, such
as cyano and nitro groups, that were incompatible with LiN-
(SiMe3)2 as reagent.
Although these results showed that the use of Zn-
[N(SiMe3)2]2 could create a mild route to primary arylamines,
reactions of Zn[N(SiMe3)2]2 required higher concentrations
of catalyst or longer reaction times than those of LiN-
(SiMe3)2.8 Fortunately, reactions of the combination of LiN-
(SiMe3)2 and ZnCl2, which we examined originally as a
means to generate Zn[N(SiMe3)2]2 in situ, revealed two sets
of conditions to conduct the couplings at room temperature
with less catalyst than the reactions of Zn[N(SiMe3)2]2 alone.
The first set of conditions involves the reaction of a zinc
silylamide generated in situ by combining LiN(SiMe3)2 and
ZnCl2 prior to the addition of the aryl halide. The results of
reactions under these conditions (Table 1) show that the
reaction is suitable for the conversion of a series of base-
sensitive aryl halides to the corresponding amines. The
reaction of LiN(SiMe3)2 and ZnCl2 with 1-bromo-4-nitroben-
zene (entry 1 and 2), 1-bromo-3-nitrobenzene (entry 3),
4-bromobenzonitrile (entry 4), and methyl and ethyl 4-bro-
mobenzoate (entry 5 and 6) occurred in excellent yield.
These reactions are easily executed without a drybox
because the silylamide and ZnCl2 are commercially available
as THF solutions. Further, one can conveniently store a stock
solution of LiN(SiMe3)2 and ZnCl2 in THF (see the Sup-
porting Information). The reaction described in entry 1 of
Table 1 conducted with a stock solution of LiN(SiMe3)2 and
ZnCl2 in THF stored for 2 days formed 4-nitroaniline in a
87% isolated yield.
Although the conditions of the reactions in Table 1 are
convenient and convert base-sensitive, activated aryl halides
to the corresponding anilines, the rates of reactions of
unactivated aryl halides were slower than desired. For
example, 4-bromotoluene reacted with LiN(SiMe3)2 and
ZnCl2 (entry 9 of Table 1) to convert only 71% of the aryl
bromide after 18 h. By comparison, the reaction of LiN-
(SiMe3)2 was complete in only 6 h. Thus, we sought
conditions to further increase the reactivity of the zinc
silylamides.
For reasons we do not yet understand, the palladium-
catalyzed reactions of aryl halides with the combination of
Zn[N(SiMe3)2]2 and LiCl, which contains the same stoichio-
metry as LiN(SiMe3)2 and ZnCl2, occurred faster than those
of LiN(SiMe3)2 and ZnCl2. The functional group tolerance
of the reactions of Zn[N(SiMe3)2]2 and LiCl remained as high
as that of the reactions of Zn[N(SiMe3)2]2 alone or that of
the reactions of the combination of LiN(SiMe3)2 and ZnCl2.
The reactions of Zn[N(SiMe3)2]2 and LiCl occurred in the
highly polar DMF and the less polar THF, but reactions in
THF were faster than those in DMF. The reaction of
4-bromobenzonitrile with Zn[N(SiMe3)2]2 and added LiCl
in DMF was 90% complete (87% yield by GC) in 12 h at
50 °C with 2 mol % catalyst, while the same reaction in
THF was complete in only 45 min at 50 °C and within 3 h
at ambient temperature.
Examples of the reaction of Zn[N(SiMe3)2]2 and LiCl with
electron-rich and electron-poor aryl bromides to form the
corresponding primary arylamines are shown in Table 2.
These reactions occurred in high yield in the presence of
Pd(dba)2 and P(t-Bu)3 as catalyst. Like those of LiN(SiMe3)2,
these reactions did not occur with ortho-substituted aryl
halides, due to the bulk of the reagent. However, bromoare-
nes that did not react with the highly basic LiN(SiMe3)2,
such as bromobenzonitrile and bromonitrobenzene (entries
1 and 2), reacted in high yield with Zn[N(SiMe3)2] and LiCl.
(12) (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
(b) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473.
1170
Org. Lett., Vol. 7, No. 6, 2005

Scheme 2
Table 2. Coupling of Aryl Halides and Zn[N(SiMe3)2]2 in the
Presence of LiCl Using Pd(dba)2 and P(t-Bu)3
a
monodentate phosphine14 led us to test the coupling of aryl
triflates with silylamides in the presence of added halides
(Scheme 2). The reaction of phenyl triflate with Zn-
[N(SiMe3)2]2 without any added halide formed only 5% of
the arylsilylamine after 12 h at 85 °C. However, the same
reaction conducted with added Bu4NBr was complete in 6
h; 94% yield of aniline was isolated after hydrolysis. The
same reaction with added LiCl occurred in high yield after
12 h. Because LiCl accelerated the reactions of Zn-
[N(SiMe3)2]2 (vide supra) and Bu4NBr accelerated the
addition of PhOTf,14 we tested reactions with a combination
of the two salts. Although the ions must exchange in solution,
the reactions with the combination of salts were compete in
a shorter 3 h.
Table 3. Coupling of Aryl Triflates and Zn[N(SiMe3)2]2 in the
Presence of Halide Salts (Scheme 2)a
isolated
entry
R )
p-tolyl
additive
time (h) yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Bu4NBr (2 equiv)
LiCl/Bu4NBr (1 equiv)
LiBr (2 equiv)
Bu4NBr (2 equiv)
LiCl/Bu4NBr (1equiv)
6
4
97
97
89
90
91
92
95
93
89
85
90
91
87
70
12
9
6
12
9
3
m-tolyl
2-naphthyl LiBr (2 equiv)
Bu4NBr (2 equiv)
a Reactions were conducted with 0.50 mmol of ArX, 0.30 mmol of
Zn[N(SiMe3)2]2, 0.30 mmol of LiCl, and a 1:1 ratio of Pd/L in 1.0 mL of
THF.
LiCl/Bu4NBr (1 equiv)
4-MeOC6H4 Bu4NBr (2 equiv)
3-MeOC6H4 Bu4NBr (2 equiv)
LiCl/Bu4NBr (1 equiv)
3-CF3C6H4 Bu4NBr (2 equiv)
4-CNC6H4
3-CNC6H4
24
24
24
6
9
12
Although bromoacetophenone did not react, 4-bromoprio-
piophenone did react in high yield without formation of
products from enolate coupling (entry 10). Thus, couplings
of the zinc amides can occur with substrates containing
slightly hindered enolizable hydrogens. Electron-neutral
bromotoluene and electron-rich bromoanisole also reacted
in high yield.
Bu4NBr (2 equiv)
Bu4NBr (2 equiv)
a
Reactions were conducted under the same conditions as those in
Scheme 2: ArOTf (0.50 mmol), Zn[N(SiMe3)2]2 (0.30 mmol), Pd(dba)2
(0.015 mmol), P(t-Bu)3 (0.015 mmol), DMF (1.0 mL), and additives.
Table 3 shows the results from reactions of various aryl
triflates with Zn[N(SiMe3)2]2 in the presence of added
halides. In most cases, the highest yields were obtained from
reactions conducted with a mixture of LiCl and Bu4NBr, but
good yields were also obtained from reactions with LiCl or
Bu4NBr alone. Aryl triflates with electron-withdrawing
groups, such as trifluoromethyl or cyano, decomposed in the
reactions conducted with added LiCl, but high yields were
obtained from reactions of these aryl triflates with added Bu4-
NBr.
The coupling of aryl triflates with LiN(SiMe3)2 in the
presence of any catalyst and the coupling of aryl triflates
with amines in the presence of palladium catalysts containing
tri-tert-butylphosphine have not been reported.13 The ac-
celerating affect of added halides on the oxidative addition
of phenyl triflate to a palladium(0) complex with a hindered
(13) (a) Louie, J.; Driver, M. S.; Hamann, B. C.; Hartwig, J. F. J. Org.
Chem. 1997, 62, 1268. (b) Ahman, J.; Buchwald, S. L. Tetrahedron Lett.
1997, 38, 6363. (c) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1158. (d) Guari, Y.; Van
Strijdonck, G. P. F.; Boele, M. D. K.; Reek, J. N. H.; Kamer, P. C. J.; Van
Leeuwen, P. W. N. M. Chem. Eur. J. 2001, 7, 475.
(14) Roy, A. H.; Hartwig, J. F. Organometallics 2004, 23, 194.
Org. Lett., Vol. 7, No. 6, 2005
1171

Scheme 3
Table 4. Amination of Bromobenzene with Amines in the
Presence of Chiral Ester
recovered
yield of naproxen
amine
(%)
ester (%)
(% ee)
entry
1a
amine
PhNH2
base (equiv)
time
The coupling of aryl halides with basic reagents racemizes
or epimerizes enolizable stereocenters. To determine if the
zinc amides reduce the level of this racemization, we
investigated the coupling of Zn[N(SiMe3)2]2 in the presence
of an optically active ester. For simplicity, we conducted
the reaction of bromobenzene in the presence of the methyl
ester of (S)-naproxen (Scheme 3). This reaction formed
aniline in 85% yield without significantly racemizing the
ester. The chiral ester was recovered (86%) in 98% enan-
tiomeric excess. When the same reaction was conducted with
LiN(SiMe3)2, the naproxen derivative was obtained in only
2% ee, and the aniline was formed in only 58% yield.
In addition to serving as a surrogate for ammonia, one
could envision Zn[N(SiMe3)2]2 as a weak base or a source
of zinc amide for the coupling of amines with aryl halides.
We have not investigated these reactions in detail, but
preliminary data show that reactions of amines can be
conducted with Zn[N(SiMe3)2]2 under conditions that are less
basic than those of reactions with other bases that induce
the C-N coupling chemistry. Both aromatic and aliphatic
amines couple under these conditions without competing
transfer of the N(SiMe3)2 unit, and this selectivity suggests
that this method may prove to be general.
The reaction of bromobenzene with aniline in the presence
of 0.6 equiv of Zn[N(SiMe3)2]2 and 2 mol % Pd(dba)2 and
P(t-Bu)3 in THF for 20 min at 85 °C or 2 h at 50 °C formed
the corresponding arylamine in 88-91% yield. To determine
the relative basicity of these conditions to those with
alkoxide, carbonate and phosphate bases, we conducted
related reactions of bromobenzene with aniline, morpholine
and dibutylamine in the presence of the methyl ester of (S)-
naproxen (Table 4).
The reaction of bromobenzene with aniline in the presence
of alkoxide or Cs2CO3 as base at 85 °C led to nearly complete
racemization of the ester. In contrast, the reaction of aniline
with Zn[N(SiMe3)2]2 or with K3PO4 as base at 85 °C occurred
in good yields and with nearly complete retention of the
stereochemistry of the ester. Although Zn[N(SiMe3)2]2 is
more expensive than K3PO4, the greater solubility of the zinc
silylamide makes it suitable for assembly of reactions with
stock solutions.
Zn[N(SiMe3)2]2 20 min
(0.6)
K3PO4 (2.5)
Cs2CO3 (2.5)
NaOtBu (1.2) 2 h
91
98 (99% ee)
2
3
4b
5a
2 h
2 h
99
92
32
87
98 (97% ee)
90 (25% ee)
63 (2% ee)
95 (98% ee)
morpholine Zn[N(SiMe3)2]2 6 h
(0.6)
6
7
K3PO4 (2.5)
Cs2CO3 (2.5)
Zn[N(SiMe3)2]2 12 h
(0.6)
K3PO4 (2.5)
12 h
18 h
87
87
78
98 (87% ee)
76 (6% ee)
88 (97% ee)
8a,b,c Bu2NH
9c
10
12 h
12 h
90
90
92 (88% ee)
93 (27% ee)
Cs2CO3 (2.5)
a LiCl (0.6 equiv) was added. b The reaction was conducted at 50 °C.
c The reaction was conducted with 3 mol % catalyst.
measurably racemized the ester. In contrast, the reaction with
Zn[N(SiMe3)2]2 as base formed the coupled product in good
yield at either 50 or 80 °C, and at either temperature the
naproxen derivative was recovered in high ee. The naproxen
was recovered in 98% ee from the reaction of morpholine
at 50 or 85 °C, and in 97% ee at 50 °C or 94% ee at 85 °C
from the reaction of dibutylamine.
Thus, we have shown that zinc bis(hexamethyldisilazide)
is a mild ammonia surrogate and base for the amination of
aryl halides. With Zn[N(SiMe3)2]2 and added halide, the
scope of substrates that undergo reaction to form silyl-
protected anilines has been broadened to include aryl halides
with base-sensitive functional groups and enolizable hydro-
gens. Further, the coupling of silylamides with aryl triflates
occurred for the first time. Finally, we showed that the
combination of Zn[N(SiMe3)2]2 and added halide is mild
enough as a base to allow coupling of aryl and alkylamines
with aryl halides with minimal racemization of an additive
with an enolizable stereocenter. Further studies on the scope
of the reactions of silylamides are in progress.
Acknowledgment. We thank NIH-NIGMS (55382) for
support of this work. D.-Y.L. thanks the KOSEF for a
postdoctoral fellowship. We also thank Boehringer Ingelheim
for an unrestricted gift and Johnson-Matthey for palladium.
The reations of alkylamines in the presence of the different
bases further distinguished reactions with the different bases
(Table 4). The reaction of PhBr with morpholine or dibu-
tylamine with the carbonate base at 85 °C formed the coupled
product in good yield, but almost completely racemized the
ester. The same reactions conducted with K3PO4 base also
Supporting Information Available: Experimental details
and spectroscopic data of compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL050141B
1172
Org. Lett., Vol. 7, No. 6, 2005