Room-temperature Pd-catalyzed amidation of aryl bromides using tert-butyl carbamate

Article abstract of DOI:10.1021/jo9004537

(Chemical Equation Presented) The scope of Pd-catalyzed synthesis of N-Boc-protected anilines from aryl bromides and commercially available tertbutyl carbamate is described. For the first time, this process can be conducted at room temperature (17-22°C) u

Full text of DOI:10.1021/jo9004537

Hartwig5 and Buchwald7 have reported catalyst systems that
support use of ammonia in the Pd-catalyzed conversion of aryl
halides to anilines. We also recently reported mild conditions
for the Pd-catalyzed conversion of aryl bromides to anilines
using benzophenone imine as the ammonia equivalent.2 The use
of benzophenone imine, however, generates an intermediate
ketimine that does not provide a convenient protecting group
for the aniline.
Room-Temperature Pd-Catalyzed Amidation of
Aryl Bromides Using tert-Butyl Carbamate
Swapna Bhagwanth,† Alex G. Waterson,
George M. Adjabeng, and Keith R. Hornberger*,§
Department of Medicinal Chemistry, Cancer Research,
Oncology R&D, GlaxoSmithKline, Research Triangle Park,
North Carolina 27709
During the course of our medicinal chemistry efforts around
an oncology target, it became desirable to perform a Pd-
catalyzed amination or amidation of an aryl bromide that directly
delivered an ammonia equivalent in a conveniently protected
form. Nearly all of the published ammonia equivalents cannot
fulfill this criterion, with one notable exception. The tert-
butyloxycarbonyl (Boc) group is a convenient and robust amine
protecting group, and there are a few examples of tert-butyl
carbamate being used as the ammonia equivalent in Cu-8 and
Pd-catalyzed9-13 amidations. In 1999, while reporting room-
temperature amination of aryl bromides using tri-tert-butylphos-
phine as ligand, Hartwig also first reported a few examples of
Pd-catalyzed amidation of aryl bromides using tert-butyl car-
bamate.9 These reactions were conducted at 100 °C and
employed sodium phenoxide as the base. Xantphos10,12,13 or
tri-tert-butylphosphine9,11 are frequently encountered as ligands
to effect this conversion, generally at elevated temperatures. Two
exceptions are a single conversion of an activated aryl bromide
at 45 °C12 and a few examples using a different carbamate (Cbz-
NH2) at 45 °C.10 As we were concomitantly pursuing milder
conditions for Pd-catalyzed aminations with benzophenone
imine, we wondered if similar conditions might be employed
to deliver a milder Pd-catalyzed amidation of aryl bromides
using tert-butyl carbamate. We now report the first reaction
conditions for amidations of aryl bromides with tert-butyl
carbamate at room temperature.
khornberger@osip.com
ReceiVed February 27, 2009
The scope of Pd-catalyzed synthesis of N-Boc-protected
anilines from aryl bromides and commercially available tert-
butyl carbamate is described. For the first time, this process
can be conducted at room temperature (17-22 °C) using a
combination of Pd2dba3 · CHCl3 and a monodentate ligand,
tert-butyl X-Phos. Use of sodium tert-butoxide is crucial to
the success of the reaction, which proceeds in 43-83% yield.
Pd-catalyzed conversion of aryl halides and their equivalents
to primary anilines traditionally incorporates an ammonia
equivalent.1 Benzophenone imine,1,2 (di)allyl amine,3 lithium
bis(trimethylsilyl)amide,4 and lithium amide5 have all been
successfully exploited to affect this conversion. Although general
scope has been established with these ammonia equivalents, the
reaction conditions remain relatively harsh because of high
temperatures and/or the use of strong bases. An exception is
the use of zinc bis(hexamethyldisilazide),6 which can be used
to convert actiVated aryl bromides to anilines at room temper-
ature. In this case, however, an air-sensitive ligand, tri-tert-butyl
phosphine, is required for the transformation. Recently, both
The reaction optimization using tert-butyl carbamate was
conducted concurrent to our benzophenone imine work. The
ligands surveyed (1-5) are shown in Figure 1, and Table 1
summarizes this study using conditions similar to our benzophe-
none imine ligand screen. 4-tert-Butylbromobenzene (6) with
tert-butyl carbamate (7) was used as the model substrate and
Pd2dba3 ·CHCl3 as the source of Pd(0). Conversion to the Boc-
(7) Surry, D. S.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 10354.
(8) (a) Minatti, A.; Buchwald, S. L. Org. Lett. 2008, 10, 2721. (b) McBriar,
M. D.; Guzik, H.; Shapiro, S.; Paruchova, J.; Xu, R.; Palani, A.; Clader, J. W.;
Cox, K.; Greenlee, W. J.; Hawes, B. E.; Kowalski, T. J.; O’Neill, K.; Spar,
B. D.; Weig, B.; Weston, D. J.; Farley, C.; Cook, J. J. Med. Chem. 2006, 49,
2294. (c) Hof, F.; Schar, M.; Scofield, D. M.; Fischer, F.; Diederich, F. HelV.
Chim. Acta 2005, 88, 2333. (d) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 7421.
† GlaxoSmithKline Summer Talent Identification Program intern from the
Department of Medicinal Chemistry, University of Minnesota, 308 Harvard St
SE, Minneapolis, MN 55455.
(9) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-
Roman, L. M. J. Org. Chem. 1999, 64, 5575.
§ Present Address: OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive,
Farmingdale, NY 11735.
(10) (a) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101. (b) Kuwahara,
A.; Nakano, K.; Nozaki, K. J. Org. Chem. 2005, 70, 413. (c) Willis, M. C.;
Brace, G. N.; Holmes, I. P. Angew. Chem., Int. Ed. 2005, 44, 403. (d) Wannberg,
J.; Dallinger, D.; Kappe, C. O.; Larhed, M. J. Comb. Chem. 2005, 7, 574. (e)
Shi, F.; Smith, M. R., III; Maleczka, R. E. Org. Lett. 2006, 8, 1411.
(11) Dallas, A. S.; Gothelf, K. V. J. Org. Chem. 2005, 70, 3321.
(12) Terazono, Y.; Lidell, P. A.; Garg, V.; Kodis, G.; Brune, A.; Hambourger,
M.; Moore, A. L.; Moore, T. A.; Gust, D. J. Porphyrins Phthalocyanines 2005,
9, 706.
(1) Wolfe, J. P.; Åhman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S. L.
Tetrahedron Lett. 1997, 38, 6367.
(2) Bhagwanth, S.; Adjabeng, G. M.; Hornberger, K. R. Tetrahedron. Lett.
2009, 50, 1582–1585.
(3) Jaime Figueroa, S.; Liu, Y.; Muchowski, J. M.; Putman, D. G. Tetrahe-
dron Lett. 1998, 39, 1313.
(4) (a) Lee, S.; Jorgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3, 2729. (b)
Huang, X.; Buchwald, S. L. Org. Lett. 2001, 3, 3417.
(5) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 10028.
(6) Lee, D-.Y.; Hartwig, J. F. Org. Lett. 2005, 7, 1169.
(13) Trabanco, A. A.; Vega, J. A.; Alejandro Fernandez, M. J. Org. Chem.
2007, 72, 8146.
4634 J. Org. Chem. 2009, 74, 4634–4637
10.1021/jo9004537 CCC: $40.75 2009 American Chemical Society
Published on Web 05/18/2009

afforded 100% conversion (76% yield) in 24 h (entry 8).
DME was unsuitable as solvent as its use led to incomplete
conversion and a lower (48%) yield (entry 9). Although
complete conversion was observed when polar solvents were
used (entries 10-12), the yields were found to be lower than
the average yields obtained with toluene (entry 8). Conver-
sions were also monitored in three control experiments: in
the absence of Pd2dba3 · CHCl3, ligand 5, and NaO-t-Bu,
respectively. No product was detected in any of the three
experiments.
The scope of this reaction is shown in Table 2. The
reactions were monitored by LC/MS until starting aryl
bromides were completely consumed. The N-Boc-protected
anilines were isolated in >95% purity by flash chromatog-
raphy. Electron-neutral (Table 2, entries 1, 13), electron-
withdrawing (entries 3-4, 12), and electron-donating (entries
7-10) bromobenzenes all gave moderate to good yields of
the corresponding N-Boc-anilines. Additionally, a protected
aldehyde (entry 2) was a competent substrate. Aryl bromides
containing a heterocycle (entry 11) or an enolizable ketone
(entry 12) afforded the desired products, albeit in more
modest yield. Although aryl bromides containing enolizable
hydrogens can undergo R-arylation under Pd-catalyzed cross-
coupling reaction conditions in the presence of sodium tert-
butoxide,15 no significant side product arising from R-ary-
lation was isolated for entry 12. Although not directly
observed, it can be reasonably hypothesized that polymeri-
zation16 and/or aldol product formation were significant side
reactions reducing the effective yield of the amidation
product. In a substrate containing both chloro and bromo
substituents (entry 3), reaction occurred selectively at the
bromo substitution. Also notable was the conversion of an
ortho-substituted substrate, 2-bromo-p-xylene, to the Boc-
protected p-xylidine in 67% yield (entry 13).
Methyl 4-bromobenzoate (entry 5) and 4-nitrobromoben-
zene (entry 6) decomposed under the reaction conditions.
Ester hydrolysis in the presence of the tert-butoxide anion17
is a possible decomposition pathway for methyl 4-bromoben-
zoate under the reaction conditions. It has been previously
hypothesized that direct reaction between a strong base and
substrates containing a nitro substituent can have a deleterious
effect on the desired Pd-catalyzed reaction.16 As noted above,
while electron-rich aryl bromides were amenable to this
transformation, increased Pd and ligand loads (5 and 15 mol
%, respectively) were required for the 4-N,N-dimethylamino
substrate (entry 10). Noteworthy, however, is that this
particular reaction with tert-butyl carbamate proceeds faster
than when conducted under the benzophenone imine protocol2
(33 h vs 7 d). The 3-methoxy (entry 8) and 3-N,N-
dimethylamino (entry 9) substrates also gave higher yields
with tert-butyl carbamate than with benzophenone imine.
There are some similarities of Pd-catalyzed amidations
using tert-butyl carbamate and our previously reported
reactions using benzophenone imine.2 The choice of ligand
(5) for a successful reaction at low temperature with both
ammonia equivalents is the same. Ligand 5, the tert-butyl
analogue of X-Phos, appears to provide the precise steric
FIGURE 1. Ligands surveyed in optimization.
TABLE 1. Optimization of tert-Butyl Carbamate as Ammonia
Equivalenta
conversion by
entry ligand
base
solvent
time (h)
LC/MSb (%)
1c
2d
3
1
2
3
4
4
5
5
5
5
5
5
5
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
K3PO4
PhMe
PhMe
PhMe
PhMe
PhMe
DME
PhMe
PhMe
DME
DMF
THF
24
22
22
48
48
24
24
24
41
28
28
28
0
0
0
0
(0)
4
5e
6f,g
7f
0
0
K3PO4
8
9
10
11
12
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
100 (76)
(48)
100 (33)
100 (65)
100 (63)
NaO-t-Bu 1,4-dioxane
a Reaction conditions: 1.3 mmol of substrate, 1.2 equiv of 7, 1.4
equiv of NaOtBu or 2.5 equiv of K3PO4, 3 mol % of Pd2(dba)3 ·CHCl3,
9 mol % of ligand, 0.25 M in solvent, room temperature (17-22 °C).
b Values in parentheses indicate yield. c 1:1 Pd/ligand; 3 mol % of
Pd2dba3 ·CHCl3, 6 mol % of ligand 1 d 2 mol % of Pd2dba3 ·CHCl3, 6
mol % of ligand 5. e Substrate: 4-bromobenzonitrile. f Inorganic bases
were ground to a fine powder using a mortar and pestle. g Room
temperature to 30 °C.
protected aniline (8) was monitored by LC/MS. Keeping with
our goal, all reactions were conducted at room temperature.
No product was detected in the presence of tri-tert-
butylphosphine (1), dppf (2), or Xantphos (3) as ligand after
22-24 h at room temperature (entries 1-3). Ligand 4, which
has recently been shown to form one of the most active Pd
complexes for aminations,14 was also unable to effect the
conversion despite increased reaction times (entry 4), even
when employing a more activated aryl bromide substrate
(entry 5). The combination of ligand 5, potassium phosphate
(K3PO4) as base, and 1,2-dimethoxyethane (DME) or toluene
as solvent, which was successful for amination using ben-
zophenone imine at 30 °C,2 also failed to form the desired
product (entries 6 and 7). The combination of ligand 5 with
sodium tert-butoxide as base and toluene as solvent, however,
(15) (a) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473.
(b) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000,
122, 1360.
(14) (a) Fors, B. P.; Krattiger, P.; Streiter, E.; Buchwald, S. L. Org. Lett.
2008, 10, 3505. (b) Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2007, 129, 13001.
(16) Lee, S.; Jorgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3, 2729.
(17) (a) Chang, F. C.; Wood, N. F. Tetrahedron Lett. 1964, 5, 2969. (b)
Gassman, P. G.; Schenk, W. N. J. Org. Chem. 1977, 42, 918.
J. Org. Chem. Vol. 74, No. 12, 2009 4635

TABLE 2. General Scope of Amidations with tert-Butyl
Carbamate Using Pd2dba3 ·CHCl3 and Ligand 5a
in the Pd-catalyzed amidations of aryl chlorides using various
amides/lactams, where it was hypothesized that the additional
o-methyl substituent next to the phosphino group in 4 would
function to inhibit formation of the κ2-amidate complexes.14b
Such complexes have a negative impact on catalytic turnover
since they prevent or reduce the rate of reductive elimina-
tion.18
We have demonstrated the reaction scope of room tem-
perature Pd-catalyzed amidations of aryl bromides using tert-
butyl carbamate. The Boc group in the reaction products can
be conveniently hydrolyzed under acidic conditions to reveal
the free primary aniline. A number of practical advantages
are inherent in this method, namely: (1) the reaction is
conducted at room temperature, an important advantage to
the industrial chemist; (2) a conveniently protected aniline
is delivered; (3) no glovebox or Schlenk techniques are
necessary; (4) the precatalyst and ligand are air stable and
commercially available; and (5) the ammonia equivalent, tert-
butyl carbamate, is a commercially available crystalline solid.
A remaining limitation of the method, even with deployment
of state-of-the-art catalyst/ligand combinations, is the con-
tinued need for a strong base. In an industrial chemistry
setting, however, the use of a strong base coupled with a
reduction in temperature may often be preferred over a
weaker base at elevated temperature. Regardless, it is hoped
that the present exploration of the capabilities and limitations
of current catalyst systems will help to inspire the design of
new catalysts with expanded reactivity.
Experimental Section
Representative Procedure: tert-Butyl N-(4-Methoxyphenyl)-
carbamate (Table 2, Entry 7). An air-dried glass reaction vessel
equipped with a magnetic stir bar was charged with, in order:
Pd2(dba)3 · CHCl3 (40 mg, 0.039 mmol), ligand 5 (51 mg, 0.117
mmol), NaO-t-Bu (175 mg, 1.82 mmol), tert-butyl carbamate
(183 mg, 1.56 mmol), and 4-bromoanisole (1.3 mmol). Anhy-
drous toluene (5.2 mL) was added, and the resultant solution
was degassed using one cycle of vacuum and nitrogen purge.
The reaction mixture was stirred at room temperature under
nitrogen. Once the reaction was judged complete by LC/MS and
TLC (30 h), it was diluted with 20 volumes of diethyl ether and
filtered through a pad of Celite. The filtrate was concentrated in
vacuo. The residue was purified by flash chromatography
(2-45% ethyl acetate/hexanes) to afford 220 mg (76%) of N-(4-
methoxyphenyl)carbamate as a crystalline solid: LC/MS purity
>95%; 1H NMR (400 MHz, CDCl3) δ 7.28-7.26 (m, 2H),
6.85-6.83 (m, 2H), 6.38 (br s, 1H), 3.78 (s, 3H), 1.52 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 155.67, 153.14, 131.40, 120.54,
114.16, 80.20, 55.49, 28.35. The spectroscopic data (1H and 13
NMR) are in good agreement with reported values.19
C
a Reaction conditions: 1.3 mmol of substrate, 1.2 equiv of 7, 1.4
equiv of NaOtBu, 3 mol % of Pd2(dba)3 ·CHCl3, 9 mol % of ligand 5,
0.25 M in PhMe, room temperature. b Times are reported for complete
conversion of aryl bromide. c Reported yields are average of two runs.
d 2 mol % of Pd2(dba)3 ·CHCl3, 6 mol % of ligand 5. e 5 mol % of
Pd2(dba)3 ·CHCl3, 15 mol % of ligand 5.
The procedure followed for the reaction and reaction workup
were the same for all aryl bromides reported in Table 2 except
for Pd and ligand loading. All products in Table 2 except entry
9 (vide infra) are known compounds and were trivially identified
by comparison to literature spectroscopic data. The purity of all
compounds was determined by 13C NMR and LC/MS.
tert-Butyl [3-(dimethylamino)phenyl]carbamate (Table 2,
1
entry 9): H NMR (400 MHz, CDCl3) δ 7.14 (t, 1H, J ) 8.1
environment required for efficient amidation. Increasing
ligand bulk further (e.g., 4) or switching to bidentate ligands
(e.g., 2, 3) completely abolishes amidation activity at room
temperature. These observations suggest that fine stereoelec-
tronic tuning is particularly important in the case of weakly
nucleophilic, sterically bulky nitrogen nucleophiles. This
reactivity contrasts with observations by Buchwald et al.14
Hz), 6.89 (br. s, 1H), 6.63 (d, 1H, J ) 7.9 Hz), 6.43 (dd, 2H, J
) 8.1, 2.2 Hz), 2.95 (s, 6H), 1.53 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 152.7, 151.3, 139.2, 129.4, 107.6, 106.9, 102.7, 80.1,
(18) Fujita, K.-i.; Yamashita, M.; Puschman, F.; Alvarez-Falcon, M. M.;
Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 9044.
(19) Varala, R.; Nuvula, S.; Adapa, S. R. J. Org. Chem. 2006, 71, 8283.
4636 J. Org. Chem. Vol. 74, No. 12, 2009

40.6, 28.4; HRMS (ESI) m/z calcd for C13H21N2O2 [M + H]+
237.1603, found 237.1598.
Lochansky and Zachary Giles for assistance with the LC/
MS instrumentation.
Acknowledgment. This work was carried out as the
summer internship project of S.B. (University of Minnesota)
as part of the GlaxoSmithKline Summer Talent Identification
Program. S.B. thanks Prof. R. L. Johnson (Department of
Medicinal Chemistry, University of Minnesota) for the
opportunity to pursue this internship. We also thank Matthew
Supporting Information Available: Experimental proce-
dures and spectral data for all compounds. This material is
available free of charge via the Internet at http://pubs.
acs.org.
JO9004537
J. Org. Chem. Vol. 74, No. 12, 2009 4637