Mild conditions for Pd-catalyzed conversion of aryl bromides to primary anilines using benzophenone imine

Article abstract of DOI:10.1016/j.tetlet.2009.01.091

Mild (30 °C) and efficient (53-91%) conversion of aryl bromides to primary anilines using a Pd-catalyzed amination strategy is described. A detailed account of the ligand optimization, base and solvent selection, and general substrate scope of this methodology is described herein.

Full text of DOI:10.1016/j.tetlet.2009.01.091

Tetrahedron Letters 50 (2009) 1582–1585
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Mild conditions for Pd-catalyzed conversion of aryl bromides to primary
anilines using benzophenone imine
*
Swapna Bhagwanth , George M. Adjabeng, Keith R. Hornberger
Department of Medicinal Chemistry, Cancer Research, Oncology R&D, GlaxoSmithKline, Research Triangle Park, NC 27709, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Mild (30 °C) and efficient (53–91%) conversion of aryl bromides to primary anilines using a Pd-catalyzed
amination strategy is described. A detailed account of the ligand optimization, base and solvent selection,
and general substrate scope of this methodology is described herein.
Received 12 January 2009
Revised 14 January 2009
Accepted 15 January 2009
Available online 23 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Amination
Palladium-catalyzed
Mild
Benzophenone imine
The area of palladium-catalyzed Caryl–N bond formation has re-
ceived increased attention in the last decade,1 particularly in
medicinal chemistry applications.2 The conversion of aryl halides
and their equivalents to primary aniline derivatives is a useful sub-
set of Pd-catalyzed amination reactions. There have been several
reports that utilize benzophenone imine,3 tert-butyl carbamate,4
lithium bis(trimethylsilyl)amide5, and lithium amide6 as ammonia
equivalents. In the last two years, Hartwig6 and Buchwald7 have
demonstrated the use of ammonia itself in the amination of aryl
halides. In 2005, Hartwig reported room-temperature aminations
of activated aryl bromides in the presence of in situ generated zinc
bis(hexamethyldisilylamide).8 While steady progress has been
made in the field, particularly in the area of atom economy, reac-
tion conditions remain relatively harsh, requiring strong bases
and/or elevated temperatures. Furthermore, despite the subse-
quent popularity of benzophenone imine as an ammonia equiva-
lent, to our knowledge, no systematic optimization of this
reaction has been reported since the initial disclosure. We set out
to explore the potential of this conversion to be conducted under
mild conditions, closer to room temperature, and in the presence
of a weak inorganic base.
as tri-tert-butylphosphine (Fig. 1, 19) and Xantphos (Fig. 1, 11), we
were interested in pursuing the use of monodentate biaryl ligands
reported by Buchwald9 and Beller10 for aminations and other mild
cross-coupling reactions. These bulky monophosphinobiaryl li-
gands form active and effective catalyst systems with different
Pd sources.11,12 Therefore, ligand selection (Fig. 1) for our screening
was based on commercial availability and literature precedent for
promoting amination of aryl halides in the presence of weak bases
or at lower temperatures.
Table 1 summarizes the ligand screen using standard literature
conditions3a (substrate 1, benzophenone imine 2, Pd2dba3ÁCHCl3 as
the pre-catalyst, sodium tert-butoxide as the base, toluene as sol-
vent). We set the initial temperature at 65 °C, with the intention
of repeating successful reactions at a lower temperature. Conver-
sion to product 3 was monitored by GC/MS. From this screening,
ligands 8, 10–12, and 18 (entries 5, 7–9, and 15) showed the high-
est GC conversions in the shortest times. In the case of ligand 12
(entry 9), the reaction was complete as determined by GC/MS in
<1 h. We then focused our screening on ligands 8, 10–12, and 18,
and lowered the temperature to room temperature. Ligand 12 (en-
try 20) gave complete GC conversion to product in just over 4 h. Li-
gand 18, which has recently shown to be outstanding in its Caryl-N
and Caryl–O-bond formation capability,13,14 gave no product at
room temperature (Table 1, entry 21).
Our first objective was to determine an efficacious combination
of ligand and Pd pre-catalyst. In addition to standard ligands such
Base optimization in the presence of ligand 12 at different tem-
peratures is shown in Table 2. Complete conversion was observed
with NaOtBu at 65 °C, 45 °C, and room temperature (Table 2, en-
tries 1–3). In the presence of weak, inorganic bases such as Cs2CO3,
KOAc, CsF, and K3PO4 (entries 4, 6–8), however, the reaction gave
poor conversions. K2CO3 (entry 5) was an exception, which
* Corresponding author at present address: OSI Pharmaceuticals, Inc., 1 Biosci-
ence Park Drive, Farmingdale, NY 11735 USA. Tel.: +1 631 962 0641; fax: +1 631
845 5671.
E-mail address: khornberger@osip.com (K.R. Hornberger).
GlaxoSmithKline Summer Talent Identification Program intern from the Depart-
ment of Medicinal Chemistry, University of Minnesota, 308 Harvard St. SE, Minne-
apolis, MN 55455 USA.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.091

S. Bhagwanth et al. / Tetrahedron Letters 50 (2009) 1582–1585
1583
iPr
P(Cy)2
P(tBu)2
N
Me
P(tBu)2
NMe2
P(Cy)2
N
iPr
iPr
P(Cy)2
8
7
4
6
5
iPr
P(tBu)2
P(Cy)2
N
N
iPr
iPr
P(tBu)2
MeO
MeO
O
O
P(tBu)2
P(tBu)2
PPh2
PPh2
9
10
13
iPr
11
12
iPr
iPr
P(tBu)2
(Cy)2P
N
N
Fe
PPh2
PPh2
iPr
Me
iPr
P(tBu)2
P(tBu)2
iPr iPr
14
Cl Pd Cl
N
Me
Me
17
15
16
Me
18
Cl
P
19
Figure 1. Ligands surveyed.
Table 2
Optimization of base and solventa
Table 1
Ligand optimization with benzophenone imine as ammonia equivalenta
Pd2dba3•(CHCl3),
Br
N
Ph
NH
Ph
ligand, base,
Pd2dba3•(CHCl3),
Br
N
Ph
NH
Ph
ligand, NaOtBu,
Ph
Ph
solvent/additive
Ph
Ph
3
2
Toluene
1
3
Entry Base (Additive)b
Temp
(°C)
Solvent
Time
(h)
GC Conversion
(%)
2
1
Entry
Ligand
Temp (°C)
Time (h)
GC conversion (%)
1
2
3
NaOtBu
NaOtBu
NaOtBu
Cs2CO3
K2CO3
KOAc
CsF
K3PO4
NEt3
DBU
DABCO
K3PO4/ 18-crown- 65
6
K3PO4/ 18-crown- rt to 45
6
K3PO4
K3PO4
K3PO4
K3PO4
65
45
rt
30
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
0.5
2.5
4.5
100
100
100
20
100
10
32
40
0
1
2
3
4
5
6
7
8
4
5
6
7
8
9
10
11
12
13
14
15
17
16
18
19
8
65
65
65
65
65
65
65
70
65
65
65
65
65
80
65
65
rtf
18
22
6.5
6
4.5
3
2
2
0.5
2
2
72
4.5
16
5.5
24
16.5
16.5
16.5
4.5
48
0
<5
50
100
100
95:5b
100
100
100
0
<5
0
67
100
100
0
4
22
5c
6
30
41
22
22
22
22
22
22
rt to 65
rt to 65
rt to 65
rt to 45
rt to 45
rt to 45
7
8
9d
10d
11d
12e
9
0
0
100
10
11
12c
13
14d
15
16e
17
18
19
20
21
1.5
13c,e
PhMe
24
100
14
45
30
30
30
DME
DME
DMF
1,4-
dioxane
THF
22
28
41
41
100
100
100
100
15c
16c
17c
0
0
0
100
0
10
11
12
18
rtf
rtf
rtf
rtf
18c
K3PO4
30
41
100
a
Reaction conditions: 1.3 mmol substrate, 1.2 equiv 2, 2.5 equiv base, 2 mol %
Pd2(dba)3ÁCHCl3, 6 mol % ligand 12, 0.5 M solvent.
a
Reaction conditions: 1.3 mmol substrate, 1.2 equiv 2, 1.4 equiv NaOtBu, 2 mol %
Pd2(dba)3ÁCHCl3, 6 mol % ligand, 0.5 M in toluene.
b
K2CO3,Cs2CO3, and K3PO4 were ground finely using a mortar and pestle before
b
95:5-desired product: unidentified side product.
use.
c
2 mol % 15, no ligand.
c
An extra 1 mol % and 3 mol % each of the catalyst and ligand were added after
d
1 mol % Pd2(dba)3ÁCHCl3, 3 mol % ligand.
24 h.
e
1:1 Pd:ligand ratio used; 2 mol % Pd2(dba)3ÁCHCl3, 4 mol % P(tBu)3.
d
1.4 equiv organic base.
Recrystallized from hot CH3CN, 1.0 equiv used with respect to base.
f
rt = 17–22 °C.
e

1584
S. Bhagwanth et al. / Tetrahedron Letters 50 (2009) 1582–1585
Table 3
Substrate scope of C–N coupling of benzophenone imine using Pd2dba3ÁCHCl3 and
afforded complete conversion after a prolonged reaction time
(41 h). For K3PO4, when no conversion was observed at room tem-
perature after 6–8 h, the reaction was warmed to 65 °C. However,
low conversion was observed even at elevated temperature (entry
8). Hypothesizing that the low solubility of inorganic bases in tol-
uene was responsible for the low conversions, we explored the use
of soluble organic bases such as NEt3, DBU, and DABCO (entries 9–
11). In the present case, however, these bases afforded no conver-
sion to product. The use of an additive was explored next. Stoichi-
ometric amounts of the crystalline acetonitrile complex of 18-
crown-615,16 along with K3PO4 gave complete conversion in less
than 2 h at 65 °C (Table 2, entry 12). A solvent change from toluene
to 1,2-dimethoxyethane (DME) obviated the need for 18-crown-6
and gave high conversions at low temperatures (entries 14–15).
Product formation was observed when other polar solvents, such
as DMF, 1,4-dioxane, and THF, were used (entries 16–18). Com-
plete conversion, however, took longer in the presence of these sol-
vents (41 h vs 28 h). Reactions were also evaluated in separate
cases in the absence of the Pd precatalyst, ligand 12, and base.
No product was detected after 24 h in all three control experi-
ments. Reducing Pd and ligand loading lower than 2 mol % and
6 mol %, respectively, reduced the conversion of the test substrate.
The optimal reaction condition is shown in entry 15.
ligand 12a
NH
Pd2(dba)3•CHCl3, ligand 12,
1)
NH2
Br
K3PO4, 30°C, DME
, Ph
Ph
2) Imine cleavage
R
R
Entry
1
Substrate
Timeb
Cleavage of iminec
Yieldd (%)
Br
24 h
A
72
Br
2
3
4
42 h
C
B
B
58
70
81
O
O
Br
28 h
Cl
Br
The scope of the optimized conditions with aryl bromide sub-
strates is shown in Table 3.17,18 The intermediate ketimines were
cleaved after minimal work-up (filtration and solvent evaporation)
and the reported yields are obtained over two steps. Product yields
were lower when the intermediate benzophenone imine was iso-
lated by flash chromatography as compared to cases where the
intermediate was not purified. It is hypothesized especially in the
case of the electron-poor substrates (e.g., Table 3, entry 6) that
the intermediate imine is unstable on silica gel.
44 h
NC
O
Br
5e
6e
28 h
B
B
91
63
OMe
Br
24 h
In general, 3- and 4-substituted aryl bromides were successfully
converted to the corresponding anilines. In particular, the methyl
4-benzoate (entry 5) reacted in 28 h to give an excellent two-step
yield of 91%. 4-Nitrobromobenzene (entry 6) and 4-cyanobromo-
benzene (entry 4) also reacted favorably. An aryl bromide contain-
ing enolizable hydrogens (entry 11) was selectively converted to
O2N
Br
7
48 h
52 h
B
B
B
B
B
57
53
82
67
74
OMe
the primary aniline; a
-arylation of the ketone was not observed.5a
Br
The reaction was also selective for the bromide in the presence of a
chloride (entry 3). Aryl bromides containing protected aldehydes
(entry 2) could also be converted to the primary aniline. Elec-
tron-rich substrates (entries 7–9) required longer reaction times
for complete conversion and the 4-N,N-dimethyl substrate re-
quired increased catalyst and ligand loading (5 and 15 mol %,
respectively). A heteroaromatic bromide (entry 10) was also con-
verted to the primary aniline under these reaction conditions. Par-
ticularly for base-sensitive substrates (e.g., entries 5 and 11), this
method shows improved substrate scope over the original report.3a
In the original method, such products were formed under milder
conditions (Cs2CO3, 65 °C) only by use of more reactive (and more
costly) aryl triflate substrates, which further require an additional
synthetic step to prepare. The single instance of a base-sensitive
aryl bromide coupled with a mild base (Cs2CO3) in this Letter re-
quired elevated temperature (100 °C).
Ligand 12 is the tert-butyl analog of X-Phos (ligand 6), another
commercially available ligand that is considered exceptional in Car-
yl–N coupling reactions. For cross-coupling reactions in general,
studies have demonstrated that increasing ligand bulk leads to
more effective reactions, presumably due to an increase in the rate
of reductive elimination.19 Comparing the conversions observed in
the present process with the series of ligands 6, 12, and 18, ligand
12 appears to offer the optimal bulk to most efficiently promote
both oxidative addition and reductive elimination. This order of
activity closely mirrors that observed by Buchwald for the forma-
tion of ortho-substituted biaryl ethers,14 and is perhaps a conse-
8
NMe2
Br
9f
10
7 d
Me2N
Br
28 h
N
Br
11
42 h
Me
O
a
Reaction conditions: 1.3 mmol substrate, 1.2 equiv 2, 2.5 equiv base, 3 mol %
Pd2(dba)3ÁCHCl3, 9 mol % ligand 12, 0.5 M solvent.
b
Times are reported for complete conversion observed in the amination reaction;
h = hours, d = days.
c
Imine cleavage ranges from 15 min to 4 h under specified conditions; A: cata-
lytic transfer hydrogenation; B: acidic hydrolysis; C: transamination with
NH2OHÁHCl See Supplementary data for details.
d
Reported isolated two-step yields are an average of two runs.
e
2 mol % Pd2(dba)3ÁCHCl3, 6 mol % ligand 12.
f
5 mol % Pd2(dba)3ÁCHCl3, 15 mol % ligand 12.
quence of the substantial steric bulk of benzophenone imine as a
nucleophile.

S. Bhagwanth et al. / Tetrahedron Letters 50 (2009) 1582–1585
1585
S.; Xu, R.; Paruchova, J.; Clader, J. W.; O’Neill, K.; Hawes, B.; Sorota, S.; Margulis,
M.; Tucker, K.; Weston, D. J.; Cox, K. Bioorg. Med. Chem. Lett. 2006, 16, 4262.
5. (a) Lee, S.; Jørgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3, 2729; (b) Huang, X.;
Buchwald, S. L. Org. Lett. 2001, 3, 3417.
6. Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 10028.
7. Surry, D. S.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 10354.
8. Lee, D-Y.; Hartwig, F. Org. Lett. 2005, 7, 1169.
9. (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722; (b)
Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2003, 125, 6653; (c) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2003, 125, 11818; (d) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int.
Ed. 1999, 38, 2413; (e) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S.
L. J. Org. Chem. 2000, 65, 1158.
10. Rataboul, F.; Zapf, A.; Jackstell, R.; Harkal, S.; Riermeier, T.; Monsees, A.;
Dingerdissen, U.; Beller, M. Chem. Eur. J. 2004, 10, 2983.
11. Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
13978.
We have demonstrated the ability to use a Pd-catalyzed amina-
tion reaction to convert diverse aryl bromides to their corresponding
primary anilines over two steps using benzophenone imine under
mild conditions. Particularly, the catalyst system described allows
this conversion to proceed at 30 °C using a weak inorganic base,
potassium phosphate. The reaction proceeds in a predictable man-
ner with respect to aryl bromide reactivities. Both Pd2dba3ÁCHCl3
and ligand 12 are air-stable and commercially available. The reac-
tions were performed in a multireaction block without the need of
a glove box or Schlenk techniques. The intermediate imines can be
easily converted to the corresponding anilines using procedures de-
scribed previously.3a Work toward Pd-catalyzed aminations of aryl
bromides with other ammonia equivalents using ligand 12 is under-
way and results will be reported in due course.
12. Strieter, E. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 925.
13. (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.
Acknowledgments
14. Burgos, C. H.; Barder, T. E.; Huang, X.; Buchwald, S. L. Angew. Chem., Int. Ed.
2006, 45, 4321.
15. Gokel, G. W.; Cram, D. J. J. Org. Chem. 1974, 39, 2445.
This work was carried out as the summer internship project of
S.B., as part of the GlaxoSmithKline Summer Talent Identification
Program. S.B. thanks Professor R. L. Johnson (Department of Medic-
inal Chemistry, University of Minnesota) for the opportunity to
pursue this internship. We also thank Matthew Lochansky and
Zachary Giles (GlaxoSmithKline, RTP, NC) for assistance with the
GC/MS instrumentation.
16. Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 6066.
17. Representative procedure: Methyl-4-aminobenzoate (Table 3, entry 5): A glass
reaction vessel part of a multireaction block equipped with a magnetic stir bar
was charged with, in order: Pd2(dba)3ÁCHCl3 (27 mg, 0.03 mmol), ligand 12
(34 mg, 0.08 mmol), K3PO4 (711 mg, 3.25 mmol), methyl-4-bromobenzoate
(279 mg, 1.30 mmol), benzophenone imine (0.26 mL, 1.56 mmol), and DME
(2.6 mL). The reaction vessel was evacuated and refilled with nitrogen twice.
The reaction mixture was stirred at 30 °C under nitrogen. After 28 h, the
reaction mixture was cooled to ambient temperature, diluted to 50 mL with
diethyl ether, filtered through a pad of Celite, and concentrated in vacuo. The
crude ketimine was suspended in 1:1 1N HCl:THF (13 mL) and stirred at room
temperature for 3 h. THF was then removed by rotary evaporation and the
aqueous residue was washed with 2:1 hexanes:ethyl acetate (50 mL). The
layers were separated and the organic layer was extracted with 4 N HCl
(100 mL). The pooled aqueous layers were basified to pH 9 using solid NaHCO3.
The aqueous layer was then extracted with ethyl acetate (2 Â 100 mL). The
combined organic fractions were dried over Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by flash chromatography (2–90% ethyl
acetate:hexanes) to afford methyl-4-aminobenzoate (179 mg, 91%) as a white,
crystalline solid. 1H NMR (400 MHz, CDCl3) d 7.76–7.92 (m, 2H), 6.55–6.68 (m,
2H), 4.01(s, 2H), 3.84 (s, 3 H); 13C NMR (100 MHz, CDCl3) d 167.15, 150.90,
131.48, 119.40, 113.66, 51.50. The spectroscopic data were in excellent
agreement with reported values.5a
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tetlet.2009.01.091.
References and notes
1. (a) Hartwig, J. F.; Shekhar, S.; Shen, Q.; Barrios-Landeros, F. In The Chemistry of
Anilines; Rappoport, Z., Ed.; John Wiley & Sons: West Sussex, England, 2007; p
455; (b) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed Cross Coupling; de Meijere,
A., Diederich, F., Eds., 2nd ed.; Wiley-VCH: Weinheim, Germany, 2004; p 699;
(c) Hartwig, J. F. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; John Wiley & Sons: Hoboken, NJ, 2002; p 1051; (d)
Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv. Synth. Catal. 2006, 348,
23.
18. The procedure followed for the reaction and work-up was the same for all aryl
bromides reported in Table 3 except for Pd and ligand loading. Three different
procedures were used for cleavage of the intermediate ketimine, depending on
the substrate, as footnoted under Table 3. The procedure B, followed above,
was used in the cleavage reactions of nine intermediates (Table 3, entries 3–
2. King, A. O.; Yasuda, N. In Organometallics in Process Chemistry; Larsen, R. D., Ed.;
Springer: Berlin, Germany, 2004; p 205.
3. (a) Wolfe, J. P.; Åhman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S. L. Tetrahedron
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2004, 841.
11). Procedure A (catalytic transfer hydrogenation) and procedure C
(transamination with hydroxylamine hydrochloride) used for Table 3, entry 1
and Table 3, entry 2, respectively, are detailed in the Supplementary data. All
products are known compounds and were easily identified by comparison of
the spectroscopic data with those reported. The purity of all compounds was
determined by 13C NMR and LC/MS.
4. (a) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-
Roman, L. M. J. Org. Chem. 1999, 64, 5575; (b) McBriar, M. D.; Guzik, H.; Shapiro,
19. Hartwig, J. F.; Richards, S.; Baranano, D.; Paul, F. J. Am. Chem. Soc. 1996, 118,
3626.