Palladium-catalyzed aminocarbonylation of heteroaryl halides using di-tert-butylphosphinoferrocene

Article abstract of DOI:10.1016/j.tetlet.2009.08.065

Pd-catalyzed aminocarbonylation of heteroaryl halides, using monodentate ligand di-tert-butylphosphinoferrocene tetrafluoroborate is reported. Good to high yields were obtained with chiral amines on a variety of substrates including 2-bromo heteroaryls.

Full text of DOI:10.1016/j.tetlet.2009.08.065

Tetrahedron Letters 50 (2009) 6126–6129
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed aminocarbonylation of heteroaryl halides using
di-tert-butylphosphinoferrocene
*
Bo Qu , Nizar Haddad, Zhengxu S. Han, Sonia Rodriguez, Jon C. Lorenz, Nelu Grinberg, Heewon Lee,
Carl A. Busacca, DhileepKumar Krishnamurthy, Chris H. Senanayake
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Pd-catalyzed aminocarbonylation of heteroaryl halides, using monodentate ligand di-tert-butylphosphi-
noferrocene tetrafluoroborate is reported. Good to high yields were obtained with chiral amines on a
variety of substrates including 2-bromo heteroaryls.
Received 27 July 2009
Revised 19 August 2009
Accepted 20 August 2009
Available online 24 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Aminocarbonylation
Heteroaryls
Di-tert-butylphosphinoferrocene
Palladium
1. Introduction
Di-tert-butylphosphinoferroceneÁHBF4 was initially tested in
the aminocarbonylation of (R)-phenylethylamine and (D)-glycine
Since the seminal report by Heck and Schoenburg in 1974,1 pal-
ladium-catalyzed three-component coupling reaction of an aryl
halide, CO, and a nucleophile has become a highly efficient method
for the synthesis of aromatic carbonyl-containing compounds.
Aminocarbonylation is a valuable and atom-efficient transforma-
tion for preparing amides of primary or secondary amines, includ-
ing chiral amino acids, as N-nucleophiles.2,3 In spite of the many
reports on aminocarbonylation, its potential utility with heteroaryl
halides has not been fully explored.4–9 While many ligands have
been successfully applied in palladium-catalyzed aminocarbonyla-
tion reactions, few of them can be applied on large scale applica-
tions due to the difficulty in synthesis or due to the highly
sensitive nature of the often pyrophoric phosphine ligands. To
the best of our knowledge, the application of monodentate ligand
di-tert-butylphosphinoferrocene P(Fc)(t-Bu)2 (Fc = ferrocenyl) in
palladium-catalyzed aminocarbonylation reactions has not been
reported. Limited success of this ligand was observed in aromatic
carbon–oxygen bond formations10,11 and Hartwig–Buchwald ami-
nation reactions.12
ethyl ester with iodobenzene (Table 1). Over 80% yields were ob-
tained using 3 mol % Pd(OAc)2 and 6 mol % of ligand at 50 psi of
CO pressure at 120 °C for 4 h (entries 1 and 2). Di-isopropylethyl-
amine was used as a base and acetonitrile or NMP was used as a
solvent.
Encouraged by the preliminary results, ligand P(Fc)(t-Bu)2ÁHBF4
was further examined in aminocarbonylation of bromobenzene
and heteroaryl bromides. We found that the typical conditions
have produced the desired products in modest to good yields.
The reaction of 5-bromo-1-methyl-1H-imidazole with either (R)-
phenylethylamine or (D)-glycine ethyl ester produced similar
yields (entries 4 and 5). 5-Bromopyrimidine was readily converted
to the desired product in 80% yield (entry 8). Slightly higher CO
pressure (200 psi) and longer reaction time (9 h) were needed to
obtain full conversion of amine with 3-bromoquinoline and bro-
mobenzene (entries 3 and 6). No epimerization of the chiral center
occurred during the reaction, aminocarbonylation product of bro-
mobenzene with either 1-(R)-ethylbenzylamine (99% ee) or 1-(S)-
ethylbenzylamine (99% ee) was obtained in 99% ee after 9 h of
reaction time at 120 °C and 200 psi of CO pressure.13
Aminocarbonylation of 2-bromo-heteroaryls was found to be
challenging under the typical reaction conditions. Arylbromide
self-dimerization was identified as the major side product along
with a small amount of direct coupling product without CO inser-
tion in the reactions of either 2-bromopyridine or 2-bromopyrim-
Herein, we report our recent findings on aminocarbonylation of
heteroaryl bromides using di-tert-butylphosphinoferrocene as a
11
supporting ligand. P(Fc)(t-Bu)2 was prepared and isolated as air
stable tetrafluoroboric acid adduct on multi-gram scale.
* Corresponding author. Tel.: +1 203 791 6177; fax: +1 203 791 6130.
E-mail address: bo.qu@boehringer-ingelheim.com (B. Qu).
idine with (D)-glycine ethyl ester. This suggests that CO insertion
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.065

B. Qu et al. / Tetrahedron Letters 50 (2009) 6126–6129
6127
Table 1
Aminocarbonylation reaction of aryl halides with amines
P
Pd(OAc)2 3 mol%
P(Fc)(t-Bu)2.HBF4 6 mol%
O
Fe
Ar-X
+
R-NH2
Ar
NHR
º
CO, 120 C
iPr2NEt, MeCN
P(Fc)(t-Bu)2
Entry
1
Ar–X
PhI
R–NH2
Product
Pressure (psi)
Time (h)
4
Yield* (%)
O
50
87
Ph
N
Ph
O
Ph
NH2
Ph
H
1
Ph
EtO
EtO
2
3
PhI
PhBr
50
200
4
9
82
69
NH2
HCl
N
Ph
H
O
O
2
O
Me
Me
N
N
Br
Ph
N
4
5
50
50
4
4
71
65
Ph
NH2
Ph
H
N
N
3
Ph
Ph
O
O
Me
N
EtO
N
H
EtO
NH2
HCl
O
O
N
O
4
EtO
Br
N
H
6
200
9
68a
N
N
5
Ph
Ph
O
O
Br
EtO
EtO
N
N
H
7
8
100
50
5
4
74b
N
N
N
O
O
N
6
Br
N
H
N
80
N
N
N
7
Ph
O
Br
EtO
9
200
4
91b
N
H
N
O
8
a
b
*
20% of quinoline-3-carboxylic acid was also isolated.
Pd/L = 3.
Isolated yield.
might be a rate-limiting step, since it takes place after oxidative-
addition step and prior to the transmetallation step. After oxidative
insertion of the Pd(0) to aryl–Br bond, instead of CO insertion, the
catalyst may form a dimeric Pd(II) structure by coordination to the
heteroatom on the arylbromide, which leads either to the self-
dimerization side product or catalyst deactivation.14 Slight
modification of the reaction temperature, CO pressure, and ligand
to palladium ratio has significantly favored the desired aminocarb-

6128
B. Qu et al. / Tetrahedron Letters 50 (2009) 6126–6129
Table 2
The reactivity of ligand P(Fc)(t-Bu)2ÁHBF4 was evaluated in com-
parison to that of other ligands7,15 that have been successfully
demonstrated in palladium-catalyzed carbonylation reactions
Aminocarbonylation at different pressures and temperatures
Pd(OAc)2 3 mol%
P(Fc)(t-Bu)2 HBF4
Br
Ph
NH2
Ph O
.
(Table 3). The reactions of 5-bromopyrimidine and (D)-glycine
EtO
EtO
N
N
+
N
ethyl ester were examined using 1 mol % Pd(OAc)2 with 3 mol %
monodentate ligand or 2 mol % bidentate ligands at 120 °C, 50 psi
of CO. Xantphos, a bidentate ligand possessing a large bite angle,
P(t-Bu)3ÁHBF4, and bis-di(tert-butylphosphino)ferrocene (DtBPF)
have demonstrated similar reactivity to P(Fc)(t-Bu)2ÁHBF4 (entries
1–4). Catacxium A, a superior ligand for aminocarbonylation of
other substrates in our hands, was found to be inferior in this case
even with 3 mol % of catalyst. Poor yield was also observed in the
iPr2NEt, CO, MeCN
H
HCl
O
O
Entry
Pd/L
Pressure (psi)
Temperature (°C)
Yield*
1
2
3
4
5
6
7
8
9
1:2
1:2
1:2
1:2
1:3
1:3
1:3
1:3
1:3
1:3
50
100
400
400
50
200
400
50
120
120
120
90
90
90
30
71
94
94
97
98
85
59
82
95
reaction of 5-bromo-1-methyl-1H-imidazole with (D)-glycine ethyl
90
ester using cataCXium A. Low yields were also obtained with Q-
PHOS, 1,4-diphenylphosphinobutane (dppb), and dicyclohexyl-
phosphinobutane (dcpb) as ligands. In situ IR monitoring of the
aminocarbonylation of 5-bromopyrimidine indicated complete
conversion in 2 h at 90 °C and 50 psi of CO using 1 mol % Pd(OAc)2
and 3 mol % P(Fc)(t-Bu)2ÁHBF4, providing the desired product 7 in
over 90% yield.
120
120
120
100
300
10
*
HPLC yields of average of two runs.
onylation reaction (Table 2). When Pd/ligand ratio stays at 1:2,
over 90% yield was obtained by increasing the pressure to
400 psi at a temperature range of 90–120 °C (entries 3 and 4); both
amination side reaction and bromide self-dimerization were sup-
pressed by employing slight increase in the CO pressure. It should
be noted that no double carbonylation product was observed at in-
creased pressure. When Pd/ligand ratio was increased to 1:3
respectively, quantitative yield was obtained with lower tempera-
ture 90 °C and 50 psi CO pressure (entry 5). Further decrease of the
temperature to 70 °C led mostly to aryl bromide self-dimerization
with a pressure range of 50–400 psi. Increasing the ligand to Pd ra-
tio stabilizes Pd(0) by favorably coordinating to the phosphine li-
gand other than CO molecule and therefore preventing catalyst
deactivation. Most aminocarbonylations of heteroaryls were re-
ported on 3-bromoaryls, only a few were investigated on 2-bromo-
pyridine using Mo(CO)6 as the CO source under microwave or
conventional heating, and lower yield was obtained.4,5 The ligand
P(Fc)(t-Bu)2ÁHBF4 furnished the desired product in 91% yield under
optimized conditions.
In summary, we have demonstrated the application of air stable
ligand P(Fc)(t-Bu)2ÁHBF4 in palladium-catalyzed aminocarbonyla-
tion of heteroaryl bromides with amines. The ligand was conve-
niently prepared and isolated on multi-gram scale and
successfully applied in the preparation of a series of heteroaro-
matic amide derivatives in good yields.
2. Synthesis of P(Fc)(t-Bu)2ÁHBF4
To a dried 2 L flask under argon were charged ferrocene (5 g,
26.9 mmol), anhydrous THF (150 mL), and t-BuOK (0.12 equiv).
The mixture was cooled to À78 °C before t-BuLi (2.0 equiv) was
added slowly while keeping the temperature below À70 °C. After
stirring for an additional 1 h, the mixture was warmed to ambient
temperature, stirred for 2 h, and then t-Bu2PCl (1.1 equiv) was added
in one portion. After stirring at room temperature for 2 h, degassed
water (100 mL) was added and the mixture was concentrated to re-
move 2/3 of THF and backfilled with argon. Ethyl acetate (100 mL)
was added followed by saturated NaHCO3 solution (1.5 equiv). The
aqueous phase was removed, then HBF4 (48% in water) (2 equiv)
was added to the organic fraction. The mixture was stirred for 4 h,
then washed with brine (50 mL). The solvent was removed under re-
duced pressure, the residue stirred with ethyl acetate (200–300 mL)
to form a slurry that was filtered and dried to give 8.5 g orange solid
in 75% yield. 1H NMR (400 Hz in CDCl3): 1.50 (s, 9H), 1.54 (s, 9H), 4.44
(s, 5H), 4.66 (s, 2H), 4.79 (s, 2H), 6.87 (d, 1H, J = 394 Hz). 13C NMR
(400 Hz in CDCl3): 28.61, 34.45, 34.75, 71.95, 73.60, 73.68, 74.11,
74.18. 31P NMR: 54.26.
Table 3
Aminocarbonylation reactions with different ligands
HClH2N
Pd(OAc)2/L
iPr2NEt
O
Ph
N
N
N
O
O
+
O
N
50 psi CO
º
H
N
O
Br
120 C, MeCN, 5 h
Yield* (%)
3. General procedure for the aminocarbonylation reactions
Entry
Pd(OAc)2 mol %
Ligand
Pd/L
1
2
3
4
5
6
7
8
1
1
1
1
3
3
3
3
P(Fc)(t-Bu)2ÁHBF4 1:3
91
90
All experiments were operated on a Biotage Endeavor system
equipped with mechanical stirrers. Reagents were used as re-
ceived. Anhydrous MeCN and NMP were nitrogen purged before
use. At the end of the reaction, monitored by HPLC based on the
disappearance of amines, the reaction mixture was concentrated
and then the residue was purified on silica.
Xantphos
P(t-Bu)3ÁHBF4
DtBPF
1:2
1:3
1:2
1:3
1:3
1:2
1:2
92
54a
36a
23a
43a
2
CataCXium A
Q-PHOS
dppb
dcpb
R
P
P
P
4. Representative procedure of preparing (R)-1-methyl-N-(1-
phenylethyl)-1H-imidazole-5-carboxamide (3)
R
P
P
R
R
O
PPh2
Fe
PPh2
R = Ph, dppb
R = c-hexyl, dcpb
cataCXium A
xantphos
DtBPF
(R)-1-Phenylethylamine (218 mg, 1.8 mmol), 5-bromo-1-
methyl-1H-imidazole (434 mg, 2.7 mmol), Pd(OAc)2 (12.1 mg,
0.054 mmol), di-tert-butylphosphinoferroceneÁHBF4 (45 mg, 0.108
mmol), and iPr2NEt (1.25 mL, 7.2 mmol) were added to the
a
Incomplete reaction.
HPLC yields of average of two runs.
*

B. Qu et al. / Tetrahedron Letters 50 (2009) 6126–6129
6129
10-mL reaction vessel followed by 4 mL of MeCN. The reaction
mixture was then purged two times with N2, then one time with
CO, heated to 120 °C, and pressurized to 50 psi for 4 h. The reaction
mixture was then cooled down to 23 °C and purged with N2 for two
times. The mixture was purified on silica using CH2Cl2/MeOH 95:5
to give 293 mg (71%) of the desired aminocarbonylation product as
a colorless liquid. 1H NMR (400 Hz in CDCl3): 7.63 (br s, 1H), 7.48
(s, 1H), 7.32–7.18 (m, 6H), 5.22 (quint, 1H, J = 7.12 Hz), 3.79 (s,
3H), 1.48 (d, 3 H, J = 7.0 Hz). 13C NMR (100 Hz in CDCl3): 159.47,
143.22, 141.08, 131.44, 128.26, 126.90, 126.05, 125.97, 48.18,
33.75, 21.39. HRMS (ESI) calcd for C13H16N3O [M+H]+: 230.1287;
found 230.1297, error = 3.9598 ppm.
(d, 1H, J = 6.8 Hz), 4.29–4.16 (m, 2H), 1.23 (t, 3H, J = 7.2 Hz). 13C
NMR (100 Hz in CDCl3): 170.54, 162.70, 160.70, 155.74, 135.89,
129.05, 128.79, 127.23, 62.36, 56.92, 13.92. HRMS (ESI) calcd
for C15H16N3O3 [M+H]+: 286.1186; found 286.1195, error =
3.0826 ppm.
4.4. (R)-Ethyl 2-phenyl-2-(picolinamido)acetate (8)
465 mg (91%) colorless liquid was obtained by a column using
hexane/EtOAc 70:30. 1H NMR (400 Hz in CDCl3): 8.95 (br d, 1H),
8.58 (d, 1H, J = 4.76 Hz), 8.15 (d, 1H, J = 7.84 Hz), 7.81 (dt, 1H,
J = 7.76 Hz and 1.64 Hz), 7.48 (d, 2H, J = 7.88 Hz), 7.36–7.30 (m,
4H), 5.76 (d, 1H, J = 7.6 Hz), 4.20 (m, 2H), 1.23 (t, 3H, J = 7.0 Hz)
13C NMR (100 Hz in CDCl3): 170.57, 163.72, 149.34, 148.25,
137.19, 136.66, 128.88, 128.40, 127.29, 126.34, 122.26, 61.81,
56.61, 13.97. HRMS (ESI) calcd for C15H17N2O3 [M+H]+: 285.1233;
found 285.1237, error = 1.1707 ppm.
4.1. (R)-Ethyl-2-(1-methyl-1H-imidazole-5-carboxamido)-2-
phenylacetate (4)
336 mg (65%) colorless liquid was obtained by a column
using CH2Cl2/MeOH 95:5. 1H NMR (400 Hz in CDCl3): 7.84 (br s,
1H), 7.48 (s, 1H), 7.35–7.23 (m, 6H), 5.62 (d, 1H, J = 7.2 Hz),
4.19–4.08 (m, 2H), 3.75 (s, 3H), 1.15 (t, 3H, J = 7.2 Hz). 13C NMR
(100 Hz in CDCl3): 170.48, 159.54, 141.44, 136.06, 132.26,
128.51, 128.09, 127.23, 125.13, 61.52, 56.16, 33.66, 13.65. HRMS
(ESI) calcd for C15H18N3O3 [M+H]+: 288.1342; found 288.1333,
error = 3.3598 ppm.
Supplementary data
Supplementary data (analytical data of compounds 1, 2 and 5
and NMR spectra of new compounds) associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.2009.
08.065.
4.2. (R)-Ethyl-2-phenyl-2-(pyrimidine-2-carboxamido)-acetate
(6)
References and notes
1. Schoenburg, A.; Heck, R. F. J. Org. Chem. 1974, 39, 3327.
2. Kuik, Á.; Skoda-Földes, R.; Jánosi, L.; Kollár, L. Synthesis 2007, 1456.
3. Horváth, L.; Berente, Z.; Kollár, L. Lett. Org. Chem. 2007, 4, 236.
4. Begouin, A.; Queiroz, M. R. P. Eur. J. Org. Chem. 2009, 2820.
5. Letavic, M. A.; Ly, K. S. Tetrahedron Lett. 2007, 48, 2339.
6. Fairlamb, I. J. S.; Grant, S.; McCormack, P.; Whittall, J. Dalton Trans. 2007, 859.
7. Neumann, H.; Brennführer, A.; Grob, P.; Riermeier, T.; Almena, J.; Beller, M. Adv.
Synth. Catal. 2006, 348, 1255. and references cited therein.
8. Takács, A.; Jakab, B.; Petz, A.; Kollár, L. Tetrahedron 2007, 63, 10372.
9. Martinelli, J. R.; Clark, T. P.; Watson, D. A.; Munday, R. H.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2007, 46, 8460.
380 mg (74%) white solid was obtained by a column using 100%
EtOAc. 1HNMR (400 Hz in CDCl3): 8.83 (br d, 1H), 8.77 (d, 2H,
J = 4.88 Hz), 7.34–7.40 (m, 3H), 7.21–7.30 (m, 3H), 5.78 (d, 1H,
J = 7.6 Hz), 4.08–4.21 (m, 2H), 1.15 (t, 3H, J = 6.8 Hz). 13CNMR
(100 Hz in CDCl3): 170.29, 161.30, 157.32, 157.06, 136.21,
128.75, 128.35, 127.11, 122.57, 61.79, 56.47, 13.81. HRMS (ESI)
calcd for C15H16N3O3 [M+H]+: 286.1186; found 286.1179, error =
2.5094 ppm.
10. Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122,
10718.
11. Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc. 1999,
121, 3224.
12. Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem. 2003, 68, 2861.
13. Chiralcel OD-H column used for ee determination with 90/10 of heptane/n-
propanol.
14. Beller, M.; Mägerlein, W.; Indolese, A. F.; Fischer, C. Synthesis 2001, 1098.
15. Martinelli, J. R.; Watson, D. A.; Freckmann, D. M. M.; Barder, T. E.; Buchwald, S.
J. Org. Chem. 2008, 73, 7102. and references cited therein.
4.3. (R)-Ethyl-2-phenyl-2-(pyrimidine-5-carboxamido)-acetate
(7)
410 mg (80%) white solid was obtained by a column using
hexane/EtOAc 50:50. 1H NMR (400 Hz in CDCl3): 9.28 (s, 1H),
9.12 (s, 2H), 7.44 (br d, NH, J = 6.4 Hz), 7.41–7.32 (m, 5H), 5.74