Palladium-catalyzed amination of 3-bromo-4-fluoro-acetophenone

Article abstract of DOI:10.1016/S0040-4039(02)02384-5

The palladium-catalyzed amination of 3-bromo-4-fluoro-acetophenone was found to predominate over both the 4-fluoro nucleophilic substitution with amines and the palladium-catalyzed α-arylation of the acetyl group.

Full text of DOI:10.1016/S0040-4039(02)02384-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9291–9294
Palladium-catalyzed amination of 3-bromo-4-fluoro-acetophenone
Li-Qiang Sun, Huan He, Jie Chen and Yong-Jin Wu*
The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA
Received 22 October 2002; accepted 23 October 2002
Abstract—The palladium-catalyzed amination of 3-bromo-4-fluoro-acetophenone was found to predominate over both the
4
-fluoro nucleophilic substitution with amines and the palladium-catalyzed a-arylation of the acetyl group. © 2002 Elsevier
Science Ltd. All rights reserved.
During the course of a medicinal chemistry program,
we wanted to convert 3-bromo-4-fluoro-acetophenone
knowledge, the palladium-catalyzed amination on sub-
strates with a fluorine ortho or para to an electron-with-
drawing group has not yet been reported. This report
describes our preliminary studies on acetophenone 1.
(
1) to arylpiperazine 3 through palladium-catalyzed
1
amination with piperazine (2) (Scheme 1). Reaction of
aryl halides with piperazine under palladium-catalyzed2
conditions has been used to prepare N-arylpiperazines,
however, bis-arylation has been shown to be a potential
Buchwald et al. had previously reported that the palla-
dium-catalyzed amination of 4-bromoacetophenone (6)
with morpholine (1.2 equiv.) in the presence of
Pd(OAc) (1 mol% Pd), ligand 8 (1.5 mol%), K PO in
2
a,b
problem.
It is worth noting that compound 1 is an
unique substrate for this type of amination reactions as
it bears a fluorine para to an electron-withdrawing and
yet enolizable ketone functionality. Palladium catalyzed
a-arylation of ketones with aryl halides in the presence
2
3
4
DME at 80°C provided N-aryl morpholine 7 in good
1c,5
yield (Scheme 2).
However, when we tried these
conditions (Table 1, entry 1) in our case, we obtained a
3
6
of a base has been well documented. It is also well
1
1
:9 mixture of the fluoride 3 and bromide 4 (Scheme
known that fluorobenzenes containing an ortho- or
para-substituted electron-withdrawing groups undergo
). After some experimentation, we found that reaction
of 1 with piperazine (4 equiv.) gave a 9:1 mixture of 3
and 4 using Pd(OAc)2 (10 mol% Pd), ligand 9 (10
mol%) in the presence of Cs CO (1.5 equiv.) in ben-
4
facile nucleophilic substitution with amines. As the
palladium-catalyzed amination reactions are usually
2
3
carried out under basic conditions (NatOBu, Cs CO ,
2
3
zene or toluene under reflux (method A) (Table 1,
entries 2 and 3). Fluoride 3 was obtained in 80% yield
after purification of the crude product through flash
chromatography on silica gel. As shown in Table 1, the
ratio of 3:4 appears to be dependent on the choice of
the ligand (entry 4), Pd catalyst (entry 5), solvent (entry
or K PO ) at 80–100°C, we were concerned about the
3
4
4-fluoro nucleophilic substitution with amines. To our
6
), and base (entry 7). In addition, the ratio of 3:4 was
Scheme 1.
*
Corresponding author. Tel.: +1-203-677-7485; fax: +1-203-677-7702;
e-mail: yong-jin.wu@bms.com
Scheme 2.
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02384-5

9
292
L.-Q. Sun et al. / Tetrahedron Letters 43 (2002) 9291–9294
Table 1. Amination of 3-bromo-4-fluoro-acetophenone (1)
with piperazine (2)
mmol), Pd(OAc) (0.5 mmol), ligand 9 (0.5 mmol) in
2
benzene (8 mL) at room temperature under nitrogen.
Cs CO (7.5 mmol) was added, and the resulting mixture
2
3
a
Entry
Conditions
3:4:5
1:9:0
9:1:0
was heated under reflux until acetophenone had been
consumed as judged by LC–MS analysis (usually
1
2
2 (1.1 equiv.), Pd(OAc)2 (1%), 8 (1.5%),
K PO4 (1.1 equiv.), DME, 80°C, 16 h
3
2 (4 equiv.), Pd(OAc)2 (10%), 9 (10%),
Cs CO3 (1.5 equiv.), C H , 80°C, 24 h
Table 2. Amination of 3-bromo-4-fluoro-acetophenone (1)
2
6
6
using Cs CO (method A)
2
3
(method A)
3
2 (4 equiv.), Pd(OAc)2 (10%), 9 (10%),
9:1:0
Cs CO3 (1.5 equiv.), C H CH , 110°C, 16 h
2
6
5
3
(method A)
4
5
6
7
8
9
2 (4 equiv.), Pd(OAc)2 (10%), 8 (10%),
Cs CO3 (1.5 equiv.), C H , 80°C, 40 h
3:1:0
1:8:0
2:1:0
2
6
6
2 (4 equiv.), Pd (dba) (10%), 9 (10%),
2
3
Cs CO3 (1.5 equiv.), C H , 80°C, 12 h
2
6
6
2 (4 equiv.), Pd(OAc)2 (10%), 9 (10%),
Cs CO3 (1.5 equiv.), DME, 80°C, 16 h
2
2 (4 equiv.), Pd(OAc)2 (10%), 9 (10%), K PO 1:34:0
3
4
(
1.5 equiv.), C H , 80°C, 40 h
6 6
2 (1 equiv.), Pd(OAc)2 (1%), 9 (1.5%),
Cs CO3 (1.5 equiv.), C H , 80°C, 24 h
1:9:0
2
6
6
2 (4 equiv.), Cs CO (1.5 equiv.), C H , 80°C, 0:1:0
2
3
6
6
1
2 h
1
0
2 (1.1 equiv.), Pd(OAc)2 (10%), 9 (10%),
NaOtBu (1.1 equiv.), C H , 80°C, 1 h
4:0:1
6
6
(method B)
a
LC–MS ratio of the crude reaction mixture.
reversed when less reagents (piperazine, Pd(OAc) , and
2
ligand 9) were applied (entry 8). As a control experiment,
1
was treated with morpholine in the presence of Cs CO3
2
in benzene under reflux (entry 9), and bromide 4 was
formed exclusively. This observation demonstrates the
requirement of palladium as a catalyst in the formation
of fluoride 3. Of special note is that all the coupling
reactions involving Cs CO did not generate any N,N%-
Table 3. Amination of 3-bromo-4-fluoro-acetophenone (1)
using NaOtBu (method B)
2
3
bis-arylpiperazine 5. We also examined the palladium-
catalyzed coupling reaction of 1 with piperazine using
NaOtBu as a base (method B, entry 10). The amination
proceeded much faster than that with Cs CO3 and
2
provided fluoride 3 and diketone 5 in 75 and 18% yields,
respectively. The formation of the bromide 4 was not
observed until an excess of piperazine was used.
We next applied the above amination conditions to
various amines, and the results are shown in Tables 2 and
3
. Conditions involving Cs CO (method A) worked well
2 3
with piperazine and morpholine analogs (Table 2), but
failed with homomorpholine hydrochloride (Et N or
3
additional Cs CO was added to neutralize hydrochlo-
2
3
ride), piperidine, and cyclohexylamine. The coupling
reactions with these amines were successfully carried out
using NaOtBu as a base (method B), and the amination
products (11) were obtained in ca. 60% yield (Table 3).
The major side products (12) in these cases were formed
through the palladium-catalyzed a-arylation of the acetyl
3
group. In the case of cyclohexylamine, we also isolated
a small amount of bromide 13.
In a typical experiment of method A, amine (20 mmol)
was added to a stirred mixture of acetophenone 1 (5

L.-Q. Sun et al. / Tetrahedron Letters 43 (2002) 9291–9294
9293
for 16 h). The mixture was cooled to room temperature,
diluted with ether, filtered, and concentrated. The crude
product was purified by flash chromatography on silica
gel eluting with appropriate solvents.
Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999,
121, 1473–1478.
4. (a) Terrier, F. Nucleophilic Aromatic Displacement; VCH:
New York, 1991; p. 376; (b) Belfield, A. J.; Brown, G. R.;
Foubister, A. J.; Ratcliffe, P. D. Tetrahedron 1999, 55,
13285–13300.
Method B was similar to method A with the exception
that 1.1 equiv. NaOtBu was used instead of Cs CO ,
5. Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem.
Soc. 1998, 120, 9722–9723.
2
3
1.1 equiv. amine was added, and the reactions were
complete within a couple of hours. In the case of
homomorpholine hydrochloride, 2.1 equiv. of NaOtBu
was added.
6. All new compounds have spectral and analytical data in
1
agreement with the indicated structures. Compound 3: H
NMR (300 MHz, C D ) l 0.87 (1H, s), 2.10 (3H, s), 2.64
6
6
(
(
4H, m), 2.75 (4H, m), 6.73 (1H, dd, J=8.4, 12.3 Hz), 7.08
1H, m), 7.64 (1H, dd, J=2.1, 8.7 Hz); C NMR (75
In summary, we have developed a useful and conve-
nient method for the preparation of 3-alkylamino-4-
fluoro-acetophenone derivatives through palladium-
catalyzed amination reactions.
13
MHz, CDCl ) l 26.6, 46.2 (2C), 51.8 (2C), 116.1 (d,
J=22.5 Hz), 118.9 (d, J=7.5 Hz), 123.6 (d, J=7.5 Hz),
1
3
34.0 (d, J=7.5 Hz), 140.9 (d, J=7.5 Hz), 158.9 (d,
J=255 Hz), 197.0; HRMS m/z calcd for C H FN O
1
2
16
2
+
1
(
M+H) 223.1247, found 223.1249. Compound 4:
H
NMR (300 MHz, CDCl ) l 2.14 (1H, s), 2.46 (3H, s), 3.01
Acknowledgements
3
(
8H, m), 6.95 (1H, d, J=8.4 Hz), 7.78 (1H, dd, J=1.8, 8.4
13
Hz), 8.07 (1H, d, J=1.8 Hz); C NMR (75 MHz, CDCl3)
l 26.4, 46.1 (2C), 52.6 (2C), 118.8, 120.1, 128.8, 132.7,
We would like to thank Drs. John Starrett and David
Smith for encouragement throughout the course of this
investigation, and Drs. Graham Poindexter, Jeffrey A.
Campbell and Laurence Wu for proofreading this
report.
1
34.5, 155.1, 195.9; HRMS m/z calcd for C H BrN O
12 16 2
+
1
(M+H) 283.0446, found 283.0442. Compound 5:
NMR (400 MHz, CDCl ) l 2.58 (6H, s), 3.35 (8H, s), 7.12
(2H, dd, J=8.4, 12.0 Hz), 7.59 (2H, m), 7.69 (1H, d,
H
3
13
J=6.4 Hz); C NMR (100 MHz, CDCl ) l 26.5 (2C), 50.4
3
(
4C), 116.2 (2C, d, J=20 Hz), 119.0 (2C), 123.9 (2C, d,
J=10 Hz), 134.0 (2C), 140.2 (2C, d, J=10 Hz), 158.8 (2C,
d, J=260 Hz), 196.8 (2C); HRMS m/z calcd for
References
+
C H N O F (M+H) 359.1571, found 359.1556. Com-
2
0
21
2
2 2
1
1
. (a) Harris, M. C.; Huang, X.; Buchwald, S. L. Org. Lett.
pound 10a: H NMR (300 MHz, CDCl ) l 1.48 (9H, s),
3
2
002, 4, 2885–2888; (b) Wolfe, J. P.; Buchwald, S. L. J.
Org. Chem. 2000, 65, 1144–1157; (c) Wolfe, J. P.; Tomori,
H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J. Org. Chem.
2
.56 (3H, s), 3.06 (4H, t, J=4.8 Hz), 3.60 (4H, t, J=5.1
13
Hz), 7.25 (1H, dd, J=9.0, 12.0 Hz), 7.56 (2H, m);
C
NMR (75 MHz, CDCl ) l 26.6, 28.5 (3C), 50.5 (2C), 77.4,
3
2
000, 65, 1158–1174; (d) Yang, B. H.; Buchwald, S. L. J.
80.1 (2C), 116.2 (d, J=22.5 Hz), 119.2, 124.0 (d, J=7.5
Organomet. Chem. 1999, 576, 125–146; (e) Wolfe, J. P.;
Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem.
Res. 1998, 31, 805–818; (f) Wolfe, J. P.; Buchwald, S. L.
Tetrahedron Lett. 1997, 38, 6359–6362; (g) Marcoux, J.-F.;
Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1997, 62,
568–1569; (h) Hartwig, J. F. Angew. Chem., Int. Ed. Engl.
998, 37, 2046–2067; (i) Hartwig, J. F.; Kawatsura, M.;
Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M.
J. Org. Chem. 1999, 64, 5575–5580.
. (a) Zhao, S.-H.; Miller, A. K.; Berger, J.; Flippin, L. A.
Tetrahedron Lett. 1996, 37, 4463–4466; (b) Nishiyama, M.;
Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39, 617–
20; (c) Morita, S.; Kitano, K.; Matsubara, J.; Ohtani, T.;
Kawano, Y.; Otsubo, K.; Uchida, M. Tetrahedron 1998,
4, 4811–4818; (d) Stauffer, S. R.; Lee, S.; Stambuli, J. P.;
Hauck, S. I.; Hartwig, J. F. Org. Lett. 2000, 2, 1423–1426;
e) Watanabe, M.; Yamamoto, T.; Nishiyama, M. Angew.
Chem., Int. Ed. 2000, 39, 2501–2504; (f) Lopez-Rodriguez,
M. L.; Benhamu, B.; Ayala, D.; Rominguera, J. L.; Mur-
cia, M.; Ramos, J.; Viso, A. Tetrahedron 2000, 56, 3245–
253.
. (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
19, 11108–11109; (b) Fox, J. M.; Huang, X.; Chieffi, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360–1370;
c) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997,
19, 12382–12383; (d) Shaughnessy, K. H.; Hamann, B.
C.; Hartwig, J. F. J. Org. Chem. 1998, 63, 6546–6553; (e)
Hz), 134.1, 140.4 (d, J=7.5 Hz), 154.8, 158.9 (d, J=255
−
Hz), 196.8; HRMS m/z calcd for C H FN O (M−H)
3
17
22
2
3
1
21.1615, found 321.1618. Compound 10b: H NMR (300
MHz, CDCl ) l 2.33 (3H, s), 2.54 (3H, s), 2.57 (4H, t,
3
J=5.1 Hz), 3.13 (4H, t, J=5.1 Hz), 7.04 (1H, dd, J=8.4,
1
1
1
3
1
2
1
2.3 Hz), 7.51 (2H, m); C NMR (75 MHz, CDCl ) l
3
6.2, 46.2 (2C), 50.4 (2C), 55.2, 116.1 (d, J=22.5 Hz),
18.9, 125.5 (d, J=7.5 Hz), 134.0 (d, J=7.5 Hz), 140.5 (d,
J=15 Hz), 158.9 (d, J=255 Hz), 197.0; HRMS m/z calcd
2
+
for C H FN O (M+H) 237.1403, found 237.1407. Com-
13 18
2
1
pound 10c: H NMR (400 MHz, CDCl ) l 2.54 (3H, s),
3
3
.09 (4H, t, J=6.4 Hz), 3.84 (4H, t, J=4.8 Hz), 7.05 (1H,
6
13
dd, J=8.4, 12.0 Hz), 7.52 (2H, m); C NMR (100 MHz,
CDCl ) l 26.5, 50.7 (2C), 66.9 (2C), 116.2 (d, J=20 Hz),
5
3
118.5 (d, J=10 Hz), 123.7 (d, J=10 Hz), 134.0, 140.2 (d,
J=10 Hz), 157.7 (d, J=250 Hz), 196.8; HRMS m/z calcd
(
+
for C H FNO (M+H) 224.1087, found 224.109. Com-
12 15
2
1
pound 10d: H NMR (400 MHz, CDCl ) l 1.23 (6H, d,
3
J=6.0 Hz), 2.48 (2H, dd, J=10.4, 11.2 Hz), 2.57 (3H, s),
3.29 (2H, dd, J=2.0, 9.2 Hz), 3.87 (2H, dq, J=2.4, 8.4
3
13
3
Hz), 7.08 (1H, dd, J=8.4, 12.0 Hz), 7.54 (2H, m);
C
1
NMR (100 MHz, CDCl ) l 19.0 (2C), 26.5, 56.1 (2C), 71.7
3
(2C), 116.2 (d, J=30 Hz), 118.6 (d, J=10 Hz), 123.6 (d,
J=10 Hz), 134.0, 140.0 (d, J=10 Hz), 158.7 (d, J=260
(
1
+
Hz), 196.9; HRMS m/z calcd for C H FNO (M+H)
14
19
2
1
252.1400, found 252.1400. Compound 11a: H NMR (400

9
294
L.-Q. Sun et al. / Tetrahedron Letters 43 (2002) 9291–9294
196.5. HRMS m/z calcd for C H F NO (M−H)
−
MHz, CDCl ) l 2.06 (2H, quintet, J=5.6 Hz), 2.55 (3H,
s), 3.49 (4H, br t), 3.83 (2H, t, J=5.6 Hz), 3.85 (2H, dd,
3
21 20
2
3
1
372.1411, found 372.1393. Compound 12b: H NMR (400
J=4.8, 9.2 Hz), 7.04 (1H, dd, J=8.4, 12.8 Hz), 7.38 (1H,
m), 7.52 (1H, dd, J=2.0, 8.8 Hz); C NMR (100 MHz,
MHz, CDCl ) l 1.56 (2H, m), 1.73 (4H, m), 2.57 (3H, s),
3
13
3.05 (4H, t, J=5.6 Hz), 4.32 (2H, s), 7.08 (1H, dd, J=8.0,
12.0 Hz), 7.15 (1H, t, J=8.0 Hz), 7.60 (1H, m), 7.62 (1H,
CDCl ) l 26.5, 30.6, 50.8, 54.8, 69.5, 70.8, 116.3 (d, J=20
3
13
Hz), 117.7, 121.0 (d, J=10 Hz), 133.8 (d, J=10 Hz), 139.9
m), 7.86 (1H, m), 7.90 (1H, m). C NMR (125 MHz,
(
1
(
d, J=10 Hz), 157.1 (d, J=250 Hz), 197.1. Compound
CDCl ) l 24.1, 26.0, 29.7, 38.6, 51.9, 115.7 (d, J=11 Hz),
3
1
1b: H NMR (400 MHz, CDCl ) l 1.59 (2H, m), 1.61
116.2 (d, J=22 Hz), 119.5, 122.6 (d, J=17.5 Hz), 122.9,
129.8 (d, J=10 Hz), 132.6 (d, J=6.3 Hz), 132.8 (d, J=6.3
Hz), 133.6 (d, J=3.8 Hz), 141.8, 159.1 (d, J=252 Hz),
3
4H, m), 2.56 (3H, s), 3.05 (4H, t, J=5.6 Hz), 7.04 (1H,
dd, J=8.4, 12.0 Hz), 7.49 (1H, m), 7.61 (1H, d, J=8.0
Hz); C NMR (100 MHz, CDCl ) l 24.1, 26.0 (2C), 26.5,
5
(
1
(
m), 1.75 (2H, m), 2.54 (3H, s), 3.36 (1H, m), 6.98 (1H, dd,
J=8.4, 11.2 Hz), 7.18 (1H, m), 7.31 (1H, dd, J=2.0, 8.4
Hz); C NMR (100 MHz, CDCl ) l 24.9, 25.8, 26.5, 33.2,
5
13
164.1 (d, J=255 Hz), 194.5, 196.5; HRMS m/z calcd for
3
−
1.9 (2C), 115.9 (d, J=20 Hz), 119.1 (d, J=10 Hz), 123.2
C
21
H
20
F
2
N
2
O
2
(M−H) 356.1462, found 356.1461. Com-
1
d, J=20 Hz), 133.8 (d, J=10 Hz), 141.7 (d, J=10 Hz),
pound 12c: H NMR (400 MHz, CDCl ) l 1.22 (4H, m),
3
1
58.9 (d, J=260 Hz), 197.0. Compound 11c: H NMR
1.37 (2H, m), 1.56 (1H, m), 1.75 (2H, m), 2.02 (2H, m),
2.57 (3H, s), 3.33 (1H, m), 4.32 (2H, s), 7.02 (1H, dd,
J=8.4, 10.8 Hz), 7.15 (1H, t, J=8.8 Hz), 7.29 (1H, m),
400 MHz, CDCl ) l 1.18 (4H, m), 1.38 (2H, m), 1.65 (1H,
3
13
7.35 (1H, m), 7.88 (2H, m); C NMR (75 MHz, CDCl ) l
3
13
25.0, 25.9, 26.6, 33.3, 38.6, 51.4, 111.8 (d, J=7.5 Hz),
114.5 (d, J=22.5 Hz), 115.7 (d, J=22.5 Hz), 117.3 (d,
J=7.5 Hz), 122.9 (d, J=22.5 Hz), 129.8 (d, J=15 Hz),
132.6 (d, J=7.5 Hz), 133.1 (d, J=7.5 Hz), 133.7 (d, J=7.5
3
1.3, 111.6, 114.3 (d, J=20 Hz), 117.7, 134.1, 136.0, 154.5
1
(
d, J=240 Hz), 197.5. Compound 12a: H NMR (400
MHz, CDCl ) l 2.06 (2H, m), 2.58 (3H, s), 3.51 (4H, m),
3
3
7
8
2
1
.81 (4H, m), 4.32 (2H, s), 7.07 (1H, dd, J=8.4, 12.8 Hz),
Hz), 154.8 (d, J=248 Hz), 164.2 (d, J=248 Hz), 195.0,
−
.15 (1H, t, J=9.2 Hz), 7.47 (1H, m), 7.54 (1H, dd, J=2.0,
196.6. HRMS m/z calcd for
C H F NO (M−H)
22 22 2 2
1
13
.8 Hz), 7.86 (2H, m); C NMR (100 MHz, CDCl ) l
370.1618, found 370.1630. Compound 13: H NMR (400
MHz, CDCl ) l 2.57 (3H, s), 4.33 (2H, s), 7.17 (1H, t,
3
6.5, 30.5, 38.6, 50.8, 54.8, 69.5, 70.8, 115.7 (d, J=20 Hz),
16.7 (d, J=30 Hz), 117.9, 120.6, 122.6, 129.8 (d, J=10
3
J=8.8 Hz), 7.22 (1H, d, J=8.0 Hz), 7.86 (1H, dd, J=2.0,
6.8 Hz), 7.92 (1H, m), 7.98 (1H, m), 8.04 (1H, m), 8.25
(1H, dd, J=2.0, 6.4 Hz).
Hz), 132.5, 132.8 (d, J=10 Hz), 133.6 (d, J=10 Hz),
40.0, 157.2 (d, J=252 Hz), 164.1 (d, J=253 Hz), 194.6,
1