Copper(II) acetate catalyzed cross-coupling of pentafluorophenylboronic acid with amines under an atmosphere of oxygen

Article abstract of DOI:10.1055/s-0028-1083568

Under an atmosphere of oxygen and a catalytic amount of Cu(OAc) ₂, pentafluorophenylboronic acid reacted with anilines at room temperature to produce the corresponding N-pentafluorophenylanilines in moderate to good yields. In the case of alkylamines, unexpected N-alkyl-2,2′,3, 3′,4′,5,5′,6,6′-nona-fluorobiphenyl-4-amines were formed under the similar conditions in moderate yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083568

2888
LETTER
Copper(II) Acetate Catalyzed Cross-Coupling of Pentafluorophenylboronic
Acid with Amines under an Atmosphere of Oxygen
C
ross-Coupling of Penta
e
fluorophen
i
ylboro
h
A
cid
w
ith
u
Amines i Zhong, Zhenyu Liu, Chuanming Yu, Weike Su*
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences,
Zhejiang University of Technology, Hangzhou 310014, P. R. of China
Fax +86(571)88320752; E-mail: suweike@zjut.edu.cn
Received 15 July 2008
Pentafluorophenylboronic acid (1) is an inactive substrate
Abstract: Under an atmosphere of oxygen and a catalytic amount
of Cu(OAc)2, pentafluorophenylboronic acid reacted with anilines
at room temperature to produce the corresponding N-pentafluoro-
phenylanilines in moderate to good yields. In the case of alkyl-
under normal conditions.7 The unique nature of pentaflu-
orophenyl group sometimes causes synthetic problems,
for instance, in Suzuki–Miyaura coupling reaction.8 This
amines, unexpected N-alkyl-2,2¢,3,3¢,4¢,5,5¢,6,6¢-nona-fluoro- reaction involves the cross-coupling of arylboronic acids
biphenyl-4-amines were formed under the similar conditions in
moderate yields.
with aryl halides in the presence of Pd catalyst and a base
such as K2CO3. However, a similar reaction conducted on
Key words: copper acetate, pentafluorophenylboronic acid,
amines, N-pentafluorophenylanilines, cross-coupling
pentafluorophenylboronic acid with aryl halides did not
proceed under the general reaction conditions. The strong
electron-withdrawing nature of the pentafluorophenyl
group might play an important role in preventing the reac-
N-Arylation reaction of amines, amides, imides, and sul- tion from happening.9 Very recently, Korenaga10a have
fonamides with arylboronic acids has recently gained con- developed an efficient coupling reaction of C6F5B(OH)2
siderable attention due to their widely application in with aryl bromides in the presence of Pd2(dba)3, P(t-Bu)3,
pharmaceutical and agrochemical industries.1 Various CsF, and Ag2O and got excellent results, while C6F5 was
carbon–nitrogen bond-formation reactions were investi- susceptible to ipso substitution when KOt-Bu as a base
gated since Chan and Lam2 demonstrated firstly was used (Scheme 1).10b,c To the best of our knowledge,
Cu(OAc)2-catalyzed cross-coupling of arylboronic acid C–N bond formation using pentafluorophenylboronic
and nitrogen-based nucleophiles. An important discovery acid as substrate has not been reported by now. We imag-
by Collman3 showed that the arylation of imidazoles ine C–N bond formation with pentafluorophenylboronic
could be catalyzed by [Cu(OH)TMEDA]2Cl2. Later, a acid is of particular interest and challenging.
new publication by Lam4 had shown that Cu(OAc)2 could
promote the cross-coupling of arylboronic acids with
Recently, we have investigated the N-arylation reaction of
pentafluorophenylboronic acid (1) with amines catalyzed
by copper catalysts. Preliminary experiments were carried
out using aniline (2a) as a typical N-nucleophile under
amines or phenols when various oxidants were employed.
Buchwald5 had also investigated a Cu(OAc)2-catalyzed
cross-coupling of arylboronic acids with aromatic amines
to give the N-arylation products in excellent yields, while
the aliphatic ones produced poor results under the similar
conditions. Based on these studies, further improvements
different reaction conditions (Scheme 2). Except for the
corresponding product 3a, pentafluorobenzene (4) and
perfluorobiphenyl (5) were also isolated as byproducts.11
When this reaction was carried out in the presence of Et3N
or pyridine, only trace amount of product 3a was isolated
to the catalytic variation of boronic acid cross-coupling
have been reported.6
OH
Ar
F
F
F
F
oxidative
reaction
Suzuki
F
F
F
F
coupling
CsF
B(OH)2
F
F
F
F
F
Ar
F
F
F
H
N
C–N coupling
reaction
F
F
F
F
Suzuki
coupling
F
F
F
Ar
1
t-BuOK
?
F
Ot-Bu
Scheme 1
SYNLETT 2008, No. 18, pp 2888–2892
1
4
.1
1
.2
0
0
8
Advanced online publication: 16.10.2008
DOI: 10.1055/s-0028-1083568; Art ID: W11308ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cross-Coupling of Pentafluorophenylboronic Acid with Amines
2889
B(OH)2
F
F
F
F
F
F
F
F
F
F
F
NHPh
F
F
F
F
Cu(OAc)2 (20 mol%)
EtOAc, O2, r.t.
F
F
PhNH2
+
+
+
F
F
F
F
F
F
F
F
1
2a
3a
4
5
Scheme 2
B(OH)2
NH2
F
H
F
F
F
F
N
Cu(OAc)2 (20 mol%)
EtOAc, O2, r.t.
+
byproducts
+
F
F
R1
R1
F
F
F
2
3 40–80%
1
R1 = alkyl, X
Scheme 3
but considerable amount of pentafluorobenzene (4) was Cu(OAc)2 was essential and acted as a more efficient cat-
formed, so we deduced that the cleavage reaction of alyst for these reactions (Table 1, entries 3, 4, 10, and 11),
pentafluorophenylboronic acid (1) was facile under basic (b) increasing the temperature or prolonging the reaction
medium (Table 1, entry 12).
time was not helpful to the reaction yields (Table 1, en-
tries 2 and 5), (c) EtOAc was a more appropriate solvent
for this reaction (Table 1, entries 6–8), and (d) no product
3a was detected in the absence of oxygen12 (Table 1, entry
9). So the optimal reaction conditions involved a
Cu(OAc)2-catalyzed cross-coupling of pentafluorophe-
nylboronic acid (1) with amines under an atmosphere of
oxygen without the addition of other bases.
In order to optimize the reaction conditions, various fac-
tors including catalysts, solvents, reaction temperature,
and time were investigated, and the results are summa-
rized in Table 1. According to Table 1, we found (a)
Table 1 Copper-Catalyzed Coupling of Pentafluorophenylboronic
Acid with Anilinea
Entry Catalyst
Solvent
Temp
(°C)
Time
(h)
Yield of 3a
Table 2 Cu(OAc)2-Catalyzed Coupling of Pentafluorophenylbo-
(%)b
ronic Acid with Aromatic Aminesa
1
2
Cu(OAc)2
Cu(OAc)2
Cu(OTf) 2
CuI
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
DMF
25
25
25
25
50
25
25
25
25
25
25
25
3
24
3
70
Entry
1
R1
Time (h)
Product 3 Yield (%)b
72
H
3
5
3a
3b
3c
3d
3e
3f
70
65
75
80
45
50
40
70
60
65
67
60
73
trace
3
50
2
4-Cl
4
24
3
ND
73
3
4-Me
3
5
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
4
4-MeO
2-Et
3
6
3
15
5
24
24
24
5
7
MeOH
THF
3
10
6
2-Me-3-Cl
2,6-(i-Pr)2
3-Me
8
3
45
7
3g
3h
3i
9
EtOAc
EtOAc
EtOAc
EtOAc
24
3
NDc
ND,d 25e
45f
8
10
11
12
9
3-Cl
6
3
10
11
12
13
14
3,5-F2
3,4-F2
2,3,4-F3
2,5-Me2
4-O2N
12
12
24
8
3j
24
traceg
3k
3l
a Conditions: 1 (1.5 mmol), 2a (1.0 mmol), Cu(OAc)2 (0.2 mmol) O2
(1.01·105 Pa).
b Isolated yields based on 2a; ND = not detected.
c The reaction was carried out under an atmosphere of argon (1.01·105
Pa).
3m
–
48
d In the absence of Cu(OAc)2.
e Cu(OAc)2 (0.1 equiv) was used.
f Cu(OAc)2 (1 equiv) was used.
a Conditions: 1 (1.5 mmol), 2 (1.0 mmol), Cu(OAc)2 (0.2 mmol),
EtOAc (15 mL), O2 (1.01·105 Pa), r.t.
g Et3N or pyridine as base.
b Isolated yields based on 2.
Synlett 2008, No. 18, 2888–2892 © Thieme Stuttgart · New York

2890
W. Zhong et al.
LETTER
Table 3 Copper-Catalyzed Coupling of Pentafluorophenylboronic
With the optimal conditions in hand, in order to assess the
scope of this method, a series of aromatic amines were in-
vestigated to react with pentafluorophenylboronic acid
(Scheme 3) and the results are summarized in Table 2.
The yields varied from 40% to 80%. It was found that both
electron-withdrawing and -donating substituents in para
or meta position were tolerated in the reaction (entries 2–
4, 8–10). The ortho substituents in aromatic amines had a
dramatic influence on the reaction yields due to the steric
hindrance (entries 5–7).
Acid with Diethylaminea
Entry
Solvent
Time
(h)
Temp
(°C)
Yield of 7a Yield of 4
(%)b
15, 10c
11
(%)b
75, 80c
75
1
2
3
4
5
6
7
8
EtOAc
EtOAc
EtOAc
DMF
12
24
12
12
12
12
12
24
25
25
50
25
25
50
25
25
20
70
45
45
After achieving satisfactory results with aromatic amines,
we further applied this catalytic system for aliphatic
amines (Scheme 4). Taking diethylamine (6a) as a typical
N-nucleophile, it was surprising to find that the product
was not N,N-diethyl-2,3,4,5,6-pentafluoroaniline but the
unexpected product N,N-diethyl-2,2¢,3,3¢,4¢,5,5¢,6,6¢-
nonafluorobiphenyl-4-amine (7a) with a large amount of
pentafluorobenzene (4, Table 3, entry 1). To our delight,
when using DMF as solvent, the yield of 7a will be greatly
increased to 45% (Table 3, entry 4). Moreover, simply
mixing diethylamine and pentafluorophenylboronic acid
led to a neutralization reaction and formed the byproduct
4 in 90% yield (Table 3, entry 8). The possible reason was
that the alkalinity of aliphatic amines was strong enough
and benefit to the decomposition of pentafluorophenylbo-
ronic acid (Scheme 5). Several aliphatic amines were test-
ed and similar results were obtained (Table 4).
DMF
25
55d
40
DMF
47
MeOH
DMF
25
60
NDe
90e
a Conditions: 6a (1.0 mmol), 1 (2.0 mmol), Cu(OAc)2 (1.0 mmol), O2
(1.01·105 Pa).
b Isolated yields based on 6a; ND = not detected.
c Cu(OAc)2 (0.2 mmol) was used.
d The ratio 6a/1 = 1.0:1.5.
e In the absence of Cu(OAc)2.
B(OH)2
F
F
F
no cat.
Et2NH
(HO)2B NEt
2 + 4
+
F
6a
+
H
According to the experimental results, we presumed that
the reaction process included two steps: the first step was
that Cu(OAc)2 promoted the transformation of pentaflu-
orophenylboronic acid (1) into perfluorobiphenyl (5) in
the presence of alkylamines; then 5 subsequently reacted
F
1
+ (HO) B NEt2
H
2
F
F
F
F
–
F
F
F
F
OH
–
F
B
N+Et2
OH
with alkylamines to form the target product
7
F
(Scheme 6).13 Actually, when the reaction of substrate 1
with diethylamine was quenched within 1 hour, a mixture
of 7a and perfluorobiphenyl (5) could be detected. If the
reaction time was prolonged to 12 hours, 7a was isolated
as the sole product. On the other hand, when the isolated
perfluorobiphenyl (5) reacted with diethylamine under the
similar condition for 12 hours, the corresponding N,N-di-
ethyl-2,2¢,3,3¢,4¢,5,5¢,6,6¢-nonafluorobiphenyl-4-amine
(7a) was also obtained. Although 5 was also isolated dur-
ing the reaction of pentafluorophenylboronic acid with ar-
omatic amines, the subsequent nucleophilic reaction did
not proceed, may be due to the weaker nucleophilicity of
aromatic amines (Scheme 6).
Scheme 5
Table 4 Cu(OAc)2-Catalyzed Coupling of Pentafluorophenylbo-
ronic Acid with Aliphatic Aminesa
Entry
Amine
Product 7 Yield of 7 (%)b Yield of 4 (%)b
1
2
3
4
Et2NH
7a
7b
7c
7d
45
45
40
45
45
47
48
42
i-PrNH
piperidine
n-BuNH2
a Conditions: 6 (1.0 mmol), 1 (2.0 mmol), Cu(OAc)2 (1.0 mmol),
DMF (25 mL), O2 (1.01·105 Pa), r.t., 12 h.
b Isolated yields based on 6.
In summary, we developed an efficient preparation of N-
pentafluorophenylanilines via Cu(OAc)2 catalyzing the
cross-coupling of pentafluorophenylboronic acid with
B(OH)2
F
F
F
F
F
F
F
R2
R3
F
F
F
H
N
Cu(OAc)2 (100 mol%)
DMF, O2, r.t.
F
N
+
4
+
R2
R3
F
F
F
1
R2,R3 = H, alkyl
7
6
Scheme 4
Synlett 2008, No. 18, 2888–2892 © Thieme Stuttgart · New York

LETTER
Cross-Coupling of Pentafluorophenylboronic Acid with Amines
2891
B(OH)2
F
F
F
F
F
F
F
F
F
F
Cu(OAc)2 (100 mol%)
DMF, O2, r.t.
+ NHR2R3
F
NR2R3
4
+
F
F
F
7
6
1
F
F
F
F
F
F
F
F
NHR2R3
ArNH2
Cu(OAc)2
F
F
no reaction
R2,R3 = H, alkyl
5
Scheme 6
aromatic amines under an atmosphere of oxygen.14 The
unexpected N-alkyl-2,2¢,3,3¢,4¢,5,5¢,6,6¢-nonafluorobiphe-
nyl-4-amine was formed in the case of alkylamines.15 Fur-
ther studies on the application of pentafluoro-
phenylboronic acid are now in progress in our laboratory.
(7) (a) Havelková, M.; Dvorřák, D.; Hocek, M. Synthesis 2001,
1704. (b) Havelková, M.; Hocek, M.; Cÿesnek, M.; Dvorřák,
D. Synlett 1999, 1145.
(8) (a) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419.
(b) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002,
58, 9633. (c) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz,
E.; Lemaire, M. Chem. Rev. 2002, 102, 1359.
(9) Korenaga, T.; Kadowaki, K.; Ema, T.; Sakai, T. J. Org.
Supporting Information for this article is available online at
Chem. 2004, 69, 7340.
http://www.thieme-connect.com/ejournals/toc/synlett.
(10) (a) Korenaga, T.; Kosaki, T.; Fukumura, R.; Ema, T.; Sakai,
T. Org. Lett. 2005, 7, 4915. (b) Chen, J.; Cammers, G. A.
Tetrahedron Lett. 2003, 44, 1503. (c) Takimiya, K.;
Niihara, N.; Otsubo, T. Synthesis 2005, 1589.
Acknowledgment
(11) (a) Chanbers, R. D.; Chivers, T. J. Chem. Soc. 1965, 3933.
(b) Frohn, H. J.; Adomin, N. Y.; Bardin, V. V.; Starichenko,
V. F. Z. Anorg. Allg. Chem. 2002, 628, 2834.
(12) (a) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.;
Averill, K.; Chan, D. M. T.; Combs, A. P. Synlett 2000, 674.
(b) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett.
1998, 39, 2937.
(13) Platonov, V. E.; Haas, A.; Schelvis, M.; Lieb, M.;
Dvornikova, K. V.; Osina, O. I. J. Fluorine Chem. 2002,
116, 3.
(14) Typical Procedure for the Preparation of Compound 3b
Copper(II) acetate (0.2 mmol) was added to a stirred mixture
of EtOAc (15 mL) and pentafluorophenylboronic acid (1.5
mmol). The mixture was stirred for 10 min at r.t. then the
4-chlorophenylamine (1.0 mmol) was slowly added to the
mixture. The reaction mixture was stirred sequentially for
5 h under the atmosphere of oxygen. The reaction was
monitored by TLC and quenched with H2O (5 mL). The
resulting mixture was filtrated through a pad of Celite and
the filtrate was extracted with EtOAc (3 × 15 mL). The
combined organic layers were dried over Na2SO4, filtered,
and concentrated under reduced pressure to give a crude
product, which was purified by column chromatography to
give N-(4-chlorophenyl)-2,3,4,5,6-pentafluoroaniline (3b).
Light yellow crystals; mp 78.5–79.8 °C. IR (KBr): 3417,
3133, 1524, 1495, 1399 cm–1. 1H NMR (500 MHz, CDCl3):
d = 5.39 (br, 1 H), 6.75 (d, 2 H, J = 7.5 Hz), 7.23 (d, 2 H,
J = 7.0 Hz). 13C NMR [100 MHz, CDCl3 (except for C6F5)]:
d = 117.7 (2 × CH), 126.9, 129.2 (2 × CH), 140.7. 19F NMR
(376 MHz, CDCl3): d = –158.98 (t, 1 F, J = 21.4 Hz),
–158.57 (dd, 2 F, J1 = 21.4 Hz, J2 = 21.4 Hz), –145.46 (d,
2 F, J = 19.6 Hz). MS (EI): m/z (%) = 293 (8) [M+], 273 (4),
238 (8), 151 (100), 88 (38). HRMS (EI): m/z calcd for
C12H5ClF5N: 293.0031; found: 293.0030.
We thank the National Key Technology R&D Program [No:
2007BAI34B01], National Natural Science Foundation of China
[20676123 and 20476098], Zhejiang Province Project of Sciences
and Technology [No: 2006C11018] for financial support.
References and Notes
(1) (a) Iizuka, K.; Akahane, K.; Momose, D. I.; Nakazawa, M.;
Tanouchi, T.; Kawamura, M.; Ohyama, I.; Kajiwara, I.;
Ignchi, Y.; Okada, T.; Taniguchi, K.; Miyamoto, T.;
Hayashi, M. J. Med. Chem. 1981, 24, 1139. (b) Cozzi, P.;
Carganico, G.; Fusar, D.; Grossoni, M.; Menichincheri, M.;
Pinciroli, V.; Tonani, R.; Vaghi, F.; Salvati, P. J. Med.
Chem. 1993, 36, 2964. (c) Lam, P. Y. S.; Vincent, G.; Clark,
C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42,
3415.
(2) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters,
M. P. Tetrahedron Lett. 1998, 39, 2933. (b) Lam, P. Y. S.;
Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan,
D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941.
(3) (a) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233.
(b) Collman, J. P.; Zhong, M.; Zeng, L.; Costano, S. J. Org.
Chem. 2001, 66, 1528. (c) Collman, J. P.; Zhong, M.;
Zhang, C.; Costanzo, S. J. Org. Chem. 2001, 66, 7892.
(4) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav,
P. K. Tetrahedron Lett. 2001, 42, 3415.
(5) (a) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077.
(b) Sasaki, M.; Dalili, S.; Yudin, A. K. J. Org. Chem. 2003,
68, 2045.
(6) (a) Kantam, M. L.; Venkanna, G. T.; Sridhar, C.; Sreedhar,
B.; Choudary, B. M. J. Org. Chem. 2006, 71, 9522. (b)Dai,
Q.; Ran, C. Z.; Harvey, R. G. Tetrahedron 2006, 62, 1764.
(c) Tzschucke, C. C.; Murphy, J. M.; Hartwig, J. F. Org.
Lett. 2007, 9, 761. (d) Lan, J. B.; Zhang, G. L.; Yu, X. Q.;
You, J. S.; Chen, L.; Yan, M.; Xie, R. G. Synlett 2004, 1095.
(15) Typical Procedure for the Preparation of Compound 7a
Copper(II) acetate (1 mmol) was added to a stirred mixture
of DMF (25 mL) and pentafluorophenylboronic acid (2
mmol). The mixture was stirred for 10 min at r.t. then the
Synlett 2008, No. 18, 2888–2892 © Thieme Stuttgart · New York

2892
W. Zhong et al.
LETTER
2917, 1644, 1503, 1384, 1046 cm–1. 1H NMR (400 MHz,
Et2NH (1.0 mmol) were slowly added to the mixture. The
reaction mixture was stirred sequentially for 12 h under the
atmosphere of oxygen. The reaction was monitored by TLC
and quenched with H2O (5 mL). The resulting mixture was
filtrated through a pad of Celite, and the filtrate was
extracted with EtOAc (3 × 15 mL). The combined organic
layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure to give a crude product, which was
purified by column chromatography to give N,N-diethyl-
2,2¢,3,3¢,4¢,5,5¢,6,6¢-nonafluorobiphenyl-4-amine (7a).
Light yellow crystal; mp 71.6–72.5 °C. IR (KBr): 2976,
CDCl3): d = 1.16 (t, 6 H, J = 7.2 Hz), 3.33 (q, 4 H, J = 7.2
Hz). 13C NMR [100 MHz, CDCl3 (except for C12F9)]:
d = 13.4 (2 × CH), 46.8 (2 × CH). 19F NMR (376 MHz,
CDCl3): d = –157.56 to –157.43 (m, 2 F), –147.96 (t, 1 F,
J = 21.4 Hz), –145.62 to –145.568 (m, 2 F), –137.16 to
–137.09 (m, 2 F), –133.91 to –133.83 (m, 2 F). MS (EI):
m/z (%) = 387 (25) [M+], 358 (15), 372 (100), 344 (75).
HRMS (EI): m/z calcd for C16H10F9N: 387.0670; found:
387.0672.
Synlett 2008, No. 18, 2888–2892 © Thieme Stuttgart · New York

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