N-heterocyclic carbene catalyzed nucleophilic acylation of trifluoromethyl ketimines

Article abstract of DOI:10.1055/s-0029-1217070

An efficient N-heterocyclic carbene (NHC)-catalyzed nucleophilic acylation of trifluoromethyl ketimines has been developed. The combination of N-aryl trifluoromethyl ketimines with various furan-2-carbaldehydes leads chemoselectively to the corresponding α-amino-α-trifluoromethyl ketones in moderate to very good yields (32-87%) providing ready access to this pharmaceutically important class of compounds. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1217070

PAPER
4125
N-Heterocyclic Carbene Catalyzed Nucleophilic Acylation of Trifluoromethyl
Ketimines
a
-Amino-
a
-trifluo
i
rometh
e
K
etonester Enders,* Alexander Henseler, Sebastian Lowins
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(214)8092127; E-mail: enders@rwth-aachen.de
Received 28 August 2009
the use of ketimines, particularly trifluoromethyl
ketimines, as electrophilic components in carbene-
catalyzed nucleophilic acylations.
Abstract: An efficient N-heterocyclic carbene (NHC)-catalyzed
nucleophilic acylation of trifluoromethyl ketimines has been devel-
oped. The combination of N-aryl trifluoromethyl ketimines with
various furan-2-carbaldehydes leads chemoselectively to the corre-
sponding a-amino-a-trifluoromethyl ketones in moderate to very
good yields (32–87%) providing ready access to this pharmaceuti-
cally important class of compounds.
In a recent communication we have reported on a crossed
direct intermolecular benzoin-type reaction by employing
aromatic and heteroaromatic aldehydes and aromatic tri-
fluoromethyl ketones (X = O; Scheme 1).9
Key words: organocatalysis, N-heterocyclic carbenes, aldehyde/
ketimine cross-coupling, a-amino-a-trifluoromethyl ketones, um-
polung
Ph
N
N
BF4
N
O
X
O
precatalyst, base
XH
The catalytic nucleophilic addition of an acyl-anion
equivalent to carbonyl compounds and Michael acceptors,
known as benzoin and Stetter reactions, respectively, be-
long to the most prominent and powerful synthetic tools in
carbene organocatalysis.1 Their broad synthetic applica-
bility has its origins in the early days of organic
chemistry2 and have evolved from there to become highly
established transformations in organic synthesis with a
great number of both inter- and intramolecular as well as
enantioselective versions.3
+
R1
R2
CF3
R1
R2 CF3
X = O, NAr
Scheme 1 Crossed direct intermolecular benzoin-type reactions
Previous mechanistic observations revealed fast and re-
versible formation of the homo-benzoin product prior to
the actual transformation,8,10 and the good results we ob-
tained for the generation of the a-hydroxy-a-trifluoro-
methyl ketones inspired us to broaden the substrate scope
of this crossed direct intermolecular benzoin-type reac-
tion by using trifluoromethyl ketimines as electrophiles
(X = NAr). We started our investigations by screening
different aromatic and heteroaromatic aldehydes 1 and tri-
fluoromethyl ketimine 2 in the presence of 10 mol% tri-
azolium salt 4 and 20 mol% base in THF (Scheme 2,
Table 1). Unfortunately, the reactivity of the benzalde-
hyde turned out to be insufficient for this transformation
since even after a prolonged reaction time, only trace
amounts of the product 3 could be observed (entry 3).
However, by using the more reactive heteroaromatic fur-
fural, the corresponding a-amino-a-trifluoromethyl ke-
tone 3 was formed with a promising preliminary yield of
45% (entry 4). By changing the employed base from DBU
to Cs2CO3, the initial result could be enhanced to 87%
yield (entry 5). Subsequently, other heteroaromatic alde-
hydes such as thiophen-2- and indol-2-carbaldehyde were
tested; however, they showed no activity in this transfor-
mation (entries 6 and 7).
However, the use of imines as electrophilic partners in
carbene-catalyzed acyl anion additions have been studied
much less, in spite of the pharmacologically importance
of the resulting a-amino-ketones.4 Since, generally, two
electrophiles (aldehyde and imine) are exposed to the car-
bene catalyst during the reaction course, the electronic na-
ture of the imine component needs to be balanced
carefully between: (i) being reactive enough to compete
with the aldehyde in the reaction with the Breslow inter-
mediate and (ii) being too reactive, leading ultimately to
stable and unreactive catalyst–imine adducts.5 Neverthe-
less, a few research groups were able to fulfill this chal-
lenging task by employing iminium salts formed in situ,6
arylsulfonylamides as acylimine precursors7 and N-
phosphinoylimines5b in combination with acylsilanes in
carbene-catalyzed acyl anion additions. Recently You et
al. reported a thiazolium-derived NHC-catalyzed cross-
coupling of aldehydes with N-aryl imines under thermo-
dynamic control.8
Besides these excellent contributions there is, to the best
of our knowledge, no literature precedence for reports on
Under the best conditions (10 mol% triazolium salt 4 and
20 mol% Cs2CO3 in THF), other N-aryl trifluoromethylat-
ed ketimines 6 and furan-carbaldehyde derivatives 5 were
then tested (Scheme 3, Table 2).
SYNTHESIS 2009, No. 24, pp 4125–4128
x
x.
x
x
.
2
0
0
9
Advanced online publication: 22.10.2009
DOI: 10.1055/s-0029-1217070; Art ID: Z18309SS
© Georg Thieme Verlag Stuttgart · New York

4126
D. Enders et al.
PAPER
4 (10 mol%)
Eight different a-amino-a-trifluoromethyl ketones 7a–h
could be isolated in moderate to very good yields (32–
87%; Table 2). Besides furfural, the best results concern-
ing the furancarbaldehyde component in combination
with trifluoromethyl ketimine 2 were obtained with 5-(4-
chlorophenyl)furan-2-carbaldehyde (7g; 71% yield) fol-
lowed by 4,5-dimethylfuran-2-carbaldehyde (7f; 59%
yield) and benzofuran-2-carbaldehyde (7h; 51% yield). It
is worth noting that the use of 5-methylfuran-2-carbalde-
hyde in the reaction of trifluoromethyl ketimine 2, result-
ed in remarkably low levels of product formation (32%
Ph
N
O
base (20 mol%)
THF, r.t., time
O
NHPh
+
R1
R1
Ph
CF3
Ph CF3
Ph
N
N
1
2
3
BF4
1 equiv
2 equiv
N
4
Scheme 2 NHC-catalyzed aldehyde/trifluoromethyl ketimine
cross-couplings
Table 1 Substrate Screening for the Direct Intermoelcular Benzoin- yield) of the corresponding a-amino-a-trifluoromethyl
ketone 7e. By changing the ketimine substituent R4 from
Type Reaction of Aldehydes with Trifluoromethyl Ketimines
N-phenyl to the more electron-rich N-4-methoxyphenyl, a
Entry
R1
Base
Time (h) Yield (%)a
decrease in yield from 87% to 66% was be observed in the
formation of the cross-product 7b. A similar decrease in
yield was also found when R3 was modified to the slightly
more electron-poor para-chlorophenyl group (7c; 69%
yield). When both R3 and R4 groups were changed to
para-chlorophenyl and para-methoxyphenyl groups, the
corresponding a-amino-a-trifluoromethyl ketone 7d
could be obtained in 55% yield. Noteworthy is the fact
that the excess ketimine component 6 employed could be
easily regained for further use during the separation of the
reaction mixture by column chromatography.
1
2
3
4
5
6
7
Ph
DBU
15
15
0
0
Ph
Cs2CO3
DBU
Ph
3d
trace
45
87
0
2-furanyl
2-furanyl
2-thiophenyl
2-indolyl
DBU
15
15
15
15
Cs2CO3
Cs2CO3
Cs2CO3
0
In summary, we have developed the first NHC-catalyzed
nucleophilic acylation of ketimines. The cross-couplings
of N-aryl trifluoromethyl ketimines with furancarbalde-
hydes chemoselectively afforded the corresponding a-
amino-a-trifluoromethyl ketones in moderate to very
good yields (32–87%). The product a-amino ketones
bearing a quaternary stereocenter and a trifluoromethyl
group are useful synthetic building blocks and valuable
pharmaceutical intermediates, which can be readily ac-
cessed via this novel protocol.
a Yield of the isolated pure product.
4 (10 mol%)
Cs2CO3 (20 mol%)
THF, r.t., 15 h
O
O
R4
NHR4
O
O
N
R1
+
R1
R3 CF3
R3
CF3
Ph
N
N
N
R2
R2
BF4
5
6
7
1 equiv
2 equiv
4
Scheme 3 Direct intermolecular benzoin-type reaction of furan-2-
carbaldehydes with trifluoromethyl ketimines
All reactions were performed in oven-dried glassware under a slight
positive pressure of argon. All solvents were dried by conventional
methods. Toluene and THF were freshly distilled from Na/Pb alloy
under argon. The furanyl-2-carbaldehydes and other starting mate-
rials and reagents were purchased from commercial suppliers and
used without further purification. The N-aryl trifluoromethyl
ketimines 6a, 6b and 6d were prepared according to literature pro-
cedures.11 Preparative column chromatography: Merck silica gel
60, particle size 0.040–0.064 mm (230–240 mesh, flash). Analyti-
cal TLC: silica gel 60, F254 plates from Merck, Darmstadt. IR spec-
tra were taken on a Perkin–Elmer FT-IR 1760 spectrophotometer.
1H, 13C and 19F NMR spectra were recorded on Varian Gemini 300,
Mercury 300 or Inova 400 spectrometers and all measurements
were performed with TMS as internal standard. High resolution
mass spectra were acquired on a Finnigan MAT 95 spectrometer.
Microanalyses were obtained with a Vario EL element analyzer.
Melting points were determined with a Tottoli melting point appa-
ratus and are uncorrected.
Table 2 Substrate Scope of the NHC-Catalyzed Aldehyde/Trifluo-
romethyl Ketimines Cross Coupling
7
R1
R2
R3
R4
Yield
(%)a
a
b
c
d
e
f
H
H
Ph
Ph
87
66
69
55
32
59
72
H
H
Ph
4-MeOC6H4
H
H
4-ClC6H4
4-BrC6H4
Ph
Ph
H
H
4-MeOC6H4
Me
H
Ph
Ph
Ph
Me
Me
H
Ph
g
4-ClC6H4
Ph
N-[1-(4-Chlorophenyl)-2,2,2-trifluoroethylidene]aniline (6c)
1-(4-Chlorophenyl)-2,2,2-trifluoroethanone (1.25 g, 6.00 mmol)
and triphenylphosphine-phenylimine (2.12 g, 6.00 mmol) were dis-
solved in toluene (25 mL) and refluxed at 120 °C for 24 h. After-
wards, the reaction mixture was treated repeatedly with n-pentane,
whereupon triphenylphosphine oxide precipitated out of the solu-
h
Ph
Ph
52
a Yield of the isolated pure product.
Synthesis 2009, No. 24, 4125–4128 © Thieme Stuttgart · New York

PAPER
a-Amino-a-trifluoromethyl Ketones
4127
tion. The precipitate was filtered off and the solvent was removed
under reduced pressure. Purification via Kugelrohr distillation (bp
120 °C, 0.1 bar) afforded the pure ketimine 6c.
19F NMR (376 MHz, CDCl3): d = –67.22 (CF3).
MS (EI, 70 eV): m/z (%) = 375 (15) [M+], 281 (17), 280 (100), 210
(20), 202 (13), 95 (22).
Yield: 1.50 g (88%); yellow oil.
Anal. Calcd for C20H16F3NO3: C, 64.00; H, 4.30; N, 3.73. Found: C,
64.20; H, 4.32; N, 3.83.
IR (film): 3441, 3066, 2918, 2850, 1941, 1906, 1789, 1715, 1660,
1593, 1540, 1489, 1450, 1400, 1384, 1330, 1266, 1232, 1198, 1135,
1094, 1018, 971, 903, 836, 776, 750, 693, 637, 578, 546, 495 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.04–7.19 (m, 6 H), 6.96 (t,
J = 7.0 Hz, 1 H), 6.64 (d, J = 7.0 Hz, 2 H).
2-(4-Chlorophenyl)-3,3,3-trifluoro-1-(furan-2-yl)-2-(phenyl-
amino)propan-1-one (7c)
Yield: 0.141 g (69%); colorless solid; mp 182 °C.
IR (film): 3430, 3126, 3057, 2925, 2845, 2543, 2323, 2172, 2105,
2020, 1907, 1834, 1798, 1735, 1665, 1603, 1556, 1499, 1456, 1436,
1409, 1390, 1316, 1266, 1237, 1200, 1165, 1098, 1021, 956, 921,
877, 830, 806, 764, 736, 689, 666 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.39–7.42 (m, 3 H), 7.29 (d,
J = 8.9 Hz, 2 H), 6.91–6.95 (m, 2 H), 6.71 (d, J = 3.7 Hz, 1 H), 6.64
(t, J = 7.3 Hz, 1 H), 6.42 (d, J = 7.9 Hz, 2 H), 6.30 (dd, J = 3.7, 1.7
Hz, 1 H), 5.75 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 179.6, 149.3, 147.8, 147.8, 135.2,
132.1, 129.9, 129.7, 129.2, 124.2 (q, J = 289.3 Hz, CF3), 123.2,
119.6, 116.9, 112.5, 72.1 (q, J = 27.4 Hz, CCF3).
19F NMR (376 MHz, CDCl3): d = –67.28 (CF3).
13C NMR (100 MHz, CDCl3): d = 155.5 [q, J = 34.1 Hz, C(N)CF3],
146.7, 136.6, 130.1, 128.9, 128.9, 128.2, 125.6, 120.3, 119.7 (q,
J = 278.7 Hz, CF3).
19F NMR (376 MHz, CDCl3): d = –69.93 (CF3).
MS (EI, 70 eV): m/z (%) = 283 (46) [M+], 262 (12), 216 (31), 215
(15), 214 (100), 139 (28), 118 (21), 77 (57), 51 (25).
Anal. Calcd for C14H9ClF3N: C, 59.28; H, 3.20; N, 4.94. Found: C,
59.07; H, 2.99; N, 5.28.
Synthesis of the a-Amino-a-trifluoromethyl Ketones 7a–h;
General Procedure
The aldehyde 5 (0.5 mmol, 1.0 equiv), trifluoromethyl ketimine 6
(1.0 mmol, 2.0 equiv), and the precatalyst 4 (14 mg, 0.05 mmol,
0.1 equiv) were dissolved in THF (1.5 mL), treated with Cs2CO3
(33 mg, 0.10 mmol, 0.2 equiv) and stirred at r.t. for 15 h. After-
wards, the reaction mixture was directly purified by flash chroma-
tography on silica gel (n-pentane–Et2O, 7:2) to afford the
corresponding a-amino-a-trifluoromethyl ketone 7.
MS (EI, 70 eV): m/z (%) = 379 (3) [M+], 286 (20), 285 (12), 284
(58), 216 (12), 214 (38), 172 (18), 95 (63), 77 (100), 51 (35).
Anal. Calcd for C19H13ClF3NO2: C, 60.09; H, 3.45; N, 3.69. Found:
C, 59.99; H, 3.40; N, 3.69.
2-(4-Bromophenyl)-3,3,3-trifluoro-1-(furan-2-yl)-2-(4-meth-
oxyphenylamino)propan-1-one (7d)
Yield: 0.125 g (55%); yellow solid; mp 117 °C.
3,3,3-Trifluoro-1-(furan-2-yl)-2-phenyl-2-(phenylamino)pro-
pan-1-one (7a)
IR (film): 3401, 3143, 3126, 3066, 3033, 3001, 2957, 2930, 2899,
2833, 2324, 2161, 2082, 2011, 1989, 1969, 1859, 1782, 1736, 1666,
1590, 1555, 1513, 1491, 1455, 1406, 1389, 1315, 1289, 1254, 1231,
1201, 1164, 1118, 1104, 1083, 1026, 1012, 954, 923, 883, 821, 805,
768, 730, 710, 688, 667 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.47–7.50 (m, 3 H), 7.36 (d,
J = 8.3 Hz, 2 H), 6.76 (d, J = 3.6 Hz, 1 H), 6.58 (d, J = 8.9 Hz, 2 H),
6.47 (d, J = 8.9 Hz, 2 H), 6.37 (dd, J = 3.7, 1.6 Hz, 1 H), 5.47 (s,
1 H), 3.66 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 180.1, 153.8, 149.4, 149.4, 144.2,
135.7, 132.0, 130.2, 128.4, 124.1 (q, J = 289.21 Hz, CF3), 123.0,
119.8, 114.1, 112.5, 72.9 (q, J = 26.53 Hz, CCF3), 55.4.
19F NMR (376 MHz, CDCl3): d = –67.32 (CF3).
Yield: 0.150 g (87%); colorless solid; mp 152 °C.
IR (film): 3432, 3127, 3061, 2927, 2738, 2927, 2320, 2110, 2029,
1989, 1744, 1666, 1601, 1555, 1500, 1455, 1434, 1390, 1312, 1265,
1236, 1199, 1165, 1086, 1023, 999, 956, 924, 880, 843, 817, 749,
691 cm-1.
1H NMR (400 MHz, CDCl3): d = 7.44–7.46 (m, 2 H), 7.40–7.41 (m,
1 H), 7.30–7.34 (m, 3 H), 6.91 (t, J = 7.8 Hz, 2 H), 6.60 (t, J = 7.3
Hz, 1 H), 6.56 (d, J = 3.7 Hz, 1 H), 6.44 (d, J = 7.9 Hz, 2 H), 6.25–
6.24 (m, 1 H), 5.78 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 180.2, 149.4, 147.3, 143.1, 133.5,
129.0, 128.7, 128.6, 124.4 (q, J = 289.4 Hz, CF3), 123.0, 120.1,
116.8, 112.4, 111.6, 72.4 (q, J = 26.9 Hz, CCF3).
19F NMR (376 MHz, CDCl3): d = –67.20 (CF3).
MS (EI, 70 eV): m/z (%) = 453 (5) [M+], 360 (60), 358 (69), 290
(11), 288 (13), 202 (13), 135 (26), 123 (13), 12 (26), 108 (20), 107
(32), 95 (100), 92 (24), 77 (35), 64 (11).
MS (EI, 70 eV): m/z (%) = 345 (3) [M+], 251 (14), 250 (100), 180
(29), 172 (16), 95 (34), 77 (50), 51 (16).
HRMS: m/z calcd for C19H14F3NO2: 345.0977; found: 345.0973.
Anal. Calcd for C20H15BrF3NO3: C, 52.88; H, 3.33; N, 3.08. Found:
C, 52.99; H, 3.04; N, 3.07.
3,3,3-Trifluoro-1-(furan-2-yl)-2-(4-methoxyphenylamino)-2-
phenylpropan-1-one (7b)
Yield: 0.124 g (66%); yellow solid; mp 183 °C.
3,3,3-Trifluoro-1-(5-methylfuran-2-yl)-2-phenyl-2-(phenyl-
amino)propan-1-one (7e)
IR (film): 3415, 3157, 3124, 3065, 3009, 2964, 2913, 2841, 2321,
2160, 2067, 1989, 1955, 1744, 1659, 1587, 1556, 1513, 1453, 1386,
1330, 1294, 1251, 1150, 1081, 1037, 1011, 954, 926, 883, 819, 767,
701 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.40–7.42 (m, 3 H), 7.28–7.31 (m,
3 H), 6.54 (d, J = 4.1 Hz, 1 H), 6.49 (d, J = 8.9 Hz, 2 H), 6.41 (d,
J = 8.9 Hz, 2 H), 6.24 (dd, J = 6.2, 1.7 Hz, 1 H), 5.45 (s, 1 H), 3.58
(s, 3 H).
Yield: 0.058 g (32%); colorless solid; mp 151 °C.
IR (film): 3645, 3433, 3122, 3062, 2923, 2858, 2197, 2162, 2114,
1987, 1658, 1600, 1498, 1434, 1366, 1306, 1263, 1234, 1199, 1166,
1087, 1026, 993, 970, 938, 913, 878, 844, 816, 797, 751, 692, 654
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.43–7.45 (m, 2 H), 7.28–7.31 (m,
3 H), 6.87–6.91 (m, 2 H), 6.60 (t, J = 7.3 Hz, 1 H), 6.41–6.43 (m,
3 H), 5.87–5.89 (m, 2 H), 2.43 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 179.1, 159.5, 148.2, 143.2, 134.0,
129.0, 128.9, 128.5, 127.4 (q, J = 289.7 Hz, CF3), 125.9, 125.3,
119.0, 116.8, 109.6, 72.4 (q, J = 27.8 Hz, CCF3), 14.1.
13C NMR (100 MHz, CDCl3): d = 186.4, 153.8, 153.5, 147.5, 136.7,
133.8, 129.0, 128.8, 128.5, 124.3 (q, J = 289.3 Hz, CF3), 122.8,
119.5, 114.0, 112.3, 73.1 (q, J = 31.0 Hz, CCF3), 55.44.
Synthesis 2009, No. 24, 4125–4128 © Thieme Stuttgart · New York

4128
D. Enders et al.
PAPER
19F NMR (376 MHz, CDCl3): d = –67.04 (CF3).
MS (EI, 70 eV): m/z (%) = 359 (10) [M+], 251 (15), 250.1 (100),
124.0, 123.7, 120.7, 119.6, 112.3, 111.1, 105.6, 72.6 (q, J = 27.2
Hz, CCF3).
19F NMR (376 MHz, CDCl3): d = –67.12 (CF3).
180 (17), 109 (10), 77 (12).
Anal. Calcd for C20H16F3NO2: C, 66.85; H, 4.49; N, 3.90. Found: C,
66.88; H, 4.54; N, 3.95.
MS (EI, 70 eV): m/z (%) = 395 (27) [M+], 251 (42), 250.2 (100),
180 (33), 172 (22), 145 (22), 89 (12), 77 (35).
Anal. Calcd for C23H16F3NO2: C, 69.87; H, 4.08; N, 3.54. Found: C,
70.30; H, 4.16; N, 3.35.
1-(4,5-Dimethylfuran-2-yl)-3,3,3-trifluoro-2-phenyl-2-(phenyl-
amino)propan-1-one (7f)
Yield: 0.110 g (59%); yellow solid; mp 180 °C.
Acknowledgment
IR (film): 3647, 3418, 3122, 3021, 2924, 2857, 2322, 2120, 1991,
1944, 1743, 1651, 1602, 1501, 1437, 1370, 1311, 1287, 1262, 1234,
1147, 1076, 1035, 987, 949, 877, 832, 741, 693 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.42–7.44 (m, 2 H), 7.27–7.31 (m,
3 H), 6.87–6.91 (m, 2 H), 6.59 (t, J = 7.3 Hz, 1 H), 6.42 (d, J = 8.1
Hz, 2 H), 6.30 (s, 1 H), 5.91 (s, 1 H), 2.11 (s, 3 H), 1.72 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 178.8, 155.9, 146.8, 143.3, 134.0,
128.8, 128.8, 128.5, 128.5, 127.0, 124.5 (q, J = 289.5 Hz, CF3),
118.9, 118.3, 116.8, 72.0 (q, J = 30.3 Hz, CCF3), 12.1, 9.6.
19F NMR (376 MHz, CDCl3): d = –67.01 (CF3).
This work was supported by the Fonds der Chemischen Industrie
and the Deutsche Forschungsgemeinschaft (priority program orga-
nocatalysis). We thank BASF AG for the donation of chemicals.
References
(1) For reviews, see: (a) Enders, D.; Niemeier, O.; Henseler, A.
Chem. Rev. 2007, 107, 5606. (b) Enders, D.; Balensiefer, T.
Acc. Chem. Res. 2004, 37, 534. Minireviews: (c) Rovis, T.
Chem. Lett. 2008, 2. (d) Marion, N.; Diez-Gonzalez, S.;
Nolan, S. P. Angew. Chem. Int. Ed. 2007, 46, 2988; Angew.
Chem. 2007, 119, 3046 . Highlights: (e) Christmann, M.
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(3) For selected examples of inter-, and intramolecular and
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MS (EI, 70 eV): m/z (%) = 374 (19), 373 (60) [M+], 251 (67), 250
(100), 180 (45), 172 (29), 123 (46), 77 (47).
Anal. Calcd for C21H18F3NO2: C, 67.55; H, 4.86; N, 3.75. Found: C,
67.25; H, 4.78; N, 3.76.
1-[5-(4-Chlorophenyl)furan-2-yl]-3,3,3-trifluoro-2-phenyl-2-
(phenylamino)propan-1-one (7g)
Yield: 0.164 g (72%); yellow solid; mp 119 °C.
IR (film): 3636, 3371, 3059, 2958, 2920, 2852, 2541, 2342, 2118,
1906, 1712, 1666, 1602, 1560, 1503, 1468, 1435, 1414, 1362, 1312,
1267, 1213, 1170, 1122, 1095, 1029, 945, 924, 883, 820, 800, 751,
709, 670, 645, 597, 531, 503, 463 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.49 (d, J = 7.8 Hz, 2 H), 7.43 (d,
J = 8.7 Hz, 2 H), 7.28–7.35 (m, 5 H), 6.88–6.92 (m, 2 H), 6.81 (d,
J = 3.8 Hz, 1 H), 6.60 (t, J = 6.0 Hz, 1 H), 6.49 (d, J = 3.8 Hz, 1 H),
6.44 (d, J = 7.9 Hz, 2 H), 5.87 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 179.4, 157.6, 148.7, 143.1, 135.6,
133.7, 129.1, 129.0, 129.0, 128.4, 128.4, 127.1, 126.4, 125.2, 124.5
(q, J = 287.1 Hz, CF3), 119.2, 116.9, 108.0, 72.4 (q, J = 27.2 Hz,
CCF3).
(e) Hachisu, Y.; Bode, J. W.; Suzuki, K. Adv. Synth. Catal.
2004, 346, 1097. (f) Hachisu, Y.; Bode, J. W.; Suzuki, K.
J. Am. Chem. Soc. 2003, 125, 8432. (g) Enders, D.;
Kallfass, U. Angew. Chem. Int. Ed. 2002, 41, 1743; Angew.
Chem. 2002, 114, 1822.
(4) Di Gioia, M. L.; Leggio, A.; Liguori, A.; Napoli, A.;
Siciliano, C.; Sindona, G. J. Org. Chem. 2001, 66, 7002; and
references therein.
(5) (a) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131.
(b) Mattson, A. E.; Scheidt, K. A. Org. Lett. 2004, 6, 4363.
(6) Castells, J.; López-Calahorra, F.; Bassedas, M.; Urrios, P.
Synthesis 1988, 314.
19F NMR (376 MHz, CDCl3): d = –67.09 (CF3).
MS (EI, 70 eV): m/z (%) = 455 (34) [M+], 251 (47), 250.2 (100),
205 (12), 180 (31), 172 (22), 149 (19), 77 (32).
HRMS: m/z calcd for C25H17ClF3NO2: 455.0899; found: 455.0895.
(7) (a) Mennen, S. M.; Gipson, J. D.; Kim, Y. R.; Miller, S. J.
J. Am. Chem. Soc. 2005, 127, 1654. (b) Frantz, D. E.;
Morency, L.; Soheili, A.; Murry, J. A.; Grabowski, E. J. J.;
Tillyer, R. D. Org. Lett. 2004, 6, 843. (c) Murry, J. A.;
Frantz, D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.;
Reider, P. J. J. Am. Chem. Soc. 2001, 123, 9696.
(8) Li, G.-Q.; Dai, L.-X.; You, S.-L. Chem. Commun. 2007, 852.
(9) Enders, D.; Henseler, A. Adv. Synth. Catal. 2009, 351, 1749.
(10) (a) Enders, D.; Han, J.; Henseler, A. Chem. Commun. 2008,
3989. (b) Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W.
J. Am. Chem. Soc. 2007, 129, 3520.
1-(Benzofuran-2-yl)-3,3,3-trifluoro-2-phenyl-2-(phenyl-
amino)propan-1-one (7h)
Yield: 0.103 g (52%); yellow solid; mp 196 °C.
IR (film): 3645, 3431, 3144, 3060, 2924, 2855, 2324, 2173, 2107,
1976, 1950, 1913, 1817, 1665, 1604, 1544, 1524, 1501, 1476, 1436,
1348, 1314, 1286, 1260, 1232, 1165, 1111, 1081, 1060, 1035, 1001,
954, 937, 913, 889, 873, 845, 742, 689 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.49–7.53 (m, 2 H), 7.40 (d,
J = 8.0 Hz, 1 H), 7.30–7.36 (m, 5 H), 7.08–7.14 (m, 1 H), 6.88–6.92
(m, 3 H), 6.59 (t, J = 7.3 Hz, 1 H), 6.49 (d, J = 8.0 Hz, 2 H), 5.75 (s,
1 H).
(11) Stauffer, S. R.; Sun, J.; Katzenellenbogen, B. S.;
Katzenellenbogen, J. A. Bioorg. Med. Chem. 2000, 8, 1293.
13C NMR (100 MHz, CDCl3): d = 182.6, 155.3, 149.2, 143.1, 133.4,
129.4, 129.2, 128.7, 126.5, 125.8, 124.4 (q, J = 289.6 Hz, CF3),
Synthesis 2009, No. 24, 4125–4128 © Thieme Stuttgart · New York