Triflic acid-mediated phenylation of N-acylaminoalkyl diethylacetals and N-acyl-2-phenyl cyclic amides

Article abstract of DOI:10.1039/c0ob01149e

The reaction of N-acylaminoalkyl diethylacetals with triflic acid in benzene gave N-acylamino-diphenylalkyls. The proposed intermediates are the N-acyl-2-phenyl cyclic amides, which themselves are similarly converted to N-acylamino-diphenylalkyls.

Full text of DOI:10.1039/c0ob01149e

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PAPER
Triflic acid-mediated phenylation of N-acylaminoalkyl diethylacetals and
N-acyl-2-phenyl cyclic amides†
Frank D. King* and Stephen Caddick
Received 10th December 2010, Accepted 7th March 2011
DOI: 10.1039/c0ob01149e
The reaction of N-acylaminoalkyl diethylacetals with triflic acid in benzene gave
N-acylamino-diphenylalkyls. The proposed intermediates are the N-acyl-2-phenyl cyclic
amides, which themselves are similarly converted to N-acylamino-diphenylalkyls.
to acetaldehyde and propionaldehyde derivatives and there have
Introduction
been no reports on the diphenylation of amido acetals. This paper
We have been investigating the use of triflic acid in electrophilic
describes the results of our investigation into the unexpected
iminium ion cyclisations and recently reported that treatment
formation of 3
of 1 and 4a with triflic acid and Lewis acids in CHCl3 forms
pyrrolo-tetra-hydroisoquinolinone, 2.1 In contrast, other N-acyl-
Results and discussion
2-hydroxypyrrolidines react with benzene in the presence of Lewis
acids to form N-acyl-2-phenylpyrrolidines via an intermolecular
Friedel Crafts reaction.2 We therefore wished to compare the rates
of the intramolecular cyclisation versus the intermolecular reaction
with benzene and triflic acid. To our surprise, we found that the
reaction of both 1 and 4a gave a mixture of 2 (30% yield) and
a second product, which proved not to be the expected N-acyl-2-
phenylpyrrolidine, but 1-amido-4,4-diphenyl-butane, 3 (50% yield)
(Scheme 1).
The introduction of electron-withdrawing groups into the pheny-
lacetyl ring would be expected to deactivate the ring to cyclisation
and, consistent with this, we observed the exclusive formation
of 4,4-diphenylbutanamides 6 (70% yield) and 8 (68% yield)
from the respective 1-acylamido-4,4-diethoxybutanes 5 and 7.
Similarly yields of 6 (82% yield) and 8 (75% yield) were obtained
from the appropriately substituted N-(phenylacetyl)-2-hydroxy-
pyrrolidines 4b and 4c. This diphenylation reaction also worked for
1-acetamido-4,4-diethoxybutane 9 and 1-(p-toluenesulfonamido)-
4,4-diethoxybutane 11 to give 10 (73% yield) and 12 (38% yield),
respectively.
Scheme 1 Reaction of 1 with triflic acid in benzene.
Although aminoacetals have been reported to undergo dipheny-
lation via a dicationic intermediate,3 that reaction was restricted
This transformation could be extended to the benzamide, with
conversion of the diethylacetal 13 to the 4,4-diphenylbutylamide
14, but only in a modest yield (36%). Improved yields were
obtained when 1 equivalent of triflic anhydride (63% yield) or
TMS triflate (61% yield) was added, which we believe limits the
Department of Chemistry, University College London, 20 Gordon Street,
London, WC1H 0AJ, UK. E-mail: a.e.aliev@ucl.ac.uk, f.d.king@ucl.ac.uk,
† Electronic supplementary information (ESI) available: Additional exper-
imental procedures and 1H NMR and 13C NMR for all novel compounds.
See DOI: 10.1039/c0ob01149e
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extent of amide hydrolysis. This protocol also worked well for the
pentylamide 15, which gave the 5,5-diphenyl-pentylamide 16 in a
good yield (77%).
acid O–N-hydroxysuccinimide ester, then 1-N-acylation with 4-
chlorophenylacetyl chloride. In contrast, both the morpholine 18e
and thio-morpholine 18f reacted rapidly, with the formation of a
number of products, none of which were the amides 19e or 19f.
The major product from both reactions was 1,1,2-triphenylethane
(75% yield in both cases). We believe that this product is formed
by reaction with 2 molecules of benzene, with elimination of
ArCH2CONHCH2CH2XH. Indeed, from the reaction of 18e, p-
Cl–C6H4CH2CONHCH2CH2OH was isolated in a 17% yield. The
azetidine 20 also ring opened under these conditions to form the
amide 21, which has recently been described as a cannabinoid CB1
receptor inverse agonist.5
Scheme 2 illustrates our mechanistic hypothesis, which invokes
phenylation of an iminium ion to form the 2-phenylpyrrolidine
amide 17, similar to the Lewis acid mediated reaction.2 Amide
17 could then ring open to give a carbonium ion which would
react further with benzene to form 6. As no 17 was isolated,
the formation of this intermediate must be slower than the
conversion of 17 to 6. In order to test this hypothesis, 17 was
prepared from commercially available 2-phenylpyrrolidine and
reacted with benzene and triflic acid to rapidly form 6 in high
yield (87%), consistent with the mechanistic proposal. To the best
of our knowledge, there is only one previous report of an amide
group acting as a leaving group for a Friedel–Crafts alkylation of
benzene.4
We then investigated the ring opening/phenylation reaction
of sulfonamides. The tosyl pyrrolidine 22 and piperidine 23
smoothly phenylated to give tosylNH(CH2)3CHPh2 12 and
tosylNH(CH2)4CHPh2 25 in a 92% and 85% yield respectively.
This result is in contrast to the poor yield of 12 from 11 and
suggests that the proposed first step, the reaction of the tosylim-
inium ion with benzene, proceeds poorly. In order to investigate
this further, 11 was hydrolysed to the 2-hydroxypyrrolidine 26.
This provides a simple alternative synthesis of 26 to that of
either oxidation of N-tosyl-pyrrolidine6 or N-tosyl-pyrrolidine-
2-methanol,7 or reduction of N-tosyl-2-pyrrolidinone.8 Reaction
of 26 with triflic acid in benzene gave both 12 (35% yield) and a
compound which was spectroscopically consistent with the ‘dimer’
27. This compound is the N-di-tosyl analogue of the previously
reported N-diacyl ‘dimer’, formed by treatment of the N-acyl-2-
hydroxypyrrolidine with conc. H2SO4.1 It was proposed that the
‘dimer’ was formed through reaction of the N-acyliminium ion
with 1-acyl-2,3-dihydropyrrole, formed by loss of a proton from
the iminium ion. Formation of the ‘dimer’ was suppressed by
using triflic acid, which was believed to be acidic enough to keep
the acyliminium ion fully protonated. However, it would appear
that triflic acid is not a strong enough acid to keep the equivalent
N-tosyliminium ion fully protonated, so that sufficient N-tosyl-
2,3-dihydropyrrole is formed to react with the iminium ion. This
is consistent with the N-tosyl group being a stronger electron
withdrawing group that the N-acyl.9 Heating 26 with trifilic acid
in CHCl3 gave an almost quantitative yield of 27.
Scheme 2 Proposed mechanism for the formation of 6.
The facile ring-opening and phenylation of 17 prompted us to
investigate the triflic acid-mediated ring opening/phenylation of
other cyclic amides. The results are presented in Table 1.
The piperidine 18a, prepared from the commercially available
2-phenylpiperidine, rapidly ring opened with triflic acid in ben-
zene to form the amide 16 in a very good yield. In contrast,
azepine 18b took much longer for all the starting material to
be consumed and MS indicated that 19b was formed together
with other unidentified products. The structural elucidation was
complicated by the presence of amide rotamers. Neither of the
piperazine derivatives 18c and 18d reacted, the only starting
material being present after 4 h reflux. 18d was prepared by selec-
tive 4-N-acylation of 2-phenylpiperazine with 4-nitrophenylacetic
Table 1 Investigation of the phenylation of cyclic amides 17a–g
Cpd. No.
X
Cpd. No.
T (h)
Yield (%)
18a
18b
18c
18d
18e
18f
CH2
(CH2)2
NMe
NRb
O
16
0.5
4
4
4
1
95
a
19b
19c
19d
19e
19f
0
0
0
0
S
1
In a manner that was analogous to the observations with
amide 18b, the N-benzenesulfonylazepine 24 gave a mixture of
a See text. b R = p-NO2–C6H4–CH2CO-.
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compounds which were inseparable by column chromatography.
Both NMR and MS indicated that the product was a 3 : 2
mixture of tosyl-NH(CH2)5CHPh2 28 and tosyl-NH(CH2)6Ph 29.
Following this finding, a reinvestigation of the product from the
reaction of 18b by HRMS indicated that both 19b and p-Cl–C6H4–
CH2CONH (CH2)6Ph was present.
under reflux in benzene (30 ml) with triflic acid (3.7 ml) for 1h.
The reaction mixture was cooled to room temperature, water
(50 ml) was added and the reaction carefully basified with solid
K2CO3. The product extracted into ethyl acetate (2 ¥ 50 ml) and
the organic extract was dried (MgSO4), concentrated in vacuo
and the residue purified by column chromatography on silica,
eluting with DCM to give 6, (1.13 g, 82% yield), mp 125–126 ◦C
1
(EtOAC/petroleum ether). H-NMR (500 MHz) d = 1.40 (2H,
Conclusion
m), 1.98 (2H, q, J = 7.9 Hz), 3.23 (2H, dt, J = 6.9, 6.2 Hz), 3.49
(2H, s), 3.85 (1H, t, J = 7.8 Hz), 5.27 (1H, brs), 7.11–7.21 (8H,
m), 7.21–7.35 (6H, m).; 13C-NMR + DEPT (125 MHz) d = 28.1
(CH2), 32.8 (CH2), 39.6 (CH2), 43.2 (CH2), 51.0 (CH), 126.3
(CH), 127.8 (CH), 128.6 (CH), 129.2 (CH), 130.8 (CH), 133.4
(C), 133.5 (C), 144.7 (C), 170.3 (C); FT-IR (neat) 3273, 2837,
1634, 1562, 1491, 1439, 1327, 1153, 1091, 809, 767, 749, 695 cm-1;
LRMS (EI) 377, 210, 167, 126, 91; HRMS calcd for C24H24ClNO
377.1541, found 377.1543.
In conclusion, we have shown that the diphenylation of amino-
acetals with triflic acid in benzene3 can be extended to butanal
and pentanal derivatives by using the amides or sulfonamides.
Investigation of the possible mechanism of this reaction led to
the novel finding that 2-phenyl-cyclic amides and sulfonamides
can also be readily ring-opened to give diphenyl products in good
yields.
Experimental
2-(4-Nitrophenyl)-N-(4,4-diphenylbutyl)acetamide 8 from 4c
All reagents were commercially available, unless otherwise spec-
ified, and used without purification. The chloroform used was
stabilised with amylene. All non-crystalline final compounds were
found to be >95% pure by HPLC, and all crystalline compounds
>98% pure. Infrared spectra were run neat on a Perkin Elmer 100
FT IR spectrometer. 1H and 13C NMR spectra were recorded on
Bruker NMR spectrometers AMX300, Avance III 400, DRX500
A solution of 2-(4-nitrophenyl)-N-(4,4-diethoxybutyl)-acetamide1
(3.2 g, 10 mmol) in THF (100 ml) and 2 M HCl (20 ml) was stirred
at room temperature for 2 h, until all the starting material had
been consumed (TLC). Water (50 ml) was added and the THF
removed in vacuo. The 2-(4-nitrophenyl)-1-(2-hydroxypyrrolidin-
1-yl)ethanone 4c formed as a pale yellow solid, which was collected
and dried (2.5 g, ~100% yield), pure by TLC and NMR showed
it to be in equilibrium with the amido-aldehyde (~5%), and was
used without further purification; 1H-NMR (500 MHz) d = 1.80–
2.15 (4H, m), 3.41–3.50 (1H, m), 3.55–3.68 (1H, m), 3.74 (2H,
s), 4.10 (1H, brs), 5.65 (1H, dd, J = 2.7, 6.1 Hz) 7.46 (2H, d,
J = 8.2 Hz), 8.19 (2H, d, J = 8.2 Hz); 13C-NMR + DEPT (150
MHz) d = 23.2 (CH2), 32.1 (CH2), 41.6 (CH2), 46.9 (CH2), 82.1
(CH), 123.8 (CH), 130.3 (CH), 141.7 (C), 147.2 (C), 169.9 (C); FT-
IR (neat) 3356, 1608, 1514, 1444, 1421, 1343, 1318, 1263, 1172,
1154, 1106, 1040, 1016, 963, 859, 820, 727 cm-1. Following the
general procedure, 4c (1 g, 4 mmol) was reacted for 1 h to give
8, purified by column chromatography, eluting with DCM (1.2 g,
and Avance III 600 equipped with z-gradient facilities. 1H and 13
C
chemical shifts are given relative to TMS.
General procedure for the diphenylation reaction
Triflic acid (10 fold excess) was added to a stirred solution of
the amide or sulfonamide (2 mmol) in benzene (20 ml) and the
reaction mixture was heated under reflux until TLC showed no
starting amide remaining. The reaction mixture was cooled to
room temperature, water (50 ml) was added and the mixture
basified with an excess of solid K2CO3. The product was extracted
into DCM (2 ¥ 50 ml), dried (MgSO4), concentrated in vacuo and
the product purified by column chromatography on SiO2.
◦
78% yield), mp 100–102 C (EtOAc/petroleum ether). 1H-NMR
(600 MHz) d = 1.40–1.48 (2H, m), 1.98–2.05 (2H, m), 3.25 (2H, q,
J = 7.0 Hz), 3.53 (2H, s), 3.87 (1H, t, J = 7.8 Hz), 6.20 (1H, t, J =
5.5 Hz), 7.127.30 (10H, m), 7.38 (2H, d, J = 8.6 Hz), 8.10 (2H, d,
J = 8.6 Hz); 13C-NMR + DEPT (150 MHz) d = 28.2 (CH2), 32.9
(CH2), 39.8 (CH2), 43.2 (CH2), 51.0 (CH), 123.9 (CH), 126.5 (CH),
127.9 (CH), 128.7 (CH), 130.3 (CH), 143.1 (C), 144.8 (C), 147.0
(C), 169.5 (C), FT-IR (neat) 3281, 1637, 1557, 1516, 1493, 1345,
1254, 1110, 1030, 747, 697 cm-1, LRMS (EI) 388, 221, 167, 137,
106, 91; HRMS calcd for C24H24N2O3 388.1781, found 388.1777.
Reaction of 1 with triflic acid in benzene
Following the general procedure, 11 was heated under reflux for
1 h. Purifi◦cation, initially eluting with DCM gave 3 (50% yield),
mp 120–1 C (EtOAc/petroleum ether). 1H-NMR (600 MHz) d =
1.38–1.45 (2H, m), 1.96–2.02 (2H, m), 3.23 (2H, q, J = 7.0 Hz), 3.54
(2H, s), 3.86 (1H, t, J = 7.8 Hz), 5.52 (1H, brs), 7.15–7.40 (15H,
m); 13C-NMR + DEPT (150 MHz) d = 28.2 (CH2), 32.9 (CH2),
39.5 (CH2), 44.0 (CH2), 51.0 (CH), 126.4 (CH), 127.5 (CH), 127.9
(CH), 128.6 (CH), 129.2 (CH), 129.6 (CH), 135.2 (C), 144.8 (C),
171.1 (C), FT-IR (neat) 3269, 2935, 1638, 1556, 1494, 1454, 1435,
1344, 751, 716, 695 cm-1, LRMS (EI) 343, 167, 92, 91, HRMS
calcd for C24H25NO 343.1931, found 343.1920. Further elution
with DCM + 2% MeOH gave 2 (30% yield), identical to that
previously reported.1
N-(4,4-Diphenylbutyl)acetamide 10
Following the general procedure, N-(4,4-diethoxybutyl) acetamide
910 gave 10, purified by eluting with a solvent gradient, initially
1 : 1 petroleum ether/DCM to 1% MeOH/DCM mp 73–74 ◦C
(EtOAc/petroleum ether), (lit. 76–78 ◦C [toluene/petroleum
ether]11). 1H-NMR (500 MHz) d = 1.47 (2H, tt, J = 6.9, 7.9 Hz),
1.92 (3H, s), 2.06 (2H, q, J = 7.9 Hz), 3.16 (2H, q, J = 6.9 Hz),
3.89 (1H, t, J = 7.9 Hz), 5.43 (1H, brs), 7.19 (1H, tt, J = 1.2,
7.2 Hz), 7.23 (2H, dd, J = 1.2, 7.1 Hz), 7.27 (2H, t, J = 7.5 Hz);
2-(4-Chlorophenyl)-N-(4,4-diphenylbutyl)acetamide, 6, from 4b
A
solution of 2-(4-chlorophenyl)-1-(2-hydroxypyrrolidin-1-
yl)ethanone1 4b (0.88 g, 3.7 mmol) was stirred and heated
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13C-NMR + DEPT (125 MHz) d = 23.4 (CH3), 28.3 (CH2), 33.0
(CH2), 39.6 (CH2), 51.1 (CH), 126.4 (CH), 127.9 (CH), 128.6 (CH),
144.8 (C), 170.1 (C), FT-IR (neat) 3278, 2928, 2865, 1635, 1557,
1494, 1451, 1367, 1294, 1032, 745, 698 cm-1, LRMS (EI) 267, 167,
100; HRMS calcd for C18H21NO 267.1618, found 267.1609.
3.40–3.50 (4H, m including 3.49, 2H, s). 3.55–3.63 (2H, m), 4.41
(1H, t, J = 5.6 Hz), 5.47 (1H, brs), 7.19 (2H, d, J = 8.3 Hz), 7.29 (2H,
d, J = 8,3 Hz); 13C-NMR + DEPT (125 MHz) d = 15.4 (CH3), 22.0
(CH2), 29.3 (CH2), 33.3 (CH2), 39.7 (CH2), 43.2 (CH2), 61.2 (CH2),
102.8 (CH), 129.1 (CH), 130.8 (CH), 133.1 (C), 133.6 (C), 170.4
(C). Following the general procedure, 15 (0.8 g, 2.4 mmol) was
heated under reflux for 1 h to give 16 (0.67 g, 70% yield), purified
by elution with DCM, mp = 75–77 ◦C (EtOAc/petroleum ether).
1H-NMR (500 MHz) d = 1.27–1.35 (2H, m), 1.47 (2H, quintet,
J = 7.4 Hz), 2.02 (2H, q, J = 7.8 Hz), 3.17 (2H, q, J = 6.8 Hz), 3.46
(2H, s), 3.84 (1H, t, J = 7.8 Hz), 5.29 (1H, brs), 7.11 (2H, d, J =
8.3 Hz), 7.14–7.35 (12H, m); 13C-NMR + DEPT (125 MHz) d =
25.3 (CH2), 29.4 (CH2), 35.2 (CH2), 39.6 (CH2), 51.3 (CH), 126.2
(CH), 127.9 (CH), 128.5 (CH), 129.2 (CH), 130.8 (CH), 133.3 (C),
133.5 (C), 145.0 (C), 170.3 (C), FT-IR (neat) 3287, 2936, 1645,
1543, 1493, 1092, 806, 754, 741, 696 cm-1, LRMS (EI) 391, 167;
HRMS calcd for C25H26ClNO 391.1697, found 391.1689.
N-(4,4-Diphenylbutyl)-4-methylbenzenesulfonamide 12 from 11
Tosyl chloride (3.8 g, 20 mmol) was added over 10 min. to a
stirred solution of 4-amino-1,1-diethoxybutane (3.4 ml, 20 mmol)
and triethylamine (3.5 ml, 25 mmol) in DCM (100 ml) at 0 ◦C.
The reaction mixture was stirred at room temperature for 1 h, then
washed with saturated aqueous NaHCO3 solution (100 ml). The
DCM was separated, dried (K2CO3) and concentrated in vacuo to
give 6.3 g of 11 (~100% yield) as an oil, pure by NMR and TLC and
used without further purification. 1H-NMR (500 MHz) d = 1.07
(6H, t, J = 7.0 Hz), 1.50–1.62 (4H, m), 2.32 (3H, s), 2.81–2.88 (2H,
m), 3.27–3.37 (2H, m), 3.44–3.54 (2H, m), 4.30 (1H, t, J = 4.9 Hz),
4.84 (1H, brs), 7.20 (2H, d, J = 8.2 Hz), 7.64 (2H, d, J = 8.2 Hz).
Crude 11 (1 g, 2.6 mmol) was reacted by the general procedure
and the product was purified by column chromatography on silica,
eluting with 3 : 1 DCM/petroleum ether to give 12 (38% yield) as
a colourless oil which crystallized from Et2O/petroleum ether, mp
2-(4-Chlorophenyl)-N-(4,4-diphenylbutyl)acetamide, 6, from 17
Following the procedure described for 15, 2-phenylpyrrolidine
(0.87 g, 5.9 mmol) was converted to 2-(4-chlorophenyl)-1-(2-
phenylpyrrolidin-1-yl) ethanone 17 (1.8 g, ~100% yield), mp
◦
1
◦
119–120 C; H-NMR (500 MHz) d = 1.37–1.48 (2H, m), 1.97–
2.05 (2H, m), 2.42 (3H, s), 2.94 (2H, q, J = 6.6 Hz), 3.80 (1H,
t, J = 7.8 Hz), 4.81 (1H, brs), 7.14–7.20 (6H, m), 7.21–7.34 (6H,
m), 7.73 (2H, d, J = 8.3 Hz), 13C-NMR + DEPT (125 MHz) d =
21.6 (CH3), 28.1 (CH2), 32.5 (CH2), 43.2 (CH2), 50.9 (CH), 126.3
(CH), 127.2 (CH), 127.8 (CH), 128.6 (CH), 129.8 (CH), 137.0 (C),
143.4 (C), 144.6 (C), FT-IR (neat) 3223, 1494, 1446, 1315, 1163,
1066, 961, 812, 753, 696 cm-1, LRMS (EI) 379, 224, 167, 129, 91;
HRMS calcd for C23H25NO2S 379.1601, found 379.1595.
1
83–85 C (EtOAc/petroleum ether). H-NMR (500 MHz) (two
rotamers) d = 1.80–2.00 (3H, m), 2.19–2.29 (0.25H, m), 2.31 0
2.41 (0.75H, m), 3.33 (0.75H, d, J = 15.1 Hz), 3.37 (0.75H, d, J =
15.1 Hz), 3.57–7.75 (1.25H, m), 4.93 (0.75H, dd, J = 2.3, 8.3 Hz),
5.22 (0.25H, dd, J = 2.8, 8.0 Hz), 6.97 (1.5H, d, J = 8.5 Hz),
7.06 (0.5H, d, J = 8.3 Hz), 7.14–7.31 (5.5H, m), 7.35 (1.5H, t,
J = 7.6 Hz); 13C-NMR + DEPT (125 MHz) d = 21.7 (CH2), 23.9
(CH2), 34.0 (CH2), 36.4 (CH2), 40.9 (CH2), 41.8 (CH2), 47.4 (CH2),
48.0 (CH2), 60.8 (CH), 61.7 (CH), 125.5 (CH), 126.8 (CH), 127.5
(CH), 128.4 (CH), 128.5 (CH), 128.8 (CH), 129.0 (CH), 130.5
(CH), 130.6 (CH), 132.6 (C), 132.8 (C), 133.3 (C), 133.5 (C), 169.0
(C), 170.1 (C), FT-IR (neat) 1621, 1490, 1422, 1170, 1090, 810,
763, 751, 700 cm-1, LRMS (EI) 299, 174, 131, 91; HRMS calcd
for C18H18ClNO 299.1071, found 299.0165. Following the general
procedure, amide 17 was converted to 6 (87% yield), purified by
elution with DCM, identical to that obtained.
N-(4,4-Diphenylbutyl)benzamide 14
N-(4,4-Diethoxybutyl)benzamide, 13,12 was reacted for 1 h follow-
ing the general procedure and purified by column chromatography
in SiO2, eluting with a solvent gradient, initially 1 : 1 petroleum
ether/DCM to 1% MeOH/DCM (36% yield), mp 102–103 ◦C
1
(EtOAc/petroleum ether). H-NMR (500 MHz) d = 1.55–1.66
(2H, m), 2.14 (2H, ddt, J = 1.9, 7.8, 9.8 Hz), 3.48 (2H, ddt, J =
1.9, 7.5, 8.9 Hz), 3.93 (1H, t, J = 7.2 Hz), 6.05 (1H, brs), 7.15–7.20
(2H, m), 7.21–7.30 (8H, m), 7.38–7.43 (2H, m), 7.46–7.51 (1H,
m), 7.69–7.73 (2H, m); 13C-NMR + DEPT (125 MHz) d = 28.4
(CH2), 33.0 (CH2), 40.0 (CH2), 51.1 (CH), 126.3 (CH), 126.9 (CH),
128.6 (CH), 131.4 (CH), 134.8 (C), 144.7 (C), 167.6 (C), FT-IR
(neat) 3389, 1635, 1536, 1490, 1449, 1290, 716, 696 cm-1, LRMS
(EI) 329, 167, 149, 148, 105; HRMS calcd for C23H23NO 329.1774,
found 329.1765. Repeating the reaction with the addition of triflic
anhydride (1 equiv.) also gave 14 (63% yield) and with trimethylsilyl
triflate (2 equiv) gave 14 (61% yield).
1-{4-[2(4-Chlorophenyl)acety]-3-phenylpiperazin-1-yl}-2-(4-
nitrophenyl)-ethanone 18d
A solution of 2-phenylpiperazine (1.6 g, 10 mmol) and 4-
nitrophenylacetic acid O-N-hydroxysuccinimide ester (2.8 g,
10 mmol) in DCM (100 ml) was stirred at ambient temperature
overnight. The reaction mixture was concentrated in vacuo and the
residue treated with EtOAc (150 ml), washed with 2 M NaOH (2
¥ 50 ml), brine (50 ml) and dried (K2CO3). Filtration and concen-
tration in vacuo gave the 2-(4-nitrophenyl)-1-(3-phenylpiperazin-
1-yl)ethanone as a pale yellow solid (2.8 g, 85% yield), mp 108–
◦
1
2-(4-Chlorophenyl)-N-(5,5-diphenylpentyl)acetamide 16 from
15. Following the procedure described for 11, 5-amino-1,1-
diethoxypentane13 (1.3 g, 7.4 mmol) was reacted with 4-
chlorophenylacetyl chloride (1.3 g, 7.4 mmol) and triethylamine
(1.4 ml, 10 mmol) to give 15 as an oil (2.6 g, ~100% yield) pure by
NMR and TLC, and used without further purification, 1H-NMR
(500 MHz) d = 1.18 (6H, t, J = 7.1 Hz), 1.24–1.34 (2H, m), 1.40–
1.50 (2H, m), 1.52–1.60 (2H, m), 3.20 (2H, quartet, J = 6.0 Hz),
110 C (EtOAc/petroleum ether). H-NMR (500 MHz) rotamer
mixture d = 1.98 (brs, 1H), 2.63 (0.4H, t, J = 12.5 Hz), 2.69–
2.90 (1.6H, m), 3.00–3.19 (1.4H, m), 3.27 (0.4H, t, J = 12 Hz), 3.47
(0.6H, d, J = 10.5 Hz), 3.61–3.87 (3.6H, m), 4.61 (2H, d, J = 11 Hz),
7.16–7.50 (7H, m), 8.20 (2H, d, J = 8 Hz); 13C-NMR + DEPT
(125 MHz) d = 40.4, 42.2, 45.9, 46.4, 46.5, 49.2, 53.7, 60.1, 61.1,
123.9, 126.9, 128.0, 128.3, 128.6, 128.8, 130.0, 140.5, 140.9, 142.8,
147.0, 167.8, FT-IR (neat) 3310, 2848, 1650, 1510, 1435, 1417,
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1338, 1237, 1223, 1143, 1100, 1047, 816, 765, 740, 709, 700 cm-1;
LRMS (EI) 325, 282, 220, 161, 132, 118, 104, 91; HRMS calcd
for C18H19N3O3 325.1421, found 325.1425. Structural assignment
was made from the NOESY spectrum which showed no NOE
between the ArCH2CO and 3-CHPh protons, but did between the
ArCH2CO and the 2-CH and 6-CH protons.
N-(5,5-Diphenylpentyl)-4-methylbenzenesulfonamide 25
Following the procedure described for 11, 2-phenylpiperidine
(0.5 g, 3.1 mmol) was reacted with tosyl chloride (0.65 g,
3.4 mmol) and triethylamine (0.6 ml, 3.5 mmol) in DCM (50 ml)
overnight at ambient temperature to give 23, purified by column
chromatography on SiO2, eluting with 1 : 1 petroleum ether/DCM
(0.88 g, 90% yield). 1H-NMR (500 MHz) d = 1.28–1.55 (4H, m),
1.62–1.71 (1H, m), 2.20–2.27 (1H, m), 2.43 (3H, s), 2.99–3.06 (1H,
m), 3.80–3.88 (1H, m), 5.26 (1H, d, J = 4.3 Hz), 7.21–7.39 (7H,
m), 7.76 (2H, d, J = 8.3 Hz); 13C-NMR + DEPT (125 MHz) d =
19.0 (CH2), 21.6 (CH3), 24.4 (CH2), 27.3 (CH2), 41.9 (CH2), 55.3
(CH), 126.9 (CH), 127.1 (CH), 127.1 (CH), 128.7 (CH), 129.8
(CH), 138.8 (C), 139.0 (C), 143.0 (C), FT-IR (neat) 2956, 2928,
2869, 1449, 1324, 1150, 1103, 1092, 1051, 948, 723, 663 cm-1;
LRMS (EI) 315, 238, 160, 159, 91; HRMS calcd for C18H21NO2S
315.1286, found 315.1281. Following the procedure, 16 (0.32 g,
1 mmol), with heating under reflux for 1 h, was converted into 25,
purified on a silica column, eluting with DCM (0.34 g, 85% yield)
Following the general procedure described for 15, 2-
(4-nitrophenyl)-1-(3-phenylpiperazin-1-yl)ethanone
(0.98
g, 3.0 mmol) was converted to 18d, purified by column
chromatography on SiO2, eluting with 2% MeOH/DCM and
◦
1
isolated as a solid, m.pt 63–65 C (1.3 g, 90% yield). H-NMR
(400 MHz, d6-DMSO, 373 K) d = 3.21–3.37 (2H, brm), 3.48–3.90
(6H,m), 4.04–4.14 (1H, brm), 4.35–4.55 (1H, brm), 5.51 (1H,
brs), 7.20–7.38 (11H, m), 8.06 (2H, d, J = 8.5 Hz); 1H-NMR (600
MHz, d6-DMSO, 298 K) d = 37.2, 37.5, 38.6, 38.9, 40.1, 41.1,
41.2, 42.1, 42.5, 43.3, 44.7, 45.1, 47.5, 48.3, 51.7, 53.5, 56.1, 56.8,
65.0, 123.2, 126.2, 126.4, 127.0, 127.4, 128.2, 128.4, 128.7, 128.9,
130.4, 130.7, 130.9, 131.2, 134.7, 134.8, 138.4, 139.3, 143.9, 146.1,
146.2, 168.6, 169.5, 169.8, 170.0, FT-IR (neat) 1638, 1515, 1413,
1344, 1089, 1016, 857, 810, 732, 698 cm-1, LRMS no molecular
ion could be detected, (EI) and (CI), 267, 167, 100. Heating a
solution of 18d (0.75 g, 1.5 mmol) in benzene (15 ml) and triflic
acid (1.5 ml) for 4 h showed only starting material by TLC.
◦
1
mp = 121–123 C. H-NMR (500 MHz) d = 1.18–1.26 (2H, m),
1.49 (2H, m), 1.98 (2H, q. J = 7.6 Hz), 2.43 (3H, s), 2.89 (2H, q, J =
6.6 Hz), 3.82 (1H, t, J = 7.6 Hz), 4.65 (1H, t, J = 5.5 Hz), 7.12–7.33
(12H, m), 7.74 (2H, d, J = 8.3 Hz); 13C-NMR + DEPT (125 MHz)
d = 21.9 (CH3), 25.4 (CH2), 30.0 (CH2), 35.5 (CH2), 43.4 (CH2),
51.6 (CH), 126.6 (CH), 127.5 (CH), 128.2 (CH), 128.7 (CH), 128.9
(CH), 130.1 (CH), 137.4 (C), 143.8 (C), 145.2 (C), FT-IR (neat)
3265, 2925, 1598, 1493, 1448, 1427, 1316, 1149, 1092, 101, 815,
736, 699 cm-1; LRMS (EI) 393, 238, 167, 91; HRMS calcd for
C24H27NO2S 393.1757, found 393.1750.
2-(4-Chlorophenyl)-N-(3,3-diphenylpropyl)acetamide, 21
Following the procedure described for 15, 2-phenylazetidine14
(0.41 g, 3.1 mmol) and triethylamine (0.7 ml) in DCM (50 ml)
was cooled to 0 ◦C and 4-chlorophenylacetyl chloride (0.45 ml
3.1 mmol) in DCM (5 ml) was added dropwise and the reaction
mixture was stirred at ambient temperature overnight. The
reaction mixture was washed with 2 M NaOH (25 ml), water
(25 ml) and 2 N HCl (25 ml), dried (K2CO3) and concentrated
in vacuo. The residue was purified by column chromatography
on silica, eluting with DCM to give 2-(4-chlorophenyl)-1-(2-
phenylazetidin-1-yl)ethanone 20 (0.74 g, 83% yield), mp 88-89 ◦C
1-(p-Toluenesulfonyl)-pyrrolidin-2-ol 26
A solution of 11 (4 g, 12.7 mmol) was dissolved in THF (50 ml) and
2 M HCl (25 ml) and was stirred for 4 h at ambient temperature
until TLC showed that no 11 remained. The THF was removed
in vacuo and the product extracted into DCM (3 ¥ 50 ml), dried
and concentrated to give 26 as an oil which solidified on standing
1
(EtOAc/petroleum ether). H-NMR (500 MHz) (two rotamers
1
and used without further purification. H-NMR (500 MHz) d =
in a 3 : 1 ratio) d = 2.11–2.21 (2H, m), 2.66–2.76 (2H, m), 3.12
(1.5H, s), 3.49 (0.5H, d, J = 2.5 Hz), 4.06–4.22 (2H, m), 5.26
(0.75H, dd, J = 5.7, 8.8 Hz), 5.37 (0.25H, dd, J = 6.0, 8.9 Hz),
6.90 (1.5H, d, J = 8.4 Hz), 7.17 (1.5H, d, J = 8.4 Hz), 7.22–7.43
(6H, m); 13C-NMR + DEPT (125 MHz) d = major rotamer: 26.3
(CH2), 38.5 (CH2), 46.0 (CH2), 65.7 (CH), minor rotamer: 25.0
(CH2), 38.8 (CH2), 48.4 (CH2), 63.4 (CH); both rotamers: 125.7
(CH), 126.2 (CH), 127.6 (CH), 128.5 (CH), 128.7 (CH), 128.8
(CH), 129.3 (CH), 130.5 (CH), 130.6 (CH), 132.6 (C), 132.9 (C),
133.1 (C), 141.5 (C), 170.8 (C), 171.3 (C), FT-IR (neat) 1626,
1489, 1455, 1425, 1089, 1015, 807, 772, 697 cm-1; LRMS (EI) 285,
181, 160, 125, 91; HRMS calcd for C17H16ClNO 285.0915, found
285.0905. Following the general procedure, 20 was converted to
21 (86%◦yield) purified by elution with DCM. mp = 103–104 ◦C.
(lit. 107 C5). 1H-NMR (500 MHz) d = 2.22 (2H, q, J = 7.8 Hz),
3.20 (2H, q, J = 7.8 Hz), 3.43 (2H, s), 3.84 (1H, t, J = 7.8 Hz),
5.25 (1H, brs), 7.12–7.19 (8H, m), 7.24–7.28 (4H, m), 7.32 (2H,
d, J = 8.4 Hz); 13C-NMR + DEPT (125 MHz) d = 35.1 (CH2),
38.8 (CH2), 43.2 (CH2), 49.3 (CH), 126.5 (CH), 127.7 (CH), 128.7
(CH), 129.2 (CH), 130.8 (CH), 133.4 (C), 133.5 (C), 144.1 (C),
170.3 (C); FT-IR (neat) 3331, 1649, 1535, 1490, 1088, 1013, 806,
750, 693 cm-1.
1.70–1.80 (2H, m), 1.85–1.94 (1H, m), 2.05–2.14 (1H, m), 2.42
(3H, s), 3.02–3.07 (1H, m), 3.10–3.17 (1H, m), 3.50–3.57 (1H, m),
5.42 (1H, m), 7.32 (2H, d, J = 8.4 Hz), 7.72 (2H, d, J = 8.4 Hz);
13C-NMR + DEPT (125 MHz) d = 21.6 (CH3), 23.1 (CH2), 33.9
(CH2), 47.6 (CH2), 84.0 (CH), 127.2 (CH), 129.9 (CH), 135.7 (C),
143.5 (C).
1,1¢-Bis-(toluene-4-sulfonyl)-2,2,4,5,4¢,5¢-hexahydro-1H,1¢H-
[2,3¢]bipyrrolyl, 27
Following the general procedure, a solution of 26 (0.48 g, 2 mmol)
was stirred and heated under reflux in CHCl3 (30 ml) and triflic
acid (2 ml, 20 mmol) for 1 h. Work-up and purification by column
chromatography on silica, eluting with DCM gave 27 as an oil
1
(0.45 g, ~100% yield), H-NMR (500 MHz) d = 1.57–1.67 (3H,
m), 1.70–1.82 (1H, m), 2.30–2.48 (8H, m including 2.42, 6H, s),
3.18–3.24 (1H, m), 3.33–3.39 (1H, m), 3.40–3.52 (2H, m), 4.22
(1H, dd, J = 3.9, 6.8 Hz), 6.37 (1H, dd, J = 1.8, 2.9 Hz), 7.26
(2H, d, J = 7.9 Hz), 7.33 (2H, d, J = 8.0 Hz), 7.63 (2H, dt, J =
1.9, 8.4 Hz), 7.71 (2H, dt, J = 2.1, 8.3 Hz); 13C-NMR + DEPT
(125 MHz) d = 21.6 (CH3), 21.7 (CH3), 24.3 (CH2), 29.5 (CH2),
30.9 (CH2), 47.9 (CH2), 48.8 (CH2), 57.9 (CH), 126.2 (C), 127.4
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(CH), 127.5 (CH), 127.9 (CH), 129.7 (CH), 129.8 (CH), 133.0 (C),
134.9 (C), 143.5 (C), 143.9 (C); HRMS calcd for C22H27N2O4S2
447.1412, found 447.1390.
(C), 140.1 (C), 142.6 (C), 145.1 (C). LRMS for mixture: 393, 317,
252, 176, 170, 167, 141, 117, 104, 91. For 28: HRMS calcd. for
C24H27NO2S 393.1764, found 393.1767; for 29: HRMS calcd. for
C18H23NO2S 317.1450, found 317.1455.
Mixture of N-(6,6-diphenylhexyl)-benzenesulfonamide, 28, and
N-(6-phenylhexyl)-benzenesulfonamide 29
Acknowledgements
By the method described for 11, 2-phenylperhydroazepine15 (0.7
g, 4 mmol) gave N-benzenesulfonyl-2-phenylperhydro-azepine 24,
purified by column chromatography on silica, eluting with DCM
and isolated as a solid (1.1 g, 85% yield), mp 78–79 ◦C; 1H-NMR
(500 MHz) d = 1.21–1.33 (1H, m), 1.53 (1H, q, J = 11.7 Hz), 1.62–
1.74 (1H, m), 1.75–1.91 (4H, m), 2.20–2.30 (1H, m), 3.20–3.30
(1H, m), 3.95 (1H, dt, J = 3.3, 15.4 Hz), 5.06 (1H, dd, J = 6.0,
11.7 Hz), 6.98–7.02 (2H, m), 7.09–7.14 (3H, m), 7.21 (2H, t, J =
7.9 Hz), 7.35 (1H, tt, J = 1.1, 7.4 Hz), 7.43 (2H, d, J = 7.4 Hz);
13C-NMR + DEPT (125 MHz) d = 25.8 (CH2), 29.5 (CH2), 31.0
(CH2), 45.5 (CH2), 61.7 (CH), 126.4 (CH), 127.0 (CH), 127.1 (CH),
128.4 (CH), 128.5 (CH), 131.8 (CH), 141.0 (C), 142.5 (C); FT-IR
(neat) 2929, 1446, 1327, 1308, 1147, 1089, 1045, 936, 888, 780,
752, 723, 691 cm-1; LRMS (EI) 315, 238, 174, 173, 145, 118, 117,
104, 91; HRMS calcd for C18H21NO2S 315.1288, found 315.1283.
Following the general procedure, 24 (0.5 g, 1.6 mmol) was heated
under reflux for 2 h until all the starting material had reacted by
TLC. The product was purified by elution with 1 : 3 petroleum
ether/DCM as an oil (0.26 g). NMR and MS showed it to be
a 3 : 2 mixture of 28 and N-(6-phenylhexyl)-benzenesulfonamide,
We would like to thank Dr Lisa D. Haigh for the mass spectra.
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as 1H d = 1.12–1.35 (4H, m), 1.48–1.50 (2H, m), 1.51–1.62 (0.8H,
m), 1.97 (1.2H, q, J = 7.8 Hz), 2.56 (0.8H, t, J = 7.6 Hz), 2.88–2.99
(2H, m), 3.83 (0.6H, t, J = 7.8 Hz), 4.75–4.72 (1H, m), 7.12–7.31
(8H, m), 7.45–7.60 (3.2H, m), 7.83–7.91 (1.8H, m); 13C-NMR +
DEPT (125 MHz) d = 26.4 (CH2), 26.5 (CH2), 27.5 (CH2), 28.7
(CH2), 29.5 (CH2), 29.6 (CH2), 31.3 (CH2), 35.5 (CH2), 35.9 (CH2),
43.2 (CH2), 43.3 (CH2), 51.3 (CH), 125.7 (CH), 126.2 (CH), 127.1
(CH), 127.9 (CH), 128.4 (CH), 128.5 (CH), 129.2 (CH), 132.7
15 M. A. M. Healy, S. A. Smith and G. Stemp, Synth. Commun., 1995, 25,
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4366 | Org. Biomol. Chem., 2011, 9, 4361–4366
This journal is
The Royal Society of Chemistry 2011
©