Efficient synthesis of thioesters and amides from aldehydes by using an intermolecular radical reaction in water

Article abstract of DOI:10.1002/chem.200400754

The combination of the water-soluble radical initiator, 2,2′-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (VA-044) and the surfactant, cetyltrimethyl-ammonium bromide (CTAB), was found to be the most suitable condition for the effective and direct synthesis of useful active thioesters (pentafluorophenyl thioesters) in water. In addition, the direct amidation of aldehydes was achieved by the addition of the amines to the thioesterification reaction mixture in water.

Full text of DOI:10.1002/chem.200400754

FULL PAPER
Efficient Synthesis of Thioesters and Amides from Aldehydes by Using an
Intermolecular Radical Reaction in Water
Hisanori Nambu, Kayoko Hata, Masato Matsugi, and Yasuyuki Kita*[a]
Abstract: The combination of the water-soluble radical initiator, 2,2’-azobis[2-(2-
imidazolin-2-yl)propane] dihydrochloride (VA-044) and the surfactant, cetyltri-
methyl-ammonium bromide (CTAB), was found to be the most suitable condition
for the effective and direct synthesis of useful active thioesters (pentafluorophenyl
thioesters) in water. In addition, the direct amidation of aldehydes was achieved
by the addition of the amines to the thioesterification reaction mixture in water.
Keywords: aldehydes · amidation ·
radical reactions
thioesters
· surfactants ·
Introduction
circumstances, the direct synthesis of thioesters from alde-
hydes using thioanions or thiyl radicals would be a useful
method.[20] Especially, no one has reported the thioesterifica-
tion with aldehydes using thiyl radicals except for Takagiꢀs
report.[21] This method is concise, but has some disadvantag-
es from the viewpoint of reagent efficiency. Namely, a large
amount of the aldehyde is required, since the aldehyde must
be used not only as the reagent, but also as the solvent. We
now wish to report the effective intermolecular radical reac-
Thioesters are synthetically as well as biologically important
compounds.[1] Their “active” esters are highly reactive
toward various nucleophiles so that they can be utilized in a
wide range of synthetic transformations. They have been
used as useful intermediates in the synthesis of amides[2]
(peptides,[3] b-lactams[4]), esters[5] (b-lactones[6]), ketones[7]
and carboxylic acids.[8] The reduction of thioesters to alde-
hydes[9] and sulfides[10] can be accomplished with various re-
ductive agents. In addition, they have been employed as
substrates in stereoselective aldol reactions[11] and as build-
ing blocks of heterocyclic compounds.[12]
ꢀ
tion of C S bond formation in a micellar system using the
combination of a water-soluble radical initiator (Figure 1)[22]
Furthermore, thioesters have been frequently utilized as
useful intermediates for the syntheses of various natural
products.[13] Accordingly, many thioesterification procedures
have been reported. The general synthetic method is the
direct coupling of a thiol with the parent carboxylic acid and
an activating agent,[14] or the coupling of a heavy metal thio-
late with an acid chloride or an acid anhydrate.[15] A disul-
fide[16] or a thiocyanate[17] can be used as a source of the
thiol moiety to prepare the thioesters. If the thioester is
used as the intermediate for the synthesis of thiols or of
their sulfur-containing derivatives, the approach will consist
of the coupling of the alkali metal thiocarboxylates with are-
nediazonium salts[18] or diaryliodonium salts.[19] Under these
Figure 1. Water-soluble radical initiators.
and surfactant[23] in water.[24] Our present method readily
produced useful pentafluorophenyl thioesters, which has al-
ready been successfully utilized by Davis et al.,[2a] in high
yields, and the reaction was carried out under mild condi-
tions.[25] Therefore, much attention is being devoted to this
reaction from the viewpoint of green chemistry.[26]
[a] Dr. H. Nambu, K. Hata, Dr. M. Matsugi, Prof. Dr. Y. Kita
Graduate School of Pharmaceutical Sciences, Osaka University
1-6, Yamada-oka, Suita, Osaka 565-0871 (Japan)
Fax : (+81)6-6879-8229
E-mail: kita@phs.osaka-u.ac.jp
Chem. Eur. J. 2005, 11, 719 – 727
DOI: 10.1002/chem.200400754
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
719

Results and Discussion
the thioesterification. The reaction did not proceed in ben-
zene or under neat conditions (entries 1–3). In addition,
when the radical initiators AIBN, V-70 L[28] and Et3B were
used in benzene, the yields of the thioester were lower than
the former case (entries 4–6).
The utility of the pentafluorophenyl thioester have been
already reported by Davis et al. The amidation of the penta-
fluorophenyl thioester occurred more effectively than that
of the phenyl thioester.[2a] Therefore, we tried to develop a
novel synthetic methodology for the active and useful penta-
fluorophenyl thioesters. We in-
First, we examined the possibility of thioesterifications in
water using 3-phenylpropionaldehyde (1a) and dipentafluoro-
phenyl disulfide (2a) with various water-soluble azo-type in-
itiators and a catalytic amount of CTAB as the first chosen
surfactant (Table 1). As a result, we could confirm the for-
mation of thioesters in these systems. Especially, VA-044
was found to be the most effective initiator among the ini-
tiators listed in Table 1 (entry 1). A side-reaction occurred
vestigated this thioesterification
using the various disulfides 2a–
Table 1. Effect of various initiators and additives.
c, and pentafluorophenyl thiol
(2a’) as the sulfur source
(Table 3). The thioesterifica-
tions with pentafluorophenyl di-
Entry
Initiator
Additive
T [8C]
t [h]
Yield [%]
sulfide (2a) gave the corre-
sponding thioesters in good
yields. On the other hand, the
reaction with diphenyl disulfide
(2b), dibenzyl disulfide (2c) or
pentafluorophenyl thiol (2a’)
gave the thioesters in lower
yields. We clarified that the
most effective sulfur source for
this thioesterification is the
1
VA-044
VA-044
VA-061
V-501
V-50
AIBN
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
none
50
50
80
70
60
18
24
2
73
2[a]
3
NR[f]
decomposition
4
5
6
7
8
9
10
11
12
13
24
24
12
24
24
24
24
24
24
24
32
45
37
trace
NR[f]
67
63
18
16
trace
80
Et3B
RT to 50
50
VA-044
VA-044
VA-044
VA-044
VA-044
VA-044
CTAC[b]
CTAHSO4
SDS[d]
50
50
50
50
[c]
Triton X-100[e]
Et4N+Brꢀ
pentafluorophenyl
disulfide.
50
These results indicated that the
yields of the thioesters might be
affected by the difference in the
[a] Reaction was carried out with galvinoxyl free radical (2 equiv). [b] CTAC: cetyltrimethylammonium chlo-
ride. [c] CTAHSO4: cetyltrimethylammonium hydrogen sulfate. [d] SDS: sodium dodecyl sulfate. [e] Triton X-
100: polyoxyethylene(10) isooctylphenylether. [f] NR: no reaction.
ꢀ
S S bond dissociation energies
with these disulfides.
when the typical radical initiator AIBN was used (entry 6);
when Et3B, a known radical initiator for low reaction tem-
peratures, was used the reaction hardly proceeded (entry 7).
In the presence of the galvinoxyl free radical as a radical
scavenger, the thioesterification did not occur at all
(entry 2), and hence this reaction would proceed via a radi-
cal mechanism. Next, we investigated the effect of surfac-
tants on the reaction using VA-044 as the initiator. The cati-
onic surfactants (CTAC, CTAHSO4) gave the thioesters in
good yields (entries 9 and 10). On the contrary, the anionic
surfactant (SDS), the nonionic surfactant (Triton X-100) and
phase-transfer catalyst (Et4N+Brꢀ) did not give satisfactory
results (entries 11–13). In the
We then investigated the generality of this thioesterifica-
tion with various aldehydes using pentafluorophenyl disul-
fide (2a), VA-044 and CTAB in water, which was the most
effective condition. These results are summarized in Table 4.
Under these conditions, the aliphatic aldehydes 1a–d
smoothly reacted and gave the corresponding thioesters
3aa–da in good yields (Table 4, entries 1–4). Similarly, we in-
vestigated this thioesterification using various aromatic alde-
hydes 1e–k. These aldehydes with electron-releasing func-
tional groups 1g–i smoothly reacted and gave the corre-
sponding thioesters 3ga–ia in good yields (Table 4, en-
tries 7–9). When benzaldehyde (1e) and p-anisaldehyde (1 f)
absence of the surfactant, the
Table 2. Effect of various solvents and initiators.
reaction did not proceed at all
(entry 8). These results clearly
show that the addition of cati-
onic surfactants is effective for
this thioesterification.[27]
The solvent effect on this re-
action by using 1a, 2a, VA-044
and CTAB is shown in Table 2.
From these results, water was
found to be the best solvent for
Entry
Initiator
Solvent
Additive
T [8C]
t [h]
Yield [%]
1
2
3
4
5
6
VA-044
VA-044
VA-044
AIBN
V-70L
Et3B
H2O
neat
benzene
benzene
benzene
benzene
CTAB
CTAB
CTAB
none
none
none
50
50
50
80
50
RT
18
24
24
24
24
24
73
trace
NR
32
29
trace
720
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Chem. Eur. J. 2005, 11, 719 – 727

Synthesis of Thioesters and Amides
FULL PAPER
Table 3. Thioesterification by using some disulfides.
Entry
Aldehyde
R1-CHO
Sulfur source
R2 =C6F5
R2 =Ph
R2 =Bn
C6F5SH
1
2
73[a] (3aa)
88[b] (3ba)
44 (3ab)
26 (3bb)
41 (3ac)
24 (3bc)
29 (3aa)
3
56 (3ca)
47 (3cb)
38 (3cc)
[a] Reaction time: 18 h. [b] Reaction time: 8 h.
Table 4. Thioesterification using various aromatic aldehydes and disul-
fides.
were treated under the same conditions, the corresponding
thioesters (3ea, 3 fa) were obtained in moderate yields
(Table 4, entries 5 and 6). The addition of 1.5 equivalents of
VA-044 brought about an improvement in the yields of the
thioesters (3ea, 3 fa). On the other hand, the thioesterifica-
tion of the aromatic aldehydes with an electron-withdrawing
substituent (1j, 1k) did not proceed at all (entries 10, 11).
These results of the thioesterifications might be affected by
the stabilities of the acyl radical[29] intermediates formed
from the aldehydes.[30]
Entry
Aldehyde
Product
t [h]
Yield [%]
1
2
3aa
3ba
18
8
73
88
3
4
5
3ca
3da
3ea
3
75
86
A plausible reaction mechanism of this thioesterification
is shown in Scheme 1. First, the disulfide 2 dissociates with
the initiator (VA-044) to give the thiyl radical A. Secondly,
the hydrogen in the aldehyde 1 is trapped by the thiyl radi-
cal A, and then the acyl radical B is formed. The acyl radical
reacts with the disulfide 2 or thiyl radical A, and the thioes-
terification 3 is achieved.[31] The thiol 2’, produced by the re-
action of the thiyl radical A and aldehyde 1, regenerates the
thiyl radical with the initiator, and this thiyl radical A takes
part in the reaction cycle again, whereas, the nucleophilic
alkyl radicals prepared by the initiator did not trap the hy-
drogen of the aldehyde as reported by Chatgilialoglu
et al.[29] The experimental results supporting this radical
cycle mechanism are shown in Scheme 2. Disulfide 2a react-
ed with the olefin compound to give the addition product
under this reaction condition [Eq. (1)]; and this reaction did
not proceed at all without the radical initiator, VA-044.
These results clearly show that disulfide is dissociated with
the initiator (VA-044) and the thiyl radical is generated. Di-
sulfide 2a was prepared from thiol 2a’ under the same con-
ditions [Eq. (2)], and the thioesterification with 1a and thiol
2a’ instead of disulfide 2a under the same conditions pro-
ceeded to give the corresponding thioester 3aa in 29% yield
[Eq. (3)]. These results clearly show that the thiyl radicals
are prepared from the thiols.
12
24
47 [54][a]
6
7
3 fa
3ga
24
24
56 [68][a]
72
8
9
3ha
3ia
8
95
90
24
10
11
24
24
NR
NR
[a] 1.5 Equivalents of VA-044 were used.
were obtained in good yields (entries 2b, 2c, 4b, 5b). Howev-
er, the thioesterification with 1a and 1g with 0.5–0.6 equiva-
lents of 2a produced only in moderate yields (entries 1b,
3b).
Pentafluorophenyl thioesters produced by our method are
relatively stable and highly active carbonyl compounds. We
then investigated the synthesis of various useful compounds
Since the mechanism showed that the amount of disulfide
to aldehyde was theoretically 0.5 equivalents, we examined
the thioesterification with a decreased equivalent of disul-
fide. These results are summarized in Table 5. When some
aldehydes (1b, 1h, 1i) were treated with 0.5–0.6 equivalents
disulfide 2a, the corresponding thioesters (3ba, 3ha, 3ia)
Chem. Eur. J. 2005, 11, 719 – 727
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Y. Kita et al.
from active pentafluorophenyl thioesters (Scheme 3). Pri-
mary and secondary amines 4a, 4b smoothly reacted with
thioesters 3aa, 3da to give the corresponding amides 5aa,
5db in quantitative yields. In particular, the amidation of
the thioester group of 3da bearing an ester group proceeded
in a chemoselective manner. Moreover, methyl ester 6a was
quantitatively obtained when the alcohol (MeOH) was used
as a nucleophile, and the hydrolysis of 3aa smoothly pro-
ceeded to give the corresponding carboxylic acid 7a in
quantitative yield. In addition, the other reaction to a
ketone from the pentafluorophenyl thioesters 3aa, 3 fa was
similarly achieved by the coupling reactions reported by
Liebeskind[7h] or Fukuyama.[7f] The treatment of thioester
3aa and 3 fa with a Pd catalyst furnished the corresponding
phenyl ketone 8a in 96% yield, and the corresponding p-
methoxyphenyl ketone 8 f in 90% yield. Thus, we clarified
that pentafluorophenyl thioesters were useful intermediates
in organic synthesis.
Scheme 1. The plausible thioesterification reaction mechanism.
Scheme 2. The experimental results supporting the mechanism.
Table 5. Thioesterification with decreased equivalent of disulfide 2a.
Scheme 3. The synthesis of various useful compounds from pentafluoro-
phenyl thioesters; [a] CuTC: copper(i) thiophene-2-carboxylate.
Finally, we investigated the direct amidation of aldehydes
via the pentafluorophenyl thioester intermediates. The gen-
eral synthetic method of amides is the direct coupling of
amines with the parent carboxylic acid and an activating
agent.[32] In contrast, a few methods involving the direct syn-
thesis of amides from aldehydes have been reported. In
these reports, metal oxidative amidations with aldehydes
and amines using Ni, Pd, Ru or Rh catalysts have been ach-
ieved.[33] Especially, no one has reported the direct synthesis
of amides from aldehydes using a radical initiator except for
Markꢂꢀs report.[34] Their method is convenient, but highly
toxic CCl4 was used as the reaction solvent. On the other
hand, the reaction solvent used in our method is water,
therefore, our method has the advantage of cost, safety and
environmental concern.
Entry
1a
Aldehyde
Disulfide (equiv)
1
t [h]
Yield [%]
73
18
b
2a
b
0.6
1
0.6
0.5
24
8
8
48
88
85
78
c
18
3a
b
1
24
24
72
51
0.5
4a
1
8
95
b
5a
b
0.5
1
24
24
24
81
90
87
We have also examined the direct amidation of aldehydes
using a one-pot synthetic methodology (Table 6). The addi-
tion of three equivalents of amines 4a, 4b to the mixture of
0.5
722
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Chem. Eur. J. 2005, 11, 719 – 727

Synthesis of Thioesters and Amides
FULL PAPER
Table 6. Direct amidation of aldehydes in one-pot synthesis.
ature procedure.[35] All other commer-
cially available compounds were used
without further purification.
Bis(2,3,4,5,6-pentafluorophenyl) disul-
fide (2a):[36] Pentafluorobenzenethiol
(5.0 g, 25.0 mmol) was added to a so-
lution of sodium perborate monohy-
drate (5.0 g, 50.0 mmol) in HOAc/H2O
Entry
1a
Aldehyde
Thioester
yield [%]
Amine[a]
Product
Amide
yield [%]
(62.5 mL HOAc
+ 25 mL H2O) at
(73)
4a
5aa
71
room temperature. After the reaction
mixture was stirred for 2 h, HOAc and
water were evaporated off, and to the
residue was added EtOAc and water.
The organic layer was washed with
water, saturated aqueous NaHCO3
and brine. The organic layer was dried
with MgSO4 and concentrated. The
residue was purified by column chro-
matography on silica gel (hexane only)
to afford 2a (5.0 g, 12.5 mmol, quant.)
as pale yellow crystals. M.p. 52.6–
52.78C (lit.[36a] m.p. 50–518C); IR
b
2a
b
3a
b
4b
4a
4b
4a
4b
5ab
5ba
5bb
5da
5db
70
82
76
84
75
(88)
(86)
4a
b
(95)
4a
4b
5ha
5hb
83 [93][b]
87 [91][b]
[a] Amine 4a: cyclohexylamine. 4b: piperidine. [b] Five equivalents of amine were used.
(KBr): n˜
=
1638, 1514, 1489, 1094,
982 cmꢀ1
;
19F NMR
(188 MHz,
CDCl3): d = ꢀ160.42 (dt, J=21.5, 4.5 Hz, 4F), ꢀ148.78 (t, J=21.5 Hz,
the thioesterification reaction (2a, VA-044 and CTAB) af-
forded the corresponding amides 5 in good yields. As these
yields of amide compounds 5 reflect the thioesterification
ones, the amidation yields are efficiently quantitative.
2F), ꢀ132.34 (dt, J=21.5, 4.5 Hz, 4F).
General procedure for the preparation of pentafluorophenyl thioester
(3aa–ia), phenyl thioester (3ab, bb, eb, fb) and benzyl thioester (3ac, bc,
ec, fc): VA-044 (48.5 mg, 0.15 mmol) was added to a solution of alde-
hydes (1a–i) (0.30 mmol), disulfide (2a–c) (0.30 mmol) and CTAB
(21.9 mg, 0.060 mmol) in H2O (3 mL) at room temperature. The reaction
mixture was then stirred and heated to 508C. After 3 h, an additional
amount of the initiator VA-044 (48.5 mg, 0.15 mmol) was added to the re-
action mixture. The progress of the reaction was monitored by TLC. The
reaction mixture was then extracted with EtOAc, and the organic layer
was washed with brine, dried with Na2SO4 and concentrated. The residue
was purified by column chromatography on silica gel (hexane/EtOAc
50:1!4:1) to afford the pure thioesters 3.
Conclusion
In summary, we found that the combination of a water-solu-
ble radical initiator, VA-044, and cationic surfactant, CTAB,
ꢀ
is an ideal reaction system to accomplish C S bond forma-
tion in water. This method is effective for the synthesis of
active thioesters under mild conditions, and could be applied
to the thioesterification of various aldehydes. In addition,
the pentafluorophenyl thioester, which was prepared by our
method, has valuable properties, since we have clarified that
it has a high activity toward various nucleophiles. We also
have achieved the direct amidation of aldehydes using a
one-pot synthetic methodology. These reactions occur under
mild conditions in water, therefore, our procedure may find
widespread use in organic chemistry.
(S)-(2,3,4,5,6-Pentafluorophenyl) 3-phenylpropanethioate (3aa): obtained
in 73% as colorless crystals; m.p. 68.7–68.88C; IR (KBr): n˜
= 1736,
1514, 1495 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 3.05 (s, 4H), 7.19–
;
7.34 (m, 5H); 13C NMR (75.5 MHz, CDCl3): d = 31.2, 45.2, 102.8 (dt, J=
21.5, 4.4 Hz), 126.7, 128.4 (2C), 128.8 (2C), 137.9 (dm, J=257 Hz, 2C),
139.2, 142.9 (dm, J=258 Hz), 147.0 (ddd, J=250, 10.6, 4.4 Hz, 2C), 191.6;
19F NMR (188 MHz, CDCl3): d = ꢀ161.55 (t, J=21.3 Hz, 2F), ꢀ150.40
(t, J=21.3 Hz, 1F), ꢀ131.55 (d, J=21.3 Hz, 2F); HRMS (FAB): m/z:
calcd for C15H9F5OSNa: 355.0192, found: 355.0206 [M+Na]+; elemental
analysis calcd (%) for C15H9F5OS: C 54.22, H 2.73; found: C 54.06, H
2.91.
(S)-(2,3,4,5,6-Pentafluorophenyl) undecanethioate (3ba): obtained in
88% as colorless oil; IR (KBr): n˜ = 2926, 2856, 1732, 1514, 1493 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d
= 0.88 (t, J=6.5 Hz, 3H), 1.27 (brs,
14H), 1.74 (quint, J=7.3 Hz, 2H), 2.73 (t, J=7.3 Hz, 2H); 13C NMR
(75.5 MHz, CDCl3): d = 14.1, 22.7, 25.5, 28.8, 29.2, 29.3, 29.4, 29.6, 31.9,
43.8, 103.2 (dt, J=21.5, 4.4 Hz), 137.9 (dm, J=256 Hz, 2C), 142.7 (dm,
J=257 Hz), 147.0 (ddd, J=249, 11.2, 4.4 Hz, 2C), 192.5; 19F NMR
Experimental Section
General methods: All melting points were measured by using a Bꢃchi
545 apparatus and are uncorrected. The IR absorption spectra were re-
corded using a Shimadzu FT/IR-8400 spectrometer with KBr pellets. The
1H and 13C NMR spectra were measured in CDCl3 by using JEOL JNM-
AL 300 spectrometers with TMS or CHCl3 as the internal standard. The
19F NMR spectra were measured in CDCl3 by using VARIAN VXR-200
spectrometers with hexafluorobenzene (ꢀ162.9 ppm) as the internal stan-
dard. Merck silica gel 60 (70–230 mesh ASTM) and Fuji Silysia Chemical
silica gel BW-300 were used for the column chromatography and flash
column chromatography. Anhydrous CH2Cl2 was distilled from P2O5. An-
hydrous THF was distilled from sodium/benzophenone under nitrogen.
(188 MHz, CDCl3): d
=
ꢀ161.67 (t, J=21.3 Hz, 2F), ꢀ150.60 (t, J=
21.3 Hz, 1F), ꢀ132.06 (d, J=21.3 Hz, 2F); elemental analysis calcd (%)
for C17H21F5OS: C 55.42, H 5.75; found: C 55.50, H 5.64.
(S)-(2,3,4,5,6-Pentafluorophenyl) cyclohexanecarbothioate (3ca): ob-
tained in 75% as colorless crystals; m.p. 41.7–41.88C; IR (KBr): n˜
=
2936, 2858, 1730, 1514, 1493 cmꢀ1 1H NMR (300 MHz, CDCl3): d
;
=
1.22–1.41 (m, 3H), 1.49–1.62 (m, 2H), 1.67–1.71 (m, 1H), 1.81–1.87 (m,
2H), 2.02–2.07 (m, 2H), 2.68 (tt, J=11.1, 3.6 Hz, 1H); 13C NMR
(75.5 MHz, CDCl3): d = 25.4 (2C), 25.6, 29.4 (2C), 52.7, 103.4 (dt, J=
21.5, 4.4 Hz), 137.9 (dm, J=255 Hz, 2C), 142.7 (dtt, J=257, 13.7, 5.0 Hz),
147.1 (ddd, J=249, 10.6, 4.4 Hz, 2C), 195.8; 19F NMR (188 MHz, CDCl3):
Compound 1a was purified by flash chromatography on silica gel
(hexane/EtOAc 10:1). Compound 1d was prepared according to the liter-
d
=
ꢀ161.82 (dt, J=21.3, 4.6 Hz, 2F), ꢀ150.90 (t, J=21.3 Hz, 1F),
Chem. Eur. J. 2005, 11, 719 – 727
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Y. Kita et al.
ꢀ132.18 (d, J=21.3 Hz, 2F); elemental analysis calcd (%) for
7.19–7.33 (m, 5H), 7.35–7.42 (m, 5H); 13C NMR (75.5 MHz, CDCl3): d =
31.4, 45.1, 126.4, 127.6, 128.4 (2C), 128.6 (2C), 129.2 (2C), 129.4, 134.5
(2C), 139.9, 196.7.
C13H11F5OS: C 50.32, H 3.57; found: C 50.43, H 3.67.
Ethyl 7-oxo-7-[(2,3,4,5,6-pentafluorophenyl)sulfanyl]heptanoate (3da):
obtained in 86% as colorless oil; IR (KBr): n˜ = 2937, 2866, 1734, 1732,
(S)-Phenyl undecanethioate (3bb): obtained in 26% as colorless oil; IR
1514, 1493 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 1.26 (t, J=7.2 Hz,
;
(KBr): n˜ = 2924, 2853, 1711, 1477, 1466, 1441 cmꢀ1 1H NMR (300 MHz,
;
3H), 1.37–1.47 (m, 2H), 1.67 (quint, J=7.3 Hz, 2H), 1.77 (quint, J=
7.3 Hz, 2H), 2.32 (t, J=7.3 Hz, 2H), 2.75 (t, J=7.3 Hz, 2H), 4.13 (q, J=
7.2 Hz, 2H); 13C NMR (75.5 MHz, CDCl3): d = 14.3, 24.5, 25.1, 28.3,
34.0, 43.5, 60.4, 103.1 (dt, J=21.2, 4.4 Hz), 137.9 (dm, J=255 Hz, 2C),
142.8 (dtt, J=257, 13.4, 5.0 Hz), 147.0 (ddd, J=249, 11.2, 4.4 Hz, 2C),
CDCl3): d = 0.88 (t, J=6.6 Hz, 3H), 1.27 (brs, 14H), 1.71 (quint, J=
7.5 Hz, 2H), 2.64 (t, J=7.5 Hz, 2H), 7.40 (s, 5H); 13C NMR (75.5 MHz,
CDCl3): d = 14.1, 22.7, 25.6, 29.0, 29.2, 29.3, 29.4, 29.5, 31.9, 43.7, 128.0,
129.1 (2C), 129.3, 134.5 (2C), 197.6; elemental analysis calcd (%) for
C17H26OS: C 73.33, H 9.41, S 11.52; found: C 73.59, H 9.37, S 11.24.
173.5, 192.2; 19F NMR (188 MHz, CDCl3): d
=
ꢀ161.58 (dt, J=21.5,
(S)-Phenyl benzenecarbothioate (3eb):[17a,18b,19,20] obtained in 35% as col-
4.5 Hz, 2F), ꢀ150.43 (t, J=21.5 Hz, 1F), ꢀ132.10 (d, J=21.5 Hz, 2F); ele-
mental analysis calcd (%) for C15H15F5O3S: C 48.65, H 4.08; found: C
48.91, H 4.16.
orless crystals; m.p. 55.6–55.78C (lit.[18b,19] m.p. 54–558C, lit.[17a] m.p. 55–
568C); IR (KBr): n˜ = 1680, 1580, 1477, 1441 cmꢀ1 1H NMR (300 MHz,
;
CDCl3): d = 7.44–7.54 (m, 7H), 7.61 (t, J=7.3 Hz, 1H), 8.03 (d, J=
7.3 Hz, 2H); 13C NMR (75.5 MHz, CDCl3): d = 127.3, 127.5 (2C), 128.8
(2C), 129.3 (2C), 129.5, 133.7, 135.1 (2C), 136.6, 190.2.
(S)-(2,3,4,5,6-Pentafluorophenyl) benzenecarbothioate (3ea): obtained in
47% as colorless crystals; m.p. 40.7–40.88C; IR (KBr): n˜ = 1697, 1514,
1495 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 7.53 (t, J=7.4 Hz, 2H),
;
(S)-Phenyl 4-methoxybenzenecarbothioate (3 fb):[17a,38] obtained in 47%
7.68 (t, J=7.4 Hz, 1H), 8.03 (d, J=7.4 Hz, 2H); 13C NMR (75.5 MHz,
CDCl3): d = 102.7 (dt, J=21.2, 4.4 Hz), 127.9 (2C), 129.0 (2C), 134.6,
135.1, 137.9 (dm, J=256 Hz, 2C), 142.9 (dtt, J=258, 13.4, 5.0 Hz), 147.4
(ddd, J=250, 11.2, 4.4 Hz, 2C), 185.0; 19F NMR (188 MHz, CDCl3): d =
ꢀ161.52 (t, J=21.5 Hz, 2F), ꢀ150.18 (t, J=21.5 Hz, 1F), ꢀ131.59 (d, J=
21.5 Hz, 2F); elemental analysis calcd (%) for C13H5F5OS: C 51.32, H
1.66; found: C 51.23, H 1.85.
as colorless crystals; m.p. 93.6–93.78C (lit.[38] m.p. 93–958C, lit.[17a] m.p.
94–958C); IR (KBr): n˜ = 1666, 1599, 1506, 1477, 1439 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d = 3.87 (s, 3H), 6.95 (d, J=8.7 Hz, 2H), 7.43–7.52
(m, 5H), 8.00 (d, J=8.7 Hz, 2H); 13C NMR (75.5 MHz, CDCl3): d =
55.5, 113.9 (2C), 127.6, 129.2 (2C), 129.3, 129.4, 129.7 (2C), 135.2 (2C),
164.0, 188.6; elemental analysis calcd (%) for C14H12O2S: C 68.83, H 4.95,
S 13.13; found: C 68.94, H 5.07, S 12.92.
(S)-(2,3,4,5,6-Pentafluorophenyl) 4-methoxybenzenecarbothioate (3 fa):
obtained in 56% as colorless crystals; m.p. 54.5–54.68C; IR (KBr): n˜ =
(S)-Benzyl 3-phenylpropanethioate (3ac): obtained in 41% as pale
yellow oil; IR (KBr): n˜ = 1688, 1495, 1454 cmꢀ1 1H NMR (300 MHz,
;
1697, 1601, 1514, 1495 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 3.90 (s,
;
CDCl3): d = 2.84–2.90 (m, 2H), 2.96–3.02 (m, 2H), 4.12 (s, 2H), 7.15–
7.31 (m, 10H); 13C NMR (75.5 MHz, CDCl3): d = 31.4, 33.2, 45.2, 126.4,
127.2, 128.3 (2C), 128.5 (2C), 128.6 (2C), 128.8 (2C), 137.6, 139.9, 197.8;
elemental analysis calcd (%) for C16H16OS: C 74.96, H 6.29, S 12.51;
found: C 75.23, H 6.55, S 12.34.
3H), 6.97 (d, J=9.0 Hz, 2H), 7.98 (d, J=9.0 Hz, 2H); 13C NMR
(75.5 MHz, CDCl3): d = 55.7, 103.2 (dt, J=21.2, 4.4 Hz), 114.3 (2C),
127.9, 130.4 (2C), 137.9 (dm, J=256 Hz, 2C), 142.8 (dt, J=257, 13.7 Hz),
147.5 (ddd, J=249, 10.6, 4.4 Hz, 2C), 164.9, 183.4; 19F NMR (188 MHz,
CDCl3): d = ꢀ161.75 (dt, J=21.5, 6.0 Hz, 2F), ꢀ150.56 (t, J=21.5 Hz,
1F), ꢀ131.68 (dt, J=21.5, 4.5 Hz, 2F); elemental analysis calcd (%) for
C14H7F5O2S: C 50.30, H 2.11; found: C 50.29, H 2.24.
(S)-Benzyl undecanethioate (3bc): obtained in 24% as colorless oil; IR
(KBr): n˜
= ;
2924, 2853, 1693, 1495, 1454 cmꢀ1 1H NMR (300 MHz,
CDCl3): d = 0.88 (t, J=6.7 Hz, 3H), 1.25 (brs, 14H), 1.66 (quint, J=
7.5 Hz, 2H), 2.56 (t, J=7.5 Hz, 2H), 4.11 (s, 2H), 7.21–7.32 (m, 5H);
13C NMR (75.5 MHz, CDCl3): d = 14.1, 22.7, 25.6, 28.9, 29.2, 29.3, 29.4,
29.5, 31.9, 33.1, 43.8, 127.2, 128.6 (2C), 128.8 (2C), 137.7, 198.9; elemental
analysis calcd (%) for C18H28OS: C 73.92, H 9.65, S 10.96; found: C
74.22, H 9.66, S 10.74.
(S)-(2,3,4,5,6-Pentafluorophenyl)
(3ga): obtained in 72% as colorless crystals; m.p. 116.0–116.18C; IR
(KBr): n˜ = 1692, 1593, 1514, 1493 cmꢀ1 1H NMR (300 MHz, CDCl3): d
3,4-dimethoxybenzenecarbothioate
;
= 3.95 (s, 3H), 3.98 (s, 3H), 6.95 (d, J=8.5 Hz, 1H), 7.44 (d, J=2.0 Hz,
1H), 7.74 (dd, J=8.5, 2.0 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d =
56.0, 56.2, 103.0 (t, J=21.5 Hz), 109.7, 110.4, 122.9, 127.9, 137.8 (dm, J=
256 Hz, 2C), 142.7 (dm, J=257 Hz), 147.4 (ddd, J=249, 11.2, 4.4 Hz, 2C),
149.2, 154.5, 183.5; 19F NMR (188 MHz, CDCl3): d = ꢀ161.70 (t, J=
20.0 Hz, 2F), ꢀ150.44 (t, J=20.0 Hz, 1F), ꢀ131.69 (d, J=20.0 Hz, 2F); el-
emental analysis calcd (%) for C15H9F5O3S: C 49.46, H 2.49; found: C
49.46, H 2.55.
(S)-Benzyl benzenecarbothioate (3ec):[20, 39] obtained in 32% as colorless
crystals; m.p. 36.6–36.78C (lit.[39b] m.p. 34.5–35.58C, lit.[39c] m.p. 38–398C);
1
IR (KBr): n˜ = 1661, 1580, 1495, 1448 cmꢀ1; H NMR (300 MHz, CDCl3):
d = 4.32 (s, 2H), 7.25–7.47 (m, 7H), 7.56 (t, J=7.3 Hz, 1H), 7.97 (d, J=
7.1 Hz, 2H); 13C NMR (75.5 MHz, CDCl3): d = 33.3, 127.3 (2C), 127.3,
128.6 (2C), 128.7 (2C), 129.0 (2C), 133.5, 136.7, 137.5, 191.3.
(S)-(2,3,4,5,6-Pentafluorophenyl)
(3ha): obtained in 95% as colorless crystals; m.p. 154.3–154.48C; IR
(KBr): n˜ = 1663, 1612, 1578, 1510, 1487, 1475 cmꢀ1 1H NMR (300 MHz,
CDCl3):
3.85 (s, 3H), 3.87 (s, 6H), 6.11 (s, 2H); 13C NMR
2,4,6-trimethoxybenzenecarbothioate
(S)-Benzyl 4-methoxybenzenecarbothioate (3 fc):[40] obtained in 38% as
;
colorless crystals; mp 51.0–51.18C (lit.[40] m.p. 51–528C); IR (KBr): n˜ =
1
d
=
1657, 1601, 1508, 1495, 1454 cmꢀ1; H NMR (300 MHz, CDCl3): d = 3.86
(75.5 MHz, CDCl3): d = 55.6, 56.1 (2C), 90.7 (2C), 104.7 (dt, J=21.2,
4.4 Hz), 109.1, 137.7 (dm, J=255 Hz, 2C), 142.5 (dtt, J=257, 13.7,
5.0 Hz), 147.2 (ddd, J=249, 10.6, 4.4 Hz, 2C), 159.8 (2C), 164.3, 183.5;
19F NMR (188 MHz, CDCl3): d = ꢀ162.31 (t, J=21.5 Hz, 2F), ꢀ151.66
(t, J=21.5 Hz, 1F), ꢀ131.79 (d, J=21.5 Hz, 2F); elemental analysis calcd
(%) for C16H11F5O4S: C 48.74, H 2.81; found: C 48.66, H 2.84.
(s, 3H), 4.30 (s, 2H), 6.91 (d, J=8.9 Hz, 2H), 7.24–7.39 (m, 5H), 7.94 (d,
J=8.9 Hz, 2H); 13C NMR (75.5 MHz, CDCl3): d = 33.2, 55.5, 113.8 (2C),
127.2, 128.6 (2C), 129.0 (2C), 129.5 (2C), 129.6, 137.7, 163.8, 189.8.
1,2-Bis-pentafluorophenylsulfanylethyl
acetate:
VA-044
(24.4 mg,
0.075 mmol) was added to a solution of 2a (60.0 mg, 0.151 mmol), vinyl
acetate (139 mL, 1.51 mmol) and CTAB (11.0 mg, 0.030 mmol) in H2O
(3.0 mL) at room temperature. The reaction mixture was then stirred and
heated to 508C. After 6 h, the reaction mixture was extracted with
EtOAc, and the organic layer was washed with brine, dried with Na2SO4
and concentrated. The residue was purified by column chromatography
on silica gel (hexane/EtOAc 20:1) to afford the title compound as color-
less crystals (65.6 mg, 0.135 mmol, 90%). M.p. 74.3–74.48C; IR (KBr): n˜
(S)-(2,3,4,5,6-Pentafluorophenyl)
2,4,6-trimethylbenzenecarbothioate
(3ia): obtained in 90% as colorless crystals; m.p. 160.5–160.68C; IR
1
(KBr): n˜ = 1692, 1514, 1497 cmꢀ1; H NMR (300 MHz, CDCl3): d = 2.31
(s, 3H), 2.38 (s, 6H), 6.90 (s, 2H); 13C NMR (75.5 MHz, CDCl3): d =
18.9 (2C), 21.2, 103.1 (t, J=21.8 Hz), 128.7 (2C), 134.2 (2C), 135.7, 138.0
(dm, J=257 Hz, 2C), 140.7, 143.0 (dm, J=258 Hz), 147.2 (ddd, J=250,
11.0, 4.4 Hz, 2C), 191.1; 19F NMR (188 MHz, CDCl3): d = ꢀ161.38 (t, J=
20.5 Hz, 2F), ꢀ150.21 (t, J=20.5 Hz, 1F), ꢀ131.97 (d, J=20.5 Hz, 2F); el-
emental analysis calcd (%) for C16H11F5OS: C 55.49, H 3.20; found: C
55.33, H 3.20.
1
= 1759, 1639, 1485, 1371 cmꢀ1; H NMR (300 MHz, CDCl3): d = 2.03 (s,
3H), 3.08 (dd, J=14.4, 9.5 Hz, 1H), 3.78 (dd, J=14.4, 3.7 Hz, 1H), 5.91
(dd, J=9.5, 3.7 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d = 20.3, 29.7
(2C), 39.0, 77.3, 104.1–108.0 (2C), 135.5–140.5 (4C), 144.3–150.0 (4C),
169.0; 19F NMR (188 MHz, CDCl3): d = ꢀ161.31 (br, 2F), ꢀ160.92 (br,
2F), ꢀ152.00 (br, 1F), ꢀ149.69 (br, 1F), ꢀ132.76 (d, J=24.4 Hz, 2F),
ꢀ131.29 (d, 22.9 Hz, 2F).
(S)-Phenyl 3-phenylpropanethioate (3ab):[37] obtained in 44% as color-
less crystals; m.p. 48.4–48.58C (lit.[37] m.p. 49–508C); IR (KBr): n˜ = 1707,
1477, 1441 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 2.93–3.06 (m, 4H),
;
724
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 719 – 727

Synthesis of Thioesters and Amides
FULL PAPER
Preparation of bis(2,3,4,5,6-pentafluorophenyl) disulfide (2a) by using
pentafluorobenzenethiol (2a’), VA-044 and CTAB: VA-044 (65.0 mg,
0.20 mmol) was added to a solution of 2a’ (80.0 mg, 0.40 mmol) and
CTAB (29.3 mg, 0.080 mmol) in H2O (4 mL) at room temperature. The
reaction mixture was then stirred and heated to 508C. After 20 min, the
reaction mixture was extracted with EtOAc, and the organic layer was
washed with brine, dried with Na2SO4 and concentrated. The residue was
purified by column chromatography on silica gel (hexane only) to afford
2a (68.5 mg, 0.17 mmol, 86%) as pale yellow crystals.
(30.0 mg, 0.20 mmol, quant.) as colorless crystals. M.p. 47.6–47.78C
(lit.[43a] m.p. 47–488C, lit.[43b] m.p. 47–498C); IR (KBr): n˜ = 3028, 2932,
1709, 1454, 1413, 1219 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 2.69 (t,
;
J=7.8 Hz, 2H), 2.96 (t, J=7.8 Hz, 2H), 7.20–7.32 (m, 5H), 11.6 (brs,
1H); 13C NMR (75.5 MHz, CDCl3): d = 30.6, 35.6, 126.4, 128.3 (2C),
128.6 (2C), 140.1, 179.1.
1,3-Diphenylpropan-1-one (8a):[44] According to the reported prcedure,[7h]
8a can be obtained in 96% yield as colorless crystals. M.p. 66.6–66.78C
(lit.[44a] m.p. 67–698C, lit.[44b] mp 70–718C); IR (KBr): n˜ = 2927, 1686,
1597, 1495, 1448, 1205 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 3.07 (t,
;
Preparation of pentafluorophenyl thioester (3aa) by using pentafluoro-
benzenethiol (2a’): VA-044 (48.5 mg, 0.15 mmol) was added to a solution
of 1a (40.3 mg, 0.30 mmol), 2a’ (120 mg, 0.60 mmol) and CTAB (21.9 mg,
0.060 mmol) in H2O (3 mL) at room temperature. The reaction mixture
was then stirred and heated to 508C. After 3 h, an additional amount of
VA-044 (48.5 mg, 0.15 mmol) was added to the reaction mixture. After
24 h, the reaction mixture was extracted with EtOAc, and the organic
layer was washed with brine, dried with Na2SO4 and concentrated. The
residue was purified by column chromatography on silica gel (hexane/
EtOAc 50:1) to afford 3aa (28.9 mg, 0.087 mmol, 29%) as colorless crys-
tals.
J=7.7 Hz, 2H), 3.30 (t, J=7.7 Hz, 2H), 7.18–7.32 (m, 5H), 7.41–7.57 (m,
3H), 7.95 (d, J=7.3 Hz, 2H); 13C NMR (75.5 MHz, CDCl3): d = 30.1,
40.4, 126.1, 128.0 (2C), 128.4 (2C), 128.5 (2C), 128.5 (2C), 128.6 (2C),
133.0, 136.8, 141.3, 199.2.
Ethyl 4-(4-methoxybenzoyl)butanoate (8 f):[45] According to the reported
prcedure,[7f] 8 f can be obtained in 90% yield as colorless crystals. M.p.
56.5–56.68C (lit.[45b] m.p. 56–588C, lit.[45a] m.p. 58.5–598C); IR (KBr): n˜ =
2982, 2960, 1734, 1668, 1602, 1281, 1259, 1186, 1175 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d = 1.25 (t, J=7.2 Hz, 3H), 2.06 (quint, J=7.2 Hz,
2H), 2.42 (t, J=7.2 Hz, 2H), 3.00 (t, J=7.2 Hz, 2H), 3.87 (s, 3H), 4.14
(q, J=7.2 Hz, 2H), 6.93 (d, J=8.9 Hz, 2H), 7.95 (d, J=8.9 Hz, 2H);
13C NMR (75.5 MHz, CDCl3): d = 14.2, 19.6, 33.4, 37.1, 55.4, 60.3, 113.6
(2C), 129.9, 130.2 (2C), 163.4, 173.3, 198.0.
N-Cyclohexyl-3-phenylpropanamide (5aa):[41] Cyclohexylamine (4a)
(18.9 mL, 0.165 mmol) and Et3N (23.0 mL, 0.165 mmol) were added to a
solution of 3aa (49.8 mg, 0.150 mmol) in dry CH2Cl2 (1.5 mL) at room
temperature under a nitrogen atmosphere. The reaction mixture was
then stirred for 5 min and concentrated. The residue was purified by
column chromatography on silica gel (hexane/EtOAc 2:1) to afford 5aa
(34.7 mg, 0.15 mmol, quant.) as colorless crystals. M.p. 111.9–112.08C
General procedure for the preparation of amide (5) from aldehyde (1a,
b, d, h): VA-044 (48.5 mg, 0.15 mmol) was added to a solution of alde-
hydes (1a, b, d, h) (0.30 mmol), 2a (119 mg, 0.30 mmol) and CTAB
(21.9 mg, 0.060 mmol) in H2O (3 mL) at room temperature. The reaction
mixture was then stirred and heated to 508C. After 3 h, an additional
amount of the initiator VA-044 (48.5 mg, 0.15 mmol) was added to the re-
action mixture. The progress of the reaction was monitored by TLC.
After the completion of the thioesterification, amine (4a or 4b)
(0.90 mmol) was added to the thioesterification mixture, and the reaction
mixture was stirred at 508C for 30 min. The reaction mixture was then
extracted with EtOAc, and the organic layer was washed with brine,
dried with Na2SO4 and concentrated. The residue was purified by column
chromatography on silica gel (hexane/EtOAc 3:1!100% EtOAc) to
afford the pure amides 5.
(lit.[41] m.p. 110–1118C); IR (KBr): n˜
= 3302, 2934, 2853, 1636,
1543 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 0.94–1.18 (m, 3H), 1.23–
;
1.40 (m, 2H), 1.55–1.68 (m, 3H), 1.80–1.85 (m, 2H), 2.43 (t, J=7.6 Hz,
2H), 2.95 (t, J=7.6 Hz, 2H), 3.67–3.79 (m, 1H), 5.19 (brd, 1H), 7.17–
7.30 (m, 5H); 13C NMR (75.5 MHz, CDCl3): d = 24.8 (2C), 25.5, 31.9,
33.1 (2C), 38.8, 48.0, 126.2, 128.4 (2C), 128.5 (2C), 140.9, 171.0; elemental
analysis calcd (%) for C15H21NO: C 77.88, H 9.15, N 6.05; found: C
77.59, H 9.05, N 5.96.
Ethyl 7-oxo-7-tetrahydropyridin-1(2H)-ylheptanoate (5db): Piperidine
(4b) (16.3 mL, 0.165 mmol) and Et3N (23.0 mL, 0.165 mmol) were added
to a solution of 3da (55.6 mg, 0.150 mmol) in dry CH2Cl2 (1.5 mL) at
room temperature under a nitrogen atmosphere. The reaction mixture
was then stirred for 5 min and concentrated. The residue was purified by
column chromatography on silica gel (hexane/EtOAc 1:1) to afford 5db
(38.3 mg, 0.15 mmol, quant.) as colorless oil. IR (KBr): n˜ = 2936, 2856,
3-Phenyl-1-tetrahydropyridin-1(2H)-ylpropan-1-one (5ab):[46] obtained in
70% as pale yellow oil; IR (KBr): n˜ = 2936, 2855, 1643, 1441 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d = 1.40–1.65 (m, 6H), 2.61 (t, J=8.0 Hz,
2H), 2.96 (t, J=8.0 Hz, 2H), 3.33 (t, J=5.5 Hz, 2H), 3.55 (t, J=5.5 Hz,
2H), 7.16–7.31 (m, 5H); 13C NMR (75.5 MHz, CDCl3): d = 24.5, 25.5,
26.4, 31.6, 35.2, 42.8, 46.7, 126.1, 128.4 (2C), 128.5 (2C), 141.4, 170.6.
1732, 1643, 1443 cmꢀ1 1H NMR (300 MHz, CDCl3): d
; = 1.25 (t, J=
7.2 Hz, 3H), 1.33–1.43 (m, 2H), 1.49–1.71 (m, 10H), 2.28–2.34 (m, 4H),
3.39 (t, J=5.4 Hz, 2H), 3.54 (t, J=5.4 Hz, 2H), 4.12 (q, J=7.2 Hz, 2H);
13C NMR (75.5 MHz, CDCl3): d = 14.2, 24.6, 24.8, 25.1, 25.6, 26.6, 29.0,
33.2, 34.2, 42.7, 46.7, 60.2, 171.3, 173.8; elemental analysis calcd (%) for
C14H25NO3: C 65.85, H 9.87, N 5.49; found: C 65.42, H 9.71, N 5.22.
Methyl 3-phenylpropionate (6a):[42] K2CO3 (27.6 mg, 0.20 mmol) was
added to a solution of 3aa (66.5 mg, 0.20 mmol) in dry MeOH (1 mL)
under a nitrogen atmosphere. The reaction mixture was stirred at 508C
for 30 min. To the reaction mixture, a saturated aqueous NH4Cl and
EtOAc were added, and the organic layer was separated and the aqueous
layer extracted with EtOAc. The organic layer was washed with brine,
dried with Na2SO4 and concentrated. The residue was purified by column
chromatography on silica gel (hexane/EtOAc 2:1) to afford 6a (32.8 mg,
0.20 mmol, quant.) as colorless oil. IR (KBr): n˜ = 3028, 2952, 2928, 2858,
N-Cyclohexylundecanamide (5ba): obtained in 82% as colorless crystals;
m.p. 81.2–81.38C; IR (KBr): n˜
= ;
3298, 2920, 2851, 1638, 1551 cmꢀ1
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J=6.6 Hz, 3H), 1.03–1.44 (m,
19H), 1.58–1.73 (m, 5H), 1.88–1.94 (m, 2H), 2.13 (t, J=7.6 Hz, 2H),
3.71–3.83 (m, 1H), 5.26 (brd, 1H); 13C NMR (75.5 MHz, CDCl3): d =
14.1, 22.7, 24.9 (2C), 25.6, 25.9, 29.3, 29.3, 29.4, 29.5, 29.6, 31.9, 33.3 (2C),
37.2, 48.0, 172.2; elemental analysis calcd (%) for C17H33NO: C 76.34; H
12.44; N 5.24; found: C 76.05; H 12.25; N 5.17.
1-Tetrahydropyridin-1(2H)-ylundecan-1-one (5bb): obtained in 76% as
colorless oil; IR (KBr): n˜
= ;
2924, 2853, 1649, 1433 cmꢀ1 1H NMR
(300 MHz, CDCl3): d = 0.88 (t, J=6.5 Hz, 3H), 1.26 (brs, 14H), 1.53–
1.64 (m, 8H), 2.31 (t, J=7.7 Hz, 2H), 3.39 (t, J=5.3 Hz, 2H), 3.54 (t, J=
5.3 Hz, 2H); 13C NMR (75.5 MHz, CDCl3): d = 14.1, 22.7, 24.6, 25.5,
25.6, 26.6, 29.3, 29.4, 29.5, 29.6, 29.6, 31.9, 33.5, 42.6, 46.8, 171.6; elemen-
tal analysis calcd (%) for C16H31NO: C 75.83; H 12.33; N 5.53; found: C
75.34; H 12.15; N 5.25.
1740, 1497, 1437 cmꢀ1 1H NMR (300 MHz, CDCl3): d
; = 2.63 (t, J=
7.8 Hz, 2H), 2.95 (t, J=7.8 Hz, 2H), 3.66 (s, 3H), 7.18–7.21 (m, 3H),
7.24–7.31 (m, 2H); 13C NMR (75.5 MHz, CDCl3): d = 31.0, 35.7, 51.6,
126.3, 128.3 (2C), 128.5 (2C), 140.5, 173.3.
3-Phenyl-1-propionic acid (7a):[43] KOH (16.8 mg, 0.30 mmol) was added
to a solution of 3aa (66.5 mg, 0.20 mmol) in acetone/H2O (1 mL acetone
+ 1 mL H2O). The reaction mixture was stirred at 508C for 1 h. To the
reaction mixture was extracted with EtOAc. The organic layer was
washed with 1n aqueous HCl and brine. The organic layer was dried
with Na2SO4 and concentrated. The residue was purified by column chro-
matography on silica gel (hexane/EtOAc/HOAc 75:25:1) to afford 7a
Ethyl 7-(cyclohexylamino)-7-oxoheptanoate (5da): obtained in 84% as
colorless crystals; m.p. 69.9–70.08C; IR (KBr): n˜ = 3296, 2932, 2855,
1736, 1638, 1541 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 1.04–1.43 (m,
;
7H), 1.25 (t, J=7.2 Hz, 3H), 1.57–1.74 (m, 7H), 1.88–1.93 (m, 2H), 2.14
(t, J=7.4 Hz, 2H), 2.30 (t, J=7.4 Hz, 2H), 3.69–3.82 (m, 1H), 4.12 (q,
J=7.2 Hz, 2H), 5.46 (brd, 1H); 13C NMR (75.5 MHz, CDCl3): d = 14.2,
24.5, 24.8 (2C), 25.4, 25.5, 28.6, 33.2 (2C), 34.0, 36.6, 48.0, 60.2, 171.8,
173.6; elemental analysis calcd (%) for C15H27NO3: C 66.88; H 10.10; N
5.20; found: C 66.71H, 9.98; N 5.15.
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Y. Kita et al.
N-Cyclohexyl-2,4,6-trimethoxybenzamide (5ha): obtained in 83% as col-
orless crystals; m.p. 147.1–147.28C; IR (KBr): n˜ 3287, 2932, 2851,
1649, 1607, 1589, 1454 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 1.15–1.26
(m, 3H), 1.35–1.48 (m, 2H), 1.59–1.75 (m, 3H), 1.99–2.04 (m, 2H), 3.79
(s, 6H), 3.80 (s, 3H), 3.93–4.05 (m, 1H), 5.63 (brd, 1H), 6.09 (s, 2H);
13C NMR (75.5 MHz, CDCl3): d = 24.8 (2C), 25.7, 33.0 (2C), 48.2, 55.4,
56.0 (2C), 90.8 (2C), 109.5, 158.5 (2C), 161.9, 164.7; elemental analysis
calcd (%) for C16H23NO4: C 65.51; H 7.90; N 4.77; found: C 65.35; H
7.77; N 4.76.
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Tetrahydropyridin-1(2H)-yl(2,4,6-trimethoxyphenyl)methanone
obtained in 87% as colorless crystals; m.p. 122.3–122.48C; IR (KBr): n˜ =
2936, 2853, 1632, 1607, 1589, 1435 cmꢀ1 1H NMR (300 MHz, CDCl3): d
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;
= 1.47 (brs, 2H), 1.61–1.64 (m, 4H), 3.19 (t, J=5.5 Hz, 2H), 3.74 (brs,
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157.4 (2C), 161.7, 165.2; elemental analysis calcd (%) for C15H21NO4: C
64.50; H 7.58; N 5.01; found: C 64.36; H 7.57; N 4.94.
Acknowledgement
We thank Wako Pure Chemical Industries, Ltd., for the generous supply
of several water-soluble azo-type initiators. This work was supported by a
Grant-in-Aid for Scientific Research (S) (No.7690) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan. H.N. ac-
knowledges the JSPS Research Fellowship for Young Scientists.
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Synthesis of Thioesters and Amides
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group of the aldehyde, and then the alkoxyl radical (X) is formed.
Next, the hydride radical is eliminated from the alkoxyl radical in-
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aldehydes with an electron-withdrawing substitute (1j, 1k) should
be nucleophilically attacked by the thiyl radical. However, these thi-
oesterification with 1j and 1k did not proceed at all (Table 4, en-
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the hydride radical, therefore, it is difficult that the hydride radical
eliminates from the alkoxyl radical intermediate (X). Accordingly, it
might be inferred from this reactivity that this thioesterification is
achieved via the acyl radical intermediate (Scheme 1).
Received: July 22, 2004
Published online: December 3, 2004
Chem. Eur. J. 2005, 11, 719 – 727
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ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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