Sequential one-pot reactions of thioformamides with organolithium and zinc reagents

Article abstract of DOI:10.1080/10426507.2010.520289

Sequential one-pot reactions of thioformamides with organolithium and zinc reagents were carried out. As thioformamides, N,N-dimethylthioformamide and N-ethoxycarbonyl N′-thioformyl piperazine were used. A variety of organolithium reagents such as alkyl, aryl, and heteroaryllithiums were used to give the corresponding amines in moderate to high yields. The efficiency of the reaction was influenced by the substituents on the aromatic rings. Thienyllithium gave the product in good yield, whereas the reaction offuryllithium was less efficient. A similar reaction with lithium acetylides was not successful. As an alternative method, methyl iodide was added to the reaction mixture ofthioformamides and lithium silylacetylide to form S,N-acetals as intermediates, and to this were added organozinc reagents to lead to propargylamines. For organozinc reagents, dialkyl zincs and 3- ethoxycarbonylpropylzinc bromide were used. The former reagents showed high efficiency when combined with several organolithium reagents, but the latter gave the corresponding product only when lithium silylacetylide was used as an initial reagent. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.520289

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Sequential One-Pot Reactions of
Thioformamides with Organolithium and
Zinc Reagents
Professor Dr. Toshiaki Murai a & Koji Matsushita a
a Department of Chemistry, Faculty of Engineering , Gifu University ,
Yanagido, Gifu, Japan
Published online: 12 Jul 2011.
To cite this article: Professor Dr. Toshiaki Murai & Koji Matsushita (2011) Sequential One-Pot Reactions
of Thioformamides with Organolithium and Zinc Reagents, Phosphorus, Sulfur, and Silicon and the
Related Elements, 186:5, 1094-1103, DOI: 10.1080/10426507.2010.520289
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Phosphorus, Sulfur, and Silicon, 186:1094–1103, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.520289
SEQUENTIAL ONE-POT REACTIONS OF
THIOFORMAMIDES WITH ORGANOLITHIUM
AND ZINC REAGENTS
Toshiaki Murai and Koji Matsushita
Department of Chemistry, Faculty of Engineering, Gifu University,
Yanagido, Gifu, Japan
Abstract Sequentialone-potreactionsofthioformamideswith organolithiumand zincreagents
were carried out. As thioformamides, N,N-dimethylthioformamide and N-ethoxycarbonyl Nꢁ-
thioformyl piperazine were used. A variety of organolithium reagents such as alkyl, aryl, and
heteroaryllithiums were used to give the corresponding amines in moderate to high yields. The
efficiency of the reaction wasinfluenced by the substituents on the aromatic rings. Thienyllithium
gave the product in good yield, whereas the reaction of furyllithium was less efficient. A similar
reaction with lithium acetylides was not successful. As an alternative method, methyl iodide was
added to the reaction mixture of thioformamides and lithium silylacetylide to form S,N-acetals
as intermediates, and to this were added organozinc reagents to lead to propargylamines. For
organozinc reagents, dialkyl zincs and 3-ethoxycarbonylpropylzinc bromide were used. The
former reagents showed high efficiency when combined with several organolithium reagents,
but the latter gave the corresponding product only when lithium silylacetylide was used as an
initial reagent.
Keywords Amines; organolithium reagents; organozinc reagents; piperazines; sequential
reaction
INTRODUCTION
Sequential one-pot reactions are important processes in organic syntheses1 because
several components can be combined in a single operation without the need to isolate
stable intermediates. For example, three-component reactions of aldehydes, amines, and
terminal acetylenes mediated by metal catalysts have been widely developed to provide
new methods for the synthesis of propargylamines.2 During our studies3 on thiocarbonyl
compounds, we found a new approach to propargylamines via thioiminium salts derived
from thioamides.4 These salts undergo sequential reactions with lithium acetylides and
Grignard reagents to lead to propargylamines with a tetra-substituted carbon atom adja-
cent to the nitrogen atom (Scheme 1). This protocol can be applied to thioiminium salts
generated from thiolactams (Scheme 2).5 These results have stimulated several groups to
Received 30 July 2010; accepted 25 August 2010.
This work was supported in part by Grant-in-Aid for Scientific Research on Innovative Areas (Integrated
Organic Syntheses) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
Address correspondence to Toshiaki Murai, Department of Chemistry, Faculty of Engineering, Gifu Uni-
versity, Yanagido, Gifu 501-1193, Japan. E-mail: mtoshi@gifu-u.ac.jp
1094

SEQUENTIAL ONE-POT REACTIONS OF THIOFORMAMIDES
1095
establish similar modified sequential reactions from thiolactams,6 amides,7 and lactams.8
We further found that thioformamides can participate in sequential reactions with alkyl,
aryllithiums, and Grignard reagents without their preactivation (Scheme 3).9 The use of
thioformamides enabled us to establish an addition reaction of two different Grignard
reagents.10 Organozinc reagents11 have also been used for carbon–carbon bond-forming
reactions and are considered to be milder reagents than Grignard regents. Therefore, some
oxygen-containing functional groups can tolerate the reaction conditions with organozinc
reagents. We then applied organozinc reagents to our sequential reactions, and the details
of these reactions are reported here.
Scheme 1
Scheme 2
Scheme 3
RESULTS AND DISCUSSION
Initially, to a diethyl ether solution of N,N-dimethyl thioformamide (1a) were added
phenyllithium (2a) (1.2 equiv.) and dimethylzinc (3a) (1.5 equiv.) in this order (Scheme 4).
As a result, amine 4a, in which these two organometallic reagents were incorporated into
1a, was obtained in 46% yield along with 12% of amine 5a. Amine 5a was formed by
reacting 1a with two molecules of 2a, but the simple mixing of 1a and excess 2a under
similar reaction conditions did not give 5a at all. Therefore, the second addition of a phenyl
group to lithium thiolate 6a may be from lithium zincate12 7a generated in situ from 2a and
3a. To avoid the formation of 5a, 2a (1 equiv.) was used to give 4a in high yield.
We then shifted our attention to thioformamides that were susceptible to the reaction
with Grignard reagents. N-Ethoxycarbonyl Nꢁ-thioformyl piperazine (1b) was chosen,
because N-alkoxylcarbonyl N-secondary alkyl piperazines are of biological interest and

1096
T. MURAI AND K. MATSUSHITA
Scheme 4
are used as key synthetic intermediates.13 As in the reaction of thioformamide 1a, 1b
was reacted with phenyllithium (2a) and 3a, but the reaction with 3a for 6 h gave no
expected product (Table 1). The reaction with 3a was then prolonged to 310 h to give the
desired product 8 in only 34% yield (entry 1). The reaction with 3a at higher temperature
gave 8 in better yield (entry 2). A variety of organolithium reagents 2 were used for the
reaction of 1b. In the second step, the reaction with 3a continued for 24 h under reflux in
tetrahydrofuran (THF). The use of BuLi (2) followed by the addition of 3a gave amine 9
(entry 3). However, in this case the reaction for a longer reaction time in the second step
reduced the yield of the product 9 (entry 4). Furfuryllithium (2c) and thienyllithum (2d)
participated in the reaction (entries 5–7), and the former gave amine 10 in lower yield.
The reaction of 1-naphthyllithium 2e and (2-methylphenyl)lithium (2f) gave amines 12 and
13 (entries 8 and 9). For the reaction of methoxyphenyllithiums 2g and 2h, the yields of
the products 14 and 15 were influenced by the position of the methoxy group (entries 10
and 11). Ortho-substituted lithium 2g gave 14 in lower yield than para-substituted lithium
2h. The reaction of (4-trifluoromethylphenyl)lithium gave amine 15 in 85% (entry 12).
Ferrocenyllithium could also be used as an organolithium reagent (entry 13).
In contrast to the successful results with alkyl and aryllithium reagents, the reaction
of thioformamide 1b with lithium acetylide and dimethylzinc (3a) did not give the desired
products at all. To confirm whether the initial addition of lithium acetylides to 1 proceeded
with high efficiency, methyl iodide was added to the reaction mixture of 1b and lithium
acetylides (Table 2). As a result, the reaction with lithium phenylacetylide (2k) gave
S,N-acetal14 18a in moderate to good yields (entries 1–3), and the reaction with lithium
(trimethylsilyl)acetylide (2l) led to the product 18b in high yield (entries 4 and 5), although
isolation of the former product 18a failed and gave a complex mixture. Methyl iodide was
then added prior to the addition of organozinc reagents 3 in sequential reactions (Scheme 5).
The reaction of 1b with lithium acetylide 2l and methyl iodide followed by the addition of
3 gave the desired products 19 in good yield, whereas the use of lithium acetylide 2k did
not give the corresponding products.
Scheme 5

SEQUENTIAL ONE-POT REACTIONS OF THIOFORMAMIDES
1097
Table 1 Sequential one-pot reaction of thioformamide 1b with organolithium 2 and zinc reagents 3
Entry
RLi 2
Conditions
Yield
Product
1
2
PhLi
2a
rt, 310 h
reflux, 48 h
34%
76%
3
4
BuLi
reflux, 24 h
reflux, 48 h
45%
23%
2b
5
reflux, 24 h
reflux, 24 h
<9%
29%
6b
7
8
reflux, 24 h
reflux, 24 h
53%
60%
9
10
11
reflux, 24 h
reflux, 24 h
reflux, 24 h
74%
29%
59%

1098
T. MURAI AND K. MATSUSHITA
Table 1 Sequential one-pot reaction of thioformamide 1b with organolithium 2 and zinc reagents 3 (Continued)
Entry
12
RLi 2
Conditions
reflux, 24 h
Yield
85%
Product
13
reflux, 24 h
43%
aIsolated yield. bLithium reagent (1.5 equiv) was used.
Finally, organozinc reagents with a carbonyl group were used (Scheme 6). Several
combinations of organolithium reagents and zinc reagent 20 were attempted. Among them,
the sequential reaction of thioformamide 1a with lithium silylacetylide 2l and the reagent
20 gave propargylamine 21 in moderate yield.
Scheme 6
Table 2 Synthesis of S,N-acetals 8.
Entry
RLi 2
Conditions 1
Conditions 2
Product
NMR yielda
1
2
3
4
5
PhCE CLi
2k
−78 ◦C then rt, 1h
−18 ◦C 1.5 h
0 ◦C 1.5 h
0 ◦C then rt, 2.5 h
−15 ◦C, 2.5 h
0 ◦C, 2.5 h
0 ◦C then rt, 2.5 h
0 ◦C, 2.5 h
18a
30
61
45
86
94
TMSC CLi
21
−78 ◦C then rt, 1h
18b
0 ◦C 1.5 h
a1,1,2,2-Tetrachloroethane was used as an internal standard.

SEQUENTIAL ONE-POT REACTIONS OF THIOFORMAMIDES
1099
In summary, the sequential one-pot reaction of thioformamides with organolithium
and zinc reagents has been demonstrated. The thioformamide with an ethoxycarbonyl group
could be used as a starting material. As organolithium compounds, aliphatic and aromatic
reagents were available, but the yields of the products depended on the substituents on
the reagents. For organozinc reagents, dialkylzinc reagents were efficiently applied to the
reaction, whereas the reaction with that having an ethoxycarbonyl group proceeded with
medium efficiency.
EXPERIMENTAL
1
The infrared (IR) spectra were obtained on a JASCO FT/IR 410 spectrometer. H
NMR (399.7 MHz) and 13C NMR (100.4 MHz) spectra were measured on a JNM-A400
spectrometer. The 1H and 13C chemical shifts are reported in δ values and refer to tetram-
ethylsilane or CDCl3 as an internal standard, respectively. All spectra were acquired in
the proton-decoupled mode. The mass spectra (MS) and the high-resolution mass spectra
(HRMS) were measured on JMS-700 mass spectrometers. Melting points were determined
by using a Yanaco MP-S2 micro melting point apparatus (Seisakusho) and are uncorrected.
4-(1-Phenylethyl)-piperazine-1-carboxylic Acid Ethyl Ester (8)
To a 20-mL two-necked flask were added 1-ethoxycarbonyl-4-thioformylpiperadine
(203 mg, 1.0 mmol) and THF (2 mL) under an Ar atmosphere, and to this was slowly added
a 1.0 M solution of phenyllithium in cyclohexane-Et2O (1.1 mL, 1.1 mmol) at −78◦C. After
the addition was complete, the mixture was stirred for 1 h at room temperature. To this was
added a 1.0 M solution of dimethylzinc in n-hexane solution (1.50 mL, 1.5 mmol) at 0◦C,
and the mixture was stirred for 48 h under reflux. The resulting mixture was poured into
a saturated aqueous solution of NH4Cl. After filtration, the organic layer was dried over
MgSO4 and concentrated in vacuo. The residue was purified by column chromatography
(SiO2, hexane/EtOAc/Et3N = 1:1:0.01) to afford the amine 8 (0.200 g, 76%) as a yellow
oil: IR (neat) 2978, 2933, 2862, 2810, 2360, 2247, 1697, 1433, 1246, 1125, 997, 911,
732, 701 cm−1; 1H NMR (CDCl3) δ: 1.15 (t, J = 7.3 Hz, 3H), 1.28 (d, J = 6.8 Hz, 3H),
2.28–2.34 (br, 4H), 3.28–3.37 (brm, 5H), 4.18 (q, 2H), 7.18 (m, 4H); 13C NMR (CDCl3)
δ: 14.6, 19.5, 43.8, 50.1, 61.1, 64.6, 127.0, 127.5, 128.2, 143.5, 155.4; MS (EI) m/z 262
(M+); HRMS (EI) Anal. Calcd. for C15H22N2O2 (M+) 262.1681; Found: 262.1667.
4-(1-Methylpentyl)-piperazine-1-carboxylic Acid Ethyl Ester (9)
A yellow oil: IR (neat) 2961, 1707, 1429, 1383, 1349, 1281, 1244, 1168, 1118, 1093,
1037, 996, 766, 732 cm−1; 1H NMR (CDCl3) δ: 0.84 (t, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8
Hz, 3H), 1.14–1.28 (m, 9H), 2.30–2.51 (brm, 5H), 3.39 (brm, 4H), 4.07 (q, 2H); 13C NMR
(CDCl3) δ: 14.0, 14.1, 14.6, 22.8, 29.1, 33.1, 44.1, 48.0, 59.2, 61.1, 155.5; MS (EI) m/z
242 (M+); HRMS (EI) Anal. Calcd. for C13H26N2O2 (M+) 242.1994; Found: 242.2025.
4-(1-Furylethyl)-piperazine-1-carboxylic Acid Ethyl Ester (10)
A yellow oil: IR (neat) 3513, 2978, 2935, 2819, 1699, 1431, 1384, 1301, 1281, 1246,
1135, 995, 767, 739, 599 cm−1; 1H NMR (CDCl3) δ: 1.19 (t, J = 6.8 Hz, 3H), 1.37 (d, J
= 6.8 Hz, 3H), 2.36–2.43 (br, 4H), 3.43 (br, 4H), 3.73 (q, J = 6.8 Hz, 1H), 4.06 (q, J =

1100
T. MURAI AND K. MATSUSHITA
6.8 Hz, 2H), 6.10 (br, 1H), 6.27 (br, 1H), 7.32 (br, 1H); 13C NMR (CDCl3) δ: 14.6, 15.5,
43.8, 49.1, 57.2, 61.2, 107.2, 109.7, 141.6, 155.1, 155.4; MS (EI) m/z 252 (M+); HRMS
(EI) Anal. Calcd. for C13H20N2O3 (M+) 252.1474; Found: 252.1439.
4-(1-Thienylethyl)-piperazine-1-carboxylic Acid Ethyl Ester (11)
A yellow oil: IR (neat) 2976, 2813, 1699, 1431, 1382, 1302, 1280, 1245, 1122, 1086,
1044, 994, 850, 832, 766, 701 cm−1; 1H NMR (CDCl3) δ: 1.24 (t, J = 6.8 Hz, 3H), 1.43
(d, J = 6.3 Hz, 3H), 2.46 (br, 4H), 3.47 (br, 4H), 3.91 (q, J = 6.8 Hz, 1H), 4.11 (q, J =
6.8 Hz, 2H), 6.86 (d, J = 3.4 Hz, 1H), 6.94 (dd, J = 3.4 Hz, 4.6 Hz, 1H), 7.32 (d, J =
3.4 Hz, 4.6 Hz, 1H); 13C NMR (CDCl3) δ: 14.6, 17.8, 43.9, 49.0, 59.4, 61.2, 124.2, 124.3,
126.2, 147.2, 155.4; MS (EI) m/z 312 (M+); HRMS (EI) Anal. Calcd. for C13H20N2O2S
(M+) 268.1245; Found: 268.1224.
4-(1-Naphthylethyl)-piperazine-1-carboxylic Acid Ethyl Ester (12)
A yellow oil: IR (neat) 3047, 2977, 2931, 2859, 2810, 1698, 1431, 1377, 1289, 1245,
1125, 995, 931, 802, 779 cm−1; 1H NMR (CDCl3) δ: 1.23 (t, J = 6.8 Hz, 3H), 1.46 (d, J
= 6.8 Hz, 3H), 2.31–2.36 (m), 2.42 (br, 2H), 3.38 (q, J = 6.83 Hz, 1H), 3.44 (t, J = 4.9
Hz, 4H) 4.11 (q, J = 7.3 Hz, 2H), 7.21–7.37 (m, 5H); 13C NMR (CDCl3) δ: 14.6, 18.5,
43.9, 50.3, 61.1, 61.4, 124.0, 124.6, 125.3, 125.3, 125.4, 127.4, 128.9, 131.5, 134.0, 140.0,
155.4; MS (EI) m/z 312 (M+); HRMS (EI) Anal. Calcd. for C19H24N2O2 (M+) 312.1832;
Found: 312.1827.
4-(2-Methylphenyl)-piperazine-1-carboxylic Acid Ethyl Ester (13)
A yellow oil: IR (neat) 2976, 2806, 1702, 1432, 1382, 1290, 1244, 1124, 994, 833,
761, 729, cm−1; 1H NMR (CDCl3) δ: 1.24 (t, J = 7.3 Hz, 3H), 1.28 (d, J = 6.4 Hz, 3H),
2.34 (br, 2H), 2.34 (s, 3H) 2.46 (br, 2H), 3.42 (br, 4H) 3.57 (q, J = 6.8 Hz, 1H), 4.12 (q, J =
7.3 Hz, 2H), 7.11–7.18 (m, 3H), 7.42 (d, J = 7.3 Hz, 1H); 13C NMR (CDCl3) δ: 14.6, 18.2,
19.3, 43.8, 50.1, 60.2, 61.1, 125.9, 126.3, 126.5, 130.3, 135.7, 142.4, 155.3; MS (EI) m/z
276 (M+); HRMS (EI) Anal. Calcd. for C16H24N2O2 (M+) 276.1832; Found: 276.1829.
4-(2-Methoxyphenyl)-piperazine-1-carboxylic Acid Ethyl Ester (14)
A yellow oil: IR (neat) 3511, 2976, 2860, 2835, 2809, 2762, 1698, 1598, 1586, 1489,
1
1435, 1379, 1287, 1245, 1158, 1123, 1048, 1030, 994, 936, 755, 731 cm−1; H NMR
(CDCl3) δ: 1.23 (t, J = 6.8 Hz, 3H), 1.30 (d, J = 6.8 Hz, 3H), 2.38 (br, 2H), 2.45 (br, 2H),
3.45 (br, 4H), 3.80 (s, 3H), 4.00 (q, J = 6.8 Hz, 1H), 4.10 (q, J = 6.8 Hz, 2H), 6.86 (d, J =
8.3 Hz, 1H), 6.95 (t, J = 7.3 Hz, 1H), 7.21 (t, J = 8.3 Hz, 1H), 7.40 (d, J = 7.3 Hz, 1H);
13C NMR (CDCl3) δ: 14.6, 19.4, 43.8, 50.1, 55.3, 55.7, 61.1, 110.5, 120.5, 127.5, 127.6,
131.4, 155.4, 156.9; MS (EI) m/z 292 (M+); HRMS (EI) Anal. Calcd. for C16H24N2O3
(M+) 292.1787; Found: 292.1764.
4-(4-Methoxyphenyl)-piperazine-1-carboxylic Acid Ethyl Ester (15)
A yellow oil: IR (neat) 3537, 2974, 2934, 2809, 1700, 1612, 1510, 1432, 1378, 1294,
1
1246, 1172, 1124, 1036, 993, 936, 834, 766, 732, 552, cm−1; H NMR (CDCl3) δ: 1.23

SEQUENTIAL ONE-POT REACTIONS OF THIOFORMAMIDES
1101
(t, J = 6.8 Hz, 3H), 1.34 (d, J = 6.8 Hz, 3H), 2.34 (br, 2H), 2.40 (br, 2H), 3.45 (br, 4H),
3.45 (q, J = 6.8 Hz, 1H), 3.80 (s, 3H), 4.10 (q, J = 6.8 Hz, 2H), 6.85 (d, J = 8.3 Hz, 2H),
7.20 (d, J = 8.3 Hz, 2H); 13C NMR (CDCl3) δ: 14.6, 19.3, 43.8, 49.9, 55.1, 61.1, 63.9,
113.5, 128.5, 135.3, 155.3, 158.8; MS (EI) m/z 292 (M+); HRMS (EI) Anal. Calcd. for
C16H24N2O3 (M+) 292.1787; Found: 292.1792.
4-(4-Trifluoromethylphenyl)-piperazine-1-carboxylic Acid Ethyl Ester (16)
A yellow oil: IR (neat) 2979, 2812, 2762, 1702, 1618, 1432, 1379, 1325, 1245, 1163,
1124, 1068, 1016, 994, 935, 845, 767, 732, 610, 591, 541, cm−1; 1H NMR (CDCl3) δ: 1.24
(t, J = 7.1 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H), 2.34 (br, 2H), 2.44 (br, 2H), 3.45 (br, 5H),
4.11 (q, J = 7.1 Hz, 2H), 7.43 (d, J = 7.8 Hz, 2H), 7.57 (d, J = 7.8 Hz, 2H); 13C NMR
(CDCl3) δ 14.5, 19.2 (CH3), 43.7, 50.0, 61.1, 64.1, 124 (1JC-F = 272.1 Hz), 125 (3JC-F
=
3.3 Hz), 129 (2JC-F = 33.1 Hz), 148.1, 155.2, 155.4; MS (EI) m/z 330 (M+); HRMS (EI)
Anal. Calcd. for C16H21F3N2O2 (M+) 330.1555; Found: 330.1540.
4-(1-Ferrocenylethyl)-piperazine-1-carboxylic Acid Ethyl Ester (17)
A brown oil: IR (neat) 3534, 3093, 2978, 2815, 1698, 1433, 1383 1299, 1279, 1243,
1
1157, 1133, 1084, 1038, 999, 901. 819, 764, 732, 489, 480 cm−1; H NMR (CDCl3) δ:
1.17 (t, J = 7.3 Hz, 3H), 1.44 (d, J = 6.8 Hz, 3H), 2.16 (br, 2H), 2.34 (br, 2H), 3.35 (br,
4H), 3.59 (q, J = 6.8 Hz, 1H), 4.02 (m, 2H), 4.08 (m, 9H); 13C NMR (CDCl3) δ 14.6, 16.6,
43.9, 48.4, 58.9, 61.1, 66.8, 67.3, 68.6, 69.3, 86.9, 155.3; MS (EI) m/z 370 (M+); HRMS
(EI) Anal. Calcd. for C19H24N2O2 (M+) 370.1344; Found: 370.1315.
4-(1-Methylthio-3-trimethylsilanyl-2-propynyl)-piperazine-1-carboxylic
Acid Ethyl Ester (18b)
To a 20-mL two-necked flask were added 1-ethoxycarbonyl-4-thioformylpiperazine
(1b) (203 mg, 1.0 mmol) and THF (1 mL) under an Ar atmosphere, and to this solution
was slowly added lithium (trimethylsilyl)acetylide, prepared from (trimethylsilyl)acetylene
(0.170 mL, 1.2 mmol) and 1.3 M solution of n-butyllithium in n-hexane (0.92 mL, 1.2 mmol)
in THF (1 mL) at 0◦C via a cannula. After the addition was complete, the mixture was
stirred for 1.5 h at 0◦C. To this mixture was added methyl iodide (0.62 mL, 1.0 mmol)
at 0◦C, and this mixture was stirred for 2.5 h at 0◦C. The resulting mixture was poured
into a saturated aqueous solution of NH4Cl. The organic layer was dried over MgSO4 and
concentrated in vacuo to afford the S,N-acetal 18b (0.301 g, 94%) as a brown oil: IR (neat)
2959, 2919, 2862, 2826, 2165, 1700, 1633, 1432, 1384, 1323, 1301, 1279, 1246, 1170,
1134, 1079, 1051, 992, 844, 788, 762, 735, 646, 545 cm−1; 1H NMR (CDCl3) δ: 0.15 (s,
9H), 1.23 (t, J = 7.1 Hz, 3H), 2.16 (s, 3H), 2.54 (brm, 2H), 2.65 (brm, 2H), 3.47 (br, 4H),
4.10 (q, J = 7.1 Hz, 2H), 4.64 (s, 1H); 13C NMR (CDCl3) δ 0.0, 14.7, 14.8, 43.5, 48.3,
61.4, 63.3, 68.0, 74.2, 93.2, 98.7, 155.5; MS (EI) m/z 314 (M+); HRMS (EI) Anal. Calcd.
for C14H26N2O2SSi(M+) 314.1484; Found: 314.1492.
4-(1-Methyl-3-(trimethylsilyl)propynyl)-piperazine-1-carboxylic Acid
Ethyl Ester (19a)
To a 20-mL two-necked flask were added 1-ethoxycarbonyl-4-thioformylpiperadine
(1b) (203 mg, 1.0 mmol) and THF (1 mL) under an Ar atmosphere, and to this mixture
was slowly added lithium (trimethylsilyl)acetylide, prepared from (trimethylsilyl)acetylene

1102
T. MURAI AND K. MATSUSHITA
(0.170 mL, 1.2 mmol) and 1.68 M solution of n-butyllithium in n-hexane (0.71 mL, 1.2
mmol) in THF (1 mL) at −78◦C via a cannula. After the addition was complete, the
mixture was stirred for 1.5 h at 0◦C. To this mixture was added methyl iodide (0.62 mL,
1.0 mmol) at 0◦C, and this mixture was stirred for 2.5 h at 0◦C. To this was added a 1.0
M solution of dimethylzinc in n-hexane solution (1.50 mL, 1.5 mmol) at 0◦C, and this
mixture was stirred for 3 h under room temperature. The resulting mixture was poured into
a saturated aqueous solution of NH4Cl. After filtration, the organic layer was dried over
MgSO4 and concentrated in vacuo. The residue was purified by column chromatography
(SiO2, hexane/EtOAc/Et3N = 1:1:0.01) to afford the amine 19a (0.153 g, 54%) as a brown
oil: IR (neat) 2959, 2863, 2157, 1704, 1430, 1384, 1298, 1244, 1221, 1163, 1123, 1095,
1
1069, 1038, 992, 960, 891, 842, 760, 699, 633, 549 cm−1; H NMR (CDCl3) δ: 0.11 (s,
9H), 1.22 (t, J = 7.2 Hz, 3H), 1.28 (d, J = 7.2 Hz, 3H), 2.36 (br, 2H), 2.56 (br, 2H),
3.39–3.53 (brm, 5H), 4.10 (q, J = 7.2 Hz, 2H); 13C NMR (CDCl3) δ: 0.1, 14.6, 19.1, 43.6,
48.7, 52.5, 61.2, 89.4, 103.9, 155.5; MS (EI) m/z 282 (M+); HRMS (EI) Anal. Calcd. for
C14H26N2O2Si (M+) 282.1764; Found: 282.1754.
4-(1-Ethyl-3-(trimethylsilyl)propynyl)-piperazine-1-carboxylic Acid Ethyl
Ester (19b)
A brown oil: IR (neat) 2964, 2820, 2159, 1705, 1430, 1384, 1326, 1279, 1243, 1216,
1158, 1123, 1045, 999, 958, 890, 842, 761, 699, 635, 543 cm−1; 1H NMR (CDCl3) δ 0.10
(s, 9H), 0.95 (t, J = 7.4 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H), 1.58 (quint, J = 7.5 Hz), 2.34
(br, 2H), 2.52 (br, 2H), 3.17 (t, J = 7.4 Hz, 1H), 3.42 (brm, 4H) 4.10 (q, J = 7.1 Hz, 2H);
13C NMR (CDCl3) δ: 0.2, 11.1, 14.7, 26.2, 43.7, 48.9, 59.7, 61.2, 90.2, 103.2, 155.5; MS
(EI) m/z 296 (M+); HRMS (EI) Anal. Calcd. for C15H28N2O2Si (M+) 296.1920; Found:
296.1898.
5-Dimethylamino-7-trimethylsilanyl-hept-6-ynoic Acid Ethyl Ester (21)
To a solution of lithium (trimethylsilyl)acetylide (2l) prepared from (trimethylsi-
lyl)acetylene (0.160 mL, 1.1 mmol) and a 1.55 M solution of n-butyllithium in
n-hexane (0.71 mL, 1.1 mmol) in Et2O (1 mL) at −78◦C was slowly added N,N-
dimethylthioformamide (1a) (87 µL, 1.0 mmol) via syringe. After the addition was
complete, the mixture was stirred for 1 h at room temperature. To this was added a 0.3
M solution of 4-ethoxy-4-oxobutylzincbromide in THF (4.0 mL, 1.2 mmol) at 0◦C, and
this mixture was stirred for 6 h under room temperature. The resulting mixture was poured
into an saturated aqueous solution of EDTA. The organic layer was dried over MgSO4
and concentrated in vacuo. The residue was purified by column chromatography (SiO2,
CH2Cl2/EtOAc/Et3N = 1:1:0.01) to afford the amine 21 (0.107 g, 40%) as yellow oil: IR
(neat) 2958, 2864, 2825, 2781, 2158, 1737, 1454, 1374, 1301, 1249, 1183, 1078, 1032,
1
997, 956, 928, 842, 760, 698, 620 cm−1; H NMR (CDCl3) δ: 0.11 (s, 9H), 1.19 (t, J =
7.2 Hz, 3H), 1.56 (quint, J = 7.6 Hz, 2H), 1.65–1.75 (m, 2H), 2.16 (s, 6H), 2.27 (t, J =
7.6 Hz, 2H), 3.24 (t, J = 7.2 Hz, 1H), 4.06 (q, J = 7.2 Hz, 2H); 13C NMR (CDCl3) δ: 0.1,
14.1, 21.9, 33.0, 33.9, 41.1, 57.8, 66.8, 90.0, 102.9, 173.3; MS (EI) m/z 269 (M+); HRMS
(EI) Anal. Calcd. for C14H27NO2Si (M+) 269.1811; Found: 269.1814.
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SEQUENTIAL ONE-POT REACTIONS OF THIOFORMAMIDES
1103
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