Novel one-pot, four-component synthesis of 3- alkyldithiocarbonyloxazolidines from aminoethanols, ketones, carbon disulfide, and halides

Article abstract of DOI:10.1055/s-0028-1087918

A novel one-pot, four-component synthesis of 3- alkyldithiocarbonyloxazolidine derivatives from aminoethanols, ketones, carbon disulfide, and halides was developed. A series of substituted 3-alkyldithiocarbonyloxazolidine derivatives were synthesized in e

Full text of DOI:10.1055/s-0028-1087918

648
LETTER
Novel One-Pot, Four-Component Synthesis of 3-Alkyldithiocarbonyl-
oxazolidines from Aminoethanols, Ketones, Carbon Disulfide, and Halides
Synthesis of
3a
n
g
azolidine
s
-bin Han,a,b Ze-mei Ge,*b Tie-ming Cheng,b Run-tao Li*a,b
a
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, P. R. of China
School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R. of China
Fax +86(10)82716956; E-mail: lirt@mail.bjmu.edu.cn
b
Received 30 September 2008
rable. However, the method lost its generality and
efficiency in generating highly functionalized molecules
with complexity and diversity using four or more compo-
nents in one-pot reaction.
Abstract: A novel one-pot, four-component synthesis of 3-alkyl-
dithiocarbonyloxazolidine derivatives from aminoethanols, ke-
tones, carbon disulfide, and halides was developed. A series of
substituted 3-alkyldithiocarbonyloxazolidine derivatives were syn-
thesized in excellent yields utilizing this newly developed method.
During our research aimed at discovering dithiocarba-
mates as novel anticancer drugs, we developed a very use-
ful methodology utilizing anhydrous K3PO4 as
promoter,19 and obtained two antitumor lead compounds
1 and 2 (Figure 1).12c,20,21 As a continuation of this work,
and in connection with oxazolidines exhibiting unique
roles in some bioactive molecules,22 a new class of dithio-
carbamic acid esters with oxazolidine moiety 3a–n was
designed (Figure 1). However, they were difficult to syn-
thesize directly from the one-pot reaction of oxazolidines,
carbon disulfide, and electrophilic reagents because most
of the oxazolidine derivatives are not commercially avail-
able. In the present work, we wish to report a novel anhy-
drous K3PO4-promoted one-pot, four-component
synthesis of 3-alkyldithiocarbonyloxazolidine derivatives
from aminoethanols, ketones, carbon disulfide, and ha-
lides (Scheme 1). In this strategy, the oxazolidine inter-
mediates, which are formed from different aminoethanols
and ketones, are not isolated from the reaction system, but
directly reacted with carbon disulfide and alkyl halides.
Therefore, 3-alkyldithiocarbonyloxazolidine derivatives
could be directly prepared from aminoethanols.
Key words: four-component synthesis, aminoethanol, 3-alkyl-
dithiocarbonyloxazolidines, dithiocarbamate, anhydrous K3PO4
Dithiocarbamates are important sulfur-containing com-
pounds, which possess broad applications in organic and
medicinal chemistry. As protecting groups1 and synthetic
precursors,2 they have been widely used in the synthesis
of trifluoromethylamines,3 thioureas,4 aminobenzimida-
zoles,5 isothiocyanates,6 alkoxyamines,7 and total synthe-
sis of (–)aphanorphine.8 On the other hand, dithio-
carbamates are of growing interest due to their biological
potencies,9 such as antihistaminic,10 antibacterial,11 and
anticancer activties.12 Owing to their strong metal-binding
capacity, they can also act as enzyme inhibitors, such as
indoleamine 2,3-dioxygenase (IDO), which plays an im-
portant role in tumor growth.13
In view of their potential chemical and biological values,
much effort has been devoted to the development of effi-
cient methods for the synthesis of this type of compounds.
Several available methodologies are: (a) utilizing thio-
phosgene,14a chlorothioformates,14b and isothiocyanates14b
as starting materials; (b) reaction of amines with carbon
disulfide and alkyl halides in the presence of strong bases
such as KOH,15a,b NaOH15b or Cs2CO3 and TBAI;16 (c) reac-
tion of amines with carbon disulfide and active methylene
compounds in the presence of CBr4.17 Although these
methods provided dithiocarbamates successfully, they
still suffered from serious drawbacks, such as toxic and
unavailable reagents,14a,b limited scope,17 and especially
the use of strong bases,15a,b which led to the difficult prep-
aration of base-sensitive compounds. Recently, Saidi and
his colleagues reported a catalyst-free and solvent-free
synthesis of dithiocarbamates from amines, carbon di-
sulfide, and alkyl halides18a or a,b-unsaturated
compounds18b,c or epoxides.18d Undoubtedly, from the or-
ganic synthesis point of view, the method was very admi-
S
CN
Me
N
N
S
R2 R3
S
1
R4
N
S
O
S
O
R1
3a–n
O
O
N
S
H
2
Figure 1 The structures of compound 1, 2, and 3a–n
O
R2 R3
S
CS2
R4X
R2
HO
R3
NH2
R1
R4
anhydrous K3PO4
r.t.
+
O
N
S
R4
SYNLETT 2009, No. 4, pp 0648–0650
x
x.
x
x.
2
0
0
9
Scheme 1 The four-component synthesis of 3a–n
Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087918; Art ID: W15508ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3-Alkyldithiocarbonyloxazolidines
649
23
Table 1 Four-Component Reaction for the Synthesis of 3a–n in the Presence of Anhydrous K3PO4
Entrya,b
R1
R2
R3
R4
Product24
3a
Mp (°C)
60–62
oil
Yield (%)c
1
2
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
87
89
86
82
84
80
81
84
83
82
81
81
81
84
H
Et
3b
3
H
i-Pr
3c
oil
4
H
cyclopentyl
PhCH2CH2
(Ph)2(CN)CCH2CH2
CNCH2CH2
EtO2CCH2
PhCH2CH2
PhCH2CH2
Et
3d
46–48
42
5
H
3e
6
H
3f
104–106
36
7
H
3g
8
H
3h
oil
9
Me
3i
54–56
oil
10
11
12
13
14
H
-(CH2)5-
-(CH2)6-
3j
H
3k
79–80
oil
H
Me
Me
Me
Et
PhCH2CH2
Et
3l
Me2CHCH2
Bn
Me
Me
3m
3n
oil
Et
oil
a Products have been characterized by 1H NMR, MS, and elemental analyses.
b For entries 1–9, 13 and 14 excess acetone was used as solvent; for entries 10–12 DMF was selected as the solvent; the molar ratios of amino-
ethanol and ketones are 1:1.1; 4 Å MS were used as additive; other conditions keep unchanged.
c Isolated yields.
Initially, the four-component reaction of aminoethanol, quently examined. Consistent with the previous studies,
acetone, carbon disulfide, and iodomethane in the pres- replacing aminoethanol with 2-methylaminoethanol, 2-
ence of anhydrous K3PO4 was chosen to investigate, and isobutylaminoethanol, or 2-benzylaminoethanol, the reac-
the desired product 3a was obtained in an excellent yield. tion performed smoothly and afforded desired products
We then used this reaction as a model to optimize the 3i,m,n in 83%, 81%, and 84% yields, respectively (entries
reaction conditions, and the result was evaluated qualita- 9, 13, and 14). When other ketones instead of acetone
tively by TLC. Different reaction temperatures (0 °C, r.t., were used, satisfactory results were also obtained (entries
reflux) and molar ratios of anhydrous K3PO4 and reagents 10–12). Therefore, the present protocol is tolerable to the
were examined. The best result was achieved by carrying structural variations of the aminoethanol, ketone, and
out the reaction with 1:2:1:2 molar ratios of aminoethanol, alkyl halide components.
carbon disulfide, iodomethane, and anhydrous K3PO4 at
Anhydrous K3PO4 plays an important role in this reaction.
room temperature for three hours. The desired product,
Though its role is not completely clear, we consider that
2,2-dimethyl-3-(methyldithiocarbonyl)oxazolidine 3a, was
anhydrous K3PO4 may have three actions, namely base,
thus obtained in 87% yield (entry 1, Table 1).
dehydrating agent, and phase-transfer catalyst.23
With the optimized conditions in hand, we then examined
In conclusion, we have developed a novel one-pot, four-
the scope and limitation of this method. Various alkyl ha-
component synthesis of 3-alkyldithiocarbonyl-oxazoli-
lides containing different functional groups, such as nitrile
dines from aminoethanols, ketones, carbon disulfide, and
and ester, were tested. All the reactions proceeded
alkyl halides. Various substituted 3-alkyl-dithiocarbony-
smoothly to give the corresponding products in high
loxazolidine derivatives were synthesized in excellent
yields (entries 2–6, Table 1). The alkyl bromides partici-
yields by using this method. The evaluation of these com-
pated in the reactions affording corresponding com-
pounds for their anticancer activity and further extension
pounds 3b–f in 80–89% yields within three hours. b-
of this methodology are in progress and will be reported
in due course.
Bromopropionitrile and ethyl a-chloroacetate were used
as alkylating agents to give products 3g in 81% and 3h in
84% yields, respectively (entries 7 and 8). Apparently, the
functional groups in halides did not have any effect on the
reaction due to the very mild reaction conditions. The sub-
stituted aminoethanols and other ketones were subse-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2009, No. 4, 648–650 © Thieme Stuttgart · New York

650
F.-b. Han et al.
LETTER
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Acknowledgment
This work is supported by the Natural Science Foundation of China
(NSFC 20672009) and the Major State Basic Research Develop-
ment Program (Grant No. 2004CB719900).
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was added anhyd K3PO4 (4 mmol), and the reaction mixture
was stirred at r.t. for 30 min. CS2 (4 mmol) was then added
dropwise. The reaction mixture was stirred for an additional
20 min, and halide (2 mmol) was then added. Stirring was
continued at r.t. until the reaction was completed (monitored
by TLC). The precipitate was filtered and washed with
acetone. The solvent was evaporated under reduced
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a silica gel column (PE–EtOAc) to give the desired
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Selected Data for Compound 3f
White solid; mp 104–106 °C. 1H NMR (300 MHz, CDCl3):
d = 1.83 (s, 6 H), 2.81 (t, J = 7.8 Hz, 2 H), 3.30 (t, J = 8.1 Hz,
2 H), 3.82 (t, J = 6.3 Hz, 2 H), 4.06 (t, J = 6.3 Hz, 2 H), 7.26–
7.49 (m, 10 H). MS (EI, 70 eV): m/z (%) = 396 (6) [M]+, 204
(7), 193 (7), 177 (55), 165 (15), 144 (57), 118 (25), 86 (100).
Anal. Calcd for C23H26N2OS2: C, 66.63; H, 6.10; N, 7.06.
Found: C, 66.71; H, 6.10; N, 7.03.
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Selected Data for Compound 3h
Light yellow oil. 1H NMR (300 MHz, CDCl3): d = 1.30 (t,
J = 7.2 Hz, 3 H), 1.83 (s, 6 H), 3.93 (t, J = 6.3 Hz, 2 H), 4.10
(t, J = 6.3 Hz, 2 H), 4.13 (s 2 H), 4.23 (q, J = 7.2 Hz, 2 H).
Anal. Calcd for C10H17NO3S2: C, 45.60; H, 6.51; N, 5.32.
Found: C, 45.45; H, 6.57; N, 5.36.
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