Synthesis of α-phthalimido-α′-dithiocarbamato propan-2-ols via a one-pot, three-component epoxide ring-opening in water

Article abstract of DOI:10.1016/j.tetlet.2014.08.017

Regioselective ring-opening of the N-(2,3-epoxypropyl)phthalimide with in situ prepared dithiocarbamic acid in water is reported for the synthesis of a new family of α-phthalimido-α′-dithiocarbamato propan-2-ols. The present method is simple, EtOAc is used for work-ups and affords excellent yield of products.

Full text of DOI:10.1016/j.tetlet.2014.08.017

Tetrahedron Letters 55 (2014) 5454–5457
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Tetrahedron Letters
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Synthesis of
a
-phthalimido-a0-dithiocarbamato propan-2-ols
via a one-pot, three-component epoxide ring-opening in water
⇑
Azim Ziyaei Halimehjani , Seyyed Emad Hooshmand, Elham Vali Shamiri
Faculty of Chemistry, Kharazmi University, 49 Mofateh St., Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Regioselective ring-opening of the N-(2,3-epoxypropyl)phthalimide with in situ prepared dithiocarbamic
acid in water is reported for the synthesis of a new family of a
-phthalimido-a0-dithiocarbamato propan-
Received 19 May 2014
Revised 19 July 2014
Accepted 6 August 2014
Available online 14 August 2014
2-ols. The present method is simple, EtOAc is used for work-ups and affords excellent yield of products.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Dithiocarbamate
Phthalimide
Propan-2-ols
Water
Catalyst-free
In recent years, many attempts have been made to synthesize
substituted
a0-substituted propan-2-ol derivatives. These com-
bond formation,15 and protection of amino groups in peptide syn-
thesis.16 The classical synthesis of dithiocarbamates involves the
use of thiophosgene and an isothiocyanate which are costly and
toxic reagents.17 Several efficient procedures for the synthesis of
these compounds have been developed by our group and others
to overcome most of the drawbacks associated with the classical
methods by using the direct condensation of amines, carbon disul-
fide, and electrophiles such as alkyl halides, activated alkenes, car-
bonyl compounds, and epoxides.18
The phthalimide group is present as the pharmacophoric
moiety in the structure of many biologically active compounds.
Compounds containing the phthalimide group have shown anti-
inflammatory and anti-angiogenic properties, and have been intro-
duced as potential candidates in the treatment of HIV and cancer.19
The phthalimide fungicides such as captan, captafol, and folpet are
a,
pounds demonstrate various pharmacological activities in the
areas of drug development such as antibacterial, antimicrobial,
antiplasmodial, antioxidant, and antimalarial agents.1 Moreover,
they often constitute key synthons in the preparation of biologically
active compounds.2 Among the various types of
a
,
a0-substituted
propan-2-ols, it is well documented that the
a
-amino-a0-dithio-
carbamato propan-2-ols (Fig. 1) have biological applications as
spermicidal, antifungal, and antitrichomonas agents and as safe
pesticides.3 Also, these compounds can be considered as glycerol
analogs with a sulfur atom in position 1 and nitrogen atom in posi-
tion 3 which have been confirmed to have various biological activ-
ities.4 The dithiocarbamate group is a valuable pharmacophore
that induces various biological activities when incorporated in a
particular structure.3,5 They constitute a large family of herbicides,
fungicides, and pesticides in agriculture and several compounds of
this category such as Zineb, Maneb, Nabam, ziram, and Ferbam
have been commercialized.6 Also, they were extensively used as
sulfur vulcanization agents in rubber manufacture,7 and radical
chain transfer agents in reversible addition-fragmentation chain-
transfer (RAFT) polymerizations.8 Furthermore, they have been
used as versatile synthetic intermediates for the preparation of
thioureas,9 isothiocyanates,10 2-imino-1,3-dithiolanes,11 cyana-
mides,12 heterocyclic rings,13 the protection of aldehydes,14 amide
O
S
R1
R3
N
N
S
N S
Cl
Cl
R2 OH
R3
OCl
captan
α-amino-α'-dithiocarbamato propan-2-ols
O
O
O
S
N S Cl
Cl
N S
N
S P O
O
Cl
Cl
O
Cl
O
Cl
folpet
Cl
O
captafol
phosmet
Figure 1. Structures of phthalimide- and dithiocarbamate-based biologically active
compounds.
⇑
Corresponding author. Tel.: +98 (21)88848949; fax: +98 (21)88820992.
E-mail address: ziyaei@khu.ac.ir (A.Z. Halimehjani).
http://dx.doi.org/10.1016/j.tetlet.2014.08.017
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

A. Z. Halimehjani et al. / Tetrahedron Letters 55 (2014) 5454–5457
5455
Table 1
the most applied surface protectants for control of plant patho-
genic fungi.20 In addition, phosmet is a phthalimide-derived orga-
nophosphate insecticide used on plants and animals (Fig. 1).21
These observations prompted us to introduce an efficient proce-
Synthesis of a
-phthalimido-a0-dithiocarbamato propan-2-ols26
O
N
O
N
OH
O
CS2, Amine
Water,rt
S
N
S
dure for the synthesis of a new family of a,
a0-substituted propan-
O
O
4
3
2-ols containing both a dithiocarbamate and a phthalimide moiety,
as potential biologically active compounds, via a one-pot, three-
component ring-opening of epoxides in water.
Entry
1
Amine
Product
Yield (%)a
O
O
NH
O
OH
4a
The use of hazardous and toxic solvents in chemical processes is
considered to be a very important problem for the health and
safety of workers, and environmental pollution. In addition,
although the use of catalysts for organic transformations has sev-
eral advantages, usually these processes need extra steps for pro-
ducing the catalyst or removing the catalyst from the reaction
medium. For this purpose, many reactions are designed to proceed
cleanly and efficiently in water, in ionic liquids, in green solvents
such as fluorinated solvents and polyols, and under solvent-free
conditions without using catalysts, which are in agreement with
the goals of green chemistry.22 In continuation of our research
toward the development of green organic chemistry using water
as the reaction medium or performing organic transformations
under solvent-free and catalyst-free conditions,23 herein we report
an efficient, novel, and environmentally benign procedure for the
N
S
N
92
95
98
90
86
98
79
O
S
O
NH
OH
4b
N
S
N
2
3
4
5
6
7
O
S
S
O
NH
NH
OH
4c
4d
N
S
N
O
O
OH
N
S
N
O
S
O
NH
OH
4e
N
S
N
O
O
S
NH
OH
4f
N
S
S
N
O
S
synthesis of
a
-phthalimido-a0-dithiocarbamato propan-2-ols via
O
NH
OH
the catalyst-free regioselective ring-opening of N-(2,3-epoxypro-
pyl)phthalimide with in situ prepared dithiocarbamic acids in
water.
4g
N
N
S
N
O
O
NH
OH
We began our investigation on the synthesis of N-(2,3-epoxy-
propyl)phthalimide (3) by reacting potassium phthalimide (1)
and epichlorohydrin (2) under solvent-free conditions as described
in the literature.24,25 Next, a one-pot, three-component reaction of
an amine, CS2, and the epoxide (3) was designed for obtaining the
title products. Different reaction conditions were examined for this
process; mixing the amine (2.5 mmol) and CS2 (3 mmol) in water
at room temperature for 0.5 h to give the corresponding dithiocar-
bamic acid and then addition of the epoxide (3) and additional stir-
ring for eight hours represents the optimum conditions
(Scheme 1). No catalyst is needed for this reaction. Although the
reaction gave acceptable yields in organic solvents, the yield was
higher in water in shorter reaction times.
With optimized conditions in hand, the scope of this reaction
was investigated using different primary and secondary aliphatic
amines (Table 1). Secondary amines such as pyrrolidine, piperidine,
dimethylamine, diethylamine, azepine, dipropylamine, diallyl
amine, and morpholine all gave excellent yields. Primary amines
such as propylamine, butylamine, allylamine, cyclohexylamine,
furfurylamine, and benzylamine reacted equally well in this proto-
col. Hindered amines such as tert-butylamine and dicyclohexyl-
amine did not give any products and the starting materials were
recovered. Aromatic amines were not suitable starting materials
4h
4i
8
9
S
S
N
86
84
78
84
80
86
82
O
O
S
S
NH2
O
OH
H
N
N
NH2
O
OH
H
N
4j
S
N
10
11
12
13
O
S
S
NH2
NH2
O
OH
H
N
4k
4l
N
O
O
S
O
OH
H
N
S
N
S
O
OH
H
N
NH2
4m
4n
S
N
O
O
S
S
O
OH
NH2
H
N
O
S
N
14
O
a
Isolated yield.
NH
HN
+
CS2
+
S
O
O
H2O, rt
80%
OH
N
S
N
N
S
S
OH
N
O
O
O
O
O
N
O
neat
120 oC, 8 h
78%
O
O
- K+
N
N
5
Cl
O
O
O
2
3
1
3
amine, CS2
H2O, rt, 8 h
Scheme 2. Synthesis of bisdithiocarbamate 5.
for this reaction. In addition, N,N-dimethylethylenediamine gave
no reaction under similar conditions.
It has been well demonstrated that the fungicidal activity of a
compound can be improved by increasing the number of dithiocar-
bamate moieties in the structure.4c,4d For this purpose, bis (dithio-
carbamate) (5) was prepared in 80% yield via the one-pot
O
N
O
OH
S
N
S
4
Scheme 1. One-pot three-component route for the synthesis of a -
-phthalimido-a0
dithiocarbamato propan-2-ols.

5456
A. Z. Halimehjani et al. / Tetrahedron Letters 55 (2014) 5454–5457
2. (a) Martinez, F.; Del Campo, C.; Sinisterra, J. V.; Llama, E. F. Tetrahedron:
1. NaBH4, 2-propanol
H2O, r.t
Asymmetry 2000, 11, 4651–4660; (b) Onishi, T.; Nakano, T.; Hirose, N.;
Nakazawa, M.; Izawa, K. Tetrahedron Lett. 2001, 42, 5887–5890; (c) Hamada,
T.; Torii, T.; Onishi, T.; Izawa, K.; Ikariya, T. J. Org. Chem. 2004, 69, 7391–7394.
3. Kiran Kumar, S. T. V. S.; Kumar, L.; Sharma, V. L.; Jain, A.; Jain, R. K.; Maikhuri, J.
P.; Kumar, M.; Shukla, P. K.; Gupta, G. J. Med. Chem. 2008, 43, 2247–2256.
4. (a) Len, C.; Postel, D.; Ronco, G.; Villa, P.; Goubert, C.; Jeufrault, E.; Mathon, B.;
Simon, H. J. Agric. Food Chem. 1997, 45, 3–6; (b) Len, C.; Boulogne-Merlot, A.;
Postel, D.; Ronco, G.; Villa, P. J. Agric. Food Chem. 1996, 44, 2856–2858; (c) Rafin,
C.; Veignie, E.; Postel, M. S.; Len, C.; Villa, P.; Ronco, G. J. Agric. Food Chem. 2000,
48, 5283–5287; (d) De Sousa, R.; Thurier, C.; Len, C.; Pouilloux, Y.; Barrault, J.;
Jérôme, F. Green Chem. 2011, 13, 1129–1132.
O
OH
overnight
HO
O
O
+ inseparable products
N
S
NH2
N
S
N
2. AcOH, 80 °C
2 h
O
S
S
4f
6
Scheme 3. Deprotection of the amino group in (4f) using the Osby method.
O
HO
NH
S
N
5. (a) Kumar, L.; Lal, N.; Kumar, V.; Sarswat, A.; Jangir, S.; Bala, V.; Kumar, L.;
Kushwaha, B.; Pandey, A. K.; Siddiqi, M. I.; Shukla, P. K.; Maikhuri, J. P.; Gupta,
G.; Sharma, V. L. Eur. J. Med. Chem. 2013, 70, 68–77; (b) Tripathi, R. P.; Khan, A.
R.; Setty, B. S.; Bhaduri, A. P. Acta Pharm. 1996, 46, 169–176; (c) Ates, O.;
Kocabalkanli, A.; Cesur, N.; Otuk, G. Il Farmaco 1998, 53, 541–544; (d) Nofal, Z.
M.; Fahmy, H. H.; Mohamed, H. S. Arch. Pharm. Res. 2002, 25, 28–38; (e) Singh,
N.; Gupta, S.; Nath, G. Appl. Organomet. Chem. 2000, 14, 484–492; (f) Nakagawa,
S.; Otake, N.; Kiyonaga, H.; Yamada, K.; Hona, H.; Ushijima, R. U.S. Patent
6,251,891, 2001; Chem. Abstr. 2001, 135, 61178s.
S
O
neat
S
NH
inseparable products
4i
N
80 oC, 8 h
+
7
NH
Scheme 4. Reaction of (4i) with piperidine.
6. (a) Kanchi, S.; Singh, P.; Bisetty, K. Arab. J. Chem. 2014, 7, 11–25; (b) Hussein, M.
A.; El-Shorbagi, A.-N.; Khallil, A.-R. Arch. Pharm. Pharm. Med. Chem. 2001, 334,
305–308; (c) Eng, G.; Song, X.; Duong, Q.; Strickman, D.; Glass, J.; May, L. Appl.
Organomet. Chem. 2003, 17, 218–225.
7. (a) Nieuwenhuizen, P. J.; Ehlers, A. W.; Haasnoot, J. G.; Janse, S. R.; Reedijk, J.;
Baerends, E. J. J. Am. Chem. Soc. 1999, 121, 163–168; (b) Messer, W. E. British
Patent 496560, 1930; Chem. Abstr. 1939, 33, 4080.
8. (a) Lai, J. T.; Shea, R. J. Polym. Sci., Part A: Polym. Chem. 2006, 44, 4298–4316; (b)
Dureaault, A.; Gnanou, Y.; Taton, D.; Destarac, M.; Leising, F. Angew. Chem., Int.
Ed. 2003, 42, 2869–2872; (c) Bathfield, M.; D’Agosto, F.; Spitz, R.; Charreyre, M.
T.; Delair, T. J. Am. Chem. Soc. 2006, 128, 2546–2547.
9. (a) Ziyaei Halimehjani, A.; Pourshojaei, Y.; Saidi, M. R. Tetrahedron Lett. 2009,
50, 32–34; (b) Sugimoto, H.; Makino, I.; Hirai, K. J. Org. Chem. 1988, 53, 2263–
2267; (c) Maddani, M.; Prabhu, K. R. Tetrahedron Lett. 2007, 48, 7151–7154.
10. Wong, R.; Dolman, S. J. J. Org. Chem. 2007, 72, 3969–3971.
three-component reaction of piperazine with carbon disulfide and
epoxide (3) in water (Scheme 2).
Having successfully synthesized
we focused our attention on the removal of the phthalimide group
to give the
-amino a0-dithiocarbamato propan-2-ols. For this pur-
a,
a0-substituted propan-2-ols,
a
pose, we tried to remove the phthalimide group using the Ing-
Manske exchange reaction,27 but no desired product was obtained.
An alternative protocol was applied for this reaction using NaBH4
in isopropanol (Osby method).28,29 We found that under these con-
ditions, the desired product (6) was obtained in 30% yield along
with other inseparable products (Scheme 3). The target compound
(6) could furnish bisdithiocarbamate of glycerol with a sulfur atom
in position 1 and nitrogen atom in position 3.4a,4b
11. Ziyaei-Halimehjani, A.; Maleki, H.; Saidi, M. R. Tetrahedron Lett. 2009, 50, 2747–
2749.
12. Jamir, L.; Sinha, U. B.; Nath, J.; Patel, B. K. Synth. Commun. 2012, 42, 951–958.
13. (a) Ziyaei Halimehjani, A.; Marjani, K.; Ashouri, A. Tetrahedron Lett. 2012, 53,
3490–3492; (b) Ziyaei Halimehjani, A.; Ashouri, A.; Marjani, K. J. Heterocycl.
Chem. 2012, 49, 939–942; (c) Aryanasab, F.; Ziyaei Halimehjani, A.; Saidi, M. R.
Tetrahedron Lett. 2010, 51, 790–792.
14. Ziyaei Halimehjani, A.; Hajiloo Shayegan, M.; Hashemi, M. M.; Notash, B. Org.
Lett. 2012, 14, 3838–3841.
15. Ziyaei Halimehjani, A.; Ranjbari, M. A.; Pasha Zanussi, H. RSC Adv. 2013, 3,
22904–22908.
In addition, we attempted to synthesize an
a -
-phthalimido a0
thiopropan-2-ol via the reaction of (4i) with piperidine under sol-
vent-free conditions at 80 °C (Scheme 4).9a Although the thiourea
(7) was obtained in pure form,30 unfortunately we did not obtain
the corresponding a
-phthalimido a0-thiopropan-2-ol.
In conclusion, we have described a novel, simple, and highly
efficient procedure for the synthesis of 3-(1,3-dioxoisoindolin-2-
yl)-2-hydroxypropylalkyl carbamodithioate derivatives via a one-
pot, three-component reaction of an amine, CS2, and epoxide (3)
in water under catalyst-free conditions. High yields, simple reac-
tion conditions, and completely regioselective reactions are advan-
tages of this process. Water may play a dual role as the solvent and
the catalyst in this reaction by activation of the epoxy group via
hydrogen bonding. In addition, the presence of the phthalimide,
dithiocarbamate, and alcohol functionalities in these compounds
may have synergic effects to provide a new family of compounds
with interesting biological activities in agriculture or pharmaceuti-
cal industry.
16. Greene, T. W.; Wuts, P. G. M. Protecting Groups in Organic Synthesis, 3rd ed.;
Wiley Interscience: New York, 1999. 484.
17. (a) Tilles, H. J. Am. Chem. Soc. 1959, 81, 714–727; (b) Chin-Hsien, W. Synthesis
1981, 622–623.
18. (a) Chaturvedi, D.; Ray, S. Tetrahedron Lett. 2006, 47, 1307–1309; (b) Azizi, N.;
Aryanasab, F.; Saidi, M. R. Org. Lett. 2006, 8, 5275–5377; (c) Azizi, N.; Ebrahimi,
F.; Akbari, E.; Aryanasab, F.; Saidi, M. R. Synlett 2007, 2797–2800; (d) Azizi, N.;
Aryanasab, F.; Torkiyan, L.; Ziyaei, A.; Saidi, M. R. J. Org. Chem. 2006, 71, 3634–
3635; (e) Azizi, N.; Pourhasan, B.; Aryanasab, F.; Saidi, M. R. Synlett 2007, 1239–
1242; (f) Ziyaei-Halimehjani, A.; Saidi, M. R. J. Sulfur Chem. 2005, 149–154; (g)
Ziyaei-Halimehjani, A.; Saidi, M. R. Can. J. Chem. 2006, 84, 1515–1519; (h)
Ziyaei Halimehjani, A.; Marjani, K.; Ashouri, A. Green Chem. 2010, 12, 1306–
1310; (i) Ziyaei Halimehjani, A.; Pasha Zanussi, H.; Ranjbari, M. A. Synthesis
2013, 1483–1488; (j) Yavari, I.; Hosseini, N.; Moradi, L.; Mirzaei, A. Tetrahedron
Lett. 2008, 49, 4239–4241; (k) McGhee, W.; Riley, D.; Christ, K.; Pan, Y.; Parnas,
B. J. Org. Chem. 1995, 60, 2820–2830; (l) Vasiliev, A. N.; Polackov, A. D. Molecules
2000, 5, 1014–1017; (m) Salvatore, R. N.; Shin, S. I.; Nagle, A. S.; Jung, K. W. J.
Org. Chem. 2001, 66, 1035–1037; (n) Salvatore, R. N.; Sahaba, S.; Jung, K. W.
Tetrahedron Lett. 2001, 42, 2055–2058; (o) Salvatore, R. N.; Ledger, J. A.; Jung, K.
W. Tetrahedron Lett. 2001, 42, 6023–6025; (p) Guo, B. G.; Ge, Z. M.; Cheng, T.
M.; Li, R. T. Synth. Commun. 2001, 31, 3021–3025; (q) Busque, F.; March, P.-D.;
Figueredo, M.; Font, J.; Gonzalez, L. Eur. J. Org. Chem. 2004, 1492–1499; (r) Fox,
D. L.; Ruxer, J. T.; Oliver, J. M.; Alford, K. L.; Salvatore, R. N. Tetrahedron Lett.
2004, 45, 401–405; (s) Ranu, B.; Saha, A.; Banerjee, S. Eur. J. Org. Chem. 2008, 3,
519–523.
Acknowledgement
We are grateful to the Faculty of Chemistry of Kharazmi
University (formerly Tarbiat Moallem University) for supporting
this work.
19. (a) Makonkawkeyoon, S.; Limsonpobre, R. N. R.; Moreira, A. L.; Schauf, V.;
Kaplan, G. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 5974; (b) Figg, W. D.; Raje, S.;
Bauer, K. S.; Tompkins, A.; Venzon, D.; Bergan, R.; Chen, A.; Hamilton, M.;
Pluda, J.; Reed, E. J. Pharm. Sci. 1999, 88, 121–125. http://
onlinelibrary.wiley.com/doi/10.1021/js980172i/abstract; (c) Al-Soud, Y. A.;
Al-Masoudi, N. A. Pharmazie 2001, 56, 372–375; (d) Henon, H.; Messaoudi,
S.; Anizon, F.; Aboab, B.; Kucharczyk, N.; Leonce, S.; Golsteyn, R. M.; Pfeiffer, B.;
Prudhomme, M. Eur. J. Pharmacol. 2007, 554, 106–112.
20. Schwack, W.; Flober-Muller, H. Chemosphere 1990, 21, 905–912.
21. Sinderhauf, K.; Schwack, W. J. Agric. Food Chem. 2003, 51, 5990–5995.
22. (a) Linthorst, J. A. Foundations Chem. 2010, 12, 55–68; (b) Anastas, P. T.;
Williamson, T. C. Green Chemistry: Designing Chemistry for the Environment; ACS
publications: Washington DC, 1996; (c) Anastas, P. T.; Warner, J. C. Green
Chemistry: Theory and Practice; Oxford Science Publications: Oxford, 1998;
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.08.
017.
References and notes
1. Singh, G. S.; Mollet, K.; D’hooghe, M.; De Kimpe, N. Chem. Rev. 2013, 113,
1441–1498.

A. Z. Halimehjani et al. / Tetrahedron Letters 55 (2014) 5454–5457
5457
(d)Green Chemistry: Frontiers in Chemical Synthesis and Processes; Anastas, P. T.,
Williamson, T. C., Eds.; Oxford University Press: Oxford, 1998; (e) Clark, J. H.
Green Chem. 1999, 1, 1–8.
the pure products were obtained without further purification. If needed, the
purifications were performed by recrystallization from diethyl ether. It should
be noted that in the case of piperazine (2 mmol), CS2 (6 mmol) and N-(2,3-
epoxypropyl)phthalimide (3) (4 mmol) were used.
23. (a) Ziyaei-Halimehjani, A.; Ebrahimi, F.; Azizi, N.; Saidi, M. R. J. Heterocycl.
Chem. 2009, 46, 347–350; (b) Ziyaei-Halimehjani, A.; Saidi, M. R. Tetrahedron
Lett. 2008, 49, 1244–1248; (c) Ziyaei-Halimehjani, A.; Aryanasab, F.; Saidi, M. R.
Tetrahedron Lett. 2009, 50, 1441–1443; (d) Ziyaei-Halimehjani, A.; Gholami, H.;
Saidi, M. R. J. Iranian Chem. Soc. 2013, 10, 7–11; (e) Ziyaei Halimehjani, A.;
Karimi, N.; Saidi, M. R. Synth. Commun. 2013, 43, 744–748; (f) Marjani, K.;
Khalesi, M.; Ashouri, A.; Jalali, A.; Ziyaei-Halimehjan, A. Synth. Commun. 2011,
41, 451–458; (g) Ziyaei Halimehjnai, A.; Marjani, K.; Ashouri, A.; Jalali, A. Synth.
Commun. 2011, 41, 1638–1643.
24. Hayashi, Y.; Kayatani, T.; Sugimoto, H.; Suzuki, M.; Inomata, K.; Uehara, A.;
Mizutani, Y.; Kitagawa, T.; Maeda, Y. J. Am. Chem. Soc. 1995, 117, 11220–11229.
25. Synthesis of N-(2,3-epoxypropyl)phthalimide (3): This compound was
synthesized according to the previously reported procedure by refluxing a
mixture of potassium phthalimide (6.50 g, 35 mmol) and epichlorohydrin
(19.5 mL) at 120 °C for 8 h. The excess epichlorohydrin was removed under
reduced pressure to give a yellowish white powder, which was purified by
washing with H2O and recrystallization in MeOH. The pure product was
obtained as a white solid in 75% yield (5.3 g); mp 95–97 °C (Lit.31 mp 98–
99 °C); 1H NMR (300 MHz, CDCl3): d (ppm) 2.68 (1H, dd, J = 4.8 and 2.5 Hz),
2.81 (1H, dd, J = 8.7 and 4.3 Hz), 3.24 (1H, m), 3.80 (1H, dd, J = 14.3 and 4.9 Hz),
3.96 (1H, dd, J = 14.3 and 4.9 Hz), 7.75 (2H,m), 7.86 (2H, m); 13C NMR (75 MHz,
CDCl3) d (ppm) 39.6, 46.0, 49.0, 123.4, 131.9, 133.9, 167.9; IR (KBr) 1770, 1713,
1430, 1396, 1043, 724 cmꢀ1; Anal. Calcd. (%) for C11H9NO3: C, 65.02; H, 4.46; N,
6.89; Found: C, 64.71; H, 4.41; N, 6.87.
27. Ing, H. R.; Manske, R. H. F. J. Chem. Soc. Abstr. 1926, 2348–2351.
28. Osby, J. O.; Martin, M. G.; Ganem, B. Tetrahedron Lett. 1984, 25, 2093–2096.
29. Synthesis of 3-amino-2-hydroxypropyl diethylcarbamodithioate (6): To
a
suspension of 3-phthalimido-2-hydroxy propyl-1-dithiocarbamate (4f)
(1.5 mmol, 0.528 g) in isopropanol (12 ml) and H2O (2 ml), NaBH4 (7.5 mmol,
0.28 g) was gradually added and the reaction mixture was stirred at room
temperature overnight. The mixture was acidified to pH = 4 with AcOH,
warmed to 80 °C, and stirred for 2 h. The volatiles were removed in vacuo, and
the resulting solution was diluted with 1 M NaOH and extracted with EtOAc
(3 ꢁ 10 mL). The combined EtOAc extractions were dried over Na2SO4 and
evaporated in vacuo, and the residue was purified by column chromatography
(silica gel; 1:4 hexane/EtOAc) to give product 6 as a yellow oil (30%, 0.1 g); 1
H
NMR (300 MHz, CDCl3): d (ppm) 1.22–1.31 (6H, m), 2.76–2.93 (2H, m), 3.38–
3.45 (4H, m), 3.59 (1H, m), 3.73–3.77 (2H, m), 3.87 (1H, m), 3.97–4.01 (2H, m);
13C NMR (75 MHz, CDCl3) d (ppm) 11.6, 12.6, 40.9, 44.6, 45.7, 50.0, 70.4, 195.4;
Anal. Calcd. (%) for C8H18N2OS2: C, 43.21; H, 8.16; N, 12.60; Found: C, 43.02; H,
8.32; N, 12.44.
30. Synthesis of N-propylpiperidine-1-carbothioamide (7): Compound (4i) (2 mmol,
0.676 g) was mixed with piperidine (3 mmol) and stirred at 80 °C for 8 h under
solvent-free conditions. The mixture was extracted with EtOAc (25 mL) and the
organic layer was washed with H2O (20 mL) and 2 M HCl solution. The organic
layer was dried and evaporated under reduced pressure to give a viscous
residue, which was purified by column chromatography. The thiourea (7) was
obtained in 50% yield (0.186 g) as a brown viscous oil; 1H NMR (300 MHz,
CDCl3): d (ppm) 0.88 (3H, t, J = 7.3 Hz), 1.51–1.63 (8H, m), 3.53 (2H, m), 3.71
(4H, m), 5.64 (1H, s); Anal. Calcd. (%) for C9H18N2S: C, 58.02; H, 9.74; N, 15.04;
Found: C, 58.22; H, 9.62; N, 15.24.
26. General procedure for the synthesis 3-phthalimido-2-hydroxy propyl-1-
dithiocarbamates (4): To a mixture of an amine (2.5 mmol) and CS2 (3 mmol)
in H2O (10 mL), N-(2,3-epoxypropyl)phthalimide (3) (2 mmol) was added and
the mixture was stirred vigorously at room temperature for 8 h. After
completion, the products were collected by filtration. In the case of oily
compounds, the products were extracted with EtOAc (2 ꢁ 10 mL). The
combined organic phase was washed with H2O, and then dried with
anhydrous Na2SO4 and evaporated under reduced pressure. In most of cases
31. (a) Pace, V.; Hoyos, P.; Fernandez, M.; Sinisterraa, J. V.; Alcantara, A. R. Green
Chem. 2010, 12, 1380–1382; (b) Heyes, J. A.; Niculescu-Duvaz, D.; Cooper, R. G.;
Springer, C. J. J. Med. Chem. 2002, 45, 99–114.