Mild and efficient synthesis of carbazates and dithiocarbazates via a three-component coupling using Cs2CO3 and TBAI

Article abstract of DOI:10.1016/j.tetlet.2003.10.144

Efficient methods for the synthesis of carbazates and dithiocarbazates have been developed. In the presence of cesium carbonate (Cs₂CO ₃) and tetrabutylammonium iodide (TBAI) a hydrazine, CO₂ or CS₂, and an alkyl halide underwent a three-component coupling at room temperature. Various unprotected hydrazines and alkyl halides were examined and the results demonstrated this methodology was highly chemoselective. Applications toward the synthesis of azadepsipeptides and other pseudopeptides are described.

Full text of DOI:10.1016/j.tetlet.2003.10.144

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 401–405
Mild and efficient synthesis of carbazates and dithiocarbazates via a
three-component coupling using Cs2CO3 and TBAI
Daniel L. Fox, John T. Ruxer, John M. Oliver, Kasey L. Alford and
Ralph Nicholas Salvatore*
Department of Chemistry, Western Kentucky University, 1 Big Red Way, Bowling Green, KY42101-3576, USA
Received 30 September 2003; revised 21 October 2003; accepted 23 October 2003
Abstract—Efficient methods for the synthesis of carbazates and dithiocarbazates have been developed. In the presence of cesium
carbonate (Cs2CO3) and tetrabutylammonium iodide (TBAI) a hydrazine, CO2 or CS2, and an alkyl halide underwenta ht ree-
component coupling at room temperature. Various unprotected hydrazines and alkyl halides were examined and the results
demonstrated this methodology was highly chemoselective. Applications toward the synthesis of azadepsipeptides and other
pseudopeptides are described.
ꢀ 2003 Elsevier Ltd. All rights reserved.
Substituted hydrazines continue to attract considerable
attention due to their widespread use in organic syn-
thesis, industrial, and biological/medicinal applications.1
In particular, carbazates and dithiocarbazates hold
unique applications serving as protecting groups,2 syn-
thetic precursors,3 and donor ligands in complexation
reactions with transition metals.4 Likewise, the carbaz-
ate moiety has enjoyed success in the synthesis of
azadepsipeptides,5 a novel class of peptidomimetics,
which have been recognized as promising targets for
novel pharmaceuticals in the treatment of various dis-
eases. In a similar fashion, the dithiocarbonyl moiety
may also serve as a novel linker in peptidomimetic
synthesis.6 Traditional synthetic methods for the prep-
aration of carbazates and dithiocarbazates are limited
by the need for the use of specialized or toxic reagents
such as phosgene7 in the presence of N-protecting
groups on the hydrazine (e.g., Boc).8 As an attractive
alternative, carbon dioxide was recently employed as a
phosgene equivalent in the synthesis of azadepsipep-
tides. However, this protocol lacks generality since the
procedure was limited to the use of N-Boc-alkylhydra-
zines with primary alkyl halides.7 Therefore, phosgene
and its equivalents still remain the common reagents of
choice.
In connection with our ongoing interest toward the
synthesis of azadepsipeptides and other pseudopeptide
analogues containing backbone modifications, we set
out to investigate the development of more efficient and
safer protocols better suited for peptidomimetic syn-
thesis. Herein, we report a three-component coupling
reaction for the synthesis of carbazates and dithiocar-
bazates in the absence of nitrogen protecting groups
with various alkyl halides.
In the presence of cesium carbonate (Cs2CO3), tetra-
butylammonium iodide (TBAI), and N,N-dimethylfor-
mamide (DMF), as the solvent of choice, various
unprotected hydrazines 1 smoothly coupled with either
carbon dioxide or carbon disulfide atambientetmper-
ature to produce the resultant carbazate or dithiocar-
bazate anion, respectively.9 Subsequentaddiiton of an
alkyl halide produced the corresponding carbazate 2 or
dithiocarbazate 3 exclusively in moderate to high yield
(Scheme 1).
The reaction conditions have shown to be highly
chemoselective facilitating the three-component cou-
pling at the least sterically hindered nitrogen atom on
the hydrazine. Moreover, employing these conditions,
direct N-alkylation products and competing overalkyl-
ations at the more nucleophilic secondary nitrogen were
Keywords: hydrazine; carbazates; dithiocarbazates; azadepsipeptide;
cesium carbonate.
* Corresponding author. Tel.: +1-270-745-3271; fax: +1-270-745-5361;
e-mail: ralph.salvatore@wku.edu
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.144

402
D. L. Fox et al. / Tetrahedron Letters 45 (2004) 401–405
Several examples illustrating the simplicity and practi-
O
R
H
H
H
N
N
N
Cs2CO3, CO2, R'X
TBAI, DMF, 23 o
R'
R'
cality of this methodology are summarized in Table 1.
As a preliminary study of feasibility, phenylhydrazine
hydrochloride (4) underwent reaction with carbon di-
oxide, which subsequently united with benzyl bromide
(5) as the halide of choice, to give the desired benzyl
carbazate in 79% isolated yield (Table 1, entry 1).
Similarly, 4 underwent insertion to CO2 followed by
reaction with an unreactive bromide, 1-bromo-3-
phenylpropane (6) to give the desired product in good
yield after the same time period (entry 2). Likewise,
benzylhydrazine dihydrochloride (7), a reactive hydra-
zine was joined with 6 via a CO2 bridge to afford the
target carbazate 2 in excellentyield (enrty 3). Having
thus established that the aforementioned protocol was
highly useful with unhindered hydrazines, we next set
out to explore the synthetic utility of these conditions by
examining a sterically bulky hydrazine. We were pleased
to find that tert-butylhydrazine hydrochloride (8)
reacted smoothly with 6 in the presence of carbon dioxide
to produce the corresponding carbazate 2 in an excellent
yield (entry 4).11
R
R
N
H
O
S
C
H
X
C
1
2
R
NH2
R'
N
H
X
X
S
R
H
H
H
X=O,S
H
N
N
N
Cs2CO3, CS2, R'X
TBAI, DMF, 23 o
N
H
C
1
3
Scheme 1.
suppressed.10 Therefore, we believe this methodology
strongly compliments the Cs2CO3-promoted carbama-
tion of primary amines previously reported.10
Initially, structurally diverse hydrazines were probed to
test the feasibility of carbazate formation employing the
given conditions. We were pleased to find that various
hydrazines underwentfacile N-alkylation to afford car-
bazates 2 in moderate to high yield. In this conversion,
the CO2 moiety was easily incorporated into the hy-
drazine by rapidly bubbling carbon dioxide gas through
the reaction mixture to afford the carbazic acid inter-
mediate, followed by addition of the alkyl halide. Con-
versely, if the reaction mixture was not initially
saturated with the environmentally benign gas prior to
halide addition, as in the case with the use of dry ice as
the CO2 source, low yields of 2 typically resulted and
direct N-alkylation products arise.
In a continuing study, we next turned our attention to
the synthesis of carbazates using aromatic hydrazines
that contain an electron-withdrawing substituent. Using
the conditions described above, m-nitrophenylhydrazine
hydrochloride (9) underwenta htree-componentcou-
pling reaction with PMBCl (10) to produce the carbaz-
ate product, albeit, in lower yield (entry 5). On the other
Table 1. Carbazate formation using hydrazines, halides, and CO2 in the presence of Cs2CO3 and TBAI
O
R
H
H
H
H
N
N
N
Cs2CO3, CO2, R'X
TBAI, DMF, 23 o
R'
R
N
H
O
C
Entry
1
Hydrazine (RNHNH2)
Halide (R0X)
Time (h)
46
Yield (%)
79
PhNHNH2ÆHCl (4)
BnBr (5)
2
4
46
73
(6)
Br
Ph
3
4
BnNHNH2Æ2HCl (7)
tBuNHNH2ÆHCl (8)
H
6
60
72
88
89
6
N
O2N
NH2 HCl
5
6
PMBCl (10)
60
72
43
67
(9)
H
N
5
5
NH2
(11)
O2N
NO2
H
N
7
8
128
45
58
NH2
(12)
O2N
Ph
NH2 HCl
N
(13)
5
28
Ph

D. L. Fox et al. / Tetrahedron Letters 45 (2004) 401–405
403
hand, p-nitrophenylhydrazine (11) reacted with BnBr
(5), generating the desired product in 67% yield after
72 h (entry 6). As expected, 2,4-dinitrophenylhydrazine
(12) was sluggish resulting in the desired carbazate
accompanied along with unreacted starting material 12,
which was recovered (entry 7). Finally, an N,N-disub-
stituted hydrazine, 1,1-diphenylhydrazine hydrochloride
(13) also underwent facile consolidation with 5 to afford
the desired product in modest yield after 28 h (entry 8).
It is important to note that side products stemming from
overalkylations and direct N-alkylation with the alkyl
halide were mitigated using this procedure.
Having established an effective procedure for the syn-
thesis of carbazates, we next decided to extend our
efforts toward the synthesis of dithiocarbazates using
carbon disulfide. As shown in Table 2, numerous bare
hydrazines were screened with various halides to test the
potential of this protocol to the full extent. For instance,
methylhydrazine (15), a very reactive hydrazine, under-
went a three-component coupling with CS2, and (2-
bromoethyl)benzene (16) in short reaction time to afford
3
in a good yield (entry 1). Likewise, p-meth-
oxyphenylhydrazine hydrochloride (17), also underwent
consolidation with 1-bromobutane (18) to form the
12
diht iocarbazaet adductin an excellentyield (enrty 2).
Owing to the above-mentioned protocols, we also un-
covered a facile three-component, one-pot synthesis of
N-alkyl carbazates (Scheme 2). Employing the condi-
tions mentioned above, 1,1-diphenylhydrazineÆHCl (13)
underwent a three-way coupling with benzyl bromide (5)
and CO2. Upon conversion of the starting hydrazine 13
to carbazate 2 (monitored via TLC), an additional
3 equiv of Cs2CO3 was added and stirred for an addi-
tional hour at room temperature. Subsequent addition
of excess 5 (3 equiv) resulted indirect N-alkylation for
the exclusive formation N-alkyl carbazate (14) in 88%
isolated yield. It is important to highlight, that isolation
of intermediate 2 proved unnecessary offering shortened
synthetic sequences. Currently, a one-pot carbazate
followed by N-alkylation procedure using a different
alkyl halide is under investigation and these results will
be reported in due course.
Similarly, benzylhydrazine dihydrochloride (7) reacted
with a secondary bromide, 2-bromobutane (19), to
afford the coupled product in high yield (entry 3). Next,
hydrazines containing either a sterically hindered or
electron-withdrawing substituent were examined to
provide a more complete picture of the synthetic utility
of the reaction conditions. tert-Butylhydrazine (8) uni-
ted with CS2, which in turn coupled with 1-bromo-3-
phenylpropane (6) offering 3 in an optimum 58% yield
(entry 4). Also, 2,4-dinitrophenylhydrazine (12) reacted
slowly with MeI (20) to afford dithiocarbazate 3 in high
yield (entry 5). In addition, heterocyclic hydrazines also
proved successful using the developed techniques. For
example, N-aminomorpholine (21), united with carbon
disulfide to form the dithiocarbazate anion after 1 h, and
then with 5 to offer 3 in acceptable yield. Finally, 1,1-
diphenylhydrazine (13) underwent a reaction with 20 to
produce the corresponding methyl dithiocarbazate in an
outstanding 92% yield (entry 7).
Ph
N
O
Keeping the synthesis of azadepsipeptides and other
peptidomimetics in mind, we next launched our efforts
toward the synthesis of short dimeric analogues, which
contain the carbazate or dithiocarbazate moiety as the
skeletal backbone. After two unreactive amino bromides
Cs2CO3, CO2, 5
13
Ph
N
O
Ph
TBAI, DMF, 23 o
C
(14, 88%)
Ph
Scheme 2.
Table 2. Dithiocarbazate formation using hydrazines, halides, and CS2 in the presence of Cs2CO3 and TBAI
S
R
H
H
H
H
N
N
N
Cs2CO3, CS2, R'X
TBAI, DMF, 23 oC
R'
R
N
H
S
Entry
1
Hydrazine (RNHNH2)
Halide (R0X)
Time (h)
18
Yield (%)
76
MeNHNH2 (15)
Ph
(16)
Br
H
N
NH2 HCl
2
3
n-BuBr (18)
34
94
90
(17)
MeO
Br
7
120
(19)
4
5
8
12
6
Mel (20)
96
144
58
74
(21)
N NH2
6
7
5
38
12
63
92
O
13
20

404
D. L. Fox et al. / Tetrahedron Letters 45 (2004) 401–405
References and Notes
Br
O
(22)
H
N
NH3
1. (a) Hydrazine and its Derivatives. 4th ed.; Kirk–Othmer
Encyclopedia of Chemical Technology; Wiley: New York,
1995; Vol. 13; (b) Schmidt, E. W. Hydrazine and its
Derivatives Preparation, Properties, Applications. 2nd ed.;
Wiley-Interscience: New York, 2001; (c) Ragnarsson, U.
Chem. Soc. Rev. 2001, 30, 205–213; (d) Atkinson, R. S. In
Comprehensive Organic Synthesis; Barton, D., Ollis, W.
D., Eds.; Pergamon: London, 1979; Vol. 2, p 219; (e)
Chemistry of Hydrazo-, Azo- and Azoxy Groups; Patai, S.,
Ed.; Wiley: New York, 1975; Chapter 4.
Cs CO , CO ,
Br
NH2
NH2
2
3
2
Bn
Ph
N
H
O
7
4
TBAI, DMF, 23 oC, 96 h
(23, 73%)
Br
S
NH
3 (24)
H
N
Cs2CO3, CS2,
Br
N
S
TBAI, DMF, 23 oC, 96 h
H
(25, 62%)
2. (a) Sakakibara, S.; Honda, I.; Naruse, M.; Kanaoka, M.
Experientia 1969, 25, 576; (b) Makarova, E. A.; Koshel-
eva, G. N. Metody Polucheniya Khim. Reakt. I Preparatov
1967, 17, 26–28; (c) Sakakisbara, S.; Honda, I.; Takada,
K.; Miyoshi, M.; Ohnishi, T.; Okumura, K. Bull. Chem.
Soc. Jpn. 1969, 42, 809; (d) Ito, M.; Morino, D. Exper-
ientia 1968, 24, 101; (e) Honda, I.; Shimonishi, Y.;
Sakakibara, S. Bull. Chem. Soc. Jpn. 1967, 40, 2415; (f)
Quibell, M.; Turnell, W. G.; Johnson, T. J. Chem. Soc.,
Perkin Trans. 1 1993, 22, 2843; (g) Sofuku, S.; Mizumura,
M.; Hagitani, A. Nippon Kagaku Zasshi 1968, 89, 721; (h)
Gray, C. J.; Quibell, M.; Baggett, N.; Hammerle, T. Int. J.
Pept. Protein Res. 1992, 40, 351.
3. (a) Connolly, T. J.; Crittall, A. J.; Ebrahim, A. S.; Ji, G.
Org. Process Res. Dev. 2000, 4, 526; (b) Henriksen, L.;
Jensen, O. R. Acta Chem. Scand. 1968, 22, 3042; (c)
Dovlatyan, V. V.; Avetissyan, F. V.; Papoyan, T. Z.;
Gevorgyan, R. A.; Kinoyan, F. S. Khim. Zh. Aremenii
2001, 54, 85; (d) Nesynov, E. P.; Pelꢀkis, P. S. Zh.
Prganicheskoi Khimii 1968, 4, 837; (e) Delaby, R.; Brust-
lein, F.; Warolin, C.; Chabrier, P. Bull. Soc. Chim. Fr.
1961, 2056; (f) Eloy, F.; Moussebois, C. Bull. Soc. Chim.
Belges 1959, 68, 423; (g) Eloy, F.; Moussebois, C. Bull.
Soc. Chim. Belges 1959, 68, 409; (h) Hauser, M. J. Org.
Chem. 1966, 31, 968; (i) Hanefeld, W.; Schlitzer, M. Arch
Pharm. 1994, 327, 413; (j) Lalezari, I. J. Heterocycl. Chem.
1985, 22, 741; (k) Gordon, M. S.; Krause, J. G.;
Linneman-Mohr, M. A.; Parchue, R. R. Synthesis 1980,
3, 244; (l) Zinner, G.; Krause, T.; Doerschner, K. Arch
Pharm. 1977, 310, 642; (m) Clive, D. L. J.; Denyer, C. V. J.
Chem. Soc., Chem. Commun. 1971, 18, 1112.
4. (a) Dutta, S. K.; Samanta, S.; Ghosh, D.; Butcher, R. J.;
Chaudhury, M. Inorg. Chem. 2002, 41, 5555; (b) Bellerby,
J. M.; Edwards, D. A.; Thompsett, D. Inorg. Chim. Acta
1986, 117, L31; (c) dos Santo-Filho, F.; Kaiser, P.;
Roland, C.; Momesso, M. A. J. Brazilian Chem. Soc.
1994, 5, 97; (d) Huan, D.; Zhiming, G.; Zhijian, H. Wuji
Huaxue Xuebao 1989, 5, 73; (e) Karra, R.; Singh, Y. P.;
Rai, A. K. Phosphorus, Sulfur, Silicon Relat. Elem. 2000,
166, 125; (f) Chauhan, A. K. S.; Misra, M. J. Indian Chem.
Soc. 1993, 70, 148.
5. (a) Marchand-Brynaert, J. Farmaco 1995, 50, 455; (b)
Dorn, C. P.; Zimmermann, M.; Yang, S. S.; Yurewicz, E.
C.; Ashe, B. M.; Frankshun, R.; Jones, H. J. Med. Chem.
1977, 20, 1464; (c) Dorn, C. P.; Yang, S. S. U.S. Patent
P2658254.7, 1975; (d) Shemyakin, M. M.; Ovchinnikov,
Yu. A.; Kiryushkin, A. A.; Ivanov, V. T. Tetrahedron Lett.
1963, 885.
Scheme 3.
22 and 24 were prepared as hydrobromide salts using a
previously reported bromination technique,13 they were
subjected to the standard conditions. As depicted in
Scheme 3, benzylhydrazine (7) reacted with isoleucine
bromide (22) via a CO2 bridge in high yield. Likewise,
phenylhydrazine (7) also underwenta similar htree-
componentcoupling wiht carbon disulfide and leucine
bromide (24) to afford the target compound 25 in a 62%
yield. In both cases, the secondary bromide rearranged
to the primary form via the corresponding aziridinium
salt during the alkylations.13 Using our developed pro-
tocol, racemizations were not detected during any
alkylations of these chiral substrates and complications
stemming from side reactions including secondary
alkylations were not observed to a noticeable extent.14
Moreover, the use of protecting groups proved unnec-
essary. Carbazate 23 and dithiocarbazate 25 in turn can
be used as interesting scaffoldings in order to fashion
higher order peptidomimetic compounds, which may
prove very interesting in further studies in organic and
medicinal chemistry.
In conclusion, a mild and efficienthtree-way coupling
was performed to combine a hydrazine with carbon di-
oxide or carbon disulfide and halides using cesium car-
bonate and tetrabutylammonium iodide at room
temperature offering a more direct synthesis of carbaz-
ates and dithiocarbazates. Various bare hydrazines
containing sterically hindered, electron-donating or
withdrawing substituents were all compatible while re-
active, unreactive, and secondary halides were examined
to demonstrate substrate versatility. In addition, chiral
substrates encompassing amino acid derivatives were
resistant to racemization offering numerous applications
in the efficient synthesis of azadepsipeptides and pepti-
domimetic synthesis. Moreover, these improved reaction
conditions are safe and more convenient when com-
pared to conventional synthetic methods averting com-
mon side reactions such as direct N-alkylation and
overalkylations offering a general synthetic protocol.
6. Nagle, A. S.; Salvatore, R. N.; Cross, R. M.; Kapxhiu, E.
A.; Sahab, S.; Yoon, C. H.; Jung, K. W. Tetrahedron Lett.
2003, 44, 5695.
7. Dyker, H.; Scherkenbeck, J.; Gondol, D.; Goehrt, A.;
Harder, A. J. Org. Chem. 2001, 66, 3760.
8. (a) Dutta, A. S.; Morley, J. S. J. Chem. Soc., Perkin Trans.
1 1975, 1712; (b) Nara, S.; Sakamoto, T.; Miyazawa, E.;
Kikugawa, Y. Synth. Commun. 2003, 33, 87, and refer-
Acknowledgements
Financial support from the National Science Founda-
tion––Kentucky EPSCoR (596166) is gratefully ac-
knowledged, as is support from Western Kentucky
University. Also, we wish to thank Chemetall for their
generous supply of cesium bases.

D. L. Fox et al. / Tetrahedron Letters 45 (2004) 401–405
405
ences cited therein; (c) Biel, J. H.; Drukker, A. E.;
Mitchell, T. F.; Sprengeler, E. P.; Nuhfer, P. A.; Conway,
A. C.; Horita, A. J. Am. Chem. Soc. 1959, 81, 2805.
9. TBAI was found to be a crucial additive in averting direct
N-alkylations and overalkylations. TBAI helps to mini-
mize or prohibit overalkylation of the produced carbazate
(or dithiocarbazate anion) presumably by enhancing the
rate of CO2 (or CS2) incorporation and/or stabilizing the
incipient anion through the conjugation with the tetrabu-
tylammonium cation. In the absence of TBAI, poor
product yields resulted along with side products stemming
from direct N-alkylation. For similar results using TBAI
in faciliating carbamate and carbonate formation, see:
Salvatore, R. N.; Chu, F.; Nagle, A. S.; Kapxhiou, E. A.;
Cross, R. M.; Jung, K. W. Tetrahedron 2002, 58, 3329;
Also, tetrabutylammonium bromide (TBAB) and various
other onium salts have been utilized in supercritical
carbon dioxide for the selective formation of urethanes.
See: Yoshida, M.; Hara, N.; Okuyama, S. Chem. Commun.
2000, 151.
10. For other chemoselective N-alkylations using cesium
bases, see: (a) Salvatore, R. N.; Shin, S. I.; Nagle, A. S.;
Jung, K. W. J. Org. Chem. 2001, 66, 1035; (b) Salvatore,
R. N.; Flanders, V. L.; Ha, D.; Jung, K. W. Org. Lett.
2000, 2, 2797; (c) Butcher, K. J. Synlett 1994, 825; (d)
McGhee, W.; Riley, D.; Christ, K.; Pan, Y.; Parnas, B. J.
Org. Chem. 1995, 60, 2820; (e) Salvatore, R. N.; Nagle, A.
S.; Jung, K. W. J. Org. Chem. 2002, 67, 674; (f) Salvatore,
R. N.; Schmidt, S. E.; Shin, S. I.; Nagle, A. S.; Worrell, J.
H.; Jung, K. W. Tetrahedron Lett. 2000, 41, 9705; (g)
Salvatore, R. N.; Ledger, J. A.; Jung, K. W. Tetrahedron
Lett. 2001, 42, 6023; (h) Salvatore, R. N.; Nagle, A. S.;
Schmidt, S. E.; Jung, K. W. Org. Lett. 1999, 1, 1893.
11. Representative experimental procedure for carbazate 2
preparation: To tert-butylhydrazine hydrochloride (8)
(200 mg, 1.61 mmol) in anhydrous N,N-dimethylforma-
mide (8 mL) were added cesium carbonate (2.1 g,
6.44 mmol, 4 equiv) and tetrabutylammonium iodide
(2.1 g, 4.83 mmol, 3 equiv). The reaction mixture was
stirred for 2 h at room temperature. Carbon dioxide gas
(flow rate ꢀ 25–30 mL/min) was rapidly bubbled into the
reaction mixture for 1 h and then 1-bromo-3-phenylpro-
pane (6) (962 mg, 4.83 mmol, 3 equiv) was added into the
suspension. The reaction proceeded at ambient tempera-
ture with CO2 gas bubbling for 72 h, during which point 8
was consumed. The reaction mixture was then poured
into water (30 mL) and extracted with EtOAc (3 · 30 mL).
The organic layer was washed with water (2 · 30 mL),
brine (30 mL), and dried over anhydrous sodium sulfate.
Evaporation of the solvent followed by flash column
chromatography (hexanes–EtOAc, 9:1 v/v) afforded car-
bazate 2 (360 mg, 89%) as an oil. 1H NMR (270 MHz,
CDCl3) d 1.08 (s, 9H), 1.89 (m, 2H), 2.55 (t, 2H,
J ¼ 7:5 Hz), 4.10 (t, 2H, J ¼ 6:5 Hz), 5.3 (br s, NH),
7.10–7.45 (m, 5H), 8.05 (s, NH). 13C NMR (70 MHz,
CDCl3) d 25.8, 30.5, 31.0, 51.0, 64.0, 125.8, 128.3, 128.6,
138.8, 157.0. MS (EI) m=z 250.17 (Mþ). Anal. Calcd for
C14H22N2O2: C, 67.17; H, 8.86; N, 11.19. Found: C, 67.12;
H, 8.82; N, 11.21.
12. Representative experimental procedure for dithiocarbaz-
ate 3 preparation: To a solution of p-methoxyphenyl-
hydrazine hydrochloride (17) (200 mg, 1.14 mmol) in
anhydrous DMF (6 mL) was added cesium carbonate
(1.48 g, 4.56 mmol, 4 equiv) and tetrabutylammonium
iodide (1.26 g, 3.42 mmol, 3 equiv) with vigorous stirring
for 1 h at ambient temperature under a nitrogen atmo-
sphere. The solution was cooled to 0 ꢁC and carbon
disulfide (0.072 mL, 1.2 mmol, 1.1 equiv) was added and
stirred for 1 h. After this time period, 1-bromobutane (18)
(0.13 mL, 1.2 mmol, 1.1 equiv) was added and stirred for
34 h with gentle warming to room temperature. The
resultant yellow reaction supension was then poured into
water (30 mL) and extracted with EtOAc (3 · 30 mL). The
organic layer was washed with water (2 · 30 mL), brine
(30 mL), and dried over anhydrous sodium sulfate. The
solution was filtered, concentrated in vacuo, and purified
via flash column chromatography (hexanes–EtOAc, 9:1
v/v) to afford dithiocarbazate 3 as a yellow oil (280 mg,
94%). 1H NMR (270 MHz, CDCl3) d 0.85 (t, 3H,
J ¼ 7:3 Hz), 1.33 (m, 2H), 1.85 (m, 2H), 2.0 (s, NH),
2.95 (t, 2H, J ¼ 6:3 Hz), 3.73 (s, 3H), 4.05 (m, NH), 6.75–
7.60 (m, 4H). 13C NMR (70 MHz, CDCl3) d 13.4, 21.7,
32.2, 33.7, 55.5, 112.0, 114.6, 134.5, 152.4. 203.0. MS (EI)
m=z 270.42 (Mþ). Anal. Calcd for C12H18N2OS2: C,
53.30; H, 6.71; N, 10.36. Found: C, 53.26; H, 6.65; N,
10.33.
13. Nagle, A. S.; Salvatore, R. N.; Chong, B. D.; Jung, K. W.
Tetrahedron Lett. 2000, 41, 3011.
14. H NMR, 13C NMR, and 2D NMR analysis indicate the
productas a single diastereomer.