Phosphonodithioformates: Efficient Three-Component Coupling of Dialkyl phosphites, Carbon Bisulfide, and Alkyl Halides in the Presence of Cesium Carbonate and Tetrabutylammonium Iodide

Article abstract of DOI:10.1055/s-2003-41482

A mild one-pot, three-component coupling reaction uniting a dialkyl phosphite, carbon disulfide (CS₂) and an alkyl halide for the mild and efficient synthesis of phosphonodithioformates using cesium carbonate (Cs₂CO₃) and tetrabutyl-ammonium iodide (TBAI) was developed. Various dialkyl phosphites were examined using a diverse array of alkyl halides, and these improved reaction conditions were found to be highly selective producing the title compounds exclusively in moderate to high yields.

Full text of DOI:10.1055/s-2003-41482

LETTER
2037
Phosphonodithioformates: Efficient Three-Component Coupling of Dialkyl
phosphites, Carbon Disulfide, and Alkyl Halides in the Presence of Cesium
Carbonate and Tetrabutylammonium Iodide
P
hosphonodithiofo
a
rmates niel L. Fox, Nathan R. Whitely, Richard J. Cohen, Ralph Nicholas Salvatore*
Department of Chemistry, Western Kentucky University, 1 Big Red Way, Bowling Green, KY, 42101-3576, USA
Fax +1(270)7455361; E-mail: ralph.salvatore@wku.edu
Received 21 August 2003
thiocarbonyl.11 However, the procedures call for
conventional conditions (low temperature and strong
base) which lack generality, since the use of chiral
halides, which are particularly prone to racemization were
Abstract: A mild one-pot, three-component coupling reaction
uniting a dialkyl phosphite, carbon disulfide (CS2) and an alkyl
halide for the mild and efficient synthesis of phosphonodithio-
formates using cesium carbonate (Cs2CO3) and tetrabutyl-
ammonium iodide (TBAI) was developed. Various dialkyl for obvious reasons not investigated. Therefore, in an
phosphites were examined using a diverse array of alkyl halides,
effort to mitigate these shortcomings, we have focused on
and these improved reaction conditions were found to be highly
the preparation of phosphonodithioformates by
selective producing the title compounds exclusively in moderate to
employing a milder and more efficient approach better
high yields.
suited toward the synthesis of phosphonopeptides.
Key words: alkylations, alkyl halides, cesium carbonate,
phosphonodithioformate, phosphorus
As mechanistically demonstrated in Scheme 1, in the
presence of Cs2CO3 and tetrabutylammonium iodide
(TBAI), three-components comprising
a
dialkyl
phosphite, CS2 and an alkyl halide were efficiently united
in one-pot. Upon stirring dialkyl phosphite 1 with Cs2CO3
and TBAI at room temperature for one hour, the corre-
sponding anion of 1 was smoothly generated, which
subsequently inserted into CS2 affording the incipient
phosphoryldithioformate adduct 2 using anhyd N,N-di-
methylformamide (DMF) as the solvent of choice. S-
Alkylation of 2 with an alkyl halide produced phosphono-
dithioformate 3 exclusively.12
a-Substituted phosphonates have demonstrated a wide
range of robust biological activity, which continue to
attract
much
interest.1
In
particular,
phosphonodithioformates (or phosphoryldithioformates)
are one such class of dithioesters functionalized by a
phosphonic ester group. These sulfur substituted
phosphonates have emerged as efficient radical trapping
agents,2 served as crucial synthetic intermediates in
nucleophilic addition reactions,3 as well as successful
agents in controlling the radical polymerization of
monomers,4 among other reactions.5 The most
straightforward synthesis for these compounds involves
the coupling of a dialkyl phosphite with CS2, followed by
subsequent alkylation using an alkyl halide.6 However,
typical reaction conditions involve the use of strong base
and low reaction temperature.7 Additionally, if reaction
conditions are not carefully controlled, other pentavalent
phosphorus side products may arise.8 Previously,
Blackburn prepared a wide variety of structurally novel
and biologically interesting a-fluorinated phosphonates
which serve as potential enzyme inhibitors and as useful
probes for the elucidation of biochemical processes.9 In
connection with our ongoing interest toward the syntheses
of novel phosphonopeptides,10 we envisioned that
incorporation of a CS2 linker a- to the phosphonate, may
offer an interesting and novel class of modified
phosphonopeptides. While we were conducting our
optimization studies, Benaglia and co-workers reported a
method for the preparation of several dithioformates
bearing a dialkoxyphosphoryl group bound to the
Cs2CO3,
CS2
O
P
S
S
O
P
O
P
1
S
RO
RO
RO
RO
RO
RO
R'X
H
TBAI, DMF,
23 °C
SR'
3
Cs
2
O
P
RO
S
Via
C
RO
R'
X
S
Scheme 1
As a preliminary study of feasibility, we set out to probe
the scope and limitations of the reaction conditions using
diethyl phosphite 4 and benzyl bromide as model
substrates. As demonstrated in Table 1, base selection
played an inherently important role in the reaction. An
assortment of bases including alkali metal carbonates and
an organic base was screened in conjunction with TBAI
for the efficient synthesis of benzyl diethoxyphosphoryl-
dithioformate 5.13 Among the bases examined, Cs2CO3
was by far superior when compared to other alkali metal
carbonates (entries 1–4), offering 5 in excellent yield
(97%; entry 5).11 We attribute this dramatic increase in
yield to the ‘cesium effect’.14 The cesium effect,
SYNLETT 2003, No. 13, pp 2037–2041
1
6
.1
0
.2
0
0
3
Advanced online publication: 08.10.2003
DOI: 10.1055/s-2003-41482; Art ID: S07703ST
© Georg Thieme Verlag Stuttgart · New York

2038
D. L. Fox et al.
LETTER
characterized by ‘naked anions’ which are in loose With the optimum reaction conditions in hand, we next
proximity with cesium cation,15 presumably behave as decided to explore the generality for phosphono-
strong nucleophiles. This effect, in turn, generally dithioformate formation utilizing a wide array of alkyl
produces higher product yields and cleaner reaction halides. As delineated in Table 2, diphenyl phosphite
conditions as reported in numerous synthetic underwent consolidation with both primary and
transformations.16 Furthermore, we also found treatment secondary bromides after CS2 installation. Using active
of 4 with a cat. amount of Cs2CO3 (0.5 equiv) in halides, such as benzyl, allyl, and crotyl halides (entries
conjunction with K2CO3 (2.5 equiv) gave rise to 5 in 1–3), alkylations of diphenyl phosphite were highly effi-
higher yield than K2CO3 alone (entry 6). Other cesium cient providing the corresponding dithioformate analogs
bases encompassing cesium hydroxide in the presence of respectively. In addition, an unreactive primary bromide,
activated molecular sieves proved to be an alternative, 1-bromobutane (9), also proved practical affording the
affording 5 in a 67% yield after the same time period product in satisfactory yield (entry 4). On the other hand,
(entry 7). However, switching the base to cesium a sterically crowded bromide, 2-iodopropane (10),
bicarbonate gave low conversion, presumably due to underwent facile three-component coupling generating
decreased basicity and solubility (entry 8). In addition, the coupled product, although longer reaction time was
employment of an organic base such as Et3N was not required (entry 5). On the basis of these successful find-
effective (entry 9).
ings, we next directed our attention toward the synthesis
of complex phosphonate analog of biological
a
Table 1 Phosphonodithioformate Formation of 5 Utilizing Various
importance: geranyl phosphate. Using the aforementioned
methodology, diphenyl phosphite smoothly incorporated
into CS2 after stirring for 1 h at ambient temperature.
Subsequent treatment with geranyl bromide (11) gave rise
to the corresponding phosphonodithioformate, cleanly, in
50% overall isolated yield (entry 6). Likewise, a similar
yield was noticed using 5-bromo-1-pentene (12)
generating the unsaturated phosphonodithioformate
accordingly (entry 7). The true versatility of this method
lies in the opportunity to explore issues of efficiency and
chemoselectivity in the synthesis of phosphono-
dithioformates, which contain other reactive functionality
present in the halide-coupling partner. To address this,
alkylations with 2-bromoethylamine·HBr (13) and 3-
chloro-1-propanol (14) reacted with diphenyl phosphite
smoothly (entries 8 and 9). Therefore, it is noteworthy to
highlight direct alkylations were found to occur exclu-
sively at sulfur, leaving both the amino- and hydroxyl
moieties untouched.18 Moreover, circumventing the use of
protecting groups is a key feature embedded in our
protocol. As a result, these unprecedented results offer a
plethora of applications, such as the use of these important
functional groups as scaffoldings in further syntheses.
Capitalizing on these findings, as well as keeping in view
the synthesis of phosphonopeptides, it was similarly
envisioned that a b-amino acid bromide would serve as an
excellent building block employing these mild and highly
chemoselective procedures. After preparation of
isoleucine bromide as a salt (15) from isoleucinol via a
similar previously reported bromination protocol,19 this
precursor was found to successfully unite with diphenyl
phosphite under the standard conditions offering the
desired product in good yield containing the CS2 moiety
as a linker (entry 10). Above all importance, retention of
configuration of this chiral template resulted. Moreover,
side products stemming from direct N-alkylation or
hydrolysis of the phosphonate were not noticed in any
case study herein.20 Therefore, these shortened synthetic
sequences, devoid from side products, reveal a more
efficacious method for generating interesting biologically
active phosphonates.21 Although the preparation of
Bases
O
O
S
Cs2CO3, CS2, BnBr
(EtO)
(EtO)
2P
H
2P
TBAI, DMF, 23 °C, 24 h
4
5
SBn
Yield (%)
35
Entry
Base
1
2
3
4
5
6
7
8
9
Li2CO3
Na2CO3
K2CO3
43
77
Rb2CO3
Cs2CO3
Cs2CO3/K2CO3
82
97
85
CsOH·H2O/4 A MS
CsHCO3
67
44
Et3N
30
At this juncture, in view of base preference for the
formation of 5, TBAI was also found to be a crucial
additive for promoting increased product yields. There-
fore, to gauge the effect with regard to the role TBAI plays
during the course of the reaction, we decided to pursue an
important study. In the presence of TBAI, 5 was produced
in nearly quantitative yield after 24 hours.17 However,
under identical reaction conditions in the absence of
TBAI, poor product yield (35%) was noticed after the
same time period (Scheme 2).
TBAI Absent
TBAI Present
O
P
Cs2CO3, CS2, BnBr
Cs2CO3, CS2, BnBr
5
5
EtO
H
TBAI, DMF, 23 °C,
DMF, 23 °C, 24 h, 35%
EtO
24 h, 97%
4
Scheme 2
Synlett 2003, No. 13, 2037–2041 © Thieme Stuttgart · New York

LETTER
Phosphonodithioformates
2039
tertiary dithioformates would possess greater synthetic Table 3 Cs2CO3-Promoted Phosphonodithioformate Synthesis Us-
ing a Dialkyl phosphite, CS2, and an Alkyl Halide
value, tertiary halides (e.g. trityl bromide), as expected,
completely failed to react using the aforementioned
O
P
O
P
S
RO
RO
Cs2CO3, CS2, R'X
TBAI, DMF, 23 °C
RO
RO
protocols.
H
Table 2 Phosphonodithioformate Formation Using Various Halides
SR'
O
P
S
O
P
PhO
PhO
PhO
Cs2CO3, CS2, R'X
TBAI, DMF, 23 °C
Entry Phosphite
Halide (R¢X)
Time
(h)
Yield
(%)
H
PhO
SR'
1
2
3
4
5
6
7
8
9
(MeO)2P(O)H
16
6
6
85
74
92
83
65
59
87
51
31
Entry
1
Halide (R¢X)
Time (h)
24
Yield (%)
90
BnBr
6
16
20
22
Ph
Br
17
n-PrBr
18
2
3
4
5
6
7
8
allyl bromide
7
5.5
6
77
81
57
64
50
50
72
(EtO)2P(O)H
4
crotyl bromide
8
(PrO)2P(O)H
19
6
6
9
28
n-BuBr
9
22
56
52
20
72
(BuO)2P(O)H
20
26
2-iodopropane
10
(BnO)2P(O)H
21
40
geranyl bromide
11
21
2-bromobutane
22
72
5-bromo-1-pentene
12
(i-PrO)2P(O)H
23
6
6
72
(LaurylO)2P(O)H
24
100
.
NH2 HBr
Br
13
9
28
72
62
65
Cl
OH
congested phosphite, diisopropyl phosphite (23) and
benzyl bromide (6) in good yield (entry 8). Finally, to
widen the scope of the reaction, the use of a lipophilic di-
alkyl phosphite, dilauryl phosphite (24), which required
longer time, also reacted efficiently (entry 9).
14
10
NH3+Br–
Br
15
In conclusion, in the presence of Cs2CO3 and TBAI, a
mild and efficient one-pot three-component coupling was
performed using a dialkyl phosphite, CS2, and a halide,
leading to the efficient synthesis of phosphonodithio-
formates. Various alkyl and aromatic phosphites were
compatible, while use of active, unreactive and secondary
halides display wide substrate versatility. Our improved
reaction protocols, exemplified by room temperature and
mild base, demonstrate superiority over the known
methodologies. Extending on these findings, chiral
templates encompassing amino acid derivatives were
found to be resistant to racemization. Currently in our
laboratories, application of this procedure is underway for
the fabrication of higher order phosphonopeptides, which
will be reported in due course.
After substantiating that our cesium-promoted P-
alkylation conditions were indeed successful, this next
prompted us to explore our synthetic efforts toward the
screening of various structurally diverse phosphono-
dithioformates. As exemplified in Table 3, various halides
as well as numerous dialkyl phosphites were subjected to
the improved procedures. Dimethyl phosphite (16) under-
went rapid alkylation with reactive halide 6, although an
unreactive halide such as 1-bromo-3-phenylpropane (17)
produced the desired product in slightly lower yield (en-
tries 1 and 2). In a continuing study, varying the alkyl
chain on the respective phosphite subunit (e.g. diethyl,
dipropyl-, and dibutyl phosphite; Table 3, entries 3–5)
also proved successful using various primary halides.
Furthermore, dibenzyl phosphite (21) reacted smoothly
employing a primary and secondary halide alike (entries 6
and 7). Likewise, benzyl diisopropylphosphoryldithio-
formate was analogously prepared using a sterically
Acknowledgment
Financial support from the National Science Foundation-Kentucky
EPSCoR (596166) is gratefully acknowledged, as is support from
Western Kentucky University. Also, we wish to thank Chemetall
for their generous supply of cesium bases.
Synlett 2003, No. 13, 2037–2041 © Thieme Stuttgart · New York

2040
D. L. Fox et al.
LETTER
TBAI (0.94 g, 2.55 mmol, 3 equiv) with vigorous stirring for
10 min at r.t. under a N2 atmosphere. CS2 (0.15 mL, 2.55
mmol, 3 equiv) was added and the fuchsia colored mixture
was stirred for 1 h. After this time period, benzyl bromide
(0.30 mL, 2.55 mmol, 3 equiv) was added and stirred for an
additional 24 h. The resultant yellow reaction suspension
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 anhyd
Na2SO4. Evaporation of the solvent followed by flash
chromatography (hexanes–EtOAc, 9:1) afforded benzyl
diethoxyphosphoryldithioformate(5) as a dark red oil (0.25
g, 97%).
References
(1) For recent leading references, see: (a) Halazy, S.; Ehrhard,
A.; Eggenspiller, A.; Berges-Gross, V.; Danzin, C.
Tetrahedron 1996, 52, 8619. (b) Kawamoto, A. M.;
Campbell, M. M. J. Chem. Soc. Perkin Trans. 1 1997, 1249.
(c) Caplan, N. A.; Pogson, C. I.; Hayes, D. J.; Blackburn, G.
M. J. Chem. Soc. Perkin Trans. 1 2000, 421.
(d) Yokomatsu, T.; Hayakawa, Y.; Kihara, T.; Koyanagi, S.;
Soeda, S.; Shimeno, H.; Shibuya, S. Bioorg. Med. Chem.
2000, 8, 2571.
(2) (a) Levillain, J.; Masson, S.; Hudson, A.; Alberti, A. J. Am.
Chem. Soc. 1993, 115, 8444. (b) Alberti, A.; Benaglia, M.;
Della Bona, A.; Macciantelli, D.; Luccioni-Heuze, B.;
Masson, S.; Hudson, A. J. Chem. Soc., Perkin Trans. 2 1996,
1057. (c) Alberti, A.; Benaglia, M.; Bonora, M.; Borzatta,
V.; Hudson, A.; Macciantelli, D.; Masson, S. Polym.
Degrad. Stab. 1998, 62, 559. (d) Albert, A.; Benaglia, B.;
Hapiot, P.; Hudson, A.; Le Coustumer, G.; Macciantelli, D.;
Masson, S. J. Chem. Soc., Perkin Trans. 2 2000, 1908.
(3) (a) Bulpin, A.; Masson, S.; Sene, A. Tetrahedron Lett. 1989,
30, 3415. (b) Bulpin, A.; Masson, S.; Sene, A. Tetrahederon
Lett. 1990, 31, 1151. (c) Bulpin, A.; Masson, S.; Sene, A. J.
Org. Chem. 1992, 57, 4507. (d) Masson, S. Phosphorus,
Sulfur Silicon Relat. Elem. 1994, 95, 127.
(4) Laus, M.; Papa, R.; Sparnacci, K.; Alberti, A.; Benaglia, M.;
Macciantelli, D. Macromolecules 2001, 34, 7269.
(5) (a) Heuze, B.; Gasparova, R.; Heras, M.; Masson, S.
Tetrahedron Lett. 2000, 41, 7327. (b) Masson, S.; Saquet,
M.; Marchand, P. Tetrahedron 1998, 54, 1523.
(c) Makomo, H.; Saquet, M.; Simeon, F.; Masson, S.;
Aboutjaudet, E.; Collignon, N.; Gulea-Purcarescu, M.
Phosphorus, Sulfur Silicon Relat. Elem. 1996, 110, 445.
(d) Mikolajczyk, M.; Mikina, M.; Graczyk, P. P.;
Balczewski, P. Synthesis 1996, 1232. (e) Bulpin, A.;
LeRoy-Gourvennec, S.; Masson, S. Phosphorus, Sulfur
Silicon Relat. Elem. 1994, 89, 119. (f) Makomo, H.;
Masson, S.; Saquet, M. Tetrahedron 1994, 50, 10277.
(6) Grisley, D. W. J. Org. Chem. 1961, 2544.
1H NMR (270 MHz, CDCl3): d = 1.36 (t, J1,2 = 7.6 Hz, 6 H),
4.26 (m, 4 H), 4.46 (s, 2 H), 7.30 (s, 5 H). 13C NMR (100
MHz, CDCl3): d = 16.20 (d, JCP = 6.34 Hz), 40.63 (d, JCP
2.72 Hz), 64.70 (d, JCP = 6.94 Hz), 128.00 (s), 128.77 (s),
129.26 (s), 133.53 (s), 228.16 [d, JCP = 174.54 PC(S)S]; 31
NMR (85 MHz, CDCl3)d from 30% H3PO4–H2O: –4.57.
=
P
MS: m/z = 91, 121, 182, 248, 276, 304 (M+). Anal. Calcd for
C12H17O3PS2: C, 47.35; H, 5.63. Found: C, 47.42; H, 5.64.
(14) For reviews on the ‘cesium effect’, see: (a) Ostrowicki, A.;
Vogtle, F. In Topics in Current Chemistry, Vol. 161; Weber,
E.; Vogtle, F., Eds.; Springer Verlag: Heidelberg, 1992, 37.
(b) Galli, C. Org. Prep. Proced. Int. 1992, 24, 287; and
references therein. (c) Blum, Z. Acta Chem. Scand. 1989,
43, 248.
(15) Formation of ‘naked anions’ by solvation of cesium ions has
been previously postulated and studied extensively: Dijstra,
G.; Kruizinga, W. H.; Kellogg, R. M. J. Org. Chem. 1987,
52, 4230.
(16) For examples of efficient cesium-promoted alkylations, see:
(a) Parrish, J. P.; Dueno, E. E.; Kim, S.-I.; Jung, K. W. Synth.
Commun. 2000, 30, 2687. (b) Salvatore, R. N.; Flanders, V.
L.; Ha, D.; Jung, K. W. Org. Lett. 2000, 2, 2797.
(c) Dueno, E. E.; Chu, F.; Kim, S.-I.; Jung, K. W.
Tetrahedron Lett. 1999, 40, 1843. (d) Salvatore, R. N.;
Nagle, A. S.; Schmidt, S. E.; Jung, K. W. Org. Lett. 1999, 1,
1893. (e) Salvatore, R. N.; Shin, S. I.; Nagle, A. S.; Jung, K.
W. J. Org. Chem. 2001, 66, 1035. (f) Salvatore, R. N.;
Sahab, S.; Jung, K. W. Tetrahedron Lett. 2001, 42, 2055.
(g) Salvatore, R. N.; Schmidt, S. E.; Shin, S. I.; Nagle, A. S.;
Worrell, J. H.; Jung, K. W. Tetrahedron Lett. 2000, 41,
9705. (h) Salvatore, R. N.; Ledger, J. A.; Jung, K. W.
Tetrahedron Lett. 2001, 42, 6023. (i) Kim, S.-I.; Chu, F.;
Dueno, E. E.; Jung, K. W. J. Org. Chem. 1999, 64, 4578.
(j) Salvatore, R. N.; Chu, F.; Nagle, A. S.; Kapxhiu, E. A.;
Cross, R. M.; Jung, K. W. Tetrahedron 2002, 58, 3329.
(k) Salvatore, R. N.; Shin, S. I.; Flanders, V. L.; Jung, K. W.
Tetrahedron Lett. 2001, 42, 1799. (l) Salvatore, R. N.;
Nagle, A. S.; Jung, K. W. J. Org. Chem. 2002, 67, 674.
(17) TBAI is strongly believed to act as a phase-transfer catalyst
in the reaction, therefore, facilitating alkylations producing
high product yields. For other phase-transfer catalyzed
phosphorus alkylations, see: (a) Kem, K. M.; Nguyen, N.
V.; Cross, D. J. J. Org. Chem. 1981, 46, 5188. (b) Weber,
W. P.; Gokel, G. W. Phase Transfer Catalysts in Organic
Synthesis; Springer Verlag: New York, 1977. (c) Starks, C.
M.; Liotta, C. Phase Transfer Catalysis: Principles and
Techniques; Academic Press: New York, 1978.
(7) Bulpin, A.; Masson, S.; Sene, A. Tetrahedron Lett. 1989, 30,
3415.
(8) Zimin, M. G.; Dvoinishnikova, T. A.; Konovalova, I. V.;
Pudovik, A. N. Zh. Obshch. Khim. 1978, 48, 2790.
(9) (a) Blackburn, G. M.; England, D. A.; Kolkmann, F. J.
Chem. Soc., Chem. Commun. 1981, 930. (b) Blackburn, G.
M.; Eckstein, F.; Kent, D. E.; Perree, T. D. Nucleosides
Nucleotides 1985, 4, 165.
(10) For a general overview for the synthesis of phosphono- and
phosphinopeptides, see: Kafarski, P.; Lejczak, B. In
Aminophosphonic and Aminophosphinic Acids, Chemistry
and Biological Activity; Kukhar, V. P.; Hudson, H. R., Eds.;
Wiley: England, 2000, 173–203; and references cited
therein.
(11) Cs2CO3 offered a higher yield than previously reported, see:
Alberti, A.; Benaglia, M.; Laus, M.; Sparnacci, K. J. Org.
Chem. 2002, 67, 7911.
(12) Inverse addition (cesium salt of dialkylphosphite to CS2)
was also tried and did not result in a higher yield. Also,
formation of secondary products resulting from the reaction
between dialkylphosphite salts with the in situ generated
cesium phosphonodithiocarboxylate leading to the expected
desulfurization forming methylene diphosphonates did not
arise as previously described for sodium salts. See: Masson,
S. Reviews in Heteroatom Chemistry, Vol. 12; Oae, S., Ed.;
VCH: Weinheim, 1995, 69–84.
(d) However, we cannot rule out an internal Finkelstein-type
reaction for the in-situ generation of alkyl iodides from
bromides and chlorides, hence improving yields. Although,
the use of alkyl iodides directly, without TBAI gave lower
product yields. Therefore, we propose TBAI minimizes or
prohibits direct alkylation of the phosphite with an alkyl
halide presumably enhancing the rate of CS2 incorporation/
(13) General Experimental Procedure: To a solution of diethyl
phosphite 4 (0.12 g, 0.85 mmol, 1 equiv) in anhyd DMF (5
mL) was added Cs2CO3 (0.83 g, 2.55 mmol, 3 equiv) and
Synlett 2003, No. 13, 2037–2041 © Thieme Stuttgart · New York

LETTER
and or stabilizing the phosphoryl dithioformate anion
Phosphonodithioformates
2041
cyclization to the phosphonothiazoline can readily occur.
Neither the aforementioned thioacylation reaction (which
usually occurs with the alkyl group in the phosphono-
moiety) or cyclization was seen. Therefore, we wish to
strongly emphasize product structures for aminodithioesters
from 13 and 15 were isolated and assigned without
ambiguity from the exact mass (MS), 1H, 13C, and 31P NMR
spectroscopy.
through conjugation with the tetrabutylammonium cation.
Whereas, the cesium ion tends to weakly coordinate to the
conjugate anions, making them more nucleophilic. Prior to
addition of the halide, the phosphite and CS2 were reacted to
pre-form the incipient dithioformate anion, which is belived
to suppress direct alkylation of the phosphite. For a similar
example, see ref.15 for a mechanistic interpretation and for
the use of TBABr and other onium salts in the formation of
urethanes: Yoshida, M.; Hara, N.; Okuyama, S. Chem.
Commun. 2000, 151.
(19) Nagle, A. S.; Salvatore, R. N.; Chong, B. D.; Jung, K. W.
Tetrahedron Lett. 2000, 41, 3011.
(20) 1H NMR, 13C NMR, 31P NMR and 2D NMR analysis
indicate the product as a single diastereomer.
(18) Since dithioesters are known to be very good thioacylating
agents for amines due to the high electrophilicity of the C=S
which is activated by the phosphono-substituent (an
electron-withdrawing group), amino bromides 13 and 15
were used as the corresponding hydrobromide salts, since a
spontaneous intermolecular reaction to give thioamides or
(21) For new biologically active phosphonates, see:
(a) Hildebrand, R. The Role of Phosphonates in Living
Systems; CRC Press: Boca Raton, 1983. (b) Engel, R.
Chem. Rev. 1977, 77, 349. (c) Kafarski, P.; Leczak, B.
Phosphorus, Sulfur Silicon Relat. Elem. 1991, 63, 193.
Synlett 2003, No. 13, 2037–2041 © Thieme Stuttgart · New York