Direct transformation of 1,3-dihalides into dithianes and dithiepines via a novel one-pot reaction with carbon disulfide and sodium borohydride

Article abstract of DOI:10.1021/ol005705k

1,3-Dithianes and -dithiepines are prepared via an experimentally simple and efficient direct transformation of 1,n-alkyl dihalides utilizing carbon disulfide and sodium borohydride.

Full text of DOI:10.1021/ol005705k

ORGANIC
LETTERS
2000
Vol. 2, No. 8
1133-1135
Direct Transformation of 1,3-Dihalides
into Dithianes and Dithiepines via a
Novel One-Pot Reaction with Carbon
Disulfide and Sodium Borohydride
Yongqin Wan, Alexei N. Kurchan, Loren A. Barnhurst, and
Andrei G. Kutateladze*
Department of Chemistry and Biochemistry, UniVersity of DenVer,
DenVer, Colorado 80208-2436
akutatel@du.edu
Received February 22, 2000
ABSTRACT
1,3-Dithianes and -dithiepines are prepared via an experimentally simple and efficient direct transformation of 1,n-alkyl dihalides utilizing
carbon disulfide and sodium borohydride.
Cyclic dithioacetals, which are normally synthesized via acid-
catalyzed reactions of 1,n-dithiols with ketones and alde-
hydes, are quite common in the chemistry of protecting
groups.1 With Corey and Seebach’s reporting of 2-lithiodi-
thiane additions to carbonyls three decades ago, cyclic
thioacetals became even more ubiquitous as synthons utilized
in many celebrated synthetic sequences.2
furnishes the desired 1,3-dithiaheterocycles in moderate to
good yields (Table 1).
Table 1
Recent findings in our laboratories3 show that the dithiane
moiety “as a whole” can also be used as photo-removable
protection for carbonyl compounds. Along these lines we
have been developing the photolytic C-C bond cleavage in
dithiane-carbonyl adducts for what we tentatively dub
photo-take-apartable molecular objects. This project required
easy access to 1,3-dithianes substituted at a position other
than 2 (mostly 5-substituted), which are not readily available
through the existing thioacetal chemistry.
We therefore have developed and now report an experi-
mentally simple one-pot direct transformation of alkyl
dihalides into dithianes and dithiepines.
We have found that the reaction of sodium borohydride,
CS2, and an alkyl 1,n-dibromide or diiodide (3:1.5:1)
(1) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991; p 201.
(2) For a review see: Gro¨bel, B.-T.; Seebach, D. Synthesis 1977, 357.
(3) McHale, W. A.; Kutateladze, A. G. J. Org. Chem. 1998, 63, 9924.
Our mechanistic rationale includes double reduction of CS2
by NaBH4 leading to the formation of methane dithiolate,
10.1021/ol005705k CCC: $19.00 © 2000 American Chemical Society
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[-S-CH2-S-],4,5 which then displaces the halogens via a
two-step (an inter- followed by an intramolecular) nucleo-
philic substitution, Scheme 1.
required to assume, at best, a gauche conformation) and the
substituent R:
Scheme 1
To improve the yields of 5-substituted dithianes, we
utilized triglyme as a solvent: (i) aprotic solvents of higher
polarity are known to enhance the efficiency of SN2 processes
and (ii) additionally, sodium borohydride is soluble in
tryglime (see ref 9 for experimental details).
As it is mentioned above, our synthetic objective was to
develop a simple method for preparation of dithianes tethered
to each other or to other molecular objects via the position
5. One of the possible approaches to such systems, that we
are currently developing, utilizes classic malonate chemistry,
Scheme 2.6
The timing of these two events is critical for a successful
reaction to occur. If for some reason the intramolecular
nucleophilic substitution (step k2) is slow, a competing
expulsion of thioformaldehyde from the intermediate A takes
place (k2 < k3). Although we do not have direct evidence of
CH2dS formation, we isolated the products of the thiolate
B reactions and detected traces of trithiane in the reaction
mixtures. We also attribute detection of methyl sulfides in
“failed” reactions to the presence of methylthiolate anion
formed by further reduction of thioformaldehyde.
Scheme 2
We will briefly discuss the two factors affecting the
efficiency of this cyclization -the leaving group and the
steric hindrance.
Another useful technique for 1,3-dibromide synthesis,
which we identified for this study, makes use of phenonium
ion rearrangement accompanying the electrophilic bromina-
tion in allylbenzenes, Scheme 3. Costa et al.7 reported that
We found that dichloroalkanes as a rule do not produce
the desired dithiaheterocycles. Only benzylic o-bis(chloro-
methyl)benzene gave a relatively good yield of benzodi-
thiepine (8), although the dibromide reacted more efficiently
(Table 1). When we used a mixed bromo-chloro substrate,
1-chloro-3-bromo-2-methylpropane, the intramolecular chlo-
rine displacement step (k2) was slow and the GC-MS analysis
of the reaction mixture showed 3-chloro-2-methyl-1-pro-
panethiol as the principal product. A 1,5-dihalide, â,â′-
dichloroethyl ether, gave 1,4-thioxane, conceivably as a result
of intramolecular cyclization in the intermediate of type B
after thioformaldehyde expulsion.
Scheme 3
The reaction is found to be quite sensitive to steric
impediments. A secondary bromide, 1,3-dibromobutane,
produced 4-methyl-1,3-dithiane in a relatively modest yield
(Table 1). Even reactions of primary 1,3-dibromides targeting
5-substituted 1,3-dithianes required a modification in our
original technique to improve the yield. The less favorable
k2/k3 ratio is probably due to the increased steric repulsion
in the transition state, k2, between the bromine atom (that is
bromination of safrole produced about 35% of the rearranged
1,3-dibromide. Dubois group found that bromination of
allylanisole in chloroform at room temperature produced 48:
52 mixture of the rearranged and the 1,2-adduct.8 We
investigated this reaction further and found that bromination
of p-allylanisole in methylene chloride at -78 °C furnishes
the rearranged 1,3-dibromide 9 almost quantitatively (>10:
(4) One of the possible actual forms of such dithiolate was previously
reported in the inorganic literature as pentasodium tetrakis(dithiomethylene)-
borate, Na5[B(SCH2S)4]: Diamantikos, W.; Heinzelmann, H.; Rath, E.;
Binder, H. Z.. Anorg. Allg. Chem. 1984 517, 111.
(5) We also cannot completely rule out a stepwise mechanism whereby
CS2 is first reduced into dithiaformate anion, which replaces one halogen,
and the resulting dithiaester is then reduced to give A.
(6) Specific details on the malonate-based systems will be reported in
the full paper.
(7) Costa, P. R. R.; Rabi, J. A. Tetrahedron Lett. 1975, 4535.
(8) Fain, D.; Dubois, J.-E. J. Org. Chem. 1982, 47, 4855.
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Org. Lett., Vol. 2, No. 8, 2000

1), which we used without additional purification in the next
step to synthesize dithiane 10, Scheme 3.9 The rearranged
1,3-dibromide is a kinetic product of allylanisole bromination.
It is known that upon equilibration at elevated temperatures
and in the presence of Lewis acids it slowly interconverts
into the 1,2-adduct with the equilibrium constant, K ) 10.1,
favoring the 1,2-adduct.8 At room temperature and in the
absence of Lewis acids, however, the 1,3-dibromide 9 that
we synthesized did not show any reverse phenonium migra-
tion.
with 1,2-dibromoethane showed 1,3-dithiolane as the major
component of the reaction mixture. It appears, however, that
the dithiolane ring is not stable under reaction conditions,
and the isolated yields of dithiolanes were low.
In conclusion, we have developed a simple and inexpen-
sive experimental procedure for direct transformation of 1,3-
and 1,4-dihalides into 1,3-dithianes and dithiepines via
reductive nucleophilic substitution with CS2 and NaBH4.12
The technique has proven most valuable for the preparation
of 5-substituted 1,3-dithianes.
Allyl methyl sulfide is also known to rearrange quantita-
tively upon bromination.10 Under our reaction conditions, a
mixture of 5-(methylthio)-1,3-dithiane (11) and 4-(methyl-
thiomethyl)-1,3-dithiolane (12) was obtained (Scheme 4).11
Acknowledgment. Support for this research from the
National Science Foundation (CHE-9876389 Career Award)
is gratefully acknowledged.
OL005705K
(10) Bland, J. M.; Stammer, C. H. J. Org. Chem. 1983, 48, 4393.
(11) As identified by GC-MS and NMR of reaction mixture. We failed
to separate the two products; it appears that they interconvert on the slurry
packed silica gel column.
Scheme 4
(12) Dithianes and dithiapines synthesized in the present work via
reductive nucleophilic substitution were previously described in the literature
(see below). We characterized them by 1H NMR, 13C NMR, and mass
spectroscopy: (a) 1,3-dithiane (2): 1H NMR (400 MHz, CDCl3, δ) 3.79
(s, 2H), 2.86-2.81 (m, 4H), 2.12-2.04 (m, 2H); MS (m/z) 120 (M+ , 100%),
105, 92, 87, 78, 74, 64, 59, 55, 51. (b) 4-methyl-1,3-dithiane (4):1H NMR
(400 MHz, CDCl3, δ) 4.08 (d, 1H, J ) 14.04 Hz), 3.53 (d, 1H, J ) 14.10
Hz), 2.94-2.84 (m, 3H), 2.19-2.11 (m, 1H), 1.78-1.72 (m, 1H), 1.22 (d,
3H, J ) 6.92 Hz); MS (m/z) 134 (M+ , 100%), 119, 106, 101, 87, 78, 73,
60, 55. (c) 1,3-dithiepane (6): 1H NMR (400 MHz, CDCl3,δ) 3.99 (s, 2H),
2.86-2.81 (m, 4H), 2.03-1.97 (m, 4H); 13C NMR (CDCl3, δ) 36.812 (CH2),
32.543 (CH2), 31.573 (CH2); MS (m/z) 134 (M+), 87 (100%), 78, 74, 60,
55, 51. (d) 1,5-dihydrobenzo[e]-1,3-dithiepine (8): 1H NMR (400 MHz,
CDCl3,δ) 7.27-7.16 (m, 4H), 4.00 (s, 4H), 3.93 (s, 2H); 13C NMR (CDCl3,
δ) 138.408 (C), 129.101(CH), 127.830 (CH), 38.480 (CH2), 36.542(CH2);
MS(m/z) 182 (M+), 135 (100%), 104, 97, 78, 63, 51. (1) Compounds 2, 4,
6, 8, 10 are described in (a) 1,3-dithiane (2): the material we obtained was
identical with the authentic sample from Aldrich.1,3-dithiepane. (b)
4-Methyl-1,3-dithiane (4): Bulman Page, P. C. Klair, S. S.; Brown, M. P.;
Smith, C. S.; Maginn, S. J.; Mulley, S. Tetrahedron, 1992, 48, 5933. (c)
1,3-Dithiepane (6): Semmelhack, C. L.; Chiu, I.-C.; Grohmann, K. G. J.
Am. Chem. Soc. 1976, 98, 2005. (d) 1,5-Dihydrobenzo[e]-1,3-dithiepine
(8): Sauriol-Lord, F.; St-Jacques, M. Can. J. Chem. 1979, 57, 3221.
Smolinski, S.; Balazy, M.; Iwamura, H.; Sugawara, T.; Kawada, Y.;
Iwamura, M. Bull. Chem. Soc. Jpn. 1982, 55, 1106. (e) 5-(4-Methoxy-
phenyl)-1,3-dithiane (10): Yuichiro, H.; Nasato, N. Liq. Cryst. 1997, 23,
263.
We investigated the synthesis of 1,3-dithiolanes starting
from vicinal dihalogenides. GC-MS analysis of the reaction
(9) Experimental details: 0.257 g (1.7 mmol) of allyl anisole was
dissolved in 15 mL of methylene chloride and cooled to -78 °C. 0.278 g
(1.7 mmol) of bromine in 5 mL of methylene chloride was added dropwise
upon stirring. The reaction was allowed to warm to room temperature, the
solvent was removed, and the residue was dissolved in 3 mL of triglyme
and cooled to 0 °C. To this solution was added 0.197 g (5.2 mmol) of
sodium borohydride followed by 0.198 g (2.6 mmol) of CS2. The reaction
turned yellow instantaneously. The reaction was stirred overnight at room
temperature, at which point it was diluted with aqueous ammonium chloride,
extracted with ether (3 × 10 mL), washed twice with brine, and dried over
sodium sulfate. The solvent was removed, and the residue was column
chromatographed (silica gel, 1: 20 ethyl acetate-hexane) to give 0.235 g
(13) General Experimental Procedure in THF. A 20 mL solution of
5 mmol of dihalide and 7.5 mmol of CS2 in dry THF was added at room
temperature to a slurry of 15 mmol of sodium borohydride in 10 mL of
THF, and the resulting solution was refluxed overnight. The reaction mixture
was then worked-up with aqueous ammonium chloride, extracted with ether,
and dried over sodium sulfate. The solvent was removed and the product
purified by column chromatography (4, 6, 8, silica gel, ethyl acetate-hexane,
1:20) or recrystallization from methanol (2).
1
(61% over two steps) of white solid (10). H NMR (400 MHz, CDCl3,δ)
7.1 (d, 2H, J ) 8.06 Hz), 6.85 (d, 2H, J ) 8.06 Hz), 4.08 (d, 1H, J ) 13.9
Hz), 3.78 (s, 3H), 3.44 (d, 1H, J ) 13.9 Hz), 3.16-2.95 (m, 3H), 2.78 (d,
2H, J ) 13.9 Hz); 13C NMR (CDCl3, δ, DEPT-assignments) 158.245 (C),
137.349 (C), 127.355 (CH), 113.947 (CH), 55.233 (CH3), 42.935 (CH),
35.884 (CH2), 31.118 (CH2) MS (m/z) 226 (M+), 180, 179, 165, 164, 148,
134 (100%), 121, 119, 91, 77, 65, 51.
Org. Lett., Vol. 2, No. 8, 2000
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