Facile synthesis and unusual methanesulfonylation reaction of (2R,3R)-1,4-dimethoxy-1,1,4,4-tetrasubstituted-2,3-butanediols

Article abstract of DOI:10.1080/00397910701462153

A facile method for the synthesis of (2R,3R)-1,4-dimethoxy-1,1,4,4- tetrasubstituted-2,3-butanediols involving oxidative cleavage of benzylidene acetal as a key step is described. These sterically hindered diols unusually formed cyclic sulfites as the major product under methanesulfonylation reaction conditions. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701462153

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Facile Synthesis and Unusual
Methanesulfonylation Reaction of
(2R,3R)‐1,4‐Dimethoxy‐1,1,4,4‐tetrasubstituted‐2
Sankareswaran Srimurugan a , Paulsamy Suresh a , Balasubramanian
Viswanathan a & Thirukkallam Kanthadai Varadarajan a
a Department of Chemistry , Indian Institute of Technology Madras ,
Chennai, India
Published online: 09 Aug 2007.
To cite this article: Sankareswaran Srimurugan , Paulsamy Suresh , Balasubramanian Viswanathan &
Thirukkallam Kanthadai Varadarajan (2007) Facile Synthesis and Unusual Methanesulfonylation Reaction
of (2R,3R)‐1,4‐Dimethoxy‐1,1,4,4‐tetrasubstituted‐2,3‐butanediols, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:15, 2483-2490, DOI:
10.1080/00397910701462153
To link to this article: http://dx.doi.org/10.1080/00397910701462153
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Synthetic Communicationsw, 37: 2483–2490, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701462153
Facile Synthesis and Unusual
Methanesulfonylation Reaction of
(2R,3R)-1,4-Dimethoxy-1,1,4,4-
tetrasubstituted-2,3-butanediols
Sankareswaran Srimurugan, Paulsamy Suresh,
Balasubramanian Viswanathan, and
Thirukkallam Kanthadai Varadarajan
Department of Chemistry, Indian Institute of Technology Madras,
Chennai, India
Abstract: A facile method for the synthesis of (2R,3R)-1,4-dimethoxy-1,1,4,4-tetra-
substituted-2,3-butanediols involving oxidative cleavage of benzylidene acetal as a
key step is described. These sterically hindered diols unusually formed cyclic
sulfites as the major product under methanesulfonylation reaction conditions.
Keywords: chiral diols, cyclic sulfate, hydroxybenzoate esters, oxidative cleavage,
steric hindrance
Methanesulfonylation of alcohols is one of the most frequently used reactions in
organic synthesis, in particular for converting primary and secondary alcohols
into a better leaving group. Similarly, under identical reaction conditions,
diols form dimethanesulfonates (dimesylates). Olefins are formed during metha-
nesulfonylation of tertiary alcohols. Sterically hindered alcohols are generally
inert under the reaction condition,[1] and in some cases, it leads to unusual
reaction products. Srikrishna and Gharpure[2] reported the formation of chloro-
methanesulfinates as major products instead of the usual mesylates in the
Received December 8, 2006
Address correspondence to Balasubramanian Viswanathan, Department of
Chemistry, Indian Institute of Technology Madras, Chennai 600 036, India. E-mail:
bvnathan@iitm.ac.in
2483

2484
S. Srimurugan et al.
methanesulfonylationof sterically hindered secondary and primary alcohols. In a
similar way, Zhang and coworkers[3] reported the unusual formation of cyclic
sulfite in the methanesulfonylation of vicinal syn diols of taxane. As an
extension of our earlier work on chiral macrocyclic Schiff bases,[4] an attempt
was made to synthesize macrocycles possessing sterically hindered and
tunable diamine components derived from (2R,3R)-1,4-dimethoxy-1,1,4,4-tetra-
substituted-2,3-butanediols (9–12). The diols (9–12) were synthesized from
various hydroxy-protected precursors derived from L(þ)-tartaric acid. The
protected diol precursors are usually acid sensitive and hence their acid-
catalyzed deprotection is unfavorable because of the unwanted side reactions.
Except for the synthesis of (2R,3R)-1,4-dimethoxy-1,1,4,4-tetramethyl-2,3-buta-
nediol 9 in moderate yield by acid hydrolysis of the isopropylidene-protected
precursor,[5] the method is not applicable for the synthesis of diols (10–12)
with alkyl (higher than methyl) or aryl groups. The other general procedures
followed in the literature for the synthesis of these acid-labile diols are (i) the
oxidative cleavage of para-methoxybenzylidene acetal using 2,3-dicyano-5,6-
dichloro-parabenzoquinone (DDQ) followed by reduction using LiAlH4[6] and
(ii) high-pressure catalytic hydrogenation of benzylidene acetal.[7] Though ben-
zylidene acetal protection can be done easily with cheap and readily available
benzaldehyde in the presence of acid, para-methoxybenzylidene protection
requires the use of costly anisaldehyde dimethyl acetal and requires costlier
DDQ for oxidative cleavage. Therefore, a simple and cheap method for the
synthesis of (2R,3R)-1,4-dimethoxy-1,1,4,4-tetrasubstituted-2,3-butanediols,
which are also starting materials for the synthesis of chiral ligands[8] in asym-
metric transformations, is needed.
In this communication, we describe a general and facile synthesis of
(2R,3R)-1,4-dimethoxy-1,1,4,4-tetrasubstituted-2,3-butanediols (9–12) in
good yields and their unusual formation of cyclic sulfites as the only
product under methanesulfonylation reaction conditions.
The transformation of benzylidene acetals to hydroxy esters by oxidative
cleavage is an important reaction because of the easy synthesis of the benzy-
lidene acetals and desymmetrization of symmetric diols. A number of reagent
systems were reported to be effective for this transformation; however, the
synthetic application of the reaction is not fully explored. An interesting
approach for the cleavage of benzyl ethers and oxidative cleavage of benzyli-
dene acetals in carbohydrate systems using NaBrO3-Na2S2O4 was reported by
Adinolfi and coworkers.[9]
The synthetic application of this reagent system is extended for oxidative
cleavage of different benzylidene acetals of (2R,3R)-1,4-dimethoxy-1,1,4,4-
tetrasubstituted-2,3-butanediols (Scheme 1). Treatment of benzylidene
acetals (1–4) with NaBrO3-Na2S2O4 in ethylacetate–water biphasic
medium for a period of 1 h afforded the hydroxy benzoate esters (5–8) in
good yields (70–78%) as tabulated in Table 1. LiAlH4 reduction of
these hydroxybenzoate esters afforded the diols (9–12) in quantitative
yield. The method applies for facile synthesis of several derivatives of

Unusual Methanesulfonylation
2485
Scheme 1. Synthesis of (2R,3R)-1,4-dimethoxy-1,1,4,4-tetrasubstituted-2,3-butane-
diols by oxidative cleavage of benzylidene acetal.
(2R,3R)-1,4-dimethoxy-1,1,4,4-tetrasubstituted-2,3-butanediols
involving
neutral reaction conditions, short reaction times, and cheap reagents.
In addition to the two-step process described previously, diol 9 is also
synthesized in one step from the methoxymethyl (MOM)-protected derivative
13 under acid hydrolysis. Acid-catalyzed hydrolysis of 13 gave diol 9 and triol
14 as the major products under different reaction conditions. Hydrolysis of 13
in the presence of pTSA in aqueous methanol at reflux temperature for 24 h
gave the liquid diol 9 in moderate yield (63%). The reaction did not
proceed to completion even after prolonged heating. The use of stronger
acid, however, gave different products. Treatment of 13 with amberlyst-15
ion exchange resin in methanol at room temperature for 2.5 h gave the triol
14 in 66% yield (Scheme 2).
The synthesis of (2R,3R)-1,4-dimethoxy-1,1,4,4-tetrasubstituted-2,3-
diaminobutane was then attempted by transforming the diols (9–12) into cor-
responding dimesylates. However, we observed that the methanesulfonylation
reaction (for example, in the case of (2R,3R)-1,4-dimethoxy-1,1,4,4-tetra-
methyl-2,3-butanediol 9) produced a liquid product in 63% yield whose
NMR spectrum did not show any signals due to CH3-group of the dimesylate
around 3.00 ppm. However, the IR spectrum of the product showed a strong
stretching around 1370 cm21, which is clearly due to a S-O stretching, indicat-
ing the presence of an -S55O or -SO2- moiety in the structure, and the absence
of O-H stretching frequency around 3400 cm21, indicating the absence of
1
free -OH group in the molecule. The H NMR spectrum of the unknown
compound displayed two sets of signals in a 1:1 ratio. Similarly, nine
carbon signals were observed in 13C NMR spectrum. ESI-MS spectrum of
the unknown compound did not display any peak due to dimesylate. On the
other hand, the spectrum had predominant peaks at m/z 275 and 253, which
correspond to the sodium and proton adducts of a compound with a
molecular weight of m/z 252. The spectral data predicted the structure of
the unknown compound as the cyclic sulfite 15 of diol 9 (Scheme 3). Such
a structure will have a molecular weight of m/z 252 and explains the
1
observed spectral data. In the case of H and 13C NMR, the appearance of

2486
S. Srimurugan et al.
Table 1. Yields of hydroxybenzoate esters obtained by oxidative cleavage of
benzylidene acetals
Benzylidene acetal
Hydroxybenzoate ester
Yield (%)
74
70
72
75
Scheme 2. Synthesis of diol 9 and triol 14 by acid hydrolysis of 13.

Unusual Methanesulfonylation
2487
Scheme 3. Unusual formation of cyclic sulfite 15 from (2R,3R)-1,4-dimethoxy-
1,1,4,4-tetramethyl-2,3-butanediol 9.
two sets of signals was due to the existence of diastereomeric cyclic sulfite
structures in a 1:1 ratio as a result of the stereogenic nature of the sulfur
atom in cyclic sulfite. The formation of cyclic sulfite 15 was chemically
proved by oxidizing it to the corresponding cyclic sulfate 16.[10] The
reaction was facile, and the sulfate was isolated in more than 90% yield.
Because the lone pair of electrons in the cyclic sulfite 15 is replaced by the
second oxygen atom, the cyclic sulfate 16 could no longer be a diastereomeric
1
structure. The H and 13C NMR spectra of the cyclic sulfate 16 displayed a
single set of NMR signals, indicating a symmetrical structure. ESI-MS
spectrum of cyclic sulfate showed a peak due to sodium adduct of the
molecular ion at m/z 291. The cyclic sulfite formed from SOCl2 and diol 9
in the presence of triethylamine[11] displayed identical spectral features as
those of cyclic sulfite 15, supporting the unusual formation of cyclic sulfite
as the only product from 9 under methanesulfonylation reaction conditions.
The generality of unusual formation of cyclic sulfite by methanesulfony-
lation of diol 9 was verified with other structurally related diols, (2R,3R)-
1,4-dimethoxy-1,1,4,4-tetrasubstituted-2,3-butanediols (10–12). In all the
cases, cyclic sulfite (19–21) was formed as the major product and no dime-
sylate was observed. The use of structurally related steric-free diol 17
produced the expected dimesylate 18 in 85% yield (Table 2, entry 1) with
no observable traces of cyclic sulfite, indicating the influence of steric
crowding around the hydroxy groups in the unusual formation of cyclic
sulfites. The yields of cyclic sulfites obtained from different diols are
given in Table 2.
In conclusion, a general method for the synthesis of (2R,3R)-1,4-
dimethoxy-1,1,4,4-tetrasubstituted-2,3-butanediols
involving
oxidative
cleavage of benzylidene acetal as a key step followed by the reduction of
hydroxybenzoate esters has been described. The method is facile, uses
cheap reagents, and avoids high-pressure hydrogenation and synthesis of
corresponding para-methoxybenzylidene acetal. The unusual methanesulfon-
ylation reaction of (2R,3R)-1,4-dimethoxy-1,1,4,4-tetramethyl-2,3-butanediol
leading to cyclic sulfite is found to be a general reaction in the case of
these sterically hindered diols. In all the substrates screened, the cyclic
sulfites were formed in good yields with no trace of the usual dimesylate
poduct.

2488
S. Srimurugan et al.
Table 2. Yields of cyclic sulfite obtained by methanesulfonylation of (2R,3R)-1,4-
dimethoxy-1,1,4,4-tetrasubstituted-2,3-butanediols
(2R,3R)-1,4-Dimethoxy-1,1,4,4-
tetrasubstituted-2,3-butanediol
Cyclic sulfite
Yield (%)
85
63
56
69
62
TYPICAL EXPERIMENTAL PROCEDURE
To a stirred solution of (2R,3R)-1,4-dimethoxy-1,1,4,4-tetramethyl-2,3-buta-
nediol 9 (150 mg, 0.73 mmol) in dry CH2Cl2 (4 mL) at 08C, Et3N (221 mg,
2.19 mmol) was added dry at the same temperature, and the resulting
solution was stirred for 30 min. Methanesulfonyl chloride (209 mg,
1.82 mmol) was added dropwise for 10 min at the same temperature, and
the solution was allowed to warm to room temperature in 1 h. Water (5 mL)
was added, and the solution was extracted three times with CH2Cl2

Unusual Methanesulfonylation
2489
(3 ꢀ 5 mL). The combined organic extracts were dried over anhydrous
Na2SO4 and concentrated to yield the crude product, which was purified by
column chromatography over silica gel using 10% EtOAc in hexane to
yield cyclic sulfite 15 as a colorless oil (116 mg, 63%). [a]2D8 ¼ 2126
1
(c 1.40, CHCl3); IR (neat) n 2980, 2942, 1466, 1370, 1218 cm21; H NMR
(CDCl3): d 1.08 (s, 3H), 1.15 (s, 3H), 1.22 (s, 3H), 1.23 (s, 3H), 3.15
(s, 3H), 3.18 (s, 3H), 4.35–4.36 (d, J ¼ 2.61 Hz, 1H), 4.60–4.61
(d, J ¼ 2.68 Hz, 1H); 13C NMR (CDCl3): d 19.1, 19.9, 20.3, 22.1, 49.6,
75.0, 75.3, 87.4, 89.1; ESI-MS: m/z 253 ([M þ H]þ), 275 ([M þ Na]þ).
Cyclic sulfite 19: colorless oil; yield 56%; [a]2D8 ¼ 2157 (c 1.27, CH2Cl2);
1
IR (neat) n 2981, 2940, 1493, 1447, 1373, 1238 cm21; H NMR (CDCl3): d
2.57 (s, 3H), 2.92 (s, 3H), 5.46–5.47 (d, J ¼ 2.61 Hz, 1H), 5.79–5.80
(d, J ¼ 2.68 Hz, 1H), 7.17–7.38 (m, 20H); 13C NMR (CDCl3): d 52.0, 53.4,
83.5, 84.4, 84.5, 86.3, 127.4, 127.7, 127.8, 127.9, 128.0, 128.1, 129.2,
129.4, 129.6, 130.4, 137.9, 138.6, 139.6, 139.9, 140.6; ESI-MS: m/z 523
([M þ Na]þ). Cyclic sulfite 20: colorless oil; yield 69%; [a]2D8 ¼ 2115
1
(c 1.48, CH2Cl2); IR (neat) n 2955, 2828, 1473, 1375, 1219 cm21; H NMR
(CDCl3): d 0.83–0.93 (m, 12H), 1.44–1.81 (m, 8H), 3.19 (s, 3H), 3.20
(s, 3H), 4.61–4.62 (d, J ¼ 2.9 Hz, 1H), 4.92–4.93 (d, J ¼ 2.9 Hz, 1H);
13C NMR (CDCl3): d 6.9, 7.4, 7.7, 8.0, 23.4, 24.1, 24.9, 26.4, 50.2, 50.7,
78.0, 79.0, 84.4, 85.8; ESI-MS: m/z 331 ([M þ Na]þ). Cyclic sulfite 21:
colorless oil; yield 62%; [a]D28 ¼ 262 (c 2.51, CH2Cl2); IR (neat) n 2947,
1
1456, 1375, 1238, 1224 cm21; H NMR (CDCl3): d 1.58–1.74 (m, 14H),
1.82–1.87 (m, 2H), 2.03–2.04 (m, 2H), 3.18 (s, 3H), 3.19 (s, 3H), 4.57–
4.58 (d, J ¼ 3.6 Hz, 1H), 4.72–4.73 (d, J ¼ 3.6 Hz, 1H); 13C NMR
(CDCl3): d 24.4, 24.5, 24.6, 24.7, 31.3, 31.4, 31.5, 31.9, 50.4, 50.6, 85.6,
86.9, 87.3, 88.0. ESI-MS: m/z 327 ([M þ Na]þ).
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