Cyanuric chloride/sodium borohydride: A new reagent combination for reductive opening of 4,6-benzylidene acetals of carbohydrates to primary alcohols

Article abstract of DOI:10.1016/j.carres.2013.09.003

In the first such example, NaBH₄ in combination with cyanuric chloride (TCT) has been used to obtain 6-hydroxy-4-benzyl ether derivatives from 4,6-benzylidene acetals of carbohydrates. The nature of hydride donor determines the regioselectivity

Full text of DOI:10.1016/j.carres.2013.09.003

Accepted Manuscript
Note
Cyanuric chloride/sodium borohydride: a new reagent combination for reduc‐
tive opening of 4,6-benzylidene acetals of carbohydrates to primary alcohols
Madhubabu Tatina, Syed Khalid Yousuf, Subramanya Aravinda, Baldev Singh,
Debaraj Mukherjee
PII:
S0008-6215(13)00346-7
DOI:
http://dx.doi.org/10.1016/j.carres.2013.09.003
CAR 6573
Reference:
To appear in:
Carbohydrate Research
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Cyanuric chloride/Sodium borohydride: A new reagent combination for
reductive opening of 4,6-benzylidene acetals of carbohydrates to primary
alcohols
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Madhubabu Tatina,1,2 Syed Khalid Yousuf,*3 Subramanya Aravinda,4 Baldev Singh,2 and
Debaraj Mukherjee*1,2
1Academy of Scientific and Innovative Research, 2CSIR-IIIM Jammu Natural Product
Chemistry Division, 3 CSIR-IIIM Jammu Medicinal Chemistry Division (Srinagar), 4CSIR-
IIIM Jammu Medicinal chemistry Division
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 Corresponding author. Tel.: +91-191-2569000; fax: +91-191-2569111. Email: debaraj@iiim.ac.in, khalidiiim@gmail.com
Abstract
In the first such example, NaBH4 in combination with cyanuric chloride (TCT) has been used
to obtain 6-hydroxy-4-benzyl ether derivatives from 4,6-benzylidene acetals of
carbohydrates. The nature of hydride donor determines the regioselectivity of acetal opening.
High regioselectivity, scope for using a broad range of substrates, functional group tolerance,
mild reaction conditions, easy handling process, inexpensive reagents and wide application
mark the benefits of the newly developed reagent system.
Keywords
Benzylidene derivative reductive opening, Sodium borohydride, TCT, Primary OH
Success story of glycobiology is largely sustained by rapid progress in
glycochemistry.1 The glycochemical assembly of oligosaccharides from monosaccharide
building blocks often requires orthogonally protected donors or acceptors due to the presence
of several hydroxyl groups. Protection of a pair of appropriately oriented 1,3 and also 1,2
hydroxy groups as the O-benzylidene acetal2 is one of the most frequently used reactions in
glycochemistry.3 This is because the acetals are highly stable under alkaline/basic conditions
and their removal can be achieved at will using acidic reagents. These derivatives are
therefore extremely useful in multi-step synthetic operations involving such substrates. A
plethora of methods are available for regioselective opening of benzylidene acetals, but only
a few of these are widely used.4 In general Lewis acids such as AlCl3,5 BF3.Et2O,6 or
triflates6-8 have been used in combination with hydrides such as BH3.THF,6-8 LAH,9 and
DIBAL-H10 to open the benzylidene acetals towards primary alcohol. The reagent
combinations used are mostly moisture sensitive (AlCl3 or BF3.Et2O, triflates), expensive
(metal triflates), lacking in functional group tolerance such as ester and amides (LAH,

DIBAL-H), unstable at room temperature (BH3.THF needs additive), or dependent on the
nature of the protective group4 at C3 and often lead to complete hydrolysis of the acetal ring
as a major side reaction.
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O
BnO
HO
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TCT
(PG)n
II
NaCNBH3
[Ref11]
O
I
Our previous work
O
Ph
O
(PG)n
O
H
TCT
HO
BnO
?
(PG)n
III
Current work
Fig 1: Cyanuric chloride (TCT) catalysed regioselective reductive ring opening of
benzylidene acetals I to give primary alcohols II or secondary alcohols III
The use of harsh reaction conditions and environmentally hazardous expensive reagents
always demand the development of new acid/reducing agent combinations. In continuation of
our recent success in the regioselective benzylidene ring opening to afford secondary OH,11
herein we present sodium borohydride in conjunction with cyanuric chloride [commercially
known as 2,4,6-trichloro-1,3,5-triazene (TCT)] as an efficient, mild and inexpensive reagent
combination for regioselective benzylidene ring opening towards primary OH. In order to
find out the appropriate reducing agent which can work in combination with TCT to give
reverse
regioselectivity,
we
took
2,3-di-O-acetyl-4,6-O-benzylidene-methyl--D-
glucopyranoside as model substrate. A number of reducing agents were applied at room
temperature under the condition optimized by us in our previous communication11 (see SI,
table 1). Depending on hydride donor and solvent, we initially obtained three products,
namely 2, 3, and 4 (scheme 1). Reducing agents Et3SiH and DIBAL-H gave only the 4-OH
product in moderate to low yield (SI, Table1 entries 2, 3). LiAlH4 and NaB(OAc)3H failed to
give any desired product at room temperature even after prolonged reaction time (SI, Table 1,
entries 4a, 5), though heating the reaction mixture to reflux with LAH yielded the
corresponding 4,6-diol 2 exclusively (SI, Table 1 entry 4b).

1
2
3
4
5
6
7
8
OH
TCT (8 equiv.)
Reducing agent
OH
OBn
O
Ph
O
O
O
O
O
BnO
AcO
HO
AcO
HO
AcO
AcO
Solvent, 0 °C to rt
OAc
AcO
AcO
AcO
OMe
OMe
OMe
1
OMe
2
4
3
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Scheme 1: Opening of 4,6-O-benzylidene acetal in presence of TCT and different hydride
donors (SI table1)
We then became interested to examine the fate of benzylidene derivative 1 using NaBH4 and
TCT in acetonitrile. To the best of our knowledge, there is no report of benzylidene ring
opening using NaBH4 as reducing agent. But we were delighted to see the complete
consumption of the starting material 1 with formation of a new spot in TLC, Rf value of
which was different from those of the products 2 and 3 (scheme 2). The structure of the
product was assigned as 412 on the basis of 1H and 13C NMR.
OH
TCT (8 equiv)
O
Ph
O
NaBH4 (10 equiv)
O
BnO
AcO
O
AcO
AcO
CH3CN, 0 °C to rt, 92%
OAc
OMe
OMe
4
1
Scheme 2: Opening of 4,6-O-benzylidene acetal to obtain 6-OH exclusively under
TCT/NaBH4 condition
Acetonitrile was found to be the best solvent for this transformation. Employment of other
nonprotic solvents like DCM or THF (SI, table 1 entries 8, 9) failed to give the desired
product in satisfactory yield, whereas a protic solvent such as MeOH led to the completely
hydrolyzed product (2). The fact that NaBH4 has not been utilised earlier for benzylidene
opening led us to study the fate of 1 with NaBH4 along with other Lewis or Bronsted acids
(SI, Table2). Except dry HCl (SI, table 2, entry 15) all other acids failed to give satisfactory
yield. However, TBS and other acid sensitive protecting groups are susceptible to cleavage in
presence of dry HCl, which restricts its use.

Table 1: Substrate scope of the TCT/NaBH4 mediated benzylidene ring opening
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Entry
Substrate
Product
Yield %(ref)
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5
6
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8
9
412
1
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2
92
87
OH
O
PMBO
AcO
OAc
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614
OMe
OH
O
Ph
O
O
O
BnO
BzO
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4
85
92
BzO
OBz
7
OBz
OMe
87
OH
OMe
O
Ph
O
O
O
BnO
BnO
BnO
OBn
9
OBn
107
OH
OMe
OMe
O
Ph
O
O
O
BnO
PivO
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6
86
88
PivO
OAc
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12
OAc
OMe
OMe
OH
O
Ph
O
O
O
BnO
TBSO
TBSO
TBSO
TBSO
13
14
OMe
STol
OMe
OH
O
Ph
O
O
O
BnO
AcO
AcO
O
STol
N
N
O
7
89
O
O
15
1613
HO
BnO
O
Ph
O
O
OBz
O
OBz
8
9
80
92
BzO
BzO
N3
N3
17
187
OH
OAc
O
O
O
AcO
Ph
OAc
O
BnO
AcO
19
20
OMe
OMe
Ph
O
OBn
OH
O
O
90
SPh
O
AcO
10
22
SPh
OAc
AcO
OAc
21
Ph
O
H
O
OBn OH
11
12
85d
87d
2415
23
OBn
OH
2616
aIn all cases standardised reaction conditions, i.e., 8 equiv. of TCT and 10 equiv. of NaBH4 were used per equiv.
substrate in 5 mL of solvent and the reactions were complete in 8 h. bCharacterised through spectroscopic analysis.
cIsolated yield after column chromatography. dReactions were complete in 3.5 h.

With this newly developed efficient reaction condition (table 1, entry 1) for the
regioselective 4,6-O-benzylidene cleavage in our hand, we next studied the substrate scope of
the reaction. The mildness of the reaction conditions is obvious from the first experiment
with the acetylated benzylidene derivative (table 1, entry 1). A series of 4,6-O-benzylidene
protected glucosides (table 1, entries 2-8) were subjected to acetal ring opening using the
optimised reaction conditions. The reactions proceeded smoothly leading to the formation of
6-OH in a regioselective manner without formation of the other regioisomer, i.e., 4-OH.
Advantage of our reagent system over LiAlH4-AlCl3 system is that irrespective of the nature
of protective group at C3 (OBn, OBz, OPiv, OTBDMS), the former gives O6-opened product
exclusively (table 1, entries 2-8).4 The survival of pivaloyl and silyl protecting groups
constitutes an added advantage of the present process as the products can be used as
monosaccharide building blocks for other transformations. In case of D-glucosamine and 2-
azido derivatives 15 and 17, the desired 6-OH products were obtained in good yields.
Similarly, D-manno derivative 19 and D-galacto derivative 21 also afforded the corresponding
products in good to excellent yields in a regiospecific manner. After getting encouraging
results from carbohydrate derivatives, we next applied our reagent system for non-
carbohydrate substrates 23 and 25. Both these acetals underwent facile ring opening to
provide primary –OH group without formation of the other regioisomer.
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In summary, TCT/NaBH4 has proven to be a mild, inexpensive, nontoxic, functional group
tolerant and environmentally benign reagent system for the generation of orthogonally
protected monosaccharide units. The high regioselectivity and substrate diversity add to the
advantages of the current methodology over the already existing ones. It is now obvious that
TCT can serve as a switchable catalyst for the generation of 6-OH and 4-OH in benzylidene
acetal opening based on the type of reducing agent used. The applicability of the reagent
system to non-sugar derivatives is another merit of the process. Finally, this is the first report
of use of NaBH4 for benzylidene ring opening.
1. Experimental section
General procedure for 4,6-O-arylidene ring opening using TCT/NaBH4 (1).
To solution of benzylidene acetal (1 mmol) in acetonitrile (10 mL) at 0 °C was added NaBH4
(10 equiv, 380 mg) and allowed to stir for 5 min. Then TCT (8 equiv, 1.47 g) was added to
the mixture. After stirring for the required time, the reaction was quenched by the addition of

ethyl acetate (5 mL). The mixture was filtered through a small pad of celite using ethyl
acetate (10 mL × 4) as eluent. The filtrate was concentrated at reduced pressure to yield the
crude product. The residue was purified by flash column chromatography on silica gel to give
the corresponding products.
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1.1. Methyl 2,3-di-O-acetyl-4-O-benzyl--D-mannopyranoside (20).
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Prepared by the general procedure 1 using 19 (368 mg, 1mmol) and column chromatography
on silica gel (20% EtOAc/hexane then 30% EtOAc/hexane) to afford 20 as gum in 92% (338
mg) yield. Rf = 0.38 (40% EtOAc/hexane); []D = +29.0 (c = 1.0, CHCl3); IR (CHCl3) ῡ
3476, 1749, 1368, 1244, 1224, 1083 cm-1; 1H NMR (CDCl3, 400 MHz)  7.35-7.26 (m, 5H),
5.34 (dd, J = 3.6, 10.0 Hz,1H), 5.24 (dd J = 2.0, 3.2 Hz, 1H), 4.71-4.63 (m, 3H), 3.92 (t, J =
10.0 Hz, 2H), 3.84-3.78 (m, 1H), 3.75-3.71 (m, 1H), 3.36 (s, 3H, OMe), 2.09 (s, 3H, OAc),
13
1.98 (s, 3H, OAc); C NMR (CDCl3, 125 MHz) 170.0, 169.8, 137.8, 128.5, 128.4, 127.8,
127.6, 127.6, 98.5, 74.8, 72.5, 71.6, 71.5, 69.9, 61.6 ,55.0, 20.8, 20.8; HRMS (ESI+) m/z
calcd for C18H24NaO8 (M+Na)+ 391.1369, found 391.1358.
Acknowledgments
Authors are thankful to Dr. Ram A Vishwakarma, Director IIIM Jammu and DST (GAP
1145) for generous funding along with fellowship under INSPIRE Faculty scheme (IFA-CH-
18). TMB thanks CSIR-New Delhi for a junior research fellowship.
Supplementary material
1
Copies of H and 13C NMR, 2D spectra of selected compounds and HRMS files. This
material is available free of charge via the Internet at http://--- /."
References and notes
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Cummings, J. D. Esko, H. H. Freeze, P. Stanley, C. R. Bertozzi, G. W. Hart and M.
E. Etzler, Cold Spring Harbor, New York, 2nd edn, 2008, pp 75–88; For recent
review articles, see: (b) Hart, G. W.; Copeland, R. J. Cell 2010, 143, 672-676; (c)
Galonić, D. P.; Gin, D.Y. Nature 2007, 446, 1000-1007.
2. (a) Masahiro, S.; Hiroshi, H. Tetrahedron Lett. 2000, 41, 5547-5551; (b) Katsuhiko,
S.; Hisato, N.; Masanori, Y. Tetrahedron Lett. 2003, 44, 1975-1977; c) Daniel,
B.W.; Heiko, S.; Tietze, L. F. Synlett 2008, 13, 1969-1972.

3. Wang, C.-C.; Lee, J.-C.; Luo, S.-Y.; Kulkarni, S. S.; Huang, Y.-W.; Lee, C.-C.;
Chang, K.-L.; Hung, S.-C. Nature 2007, 446, 896-899 and references cited therein.
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1496-1499.

Cyanuric Chloride/sodiumborohydride: A new reagent combination for
reductive opening of benzylidine acetals
Madhubabu Tatina,1,2 Syed Khalid Yousuf ,*3 S.Aravinda,4 Baldev Singh,2 Anil.K.Tripati,2
and Debaraj Mukherjee *1,2
1Academy of Scientific and Innovative Research, 2CSIR-IIIM jammu Natural product
Chemistry division, 3 CSIR-IIIM Medicinal Chemistry division, Srinagar, 4CSIR-IIIM jammu
Instrumentation division
Ar
Ar
OH O
Cynuric Chloride/NaBH4
CH3CN
O
O
R2
80-92% 00C to rt
R2
R1
R1

Highligts
 First report of benzylidine acetals reductive opening towards 6-OH using cyanuric
chloride/ NaBH4 reagent system.
 Inexpensive reagent, mild reaction condition, high yield with broad functional group
tolerance
 High regioselectivity of reagent system.
 Application to both carbohydrate and non-carbohydrate systems.