Reaction of carbohydrates with Vilsmeier reagent: A tandem selective chloro O-formylation of sugars

Article abstract of DOI:10.1039/b900026g

A convenient and efficient method for selective replacement of the primary hydroxyl groups of sugars by chlorine with concomitant O-formylation, compatible with the presence of a variety of functional groups, has been developed using the Vilsmeier-Haack r

Full text of DOI:10.1039/b900026g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Reaction of carbohydrates with Vilsmeier reagent: a tandem selective chloro
O-formylation of sugars†
Niranjan Thota, Debaraj Mukherjee,* Mallepally Venkat Reddy, Syed Khalid Yousuf, Surrinder Koul* and
Subhash Chandra Taneja
Received 5th January 2009, Accepted 30th January 2009
First published as an Advance Article on the web 13th February 2009
DOI: 10.1039/b900026g
A convenient and efficient method for selective replacement
of the primary hydroxyl groups of sugars by chlorine with
concomitant O-formylation, compatible with the presence
of a variety of functional groups, has been developed using
the Vilsmeier–Haack reaction. Sugars having free primary
hydroxyl groups mostly afforded the chloro-O-formylated
product while sugars devoid of primary hydroxyl groups
yielded only O-formylated products.
such as formyl fluoride,10 formic anhydride,11 acetic–formic
anhydride,12 2-(N-methyl-N-formylamino) pyridine,13 dimethyl-
chloromethyl-ammonium chloride,13 N-formylbenzotriazole,13
N,N-dimethylformamide,14
HCOOH,15
HCOOH–HClO4,16
HCOOH–BF3·MeOH,17 HCOOH–Al(HSO4)3
and chloral–
18
K2CO3 among many others.20–22 Some applications that are
pertinent to synthetic carbohydrate chemistry include the one
step and selective conversion of silyl ethers of sugar derivatives
into their corresponding formates using either PPh3/CBr4
in HCOOEt/H2O23 or Vilsmeier reagent,24 and reaction of
halomethyleniminium salts with various sugar alcohols to afford
formate esters and chlorodeoxy sugars under different sets of
experimental conditions. All these halo and formylating reagents
have their limitations. As a result of the rather harsh experimental
conditions such as medium acidity and higher temperatures
and/or accompanying side reactions such as migration of
isopropylidene rings,9,25,26 none of them has given halo-deoxy
O-formylated sugars exclusively. Moreover, to date there is only
one report of tandem chlorination acetylation of sugar hydroxy
compounds.2,3
19
An efficient protecting group strategy is critical for achieving
the synthesis of useful intermediates in carbohydrate chemistry.1
Development of a strategy wherein more than one useful transfor-
mation can be carried out under the same reaction conditions with-
out adding additional reagents and catalysts makes the process
more advantageous and environmentally benign. In this respect,
synthesis of the terminal chlorodeoxy sugars via direct substitution
of hydroxyl groups by chlorine is of particular interest as they are
in demand as precursors2–5 for the synthesis of deoxy, amino-deoxy
and unsaturated sugars and also as sweetening, anticarcinogenic,
and potential male contraceptive agents. Similarly, O-formylation
could be the method of choice for protecting sugar hydroxyl groups
in a complex synthetic sequence because de-esterification can
be effected selectively in the presence of other ester protecting
groups e.g. a formate ester can be cleaved selectively in the
presence of acetate and/or benzoate even in neutral alcoholic
conditions.6a Further, if the alcohol group is planned to be oxidised
later in a multistep synthetic scheme, the formylated alcohol can
be directly oxidised under Oppenauer conditions.6b Moreover
formate esters can also serve as intermediates for the preparation
of glycopolymers.6c,7
Presently several methods are available for selective
halogenation and O-formylation using different sets of reaction
conditions. Garegg and Samuelsson8 converted 3-hydroxy sugar
derivatives to 3-deoxy-3-iodo sugars using triphenylphosphine,
iodine and imidazole in toluene under reflux conditions, whereas
Hanessian and Plessas9 converted 1,2:5,6-di-O-isopropylidene
D-glucofuranoside to the 6-bromo-6-deoxy derivative by
treatment with N-bromosuccinimide and triphenylphosphine
in N,N-dimethylformamide. Numerous other reagents have
been developed for the O-formylation of sugar hydroxyl groups,
The Vilsmeier–Haack (V–H) reaction (discovered 1927)24 is
recognized as one of the best methods for the direct formylation
of electron-rich aromatic nuclei, enolizable ketones, enol ethers
and other active hydrogen compounds. This reaction continues
to receive wide attention in organic chemistry because of its
simplicity and convenience. However according to our knowl-
edge there is no report to date of one pot chloro-esterification
under Vilsmeier conditions. In continuation of our research
activities directed towards the development of one pot reaction
strategies in carbohydrate chemistry,27,28 we now disclose a novel
method for the tandem one pot selective chloro-O-formylation of
sugars.
We initially chose methyl glucoside 1a as a model in order to
evaluate the efficacy of chloroformylation using halomethyleni-
minium salt under different conditions (Scheme 1). Treatment of
1a with DMF–POCl3 complex (6 eq.) at 0 ◦C–rt indeed proceeded
to completion in 1 h, but afforded a mixture of two products 1b
and 1c in almost equal amounts.
Bio-organic Chemistry Division, Indian Institute of Integrative Medicine
(CSIR), Canal Road, Jammu, India-180001. E-mail: debarajrrl@
gmail.com, surrinderkoul@gmail.com; Fax: +91-191-2569111-333;
Tel: +91-191-2569000-006
Scheme 1
† Electronic supplementary information (ESI) available: Experimental
procedures and characterizations, as well as 1H and 13C NMR spectra
for compounds 1b–3b, 7b, 9b. See DOI: 10.1039/b900026g
Compound 1b was identified as methyl-2,3,4-tri-O-formyl-6-
chloro-6-deoxy-a-D-glucopyranoside on the basis of NMR and
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Table 1 Optimization of reaction conditions for methyl glucoside 1a
Entry
Chlorinating agent
Ratioa
Temp (◦C)
Time (h)
Yieldb (1b)
1
2
3
3
4
5
6
7
8
DMF+POCl3
DMF+POCl3
DMF+POCl3
DMF+POCl3
DMF+POCl3
DMF+SOCl2
DMF+SOCl2
DMF+PhCOCl
DMF+(COCl)2
1:6 eqv
1:6 eqv
0 to rt
0 to rt
0 to rt
0 to 60
rt to 60
0 to rt
rt to 60
rt to 60
rt to 60
0.5
1
1
1
6
6
6
6
6
50
55
70
55
85
45
45
30
50
1:10 eqv
1:6 eqv
1:10 eqv
1:10 eqv
1:10 eqv
1:10 eqv
1:10 eqv
a Ratio between methyl glucoside and V–H-complex. b Yield obtained after column chromatography.
Table 2 Reaction of different sugar derivatives with V–H reagent
Entry
1
Substrate
Producta
Timeb (h)
6
Yield (%)c
85
1a
1b
2
2a
2b
5
83
3
4
3a
3b
4
7
82
78
4a
4b
5
6
5a
5b
4
8
83
82
6af
6b
7
7a
7b
7
72
8
9
8a
8b
5
4
5
5
25d
79
81
77
9a
9b
10
11
10a
10b
11a
11b
12
12a
12b
6
72
13
14
13a
13b
2
1
80e
91e
14a
14b
a Characterized by 1H NMR and 13C NMR (data available). b Total reaction time (sugar:V–H complex, 1:10). c Yield of the chloro-formylated product after
column chromatography. d Performylated product obtained in major amount (65%). e Only performylated products obtained. f SE = 2-(trimethylsilyl)ethyl.
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mass-spectral data. The signals for H-6,6¢ and C-6 in the 1H NMR
and 13C NMR spectra of 1b were shifted upfield compared to
those of the corresponding nuclei in the performylated product
1c thereby indicating the introduction of the chlorine substituent
at position 6. Using different chlorinating agents such as SOCl2,
oxalyl chloride and benzoyl chloride along with DMF at room
temperature failed to improve the yield of 1b. Gratifyingly,
increasing the amount of the Vilsmeier reagent up to 10 equiv.
afforded 1b in 70% yield (entry no. 3, Table 1) but still failed to
ensure the sole formation of 1b.
Conclusions
In conclusion, a method for tandem one pot selective chloro-O-
formylation of sugars has been developed utilizing the Vilsmeier–
Haack reaction conditions. It offers operational simplicity and
proceeds with moderate to high yields. This together with the
enormous importance of the downstream products in the synthesis
of glycopolymers and glycoconjugates establishes the utility of the
method.
To obtain 1b as a sole product, modifications in experimental
conditions were effected such as raising the temperature to
60 ◦C and also allowing more time (6 h) and this afforded
1b in 85% yield along with only a trace amount of 1c. In a
separate control experiment treatment of 1c with DMF–POCl3
complex (6 eq.) at rt indeed afforded 1b almost exclusively sug-
gesting that the latter could be the thermodynamically controlled
product.
Acknowledgements
TN, MVR and SKY are thankful to CSIR New Delhi for
fellowship.
Notes and references
1 A. Lipta´k, A. Borba´s and I. Bajza, Protecting Group Manipulation
in Carbohydrate Synthesis, Comprehensive Glycoscience, Elsevier B. V.,
2007, p. 203.
Having optimized the reaction conditions,29 the scope and
generality of the method was explored. Initially the response
of a free monohydroxyl sugar compound was investigated by
using di-O-isopropylidene-a-D-glucofuranose (Entry 14, Table 2)
which delivered only the O-formylated product. It may be noted
that Hanessian and Plessas4 failed to obtain such a product
while working with dimethylchloroformiminium chloride. Further
studies were performed using different polyhydroxy glycosides
(Entries 1–8, Table 2) which were allowed to react with the V–H
reagent under the optimized conditions and the results are
summarized in Table 2. In all the cases the chloro-formylated prod-
ucts were obtained in good yield except with galactopyranoside
where the O-formylated product was isolated with traces of the
chloro-formylated product 8b. It is noteworthy that the reaction
proceeded smoothly without affecting other protecting groups. In
all the cases chlorination took place selectively at the sterically
less crowded primary hydroxy group of the sugar moiety leaving
the secondary hydroxy groups, perhaps due to easy access of the
bulky chloride ion. The anomalous behaviour of the galactose
derivative can be rationalized as follows. The C6–O bond needs to
be oriented anti to the C5–H for smooth attack by the chloride
ion (Scheme 2). However this conformation is less favoured in the
galactose series (Newman projection-A) than in the glucose series
(Newman projection-B) due to torsional strain involving the axial
C4–OR group in the case of the former. Therefore the galactose
substrate furnishes the performate as the major product. With the
exception of galactosides our results clearly show that compounds
having primary hydroxyl groups afforded the chloro-formylated
product.
2 A. A. Akhrem, G. V. Zaitseva and I. A. Mikhailopulo, Carbohydrate
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29 Typical procedure for chloro-O-formylation: A stirred, cooled DMF
solution of the complex POCI3/DMF (prepared from 1.52 g POCl3, in
5 mL anhydrous DMF, 0 ◦C) was added dropwise to a cold solution of
a-D-methyl-glucopyranoside (0.2 g, 1.0 mmol in 10 mL DMF) under
an inert atmosphere. The mixture was then agitated at 60 ◦C and the
reaction monitored by TLC. After completion of the reaction (reaction
Scheme 2
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time given in table-2) the contents were treated with saturated NaHCO3
solution (30 mL), then extracted with solvent ether (4 ¥ 30 mL), the
organic solvent was evaporated, and the crude product was purified by
column chromatography over silica gel to afford a syrupy mass. Methyl
6-chloro-2,3,4-tri-O-formyl-a-D-glucopyranoside (1b). Anal. calc. for
C10H13ClO8: C, 40.49; H, 4.42; Cl, 11.95. Found: C, 40.52; H, 4.49;
(500 MHz; CDCl3; Me4Si); d 3.47 (s, 3H, OCH3), 3.59 (dd, 1H, J =
12.2, 6.1 Hz, H-6a), 3.69 (dd, 1H, J = 12.2, 2.4 Hz, H-6b), 4.10 (ddd,
1H, J = 9.6, 6.1, 2.4 Hz, H-5), 5.03–5.05 (m, 1H, H-2), 5.08 (d, 1H,
J = 3.4 Hz, H-1), 5.23 (t, 1H, J = 9.6 Hz, H-3/H-4), 5.69 (t, 1H, J =
9.5 Hz, H-3/H-4), 8.05 (s, 2H, 2¥CHO), 8.08 (s, 1H, CHO). 13C NMR
(75 MHz, CDCl3): d 43.6, 56.1, 68.9, 69.2, 69.6, 71.5, 96.7, 159.9, 160.7,
160.9.
26
Cl, 11.99. MS (%) M+ at m/z 297. [a]D +60.0 (c 1.0, CHCl3); dH
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