1,6-C-H and 1,5-O-Si insertion reactions of alkylidenecarbene derivatives of monosaccharides

Article abstract of DOI:10.1081/CAR-200066924

A new protocol has been developed for the generation of alkylidenecarbene derivatives of monosaccharides based on the reaction of trimethylsilylazide and Bu₂SnO with α-cyanomesylates derived from uloses. When this method is applied to convenien

Full text of DOI:10.1081/CAR-200066924

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1,6‐C‐H and 1,5‐O‐Si Insertion Reactions
of Alkylidenecarbene Derivatives of
Monosaccharides
Albert Nguyen Van Nhien a , Rafael León b c , Denis Postel a , M.
Carmo Carreiras d , Antonio G. García c & José Marco‐Contelles
a Laboratoire des Glucides , Université de Picardie‐Jules Verne, Fac.
des Sciences , Amiens, France
b Laboratorio de Radicales Libres , Instituto de Química Orgánica
(CSIC) , Madrid, Spain
c Departamento de Farmacología , Fac. de Medicina, U. Autónoma
de Madrid , Madrid, Spain
d Centro de Estudos Ciências Farmacêuticas , Fac. Farmácia, Univ.
Lisboa , Lisboa, Portugal
Published online: 16 Aug 2006.
To cite this article: Albert Nguyen Van Nhien , Rafael León , Denis Postel , M. Carmo Carreiras ,
Antonio G. García & José Marco‐Contelles (2005) 1,6‐C‐H and 1,5‐O‐Si Insertion Reactions of
Alkylidenecarbene Derivatives of Monosaccharides , Journal of Carbohydrate Chemistry, 24:4-6,
369-377
To link to this article: http://dx.doi.org/10.1081/CAR-200066924
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Journal of Carbohydrate Chemistry, 24:369–377, 2005
Copyright # Taylor & Francis, Inc.
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1081/CAR-200066924
1,6-C-H and 1,5-O-Si
Insertion Reactions of
Alkylidenecarbene
Derivatives of
Monosaccharides
Albert Nguyen Van Nhien
´
Laboratoire des Glucides, Universite de Picardie-Jules Verne, Fac. des Sciences,
Amiens, France
´
Rafael Leon
´
´
Laboratorio de Radicales Libres, Instituto de Quımica Organica (CSIC), Madrid, Spain
´
´
and Departamento de Farmacologıa, Fac. de Medicina, U. Autonoma de Madrid,
Madrid, Spain
Denis Postel
´
Laboratoire des Glucides, Universite de Picardie-Jules Verne, Fac. des Sciences,
Amiens, France
M. Carmo Carreiras
ˆ
ˆ
´
Centro de Estudos Ciencias Farmaceuticas, Fac. Farmacia, Univ. Lisboa,
Lisboa, Portugal
Antonio G. Garc´ıa
´
´
Departamento de Farmacologıa, Fac. de Medicina, U. Autonoma de Madrid,
Madrid, Spain
Received November 17, 2004; accepted April 20, 2005.
This work is dedicated to the memory of Professor Jacques H. van Boom.
´
Address correspondence to Jose Marco-Contelles, Laboratorio de Radicales Libres,
´
´
Instituto de Quımica Organica (CSIC), C/Juan de la Cierva, 3, 28006 Madrid, Spain.
´
E-mail: iqoc21@iqog.csic.es and Denis Postel, Laboratoire des Glucides, Universite de
Picardie-Jules Verne, Fac. des Sciences, 33, rue Saint Leu, 80039, Amiens, France.
E-mail: denis.postel@u-picardie.fr
369

A. N. Van Nhien et al.
370
´
Jose Marco-Contelles
´
´
Laboratorio de Radicales Libres, Instituto de Quımica Organica (CSIC), Madrid, Spain
A new protocol has been developed for the generation of alkylidenecarbene derivatives
of monosaccharides based on the reaction of trimethylsilylazide and Bu2SnO with
a-cyanomesylates derived from uloses. When this method is applied to conveniently
functionalized carbohydrate derivatives it provides novel heterocyclic ring systems by
the rare 1,6-C-H or 1,5-O-Si insertion reactions.
Keywords Alkylidenecarbenes, a-Cyanomesylates, Trimethylsilylazide, Dibutyltin
oxide, Sugar templates, 1,6-C-H Insertion, 1,5-O-Si Insertion
The synthesis and subsequent transformations of alkylidenecarbenes continue
to attract much interest.[1] Therefore, a number of methods have now been
documented for the generation of such highly reactive species.[2] In sugar
chemistry, Czernecki was the first to use a-cyanomesylates derived from
uloses to produce acetylenic derivatives[3] by treatment with sodium azide/
DMF. Such conversions are presumed to involve an alkylidenecarbene
intermediate, which undergoes a 1,2-H shift. A few years later it was
reported that the reaction of sodium azide in methylene chloride with various
a-cyanomesylates, in the presence of tetrabutylammonium hydrogen sulfate,
rendered the corresponding branched-chain sugars and nucleosides via a
mechanism involving an alkylidenecarbene being trapped in intermolecular
association with an azide anion, solvent, and an appropriatealkene.[4] The advan-
tage of such direct route has been offset by the potential explosive combination of
sodium azide and halogenated solvents. In fact, with this result relatively
few papers[3,4] referring to its use have been published. In spite of this
drawback, Czernecki’s discovery[3] paved the way for further improvements.[4,5]
In this paper we report a safer and improved protocol for the synthesis
of alkylidenecarbene derivatives of monosaccharides and some intramolecular
transformations of these species, including the rare 1,6-C-H insertion reaction.[6]
Taking into account the accepted mechanism for the generation of alkylide-
necarbenes from a-cyanomesylates,[4] involving reaction of an azide anion
with a nitrile to afford a tetrazolyl anion, which undergoes rearrangement,
a-elimination of the mesyl group, and subsequent loss of nitrogen, we
reasoned that Wittenberger’s method for the synthesis of 5-substituted tetra-
zoles (trimethylsilyl azide, dibutyltin oxide, in toluene)[7] would most likely
provide a-mesyltetrazolyl intermediates easily as precursors of the expected
alkylidenecarbenes and under mild reaction conditions.
For our preliminary experiments we made a comparative study with the
reported[4] intermolecular reaction of the alkylidenecarbene derived from the

Monosaccharide Alkylidenecarbene Derivative Insertion Reactions
371
benzoate 1a with cyclohexene to generate the exo methylenecyclopropyl deriva-
tive 2. Using our conditions, the reaction of 1a with cyclohexene (40, equiv.) in
the presence of TMSN3 (1.2 equiv.) and Bu2SnO (1 equiv.) at 988C for 6 hr
afforded 2 in a higher yield, 42% (vs. 35%)[4] in the isomeric ratio 1 : 1.2
(Sch. 1), than the previously reported reaction.[4] Interestingly, using the
same experimental conditions [TMSN3 (1.2–1.5 equiv.), Bu2SnO (1–1.5
equiv.), 988C, 16–20 hr] precursor 1b afforded an isomeric mixture of 3a and
3b in 45% yield, in a 4 : 1 ratio (Sch. 2).a It is important to note that the use
of TBAF[8] (0.5–1 equiv.) in this reaction gave a similar result. The isomers
1
3a and 3b were separated and their structures readily assigned by H NMR,
13C NMR, IR, MS(ES), and elemental analysis data.b The absolute configur-
ation at the newly formed stereocenter was determined by the selective
positive n.O.e effects observed between the protons H-5b and H-7 in
compound 3a, showing that the major isomer (3a) has a trans arrangement
between these protons H-4 and H-7. These compounds are the result of a
very unusual 1,6-C-H insertion reaction[6] on the intermediate alkylidenecar-
bene A. To the best of our knowledge, this is the first example of such a
aIn a typical experiment, to a solution of compound 1b (400 mg, 1.04 mmol) in dry
toluene (16 mL) under argon, dibutyltin oxide (260 mg, 1.04 mmol) and TMSN3
(0.21 mL, 1.56 mmol) were added. The reaction was heated to 988C and stirred
for 16 hr and then the solvent was removed under vacuo. The crude product
was submitted to flash chromatography (EtOAc: petroleum ether, 18 : 82) to give suc-
cessively compound 3b (26 mg) and 3a (105 mg). Total 3b þ 3a (131 mg, 45%, 1 : 4
ratio).
bAll new compounds showed excellent analytical data. Selected spectroscopic data. 3b:
pale yellow solid: mp 100–1028C; [a]2D0 þ29 (c 0.18, CHCl3); IR (ATR) ? 2921, 2351,
2110, 1452, 1370, 1244, 1162, 1040, 1011 cm21 1H NMR (CDCl3, 300 MHz) d 7.37
;
(m, 5 H, C6H5), 6.20 (t, J6,4 ¼ 2.0 Hz, J6,7 ¼ 2.0 Hz, 1 H, H-6), 5.90 (d, J1,2 ¼ 3.7 Hz, 1
H, H-1), 5.30 (t, J7,4 ¼ 2.0 Hz, 1 H, H-7), 5.03 (d, 1 H, H-2), 4.73 (m, 1 H, H-4), 4.08
(dd, J4,5a ¼ 6.0 Hz J5a,5b ¼ 10.4 Hz, 1 H, H-5a), 3.29 (dd, J4,5b ¼ 8.6 Hz, 1 H, H-5b),
1.61 (s, 3 H, CH3), 1.41 (s, 3 H, CH3); 13C NMR (CDCl3, 75 MHz) d 139.5–127.8 (C-3,
C6H5), 125.3 (C-6), 113.4 [OC(CH3)2], 105.8 (C-1), 80.0 (C-2), 73.9 (C-7), 70.2 (C-4),
62.5 (C-5), 27.4 (CH3), 27.0 (CH3); MS (ES): 297.1 [M þ Na]þ. 3a: pale yellow
solid: mp 93–948C; [a]D20 þ 176 (c 0.16, CHCl3); IR (ATR) ? 2981, 2932, 2104, 1441,
1370, 1216, 1161, 1047, 1017 cm21 1H NMR (CDCl3, 300 MHz) d 7.34 (m, 5 H,
;
C6H5), 5.99 (t, J6,4 ¼ J6,7 ¼ 2.0 Hz, 1 H, H-6), 5.87 (d, J1,2 ¼ 3.7 Hz, 1 H, H-1), 5.08
(t, J7,4 ¼ 2.0 Hz, 1 H, H-7), 4.97 (d, 1 H, H-2), 4.81 (m, 1 H, H-4), 4.45 (dd,
J4,5a ¼ 5.9 Hz, J5a,5b ¼ 10.0 Hz, 1 H, H-5a), 3.35 (dd, J4,5b ¼ 9.1 Hz, 1 H, H-5b), 1.61
(s, 3 H, CH3), 1.40 (s, 3 H, CH3); 13C NMR (CDCl3, 75 MHz) d 139.6–127.8 (C-3,
C6H5), 126.2 (C-6), 113.4 [OC(CH3)2], 105.3 (C-1), 80.3 (C-2), 77.4 (C-7), 70.3 (C-4),
69.0 (C-5), 27.5 (CH3), 27.0 (CH3); MS (ES): 297.1 [M þ Na]þ. 16: 1H NMR (CDCl3,
300 MHz) d 7.68 (d, J4,5 ¼ 1.8 Hz, 1 H, H-4), 6.63 (d, 1 H, H-5), 4.64 (dd,
J1a,OH ¼ 4.6 Hz, J1a,1b ¼ 19.8 Hz, 1 H, H-1a), 4.57 (dd, J1b,OH ¼ 4.6 Hz, 1 H, H-1b),
3.45 (t, 1 H, OH), 0.97 [s, 9 H, SiC(CH3)3], 0.36 (s, 6 H, 2 ꢀ SiCH3); 13C NMR (CDCl3,
75 MHz) d 194.6 (C ¼ O), 167.3 (C-6), 147.4 (C-5), 132.3 (C-3), 108.6 (C-4), 67.0 (C-1),
27.0 [Si(CH3)2C(CH3)3], 18.4 [Si(CH3)2C(CH3)3], –5.8 [Si(CH3)2C(CH3)3].

A. N. Van Nhien et al.
372
Scheme 1
reaction involving a sugar derivative. The major isomer 3a was possibly
obtained by intramolecular cyclization and a subsequent 1,2-H shift on a
chairlike conformer of type A1 (Sch. 2) with most of the substituents being in
a favored pseudoequatorial orientation (compared to less stable conformer
A2, Sch. 2). The tosyl derivative 1c (Sch. 2) also gave 3a and 3b in 46 to 51%
in a 4 : 1 ratio.
Scheme 2

Monosaccharide Alkylidenecarbene Derivative Insertion Reactions
373
Scheme 3
In contrast, and surprisingly, the reaction of 1b with NaN3, DMF[3]
provided the CSIC[9] product 4 (Sch. 3) in 46% yield.
The 1,6-C-H insertion reaction has been previously observed by Feldman in
naphthol and anthrol derived alkylidenes rendering modest yields of the
Scheme 4

A. N. Van Nhien et al.
374
Scheme 5
products.[6] This unusual conversion has been scarcely explored in other
systems. Hence, we were prompted to investigate the use of similar reaction
conditions to the suitably functionalized monosaccharides 5–7. Interestingly,
these compounds produced inseparable mixtures of isomers of the 1,6-C-H
insertion products 8–10, respectively, in albeit low to moderate yield (yields
have not been optimized), with one stereoisomer predominating in each case,
as illustrated in Scheme 4.[10]
We extended the scope of this reaction to include the monosaccharide
derivative 11. Surprisingly, the reaction took a different course and gave the
unexpected product 12 in 55% yield (Sch. 5). Tronchet[11] reported a similar
result in a related study a few years ago.
Interestingly, when the O-benzyl was substituted with an O-TBDMS group
in compound 13, compound 14 was obtained (Sch. 6) in 33% yield. This product
is the expected 1,5-O-Si insertion product, which is in keeping with the known
chemistry of alkylidenecarbenes[12,13] but is the first example of such a conver-
sion in carbohydrate chemistry.
In contrast, compound 15 produced the unexpected 2,3-disubstituted
furan 16 in 25% yield (Sch. 7). The formation of this product can be
rationalized by
a sequential process involving a 1,5-O-Si insertion
to generate intermediate (B), not isolated, followed by a concerted fragmen-
tation reaction initiated by H-5 abstraction, probably caused by an excess of
TMSN3.
In summary, we have reported a series of interesting and unexpected 1,6-C-
H and 1,5-O-Si insertion reactions on alkylidenecarbene derivatives of
Scheme 6

Monosaccharide Alkylidenecarbene Derivative Insertion Reactions
375
Scheme 7
carbohydrates using a new and direct protocol based on the reactions of con-
veniently functionalized a-cyanomesyl groups with TMSN3 and Bu2SnO.
Work is in progress to extend these results to other precursors and will be
reported in due course.
ACKNOWLEDGMENTS
RL thanks the MECD (Spain) for a short-term grant to visit Laboratoire des
´
´
Glucides, Universite de Picardie-Jules Verne; Faculte des Sciences, Amiens
´
(France), and for a predoctoral fellowship. DP thanks the Conseil Regional
`
de Picardie (France) and the Ministere Franc¸ais de la Recherche for financial
support. MCC thanks the Portuguese FCT for a short-term sabbatical grant
´
to visit the Radical Chemistry Laboratory in the Instituto de Quımica
´
Organica General (CSIC), Madrid.
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