A more convenient and general procedure for O-monobenzylation of diols via Stannylenes: A critical reevaluation of the Bu2SnO method

Article abstract of DOI:10.1021/jo026794c

A more consistent, straightforward, and economical protocol for generation of stannylene species and their reaction with BnBr leading to products of O-monobenzylation of diols has been set. It has shown to be specially indicated for substrates bearing vicinal trans 1,2-diol moieties on cyclohexane backbones, which are more resistant to these transformations. Such protocol has been successfully applied to myo-inositol derivatives and acyclic diols.

Full text of DOI:10.1021/jo026794c

SCHEME 1. Selective O-Mon oben zyla tion of Diols
via Sta n n ylen e Aceta ls
A Mor e Con ven ien t a n d Gen er a l P r oced u r e
for O-Mon oben zyla tion of Diols via
Sta n n ylen es: A Cr itica l Reeva lu a tion of
th e Bu 2Sn O Meth od
Alessandro B. C. Simas,* Karla C. Pais, and
Angelo A. T. da Silva
SCHEME 2. Syn th esis of m yo-In ositols 5 a n d 6
Universidade Federal do Rio de J aneiro, Nu´cleo de
Pesquisas de Produtos Naturais (NPPN), Laborato´rio
Roderick A. Barnes, Ilha da Cidade Universita´ria, CCS,
bloco H, Rio de J aneiro RJ 21941-590, Brazil
abcsimas@nppn.ufrj.br
On inspection of representative examples within the
vast collection of data in the literature dealing with the
use of stannylene acetals, we noticed an uncertainty on
the conditions actually needed for both the tin intermedi-
ate generation and, more importantly, its reaction with
alkylating agents such as BnBr. As the following discus-
sion demonstrates, such indecision does not seem to be
reasonable whatsoever. Apparently, it is not related to
the molecular diversity of the suitable substrates.
First, we concluded that the stannylene intermediate
formation does not require H2O removal (e.g., by use of
Dean-Stark apparatus), as it is observed in most of the
works in the literature.4,5 A simple reflux of the reactants
in CH3OH/toluene, followed by careful evaporation of the
solvents suffices for the reactions of both cyclic substrates
(bearing either cis-diol or trans-diol moieties) and acyclic
ones, as the following results will confirm. This aspect is
particularly important if it is taken into account that the
unnecessary use of the Dean-Stark apparatus requires
bath temperatures well above the reflux ones (140-150
°C in the case of toluene as solvent). So, when subjected
to the mentioned conditions, myo-inositols 4 and 5 were
converted to stannylene acetals 7 and 8 (Figure 1),
respectively.
Received December 3, 2002
Abstr a ct: A more consistent, straightforward, and eco-
nomical protocol for generation of stannylene species and
their reaction with BnBr leading to products of O-monoben-
zylation of diols has been set. It has shown to be specially
indicated for substrates bearing vicinal trans 1,2-diol moi-
eties on cyclohexane backbones, which are more resistant
to these transformations. Such protocol has been successfully
applied to myo-inositol derivatives and acyclic diols.
The introduction of tributyltin ethers and dibutylstan-
nylene acetals derived from alcohol and diol moieties,
respectively, provided a major leap to carbohydrate
chemistry, most notably.1 On reacting with activated
alkyl halides (the main use of these organometallic
intermediates), they combine an adequate nucleophilicity
with a negligible basicity. Stannylene acetals 2 (Scheme
1) are produced by reaction of diol moieties 1 and Bu2-
SnO.1,2 Such species may undergo substitution to 3 under
essentially neutral conditions. Remarkable features of
these reactions are the regiochemical (substitution on
primary hydroxyl groups prevails over those on secondary
or tertiary ones) and stereochemical (equatorial hydroxyl
groups, and not axial ones, react preferentially) controls
that they enable. Besides, the Bu2SnO method is able to
selectively afford O-monosubstituted diol moieties even
in the presence of other unprotected hydroxyl groups.
Due to such assets, this powerful methodology is not
paralleled by anionic chemistry, which usually leads to
mixtures of isomers.1
For the benzylation of the tin species 7, we chose the
Veyrie`res-David conditions.6 Reaction of this organo-
metallic compound with BnBr in toluene in the presence
of Bu4NBr (0.2 molar equiv; condition A of stannylene
alkylation) occurred uneventfully to provide 5 (Table 1,
entry 1). It is not necessary to employ either stoichio-
metric or excess amounts of ammonium halide additive,7
(4) (a) Ramos, D.; Rollin, P.; Klaffke, W. J . Org. Chem. 2001, 66,
2948. (b) Bernardi, A.; Arosio, D.; Manzoni, L.; Micheli, F.; Pasquarello,
A.; Seneci, P. J . Org. Chem. 2001, 66, 6209. (c) Hanessian, S.; Huynh,
H. K.; Reddy, G. V.; Duthaler, R. O.; Katopodis, A.; Streiff, M. B.; Kinzy,
W.; Oehrlein, R. Tetrahedron 2001, 57, 3281. (d) Mart´ınez-Bernhardt,
R.; Castro, P. P.; Godjoian, G.; Gutie´rrez, C. G. Tetrahedron 1998, 54,
8919. (e) Hanessian, S.; Pan, J .; Carnell, A.; Bouchard, H.; Lesage, L.
J . Org. Chem. 1997, 62, 465. (f) Riley, A. M.; J enkins, D. J .; Potter, B.
V. L. J . Am. Chem. Soc. 1995, 117, 3300. (g) J enkins, D. J .; Potter, B.
V. L. Carbohydr. Res. 1994, 265, 145. (h) Nagashima, N.; Ohno, M.
Chem. Lett. 1987, 141.
(5) The exceptions almost invariably deal with the preparation of
stannylenes from cis diol moieties on furanoside backbones, following
the pioneering work of Moffatt’s group: Wagner, D.; Verheyden, J . P.
H.; Moffatt, J . G. J . Org. Chem. 1974, 39, 24. Boger, D. L.; Ichikawa,
S.; Zhong, W. J . Am. Chem Soc. 2001, 123, 4161. Danishefsky, S. J .;
Hungate, R.; Schulte, G. J . Am. Chem. Soc. 1988, 110, 7434.
(6) (a) David, S.; Thieffry, A.; Veyrie`res, A. J . Chem. Soc., Perkin
Trans. 1 1981, 1796. (b) Veyrie`res, A. J . Chem. Soc., Perkin Trans. 1
1981, 1629.
In the course of our studies on inositol chemistry, we
were required to prepare large amounts of tetrabenzyl
ethers 6a and 6b (Scheme 2). After some disappointing
results of direct dibenzylation of tetrol 4 via (bis)stan-
nylene acetals,3 we realized that the stepwise process
(through triol 5) would yield a more consistent route to
those materials. However, the early work with these two
reactions indicated that there was some space for pro-
cedure improvement. The development of a protocol for
general application was clearly demanded.
(1) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643.
(2) Auge´, C.; David, S.; Veyrie`res, A. J . Chem. Soc., Chem Commun.
1976, 375.
(3) Offer, J . L.; Voorheis, H. P.; Metcalfe, J . C.; Smith, G. A. J . Chem.
Soc., Perkin Trans. 1 1992, 953.
10.1021/jo026794c CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/29/2003
5426
J . Org. Chem. 2003, 68, 5426-5428

F IGUR E 1. Monomeric structures of stannylene acetals 7
and 8.
TABLE 1. O-Mon oben zyla tion of Diol Moieties via th e
Op tim ized Bu 2Sn O Meth od
yield
reaction
entry substrate
product (s)
(%) conditionsa time (h)
1
2
3
4
5
6
7
4
5
9
10
12
13
15
5
77
70
89
A
B
4
FIGURE 2. Additional substrates and products of O-monoben-
zylation of diol moieties.
6a , 6b (1:1.4)b
9.5
2.5
6
6
1.5
1.5
6a
A
11a , 11b (1:1.5)b 72
Bc
Bd
A
A, as had occurred with compound 4 (Table, entry 3). On
the other hand, acetal 10, bearing a trans vicinal diol
moiety, as expected, was more resistant to alkylation.
Employment of condition B nonetheless led to tribenzyl
ethers 11a and 11b in good yields and a satisfactory
reaction time (Table, entry 4). In cases such as those of
substances 5 and 10, it is rewarding to employ a slightly
higher amount of BnBr (3.5 molar equiv).
10
14
16
93
93
78
A
a
Condition for stannylene acetal reaction with BnBr: (A) BnBr
(2.0 molar equiv); Bu4NBr (0.2 molar equiv), toluene, 130 °C; (B)
b
same as A, except for Bu4NBr (0.6 molar equiv). Respectively.
c 3.5 molar equiv of BnBr was employed. 2.5 molar equiv of
d
Bu2SnO and 3.0 equiv of BnBr were employed.
Gigg et al. showed that the bis-stannylene generated
from acetal 12 can be regioselectively dibenzylated at C-3
and C-6 hydroxyl groups to 10.8 We applied our general
protocol (condition B) to this interesting transformation
and, thus, achieved a better reaction profile (Table, entry
5). Besides a markedly higher yield (93% against litera-
ture 63%),8a the reaction proceeded considerably faster
with the same 0.6 molar equiv of the ammonium salt
additive. Dibenzyl ether 10 and other dialkylated coun-
terparts have been shown to be preeminent starting
materials in the synthesis of bioactive inositol deriva-
tives.9
We also studied the replacement of toluene for CH3-
CN as the solvent for the stannylene benzylation step as
prescribed by a few works in the literature.10 The former
one proved superior. For instance, in the monobenzyla-
tion of triol 9 in CH3CN at 90 °C, 27% of starting material
was recovered after 6-7 h, while in toluene at the same
temperature, this reaction was carried out in less than
5 h. Furthermore, the dibenzylation step in the reaction
of acetal 12 (whose reaction we have already demon-
strated to afford an excellent result via our protocol) in
CH3CN at 90 °C did not occur completely after 15-17 h
affording both the desired diether 10 (only 33%) along
with a more polar fraction composed by an inseparable
mixture of ethers benzylated at C-3 and C-6-hydroxyl
groups. Of course, this result is partially justified by the
lower reaction temperature imposed by the use of CH3-
CN. That regioisomeric mixture was monobenzylated to
produce 10 through the Bu2SnO method. The low rates
observed with this solvent may also be related to the
issue of stannylene solubility, as the reaction mixtures
in CH3CN were heterogeneous.
a common feature of these reactions in the literature, to
achieve high rates and chemical yields. Moreover, Bu4-
NBr successfully replaces more expensive Bu4NI.6a Ex-
tension of the same benzylation condition to the reaction
of stannylene 8 did not reproduce the satisfactory results
obtained for 7. Species 8 (whose stannylene portion was
built on a trans-diol moiety) is clearly more resistant to
alkylation. Besides slow reaction, conversion to 6a and
6b was not complete after >15 h (41% based upon 29%
of recovered starting material; 6b/6a ratio ) 1.2:1.0,
respectively). Adding 0.2 molar equiv of Bu4NI to the
previous reaction mixture in order to generate more
reactive BnI in situ actually managed to accelerate the
transformation. Substrate consumption was essentially
complete (6.5 h), and product ratio also changed (6b/6a
ratio ) 2.5:1.0, respectively). However, higher conversion
was not followed by the corresponding yield increase (43%
yield), which may indicate product/substrate degradation.
Thus, at least in (more desirable) lesser quantities and
with resisting substrates, the employment of Bu4NI (an
indication of the original procedure)6a does not seem to
afford the best results.
As a matter of fact, we found that a modest increase
in Bu4NBr quantity led to a very satisfactory reaction.
Stannylene 8 reacted with BnBr (2.0 molar equiv) in the
presence of a still substoichiometric amount of Bu4NBr
(0.6 molar equiv; condition B of stannylene alkylation)
providing tetrabenzyl ethers 6a and 6b (Table, entry 2)
in an efficient manner. It is noteworthy that, even in
more difficult benzylations, it is possible to achieve a
satisfactory compromise between efficiency (yields and
rates) and reaction economy.
This straightforward protocol involving easy generation
of stannylene acetals and differential conditions A/B for
benzylation was successfully applied to various sub-
strates (Figure 2). Triol 9 underwent fast monobenzyla-
tion at C3-hydroxyl to 6a through benzylation condition
Finally, we wondered whether our procedure could be
extended to acyclic diols. Good results of O-benzylation
(8) (a) Desai, T.; Gigg, J .; Gigg, R.; Mart´ın-Zamora, E.; Schnetz, N.
Carbohydr. Res. 1994, 258, 135. (b) Gigg, J .; Gigg, R.; Mart´ın-Zamora,
E. Tetrahedron Lett. 1993, 34, 2827.
(9) Ballereau, S.; Gue´dat, P.; Poirier, S. N.; Guillemette, G.; Spiess,
B.; Schlewer, G. J . Med. Chem. 1999, 42, 4824. See also refs 7a and
8b.
(7) (a) Desai, T.; Gigg, J .; Gigg, R.; Mart´ın-Zamora, E. Carbohydr.
Res. 1994, 262, 59. (b) Desai, T.; Gigg, J .; Gigg, R.; Mart´ın-Zamora, E.
Carbohydr. Res. 1996, 296, 97. See also refs 4b,g, 6a, and 8.
(10) See refs 7a,b and 8.
J . Org. Chem, Vol. 68, No. 13, 2003 5427

Gen er a l P r oced u r e. A mixture of the diol (1.0 mmol) and
Bu2SnO (1.0-1.2 mmol) in CH3OH/toluene (1:1) (2-4 mL) was
heated to 130 °C for 3 h. The solvents were evaporated, dry
toluene (4 mL) was added to the residue, and a second evapora-
tion to dryness was effected, which was completed under high
vacuum. Then, a mixture of the crude stannylene derivative,
Bu4NBr (0.2 mol), and BnBr (2.0 mmol) (condition A of stan-
nylene alkylation) in dry toluene (2-4 mL) under argon was
heated to 130 °C until the reaction went to completion. After
solvent evaporation, the residue was purified by chromatogra-
phy. This procedure is essentially maintained for both condition
B and O-dibenzylation of inositol acetal 12 (see text and Table
1 for details).
of 13 (to 14) and 15 (to 16) show that this is indeed the
case (Table 1, entries 6 and 7).
The application of this protocol to the alkylation with
other compatible electrophiles (allyl and crotyl bromides,
p-methoxybenzyl bromide) will further expand its scope.
The more consistent reaction conditions advanced herein
may facilitate initial experiments (small scales) involving
stannylene acetals. It will also be useful in large-scale
preparations enabling easier product purifications. And
last but not least, this procedure may provide a safer
ground for reaction optimization in the prospective cases
of even more recalcitrant substrates (than diols 5 and
10).
Substances 5,7a 6(a ,b),3 10,8a and 11(a ,b)7b (all racemic) are
known substances. Their physical data were consistent with
those of literature. Commercial samples of substances 14 and
16 are available.
Exp er im en ta l Section
Ack n ow led gm en t. We thank CNPq and UFRJ for
a PIBIC fellowship to K.C.P. and Profs. Vera L. P.
Pereira, Me´cia M. Oliveira, and Antoˆnio V. Pinto for
generous gifts of some of the materials employed in this
work.
Gen er a l Meth od s. Toluene was distilled from benzophenone/
Na0. BnBr was treated with CaH2, decanted, transferred to a
dry distillation apparatus, and purified under vacuum. Crude
products were purified by medium-pressure column chromatog-
raphy and eluted (AcOEt/hexanes or AcOEt/toluene mixtures)
on 230-400 mesh silica gel.
J O026794C
5428 J . Org. Chem., Vol. 68, No. 13, 2003