Organotin-mediated monoacylation of diols with reversed chemoselectivity. Mechanism and selectivity

Article abstract of DOI:10.1021/jo960453f

The monoesterification of unsymmetrically substituted diols, which occurs at the most substituted hydroxyl when activation of the substrate is achieved through its dibutylstannylene acetal, has been investigated to ascertain the origin of the unusual reversal of chemoselectivity. A mechanism in which the dibutylstannylene acetal plays the double role of reagent and catalyst has been established, which accounts for the reactivity, selectivity, and product distribution of the reaction. The reaction pathway involves three subsequent steps, namely, (a) esterification, (b) intra- and intermolecular transesterification, and (c) quench; interplay between kinetic and thermodynamic control over the three steps is responsible for the observed product distribution. The knowledge of the reaction mechanism allows for adjustment of experimental conditions to achieve optimum selectivity, which can be > 99% with the appropriate choice of reagents. The stannylation procedure converts hydroxyls into functional groups highly chemoselective toward acyl reagents, but inert toward sulfonyl halides and alkylating reagents. The reactivity of the Sn-O bond has been found to decrease with decreasing the electronegativity of ligands on tin, while halide ligands appear to be essential for reversal of chemoselectivity. A structure has been proposed for the catalytic species, in which complexation of the stannyl monoester intermediates with the starting dioxastannolane reagent activates the stannylated oxygen toward addition to the carbonyl and at the same time accounts for the steric hindrance that biases the intramolecular transesterification equilibrium toward the thermodynamically most stable monoester of the most substituted hydroxyl.

Full text of DOI:10.1021/jo960453f

J . Org. Chem. 1996, 61, 5257-5263
5257
Or ga n otin -Med ia ted Mon oa cyla tion of Diols w ith Rever sed
Ch em oselectivity. Mech a n ism a n d Selectivity1
Stefano Roelens
CNR, Centro di Studio sulla Chimica e la Struttura dei Composti Eterociclici e loro Applicazioni,
Dipartimento di Chimica Organica, Universita’ di Firenze,
I-50121 Firenze, Italy
Received March 5, 1996X
The monoesterification of unsymmetrically substituted diols, which occurs at the most substituted
hydroxyl when activation of the substrate is achieved through its dibutylstannylene acetal, has
been investigated to ascertain the origin of the unusual reversal of chemoselectivity. A mechanism
in which the dibutylstannylene acetal plays the double role of reagent and catalyst has been
established, which accounts for the reactivity, selectivity, and product distribution of the reaction.
The reaction pathway involves three subsequent steps, namely, (a) esterification, (b) intra- and
intermolecular transesterification, and (c) quench; interplay between kinetic and thermodynamic
control over the three steps is responsible for the observed product distribution. The knowledge of
the reaction mechanism allows for adjustment of experimental conditions to achieve optimum
selectivity, which can be >99% with the appropriate choice of reagents. The stannylation procedure
converts hydroxyls into functional groups highly chemoselective toward acyl reagents, but inert
toward sulfonyl halides and alkylating reagents. The reactivity of the Sn-O bond has been found
to decrease with decreasing the electronegativity of ligands on tin, while halide ligands appear to
be essential for reversal of chemoselectivity. A structure has been proposed for the catalytic species,
in which complexation of the stannyl monoester intermediates with the starting dioxastannolane
reagent activates the stannylated oxygen toward addition to the carbonyl and at the same time
accounts for the steric hindrance that biases the intramolecular transesterification equilibrium
toward the thermodynamically most stable monoester of the most substituted hydroxyl.
Sch em e 1
In tr od u ction
Selective manipulation of diols and polyols is a central
matter in synthetic organic chemistry,2 particularly in
the area of carbohydrates and polyhydroxylated com-
pounds, where preparative procedures typically have to
cope with repeated protection/deprotection steps.3 Selec-
tive activation of hydroxyl groups by the stannylation
procedure has become an established practice to ef-
ficiently achieve the target,4 because of the easy prepara-
tion of the stannyl intermediates, their simple usage, and
the good yields and selectivities obtained.
In this context, following a preliminary experimental
observation,5 a few years ago we developed a synthetic
method that allows for the selective esterification of
unsymmetrical diols at the most substituted hydroxyl,6
that is, with reversal of chemoselectivity with respect to
the natural reactivity of hydroxyl groups (Scheme 1). The
described method7 provides easy access to complementary
products to those obtained by standard literature proce-
dures, normally affording monoesters of the least sub-
stituted hydroxyl. Besides the good to excellent selectivi-
ties, a further aspect of interest of this method is that
hindered monoesters can be prepared, with some remark-
able achievements such as the esterification at the
tertiary hydroxyl of a tertiary-primary diol and the
secondary pivalate of a secondary-primary diol.6
The interest in synthetic potentials and mechanistic
aspects of this method have stimulated an investigation
of the origin of such an unusual reversal of chemoselec-
tivity, in the belief that the elucidation of the mechanism
would open the way to full exploitation of the reaction.
The investigation was based on previous findings on the
organotin-mediated monoesterification of ethylene glycol
with acyl chlorides,8 for which a three-step reaction
scheme had been established (Scheme 2). In the first step
(A), an irreversible esterification of the dibutylstannylene
acetal of ethylene glycol with 1 equiv of acyl chloride
affords a stannyl monoester. The high monoesterification
selectivity is due to a substantial deactivation of the
second Sn-O bond toward further esterification by the
presence of the chloride ligand on tin (vide infra). In the
second step (B), an intermolecular transesterification
reaction produces the diester from the stannyl monoester.
Although the equilibrium favors the formation of the
diester, the reaction is sufficiently slow not to interfere
with the completion of the subsequent quench step (C)
with an appropriate destannylating reagent, which af-
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
(1) Group 14 Organometallic Reagents. 12. For part 11, see: Ro-
elens, S.; Dalla Cort, A.; Mandolini, L. J . Org. Chem. 1992, 57, 1472.
(2) (a) Wilkinson, S. G. In Comprehensive Organic Chemistry;
Pergamon Press: New York, 1979; Vol. 1, p 681. (b) Greene, T. W.;
Wuts, P. G. M. Protective Groups in Organic Synthesis; Wiley: New
York, 1991.
(3) Methods in Carbohydrate Chemistry; Whistler, R. L., Wolfrom,
M. L., Eds.; Academic Press: San Diego, 1963; Vol. 2.
(4) (a) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643. (b)
Pereyre, M.; Quintard, J . P.; Rahm, A. In Tin in Organic Synthesis;
Butterworths: London, 1987; p 261.
(5) Ricci, A.; Roelens, S.; Vannucchi, A. J . Chem. Soc., Chem.
Commun. 1985, 1457.
(6) Reginato, G.; Ricci, A.; Roelens, S.; Scapecchi, S. J . Org. Chem.
1990, 55, 5132.
(7) For recent alternative methods, see: Bailey, W. F.; Zarcone, L.
M. J .; Rivera, A. D. J . Org. Chem. 1995, 60, 2532 and references cited
therein.
(8) Roelens, S. J . Chem. Soc., Perkin Trans 2 1988, 2105.
S0022-3263(96)00453-7 CCC: $12.00 © 1996 American Chemical Society

5258 J . Org. Chem., Vol. 61, No. 16, 1996
Roelens
Sch em e 2
Sch em e 4
Resu lts a n d Discu ssion
Because of the excellent selectivities observed,6 1-phen-
yl-1,2-ethanediol was selected as a “labeled” substrate
and converted into the corresponding dibutylstannylene
acetal, and the investigation was carried out using
appropriate acylating and quenching reagents. Selective
monoesterification was performed according to the previ-
ously reported general procedure.6 Crystallized 4-phenyl-
2,2-dibutyl-1,3,2-dioxastannolane (1), prepared from the
diol and Bu2SnO by azeotropic dehydration, was allowed
to react with 1 equiv of the selected acyl chloride 2 in
CDCl3 solution at room temperature, and the formation
of the isomeric stannyl monoesters 3 and 4 was followed
Sch em e 3
1
by H NMR (Scheme 4). All the experiments were run
fords a stable, isolable monoester.9 The described trans-
esterification reaction can also occur intramolecularly
(Scheme 2, B), giving rise to a virtual equilibrium that
scrambles the acyl group between the oxygen atoms of
the diol through a five-membered tetrahedral intermedi-
ate. This reaction, taking advantage of the large in-
tramolecularity factors that favor five-membered rings,10
experiences a substantial rate increase with respect to
its intermolecular counterpart, so that the equilibrium
is established before quench can take place. Convincing
evidence for the existence of the intramolecular equilib-
rium was provided by coalescence of the CH2OSn and
CH2OCOR signals in the 1H NMR spectra.8 In this
scheme, a key role is played by the bis-stannylated diol
formed in step B as a side product of the diester. This
species has been shown to take part in a fast equilibrium
in which the starting dioxastannolane is regenerated, by
elimination of 1 equiv of dibutyltin dichloride (Scheme
3).11
under comparable concentrations of substrate (0.3 M ca.).
Subsequent treatment with a second equivalent of the
appropriate acyl or silyl chloride 5 quenched the reaction,
affording the isomeric mixed diesters or the silyl mo-
noesters 6 and 7 (Scheme 4). The final mixtures were
quantitatively analyzed by 1H NMR in the reaction
medium without further manipulation.
Selectivity. The attention was focused on the regio-
isomeric distribution of monoesters, neglecting the monose-
lectivity of the reaction, which was analogous to that
observed for ethylene glycol.12 Reaction of 1 with 1.2
equiv of p-nitrobenzoyl chloride (2a ) gave an approxi-
mately 2:1 mixture of secondary/primary (3a /4a ) stannyl
monoesters. As with ethylene glycol, broadening of lines
in the 1H NMR spectra revealed chemical exchange
phenomena involving the stannyl monoesters. The mix-
ture was quenched with a slight excess of Me3SiCl (5a )
at room temperature, monitoring the formation of silyl
1
monoesters 6a and 7a vs time by H NMR (Figure 1). It
On this basis, the investigation of the reversal of
chemoselectivity translates into marking one of the two
equivalent positions of ethylene glycol, which has been
achieved by placing a substituent on one carbon of the
dioxastannolane ring and monitoring the steps and the
intermediates that lead to the observed product distribu-
tion. It should be noted that regioselectivity (preference
for the ester of the “labeled” oxygen) and chemoselectivity
(preference for the ester of the most substituted hy-
droxyl), i.e., chemical and positional selectivities, are
superimposed features for this reaction.
is clearly observed that 3a and 4a were converted in 15
min ca. into a 22:1 mixture of 6a and 7a (Table 1, entry
2), indicating that extensive redistribution of regioiso-
mers had taken place during quench. Corresponding
hydroxy esters 3* and 4*, which where caused by
hydrolytic destannylation and were present in the mix-
ture in their “natural” distribution, i.e., primary ester
predominant over the secondary, do not interfere with
quench, remaining unaffected in the time required for
quench to be complete. Similarly, a mixture of 3a and
(12) It was noted, however, that mixing effects in concentrated
solution could significantly alter the selectivity of monoesterification,
but not the regioisomeric distribution. This behavior indicates local
concentration phenomena occurring in the fast esterification step (A),
as supported by incresing sensitivity to mixing effects with increasing
the electrophilic reactivity of the acyl chloride (acetyl > p-NO2-benzoyl
> p-MeO-benzoyl).
(9) Hydroxy esters of 1,2-diols are known to isomerize. See, for
example: (a) Cohen, T.; Dughi, M.; Notaro, V. A.; Pinkus, G. J . Org.
Chem. 1962, 27, 814.
(10) Mandolini, L. In Advances in Physical Organic Chemistry;
Academic Press: London, 1986; Vol. 22, p 1.
(11) Roelens, S. J . Chem. Soc., Perkin Trans 2 1988, 1617.

Organotin-Mediated Monoacylation of Diols
J . Org. Chem., Vol. 61, No. 16, 1996 5259
Sch em e 5
chloride, i.e., for the largest reactivity difference between
the acylating and the quenching reagents (Table 1,
entries 7 and 8). An interesting result was obtained
when 1 was treated with 2 equiv of a 1:1 mixture of
p-nitro and p-methoxybenzoyl chlorides, i.e., with pre-
mixed “acylating” and “quenching” reagents (Table 1,
entry 5). Selectivity is still observed, giving the second-
ary p-nitrobenzoate in a 7:1 ratio. Since for the two
benzoyl chlorides reactivity is essentially determined by
electronic effects, the most electrophilic acyl chloride
behaves as the acylating reagent and reorganization
takes place during quench carried out by the least
reactive acyl chloride.
In striking contrast to the generally high reactivity of
stannoxane reagents toward carboxyl halides, the stannyl
monoesters were unexpectedly inert toward other quench-
ers. For example, no evidence of reaction was obtained
after 16 h at room temperature when a mixture 3a and
4a was treated with methanesulfonyl chloride. Even the
extremely powerful methylating reagent methyl trifluo-
romethanesulfonate failed to quench the stannyl ester
mixture. Such remarkable chemoselectivity suggested
that these stannoxane reagents may be confined to react
through an addition-elimination mechanism. Silyl-
destannylation carried out by 5a is only apparently an
exception, since it likely proceeds itself through an
addition-elimination mechanism, involving a five-coor-
dinate silicon center (Scheme 5A).13 This hypothesis was
tested by reacting 1 with bromoacetyl chloride, a reagent
in which the two activated electrophilic centers would
react through different mechanisms. Acylation products
were observed exclusively, demonstrating complete lack
of competition between acylation and alkylation (Scheme
5, B).
Esterification was further investigated with various
reagents. Acetylation of 1 was attempted using an
activated ester, p-nitrophenyl acetate, which turned out
to be a far more sluggish acylating agent than acyl
chlorides. Under similar conditions (0.2 M in CDCl3, rt),
it took hours to react appreciably, while reaction with
acetyl chloride was complete right after mixing. Fur-
thermore, monoesters were only 10% of the acylation
mixture, exhibiting a secondary/primary ratio of 0.36:1.
Quench with 2a was fast, but preferentially gave the
primary acetate (secondary/primary ) 0.22:1). Acylation
with benzoyl bromide (Table 1, entry 6) did not show any
appreciable reactivity difference when compared to acyl-
ation with 2a , except for a somewhat slower quench with
5a , which was complete in 2 h under analogous condi-
tions. Reaction of 1 with acetic anhydride (0.3 M in
CDCl3, rt) was complete at the first check after 6 min,
but only 30% of the reaction mixture consisted of stannyl
mono esters, predominantly the primary acetate (second-
F igu r e 1. Quench of a mixture of stannyl monoesters 3a and
4a with 5a at room temperature, monitored by 1H NMR vs
time. Only the PhCHO region is shown. DB: 1-phenyl-1,2-
ethanediol bis(p-nitrobenzoate).
Ta ble 1. Regioisom er Distr ibu tion in th e Acyla tion of
1-P h en yl-1,2-eth a n ed iola
entry
RCOX
3:4
R1Cl
6:7
1
2
3
4
5
p-NO2-BzCl
p-NO2-BzCl
p-NO2-BzCl
p-NO2-BzCl
(p-NO2-BzCl +
p-MeO-BzCl)c
BzBr
3:1 AcCl
2:1 TMSCl
2:1 TMSCl (5 equiv) 7:1
3:1 p-MeO-BzCl
10:1
22:1
14:1b
7(NO2):1(MeO)
6
7
8
2:1 TMSCl
4:1 p-NO2-BzCl
3:1 p-NO2-BzCl
16:1
>99:1
99:1
AcCl
Br-AcCl
a
All reaction were run at rt in CDCl3, 0.3 M in substrate 1.
Determined by 13C NMR. c Pre-mixed reagents.
b
4a , quenched with an excess of acetyl chloride (5b),
showed complete reaction at the first check after 3 min
and afforded the mixed diesters 6b and 7b in a 10:1 ratio
(Table 1, entry 1). Quenching experiments showed a
reorganization, favoring products acylated on the second-
ary hydroxyl, that was more extensive the slower the
quench. This evidence suggested that selectivity could,
in principle, be modulated, up to complete monoacylation
of the secondary hydroxyl, by appropriately tuning the
reactivity of the acylating and the quenching reagents.
Results obtained with a variety of reagents are reported
in Table 1 and show that a very high level of selectivity
can indeed be obtained. While distribution of the stannyl
monoesters varied within a narrow range (2-4:1), that
of quenched regioisomers spanned a much broader range,
with secondary esters prevailing in all cases. Highest
selectivities were obtained by quenching acylation mix-
tures of aliphatic acyl chlorides with p-nitrobenzoyl
(13) (a) Corriu, R. J . P.; Guerin, C.; Moreau, J . J . E. In The
Chemistry of Functional Groups: The Chemistry of Organic Silicon
Compounds, Part 1; Patai, S., Rappoport, Z., Eds.; Wiley: Chichester,
1989; p 305. (b) Chuit, C.; Corriu, R. J . P.; Reye, C.; Young, J . C. Chem.
Rev. 1993, 93, 1371.

5260 J . Org. Chem., Vol. 61, No. 16, 1996
Roelens
ary/primary ) 0.6:1). Quench with 5a was complete right
after mixing, but gave only trace amounts of the second-
ary acetate. Comparative analysis of data lead to the
conclusion that the reactivity of the Sn-O bond, which
decreases in the order O-Sn-OR > O-Sn-OAc, O-Sn-
O(p-NO2-Ph) > O-Sn-Cl > O-Sn-Br, can be ap-
propriately explained in terms of electronegativity of
ligands on tin. Such electronegativity/reactivity order
accounts for the preferential formation of monoesters, due
to the deactivation of the second Sn-O bond with respect
to the first induced by the approach of a less electro-
negative Cl ligand. By the same argument, the larger
electronegativity of the Cl compared to the S ligands is
expected to induce a substantial activation of the second
Sn-S bond when dithiastannanes are reacted with acyl
chlorides, thus favoring diesterification. Such has indeed
been shown to be the case in the acetylation of 2,2-
dibutyl-1,3,2-dithiastannolane with acetyl chloride,14 in
which exclusive formation of the diester was observed,
caused by a large increase of reactivity of the second
Sn-S bond after the esterification of the first. However,
even if the reactivity of stannoxane reagents can be
accounted for, the need for halide ligands, which seems
to be a requirement for chemoselectivity reversal, is still
difficult to explain.
In conclusion, the stannylation procedure chemoselec-
tively activates hydroxyls toward the acyl group and, in
general, toward groups capable of reacting through an
addition-elimination mechanism. Stannoxanes are eas-
ily silylated and esterified and they exhibit a marked
preference toward acyl halides and anhydrides when
compared to esters but are largely inert toward sulfonyl
halides, alkylating reagents, and, most likely, other
electrophiles which are unable to give addition-elimina-
tion reactions. In the monoesterification of diols, the
presence of halide ligands on tin appears to be a
prerequisite for reversal of chemoselectivity.
Mech a n ism . To gain an insight into the observed
dynamic processes, a mixture obtained by reacting 1 with
1.2 equiv of 2a was submitted to variable temperature
experiments. An excess of acyl chloride was employed
to provide an amount of diester useful as internal
reference and to ensure complete consumption of the
starting dioxastannolane 1. Dynamic phenomena were
conveniently monitored through the PhCH signals, which
gave well-resolved resonances in a clean region of the 1H
NMR spectrum for all the species involved. Surprisingly,
no tendency toward coalescence was observed between
signals of 3a and 4a in the temperature range from -44
to 57 °C (Figure 2). Coalescence was instead observed
in the higher temperature range between signals of 3a
and 4a and those of the corresponding hydroxy esters 3*
and 4*, originating from destannylation caused by ad-
ventitious hydrolysis. On the other hand, a dramatic
variation of the 3a /4a ratio with temperature was
evident, rising to 19:1 at -44 °C and falling to 0.8:1 at
57 °C. Although lack of coalescence was apparently in
contrast, the full reversibility of the process unambigu-
ously demonstrated that the stannylesters were involved
in a fast exchange equilibrium with each other. It is
noteworthy that while at low temperature the secondary
monoester is strongly favored over the primary, at high
temperature such preference vanishes. Thus, the bulky
stannyl group preferentially resides on the less hindered
primary oxygen at low temperature, but this constraint
F igu r e 2. 1H NMR spectra of a mixture of 3a and 4a at
various temperatures. Only the PhCHO region is shown. DB:
1-phenyl-1,2-ethanediol bis(p-nitrobenzoate).
is progressively lost the higher the temperature. Such
preference is reasonably steric in origin; a support is
provided by the marked insensitivity of the 3a /4a ratio
to significant variation in electronic demand of the acyl
group (Table 1).
It is relevant to stress here that this is the picture
revealed in the absence of dioxastannolane 1. The
influence of the latter was investigated by adding 2a to
1 in subsequent portions, up to 1.2 equiv, and following
the stepwise formation of the intermediates at room
temperature. Inspection of the resulting spectra in
reverse order shows the effect corresponding to the
addition of incresing amounts of 1 to the mixture of
stannyl monoesters. In Figure 3, the spectra for various
1/(3a + 4a ) ratios are reported, ranging from the absence
to a 10-fold excess of 1. Coalescence of signals is
unambiguously observed, proving that 1 exerts the role
of increasing the rate of exchange between 3a and 4a .
On the contrary, hydroxy esters 3* and 4* are not
significantly affected by increasing amounts of 1. It can
be noted that the 3a /4a ratio is substantially insensitive
to variable excess of 1. Thus, only the rate of exchange
is affected by the latter, not the equilibrium position, so
the dioxastannolane behaves as a true catalyst for the
transesterification reaction. Unexpectedly, when a mix-
ture of 1, 3a , and 4a , appropriately prepared at such a
ratio of reagents as to be at coalescence of signals at room
temperature, was submitted to variable temperature
experiments divergence of signals for 3a and 4a was
observed with increasing temperature (Figure 4), as
would be expected for a decreasing rate of exchange. A
complex and not easily interpretable pattern of process
(14) Dalla Cort, A.; Mandolini, L.; Roelens, S. J . Org. Chem. 1992,
57, 766.

Organotin-Mediated Monoacylation of Diols
J . Org. Chem., Vol. 61, No. 16, 1996 5261
Sch em e 6
stannyl esters should be ascribed to the fast equilibria
of formation of the complex between 3 (and 4) and 1,
rather than to the transesterification equilibrium itself.
In the subsequent quench step, 3 and 4 are captured into
the corresponding stable regioisomers, according to their
specific reactivity toward 5. The secondary monoester 3
is therefore expected to react faster than 4, because of
the higher reactivity of the primary oxygen when com-
pared to the secondary. For comparable rates of in-
tramolecular transesterification and quench, the final
product distribution is determined by a combination of
relative rate and equilibrium constants, configuring a
Curtin-Hammett-type reaction scheme,15 in which the
more the secondary monoester 6 accumulates, the larger
the amount of 3 at equilibrium and the faster this is
established as compared to quench. The actual selectiv-
ity toward the secondary monoester 6 will range from a
minimum, corresponding to the equilibrium position
determined by the temperature, to a maximum of 100%,
depending on whether quench will be very much faster
or slower than equilibration, respectively. It appears that
the elucidation of the reaction mechanism allows for a
rationalization of the reversal of chemoselectivity and a
correct tuning of conditions to achieve optimum selectiv-
ity.
F igu r e 3. 1H NMR spectra of a mixture of 1, 3a , and 4a for
different 1/(3a + 4a ) ratios, ranging from the absence to a 10-
fold excess of 1. Only the PhCHO region is shown. DB:
1-phenyl-1,2-ethanediol bis(p-nitrobenzoate).
According to the pathway described in Scheme 6, the
first esterification step should preferentially afford the
primary monoester 4, owing to the greater reactivity of
primary vs secondary oxygens; 4 would subsequently
isomerize to the secondary monoester 3 through the
5-membered tetrahedral intermediate.16 If this were
true, it should, in principle, be possible to observe the
initial formation of 4 and its subsequent isomerization
to 3. Thus, 1 was reacted with 1 equiv of 2a at -40 °C,
monitoring the formation of 3a and 4a vs time. The
results reported in Figure 5 show the initial preferential
formation of the primary monoester 4a , which evolves
into the secondary 3a and approaches the equilibrium
position in ca. 1 h. At this stage, variable temperature
F igu r e 4. 1H NMR spectra of a mixture of 3a and 4a at
various temperatures in the presence of a 10-fold excess of 1.
Only the PhCHO region is shown.
freezing occurred below rt. The described results lead
to the formulation of a mechanism in which, after the
initial esterification step, complexation between 1 and
the stannyl monoesters 3 and 4 generates the active
species responsible for transesterification catalysis (Scheme
6). Apparent inconsistencies thus find an explanation,
since increasing concentration of 1 increases the amount
of active species, with corresponding rate increase; on the
other hand, temperature increase favors dissociation of
complexes, thus slowing the exchange rate. In this
context, broadening of lines observed in the spectra of
(15) For a comprehensive review on the Curtin-Hammett principle
and its analytical description, see: Seeman, J . I. Chem. Rev. 1983,
83, 83.
(16) Although tetrahedral intermediates have been established for
intramolecular reactions of substituted ethylene glycols (see, for
example: (a) Santry, L. J .; Azer, S.; McClelland, R. A. J . Am. Chem.
Soc. 1988, 110, 2909. (b) McClelland, R. A.; Seaman, N. E.; Cramm,
D. J . Am. Chem. Soc. 1984, 106, 4511), the present data do not allow
the assessment of this species as a real intermediate or a transition
state.

5262 J . Org. Chem., Vol. 61, No. 16, 1996
Roelens
Sch em e 7
tially acylated on the “natural” primary oxygen, providing
an unambiguous check for the proposed mechanism.
Th e Ca ta lytic System . Convincing evidence of the
formation of a complex between the starting dioxastan-
nolane and the stannyl esters and of its ability to catalyze
isomerization has been presented. Although the struc-
ture of such a complex is not yet experimentally avail-
able, a model that accommodates the present data can
be inferred.
Dioxastannolanes have been shown to form aggregates
in solution by associating on Sn-O bonds; aggregates,
predominantly dimers, self-stabilize by expanding coor-
dination at tin up to five and six.17 In the presence of
Bu2SnCl2, deaggregation occurs to form a 1:1 adduct
between the latter and dioxastannolane,8,11 indicating
that binding of chloride to tin stabilizes the stannyl
species to a greater extent than binding of oxygen
(Scheme 7). Analysis of spectra of dioxastannolane 1 in
the presence of Bu2SnCl2 analogously showed deaggre-
gation and formation of a 1:1 complex with the latter.
Shift of signals, reaching a maximum for a 1:1 molar
ratio, was markedly larger for CH2 than for CH, indicat-
ing that the complex is preferentially formed on the less
hindered Sn-O bond. While dioxastannolanes them-
selves are unable to exert catalytic activity,18 adducts
between dioxastannolanes and dibutyltin dichloride have
been shown to efficiently promote transesterification
reactions.8,11,18
1
F igu r e 5. Reaction of 1 with 2a at -40 °C monitored by H
NMR vs time. Only the PhCHO region is shown.
Using this information to model the active species
responsible for the intramolecular interconversion of the
stannyl intermediates 3 and 4, it appears that of the two
possible binding modes, depicted as A and B in Scheme
7, the former is preferred, involving one stabilizing Sn-
Cl interaction. This binding mode should activate the
reagent toward intramolecular nucleophilic addition to
the carbonyl, by enhancing the negative charge density
on the stannylated oxygen; the reverse should occur to
the disfavored adduct, which should be deactivated by
the electron-withdrawing effect of tin on the nucleophilic
oxygen. This model is in agreement with the reactivity
observed in transesterification, which follows the elec-
tronegativity order of ligands on the five-coordinate tin.
Thus, the stabilization provided by the binding of ligands
on tin is the driving force to the formation of the activated
F igu r e 6. 1H NMR spectra of (A) reaction mixture of 1 with
2a after 10 min at -40 °C and (B) reaction mixture of A
quenched at -40 °C with 5b (spectrum at rt). Only the PhCHO
region is shown.
experiments on the sample up to 52 °C showed the
expected reversible shift of the equilibrium position, along
with the slow formation of diester at the highest tem-
peratures. In a parallel experiment, the acylation mix-
ture, prepared and quenched with acetyl chloride both
at -40 °C, gave diesters 6b and 7b in a 0.65:1 ratio
(Figure 6). Thus, formation of the primary monoester
at low temperature and quench of the mixture before
equilibration can take place affords products preferen-
(17) (a) Roelens, S.; Taddei, M. J . Chem. Soc., Perkin Trans 2 1985,
799. (b) Luchinat, C.; Roelens, S. . J . Am. Chem. Soc. 1986, 108, 4873.
(c) Luchinat, C.; Roelens, S. J . Org. Chem. 1987, 52, 4444.
(18) Roelens, S. J . Chem. Soc., Chem. Commun. 1990, 58.

Organotin-Mediated Monoacylation of Diols
J . Org. Chem., Vol. 61, No. 16, 1996 5263
Sch em e 8
over a three-step pathway in which the dibutylstannylene
acetal of the starting diol plays the double role of reagent
and catalyst. The initially formed primary stannyl
monoester isomerizes to the secondary regioisomer,
thermodynamically more stable regioisomer, by over 4
kcal mol-1, through a fast intramolecular transesterifi-
cation equilibrium. Subsequent treatment with a quench-
ing reagent affords increasing amounts of a secondary
monoester the slower the quench. It has been shown that
selectivity can be optimized up to complete formation of
the secondary monoester by appropriately tuning the
reactivity difference between the acylating and the
quenching reagents. Thus, reversal of chemoselectivity
has been explained on the basis of the Curtin-Hammett
principle. It has been ascertained that the stannylation
procedure highly chemoselectively activates hydroxyl
groups toward acyl reagents, particularly acyl halides.
The reactivity of the Sn-O bond has been found to follow
the electronegativity order of ligands on tin, while halide
ligands have been found essential for reversal of chemo-
selectivity. A structure has been proposed for the
catalytic species that accounts for steric effects and the
observed reactivity.
stannyl ester A, while the reactivity of the latter de-
creases with decreasing electronegativity of ligands.
Scheme 6 can thus be expanded to include the equilibria
reported in Scheme 8.
This model also accounts for the relevance of steric
effects in this reaction. It can be seen in fact that the
bulk of the stannyl group increases dramatically in the
adduct. Such a conspicuous steric hindrance is reason-
ably the cause that biases the equilibrium toward the
secondary monoester in order to relieve strain. Having
the concentration ratios of the two regioisomers available
with reasonable accuracy in a significantly large tem-
perature range, an estimate of the stability gap between
the interconverting monoesters 3a and 4a can be at-
tempted. A plot of the ln K values vs 1/T for the
equilibrium constants measured from NMR data in the
investigated range of temperature gives van’t Hoff plot
of good linearity (r ) 0.981), with ∆H° ) 4.2 kcal mol-1
and ∆S° ) 12.8 eu. The enthalpy difference provides a
quantitative estimate of the preference for the most
stable secondary monoester, while the unexpectedly large
entropy difference that favors the primary monoester
accounts for the efficient compensation of contributions,
which level off at ca. 50 °C to afford equally abundant
regioisomers.19
Exp er im en ta l Section
Ma ter ia ls. 4-Phenyl-2,2-dibutyl-1,3,2-dioxastannolane (1)
was prepared and purified as previously described.17b Acetyl
chloride (Carlo Erba RPE, 99+%), benzoyl bromide (Aldrich,
97%), bromoacetyl chloride (Aldrich, 98%), 4-nitrophenyl
acetate (Fluka, >99%), p-anisoyl chloride (Aldrich, 99%), and
methyl trifluoromethanesulfonate (Aldrich, 99+%) were used
without further purification. 4-Nitrobenzoyl chloride (Aldrich,
98%) was used as such or purified by filtering off the insoluble
fraction of a concentrated solution in toluene and subsequently
evaporating the solvent. Chlorotrimethylsilane (Carlo Erba
RPE) was used as such or distilled over quinoline. Methane-
sulfonyl chloride (Aldrich, 99+%) was purified by distillation.
Gen er a l. Standard acylation and quench procedures, isola-
tion, and characterization of products have been described
elsewhere.6 All reactions were run in CDCl3 (Merck, 99.8%)
stored on activated 13 X molecular sieves and Ag foil. Room
temperature 1H NMR spectra were run at 200 MHz. Variable
temperature experiments and kinetic measurements were
carried out at 300 MHz. Reactions were performed in 5 mm
screw-capped NMR tubes, mixing the reactants with syringes
through a septum cap. Variable temperature experiments
were carried out under an inert atmosphere; this was not
necessary for room temperature experiments. For all the
experiments, mixing of reactants was carried out batchwise
by injecting the solution of one reagent onto the other, neat
or in solution depending on the reactivity of the substrate, so
as to achieve a 0.3 ( 0.1 M concentration in each of the two
reagents. Subsequent quench was carried out quantitatively
by transferring with a syringe the mixture into a second screw-
capped tube containing the appropriate amount of quenching
reagent. Reproducibility of the results was checked by per-
forming each experiment at least in duplicate and using
different lots of reagents when possible. Taking into account
variable extent of adventitious hydrolysis and diester forma-
tion due to reactants unbalance, results were satisfactorily
reproducible.
In conclusion, the structure proposed for the catalytic
adduct is consistent with the observed reactivity, explains
steric effects, and adequately represents the key inter-
mediate responsible for the reversal of chemoselectivity.
Con clu sion s. The investigation of the mechanism of
the organotin-mediated monoacylation of diols has re-
vealed that product distribution is determined by an
interplay between kinetic and thermodynamic control
(19) It must be emphasized, however, that the reaction scheme
consists of a system of multiple equilibria that, besides intramolecular
transesterification, involve association processes with 1. According to
this scheme, the measured concentration ratios are not directly
amenable to a “true” equilibrium constant, but only to an “apparent”
global constant. Thus, thermodynamic parameters may appear anoma-
lous in value, being the net result of a complex situation. The entropy
difference, in particular, exhibits an unexpectedly large value for an
isomerization reaction; this might be due to contributions from
dissociation equilibria, reasonably unbalanced between the two iso-
mers. Clearly, the multiple equilibria system is too complex for a
quantitative treatment. Analytical relationships show however that
concentration ratios are dependent, inter alia, on the equilibrium
concentration of 1; the estimated thermodynamic parameters are
therefore meaningful for the set of conditions used, but may vary with
the concentration of 1. Fortunately, such does not seem to be the case,
as shown by the experiment described in Figure 3, so that the overall
thermodynamic analysis is correct.
Ack n ow led gm en t. The author is grateful to Profes-
sor L. Mandolini at the University of Roma “La Sapi-
enza” for discussion and helpful suggestions in the
preparation of the manuscript.
J O960453F