Sodium borohydride and vinyl triflates of α-keto esters: A new combination toward monoalkylated 1,2-diols

Article abstract of DOI:10.1016/S0040-4039(02)00120-X

NaBH₄ converts a range of methyl 2-trifluoromethanesulfonyloxy 3-substituted propenoates to the corresponding monoalkylated 1,2-diols smoothly with total regiocontrol.

Full text of DOI:10.1016/S0040-4039(02)00120-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1657–1660
Sodium borohydride and vinyl triflates of a-keto esters:
a new combination toward monoalkylated 1,2-diols
Vincent Dalla* and Bernard Decroix
Unite´ de Recherche en Chimie Organique et Macromole´culaire, Faculte´ des Sciences et Techniques de l’Universite´ du Havre,
25 rue Philippe Lebon, BP 540, 76058 Le Havre cedex, France
Received 18 December 2001; revised 10 January 2002; accepted 16 January 2002
Abstract—NaBH4 converts a range of methyl 2-trifluoromethanesulfonyloxy 3-substituted propenoates to the corresponding
monoalkylated 1,2-diols smoothly with total regiocontrol. © 2002 Elsevier Science Ltd. All rights reserved.
Vinyl triflates have emerged as very important substruc-
tures in organic synthesis during the two last decades,
and their use has notably culminated in carbonꢀcarbon
bond forming processes through transition-metal-cata-
lyzed cross coupling reactions with nucleophilic part-
ners.1 Curiously, organic compounds bearing a vinyl
triflate adjacent to an electrophilic functional group
have not been frequently exploited, despite the promis-
ing potential that such densely functionalized units
could offer.2 Notably, non-coupling tandem reactions
are expected for vinyl triflates of a-keto acid derivatives
due to the presumed high Michael acceptor capacity of
such compounds, and the exceptional leaving group
properties of the triflate group. While vinyl triflates of
b-keto esters have been elegantly exploited in the syn-
thesis of stereocontrolled enynes,3 the chemistry of
vinyl triflates of a-keto esters remains relatively
dormant.4
of the vinyl triflate 1a into the monomethoxy diol 2a
(Scheme 1).
The reaction proved very rapid, yielding 2a within 5
min as a sole regioisomer in 50% yield. However, 2a
was accompanied by the side-products 3a and 4a (Fig.
1) from which it could be easily separated by flash
chromatography (FC).
Obviously, a conjugate addition of hydride occurred
initially,5 and this was followed by multiple hydride
addition with concomitant functional group recombina-
tion. The mechanism will be debated in the last part of
the article.
The question then arose whether NaBH4 could process
a variety of such compounds to afford the correspond-
ing monoprotected diols in mild conditions.
The high potential of such compounds led us to explore
their tandem reactions. The work presented here was
inspired by the known 1,4-addition of sodium borohy-
dride to conjugated esters a-substituted by an electron-
withdrawing group.5 In the context of our recent
studies on borohydride reductions of esters,6–8 we felt
that applying this process to vinyl triflates of a-keto
esters may set the stage for tandem reactions since the
resulting addition products will combine two contigu-
ous highly electrophilic centers. Therefore, we decided
to begin exploring the chemistry of vinyl triflates of
a-keto esters in the field of borohydride reductions. To
our satisfaction, our first experiment led us to discover
an unprecedented reaction, that is the transformation
We report herein our preliminary results demonstrating
that NaBH4 combines with vinyl triflates of a-keto
Scheme 1.
Figure 1.
* Corresponding author. Tel.: +0-02-32-74-44-03; fax: 0-02-32-74-43-
91; e-mail: vincent.dalla@univ-lehavre.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00120-X

1658
V. Dalla, B. Decroix / Tetrahedron Letters 43 (2002) 1657–1660
correspond to the use of 3 equiv. of NaBH4, with
ethanol as the solvent at room temperature. With the
optimized conditions in hand, we next turned our atten-
tion toward evaluating the possibility of processing
other analogous methyl esters. Five triflates 1b–f were
synthesized (Scheme 2), either by direct triflation of the
parent keto esters6 (1b–e) or by sequential desilylation–
triflation reactions12 (1f) from the corresponding
enoxysilanes.8
esters to provide a reliable method of formation of
monoalkylated 1,2-diols. We also discuss the mecha-
nism of the reaction.
In order to optimize the reaction, we performed a first
set of experiments with 1a on a 1 mmol scale (Table 1).
It can be seen that using a large excess of reductant did
not improve the production of 2a; the optimum yield
was obtained with 3 equiv. of NaBH4 (run 3 versus 4).
Reducing the stochiometry of NaBH4 led to incomplete
conversion and low yield of 2a (runs 1 and 2 versus 3).
The triflations were readily achieved within less than 5
min at 0°C either by using the DiPEA/Tf2O procedure
or a strong base/HMPA/PhNTf2 system. In the latter
case, NaH, NaHMDS and LiHMDS were equally
effective as the base. The reaction did not proceed in
the absence of HMPA. The six vinyl triflates used in
this work were stable, they could be purified by FC and
stored for months at room temperature (1a–e) or in the
freezer (1f) without notable decomposition. 1b–f were
treated in our standard procedure and results are col-
lected in Table 2.
No significant effect was observed when NaBH4 was
added at −80°C and the temperature subsequently
allowed to slowly rise, 2a being isolated in this case in
a comparable yield (run 5 versus runs 3 and 4). Runs 6
and 7 show that neither working at higher concentra-
tion nor on larger scale appreciably affected the out-
come of the reaction, both in terms of yield and
regiocontrol.9,10 On the other hand, heating the ethano-
lic solution prior to adding NaBH4 proved to be
slightly detrimental, some new side-products11 being
formed at the expense of 2a whose yield fell to 38%
(run 8). EtOH substitution for MeOH or THF as the
solvent met with poor success (runs 9, 10), particularly
for the last case wherein new by-products appeared.11
When NaBH4 was exchanged for LiBH4 as the reduc-
tant, the reaction profile was similar as above, but a
slight improvement of the proportion of the impurities
3a and 4a versus 2a was observed (run 11 versus 3).
With the hope of suppressing 3a and 4a, the less
reactive triacetoxy sodium borohydride and cyanoboro-
hydride were tested. Unfortunately, both of them left
1a untouched after 24 h (runs 12 and 13). In conclusion
to this first set of experiments, the optimal conditions
Scheme 2. (i) Tf2O, Pri2NEt, CH2Cl2, 0°C, 5 min, >85% (or
NaH, THF, HMPA, PhNTf2, 0°C, 5 min, >85%); (ii) CsF,
CH3CN, AcOH.
Table 1. Reaction of 1a with hydrides in various conditionsa
Run
Reductant (equiv.)
Solvent
Yields (%)b
3a
Conv. (%)
2a
4a
1
2
3
4
NaBH4 (1)
NaBH4 (2)
NaBH4 (3)
NaBH4 (10)
NaBH4 (3)
NaBH4 (3)
NaBH4 (3)
NaBH4 (3)
NaBH4 (3)
NaBH4 (3)
LiBH4 (3)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
THF
17
29
24
15
26
68
100
100
100
100
100
100
100
40
50
49
54
50
52
38
19
–
10
19
9
5c
6d
7e
8f
Not isolated
Not isolated
Not isolated
9g
10h
11
12i
13i
10
12
18
–
–
26
8
–
–
100
100
0
EtOH
EtOH
EtOH
39
–
Trace
NaB(OAc)3 (3)
NaBH3CN (3)
–
B95
a Without any comments, the reactions were performed on a 1 mmol scale (370 mg) at a concentration of 0.2 M at rt for a period of 15 min.
b Isolated yields are given.
c NaBH4 was added at −80°C, then the temperature was allowed to rise to rt.
d The reaction was performed on a 1 mmol scale at a concentration of 1 M.
e The reaction was performed on a 1 g scale.
f The mixture was heated to reflux prior to add NaBH4.
g The reaction was pursued for an additional 45 min.
h The reaction was allowed to stir for 17 h.
i The reaction was allowed to stir for 24 h.

V. Dalla, B. Decroix / Tetrahedron Letters 43 (2002) 1657–1660
1659
Table 2. Reaction of various esters 1b–f with NaBH4 in
As a consequence of the increased formation of diol
monoethers 2b–f as compared with the model 1a, com-
mon types 3 and 4 by-products were uniformly pro-
duced in lower yields than previously (runs 1–5 versus
run 3 in Table 1). The two para-substituted substrates
1c and 1d led to the methyl ethyl acetals 5c–d (Fig. 2) in
non negligible amounts (10 and 11%, respectively),
providing revealing information about the mechanism
(see later).
optimized conditionsa
Run
R
1
2 (%)b
3 (%)
2 (%)
1
2
3
4
5
Ph
1b
1c
1d
1e
1f
2b (60)
2c (65)
2d (63)
2e (71)
2f (55)
3b (25)
3c (14)
3d (20)
3e (17)
3f (18)
4b (4)
4c (2)
4d (2)
4e (5)
4f (10)
4-ClC6H4
4-NO2C6H4
3-NO2C6H4
Furyl
a The reactions were performed at rt on a 1 mmol scale for a period
The mechanism of formation of the main products 2, 3
and 4 may be explained as follows (Scheme 3): conju-
gate hydride addition5 would give the saturated triflate
I. Once formed, this transient compound could evolve
according to three routes. The first involves nucle-
ophilic substitution (SN) of the triflate by a hydride,
providing the propionyl esters 3 (path a). Another
possibility is monoreduction of the ester function lead-
ing to hemiacetal II, followed by intramolecular SN2
ring closing to produce a highly reactive oxiranyl acetal
III which is opened regiospecifically by hydride delivery
in a final stage (path b). The third route involves an
ester reduction which provides the monotriflyloxy diol
IV. After SN by a hydride, the latter gives the alcohols
4 (path c).
of 15 min.
b Isolated yields are given.
Figure 2.
Additional proof for this mechanism is provided by the
sequential two-step reaction depicted in Scheme 4. Trifl-
ation of the a-hydroxy methyl ester 6 derived of benzyl
pyruvic acid gave the expected triflate I quantitatively.
Without purification, the latter was submitted to
NaBH4
reduction
to
provide
the
expected
monomethoxy diol 2b along with the acetal 5b and the
ester 3b in overall 50, 20 and 12% yield, respectively. In
this experiment, the alcohol 4b was only isolated in
trace amounts.
Path b is further supported by the identification in
certain cases, notably in the above reaction (Scheme 4),
of type 5 methyl ethyl acetals whose formation can be
explained by the opening of intermediate III by the
ethoxide formed from the interaction between NaBH4
and ethanol.
Scheme 3.
The distribution of products is the result of a subtle
balance between the three pathways described above,
which may be largely governed, at a first extent, by
electronic factors (see Table 1, run 3 versus Table 2,
runs 1–4). By comparing the combined yields of 2 and
4 with those of 3, it appears that intermediates I
consistently undergo the ordinary slow reduction of the
ester (paths b and c),6,7 faster than the normally favor-
able SN process (path a). This attests the exceptional
propensity of the triflate to activate the adjacent car-
bonyl center to nucleophilic addition.
The unsubstituted phenylic substrate 1b proved slightly
superior to the electron-rich model 1a, and gave the
expected product in 60% yield (run 1 versus 3 in Table
1). Electron-deficient aromatic triflates 1c–e were
exceedingly reactive since they disappeared totally
within less than 1 min and furnished the desired prod-
ucts 2c–e in fair yields (runs 2–4). Finally, the reaction
was also compatible with heteroaromatic esters, as illus-
trated by the furanic substrate 1f (run 5).
Scheme 4.

1660
V. Dalla, B. Decroix / Tetrahedron Letters 43 (2002) 1657–1660
This unusual reaction involves four successive one-pot
procedures, and offers a facile new route to monopro-
tected diols. Beside its synthetic interest, the work
reported herein emphasizes the intuitive powerful
capacity of the triflate group to boost the electrophilic
character of a contiguous center. This finding comple-
ments the exceptional leaving group properties of the
triflate group13 and expands the scope of the fascinating
chemistry of triflates.
6. Dalla, V.; Cotelle, P.; Catteau, J. P. Tetrahedron Lett.
1997, 38, 1577–1580.
7. Dalla, V.; Pale, P.; Catteau, J. P. Tetrahedron Lett. 1999,
40, 5193–5196.
8. Dalla, V.; Catteau, J. P. Tetrahedron 1999, 55, 6497–
6510.
9. Typical procedure and data illustrating the 1 g scale
experiment (Table 1, entry 7): NaBH4 (306 mg) was
added in one portion to a solution of 1a (1 equiv.) in
ethanol (15 ml). The reaction was monitored by TLC and
after total consumption of the starting material (5 min),
the solution was carefully hydrolyzed by using water
initially (10 ml) and then a volume of an aqueous solu-
tion of hydrochloric acid 1 M (11 ml, 4 molar equiv.).
Ether (25 ml) was added and the mixture was stirred for
30 min. The aqueous phase was saturated by sodium
chloride and extracted three times with ether. The organic
layer was washed with 10 ml of an aqueous solution of
sodium hydrogenocarbonate 1 M and then with 10 ml of
brine. After drying over sodium sulfate, filtration and
evaporation, the crude mixture was purified by flash
chromatography (gradient 7:3 to 5:5 hexane–ethyl ace-
tate).
In summary, we have shown that reaction of NaBH4
and vinyl triflates of a-keto methyl esters provides a
new, totally regiocontrolled and mild access to
monomethoxy 1,2-diols. Due to easy access to a-keto
esters,14 this reaction holds promise in organic synthesis
and should expand the scope of NaBH4 reactions and
triflate chemistry. A study aimed at developing the
synthetic potential of this new reaction by addressing
other esters (allyl, benzyl, silyl) and amides is currently
underway in our laboratory and will be reported in due
course.
3-[3,4-Dimethoxyphenyl] 2-hydroxy 1-methoxy propane
2a: Yield 50%. Colorless oil. The H NMR spectrum of
Acknowledgements
1
2a was identical to that of the enantiopure analogue
1
described in Ref. 10: H NMR (200 MHz, CDCl3): l 2.3
The authors thank Dr. Jean-Christophe Plaquevent
(IRCOF, University of Rouen) for helpful discussions
and Dr. Ivan Jabin (URCOM) for improving the level
of the manuscript.
(s, large, OH), 2.7 (d, J=6.7 Hz, 2H), 3.28 (dd, J=9.5
Hz, J=7.1 Hz, 1H), 3.38 (s, 3H), 3.39 (dd, J=9.5 Hz,
J=3.5 Hz, 1H), 3.84 (s, 3H), 3.85 (s, 3H), 3.95 (dtd,
J=7.1 Hz, J=6.7 Hz, J=6.7 Hz, J=3.5 Hz, 1H), 6.7–
6.82 (m, 3H).
10. Jungen, M.; Gais, M. J. Tetrahedron: Asymmetry 1999,
10, 3747–3758.
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