Facile reduction of malonate derivatives using NaBH4/Br2: an efficient route to 1,3-diols

Article abstract of DOI:10.1016/j.tetlet.2007.12.001

Borane-dimethoxyethane generated from sodium borohydride-bromine mixtures efficiently reduces a wide range of malonate derivatives to the corresponding 1,3-diols. This new reagent system represents a milder alternative to current methods available, providing the requisite 1,3-diols in higher yields over shorter reaction times.

Full text of DOI:10.1016/j.tetlet.2007.12.001

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1041–1044
Facile reduction of malonate derivatives using NaBH4/Br2:
an efficient route to 1,3-diols
Matthew Tudge *, Hiroko Mashima, Cecile Savarin, Guy Humphrey, Ian Davies
Department of Process Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 25 October 2007; revised 29 November 2007; accepted 1 December 2007
Available online 4 December 2007
Abstract
Borane–dimethoxyethane generated from sodium borohydride–bromine mixtures efficiently reduces a wide range of malonate deriva-
tives to the corresponding 1,3-diols. This new reagent system represents a milder alternative to current methods available, providing the
requisite 1,3-diols in higher yields over shorter reaction times.
Ó 2007 Elsevier Ltd. All rights reserved.
The reduction of malonate derivatives is a convenient
method for the preparation of symmetrical 1,3-diols.1a–f
This reaction has received a significant amount of attention
over recent years and has been employed in numerous syn-
thetic efforts.1a,b Generally, powerful hydride reducing
agents such as lithium aluminum hydride1c and DIBAL1d
are employed to achieve this transformation. Unfortu-
nately, deactivation of these basic reagents via enolization
of the malonate starting materials often results in mixtures
of the desired 1,3-diol products and other higher oxidation
state reduction products.1f In an attempt to minimize the
formation of undesired side products, milder reagents such
as borane complexes2a–c have been utilized; however,
extended reaction times and large reagent excesses are
often required to obtain appreciable conversions.2b,c In
some cases this has been attributed to a-deprotonation of
the malonate by the borane complex.1c,3
Attempts to reduce malonate 1 to diol 2 via the mixed
anhydride4 or with the strong reducing agent, super-
hydride5 (Table 1, entries 1 and 2) provided none of
the desired product. Although Red-Al did reduce the
b-carboxyester functionality, concomitant removal of
the aromatic bromide was also observed affording exclu-
sively diol 3 (entry 3).6 To minimize these problems, the
commercially available reducing agents BH3ÁTHF2a and
BH3ÁDMS2b were investigated. Several unidentified by-
products in addition to the two cyclopropyl by-products
4 and 5 (entries 4 and 5) were obtained under these condi-
tions. These could be minimized to ca. 10% by preparing
the borane solution in situ from sodium borohydride and
boron trifluoride7 complexes (entries 6 and 7); however,
these conditions proved to be somewhat capricious afford-
ing the desired product in irreproducible quantities. Other
methods for producing borane solutions such as sodium
borohydride–iodine in THF8 (entry 8) resulted in the
formation of significant quantities of 4-iodo-butanol,8
cyclopropane by-products 4 and 5, and several other
unidentified products in variable amounts. The formation
of the 4-iodo-butanol impurity could be eliminated by
employing DME as a solvent; however, significantly
longer reaction times were required and increased quanti-
ties of the cyclopropane compounds 4 and 5 were observed.
Interestingly, when bromine was substituted for iodine
the cyclopropane by-products were only formed in
Recently, we required a highly efficient reduction of
malonate 1 to the corresponding diol 2, a key intermediate
in the synthesis of a potential drug candidate. Our preli-
minary investigations into this transformation are detailed
in Table 1.
*
Corresponding author. Tel.: +1 732 594 1944; fax: +1 732 594 1499.
E-mail address: matthew_tudge@merck.com (M. Tudge).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.001

1042
M. Tudge et al. / Tetrahedron Letters 49 (2008) 1041–1044
Table 1
Screen of standard reducing agents
HO
OH OH
H
OH OH
H
CO2H
+
MeO2C
CO2H
MeO2C
HO
H
Conditions
F
F
F
F
F
F
+
+
F
F
Br
Conditions
Br
Br
Br
Assay yield 2a (%)
1
2
3
4
5
Entry
1
2
3
4
5
6
7
8
9
a
NaBH4/iBuCO2Cl
Superhydride
Red-Al
—
—
0
<10
<10
50–90
BH3ÁTHF
BH3ÁDMS
NaBH4/BF3ÁOEt2
NaBH4/BF3ÁTHF
NaBH4/I2
ꢀ90
90 in THF 65 in DME
94–98
NaBH4/Br2
Assay yield was determined by HPLC calibrated with analytically pure product.
OH
X2 = Br2
X2 = I2
95%, 24 h
2%, 24 h
CO2Et
NaBH4 (5 eqiv.)
OH
CO2Et
X2, (2.2 equiv.)
X2 = Br2 + NaI (4 equiv.) 11% 48 h
DME
0 °C to 20 °C
6
7
Scheme 1.
small quantities (ꢀ5%) increasing the yield of the desired
product to ꢀ94%. Furthermore, the relative rate of the
reaction was higher, resulting in reaction times of around
3–4 h versus >24 h as in the sodium borohydride–iodine
reaction.
With a robust, practical reduction protocol established,
we began to evaluate other carboxylate derivatives bearing
functionality that has proven problematic for other meth-
ods. As shown in Table 2, the reaction cleanly reduced
phenylacetic acid, the corresponding ethyl ester and the
N-methylamide to their alcohol and amine products in
good yield (entries 1–3). More importantly, several chal-
lenging malonate derivatives were smoothly converted to
their corresponding 1,3-diols.
With this interesting result in hand, we decided to probe
the substrate scope of this reduction. We initially investi-
gated the curious discontinuity in rate between the reac-
tions with iodine and bromine. As shown in Scheme 1,
reduction of model diester 6 to diol 7 was carried out using
the sodium borohydride–bromine and the sodium borohy-
dride–iodine protocols described previously. As observed
for the more complex malonate derivative 1, the reduction
rate of diester 6 with NaBH4/Br2 was greater than that of
the NaBH4/I2 method affording 91% and 2% assay yields
of diol 7, respectively (Scheme 1). Since the sodium iodide
by-product was completely solubilized in DME, we sus-
pected that this may inhibit the reaction. Moreover, when
excess sodium iodide was added to the reaction significant
retardation of the rate was observed yielding only 11% of
product after 48 h at room temperature further supporting
our hypothesis. Indeed, theoretical studies by Frenking
et al. indicated that complexation of p-donor groups such
as iodide increases the hydride affinity of boron.9 In princi-
ple, this could lead to a reducing agent with much less
reduction potential than the corresponding borane–DME
complex.
Hindered malonates1b (entry 9), electron rich aryl malo-
nates1b,2d (entry 6) and nitro-aryl malonates1b,c (entry 7)
were readily reduced to their 1,3-diol derivatives in signifi-
cantly greater yield than previously obtained under existing
protocols.1b,c,2d As expected from our lead result, reduction
of other malonic acid derivatives using this protocol was
readily achieved (entries 5 and 10). In particular, the reduc-
tion of malonate derivative 8 (entry 10) described by Jar-
vest et al. had proved to be particularly problematic only
affording the desired diol in 31% yield.10a Pleasingly, our
improved procedure provided the diol product in 87%
yield.
In summary, we have developed a robust reduction of
esters, acids, amides and malonate derivatives using
NaBH4/Br2.11 In particular, challenging aryl malonates
proved to be excellent substrates for reduction providing
the corresponding 1,3-diols in high yield. Studies are cur-
rently underway to extend the scope of this methodology

M. Tudge et al. / Tetrahedron Letters 49 (2008) 1041–1044
1043
Table 2
Entry
Substratea
Productb
Ph
Temperature (°C)/time (h)
Isolated yield (%)
92c
OH
OH
1
2
À10 to 20/1.5
À10 to 20/1.5
Ph
Ph
CO2Et
CO2H
NHMe
93c
82d
Ph
Ph
NHMe
3
4
À10 to 20/48
Ph
O
OH
OH
CO2Et
0 to 20/24
91d
92d
Ph
Ph
CO2Et
Ph
Ph
OH
OH
CO2Me
CO2H
5
6
À10 to 20/0.5
OH
OH
CO2Me
CO2Me
0 to 20/24
91d
MeO
O2N
MeO
OH
OH
CO2Me
CO2Me
7
8
0 to 20/4
92d
O2N
Bn
OH
OH
CO2Et
CO2Et
0 to 20/15
98d
Bn
Ph
OH
CO2Et
9
0 to 20/15
91d
87d
OH
CO2Et
Ph
Me
Me
CO2Et
CO2H
OH
OH
10
À10 to 20/15
BnO
BnO
8
OH
CO2Et
11
0 to 20/15
88d,e
OH
CO2Et
a
All substrates were obtained commercially unless otherwise indicated.
All known products were characterized via direct comparison of 1H NMR data to the literature references detailed within the text, or commercially
b
available samples from Aldrich Chemical Co.
c
2.2 equiv NaBH4/1 equiv Br2 required.
5 equiv NaBH4/2.2 equiv Br2 required.
Characterized via comparison of melting point data11 and 1H NMR.
d
e
122, 10781; (d) Tercel, M.; Denny, W. A. J. Chem. Soc., Perkin
Trans. 1 1998, 3, 509; (e) Zhang, W.; Oya, S.; Kung, M.-P.; Hou, C.;
Maier, D. L.; Kung, H. F. J. Med. Chem. 2005, 48, 5980; (f)
Marshall, J. A.; Anderson, N. H.; Hochstetler, A. R. J. Org. Chem.
1967, 32, 113.
into other borane mediated processes, the results of which
will be reported in due course.
References and notes
2. (a) Yoon, N. M.; Pak, C. S.; Brown, H. C.; Krishnamurthy, S.;
Stocky, T. P. J. Org. Chem. 1973, 38, 2786; (b) Brown, H. C.; Choi, Y.
M. Synthesis 1981, 439; (c) Lewis, E. A.; Allan, C. C.; Boyle, R. W.;
Archibald, S. J. Tetrahedron 2004, 45, 3059; (d) Choi, Y. M.;
Kucharczyk, N.; Sofia, R. D. Tetrahedron 1986, 42, 6399.
1. (a) Lee, J.; Lee, J.-H.; Kim, S. Y.; Perry, N. A.; Lewin, N. E.; Ayres,
J. A.; Blumberg, P. M. Bioorg. Med. Chem. Lett. 2006, 14, 2022; (b)
´
Katz, C. E.; Aube, J. J. Am. Chem. Soc. 2003, 125, 13948; (c)
Fellows, I. M.; Kaelin, D. E.; Martin, S. F. J. Am. Chem. Soc. 2000,

1044
M. Tudge et al. / Tetrahedron Letters 49 (2008) 1041–1044
3. Choi, Y. M.; Emblidge, R. W. J. Org. Chem. 1989, 54, 1198.
11. General experimental procedure, Table 2 entry 5: To a cold (À20 °C),
stirred slurry of NaBH4 (946 mg, 25 mmol) in DME (10 mL) was
added bromine (0.565 mL, 11 mmol) dropwise over 1 h, maintaining
the exotherm between À20 and À10 °C. The slurry was stirred for 1 h
until the orange color disappeared to give a white slurry of sodium
bromide. At this point, the slurry was warmed to À5 °C and treated
with b-carboxyester 8 (971 mg, 5 mmol). The reaction was stirred for
30 min until no starting material remained by HPLC. The reaction
mixture was then added into a solution pre-cooled (5 °C) 1 N HCl
(15 mL) and isopropyl acetate (15 mL). The mixture was stirred for
5 min before separating the organic and washing sequentially with
2 N K2CO3 (3 Â 15 mL) and water (15 mL). The organic solution was
dried (Na2SO4) and concentrated to give the crude product. The crude
product was recrystallized from 3:1 heptane/MTBE to afford diol 7 as
a white solid. Mp: 52–53 °C, lit. 51–53 °C;3 1H NMR (400 MHz,
CDCl3) d: 7.37–7.24 (5H, m, 5 Â ArH), 4.00 (4H, m, 2 Â CH2), 3.12
(1H, tt, J = 7.5, 5.6 Hz, CH), 2.02 (2H, br s, 2 Â OH).
´
4. De Saint Laumer, J.-Y.; Frerot, E.; Herrmann, A. Helv. Chim. Acta
2003, 86, 2871.
5. Lane, C. F. Aldrichim. Acta 1974, 7, 32.
6. For examples of aromatic dehalogenation with aluminum hydride
reagents see: Karabatsos, G. J.; Shone, R. L.; Scheppele, S. E.
Tetrahedron Lett. 1964, 5, 2113.
7. (a) Brown, H. C. In Organic Synthesis Via Boranes; Aldrich Chemical
Co.: Milwaukee, 1997; Vol. 1; (b) Kanth, J. V. B.; Brown, H. C. Inorg.
Chem. 2000, 39, 1795.
8. Prasad, A. S. B.; Kanth, J. V. B.; Periasamy, M. Tetrahedron 1992, 48,
4623.
9. Frenking, G.; Fau, S.; Marchand, C. M.; Grutzmecher, H. J. Am.
¨
Chem. Soc. 1997, 119, 6648.
10. (a) Jarvest, R. L.; Barnes, R. D.; Earnshaw, D. L.; O’Toole, K. J.;
Sime, J. T.; Vere Hodge, R. A. J. Chem. Soc., Chem. Cummun. 1990,
555; (b) Rastetter, W.; Phillion, D. P. J. Org. Chem. 1981, 46, 3204.