Biomass conversion to high value chemicals: From furfural to chiral hydrofuroins in two steps

Article abstract of DOI:10.1021/ol3018402

Catalytic asymmetric transfer hydrogenation of rac-furoin and furil produces hydrofuroin with up to 99% ee and 9:1 dr. This reaction provides an exceptionally easy access to optically active hydrofuroins in two straightforward steps from biomass-derived f

Full text of DOI:10.1021/ol3018402

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Biomass Conversion to High Value
Chemicals: From Furfural to Chiral
Hydrofuroins in Two Steps
ꢀ
Anzhelika Kabro, Eduardo C. Escudero-Adan, Vladimir V. Grushin,* and
Piet W. N. M. van Leeuwen*
Institute of Chemical Research of Catalonia (ICIQ), Av. Paısos Catalans 16,
¨
Tarragona 43007, Spain
vgrushin@iciq.es; pvanleeuwen@iciq.es
Received July 5, 2012
ABSTRACT
Catalytic asymmetric transfer hydrogenation of rac-furoin and furil produces hydrofuroin with up to 99% ee and 9:1 dr. This reaction provides an
exceptionally easy access to optically active hydrofuroins in two straightforward steps from biomass-derived furfural (global production
200 000ꢀ300 000 t annually) using benzoin condensation.
The modern chemical industry is almost entirely based
onpetrochemicalfeedstock. Asthe limited natural supplies
of crude oil run out fast, there is an increasing need to
develop routes to chemicals, materials, and fuels from
renewable feedstock such as biomass.1 Although consider-
able progress has been made in the area of Green Chem-
istry, the development of new industrially feasible methods
for efficient biomass conversion to useful fine chemicals
remains a challenge that is being actively pursued.
nonedible biomass, including crop residues (e.g., corncobs)
and waste aqueous hemicellulose solutions from the pulp
and paper industry and cellulosic ethanol manufacturing.
Current annual production of furfural amounts to ap-
proximately 200 000ꢀ300 000 t,3a and the global produc-
tion capacity is estimated at 500 000 t. It has been noted4
that the modern technologies using continuous two-zone
biphasic reactors might produce furfural at $366 per t, just
one-quarter of its current, already low selling price on the
U.S. market.
Furfural (furan-2-carboxaldehyde; 1)2,3 is one of the
most readily available individual organic compounds from
All of the above makes furfural a particularly attractive
candidate for use as a starting material for industrially
viable chemical transformations. Although the chemistry
of furfural is very well developed,2 there is a significant
need for new applications of this readily available simple
aldehyde, especially for the preparation of high-value
materials such as optically active compounds. Herein we
report a highly efficient, chemo- and stereoselective synth-
esis of chiral hydrofuroins via asymmetric transfer hydro-
genation of racemic furoin and furil that are easily
prepared from furfural in one step.
(1) For selected books, see: (a) Hood, E. E.; Nelson, P.; Powell, R.,
Eds. Plant Biomass Conversion; Wiley-Blackwell: Chichester, 2011.
(b) Brown, R. C., Ed. Thermochemical Processing of Biomass: Conversion
into Fuels, Chemicals and Power; John Wiley & Sons: Chichester, 2011.
(c) Lancaster, M. Green Chemistry: An Introductory Text; RSC Publishing:
Cambridge, U.K., 2010. (d) Clark, J. H., Deswarte, F., Eds. Introduction to
Chemicals from Biomass; John Wiley & Sons: Chichester, 2008. (e) Anastas,
P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford
University Press: New York, 1998.
(2) For a monograph, see: Zeitsch, K. J. The Chemistry and Technol-
ogy of Furfural and its Many By-Products; Sugar Series, Vol. 13; Elsevier:
Amsterdam, 2000.
(3) For selected most recent reviews, see: (a) Karinen, R.; Vilonen,
K.; Niemelae, M. ChemSusChem 2011, 4, 1002. (b) Martel, F.; Estrine,
B.; Plantier-Royon, R.; Hoffmann, N.; Portella, C. Top. Curr. Chem.
2010, 294, 79. (c) Corma, A.; Iborra, S.; Velty, A. Chem. Rev. 2007, 107,
2411. (d) Hoydonckx, H. E.; Van Rhijn, W. M.; Van Rhijn, W.; De Vos,
D. E.; Jacobs, P. A. Furfural and derivatives. Ullmann’s Encyclopedia of
Industrial Chemistry; Wiley-VCH: Weineheim, 2007.
Benzoin condensation of furfural is known2,5 to give
furoin (2) in up to quantitative yield. We hypothesized that
asymmetric reduction of the carbonyl group of furoin
(4) Xing, R.; Qi, W.; Huber, G. W. Energy Environ. Sci. 2011, 4, 2193.
r
10.1021/ol3018402
XXXX American Chemical Society

would produce chiralhydrofuroin (3), therebyprovidingan
exceptionally easy entry to this valuable diol (Scheme 1).
Note that optically active C2-symmetric 1,2-diols are ex-
cellent chiral inducers in various types of asymmetric
transformations.6 While both (R,R)-(þ)-hydrobenzoin
and (S,S)-(ꢀ)-hydrobenzoin are commercially available
and find numerous applications,7 no practical synthetic
methods have been reported for hydrofuroins of high
optical purity. Thus, asymmetric pinacol coupling of fur-
fural to hydrofuroin, catalyzed by chiral Ti8 and V9 com-
plexes, provided an enantioselectivity of only 50% and
37%, respectively. The asymmetric reduction of furil with
Me2SBH3 in the presence of a chiral oxazaborolidine
furnished 3 with excellent ee > 99% (de = 78%).10
However, a high chiral catalyst loading of 20 mol % was
needed and the chemical yield achieved was only 70%.
lack of reports on a similar process involving furan deri-
vatives is unsurprising, considering the well-recognized
and long-established13 fact that furan derivatives differ
considerably from their benzene analogues in terms of
chemical reactivity and stability. Furthermore, the pre-
sence in 2 and 3 of oxygen atoms in a potentially strongly
chelating arrangement, along with the oxophilicity of
ruthenium, casts serious doubts on the success of Ru-
catalyzed ATH of furoin to hydrofuroin. Nonetheless,
we attempted ATH of 2 to 3 and, to our delight, obtained
results that surpassed our expectations.
We found that ATH of rac-furoin was efficiently cata-
lyzed by Ru complex 4a and its analogues 4b and 4c,14
as well as by Ir complex 5 (Scheme 2). Results of these
experiments are summarized in Table 1.
Scheme 2. Chiral Catalysts Used in this Work
Scheme 1. Two-Step Synthesis of Hydrofuroin from Furfural
Among various methods for the synthesis of chiral
1,2-diols, metal-catalyzed Asymmetric Transfer Hydroge-
nation (ATH) of the corresponding prochiral R-diketones
or R-hydroxy ketones is considered to be particularly
convenient and efficient.11 A highly efficient synthesis of
(R,R)-hydrobenzoin from rac-benzoin (or benzil) has
been developed12 via ATH with a mixture of triethylamine
(Et3N; TEA) and formic acid (HCO2H; FA), catalyzed
by [RuCl(p-cymene)((S,S)-TsDPEN)] (4a; TsDPEN =
N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine). The
In the commercially available azeotropic mixture TEAF
(FA/TEA = 5:2 mol/mol), ATH of rac-2 smoothly oc-
curred in the presence of 4a (0.5 mol %) to give hydro-
furoin (þ)-3 in 97% isolated yield with 99% ee and 76% de
after 2 h at 60 °C (Table 1, entry 1; for absolute config-
uration assignment, see below). This level of selectivity
is apparently due to the dynamic kinetic resolution of
rac-furoin, as in the previously reported ATH reactions
of racemic benzoin12b and aryl-substituted R-hydroxy
ketones.15
While nearly identical results were obtained with 0.4 mol
% of 4a, further catalyst loading reduction to 0.3 mol %
under otherwise identical conditions significantly affected
both the rate and stereoselectivity of the reaction (entries
2 and 3). A similar effect was observed when 4b was
employed as the catalyst (entries 5 and 6). Therefore,
to achieve high chemical yields and stereoselectivity both
4b and 4c were used in the amount of 0.5 mol % (entries 5
and 7). It has been reported12b,15 that ATH of aryl-
substituted R-hydroxy ketones in a freshly prepared
3.1:2.6 (mol/mol) mixture of FA/TEA can efficiently
proceed at 40 °C with as little as 0.1 mol % of 4a. When
we applied such conditions to the reduction of 2, full
conversion was reached after 24 h and the product with
99% ee and 80% de was isolated in 94% yield (entry 4).
(5) See, for example: (a) Stetter, H.; Raemsch, R. Y.; Kuhlmann, H.
Synthesis 1976, 733. (b) Lee, C. K.; Kim, M. S.; Gong, J. S.; Lee, I.-S. H.
J. Heterocycl. Chem. 1992, 29, 149. (c) Miyashita, A.; Suzuki, Y.;
Iwamoto, K.-i.; Higashino, T. Chem. Pharm. Bull. 1994, 42, 2633.
(d) Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743.
(e) Iwamoto, K.-i.; Hamaya, M.; Hashimoto, N.; Kimura, H.; Suzuki, Y.;
Sato, M. Tetrahedron Lett. 2006, 47, 7175. (f) Iwamoto, K.-i.; Kimura, H.;
Oike, M.; Sato, M. Org. Biomol. Chem. 2008, 6, 912. (g) Baragwanath, L.;
Rose, C. A.; Zeitler, K.; Connon, S. J. J. Org. Chem. 2009, 74, 9214. (h) Ma,
Y.; Xue, C. Huaxue Xuebao 2010, 68, 897. (i) Shimakawa, Y.; Morikawa,
T.; Sakaguchi, S. Tetrahedron Lett. 2010, 51, 1786.
(6) (a) Kolb, H.; VanNieuwenhze, M.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483. (b) Bhowmick, K. C.; Joshi, N. N. Tetrahedron:
Asymmetry 2006, 17, 1901.
(7) Okano, K. Tetrahedron 2011, 67, 2483.
(8) Chatterjee, A.; Bennur, T. H.; Joshi, N. N. J. Org. Chem. 2003, 68,
5668.
(9) Sun, J.; Dai, Z.; Li, C.; Pan, X.; Zhu, C. J. Organomet. Chem.
2009, 3219.
(10) Prasad, K. R. K.; Joshi, N. N. J. Org. Chem. 1996, 61, 3888.
(11) For recent reviews, see: (a) Gladiali, S.; Alberico, E. Chem. Soc.
Rev. 2006, 35, 226. (b) Morris, R. H. Chem. Soc. Rev. 2009, 38, 2282.
(c) Wu, X.; Wang, C.; Xiao, J. Platinum Metals Rev. 2010, 54, 3. (d) Wang,
C.; Wu, X.; Xiao, J. Chem.;Asian J. 2008, 3, 1750. (e) Malacea, R.; Poli,
R.; Manoury, E. Coord. Chem. Rev. 2010, 254, 729. (f) Noyori, R.;
Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. (g) Wills, M.; Palmer, M.;
Smith, A.; Kenny, J.; Walsgrove, T. Molecules 2000, 5 (1), 4. (h) Ikariya, T.;
Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300.
(13) Dunlop, A. P.; Peters, F. N. The Furans; Reinhold Publishing
Corporation: New York, 1953.
(14) (a) Catalysts 4aꢀc are commercially available. Well-defined
[RuCl(η6-arene)(N-TsDPEN)]-type complexes have been extensively
modified and found numerous applications.14b (b) For a recent review,
ꢁ
ꢀ
ꢁ
see: Vaclavık, J.; Kacer, P.; Kuzma, M.; Cerveny, L. Molecules 2011, 16,
5460.
(12) (a) Murata, K.; Okano, K.; Miyagi, M.; Iwane, H.; Noyori, R.;
Ikariya, T. Org. Lett. 1999, 1, 1119. (b) Ikariya, T.; Hashiguchi, S.;
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. ATH of Furoin, Catalyzed by Ru (4aꢀc) and Ir (5)
Table 2. ATH of Furil, Catalyzed by Ru (4aꢀc) and Ir (5)
Complexesa
Complexesa
cat.
t
yield
(%)
dl/
meso
ee, %
cat.
t
yield
(%)
dl/
meso
ee, %
methodb
(h)
(config)
entry
(mol %)
methodb
(h)
(config)
entry
(mol %)
1
4a (0.5)
4a (0.4)
4a (0.3)
4a (0.1)
4b (0.5)
4b (0.3)
4c (0.5)
4a (1.0)
5 (1.0)
A
2
97
96
86
94
93
7
88/12
88/12
68/32
90/10
87/13
85/15
81/19
59/41
63/37
66/34
62/38
59/41
57/43
56/44
99 (S,S)
99 (S,S)
93 (S,S)
99 (S,S)
99 (S,S)
98 (S,S)
95 (R,R)
95 (S,S)
91 (S,S)
93 (S,S)
93 (S,S)
93 (S,S)
92 (S,S)
94 (S,S)
1
4a (0.5)
4b (0.5)
4c (0.5)
4a (1.0)
5 (1.0)
5 (0.8)
5 (0.6)
5 (0.2)
5 (0.2)
5 (0.2)
5 (0.1)
A
2
96
93
96
24
89
87
93
91
63
64
58
90/10
85/15
82/18
74/26
81/19
82/18
82/18
86/14
87/13
90/10
92/8
99 (S,S)
99 (S,S)
98 (R,R)
98 (S,S)
97 (S,S)
97 (S,S)
97 (S,S)
97 (S,S)
97 (S,S)
98 (S,S)
98 (S,S)
2
A
4
2
A
2
3
A
24
24
2
3
A
3
4
B
4
B (5)
B (5)
B (5)
B (5)
B (5)
B (2)
B (5)
B (5)
48
0.7
0.7
1
5
A
5
6
A
48
2.5
18
24
3
6
7
A
92
63
57
96
91
95
95
86
7
8
C (5)
C (1)
C (2)
C (3)
C (5)
C (7)
C (5)
8
1.5
24
24
24
9
9
10c
11
10
11
12
13
14c
5 (1.0)
5 (1.0)
2
5 (1.0)
2
a See the Supporting Information for details and specifics. b A: molar
ratio 6/FA/TEA = 1/10/4, 60 °C. B: HCOONa (number of equiv in
parentheses) in H2O, 60 °C. c At 40 °C.
5 (1.0)
1
5 (1.0)
20
a See the Supporting Information for details and specifics. b A: molar
ratio 2/FA/TEA = 1/10/4, 60 °C. B: molar ratio 2/FA/TEA = 1/3.1/2.6,
40 °C. C: HCOONa (number of equiv in parentheses) in H2O, 60 °C.
c At 40 °C.
(entry 1). With complexes 4b and 4c, the reaction was also
highly enantioselective, albeit the dl to meso ratio was
lower (entries 2 and 3).
It has been recently shown11c,16 that Ir-, Rh-, and Ru-
TsDPEN complexes can catalyze ATH of simple aromatic
ketones with sodium formate in water with excellent ee of
up to 99%. These reports prompted us to examine both Ru
(4a) and Ir (5) catalysts generated in situ16b,c for ATH of 2
with HCOONa in water. However, while chemical yields
of up to 96% were obtained, these systems appeared
inferior in terms of both de and ee even at a high catalyst
loading (1 mol %) and in the presence of up to 7 equiv of
HCOONa (Table 1, entries 8ꢀ14).
Similar to the 4a-catalyzed ATH of 2 with aqueous
sodium formate (Table 1, entry 8), the reduction of 6 under
the same conditions occurred with high enantioselectivity
(98% ee), yet considerably lower diastereoselectivity (48%
de) and chemical yield (24%; Table 2, entry 4). The Ir
complex (5) appeared more efficient in the reaction of
furil.18 With only 1.0ꢀ0.2 mol % of 5, the reduction of 6
to 3 occurred in 63ꢀ93% chemical yield (entries 5ꢀ10)
with 97ꢀ98% ee and up to 80% diastereoselectivity. The
highest de of 84% was observed with only 0.1% of 5 in a
slower reaction that produced 3 in 58% yield after 24 h
(entry 11).
To demonstrate the generality of the method, we then
reduced substituted rac-furoins 7aꢀd to the corresponding
hydrofuroins 8aꢀd using the protocol developed for 2
(Table 3). With only 0.1 mol % of 4a these reactions
occurred with excellent enantioselectivity (99% ee) to
produce the diols in 59ꢀ92% chemical yield. The dia-
stereomeric ratio (dl/meso) varied from 90:10 for 8b to
83:17 for 8d bearing a more electron-deficient aryl sub-
stituent in the R-position of the furan ring.
Under certain conditions, benzoin condensation of fur-
fural coproduces furil (6),2,13,17 apparently because of air
oxidation of the primary product, furoin. Therefore, it was
important to study ATH of 6 to demonstrate the applic-
ability of the method not only to pure furoin but also to
furil. We were pleased to find that like 2, 6 can be cleanly
and stereoselectively reduced to 3 under similar conditions
(Table 2). For the Ru complexes 4aꢀc in TEAF, the
reaction smoothly proceeded with a substrate to a catalyst
molar ratio of 200 to give hydrofuroin 3 in nearly quanti-
tative yield with high stereoselectivity (entries 1ꢀ3). En-
antiomerically pure (þ)-3 (99% ee) containing only 10%
of the meso diastereomer was obtained using catalyst 4a
While dl-3 is a liquid at rt, its substituted analogues 8 are
crystallinesolids. Single-crystal X-ray diffraction of8athat
was isolated enantiomerically pure (>99% ee) from the
reduction of 7a (Table 3) allowed for the determination of
its absolute configuration. As shown in Figure 1, (þ)-8a is
(S,S) suggesting that this is the absolute configuration of
(16) (a) Wu, X.; Xiao, J. Chem. Commun. 2007, 2449. (b) Wu, X.; Li,
X.; Zanotti-Gerosa, A.; Pettman, A.; Liu, J.; Mills, A. J.; Xiao, J.
Chem.;Eur. J. 2008, 14, 2209. (c) Wu, X.; Li, X.; Hems, W.; King,
F.; Xiao, J. Org. Biomol. Chem. 2004, 2, 1818. (d) Wu, X.; Li, X.; King,
F.; Xiao, J. Angew. Chem., Int. Ed. 2005, 44, 3407.
(17) For a recent example of coproduction of 6 in the formation of 2
from 1 in a study of hydrogenation of 1, see: Strassberger, Z.; Mooijman,
M.; Ruijter, E.; Alberts, A. H.; Maldonado, A. G.; Orru, R. V. A.;
Rothenberg, G. Adv. Synth. Catal. 2010, 352, 2201.
(18) ATH of benzil with Ir/Rh-TsDPEN with formate in water to
give hydrobenzoin with 97ꢀ99% ee and unspecified de has been
reported.16b
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 3. ATH of Furoins 7aꢀd, Catalyzed by 4aa
t
yield
(%)
dl/
meso
ee, %
7
R1
R2
(h)
(config)
7a
7b
7c
7d
Me
Me
Ph
H
24
24
40
18
92
59
85
83
89/11
90/10
87/13
83/17
99 (S,S)
99 (S,S)
99 (S,S)
99 (S,S)
Me
H
Figure 1. ORTEP drawing of (S,S)-(þ)-8a with thermal ellip-
soids drawn to the 50% probability level.
3-CF3-C6H4
H
a Molar ratio 7/FA/TEA = 1/3.1/2.6. See the Supporting Informa-
tion for further details.
furoin product is then reduced to optically active hydro-
furoin via asymmetric transfer hydrogenation in the pre-
sence of readily available, inexpensive chiral Ru catalysts
(0.1ꢀ0.5 mol %). This asymmetric reduction occurs under
mild conditions with 99% ee and up to 80% de to furnish
(R,R)- or (S,S)-hydrofuroin that is easily isolated in
>90% yield. Notably, furil that is often formed as a side
product of benzoin condensation of furfural can also be
converted to hydrobenzoin with similar chemo- and
stereoselectivities under identical conditions and catalyst
loadings. The use of formic acid as the reducing agent is
particularly fitting, as HCOOH is a coproduct in the
furfural production from biomass. Considering the im-
portance of C2-symmetric 1,2-diols as chiral inducers in a
variety of asymmetric transformations, we hope that the
easy access to chiral hydrofuroins described herein23 will
lead to new practicable developments in the area.
all (þ)-hydrofuroins prepared in this work. Both the
Flack19 (x = ꢀ0.05(17)) and Hooft20 (y = 0.01(5)) param-
eters were employed. The obtained values of x and its
standard deviation are translated21 into 99.59% probabil-
ity for 8a being (S,S) in the crystal. In fact, this probability
is effectively 100%, as can be judged by the Hooft para-
meter. X-ray analysis of another single crystal from the
same batch of enantiomerically pure (þ)-8a confirmed its
absolute configuration as (S,S).22
In conclusion, we have developed the first two-step
synthesis of highly enantiomerically pure hydrofuroin
from furfural that is readily available in large quantities
from renewable resources. Furfural is first easily converted
to rac-furoin using well-known benzoin condensation. The
(19) Flack, H. D. Acta Crystallogr. 1983, A39, 876.
(20) (a) Hooft, R. W. W.; Straver, L. H.; Spek, A. L. J. Appl.
Crystallogr. 2008, 41, 96. (b) Spek, A. L. PLATON, A Multipurpose
Crystallographic Tool; Utrecht University: Utrecht, The Netherlands, 2010.
(21) Flack, H. D.; Bernardinelli, G. J. Appl. Crystallogr. 2000, 33,
1143.
Acknowledgment. We thank the ICIQ Foundation and
Consolider Ingenio 2010 (Grant CSD2006-0003) for sup-
port of this research.
(22) Our crystallographic studies of (þ)-8a suggest that the originally
reported10 and subsequently used8 assignment of the (S,S) configuration
to (ꢀ)-3 might be incorrect. The literature assignment10 was made by
analogy with hydrobenzoin while apparently overlooking the fact that
the formal replacement of the phenyls in (S,S)-PhCH(OH)CH(OH)Ph
with 2-furyls without any other changes produces (R,R)-hydrofuroin,
not the (S,S) form, as follows from the CahnꢀIngoldꢀPrelog priority
rules. It is also worth noting that although it has been reported8,10 that 3
“deteriorates rapidly at ambient temperature”, all diols obtained in our
work, 3 included, are stable compounds exhibiting no signs of
decomposition.
Supporting Information Available. Full details of the
synthetic procedures including spectral data (PDF) and
crystallographic studies of 8a (CIF). This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(23) Patent application (to ICIQ) filed.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX