Asymmetric hydroformylation of vinylfurans catalyzed by {(11bS)-4-{[(1R)-2′-phosphino[1,1′-binaphthalen]-2-yl]oxy} dinaphtho[2,1-d:1′,2′-f]-[1,3,2]dioxaphosphepin}rhodium(I) [Rh I{(R,S)-binaphos}] derivatives

Article abstract of DOI:10.1002/hlca.200690166

The asymmetric hydroformylation of 2- and 3-vinylfurans (2a and 2b, resp.) was investigated by using [Rb{(R,S)-binaphos}] complexes as catalysts ((R,S)-binaphos=(11bS)-4-{[1R)-2′-phosphino[1,1′-binaphthalen]-2-yl] oxy}dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin; 1). Hydroformylation of 2 gave isoaldehydes 3 in high regio- and enantioselectivities (Scheme 2 and Table). Reduction of the aldehydes 3 with NaBH₄ successfully afforded the corresponding alcohols 5 without loss of enantiomeric purity (Scheme 3).

Full text of DOI:10.1002/hlca.200690166

Helvetica Chimica Acta – Vol. 89 (2006)
1681
Asymmetric Hydroformylation of Vinylfurans Catalyzed by {(11bS)-4-{[(1R)-
2
’-Phosphino[1,1’-binaphthalen]-2-yl]oxy}dinaphtho[2,1-d:1’,2’-f]-
I
[
1,3,2]dioxaphosphepin}rhodium(I) [Rh {(R,S)-binaphos}] Derivatives
by Koji Nakano, Ryo Tanaka, and Kyoko Nozaki*
Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo,
-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
phone & fax: +81-3-5841-7261; e-mail: nozaki@chembio.t.u-tokyo.ac.jp)
7
(
Dedicated to Professor Giambattista Consiglio on the occasion of his 65th birthday
The asymmetric hydroformylation of 2- and 3-vinylfurans (2a and 2b, resp.) was investigated by using
Rh{(R,S)-binaphos}] complexes as catalysts ((R,S)-binaphos=(11bS)-4-{[1R)-2’-phosphino[1,1’-binaph-
[
thalen]-2-yl]oxy}dinaphtho[2,1-d:1’,2’-f][1,3,2]dioxaphosphepin; 1). Hydroformylation of 2 gave isoalde-
hydes 3 in high regio- and enantioselectivities (Scheme 2 and Table). Reduction of the aldehydes 3 with
NaBH successfully afforded the corresponding alcohols 5 without loss of enantiomeric purity (Scheme
4
3).
Introduction. – Transition-metal-catalyzed hydroformylation is one of the most
important reactions that transform a CÀC moiety to a formyl group, a versatile func-
tional group. In the last 15 years, many efforts have been devoted to develop new asym-
metric-hydroformylation catalysts, since optically active aldehydes are useful inter-
mediates for the synthesis of biologically active compounds as well as new chiral mate-
rials [1–4]. We have previously reported the asymmetric hydroformylation of a variety
of olefins such as styrene and its substituted analogs, 1,3-dienes, vinyl esters, N-vinyl-
phthalimide, and cyclic alkenes such as dihydrofurans and dihydropyrroles by using
I
[
Rh {(R,S)-binaphos}] complexes ((R,S)-binaphos=(11bS)-4-{[(1R)-2’-phos
A
H
R
U
G
binaphthalen]-2-yl]oxy}dinaphtho[2,1-d:1’,2’-f][1,3,2]dioxaphosphepin; 1) [5–10]. In
the field of hydroformylation, olefins with a heteroaryl group such as pyridyl
[
11–16], pyrrolyl [17–19], furanyl [20], and thienyl [21] groups have been found to
be employable to give the corresponding aldehydes. These aldehydes also have a poten-
tial utilization as synthetic building blocks: thus, (2R)-2-(furan-2-yl)propanal could be a
starting material to synthesize monensin (Scheme 1) [22]. In addition, (2S)-2-(furan-2-
yl)propan-1-ol, which should be obtained by reduction of the asymmetric hydroformy-
lation product of 2-vinylfuran, is a key starting material for the 1,10-seco-eudesmano-
lide synthesis [23][24]. However, asymmetric hydroformylation of vinylheteroarenes is
confined to that of vinylthiophene [25].
HI erein, we describe the asymmetric hydroformylation of vinylfurans 2 by using
[
Rh {(R,S)-binaphos}] complexes.
©
2006 Verlag Helvetica Chimica Acta AG, Zürich

1
682
Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 1. Synthesis of Biologically Active Compounds from (2R)-2-(Furan-2-yl)propanal
Results and Discussion. – Hydroformylation of vinylfurans 2 was carried out in the
presence of [Rh(acac)(CO) ] (acac=pentane-2,4-dionato) and (R,S)-binaphos (1) in
2
benzene under H /CO 1:1 pressure (p=2.0 MPa, Scheme 2). The yields and iso/normal
2
1
ratios of products, i.e., of 3/4, were determined by H-NMR spectroscopy of the reaction
mixtures by using naphthalene as an internal standard (see Table). The enantiomer
excess (ee) of the isoaldehydes 3 was determined by HPLC or GC analyses of the reac-
tion mixtures. In all reactions, no hydrogenated products, i.e., ethylfurans, were
1
detected by H-NMR spectroscopy. Thus, 2-vinylfuran (2a) was hydroformylated in a
À1
À1
quantitative conversion within 2 h (TOF=96 mol aldehyde·mol Rh ·h ) by using
the [Rh(1a)] system (Table, Entry 1). A formyl group was selectively introduced at
the a-position of the furan ring to give isoaldehyde 3a with the iso/normal ratio 3a/
4a of 97:3. The ee of 3a was 79%. The isoaldehyde 3a was isolated in 92% yield without
reduction of the ee. Compared to the [Rh(1a)] system, the [Rh(1b)] system showed
slightly lower catalytic activity (89% conversion; TOF=89 mol aldehyde·mol
À1
À1
1
Rh ·h ), 86% yield by H-NMR for 3a) and a lower enantioselectivity (76% ee for
a) as demonstrated in our previous report on the asymmetric hydroformylation of sty-
3
rene (Table, Entry 2) [26][27].
Hydroformylation of 3-vinylfuran (2b) also gave the corresponding isoaldehyde 3b
1
with high ee (>98%) in good yields (73–90% by H-NMR) (Table, Entries 3 and 4),
although longer reaction times of 6 h were required for high conversion of substrate
À1
À1
(
TOF=28–33 mol aldehyde·mol Rh ·h ). The regioselectivity in the reaction of
2b (3b/4b ca. 90 :10) was lower than in the case of 2a. The differences in reactivity
and regioselectivity between the hydroformylations of 2a and 2b could be attributed
to a resonance effect: greater conjugation between the furan and vinyl moieties of 2a
than between those of 2b [28] causes higher reactivity and more-favorable 2,1-insertion
to give the isoaldehyde [7].
The hydroformylation products 3 of vinylfurans 2 were successfully reduced without
loss of ee by NaBH to give the corresponding alcohols 5 with high ee (Scheme 3). The
4
optical rotation of the obtained 2-furanylpropan-1-ol 5a (see Exper. Part) established

Helvetica Chimica Acta – Vol. 89 (2006)
1683
Table. Results of the Asymmetric Hydroformylation of Vinylfurans by Using [Rh(I){(R,S)-binaphos})
a
Complexes )
b
b
c
b
b
Entry Furan Ligand Time [h] Conversion [%] ) TOF ) ) 3/4 ) NMR yield of 3 (%) ) ee of 3 [%]
e
1
2
3
4
2a
2b
1a
1b
1a
1b
2
2
6
6
100
89
100
85
96
89
33
28
97:3 93 (92)d)
97:3 86
92 :8 90 (80) )
79 ) (R)
e
76 ) (R)
d
f
99 ) (R)
f
88 :12 73
98 ) (R)
a) Reaction conditions: vinylfuran 2 (2.0 mmol), H
ligand 1 (0.040 mmol), benzene (1.0 ml), 608. ) Determined by H-NMR spectroscopic analyses of the
2
2
/CO 1:1 (2.0 MPa), [Rh(acac)(CO) ] (0.010 mmol),
b
1
c
reaction mixtures by using naphthalene as an internal standard. ) TOF=turnover frequency in mol alde-
À1
À1
d
e
hyde·mol Rh ·h . ) Isolated yield in parenthesis. ) Determined by GC analyses (Chrompack Chirasil-
f
DEX-CB column). ) Determined by HPLC analyses (Daicel-Chiralpak-IA column).
Scheme 2. Asymmetric Hydroformylation of Vinylfurans 2
the absolute configuration of the major enantiomer to be (2S) [24]. This demonstrates
I
that asymmetric hydroformylation of 2-vinylfuran (2a) by using [Rh {(R,S)-binaphos}]
complexes predominantly gave the (2R)-aldehyde, and that the sense of enantiofacial
selection is the same as that observed for styrene and its substituted analogs [5]. The
absolute configuration of 2-furanylpropan-1-ol 5b was determined to be (2R) based
on the known optical rotation of (2S)-3-hydroxy-2-methylpropanoic acid (6) (see
Exper. Part), which was obtained by oxidation of 5b with RuCl /NaIO in 78% yield
3
4
(
Scheme 4) [29–31]. Thus, olefin insertion into the RhÀH bond also proceeded through
the same enantiofacial selection in this case.
In summary, we have reported the asymmetric hydroformylation of vinylfurans by
I
use of [Rh {(R,S)-binaphos}] complexes. To the best of our knowledge, the present work
is the first successful example of asymmetric hydroformylation of vinylfurans. The pro-
duced furanylpropanals should have a potential use as synthetic intermediates. Thus,
the hydroformylation of vinylfurans should be a new convenient access to such useful
compounds.

1
684
Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 3. Hydroformylation of Vinylfurans 2 and Subsequent Reduction of the Aldehydes 3
Scheme 4. Determination of the Absolute Configuration of 5b
The authors are grateful for the financial support by The Naito Foundation.
Experimental Part
General. All the solvents used for reactions were distilled under Ar after drying over an appropriate
drying agent, or passed through solvent-purification columns. Most of the agents, were purchased from
Aldrich Chemical Co., Tokyo Kasei Kogyo Co., Ltd., or Kanto Kagaku Co., Ltd., and were used without
further purification unless otherwise specified. 2-Vinylfuran (2a) [32] and 3-vinylfuran (3a) [33] were syn-
thesized according to the literature. All manipulations involving air- and/or moisture-sensitive com-
pounds were carried out by using the standard Schlenk technique under Ar purified by passing through
a hot column packed with BASF catalyst R3-11. Anal. TLC: glass plates coated with 0.25 mm 230–400
mesh silica gel containing a fluorescent indicator (Merck). Column chromatography (CC): silica gel 60N
(
(
spherical neutral, particle size 63–210 mm, Kanto Kagaku Co., Ltd.). HPLC: Jasco-LC-2000Plus system
PU-2080 pump, LG-2080-02 gradient unit, DG-2080-53 degasser, CO-2060 column oven and MD-2010
®
UV detector); Daicel-Chiralpak -IA column (4.6 mm×250 mm). GC: Shimadzu-GC-2010; Chrompack-
Chirasil-DEX-CB column; He as carrier gas. IR Spectra: Shimadzu-FTIR-8100A spectrometer; ~n in
cm . NMR Spectra: Jeol-JNM-ECP500 ( H, 500 MHz; C, 125 MHz) spectrometer; CDCl solns.; d
À1
1
13
3
4
in ppm rel. to the internal standard SiMe (0 ppm), J in Hz. Elemental analyses were performed by
the Microanalytical Laboratory of the Department of Chemistry, Faculty of Science, The University of
Tokyo.
Rhodium-Catalyzed Hydroformylation of Vinylfurans: General Procedure (G. P.). A mixture of
vinylfuran 2 (2.0 mmol), [Rh(acac)(CO) ] (2.8 mg, 0.010 mmol), and (R,S)-binaphos 1a (33 mg, 0.040
2
mmol) in benzene (1.0 ml) was degassed by three freeze-thaw cycles (Schlenk tube). The soln. was trans-
ferred into a 50-ml autoclave under Ar, and then H /CO was introduced. The mixture was stirred at 608
2
for the appropriate time and then cooled down to r.t. After the H /CO pressure was released, naphtha-
2
lene was added and the mixture was stirred for a few minutes. An aliquot of the resulting mixture was
1
diluted with CDCl and analyzed by H-NMR to determine the conversion and the yields of products
3
3
®
and 4. Another aliquot of the mixture was analyzed by HPLC (Daicel-Chiralpak IA) or by GC
(Chrompack Chirasil-DEX CB) to determine the ee of aldehyde 3.

Helvetica Chimica Acta – Vol. 89 (2006)
1685
Hydroformylation of 2-Vinylfuran (2a). According to the G. P., with 2a (0.20 ml, 2.0 mmol). GC (708)
of the product: t 16.4 min for (S)-3a and 16.6 min for (R)-3a; 79% (R) ee. The product was purified by
R
CC (hexane/AcOEt (5 :1; R 0.55): (2R)-2-(furan-2-yl)propanal (3a; 228 mg, 92%) [34]. Colorless oil. GC
f
16
of isolated 3a: 79% (R) ee. [a] =À27.0 (c=0.90, CHCl ).
D
3
Hydroformylation of 3-Vinylfuran (2b). According to the G. P., with 2b (0.20 ml, 2.0 mmol) (hexane,
À1
1
.0 ml·min ) of the product: t 24.5 min for (S)-3b and 25.3 min for (S)-3b; 99% (R) ee. The product was
R
purified by CC (hexane/AcOEt 10 :1; R 0.40): (2R)-2-(furan-3-yl)propanal (3b; 199 mg, 80%). Colorless
f
2
D
0
1
oil. HPLC of isolated 3b: 99% (R) ee. [a] =À57.4 (c=0.85, CHCl ). IR (neat): 1732. H-NMR (CDCl ):
3
3
9
7
.63 (d, J=1.6, 1 H); 7.44 (t, J=1.7, 1 H); 7.37 (m, 1 H); 6.33 (dd, J=1.7, 0.8, 1 H); 3.54 (m, 1 H); 1.40 (d,
13
.1, 3 H). C-NMR (CDCl ): 200.66; 143.69; 139.75; 121.80; 109.84; 43.66; 13.88. Anal. calc. for C H O :
3
7
8
2
C 67.73, H 6.50; found: C 67.58, H 6.49.
Hydroformylation of 2a and Subsequent Reduction of 3a. According to the G. P., 2a (0.20 ml, 2.0
1
mmol) was hydroformylated, and the yield ( H-NMR) and ee (GC) of the formed 3a were determined
to be 93% and 79%, resp. Then, the reaction mixture was transferred into a Schlenk tube under Ar,
and EtOH (4.0 ml) was added. The resulting soln. was cooled to À788, and powdered NaBH (76 mg,
4
2
.0 mmol) was added in small portions over 10 min. After stirring at À788 for 21 h, H O was added to
2
quench the reaction. Then the mixture was extracted with CH Cl (3×5.0 ml), the combined org. layer
2
2
was dried (Na SO ) and evaporated, and the residue was purified by CC (hexane/AcOEt 3 :2; R
2
4
f
18
0
.42): (2S)-2-(furan-2-yl)propan-1-ol (5a; 218 mg, 86%) [24]. Colorless oil. [a] =+15.7 (c=0.58,
D
25
CHCl ) ([24]: [a] =+6.5 (c=1.00, CHCl ) for (S)-5a (>95% ee)). The ee of isolated 5a was determined
3
D
3
1
to be 79% (S) by H-NMR analysis (C
A
H
R
U
G
6
6
acetic acid (MTPA) ester.
Hydroformylation of 2b and Subsequent Reduction of 3b. According to the G. P., 2b (0.20 ml, 2.0
1
mmol) was hydroformylated and the produced aldehyde 3b (84% yield ( H-NMR), 99% ee (HPLC))
was reduced as described for 3a. Purification by CC (hexane/AcOEt 3 :2; R 0.37) gave (2R)-2-(furan-
f
3
-yl)propan-1-ol (5b) (185 mg, 74%). Colorless oil. GC (958): t
R
22.7 min for (R)-5b; 99% (R) ee.
19
1
[
a] =+20.0 (c=0.73, CHCl ). IR (neat): 3356. H-NMR (CDCl ): 7.40 (t, J=1.7, 1 H); 7.31 (m, 1 H);
D
3
3
6
1
1
.34 (dd, J=1.7, 0.8, 1 H); 3.66 (ddd, J=10.7, 7.0, 5.8, 1 H); 3.61 (ddd, J=10.7, 7.0, 5.4, 1 H); 2.88 (m,
13
H); 1.39 (dd, J=7.0, 5.4, 1 H); 1.23 (d, J=7.1, 3 H). C-NMR (CDCl ): 143.24; 139.10; 127.11;
3
09.38; 67.92; 33.16; 17.00. Anal. calc. for C H O : C 66.65, H 7.99; found: C 66.45, H 8.05.
7
10
2
Transformation of 5b to (2S)-3-Hydroxy-2-methylpropanoic Acid (6). To a mixture of RuCl (2.6 mg,
3
0
.013 mmol) and NaIO (593 mg, 2.8 mmol) in H O (1.6 ml) (Schlenk tube), 5b (53 mg, 0.42 mmol) in
4
2
AcOEt (2 ml) was added via a syringe. The mixture was stirred at r.t. for 3 h, and then the reaction
was quenched by adding 1M aq. HCl (5 ml). The resulting mixture was extracted with CHCl (5×10
3
ml), the combined org. layer was evaporated, and the crude residue was purified by CC (hexane/acetone
1
D
8
25
1
:1; R 0.16): 6 (34 mg, 78%). Colorless oil. [a] =+5.9 (c=0.54, EtOH) ([30]: [a]D =+12.7 (c=12.5,
f
20
EtOH); [31]: [a] =+ 4.4 (c=11.5, EtOH)), confirming the absolute configuration (2R) of the isolated
578
5
b.
REFERENCES
[
[
[
[
[
1] K. Nozaki, I. Ojima, in ‘Catalytic Asymmetric Synthesis’, 2nd edn., Ed. I. Ojima, Wiley-VCH, New
York, 2000, Chapt. 7.
2] K. Nozaki, in ‘Comprehensive Asymmetric Catalysis’, Eds. E. N. Jacobsen, A. Pfaltz, H. Yamamoto,
Springer, Berlin, 1999, Vol. 1, Chapt. 11.
3] ‘Rhodium Catalyzed Hydroformylation’, Eds. P. W. N. M. van Leeuwen, C. Claver, Kluwer Aca-
demic Publishers, Dordrecht, 2000.
4] G. J. H. Buisman, L. A. vanderVeen, A. Klootwijk, W. G. J. deLange, P. C. J. Kamer, P. W. N. M. van
Leeuwen, D. Vogt, Organometallics 1997, 16, 2929.
5] K. Nozaki, N. Sakai, T. Nanno, T. Higashijima, S. Mano, T. Horiuchi, H. Takaya, J. Am. Chem. Soc.
1997, 119, 4413.
[
[
6] T. Horiuchi, T. Ohta, E. Shirakawa, K. Nozaki, H. Takaya, Tetrahedron 1997, 53, 7795.
7] T. Horiuchi, T. Ohta, K. Nozaki, H. Takaya, Chem. Commun. 1996, 155.

1
686
Helvetica Chimica Acta – Vol. 89 (2006)
[
[
8] T. Nanno, N. Sakai, K. Nozaki, K. Takaya, Tetrahedron: Asymmetry 1995, 6, 2583.
9] N. Sakai, S. Mano, K. Nozaki, H. Takaya, J. Am. Chem. Soc. 1993, 115, 7033.
[
10] T. Horiuchi, T. Ohta, E. Shirakawa, K. Nozaki, H. Takaya, J. Org. Chem. 1997, 62, 4285.
[
11] R. Lazzaroni, R. Settambolo, S. Rocchiccioli, S. Paganelli, M. Marchetti, J. Organomet. Chem. 2005,
690, 1699.
[12] R. Lazzaroni, R. Settambolo, A. Caiazzo, M. A. Bennett, Organometallics 2002, 21, 2454.
[13] A. Caiazzo, R. Settambolo, L. Pontorno, R. Lazzaroni, J. Organomet. Chem. 2000, 599, 298.
[14] R. Settambolo, S. Scamuzzi, A. Caiazzo, R. Lazzaroni, Organometallics 1998, 17, 2127.
[15] R. Settambolo, S. Pucci, S. Bertozzi, R. Lazzaroni, J. Organomet. Chem. 1995, 489, C50.
[16] C. Basoli, C. Botteghi, M. A. Cabras, G. Chelucci, M. Marchetti, J. Organomet. Chem. 1995, 488,
C20.
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
17] R. Lazzaroni, R. Settambolo, M. Mariani, A. Caiazzo, J. Organomet. Chem. 1999, 592, 69.
18] A. Caiazzo, R. Settambolo, G. Uccello-Barretta, R. Lazzaroni, J. Organomet. Chem. 1997, 548, 279.
19] R. Settambolo, A. Caiazzo, R. Lazzaroni, J. Organomet. Chem. 1996, 506, 337.
20] P. Kalck, F. Sereinspirau, New J. Chem. 1989, 13, 515.
21] A. F. Browning, A. D. Bacon, C. White, D. J. Milner, J. Mol. Catal. 1993, 83, L11.
22] G. Schmid, T. Fukuyama, K. Akasaka, Y. Kishi, J. Am. Chem. Soc. 1979, 101, 259.
23] J. Merten, R. Fröhlich, P. Metz, Angew. Chem., Int. Ed. 2004, 43, 5991.
24] A. Bierstedt, J. Stolting, R. Fröhlich, P. Metz, Tetrahedron: Asymmetry 2001, 12, 3399.
25] J. K. Stille, H. Su, P. Brechot, G. Parrinello, L. S. Hegedus, Organometallics 1991, 10, 1183.
26] K. Nozaki, T. Matsuo, F. Shibahara, T. Hiyama, Organometallics 2003, 22, 594.
27] K. Nozaki, T. Matsuo, F. Shibahara, T. Hiyama, Adv. Synth. Catal. 2001, 343, 61.
28] I. G. John, L. Radom, J. Am. Chem. Soc. 1978, 100, 3981.
29] W. H. Miles, E. J. Fialcowitz, E. S. Halstead, Tetrahedron 2001, 57, 9925.
30] N. Cohen, W. F. Eichel, R. J. Lopresti, C. Neukom, G. Saucy, J. Org. Chem. 1976, 41, 3505.
31] J. Retey, F. Lynen, Biochem. Z. 1965, 342, 256.
32] U. Schmidt, J. Werner, Synthesis 1986, 986.
33] U. Hersel, M. Steck, K. Seifert, Eur. J. Org. Chem. 2000, 1609.
34] U. Schmidt, J. Gombos, E. Haslinger, H. Zak, Chem. Ber. 1976, 109, 2628.
Received March 11, 2006