Accessible protocol for asymmetric hydroformylation of vinylarenes using formaldehyde

Article abstract of DOI:10.1039/c5ob00378d

We report herein on an accessible protocol for the asymmetric hydroformylation of vinylarenes using formaldehyde as a substitute for syngas. The regioselectivity (branched/linear = up to 96/4) and enantioselectivity (up to 95% ee) can be attributed to the use of chiral Ph-bpe as a ligand. This journal is

Full text of DOI:10.1039/c5ob00378d

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Tsumoru Morimoto et al.
Accessible protocol for asymmetric hydroformylation of vinylarenes using
formaldehyde

Organic &
Biomolecular Chemistry
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Accessible protocol for asymmetric
hydroformylation of vinylarenes using
formaldehyde†
Cite this: Org. Biomol. Chem., 2015,
13, 4632
Received 25th February 2015,
Accepted 12th March 2015
Tsumoru Morimoto,* Tetsuji Fujii, Kota Miyoshi, Gouki Makado, Hiroki Tanimoto,
Yasuhiro Nishiyama and Kiyomi Kakiuchi
DOI: 10.1039/c5ob00378d
www.rsc.org/obc
We report herein on an accessible protocol for the asymmetric
hydroformylation of vinylarenes using formaldehyde as a substi-
tute for syngas. The regioselectivity (branched/linear = up to 96/4)
and enantioselectivity (up to 95% ee) can be attributed to the use
of chiral Ph-bpe as a ligand.
Asymmetric hydroformylation has attracted the interest of
numerous synthetic organic researchers because it can
produce versatile chiral aldehydes which have intrinsic value
as synthetically useful intermediates.1 The products are easily
converted to enantiomerically enriched alcohols, carboxylic
acids and their derivatives, amines, and imines.2 Since the pio-
neering discovery of a highly effective ligand for rhodium-
catalyzed hydroformylation, BINAPHOS,3 numerous efforts to
Scheme 1 Selective hydroformylation using formaldehyde.
ligands, BIPHEP and Nixantphos, led to a highly linear-selec-
tive hydroformylation (L/B = >95/5). The findings showed that
BIPHEP and Nixantphos are responsible for the decarbonyla-
tion and the hydroformylation processes, respectively, totally
resulting in a linear-selective hydroformylation. In developing
the method, we first examined the simultaneous use of two
phosphines, BIPHEP for decarbonylation and a chiral phos-
phine for the branched- and enantioselective hydroformylation,
in the rhodium-catalyzed reaction of styrene with formal-
dehyde. When styrene (1) was treated with formalin (37 wt%
aqueous solution of formaldehyde) in the presence of 0.5 mol%
[RhCl(cod)]2, 0.6 mol% BIPHEP, and 0.6 mol% (S)-BINAP10
in toluene at 80 °C for 10 h, the hydroformylation proceeded
branched-selectively (2-B/2-L = 84/16) to give a mixture of
branched and linear aldehydes in 28% yield with a low
enantioselectivity (18% ee (R)) (Table 1, entry 1). The use of
(S,S)-BDPP11 instead of (S)-BINAP led to more smooth reaction
with moderate regioselectivity (2-B/2-L = 78/22), although the
enantioselectivity was still moderate (52% ee (R)) (entry 2).
When (R,S)-BINAPHOS3 was used for the asymmetric hydrofor-
mylation process, the regioselectivity and enantioselectivity
were very low (entry 3). The simultaneous use of BIPHEP and
(R,R)-Ph-bpe4b proceeded much more smoothly to give the
aldehydes in extremely high yield (96%) with higher branched-
and enantioselectivities (2-B/2-L = 90/10, 81% ee (R)) (entry 4).
Contrary to our expectation, when (R,R)-Ph-bpe was used
alone, a higher regio- and enantioselectivities was observed:
achieve
a higher degree of enantioselectivity have been
focused on the discovery of novel ligands.4
For the next-stage progress in asymmetric hydroformylation
methodology, we investigated the use of formaldehyde as a
substitute for synthesis gas (CO + H2, syngas). Using form-
aldehyde is highly attractive, because it is constructed from the
same elements (one carbon, one oxygen and two hydrogen
atoms) as syngas, thus making it atom-economical. The
success of using formaldehyde would lead to operational sim-
plicity and convenience for the transformation. To our
knowledge,5–9 to date, asymmetric hydroformylation without
the direct use of syngas has never been reported. We describe
here the first asymmetric hydroformylation of vinylarenes with
formaldehyde (Scheme 1b). This represents a promising syn-
thetic tool for producing chiral aldehydes and derivatives thereof.
We recently developed a new method for the highly linear-
selective hydroformylation of 1-alkenes using formaldehyde as
a syngas-substitute (Scheme 1a).5f This report revealed that, in
the rhodium-catalyzed reaction of 1-alkenes with formal-
dehyde, the simultaneous use of two types of phosphine
Graduate School of Materials Science, Nara Institute of Science and Technology
(NAIST), Ikoma, Nara 630-0192, Japan. E-mail: morimoto@ms.naist.jp
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob00378d
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>99% yield with a 93% branched aldehyde-selectivity and
90% ee (R) (entry 5).12 Thus, (R,R)-Ph-bpe was found to be
sufficiently effective for both of the decarbonylation and
stereoselective hydroformylation processes. Furthermore,
when paraformaldehyde was used as a source of formaldehyde
under the above conditions, the conversion of styrene
decreased, but the branched aldehyde was produced more pre-
dominantly with a higher enantioselectivity (93% ee (R)).
Table 1 The Rh(I)-catalyzed asymmetric hydroformylation of styrene
using formaldehydea
Various vinylarenes were converted to the corresponding
branched-aldehydes with high enantioselectivity using the fol-
lowing reaction protocol: vinylarene (1 mmol), formaldehyde
(for formalin, 2.5 mmol (A); for paraformaldehyde, 5 mmol
(B)), [RhCl(cod)]2 (0.5 mol%), (R,R)-Ph-bpe (1.2 mol%), and
toluene (5 mL) at 80 °C in a 10 mL of screw-capped vial. The
results are summarized in Table 2. Vinylarenes with electron-
donating groups, 4-MeO- (3), 4-Me- (5), and 3-Me- (7), were
hydroformylated to give the corresponding branched-alde-
hydes more highly enantioselectively, although the reaction
efficiencies were slightly lower compared to the reaction of
I
Chiral ligand Conv.b Yieldb
ee of 2-Bc styrene (entries 1 and 3). On the other hand, the reactions of
Entry (mol%) (mol%)
(%)
(%)
2-B/2-Lb (%)
compounds with electron-withdrawing groups, 4-F- (9), 4-Cl-
(11), and 4-CF3- (13), proceeded more smoothly, however the
regio- and enantioselectivities decreased (entries 7, 9, and 11).
In the reactions of all of the vinylarenes examined, the use of
paraformaldehyde led to the higher branched- and enantio-
selectivities, predominantly giving the corresponding
branched-aldehydes (entries 2, 4, 6, 8, 10, and 12).
1
2
3
4
0.6
0.6
0.6
0.6
—
II 0.6
III 0.6
IV 0.6
V 0.6
V 1.2
VI 1.2
V 1.2
39
71
60
28
69
54
96
84/16
78/22
47/53
90/10
18 (R)
52 (R)
37 (R)
81 (R)
90 (R)
90 (R)
93 (R)
93
5
>99
>99
75
>99 (92) 93/7
>99
73
6
—
—
94/6
95/5
7d
a Reaction conditions: styrene (1 mmol), formalin (37 wt% aqueous
solution, 0.19 mL, 2.5 mmol), [RhCl(cod)]2 (0.5 mol%), ligands
(1.2 mol% totally) in toluene (5 mL) at 80 °C for 10 h. b Determined by
GC using n-dodecane as an internal standard; yield of isolated product
in parentheses. c Determined by HPLC after conversion to the
corresponding alcohol. The absolute configurations were determined
from specific optical rotation measurement. d Paraformaldehyde
(5 equiv.) was used instead of formalin, and the reaction was run
for 20 h.
We next applied the present protocol to the synthesis of
some pharmaceutical precursors. Under the standard con-
ditions (Table 1, entry 6), 4-isobutylstyrene (15) and 2-methoxy-
6-vinylnaphthalene (17) reacted smoothly with formalin to
give the corresponding branched aldehydes, 16-B and 18-B,
in high yields with both high regio- and enantioselecti-
vities (Scheme 2). These aldehydes can easily be converted
by classical oxidation methodology to the non-steroidal
Table 2 Asymmetric reactions of various vinylarenes with formaldehydea
Conversionc
(%)
Time
(h)
Yieldc
(%)
ee of
Entry
Vinylarene
HCHOb
B/Lc
Bd (%)
1
2
3
4
5
6
7
8
3 4-MeO–C6H4–CHvCH2
3
5 4-Me–C6H4–CHvCH2
5
7 3-Me–C6H4–CHvCH2
7
9 4-F–C6H4–CHvCH2
9
11 4-Cl–C6H4–CHvCH2
11
13 4-CF3–C6H4–CHvCH2
13
A
B
A
B
A
B
A
B
A
B
A
B
97
64
>99
76
98
82
94
69
>99
80
>99
>99
15
40
15
40
15
40
10
20
10
20
10
20
4 93
4 63
6 >99
6 76
8 95
94/6
96/4
93/7
96/4
94/6
96/4
94/6
96/4
91/9
96/4
86/14
88/12
91 (R)
95 (R)
86 (R)
91 (R)
89 (R)
94 (R)
92 (R)
95 (R)
80 (R)
92 (R)
62 (R)
67 (R)
8 78
10 93
10 69
12 >99
12 80
14 96
14 96
9
10
11
12
a Reaction conditions: vinylarene (1 mmol), formaldehyde, [RhCl(cod)]2 (0.5 mol%), (R,R)-Ph-bpe (1.2 mol%) in toluene (5 mL) at 80 °C. b A =
formalin (37 wt% aqueous solution, 0.19 mL, 2.5 mmol); B = paraformaldehyde (5 mmol). c Determined by GC using n-dodecane as an internal
standard. d Determined by HPLC after conversion to the corresponding alcohol. The absolute configurations were determined from specific
optical rotation measurement.
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analysis of the alcohol which was produced by reduction with
NaBH4 revealed that only 29% of the 13C was introduced into
the –CH2–OH group (originally, –CHO). This suggests that the
pathway for the present hydroformylation reaction involves the
incorporation of a carbonyl unit in the form of a CO ligand;
thus, the carbonyl group of formaldehyde is transformed once
to a CO ligand, which can be easily exchanged with external
CO, on the rhodium center. It also means that rhodium-
hydride species, which is essential for the hydroformylation, is
also generated as well as a carbonyl moiety.
A possible reaction pathway is as follows (Scheme 4). The
reaction begins with the decarbonylation of formaldehyde to
produce formally a carbonyl moiety and two hydrogen moieties
(left cycle). It includes the oxidative addition of formaldehyde
to a rhodium center of A (B), the migratory extrusion of the
carbonyl moiety (C), and the subsequent reductive elimination
of H2 (D), followed by the release of CO along with the regener-
ation of the decarbonylation catalyst A. The vinylarene is then
enantioselectively hydroformylated using the resulting carbo-
nyl, free CO and/or a CO ligand ([CO] in Scheme 4), and the
resulting hydrogen, free H2 and/or a hydride ligand (right
cycle). The hydroformylation cycle is catalysed by the rhodium(I)-
hydride species (E), which is generated from (i) A, [CO] and H2,
(ii) D and H2, and/or C. Although it is, at present, unclear
in what form the carbonyl and hydrogen are introduced into
the hydroformylation process (free CO or a carbonyl ligand
and free H2 or a hydride ligand, respectively), these two pro-
cesses are catalyzed by a singly-loaded rhodium catalyst pre-
cursor, Rh(I)/chiral Ph-bpe. The results for the reaction using
13C-labeled formaldehyde supports the conclusion that the
hydroformylation pathway may not involve the direct addition
of a formyl-rhodium-H species B,13 which is generated from
the oxidative addition of formaldehyde to the rhodium
center.14 Thus, formaldehyde acts as if it was syngas in the
present protocol. Consequently, the sequence of events
leads to a highly regio- and enantioselective hydroformylation
without the direct use of syngas.
Scheme 2 Synthesis of pharmaceutical precursors.
anti-inflammatory drugs, (S)-(+)-Ibuprofen and Naproxen,
respectively.
Lastly, we investigated whether the hydroformylation
system developed here involves the decarbonylative degra-
dation of formaldehyde to a carbonyl moiety and H2. Using
catalytic conditions similar to those for entry 5 in Table 1, the
reaction of styrene with 13C-labeled formaldehyde (>99% of
13C) under 13C-unlabeled carbon monoxide at atmospheric
pressure was examined. Although the complete consumption
of the substrate required a somewhat longer reaction time
mainly due to the presence of external CO, the corresponding
aldehydes were obtained with regio- and enantioselectivities
similar to those for entry 5 in Table 1 (Scheme 3). A 13C NMR
In conclusion, we report on the asymmetric hydroformyla-
tion of vinylarenes using formaldehyde as a syngas-substitute.
The regioselectivity (branched/linear = up to 96/4) and enantio-
Scheme 3 Reaction of styrene with formaldehyde-13C in the presence
of 12CO.
Scheme 4 Possible reaction pathway.
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selectivity (up to 95% ee) can be attributed to the use of chiral
Ph-bpe as a ligand. Both the decarbonylative degradation of
formaldehyde to a CO moiety and hydrogen and the sub-
sequent hydroformylation of vinylarenes are catalyzed by a
singly-loaded catalyst, Rh(I)/chiral Ph-bpe. Although further
efforts will be necessary for improving the reaction from the
standpoint of the amount of the catalyst loading and reaction
efficiency, the present protocol has the potential to be a more
practical synthesis of enantiomerically enriched aldehydes and
their derivatives because all of the reagents used, except for
vinylarenes, are readily commercially available. The mechanis-
tic details of the reaction, including the origin of the enantio-
selectivity,15 are currently unclear but will be a subject of a
future study.
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Acknowledgements
This work was financially supported, in part, by a Grant-in-Aid
for Scientific Research on Innovative Area “Molecular Acti-
vation Directed toward Straightforward Synthesis” from MEXT.
We wish to acknowledge Prof. Kyoko Nozaki of the University
of Tokyo for the gift of a sample of (R,S)-BINAPHOS. We
thank Ms. Mika Yamamura and Ms. Yuriko Nishiyama, and
Ms. Yoshiko Nishikawa for assistance in obtaining HRMS.
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addition of the formyl C–H bond of formaldehyde to the
rhodium center, to a CvC bond (formylrhodation) is
formaldehyde under the catalytic conditions occurs. See
the ESI.†
included in RhH(CO)(PPh3)3-catalyzed hydroformylation of 15 (a) A. T. Axtell and J. Klosin, Organometallics, 2006, 25,
allyl alcohol with paraformaldehyde. See ref. 5c.
14 It has also been confirmed that no exchange of
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Organometallics, 2009, 28, 2993–2999.
a
carbonyl group between the formed aldehydes and
4636 | Org. Biomol. Chem., 2015, 13, 4632–4636
This journal is © The Royal Society of Chemistry 2015