Highly regioselective hydroformylation of Styrene and its derivatives catalyzed by Rh complex with tetraphosphorus ligands

Article abstract of DOI:10.1021/ol802479y

Styrene has been hydroformylated to the linear aldehyde with surprisingly high regioselectivity (l/b up to 22 for styrene) by using Rh complex with tetraphosphorus ligand. To the best of our knowledge, this is the highest linear regioselectivity reported for the hydroformylation of styrene and its derivatives. This protocol is in sharp contrast to other processes that favor producing branched aldehyde (typically >95% branched for most bidentate systems).

Full text of DOI:10.1021/ol802479y

ORGANIC
LETTERS
2
009
Vol. 11, No. 1
41-244
Highly Regioselective Hydroformylation
of Styrene and Its Derivatives Catalyzed
by Rh Complex with Tetraphosphorus
Ligands
2
Shichao Yu, Yu-ming Chie, Zheng-hui Guan, Yaping Zou, Wei Li, and
Xumu Zhang*
Department of Chemistry and Chemical Biology and Department of Pharmaceutical
Chemistry, Rutgers, The State UniVersity of New Jersey,
Piscataway, New Jersey 08854-8020
xumu@rci.rutgers.edu
Received November 5, 2008
ABSTRACT
Styrene has been hydroformylated to the linear aldehyde with surprisingly high regioselectivity (l/b up to 22 for styrene) by using Rh complex
with tetraphosphorus ligand. To the best of our knowledge, this is the highest linear regioselectivity reported for the hydroformylation of
styrene and its derivatives. This protocol is in sharp contrast to other processes that favor producing branched aldehyde (typically >95%
branched for most bidentate systems).
2
Hydroformylation of olefins represents one of the most
important reactions in homogeneous catalysis and leads to
products containing an aldehyde group, which are versatile
intermediates and building blocks for various pharmaceuti-
contribute to this regioselectivity (Scheme 1). Thus, most
previous studies have been focused on the development of
chiral ligands or processes to efficiently produce the desired
3
branched enantioisomer in high optical purity.
1
cals, agrochemicals, and other fine chemicals. Most com-
However, recent progress on the Rh-catalyzed hydro-
formylation of styrene has revealed that contrary selectivity
for linear aldehyde may also be possible through the choice
of solvent, biphasic system, another catalytic system (for
2 2
/SnCl , l/b ) 3.35, for Co-W bimetallic catalyst l/b
) 1.30 ), or fine-tuned ligands (xanphosphite afforded l/b
up to 2.3, calixarenes diphosphane led to a l/b ) 77/23,
and so far, the bulky phosphite ligands of UCC gave the
highest linear regioselectivity, a value of l/b ) 14 ). Both
mercial hydroformylation processes use rhodium catalysts
modified with monophosphorus ligands or bisphosphorus
ligands to address the issue of regioselectivity and stereo-
selectivity. Styrene is an interesting class of substrates that
favor producing branched aldehyde. It was suggested that
the formation of a stable benzylic Rh-species induced by
the η2 electron donation from the benzene ring might
4
5
6
PtCl
7
8
9
1
0
(
1) (a) Organic Syntheses Via Metal Carbonyls; Wender, I., Pino, P.,
the linear and branched aldehydes are very important, as the
Eds.; Wiley: New York, 1977; (b) New Syntheses with Carbon Monoxide;
Falbe, J., Eds.; Springer: Berlin, 1980; pp 1-225. (c) Kohlpaintner, C. W.;
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Vol. 1, pp 1-39.
(2) Tolman, C. A.; Faller, J. W. In Homogeneous Catalysis with Metal
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81.
10.1021/ol802479y CCC: $40.75
Published on Web 11/24/2008
 2009 American Chemical Society

by rather sophisticated and tedious procedures (e.g., by the
1
3
reduction of trans-cinnamaldehyde or 3-phenylpropionyl
Scheme 1
1
4
chloride or its derivatives or by the oxidation of 3-aryl-
1
5
propanol ), which inhibits its wide applications. Therefore,
it is highly desirable to develop new, economic, and efficient
1
6
methodologies for the synthesis of 3-arylpropanal.
Recently, we reported the synthesis and application of a
class of new tetraphosphorus ligands (biphenyl-2,2′,6,6′-
tetrakis(dipyrrolylphosphoramidite)) (Figure 1), which shows
latter constitute an important class of anti-inflammatory drugs
and the linear aldehyde is widely used for the production of
detergents and plasticizers and in organic synthesis as an
11
important intermediate (for example, it can be used as key
starting material for the synthesis of enalapril, marketed by
1
2
Merck & Co. as a drug for lowering blood pressure ). In
the literature, 3-arylpropanal is usually obtained indirectly
Figure 1. Ligands used in this study.
(
3) For recent publications, see: (a) Breeden, S.; Cole-Hamilton, D. J.;
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Pamies, O.; Ruiz, A.; Castillon, S.; Claver, C. Chem.sEur. J. 2001, 7, 3086–
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high regioselectivity for the homogeneous isomerization-
17
hydroformylation of internal olefins. The high regioselec-
tivity prompted us to assess our ligands further in the
hydroformylation of styrene and its derivatives. Herein, we
disclose our recent studies on the hydroformylation of styrene
and its derivatives with unprecedented high linear selectivity.
Initially, we set out to identify the optimal conditions for
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Table 1. An increase in the temperature from 40 to 80 °C
led to improved activity and regioselectivity (Table 1, entries
4
3
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tallics 2007, 26, 6428–6436. (j) Leclercq, L.; Suisse, I.; Agbossou-
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1
, 2, and 7). Further increase in the temperature from 80 to
100 °C gave lower regioselectivity, albeit the conversion
increased somewhat (Table 1, entry 8). The pressure
dependency of the catalytic system is also pronounced, as
the activity and selectivity decreased sharply with the
increased pressure (Table 1, entries 2-4). A lower ligand
(
4) Tissot, O.; Gouygou, M.; Dallemer, F.; Daran, J.-C.; Balavoine,
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8) Dieleman, C. B.; Kamer, P. C. J.; Reek, J. N. H.; Van Leeuwen,
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(
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Bioorg. Med. Chem. Lett. 2006, 16, 6231–6235.
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242
Org. Lett., Vol. 11, No. 1, 2009

A series of styrene derivatives were then hydroformylated
using the Rh/L7 catalyst. The substrate to catalyst ratio was
Table 1. Hydroformylation of Styrene Using Ligand L1 under
Different Reaction Conditions
1
0000, and the catalyst concentration was 0.17 mM. The
a
reaction was terminated after 12 h (Table 3). It was found
linear selectivity
b
c
e
T
H
2
/CO convn ald sel
linear
(%)
d
entry (°C) L/Rh (atm)
(%)
(%)
l/b
Table 3. Hydroformylation of Styrene and Its Derivatives with
Rh-L7 Catalyst
a
1
2
3
4
5
6
7
8
40
60
3
3
3
3
2
1
3
3
5/5
5/5
7
43
44
29
46
53
80
99
99
97
98
98
98
98
97
93
2.9
6.7
3.2
1.9
5.2
4.9
6.8
5.9
74
87
76
66
84
83
87
86
60
10/10
20/20
5/5
linear selectivity
ald
60
b
c
e
convn sel
(%) (%) l/b
linear
(%)
60
d
f
entry
substrate
styrene
4-F-styrene
4-Me-styrene
4-MeO-styrene
2-Me-styrene
2,4,6-trimethylstyrene
TOF
60
5/5
80
5/5
3
3
2
2
3
1
2
3
4
5
98
99
83
80
99
16
91
89
95
96
90
21.2
14.2
19.4
26.0
144.7
95.5 1.1 ×10
93.4 1.3 ×10
95.0 9.7 ×10
96.3 7.4 ×10
99.3 1.8 ×10
100
5/5
a
S/C ) 1,000, [Rh] ) 1.0 mM, t ) 1 h, toluene as solvent, decane as
b
internal standard. Conversion of the styrenes, determined on the basis of
GC. The hydrogenated product accounts for the product balance.
Linear/branched ratio, determined on the basis of GC analysis. The reaction
was repeated twice, error is estimated <0.3. Percentage of linear aldehyde
in all aldehydes.
c
d
g
6
94 >99
>99
7.0 × 10
e
a
S/C ) 10,000, [Rh] ) 0 0.17 mM, temperature ) 80 °C, CO/H )
2
b
5
/5 atm, t ) 12 h, toluene as solvent, decane as internal standard. See
Table 1. See Table 1. See Table 1. See Table 1. Average turnover
frequency after reaction for 1 h: mole of aldehyde formed per mole of
c d e f
g
loading was also investigated, and it was found that although
there is not much effect on catalytic activity, the regiose-
lectivity is somewhat lowered (Table 1, entries 5 and 6).
Thus, the preliminary optimal conditions (toluene, 80 °C, 5
atm H /CO, substrate/L/Rh ) 1000/3/1) were chosen for the
ligand screening.
Based on the best reaction conditions for ligand L1, ligands
L2-L7 were tested. It was found that the introduction of
substituents on the 3,3′,5,5′-position of the biphenyl moiety
greatly increased the regioselectivity for the linear aldehyde
as shown in Table 2. The use of ligand L2 bearing a chlorine
catalyst per hour, determined based on GC. L1 was used as ligand.
that styrene substituted with electron-withdrawing group gave
a lower linear to branch ratio than that of styrene with
electron-donating groups (entries 2-4). The steric hindrance
of the substrates on the regioselectivity of the hydroformy-
lation is also remarkable. When one methyl group was
introduced to the ortho position of the styrene, the reactivity
and the regioselectivity were improved greatly (entry 5). This
can be explained by the inhibition of the formation of the
benzylic Rh-species that would favor producing branched
aldehyde due to the presence of ortho substituent and fast
2
1
8
reduction elimination stemming from the steric interactions.
Table 2. Hydroformylation of Styrene Using Ligand L2-L7
However, when one more ortho methyl group was intro-
duced, the reactivity of this substrate was greatly decreased
which might be the hindrance blocking the coordination of
the substrate to the metal center.
under Optimized Pressure and Temperature
linear selectivity
b
c
d
e
entry ligand convn(%)
ald sel (%)
l/b
linear (%)
Although further studies are required to reconcile these
results, the present observation may be rationalized as
follows. The high regioselectivity for the hydroformylation
of styrene to linear aldehyde might be accounted for by the
steric interactions between the ligands and the substrate. It
was previously proposed for the reaction of vinylidene-type
olefins catalyzed by Rh complex that the significant differ-
ence in the steric environment between the two ends of the
olefinic bond gave excellent regioselectivity for the linear
1
2
3
4
5
6
L2
L3
L4
L5
L6
L7
98
71
54
99
99
95
93
93
94
92
92
97
12.9
15.9
17.2
19.3
20.2
22.4
92.8
94.1
94.5
95.1
95.3
95.7
a
S/C ) 1,000, [Rh] ) 1.0 mM, 80 °C, H /CO ) 5/5 atm, t ) 1 h,
b c
2
toluene as solvent, decane as internal standard. See Table 1. See Table
d
e
1
. See Table 1. See Table 1.
1
9
aldehyde. In the present system, the dependency of the
selectivity on the steric nature of the ligand was similar, as
observed when higher linear to branch ratio was obtained
with the more hindric ligand. It is very likely that the
hindrance of the ligand creates an obstacle for the formation
of η3 Rh-complex that would favor the formation of
branched aldehyde. UCC’s bulky phosphite ligands for
hydroformylation of styrene afforded a linear to branch ratio
substituent increased the linear to branch ratio to 12.9:1
Table 2, entry 1). Alkyl-substituted ligands L3 and L4 gave
a higher regioselectivity affording linear to branch ratios of
5.9:1 and 17.2:1, respectively; however, the conversion was
dropped somewhat (Table 2, entries 2 and 3). This phenom-
enon indicates that the electronic property of ligand has some
effect on the catalytic activity. Aryl substituents showed
comparable regioselectivity, of which ligand L7 afforded the
best result (Table 2, entries 4-7). The overall results clearly
demonstrated that the steric property of the substituents
determined the regioselectivity of the hydroformylation
process.
(
1
1
0
of 14 is another example of this steric effect.
(
18) van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Reek, J. N. H.; Dierkes,
P. Chem. ReV. 2000, 100, 2741–2769.
19) (a) Consiglio, G.; Morandini, F.; Scalone, M.; Pino, P. J. Orga-
(
nomet. Chem. 1985, 279, 193–202. (b) Koll a´ r, L.; S a´ nder, P.; Szalontai,
G.; Heil, B. J. Organomet. Chem. 1990, 393, 153–158.
Org. Lett., Vol. 11, No. 1, 2009
243

In summary, we have shown that the hydroformylation of
styrene and its derivatives can be achieved with high regiose-
lectivity for linear aldehyde (l/b up to 22 for styrene) using Rh
complex with 3,3′,5,5′-substituted tetraphosphorus ligands. To
the best of our knowledge, this is the highest linear regiose-
lectivity reported for the hydroformylation of styrene and its
derivatives. The high regioselectivity was accounted for by the
steric interactions between the ligands and the substrate. This
protocol is in sharp contrast to other processes that favor
producing branched aldehyde (typically >95% branched for
most bidentate systems). Further mechanistic study is under
investigation and will be disclosed in due course.
Acknowledgment. We thank the National Institutes of
Health (GM58832) and Merck & Co., Inc for finacial
support.
Supporting Information Available: General procedure
for hydroformylation. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL802479Y
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Org. Lett., Vol. 11, No. 1, 2009