Highly enantioselective hydroformylation of aryl alkenes with diazaphospholane ligands

Article abstract of DOI:10.1021/ol801723a

(Chemical Equation Presented) Asymmetric, rhodium-catalyzed hydroformylation of terminal and internal aryl alkenes with diazaphospholane ligands is reported. Under partially optimized reaction conditions, high enantioselectivity (>90% ee) and regioselectivities (up to 65:1 α:β) are obtained for most substrates. For terminal alkenes, both enantioselectivity and regioselectivity are proportional to the carbon monoxide partial pressure, but independent of hydrogen pressure. Hydroformylation of para-substituted styrene derivatives gives the highest regioselectivity for substrates bearing electron-withdrawing substituents. A Hammett analysis produces a positive linear correlation for regioselectivity.

Full text of DOI:10.1021/ol801723a

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4553-4556
Highly Enantioselective
Hydroformylation of Aryl Alkenes with
Diazaphospholane Ligands
Avery L. Watkins, Brian G. Hashiguchi, and Clark R. Landis*
Department of Chemistry, UniVersity of Wisconsin-Madison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706
landis@wisc.edu
Received July 31, 2008
ABSTRACT
Asymmetric, rhodium-catalyzed hydroformylation of terminal and internal aryl alkenes with diazaphospholane ligands is reported. Under partially
optimized reaction conditions, high enantioselectivity (>90% ee) and regioselectivities (up to 65:1 r:ꢀ) are obtained for most substrates. For
terminal alkenes, both enantioselectivity and regioselectivity are proportional to the carbon monoxide partial pressure, but independent of
hydrogen pressure. Hydroformylation of para-substituted styrene derivatives gives the highest regioselectivity for substrates bearing electron-
withdrawing substituents. A Hammett analysis produces a positive linear correlation for regioselectivity.
Asymmetric hydroformylation (AHF) is an atom efficient
method for synthesizing optically active aldehydes from
simple alkenes1 (eq 1). Such aldehydes are versatile inter-
mediates for pharmaceuticals and agrochemicals.2 Aryl
alkenes are important substrates for AHF because oxidation
of the resulting aldehyde to 2-arylpropionic
Highly enantioselective styrene hydroformylation was first
reported by Stille,4 using platinum complexes of BPPM (1) as
the catalyst (Figure 1). However, in situ conversion of the
aldehydes to the corresponding acetals was required to achieve
high enantioselectivity. Whiteker and co-workers at Union
Carbide reported the first highly enantioselective hydroformy-
lation under rhodium catalysis.5 Using bisphosphite ligand
(R,R)-Chiraphite, up to 90% ee was obtained for styrene. In a
major breakthrough in enantioselective hydroformylation, Takaya
and co-workers reported 94% ee for styrene using
phosphine-phosphite ligand (R,S)-BINAPHOS (2).6 Since
then, only a handful of chiral ligands have been successfully
applied to AHF. Among the most effective are (S,S)-Kelliphite7
and (S,S)-ESPHOS,8 which give high enantioselectivity for vinyl
acids yields pharmacologically active, anti-inflammatory
analgesics such as ibuprofen, ketoprofen, and naproxen.
However, even for styrene, only a handful of catalyst systems
are capable of producing useful enantioselectivities (>90%
ee).3
(3) Reviews: (a) Agbossou, F.; Carpentier, J.-F.; Mortreux, A. Chem.
ReV. 1995, 95, 2485–2506. (b) Breit, B.; Seiche, W. Synthesis 2000, 1–36.
(c) Klosin, J.; Landis, C. R. Acc. Chem. Res. 2007, 40, 1251–1259.
(4) Stille, J. K.; Su, H.; Brechot, P.; Parrinello, G.; Hegedus, L. S.
Organometallics 1991, 10, 1183–1189.
(5) Whiteker, G. T.; Babin, J. E., WO9393839, 1993.
(6) Sakai, N.; Mano, S.; Nozaki, K.; Takaya, H. J. Am. Chem. Soc. 1993,
115, 7033–7034.
(1) Claver, C.; van Leeuwen, P. W. N. M. Rhodium Catalyzed
Hydroformylation; Kluwer Academic Publishers: Dordrecht, The Nether-
lands, 2000.
(7) Cobley, C. J.; Gardner, K.; Klosin, J.; Praquin, C.; Hill, C.; Whiteker,
G. T.; Zanotti-Gerosa, A.; Petersen, J. L.; Abboud, K. A. J. Org. Chem.
2004, 69, 4031–4040.
(2) Botteghi, C.; Paganelli, S.; Marchetti, M. Chirality 1991, 3, 355–
369.
10.1021/ol801723a CCC: $40.75
Published on Web 09/24/2008
2008 American Chemical Society

obtained with 3,4-diazaphospholane ligands in AHF prompted
us to examine these ligands in AHF of other challenging
substrates. In this contribution, we report the application of
three diazaphospholane ligands (Figure 2)15 to the AHF of
terminal and internal aryl alkenes.
Figure 1. Prominent ligands for AHF of aryl alkenes.
acetate and allyl cyanide, respectively, the sugar-based bisphos-
phite ligand (3) developed by Claver and co-workers,9 which
yields 93% ee for styrene, and phosphine-phosphoramidite
ligand YanPhos (4),10 developed by Zhang and co-workers,
which gives 98% ee for styrene. Despite the high enantiose-
lectivity observed with these ligands, the regioselectivities are
modest (<15:1 R:ꢀ), and the reactions are slow (20-50 catalytic
turnovers per hour).
Figure 2. Chiral diazaphospholane ligands screened in this study.
An initial screen of chiral ligands 7, 8a, and 8b in AHF
under a standard set of conditions was performed (80 °C,
substrate:catalyst 1:0.002 ) 500, 150 psi of 1:1 CO:H2
pressure, L:Rh ) 1.2, toluene solvent) for a variety of aryl
alkene substrates. In general, the chemoselectivities are
Recently, we11 reported the first successful application
of chiral bisphosphine ligands, diazaphospholanes, to
AHF.12 Of these ligands, (S,S,S)-bisdiazaphos (7) is
particularly active and selective (87% ee for allyl cyanide,
89% ee for styrene, 97% ee for vinyl acetate, up to 9000
turnovers per hour with styrene). Subsequently, Klosin
and co-workers13 at Dow Chemical Company reported
successful AHF using bisphosphine ligands (R,R)-Bina-
phine (5) and (R,R)-Ph-BPE (6), which both give excellent
enantioselectivity (94% ee).
Although several chiral ligands produce high enantiose-
lectivity in AHF of a few simple alkenes, there are few
reports of successful AHF applied to more diverse alkenes.
AHF of internal alkenes is particularly challenging due to
their lower reactivity compared to terminal alkenes. To date,
only BINAPHOS exhibits high enantioselectivity for the
AHF of both terminal and internal alkenes.14 However, poor
regioselectivity and low catalyst activity limit the synthetic
utility of this ligand. The high activity and selectivity
1
excellent; no hydrogenation products were detected by H
NMR. For each alkene examined, the R aldehyde constitutes
the major regioisomer. Hydroformylation of terminal alkenes
generally is fast with complete conversion in most cases.
AHF of internal alkenes is slower, but selectively produces
internal aldehydes, only. Under screening conditions, bis-
phosphine ligand 7 provides good to excellent enantioselec-
tivities (80-93% ee) and regioselectivity (4:1 to 20:1 R:ꢀ)
for both terminal and internal alkenes (Table 1). Conversely,
phosphine-phosphite ligands 8a and 8b give only modest
enantio- and regioselectivities. (See the Supporting Informa-
tion for complete screening results.)
Previously we observed11 that AHF of styrene proceeded
with improved enantioslectivity and regioselectivity at lower
temperature and higher syngas pressure: at 60 °C and 500
psi (1:1 CO:H2), selectivities up to 89% ee and 17:1 R:ꢀ are
obtained. To optimize reaction conditions, we examined the
independent effect of CO and H2 pressures and found that
(8) Cobley, C. J.; Klosin, J.; Qin, C.; Whiteker, G. T. Org. Lett. 2004,
6, 3277–3280.
(9) Dieguez, M.; Pamies, O.; Ruiz, A.; Claver, C. New J. Chem. 2002,
26, 827–833.
(14) (a) Tanaka, R.; Nakano, K.; Nozaki, K. J. Org. Chem. 2007, 72,
8671–8676. (b) Sakai, N.; Nozaki, K.; Takaya, H. J. Chem. Soc., Chem.
Commun. 1994, 395–396. (c) Nozaki, K.; Li, W.; Horiuchi, T.; Takaya, H.
Tetrahedron Lett. 1997, 38, 4611–4614. (d) Nanno, T.; Sakai, N.; Nozaki,
K.; Takaya, H. Tetrahedron: Asymmetry 1995, 6, 57. (e) Horiuchi, T.; Ohta,
T.; Shirakawa, E.; Nozaki, K.; Takaya, H. Tetrahedron 1997, 53, 7795–
7804.
(10) Yan, Y. J.; Zhang, X. M. J. Am. Chem. Soc. 2006, 128, 7198–
7202.
(11) Clark, T. P.; Landis, C. R.; Freed, S. L.; Klosin, J.; Abboud, K. A.
J. Am. Chem. Soc. 2005, 127, 5040–5042.
(12) A selection of these ligands are available from Sigma Aldrich.
(13) Axtell, A. T.; Klosin, J.; Abboud, K. A. Organometallics. 2006,
25, 5003–5009.
(15) Landis, C. R.; Hashiguchi, B. G. Manuscript in preparation.
4554
Org. Lett., Vol. 10, No. 20, 2008

hydroformylation of styrene at 40 °C with PCO ) 120 psi
and PH ) 40 psi with ligand 7 resulted in 94% ee and 64:1
2
Table 1. Initial Screening Results for the Asymmetric
Hydroformylation of Aryl Alkenes with Ligand 7e
R:ꢀ ratio (Table 2 entry 1). Varying the hydrogen pressure
had little effect on either percent ee or R:ꢀ. Apparently,
hydroformylation selectivity is much more sensitive to CO
partial pressure than H2 partial pressure. Hydroformylation
under these conditions effected increased selectivity with
phosphine-phosphite ligands 8a and 8b: 90% ee is obtained
for styrene with ligand 8b (Table 2 entry 3). Nozaki and
co-workers previously have reported modestly reduced
enantio- and regioselectivity for styrene with BINAPHOS
at 1 atm of syngas pressure.16
Application of optimized conditions to the hydroformylation
of other terminal aryl alkenes results in significant selectivity
gains. Notably, hydroformylation of 2-vinyl naphthalene with
ligand 7 proceeds with 97% ee and no linear isomer, as detected
by 1H NMR (Table 2 entry 5). Naproxen precursor 6-methoxy-
2-vinyl naphthalene yields similar results: 96% ee and no
detectable linear isomer (Table 2 entry 8). The optimized
reaction conditions result in substantially increased enantiose-
lectivity for AHF of other aryl alkenes with ligands 8a and 8b.
Ligand 8a provides nearly complete regioselectivity for both
substituted and unsubstituted vinyl naphthalenes (Table 2 entries
7 and 10), while modest to good enantioselectivities (64-84%
ee) were obtained with ligand 8b (see the Supporting Informa-
tion, Table 2).
a
Determined via H NMR. b Determined via chiral GC. c Determined
1
by converting the aldehdye to the corresponding alcohol with NaBH4
followed by chiral SFC analysis. d Percent ee is shown as (% R,% ꢀ).
Absolute stereochemistry was determined by comparing the sign of the
optical rotation with the literature values. e All reactions run at 80 °C, 150
psia syngas, [alkene] ) 1 M, [Rh] ) 0.002 M,
Table 2. Optimized Results for the Asymmetric Hydroformylation of Vinyl Arenes with Ligands 7, 8a, and 8bg
a No ꢀ-aldehyde was detected by 1H NMR. b Pressure measured in psia. c Percent ee was determined via chiral GC. d Percent ee was determined by
e
1
converting the aldehdye to the corresponding alcohol with NaBH4 followed by chiral SFC analysis. Determined via H NMR. Absolute stereochemistry
was determined by comparing the sign of the optical rotation with the literature values. f Percent ee is shown as (% R,% ꢀ). g Conditions: [alkene]) 1 M,
[Rh]) 0.002 M, [ligand] ) 0.0024 M..
Org. Lett., Vol. 10, No. 20, 2008
4555

In contrast with terminal aryl alkenes, the regio- and
enantioselectivity for AHF of internal alkenes are largely
independent of total syngas pressure. In some cases modest
increases in enantioselectivity were achieved by lowering the
reaction temperature, albeit with reduced regioselectivity. Hy-
droformylation of trans-ꢀ-methylstyrene with ligand 8a at 40
°C gives the corresponding R-aldehyde, a precursor of antitus-
sive butethamate,2 in 86% ee and 14:1 R:ꢀ (Table 2, entry 11).
For cis-ꢀ-methylstyrene, ligand 7 gives high ee (91%) and good
regioselectivity (10:1 R:ꢀ). Excellent enantioselectivity (93%
ee) was obtained for cis-stilbene with ligand 7. In this case,
reduced syngas pressure accelerates AHF relative to cis-trans
isomerization of stilbene: trans-stilbene reacts slowly in AHF.
Selectivities for AHF of indene were essentially identical at high
and low temperatures.
creases with more electron-withdrawing substituents; the
Hammett plot of log (R:ꢀ) vs σp (Figure 3) is linear with a
Because R-aryl aldehydes are susceptible to racemization,
we have examined the influence of extended reaction times
for some ligand/substrate combinations which gives >90%
ee. With ligand 7, prolonged reactions do not result in
significant erosion of percent ee (Table 2, entries 2, 6, 9,
14, and 16). As has been reported for phosphine-phosphite
ligands such as BINAPHOS, ligands 8a and 8b at prolonged
reaction times result in lowered ee values (Table 2, entries
4 and 12). In comparing diazaphospholanes with other
ligands (see the Supporting Information, Table 3), we find
that diazaphospholanes yield similar or superior selectivities
to those previously reported for AHF of aryl alkenes.16
Figure 3. Hammett plot for the asymmetric hydroformylation of
para-substituted styrenes with ligand 7.
positive slope (F ) +0.56, R2 ) 0.93). The positive slope
indicates negative charge buildup in the regioselectivity-
determining transition state. Stabilization of this charge via
delocalization onto the aryl ring has previously been posed
to explain the greater preference for branched aldehyde in
the hydroformylation of styrene versus simple alkyl alk-
enes.17 Interestingly, there is no obvious correlation of
enantioselectivity with Hammett parameters.
The influence of substrate electronics on selectivity was
examined for AHF of para-substituted styrenes with ligand
7. The results are shown in Table 3.
In summary, we have demonstrated useful selectivity and
activity for the AHF of both terminal and internal aryl
alkenes using rhodium catalysts and diazaphospholane
ligands. For terminal alkenes, strong correlation between
carbon monoxide pressure and enantio- and regioselectivity
is found, with higher CO pressure yielding higher selectivity.
Applications of these diazaphospholane ligands to AHF of
diverse, nonaryl alkenes are underway.
Table 3. Hydroformylation of Para-Substituted Styrenes with
Ligand 7a
Acknowledgment. We would like to thank Jerzy Klosin,
Susan Freed, and Greg Whiteker of Dow Chemical for their
generous donation of Rh(acac)(CO)2 and assistance in
resolution of chiral ligands. We are also grateful Prof.
Tehshik Yoon and co-workers for access to SCF instrumen-
tation.
entry
R
R:ꢀ
ee (%)b
1
2
3
4
5
6
OMe
Me
H
20
31
33
36
54
65
70
89
90
83
77
80
Supporting Information Available: Complete asym-
metric hydroformylation results (optimized and nonopti-
mized) for each diazaphospholane ligand, detailed experi-
mental procedures, and conditions for the determination of
enantiomeric excess. This material is available free of charge
via the Internet at http://pubs.acs.org.
F
Cl
CF3
a Reaction conditions; substrate:catalyst ) 200:1, 4 0 °C, 150 psia 1:1
CO:H2, 100% convn was achieved for each substrate in 3 h. b Determined
by chiral GC.
OL801723A
(16) Horiuchi, T.; Shirakawa, E.; Nozaki, K.; Takaya, H. Organome-
tallics. 1997, 16, 2981–2986.
In general, AHF of para-substituted styrenes provides good
enantioselectivity (77% to 90% ee) and high regioselectivities
(20-65:1). Branched isomer selectivity systematically in-
(17) Lazzaroni, R.; Raffaelli, A.; Settambolo, R.; Bertozzi, S.; Vitulli,
G. J. Mol. Catal. 1989, 50, 1.
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Org. Lett., Vol. 10, No. 20, 2008