Asymmetric hydroformylation of vinyl acetate: Application in the synthesis of optically active isoxazolines and imidazoles

Article abstract of DOI:10.1021/ol070900l

Equation Presented (R)- and (S)-2-(Acetyloxy)-propanal were prepared [93.8% ee, 102 b/l for (R), 96.9% ee, 149 b/l for (S)] via asymmetric hydroformylation of vinyl acetate on a 150-180 g scale and were used as the starting materials in the synthesis of chiral isoxazoline and imidazole derivatives which proceeded without racemization of the chiral center.

Full text of DOI:10.1021/ol070900l

ORGANIC
LETTERS
2007
Vol. 9, No. 14
2665-2668
Asymmetric Hydroformylation of Vinyl
Acetate: Application in the Synthesis of
Optically Active Isoxazolines and
Imidazoles
P. J. Thomas,*,† Alex T. Axtell,† Jerzy Klosin,*,† Wei Peng,† Cynthia L. Rand,†
Thomas P. Clark,‡,# Clark R. Landis,‡ and Khalil A. Abboud§
Corporate R&D, The Dow Chemical Company, 1776 Building,
Midland, Michigan 48674, Department of Chemistry, UniVersity of
Wisconsin-Madison, 1101 UniVersity AVenue, Madison, Wisconsin 53706, and
Department of Chemistry, UniVersity of Florida, GainesVille, Florida 32611
pjthomas@dow.com; jklosin@dow.com
Received April 17, 2007
ABSTRACT
(R)- and (S)-2-(Acetyloxy)-propanal were prepared [93.8% ee, 102 b/l for (R), 96.9% ee, 149 b/l for (S)] via asymmetric hydroformylation of vinyl
acetate on a 150 180 g scale and were used as the starting materials in the synthesis of chiral isoxazoline and imidazole derivatives which
−
proceeded without racemization of the chiral center.
Asymmetric hydroformylation (AHF) is an atom economic,
highly chemoselective transformation that allows conversion
of olefins into chiral aldehydes in a single catalytic step.1
Since aldehydes can be easily transformed into a variety of
useful chemicals, such as amines, imines, alcohols, and acids,
AHF constitutes an attractive entry to chiral intermediates.
We recently have identified several highly selective ligands
based on bis-phosphacycles for rhodium-catalyzed asym-
metric hydroformylation reactions.2-4 Out of this ligand class,
diazaphospholane (S,S)-12 and (R,R)-Ph-BPE (2)3 exhibit
remarkable selectivity while maintaining high catalytic
activity (Figure 1). For example, (S,S)-1 gave 97% ee
(branched-to-linear ratio (b/l) ) 40) in the AHF of vinyl
acetate at 80 °C while 2 led to 94% ee and unprecedented
regioselectivity (b/l ) 45) in the AHF of styrene at 80 °C.
Very high selectivity and hydroformylation rates achieved
with (S,S)-1 and its diastereoisomer (R,R)-35 in AHF of vinyl
† The Dow Chemical Company.
‡ University of Wisconsin.
§ University of Florida.
# Current address; The Dow Chemical Company, 1776 Building, Midland,
MI 48674.
(2) Clark, T. P.; Landis, C. R.; Freed, S. L.; Klosin, J.; Abboud, K. A.
J. Am. Chem. Soc. 2005, 127, 5040-5042.
(3) Axtell, A. T.; Cobley, C. J.; Klosin, J.; Whiteker, G. T.; Zanotti-
Gerosa, A.; Abboud, K. A. Angew. Chem., Int. Ed. 2005, 44, 5834-5838.
(4) Axtell, A. T.; Klosin, J.; Abboud, K. A. Organometallics 2006, 25,
5003-5009.
(1) (a) Claver, C., van Leeuwen, P. W. N. M. In Rhodium Catalyzed
Hydroformylation; Claver, C., van Leeuwen, P. W. N. M., Eds.; Kluwer
Academic Publishers: Dordrecht, The Netherlands, 2000; Chapter 5. (b)
Claver, C.; Dieguez, M.; Pamies, O.; Castillon, S. Top. Organomet. Chem.
2006, 18, 35-64.
10.1021/ol070900l CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/08/2007

Table 1. AHF of Vinyl Acetate with (S,S)-1a
d
entry pressure % conversion
b/lb
% eec TOF (h-1
)
1
2
3
4
5
50
100
200
300
400
14
72
97
97
94
22.5
29.9
28.7
26.1
29.0
91
95
95
96
96
2800
14400
19400
19400
18800
a Conditions: temp ) 80 °C, vinyl acetate/Rh molar ratio ) 100000,
(S,S)-1/Rh ) 1.2, 4 mL of vinyl acetate, 5 h reaction time. b ratio of branched
to linear isomers. c % ee ) enantiomeric excess of branched isomer. d TOF
) turnover frequency (average).
Enantio- and regioselectivities were maintained at very
high levels (95-96% ee, b/l ) 26-30) regardless of the
pressure used (within the range of 100-450 psi). With this
information in hand, a scale-up of vinyl acetate AHF was
undertaken in a 300 mL Parr reactor. Tetraglyme was used
(25 g) during the reaction to allow for easy product recovery
and catalyst recycling.6 Vinyl acetate (135 g) was reacted
under hydroformylation conditions for 23 h using (S,S)-1/
Rh catalyst (VA/Rh ) 100000) at 75 °C and 475 psi syngas
pressure. This led to 98.9% substrate conversion and clean
product formation (96.8% ee and b/l ) 46.9). The product
(S-5) was recovered from the reaction mixture by distillation
under reduced pressure (155 g, 85.5% yield, 96.8% ee, b/l
) 139). Hydroformylation of vinyl acetate with (R,R)-3 at
50 °C gave 92.8% yield of R-5 (93.8% ee and b/l ) 102)
after distillation. Enhanced product regioselectivity upon
distillation is due to the lower boiling point of the branched
isomer. These experiments demonstrate that diazaphos-
pholanes (S,S)-1 and (R,R)-3 enable highly efficient and
highly enantio- and regioselective hydroformylation of vinyl
acetate on a large scale.
Figure 1. Structures of highly selective ligands in AHF.
acetate (4) coupled with a high degree of synthetic func-
tionality offered by its hydroformylation product, 2-(acetyl-
oxy)-propanal (5), prompted us to explore the synthesis and
utilization of 5 (Scheme 1).
Scheme 1. Asymmetric Hydroformylation of Vinyl Acetate
Having synthesized large quantities of (S)- and (R)-2-
(acetyloxy)-propanal (5), we focused on the application of
5 to the synthesis of chiral intermediates of varying molecular
complexity. At the outset, (S)-1-amino-2-propanol (7) was
synthesized as shown in Scheme 2 to ensure that the
In this communication, we report the large scale prepara-
tion of both enantiomers of 5 (150-180 g scale) by AHF of
vinyl acetate using (S,S)-1 and (R,R)-3 and the application
of both enantiomers of 5 in the preparation of various
heterocyclic compounds, specifically chiral isoxazoline (10-
12) and imidazole (15) derivatives.
Scheme 2. Synthesis of (S)-Amino-2-propanol 7
Since the previous AHF experiments with (S,S)-1 were
conducted on a mixture of olefins,2 it was important to
determine catalytic properties of (S,S)-1 in AHF of pure vinyl
acetate. For this purpose, a series of runs with vinyl acetate
were conducted using an Endeavor parallel reactor at 80-
100 °C and 50-450 psi syngas pressure with the substrate
to a Rh molar ratio varying from 5000 to 150000. We found
that even at a Rh to substrate ratio of 100000 and 200 psi
syngas pressure, reactions were 97% complete within 5 h,
which translates into an average TOF of 19400 h-1 (Table
1).
enantioselectivity established during AHF can be maintained
during synthetic transformations (Scheme 2). The aldoxime
6 was obtained as a mixture of Z and E isomers in 90%
yield by treatment of 5 with hydroxylamine hydrochloride
in the presence of pyridine. Lithium aluminum hydride
(5) (S,S)-1 and (R,R)-3 diastereoisomers differ in chirality of the
phosphacycle fragment of the ligand which determines absolute configu-
ration of AHF products.
(6) See Supporting Information for more details.
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Org. Lett., Vol. 9, No. 14, 2007

reduction of the aldoxime 6 gave (S)-1-amino-2-propanol (7)
in 70% yield. Optical purity of 7 was found to be the same
(94% ee) as that of 5, thereby establishing the complete
retention of the chiral center during aldoxime formation and
the subsequent reduction. Interestingly, when triethylamine
was used as a base for the preparation of aldoxime, the
enantioselectivity of 7 was significantly reduced to 28% ee.
After obtaining the chiral oxime S-6, its application toward
the synthesis of two classes of heterocyclic compounds was
explored. Conversion of oxime derivatives to nitrile oxides
and subsequent cycloaddition reactions with various di-
polarophiles is a well-known method to generate isoxazoline
derivatives.7 Hydrolysis and reduction of the isoxazolines
provides entry into hydroxyl ketones and hydroxylamines,
respectively.
compounds. We have utilized this compound to synthesize
substituted imidazole derivatives containing a chiral side
chain (Scheme 4). The aldoxime R-6 and hydroximoyl
Scheme 4. Synthesis of Chiral Imidazole Derivatives
A broad range of isoxazoline derivatives having a chiral
side chain (Scheme 3) can be envisioned from nitrile oxide
Scheme 3. Synthesis of Chiral Isoxazolines
chloride R-9 were prepared by following the same procedures
employed for S-6 and S-9. In addition to spectroscopic
methods, R-9 was characterized by X-ray analysis (vide
infra). The critical step in this synthesis is an amino Heck
reaction. The key substrate R-14 was prepared from R-9 first
by reaction with allylbenzylamine to obtain R-13 followed
by its treatment with pentafluorobenzoyl chloride. Both
intermediates R-13 and R-14 were obtained as a mixture of
E and Z isomers. The intermediate R-14 was subjected to
an amino Heck reaction according to a literature procedure9
to obtain imidazole derivative R-15 in 63% yield.
To determine the optical purity of R-15, the other
enantiomer, S-15, was prepared from S-9 following the same
reaction sequence presented in Scheme 4. The optical purity
of R-15 and S-15 evaluated by Chiral HPLC analysis
(Chiralpack AD column) was found to be 94.2% ee and
94.9% ee, respectively. These results clearly demonstrate that
no decrease of optical purity has taken place during the
synthesis of imidazole derivatives.
Finally, the existence of hydroximoyl chloride R-9 as a
solid provided an opportunity to determine unambiguously
by X-ray crystallography the absolute configuration of
2-(acetyloxy)-propanal obtained by AHF of vinyl acetate
employing bisdiazaphospholane ligands. Our original as-
signment2 of the absolute configuration of 2-(acetyloxy)-
propanal (5), obtained via AHF of vinyl acetate using (S,S)-1
and (R,R)-3, was based on the comparison with previously
reported AHF data.10 Accordingly, the absolute configuration
of 2-(acetyloxy)-propanal produced by (S,S)-1 and (R,R)-3
was assigned as S and R, respectively. Large colorless
S-8 by choosing appropriate dipolarophiles. To demonstrate
the generality of this strategy, we synthesized isoxazoline
10, 11, and 12. Nitrile oxide S-8 was prepared in situ from
S-6 using aqueous sodium hypochlorite (5% solution) and a
catalytic amount of triethylamine in methylene chloride.
Reaction of in situ generated S-8 with styrene furnished 10
in 64% yield as diastereomeric mixture (1:1). Similarly,
reaction between S-8 and p-methoxystyrene led to the
formation of 11 in 65% yield. However, reaction of S-8 with
4-vinylpyridine did not give the desired cycloadduct 12 under
these conditions. The failure of this reaction was attributed
to the instability of 4-vinylpyridine in the presence of
hypochlorite. To circumvent this difficulty, an alternative
approach to generate nitrile oxide S-8 was employed. For
this purpose, hydroximoyl chloride S-9 was prepared in 85%
yield from S-6 by chlorination with N-chlorosuccinimide.8
Unlike S-6, which exists as a mixture of isomers, hydroxi-
moyl chloride S-9 exists as a single isomer (Z) as shown by
NMR analysis. Reaction of nitrile oxide S-8 with 4-vinylpy-
ridine afforded 12 in 80% yield.
Hydroximoyl chloride 9 with its chlorine moiety provides
a useful handle for further elaboration to other heterocyclic
(7) Lee, G. A. Synthesis 1982, 508-509.
(8) Liu, K-C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45,
3916-3918.
(9) Zaman, S.; Mitsuru, K.; Abell, A. D. Org. Lett. 2005, 7, 609-611.
(10) Nozaki, K.; Sakai, N.; Nanno, T.; Higashijima, T.; Mano, S.;
Horiuchi, T.; Takaya, H. J. Am. Chem. Soc. 1997, 119, 4413-4423.
Org. Lett., Vol. 9, No. 14, 2007
2667

determined the compound to be of R configuration12 thus
confirming previous assignment.
In conclusion, we have demonstrated that both enantiomers
of 2-(acetyloxy)-propanal (5) are easily accessible on a large
scale using highly efficient and highly selective asymmetric
hydroformylation of vinyl acetate. The turnover frequencies
achieved are the highest reported for any ligand or any
substrate in rhodium-catalyzed asymmetric hydroformylation.
The 2-(acetyloxy)-propanal (5) was shown to be a versatile
chiral intermediate that can be transformed into various
isoxazoline and imidazole derivatives without loss of optical
purity. Extension of this approach should allow the synthesis
of other chiral substituted imidazoles as well as chiral
heterocyclic compounds containing sulfur or oxygen.
Acknowledgment. We thank Susan Freed and Larry
Nicholson of The Dow Chemical Company for assistance
with chiral analysis and Dowpharma for financial support.
Figure 2. Thermal ellipsoid drawing of (R)-9 shown at 40%
probability level.
Supporting Information Available: Experimental pro-
cedures, NMR spectra for 10, 11, 12, and 15, and single-
crystal X-ray analysis data for (R)-9. This material is
available free of charge via the Internet at http://pubs.acs.org.
crystals of 9, originated from AHF of vinyl acetate with
(R,R)-3, were obtained from a THF/hexane mixture at -40
°C. Hydroximoyl chloride (9) crystallized in noncentrosym-
metric space group P212121.11 X-ray analysis (Figure 2)
OL070900L
(11) Structure of (R)-9. C5H8ClNO3, Mw ) 165.57, orthorhombic,
P212121, colorless plates (0.24 × 0.18 × 0.11 mm3), a ) 6.1304(6) Å, b )
10.4292(10) Å, c ) 11.9236 Å, temp ) 173(2) K, Z ) 4, V ) 762.34(13)
Å (3), R1 ) 0.0319, 0.0325, wR2 ) 0.0787, 0.793 (I > 2σ(I), all data),
GOF ) 1.084.
(12) Since the compound used to grow crystals was not pure enantiomer
(94% ee) it was necessary to confirm whether the crystal used for X-ray
analysis was indeed the major enantiomer. To accomplish this, single crystal
used to supply small crystal for X-ray analysis was later analyzed by chiral
HPLC. The analysis showed it to be pure enantiomer of the major isomer.
2668
Org. Lett., Vol. 9, No. 14, 2007