Highly active, regioselective, and enantioselective hydroformylafion with Rh catalysts ligated by bis-3,4-diazaphospholanes

Article abstract of DOI:10.1021/ja050148o

Azines made by the reaction of hydrazine with ortho-formylbenzoic acid react with 1,2-diphosphinobenzene and either succinyl chloride or phthaloyl chloride in ca. 30% yield to give rac-bis-3,4-diazaphospholanes bearing benzoic acid groups in the 2 and 5 positions. Condensation of the benzoic acid functionalities with enantiomerically pure amines affords diastereomeric benzoamides which can be separated by flash chromatography. Application of the resolved bis-3,4-diazaphosholanes to Rh-catalyzed enantioselective hydroformylation of styrene, allyl cyanide, and vinyl acetate under mild pressures (20-500 psig of CO/H₂) and temperatures (40-120 °C) reveals high activities and selectivities for all three substrates. At 60 °C and 500 psig syn gas, the best ligand provides outstanding regio- and enantioselectivities (styrene, 89% ee, b:l = 30:1; allyl cyanide, 87% ee, b:l = 4.8:1; vinyl acetate, 95% ee, b:l = 40:1) while achieving turnover frequencies of ca. 3000 h^-1. Copyright

Full text of DOI:10.1021/ja050148o

Published on Web 03/17/2005
Highly Active, Regioselective, and Enantioselective Hydroformylation with Rh
Catalysts Ligated by Bis-3,4-diazaphospholanes
Thomas P. Clark,§ Clark R. Landis,*,§ Susan L. Freed,† Jerzy Klosin,*,† and Khalil A. Abboud‡
Department of Chemistry, UniVersity of WisconsinsMadison, 1101 UniVersity AVenue, Madison, Wisconsin 53706,
Chemical Sciences, The Dow Chemical Company, 1776 Building, Midland, Michigan 48674, and
Department of Chemistry, UniVersity of Florida, GainesVille, Florida 32611
Received January 10, 2005; E-mail: landis@chem.wisc.edu; jklosin@dow.com
As with catalytic hydrogenation of alkenes by rhodium com-
plexes, key attributes of rhodium-catalyzed alkene hydroformyla-
tion1 (perfect atom economy, inexpensive reactants, demonstrated
performance on industrial scales, readily modified phosphorus
ligands) make pursuit of the enantioselective transformation ir-
resistible. Whereas hydrogenation effects net loss of the CdC
functional group, hydroformylation results in its transformation to
a more versatile functional group, the aldehyde. Although new
ligand developments over the last fifteen years have yielded
significant progress, the general application of enantioselective
hydroformylation lags well behind that of enantioselective hydro-
genation. Several factors are responsible: (1) enantioselective
hydroformylation is relatively slow, with turnover frequencies
commonly in the range of tens to hundreds per hour for terminal
alkenes and much slower rates for internal alkenes; (2) effective
enantioselective hydroformylation of terminal alkenes requires
control of regioselectivity that favors branched isomers; and (3)
few of the effective ligands exhibit good activity and selectivity
for a range of different substrates, even when one considers only
1-alkenes. We report new chiral bis-3,4-diazaphospholane ligands
that constitute unusually active and selective ligands for rhodium-
catalyzed hydroformylation of styrene, allyl cyanide, and vinyl
acetate.
3 proceeds with ca. 30% yield upon reaction of the azine 1 with
1,2-diphosphinobenzene in the presence of either succinyl chloride
or phthaloyl chloride (Scheme 1). Coupling the carboxylic acid
groups of either 2 or 3 with resolved chiral amines followed by
chromatographic separation of the resulting diastereomers yields
enantiomerically pure bis-3,4-diazaphospholanes 4, 5, 6, and 7.
The crystallographic structure of 7a is shown in Figure 1.
Recently, we reported the facile synthesis of a wide variety of
chiral mono- and bis-3,4-diazaphospholanes2 that are readily
resolved, extended into small libraries, and applied to asymmetric
allylic alkylation both in solution3 and on bead.4 This work
demonstrated that mono-3,4-diazaphospholanes bearing carboxylic
acid functionalized substituents in the 2 and 5 positions can be
Scheme 1
Figure 1. Two views of the crystallographic structure of 7a. For clarity,
only one of the nearly C2-related diazaphospholane rings is shown.
Hydrogens are shown for the phospholane 2 and 5 positions, only. The
succinyl group was eliminated from the lower view for ease of viewing.
expanded to collections of new ligands using simple coupling
chemistry. One-step synthesis of bis-3,4-diazaphospholanes 2 and
Prominent ligands for enantioselective hydroformylation include
BINAPHOS (10),5 Kelliphite (11),6,7 ESPHOS (12),8 Chiraphite
(13),9 and the sugar-derived phosphite (14).10 Literature data for
these ligands suggest that 10 is generally the most useful.
§ The University of WisconsinsMadison.
† The Dow Chemical Company.
‡ University of Florida.
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J. AM. CHEM. SOC. 2005, 127, 5040-5042
10.1021/ja050148o CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Percent Conversion (conv), Branched:Linear Ratio (b:l),
and Enantioselectivity (% ee) for Hydroformylationa of Styrene,
Allyl Cyanide, and Vinyl Acetate with Chiral Phosphorus Ligands
(L)
Styrene
b:l
Allyl Cyanide
b:l % ee
Vinyl Acetate
b:l % ee
L
conv
% ee
conv
conv
10
11
13
8a
4a
96 4.5 82(R)
78 8.9 2(R)
90 9.0 49(R) 100 5.5 13(R)
28 1.1 12(R) 93 1.3 10(R)
93 8.4 76(S) 100 5.3 64(S)
98 2.1 72(R)
100 9.3 66(S)
72
78
75 190
31
94
8.2 48(S)
61
73(R)
50(R)
23(S)
85(R)
92(S)
79(R)
83(S)
83(R)
92(S)
86(R)
96(S)
91(R)
96(S)
39
24
22
19
26
22
19
36
41
31
37
5a 100 8.1 75(R) 100 4.1 75(R) 100
4b
5b
4c
51 9.7 76(S)
75 6.9 70(R) 100 5.0 61(R)
97 8.5 76(S) 100 5.5 67(S)
97 5.7 61(S)
54
81
98
5c 100 7.4 63(R) 100 3.7 75(R) 100
6c 100 5.7 65(S) 100 4.0 69(S) 100
7c 100 5.3 73(R) 100 3.5 82(R) 100
6a 100 6.3 73(S) 100 4.1 77(S) 100
7a 100 6.6 82(R) 100 4.1 87(R) 100
Styrene, vinyl acetate, and allyl cyanide undergo hydroformy-
lation with generally high enantioselectivities (94, 92, and 69%,
respectively), modest branched:linear (b:l) ratios (7.3:1, 6.2:1, and
2.2:1, respectively), and modest turnover frequencies (ca. 200 h-1
for all substrates) under reaction conditions of 60-70 °C and ca.
10 atm of 1:1 CO:H2.5 Ligands 11-14, in contrast, have more
specialized utility. The ESPHOS ligand 12 is highly selective for
vinyl acetate (ee ) 90%, b:l ) 16:1) but exhibits low enantio-
selectivity for styrene.8 Of the three bisphosphite ligands shown
above, 139 and 1410 are effective for styrene in the temperature
range of 20-35 °C, yielding enantioselectivities of 76.4 and 89%,
respectively, with very high regioselectivity control (b:l ) 47:1
and 49:1, respectively). Kelliphite (11) is particularly well suited
for hydroformylation of allyl cyanide (ee ) 75 %, b:l ) 16:1) and
vinyl acetate (ee ) 87.7%, b:l ) 56:1) at low temperatures.
Enantioselective hydroformylation turnover frequencies commonly
fall in the range of 10-600 turnovers h-1 over the temperature
range of ca. 35-60 °C, with BINAPHOS generally leading to the
lowest activity. For comparison, modern enantioselective hydro-
genation catalysts have been reported, in favorable cases, with
turnover frequencies of over 100 000 turnovers h-1 and nearly
quantitative enantioselectivity with ketone, itaconate, and enamide
substrates.11
a All reactions performed at 80 °C in toluene with 150 psig 1:1 CO:H2
with L:Rh ) 1.2 (2.1 for monophosphine 8a), total substrate:Rh ) 5000,
and 3 h reaction time.
Following a previously published screening protocol,7 the
performance of rhodium hydroformylation catalysts modified by
ligands 4-8, 10, 11, and 13 has been examined by simultaneous
hydroformylation of allyl cyanide, styrene, and vinyl acetate (see
Table 1). Under the screening conditions (150 psig, 80 °C, total
substrate:catalyst loading of 5000:1, toluene solvent, L:Rh ) 1.2,
CO:H2 ) 1:1), bis-3,4-diazaphospholanes consistently exhibit state-
of-the-art selectivities and activities for aldehyde production from
all three substrates with no indication of hydrogenation or other
side reactions. In contrast, the mono-3,4-diazaphospholane 8a is
slow and unselective, at least at the P:Rh ratios used in screening
runs. We note that these conditions of low P:Rh ratios, modest
pressure, and relatively high temperature lead to substantially poorer
selectivity, but significantly higher activity, with BINAPHOS 10
than has been previously reported. Such observations serve to
caution against indiscriminate comparisons of selectivities without
noting details of the reaction conditions. Particularly effective
ligands emerging from this screen are those bearing benzoamides
of methyl benzylamine in the 2 and 5 positions of the phospholane
ring. Comparison of aldehyde configurations obtained with the
diastereomeric pairs 4/5 and 6/7 demonstrates that the stereochem-
istry of the phospholane ring, rather than the stereochemistry of
the chiral amine, controls the absolute chirality of the product and
reveals a small mismatching effect of ca. 10% ee.
Figure 2. Graphs depicting the influence of 1:1 CO:H2 pressure and
temperature on the enantiomeric excess (% ee, top left and right) and
regioselectivity (b:l ratio, bottom left and right) of hydroformylation of allyl
cyanide, styrene, and vinyl acetate as catalyzed by 7a and Rh(acac)(CO)2.
(L:Rh ) 1.2, total substrate:Rh ) 5000, toluene solvent, standard temper-
ature of 80 °C, and standard pressure of 150 psig 1:1 CO:H2).
of pressure and temperature on enantioselectivities (Figure 2) varies
significantly with substrate. Whereas higher pressures and lower
temperatures increase the percent of enantiomeric excess for styrene
hydroformylation, temperature only affects allyl cyanide enanti-
oselectivities, and the percent enantiomeric excess for vinyl acetate
is largely insensitive to both temperature and pressure. Regio-
selectivities follow a similar pattern. For styrene hydroformylation
at 60 °C, the branched-to-linear ratio increases from 16:1 to 30:1
upon increasing the syn gas pressure from 150 to 500 psig,
respectively. Over the same pressure range at 60 °C, both allyl
cyanide and vinyl acetate exhibit unperturbed regioselectivities
(4.7:1 and 40:1, respectively). OVerall, 60°C and 500 psig syn gas
enable outstanding regio- and enantioselectiVities for all three
substrates (styrene, 89% ee, b:l ) 30:1; allyl cyanide, 87% ee, b:l
) 4.8:1; Vinyl acetate, 95% ee, b:l ) 40:1) while achieVing aVerage
The influence of reaction conditions on hydroformylation was
explored with special focus on ligand 7a. Interestingly, the influence
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J. AM. CHEM. SOC. VOL. 127, NO. 14, 2005 5041

C O M M U N I C A T I O N S
turnoVer frequencies greater than ca. 3000 h-1 oVer 90% consump-
tion of the substrate.
the CdC double bond occurs at the same enantioface for all
substrates. A useful quadrant diagram, based on the assumption of
a trigonal bipyramidal coordination environment with diequatorial
phosphorus atoms, for rationalizing the product stereochemistry is
shown. We emphasize that this model is purely mnemonic. Better
characterization of catalyst coordination geometries through spec-
troscopic and computational model studies is underway.
Both the high cost of rhodium catalysts and the attractiveness
of applying hydroformylation to more substituted alkenes emphasize
the importance of hydroformylation activity. Our reaction screening
conditions lead to higher catalyst activities than commonly are
reported, particularly, with bis-3,4-diazaphospholane ligands. For
example, in the presence of 1.2 equiv of 7a at a total substrate:Rh
loading of 30 000:1 under 500 psig of syn gas at 80 °C, conversions
of styrene, allyl cyanide, and vinyl acetate are 85, 100, and 86% in
just 3 h. Analysis of gas uptake curves under these conditions
reveals average turnover frequencies of at least ca. 9000 h-1, or
2.5 turnovers s-1, over 90% conversion of substrate. Under
otherwise identical conditions, hydroformylations with bis-3,4-
diazaphospholane-modified catalysts proceed approximately twice
as fast as bisphosphites 11 and 13 and the mixed phosphine-
phosphite 10.
Interestingly, hydroformylation rate laws with bis-3,4-diaza-
phospholanes are approximately first-order in alkene and indepen-
dent of the synthesis gas pressure in the range of 100-500 psi.
Preliminary data suggest that the rate law for hydroformylation is
zero-order in both H2 and CO concentrations over the 60-80 °C
temperature range. Furthermore, the data indicate that styrene
enantioselectivities and regioselectivities primarily respond to
changes in CO pressure; lower CO partial pressure results in lower
selectivity. Allyl cyanide selectivities also decrease with decreased
CO pressure, but the effect is not so large. These rate laws are
consistent with bimolecular reaction of the catalyst and substrate
comprising or preceding the turnover-limiting step. Presumably,
the influence of CO pressure on hydroformylation selectivity for
styrene (both enantiomeric excess and b:l ratio), combined with
the absence of any influence of gas pressures on the rate of styrene
conversion, reflects the interruption of Rh-alkyl isomerizations
occurring after the turnover-limiting step. More detailed examination
of the reaction kinetics is underway.
In summary, bis-3,4-diazaphospholanes bearing benzoic acid in
the 2 and 5 positions are readily accessible and extensible ligands
for enantioselective hydroformylation with rhodium catalysts.
Significantly, these ligands demonstrate effective control of regio-
and enantioselectivity for three different classes of substrates while
achieving very high catalyst activity. These properties suggest broad
applicability to catalytic, enantioselective synthesis of aldehydes.
Acknowledgment. We thank Dowpharma for financial support
of this research. We thank Mr. Ryan Nelson for numerous
contributions.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds. Crystallographic data for 7a,
including a CIF file. This material is available free of charge via the
Internet at http://pubs.acs.org.
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