Synthesis and Application of a New Bisphosphite Ligand
Collection for Asymmetric Hydroformylation of Allyl Cyanide
Christopher J. Cobley,* Kelli Gardner,� Jerzy Klosin,*,� Celine Praquin, Catherine Hill,
´
Gregory T. Whiteker,*,� and Antonio Zanotti-Gerosa§
Dowpharma, Chirotech Technology Limited, a subsidiary of The Dow Chemical Company,
321 Cambridge Science Park, Cambridge CB4 0WG, UK
Jeffrey L. Petersen
Department of Chemistry, West Virginia University, Morgantown, West Virginia 26506
Khalil A. Abboud
Department of Chemistry, University of Florida, Gainesville, Florida 32611
whitekgt2@dow.com
Received February 5, 2004
A series of mono- and bidentate phosphites was prepared with (S)-5,5�,6,6�-tetramethyl-3,3�-di-tert-
butyl-1,1�-biphenyl-2,2�-dioxy [(S)-BIPHEN] as a chiral auxiliary and screened in the asymmetric
hydroformylation of allyl cyanide. These hydroformylation results were compared with those of
two existing chiral ligands, Chiraphite and BINAPHOS, whose utility in asymmetric hydrofor-
mylation has been previously demonstrated. Bisphosphite 11 with a 2,2�-biphenol bridge was found
to be the best overall ligand for asymmetric hydroformylation of allyl cyanide with up to 80% ee
and regioselectivities (branch-to-linear ratio, b/l) of 20 with turnover frequency of 625 [h -1] at
35 °C. BINAPHOS gave enantioselectivities up to 77% ee when the reaction was conducted in either
acetone or neat but with poor regioselectivity (b/l 2.8) and activities 7 times lower than that of 11.
The product of allyl cyanide hydroformylation using (R,R)-11 was subsequently transformed into
(R)-2-methyl-4-aminobutanol, a useful chiral building block. Single-crystal X-ray structures of (S,S)-
11 and its rhodium complex 19 were determined.
Introduction introduces a highly versatile aldehyde functional group
that is amenable to a number of synthetic transforma-
Asymmetric chemocatalysis is one of the most powerful tions.3 It is therefore surprising that the development of
synthetic methodologies for producing high value added such a route for the production of highly functionalized
chiral compounds. Its success and potential are due to chiral building blocks has not been utilized industrially.
the achievable combination of high selectivity, high To date, most efforts in this field have concentrated
activity, and reduced environmental impact.1 This has on a relatively narrow substrate range, notably the
been best demonstrated in the field of asymmetric asymmetric hydroformylation of vinylarenes to access
hydrogenation, which can be regarded as the most highly enantiomerically enriched 2-aryl propionic acids (the
developed asymmetric chemocatalytic technology to date.2 profen class of nonsteroidal antiinflammatory drugs).4 An
Conversely, while hydroformylation is the largest volume important breakthrough in this area was made during
homogeneous transition-metal-catalyzed reaction used the early 1990s with the introduction by Union Carbide
today, its asymmetric version is relatively underdevel- of a rhodium-catalyzed system involving chiral bisphos-
oped. Asymmetric hydroformylation enantioselectively phites, such as (R,R)-Chiraphite (1). Enantioselectivities
of up to 90%, along with high branched regioselectivity,
� Chemical Sciences, The Dow Chemical Company, South Charles-
were obtained for several prochiral vinylarenes.5 Van
ton, WV.
Leeuwen et al. reported detailed studies of the effects of
� Chemical Sciences, The Dow Chemical Company, Midland, MI.
§ Current address: Johnson Matthey Catalysts, 28 Cambridge
Science Park, Cambridge CB4 0FP, U.K. (3) Stille, J. K. In Comprehensive Organic Synthesis; Trost, B. M.,
(1) Blaser, H. U.; Spindler, F.; Studer, M. App. Catal. A 2001, 221, Flemming, I., Paquette, L. A., Eds.; Pergamon Press: Oxford: 1991;
119. Vol. 4, p 913.
(2) (a) Noyori, R. In Asymmetric Catalysis in Organic Synthesis; (4) Claver, C., van Leeuwen, P. W. N. M. In Rhodium Catalysed
Noyori, R., Ed.; Wiley-Interscience: New York: 1994; Chapter 2, p Hydroformylation; Claver, C., van Leeuwen, P. W. N. M., Eds.; Kluwer
16. (b) Brown, J. M.; Ohkuma, T.; Noyori, R. In Comprehensive Academic Publishers: Dordrecht: 2000; Chapter 5, p 107 and refer-
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; ences therein.
Springer, Berlin: 1999; Vol. 1, Chapters 5 and 6, pp 101 and 199. (c) (5) (a) Babin J. E.; Whiteker G. T. Patent WO 93/03830, 1992. (b)
Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asymmetric Whiteker, G. T.; Briggs, J. R.; Babin, J. E.; Barner, B. A. In Catalysis
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York: 2000; of Organic Reactions; Morrell, D. G., Ed.; Marcel Dekker: New York,
Chapter 1, p 1. 2003; p 359.
10.1021/jo040128p CCC: $27.50 © 2004 American Chemical Society
J. Org. Chem. 2004, 69, 4031-4040 4031
Published on Web 05/19/2004
Cobley et al.
SCHEME 1. Proposed Routes to (R)-2-Methyl-4-aminobutanol
structural changes in this ligand class and found that The application of these ligands for asymmetric hy-
product selectivity was influenced by the bridge length, droformylation of allyl cyanide is also described (Scheme
1).8,9 The chiral, branched aldehyde product is converted
biphenol substituents and relative configuration of chiral
centers in these bisphosphites.6 Considerable success was to 4-hydroxy-3-methylbutyronitrile (5) and 2-methyl-4-
also made by Takaya et al. using (R,S)-BINAPHOS (2),7 aminobutanol (6), both being important chiral building
blocks found in several molecules of biological interest.10
with enantioselectivities as high as 96% reported for the
hydroformylation of styrene, although the regioselectivity For example, (S)-4-hydroxy-3-methylbutyronitrile has
with BINAPHOS was substantially lower than that for been used by Merck in the synthesis of a potent nonpep-
tide gonadotropin releasing hormone antagonist (7),10c
Chiraphite.
whereas (R)-2-methyl-4-aminobutanol has been in the
preparation of a novel tachykinin NK1 receptor antago-
nist (8) by Takeda.10a,b We have previously demonstrated
a highly efficient and selective route to a precursor of 6
via asymmetric hydrogenation,11 albeit hindered by the
downstream chemistry which required a stoichiometric
hydride reduction to obtain the final amino alcohol. This
alternative approach via asymmetric hydroformylation
uses an entirely catalytic approach that circumvents this
problem.
Results and Discussion
Ligand Design and Synthesis. Phosphites are highly
effective ligands for olefin hydroformylation. Bisphosphite
ligands, in particular, allow dramatic control of hydro-
formylation regioselectivity through structural manipula-
tion. For biphenol-based bisphosphites, the nature and
position of substituents can lead to a predominance of
either the linear or the branched aldehyde regioisomer.
For example, the biphenol-based bisphosphite (3), which
is bridged by a biphenol unit with 3,3�-tert-butyl substit-
uents, is highly selective for the production of linear
aldehydes from hydroformylation of terminal olefins.12
Chiraphite, which has tert-butyl substituents on the cyclic
dibenzo[d,f][1,3,2]dioxaphosphepin moiety, leads to a
preference for branched aldehyde from terminal olefins.
Herein, we report the extension of the bisphosphites
(8) Asymmetric hydroformylation of allyl cyanide was recently
originally developed at Union Carbide to optically active reported: Lambers-Verstappen, M. M. H.; de Vries, J. G. Adv. Synth.
ligands that are bridged by achiral diolate groups. Such Catal. 2003, 345, 478.
(9) For an example of achiral hydroformylation of allyl cyanide,
a ligand design has the combined advantages of a
see: El Ali, B.; Vasapollo, G.; Alper, H. J. Mol. Catal. A 1996, 112,
modular nature and an ease of synthesis, which allows 195.
for the introduction of a wide variety of stereoelectronic (10) (a) Ikeura, Y.; Ishimaru, T.; Doi, T.; Kawada, M.; Fujishima,
A.; Natsugari, H. Chem. Commun. 1998, 2141. (b) Natsugari, H.;
properties.
Ikeura, Y.; Kamo, I.; Ishimaru, T.; Ishichi, Y.; Fujishima, A.; Tanaka,
T.; Kasahara, F.; Kawada, M.; Doi, T. J. Med. Chem. 1999, 42, 3982.
(6) (a) Buisman, G. J. H.; Vos, E. J.; Kamer, P. C. J.; van Leeuwen, (c) Simeone, J. P.; Bugianesi, R. L.; Ponpipom, M. M.; Goulet, M. T.;
P. W. N. M. J. Chem. Soc., Dalton Trans. 1995, 409. (b) Buisman, G. Levorse, M. S.; Desai, R. C. Tetrahedron Lett. 2001, 42, 6459. (d)
J. H.; van der Veen, L. A.; Klootwijk, A.; de Lange, W. G. J.; Kamer, Taniguchi, N.; Kobayashi, K. Patent JP10182618, 1998.
P. C. J.; van Leeuwen, P. W. N. M.; Vogt, D. Organometallics 1996, (11) Cobley, C. J.; Lennon, I. C.; Praquin, C.; Zanotti-Gerosa, A.;
16, 2929. Appell, R. B.; Goralski, C. T.; Sutterer, A. C. Org. Process Res. Dev.
(7) (a) Sakai, N.; Mano, S.; Nozaki, K.; Takaya, H. J. Am. Chem. 2003, 7, 407.
Soc. 1993, 115, 7033. (b) Nozaki, K.; Sakai, N.; Nanno, T.; Higashijima, (12) (a) Billig, E.; Abatjoglou, A. G.; Bryant, D. R. U.S. Patents
T.; Mano, S.; Horiuchi, T.; Takaya, H. J. Am. Chem. Soc. 1997, 119, 4,668,651, 1987; 4,769,498, 1988; (b) Cuny, G. D.; Buchwald, S. L. J.
4413. Am. Chem. Soc. 1993, 115, 2066.
4032 J. Org. Chem., Vol. 69, No. 12, 2004
Asymmetric Hydroformylation of Allyl Cyanide
alcohol or diol (Scheme 2). Reactions were performed in
the presence of NEt3 (1.1 equiv/OH) at ambient temper-
ature in toluene in an N2-filled glovebox. Use of the
phosphorobromidite or phosphoroiodite reagents avoided
the need for elevated reaction temperatures often used
with analogous phosphorochloridite reagents. Bisphos-
phites were obtained as white powders after filtration,
evaporation of toluene from the filtrate, and trituration
of the resulting solid with MeCN. Products were char-
acterized by 1H, 13C{1H}, and 31P{1H} NMR, HRMS, and
elemental analysis.
Monodentate phosphites (15-17)13 each exhibit a sin-
glet in the 31P{1H} NMR spectrum at approximately 135
ppm. The 1H and 13C{1H} NMR spectra are consistent
with C1 symmetry of these ligands as they show the
presence of two and four nonequivalent t-Bu and Me
groups, respectively. Bisphosphites 11, 12, and 14 each
exhibit a single resonance in the 31P{1H} NMR spectrum,
as well as two t-Bu and four Me resonances in the 1H
Indeed for Chiraphite, the nature of the substituents at
and 13C{1H} NMR spectra, which is consistent with the
the 3,3�-positions is critical for obtaining both high
C2 symmetry of these ligands. Biaryl-bridged bisphos-
regioselectivity and enantioselectivity with vinylarenes.
phites 11-13 can contain an additional element of
Van Leeuwen has found that trimethylsilyl substituents
chirality and potentially exist in two diastereomeric
also lead to highly enantioselective ligands.6b In addition,
forms, depending upon the configuration of the bridging
for optically active bisphosphites, the nature of the
biaryl moiety. Bisphosphites 11 and 12, however, exhibit
bridging diolate moiety plays a crucial role. This chiral
a single resonance in the 31P{1H} NMR spectra, consis-
auxiliary effectively transfers stereochemical information
tent with either formation of a single diastereoisomer or
to the tert-butyl-substituted biphenol rings, which form
two diastereoisomers undergoing rapid interconversion.
a chiral environment around the Rh catalytic center,
The 1H NMR spectra of 11 and 12 also contained only
leading to chiral cooperativity. The bridging diolate also
resonances assignable to a single species. Previous NMR
controls the chelate bite angle, a structural feature that
and chiral HPLC studies have found that rotation about
has been proposed to influence hydroformylation regio-
the central biphenol axis is slow in related biphenol-
selectivity.4 For Chiraphite, the (2R,4R)-pentanediolate
bridged bisphosphites.14 The biphenylmethyl-bridged bis-
moiety, in combination with 3,3�-di-tert-butylbiphenol
phosphite 13, however, exhibits two singlets of equal
units, leads to high regioselectivity and enantioselectivity
intensity in the 31P{1H} NMR spectrum. In addition, four
for hydroformylation of vinylarenes.
resonances for the methylene groups were observed in
Unfortunately, as with most asymmetric catalysts, no
the 1H NMR spectrum of 13. These results are consistent
single ligand structure is generally useful for all types
with formation of a 1:1 mixture of the (S,S,S) and (S,R,S)
of substrates. Therefore, the development of asymmetric
diastereomers of 13, which differ by the configuration of
hydroformylation into a synthetic method of broad utility
the biphenylmethyl moiety. No evidence for interconver-
requires access to a structurally diverse family of ligands.
sion of these two diastereomers was obtained from
Such diversity is quite difficult with phosphine ligands,
NOESY experiments at room temperature, suggesting
whose syntheses can often require multiple steps. Phos-
the rotational barrier about the central biaryl bond of
phites, however, can be assembled in a much easier way
13 is greater than 19 kcal/mol.
by reacting an alcohol or diol with a phosphorus halide.
Hydroformylation Screening Study. Asymmetric
Bisphosphites can be prepared by reaction of a phospho-
hydroformylation studies were performed in an 8-cell
rochloridite, (RO)2PCl, with a diol. This diol bridges the
parallel stirred reactor system. Catalysts were generated
two phosphite moieties and controls the bite angle of the
in situ from the reaction of the appropriate ligand with
resulting ligand. For ligands such as Chiraphite, how-
Rh(CO)2(acac) in toluene at 150 psi syn gas (H2:CO 1:1).
ever, the requirement for this bridging diol to be optically
Under these conditions the active catalyst precursor Rh-
active limits the diversity of readily accessible structures.
(bisphosphite)(CO)2H is formed.4 Hydroformylation reac-
For this reason we sought to develop a related class of
tions were performed for 3 h in toluene with substrate-
bisphosphite ligands based on achiral diols. By utilizing
to-catalyst ratios of 300 and 500 to 1 for runs at 35 and
the commercially available (S)-3,3�-di-tert-butyl-5,5�,6,6�-
70 °C, respectively. These parameters were chosen in
tetramethyl-biphenyl-2,2�-diol (BIPHEN-H2), as the chiral
order to ensure significant conversions and relatively
auxiliary, achiral diols could be used to prepare a much
rapid throughput were obtained. Reaction mixtures were
more diverse collection of bisphosphite ligands. Using this
analyzed by chiral stationary phase GC using a Chiraldex
strategy we have prepared a library of bisphosphite
A-TA column. This analytical method allowed determi-
ligands for evaluation in asymmetric hydroformylation
nation of conversion, regioselectivity (branched/linear)
of a variety of olefinic substrates. In this paper, we
and enantioselectivity, as well as the extent of olefin
describe the synthesis and characterization of a subset
of this bisphosphite library, along with related mono-
(13) Compound 15 was recently reported as a ligand in asymmetric
dentate phosphites for comparison.
hydrogenation: Hua, Z.; Vassar, V. C.; Ojima, I. Org. Lett. 2003, 5,
Phosphite ligands were prepared by the reaction of (S)- 3831.
(BIPHEN)PX (X ) Br (9), I (10)) with the corresponding (14) Briggs, J. R.; Whiteker, G. T. Chem. Commun. 2001, 21, 2174.
J. Org. Chem, Vol. 69, No. 12, 2004 4033
Cobley et al.
SCHEME 2. Synthesis of Novel Phosphites
TABLE 1. Asymmetric Hydroformylation of Allyl to occur with 66% ee and b/l of 2.6.8 Under our condi-
Cyanide with Ligands 1, 2, and 11-17a tions, BINAPHOS gave similar results (51.5% ee, b/l 2.9)
(entry 2). Slightly lower ee values might be due to
T conv regio- % ee
(%)b selectivity (b/l)c
entry ligand (°C) (configuration) differences in the Rh/BINAPHOS ratio used. Chiraphite,
which is very effective for asymmetric hydroformylation
1 1 35 21.9 7.3 15.3 (R)
70 100 6.1 15.0 (R) of vinylarenes, gave low enantioselectivity for allyl
2 2 35 65.0 2.9 51.5 (S) cyanide hydroformylation. The regioselectivity for allyl
70 100 2.3 52.6 (S)
cyanide hydroformylation with Chiraphite, however, was
2d
3 35 47.8 2.7 75.6 (S)
significantly higher (b/l 7.3) than that observed with
4 11 35 84.8 15.5 78.1 (S)
70 100 11.2 68.3 (S) BINAPHOS (entry 1). The results reported in Table 1
11d
5 35 100 15.1 74.5 (S) show that the best combination of enantio- and regiose-
6 12 35 100 12.4 12.1 (S)
lectivity was obtained by employing (S)-BIPHEN units
70 100 9.3 17.9 (S)
in combination with 2,2�-biphenol (ligand 11), which gave
7 13 35 8.7 7.1 9.2 (R)
78.1% ee and b/l of 15.5 at 35 °C (entry 4). The remaining
70 100 5.2 2.3 (R)
8 14 35 73.3 8.5 0.7 (S) bisphosphites gave very poor enantioselectivities with
70 100 6.7 5.5 (S)
moderate regioselectivity ranging from 2.4 to 7.1. Inter-
9 15 35 11.3 6.3 43.7 (R)
estingly, monodentate phosphites 15 and 16 gave higher
70 100 4.3 32.7 (R)
enantioselectivities (39.1-43.7% ee) than bisphosphites
10 16 35 65.0 5.2 39.1 (R)
70 100 3.8 28.5 (R) 12-14 but with lower regioselectivity. The fastest hy-
11 17 35 30.5 5.0 14.1 (R)
droformylation rate was observed for ligand 12 with
70 100 3.9 6.7 (R)
complete conversion attained in 2 h, based on gas
a Pressure 150 psi. Ligand:Rh ) 1.2:1 for bidentate and 2.2:1
consumption curves. As expected, runs conducted at
for monodentate phosphites. Solvent ) toluene (2.5 mL). Molar
higher temperature (70 °C) led to significantly faster
allyl cyanide:Rh ) 300:1 at 35 °C and 500:1 at 70 °C. b Percentage
conversions at the cost of lower regio- and enantioselec-
conversion of allyl cyanide after 3 h. c b/l ) branched-to-linear
tivities. A brief examination of alternative solvents
ratio. d Runs performed in acetone.
revealed that when the reaction is conducted in acetone,
product enantioselectivity using BINAPHOS is surpris-
hydrogenation to butyronitrile and olefin isomerization
ingly increased from 51.5% to 75.6% ee (entries 2 and
to crotonitrile.
3), whereas no major change in performance is observed
Results of allyl cyanide hydroformylation are given in
in the case of 11 (entries 4 and 5). No significant changes
Table 1. BINAPHOS and Chiraphite were included in the
in enantioselectivities were observed for phosphites 12-
study for comparison. Asymmetric hydroformylation of
17 in acetone. To compare bisphosphite 11 and BINA-
allyl cyanide using Rh-BINAPHOS was recently reported
4034 J. Org. Chem., Vol. 69, No. 12, 2004
Asymmetric Hydroformylation of Allyl Cyanide
SCHEME 3. Synthesis of 2-Methyl-4-aminobutanol via a Catalytic Asymmetric
Hydroformylation-Hydrogenation Sequence
TABLE 2. Comparison between BINAPHOS (2) and refer to as Kelliphite, is by far the best overall ligand for
Kelliphite (11) in Asymmetric Hydroformylation of Allyl asymmetric hydroformylation of allyl cyanide.
Cyanide at Low Catalyst Loadingsa
To demonstrate the feasibility of performing asym-
regio- % ee time for metric hydroformylation on a larger scale, allyl cyanide
conv selectivity (config- complete
(75 mL) was hydroformylated in a 300 mL pressure vessel
AC/Rhb (%)c d uration) conversione
entry ligand (b/l)
using (R,R)-Kelliphite (11). Running the reaction at
1 2 2,000 64.0 2.8 74.7 (S) substrate to catalyst (S:C) molar ratio of 1,500:1, 30 °C,
4,000 37.1 2.9 75.1 (S)
and 145 psi syn gas (1:1) gave complete conversion in 5
10,000 14.8 2.7 77.2 (S)
h with 80% ee and b/l ratio of 20. Synthesis of the
2 11 2,000 100 17.8 77.8 (S) 6h
aforementioned chiral building block, 2-methyl-4-ami-
4,000 100 17.3 78.8 (S) 8h
10,000 100 18.5 78.8 (S) 16 h nobutanol, was demonstrated, as shown in Scheme 3.
Stepwise reduction of the aldehyde and nitrile function-
a Pressure 150 psi. Ligand:Rh ) 1.2:1. Temp ) 35 °C; 3.5 mL
alities was performed using 10% Pt on carbon catalyst.
of allyl cyanide. b Molar AC (allyl cyanide)/Rh ratio. c Percent
conversion of allyl cyanide after 17 h. d b/l ) branched-to-linear Reduction of the aldehyde group of 4 with Pt/C gave the
ratio. e Estimated based on gas consumption profiles. nitrile alcohol 5 without racemization. The nitrile alcohol
5 was subsequently reduced with Pt/C and oxalic acid to
yield 18, the oxalate salt of the desired amino alcohol,
PHOS more extensively, a series of hydroformylation
again with no loss of enantioselectivity. Alternatively,
reactions of allyl cyanide was conducted at low catalyst
both reactions could be performed in one pot by the
loading (allyl cyanide:Rh of 2,000-10,000:1) in neat olefin
addition of oxalic acid after reduction of the aldehyde
as we observed that reaction rates were highest when
functionality was complete. Treatment of salt 18 with
the reaction was conducted without solvent. As shown
basic resin IRN78 afforded the amino alcohol free base
in Table 2, the catalyst prepared from 11 is about 7 times
6 in 80% ee. A limited crystallization screen of several
more active than BINAPHOS at 10,000:1 allyl cyanide:
chiral and achiral acids identified (-)-camphanic acid as
Rh catalyst loadings. Under these conditions allyl cyanide
being suitable for upgrading the enantioselectivity to 96%
hydroformylation was complete with ligand 11 within 16
ee and removing the linear adducts albeit with a low
h, which translates into an average turnover frequency
recovery (10% isolated yield); this study is currently
of 625 turnovers per hour. Unexpectedly, the regioselec-
ongoing.
tivity with 11 increased from 15.5 (Table 1, entry 4) to
18.5 (Table 2, entry 2) at the lowest catalyst loadings. Synthesis of [(S,R,S)-Kelliphite]Rh(acac) (19). To
This appears to be a result of performing these reactions investigate the coordination mode of ligand Kelliphite 11,
without solvent.15 Under the same conditions, the regio- the synthesis of a representative Rh complex was un-
selectivity with BINAPHOS was not affected. On the dertaken. Bisphosphite 11 was reacted with 1 equiv of
other hand, the hydroformylation enantioselectivity with (COD)Rh(acac) in toluene solution, which led to quantita-
11 remained unchanged, whereas that with BINAPHOS tive formation of [(S,R,S)-Kelliphite]Rh(acac), 19. Com-
increased by 25% ee to a maximum value of 77.2% ee at plex 19 was characterized by multinuclear and multidi-
the lowest catalyst loading. This increase in enantiose- mensional NMR spectroscopy, HRMS, and X-ray single-
lectivity with BINAPHOS seems to correlate with solu- crystal analysis (see below). The complex exhibits C2
tion polarity, as higher values were obtained in either
acetone or neat allyl cyanide than in toluene solution. A
preliminary study to examine the consequences of vary-
ing the CO and H2 partial pressures gave no improve-
ment over the results obtained with a 1:1 CO:H2 syn gas
mixture. In all cases, levels of substrate hydrogenation
or isomerization were found to be negligible (<0.5%).
These results demonstrate that 11, which we will now
(15) A small amount of toluene was present in these runs as a result
of addition of toluene stock solutions of catalyst and ligand.
J. Org. Chem, Vol. 69, No. 12, 2004 4035
Cobley et al.
FIGURE 1. Molecular structure and labeling scheme for (S,R,S)-Kelliphite ligand (11) with 40% probability of thermal ellipsoids.
Hydrogen atoms were removed for clarity.
TABLE 3. Selected Bond Lengths (Ã…) and Angles (deg)
for Ligand 11 and Complex 19
1919
bond/angle 11
P1-O1 1.628(1) 1.601(5), 1.614(5)
P1-O2 1.617(2) 1.610(4), 1.625(4)
P1-O3 1.639(2) 1.636(5), 1.622(5)
P2-O4 1.644(2) 1.608(5), 1.611(5)
P2-O5 1.631(2) 1.631(4), 1.611(5)
P2-O6 1.607(2) 1.619(4), 1.615(5)
O1-P1-O2 102.92(8) 100.3(2), 100.4(2)
O1-P1-O3 92.11(8) 96.5(2), 98.0(2)
O2-P1-O3 101.96(8) 103.2(2), 103.2(2)
O4-P2-O5 91.80(8) 98.1(2), 97.1(2)
O4-P2-O6 103.12(8) 99.9(2), 101.2(3)
O5-P2-O6 102.14(7) 103.0(2), 102.2(2)
Rh-O7 2.077(5), 2.084(5)
Rh-O8 2.085(5), 2.053(4)
P1-P2 7.704 3.234, 3.234
FIGURE 2. Molecular structure and labeling scheme for
Rh-P1 2.149(2), 2.140(2)
Rh-P2 2.145(2), 2.147(2) [(S,R,S)-Kelliphite]Rh(acac) complex (19) with 40% probability
P2-Rh-P1 97.74(8), 97.94(7) of thermal ellipsoids. Carbon atoms of acac fragment and all
P1-Rh-O8 88.6(2), 85.5(2) hydrogen atoms were removed for clarity.
P2-Rh-O7 85.0(2), 87.2(2)
O7-Rh-O8 88.9(2), 88.9(2)
fragment. For example, this dihedral angle is much larger
(102.2°) in a molybdenum carbene complex17 containing
symmetry in solution based on NMR spectroscopy. The BIPHEN unit, which is a direct consequence of a larger
1
H NMR spectrum of 19 exhibited only one set of O-Mo-O bond angle (127.0°) as compared to the en-
BIPHEN resonances (two t-Bu and four Me signals) and docyclic O-P-O in 11 (102.0°). The dihedral angle
four aromatic signals for the bridging 2,2�-biphenyldiol. between aryl rings in analogous 3,3�,5,5�-tetra-tert-butyl-
The 31P{1H} NMR spectrum of 19 shows a doublet at δ 2,2�-bisphenoxyphosphite ligands is significantly smaller
130.57 (1JRh-P ) 317.3 Hz). (48-55°)18 suggesting that steric repulsions between the
Crystal Structure Analysis of (S,R,S)-Kelliphite two methyl groups in the 6,6�-position of BIPHEN
(11) Ligand. Crystals of 11 were obtained from aceto- contribute to widening of this angle in 11. The stereo-
nitrile solution at -35 °C. A thermal ellipsoid drawing chemistry around the central 2,2�-biphenoxy unit is of (R)
of 11 is shown in Figure 1. Selected bond distances and configuration and is the same as that found in rhodium
angles are included in Table 3. Bisphosphite 11 crystal- complex 19 (vide infra). The dihedral angle between aryl
lizes in the monoclinic, noncentrosymmetric space group rings in the 2,2�-biphenoxy fragment is 123.9°. The two
P21 together with two acetonitrile solvent molecules in phosphorus atoms are separated by 7.7 Ã…. The sum of
the asymmetric unit. In the solid state the ligand has
molecular C2 symmetry with a 2-fold axis positioned at
(16) Suarez, A.; Mendez-Rojas, M. A.; Pizzano, A. Organometallics
´ ´
the center of the C30-C31 bond. The dihedral angles 2002, 21, 4611.
between the aryl rings of the dibenzo[d,f][1,3,2]dioxaphos- (17) Alexander, J. B.; Schrock R. R.; Davis, W. D.; Hultzsch, K. C.;
Hoveyda, A. H.; Houser, J. H. Organometalllics 2000, 19, 3700.
phepin rings are 62.2° and 62.4°. This torsion angle is
(18) (a) Pastor, S. D.; Shum, S. P.; Rodebaugh, R. K.; Delellis, A.
very similar to that in the only other known phosphite D.; Clarke, F. H. Helv. Chem. Acta 1993, 76, 900. (b) Pastor, S. D.;
structure containing a 3,3�-di-tert-butyl-5,5�,6,6�-tetra- Shum, S. P.; DeBellis, A. D.; Burke, L. P.; Rodebaugh, R. K.; Clarke,
F. H.; Rihs, G. Inorg. Chem. 1996, 35, 949. (c) DeBellis, A. D.; Pastor,
methyl-2,2�-bisphenoxy (BIPHEN) unit (63.5°).16 The
S. D.; Rihs, G.; Rodebaugh, R. K.; Smith, A. R. Inorg. Chem. 2001, 40,
magnitude of this dihedral angle strongly depends on the 2156. (d) Shum, Sai P.; Pastor, S. D.; Rihs, G. Inorg. Chem. 2002, 41,
O-X-O (X ) heteroatom) bond angle of the BIPHEN 127.
4036 J. Org. Chem., Vol. 69, No. 12, 2004
Asymmetric Hydroformylation of Allyl Cyanide
FIGURE 3. Stereoview of [(S,R,S)-Kelliphite]Rh(acac) complex (19).
dihedral angles between aryl rings of the dibenzo[d,f]-
bond angles around phosphorus atoms is 297.0°, which
[1,3,2]-dioxaphosphepin rings are 63.1° (62.3°) and 62.8°
is very similar to the values observed in other phosphites
of this type.18 (58.4°) and are very similar to those found in free ligand
11 (vide supra). The central 2,2�-biphenoxy unit has (R)
Crystal Structure Analysis of [(S,R,S)-Kelliphite]-
absolute configuration with a biaryl dihedral angle of
Rh(acac) (19). Crystals of 19 were obtained at room
60.5° (59.8°). Unlike in the case of 11 where it is not
temperature by slow evaporation of an acetonitile solu-
clearly apparent why there is a preference for (R)
tion that contained a small amount of toluene. Thermal
configuration in the middle biphenoxy unit in the solid
ellipsoid drawing and stereoview of 19 are shown in
state,22 the metal complex of 19 with (S,S,S) configura-
Figures 2 and 3, respectively. Selected bond distances and
angles are included in Table 3. The complex crystallizes tion would certainly be disfavored as a result of steric
in the orthorhombic, noncentrosymmetric space group repulsions between BIPHEN tert-butyl groups and the
C2221. Two crystallographically independent molecules bridging 2,2�-biphenoxy fragment. In metal complexes
of complex 19 are present in the asymmetric unit containing the sterically less crowded tris(2,2�-biphenyl)-
together with two molecules of acetonitrile and one-half bisphosphite ligand, both (S,S,S)/(R,R,R) and (S,R,S)/
(R,S,R) configurations are encountered.22 The distance
molecule of toluene. The geometry around the rhodium
atom is close to idealized square planar with mean between the two phosphorus atoms in 19 equals 3.234
deviation from planarity of 0.03 Ã…. The chelate bond Ã…. The sum of bond angles around phosphorus atoms in
angle P1-Rh-P2 (97.74(8)°, 97.94(7)°)19 is larger than 19 is also very similar to that in 11 (297.0°) and equals
found in analogous complexes containing monodentate 300.0° (301.6°) and 301.0° (300.5°) for P1 and P2,
phosphites20 (e.g., cis-[P(OPh)3]2Rh(acac), 93.8°)20b but is respectively.
similar to related complexes containing bidentate21 phos-
Conclusion
phite ligands coordinated to the Rh(acac) fragment, which
fall in the range of 96.7-99.9°. This increase in the P1- Novel mono- and bidentate phosphites were prepared
Rh-P2 bite angle is a consequence of steric congestion from commercially available (S)-5,5�-6,6�-tetramethyl-3,3�-
between the two very bulky phosphite groups. In the solid di-tert-butyl-1,1�-biphenyl-2,2�-diol [(S)-BIPHEN-H2] and
state the complex has molecular C2 symmetry with 2-fold phenols in high yields. All new ligands were investigated
axis positioned at the center of the C30-C31 bond. in asymmetric hydroformylation of allyl cyanide as the
Because of the substantial size and C2 symmetry of the product of this reaction can be transformed into enan-
bisphosphite, fragments of the ligand extend into the tiomerically enriched 2-methyl-4-aminobutanol, a useful
rhodium coordination sphere (see Figure 3). Two methyl chiral building block. The C2 symmetric bisphosphite 11
carbons of t-Bu groups that are related by C2 symmetry (Kelliphite) with 2,2�-biphenoxy bridge was found to be
(C15 and C50) are positioned only 3.3-3.7 Ã… above and the best ligand for asymmetric hydroformylation of allyl
below the Rh-O8 and Rh-O7 bond vectors, indicating cyanide with up to 80% ee and regioselectivities (branch-
close proximity of these t-Bu groups to the coordination to-linear ratio, b/l) of 20 with turnover frequency of 625
[h-1] at 35 °C. It was also found that enantioselectivities
environment of rhodium. Presumably, this sterically
restricted C2 symmetric environment is responsible for induced by BINAPHOS increased from 51% ee, when
the high enantioselectivity observed with ligand 11. The reaction was performed in toluene, to 77% ee when the
reaction was conducted in either acetone or neat. In all
(19) Because there are two independent molecules in the asymmetric cases, however, the regioselectivity (b/l 2.8) and catalytic
unit, two values for each bond distance and angle are provided.
activity was substantially lower than that of 11. The
(20) (a) Lamprecht, G. J.; Leipoldt, J. G.; Van Zyl, G. J. Inorg. Chem.
product of allyl cyanide hydroformylation was further
Acta 1985, 97, 31. (b) Leipoldt, J. G.; Lamprecht, G. J.; Van Zyl, G. J.
Inorg. Chem. Acta 1985, 96, L31. (c) Van Zyl, G. J.; Lamprecht, G. J.; converted to (R)-2-methyl-4-aminobutanol via two reduc-
Leipoldt, J. G. Inorg. Chem. Acta 1985, 102, L1. (d) Heaton, B. T.;
tion steps without any loss of enantioselectivity.
Jacob, C.; Markopoulos, J.; Markopoulou, O.; Nahring, J.; Skylaris, C.
K.; Smith, A. K. J. Chem. Soc., Dalton Trans. 1996, 1701.
Experimental Section
(21) (a) Van den Beuken, E. K.; de Lange, W. G. J.; Van Leeuwen,
P. W. N. M.; Veldman, N.; Spek, A. L.; Feringa, B. L. J. Chem. Soc.,
The 6,6�-(((1R,3R)-1,3-dimethyl-1,3-propanediyl)bis(oxy))bis-
Dalton Trans. 1996, 3561. (b) Meetsma. A.; Jongsma, T.; Challa, G.;
(4,8-bis(1,1-dimethylethyl)-2,10-dimethoxy-dibenzo(d,f)(1,3,2)-
Van Leeuwen, P. W. N. M. Acta Crystallogr. 1993, C49, 1160. (c) Jiang,
Y.; Xue, S.; Yu, K.; Li, Z.; Deng, J.; Mi A.; Chan, A. S. C. J. Organomet.
Chem. 1999, 586, 159. (d) Van Rooy, A.; Kamer, P. C. J.; Van Leeuwen, (22) Interestingly the stereochemistry of tris(2,2�-biphenyl)bisphos-
P. W. N. M.; Goubitz, K.; Fraanje, J.; Veldman, N.; Spek, A. L. phite ligand is (R, R, R)/(S, S, S). Baker, M. J.; Harrison, K. N.; Orpen,
Organometallics 1996, 15, 835. A. G.; Pringle, P. G.; Shaw, G. Chem. Commun. 1991, 803.
J. Org. Chem, Vol. 69, No. 12, 2004 4037
Cobley et al.
JC-P ) 1.6 Hz, quat), 138.73 (d, JC-P ) 3.4 Hz, quat), 145.45
dioxaphosphepin5 (Chiraphite) and (R,S)-2-(diphenylphos-
(d, JC-P ) 5.3 Hz, quat), 147.00 (d, JC-P ) 2.3 Hz, quat).
phino)-(1,1�-binaphthalen-2�-yl-1,1-binaphthalene-2,2�-diyl)phosphite
[(R,S)-BINAPHOS)] 7 were prepared according to literature 31
P{1H} NMR (C6D6): δ 182.4.
procedures. Preparation of (S)-4,8-Di-tert-butyl-6-iodo-1,2,10,11-
Crystal Structures of 11 and 19. Data were collected on tetramethyl-5,7-dioxa-6-phospha-dibenzo[a,c]cyclohep-
diffractometers equipped with graphite monochromatic crys- tene (10). (S)-4,8-Di-tert-butyl-6-chloro-1,2,10,11-tetramethyl-
tals, Mo KR radiation sources (λ ) 0.71073 Å), and SMART 5,7-dioxa-6-phospha-dibenzo[a,c]cycloheptene (5.4 g, 12.89
CCD detectors. Cell parameters were refined using 4918 and mmol) was dissolved in 50 mL of toluene. To this solution was
8192 reflections for 11 and 19, respectively. The structures added TMS-I (3.10 g, 15.5 mmol) dissolved in 5 mL of toluene.
were solved by direct methods in SHELXTL6.123 from which After addition of TMS-I the solution assumed a light yellow
the positions of all non-H atoms were obtained. The non-H color. The reaction mixture was stirred overnight. Solvent was
atoms were refined with anisotropic thermal parameters, and removed under reduced pressure to give 6.57 g of product as
all of the H atoms were calculated in idealized positions, an off-white powder. Yield 99.9%. 1H NMR (C6D6): δ 1.45 (s,
refined riding on their parent atoms. The asymmetric unit of 9H, C(CH3)2), 1.57 (s, 9H, C(CH3)2), 1.61 (s, 3H, CH3), 1.63 (s,
11 consists of the ligand and two acetonitrile molecules. The 3H, CH3), 1.98 (s, 3H, CH3), 1.99 (s, 3H, CH3), 7.13 (1H), 7.24
asymmetric unit of 19 contains two Rh complexes, two aceto- (1H). NOESY1D (C6D6): irradiation at 7.13 ppm, NOE re-
nitrile molecules and one-half of a toluene molecule. The sponse at 1.45 and 1.98 ppm; irradiation at 7.24 ppm, NOE
solvent molecules in both structures were disordered and could response at 1.57 and 1.99 ppm. 13C{1H} NMR (C6D6): δ 16.34
not be modeled properly; thus the program SQUEEZE, a part (CH3), 16.73 (CH3), 20.40 (2xCH3), 31.02 (d, JC-P ) 4.8 Hz,
of the PLATON package24 of crystallographic software, was C(CH3)2), 33.17 (C(CH3)2), 34.61 (C(CH3)2), 35.58 (C(CH3)2),
used to calculate the solvent disorder area and remove its 128.70 (CH), 129.88 (d, JC-P ) 1.4 Hz, CH), 131.00 (d, JC-P )
contribution to the overall intensity data. For 11 a total of 633 3.3 Hz, quat), 131.96 (d, JC-P ) 6.0 Hz, quat), 133.32 (quat),
parameters were refined in the final cycle using 9856 observed 134.12 (quat), 135.15 (quat), 135.93 (quat), 136.99 (d, JC-P )
reflections with I > 2σ(I) to yield R1, wR2 and S (goodness of 2.0 Hz, quat), 138.52 (d, JC-P ) 3.1 Hz), 147.32 (d, JC-P ) 6.6
fit) of 5.45%, 10.65% and 0.853, respectively. For 19 a total of Hz), 148.48 (d, JC-P ) 2.0 Hz). HSQC (C6D6): δ 1.45/31.02,
1427 parameters were refined in the final cycle using 10710 1.57/33.17, 1.61/16.34, 1.63/16.73, 1.98/20.40, 1.99/20.40, 7.13/
observed reflections with I > 2σ(I) to yield R1, wR2, and S 128.70, 7.24/129.88. 31P{1H} NMR (C6D6): δ 209.1. Anal. Calcd
(goodness of fit) of 4.68%, 9.56% and 0.909, respectively. for C24H32IO2P: C, 56.48; H, 6.32. Found: C, 56.60; H, 6.59.
Preparation of (S)-4,8-Di-tert-butyl-6-chloro-1,2,10,11- Preparation of (S,S)-6,6�-((1,1�-Biphenyl)-2,2�-diylbis-
tetramethyl-5,7-dioxa-6-phospha-dibenzo[a,c]cyclohep- (oxy))bis(4,8-bis(1,1-dimethylethyl)-1,2,10,11-tetramethyl-
tene. To a 200 mL toluene solution containing (S)-3,3�-di-tert- dibenzo(d,f)(1,3,2)dioxaphosphepin (11). A solution of 2,2�-
butyl-5,5�,6,6�-tetramethyl-biphenyl-2,2�-diol [(S)-BIPHEN-H2] biphenol (212 mg, 1.14 mmol) and 300 µL NEt3 in 15 mL of
(4.3395 g, 12.2 mmol) was added 1.7146 g (14.49 mmol) of PCl3 toluene was added to a solution of (S)-4,8-di-tert-butyl-6-bromo-
followed by addition of 4.1 mL of NEt3. During amine addition 1,2,10,11-tetramethyl-5,7-dioxa-6-phospha-dibenzo[a,c]cyclo-
copious amounts of white precipitate appeared. After stirring heptene (9) (983 mg, 2.27 mmol) in 20 mL toluene. The solution
overnight the solvent volume was reduced to 80 mL and the was stirred for 18 h at ambient temperature and then filtered.
solution was filtered. The solid was filtered and washed with The filtrate was evaporated to a white solid that was triturated
20 mL of cold toluene. Solvent was removed under reduced with MeCN. The supernatant was decanted, and the solid
pressure to give 5.10 g of white solid. Yield 99.5%. 1H NMR product was dried under vacuum (737 mg, 68% yield). 1H NMR
(C6D6): δ 1.47 (s, 9H, C(CH3)), 1.53 (s, 9H, C(CH3)), 1.64 (s, (C6D6): δ 1.38 (s, 18H, C(CH3)3), 1.42 (s, 18H, C(CH3)3), 1.70
3H, CH3) 1.65 (s, 3H, CH3), 2.00 (s, 3H, CH3), 2.01 (s, 3H, CH3), (s, 6H, CH3), 1.77 (s, 6H, CH3), 2.05 (s, 6H, CH3), 2.12 (s, 6H,
7.16 (1H), 7.24 (1H). 13C{1H} NMR (C6D6): δ 16.46 (CH3), 16.73 CH3), 6.81 (ddd, 2H, 3JH-H ) 7.5 Hz, 3JH-H ) 7.5 Hz, 4JH-H )
(CH3), 20.38 (CH3), 20.42 (CH3), 31.29 (d, JC-P ) 5.4 Hz, 1.2 Hz), 6.98 (ddd, 2H, 3JH-H ) 8.1 Hz, 3JH-H ) 7.5 Hz,
C(CH3)3), 32.49 (C(CH3)3), 34.81 (C(CH3)3), 35.31 (C(CH3)3), JH-H ) 1.8 Hz), 7.17 (s, 2H), 7.19 (s, 2H), 7.22 (d, 2H,
4
128.56 (CH), 129.28 (CH), 131.91 (d, JC-P ) 3.3 Hz, quat), JH-H ) 8.1 Hz), 7.40 (dd, 2H, 3JH-H ) 7.8 Hz, 4JH-H ) 1.5
3
132.27 (d, JC-P ) 6.0 Hz, quat), 133.18 (quat), 134.00 (quat), Hz). COSY (C6D6): δ 6.81/6.98, 7.40; 6.98/6.81, 7.22; 7.22/6.98;
135.03 (d, JC-P ) 1.4 Hz, quat), 135.85, 137.91 (d, JC-P ) 2.0 7.40/6.81, 6.98 (weak). NOESY1D (C6D6): irradiation at 2.05
Hz, quat), 138.72 (d, JC-P ) 4.1 Hz, quat), 144.52 (d, JC-P ) ppm, NOE response at 7.17, 1.70 ppm; irradiation at 2.12 ppm,
6.0 Hz), 146.14 (d, JC-P ) 2.0 Hz, quat). 31P{1H} NMR (C6D6): NOE response at 7.19, 1.77 ppm. 13C{1H} NMR (C6D6): δ 16.58
δ 166.1. (CH3), 16.86 (CH3), 20.38 (CH3), 20.43 (CH3), 31.38 (C(CH3)3),
Preparation of (S)-4,8-Di-tert-butyl-6-bromo-1,2,10,11- 31.58 (C(CH3)3), 34.81 (C(CH3)), 34.90 (C(CH3)3), 121.97 (t,
tetramethyl-5,7-dioxa-6-phospha-dibenzo[a,c]cyclohep- JC-P ) 5.4 Hz, CH), 123.79 (CH) 128.19 (CH), 128.51 (CH),
tene (9). (S)-3,3�-Di-tert-butyl-5,5�,6,6�-tetramethyl-biphenyl- 128.69 (CH), 130.49 (quat), 131.11 (quat), 131.82 (quat), 132.77
2,2�-diol [(S)-BIPHEN-H2] (4.06 g, 11.45 mmol) was dissolved (d, JC-P ) 2.7 Hz, quat), 132.92 (quat), 133.01 (CH), 134.47
in 100 mL of toluene. NEt3 (3.25 mL, 23.31 mmol) was added. (quat), 135.52 (quat), 137.94 (quat), 138.64 (quat) 145.35
PBr3 (1.1 mL, 11.6 mmol) was added to the reaction mixture, (quat), 145.92 (t, JC-P ) 3.3 Hz), 149.67 (quat). HSQC (C6D6):
which was then stirred for 18 h. The suspension was filtered, δ 1.38/31.58, 1.42/31.38, 1.70/16.58, 1.77/16.86, 2.05/20.38,
and the filtrate was evaporated to give the product as a white 2.12/20.43, 6.81/123.79, 6.98/128.51, 7.17/128.19, 7.19/128.69,
solid (3.41 g, 7.87 mmol, 69% yield). 1H NMR (C6D6): δ 7.18 7.22/121.97, 7.40/133.01. 31P{1H} NMR (C6D6): δ 134. Single
(s, 1H), 7.08 (s, 1H), 1.93 (s, 3H), 1.92 (s, 3H), 1.57 (s, 3H), crystals were grown from acetonitrile solution at -35 °C.
1.56 (s, 3H), 1.48 (s, 9H), 1.39 (s, 9H). 13C{1H} NMR (C6D6): δ HRMS (ESI, (M + Na)+) (m/z): calcd for C60H72O6P2Na
16.39 (s, CH3), 16.72 (s, CH3), 20.34 (s, CH3), 20.37 (s, CH3), 973.470, found 973.469. Anal. Calcd for C60H72O6P2: C, 75.76;
31.20 (d, JC-P ) 3.7 Hz, CCH3), 32.76 (s, CCH3), 34.74 (s, H, 7.63. Found: C, 76.32; H, 8.39.
CCH3), 35.44 (s, CCH3), 128.65 (CH), 129.55 (s, CH), 130.89
Preparation of (S)-4,8-Bis(1,1-dimethylethyl)-1,2,10,-
(d, JC-P ) 3.0 Hz, quat), 132.16 (d, JC-P ) 6.0 Hz, quat), 133.27
11-tetramethyl-6-phenoxy-dibenzo(d,f)(1,3,2)dioxaphos-
(quat), 134.10 (quat), 135.08 (quat), 135.89 (quat), 137.65 (d,
phepin (15). To 447.7 mg (0.88 mmol) of (S)-4,8-di-tert-butyl-
6-iodo-1,2,10,11-tetramethyl-5,7-dioxa-6-phospha-dibenzo[a,c]-
(23) SHELXTL6.1; Bruker-AXS: Madison, WI, 2000. cycloheptene (10) dissolved in 5 mL of toluene was added 82.6
(24) PLATON, written by Professor Anthony L. Spek, Bijvoet Centre mg (0.88 mmol) of phenol followed by addition of 1.6 mL (1.14
for Biomolecular Research, Utrecht University. Current versions
mmol) of NEt3. During amine addition, a white solid appeared.
of PLATON for Windows are available from Professor Louis J.
After stirring overnight the solution was filtered and solvent
Farrugia, Department of Chemistry, University of Glasgow at
was removed under reduced pressure. The residue was redis-
www.chem.gla.ac.uk/∼louis/software/.
4038 J. Org. Chem., Vol. 69, No. 12, 2004
Asymmetric Hydroformylation of Allyl Cyanide
solved in 4 mL of hexane and filtered, and solvent was removed nitrogen. In a typical 70 °C run, 0.153 mL of ligand and 0.153
under reduced pressure to give 410 mg of product as a white mL of Rh(CO)2(acac) stock solutions were added to 2.697 mL
solid. Yield 98.0%. 1H NMR (C6D6): δ 1.52 (s, 9H, C(CH3)3), of toluene followed by addition of 0.5 mL of allyl cyanide
1.62 (s, 9H, C(CH3)3), 1.75 (s, 6H, CH3) 2.07 (s, 6H, CH3), 6.78 solution (Rh:allyl cyanide 1:500). This solution was transferred
(tm, 3JH-H ) 7.5 Hz, 1H), 6.97 (tm, 3JH-H ) 8.1 Hz, 2H), 7.14 to the reactor system housed in the inert atmosphere glovebox.
(dm, 3JH-H ) 8.3 Hz, 2H), 7.21 (s, 1H), 7.28 (s, 1H). NOESY1D The reactors were pressurized with 150 psi of H2:CO 1:1 and
(C6D6): irradiation at 1.52 ppm, NOE response at 7.21 ppm; then heated to 70 °C while stirring at 800 rpm. After 3 h
irradiation at 1.62 ppm, NOE response at 7.28 ppm; irradiation reactors were cooled, vented, and purged with nitrogen. Upon
at 2.07 ppm, NOE response at 7.21, 7.28 ppm. 13C{1H} NMR opening the reactor 0.1 mL of each reaction mixture was taken
(C6D6): δ 17.10 (CH3), 17.27 (CH3), 20.84 (2xCH3), 31.83 (d, out and diluted with 1 mL of toluene, and this solution was
JC-P ) 5.4 Hz C(CH3)3), 32.41 (C(CH3)3), 35.26 (C(CH3)), 35.59 analyzed by gas chromatography (Astec Chiraldex A-TA
(C(CH3)), 120.76 (d, JC-P ) 8.0 Hz, o-PhO), 124.10 (p-PhO) column, temperature program of 90 °C for 7 min, then 5 °C/
128.24 (CH), 128.64 (CH), 129.91 (m-PhO), 131.35 (d, JC-P ) min to 180 °C. Retention times: 6.44 min for allyl cyanide,
3.4 Hz, quat), 132.28 (quat), 132.28, 132.72 (d, JC-P ) 5.4 Hz, 17.42 and 17.77 min for the enantiomers of the aldehyde-nitrile
branched regioisomer, and 21.78 for the linear aldehyde-nitrile
quat), 133.01 (quat), 134.84 (quat), 135.58 (quat), 138.50 (d,
JC-P ) 2.6 Hz), 145.40 (d, JC-P ) 6.0 Hz), 152.62 (d, JC-P ) regioisomer). Reaction mixtures for the runs included in Table
2 were prepared by mixing 3.5 mL of neat allyl cyanide with
7.4 Hz). HSQC (C6D6): δ 1.52/31.83, 1.62/32.41, 1.75/17.10,
catalyst and ligand toluene solutions described above.
17.27, 2.07/20.84, 6.78/124.10, 6.97/129.91, 7.14/120.76, 7.21/
128.24, 7.28/128.64. 31P{1H} NMR (C6D6): δ 135.60. HRMS Scale-Up of Asymmetric Hydroformylation of Allyl
(ESI, (M + Na)+) (m/z): calcd for C30H37O3PNa 499.2378, found Cyanide. A 300 mL mechanically stirred pressure vessel fitted
499.2384. Anal. Calcd for C30H37O3P: C, 75.60; H, 7.83. with a glass liner was charged with [Rh(CO)2(acac)] (160 mg,
Found: C, 75.56; H, 7.86. 0.62 mmol) and (R,R)-Kelliphite (11) (65 mg, 0.68 mmol). The
Preparation of (S,R,S)-(6,6�-(((1,1�-Biphenyl)-2,2�-diyl)- vessel was sealed and purged three times with nitrogen (145
bis(oxy))bis(4,8-bis(1,1-dimethylethyl)-1,2,10,11-tetra- psi). Allyl cyanide (75 mL, 0.93 mmol, deoxygenated) was
methyldibenzo(d,f)(1,3,2)dioxaphosphepin-kappaP6))- added via the injection port, and the vessel was purged a
(2,4-pentanedionato-O,O�)-rhodium [(S,R,S)-Kelliphite further three times with nitrogen (145 psi). The reaction
Rh(acac)] (19). To a vial was added 150 mg (0.16 mmol) of mixture was stirred at 1,000 rpm and heated to 30 °C. The
(S,S)-6,6�-((1,1�-biphenyl)-2,2�-diylbis(oxy))bis(4,8-bis(1,1-di- vessel was then pressurized with H2/CO (145 psi, 1:1), and the
methylethyl)-1,2,10,11-tetramethyl-dibenzo(d,f)(1,3,2)dioxa- gas consumption was monitored, recharging the syn gas
phosphepin (11) and 48.3 mg (0.16 mmol) of [(COD)Rh(acac)]. pressure as required. After 5 h, gas consumption was complete.
To this was added 5 mL of toluene, and the yellow solution The vessel was vented, purged once with nitrogen (145 psi),
was stirred overnight. Solvent was removed under reduced and opened. The crude reaction mixture was obtained with
>99% conversion, 80% ee, b/l 20.1 as determined by chiral GC.
pressure, leaving 180 mg of product as a yellow solid. 1H NMR
This crude product was used in subsequent reactions without
(C6D6): δ 1.24 (s, 6H, acac-CH3), 1.33 (s, 18H, C(CH3)3), 1.85
further purification. NMR spectra were obtained by evapora-
(s, 6H, CH3), 1.92 (s, 18H, C(CH3)3), 1.97 (s, 6H, CH3), 2.10 (s,
6H, CH3), 5.19 (s, 1H, acac-CH), 6.77 (ddd, 2H, 3JH-H ) 7.2 tion of a sample of the reaction mixture to an oil that was
Hz, 3JH-H ) 7.5 Hz, 4JH-H ) 1.5 Hz), 6.84 (ddd, 2H, 3JH-H ) redissolved in CDCl3. NMR data for the linear regioisomers
8.3 Hz, 3JH-H ) 7.5 Hz, 4JH-H ) 2.1 Hz), 6.92 (dd, 2H, 3JH-H ) (aldehyde product and derivatives) were obtained from prod-
7.5 Hz, 4JH-H ) 2.1 Hz), 7.11 (s, 2H), 7.26 (s, 2H) 7.81 (dd, ucts prepared by hydroformylation of allyl cyanide (100 mL
2H, 3JH-H ) 8.1 Hz, 4JH-H ) 1.2 Hz), one methyl group allyl cyanide (83.4 g), allyl cyanide:Rh ) 2000:1, 147 psi, 30
resonance is overlapping with t-Bu peak at 1.92 ppm. 13C{1H} °C, neat, ligand:Rh 1:1) using Chiraphite (1) as ligand (b/l 6.6,
20.1% ee). 3-Methyl-4-oxo-butyronitrile (4): 1H NMR (400
NMR (C6D6): δ 16.75 (CH3), 17.00 (CH3), 20.32 (CH3), 20.40
(CH3), 27.32 (JC-P ) 5.1 Hz, acac-CH3), 32.12 (C(CH3)), 33.59 MHz, CDCl3) δ 1.31 (d, 3H, 3JHH ) 7.5 Hz, CH3), 2.43 (dd, 1H,
JHH ) 17.1 Hz, 3JHH ) 7.6 Hz, CHHCN), 2.61 (dd, 1H, 2JHH )
2
(C(CH3)), 35.09 (C(CH3)), 35.77 (C(CH3)), 99.76 (acac-CH),
17.1 Hz, 3JHH ) 5.2 Hz, CHHCN), 2.75 (m, 1H, CH), 9.59 (s,
120.14 (CH), 124.15 (CH), 128.65 (CH), 129.34 (CH), 129.47
1H, CHO); 13C{1H} NMR (100 MHz, CDCl3) δ 13.3 (CH3). 18.0
(CH), 130.50 (quat), 130.74 (quat) 131.45 (quat) 132.03 (CH),
132.25 (quat), 134.77 (quat), 135.05 (quat), 138.14 (quat), (CH2), 42.7 (CH), 118.0 (CN), 200.3 (CHO). 5-Oxo-pentaneni-
145.52 (t, JC-P ) 7.3 Hz, quat), 146.42 (quat), 150.80 (t, trile (4a): 1H NMR (400 MHz, CDCl3) δ 1.91 (m, 2H, CH2),
JC-P ) 6.6 Hz, quat), 184.45 (acac-C-O). HSQC (C6D6): δ 1.24/ 2.40 (t, 2H, 3JHH ) 6.9 Hz, CH2CN), 2.63 (t, 2H, 3JHH ) 7.2
Hz, CH2CHO), 9.74 (s, 1H, CHO); 13C{1H} NMR (100 MHz,
27.32, 1.33/32.12, 1.85/16.75, 1.92/33.59, 1.92/17.00, 1.97/20.40,
2.10/20.32, 5.19/99.76, 6.77/124.15, 6.84/128.65, 6.92/132.03, CDCl3) δ 16.6 (CH2), 18.1 (CH2CN), 42.0 (CH2CHO), 117.3
7.11/129.47, 7.26/129.34, 7.81/120.14. 31P{1H} NMR (C6D6): δ (CN), 200.5 (CHO).
130.57 (d, 1JRh-P ) 317.3 Hz). HRMS (FAB (positive)) (m/z): Reduction of 3-Methyl-4-oxo-butyronitrile and 5-Oxo-
calcd for C65H79O8P2Rh 1152.4305, found 1152.4377. pentanenitrile. A 300 mL pressure vessel fitted with a glass
Asymmetric Hydroformylation of Allyl Cyanide. Hy- liner was charged with 10% platinum on activated carbon (2.7
g, �1 mol %), the crude hydroformylation product mixture
droformylation solutions were prepared by addition of ligand
and Rh(CO)2(acac) stock solutions to toluene solvent, followed containing 3-methyl-4-oxo-butyronitrile and 5-oxo-pentaneni-
by addition of allyl cyanide solution. Ligand solutions (0.06 M trile (11.25 g, 0.116 mol, 80% ee, b/l 20.1) and methanol (50
for bidentate ligands and 0.11 M for monodentate ligands) and mL). The vessel was sealed and purged three times with
Rh(CO)2(acac) (0.05 M) were prepared in the drybox by nitrogen (145 psi). The reaction mixture was then stirred at
dissolving appropriate amount of compound in toluene at room room temperature under nitrogen (87 psi) for 30 min in order
temperature. The allyl cyanide solution was prepared by to deoxygenate the solvent. After venting, the vessel was
mixing 15.3206 g of allyl cyanide, 3.2494 g of decane (as a GC purged twice with hydrogen (145 psi), then charged with
internal standard), and 6.3124 g of toluene (1:0.1:0.3 molar hydrogen (145 psi), and stirred at room temperature, repres-
ratio). Hydroformylation reactions were conducted in a reactor surizing with hydrogen as necessary. Once consumption was
system housed in an inert atmosphere glovebox. The reactor complete, the vessel was purged once with nitrogen (145 psi)
system consists of eight parallel, mechanically stirred pressure and opened. The reaction mixture was filtered through Celite,
reactors with individual temperature and pressure controls. and the filtrate was concentrated in vacuo to give a dark liquid
Upon charging the catalyst solutions, the reactors were in 96% yield with 80% ee and b/l 20.1. The compound was
pressurized with 150 psi of syn gas (H2:CO 1:1) and then derivatized in situ with trifluoroacetic anhydride prior to GC
heated to the desired temperature (35 or 70 °C). The runs were analysis, which was performed on an Astec Chiraldex A-TA
column (30 m × 0.25 mm, 0.25 µm, temperature program 125
stopped after 3 h by venting the system and purging with
J. Org. Chem, Vol. 69, No. 12, 2004 4039
Cobley et al.
°C for 15 min, then 15 °C/min to 180 °C. Retention times ) termination by chiral GC analysis (Chirasil Dex CB column,
25 m × 0.25 mm × 0.25 µm), indicating no racemization had
11.63 and 12.20 min for branched enantiomers and 21.0 min
for the linear regioisomer). 4-Hydroxy-3-methyl-butyroni- occurred (temperature program: 100 °C for 15 min then 5 °C/
trile (5): 1H NMR (400 MHz, CDCl3) δ 1.07 (d, 3H, 3JHH ) min to 220 °C. Retention times ) 20.7 and 20.9 min for
6.7 Hz, CH3), 2.06 (m, 1H, CH), 2.38 (dd, 1H, 2JHH ) 16.5 Hz, branched enantiomers). The linear isomer was not observed.
JHH ) 6.3 Hz, CHHCN), 2.50 (dd, 1H, 2JHH ) 16.5 Hz, 3JHH )
3
2-Methyl-4-aminobutanol (6): 1H NMR (400 MHz, CDCl3)
5.6 Hz, CHHCN), 3.49 (dd, 1H, 2JHH ) 10.9 Hz, 3JHH ) 7.5 δ 0.90 (d, 3H, 3JHH ) 6.5 Hz, CH3), 1.77-1.61 (m, 1H, CH),
Hz, CHHOH), 3.65 (dd, 1H, 2JHH ) 10.9 Hz, 3JHH ) 5.0 Hz, 1.53-1.46 (m, 2H, CH2), 2.65-2.52 (m, 1H, CHHNH2), 2.82-
2.69 (m, 1H, CHHNH2), 3.33 (dd, 1H, 2JHH ) 11.0 Hz, 3JHH )
CHHOH); 13C{1H} NMR (100 MHz, CDCl3) δ 14.9 (CH3), 19.9
7.6 Hz, CHHOH), 3.45 (dd, 1H, 2JHH ) 11.0 Hz, 3JHH ) 4.5
(CH2CN), 31.9 (CH), 64.8 (CH2OH), 117.7 (CN). NMR data are
identical to those reported in the literature.25 5-Hydroxy- Hz, CHHOH), 4.05 (br s); 13C{1H} NMR (100 MHz, CDCl3) δ
pentanenitrile (5a): 1H NMR (400 MHz, CDCl3) δ 1.75 (m, 17.8 (CH3), 35.3 (CH2), 35.6 (CH), 47.8 (CH2NH2), 68.2 (CH2-
4H, CH2CH2), 2.41 (t, 2H, 3JHH ) 6.3 Hz, CH2CN), 3.70 (t, 2H, OH). NMR and GC data of this sample are identical to those
JHH ) 6.0 Hz, CH2OH); 13C{1H} NMR (100 MHz, CDCl3) δ
3
obtained from commercially available sample.
16.0 (CH2CH2CN), 21.0 (CH2CN), 30.3 (CH2CH2OH), 60.6 General Method for Crystallization Screen. A scintil-
(CH2OH), 118.7 (CN). lation vial was charged with 2-methyl-4-aminobutanol (130
Formation of 2-Methyl-4-aminobutanol (6). A 300 mL mg, 1.26 mmol), ethanol (2 mL), and the desired acid (1 or 2
pressure vessel fitted with a glass liner was charged with a equiv). The solution was stirred for 24 h at room temperature.
mixture of 4-hydroxy-3-methyl-butyronitrile and 5-hydroxy- If no precipitation was observed, ethanol was removed in vacuo
pentanenitrile (20.1:1, 5.07 g, 51.2 mmol), oxalic acid dihydrate and replaced with 2-propanol (1.5 mL). If precipitation was
(6.44 g, 51.2 mmol), 10% platinum on activated carbon (1.03 still not observed after an additional 24 h, 2-propanol was
g), and methanol (100 mL). The vessel was sealed and purged removed in vacuo and replaced with ethyl acetate (1.5 mL). If
3 times with nitrogen (145 psi). The vessel was then heated no precipitation was obtained after an additional 24 h, ethyl
to 60 °C, and the reaction mixture was stirred under nitrogen acetate was removed in vacuo and replaced with MTBE (1.5
(145 psi) for 30 min in order to deoxygenate the solvent. After mL). Any crystalline salts that formed were filtered off. These
venting, the vessel was purged twice with hydrogen (145 psi), salts were then cracked with IRN78 resin using the method
then charged with hydrogen (145 psi) and stirred at 60 °C, described above. The resulting free amines were then analyzed
repressurizing with hydrogen as necessary. Once consumption for enantiomeric excess by chiral GC.
was complete, the vessel was cooled to room temperature,
Acknowledgment. We are grateful to Drs. Cynthia
purged once with nitrogen, and opened. The reaction mixture
was filtered through Celite that had been prewashed with Rand, Ian Lennon, Robert Appell, and Chris Goralski
methanol. IRN78 resin (45 g, 4meq/g) was added, and the from Dowpharma for useful discussions and sugges-
reaction mixture was stirred at room temperature for 48 h. tions.
The resin was filtered off and washed with methanol (50 mL)
and water (40 mL). The filtrate was concentrated on a rotary Supporting Information Available: Preparation proce-
evaporator to give crude 2-methyl-4-aminobutanol as a yellow dures for compounds 12, 13, 14, 16, and 17; stereoview of 9;
oil (76% with 80% ee). The compound was derivatized in situ NMR spectra of compounds 4, 9, and 19; and crystallographic
with trifluoroacetic anhydride prior to enantioselectivity de- tables for compounds 9 and 16. This material is available free
of charge via the Internet at http://pubs.acs.org.
(25) Xie, Z.-F.; Suemune, H.; Sakai, K. Tetrahedron: Asymmetry
JO040128P
1993, 4, 973.
4040 J. Org. Chem., Vol. 69, No. 12, 2004
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