Synthesis and application of a new bisphosphite ligand collection for asymmetric hydroformylation of allyl cyanide

Article abstract of DOI:10.1021/jo040128p

A series of mono- and bidentate phosphites was prepared with (S)-5,5',6,6'-tetramethyl-3,3'-di-tertbutyl-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 hydroformylation 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.

Full text of DOI:10.1021/jo040128p

Syn th esis a n d Ap p lica tion of a New Bisp h osp h ite Liga n d
Collection for Asym m etr ic Hyd r ofor m yla tion of Allyl Cya n id e
Christopher J . Cobley,* Kelli Gardner,† J erzy Klosin,*,‡ Ce´line 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
J effrey 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.
In tr od u ction
introduces a highly versatile aldehyde functional group
that is amenable to a number of synthetic transforma-
tions.3 It is therefore surprising that the development of
such a route for the production of highly functionalized
chiral building blocks has not been utilized industrially.
To date, most efforts in this field have concentrated
on a relatively narrow substrate range, notably the
asymmetric hydroformylation of vinylarenes to access
enantiomerically enriched 2-aryl propionic acids (the
profen class of nonsteroidal antiinflammatory drugs).4 An
important breakthrough in this area was made during
the early 1990s with the introduction by Union Carbide
of a rhodium-catalyzed system involving chiral bisphos-
phites, such as (R,R)-Chiraphite (1). Enantioselectivities
of up to 90%, along with high branched regioselectivity,
were obtained for several prochiral vinylarenes.5 Van
Leeuwen et al. reported detailed studies of the effects of
Asymmetric chemocatalysis is one of the most powerful
synthetic methodologies for producing high value added
chiral compounds. Its success and potential are due to
the achievable combination of high selectivity, high
activity, and reduced environmental impact.1 This has
been best demonstrated in the field of asymmetric
hydrogenation, which can be regarded as the most highly
developed asymmetric chemocatalytic technology to date.2
Conversely, while hydroformylation is the largest volume
homogeneous transition-metal-catalyzed reaction used
today, its asymmetric version is relatively underdevel-
oped. Asymmetric hydroformylation enantioselectively
† Chemical Sciences, The Dow Chemical Company, South Charles-
ton, WV.
‡ Chemical Sciences, The Dow Chemical Company, Midland, MI.
§ Current address: J ohnson Matthey Catalysts, 28 Cambridge
Science Park, Cambridge CB4 0FP, U.K.
(3) Stille, J . K. In Comprehensive Organic Synthesis; Trost, B. M.,
Flemming, I., Paquette, L. A., Eds.; Pergamon Press: Oxford: 1991;
Vol. 4, p 913.
(1) Blaser, H. U.; Spindler, F.; Studer, M. App. Catal. A 2001, 221,
119.
(2) (a) Noyori, R. In Asymmetric Catalysis in Organic Synthesis;
Noyori, R., Ed.; Wiley-Interscience: New York: 1994; Chapter 2, p
16. (b) Brown, J . M.; Ohkuma, T.; Noyori, R. In Comprehensive
Asymmetric Catalysis; J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer, Berlin: 1999; Vol. 1, Chapters 5 and 6, pp 101 and 199. (c)
Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York: 2000;
Chapter 1, p 1.
(4) Claver, C., van Leeuwen, P. W. N. M. In Rhodium Catalysed
Hydroformylation; Claver, C., van Leeuwen, P. W. N. M., Eds.; Kluwer
Academic Publishers: Dordrecht: 2000; Chapter 5, p 107 and refer-
ences therein.
(5) (a) Babin J . E.; Whiteker G. T. Patent WO 93/03830, 1992. (b)
Whiteker, G. T.; Briggs, J . R.; Babin, J . E.; Barner, B. A. In Catalysis
of Organic Reactions; Morrell, D. G., Ed.; Marcel Dekker: New York,
2003; p 359.
10.1021/jo040128p CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/19/2004
J . Org. Chem. 2004, 69, 4031-4040
4031

Cobley et al.
SCHEME 1. P r op osed Rou tes to (R)-2-Meth yl-4-a m in obu ta n ol
structural changes in this ligand class and found that
product selectivity was influenced by the bridge length,
biphenol substituents and relative configuration of chiral
centers in these bisphosphites.6 Considerable success was
also made by Takaya et al. using (R,S)-BINAPHOS (2),7
with enantioselectivities as high as 96% reported for the
hydroformylation of styrene, although the regioselectivity
with BINAPHOS was substantially lower than that for
Chiraphite.
The application of these ligands for asymmetric hy-
droformylation of allyl cyanide is also described (Scheme
1).8,9 The chiral, branched aldehyde product is converted
to 4-hydroxy-3-methylbutyronitrile (5) and 2-methyl-4-
aminobutanol (6), both being important chiral building
blocks found in several molecules of biological interest.10
For example, (S)-4-hydroxy-3-methylbutyronitrile has
been used by Merck in the synthesis of a potent nonpep-
tide gonadotropin releasing hormone antagonist (7),10c
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.
Resu lts a n d Discu ssion
Ligan d Design an d Syn th esis. 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
originally developed at Union Carbide to optically active
ligands that are bridged by achiral diolate groups. Such
a ligand design has the combined advantages of a
modular nature and an ease of synthesis, which allows
for the introduction of a wide variety of stereoelectronic
properties.
(8) Asymmetric hydroformylation of allyl cyanide was recently
reported: Lambers-Verstappen, M. M. H.; de Vries, J . G. Adv. Synth.
Catal. 2003, 345, 478.
(9) For an example of achiral hydroformylation of allyl cyanide,
see: El Ali, B.; Vasapollo, G.; Alper, H. J . Mol. Catal. A 1996, 112,
195.
(10) (a) Ikeura, Y.; Ishimaru, T.; Doi, T.; Kawada, M.; Fujishima,
A.; Natsugari, H. Chem. Commun. 1998, 2141. (b) Natsugari, H.;
Ikeura, Y.; Kamo, I.; Ishimaru, T.; Ishichi, Y.; Fujishima, A.; Tanaka,
T.; Kasahara, F.; Kawada, M.; Doi, T. J . Med. Chem. 1999, 42, 3982.
(c) Simeone, J . P.; Bugianesi, R. L.; Ponpipom, M. M.; Goulet, M. T.;
Levorse, M. S.; Desai, R. C. Tetrahedron Lett. 2001, 42, 6459. (d)
Taniguchi, N.; Kobayashi, K. Patent J P10182618, 1998.
(11) Cobley, C. J .; Lennon, I. C.; Praquin, C.; Zanotti-Gerosa, A.;
Appell, R. B.; Goralski, C. T.; Sutterer, A. C. Org. Process Res. Dev.
2003, 7, 407.
(6) (a) Buisman, G. J . H.; Vos, E. J .; Kamer, P. C. J .; van Leeuwen,
P. W. N. M. J . Chem. Soc., Dalton Trans. 1995, 409. (b) Buisman, G.
J . H.; van der Veen, L. A.; Klootwijk, A.; de Lange, W. G. J .; Kamer,
P. C. J .; van Leeuwen, P. W. N. M.; Vogt, D. Organometallics 1996,
16, 2929.
(7) (a) Sakai, N.; Mano, S.; Nozaki, K.; Takaya, H. J . Am. Chem.
Soc. 1993, 115, 7033. (b) Nozaki, K.; Sakai, N.; Nanno, T.; Higashijima,
T.; Mano, S.; Horiuchi, T.; Takaya, H. J . Am. Chem. Soc. 1997, 119,
4413.
(12) (a) Billig, E.; Abatjoglou, A. G.; Bryant, D. R. U.S. Patents
4,668,651, 1987; 4,769,498, 1988; (b) Cuny, G. D.; Buchwald, S. L. J .
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
1
ppm. The H 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
and 13C{1H} NMR spectra, which is consistent with the
C2 symmetry of these ligands. Biaryl-bridged bisphos-
phites 11-13 can contain an additional element of
chirality and potentially exist in two diastereomeric
forms, depending upon the configuration of the bridging
biaryl moiety. Bisphosphites 11 and 12, however, exhibit
a single resonance in the 31P{1H} NMR spectra, consis-
tent with either formation of a single diastereoisomer or
two diastereoisomers undergoing rapid interconversion.
Indeed for Chiraphite, the nature of the substituents at
the 3,3′-positions is critical for obtaining both high
regioselectivity and enantioselectivity with vinylarenes.
Van Leeuwen has found that trimethylsilyl substituents
also lead to highly enantioselective ligands.6b In addition,
for optically active bisphosphites, the nature of the
bridging diolate moiety plays a crucial role. This chiral
auxiliary effectively transfers stereochemical information
to the tert-butyl-substituted biphenol rings, which form
a chiral environment around the Rh catalytic center,
leading to chiral cooperativity. The bridging diolate also
controls the chelate bite angle, a structural feature that
has been proposed to influence hydroformylation regio-
selectivity.4 For Chiraphite, the (2R,4R)-pentanediolate
moiety, in combination with 3,3′-di-tert-butylbiphenol
units, leads to high regioselectivity and enantioselectivity
for hydroformylation of vinylarenes.
Unfortunately, as with most asymmetric catalysts, no
single ligand structure is generally useful for all types
of substrates. Therefore, the development of asymmetric
hydroformylation into a synthetic method of broad utility
requires access to a structurally diverse family of ligands.
Such diversity is quite difficult with phosphine ligands,
whose syntheses can often require multiple steps. Phos-
phites, however, can be assembled in a much easier way
by reacting an alcohol or diol with a phosphorus halide.
Bisphosphites can be prepared by reaction of a phospho-
rochloridite, (RO)2PCl, with a diol. This diol bridges the
two phosphite moieties and controls the bite angle of the
resulting ligand. For ligands such as Chiraphite, how-
ever, the requirement for this bridging diol to be optically
active limits the diversity of readily accessible structures.
For this reason we sought to develop a related class of
bisphosphite ligands based on achiral diols. By utilizing
the commercially available (S)-3,3′-di-tert-butyl-5,5′,6,6′-
tetramethyl-biphenyl-2,2′-diol (BIPHEN-H2), as the chiral
auxiliary, achiral diols could be used to prepare a much
more diverse collection of bisphosphite ligands. Using this
strategy we have prepared a library of bisphosphite
ligands for evaluation in asymmetric hydroformylation
of a variety of olefinic substrates. In this paper, we
describe the synthesis and characterization of a subset
of this bisphosphite library, along with related mono-
dentate phosphites for comparison.
1
The H NMR spectra of 11 and 12 also contained only
resonances assignable to a single species. Previous NMR
and chiral HPLC studies have found that rotation about
the central biphenol axis is slow in related biphenol-
bridged bisphosphites.14 The biphenylmethyl-bridged bis-
phosphite 13, however, exhibits two singlets of equal
intensity in the 31P{1H} NMR spectrum. In addition, four
resonances for the methylene groups were observed in
the 1H NMR spectrum of 13. These results are consistent
with formation of a 1:1 mixture of the (S,S,S) and (S,R,S)
diastereomers of 13, which differ by the configuration of
the biphenylmethyl moiety. No evidence for interconver-
sion of these two diastereomers was obtained from
NOESY experiments at room temperature, suggesting
the rotational barrier about the central biaryl bond of
13 is greater than 19 kcal/mol.
Hyd r ofor m yla tion Scr een in g Stu d y. Asymmetric
hydroformylation studies were performed in an 8-cell
parallel stirred reactor system. Catalysts were generated
in situ from the reaction of the appropriate ligand with
Rh(CO)2(acac) in toluene at 150 psi syn gas (H2:CO 1:1).
Under these conditions the active catalyst precursor Rh-
(bisphosphite)(CO)2H is formed.4 Hydroformylation reac-
tions were performed for 3 h in toluene with substrate-
to-catalyst ratios of 300 and 500 to 1 for runs at 35 and
70 °C, respectively. These parameters were chosen in
order to ensure significant conversions and relatively
rapid throughput were obtained. Reaction mixtures were
analyzed by chiral stationary phase GC using a Chiraldex
A-TA column. This analytical method allowed determi-
nation of conversion, regioselectivity (branched/linear)
and enantioselectivity, as well as the extent of olefin
(13) Compound 15 was recently reported as a ligand in asymmetric
hydrogenation: Hua, Z.; Vassar, V. C.; Ojima, I. Org. Lett. 2003, 5,
3831.
Phosphite ligands were prepared by the reaction of (S)-
(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. Syn th esis of Novel P h osp h ites
to occur with 66% ee and b/l of 2.6.8 Under our condi-
tions, BINAPHOS gave similar results (51.5% ee, b/l 2.9)
(entry 2). Slightly lower ee values might be due to
differences in the Rh/BINAPHOS ratio used. Chiraphite,
which is very effective for asymmetric hydroformylation
of vinylarenes, gave low enantioselectivity for allyl
cyanide hydroformylation. The regioselectivity for allyl
cyanide hydroformylation with Chiraphite, however, was
significantly higher (b/l 7.3) than that observed with
BINAPHOS (entry 1). The results reported in Table 1
show that the best combination of enantio- and regiose-
lectivity was obtained by employing (S)-BIPHEN units
in combination with 2,2′-biphenol (ligand 11), which gave
78.1% ee and b/l of 15.5 at 35 °C (entry 4). The remaining
bisphosphites gave very poor enantioselectivities with
moderate regioselectivity ranging from 2.4 to 7.1. Inter-
estingly, monodentate phosphites 15 and 16 gave higher
enantioselectivities (39.1-43.7% ee) than bisphosphites
12-14 but with lower regioselectivity. The fastest hy-
droformylation rate was observed for ligand 12 with
complete conversion attained in 2 h, based on gas
consumption curves. As expected, runs conducted at
higher temperature (70 °C) led to significantly faster
conversions at the cost of lower regio- and enantioselec-
tivities. A brief examination of alternative solvents
revealed that when the reaction is conducted in acetone,
product enantioselectivity using BINAPHOS is surpris-
ingly increased from 51.5% to 75.6% ee (entries 2 and
3), whereas no major change in performance is observed
in the case of 11 (entries 4 and 5). No significant changes
in enantioselectivities were observed for phosphites 12-
17 in acetone. To compare bisphosphite 11 and BINA-
TABLE 1. Asym m etr ic Hyd r ofor m yla tion of Allyl
Cya n id e w ith Liga n d s 1, 2, a n d 11-17a
T
conv
(%)b
regio-
% ee
entry ligand (°C)
selectivity (b/l)c (configuration)
1
2
1
2
35
70
35
70
35
35
70
35
35
70
35
70
35
70
35
70
35
70
35
70
21.9
100
65.0
100
47.8
84.8
100
100
100
100
8.7
100
73.3
100
11.3
100
65.0
100
30.5
100
7.3
6.1
2.9
15.3 (R)
15.0 (R)
51.5 (S)
52.6 (S)
75.6 (S)
78.1 (S)
68.3 (S)
74.5 (S)
12.1 (S)
17.9 (S)
9.2 (R)
2.3 (R)
0.7 (S)
5.5 (S)
43.7 (R)
32.7 (R)
39.1 (R)
28.5 (R)
14.1 (R)
6.7 (R)
2.3
3
4
2d
11
2.7
15.5
11.2
15.1
12.4
9.3
7.1
5.2
8.5
6.7
6.3
4.3
5.2
3.8
5.0
3.9
5
6
11d
12
7
13
14
15
16
17
8
9
10
11
a
Pressure 150 psi. Ligand:Rh ) 1.2:1 for bidentate and 2.2:1
for monodentate phosphites. Solvent ) toluene (2.5 mL). Molar
b
allyl cyanide:Rh ) 300:1 at 35 °C and 500:1 at 70 °C. Percentage
conversion of allyl cyanide after 3 h. c b/l ) branched-to-linear
d
ratio. Runs performed in acetone.
hydrogenation to butyronitrile and olefin isomerization
to crotonitrile.
Results of allyl cyanide hydroformylation are given in
Table 1. BINAPHOS and Chiraphite were included in the
study for comparison. Asymmetric hydroformylation of
allyl cyanide using Rh-BINAPHOS was recently reported
4034 J . Org. Chem., Vol. 69, No. 12, 2004

Asymmetric Hydroformylation of Allyl Cyanide
SCHEME 3. Syn th esis of 2-Meth yl-4-a m in obu ta n ol via a Ca ta lytic Asym m etr ic
Hyd r ofor m yla tion -Hyd r ogen a tion Sequ en ce
TABLE 2. Com p a r ison betw een BINAP HOS (2) a n d
Kellip h ite (11) in Asym m etr ic Hyd r ofor m yla tion of Allyl
Cya n id e a t Low Ca ta lyst Loa d in gsa
refer to as Kelliphite, is by far the best overall ligand for
asymmetric hydroformylation of allyl cyanide.
To demonstrate the feasibility of performing asym-
metric hydroformylation on a larger scale, allyl cyanide
(75 mL) was hydroformylated in a 300 mL pressure vessel
using (R,R)-Kelliphite (11). Running the reaction at
substrate to catalyst (S:C) molar ratio of 1,500:1, 30 °C,
and 145 psi syn gas (1:1) gave complete conversion in 5
h with 80% ee and b/l ratio of 20. Synthesis of the
aforementioned chiral building block, 2-methyl-4-ami-
nobutanol, was demonstrated, as shown in Scheme 3.
Stepwise reduction of the aldehyde and nitrile function-
alities was performed using 10% Pt on carbon catalyst.
Reduction of the aldehyde group of 4 with Pt/C gave the
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,
again with no loss of enantioselectivity. Alternatively,
both reactions could be performed in one pot by the
addition of oxalic acid after reduction of the aldehyde
functionality was complete. Treatment of salt 18 with
basic resin IRN78 afforded the amino alcohol free base
6 in 80% ee. A limited crystallization screen of several
chiral and achiral acids identified (-)-camphanic acid as
being suitable for upgrading the enantioselectivity to 96%
ee and removing the linear adducts albeit with a low
recovery (10% isolated yield); this study is currently
ongoing.
regio-
% ee
time for
conv selectivity (config-
complete
entry ligand AC/Rhb (%)c
(b/l)d
uration) conversione
1
2
2,000
4,000
10,000
64.0
37.1
14.8
2.8
2.9
2.7
74.7 (S)
75.1 (S)
77.2 (S)
2
11
2,000 100
4,000 100
10,000 100
17.8
17.3
18.5
77.8 (S)
78.8 (S)
78.8 (S)
6 h
8 h
16 h
a
Pressure 150 psi. Ligand:Rh ) 1.2:1. Temp ) 35 °C; 3.5 mL
of allyl cyanide. Molar AC (allyl cyanide)/Rh ratio. c Percent
b
d
conversion of allyl cyanide after 17 h. b/l ) branched-to-linear
ratio. e Estimated based on gas consumption profiles.
PHOS more extensively, a series of hydroformylation
reactions of allyl cyanide was conducted at low catalyst
loading (allyl cyanide:Rh of 2,000-10,000:1) in neat olefin
as we observed that reaction rates were highest when
the reaction was conducted without solvent. As shown
in Table 2, the catalyst prepared from 11 is about 7 times
more active than BINAPHOS at 10,000:1 allyl cyanide:
Rh catalyst loadings. Under these conditions allyl cyanide
hydroformylation was complete with ligand 11 within 16
h, which translates into an average turnover frequency
of 625 turnovers per hour. Unexpectedly, the regioselec-
tivity with 11 increased from 15.5 (Table 1, entry 4) to
18.5 (Table 2, entry 2) at the lowest catalyst loadings.
This appears to be a result of performing these reactions
without solvent.15 Under the same conditions, the regio-
selectivity with BINAPHOS was not affected. On the
other hand, the hydroformylation enantioselectivity with
11 remained unchanged, whereas that with BINAPHOS
increased by 25% ee to a maximum value of 77.2% ee at
the lowest catalyst loading. This increase in enantiose-
lectivity with BINAPHOS seems to correlate with solu-
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
Syn th esis of [(S,R,S)-Kellip h ite]Rh (a ca c) (19). To
investigate the coordination mode of ligand Kelliphite 11,
the synthesis of a representative Rh complex was un-
dertaken. Bisphosphite 11 was reacted with 1 equiv of
(COD)Rh(acac) in toluene solution, which led to quantita-
tive formation of [(S,R,S)-Kelliphite]Rh(acac), 19. Com-
plex 19 was characterized by multinuclear and multidi-
mensional NMR spectroscopy, HRMS, and X-ray single-
crystal analysis (see below). The complex exhibits C2
(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.
F IGURE 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 Bon d Len gth s (Å) a n d An gles (d eg)
for Liga n d 11 a n d Com p lex 19
bond/angle
11
1919
P1-O1
1.628(1)
1.617(2)
1.639(2)
1.644(2)
1.631(2)
1.607(2)
102.92(8)
92.11(8)
101.96(8)
91.80(8)
103.12(8)
102.14(7)
1.601(5), 1.614(5)
1.610(4), 1.625(4)
1.636(5), 1.622(5)
1.608(5), 1.611(5)
1.631(4), 1.611(5)
1.619(4), 1.615(5)
100.3(2), 100.4(2)
96.5(2), 98.0(2)
P1-O2
P1-O3
P2-O4
P2-O5
P2-O6
O1-P1-O2
O1-P1-O3
O2-P1-O3
O4-P2-O5
O4-P2-O6
O5-P2-O6
Rh-O7
103.2(2), 103.2(2)
98.1(2), 97.1(2)
99.9(2), 101.2(3)
103.0(2), 102.2(2)
2.077(5), 2.084(5)
2.085(5), 2.053(4)
3.234, 3.234
2.149(2), 2.140(2)
2.145(2), 2.147(2)
97.74(8), 97.94(7)
88.6(2), 85.5(2)
Rh-O8
P1-P2
7.704
Rh-P1
F IGURE 2. Molecular structure and labeling scheme for
[(S,R,S)-Kelliphite]Rh(acac) complex (19) with 40% probability
of thermal ellipsoids. Carbon atoms of acac fragment and all
hydrogen atoms were removed for clarity.
Rh-P2
P2-Rh-P1
P1-Rh-O8
P2-Rh-O7
O7-Rh-O8
85.0(2), 87.2(2)
88.9(2), 88.9(2)
fragment. For example, this dihedral angle is much larger
(102.2°) in a molybdenum carbene complex17 containing
BIPHEN unit, which is a direct consequence of a larger
O-Mo-O bond angle (127.0°) as compared to the en-
docyclic O-P-O in 11 (102.0°). The dihedral angle
between aryl rings in analogous 3,3′,5,5′-tetra-tert-butyl-
2,2′-bisphenoxyphosphite ligands is significantly smaller
(48-55°)18 suggesting that steric repulsions between the
two methyl groups in the 6,6′-position of BIPHEN
contribute to widening of this angle in 11. The stereo-
chemistry around the central 2,2′-biphenoxy unit is of (R)
configuration and is the same as that found in rhodium
complex 19 (vide infra). The dihedral angle between aryl
rings in the 2,2′-biphenoxy fragment is 123.9°. The two
phosphorus atoms are separated by 7.7 Å. The sum of
symmetry in solution based on NMR spectroscopy. The
1H NMR spectrum of 19 exhibited only one set of
BIPHEN resonances (two t-Bu and four Me signals) and
four aromatic signals for the bridging 2,2′-biphenyldiol.
The 31P{1H} NMR spectrum of 19 shows a doublet at δ
130.57 (1J Rh-P ) 317.3 Hz).
Cr ysta l Str u ctu r e An a lysis of (S,R,S)-Kellip h ite
(11) Liga n d . Crystals of 11 were obtained from aceto-
nitrile solution at -35 °C. A thermal ellipsoid drawing
of 11 is shown in Figure 1. Selected bond distances and
angles are included in Table 3. Bisphosphite 11 crystal-
lizes in the monoclinic, noncentrosymmetric space group
P21 together with two acetonitrile solvent molecules in
the asymmetric unit. In the solid state the ligand has
molecular C2 symmetry with a 2-fold axis positioned at
the center of the C30-C31 bond. The dihedral angles
between the aryl rings of the dibenzo[d,f][1,3,2]dioxaphos-
phepin rings are 62.2° and 62.4°. This torsion angle is
very similar to that in the only other known phosphite
structure containing a 3,3′-di-tert-butyl-5,5′,6,6′-tetra-
methyl-2,2′-bisphenoxy (BIPHEN) unit (63.5°).16 The
magnitude of this dihedral angle strongly depends on the
O-X-O (X ) heteroatom) bond angle of the BIPHEN
(16) Sua´rez, A.; Me´ndez-Rojas, M. A.; Pizzano, A. Organometallics
2002, 21, 4611.
(17) Alexander, J . B.; Schrock R. R.; Davis, W. D.; Hultzsch, K. C.;
Hoveyda, A. H.; Houser, J . H. Organometalllics 2000, 19, 3700.
(18) (a) Pastor, S. D.; Shum, S. P.; Rodebaugh, R. K.; Delellis, A.
D.; Clarke, F. H. Helv. Chem. Acta 1993, 76, 900. (b) Pastor, S. D.;
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,
S. D.; Rihs, G.; Rodebaugh, R. K.; Smith, A. R. Inorg. Chem. 2001, 40,
2156. (d) Shum, Sai P.; Pastor, S. D.; Rihs, G. Inorg. Chem. 2002, 41,
127.
4036 J . Org. Chem., Vol. 69, No. 12, 2004

Asymmetric Hydroformylation of Allyl Cyanide
F IGURE 3. Stereoview of [(S,R,S)-Kelliphite]Rh(acac) complex (19).
bond angles around phosphorus atoms is 297.0°, which
is very similar to the values observed in other phosphites
of this type.18
dihedral angles between aryl rings of the dibenzo[d,f]-
[1,3,2]-dioxaphosphepin rings are 63.1° (62.3°) and 62.8°
(58.4°) and are very similar to those found in free ligand
11 (vide supra). The central 2,2′-biphenoxy unit has (R)
absolute configuration with a biaryl dihedral angle of
60.5° (59.8°). Unlike in the case of 11 where it is not
clearly apparent why there is a preference for (R)
configuration in the middle biphenoxy unit in the solid
state,22 the metal complex of 19 with (S,S,S) configura-
tion would certainly be disfavored as a result of steric
repulsions between BIPHEN tert-butyl groups and the
bridging 2,2′-biphenoxy fragment. In metal complexes
containing the sterically less crowded tris(2,2′-biphenyl)-
bisphosphite ligand, both (S,S,S)/ (R,R,R) and (S,R,S)/
(R,S,R) configurations are encountered.22 The distance
between the two phosphorus atoms in 19 equals 3.234
Å. The sum of bond angles around phosphorus atoms in
19 is also very similar to that in 11 (297.0°) and equals
300.0° (301.6°) and 301.0° (300.5°) for P1 and P2,
respectively.
Cr ysta l Str u ctu r e An a lysis of [(S,R,S)-Kellip h ite]-
Rh (a ca c) (19). Crystals of 19 were obtained at room
temperature by slow evaporation of an acetonitile solu-
tion that contained a small amount of toluene. Thermal
ellipsoid drawing and stereoview of 19 are shown in
Figures 2 and 3, respectively. Selected bond distances and
angles are included in Table 3. The complex crystallizes
in the orthorhombic, noncentrosymmetric space group
C2221. Two crystallographically independent molecules
of complex 19 are present in the asymmetric unit
together with two molecules of acetonitrile and one-half
molecule of toluene. The geometry around the rhodium
atom is close to idealized square planar with mean
deviation from planarity of 0.03 Å. The chelate bond
angle P1-Rh-P2 (97.74(8)°, 97.94(7)°)19 is larger than
found in analogous complexes containing monodentate
phosphites20 (e.g., cis-[P(OPh)3]2Rh(acac), 93.8°)20b but is
similar to related complexes containing bidentate21 phos-
phite ligands coordinated to the Rh(acac) fragment, which
fall in the range of 96.7-99.9°. This increase in the P1-
Rh-P2 bite angle is a consequence of steric congestion
between the two very bulky phosphite groups. In the solid
state the complex has molecular C2 symmetry with 2-fold
axis positioned at the center of the C30-C31 bond.
Because of the substantial size and C2 symmetry of the
bisphosphite, fragments of the ligand extend into the
rhodium coordination sphere (see Figure 3). Two methyl
carbons of t-Bu groups that are related by C2 symmetry
(C15 and C50) are positioned only 3.3-3.7 Å above and
below the Rh-O8 and Rh-O7 bond vectors, indicating
close proximity of these t-Bu groups to the coordination
environment of rhodium. Presumably, this sterically
restricted C2 symmetric environment is responsible for
the high enantioselectivity observed with ligand 11. The
Con clu sion
Novel mono- and bidentate phosphites were prepared
from commercially available (S)-5,5′-6,6′-tetramethyl-3,3′-
di-tert-butyl-1,1′-biphenyl-2,2′-diol [(S)-BIPHEN-H2] and
phenols in high yields. All new ligands were investigated
in asymmetric hydroformylation of allyl cyanide as the
product of this reaction can be transformed into enan-
tiomerically enriched 2-methyl-4-aminobutanol, a useful
chiral building block. The C2 symmetric bisphosphite 11
(Kelliphite) with 2,2′-biphenoxy bridge was found to be
the best 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. It was also found that enantioselectivities
induced by BINAPHOS increased from 51% ee, when
reaction was performed in toluene, to 77% ee when the
reaction was conducted in either acetone or neat. In all
cases, however, the regioselectivity (b/l 2.8) and catalytic
activity was substantially lower than that of 11. The
product of allyl cyanide hydroformylation was further
converted to (R)-2-methyl-4-aminobutanol via two reduc-
tion steps without any loss of enantioselectivity.
(19) Because there are two independent molecules in the asymmetric
unit, two values for each bond distance and angle are provided.
(20) (a) Lamprecht, G. J .; Leipoldt, J . G.; Van Zyl, G. J . Inorg. Chem.
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 .;
Leipoldt, J . G. Inorg. Chem. Acta 1985, 102, L1. (d) Heaton, B. T.;
J acob, C.; Markopoulos, J .; Markopoulou, O.; Nahring, J .; Skylaris, C.
K.; Smith, A. K. J . Chem. Soc., Dalton Trans. 1996, 1701.
(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.,
Dalton Trans. 1996, 3561. (b) Meetsma. A.; J ongsma, T.; Challa, G.;
Van Leeuwen, P. W. N. M. Acta Crystallogr. 1993, C49, 1160. (c) J iang,
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,
P. W. N. M.; Goubitz, K.; Fraanje, J .; Veldman, N.; Spek, A. L.
Organometallics 1996, 15, 835.
Exp er im en ta l Section
The 6,6′-(((1R,3R)-1,3-dimethyl-1,3-propanediyl)bis(oxy))bis-
(4,8-bis(1,1-dimethylethyl)-2,10-dimethoxy-dibenzo(d,f)(1,3,2)-
(22) Interestingly the stereochemistry of tris(2,2′-biphenyl)bisphos-
phite ligand is (R, R, R)/ (S, S, S). Baker, M. J .; Harrison, K. N.; Orpen,
A. G.; Pringle, P. G.; Shaw, G. Chem. Commun. 1991, 803.
J . Org. Chem, Vol. 69, No. 12, 2004 4037

Cobley et al.
dioxaphosphepin5 (Chiraphite) and (R,S)-2-(diphenylphos-
phino)-(1,1′-binaphthalen-2′-yl-1,1-binaphthalene-2,2′-diyl)phosphite
[(R,S)-BINAPHOS)] were prepared according to literature
J C-P ) 1.6 Hz, quat), 138.73 (d, J C-P ) 3.4 Hz, quat), 145.45
(d, J C-P ) 5.3 Hz, quat), 147.00 (d, J C-P ) 2.3 Hz, quat).
31P{1H} NMR (C6D6): δ 182.4.
7
procedures.
P r ep a r a tion of (S)-4,8-Di-ter t-bu tyl-6-iod o-1,2,10,11-
tetr a m eth yl-5,7-d ioxa -6-p h osp h a -d iben zo[a ,c]cycloh ep -
ten e (10). (S)-4,8-Di-tert-butyl-6-chloro-1,2,10,11-tetramethyl-
5,7-dioxa-6-phospha-dibenzo[a,c]cycloheptene (5.4 g, 12.89
mmol) was dissolved in 50 mL of toluene. To this solution was
added TMS-I (3.10 g, 15.5 mmol) dissolved in 5 mL of toluene.
After addition of TMS-I the solution assumed a light yellow
color. The reaction mixture was stirred overnight. Solvent was
removed under reduced pressure to give 6.57 g of product as
Cr ysta l Str u ctu r es of 11 a n d 19. Data were collected on
diffractometers equipped with graphite monochromatic crys-
tals, Mo KR radiation sources (λ ) 0.71073 Å), and SMART
CCD detectors. Cell parameters were refined using 4918 and
8192 reflections for 11 and 19, respectively. The structures
were solved by direct methods in SHELXTL6.123 from which
the positions of all non-H atoms were obtained. The non-H
atoms were refined with anisotropic thermal parameters, and
all of the H atoms were calculated in idealized positions,
refined riding on their parent atoms. The asymmetric unit of
11 consists of the ligand and two acetonitrile molecules. The
asymmetric unit of 19 contains two Rh complexes, two aceto-
nitrile molecules and one-half of a toluene molecule. The
solvent molecules in both structures were disordered and could
not be modeled properly; thus the program SQUEEZE, a part
of the PLATON package24 of crystallographic software, was
used to calculate the solvent disorder area and remove its
contribution to the overall intensity data. For 11 a total of 633
parameters were refined in the final cycle using 9856 observed
reflections with I > 2σ(I) to yield R1, wR2 and S (goodness of
fit) of 5.45%, 10.65% and 0.853, respectively. For 19 a total of
1427 parameters were refined in the final cycle using 10710
observed reflections with I > 2σ(I) to yield R1, wR2, and S
(goodness of fit) of 4.68%, 9.56% and 0.909, respectively.
P r ep a r a tion of (S)-4,8-Di-ter t-bu tyl-6-ch lor o-1,2,10,11-
tetr a m eth yl-5,7-d ioxa -6-p h osp h a -d iben zo[a ,c]cycloh ep -
ten e. To a 200 mL toluene solution containing (S)-3,3′-di-tert-
butyl-5,5′,6,6′-tetramethyl-biphenyl-2,2′-diol [(S)-BIPHEN-H2]
(4.3395 g, 12.2 mmol) was added 1.7146 g (14.49 mmol) of PCl3
followed by addition of 4.1 mL of NEt3. During amine addition
copious amounts of white precipitate appeared. After stirring
overnight the solvent volume was reduced to 80 mL and the
solution was filtered. The solid was filtered and washed with
20 mL of cold toluene. Solvent was removed under reduced
pressure to give 5.10 g of white solid. Yield 99.5%. 1H NMR
(C6D6): δ 1.47 (s, 9H, C(CH3)), 1.53 (s, 9H, C(CH3)), 1.64 (s,
3H, CH3) 1.65 (s, 3H, CH3), 2.00 (s, 3H, CH3), 2.01 (s, 3H, CH3),
7.16 (1H), 7.24 (1H). 13C{1H} NMR (C6D6): δ 16.46 (CH3), 16.73
(CH3), 20.38 (CH3), 20.42 (CH3), 31.29 (d, J C-P ) 5.4 Hz,
C(CH3)3), 32.49 (C(CH3)3), 34.81 (C(CH3)3), 35.31 (C(CH3)3),
128.56 (CH), 129.28 (CH), 131.91 (d, J C-P ) 3.3 Hz, quat),
132.27 (d, J C-P ) 6.0 Hz, quat), 133.18 (quat), 134.00 (quat),
135.03 (d, J C-P ) 1.4 Hz, quat), 135.85, 137.91 (d, J C-P ) 2.0
1
an off-white powder. Yield 99.9%. H NMR (C6D6): δ 1.45 (s,
9H, C(CH3)2), 1.57 (s, 9H, C(CH3)2), 1.61 (s, 3H, CH3), 1.63 (s,
3H, CH3), 1.98 (s, 3H, CH3), 1.99 (s, 3H, CH3), 7.13 (1H), 7.24
(1H). NOESY1D (C6D6): irradiation at 7.13 ppm, NOE re-
sponse at 1.45 and 1.98 ppm; irradiation at 7.24 ppm, NOE
response at 1.57 and 1.99 ppm. 13C{1H} NMR (C6D6): δ 16.34
(CH3), 16.73 (CH3), 20.40 (2xCH3), 31.02 (d, J C-P ) 4.8 Hz,
C(CH3)2), 33.17 (C(CH3)2), 34.61 (C(CH3)2), 35.58 (C(CH3)2),
128.70 (CH), 129.88 (d, J C-P ) 1.4 Hz, CH), 131.00 (d, J C-P
3.3 Hz, quat), 131.96 (d, J C-P ) 6.0 Hz, quat), 133.32 (quat),
134.12 (quat), 135.15 (quat), 135.93 (quat), 136.99 (d, J C-P
)
)
2.0 Hz, quat), 138.52 (d, J C-P ) 3.1 Hz), 147.32 (d, J C-P ) 6.6
Hz), 148.48 (d, J C-P ) 2.0 Hz). HSQC (C6D6): δ 1.45/31.02,
1.57/33.17, 1.61/16.34, 1.63/16.73, 1.98/20.40, 1.99/20.40, 7.13/
128.70, 7.24/129.88. 31P{1H} NMR (C6D6): δ 209.1. Anal. Calcd
for C24H32IO2P: C, 56.48; H, 6.32. Found: C, 56.60; H, 6.59.
P r ep a r a tion of (S,S)-6,6′-((1,1′-Bip h en yl)-2,2′-d iylbis-
(oxy))bis(4,8-bis(1,1-dim eth yleth yl)-1,2,10,11-tetr am eth yl-
d iben zo(d ,f)(1,3,2)d ioxa p h osp h ep in (11). A solution of 2,2′-
biphenol (212 mg, 1.14 mmol) and 300 µL NEt3 in 15 mL of
toluene was added to a solution of (S)-4,8-di-tert-butyl-6-bromo-
1,2,10,11-tetramethyl-5,7-dioxa-6-phospha-dibenzo[a,c]cyclo-
heptene (9) (983 mg, 2.27 mmol) in 20 mL toluene. The solution
was stirred for 18 h at ambient temperature and then filtered.
The filtrate was evaporated to a white solid that was triturated
with MeCN. The supernatant was decanted, and the solid
product was dried under vacuum (737 mg, 68% yield). 1H NMR
(C6D6): δ 1.38 (s, 18H, C(CH3)3), 1.42 (s, 18H, C(CH3)3), 1.70
(s, 6H, CH3), 1.77 (s, 6H, CH3), 2.05 (s, 6H, CH3), 2.12 (s, 6H,
3
3
4
CH3), 6.81 (ddd, 2H, J H-H ) 7.5 Hz, J H-H ) 7.5 Hz, J H-H
)
3
3
1.2 Hz), 6.98 (ddd, 2H, J H-H ) 8.1 Hz, J H-H ) 7.5 Hz,
4J H-H ) 1.8 Hz), 7.17 (s, 2H), 7.19 (s, 2H), 7.22 (d, 2H,
3
4
3J H-H ) 8.1 Hz), 7.40 (dd, 2H, J H-H ) 7.8 Hz, J H-H ) 1.5
Hz). COSY (C6D6): δ 6.81/6.98, 7.40; 6.98/6.81, 7.22; 7.22/6.98;
7.40/6.81, 6.98 (weak). NOESY1D (C6D6): irradiation at 2.05
ppm, NOE response at 7.17, 1.70 ppm; irradiation at 2.12 ppm,
NOE response at 7.19, 1.77 ppm. 13C{1H} NMR (C6D6): δ 16.58
(CH3), 16.86 (CH3), 20.38 (CH3), 20.43 (CH3), 31.38 (C(CH3)3),
31.58 (C(CH3)3), 34.81 (C(CH3)), 34.90 (C(CH3)3), 121.97 (t,
J C-P ) 5.4 Hz, CH), 123.79 (CH) 128.19 (CH), 128.51 (CH),
128.69 (CH), 130.49 (quat), 131.11 (quat), 131.82 (quat), 132.77
(d, J C-P ) 2.7 Hz, quat), 132.92 (quat), 133.01 (CH), 134.47
(quat), 135.52 (quat), 137.94 (quat), 138.64 (quat) 145.35
(quat), 145.92 (t, J C-P ) 3.3 Hz), 149.67 (quat). HSQC (C6D6):
δ 1.38/31.58, 1.42/31.38, 1.70/16.58, 1.77/16.86, 2.05/20.38,
2.12/20.43, 6.81/123.79, 6.98/128.51, 7.17/128.19, 7.19/128.69,
7.22/121.97, 7.40/133.01. 31P{1H} NMR (C6D6): δ 134. Single
crystals were grown from acetonitrile solution at -35 °C.
HRMS (ESI, (M + Na)+) (m/z): calcd for C60H72O6P2Na
973.470, found 973.469. Anal. Calcd for C60H72O6P2: C, 75.76;
H, 7.63. Found: C, 76.32; H, 8.39.
Hz, quat), 138.72 (d, J C-P ) 4.1 Hz, quat), 144.52 (d, J C-P
)
6.0 Hz), 146.14 (d, J C-P ) 2.0 Hz, quat). 31P{1H} NMR (C6D6):
δ 166.1.
P r ep a r a tion of (S)-4,8-Di-ter t-bu tyl-6-br om o-1,2,10,11-
tetr a m eth yl-5,7-d ioxa -6-p h osp h a -d iben zo[a ,c]cycloh ep -
ten e (9). (S)-3,3′-Di-tert-butyl-5,5′,6,6′-tetramethyl-biphenyl-
2,2′-diol [(S)-BIPHEN-H2] (4.06 g, 11.45 mmol) was dissolved
in 100 mL of toluene. NEt3 (3.25 mL, 23.31 mmol) was added.
PBr3 (1.1 mL, 11.6 mmol) was added to the reaction mixture,
which was then stirred for 18 h. The suspension was filtered,
and the filtrate was evaporated to give the product as a white
1
solid (3.41 g, 7.87 mmol, 69% yield). H NMR (C6D6): δ 7.18
(s, 1H), 7.08 (s, 1H), 1.93 (s, 3H), 1.92 (s, 3H), 1.57 (s, 3H),
1.56 (s, 3H), 1.48 (s, 9H), 1.39 (s, 9H). 13C{1H} NMR (C6D6): δ
16.39 (s, CH3), 16.72 (s, CH3), 20.34 (s, CH3), 20.37 (s, CH3),
31.20 (d, J C-P ) 3.7 Hz, CCH3), 32.76 (s, CCH3), 34.74 (s,
CCH3), 35.44 (s, CCH3), 128.65 (CH), 129.55 (s, CH), 130.89
(d, J C-P ) 3.0 Hz, quat), 132.16 (d, J C-P ) 6.0 Hz, quat), 133.27
(quat), 134.10 (quat), 135.08 (quat), 135.89 (quat), 137.65 (d,
P r ep a r a tion of (S)-4,8-Bis(1,1-d im eth yleth yl)-1,2,10,-
11-tetr a m eth yl-6-p h en oxy-d iben zo(d ,f)(1,3,2)d ioxa p h os-
p h ep in (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]-
cycloheptene (10) dissolved in 5 mL of toluene was added 82.6
mg (0.88 mmol) of phenol followed by addition of 1.6 mL (1.14
mmol) of NEt3. During amine addition, a white solid appeared.
After stirring overnight the solution was filtered and solvent
was removed under reduced pressure. The residue was redis-
(23) SHELXTL6.1; Bruker-AXS: Madison, WI, 2000.
(24) PLATON, written by Professor Anthony L. Spek, Bijvoet Centre
for Biomolecular Research, Utrecht University. Current versions
of PLATON for Windows are available from Professor Louis J .
Farrugia, Department of Chemistry, University of Glasgow at
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
under reduced pressure to give 410 mg of product as a white
solid. Yield 98.0%. 1H NMR (C6D6): δ 1.52 (s, 9H, C(CH3)3),
1.62 (s, 9H, C(CH3)3), 1.75 (s, 6H, CH3) 2.07 (s, 6H, CH3), 6.78
(tm, J H-H ) 7.5 Hz, 1H), 6.97 (tm, J H-H ) 8.1 Hz, 2H), 7.14
(dm, 3J H-H ) 8.3 Hz, 2H), 7.21 (s, 1H), 7.28 (s, 1H). NOESY1D
(C6D6): irradiation at 1.52 ppm, NOE response at 7.21 ppm;
irradiation at 1.62 ppm, NOE response at 7.28 ppm; irradiation
at 2.07 ppm, NOE response at 7.21, 7.28 ppm. 13C{1H} NMR
(C6D6): δ 17.10 (CH3), 17.27 (CH3), 20.84 (2xCH3), 31.83 (d,
J C-P ) 5.4 Hz C(CH3)3), 32.41 (C(CH3)3), 35.26 (C(CH3)), 35.59
(C(CH3)), 120.76 (d, J C-P ) 8.0 Hz, o-PhO), 124.10 (p-PhO)
nitrogen. In a typical 70 °C run, 0.153 mL of ligand and 0.153
mL of Rh(CO)2(acac) stock solutions were added to 2.697 mL
of toluene followed by addition of 0.5 mL of allyl cyanide
solution (Rh:allyl cyanide 1:500). This solution was transferred
to the reactor system housed in the inert atmosphere glovebox.
The reactors were pressurized with 150 psi of H2:CO 1:1 and
then heated to 70 °C while stirring at 800 rpm. After 3 h
reactors were cooled, vented, and purged with nitrogen. Upon
opening the reactor 0.1 mL of each reaction mixture was taken
out and diluted with 1 mL of toluene, and this solution was
analyzed by gas chromatography (Astec Chiraldex A-TA
column, temperature program of 90 °C for 7 min, then 5 °C/
min to 180 °C. Retention times: 6.44 min for allyl cyanide,
17.42 and 17.77 min for the enantiomers of the aldehyde-nitrile
branched regioisomer, and 21.78 for the linear aldehyde-nitrile
regioisomer). Reaction mixtures for the runs included in Table
2 were prepared by mixing 3.5 mL of neat allyl cyanide with
catalyst and ligand toluene solutions described above.
3
3
128.24 (CH), 128.64 (CH), 129.91 (m-PhO), 131.35 (d, J C-P
3.4 Hz, quat), 132.28 (quat), 132.28, 132.72 (d, J C-P ) 5.4 Hz,
quat), 133.01 (quat), 134.84 (quat), 135.58 (quat), 138.50 (d,
)
J C-P ) 2.6 Hz), 145.40 (d, J C-P ) 6.0 Hz), 152.62 (d, J C-P
)
7.4 Hz). HSQC (C6D6): δ 1.52/31.83, 1.62/32.41, 1.75/17.10,
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
(ESI, (M + Na)+) (m/z): calcd for C30H37O3PNa 499.2378, found
499.2384. Anal. Calcd for C30H37O3P: C, 75.60; H, 7.83.
Found: C, 75.56; H, 7.86.
Sca le-Up of Asym m etr ic Hyd r ofor m yla tion of Allyl
Cya n id e. A 300 mL mechanically stirred pressure vessel fitted
with a glass liner was charged with [Rh(CO)2(acac)] (160 mg,
0.62 mmol) and (R,R)-Kelliphite (11) (65 mg, 0.68 mmol). The
vessel was sealed and purged three times with nitrogen (145
psi). Allyl cyanide (75 mL, 0.93 mmol, deoxygenated) was
added via the injection port, and the vessel was purged a
further three times with nitrogen (145 psi). The reaction
mixture was stirred at 1,000 rpm and heated to 30 °C. The
vessel was then pressurized with H2/CO (145 psi, 1:1), and the
gas consumption was monitored, recharging the syn gas
pressure as required. After 5 h, gas consumption was complete.
The vessel was vented, purged once with nitrogen (145 psi),
and opened. The crude reaction mixture was obtained with
>99% conversion, 80% ee, b/l 20.1 as determined by chiral GC.
This crude product was used in subsequent reactions without
further purification. NMR spectra were obtained by evapora-
tion of a sample of the reaction mixture to an oil that was
redissolved in CDCl3. NMR data for the linear regioisomers
(aldehyde product and derivatives) were obtained from prod-
ucts prepared by hydroformylation of allyl cyanide (100 mL
allyl cyanide (83.4 g), allyl cyanide:Rh ) 2000:1, 147 psi, 30
°C, neat, ligand:Rh 1:1) using Chiraphite (1) as ligand (b/l 6.6,
20.1% ee). 3-Meth yl-4-oxo-bu tyr on itr ile (4): 1H NMR (400
MHz, CDCl3) δ 1.31 (d, 3H, 3J HH ) 7.5 Hz, CH3), 2.43 (dd, 1H,
P r ep a r a tion of (S,R,S)-(6,6′-(((1,1′-Bip h en yl)-2,2′-d iyl)-
b is(oxy))b is(4,8-b is(1,1-d im et h ylet h yl)-1,2,10,11-t et r a -
m et h yld ib en zo(d ,f)(1,3,2)d ioxa p h osp h ep in -k a p p a P 6))-
(2,4-p en ta n ed ion a to-O,O′)-r h od iu m [(S,R,S)-Kellip h ite
Rh (a ca c)] (19). To a vial was added 150 mg (0.16 mmol) of
(S,S)-6,6′-((1,1′-biphenyl)-2,2′-diylbis(oxy))bis(4,8-bis(1,1-di-
methylethyl)-1,2,10,11-tetramethyl-dibenzo(d,f)(1,3,2)dioxa-
phosphepin (11) and 48.3 mg (0.16 mmol) of [(COD)Rh(acac)].
To this was added 5 mL of toluene, and the yellow solution
was stirred overnight. Solvent was removed under reduced
pressure, leaving 180 mg of product as a yellow solid. 1H NMR
(C6D6): δ 1.24 (s, 6H, acac-CH3), 1.33 (s, 18H, C(CH3)3), 1.85
(s, 6H, CH3), 1.92 (s, 18H, C(CH3)3), 1.97 (s, 6H, CH3), 2.10 (s,
3
6H, CH3), 5.19 (s, 1H, acac-CH), 6.77 (ddd, 2H, J H-H ) 7.2
3
4
3
Hz, J H-H ) 7.5 Hz, J H-H ) 1.5 Hz), 6.84 (ddd, 2H, J H-H
)
)
8.3 Hz, 3J H-H ) 7.5 Hz, 4J H-H ) 2.1 Hz), 6.92 (dd, 2H, 3J H-H
4
7.5 Hz, J H-H ) 2.1 Hz), 7.11 (s, 2H), 7.26 (s, 2H) 7.81 (dd,
3
4
2H, J H-H ) 8.1 Hz, J H-H ) 1.2 Hz), one methyl group
resonance is overlapping with t-Bu peak at 1.92 ppm. 13C{1H}
NMR (C6D6): δ 16.75 (CH3), 17.00 (CH3), 20.32 (CH3), 20.40
(CH3), 27.32 (J C-P ) 5.1 Hz, acac-CH3), 32.12 (C(CH3)), 33.59
(C(CH3)), 35.09 (C(CH3)), 35.77 (C(CH3)), 99.76 (acac-CH),
120.14 (CH), 124.15 (CH), 128.65 (CH), 129.34 (CH), 129.47
(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),
145.52 (t, J C-P ) 7.3 Hz, quat), 146.42 (quat), 150.80 (t,
J C-P ) 6.6 Hz, quat), 184.45 (acac-C-O). HSQC (C6D6): δ 1.24/
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,
7.11/129.47, 7.26/129.34, 7.81/120.14. 31P{1H} NMR (C6D6): δ
2J HH ) 17.1 Hz, 3J HH ) 7.6 Hz, CHHCN), 2.61 (dd, 1H, 2J HH
)
3
17.1 Hz, J HH ) 5.2 Hz, CHHCN), 2.75 (m, 1H, CH), 9.59 (s,
1H, CHO); 13C{1H} NMR (100 MHz, CDCl3) δ 13.3 (CH3). 18.0
(CH2), 42.7 (CH), 118.0 (CN), 200.3 (CHO). 5-Oxo-p en ta n en i-
tr ile (4a ): 1H NMR (400 MHz, CDCl3) δ 1.91 (m, 2H, CH2),
3
3
2.40 (t, 2H, J HH ) 6.9 Hz, CH2CN), 2.63 (t, 2H, J HH ) 7.2
Hz, CH2CHO), 9.74 (s, 1H, CHO); 13C{1H} NMR (100 MHz,
CDCl3) δ 16.6 (CH2), 18.1 (CH2CN), 42.0 (CH2CHO), 117.3
(CN), 200.5 (CHO).
1
130.57 (d, J Rh-P ) 317.3 Hz). HRMS (FAB (positive)) (m/z):
Red u ction of 3-Meth yl-4-oxo-bu tyr on itr ile a n d 5-Oxo-
p en ta n en itr ile. A 300 mL pressure vessel fitted with a glass
liner was charged with 10% platinum on activated carbon (2.7
g, ∼1 mol %), the crude hydroformylation product mixture
containing 3-methyl-4-oxo-butyronitrile and 5-oxo-pentaneni-
trile (11.25 g, 0.116 mol, 80% ee, b/l 20.1) and methanol (50
mL). The vessel was sealed and purged three times with
nitrogen (145 psi). The reaction mixture was then stirred at
room temperature under nitrogen (87 psi) for 30 min in order
to deoxygenate the solvent. After venting, the vessel was
purged twice with hydrogen (145 psi), then charged with
hydrogen (145 psi), and stirred at room temperature, repres-
surizing with hydrogen as necessary. Once consumption was
complete, the vessel was purged once with nitrogen (145 psi)
and opened. The reaction mixture was filtered through Celite,
and the filtrate was concentrated in vacuo to give a dark liquid
in 96% yield with 80% ee and b/l 20.1. The compound was
derivatized in situ with trifluoroacetic anhydride prior to GC
analysis, which was performed on an Astec Chiraldex A-TA
column (30 m × 0.25 mm, 0.25 µm, temperature program 125
calcd for C65H79O8P2Rh 1152.4305, found 1152.4377.
Asym m etr ic Hyd r ofor m yla tion of Allyl Cya n id e. Hy-
droformylation solutions were prepared by addition of ligand
and Rh(CO)2(acac) stock solutions to toluene solvent, followed
by addition of allyl cyanide solution. Ligand solutions (0.06 M
for bidentate ligands and 0.11 M for monodentate ligands) and
Rh(CO)2(acac) (0.05 M) were prepared in the drybox by
dissolving appropriate amount of compound in toluene at room
temperature. The allyl cyanide solution was prepared by
mixing 15.3206 g of allyl cyanide, 3.2494 g of decane (as a GC
internal standard), and 6.3124 g of toluene (1:0.1:0.3 molar
ratio). Hydroformylation reactions were conducted in a reactor
system housed in an inert atmosphere glovebox. The reactor
system consists of eight parallel, mechanically stirred pressure
reactors with individual temperature and pressure controls.
Upon charging the catalyst solutions, the reactors were
pressurized with 150 psi of syn gas (H2:CO 1:1) and then
heated to the desired temperature (35 or 70 °C). The runs were
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
occurred (temperature program: 100 °C for 15 min then 5 °C/
min to 220 °C. Retention times ) 20.7 and 20.9 min for
branched enantiomers). The linear isomer was not observed.
11.63 and 12.20 min for branched enantiomers and 21.0 min
for the linear regioisomer). 4-Hyd r oxy-3-m eth yl-bu tyr on i-
3
tr ile (5): 1H NMR (400 MHz, CDCl3) δ 1.07 (d, 3H, J HH
)
2
6.7 Hz, CH3), 2.06 (m, 1H, CH), 2.38 (dd, 1H, J HH ) 16.5 Hz,
3J HH ) 6.3 Hz, CHHCN), 2.50 (dd, 1H, 2J HH ) 16.5 Hz, 3J HH
)
2-Meth yl-4-a m in obu ta n ol (6): H NMR (400 MHz, CDCl3)
1
2
3
3
5.6 Hz, CHHCN), 3.49 (dd, 1H, J HH ) 10.9 Hz, J HH ) 7.5
δ 0.90 (d, 3H, J HH ) 6.5 Hz, CH3), 1.77-1.61 (m, 1H, CH),
2
3
Hz, CHHOH), 3.65 (dd, 1H, J HH ) 10.9 Hz, J HH ) 5.0 Hz,
CHHOH); 13C{1H} NMR (100 MHz, CDCl3) δ 14.9 (CH3), 19.9
(CH2CN), 31.9 (CH), 64.8 (CH2OH), 117.7 (CN). NMR data are
identical to those reported in the literature.25 5-Hyd r oxy-
p en ta n en itr ile (5a ): 1H NMR (400 MHz, CDCl3) δ 1.75 (m,
4H, CH2CH2), 2.41 (t, 2H, 3J HH ) 6.3 Hz, CH2CN), 3.70 (t, 2H,
3J HH ) 6.0 Hz, CH2OH); 13C{1H} NMR (100 MHz, CDCl3) δ
16.0 (CH2CH2CN), 21.0 (CH2CN), 30.3 (CH2CH2OH), 60.6
(CH2OH), 118.7 (CN).
1.53-1.46 (m, 2H, CH2), 2.65-2.52 (m, 1H, CHHNH2), 2.82-
2
3
2.69 (m, 1H, CHHNH2), 3.33 (dd, 1H, J HH ) 11.0 Hz, J HH
)
2
3
7.6 Hz, CHHOH), 3.45 (dd, 1H, J HH ) 11.0 Hz, J HH ) 4.5
Hz, CHHOH), 4.05 (br s); 13C{1H} NMR (100 MHz, CDCl3) δ
17.8 (CH3), 35.3 (CH2), 35.6 (CH), 47.8 (CH2NH2), 68.2 (CH2-
OH). NMR and GC data of this sample are identical to those
obtained from commercially available sample.
Gen er a l Meth od for Cr ysta lliza tion Scr een . A scintil-
lation vial was charged with 2-methyl-4-aminobutanol (130
mg, 1.26 mmol), ethanol (2 mL), and the desired acid (1 or 2
equiv). The solution was stirred for 24 h at room temperature.
If no precipitation was observed, ethanol was removed in vacuo
and replaced with 2-propanol (1.5 mL). If precipitation was
still not observed after an additional 24 h, 2-propanol was
removed in vacuo and replaced with ethyl acetate (1.5 mL). If
no precipitation was obtained after an additional 24 h, ethyl
acetate was removed in vacuo and replaced with MTBE (1.5
mL). Any crystalline salts that formed were filtered off. These
salts were then cracked with IRN78 resin using the method
described above. The resulting free amines were then analyzed
for enantiomeric excess by chiral GC.
F or m a tion of 2-Meth yl-4-a m in obu ta n ol (6). A 300 mL
pressure vessel fitted with a glass liner was charged with a
mixture of 4-hydroxy-3-methyl-butyronitrile and 5-hydroxy-
pentanenitrile (20.1:1, 5.07 g, 51.2 mmol), oxalic acid dihydrate
(6.44 g, 51.2 mmol), 10% platinum on activated carbon (1.03
g), and methanol (100 mL). The vessel was sealed and purged
3 times with nitrogen (145 psi). The vessel was then heated
to 60 °C, and the reaction mixture was stirred under nitrogen
(145 psi) for 30 min in order to deoxygenate the solvent. After
venting, the vessel was purged twice with hydrogen (145 psi),
then charged with hydrogen (145 psi) and stirred at 60 °C,
repressurizing with hydrogen as necessary. Once consumption
was complete, the vessel was cooled to room temperature,
purged once with nitrogen, and opened. The reaction mixture
was filtered through Celite that had been prewashed with
methanol. IRN78 resin (45 g, 4meq/g) was added, and the
reaction mixture was stirred at room temperature for 48 h.
The resin was filtered off and washed with methanol (50 mL)
and water (40 mL). The filtrate was concentrated on a rotary
evaporator to give crude 2-methyl-4-aminobutanol as a yellow
oil (76% with 80% ee). The compound was derivatized in situ
with trifluoroacetic anhydride prior to enantioselectivity de-
Ack n ow led gm en t. We are grateful to Drs. Cynthia
Rand, Ian Lennon, Robert Appell, and Chris Goralski
from Dowpharma for useful discussions and sugges-
tions.
Su p p or tin g In for m a tion Ava ila ble: Preparation proce-
dures for compounds 12, 13, 14, 16, and 17; stereoview of 9;
NMR spectra of compounds 4, 9, and 19; and crystallographic
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
1993, 4, 973.
J O040128P
4040 J . Org. Chem., Vol. 69, No. 12, 2004