P-chirogenic α-carboxyphosphine boranes as effective pre-ligands in palladium-catalyzed asymmetric reactions

Article abstract of DOI:10.1055/s-2006-956465

P-Chirogenic α-carboxyphosphine boranes have been applied directly as pre-ligands in palladium-catalyzed asymmetric allylic alkylation and amination reactions, with in situ deprotection of the borane moiety. Using dimethylmalonate as the nucleophile afforded the alkylated product in up to 91% ee, while reaction with benzylamine gave amination in up to 94% ee. In both cases, the opposite enantiomer could be accessed in high ee by using the antipode of the ligand, easily accessible by exchanging (-)-sparteine for a (+)-sparteine mimic in the desymmetrization process used for preparing the ligands. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-956465

LETTER
3389
P-Chirogenic a-Carboxyphosphine Boranes as Effective Pre-Ligands in
Palladium-Catalyzed Asymmetric Reactions
P
a
-Chirogenic
a
r
-Carbox
a
yphosphine
n
Borane
s
in
c
Pd-Catalyz
k
ed
A
A
A
Dolhem,a Magnus J. Johansson,a Thomas Antonsson,b Nina Kann*a
Organic Chemistry, Department of Chemical and Biological Engineering, Chalmers University of Technology, 41296 Göteborg, Sweden
Fax +46(31)7723657; E-mail: kann@chalmers.se
b
Medicinal Chemistry, AstraZeneca R&D Mölndal, 43183 Mölndal, Sweden
Received 6 July 2006
H
H
N
N
N
H
Abstract: P-Chirogenic a-carboxyphosphine boranes have been
applied directly as pre-ligands in palladium-catalyzed asymmetric
allylic alkylation and amination reactions, with in situ deprotection
of the borane moiety. Using dimethylmalonate as the nucleophile
afforded the alkylated product in up to 91% ee, while reaction with
benzylamine gave amination in up to 94% ee. In both cases, the op-
posite enantiomer could be accessed in high ee by using the anti-
pode of the ligand, easily accessible by exchanging (–)-sparteine for
a (+)-sparteine mimic in the desymmetrization process used for pre-
paring the ligands.
N
(–)-sparteine
(+)-1
Figure 1
ranes, affording the corresponding P-chirogenic ligand in
up to 92% ee.8
Key words: asymmetric catalysis, allylic alkylation, allylic amina-
By using carbon dioxide as the electrophile in the Evans’
desymmetrization, a-carboxyphosphines can be prepared,
and Imamoto et al. have used such derivatives as interme-
diates in the preparation of P-chirogenic bisphosphine
ligands.9 Although a few examples of chiral a-carboxy-
phosphine ligands that are not P-chirogenic have been de-
scribed,10 there are to our knowledge only two reports of
the use of the corresponding P-chiral a-carboxyphosphine
ligands in catalytic asymmetric reactions. Hii and co-
workers recently described two diarylic P-chirogenic a-
carboxyphosphines and their application in palladium-
catalyzed asymmetric allylic alkylation (AAA) with up to
81% ee.11 Kobayashi and co-workers have also reported
one example of a cyclic P-chirogenic phosphine carboxy-
lic acid in AAA in 77% ee.12 In the latter case, however,
optical resolution with quinine was required to obtain
enantiopure ligand. These two reports prompted us to dis-
close our recent results using P-chirogenic alkyl and aryl
phosphine borane carboxylic acids directly as pre-ligands
in asymmetric allylic alkylation and amination reactions
catalyzed by palladium, with in situ deprotection of the
phosphine borane.
tion, phosphine ligands, P-chiral
P-Chirogenic phosphine ligands in asymmetric catalysis
are a useful alternative to phosphine ligands with chirality
situated in the surrounding carbon skeleton.1 Several
routes are available for the formation of P-chirogenic
phosphines. Jugé and Genêt used ephedrine as a chiral
auxiliary in a practical method that affords highly enan-
tiopure phosphine, but requires several steps for the trans-
formation.2 A one-pot method was reported by Evans in
1995, involving the asymmetric deprotonation of borane-
protected prochiral dimethyl aryl phosphine using (–)-
sparteine–alkyllithium complexes (Scheme 1).3
OH
BH3
P
BH3
P
1) s-BuLi·(–)-sparteine
Ph
Ph
Ar
Ar
2) Ph2CO
up to 87% ee
Scheme 1 Evans’ method for the desymmetrization of prochiral
phosphine boranes.
The a-carboxyphosphine boranes (Figure 2) were pre-
pared in one step from the corresponding prochiral
dimethyl phosphine boranes13 via asymmetric deprotona-
tion with sec-butyllithium and (–)-sparteine followed by
quenching with carbon dioxide (Scheme 2),14 affording
enantioenriched pre-ligands 3a–i.15 Purification via re-
crystallization improved the initial enantioselectivity ob-
tained to 90–96% ee in most cases with the exception of
the more sterically hindered ligands 3e,h,i, where lower
enantioselectivities were obtained. For R = tert-butyl, the
antipode of the ligand was also synthesized by exchanging
(–)-sparteine for (+)-1, providing pre-ligand 4.16
The latter method has been further extended by Living-
house in the dynamic kinetic resolution of a racemic sec-
ondary phosphine borane.4 However, both these methods
suffer from the unavailability of (+)-sparteine, and there
are in general few examples of methods where both enan-
tiomers of a P-chirogenic phosphine ligand are prepared.5
We have shown that O’Brien’s (+)-sparteine mimic, (+)-1
(Figure 1),6 derived from easily accessible (–)-cytisine,7
can be applied in the desymmetrization of phosphine bo-
SYNLETT 2006, No. 20, pp 3389–3394
Advanced online publication: 08.12.2006
DOI: 10.1055/s-2006-956465; Art ID: D19606ST
© Georg Thieme Verlag Stuttgart · New York
1
8
.1
2
.2
0
0
6
The phosphine boranes were subsequently applied direct-
ly in the palladium-catalyzed asymmetric allylic alkyla-

3390
F. Dolhem et al.
LETTER
O
O
O
O
O
BH3
BH3
P
BH3
P
BH3
P
BH3
P
P
OH
OH
OH
OH
OH
Fe
3b
3e
3c
3d
3a
O
O
O
O
BH3
P
BH3
P
BH3
P
BH3
P
OH
OH
OH
OH
MeO
3f
3h
3g
3i
Figure 2 P-Chirogenic a-carboxyphosphine boranes 3a–i used as pre-ligands in the asymmetric allylic alkylation and amination reactions.
Table 1 Optimization of Conditions for Palladium-Catalyzed AAA
Using Ligand 3a and Acetate 5
1) s-BuLi·(–)-sparteine
O
BH3
P
Et2O, –78 °C, 1 h
OH
Pd(OAc)2 (5 mol%)
OAc
R
2) CO2, –78 °C to r.t., 1 h
MeO2C
CO2Me
Ph
3a (9.5–20 mol%)
BH3
P
3a–i
Ph
Ph
CH2(CO2Me)2
BSA, THF
Ph
R
racemic 5
BH3
P
1) s-BuLi·(+)-1
2a–i
Entry Ratio
Additive Time
(h)
Temp
(°C)
Conv.
ee
O
Et2O, –78 °C, 1 h
(%)a
(%)b
R
3a:Pd
2) CO2, –78 °C to r.t., 1 h
OH
4 (R = t-Bu)
1
2
3
4
5
2
KOAc
36
16
20
12
12
20
20
0
33
47
63
91
89
86
4
KOAc
99
Scheme 2 Preparation of P-chirogenic a-carboxyphosphine bora-
nes 3a–i and 4. See Figure 2 for structures of 3a–i.
2
–
–
–
30
1.9
4
20
20
100
100
tion of 1,3-diphenylpropenyl acetate with dimethyl
malonate.17 To avoid an extra step, the in situ deborona-
tion method of Jugé and co-workers was applied, where
Pd(II) is reduced to Pd(0) by the phosphine–borane com-
plex with concomitant deprotection of the phosphine.18
This also evades handling of the air-sensitive free phos-
phine ligand. Some initial optimization studies were car-
a Conversion measured by HPLC.
b Enantiomeric excess measured by chiral HPLC, see experimental
part for details.
ried out with pre-ligand 3a to determine the optimal 89% ee. The enantiomeric product could be prepared in
conditions for the reaction (Table 1).
86% ee by employing ligand 4 (entry 11). Somewhat sur-
prisingly, ligand 3c with a cyclohexyl substituent, also af-
forded the opposite enantiomer and we have no good
explanation for this observation.
The highest enantioselectivity (entry 3, 91%), was at-
tained using a ligand-to-Pd ratio of 2 at 0 °C. The rather
low conversion at this temperature was not practical, how-
ever, and we opted instead for running the reaction at Asymmetric alkylations with the corresponding carbonate
room temperature. A ligand to metal ratio of 1.9 equiva- 6 were also pursued (Table 3). A similar trend was seen in
lents (entry 4) gave a slightly better selectivity than run- that ligands 3a and 4 gave the best results, affording the
ning the reaction with 4 equivalents (entry 5), while the two enantiomeric products in 91% and 88% ee, respec-
addition of potassium acetate (entries 1 and 2) was detri- tively (entries 1 and 10). In this case, not only ligands 3c
mental for the enantioselectivity. Therefore, these opti- (entry 3) and 4 gave the opposite product enantiomer, but
mized conditions were used to scan through the different ligand 3i (entry 9) also afforded the S-enantiomer. This is
a-carboxyphosphine boranes (Table 2).19
less surprising, however, as the corresponding reaction
with the acetate 5 (Table 2, entry 10) gave racemic prod-
uct.
Enantioselectivities were moderate (40–64% ee) with
ligands 3b and 3d–f (entries 2, 3 and 5–7), while the biaryl
ligand 3g gave an ee of only 9% (entry 8). The more ster- Exchanging the malonate for an amine nucleophile like
ically hindered ligands 3h and 3i (entries 9 and 10) gave benzylamine gives access to a different product class and
low conversion and racemic product. Best results were we therefore applied the two best pre-ligands, 3a and 4, in
obtained with the tert-butyl-substituted ligand 3a (entry 1) the palladium-catalyzed asymmetric allylic amination of
substrates 5 and 6 (Table 4).20,21 Due to the high intrinsic
which afforded the chiral malonyl-substituted product in
Synlett 2006, No. 20, 3389–3394 © Thieme Stuttgart · New York

LETTER
P-Chirogenic a-Carboxyphosphine Boranes in Pd-Catalyzed AAA
3391
Table 4 Palladium-Catalyzed Asymmetric Allylic Aminations of
Acetate 5 and Carbonate 6
Table 2 Palladium-Catalyzed Asymmetric Allylic Alkylation with
Acetate 5
Pd(OAc)2 (5 mol%)
OAc
Pd(OAc)2 (5 mol%)
HN
Ph
MeO2C
CO2Me
Ph
ligand (9.5 mol%)
ligand (9.5 mol%)
5 or 6
*
Ph
Ph
Ph
Ph
*
benzylamine, THF
12 h
CH2(CO2Me)2
BSA, THF
Ph
racemic 5
Conv. (%)a
100
30
ee (%)b
89 (R)
40 (R)
50 (R)
44 (S)
60 (R)
64 (R)
47 (R)
9 (R)
0
Entry Ligand
Substrate Temp. (°C) Conv. (%)a ee (%)b
Entry
Ligand
3a
Time (h)
12
1
2
3
4
5
3ac
3a
3a
4d
5
5
6
5
5
20
5
100
100
99
76 (S)
94 (S)
60 (S)
66 (R)
87 (R)
1
2
3bc
3bd
3cd
3d
16
20
20
5
3
36
60
95
4
16
95
4
95
5
16
85
a Conversion measured by HPLC.
6
3e
12
100
100
42
b Enantiomeric excess measured by chiral HPLC, see experimental
7
3f
12
part.
c Ligand to metal ratio 2.2.
d Ligand to metal ratio 2.
8
3g
24
9
3h
12
33
reactivity of the nucleophile in this case, the reaction
could be carried out at 5 °C and still give complete con-
version, affording the amine-substituted product in up to
94% ee (entry 1). The other enantiomer was prepared in a
somewhat lower, but still respectable, 87% ee (entry 5).
10
11
3i
12
12
0
4
12
100
86 (S)
a Conversion measured by HPLC.
b Enantiomeric excess measured by chiral HPLC, see experimental
part for details.
To investigate if the ligands were acting in a bidentate
chelating fashion or as monodentate ligands, NMR studies
were carried out. 13C NMR on a complex formed using a
2:1 ligand-to-metal ratio in CD2Cl2 showed six signals in
the region of d = 120–150 ppm which could correspond to
the four aromatic and two different allylic carbons of a
symmetrically substituted p-allyl diphosphine complex.
The singlet arising from the carboxyl group remained at
d = 174 ppm, corresponding to that of the free ligand.
These observations, together with the fact that the use of
one equivalent of ligand was detrimental to the reaction,
lead us to believe that the phosphine is in fact coordinating
to palladium in a monodentate fashion, with two ligands
attached to each metal atom. Further studies are underway
to clarify this issue.
c Ligand to metal ratio 1.
d Ligand to metal ratio 2.
Table 3 Palladium-Catalyzed Asymmetric Allylic Alkylation of
Carbonate 6
O
Pd(OAc)2 (5 mol%)
MeO2C
CO2Me
Ph
O
OEt
ligand (9.5 mol%)
*
Ph
Ph
CH2(CO2Me)2
BSA, THF
Ph
racemic 6
Entry
Ligand
3a
3b
3c
Time (h)
12
Conv. (%)a
100
85
ee (%)b
91 (R)
27 (R)
26 (S)
40 (R)
64 (R)
44 (R)
30 (R)
0
1
2
In conclusion, we have shown that enantioenriched P-chi-
rogenic dialkyl and alkyl aryl a-carboxyphosphine bo-
ranes, easily prepared in one step from non-chiral starting
materials, are efficient pre-ligands in the palladium-cata-
lyzed asymmetric allylic alkylation and amination of race-
mic 1,3-diphenylpropenyl acetate and carbonate with
stereoselectivities of up to 94% ee. The opposite enantio-
mer of the product can be easily accessed by use of the
phosphine ligand antipode.
16
3
16
90
4
3d
3e
16
85
5
12
100
100
100
60
6
3f
12
7
3g
3h
3i
12
8
12
Acknowledgment
9
12
10
6 (S)
We thank AstraZeneca R&D Mölndal, Chalmers University of
Technology and the Swedish Foundation for Strategic Research for
the financing of this project. Lena von Sydow and Gustaf Hulthe are
kindly acknowledged for assistance with MS analysis. We thank
Prof. Jan Kihlberg for his interest in this project.
10
4
12
100
88 (S)
a Conversion measured by HPLC.
b Enantiomeric excess measured by chiral HPLC, see experimental
part for details.
Synlett 2006, No. 20, 3389–3394 © Thieme Stuttgart · New York

3392
F. Dolhem et al.
LETTER
2383, 1466, 1433, 1300, 1064, 952, 921 cm–1. 1H NMR
References and Notes
(CDCl3): d = 1.22 (d, J = 10.0 Hz, 6 H), 7.24–7.52 (m, 8 H),
7.97 (dd, J = 13.6, 8.8 Hz, 1 H). 13C NMR (CDCl3): d =
13.76 (d, J = 39.4 Hz), 127.48 (d, J = 11.4 Hz), 127.97 (s),
128.10 (s), 128.79 (d, J = 50.0 Hz), 129.53 (s), 130.56 (d,
J = 2.2 Hz), 131.24 (d, J = 6.1 Hz), 133.61 (d, J = 15.9 Hz),
141.09 (d, J = 2.3 Hz), 146.29 (d, J = 2.3 Hz). Anal. Calcd
for C14H18BP: C, 73.72; H, 7.95. Found: C, 73.64; H, 8.06.
P,P-Dimethyl[3,5-di(tert-butyl)-6-methoxyphenyl]phos-
phine Sulfide (Precursor to 2h)
White powder; 25% yield; mp 150–155 °C. IR (KBr): n =
2970, 2840, 1590, 1576, 1475, 1270, 1240, 1000, 920 cm–1.
1H NMR (CDCl3): d = 1.33 (s, 18 H), 1.86 (d, J = 13.2 Hz, 6
H), 3.60 (s, 3 H), 7.63 (d, J = 14.0 Hz, 2 H). 13C NMR
(CDCl3): d = 23.21 (d, J = 56.9 Hz), 32.00 (s), 36.20 (s),
64.54 (s), 126.90 (d, J = 83.5 Hz), 128.58 (d, J = 12.9 Hz),
144.36 (d, J = 12.1 Hz), 162.55 (d, J = 3.8 Hz). Anal. Calcd
for C17H29OPS: C, 65.35; H, 9.36. Found: C, 65.12; H, 9.27.
P,P-Dimethyl[3,5-di(tert-butyl)-6-methoxyphenyl]phos-
phineborane (2h)
White powder; 79% yield; mp 120–126 °C. IR (KBr): n =
2960, 2367, 1500, 1400, 1230, 1150, 1067, 1006, 930 cm–1.
1H NMR (CDCl3): d = 1.45 (s, 18 H), 1.55 (d, J = 10.0 Hz, 6
H), 3.72 (s, 3 H), 7.59 (d, J = 11.6 Hz, 2 H). 13C NMR
(CDCl3): d = 13.14 (d, J = 38.7 Hz), 31.68 (s), 35.83 (s),
64.15 (s), 123.66 (d, J = 58.5 Hz), 129.14 (d, J = 11.4 Hz),
144.22 (d, J = 9.9 Hz), 162.0 (br s). Anal. Calcd for
C17H32BOP: C, 69.40; H, 10.96. Found: C, 69.26; H, 11.07.
P,P-Dimethyl[2,4,6-tri(isopropyl)phenyl]phosphine-
borane (2i).
(1) For some recent reviews on P-chirogenic phosphine ligands,
see: (a) Ohff, M.; Holz, J.; Quirmbach, M.; Börner, A.
Synthesis 1998, 1391. (b) Crépy, K. V. L.; Imamoto, T. Adv.
Synth. Catal. 2003, 345, 79. (c) Crépy, K. V. L.; Imamoto,
T. Top. Curr. Chem. 2003, 229, 1. (d) Johansson, M. J.;
Kann, N. C. Mini-Rev. Org. Chem. 2004, 1, 233.
(2) Jugé, S.; Stephan, M.; Laffitte, J. A.; Genêt, J. P.
Tetrahedron Lett. 1990, 31, 6357.
(3) Muci, A. R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc.
1995, 117, 9075.
(4) (a) Wolfe, B.; Livinghouse, T. J. Am. Chem. Soc. 1998, 120,
5116. (b) Heath, H.; Wolfe, B.; Livinghouse, T.; Bae, S. K.
Synthesis 2001, 2341.
(5) For some examples, see: (a) Hoge, G. J. Am. Chem. Soc.
2003, 125, 10219. (b) Liu, D.; Zhang, X. Eur. J. Org. Chem.
2005, 646. (c) Wiktelius, D.; Johansson, M. J.; Luthman, K.;
Kann, N. Org. Lett. 2005, 7, 4991.
(6) (a) Dearden, M. J.; Firkin, C. R.; Hermet, J. P. R.; O’Brien,
P. J. Am. Chem. Soc. 2002, 124, 11870. (b) Hermet, J. P. R.;
Porter, D. W.; Dearden, M. J.; Harrison, J. R.; Koplin, T.;
O’Brien, P.; Parmene, J.; Tyurin, V.; Whitwood, A. C.;
Gilday, J.; Smith, N. M. Org. Biomol. Chem. 2003, 1, 3977.
(c) Dearden, M. J.; McGrath, M. J.; O’Brien, P. J. Org.
Chem. 2004, 69, 5789.
(7) Marriere, E.; Rouden, J.; Tadino, V.; Lasne, M.-C. Org. Lett.
2000, 2, 1121.
(8) (a) Johansson, M. J.; Schwartz, L. O.; Amedjkouh, M.;
Kann, N. C. Eur. J. Org. Chem. 2004, 1894. (b) Johansson,
M. J.; Schwartz, L.; Amedjkouh, M.; Kann, N. Tetrahedron:
Asymmetry 2004, 15, 3531. (c) See also: McGrath, M. J.;
O’Brien, P. J. Am. Chem. Soc. 2005, 127, 16378.
(9) (a) Ohashi, A.; Imamoto, T. Tetrahedron Lett. 2001, 42,
1099. (b) Ohashi, A.; Kikuchi, S.; Yasutake, M.; Imamoto,
T. Eur. J. Org. Chem. 2002, 2535. (c) Danjo, H.; Higuchi,
M.; Yada, M.; Imamoto, T. Tetrahedron Lett. 2004, 45, 603.
(10) See for example: (a) Minami, T.; Okada, Y.; Otaguro, T.;
Tawaraya, S.; Furuichi, T.; Okauchi, T. Tetrahedron:
Asymmetry 1995, 6, 2469. (b) Okauchi, T.; Fujita, K.;
Ohtaguro, T.; Ohshima, S.; Minami, T. Tetrahedron:
Asymmetry 2000, 11, 1397. (c) Ebran, J. P.; Jubault, P.;
Pannecoucke, X.; Quirion, J. C. Tetrahedron: Asymmetry
2003, 14, 1637.
White powder; 60% yield; mp 158–162 °C. IR (KBr): n =
2961, 2370, 1601, 1555, 1458, 1150, 1074, 939 cm–1. 1H
NMR (CDCl3): d = 1.10 (br m, 3 H), 1.26 (d, J = 7.2 Hz, 6
H), 1.27 (d, J = 6.8 Hz, 12 H), 1.75 (d, J = 9.6 Hz, 6 H), 2.89
(q, J = 6.8 Hz, 1 H), 3.88 (q, J = 6.8 Hz, 2 H), 7.09 (d, J = 3.2
Hz, 2 H). 13C NMR (CDCl3): d = 16.94 (d, J = 41.0 Hz),
23.58 (s), 25.07 (s), 30.56 (d, J = 6.1 Hz), 34.03 (s), 121.0 (d,
J = 49.8 Hz), 123.12 (d, J = 8.3 Hz), 151.75 (d, J = 2.3 Hz),
154.33 (d, J = 9.1 Hz). Anal. Calcd for C17H32BP: C, 73.39;
H, 11.59. Found: C, 73.31; H, 11.68.
(14) Compounds 3a–d were prepared according the literature,22,23
affording ligands of the following enantiopurity as
determined by reduction to the corresponding alcohol: 3a
(96%), 3b (85%), 3c (90%), 3d (92%).
(11) Lam, H.; Horton, P. N.; Hursthouse, M. B.; Aldous, D. J.;
Hii, K. K. Tetrahedron Lett. 2005, 46, 8145.
General Procedure for 3e–i
To a solution of (–)-sparteine or (+)-1 (1.12 equiv) in anhyd
Et2O (2.5 mL/mmol) under argon at –78 °C was added a 1.3
M solution (1.1 equiv) of sec-BuLi in hexane. The mixture
was stirred for 30 min at –78 °C before the slow addition of
a Et2O solution (3 mL/mmol) of the prochiral phosphine
borane. The mixture was stirred at –78 °C for 3 h before CO2
was bubbled through the solution. The flask was slowly
warmed up to r.t. over a period of 1 h and then acidified with
1 M HCl. The aqueous layer was extracted with EtOAc
(3 ×). The pH of the combined organic layers was adjusted
to pH 12 using sat. Na2CO3. After phase separation, the
aqueous layer was acidified with HCl and extracted with
EtOAc. The organic layer was washed with brine, dried over
Na2SO4, filtered and concentrated to afford the P-chirogenic
a-carboxyphosphine boranes. To measure the enantiomeric
excess, the ligands were first reduced to their corresponding
alcohol using BH3·DMS, and then subjected to analysis by
HPLC on a Chiralcel OD-H column, eluting with n-hexane–
i-PrOH.
(12) Sun, X. M.; Manabe, K.; Lam, W. W. L.; Shiraishi, N.;
Kobayashi, J.; Shiro, M.; Utsumi, H.; Kobayashi, S. Chem.
Eur. J. 2005, 11, 361.
(13) Compounds 2a,c,d,22 2b,23 2e24 and 2f3 were prepared as
described in the literature. Compounds 2g and 2h were
prepared via the corresponding phosphine sulfides using the
same procedure as for 2f.3 Compound 2i was prepared from
PCl3 and 2,4,6-tri(isopropyl)-1-phenylmagnesium bromide,
following a literature procedure.25
P,P-Dimethyl(2-biphenyl)phosphine Sulfide (Precursor
to 2g)
Waxy solid; 89% yield; mp 99–101 °C. IR (KBr): n = 2986,
2873, 1770, 1458, 1383, 1140 cm–1. 1H NMR (CDCl3): d =
1.58 (d, J = 13.2 Hz, 6 H), 7.18–7.47 (m, 8 H), 8.20–8.27 (m,
1 H). 13C NMR (CDCl3): d = 23.56 (d, J = 56.9 Hz), 127.39
(d, J = 12.2 Hz), 127.87, 128.05, 129.54, 130.80 (d, J = 3.1
Hz), 131.23 (d, J = 9.1 Hz), 131.96 (d, J = 75.8 Hz), 132.23
(d, J = 12.1 Hz), 140.88 (d, J = 3.1 Hz), 144.07 (d, J = 8.3
Hz). Anal. Calcd for C14H15PS: C, 68.27; H, 6.14. Found: C,
68.21; H, 6.10.
(15) (S)-(–)-Mesityl(ethanoic acid)methylphosphine-borane
(3e)
P,P-Dimethyl(2-biphenyl)phosphineborane (2g)
White powder; 90% yield; mp 91–93 °C. IR (KBr): n = 2918,
Transparent gel; 90% yield. IR (KBr): n = 3100, 2960, 2720,
2520, 2170, 1705, 1640, 1340, 1180, 995 cm–1. 1H NMR
Synlett 2006, No. 20, 3389–3394 © Thieme Stuttgart · New York

LETTER
P-Chirogenic a-Carboxyphosphine Boranes in Pd-Catalyzed AAA
3393
(CDCl3): d = 1.1 (m, 3 H), 1.88 (d, J = 9.2 Hz, 3 H), 2.24 (s,
mp 116–123 °C. IR (KBr): n = 3000, 2414, 1834, 1713,
1500, 1424, 1260, 1130, 920, 840, 800, 770 cm–1. 1H NMR
(CDCl3): d = 1.20 (br m, 3 H), 1.26 (d, J = 6.8 Hz, 6 H), 1.26
(dd, J = 6.4, 4.8 Hz, 12 H), 1.90 (d, J = 8.8 Hz, 3 H), 2.89 (q,
J = 6.8 Hz, 1 H), 3.13 (d, J = 9.6 Hz, 2 H), 3.85 (dq, J = 6.8,
3 H), 2.55 (s, 6 H), 2.98 (dd, J = 14.0, 9.6 Hz, 1 H), 3.18 (dd,
J = 14.0, 9.6 Hz, 1 H), 6.85 (d, J = 3.2 Hz, 2 H), 10.96 (br s,
1 H). 13C NMR (CDCl3): d = 15.9 (d, J = 39.5 Hz), 21.04 (s),
24.10 (d, J = 4.6 Hz), 35.61 (d, J = 27.3 Hz), 121.14 (d,
J = 47.0 Hz), 131.38 (d, J = 9.1 Hz), 141.16 (d, J = 3.1 Hz),
143.26 (d, J = 9.9 Hz), 173.69 (d, J = 4.5 Hz). [a]D21 –15.0
(c 1, CHCl3, 80% ee). Anal. Calcd for C12H20BO2P: C,
60.54; H, 8.47. Found: C, 60.28; H, 8.43. Retention times for
alcohol (90% n-hexane, 10% i-PrOH): 0.5 mL/min, 228 nm,
tR (–) = 19.4 min, tR (+) = 20.4 min.
2.0 Hz, 2 H), 7.10 (d, J = 3.2 Hz, 2 H), 8.90 (br s, 1 H). 13
C
NMR (100 MHz, CDCl3): d = 16.15 (d, J = 40.2 Hz), 23.79
(s), 25.26 (d, J = 11.4 Hz), 30.84 (d, J = 6.0 Hz), 34.30 (s),
36.53 (d, J = 28.1 Hz), 120.14 (d, J = 47.8 Hz), 123.76 (d,
J = 9.1 Hz), 152.76 (s), 155.04 (d, J = 9.9 Hz), 173.4 (d,
J = 3.0 Hz). [a]D21 –3.6 (c 1, CHCl3, 71% ee). Anal. Calcd
for C18H32BO2P: C, 67.09; H, 10.01. Found: C, 66.87; H,
9.89. Retention times for alcohol (99% n-hexane, 1% i-
PrOH): 0.75 mL/min, 227 nm, tR (–) = 24.25 min, tR
(+) = 25.91 min.
(S)-(+)-1-Naphtyl(ethanoic acid)methylphosphine-
borane (3f)
Recrystallized from n-hexane–Et2O; white solid, 86% yield;
mp 92–98 °C. IR (KBr): n = 3000, 2414, 1834, 1713, 1500,
1424, 1260, 1130, 920, 840, 800, 770 cm–1. 1H NMR
(CDCl3): d = 1.1 (br m, 3 H), 1.95 (d, J = 9.6 Hz, 3 H), 3.09
(dd, J = 13.6, 9.2 Hz, 1 H), 3.31 (dd, J = 13.6, 10.8 Hz, 1 H),
7.49 (dt, J = 8.8, 1.6 Hz, 1 H), 7.55 (dt, J = 8.8, 0.8 Hz, 1 H),
7.63 (dt, J = 8.8, 1.2 Hz, 1 H), 7.87 (dd, J = 7.2, 0.8 Hz, 1 H),
7.91 (d, J = 7.6 Hz, 1 H), 7.99 (d, J = 8.4 Hz, 1 H), 8.40 (d,
J = 8.4 Hz, 1 H), 10.00 (br s, 1 H). 13C NMR (CDCl3): d =
11.14 (d, J = 39.5 Hz), 33.86 (d, J = 25.8 Hz), 123.79 (d,
J = 50.1 Hz), 124.8 (d, J = 12.2 Hz), 125.18 (d, J = 6.8 Hz),
126.46 (s), 127.36 (s), 129.64 (s), 132.75 (d, J = 10.6 Hz),
132.85 (d, J = 9.1 Hz), 133.20 (d, J = 2.3 Hz), 133.71 (d,
J = 6.9 Hz), 173.01 (d, J = 5.3 Hz). [a]D21 +24.0 (c 1, CHCl3,
94% ee). Anal. Calcd for C13H16BO2P: C, 63.46; H, 6.55.
Found: C, 63.34; H, 6.43. Retention times for alcohol (90%
n-hexane, 10% i-PrOH): 1 mL/min, 224 nm, tR (+) = 16.99
min, tR (–) = 20.38 min.
(16) (S)-(–)-tert-Butyl(ethanoic acid)methylphosphine-
borane (4)
Recrystallized from n-hexane–Et2O; white solid; 86% yield;
mp 107–112 °C. IR (KBr): n = 2970, 2910, 2370, 1705,
1295, 925 cm–1. 1H NMR (CDCl3): d = 0.42 (br q, J = 88.0
Hz, 3 H), 1.19 (dd, J = 14.4, 4.0 Hz, 9 H), 1.41 (dd, J = 10.0,
3.6 Hz, 3 H), 2.72 (m, 2 H), 9.93 (br s, 1 H). 13C NMR
(CDCl3): d = 5.67 (d, J = 32.4 Hz), 24.96 (s), 28.15 (d,
J = 31.9 Hz), 29.26 (d, J = 21.3 Hz), 174.17 (d, J = 4.5 Hz).
[a]D21 –9.2 (c 1, CHCl3, 90% ee). Anal. Calcd for
C7H18BO2P: C, 47.77; H, 6.14. Found: C, 47.86; H, 10.30.
(17) For a comprehensive review on this reaction, see: (a) Trost,
B. M.; VanVranken, D. L. Chem. Rev. 1996, 96, 395. For
some more recent reviews, see: (b) Trost, B. M. Chem.
Pharm. Bull. 2002, 50, 1. (c) Trost, B. M. J. Org. Chem.
2004, 69, 5813. (d) Kazmaier, U.; Pohlman, M. In Metal-
Catalyzed Cross-Coupling Reactions; de Meijere, A.;
Diederich, F., Eds.; Wiley-VCH: Weinheim Germany, 2004,
Chap. 9. (e) Heumann, A. In Transition Metals for Organic
Synthesis; Beller, M.; Bolm, C., Eds.; Wiley-VCH:
Weinheim, 2004, Chap. 2.14. (f) For some mechanistic
considerations, see: Amatore, C.; Gamez, S.; Jutand, A.
Chem. Eur. J. 2001, 7, 1273.
(S)-(+)-[(2-Phenyl)phenyl](ethanoic
acid)methylphosphine-borane (3g)
Recrystallized from n-hexane–Et2O; white solid; 93% yield;
mp 98–106 °C. IR (KBr): n = 3000, 2360, 1695, 1440, 1300,
1130, 1064, 920, 840, 800, 770 cm–1. 1H NMR (CDCl3): d =
0.90 (br m, 3 H), 1.35 (d, J = 10.0 Hz, 3 H), 2.68 (dd,
J = 10.0, J = 2.0 Hz, 2 H), 7.28 (ddd, J = 7.6, J = 3.2, J = 1.2
Hz, 1 H), 7.36 (m, 2 H), 7.48 (m, 5 H), 7.94 (dd, J = 13.6,
J = 7.6 Hz, 1 H), 10.00 (br s, 1 H). 13C NMR (CDCl3): d =
11.97 (d, J = 38.7 Hz), 34.28 (d, J = 28.1 Hz), 125.56 (d,
J = 50.1 Hz), 127.46 (d, J = 12.2 Hz), 127.96 (s), 128.25 (s),
129.36 (s), 131.01 (s), 131.32 (d, J = 6.8 Hz), 133.68 (d,
J = 16.7 Hz), 140.39 (s), 146.36 (s), 172.6 (d, J = 5.3 Hz).
[a]D21 +13.0 (c 1, CHCl3, 95% ee). Anal. Calcd for
C15H18BO2P: C, 66.21; H, 6.67. Found: C, 66.03; H, 6.58.
Retention times for alcohol (95% n-hexane, 5% i-PrOH): 0.4
mL/min, 220 nm, tR (–) = 59.80 min, tR (+) = 62.30 min.
(S)-(–)-[3,5-Di(tert-butyl)-6-methoxyphenyl](ethanoic
acid)methylphosphine-borane (3h)
Precipitated in n-hexane; white solid; 89% yield; mp 118–
121 °C. IR (KBr): n = 2960, 2360, 1725, 1410, 1225, 1130,
1064, 1000, 920, 840, 800, 770 cm–1. 1H NMR (CDCl3): d =
0.88 (br m, 3 H), 1.42 (s, 18 H), 1.77 (d, J = 10.0 Hz, 3 H),
2.94 (dd, J = 10.4, 6.4 Hz, 2 H), 3.71 (s, 3 H), 7.63 (d,
J = 12.0 Hz, 2 H), 9.05 (br s, 1 H). 13C NMR (CDCl3): d =
10.41 (d, J = 37.9 Hz), 31.78 (s), 35.13 (d, J = 26.5 Hz),
36.04 (s), 64.39 (s), 120.0 (d, J = 50.0 Hz), 130.03 (d,
J = 11.4 Hz), 144.65 (d, J = 11.4 Hz), 162.8 (s)173.7 (d,
J = 5.3 Hz). [a]D21 –21.5 (c 1, CHCl3, 81% ee). Anal. Calcd
for C18H32BO3P: C, 63.92; H, 9.57. Found, C: 64.04; H, 9.49.
Retention times for alcohol (99% n-hexane, 1% i-PrOH):
0.75 mL/min, 224 nm, tR (–) = 30.7 min, tR (+) = 32.9 min.
(S)-(–)-[2,3,6-Tri(isopropyl)phenyl](ethanoic
(18) Darcel, C.; Kaloun, E. B.; Merdes, R.; Moulin, D.; Riegel,
N.; Thorimbert, S.; Genêt, J. P.; Jugé, S. J. Organomet.
Chem. 2001, 624, 333.
(19) General Procedure for the Palladium-Catalyzed Allylic
Asymmetric Alkylation Reactions.
To the phosphine-borane (0.019 mmol, 9.5% mol) under an
argon atmosphere was added an anhyd degassed solution of
Pd(AcO)2 (2.3 mg, 5 mol%) in 0.8 mL THF. This mixture
was stirred at r.t. for 15 min whereupon 1,3-diphenyl-
propenyl acetate (5, 50 mL, 1 equiv) or 1,3-diphenylpropenyl
ethylcarbonate (6, 56 mL, 1 equiv) was added. After 15 min
at r.t., dimethylmalonate (70 mL, 3 equiv) and BSA (150 mL,
3 equiv) were successively added. The mixture was stirred at
r.t. and the reaction was monitored by HPLC and TLC. The
mixture was purified by flash chromatography on silica gel,
eluting with PE–EtOAc 95:5. The enantiomeric excess was
determined by chiral HPLC, Chiralpak AD-H, n-hexane–i-
PrOH (9:1) 1 mL/min, 254 nm, retention time: tR (R) = 9.60
min, tR (S) = 13.22 min.
(20) For some recent examples, see: (a) Faller, J. W.; Wilt, J. C.
Org. Lett. 2005, 7, 633. (b) Faller, J. W.; Wilt, J. C.
Organometallics 2005, 24, 5076. (c) Zheng, W.-H.; Sun, N.;
Hou, X. L. Org. Lett. 2005, 7, 5151. (d) Nemoto, T.;
Masuda, T.; Akimoto, Y.; Fukuyama, T.; Hamada, Y. Org.
Lett. 2005, 7, 4447. (e) Uozumi, Y.; Tanaka, H.; Shibatomi,
K. Org. Lett. 2004, 6, 281. (f) Jin, M. J.; Kim, S. H.; Lee, S.
J.; Kim, Y. M. Tetrahedron Lett. 2002, 43, 7409.
acid)methylphosphine-borane (3i)
Recrystallized from n-hexane–Et2O; white solid; 72% yield;
Synlett 2006, No. 20, 3389–3394 © Thieme Stuttgart · New York

3394
F. Dolhem et al.
LETTER
(21) General Procedure for the Palladium-Catalyzed
Asymmetric Allylic Amination Reactions.
PE–EtOAc 95:5. The enantiomeric excess was determined
by chiral HPLC, Chiralpak AD-H, n-hexane–i-PrOH (9:1)
0.35 mL/min, 254 nm, retention time : tR (S) = 28.64 min, tR
(R) = 33.92 min.
To the phosphine-borane (0.019 mmol, 9.5 mol%),
evacuated and flushed with argon, was added an anhyd,
degassed THF solution (0.8 mL) of Pd(OAc)2 (2.3 mg, 5
mol%). This mixture was stirred at r.t for 15 min, followed
by the addition of 1,3-diphenylpropenyl acetate (5, 50 mL, 1
equiv) or 1,3-diphenylpropenyl ethylcarbonate (6, 56 mL, 1
equiv). After 15 min the reaction was cooled to 5 °C and
benzylamine (66 mL) was added. The mixture was stirred at
5 °C and monitored by HPLC and TLC. The mixture was
purified by flash chromatography on silica gel, eluting with
(22) Imamoto, T.; Watanabe, J.; Wada, Y.; Masuda, H.; Yamada,
H.; Tsuruta, H.; Matsukawa, S.; Yamaguchi, K. J. Am.
Chem. Soc. 1998, 120, 1635.
(23) Oohara, N.; Katagiri, K.; Imamoto, T. Tetrahedron:
Asymmetry 2003, 14, 2171.
(24) Maienza, F.; Spindler, F.; Thommen, M.; Pugin, B.; Malan,
C.; Mezzetti, A. J. Org. Chem. 2002, 67, 5239.
(25) Yamanoi, Y.; Imamoto, T. J. Org. Chem. 1999, 64, 2988.
Synlett 2006, No. 20, 3389–3394 © Thieme Stuttgart · New York