Camphane-based phosphino-carboxamide ligands as P,O-chelates in Pd-catalyzed enantioselective allylic alkylation

Article abstract of DOI:10.1016/j.tetasy.2012.06.012

A practical synthesis for new chiral phosphino-carboxamide ligands has been accomplished. These ligands were effectively modified both on the amide moiety and the phosphine atom. Application of these ligands in the Pd-catalyzed allylic alkylation of (E)-1

Full text of DOI:10.1016/j.tetasy.2012.06.012

Tetrahedron: Asymmetry 23 (2012) 927–930
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Tetrahedron: Asymmetry
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Camphane-based phosphino-carboxamide ligands as P,O-chelates
in Pd-catalyzed enantioselective allylic alkylation
Irena Philipova a, Georgi Stavrakov b, Vladimir Dimitrov a,
⇑
a Institute of Organic Chemistry with Center of Phytochemistry, Bulgarian Academy of Science, Acad. G. Bonchev 9, Sofia 1113, Bulgaria
b Faculty of Pharmacy, Medical University of Sofia, str. Dunav 2, Sofia 1000, Bulgaria
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical synthesis for new chiral phosphino-carboxamide ligands has been accomplished. These
ligands were effectively modified both on the amide moiety and the phosphine atom. Application of these
ligands in the Pd-catalyzed allylic alkylation of (E)-1,3-diphenyl-2-propenyl acetate proceeded with
excellent conversions and with ee’s of up to 92%. The use of a camphane based chiral auxiliary was found
to be crucial for the asymmetric induction.
Received 9 May 2012
Accepted 21 June 2012
Available online 21 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
R*
R
N
Ph
Ph
Phosphino-carboxamides have emerged as a specific class of
molecules, finding manifold use in various fields, particularly in
coordination chemistry, biomedical sciences, and in catalysis.1
The structure of phosphino-carboxamide ligands bearing the com-
bination of weak and strong donor heteroatom pairs enables them
to bind to almost any metal, thus generating electronic asymme-
try.2 The different donor moieties also allow independent modifi-
cations, thus ensuring the possibility for unlimited variations.1
Another privilege is their stability and the ease with which they
can be accessed.
Despite all of the advantages presented above and the unambig-
uous proof that the P,O-mode of coordination with the palladium
center gives catalytically active complex (Fig. 1. I),3a–c the applica-
tion of amido-phosphine ligands in the asymmetric allylic alkyl-
ation (AAA) has been rarely studied.3 Recently, we accomplished
the practical synthesis of planar chiral phosphino-ferrocenecarb-
oxamide ligands via highly diastereoselective amide-directed
ortho-metallation (Fig. 1. II).4 Camphane-based skeletons, available
inexpensively through the ‘chiral pool’, were found to be excellent
auxiliaries for the diastereoselective deprotonation of ferrocene.
The synthesized (+)-camphor derived ligands, possessing both pla-
nar and central chirality (Fig. 1 II), proved to be effective for the
AAA.4b We were thus inspired to examine which of the two chiral
elements is the major contributor to asymmetric induction in the
catalytic process. The synthesis of analogous structures lacking
planar chirality was a logical extension of our investigations
(Fig. 1 III). Herein, we report a further development of the cam-
O
Pd
PPh2
I
R
N
O
O
O
R
N
O
PPh2
Fe
PPh2
II
III
Figure 1.
phane-based chiral template for the design of phosphino-carbox-
amide ligands.
2. Results and discussion
Our aim was to obtain the target structures using simple and
effective synthetic procedures. The construction of the required
phosphino-carboxamides was performed in three straightforward
steps starting from readily available (+)-camphor derived aminoal-
cohols5 and amines.6 Condensation of (2S)-(ꢀ)-3-exo-aminoisobor-
neol with 2-bromobenzoyl chloride afforded benzamide
1
(Scheme 1).7 The corresponding tertiary amides 2a–c were
achieved by N-alkylation and a simultaneous O-alkylation with
NaH as the deprotonating reagent followed by the addition of an
⇑
Corresponding author.
E-mail address: vdim@orgchm.bas.bg (V. Dimitrov).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.06.012

928
I. Philipova et al. / Tetrahedron: Asymmetry 23 (2012) 927–930
R
N
1. nBuLi
THF, -78 °C
R
N
H
N
NaH, RX
DMF
OH
OR
OR
2. ClPR'2
O
Br
O
Br
O
PR'2
1
2a, R = Et, 81%
2b, R = nBu, 45%
2c, R = Bn, 54%
3a, R = Et, R' = Ph, 85%
3b, R = nBu, R' = Ph, 50%
3c, R = Bn, R' = Ph, 45%
3d, R = Et, R' = Cy, 52%
Scheme 1.
appropriate haloalkane.8 In addition to the ethyl group 2a, we also
introduced butyl 2b and benzyl groups 2c in order to investigate
the influence of their steric effects on the undertaken ligand struc-
ture/activity study. A consecutive brom-lithium exchange followed
by reaction with ClPPh2 gave a set of the desired phosphine-car-
boxamide ligands 3a–c. Changing the electrophile to ClPCy2 affor-
ded 3d (Scheme 1).9 The latter was selected as an electronically
and sterically varied analogue, opening up the possibility for addi-
tional tuning.
Another aspect of our work was the synthesis of structures con-
taining a bulky iPr-group on the amide nitrogen. The tertiary amide
5 was synthesized following the already described procedure,
starting from secondary amine 4, which was prepared by reductive
amination with acetone.10 Subsequent alkylation of the OH-group
with MeI gave 6. The Br–Li exchange/electrophile quench sequence
furnished ligand 7 (Scheme 2). Attempts to synthesize the O-ethyl
analogue of 6 were unsuccessful. Over the course of the reaction,
decomposition of the starting amide 5 was observed, probably
due to steric hindrance.
iPr
NH
OH
iPr
i
N
OH
O
O
Br
Br
5
4
ii
iPr
N
iPr
N
iii
O
O
O
PPh2
6
7
Scheme 2. Reagents and conditions: (i) 2-Br–C6H4COCl, Et3N, CH2Cl2, 75%; (ii) NaH,
MeI, DMF, 86%; (iii) nBuLi, THF, 30 min, ꢀ78 °C then ClPPh2, 72%.
Further investigation of the influence of the camphane chiral
element forced us to synthesize ligands based on the endo-ami-
no-diastereoisomer of 3-aminoborneol. The formation of the amide
linkage was accomplished by the reaction of (2R)-3-endo-amino-
i
NH
NEt
HO
EtO
borneol in an analogous fashion to the previous series
8
O
Br
O
ii
Br
(Scheme 3).7 The N,O-bis-ethylated compound 9 and the phos-
phine-amide 10 were synthesized following the above described
protocol.
8
9
The design of phosphino-carboxamides derived from isobornyl-
amine and bornylamine as the source of chirality, was considered
as an alternative to the above described structures. The reaction
with 2-bromobenzoyl chloride afforded the corresponding amides
11 and 14 in excellent yields (Scheme 4). Conversion to the tertiary
amides 12 and 15 was accomplished by an ethylation protocol. The
lithiation-quench sequence resulted in the desired 13 and 16. In all
cases, the oxidation of phosphines to the corresponding phosphine
oxides was minimized by using a non-aqueous work-up procedure.
NEt
EtO
O
PPh2
10
Scheme 3. Reagents and conditions: (i) NaH, EtI, DMF, 77%; (ii) nBuLi, THF, 30 min,
ꢀ78 °C then ClPPh2, 65%.
Et
N
Et
i
ii
H
N
N
O
Br
O
Br
O
PPh2
11
12
13
i
ii
N
N
HN
Et
Et
O
Br
O
Br
O
PPh2
14
15
16
Scheme 4. Reagents and conditions: (i) NaH, EtI, DMF, 27%, 12; 62%, 15; (ii) nBuLi, THF, 30 min, ꢀ78 °C then ClPPh2, 43%, 13; 37%, 16.

I. Philipova et al. / Tetrahedron: Asymmetry 23 (2012) 927–930
929
The chiral phosphine-amide ligands were tested in the Pd-cata-
excellent conversions. However, the substitution product was ob-
tained with very low enantioselectivity (30% ee, entry 11) or as a
racemate (entry 12). It is obvious that the catalytic performance
is greatly influenced by modifications of the camphane chiral aux-
iliary. We speculate that the presence of an alkoxy group in the
bicyclic skeleton has either a steric influence or participates as an
additional coordinating center in the formation of the catalytic
complex.
lyzed AAA of racemic (E)-1,3-diphenyl-2-propenyl acetate with di-
methyl malonate using [Pd(g
3-C3H5)Cl]2 as the palladium source
(Scheme 5). The nucleophile was generated in situ by Trost’s pro-
cedure using N,O-bis(trimethylsilyl)acetamide (BSA) and a cata-
lytic amount of alkali metal acetates.12
MeOOC
COOMe
Ph
[Pd(C3H5)Cl]2
ligand
OAc
Ph
3. Conclusion
Ph
Ph
CH2(COOMe)2
BSA
In conclusion, we have accomplished a practical synthesis of
new chiral phosphino-carboxamide ligands. The latter were effec-
tively modified both on the amide moiety and the phosphine atom,
thus enabling fine tuning of their coordination properties. Applica-
tion of these ligands in the Pd-catalyzed AAA proceeded with a
promising degree of enantioselectivity (up to 92%). The use of a
camphane based chiral auxiliary proved to be crucial for the asym-
metric induction. The possibility for independent modifications of
the amidophosphine donors and the camphane fragment is
encouraging for future ligand design concerning many key asym-
metric catalytic reactions. Work is currently in progress.
base, solvent
Scheme 5.
Initially, the reaction was performed with ligand 3a, as a repre-
sentative, using BSA/KOAc in toluene.5 Under these conditions the
alkylated product was isolated in excellent yield and with an
enantioselectivity of 76% in favor of the (R)-enantiomer (Table 1,
entry 1). By using LiOAc as a base additive, the enantioselectivity
increased to 91% ee (entry 2). Upon testing different solvents, it
was found that the selectivity in Et2O remains high (91% ee, entry
3) but slightly decreased in THF and CH3CN (entries 4 and 5). Sur-
veying the reaction conditions we selected LiOAc as the base addi-
tive and Et2O as the solvent to estimate the whole series of ligands.
Acknowledgement
Financial support of National Science Fund, Bulgaria (DID02/33/
2009) is gratefully acknowledged.
Table 1
Palladium-catalyzed AAA of racemic (E)-1,3-diphenyl-2-propenyl acetate with
dimethyl malonatea
References
Entry
L⁄
Solvent
Base
Yieldb (%)
ee (%), confc
1. Stepnicka, P. Chem. Soc. Rev. 2012, 41, 4273–4305.
2. Bader, A.; Lindner, E. Coord. Chem. Rev. 1991, 108, 27–110.
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3b
3c
3d
7
PhCH3
PhCH3
Et2O
THF
CH3CN
Et2O
Et2O
Et2O
Et2O
Et2O
KOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
99
99
99
96
99
99
99
99
99
99
99
99
76, (R)
91, (R)
91, (R)
90, (R)
89, (R)
92, (R)
91, (R)
91, (R)
54, (S)
68, (S)
30, (R)
0
3. (a) Butts, C. P.; Filali, E.; Lloyd-Jones, G. C.; Per-Ola Norrby, P.-O.; Sale, D. A.;
Schramm, Y. J. Am. Chem. Soc. 2009, 131, 9945–9957; (b) Marinho, V. R.;
Rodrigues, A. I.; Burke, A. J. Tetrahedron: Asymmetry 2008, 19, 454–458; (c)
Butts, C. P.; Crosby, J.; Lloyd-Jones, G. C.; Stephen, S. C. Chem. Commun. 1999,
1707–1708; (d) Mahadik, G. S.; Knott, S. A.; Szczepura, L. F.; Hitchcock, S. R.
Tetrahedron: Asymmetry 2009, 20, 1132–1137; (e) Mahadik, G. S.; Knott, S. A.;
Szczepura, L. F.; Peters, S. J.; Standard, J. M.; Hitchcock, S. R. J. Org. Chem. 2009,
74, 8164–8173; (f) Mahadik, G. S.; Hitchcock, S. R. Tetrahedron: Asymmetry
2010, 21, 33–38; (g) Benessere, V.; Ruffo, F. Tetrahedron: Asymmetry 2010, 21,
171–176; (h) Marinho, V. R. D.; Ramalho, J. P. P.; Rodrigues, A. I.; Burke, A. J.
Chirality 2011, 23, 383–388; (i) Tauchman, J.; Cısarova, I.; Stepnicka, P. Dalton
Trans. 2011, 40, 11748–11757.
9
10
11
12
10
13
16
Et2O
Et2O
4. (a) Stavrakov, G.; Philipova, I.; Ivanova, B.; Dimitrov, V. Tetrahedron: Asymmetry
2010, 21, 1845–1854; (b) Philipova, I.; Stavrakov, G.; Chimov, A.; Nikolova, R.;
Shivachev, B.; Dimitrov, V. Tetrahedron: Asymmetry 2011, 22, 970–979.
5. (a) Chittenden, R. A.; Cooper, G. H. J. Chem. Soc. C 1970, 49–54; (b) Gawley, R. E.;
Zhang, P. J. Org. Chem. 1996, 61, 8103–8112.
6. (a) Carman, R. M.; Greenfield, K. L. Aust. J. Chem. 1984, 37, 1785–1790; (b)
Ipaktschi, J. Chem. Ber. 1984, 117, 856–858.
7. Bourland, T. C.; Carter, R. G.; Yokochi, A. F. T. Org. Biomol. Chem. 2004, 2, 1315–
1329.
a
Reaction conditions: 1 equiv of substrate, 0.03 equiv of [Pd(g
3-C3H5)Cl]2,
0.06 equiv of ligand, 3 equiv of N,O-bis(trimethylsilyl)acetamide (BSA), 3 equiv of
dimethylmalonate, catalytic amount of additive salts, 24 h.
b
Isolated pure products after column chromatography.
Enantiomeric excess was determined by HPLC analysis (Chiralpak IA chiral
c
column). The absolute configuration was determined by comparison of the specific
rotation with the literature.11
8. A typical procedure for the preparation of tertiary amides 2a–c, 6, 9, 12, and 15:
To a stirred solution of starting amide (1 equiv) in DMF at 0 °C was added NaH
(5 equiv.). The mixture was stirred for 30 min at rt and then RX (5 equiv)
(RX = EtI, nBuBr, BnBr) was added. The reaction was stirred at rt until the
starting material was completely consumed (TLC). Next, it was cooled to 0 °C
and treated with sat. aq. NH4Cl. The organic phase was separated, and the
aqueous phase was extracted three times with Et2O. The combined organic
phases were dried over Na2SO4 and the solvent was removed in vacuo. The
residue was purified by flash column chromatography on silica gel. Data for 2-
bromo-N-((1S,2R,3S,4R)-3-ethoxy-4,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)-
Ligands 3a–c allowed us to evaluate the steric effects of differ-
ent alkyl groups bonded to the nitrogen and the oxygen on the
asymmetric induction. Replacement of the ethyl groups with n-bu-
tyl 3b led to a slight increase in enantioselectivity (92% ee, entry 6).
Ligand 3c, bearing benzyl groups, did not modify the catalytic per-
formance (91% ee, entry 7). The electronically and sterically varied
analogue 3d also afforded similar results (91% ee, entry 8).
Switching the ligand to 7, which contains a bulky iPr-group on
the amide nitrogen, greatly decreased the enantioselectivity (54%
ee, entry 9). Moreover, it is noteworthy that the alkylation product
had the opposite (S)-configuration in contrast to the one observed
with the phosphine-amide ligands 3a–d. This result could be ex-
plained by a competing P,O-chelation including the methoxy group.
Ligand 10, the endo-diastereoisomer of 3a, induced lower
enantioselectivity (68% ee, entry 10), favoring the opposite (S)-con-
figuration of the substitution product. Phosphino-carboxamides 13
and 16, derived from isobornylamine and bornylamine, afforded
N-ethylbenzamide 2a: mp 82–84 °C. ½a D20
ꢁ
¼ þ23:7 (c 0.50, CHCl3). 1H NMR
(CDCl3, 600 MHz) d = 0.83 (s, 3H, 9-H), 0.96 (s, 3H, 10-H), 1.01 (t, JH,H = 7.0 Hz,
3H, OCH2CH3), 1.07 (t, JH,H = 7.0 Hz, 3H, NCH2CH3), 1.10 (s, 3H, 8-H), 1.18–1.24
(m, 2H, 5-Hendo, 6-Hendo), 1.49–1.55 (m, 1H, 6-Hexo), 1.76–1.83 (m, 1H, 5-Hexo),
2.05 (d, JHH = 4.5 Hz, 1H, 4-H), 3.22 (dq, JH,H = 15.1, 7.1 Hz, 1H, NCH2CH3), 3.04–
3.49 (m, 2H, OCH2CH3, NCH2CH3), 3.50–3.57 (m, 1H, OCH2CH3), 3.55 (d,
JH,H = 7.1 Hz, 1H, 2-H), 4.01 (d, JH,H = 7.1 Hz, 1H, 3-H), 7.22 (dt, JH,H = 7.4, 1.8 Hz,
1H, arom.), 7.32 (t, JH,H = 7.4 Hz, 1H, arom.), 7.35 (dd, JH,H = 7.5, 1.7, 1H, arom.),
7.62 (d, JH,H = 8.0 Hz, 1H, arom.) ppm. 13C NMR (CDCl3, 150.9 MHz) d = 11.57 (C-
10), 15.80 (NCH2CH3), 15.84 (OCH2CH3), 21.21 (C-9), 21.43 (C-8), 27.66 (C-5),
32.24 (C-6), 42.92 (NCH2CH3), 45.72 (C-4), 47.62 (C-7), 49.50 (C-1), 62.73 (C-3),
69.16 (OCH2CH3), 89.63 (C-2), 120.47 (1 arom. C), 127.04 (1 arom. CH), 128.92
(1 arom. CH), 129.99 (1 arom. CH), 133.67 (1 arom. CH), 139.08 (1 arom. C),

930
I. Philipova et al. / Tetrahedron: Asymmetry 23 (2012) 927–930
170.63 (CO) ppm. MS (CI) m/z (rel. int.) = 408 (100) [M+H]+. C21H30BrNO2
(408.37): calcd. C 61.76, H 7.40, N 3.43, found C 61.82, H 7.51, N 3.56.
JH,H = 7.4 Hz, 1H, arom.), 7.48 (dd, JH,H = 7.2, 3.1 Hz, 1H, arom.) ppm. 13C NMR
(CDCl3, 150.9 MHz) d = 11.67 (C-10), 15.85 (OCH2CH3), 16.60 (NCH2CH3), 21.29
(C-9), 21.52 (C-8), 27.68 (C-5), 32.28 (C-6), 42.96 (NCH2CH3), 45.89 (C-4), 47.64
(C-7), 49.47 (C-1), 62.62 (C-3), 69.06 (OCH2CH3), 89.56 (C-2), 127.85 (CCO),
9. Typical procedure for the preparation of ligands 3a–d, 7, 10, 13, and 16: n-
Butyllithium (1.2 equiv) was added to a solution of benzamides 2a–c, 6, 9, 12,
and 15 (1 equiv) in THF at ꢀ78 °C. After stirring for 30 min Ph2PCl or Cy2PCl
(1.5 equiv.) was added. The reaction was stirred at ꢀ78 °C for 1.5 h. Next, it was
poured quickly through a pad of Celite. The flask and the Celite were washed
with ether, and the filtrate was concentrated under reduced pressure. The
resulting sticky oil was purified by flash column chromatography. Data for 2-
(diphenylphosphino)-N-((1S,2R,3S,4R)-3-ethoxy-4,7,7-trimethylbicyclo[2.2.1]
127.93 (1 arom. CH), 128.06 (d, J
= 6.6 Hz, 2arom. CH), 128.28 (2arom.
31 P;13C
CH), 128.30 (d, J
= 8.2 Hz, 2arom. CH), 128.73 (2arom. CH), 133.20 (d,
31P;13
C
J
J
J
= 17.8 Hz, 2arom. CH), 133.65 (d, J
= 2.9 Hz, 1arom. CH), 137.44 (d, J
= 12.7 Hz, 1arom. C), 145.06 (d, J
= 19,7 Hz, 2arom. CH), 135.49 (d,
= 10.1 Hz, 1arom. C), 138.96 (d,
31 P;13 C
31 P;13 C
31 P;13 C
31 P;13 C
31 P;13 C
= 34.1 Hz, CPPh2), 172.45 (CO)
31P;13 C
ppm. 31P NMR (CDCl3, 242.92 MHz): d = ꢀ13.14 (s) ppm. MS (CI) m/z (rel. int.)
= 514 (100) [M+H]+. C33H40NO2P (513.65): calcd. C 77.16, H 7.85, N 2.73, found
C 77.24, H 7.79, N 2.75.
heptan-2-yl)-N-ethylbenzamide 3a: mp >64 °C decomp. ½a D20
¼ þ58:8 (c 0.148,
ꢁ
CHCl3). 1H NMR (CDCl3, 600 MHz) d = 0.82 (s, 3H, 9-H), 0.94 (s, 3H, 10-H), 0.98
(t, JH,H = 7.0 Hz, 3H, OCH2CH3), 1.09 (t, JH,H = 6.5 Hz, 3H, NCH2CH3), 1.15 (s, 3H,
8-H), 1.13–1.18 (m, 1H, 6-Hendo), 1.20–1.25 (m, 1H, 5-Hendo), 1.46–1.50 (m, 1H,
6-Hexo), 1.75–1.79 (m, 1H, 5-Hexo), 2.06 (d, JH,H = 4.0 Hz, 1H, 4-H), 3.22–3.26 (m,
1H, NCH2CH3), 3.36–3.39 (m, 1H, OCH2CH3), 3.43 (dq, JH,H = 15.0, 7.2 Hz, 1H,
OCH2CH3), 3.52 (d, JH,H = 7.0 Hz, 1H, 2-H), 4.08 (d, JH,H = 7.0 Hz, 1H, 3-H), 7.20
(dd, JH,H = 7.4, 3.2 Hz, 1H, arom.), 7.27–7.30 (m, 11H, arom.), 7.36 (t,
10. (a) Denmark, S. E.; Rivera, I. J. Org. Chem. 1994, 59, 6887–6889; (b) Bonner, M.
P.; Thornton, E. R. J. Am. Chem. Soc. 1991, 113, 1299–1308.
11. Hayashi, T.; Yamamoto, A.; Hagihara, T.; Ito, Y. Tetrahedron Lett. 1986, 27, 191–
194.
12. Trost, B. M.; Murphy, D. J. Organometallics 1985, 4, 1143–1145.