Study of incidence of DiPAMP ligand modification on the rhodium(I)-catalyzed asymmetric hydrogenation of α-acetamidostyrene

Article abstract of DOI:10.1016/j.tetlet.2009.10.088

A series of P-stereogenic enantiopure 1,2-bis[(aryl)(phenyl)phosphino]ethane ligands was prepared through an extensive systematic incorporation of various substituents onto the P-o-anisyl rings of Knowles' DiPAMP (DiPAMP = 1,2-bis[(o-anisyl)(phenyl)phosph

Full text of DOI:10.1016/j.tetlet.2009.10.088

Tetrahedron Letters 50 (2009) 7382–7384
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Study of incidence of DiPAMP ligand modification on the
rhodium(I)-catalyzed asymmetric hydrogenation of a-acetamidostyrene
a,
a,b,
ˇ ˇ a
*
*
Borut Zupancic , Barbara Mohar , Michel Stephan
a Laboratory of Organic and Medicinal Chemistry, National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia
b PhosPhoenix SARL, 115, rue de l’Abbé Groult, F-75015 Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of P-stereogenic enantiopure 1,2-bis[(aryl)(phenyl)phosphino]ethane ligands was prepared
through an extensive systematic incorporation of various substituents onto the P-o-anisyl rings of Know-
les’ DiPAMP (DiPAMP = 1,2-bis[(o-anisyl)(phenyl)phosphino]ethane). The study of incidence of such
Received 14 September 2009
Revised 13 October 2009
Accepted 16 October 2009
Available online 22 October 2009
modification on the Rh(I)-catalyzed hydrogenation of
a-acetamidostyrene is reported revealing that
substitution on position 3 is detrimental, while it is beneficial on position 5. Namely, a 2.5-fold increased
catalyst activity coupled with a higher enantioselectivity (90% ee) was attained with the P-(2-MeO-3-
naphthyl)-substituted ligand under mild conditions (1 bar H2, rt in MeOH).
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Hydrogenation
P Ligands
Rhodium
OMe
In their P-stereogenic phosphine ligand optimization for the
Rh(I)-catalyzed L-DOPA process, Knowles and co-workers’ chelating
R
P
P
Ph
R
R= H : DiPAMP
R
R= OMe: 4MeBigFUS
DiPAMP ligand (DiPAMP = 1,2-bis[(o-anisyl)(phenyl)phosphino]-
ethane) proved to be less sensitive to impurities and reaction
variables compared to monophosphines.1 Since their pioneering re-
search, a relatively small group of P-stereogenic diphosphines
emerged compared to the plethora of stereogenic backbone ones.2
Design of P-stereogenic bis(diarylphosphino)-containing ligands
has been sporadic,3 while the interest in P-stereogenic phosphine li-
gands has been progressively revitalized due to advances in efficient
synthetic strategies towards them.3c–e,m,4 In particular, the mile-
stone contribution to Rh(I)-catalyzed asymmetric hydrogenation
by Zhang5 and Imamoto6 groups was highlighted by the introduc-
tion of the aliphatic TangPhos, BisP*, and MiniPHOS diphosphines.
Interestingly, by contrast to the early explored and commonly
Ph
MeO
R
R
R
Rh(I)-Catalyzed asymmetric hydrogenation of
renes is a powerful method to prepare a variety of chiral
a-acetamidosty-
a
-aryl
amines.4b,5a,6d,9 To our knowledge, sparse study-cases exist that
are targeted to understanding the effect of variations brought to
a ligand structure on hydrogenation.4b,9i P-Stereogenic tetraarylic
diphosphines are easy to prepare, handle, and store, less capricious
to reaction parameters (solvent, temperature, pressure, etc.), and
could be readily accessible in both enantiomeric forms. Further-
more, few P-stereogenic tetraarylic diphosphines were prepared
wherein the substituted phenyl rings were devoid of o-substitu-
ents (as for example P-b-naphthyl), and to a lesser extent their
testing in Rh-catalyzed hydrogenation was reported.3c–e In the
present work, we aimed to study the impact of a systematic incor-
poration of various substituents onto the P-o-anisyl groups of DiP-
AMP, in addition to the effect on hydrogenation of meta- and/or
para-MeO substituents of its analogs.
accepted unsaturate Rh-DiPAMP hydrogenation route of a-acetam-
idocinnamates,7 an extensive mechanistic study by Gridnev et al.
pointed out an underlying solvate dihydride pathway using the
electron-rich BisP* with
a
-substituted acetamidoethylenes.6b
Moreover, we have recently shown that mutant DiPAMP-type
ligands, particularly our 4MeBigFUS ligand (4MeBigFUS = 1,2-bis
[(phenyl)(2,3,4,5-tetramethoxyphenyl)phosphino]ethane), boosted
the Rh(I)-catalyzed hydrogenation of a variety of olefins compared
to the original Knowles’ mid-70s design.8
Inourongoingresearchprogramonstereogenicphosphines,3m,p,4c
wepresent hereafter ourin-depthstudyofthe Rh(I)-catalyzedhydro-
genation of the model substrate
a-acetamidostyrene employing a
large series of P-stereogenic 1,2-bis(diphenylphosphino)ethane
derivatives.
By analogy to our previously disclosed library of DiPAMP deriv-
atives,3p the screened new enantiopure P-stereogenic ligands were
readily prepared in high overall yields via the Jugé–Stephan
* Corresponding authors.
E-mail addresses: mstephan@phosphoenix.com, michel.stephan@ki.si (M. Ste-
phan).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.088

ˇ ˇ
B. Zupancic et al. / Tetrahedron Letters 50 (2009) 7382–7384
7383
phosphine-P-borane asymmetric route.3c This expedient route re-
Table 1
[Rh((R,R)-L*)(MeOH)2]BF4 catalyzed hydrogenation of
a
-acetamidostyrenea
lies upon the sequential displacement of the ephedrine auxiliary
from the 1,3,2-oxazaphospholidine-2-borane complex (oxazaPB)
with organolithium reagents and both enantiomers can be attained
starting from either (+)- or (ꢀ)-ephedrine (Scheme 1).
Me
+
[Rh(R,R)-L*] / H (1 bar)
2
MeOH, rt
Ph
NHAc
Ph
NHAc
(S)
The preliminary screening results of the Rh(I)-catalyzed hydro-
P
P
(R,R)-L*:
Ar
Ph
Ar
genation of
a-acetamidostyrene using diphosphines L* 1–16 are
Ph
1-16
compiled in Table 1 and correspond to un-optimized reaction con-
ditions. The observed sense of enantioselection is the same as with
DiPAMP.
The ligands 11 (Ar = 2-MeO-3-TMS-Ph) and 12 (Ar = 2-MeO-3,5-
di(tBu)Ph) yielded 83 and 80% ee, respectively, which is in the
same range as obtained with DiPAMP (83% ee) but with faster reac-
tion rates. Also, the o-unsubstituted ligands 1–4 exhibited twofold
faster reaction rates compared to DiPAMP, with the best ee of up to
L*
Ar
Time (min)
ee (%)
DiPAMP
1
2
3
4
5
6
7
8
9
10
11
12
2-MeO-Ph
3-MeO-Ph
4-MeO-Ph
3,4-di(MeO)Ph
3,5-di(MeO)Ph
2,3-di(MeO)Ph
2-MeO-3-iPrO-Ph
2,4-di(MeO)Ph
2,5-di(MeO)Ph
2,3,4-tri(MeO)Ph
13
6
83
1
15
27
5
71
71
88
88
71
87
83
80
5
7
7
4
4
27% being attained with ligand
3 bearing P-[3,4-di(MeO)Ph]
18
7
groups. Thus, albeit low, still a perceptible level of asymmetric bias
was reached using ligands devoid of o-substituents on the P-phen-
yls of P-stereogenic 1,2-bis(diphenylphosphino)ethane derivatives.
The results transpire also that the p-MeO substituent has a benefi-
cial influence compared to the m-MeO substituent.
4
4
7
9
2,3,4,5-tetra(MeO)Ph
2-MeO-3-TMS-Ph
2-MeO-3,5-di(tBu)Ph
MeO
Ligand 14 possessing a phenyl substituent at position 3 of the
o-anisyl moiety gave low ee (65%) versus 80–83% ee with ligands
11 and 12 possessing a TMS or tBu group, respectively, at the same
position. Ligands 5 and 6 possessing a MeO or iPrO group at posi-
tion 3 on the one hand, and ligands 9, 13, and 15 possessing MeO
groups or a fused cycle at positions 3 and 4 on the other hand, fur-
nished ees in the narrow range of 69–72%. This reflects that the
variations brought to DiPAMP at position 3 are to a certain extent
detrimental. Conversely, ligands 7, 8, and 16 with no substituent at
position 3 exerted a slightly higher ee (88–90%) compared to DiP-
AMP. It is also noticeable that ligand 7 bearing a P-[2,4-di(MeO)Ph]
group led to a protracted reaction time, probably attributable to
the nature of the electron-donating MeO group at para-position
to the phosphorous atom; the reverse effect was encountered with
the ligand 16 wherein Ar = 2-MeO-3-naphthyl. Noteworthy, the
87% ee achieved with ligand 10 (4MeBigFUS; Ar = 2,3,4,5-tetra
(MeO)Ph) versus the 71% ee with ligand 5 (2MeBigFUS) or 9
(3MeBigFUS) points out the beneficial incidence of the MeO group
at position 5 as also observed with ligand 8 (Ar = 2,5-di(MeO)Ph).
We believe that the steric effect engaging the ortho-MeO group is
responsible for the observed decrease in enantioselectivity in case
of a substituent on position 3, and that an electronic effect on
position 5 influencing the basicity of the phosphorus atom is
responsible for the increase in enantioselectivity. Thus, in the P-
(2-MeO-3-naphthyl)-substituted ligand 16, steric and electronic
effects are acting in concert in favor of a higher enantioselectivity
and activity of the Rh(I)-catalyst.
Me
Me
O
13
14
15
7
8
6
69
65
72
(2-MeO-3-Ph)Ph
MeO
5
90
90
45b
16
OMe
a
For convenient comparison of the catalysts’ activities, the induction period was
eliminated by preforming the catalysts in situ. Runs were carried out with 0.5 mmol
of -acetamidostyrene in 7.5 mL MeOH with a substrate/catalyst molar ratio (S/C)
of 100 at 25 °C for the time indicated (100% conversion). Conversion and ee were
determined by GC on CP-Chiralsil-DEX CB column.
a
b
S/C = 1000.
Table 2
Solvent and pressure dependencea
Solvent
pH2 (bar)
Time (min)
ee (%)
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
iPrOH
EtOAc
Acetone
THF
1
1
1
10
20
1
1
1
1
1
5
90
91
85
89
89
90
91
87
88
88
88
88
87
12b
4c
5
5
7
8
8
6
Next, we have investigated the susceptibility of [Rh(L* 16)]+-
catalyzed hydrogenation to reaction parameters (Table 2). An
enantiomeric excess in the range of 87–91% was maintained in var-
ious reaction media; however, protracted reaction times occurred
in THF, CH2Cl2, and CHCl3 (probably due to H2 gas solubility10a),
and in toluene (aromatic solvents are known to inhibit hydrogena-
17
12
13
25
CH2Cl2
CHCl3
Toluene
1
1
1
a
Runs were carried out under conditions of Table 1. For runs under 10 or 20 bar
H2, the reaction mixture was only analyzed after 5 min (100% conversion).
b
Hydrogenation at 0 °C.
Hydrogenation at 50 °C.
c
BH
P
3
Ph
P
P
a) - e)
Ar
Ph
Ar
O
Me
tion10b). Also, carrying out the reaction at 0 °C in MeOH did not af-
fect the ee much, but a noticeable drop in enantioselectivity (85%
ee) occurred at 50 °C. In general, H2 pressure markedly affects
the hydrogenation,10c but interestingly with L* 16 an 89% ee was
maintained up to 20 bar of H2.
In conclusion, we have prepared a large series of enantiomeri-
cally pure P-stereogenic 1,2-bis[(aryl)(phenyl)phosphino]ethane
ligands through a systematic modification of the P-o-anisyl rings
Ph
N
Ph
12-64%
overall yield
Me
(-)-OxazaPB
(derived from (+)-ephedrine)
(R,R)-L* 1-16
100% ee
Scheme 1. Synthesis of 1,2-bis[(aryl)(phenyl)phosphino]ethane ligands (R,R)-L* 1–
16. Reagents and conditions: (a) ArLi, THF, ꢀ20 °C to rt; (b) MeOH, H2SO4, rt; (c)
MeLi, THF, ꢀ20 °C to rt; (d) sBuLi, THF, ꢀ30 °C, then CuCl2, ꢀ30 °C; (e) Et2NH, 55–
60 °C.

ˇ ˇ
B. Zupancic et al. / Tetrahedron Letters 50 (2009) 7382–7384
7384
3. For P-stereogenic bis- or poly-(diarylphosphino)-containing ligands, see: (a)
Johnson, C. R.; Imamoto, T. J. Org. Chem. 1987, 52, 2170–2174; (b) Imamoto, T.;
Oshiki, T.; Onozawa, T.; Kusumoto, T.; Sato, K. J. Am. Chem. Soc. 1990, 112,
5244–5252; (c) Jugé, S.; Stephan, M.; Laffitte, J. A.; Genêt, J.-P. Tetrahedron Lett.
1990, 31, 6357–6360; (d) Jugé, S.; Genêt, J.-P. WO9100286, 1991.; (e) Laffitte, J.
A.; Jugé, S.; Genêt, J.-P.; Stephan, M. FR2672603, 1991; WO9214739, 1992.; (f)
Burgess, K.; Ohlmeyer, M. J.; Whitmire, K. H. Organometallics 1992, 11, 3588–
3600; (g) Nagel, U.; Krink, T. Chem. Ber. 1995, 128, 309–316; (h) Zhu, G.; Terry,
M.; Zhang, X. Tetrahedron Lett. 1996, 37, 4475–4478; (i) Gómez, M.; Jansat, S.;
Muller, G.; Panyella, D.; van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Goubitz, K.;
Fraanje, J. Organometallics 1999, 18, 4970–4981; (j) Nettekoven, U.; Widhalm,
M.; Kalchhauser, H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Lutz, M.; Spek, A.
L. J. Org. Chem. 2001, 66, 759–770; (k) Maienza, F.; Santoro, F.; Spindler, F.;
Malan, C.; Mezzetti, A. Tetrahedron: Asymmetry 2002, 13, 1817–1824; (l) Wada,
Y.; Imamoto, T.; Tsuruta, H.; Yamaguchi, K.; Gridnev, I. D. Adv. Synth. Catal.
2004, 346, 777–788; (m) Stephan, M.; Mohar, B. FR2887253, 2005;
WO2006136695, 2006.; (n) Rodríguez, L.-I.; Rossell, O.; Seco, M.; Grabulosa,
A.; Muller, G.; Rocamora, M. Organometallics 2006, 25, 1368–1376; (o) Chen,
W.; McCormack, P. J.; Mohammed, K.; Mbafor, W.; Roberts, S. M.; Whittall, J.
of DiPAMP. Their screening in the Rh(I)-catalyzed hydrogenation of
-acetamidostyrene identified the P-(2-MeO-3-naphthyl)-substi-
a
tuted ligand which led to 90% ee coupled with 2.5-fold shorter
reaction time under mild conditions (1 bar H2, rt). In addition, this
study revealed that for this substrate, substitution on position 3 of
the P-o-anisyl rings is detrimental while it is beneficial on position
5. It seems that an increased steric effect on position 3 has a neg-
ative effect on enantioselectivity, while substituents on position 5
can exert an increase in enantioselectivity due to electronic rea-
sons. Catalysis continues to be a very sensitive function of ligand
structure and key challenges remain associated with the complex-
ity of rational design of an optimum ligand. The P-(2-MeO-3-naph-
thyl) groups of the ligand increase its overall steric requirements
and we believe that they induce a favored conformation of its
Rh(I) complex which may facilitate the turnover-limiting and
enantiodetermining H2 oxidative-addition step. Nevertheless, cau-
tion should be exercised in extrapolation of these results to other
ˇ ˇ
Angew. Chem., Int. Ed. 2007, 46, 4141–4144; (p) Zupancic, B.; Mohar, B.;
Stephan, M. Adv. Synth. Catal. 2008, 350, 2024–2032.
4. (a) Muci, A. R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc. 1995, 117, 9075–
9076; (b) Ohashi, A.; Kikuchi, S.; Yasutake, M.; Imamoto, T. Eur. J. Org. Chem.
2002, 15, 2535–2546; (c) Stephan, M. M. S.; Šterk, D.; Modec, B.; Mohar, B. J.
Org. Chem. 2007, 72, 8010–8018.
a
-acetamidostyrenes as changes in a substrate structure could
necessitate other requirements/matching for the catalyst.11 Ongo-
ing progress in our group in this area shall be communicated in due
time.
5. For (RP,SC)-TangPhos ((RP,SC)-1,10-di-t-butyl-[2,20]-diphospholane), see: (a)
Tang, W.; Zhang, X. Angew. Chem., Int. Ed. 2002, 41, 1612–1614; (b) Tang, W.;
Zhang, X. Org. Lett. 2002, 4, 4159–4161; (c) Tang, W.; Zhang, X. Org. Lett. 2003,
5, 205–207; (d) Yang, Q.; Gao, W.; Deng, J.; Zhang, X. Tetrahedron Lett. 2006, 47,
821–823.
Acknowledgments
6. For (S,S)-R-BisP* series ((S,S)-1,2-bis(alkylmethylphosphino)ethanes) and (R,R)-
R-MiniPHOS series ((R,R)-1,2-bis(alkylmethylphosphino)methanes), see: (a)
Yamanoi, Y.; Imamoto, T. J. Org. Chem. 1999, 64, 2988–2989; (b) Gridnev, I. D.;
Higashi, N.; Asakura, K.; Imamoto, T. J. Am. Chem. Soc. 2000, 122, 7183–7194; (c)
Gridnev, I. D.; Yamanoi, Y.; Higashi, N.; Tsurata, H.; Yasutake, M.; Imamoto, T.
Adv. Synth. Catal. 2001, 343, 118–136; (d) Gridnev, I. D.; Yasutake, M.; Higashi,
N.; Imamoto, T. J. Am. Chem. Soc. 2001, 123, 5268–5276.
This work was supported by the Ministry of Higher Education,
Science, and Technology of the Republic of Slovenia (Grant J1-
9806), and by the Ministry of National Education, Research, and
Technology of France (Grant 00P141 to PhosPhoenix SARL).
7. Landis, C. R.; Halpern, J. J. Am. Chem. Soc. 1987, 109, 1746–1754.
8. A series of closely related analogs of DiPAMP were prepared with different
substitution patterns on the P-o-An groups with substituents such as: MeO,
TMS, tBu, Ph, or a fused benzene ring. For this, see Ref. 3p.
Supplementary data
9. For phosphines, see: (a) Burk, M. J.; Wang, Y. M.; Lee, J. R. J. Am. Chem. Soc. 1996,
118, 5142–5143; (b) Burk, M. J.; Casy, G.; Johnson, N. B. J. Org. Chem. 1998, 63,
6084–6085; (c) Zhang, Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Zhang, X. J. Org. Chem.
1999, 64, 1774–1775; (d) Lee, S.-G.; Zhang, Y. J.; Song, C. E.; Lee, J. K.; Choi, J. H.
Angew. Chem., Int. Ed. 2002, 41, 847–849; For phosphites, see: (e) Huang, H.;
Zheng, Z.; Luo, H.; Bai, C.; Hu, X.; Chen, H. J. Org. Chem. 2004, 69, 2355–2361;
For phosphoramidites, see: (f) Hu, A.-G.; Fu, Y.; Xie, J.-H.; Zhou, H.; Wang, L.-X.;
Zhou, Q.-L. Angew. Chem., Int. Ed. 2002, 41, 2348–2350; (g) Jia, X.; Li, X.; Xu, L.;
Shi, Q.; Yao, X.; Chan, A. S. C. J. Org. Chem. 2003, 68, 4539–4541; (h) Hu, X.-P.;
Zheng, Z. Org. Lett. 2004, 6, 3585–3588; (i) Bernsmann, H.; van den Berg, M.;
Hoen, R.; Minnaard, A. J.; Mehler, G.; Reetz, M. T.; De Vries, J. G.; Feringa, B. L. J.
Org. Chem. 2005, 70, 943–951; (j) Liu, Y.; Ding, K. J. Am. Chem. Soc. 2005, 127,
10488–10489; (k) Zhang, W.; Zhang, X. Angew. Chem., Int. Ed. 2006, 45, 5515–
5518; (l) Zeng, Q.-H.; Hu, X.-P.; Duan, Z.-C.; Liang, X.-M.; Zheng, Z. J. Org. Chem.
2006, 71, 393–396.
Supplementary data (experimental procedures and characteriza-
tion data for all new compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.10.088.
References and notes
1. (a) Knowles, W. S.; Christopfel, W. C.; Koenig, K. E.; Hobbs, C. F. Adv. Chem. Ser.
1982, 196, 325–336; (b) Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J. J. Mol.
Catal. 1983, 19, 159–169; (c) Knowles, W. S. Angew. Chem., Int. Ed. 2002, 41,
1998–2007.
2. For general literature regarding phosphines, see: (a) Noyori, R. Asymmetric
Catalysis in Organic Synthesis; John Wiley
& Sons: New York, 1994;
(b) Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer: Berlin, 1999; Vol. 1–3; (c) Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; Wiley-VCH: Weinheim, 2000; (d) Asymmetric Catalysis on
Industrial Scale; Blaser, H. U., Schmidt, E., Eds.; Wiley-VCH: Weinheim, 2004;
(e) Transition Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH:
Weinheim, 2004; Vol. 1–2; (f) van Leeuwen, P. W. N. M. Homogeneous
Catalysis; Kluwer Academic Publishers: Dordrecht, 2004; For literature
overview on P-stereogenic phosphines, see: (g) Tang, W.; Zhang, X. Chem. Rev.
2003, 103, 3029–3069; (h) Grabulosa, A.; Granell, J.; Muller, G. Coord. Chem. Rev.
2007, 251, 25–90; (i) Phosphorus Ligands in Asymmetric Catalysis; Börner, A., Ed.;
Wiley-VCH: Weinheim, 2008; Vol. 1–3.
10. (a) Sun, Y.; Landau, R. N.; Wang, J.; LeBlond, C.; Blackmond, D. G. J. Am. Chem.
Soc. 1996, 118, 1348–1353; (b) Heller, D.; Drexler, H.-J.; Spannenberg, A.;
Heller, B.; You, J.; Baumann, W. Angew. Chem., Int. Ed. 2002, 41, 777–780; (c) In
case of DiPAMP, a dramatic decay of ee was observed in hydrogenation of
methyl (Z)-a-acetamidocinnamate at elevated pressures. For this, see Ref. 7.
11. For example, hydrogenation of
a
-phenyl- and -tert-butyl-acetamidoethylene
a
led to opposite configurations of the products using the same Rh-[(S,S)-tBu-
BisP*]. For this, see: Gridnev, I. D.; Higashi, N.; Imamoto, T. J. Am. Chem. Soc.
2000, 122, 10486–10487.