Steric tuning of the amidomonophosphane-rhodium(l) catalyst in asymmetric addition of arylboroxines to n-phosphinoyl aldimines

Article abstract of DOI:10.1021/ol901866y

Highly enantioselective rhodium-catalyzed addition of arylboroxlnes to N-phosphinoylaldimines was realized by the steric tuning of a dlphenylphosphorus moiety to a di(o-tolyl)phosphorus moiety of a chiral amidomonophosphane. The presence of MS 4 A in a 5:1 solvent mixture of dioxane-propanol was essential to afford the corresponding dlarylmethylamines In high yield.

Full text of DOI:10.1021/ol901866y

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4470-4473
Steric Tuning of the
Amidomonophosphane-Rhodium(I)
Catalyst in Asymmetric Addition of
Arylboroxines to N-Phosphinoyl
Aldimines
Xinyu Hao,† Masami Kuriyama,† Qian Chen,‡ Yasutomo Yamamoto,†
Ken-ichi Yamada,† and Kiyoshi Tomioka*,†
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan and The Academy of Fundamental and Interdisciplinary
Science, Harbin Institute of Technology, Harbin, Heilongjiang, 150080, P. R. China
tomioka@pharm.kyoto-u.ac.jp
Received August 11, 2009
ABSTRACT
Highly enantioselective rhodium-catalyzed addition of arylboroxines to N-phosphinoylaldimines was realized by the steric tuning of a
diphenylphosphorus moiety to a di(o-tolyl)phosphorus moiety of a chiral amidomonophosphane. The presence of MS 4 Å in a 5:1 solvent
mixture of dioxane-propanol was essential to afford the corresponding diarylmethylamines in high yield.
Diarylmethylamines are key building blocks and potential
intermediates for some biologically significant pharmaceu-
ticals.1 Asymmetric addition of arylmetal reagents to CdN
double bonds of arylimines is a fundamentally important
process2 that provides convenient and versatile routes to this
class of optically active amines.3 In contrast to the extensively
studied catalytic asymmetric alkylation reactions of imines,4
however, the arylation counterpart has been less well
explored. The earliest success of this type of arylation was
the asymmetric addition of phenyllithium to N-(4-methoxy-
phenyl)imines with a substoichiometric amount of (-)-
sparteine reported by Denmark.4c In 2000, Hayashi developed
a brilliant catalytic asymmetric addition of arylstannane to
N-sulfonylimines.5 The toxic tin reagents were later replaced
by aryltitanium reagents.6 Bra¨se reported the asymmetric
addition of diphenylzinc to N-formylimines, generated in situ,
(2) Reviews: (a) Denmark, S. E.; Nicaise, O. J.-C. J. Chem. Soc., Chem.
Commun. 1996, 999–1004. (b) Arend, M.; Westermann, B.; Risch, N.
Angew. Chem., Int. Ed. 1998, 37, 1044–1070. (c) Kobayashi, S.; Ishitani,
H. Chem. ReV. 1999, 99, 1069–1094. (d) Friestad, G. K.; Mathies, A. K.
Tetrahedron 2007, 63, 2541–2569. (e) Bra¨se, S.; Baumann, T.; Dahmen,
S.; Vogt, H. Chem. Commun. 2007, 1881–1890. (f) Yamada, K.; Tomioka,
K. Chem. ReV. 2008, 108, 2874–2886.
† Kyoto University.
‡ Harbin Institute of Technology.
(1) (a) Spencer, C. M.; Foulds, D.; Peters, D. H. Drugs 1993, 46, 1055–
1080. (b) Bishop, M. J.; McNutt, R. W. Bioorg. Med. Chem. Lett. 1995, 5,
1311–1314. (c) Sakurai, S.; Ogawa, N.; Suzuki, T.; Kato, K.; Ohashi, T.;
Yasuda, S.; Kato, H.; Ito, Y. Chem. Pharm. Bull. 1996, 44, 765–777.
10.1021/ol901866y CCC: $40.75
Published on Web 09/09/2009
 2009 American Chemical Society

using a catalytic amount of an N,O-ligand.7 We have also
contributed to this research field by developing a rhodium-
catalyzed asymmetric addition of arylboroxine to N-sulfo-
nylimine using N-Boc-L-valine-connected amidomonophos-
phane 1 as a chiral ligand.8 Arylboronic acid and arylboroxine
are attractive arylating reagents because of their lower
toxicity, stability in air and moisture, commercial availability,
and good tolerance to a wide range of functional groups.9
Other research groups have also reported the rhodium-
catalyzed asymmetric addition of arylboronic reagents to
N-tosylaldimines using ligands such as C2-symmetric chiral
diene,10 a spirocyclic phosphite,11 or N-linked bidentate
phosphoramidite.12 Although these methods yield products
with high enantioselectivity, the conditions required for the
reductive removal of a tosyl group from nitrogen, such as
samarium(II) iodide with HMPA in refluxing THF, are
incompatible with electron-accepting functional groups, e.g.
carbonyl, nitro, and halogens. Recently, the rhodium-
catalyzed asymmetric addition of arylboronic acid to N-
diphenylphosphinoyl-(Dpp)13 and N-Boc-imines14 generated
in situ using chiral bisphosphine ligand and to N-sulfa-
moylimines15 using phosphoramidite ligands were reported,
but the scope of N-Dpp-imines has not been examined.
Herein, we report a highly enantioselective rhodium-
catalyzed addition reaction of arylboroxines to N-Dpp-
arylimines, utilizing a sterically tuned amidomonophosphane
as the ligand, which provides a versatile entry to a wide range
of optically active diarylmethylamines.
The initial stage of our study was performed using 1.67
equiv of biphenylboroxine 4a in the presence of a chiral
amidomonophosphane 1-Rh complex (6 mol %) in pro-
panol, the conditions we previously developed for the
enantioselective addition of N-tosylimines 2 (Table 1).8
Table 1. Rh(I)-1-Catalyzed Asymmetric Arylation of N-Tosyl-
and N-Dpp-imines 2 and 3 with 4-Biphenylboroxine 4aa
entry imine
Ar
R
time (h) yieldb (%) eec (%)
1
2
3
4
2a
3a
Ph
Ph
Ts
P(dO)Ph2
3
83
95
98
74
66
70
91
81
(3) Selected examples for asymmetric synthesis of diarylmethylamines:
(a) Tomioka, K.; Inoue, I.; Shindo, M.; Koga, K. Tetrahedron Lett. 1990,
31, 6681–6684. (b) Pridgen, L. N.; Mokhallalati, M. K.; Wu, M. J. J. Org.
Chem. 1992, 57, 1237–1241. (c) Corey, E. J.; Helal, C. J. Tetrahedron Lett.
1996, 37, 4837–4840. (d) Delorme, D.; Berthelette, C.; Lavoie, R.; Roberts,
E. Tetrahedron: Asymmetry 1998, 9, 3963–3966. (e) Taniyama, D.;
Hasegawa, M.; Tomioka, K. Tetrahedron Lett. 2000, 41, 5533–5536. (f)
Pflum, D. A.; Krishnamurthy, D.; Han, Z.; Wald, S. A.; Senanayake, C. H.
Tetrahedron Lett. 2002, 43, 923–926. (g) Plobeck, N.; Powell, D. Tetra-
hedron: Asymmetry 2002, 13, 303–310. (h) Han, Z.; Krishnamurthy, D.;
Grover, P.; Fang, Q. K.; Pflum, D. A.; Senanayake, C. H. Tetrahedron Lett.
2003, 44, 4195–4197. (i) Cabello, N.; Kizirian, J.-C.; Alexakis, A.
Tetrahedron Lett. 2004, 45, 4639–4642.
3
2b 2-TMSC6H4 Ts
3
3.5
3b 2-TMSC6H4 P(dO)Ph2
a Reaction of 0.2 mmol of 2 or 3 with 6 mol % of Rh(acac)(C2H4)2 and
6.6 mol % of 1 at 80 °C. b Isolated yield. c Determined by chiral HPLC.
Reaction of Dpp-imine 3a was complete within 3 h, and the
addition product 6aa16 with 70% ee was obtained in 95%
yield (entry 2). This enantioselectivity paralleled that of
tosylimine 2a (entry 1). The 2-TMSC6H4 imine 3b, which
was effective in the reaction of tosylimine 2b (91% ee, entry
3), slightly improved the enantioselectivity to 81% ee (entry
4). Because the enantioselectivity was not satisfactory for
N-Dpp-imines 3 (entries 2 and 4), however, steric tuning of
the amidophosphane was the target of the second stage of
the study based on the stereochemical analysis.
(4) Selected examples of catalytic asymmetric alkylation of imines: (a)
Tomioka, K.; Inoue, I.; Shindo, M.; Koga, K. Tetrahedron Lett. 1991, 32,
3095–3098. (b) Soai, K.; Hatanaka, T.; Miyazawa, T. J. Chem. Soc., Chem.
Commun. 1992, 1097–1098. (c) Denmark, S. E.; Nakajima, N.; Nicaise,
O. J.-C. J. Am. Chem. Soc. 1994, 116, 8797–8798. (d) Fujihara, H.; Nagai,
K.; Tomioka, K. J. Am. Chem. Soc. 2000, 122, 12055–12056. (e) Dahmen,
S.; Bra¨se, S. J. Am. Chem. Soc. 2002, 124, 5940–5941. (f) Boezio, A. A.;
Charette, A. B. J. Am. Chem. Soc. 2003, 125, 1692–1693. (g) Pizzuti, M. G.;
Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2008, 73, 940–947.
(5) (a) Hayashi, T.; Ishigetani, M. J. Am. Chem. Soc. 2000, 122, 976–
977. (b) Hayashi, T.; Ishigetani, M. Tetrahedron 2001, 57, 2589–2598.
Review: (c) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829–2844.
(6) Hayashi, T.; Kawai, M.; Tokunaga, N. Angew. Chem., Int. Ed. 2004,
43, 6125–6128.
The X-ray crystal structure of rhodium(I)-717 suggests
that the CdN double bond of N-Dpp-imine 3a coordinates
to rhodium(I)18 on the Re-face (A) to give the product with
the observed S-configuration (Figure 1). Coordination on the
Si-face (B) is unfavorable due to steric repulsion between
the axial phenyl of the phosphorus and the phenyl group of
Dpp. This analysis indicated that the bulkiness of the phenyl
(7) Hermanns, N.; Dahmen, S.; Bolm, C.; Bra¨se, S. Angew. Chem., Int.
Ed. 2002, 41, 3692–3694.
(8) Kuriyama, M.; Soeta, T.; Hao, X.; Chen, Q.; Tomioka, K. J. Am.
Chem. Soc. 2004, 126, 8128–8129.
(9) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483.
(10) (a) Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani,
R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584–13585. (b) Otomaru,
Y.; Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett. 2005, 7, 307–310.
(c) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. J. Am. Chem. Soc.
2007, 129, 5336–5337.
(16) The first “a” and second “a” of 6aa are derived from the suffixes
of 3a and 4a, respectively.
(17) Kuriyama, M.; Nagai, K.; Yamada, K.; Miwa, Y.; Taga, T.;
Tomioka, K. J. Am. Chem. Soc. 2002, 124, 8932–8939.
(18) The Ar-Rh(I) species is formed by transmetalation between
rhodium(I) and arylboroxine at the trans side to phosphorus, which is the
most vacant coordination site and influenced by the trans effect of phosphine.
See ref 17.
(11) Duan, H.-F.; Jia, Y.-X.; Wang, L.-X.; Zhou, Q.-L. Org. Lett. 2006,
8, 2567–2569.
(12) Kurihara, K.; Yamamoto, Y.; Miyaura, N. AdV. Synth. Catal. 2009,
351, 260–270.
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127, 1092–1093. (b) Trincado, M.; Ellman, J. A. Angew. Chem., Int. Ed.
2008, 47, 5623–5626.
(19) Casalnuovo, A. L.; RajanBabu, T. V.; Ayers, T. A.; Warren, T. H.
J. Am. Chem. Soc. 1994, 116, 9869–9882.
(14) Nakagawa, H.; Rech, J. C.; Sindelar, R. W.; Ellman, J. A. Org.
Lett. 2007, 9, 5155–5157.
(20) Bis(3,5-diphenylphenyl)phosphoryl chloride was synthesized from
(Et2N)PCl2 and 3,5-diphenylphenylmagnesium bromide, which was prepared
from known aryl bromide. Du, C. F.; Hart, H.; Na, K. D. J. Org. Chem.
1986, 51, 3165–3169.
(15) Jagt, R. B. C.; Toullec, P. Y.; Geerdink, D.; de Vries, J. G.; Feringa,
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Org. Lett., Vol. 11, No. 19, 2009
4471

which was increased by o-methyl groups, would prevent
imine 3a coordination to the rhodium metal. Very bulky
bis(3,5-diphenylphenyl)phosphane 15 was not effective and
resulted in poor yield and enantioselectivity (entry 2).
Screening of the reaction solvents revealed that a 5:1 mixture
of dioxane and propanol at 80 °C afforded 6aa with
excellently high 98% ee in 81% yield (entries 3 and 4).
Almost the same selectivity was observed with the same
facial selectivity in the reactions using N-Boc-L-valine-
connected ligand 11 (81%, 98% ee), N-Boc-D-valine-con-
nected ligand 12 (80%, 95% ee), and N-Cbz-L-valine-
connected ligand 13 (84%, 96% ee) (entries 4-6). Ligand
14 under the same conditions gave 6aa with 90% ee in 61%
yield (entry 7). These results indicated the o-methyl groups
on the benzene ring of phosphorus are very helpful for
producing high enantioselectivity and that the amide group
of the pyrrolidine nitrogen was not crucial for enantiofacial
selectivity.
The significant amount of benzaldehyde (entries 1-7)
observed indicates hydrolysis by water, which would be
generated by alcoholysis of boroxine.21,22 Actually, the
addition of 5 equiv of water resulted in hydrolysis of the
imine 3a, and no addition product 6aa was obtained (entry
8). In the presence of MS 4 Å, the yield of 6aa was greatly
improved to 93%, and no benzaldehyde was observed, even
in the crude mixture of the reaction (entry 9). The use of
alcoholic solvent was important; the reaction in dioxane as
a sole solvent gave a yellow suspension due to insolubility
of the boroxine 4a, providing 6aa in poor yield (9%; entry
10). The use of MS 4 Å as an additive in propanol did not
increase the chemical yield (entry 11).
Figure 1. Stereochemical analysis of enantioselective pathway.
group of the phosphorus favors A over B, and therefore,
increased bulkiness should improve the enantioselectivity of
the reaction.
The sterically tuned di(o-tolyl)phosphanes 11-14 and
bis(3,5-diphenylphenyl)phosphane 15 were synthesized as
shown in Scheme 1. Commercially available di(o-tolyl)phos-
Having established the optimal protocol (Table 2, entry 9),
arylation with other arylboroxines and N-Dpp-aldimines was
examined (Table 3). Arylation of 3a with p-methyl-, p- and
m-methoxy-, and p-chlorophenylboroxines proceeded satisfac-
torily in high to excellent yield (88-96%) and excellent
enantioselectivity (95-98% ee) (entries 1-4). This high
performance indicates that the arylboroxines bearing both
electron-donating and -withdrawing substituents on the phenyl
group are tolerated in this arylation reaction. Excellent enan-
tioselectivity (98% ee) was also observed with bulky 4-biphe-
nylboroxine (entry 5). This rhodium-catalyzed asymmetric
arylation was applicable to a variety of N-Dpp-imines 3.
Arylation of 3c and 3d derived from arylaldehydes bearing an
electron-donating p-methyl- or a sterically demanding o-
methylphenyl group gave the corresponding addition products
in high yield (86-95%) and high to excellent enantioselectivity
(94-99% ee; entries 7-9). Arylation of electron-deficient
imines 3e and 3f bearing a chloro or a trifluoromethyl group at
Scheme 1. Synthesis of Sterically Tuned Ligands 11-15
a Synthesized from 10 in 91% yield by (i) HCl-dioxane and (ii) PivCl.
phoryl chloride 819 was coupled with 9 to give N-Boc
phosphane 10. The N-Boc group was then replaced with
N-Boc-L- or -D-Val (11 and 12), N-Cbz-L-Val (13), and a
pivaloyl group (14). Bis(3,5-diphenylphenyl)phosphane 15
was also synthesized in the same manner.20
The reaction of biphenylboroxine 4a and N-Dpp-imine 3a
was catalyzed by Rh(I)-11 to give 6aa with 90% ee (Table
2, entry 1). The reaction was sluggish, however, and did not
reach completion after 12 h, even at 80 °C. The bulkiness,
(21) Lappert, M. F. Chem. ReV. 1956, 959–1064
.
(22) Another possibility is a boronic acid impurity in the boroxines,
which were prepared by heating the corresponding boronic acids at 120 °C
under 10 mmHg for 12 h. If the boronic acids remain impure, water is
generated by forming boroxine in situ. The use of 4a, dried at 220 °C under
0.5 mmHg for 4 h prior to use, however, did not make a significant
difference (6aa, 82%, 98% ee; PhCHO, 6%) under the conditions shown
in Table 2, entry 4. Therefore, this possibility was excluded.
(23) Ramage, R.; Hopton, D.; Parrott, M.; Kenner, G. W.; Moore, G. A.
J. Chem. Soc., Perkin Trans. 1 1984, 1357–1370
(24) Botta, M.; Corelli, F.; Gasparrini, F.; Messina, F.; Mugnaini, C. J.
Org. Chem. 2000, 65, 4736–4739
.
.
4472
Org. Lett., Vol. 11, No. 19, 2009

Table 2. Asymmetric Arylation of N-Phosphinoylbenzaldimine 3a with 4-Biphenylboroxine 4a Catalyzed by Ligand-Rh(I)a
entry
ligand
solvent
MS 4 Å
time (h)
yieldb (%)
eec (%)
3a (%)
PhCHO (%)
1
11
15
11
11
12
13
14
11
11
11
11
PrOH
PrOH
none
none
none
none
none
none
none
none
12
18
12
12
12
12
12
12
12
12
12
48
22
60
81
80
84
61
0
90
36
94
98
95
96
90
6
42
5
0
0
0
0
8
0
18
30
10
9
12
11
30
92
0
2d
3
PhMe/PrOH (10/1)
dioxane/PrOH (5/1)
dioxane/PrOH (5/1)
dioxane/PrOH (5/1)
dioxane/PrOH (5/1)
dioxane/H2Oe
dioxane/PrOH (5/1)
dioxane
PrOH
4
5
6
7
8
9
10
11
200 mg
200 mg
200 mg
93
98
nd
89
9f
52
39
39
9
17
a Reaction of 0.2 mmol of 3a with 6 mol % of Rh(acac)(C2H4)2 and 6.6 mol % of amidophosphane 11-15 at 80 °C. b Isolated yield. c Determined by
f
chiral HPLC. d The reaction was run at 60 °C. e 1 mmol of water was added. Based on the crude H NMR.
1
the para position of the benzene ring gave the addition products
with 90-96% ee (entries 10-12). 1-Naphthaldimine 3g,
2-naphthaldimine 3h, and 2-furancarboaldimine 3i were also
applicable to give the products with 86%, 97%, and 92% ee,
respectively (entries 13-15).
It is also important to note that catalyst loading could be
reduced to 1 mol % to give 6aa with 96% ee in 76% yield
(entry 6).
The N-phosphinoyl group was readily removed without
any racemization under the reported mildly acidic conditions
(HCl in dioxane/MeOH at room temperature).23 The products
6aa and 6ac gave the corresponding diarylmethylamines24,6
in 97% and 93% yield, respectively. The stereochemistry of
6aa was determined by applying Mosher’s method to this
deprotected amine. The stereochemistry of 6ac and 6ae was
confirmed by comparing the specific rotation to those
reported.13a The stereochemistry of the other products was
tentatively assigned by analogy.
In conclusion, steric tuning of the amidophosphane ligand
improved the enantioselectivity up to 99% ee in Rh(I)-
catalyzed asymmetric addition of N-Dpp-aldimines with
arylboroxines. The increased bulkiness of the ligand slowed
the reaction rate, causing competitive hydrolysis of the imine.
The removal of water generated in situ by the addition of
MS 4 Å was important to obtain the addition product in good
yield. The N-Dpp group was easily removed to form
diarylmethylamines under a mildly acidic condition. This
method provides a convenient and versatile access to a
variety of optically active diarylmethylamine derivatives.
Table 3. Amidomonophosphane-Rh-Catalyzed Asymmetric
Arylation of N-Dpp-imines 3
entry
Ar1
Ph (3a)
Ar2
yield/%
ee/%
1
2
4-CH3C6H4 (4b)
4-MeOC6H4 (4c)
96 (6ab)
92 (6ac)
98
98
95
98
98
96
99
94
95
92
96
90
86
97
92
Ph (3a)
Acknowledgment. This research was partially supported
by the 21st Century COE (Center of Excellence) Program
“Knowledge Information Infrastructure for Genome Sci-
ence”, a Grant-in-Aid for Scientific Research in Priority
Areas “Advanced Molecular Transformations of Carbon
Resources”, a Grant-in-Aid for Scientific Research (A), and
the Targeted Proteins Research Program of the Ministry of
Education, Culture, Sports, Science, and Technology, Japan.
3
Ph (3a)
3-MeOC6H4 (4d) 88 (6ad)
4
Ph (3a)
Ph (3a)
Ph (3a)
4-CH3C6H4 (3c)
2-CH3C6H4 (3d) Ph (4f)
2-CH3C6H4 (3d) 4-PhC6H4 (4a)
4-ClC6H4 (3e)
4-ClC6H4 (3e)
4-CF3C6H4 (3f)
1-Naph (3g)
2-Naph (3h)
2-furyl (3i)
4-ClC6H4 (4e)
4-PhC6H4 (4a)
4-PhC6H4 (4a)
4-PhC6H4 (4a)
90 (6ae)
93 (6aa)
76 (6aa)
93 (6ca)
86 (6df)
95 (6da)
80 (6ef)
85 (6ea)
83 (6fa)
76 (6gb)
92 (6hb)
84 (6ib)
5
6a
7
8
9
10
11
12
13
14
15
Ph (4f)
4-PhC6H4 (4a)
4-PhC6H4 (4a)
4-CH3C6H4 (4b)
4-CH3C6H4 (4b)
4-CH3C6H4 (4b)
Supporting Information Available: Experimental details;
analytical and spectral characterization data of the ligands
and the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Rh(acac)(C2H4)2 (1 mol %) and 11 (1.1 mol %) were used.
OL901866Y
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4473