Readily available biaryl P,N ligands for asymmetric catalysis

Article abstract of DOI:10.1002/anie.200461286

A short and modular synthesis of novel P,N ligands (pinap; see scheme; X = O or NH) is presented. A covalently bound chiral group allows the separation of the atropisomeric diastereomers, thus avoiding resolution involving chiral Pd-amine complexes. The utility of the ligands is demonstrated for three reactions catalyzed by different transition metals; in each case products are obtained with high enantiomeric excess (up to 99% ee).

Full text of DOI:10.1002/anie.200461286

Angewandte
Chemie
available atropisomeric P,N ligands (pinap)[5] that are struc-
turally similar to quinap and have parallel reactivity. They
have the additional advantage, however, that, unlike quinap,
they are conveniently prepared and resolved as well as easily
amenable to structural and electronic modifications. We
describe their synthesis, as well as applications in reactions
involving Rh, Ag, and Cu catalysts, which demonstrate their
utility. In the Cu-catalyzed coupling of acetylenes and imines
they are superior to quinap and afford products with the
highest enantioselectivity reported to date.
Quinap was developed by Brown and co-workers in
1993.[6] The six-step sequence for its synthesis includes a Pd-
catalyzed coupling of 2-methoxy-1-naphthylboronic acid and
1-chloroisoquinoline to generate the biaryl scaffold. After
introduction of the phosphinyl group, the resolution of the
enantiomeric atropisomers is carried out as the final step by
treatment of (Æ )-quinap with a preformed chiral Pd complex
prepared from (R)- or (S)-N,N-dimethyl-1-naphthalen-1-
ylethylamine.[7] Quinap is commercially available, but it is
rather expensive.[8] The design and synthesis of related biaryl
P,N ligands has been the focus of numerous research
groups.[2a,c] However, resolution of the ligands has proven
difficult and has inevitably involved fractional crystallization
of diastereomeric Pd complexes. This has limited the extent of
structural and electronic modification that can be examined
with this scaffold.
Asymmetric Catalysis
Readily Available Biaryl P,N Ligands for
Asymmetric Catalysis**
Thomas F. Knöpfel, Patrick Aschwanden,
Takashi Ichikawa, Takumi Watanabe, and
Erick M. Carreira*
Key to our ligand design is the use of a covalently bound
chiral group, which facilitates resolution at any of the various
steps of the ligand synthesis. As shown in Scheme 1, the core
of the ligand is easily accessed by coupling 1,4-dichloro-
phthalazine with 2-naphthol to give 1 in 77% yield.[9]
Importantly, the use of the dichlorophthalazine allows both
convenient construction of the biaryl unit and subsequent
introduction of a chiral amine or an alcohol.
The discovery and development of new chiral ligands for
transition-metal complexes is critical for expanding the scope
of catalytic asymmetric synthesis.[1] The P,N ligands are a
highly successful class,[2] in which quinap[3] holds a special
place because it displays unique reactivity and selectivity[4]
(e.g. in hydroboration,[4a] alkyne addition,[4c] diboration[4d] and
azomethine cycloaddition).[4e] Herein, we present new, readily
Treatment of 1 with (R)-phenylethanol afforded the
diastereomeric aryl ethers (82% yield, d.r. = 1:1), which
were subsequently converted into triflates 2 (91% yield).
Ni-catalyzed coupling of 2 with HPPh2 furnished ligands 3a
and 3b in 70% combined yield. The two atropisomeric
diastereomers were separated at this stage either by chroma-
tography on silica gel or, alternatively, by crystallization.[10]
The absolute configuration of 3a was shown to be R,M by X-
ray structure analysis.[11]
[*] T. F. Knöpfel, P. Aschwanden, Dr. T. Ichikawa, Dr. T. Watanabe,
Prof. Dr. E. M. Carreira
Laboratorium für Organische Chemie
ETH Hönggerberg, HCI H335
8093 Zürich (Switzerland)
Fax: (+41)1-632-1328
E-mail: carreira@org.chem.ethz.ch
[**] This work was generously supported by Sumika Fine Chemicals
(now Sumitomo Chemical Co., Ltd.).
The synthesis of a related structure incorporating (R)-(+)-
a-phenethylamine was carried out similarly (Scheme 1).
Ligands 5a and 5b were isolated in 69% yield over three
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 5971 –5973
DOI: 10.1002/anie.200461286
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
Scheme 1. a) AlCl3, DCE, 808C, 77%; b) (R)-phenylethanol, NaH (2 equiv), THF, 238C, 82%; c) Tf2O, pyridine, CH2Cl2, 08C, 91%; d) [NiCl2(dppe)]
(10 mol%), HPPh2, DABCO, DMF, 1008C, 70%; e) Tf2O, pyridine, CH2Cl2, 08C, 93%; f) (R)-phenylethylamine (5 equiv), neat, 1208C, 93%,
g) [NiCl2(dppe)] (10 mol%), HPPh2, DABCO, DMF, 1308C, 80%. DABCO=1,4-diazabicyclo[2.2.2]octane, DCE=1,2-dichloroethane, Tf=trifluoro-
methanesulfonyl.
steps (d.r. = 1:1.2). These ligands are conveniently separated
by crystallization or chromatography on silica gel.[10] The
stereochemistry of 5a was assigned unambiguously by X-ray
structure analysis.[11]
that 3 mol% of the putative AgI complex of 3a catalyzes the
reaction, affording adducts with high yields and enantiose-
lectivities (Scheme 2).[15]
We tested these ligands in three different reactions. In the
Rh-catalyzed hydroboration[12] the cationic RhI complex
formed with 3a proved to be optimal,[13] leading to optically
active alcohols in 2 h using 1 mol% catalyst (room temper-
ature). The regio- (86:14 to > 99:1) and enantioselectivity
(84–92% ee; Table 1) are comparable to those reported for
Table 1: Rh-catalyzed hydroboration.
Scheme 2. Ag-catalyzed azomethine cycloaddition reaction with acryl-
ates.
Our interest in the chemistry of terminal acetylenes[16]
compelled us to examine the ligands in the Cu-catalyzed
reaction of alkynes and imines. First reported in 1963,[17] these
additions have been recently investigated by Knochel et al.
with the complex formed by quinap and CuBr.[4c] We have
observed that the CuI complexes of 5a and 5b catalyze the
formation of the propargylic amines in 90–99% ee,[18] which
are the best values obtained to date (Table 2).
Entry
R
Yield [%]
ee [%]
Quinap [%ee][4a]
1
2
3
4
5
6
Ph
p-Tol
m-Tol
o-Tol
p-MeO-C6H4
p-Cl-C6H4
73
94
85
81
80
87
92
92
84
91
90
87
92
89
86
92
94
78
quinap, which is the ligand that demonstrates the broadest
scope for this reaction.[4a] Interestingly, an important differ-
ence in reactivity was observed for the RhI complex of 3a
when compared to previous work. Thus, in contrast to
reactions with quinap, the electronics of the aryl substrate
exerted little influence on the ee value of the product
(Table 1, entries 5 and 6), indicating an unanticipated advant-
age of the complex derived from 3a.
The asymmetric, Ag-catalyzed azomethine cycloaddition
reaction with acrylates first reported by Zhang et al.[14] was
examined next. Its substrate scope has been recently
expanded by using a Ag–quinap catalyst.[4e] We have observed
Table 2: Cu-catalyzed addition of alkynes to imines.
R
R’
Ligand
Yield [%]
ee [%]
Quinap [%ee][4c]
iPr
Me3Si
5a
5b
5a
5b
5a
5b
84
82
88
82
74
72
98 (R)
99 (S)
90 (R)
95 (S)
91 (R)
94 (S)
92
iPr
Ph
84
82
iBu
nBu
5972
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ving.html (or from the Cambridge Crystallographic Data Centre,
12, Union Road, Cambridge CB21EZ, UK; fax: (+ 44)1223-
336-033; or deposit@ccdc.cam.ac.uk).
In the examined reactions, the configuration of the biaryl
moiety dictates stereoinduction. It is noteworthy that in this
process subtle remote effects are observed with respect to the
stereogenic center in the phenethyl group. Thus, when
compared to 5a, the use of the diastereomeric ligand 5b can
lead to a measurable and consistent increase (up to 5%) in
the ee value of the product (Table 2). Interestingly, in these
additions it is the R,P-configured ligand that affords the
higher selectivities, whereas in the hydroboration and cyclo-
addition reactions the R,M-configured ligands proved supe-
rior.
[12] a) T. Hayashi, Y. Matsumoto, Y. Ito, J. Am. Chem. Soc. 1989, 111,
3426 – 3428; b) J. M. Brown, D. I. Hulmes, T. P. Layzell, J. Chem.
Soc. Chem. Commun. 1993, 1673 – 1674; c) A. Schnyder, L.
Hintermann, A. Togni, Angew. Chem. 1995, 107, 628 – 630;
Angew. Chem. Int. Ed. Engl. 1995, 34, 931 – 933.
[13] Ligand 3b gave slightly lower enantioselectivities (89% ee in the
hydroboration of styrene). The complexes with ligands 5a and
5b gave lower enantioselectivities and yields.
[14] J. M. Longmire, B. Wang, X. Zhang, J. Am. Chem. Soc. 2002, 124,
13400 – 13401.
In conclusion, we have presented a new class of P,N li-
gands and demonstrated their utility in three different
asymmetric reactions with three different metals. The effi-
ciency (four steps from commercially available material) and
modular nature of the synthesis should permit fine tuning of
the ligand to accommodate a broad scope of asymmetric
transformations. Further studies aimed at diversifying the
structure of the ligands and their application in new reactions
are underway in our laboratories.
[15] Ligand 3b gave slightly lower enantioselectivities (93% ee for
R = CN). The complexes with ligands 5a and 5b gave lower
enantioselectivities and yields.
[16] a) D. E. Frantz, R. Fꢀssler, E. M. Carreira, J. Am. Chem. Soc.
2000, 122, 1806 – 1807; b) N. K. Anand, E. M. Carreira, J. Am.
Chem. Soc. 2001, 123, 9687 – 9688; c) D. E. Frantz, R. Fꢀssler,
E. M. Carreira, J. Am. Chem. Soc. 1999, 121, 11245 – 11246;
d) C. Fischer, E. M. Carreira, Org Lett. 2001, 3, 4319 – 4321;
e) T. F. Knꢁpfel, E. M. Carreira, J. Am. Chem. Soc. 2003, 125,
6054 – 6055.
[17] K. C. Brannock, R. D. Burpitt, J. G. Thweatt, J. Org. Chem. 1963,
28, 1462 – 1464.
Received: July 13, 2004
[18] Ligands 3a and 3b gave comparable results (for R = iPr and R’ =
Ph; 3a: 92% ee (R) and 3b: 94% ee (S)).
Keywords: asymmetric catalysis · atropisomerism ·
heterocycles · hydroboration · P,N ligands
.
[1] Comprehensive Asymmetric Catalysis, Vol. 1–3 (Eds.: E. N.
Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999.
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[3] Quinap: 1-(2-diphenylphosphino-1-naphthyl)isoquinoline.
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[5] We suggest the acronym pinap in analogy to quinap, where “pi”
refers to phthalazine.
[6] N. W. Alock, J. M. Brown, D. I. Hulmes, Tetrahedron: Asymme-
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[7] C. W. Lim, O. Tissot, A. Mattison, M. W. Hooper, J. M. Brown,
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[8] 50 mg (P)- or (M)-quinap costs E 143 at STREM.
[9] M. Pal, V. R. Batchu, K. Parasuraman, K. Yeleswarapu, J. Org.
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[10] Depending on the scale, different separation procedures were
applied. Typically on > 2 g scale either 3a or 5a was selectively
crystallized from the mixture (see Supporting Information for
details), and the residue was purified by flash chromatography.
On a smaller scale the diastereomers were separated by flash
chromatography; for example, 1.21 g of a mixture of 3a/3b was
separated by flash chromatography to give 3a (595 mg) and 3b
(501 mg; 91% mass recovery).
[11] CCDC-243850 (3a) and CCDC-243851 (5a) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrie-
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