Asymmetric synthesis of functionalized diarylmethanols catalyzed by a new γ-amino thiol

Article abstract of DOI:10.1021/jo052017b

A mild asymmetric arylation of aromatic aldehydes catalyzed by γ-amino thiol 5 gave the corresponding diarylmethanols with 95 to >99.5% ee.

Full text of DOI:10.1021/jo052017b

Asymmetric Synthesis of Functionalized
Diarylmethanols Catalyzed by a New γ-Amino
Thiol
Ping-Yu Wu, Hsyueh-Liang Wu, and Biing-Jiun Uang*
Department of Chemistry, National Tsing Hua UniVersity,
Hsinchu, 300 Taiwan
bjuang@mx.nthu.edu.tw
ReceiVed September 27, 2005
FIGURE 1. Biologically active diarylmathanol derivatives and CDP-
840.
by nucleophilic displacement5 at the hydroxyl-bearing stereo-
genic center in optically active diarylmethanols.
Among the methods available for the synthesis of chiral
diarylmethanols,6 the asymmetric addition of diphenylzinc7-9
(5) (a) Hillier, M. C.; Desrosiers, J.-N.; Marcoux, J.-F.; Grabowski, E.
J. J. Org. Lett. 2004, 6, 573-576. (b) O’Shea, P. D.; Chen, C.-Y.; Chen,
W. R.; Dagneau, P.; Frey, L. F.; Grabowski, E. J. J.; Marcantonio, K. M.;
Reamer, R. A.; Tan, L.; Tillyer, R. D.; Roy, A.; Wang, X.; Zhao, D. L. J.
Org. Chem. 2005, 70, 3021-3030. (c) Bolshan, Y.; Chen, C.-Y.; Chilenski,
J. R.; Gosselin, F.; Mathre, D. J.; O’Shea, P. D.; Roy, A.; Tillyer, R. D.
Org. Lett. 2004, 6, 111-114.
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Hildebrand, J. P.; Mun˜iz, K.; Hermanns, N. Angew. Chem., Int. Ed. 2001,
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1986-2012.
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Lett. 2005, 7, 1407-1409. (b) Bolm, C.; Kesselgruber, M.; Hermanns, N.;
Hildebrand, J. P.; Raabe, G. Angew. Chem., Int. Ed. 2001, 40, 1488-1490.
(c) Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Mun˜iz, K. Angew. Chem.,
Int. Ed. 2000, 39, 3465-3467. (d) Bolm, C.; Mun˜iz, K. Chem. Commun.
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Fontes, M.; Verdaguer, X.; Sola`, L.; Perica`s, M. A.; Riera, A. J. Org. Chem.
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4, 3759-3762. (j) Zhao, G.; Li, X.-G.; Wang, X.-R. Tetrahedron:
Asymmetry 2001, 12, 399-403. (k) Dosa, P. I.; Ruble, J. C.; Fu, G. C. J.
Org. Chem. 1997, 62, 444-445.
A mild asymmetric arylation of aromatic aldehydes catalyzed
by γ-amino thiol 5 gave the corresponding diarylmethanols
with 95 to >99.5% ee.
Chiral diarylmethanols play an important role in the synthesis
of biologically active compounds,1 such as orphenadrine (1),
neobenodine (2),1d carbinoxamine (3)1e (Figure 1) and others2
which possess a common core feature in novel drug design. In
addition to their direct applications, chiral diarylmethanols could
also serve as useful intermediates in the synthesis of drugs. For
example, CDP-840 (4) (Figure 1)3 and its analogues are PDE-
IV inhibitors that are potent therapeutic agents for the treatment
of asthma and chronic obstructive pulmonary disease.4 Prepara-
tion of optically active trisubstituted diarylmethanes in this
analogues can be achieved without any loss of optical purity
* To whom correspondence should be addressed. Fax: 886-3-5711082. Tel:
886-3-5721224.
(1) (a) Meguro, K.; Aizawa, M.; Sohda, T.; Kawamatsu, Y.; Nagaoka,
A. Chem. Pharm. Bull. 1985, 33, 3787-3797. (b) Toda, F.; Tanaka, K.;
Koshiro, K. Tetrahedron: Asymmetry 1991, 2, 873-874. (c) Stanchev, S.;
Rakovska, R.; Berova, N.; Snatzke, G. Tetrahedron: Asymmetry 1995, 6,
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B.; Turner, P.; Boyce, B.; Barnes, D.; Mason, B.; Cannell, A.; Taylor, R.
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M.; Allen, R. A.; Gozzard, N.; Hughes, B.; Higgs, G. Bioorg. Med. Chem.
Lett. 2002, 12, 1451-1456. (b) Guay, D.; Hamel, P.; Blouin, M.; Brideau,
C.; Chan, C. C.; Chauret, N.; Ducharme, Y.; Huang, Z.; Girard, M.; Jones,
T. R.; Laliberte, F.; Masson, P.; McAuliffe, M.; Piechuta, H.; Silva, J.;
Young, R. N.; Girard, Y. Bioorg. Med. Chem. Lett. 2002, 12, 1457-1461.
(8) For some theoretical studies on diphenylzinc addition reactions, see:
(a) Rudolph, J.; Bolm, C.; Norrby, P.-O. J. Am. Chem. Soc. 2005, 127,
1548-1552. (b) Rudolph, J.; Rasmussen, T.; Bolm, C.; Norrby, P.-O.
Angew. Chem., Int. Ed. 2003, 42, 3002-3005.
(9) For recent studies of other organozinc reagents, see: (a) Jeon, S.-J.;
Chen, Y.-K.; Walsh, P. J. Org. Lett. 2005, 7, 1729-1732. (b) Lurain, A.
E.; Carroll, P. J.; Walsh, P. J. J. Org. Chem. 2005, 70, 1262-1268. (c)
Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125, 10677-10683.
(d) Lurain, A. E.; Maestri, A.; Kelly, A. R.; Carroll, P. J.; Walsh, P. J. J.
Am. Chem. Soc. 2004, 126, 13608-13609. (e) Chen, Y. K.; Lurain, A. E.;
Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 12225-12231. (f) Ji, J.-X.; Qiu,
L.-Q.; Yip, C. W.; Chan, A. S. C. J. Org. Chem. 2003, 68, 1589-1590. (g)
Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2003, 125,
761-768. (h) Wipf, P.; Kendall, C. Chem. Eur. J. 2002, 8, 1778-1784. (i)
Oppolzer, W.; Radinov, R. N. HelV. Chim. Acta 1992, 75, 170-173. (j)
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10.1021/jo052017b CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/06/2005
J. Org. Chem. 2006, 71, 833-835
833

SCHEME 1. Synthesis of a New γ-Amino Thiol Ligand
showed the advantages of wide substituent tolerance, mild
reaction conditions, and the use of low-toxic zinc metal.
Although high enantioselectivities have been achieved, the
nonsubstituted phenyl group as a transferring nucleophile limited
the application. More recently, an elegant method where arylzinc
reagent was prepared by transmetalation between arylboronic
acids and diethylzinc was reported by Bolm’s group10 and later
by others including other arylation compounds as aryltransfer
reagents.11 This modified methodology broadened the scope of
such an addition reaction and enabled synthetic chemists to
elaborate functionalized arylzinc reagents as nucleophiles in salt-
free conditions. Nevertheless, unlike some of the previous
reports in the asymmetric addition of diphenylzinc, an additive
such as DiMPEG12 was usually used to ensure high selectivities
in Bolm’s and Chan’s examples. Therefore, the search for a
catalytic system that catalyzes the asymmetric arylation of
aromatic aldehydes and will not require an additive remains
attractive.
TABLE 1. Asymmetric Phenylation of 4-Tolualdehyde Catalyzed
by 5a
entry
temp (°C)
time (h)
T/Hb
yield (%)c
ee (%)d
1
2
3
4
5
6
7e
18
18
18
5
5
5
12
24
48
24
0/1
1/3
5/3
1/3
1/3
1/3
1/3
81
90
80
83
83
84
67
90
92
90
95
96
97
95
0
-20
-35
0
a Conditions: 2 equiv of PhB(OH)2 and 6 equiv of Et2Zn was used with
respect to ArCHO. b The ratio of solvents: T, toluene; H, hexanes. c Isolated
yield. d Determined by chiral HPLC; see the Supporting Information. e 10
mol % of DiMPEG was added.
We are interested in employing camphor-derived ligands in
asymmetric catalysis.13 Here, we report our findings in the
asymmetric arylation reaction of aromatic aldehydes catalyzed
by (-)-2-exo-morpholinoisobornane-10-thiol 5. Amino thiol 5
was prepared from keto thiol 614 in five steps, as outlined in
Scheme 1. Direct formation of 10 from 7 by reductive amination
with morpholine was unsuccessful. As a result, 10 was prepared
by the condensation of 7 with hydroxyamine, followed by
The asymmetric phenylation reaction catalyzed by 5 was first
tested in the case of 4-tolualdehyde. The phenylzinc reagent
was prepared in situ by heating a mixture of diethylzinc and
phenylboronic acid in hexanes to 60 °C for 12 h. When the
phenylzinc reagent was mixed sequencially with 10 mol % of
5 and 4-tolualdehyde in hexanes at 18 °C and stirred for 5 h,
the corresponding diarylmethanol was obtained in 90% ee (Table
1, entry 1), and 5 was recovered in >95% yield. It was found
that a slightly better selectivity could be achieved simply by
using a mixed solvent containing toluene and hexanes in a 1:3
ratio (entry 2). There was no improvement of the enantiose-
lectivity on increasing the content of toluene in the mixed
solvent (Table 1, entry 3). With this encouraging result, the
temperature effect of the catalytic phenylation reaction was
studied. When the reaction was conducted at 0 °C, improvement
of the enantioselectivity was observed (entry 4). There was some
improvement of the enantioselectivity if the reaction was
conducted at a lower reaction temperature (entries 5 and 6).
These results were compatible with those observed in the
literature,10,11a where 10 mol % of DiMPEG was required as
an additive. It is interesting to note that the asymmetric
phenylation reaction catalyzed by 5 took a longer reaction time
and gave a lower yield with a similar ee in the presence of 10
mol % of DiMPEG (entries 4 and 7). Similar observations were
reported recently by Ito11b and Zhao.11d The synthesis of a direct
precursor for (R)-neobenodine (2) (Figure 1), an antihistamine
drug, was achieved by the addition of phenylzinc reagent with
4-tolualdehyde in a simple operation with high ee.
t
reduction with TiCl3 and BuNH2‚BH3 with >95% diastereo-
selectivity15 and N,N-dialkylation with 2-bromoethyl ether in a
reasonable yield. Amino thiol 5 was obtained from the reduction
of 10 with sodium in liquid ammonia at -78 °C in 64% yield.
(10) Bolm, C.; Rudolph, J. J. Am. Chem. Soc. 2002, 124, 14850-14851.
(11) (a) Ji, J.-X.; Wu, J.; Au-Yeung, T. T.-L.; Yip, C.-W.; Haynes, R.
K.; Chan, A. S. C. J. Org. Chem. 2005, 70, 1093-1095. (b) Ito, K.; Tomita,
Y.; Katsuki, T. Tetrahedron Lett. 2005, 46, 6083-6086. For other arylboron
compounds as reagents, see: (c) Ruldolph, J.; Schmidt, F.; Bolm, C. AdV.
Synth. Catal. 2004, 346, 867-772. (d) Wu, X.; Liu, X.; Zhao, G.
Tetrahedron: Asymmetry 2005, 16, 2299-2305. (e) Dahmen, S.; Lormann,
M. Org. Lett. 2005, 7, 4597-4600.
(12) (a) Rudolph, J.; Hermanns, N.; Bolm, C. J. Org. Chem. 2004, 69,
3997-4000. (b) Ruldoph, J.; Lormann, M.; Bolm, C.; Dahmen, S. AdV.
Synth. Catal. 2005, 347, 1361-1368.
(13) (a) Hwang, C.-D.; Uang, B.-J. Tetrahedron: Asymmetry 1998, 9,
3979-3984. (b) Hwang, C.-D.; Hwang, D. R.; Uang, B.-J. J. Org. Chem.
1998, 63, 6762-6763. (c) Chang, C.-W.; Yang, C.-T.; Hwang, C.-D.; Uang,
B.-J. Chem. Commun. 2002, 54-55. (d) Wu, H.-L.; Uang, B.-J. Tetrahe-
dron: Asymmetry 2002, 13, 2625-2628. (e) Uang, B.-J.; Fu, I.-P.; Hwang,
C.-D.; Chang, C.-W.; Yang, C.-T.; Hwang, D.-R. Tetrahedron 2004, 60,
10479-10486.
(14) Oae, S.; Togo, H. Bull. Chem. Soc. Jpn. 1983, 56, 3802-3812.
(15) Campos, K. R.; Journet, M.; Cai, D.; Kowai, J. J.; Lee, S.; Larsen,
R. D.; Reider, P. J. J. Org. Chem. 2003, 68, 2338-2342.
834 J. Org. Chem., Vol. 71, No. 2, 2006

TABLE 2. Asymmetric Arylation with Aromatic Aldehydes
Catalyzed by 5a
high chemical yields and enantioselectivities without the pres-
ence of an additional additive.16
In conclusion, an efficient and catalytic asymmetric synthesis
of diarylmethanols by the γ-amino thiol 5 was demonstrated.
This method provides a direct and convenient way to synthesize
functionalized diarylmethanols with high enantioselectivities
from the combination of readily available arylboronic acids and
aldehydes. This is the first example of γ-amino thiol catalyzed
asymmetric addition of arylzinc to aldehydes.
entry
Ar
4-Tol
3-Tol
2-Tol
4-Cl-Ph
3-Cl-Ph
2-Cl-Ph
4-MeO-Ph
4-CF3-Ph
4-CO2Me-Ph
2-Naph
Ph
Ar′
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-Tol
4-Cl-Ph
yield (%)b
ee (%)c,d
1
2
3
4
5
6
7
8
9
84
90
95
96
96
90
73
83
84
73e
86
98
97
97
>99.5
96
95
98
97
97
96
95
97
96
Experimental Section
Typical Experimental Procedure: Asymmetric Arylation of
4-Tolualdehyde Catalyzed by 5. A flask containing toluene (2
mL), phenylboronic acid (122 mg, 1 mmol), and diethylzinc (3.0
mmol, 1.0 M solution in hexanes) was heated at 60 °C for 12 h.
After the flask was cooled to room temperature, the mixture was
added into another flask containing 5 (12.8 mg, 0.05 mmol) and
was stirred for 10 min. It was cooled to -35 °C, and a solution of
4-tolualdehyde (60 mg, 0.5 mmol) in hexanes (3 mL) was added
with stirring. After 48 h at -35 °C, the reaction mixture was
quenched with saturated aqueous ammonium chloride and then
extracted with CH2Cl2 (3 × 70 mL). The organic extracts were
combined, dried, and concentrated in vacuo to give the crude
product. The crude product was purified on silica gel (EtOAc:
hexanes ) 1:6) to afford phenyl-p-tolylmethanol (83 mg, 84%; mp
58.5-59.5 °C) as colorless crystals.
10
11
12
Ph
a Conditions: 2 equiv of PhB(OH)2 and 6 equiv of Et2Zn was used with
respect to ArCHO. b Isolated yield. c Determined by chiral HPLC; see the
Supporting Information. d In entries 1-10, the R form of the products was
obtained, and in entries 11 and 12, the S form of the products was obtained.
e 27% of the ethylation product was isolated.
To test the scope and limitations of 5 in the asymmetric
catalytic arylation, we turned our attention to studying phenyl-
ation reactions with various aromatic aldehydes. When substi-
tuted aromatic aldehydes underwent phenylation under similar
reaction conditions, 95 to >99.5% ee’s and good to excellent
chemical yields of the corresponding diarylmethanols were
obtained (Table 2), except in the case of 2-naphthaldehyde,
where the ethylation product was obtained in 27% yield (entry
10). An excellent enantioselectivity was observed in the case
of 2-tolualdehyde, in which the product was obtained in >99.5%
ee and 96% yield. The synthesis of a direct precursor for (S)-
orphenadrine 1 (Figure 1) can be achieved by the reaction of
2-tolualdehyde in quite high efficiency. Other aryl transferring
reagents also reacted very well, as demonstrated in entries 11
and 12. In general, γ-amino thiol 5 catalyzed arylation gave
Acknowledgment. We thank the National Science Council,
Republic of China, for financial support.
Note Added after ASAP Publication. There were errors in
the version of Scheme 1 published ASAP December 6, 2005;
the corrected version was published ASAP December 7, 2005.
Supporting Information Available: Text giving experimental
procedures, ligand synthesis details, and HPLC data. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO052017B
(16) In the case of aliphatic aldehydes, cyclohexanecarboxaldehyde was
examined. The corresponding alcohol, cyclohexylphenylmethanol, was
obtained in 78% yield and 98% ee.
J. Org. Chem, Vol. 71, No. 2, 2006 835