Ag-catalyzed stereoselective cyclohexadienyl transfer: A novel entry into arylphenylmethanols

Article abstract of DOI:10.1021/ol703080a

The letter describes a novel concept for the synthesis of biologically important arylphenylmethanols. Stereoselective cyclohexadienyl transfer from 1,4-cyclohexadienyltributyltin to various aromatic aldehydes using AgOTf/BINAP as a catalyst precursor provides 1,4-cyclohexadienylphen-ylmethanols that are readily oxidized to the corresponding arylphenylmethanols. Fifteen examples are presented.

Full text of DOI:10.1021/ol703080a

ORGANIC
LETTERS
2008
Vol. 10, No. 5
993-996
Ag-Catalyzed Stereoselective
Cyclohexadienyl Transfer: A Novel
Entry into Arylphenylmethanols
Rui Umeda and Armido Studer*
Fachbereich Chemie, Organisch-Chemisches Institut, Westfa¨lische
Wilhelms-UniVersita¨t, Corrensstrasse 40, 48149 Mu¨nster, Germany
studer@uni-muenster.de
Received December 21, 2007
ABSTRACT
The letter describes a novel concept for the synthesis of biologically important arylphenylmethanols. Stereoselective cyclohexadienyl transfer
from 1,4-cyclohexadienyltributyltin to various aromatic aldehydes using AgOTf/BINAP as a catalyst precursor provides 1,4-cyclohexadienylphen-
ylmethanols that are readily oxidized to the corresponding arylphenylmethanols. Fifteen examples are presented.
Diarylmethanols are an important class of biologically active
compounds.1,2 An obvious approach to diarylmethanols is
the stereoselective aryl transfer to aromatic aldehydes.2,3
Recently, many papers on this particular reaction have
appeared; however, as compared to the aryl transfer reaction,
the stereoselective allyl transfer to aldehydes using allylmetal
compounds is far more intensively investigated and better
understood. In the allyl transfer, the reaction mostly occurs
via a well-organized rigid 6-membered chair transition state.4
As a new concept for aryl transfer to aldehydes, we there-
fore suggest following a two-step protocol comprising a
stereoselective cyclohexadienyl transfer, which might occur
via a 6-membered chair transition state and a subsequent
oxidation of the cyclohexadiene substituent (Scheme 1). We
have recently shown that 1,3-cyclohexadienyl compounds 2
are readily prepared with high stereoselectivity either by
using chiral cyclohexadienyl-Ti-complex 15 or by using the
achiral silylated cyclohexadienyl derivative 3 in combination
with a chiral Cu(I) catalyst.6 Unfortunately, we were not able
to find a suitable oxidation protocol for the aromatization
of diene 2 to the corresponding arene 6. Therefore, we
attempted to find a method for the stereoselective synthesis
of 1,4-dienes of type 5. We assumed that the 1,4-cyclohexa-
dienes are readily oxidized to the corresponding arenes 6.7
We have shown that the AgF or AgOTf-catalyzed reaction
of diene 3 with aromatic aldehydes afforded substantial
(1) Harms, A. F.; Hespe, W.; Nauta, W. T.; Rekker, R. F. Drug Des.
1976, 6, 1.
(2) Review: Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm, C. Chem.
Soc. ReV. 2006, 35, 454.
(3) (a) Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997, 62, 444.
(b) Huang, W.-S.; Pu, L. J. Org. Chem. 1999, 64, 4222. (c) Bolm, C.;
Hermanns, N.; Hildebrand, J. P.; Mun˜iz, K. Angew. Chem., Int. Ed. 2000,
39, 3465. (d) Zhao, G.; Li, X.-G.; Wang, X.-R. Tetrahedron: Asymmetry
2001, 12, 399. (e) Ko, D.-H.; Kim, K. H.; Ha, D.-C. Org. Lett. 2002, 4,
3759. (f) Rudolph, J.; Bolm, C. J. Am. Chem. Soc. 2002, 124, 14850. (g)
Rudolph, J.; Schmidt, F.; Bolm, C. AdV. Synth. Catal. 2004, 346, 867. (h)
Rudolph, J.; Hermanns, N.; Bolm, C. J. Org. Chem. 2004, 69, 3997. (i)
Fontes, M.; Verdaguer, X.; Sola`, L.; Perica`s, M. A.; Riera, A. J. Org. Chem.
2004, 69, 2532. (j) 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. (k) Hatano,
M.; Miyamoto, T.; Ishihara, K. AdV. Synth. Catal. 2005, 347, 1561. (l)
Pizzuti, M. G.; Superchi, S. Tetrahedron: Asymmetry 2005, 16, 2263. (m)
Qin, Y.-C.; Pu, L. Angew. Chem., Int. Ed. 2006, 45, 273. (n) Kim, J. G.;
Walsh, P. J. Angew. Chem., Int. Ed. 2006, 45, 4175. (o) Schmidt, F.;
Rudolph, J.; Bolm, C. AdV. Synth. Catal. 2007, 349, 703. (p) Sedelmeier,
J.; Bolm, C. J. Org. Chem. 2007, 72, 8859. (q) Sato, I.; Toyota, Y.; Asakura,
N. Eur. J. Org. Chem. 2007, 2608. (r) Tomita, D.; Kanai, M.; Shibasaki,
M. Chem. Asian. J. 2006, 1-2, 161. (s) Shannon, J.; Bernier, D.; Rawson,
D.; Woodward, S. Chem. Commun. 2007, 3945.
(4) (a) In Houben-Weyl, Vol. E21b; Helmchen, G., Hoffmann, R. W.,
Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart, 1995; pp 1357-1602.
(b) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207. (c) Denmark, S.
E.; Fu, J. Chem. ReV. 2003, 103, 2763.
(5) (a) Schleth, F.; Studer, A. Angew. Chem., Int. Ed. 2004, 43, 313. (b)
Schleth, F.; Vogler, T.; Harms, K.; Studer, A. Chem.-Eur. J. 2004, 10,
4171. (c) Studer, A.; Schleth, F. Synlett 2005, 3033.
(6) Umeda, R.; Studer, A. Org. Lett. 2007, 9, 2175.
10.1021/ol703080a CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/13/2008

Scheme 1. Stereoselective Cyclohexadienyl Transfer and
Table 1. Screening of Various Chiral Ligands (product 5a with
R ) 4-FC6H4)
Subsequent Oxidation
entry
ligand
er
yield [%]a
1
2
3
4
5
6
7
8
7a
7b
7c
8a
8b
9
10
11
12a
12b
12c
95:5
94:6
84:16
78:22
87.5:12.5
80:20
86:14
94.5:5.5
41.5:58.5
25.5:74.5
34.5:65.5
99
99
86
51
99
30
76
81
25
46
66
9
10
11
a Isolated yield. The regioisomeric diene 2 was not formed.
amounts of the symmetrical diene 5 along with 2.6 Since
Yamamoto successfully used allyltin derivatives as precursors
for allyl-Ag-compounds,8 we decided to investigate the
stereoselective Ag-catalyzed cyclohexadienyl transfer from
stannylated diene 45b to various aldehydes. Enantioselectivity
and regiochemistry had to be controlled in this reaction. The
challenge was to suppress the formation of the unwanted
1,3-diene 2, which was obtained as the major or only product
in our pervious studies.5,6 Initial experiments were performed
with AgOTf and para-fluorobenzaldehyde to give diene 5a
(R ) 4-FC6H4). Reactions were conducted with 10 mol %
of AgOTf in the presence of various chiral diphosphine
ligands (10 mol %) in toluene at -30 °C for 16 h. A 2-fold
excess of 4 was used and the selectivity was determined by
gas chromatography (see Supporting Information). Some of
the ligands used in this study are depicted in Figure 1, and
the results are presented in Table 1.
A quantitative yield and a good selectivity were obtained
with (S)-BINAP 7a9 (er ) 95:5, entry 1). Pleasingly, the
regioisomeric diene 2 and its anti isomer were not formed.
tol-BINAP 7b delivered a similar result whereas xyl-BINAP
7c provided a lower selectivity and a slightly lower yield
(entries 2 and 3). The reaction with MeO-BIPHEP10 8a
occurred with a lower yield and a lower selectivity (entry
4). Unreacted diene 4 remained. The yield increased with
the more electrophilic Cl-MeO-BIPHEP11 8b; however, as
compared to BINAP, a lower selectivity was obtained (entry
5). SEGPHOS12 9 provided the worst result (entry 6). Hence,
for the atropoisomeric chiral diphosphines, higher yields were
obtained with more electrophilic ligands, and the dihedral
angle of the biaryl backbone13 was obviously important for
the stereochemical outcome. A larger angle seemed to lead
to higher selectivities. Therefore, H8-BINAP 10 was tested
(entry 7). Disappointingly, selectivity was lower. A good
result was achieved with Phanephos14 11 (entry 8). Josiphos
type compounds15 12a-c turned out to be not efficient
ligands for this reaction (entries 9-11). Based on the initial
(7) Some examples: (a) Tori, M.; Miyake, T.; Hamaguchi, T.; Sono,
M. Tetrahedron: Asymmetry 1997, 8, 2731. (b) Davies, H. M. L.; Stafford,
D. G.; Hansen, T. Org. Lett. 1999, 1, 233. (c) Nayek, A.; Ghosh, S.
Tetrahedron Lett. 2002, 43, 1313. (d) Nayek, A.; Drew, M. G. B.; Ghosh,
S. Tetrahedron 2003, 59, 5175.
(8) (a) Yanagisawa, A.; Nakashima, H.; Ishiba, A.; Yamamoto, H. J.
Am. Chem. Soc. 1996, 118, 4723. (b) Yanagisawa, A.; Nakatsuka, Y.;
Nakashima, H.; Yamamoto, H. Synlett 1997, 933. (c) Yanagisawa, A.;
Nakashima, H.; Nakatsuka, Y.; Ishiba, A.; Yamamoto, H. Bull. Chem. Soc.
Jpn. 2001, 74, 1129.
(9) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi,
T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932.
(10) Schmid, R.; Broger, E. A.; Cereghetti, M.; Crameri, Y.; Foricher,
J.; Lalonde, M.; Mu¨ller, R. K.; Scalone, M.; Schoettel, G.; Zutter, U. Pure
Appl. Chem. 1996, 68, 131.
(11) (a) Laue, C.; Schro¨der, G.; Arlt, D. (Bayer AG), U.S. Patent 5,-
710,339, 1998. (b) Laue, C.; Schro¨der, G.; Arlt, D. (Bayer AG) U.S. Patent
5,801,261, 1998.
(12) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264.
(13) (a) Zhang, Z.; Qian, H.; Longmire, J.; Zhang, X. J. Org. Chem.
2000, 65, 6223. (b) Jeulin, S.; Duprat de Paule, S.; Ratovelomana-Vidal,
V.; Genet, J.-P.; Champion, N.; Dellis, P. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5799.
(14) Pye, P. J.; Rossen, K.; Reamer, R. A.; Tsou, N. N.; Volante, R. P.;
Reider, P. J. J. Am. Chem. Soc. 1997, 119, 6207.
(15) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert, H.;
Tijani, A. J. Am. Chem. Soc. 1994, 116, 4062.
Figure 1. Chiral ligands 7-12 used in this study.
994
Org. Lett., Vol. 10, No. 5, 2008

screening, all the following experiments were conducted with
(S)-BINAP.
Scheme 2. Oxidation of 5a
The effects of the solvent and of the Ag counteranion were
investigated next (Table 2). The influence of the solvent was
Table 2. Reaction of Diene 4 (2 Equiv) and 4-F-C6H4CHO in
the Presence of an Ag(I)-salt (10 mol %) and (S)-BINAP (10
mol %) in Various Solvents at -30 °C for 16 h
alcohols 5b-o which were further oxidized with DDQ to
the arylphenylmethanols 6b-o (Table 3). The enantioselec-
entry
solvent
Ag-salt
er
yield [%]a
1
2
3
4
5
6
7
8
THF
AgOTf
88:12
92.5:7.5
93:7
92.5:7.5
93:7
86.5:13.5
93:7
99
99
99
99
99
30
10
76
99
51
61
-
ClC6H5
FC6H5
Et2O
MeOCH2CH2OMe AgOTf
DMF
MeCN
MeOH
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
AgOTf
AgOTf
AgOTf
Table 3. Reaction of 4 in Toluene at -50 °C for 40 h with
Various Aromatic Aldehydes in the Presence of AgOTf (10 mol
%) and (S)-BINAP (10 mol %) and Subsequent Oxidation
AgOTf
AgOTf
AgOTf
AgOTf
AgOCOCF3 87.5:12.5
AgOCOCH3 78:22
AgNO3
AgSbF6
AgOTfb
AgOTfc
AgOTfd
yield [%]a
(compound)
yield [%]a
(compound)
93:7
93.5:6.5
entry
substituent R
erb
9
1
2
3
4
5
6
7
8
4-MeC6H4
4-i-PrC6H4
4-t-BuC6H4
4-ClC6H4
4-BrC6H4
4-IC6H4
4-CF3C6H4
4-MeOC6H4
2-MeC6H4
2-MeOC6H4
3-MeC6H4
3-BrC6H4
3-MeOC6H4
2-naphthyl
90 (5b)
78 (5c)
96 (5d)
99 (5e)
89 (5f)
84 (5g)
99 (5h)
80 (5i)
84 (5j)
92 (5k)
80 (5l)
96 (5m)
86 (5n)
91 (5o)
77 (6b)
88 (6c)
79 (6d)
81 (6e)
88 (6f)
85 (6g)
89 (6h)
78 (6i)
86 (6j)
74 (6k)
72 (6l)
90 (6m)
69 (6n)
68 (6o)
88:12
86:14
88:12
94:6
93:7
92:8
92:8
83:17
94:6
78:22
89:11
91:9
90:10
95:5
10
11
12
13
14
15
16
-
89.5:10.5
85.5:14.5
90:10
96:4
15
36
99
99
a Combined yield. The regioisomeric diene 2 was not formed. b Twenty
mol % of AgOTf were used. c Ten mol % of AgOTf and 20 mol % of
(S)-BINAP were used. d Reaction was conducted at -50 °C.
9
10
11
12
13
14
studied with AgOTf as catalyst precursor. Reaction in THF
went to completion; however, a lower selectivity was
obtained as compared to the toluene experiment (entry 1).
Halogenated arenes as solvents delivered 5a in quantita-
tive yield with acceptable selectivities (entries 2 and 3).
Similar results were obtained in Et2O, MeOCH2CH2OMe,
and CH2Cl2 (entries 4, 5, and 9). Reaction in DMF and
MeCN provided low yields (entries 6 and 7). Polar protic
solvents were tolerated as reaction in MeOH occurred with
excellent yield and good selectivity (entry 8). As a summary
of the solvent screening, we could state that various sol-
vents could be used, and the best result was obtained in
toluene. Other Ag-salts than AgOTf such as AgOCOCF3,
AgOCOCH3, and AgSbF6 provided worse results, and no
reaction occurred in the presence of AgNO3 (entries 10-
13). If 20 mol % of AgOTf was used, a lower yield and a
lower selectivity were achieved (entry 14). An excess of
BINAP with respect to AgOTf led to a slightly lower
selectivity without affecting the yield (entry 15). The highest
selectivity was obtained with AgOTf in toluene at -50 °C
(er ) 96:4, entry 16). However, to get a quantitative yield,
the reaction time had to be increased to 40 h.
a Isolated yield. b er determined by HPLC on compounds 6a-o, see
Supporting Information.
tivity was determined on the oxidized products 6b-o. The
absolute stereochemistry (S enantiomer) was assigned by
comparison of the optical rotations of 6b and 6k with those
reported in the literature (see Supporting Information). The
absolute configurations of all other compounds were assigned
in analogy.
The less electrophilic para-alkyl- and para-alkoxy-
substituted benzaldehyde derivatives provided slightly lower
yields in the cyclohexadienyl transfer reaction. After oxida-
tion, the phenylarylmethanols were isolated in moderate
selectivity (entries 1-3, 8). A higher yield and a higher
selectivity were obtained for the para-chloro derivative (entry
4), whereas slightly worse results were achieved with the
corresponding Br- and I-congeners. Cyclohexadienyl transfer
to the para-CF3-substituted benzaldehyde occurred with high
yield and moderate selectivity (entry 5). A good selectivity
was obtained for the reaction with the ortho-methyl substi-
tuted benzaldehyde derivative (entry 9), but the ortho-OMe-
compound delivered a lower selectivity. Acceptable yields
and selectivities were achieved for the meta-substituted
benzaldehyde derivatives (entries 11-13), and a good
We were pleased to find that diene 5a was stereospe-
cifically oxidized with DDQ in benzene at room tempera-
ture to arylphenylmethanol 6a, validating our concept
(Scheme 2).16
To test the substrate scope of the novel arlylphenylmetha-
nol synthesis, various aromatic aldehydes were reacted with
diene 4 under optimized conditions to give the corresponding
(16) As a side product the corresponding ketone was formed in 19%
yield.
Org. Lett., Vol. 10, No. 5, 2008
995

selectivity was obtained for 2-naphthaldehyde (entry 14). For
all substrates tested, the oxidation occurred in good yields
(68-90%).
We believe that the reaction occurs via a cyclohexadienyl-
Ag-complex of type B (see Scheme 3). Compound B can
axial phenyl group at the P-atom in the (S)-BINAP-Ag(I)-
complex, the aldehyde approaches the metal as suggested
in model structure D. Intramolecular “allylation” using (S)-
BINAP as a ligand should then occur from the Si-face as
observed in the experiment. We do not consider an open
transition state where a chiral Ag complex (probably cationic)
acts as a Lewis acid because we could previously show that
the Lewis acid mediated cyclohexadienyl transfer from 4 to
benzaldehyde delivered syn-2 (R ) Ph) as major isomer.
The syn isomer was not formed in the Ag-catalyzed process
studied herein.5b
Scheme 3. Possible Mechanism
In summary, we presented a novel approach to arylphen-
ylmethanols comprising an Ag-catalyzed stereoselective
cyclohexadienyl transfer with subsequent oxidation. As
previously shown,6 cyclohexadienyl transfer from silylated
diene 3 to aldehydes using Cu-catalysis provided 1,3-dienes
2 whereas the analogous Ag-catalyzed reaction with diene
4 afforded 1,4-dienes 5 exclusively. Hence, the two devel-
oped methods are complementary. Importantly, arylphenyl-
methanols are biologically interesting compounds.
Acknowledgment. We thank Novartis Pharma AG (Young
Investigator Award to A.S.) and the Deutsche Forschungs-
gemeinschaft (International Research Training Group Mu¨n-
ster/Nagoya) for supporting our work. R.U. thanks the
Alexander von Humboldt Foundation for a postdoctoral
fellowship. Takasago Intenational Corporation and Solvias
AG are acknowledged for donation of ligands.
be in equilibrium with complex A; however, considering a
six-membered chair transition state (see E), the reacting
complex is assumed to be B. The Ag-alcoholate C generated
should then react with diene 4 to the corresponding Sn-
alcoholate and the cyclohexadienyl-Ag-complexes A/B.8 The
stereochemistry can be explained using the quadrant-shield-
ing model of BINAP-metal complexes introduced by Noy-
ori.17 To minimize the interactions of the aldehyde with the
Supporting Information Available: Experimental details
and characterization data for the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL703080A
(17) Kitamura, M.; Tsukamoto, M.; Bessho, Y.; Yoshimura, M.; Kobs,
U.; Widhalm, M.; Noyori, R. J. Am. Chem. Soc. 2002, 124, 6649.
996
Org. Lett., Vol. 10, No. 5, 2008