Enantioselective synthesis of chromanes by iridium-catalyzed asymmetric hydrogenation of 4H-chromenes

Article abstract of DOI:10.1055/s-0028-1087359

Iridium complexes of chiral oxazoline-based P,N-ligands proved to be efficient catalysts for the enantioselective hydrogenation of 2-aryl- and 2-alkyl-4H-chromenes. The best results were obtained with a ligand derived from threonine (ThrePHOX), which induced ee values of 95% to >99% in the hydrogenation of 2-methyl-, 2-cyclohexyl- and various 2-aryl-substituted chromenes. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087359

LETTER
3167
Enantioselective Synthesis of Chromanes by Iridium-Catalyzed Asymmetric
Hydrogenation of 4H-Chromenes
I
ridium-Catalyz
e
a
A
symme
r
H
ydr
i
ogenati
n
on of Chrom
e
enes Valla, Alejandro Baeza, Frederik Menges, Andreas Pfaltz*
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax +41(61)2671103; E-mail: andreas.pfaltz@unibas.ch
Received 13 June 2008
Herein we report the successful realization of this strate-
Abstract: Iridium complexes of chiral oxazoline-based P,N-
ligands proved to be efficient catalysts for the enantioselective hy-
drogenation of 2-aryl- and 2-alkyl-4H-chromenes. The best results
were obtained with a ligand derived from threonine (ThrePHOX),
which induced ee values of 95% to >99% in the hydrogenation of 2-
methyl-, 2-cyclohexyl- and various 2-aryl-substituted chromenes.
gy, which gives access to a variety of 2-monosubstitued
chromanes in high enantiomeric purity.7
4H-Chromenes can be prepared by numerous synthetic
routes starting from flavylium ions,8 diketones,9
chalcones10 or other precursors. The general route that we
used is shown in Scheme 1. Chalcones 1a–f, obtained in
high yields from inexpensive commercially available
starting materials,11 were readily converted to flavones
2a–e by iodine-promoted ring closure using 1.2 equiva-
lents of iodine.10c For the cyclization of the furyl-substi-
tuted derivative 1f only a catalytic amount of iodine was
used in order to avoid iodination of the furan ring.12 Final-
Key words: asymmetric hydrogenation, iridium, P,N-ligands, fla-
vanes, chromanes
Chiral chromanes, especially the 2-aryl-substituted deriv-
atives known as flavanes, occur in many plants and exhib-
it a wide spectrum of biological activities. Because of
their pharmacological properties, numerous synthetic de-
rivatives have been prepared and studied as drug candi-
dates. Representative examples are tupichinol C, used in
Chinese folk medicine;1 tephrowatsin E, isolated from the
aerial parts of tephrosia watsoniana;2 and BW683C, a po-
tent inhibitor of rhinovirus replication in vitro3 (see
Figure 1).
8a
ly, reduction with LiAlH4–AlCl3 led to the desired
chromenes 3a–f in good to moderate yields.13
O
O
a
R1
R1CHO
+
83–100%
R2
OH
R2
OH
1a–f
Cl
b for 1a–e
or c for 1f
53–85%
O
HO
O
O
OH
Cl
BW683C
tupichinol C
d
OMe
32–95%
R2
R2
O
R1
O
R1
3a–f
2a–f
3a R1 = 4-MeC6H4, R2 = H
3b R1 = 2-FC6H4, R2 = H
3c R1 = 4-BrC6H4, R2 = H
3d R1 = 4-ClC6H4, R2 = 6-Cl
3e R1 = Ph, R2 = 7-OMe
3f R1 = 2-furyl, R2 = H
MeO
O
tephrowatsin E
Scheme 1 Synthesis of 4H-chromenes. Reagents and conditions:
(a) KOH, EtOH, r.t., 14 h; (b) I2 (1.2 equiv), triethylene glycol, 150
ºC, 4 h; (c) 1 crystal of I2, DMSO, reflux, 10 min and then at r.t., 30
min; (d) LiAlH4–AlCl3, THF, 0 ºC, 30 min.
Figure 1
Despite the obvious interest in this class of compounds,
only a few synthetic methods have been developed that
give access to enantiomerically enriched chromanes, the
main strategies being based on the Sharpless asymmetric
epoxidation4 or the Mitsunobu reaction.5 In connection
with our work on iridium-catalyzed asymmetric hydroge-
nation,6 we thought that the enantioselective reduction of
the enol ether unit of the corresponding chromenes would
open up an attractive route to optically active chromanes.
The cyclohexyl-substituted chromene 5 could not be syn-
thesized by this route because the reduction of cyclohex-
ylchromanone led to formation of decomposition
products. Therefore, an alternative synthesis starting from
dihydrocoumarin was undertaken (Scheme 2). Grignard
reaction with cyclohexylmagnesium chloride followed by
dehydration of the crude hemiacetal 4 after 48 hours af-
forded the cyclohexylchromene 5 in 23% overall
yield.14,15
SYNLETT 2008, No. 20, pp 3167–3171
1
6
.1
2
.2
0
0
8
Advanced online publication: 24.11.2008
DOI: 10.1055/s-0028-1087359; Art ID: D21808ST
© Georg Thieme Verlag Stuttgart · New York

3168
C. Valla et al.
LETTER
All substrates reacted cleanly under these conditions to af-
ford the desired 2-substituted chromanes as the only de-
tectable products (Tables 1 and 2).
a
O
O
O
4
OH
Cy
Complexes 8a–c derived from phosphinoimidazoline
ligands gave low conversion in most cases and the enantio-
selectivities were moderate at best (Table 1). Higher con-
versions and better enantioselectivities were obtained
with the Ir(PHOX) catalyst 9 and the corresponding com-
plexes 10a,b derived from threonine-derived ligands
(ThrePHOX) (Table 2). Clearly the best results were
achieved with complex 10b bearing an electron-rich dicy-
clohexylphosphino group. This catalyst showed the high-
est reactivity and gave full conversion for all substrates
except for 3c and 3d. Excellent enantioselectivities of
>95% ee were obtained in all cases with the exception of
the hydrogenation of the 4-bromophenyl-substituted
chromene 3c, which gave 91% ee.
b
O
5
Cy
23% overall yield
Scheme 2 Synthesis of 2-cyclohexylchromene 5. Reagents and
conditions: (a) CyMgCl (4 equiv), Et2O, reflux, 48 h; (b) p-toluene-
sulfonic acid (cat.), toluene, reflux, 2 h.
2-Phenyl-4H-chromene (6) and 2-phenyl-4H-benzo[h]-
chromene (7; Figure 2) were obtained by reduction of
commercially available flavone and b-naphthoflavone, re-
spectively, with LiAlH4–AlCl3.
Next we studied the hydrogenation of 2-methylchromene
15,16 prepared by cyclization of 4-(2-hydroxyphenyl)bu-
tan-2-one followed by dehydration.17 Again, high conver-
sion and excellent enantioselectivity, were obtained under
standard conditions (Equation 2). This substrate had been
hydrogenated before using a Ru-BINAP complex (1
mol%, 100 bar H2, 50 ºC, >24 h). Although full conver-
sion was observed under these rather forcing conditions,
the enantiomeric excess was only 64%.18
O
O
6
7
Figure 2 Flavenes prepared from commercially available flavones
With the various chromene derivatives in hand, the enan-
tioselective hydrogenation of the enol ether double bond
was studied, employing iridium complexes 8–10 as cata-
lysts (Figure 3).6a–6c
10b (1 mol%)
CH2Cl2, 25 °C, 50 bar, H2
O
15
O
2 h, r.t.
R1
16
93% conversion, 95% ee
N
O
Equation 2 Asymmetric hydrogenation of methylchromene 17
R22P
(o-Tol)2P
N
–
–
N
BArF
BArF
+
+
Ir
Ir
We also attempted the synthesis of the tephrowatsin E, by
asymmetric hydrogenation of the corresponding flavene,
which was obtained from commercially available 5,7-di-
hydroxyflavone by methylation of the hydroxyl groups
and subsequent reduction. When 2 mol% of catalyst 10b
was used 97% conversion was obtained in four hours, but
surprisingly the ee was only 5%.
8a R1 = o-Tol, R2 = Cy
8b R1 = Bn, R2 = o-Tol
8c R1 = Ph, R2 = o-Tol
9
Bn
Bn
O
R12P
O
N
–
BArF
+
Ir
A chromene derivative with a tetrasubstituted C=C bond,
3-methyl-2-phenyl-4H-chromene, was also tested. How-
ever, no reaction was observed in this case under a range
of reaction conditions.19 Other catalysts, derived from py-
ridine-based ligands,6b,c were examined, but again, gave
no hydrogenation.
Ph
10a R1 = Ph
10b R1 = Cy
Figure 3 Iridium catalysts employed in chromene hydrogenation
Finally, 2-phenyl-4H-thiochromene (17),14 which was
prepared by reduction of commercially available 2-phe-
nyl-4H-thiochromen-4-one with LiAlH4–AlCl3, was ex-
amined as substrate (Equation 3). Under standard
conditions conversion was low (15%), but the enantiose-
lectivity was very high (99% ee). Higher catalyst loading
of 2 mol% and a reaction time of 24 hours led to 54%,
conversion, while the ee remained at 99%. When the reac-
tion was performed at 40 ºC the conversion reached 73%,
but the enantioselectivity decreased to 91% ee.
The reactions were performed with 1 mol% of iridium
complex in dichloromethane under 50 bar hydrogen pres-
sure at room temperature in an autoclave (Equation 1).
Ir-P,N complex (1 mol%)
CH2Cl2, 50 bar, H2
R1
11a–f, 12, 13, 14
O
R1
3a–f, 5, 6, 7
R2
2 h, r.t.
R2
O
Equation 1 Asymmetric hydrogenation of chromenes
Synlett 2008, No. 20, 3167–3171 © Thieme Stuttgart · New York

LETTER
Iridium-Catalyzed Asymmetric Hydrogenation of Chromenes
3169
Table 1 Asymmetric Hydrogenation of Chromenes using Iridium Complexes 8a–ca
Catalysts
8a
8b
8c
Conversion (%)b ee (%)c
Entry
Substrates
Products
11a
11b
11c
11d
11e
11f
Conversion (%)b ee (%)c
Conversion (%)b ee (%)c
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
5
50
2
84
53
15
44
60
40
45
28
50
35
35
26
44
23
58
75
50
69
48
60
69
53
35
d
–
6
34
52
63
72
20
26
38
11
10
9
26
47
40
37
21
32
12
75
>99
42
>99
75
e
e
6
13
–
–
7
14
25
70
60
73
a Reaction conditions: see general procedure in experimental section.
b Determined by GC analysis.
c Determined by HPLC analysis (CHIRACEL OD-H).
d Not determined.
e Not tested.
Table 2 Asymmetric Hydrogenation of Chromenes using Iridium Complexes 9 and 10a,ba
Catalysts
9
10a
Conversion (%)b ee (%)c
10b
Entry
Substrates
Products
11a
11b
11c
11d
11e
11f
Conversion (%)b ee (%)c
Conversion (%)b ee (%)c
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
5
97
67
75
69
60
79
70
63
50
72
58
77
77
86
93
80
81
70
90
93
80
82
>99
>99
95
98
>99
91
61
42
77
32
90
97
49
32
>99
>99
>99
>99
>99
>99
97
93
76
12
>99
99
>99
74
95
6
13
99
7
14
>99
91
96
a Reaction conditions: see general procedure in experimental section.
b Determined by GC analysis.
c Determined by HPLC analysis (CHIRACEL OD-H).
The absolute configuration of the hydrogenation products
was assigned by comparison of the optical rotation of the
products 13, enantioenriched BW683C (11d) and 16 with
literature values.5,18,20
10b (2 mol%)
CH2Cl2, 40 °C, 50 bar, H2
S
17
Ph
S
Ph
24 h, r.t.
18
73% conversion, 91% ee
In summary, iridium-catalyzed asymmetric hydro-
genation21 of 2-substituted chromenes provides an effi-
cient, highly enantioselective route to chiral chromanes. A
variety of differently substituted products, including flav-
anes which are of interest because of their biological ac-
tivity, can be readily prepared in this way.
Equation 3 Asymmetric hydrogenation of thioflavene
Synlett 2008, No. 20, 3167–3171 © Thieme Stuttgart · New York

3170
C. Valla et al.
LETTER
(13) The chromenes were fully characterized. For the known
Acknowledgment
compounds, the spectroscopic and physical data are in
agreement with those previously reported in literature. These
chromenes are generally air and temperature sensitive, and
therefore should be stored under argon at –20 ºC to avoid
decomposition.
A. Baeza would like to thank the Spanish Ministerio de Educación,
Ciencia y Deporte (MECD) and the Fundación Española para la
Ciencia y la Tecnologia (FECYT) for a postdoctoral fellowship.
Support of this work by the Swiss National Science Foundation and
the Federal Commission for Technology and Innovation (KTI) is
gratefully acknowledged.
Representative example:
2-(4-Bromophenyl)-4H-chromene (3c): The product was
isolated after flash chromatography on silica gel (pentane–
EtOAc, 99:1) as a white solid in 95% yield; mp 105 ºC;
Rf 0.42 (pentane–EtOAc, 9:1). IR (KBr): 3043, 2830, 1667,
1583, 1488, 1239 cm–1. 1H NMR (500 MHz, C6D6): d = 3.12
(d, J = 3.9 Hz, 2 H), 4.99 (t, J = 3.9 Hz, 1 H), 6.78 (m, 1 H),
6.84 (m, 1 H), 6.97 (m, 2 H), 7.26–7.29 (m, 4 H). 13C NMR
(125 MHz, C6D6): d = 24.5, 97.2, 117.0, 119.7, 122.5, 123.7,
126.5, 128.0, 129.2, 131.7, 133.8, 148.4, 152.2. MS (EI):
m/z (%) = 226.2 (66.3) [M+], 225.1 (100), 131.1 (19.3). Anal.
Calcd for C15H11OBr: C, 62.74; H, 3.86. Found: C, 62.79; H,
3.85.
References and Notes
(1) Pan, W. B.; Chang, F. R.; Wei, L.; Wu, Y. C. J. Nat. Prod.
2003, 66, 161.
(2) (a) Gomez, F.; Quijano, L.; Calderon, J. S.; Rodriguez, C.;
Tirso, R. Phytochemistry 1985, 24, 1057. (b) Arnone, A.;
Nasini, G.; Merlini, L. J. Chem. Soc., Perkin Trans. 1 1990,
2637.
(3) (a) Bauer, D. J.; Selway, J. W. T.; Batchelor, J. F.; Tisdale,
M.; Caldwell, I. C.; Young, D. A. Nature (London) 1981,
292, 369. (b) Batchelor, J. F.; Bauer, D. J.; Hodson, H. F.;
Selway, J. W. T.; Young, D. A. B. U.S. Patent, US 4461907,
1984.
(14) Zacheis, D.; Dhar, A.; Lu, S.; Madler, M. M.; Klucik, J.;
Brown, C. W.; Liu, S.; Clement, F.; Subramanian, S.;
Weerasekare, G. M.; Berlin, K. D.; Gold, M. A.; John, R.;
Houck, J.; Fountain, K. R.; Benbrook, D. M. J. Med. Chem.
1999, 42, 4434; and references therein.
(4) Chandrasekhar, S.; Reddy, M. V. Tetrahedron 2000, 56,
6339.
(15) 2-Cyclohexyl-4H-chromene (5): The product was isolated
after flash chromatography on silica gel (100% pentane) as a
pale yellow oil (23% yield); Rf 0.75 (pentane–EtOAc, 9:1).
IR (neat): 3026, 2926, 1693, 1586, 1488, 1235 cm–1. 1H
NMR (500 MHz, C6D6): d = 1.06–1.22 (m, 3 H), 1.33 (m,
2 H), 1.57 (m, 1 H), 1.68 (m, 2 H), 1.94 (m, 2 H), 2.04 (m,
1 H), 3.17 (d, J = 3.5 Hz, 2 H), 4.49 (br dt, J = 0.7, 3.5 Hz,
1 H), 6.78–6.83 (m, 2 H), 6.92–6.95 (m, 2 H). 13C NMR (125
MHz, C6D6): d = 24.2, 26.6, 26.7, 30.9, 42.2, 93.2, 116.7,
120.5, 123.1, 127.6, 129.3, 152.9, 156.3. MS (EI): m/z (%) =
214.2 (18.2) [M+], 213.3 (21.3), 131.1 (100). Anal. Calcd for
C15H18O: C, 84.07; H, 8.47. Found: C, 83.83; H, 8.60.
(16) Baker, W.; Walker, J. J. Chem. Soc. 1935, 646.
(17) 2-Methyl-4H-chromene (15): Salicylaldehyde (0.53 mL,
5 mmol) was added to a solution of DL-proline (99 mg, 20
mol%) and acetone (7.4 mL, 20 equiv) in DMF–H2O (1:1, 20
mL). The mixture was heated for 48 h at 90 ºC. The mixture
was cooled to r.t., extracted with EtOAc (2 ×) and washed
with brine (4 ×), affording, after removal of the organic
solvent, the corresponding hydroxy chalcone as an orange
solid. The crude product was dissolved in EtOH (5 mL) and
hydrogenated under 1 bar H2 pressure using Raney-Ni as
catalyst. The reaction was monitored by GC (Machary-
Nagel, Optima Amin-5 column). When the reaction was
complete, the solution was filtered through celite, extracted
with Et2O (2 ×) and washed with brine (2 ×). The organic
layer was concentrated under reduced pressure to give the
corresponding hydroxy ketone, which, without purification,
was refluxed in toluene (10 mL) with a catalytic amount of
p-toluenesulfonic acid (100 mg) and 4 Å molecular sieves (2
g) for 2 h. After this time, the mixture was cooled to r.t.,
filtered, washed with sat. aq NaHCO3 solution, and brine.
The organic solvent was then removed and the crude product
was purified by flash chromatography to give the pure 15 in
29% yield as colorless oil.
(5) (a) Hodgetts, K. J. Tetrahedron Lett. 2000, 41, 8655.
(b) Hodgetts, K. J. Tetrahedron Lett. 2001, 42, 3763.
(c) Hodgetts, K. J. Tetrahedron 2005, 61, 6860. (d) The
same strategy, but using a previous kinetic resolution of b-
hydroxy esters is described in: Choi, E. T.; Lee, M. H.; Kim,
Y.; Park, Y. S. Tetrahedron 2008, 64, 1515.
(6) (a) Pfaltz, A.; Blankestein, J.; Hilgraf, R.; Hörmann, E.;
McIntyre, S.; Menges, F.; Schonleber, M.; Smidt, S. P.;
Wüstenberg, B.; Zimmermann, N. Adv. Synth. Catal. 2003,
345, 33. (b) Bell, S.; Wüstenberg, B.; Kaiser, S.; Menges, F.;
Netscher, T.; Pfaltz, A. Science 2006, 311, 642.
(c) Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res. 2007, 40,
1402. For contributions of other research groups, see:
(d) Cui, X.; Burgess, K. Chem. Rev. 2005, 105, 3272.
(e) Källström, K.; Munslow, I.; Andersson, P. G. Chem. Eur.
J. 2006, 12, 3194. (f) Zhu, Y.; Burgess, K. Adv. Synth.
Catal. 2008, 350, 975. (g) Kaukoranta, P.; Engman, M.;
Hedberg, C.; Bergquist, J.; Andersson, P. G. Adv. Synth.
Catal. 2008, 350, 1168.
(7) During the realization of this work a method for the
preparation of 3-substituted chromanes(isoflavanes) using
iridium-catalyzed asymmetric hydrogenation of the
corresponding chromenes was reported: Setchell, K. D. R.;
Sorokin, V. D. U.S. Patent, US 2007/0027329A1, 2007.
(8) For example, see: (a) Bird, T. G. C.; Brown, B. R.; Stuart,
I. A.; Tyrrell, A. W. R. J. Chem. Soc., Perkin Trans 1 1983,
1831. (b) Fichtner, C.; Remmenikov, G.; Mayr, H. Eur. J.
Org. Chem. 2001, 4451; and references therein.
(9) Trost, B. M.; Shen, H. C.; Dong, L.; Surivet, J.-P.; Sylvain,
C. J. Am. Chem. Soc. 2004, 126, 11966.
(10) For example, see: (a) Nam, N. H.; Kim, Y.; You, Y. J.;
Hong, D. H.; Kim, H. M.; Ahn, B. Z. Eur. J. Med. Chem.
2003, 38, 179. (b) Joo, Y. H.; Kim, J. K.; Kang, S.-H.; Noh,
M.-S.; Ha, J.-Y.; Choi, J. K.; Lim, K. M.; Lee, C. H.; Chung,
S. Bioorg. Med. Chem. Lett. 2003, 13, 413. (c) Miyake, H.;
Takizawa, E.; Sasaki, M. Bull. Chem. Soc. Jpn. 2003, 76,
835. (d) Bianco, A.; Cavarischia, C.; Guiso, M. Eur. J. Org.
Chem. 2004, 2894; and references therein.
(18) Ohta, T.; Miyake, T.; Seido, N.; Kumobayashi, H.; Takaya,
H. J. Org. Chem. 1995, 60, 357.
(19) The reaction failed even at high catalyst loadings of up to
4 mol%, 100 bar hydrogen pressure, and with long reaction
times.
(20) For other products the absolute configuration was assumed
to be the same because the same catalysts were used in the
hydrogenation.
(11) Cechinel, V.; Vaz, Z. R.; Zunino, L.; Calixto, J. B.; Yunes,
R. A. Eur. J. Med. Chem. 2003, 38, 179.
(12) Gupta, S. C.; Sharma, S.; Saini, A.; Dhawan, S. N. J. Chem.
Soc., Perkin Trans. 1 1999, 2391.
Synlett 2008, No. 20, 3167–3171 © Thieme Stuttgart · New York

LETTER
Iridium-Catalyzed Asymmetric Hydrogenation of Chromenes
3171
(21) Typical Procedure for the Catalytic Asymmetric
Hydrogenation of Chromenes: A solution of chromene
(0.5 mmol) and iridium complex 10b (8.7 mg, 5 mmol, 1
mol%) in anhyd dichloromethane (2.5 mL, Fluka anhyd
solvents grade) under an argon atmosphere was placed in an
autoclave, which was sealed, pressurized (50 bar hydrogen
gas) and stirred at r.t. for 2 h. The solvent was evaporated
and the catalyst was removed by filtration through a short
silica gel column (3 × 1 cm) with a mixture of pentane and
ethyl acetate (1:1) as eluent to give the desired chromane
after evaporation of the solvent.
4 H). 13C NMR (100 MHz, CDCl3): d = 24.7, 30.6, 55.0,
78.0, 102.2, 108.2, 114.2, 126.5, 128.2, 128.7, 130.4, 142.6,
156.7, 160.1. HPLC: Chiracel OD-H, 100% heptane, 20 ºC,
flow rate: 0.5 mL/min, tR(R) = 49.2 min, tR(S) = 54.6 min.
(R)-2-(2-Furanyl)chromane (11f): [a]D20 –4.7 (c = 0.9,
CHCl3; 97% ee); mp 50 ºC; Rf 0.85 (pentane–EtOAc, 9:1).
IR (KBr): 2932, 1562, 1456, 1232 cm–1. 1H NMR (400 MHz,
C6D6): d = 1.84 (m, 1 H), 2.07 (m, 1 H), 2.48 (m, 2 H), 4.92
(dd, J = 2.5, 9.8 Hz, 1 H), 6.14 (dd, J = 1.8, 3.3 Hz, 1 H), 6.24
(d, J = 3.3 Hz, 1 H), 6.87 (br dt, J = 1.5, 7.1 Hz, 1 H), 6.94
(d, J = 7.1 Hz, 1 H), 7.04–7.10 (m, 2 H), 7.15 (d, J = 1.0 Hz,
1 H). 13C NMR (100 MHz, C6D6): d = 24.7, 26.4, 71.5,
107.5, 110.6, 117.5, 120.9, 121.9, 128.1, 129.9, 142.4,
154.7, 155.3. MS (EI): m/z (%) = 240.2 (100) [M+], 136.1
(20.5). Anal. Calcd for C13H12O2: C, 77.98; H, 6.04. Found:
C, 78.11; H, 5.99. HPLC: Chiracel OD-H, 100% heptane, 20
ºC, flow rate: 0.5 mL/min, tR(R) = 27.9 min, tR(S) = 31.4 min.
(R)-2-Cyclohexylchromane (12): [a]D20 –62.1 (c = 1.0,
CHCl3; 95% ee); Rf 0.88 (pentane–EtOAc, 9:1). IR (neat):
2925, 1582, 1488, 1236 cm–1. 1H NMR (400 MHz, CDCl3):
d = 1.11–1.43 (m, 6 H), 1.55–1.80 (m, 5 H), 1.94–2.00 (m,
2 H), 2.70–2.85 (m, 2 H), 3.73 (ddd, J = 2.8, 5.9, 9.8 Hz, 1
H), 6.88 (br ddd, J = 1.7, 7.4, 8.6 Hz, 1 H), 7.02 (d, J = 7.3
Hz, 1 H), 7.05–7.12 (m, 2 H). 13C NMR (100 MHz, CDCl3):
d = 24.7, 25.5, 26.7, 28.8, 30.2, 42.5, 80.3, 117.4, 120.3,
122.6, 127.7, 129.9, 156.2. MS (EI): m/z (%) = 216.2 (29.5)
[M+], 120.1 (100). Anal. Calcd for C15H20O: C, 83.28; H,
9.32. Found: C, 83.01; H, 9.33. HPLC: Chiracel OD-H,
100% heptane, 15 ºC, flow rate: 0.5 mL/min, tR(S) = 18.6
min, tR(R) = 19.9 min.
For catalyst screening, reactions were carried out on a
0.1-mmol scale.
Analytical data for new compounds are given below. For
known compounds, the observed spectra were in agreement
with the reported data.5,18 For products which were reported
in the literature as racemates, only [a]D, 1H, 13C NMR and
HPLC data are listed.
(R)-2-(2-Fluorophenyl)chromane (11b): [a]D20 +28.9 (c =
0.5, CHCl3; >99% ee); Rf 0.82 (pentane–EtOAc, 9:1). IR
(KBr): 2929, 1582, 1488, 1234 cm–1. 1H NMR (400 MHz,
CDCl3): d = 2.06 (m, 1 H), 2.26 (m, 1 H), 2.79 (ddd, J = 3.8,
4.8, 16.5 Hz, 1 H), 3.03 (ddd, J = 5.8, 11.4, 16.5 Hz, 1 H),
5.40 (dd, J = 2.2, 10.1 Hz, 1 H), 6.88 (m, 2 H), 7.05–7.20 (m,
4 H), 7.30 (m, 1 H), 7.55 (dt, J = 1.5, 7.6 Hz, 1 H). 13C NMR
(100 MHz, CDCl3): d = 25.4, 29.3, 72.2 (d, J = 3.5 Hz),
115.7 (d, J = 21.5 Hz), 117.3, 120.9, 122.2, 124.7 (d, J = 3.5
Hz), 127.8 (d, J = 3.8 Hz), 127.9, 129.4 (d, J = 12.6 Hz),
129.5 (d, J = 8.4 Hz), 130.0, 158.7, 160.0 (d, J = 276.3 Hz).
MS (EI): m/z (%) = 228.2 (100) [M+], 119.1 (46.4). Anal.
Calcd for C15H13FO: C, 78.93; H, 5.74. Found: C, 78.65; H,
5.93. HPLC: Chiracel OD-H, 100% heptane, 20 ºC, flow
rate: 0.5 mL/min, tR(R) = 27.6 min, tR(S) = 29.6 min.
(R)-2-(4-Bromophenyl)chromane (11c): [a]D20 +22.4 (c =
0.5, CHCl3; 91% ee, 95% conversion); mp 85 ºC; Rf 0.80
(pentane–EtOAc, 9:1). IR (KBr): 2926, 1579, 1487, 1235
cm–1. 1H NMR (400 MHz, CDCl3): d = 2.04 (m, 1 H), 2.20
(m, 1 H), 2.79 (br ddd, J = 3.9, 5.0, 16.7 Hz, 1 H), 2.99 (ddd,
J = 5.8, 11.4, 16.7 Hz, 1 H), 5.03 (dd, J = 2.5, 10.1 Hz, 1 H),
6.87–6.91 (m, 2 H), 7.06–7.15 (m, 2 H), 7.31 (m, 2 H), 7.51
(m, 2 H). 13C NMR (100 MHz, CDCl3): d = 25.3, 30.3, 77.6,
117.3, 120.9, 122.0, 122.1, 127.8, 128.1, 130.0, 132.0,
141.2, 155.2. MS (EI): m/z (%) = 290.1 (76.2) [M+], 289.1
(15.8), 209.1 (100). Anal. Calcd for C15H13OBr: C, 62.30; H,
4.53. Found: C, 62.27; H, 4.49. HPLC: Chiracel OD-H,
heptane–2-propanol, 99.5/0.5, 20 ºC, flow rate: 0.5 mL/min,
tR(S) = 18.0 min, tR(R) = 20.6 min.
(R)-2-Phenyl-3,4-dihydro-2H-benzo[h]chromene (14):
[a]D20 +139.5 (c = 0.6, CHCl3; 96% ee). 1H NMR (400 MHz,
CDCl3): d = 2.17 (m, 1 H), 2.34 (m, 1 H), 2.88 (m, 1 H), 3.13
(m, 1 H), 5.25 (dd, J = 2.3, 9.9 Hz, 1 H), 7.18 (d, J = 8.3 Hz,
1 H), 7.33–7.46 (m, 6 H), 7.51 (d, J = 7.4 Hz, 2 H), 7.76 (m,
1 H), 8.25 (m, 1 H). 13C NMR (125 MHz, CDCl3): d = 25.3,
30.2, 77.9, 115.8, 120.2, 122.2, 125.6, 126.1, 126.3, 127.0,
127.9, 128.0, 128.7, 128.8, 134.0, 142.5, 150.3. HPLC:
Chiracel OD-H, heptane–2-propanol, 98:2, 20 ºC, flow rate:
0.5 mL/min, tR(R) = 11.4 min, tR(S) = 13.2 min.
(R)-2-Phenylthiochromane (18): [a]D20 –98.5 (c = 0.4,
CHCl3; 91% ee, 73% conversion); mp 53 ºC; Rf = 0.48
(pentane). IR (KBr): 2932, 1452, 1436 cm–1. 1H NMR (400
MHz, CDCl3): d = 2.19–2.28 (m, 1 H), 2.38–2.44 (m, 1 H),
2.95 (m, 2 H), 4.45 (dd, J = 3.3, 7.6 Hz, 1 H), 6.99 (m, 1 H),
7.06–7.12 (m, 3 H), 7.29 (m, 1 H), 7.30–7.36 (m, 2 H), 7.41
(dd, J = 1.3, 8.1 Hz, 2 H). 13C NMR (100 MHz, CDCl3): d =
30.0, 31.1, 46.3, 124.0, 125.9, 126.5, 127.6, 127.7, 128.6,
129.8, 133.0, 134.0, 141.9. Anal. Calcd for C15H14S: C,
79.60; H, 6.23. Found: C, 79.29; H, 6.47. HPLC: Chiracel
OD-H, heptane–2-propanol, 80:20, 20 ºC, flow rate: 0.5 mL/
min, tR(R) = 10.1 min, tR(S) = 11.3 min.
(R)-7-Methoxy-2-phenylchromane(11e): [a]D20 +26.7 (c =
1.0, CHCl3; >99% ee). 1H NMR (400 MHz, CDCl3): d = 2.06
(m, 1 H), 2.26 (m, 1 H), 2.76 (m, 1 H), 2.94 (m, 1 H), 3.77
(s, 3 H), 5.40 (dd, J = 2.2, 10.1 Hz, 1 H), 6.49 (m, 2 H), 6.96
(br d, J = 7.2 Hz, 1 H), 7.31–7.34 (m, 1 H), 7.38–7.41 (m,
Synlett 2008, No. 20, 3167–3171 © Thieme Stuttgart · New York

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