Organocatalytic asymmetric Friedel-Crafts alkylation/cyclization cascade reaction of 1-naphthols and α,β-unsaturated aldehydes: An enantioselective synthesis of chromanes and dihydrobenzopyranes

Article abstract of DOI:10.1021/jo901409d

(Chemical Equation Presented) An enantioselective Friedel-Crafts alkylation/cyclization cascade reaction of 1-naphthols and α,β- unsaturated aldehydes promoted by diphenylprolinol ether has been developed. The method affords one-pot access to chiral and s

Full text of DOI:10.1021/jo901409d

pubs.acs.org/joc
successful examples of such a process are focused on relatively
Organocatalytic Asymmetric Friedel-Crafts
Alkylation/Cyclization Cascade Reaction of
1-Naphthols and r,β-Unsaturated Aldehydes: An
Enantioselective Synthesis of Chromanes and
Dihydrobenzopyranes
more reactive furans, pyrroles and indoles, and a few excep-
tions are the benzene derivatives bearing highly electron-
donating groups.3 Therefore, there is an urgent requirement
to develop novel enantioselective Friedel-Crafts reactions,
especially for these undeveloped arenes. Naphthols have been
demonstrated to be good Friedel-Crafts donors with a range
of electrophiles.4 However, their applications in catalytic
asymmetric Friedel-Crafts reaction have rarely been ex-
plored.5 To the best of our knowledge, the enantioselective
Michael-type Friedel-Crafts alkylation of 1-naphthols and
R,β-unsaturated aldehydes has not been reported to date.
The chromane and benzopyrane structures are abundant in
natural products that possess a broad array of biological
activities such as antimicrobial, antiviral, mutagenicity, antipro-
liferative, sex pheromone, antitumor, and central nervous system
activity.6 Accordingly, a number of synthetic strategies have
been developed for the construction of these “privileged” struc-
tural motifs.7 Although many synthetic methods for these
Liang Hong,† Lei Wang,† Wangsheng Sun,†
Kwokyin Wong,‡ and Rui Wang*,†,‡
†State Key Laboratory of Applied Organic Chemistry and
Institute of Biochemistry and Molecular Biology, Lanzhou
University, Lanzhou 730000, China, and ‡Department of
Applied Biology and Chemical Technology, The Hong Kong
Polytechnic University, Kowloon, Hong Kong
wangrui@lzu.edu.cn
Received July 8, 2009
(3) (a) Jensen, K. B.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A.
Angew. Chem. 2001, 113, 164–167. Angew. Chem., Int. Ed. 2001, 40, 160-
163. (b) Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030–9031.
(c) Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcıa, J. M.; Linden, A.
J. Am. Chem. Soc. 2005, 127, 4154–4155. (d) Evans, D. A.; Fandrick, K. R.;
Song, H. J. J. Am. Chem. Soc. 2005, 127, 8942–8943. (e) Zhao, J. L.; Liu, L.;
Sui, Y.; Liu, Y. L.; Wang, D.; Chen, Y. J. Org. Lett. 2006, 8, 6127–6130.
(f) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370–
4371. (g) Terada, M.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292–293.
(h) Kang, Q.; Zhao, Z. A.; You, S. L. J. Am. Chem. Soc. 2007, 129, 1484–
1485. (i) Chen, W.; Du, W.; Yue, L.; Li, R.; Wu, Y.; Ding, L. S.; Chen, Y. C.
Org. Biomol. Chem. 2007, 5, 816–821. (j) Austin, J. F.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 1172–1173. (k) Paras, N. A.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894–7895.
(4) For limited examples of naphthols in Friedel-Crafts reaction in a
racemic form, see: (a) Kidwai, M.; Saxena, S.; Khan, M. K.; Thukral, S. S.
Bioorg. Med. Chem. Lett. 2005, 15, 4295–4298. (b) Aoki, S.; Amamoto, C.;
Oyamada, J.; Kitamura, T. Tetrahedron 2005, 61, 9291–9297.
(5) For limited examples of naphthols in asymmetric Friedel-Crafts
reaction, see: (a) Erker, G.; van der Zeijden, A. A. H. Angew. Chem. 1990,
102, 543–545. Angew. Chem., Int. Ed. 1990, 29, 512-514. (b) Brandes, S.;
Bella, M.; Kjærsgaard, A.; Jørgensen, K. A. Angew. Chem. 2006, 118, 1165–
1169. Angew. Chem., Int. Ed. 2006, 45, 1147-1151. (c) Liu, T. Y.; Cui, H. L.;
Chai, Q.; Long, J.; Li, B. J.; Wu, Y.; Ding, L. S.; Chen, Y. C. Chem. Commun.
2007, 2228–2230.
(6) (a) Ellis, G. P.; Lockhart, I. M. The Chemistry of Heterocyclic Com-
pounds, Chromenes, Chromanones, and Chromones; Ellis, G. P., Ed.;Wiley-VCH:
New York, 2007; Vol. 31, pp 1-1196. (b) Horton, D. A.; Bourne, G. T.; Smythe, M.
L. Chem. Rev. 2003, 103, 893–930. (c) Geen, G. R.; Evans, J. M.; Vong, A. K.
Comprehensive Heterocyclic Chemistry II: Pyrans and their Benzo Derivatives:
Applications; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, UK, 1996; Vol. 5, pp 469-500. (d) Neugebauer, R. C.; Uchiechowska, U.;
Meier, R.; Hruby, H.; Valkov, V.; Verdin, E.; Sippl, W.; Jung, M. J. Med. Chem.
2008, 51, 1203–1213. (e) Posakony, J.; Hirao, M.; Stevens, S.; Simon,J. A.; Bedalov,
A. J. Med. Chem. 2004, 47, 2635–2644. (f) Wilkinson, J.; Foretia, D.; Rossington,
S.; Heagerty, A.; Leonard, J.; Hussain, N.; Austin, C. Eur. J. Pharmmacol. 2007,
561, 160–163. (g) Maloney, D. J.; Deng, J. Z.; Starck, S. R.; Gao, Z.; Hecht, S. M
J. Am. Chem. Soc. 2005, 127, 4140–4141. (h) Kumar, S.; Malachowski, W. P.;
DuHadaway, J. B.; LaLonde, J. M.; Carroll, P. J.; Jaller, D.; Metz, R.; Prendergast,
G. C.; Muller, A. J. J. Med. Chem. 2008, 51, 1706–1718.
An enantioselective Friedel-Crafts alkylation/cyclization
cascade reaction of 1-naphthols and R,β-unsaturated alde-
hydes promoted by diphenylprolinol ether has been devel-
oped. The method affords one-pot access to chiral and
synthetically useful chromanes and dihydrobenzopyranes in
high yields and enantioselectivities from readily available
compounds. In addition, the addition/cyclization products
could be afterward transformed to various natural products
and biologically active derivatives. On the basis of the experi-
mental results and the observed absolute configurations of the
products, a plausible mechanism has been proposed to explain
the origin of the activation and the asymmetric induction.
The Friedel-Crafts alkylation is one of the most powerful
methods for the formation of a new carbon-carbon bond and
has been widely utilized from academic experiments to indus-
trial processes.1 The asymmetric version of this reaction has
attracted considerable interest and witnessed significant pro-
gress recently.2 In spite of considerable effort, most of the
(7) (a) Youn, S. W.; Pastine, S. J.; Sames, D. Org. Lett. 2004, 6, 581–584.
(b) Shi, Z.; He, C. J. Am. Chem. Soc. 2004, 126, 13596–13597. (c) Volonterio,
A.; Zanda, M. Tetrahedron Lett. 2005, 46, 8723–8726. (d) Ulgheri, F.;
Marchetti, M.; Piccolo, O. J. Org. Chem. 2007, 72, 6056–6059. (e) Jagdale,
A. R.; Sudalai, A. Tetrahedron Lett. 2007, 48, 4895–4898. (f) Hedberg, C.;
Andersson, P. G. Adv. Synth. Catal. 2005, 347, 662–666. (g) Botteghi, C.;
Corrias, T.; Marchetti, M.; Paganelli, S.; Piccolo, O. Org. Process Res. Dev.
2002, 6, 379–383. (h) Aoki, S.; Amamoto, C.; Oyamada, J.; Kitamura, T.
Tetrahedron 2005, 61, 9291–9297. (i) Li, K.; Tunge, J. A. J. Org. Chem. 2005,
70, 2881–2883. (j) Keukeleire, D. D.; Saeyens, W. Synth. Commun. 1996, 26,
4397–4402.
(1) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S. Friedel-Crafts
alkylation. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, UK, 1991; Vol. 3, pp 293-339.
(2) For recent reviews on Friedel-Crafts alkylation, see: (a) Poulsen, T.
B.; Jørgensen, K. A. Chem. Rev. 2008, 108, 2903–2915. (b) Bandini, M.;
Melloni, A.; Umani-Ronchi, A. Angew. Chem. 2004, 116, 560–566. Angew.
Chem., Int. Ed. 2004, 43, 550-556. (c) Bandini, M.; Melloni, A.; Tommasi,
S.; Umani-Ronchi, A. Synlett 2005, 1199–1222. (d) Jørgensen, K. A. Synth-
esis 2003, 1117–1125. (e) Wang, Y.; Ding, K. Chin. J. Org. Chem. 2001, 21,
763–767. (f) Wang, Y.; Ding, K.; Dai, L. Chemtracts 2001, 14, 610–615.
DOI: 10.1021/jo901409d
r
Published on Web 08/07/2009
J. Org. Chem. 2009, 74, 6881–6884 6881
2009 American Chemical Society

Hong et al.
SCHEME 1. Difficulties Encountered When Attempting the
Friedel-Crafts Alkylation/Cyclization Cascade Reaction of 1-
Naphthol and R,β-Unsaturated Aldehydes
JOCNote
compounds have been reported, most procedures are
run under harsh conditions with either high concentra-
tions of acids or large amounts of strong Lewis acids, which
can hardly be tolerated by many functional groups.
In particular, the enantioselective synthesis of this chiral
scaffold has been rarely explored.8 Given the importance
of these valuable chromanes and dihydrobenzopyranes
as well as the lack of efficient methods for the prepara-
tion of these important active agents, the development
of a new catalytic asymmetric synthesis of these compounds
appeared to be of great importance. In this context,
we reported the organocatalytic asymmetric synthesis
of chromanes and dihydrobenzopyranes from readily
available 1-naphthols 1 and R,β-unsaturated aldehydes
2 by the Friedel-Crafts alkylation/cyclization cascade
reaction.9
We envisioned that it might be possible to develope an
organocatalytic process10 for the formation of enantioen-
riched chromanes and dihydrobenzopyranes by the initial
Friedel-Crafts alkylation of 1-naphthol to an R,β-unsatu-
rated aldehyde in the presence of an organocatalyst followed
by a subsequent cyclization reaction. However, achieving
this process is thought to be difficult because of the compe-
titive addition of oxygen nucleophiles to R,β-unsaturated
aldehydes (Scheme 1).11
The recent success with the use of diarylprolinol ethers12
prompted us to try the catalyst 3a for the asymmetric
Friedel-Crafts alkylation/cyclization cascade reaction.13
We initially investigated the reaction of 1-naphthol 1a
with cinnamaldehyde 2a in the presence of the catalyst 3a
(10 mol %) and benzoic acid (10 mol %) in THF for 60 h. The
product 4a was formed in low yield probably due to the
formation of a rather stable compound 5 (Table 1, entry 1).14
The same phenomenon was observed in other solvents
(Table 1, entries 2-6). To our delight, the addition of water
led to a dramatic increase of the yield (Table 1, entries 7 and
8).15 Apparently, water is helpful for the hydrolysis of
intermediate 5 to release the catalyst 3a and thus enable
catalytic turnover. The acid additive also had a great effect
on the reaction; almost no reaction occurred when the
stronger p-toluenesulfonic acid (p-TSA) or CF3CO2H
was used in place of benzoic acid (Table 1, entries 9 and
10). The enantioselectivity could be improved greatly by
adding 2-nitrobenzoic acid with a slight decrease of the yield
(Table1, entry 12). The screening of different amine catalysts
showed that diphenylprolinol ether 3a was an effective
organocatalyst for the reaction in terms of the yield and
enantioselectivity (Table1, entries 12-15). To our surprise,
catalyst 3b, a general catalyst for the Michael addition of
R,β-unsaturated aldehyde, was not active in the present
reaction (Table1, entry 13). After finding the appropriate
solvent, acid additive, and catalyst for the reaction, tempera-
ture was next screened. Decreasing the reaction temperature
to 4 °C resulted in an improved enantioselectivity (95:5 er),
but the time required for completion was significantly
(8) (a) Chen, G.; Tokunaga, N.; Hayashi, T. Org. Lett. 2005, 7, 2285–
2288. (b) Hayashi, T. Pure. Appl. Chem. 2004, 76, 465–475. (c) Rueping, M.;
Sugiono, E.; Merino, E. Chem.;Eur. J. 2008, 14, 6329–6332. (d) Paquin, J.
F.; Defieber, C.; Stephenson, C. R.; Carreira, E. M. J. Am. Chem. Soc. 2005,
127, 10850–10851. (e) Fessard, T. C.; Andrews, S. P.; Motoyoshi, H.;
Carreira, E. M. Angew. Chem. 2007, 119, 9492–9495. Angew. Chem., Int.
Ed. 2007, 46, 9331-9334. (f) Halland, N.; Hansen, T.; Jørgensen, K. A.
Angew. Chem. 2003, 115, 5105–5107. Angew. Chem., Int. Ed. 2003, 42, 4955-
4957. (g) Franke, P. T.; Richter, B.; Jørgensen, K. A. Chem.;Eur. J. 2008,
14, 6317–6321. (h) Rueping, M.; Merino, E.; Sugiono, E. Adv. Synth. Catal.
2008, 350, 2127–2131. (i) Albrecht, y.; Richter, B.; Krawczyk, H.; Jørgensen,
K. A. J. Org. Chem. 2008, 73, 8337–8343.
(9) For a similar type reaction employing NaOH as a reagent, see:
Nakazawa, T.; Furukawa, H.; Torii, K.; Itabashi, K. Nippon Kagaku Kaishi
1989, 2, 244–50.
(10) For selected reviews of organocatalysis, see: (a) Dalko, P. I.; Moisan,
L. Angew. Chem. 2004, 116, 5248–5286. Angew. Chem., Int. Ed. 2004, 43,
5138-5175. (b) Special issue on organocatalysis: Acc. Chem. Res. 2004, 37 (8).
(c) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719–724. (d) List, B.; Yang, J.
W. Science 2006, 313, 1584–1586. (e) List, B. Chem. Commun. 2006, 819–824.
(f) Gaunt, M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug Discovery
Today 2007, 12, 8–27. (g) Special issue on organocatalysis: Chem. Rev. 2007,
107 (12). (h) Dalko, P. I. Enantioselective Organocatalysis; Wiley-VCH:
Weinheim, Germany, 2007. (i) Dondoni, A.; Massi, A. Angew. Chem. 2008,
120, 4716–4739. Angew. Chem., Int. Ed. 2008, 47, 4638-4660.
(11) (a) Bertelsen, S.; DinMr, P.; Johansen, R. L.; Jørgensen, K. A. J. Am.
Chem. Soc. 2007, 129, 1536–1537. (b) Li, H.; Wang, J.; E-Nunu, T.; Zu, L.;
ꢀ
Jiang, W.; Wei, S.; Wang, W. Chem. Commun. 2007, 507–509. (c) Sunden, H.;
Ibrahem, I.; Zhao, G. L.; Eriksson, L.; Cordova, A. Chem.;Eur . J. 2007, 13,
ꢀ
574–581. (d) Li, D. R.; Murugan, A.; Falck, J. R. J. Am. Chem. Soc. 2008,
130, 46–48. (e) Biddle, M. M.; Lin, M.; Scheidt, K. A. J. Am. Chem. Soc.
2007, 129, 3830–3831.
(12) For selected leading references, see: (a) Marigo, M.; Wabnitz, T. C.;
Fielenbach, D.; Jørgensen, K. A. Angew. Chem. 2005, 117, 804–807. Angew.
Chem., Int. Ed. 2005, 44, 794-797. (b) Hayashi, Y.; Gotoh, H.; Hayashi, T.;
Shoji, M. Angew. Chem. 2005, 117, 4284–4287. Angew. Chem., Int. Ed. 2005,
44, 4212-4215. (c) Marigo, M.; Franzen, J.; Poulsen, T. B.; Zhuang, W.;
Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964–6965. (d) Enders, D.;
(13) For selected reviews of organocatalytic cascade reactions, see: (a)
€
Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem. 2007, 119, 1590–
€
Huttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861–863. (e)
1601. Angew. Chem., Int. Ed. 2007, 46, 1570-1581. (b) Guo, H. C.; Ma, J. A.
Angew. Chem. 2006, 118, 362–375. Angew. Chem., Int. Ed. 2006, 45, 354-
366. (c) Pellissier, H. Tetrahedron 2006, 62, 1619–1665. (d) Pellissier, H.
Tetrahedron 2006, 62, 2143–2173.
(14) (a) Juhl, K.; Jørgensen, K. A. Angew. Chem. 2003, 115, 1536–1539.
Angew. Chem., Int. Ed. 2003, 42, 1498-1501. (b) Wang, J.; Yu, F.; Zhang, X.;
Ma, D. W. Org. Lett. 2008, 10, 2561–2564.
(15) For a discussion on the effects of water in aminocatalysis, see: (a)
Hayashi, Y. Angew. Chem. 2006, 118, 8281–8282. Angew. Chem., Int. Ed.
2006, 45, 8103-8104. (b) Brogan, A. P.; Dickerson, T. J.; Janda, K. D.
Angew. Chem. 2006, 118, 8278–8280. Angew. Chem., Int. Ed. 2006, 45, 8100-
8102. (c) Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A. Angew.
Chem. 2007, 119, 3872–3874. Angew. Chem., Int. Ed. 2007, 46, 3798-3800.
Wang, W.; Li, H.; Wang, J.; Zu, L. J. Am. Chem. Soc. 2006, 128, 10354–
10355. (f) Carlone, A.; Cabrera, S.; Marigo, M.; Jørgensen, K. A. Angew.
Chem. 2007, 119, 1119–1122. Angew. Chem., Int. Ed. 2007, 46, 1101-1104.
(g) Chi, Y.; Guo, L.; Kopf, N. A.; Gellman, S. H. J. Am. Chem. Soc. 2008,
ꢀ ^
130, 5608–5609. (h) Garcıa-Garcıa, P.; Ladepeche, A.; Halder, R.; List, B.
Angew. Chem. 2008, 120, 4797–4799. Angew. Chem., Int. Ed. 2008, 47, 4719-
4721. (i) Hayashi, Y.; Itoh, T.; Ohkubo, M.; Ishikawa, H. Angew. Chem.
2008, 120, 4800–4802. Angew. Chem., Int. Ed. 2008, 47, 4722-4724. (j)
Ibrahem, I.; Rios, R.; Vesely, J.; Hammar, P.; Eriksson, L.; Himo, F.;
ꢀ
Cordova, A. Angew. Chem. 2007, 119, 4588–4590. Angew. Chem., Int. Ed.
2007, 46, 4507-4510. (k) Zhu, S.; Yu, S.; Ma, D. W. Angew. Chem. 2008, 120,
555–558. (l) Angew. Chem., Int. Ed. 2008, 47, 545-548.
6882 J. Org. Chem. Vol. 74, No. 17, 2009

Hong et al.
JOCNote
TABLE 1. Reaction Conditions Optimization for the Addition of
1-Naphthol 1a to Cinnamaldehyde 2aa
TABLE 2. Organocatalytic Asymmetric Friedel-Crafts Alkylation/
Cyclization Cascade Reactions of Representative 1-Naphthols with R,
β-Unsaturated Aldehydesa
t (h) yield (%)b drc
er (%)d
entry
3
acid
solvent
THF
DMSO
CHCl2
CHCl3
ether
toluene
H2O
yield (%)b er (%)c
entry
1
R
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16 f
17g
1a Ph (2a)
60
72
48
24
48
48
48
24
84
72
72
84
60
72
60
168
84
81 (4a)
73 (4b)
85 (4c)
93 (4d)
87 (4e)
85 (4f)
87 (4g)
91 (4h)
68 (4i)
79 (4j)
76 (4k)
63 (4l)
70 (4m)
72 (4n)
83 (4o)
<10
7:2 92:8 (>99:1)e
3:1 93:7
3:1 95:5
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16f
3a PhCO2H
3a PhCO2H
3a PhCO2H
3a PhCO2H
3a PhCO2H
3a PhCO2H
3a PhCO2H
3a PhCO2H
3a p-TSA
45
28
38
35
44
51
73
85
68:31
78:22
83:17
86:14
68:32
82:18
85:15
83:17
1a o-Cl-Ph (2b)
1a m-Cl-Ph (2c)
1a m-NO2-Ph (2d)
1a p-F-Ph (2e)
1a p-Cl-Ph (2f)
1a p-Br-Ph (2g)
1a p-NO2-Ph (2h)
1a o-MeO-Ph (2i)
1a m-MeO-Ph (2j)
1a p-Me-Ph (2k)
1a 2-furyl (2l)
1a Me (2m)
3:1 93:7
3:1 92:8
3:1 93:7 (>99:1)e
3:1 92:8 (>99:1)e
3:1 92:8
toluene/H2Oe
toluene/H2Oe
toluene/H2Oe
toluene/H2Oe
<10
<10
78
n.d.d
n.d.d
81:19
92:8
n.d.d
78:22
85:15
95:5
3:1 90:10
3:1 92:8
3:1 91:9
7:2 87:13
2:1 86:14
4:1 88:12
5:1 92:8
3a CF3CO2H
3a AcOH
3a o-NO2PhCO2H toluene/H2Oe
3b o-NO2PhCO2H toluene/H2Oe
3c o-NO2PhCO2H toluene/H2Oe
3d o-NO2PhCO2H toluene/H2Oe
3a o-NO2PhCO2H toluene/H2Oe
81
<10
52
73
1b Ph (2a)
1c Ph (2a)
1d Ph (2a)
1a Ph (2a)
43
aUnless otherwise specified, the reaction was carried out
with 1a (0.36 mmol) and 2a (0.30 mmol) in the presence of
an organocatalyst 3 (0.03 mmol), acid (0.03 mmol), and
solvent (1.0 mL) for 60 h. bIsolated yield of both diastereo-
mers. Determined by chiral HPLC analysis. Not deter-
e
mined. 0.15 mmol of H2O was added. Performed at 4 °C
for 120 h.
88 (4a)
7:2 92:8
aThe reaction conditions were the same as those in Table 1,
entry 12. bIsolated yield of both diastereomers. cDiastereomeric
ratio determined by 1H NMR spectroscopy of the crude mixture.
dDetermined by chiral HPLC analysis after NaBH4 reduction
of both diastereomers (see the Supporting Information). eAfter a
c
d
f
f
g
single recrystallization. No reaction. The reaction was per-
formed on a gram scale (20 mmol) for 84 h.
lengthened (120 h) and the yield was decreased as well
(Table1, entry 16). Considering the practical usage, we gave
up this condition.
To extend the scope of the reaction further, several
other substituted 1-naphthols and phenol were utilized as
nucleophiles in the reaction. The reaction proceeded in good
yields and enantioselectivities when using 1-naphthol bear-
ing either electron-withdrawing or electron-donating sub-
stituents (Table 2, entries 14 and 15). The reaction failed to
proceed when the less reactive phenol 1d was employed
(Table 2, entry 16).
Importantly, this reaction could be carried out on a gram
scale to demonstrate the synthetic utility of the present
system. When the reaction was performed with 20 mmol of
2a for 84 h, the corresponding adduct 4a was obtained in high
chemical yield without any loss of enantioselectivity
(Table 2, entry 17).
After the optimal conditions had been established, the
generality of the cascade Friedel-Crafts alkylation/cycliza-
tion processes was explored. As the data show in Table 2, the
reactions proceeded in respectively high yields and good
levels of enantioselectivities. The process appeared to have
a broad scope, but efficiencies and enantioselectivities varied
with the electronic nature of the R,β-unsaturated aldehydes
2. R,β-Unsaturated aldehydes 2 bearing electron-withdraw-
ing groups generally afforded products in higher yields and
higher enantioselectivities (Table 2, entries 2-8) than those
not possessing electron-withdrawing groups. Relatively low-
er enantioselectivities were observed for reactions of R,β-
unsaturated aromatic aldehydes 2 that bear neutral (Table 2,
entry 1) or electron-donating (Table 2, entries 9-11) sub-
stituents. The cascade processes also took place with less
reactive alkyl or heteroaromatic substituted R,β-unsaturated
aldehydes (Table 2, entries 12 and 13), albeit with lower
yields and enantioselectivities. It should be noted that the
enantioselectivities could be improved to 99:1 er after a single
recrystallization (Table 2, entries 1, 6, and 7).
The relative configuration of the major product obtained
in entry 15 of Table 2 was determined by X-ray diffraction
analysis to be 2S*,4S* (Figure 1).16 The absolute stereo-
chemistry at C4 was determined by comparison with a
(16) CCDC-728164 and 728165 contain the supplementary crystallo-
graphic data for this paper (4o and 6a, respectively). These data can be
obtained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/ data_request/cif.
J. Org. Chem. Vol. 74, No. 17, 2009 6883

Hong et al.
JOCNote
SCHEME 2. Chemical Transformation of 4a
aReaction conditions: (a) NaBH4, MeOH; (b) NaBH4, 20% H2SO4;
(c) PCC, CH2Cl2;(d) Ac2O, Et3N, DMAP, CH2Cl2;(e) Raney nickel,
toluene.
FIGURE 1. Proposed mechanism.
literature known compound 10a.17 This was accomplished by
dehydroxy-methylation of 6a with Raney nickel (Scheme 2).
By comparing the analytical data and X-ray crystallography,
we could establish the stereochemistry of our reaction product
4o as 2S,4S.
The chromanes 4 are not only components of many
natural products, but also valuable substrates for the synth-
esis of further pharmacologically interesting compounds
(Scheme 2). For instance, the reduction of 4a leads to the
formation of 6a in 78% yield. The chromane 4a can also be
transformed into the corresponding cyclic ether 7a in two
simple steps. Besides, 4a can be readily oxidized to the
benzochromanone 8a in the presence of PCC. The hydroxy
group of 4f can be acetylated to give 9f. Furthermore, 4a can
be transformed into fendiline 11a according to the procedure
developed by Hayashi.8a
With regard to the mechanism, we assume that the activa-
tion of R,β-unsaturated aldehydes 2 by the diphenylprolinol
ether 3a results in the intermediary iminium ion A, and then
reacts with the 1-naphthol in a 1,4-addition way to give the
intermediate B. Subsequent hydrolysis and half acetalization
provides the desired chromanes 4, and the catalyst is regen-
erated (Figure 1).
In summary, we have developed a new organocatalytic
asymmetric Friedel-Crafts alkylation/cyclization cascade
reaction for the synthesis of chromanes and dihydrobenzo-
pyranes starting from readily available 1-naphthols and R,β-
unsaturated aldehydes in good yields and enantioselectiv-
ities. Since these compounds could be transformed afterward
to various natural products and biologically active deriva-
tives, there is a possibility that this reaction may be devel-
oped into a synthetically useful process, although further
work is needed to improve both the chemical yield and the
enantioselectivity.
Experimental Section
General Procedure for the Synthesis of 4. To a solution of
catalyst 3a (0.03 mmol), o-NO2PhCO2H (0.03 mmol), and R,β-
unsaturated aldehyde 2a (0.30 mmol) in toluene (1.0 mL) and
H2O (30 μL) was added 1-naphthol 1a (0.36 mmol) at room
temperature. The resulting solution was then stirred for 24-84
h. After the complete consumption of the aldehyde (as mon-
itored by TLC), the reaction mixture was poured into water,
extracted with EtOAc, dried over Na2SO4, evaporated, and then
loaded onto silica gel and the products 4a-o were obtained by
column chromatography.
(4S)-4-Phenyl-3,4-dihydro-2H-benzo[h]chromen-2-ol (4a). 4a
was prepared according to the above method in 81% yield as a
1
mixture of diastereomers (7:2). Major diastereomer: H NMR δ
8.27-8.20 (m, 1H), 7.74-7.70 (m, 1H), 7.48-7.41 (m, 2H), 7.33-
7.14 (m, 6H), 6.88 (d, J = 8.4 Hz, 1H), 5.78 (s, 1H), 4.42 (dd, J =
9.9, 6.0 Hz, 1H), 3.29 (s, 1H), 2.40-2.32(m,1H),2.25-2.17(m,1H);
13C NMR δ 146.9, 144.6, 133.5, 128.8, 128.6, 127.5, 127.2, 126.7,
126.0, 125.4, 125.1, 121.6, 120.3, 118.5, 91.6, 37.5, 36.6; IR (film)
3404, 3056, 2934, 1709, 1575, 1497, 1451, 1395, 1261, 1189, 1049,
970, 894, 810, 752, 702; HRMS calcd for [C19H16O2 þ H]þ
277.1223, found 277.1217; [R]rtD þ58 (c 1.12, CHCl3); the ee was
determined by HPLC analysis, using a Chiralpak OD-H column
[hexane/EtOH (90:10)], flow rate 1.0 mL/min, tmajor=13.6 min,
t
minor=11.8 min (92:8 er).
Acknowledgment. We gratefully acknowledge financial
support from NSFC (20525206, 20772052, 90813012, and
20621091) and the Chang Jiang Scholar Program of the
Ministry of Education of China, and thank Prof. Richard
G. Weiss of Georgetown University for providing the origi-
nal HPLC spectra of the 10a.
Supporting Information Available: Experimental details and
characterization data for the products as well as X-ray crystal-
lography of 4o and 6a. This material is available free of charge
via the Internet at http://pubs.acs.org.
(17) (a) Xu, J.; Weiss, R. G. J. Org. Chem. 2005, 70, 1243–1252. (b) Xu, J.;
Weiss, R. G. Org. Lett. 2003, 5, 3077–3080.
6884 J. Org. Chem. Vol. 74, No. 17, 2009