Synthesis of chiral 1,2-dihydronaphtho[2,1-b]furans by organocatalytic domino reactions catalyzed with multiple catalysis

Article abstract of DOI:10.1071/CH13317

A chiral multiple catalysis with two chiral units has been proved effective in the domino Friedel-Crafts alkylation of β-naphthols with α-bromonitroalkenes. This novel and efficient domino reaction affords chiral 1,2-dihydronaphtho[2,1-b]furans in good to high yields and enantioselectivities (up to 93% yield, 91% enantiomeric excess). CSIRO 2013.

Full text of DOI:10.1071/CH13317

CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
http://dx.doi.org/10.1071/CH13317
Synthesis of Chiral 1,2-Dihydronaphtho[2,1-b]furans
by Organocatalytic Domino Reactions Catalyzed
with Multiple Catalysis
A
A
A
A B
,
Jin-Yun Pan, Xin-Sheng Li, Dong-Cheng Xu, and Jian-Wu Xie
A
Department of Chemistry and Life Science, Zhejiang Normal University,
321004 Jinhua, China.
B
Corresponding author. Email: xiejw@zjnu.cn
A chiral multiple catalysis with two chiral units has been proved effective in the domino Friedel–Crafts alkylation of
b-naphthols with a-bromonitroalkenes. This novel and efficient domino reaction affords chiral 1,2-dihydronaphtho[2,1-b]
furans in good to high yields and enantioselectivities (up to 93 % yield, 91 % enantiomeric excess).
Manuscript received: 23 June 2013.
Manuscript accepted: 26 July 2013.
Published online: 28 August 2013.
Introduction
bifunctional thiourea catalyst 1a in combination with
N,N-diisopropylethylamine (DIPEA), which have been success-
fully used in the asymmetric domino reactions of 1,3-dicarbonyl
compounds with a-bromonitroalkenes,[14] also exhibited
high catalytic activity for the reaction of naphthol 2a to
a-bromonitroalkene 3a (Scheme 1b). Unfortunately, the enan-
tioselectivity was very low.
Herein we present a metal-free and novel method for
the synthesis of chiral 1,2-dihydronaphtho-[2,1-b]furans
based on the development of a new organocatalytic enantio-
selective domino Friedel–Crafts alkylation of b-naphthols to
a-bromonitroalkenes. Notably, the designed reactions were
catalyzed by multiple catalysis with two chiral units and the
new transformations are highly regio-, chemo-, diastereo-, and
enantioselective, which simultaneously give the desired pro-
ducts with two vicinal chiral carbon centers.
Furans are an important class of heterocycles and play an
important role in organic chemistry, not only as key structural
units in many natural products and important pharmaceuticals,[1]
but also as useful building blocks in synthetic chemistry.[2] In
particular, arene ring-fused furans have attracted widespread
interest in view of their presence in natural products, and their
biological and pharmacological activities.[3–6] Although ben-
zofurans have been the subject of the most extensive studies, and
numerous synthetic methods have been developed for
them,[3,7–9] the reports on the synthesis of naphthofurans[8,10,11]
are rather limited. In particular, to the best of our knowledge,
there are few reports on the direct catalytic asymmetric method
for the synthesis of chiral 1,2-dihydronaphtho[2,1-b]furans.[12]
In recent years, the naphthofuran nucleus has been found to
be a key structural motif in some natural products such as
(ꢀ)-laevigatin.[13] In addition, several synthetic compounds
containing a naphthofuran scaffold have been shown to possess
diverse biological activitiessuch asantifungal,[13]antibacterial,[11]
antiviral,[13a] b-adrenolytic,[13b-c] antitumour,[13d] and anthel-
mintic[13e–f] activity. As such, the development of new and more
general catalytic asymmetric methods for the preparation of chiral
1,2-dihydronaphtho[2,1-b]furans are of significant interest.
Recently, the a-bromonitroalkenes turned out to be highly
reactive and versatile because the bromo or nitro group could
behave as a better leaving group in reactions in comparison with
bromoalkenes or nitroalkenes in organic synthesis. We have also
reported that the electron-deficient a-bromonitroalkenes
could act as versatile acceptors in asymmetric domino reactions
of 1,3-dicarbonyl compounds with excellent chemo- and stereo-
selectivity (Scheme 1a).[14] Inspired by the successful results,
we envision that the new tandem Friedel–Crafts alkylation
would be possible between naphthols, a,a-dicyanoolefins,
and a-bromonitroalkenes, as outlined in Scheme 1b, giving a
facile protocol to chiral 1,2-dihydronaphtho[2,1-b]furans
with two vicinal chiral carbon centers. We found that the
Results and Discussion
To explore the feasibility of the proposed catalytic cascade
Friedel–Crafts alkylation process, we selected the reaction
between b-naphthol 2a and a-bromonitroalkene 3a in the
presence of various organocatalysts 1a–1j (Fig. 1, Table 1).
First, the reaction was performed in CHCl3 at room temperature
in the presence of cinchona alkaloid amine–thiourea catalysts 1a
and 1b, independently developed by the Connon and Soo´s
groups.[15] The desired product 4a was afforded by catalyst 1a
with 65 % yield and high diastereoselectivity, while the enan-
tioselectivity was only moderate (Table 1, entry 1). Similar
results were achieved when the reaction was catalyzed by 1b
(entry 2). Other thiourea catalysts, such as Takemoto’s catalyst
1c[16] and Tang’s catalyst 1d[17] were screened and poor results
were achieved (entries 3–4). Subsequently, the readily acces-
sible cinchona alkaloids and derivatives 1e–1j also proved to be
inferior to 1a and poor results were achieved (entries 5–10). By
lowering the temperature to ꢁ408C, good enantioselectivity
(71 % enantiomeric excess (ee)) and yield (79 %) in the presence
Journal compilation Ó CSIRO 2013
www.publish.csiro.au/journals/ajc

B
J.-Y. Pan et al.
NO2
Ar
O
O
30 mol-% 1a
O
NO2
Br
30 mol-% DIPEA
ꢀ
Ar
(a)
CHCl3, ꢁ40ꢂC, N2, 96h
O
O
O
86–99 % yield
79–92 % ee
H
N
H
N
F3C
N
OCH3
S
NO2
Ph
30 mol-% 1a
CF3
OH
NO2
Br
O
30 mol-% DIPEA
1a
ꢀ
Ph
CHCl3, ꢁ40ꢂC, N2, 96h
(b)
3a
2a
3a
quant. yield
38 % ee
Scheme 1. Previous work and this work. DIPEA: N,N-diisopropylethylamine.
CF3
H
N
H
N
H
N
H
N
F3C
N
S
F3C
N
S
N
H
N
F3C
OCH3
S
H
CF3
OH
N
CF3
1a
1b
1c
R
N
CF3
N
OH
1g R ꢃ H
1h R ꢃ F
1i R ꢃ Cl
S
N
H3CO
N
N
H
N
CF3
H
OCH3
OH
N
1j R ꢃ CH3O
1d
1e
1f
Fig. 1. The structures of organocatalysts 1a 1j.
]
Table 1. Catalyst screeningA
NO2
O
Ph
OH
NO2
20 mol-% catalyst
ꢀ
Ph
CHCl3, rt, 48h
Br
2a
3a
4a
Entry
Catalyst
YieldB [%]
eeC [%]
1
1a
1b
1c
1d
1e
1f
56
55
68
49
69
57
27
31
35
41
79
56
50
48
34
47
0
2
3
4
5
6
25
15
36
21
10
71
70
7
1g
1h
1i
8
9
10
11D
12E
1j
1a
1a
AReaction conditions: 0.30 mmol of 2a, 0.10 mmol of 3a, 20 mol-% of 1g in 1 mL, solvent at ꢁ408C under
N2 for 48 h.
BIsolated yields.
CEnantiomeric excess (ee) determined by chiral HPLC analysis.
D–408C, 96 h.
E10 mol-% of 1a, ꢁ408C, 96 h.

Synthesis of Chiral 1,2-Dihydronaphtho[2,1-b]furans
C
Table 2. Optimization of reaction conditionsA
DIPEA: N,N-diisopropylethylamine; DABCO: 1,4-diazabicyclo[2.2.2]octane; DCM: dichloromethane. Entry 7
corresponds to optimized conditions
NO2
Ph
OH
NO2
Br
10 mol-% 1a, 30 mol-% base
O
ꢀ
Ph
CHCl3, ꢁ40ꢂC, N2, 96h, 4 Å molecular sieves
2a
3a
4a
Entry
Base
Solvent
YieldB [%]
eeC [%]
1
DIPEA
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCM
quant.
89
38
65
68
75
81
75
85
78
68
81
75
81
70
72
2
DABCO
Na2CO3
3
83
4
Imidazole
77
5
1e
1f
76
6
79
7
1g
1h
1i
83
8
78
9
74
10
11
12
13
14D
1j
75
1g
1g
1g
1g
69
Toluene
THF
78
75
CHCl3
80
A
˚
Reaction conditions: 0.30 mmol of 2a, 0.10 mmol of 3a, 10 mol-% of 1g and 4 A molecular sieves in 1 mL of
solvent at ꢁ408C under N2 for 96 h.
BIsolated yields.
CEnantiomeric excess (ee) determined by chiral HPLC analysis.
D–208C, 96 h.
of 1a (20 mol-%) was achieved with extended reaction time
(entry 11). There is little effect on the enantioselectivity when
the catalyst loadings were reduced to 10 mol-% (entry 12).
Many achiral and chiral bases were used as additives in the
domino reaction and afforded good to excellent yields with
excellent diastereoselectivities (.99 : 1) and varied enantio-
selectivities (Table 2, entries 1–10). Clean and quantitative
product 4a was obtained while the enantioselectivity was very
low when DIPEA was used as additive (entry 1). All achiral
bases tended to decrease enantioselectivity except imidazole.
A combinatorial approach based on chiral multiple catalysis
with two chiral units has been proved to be effective in many
asymmetric reactions.[18] A catalytic system is formed by two
chiral molecules that has a good synergistic effect in the domino
reaction (entries 5–8, 10). Among the chiral additives, the
additive 1g gave the best result (entry 7). Various commonly
used solvents, such as dichloromethane (DCM, 78 % yield, 81 %
ee), toluene (69 % yield, 75 % ee), and tetrahydrofuran (THF,
75 % yield, 73 % ee), were screened, and chloroform turned out
to be optimal to give the product in higher enantioselectivities
and yields (entry 7).
With the optimal reaction conditions in hand, the scope of the
present organocatalytic asymmetric domino Friedel–Crafts
alkylation using chiral multiple catalysis (1a and 1g) was
extended to various b-naphthols and a-bromonitroalkenes. Only
the anti-products were detected for all the reactions (Fig. 2). The
absolute stereochemistries of the products formed are assigned
on the basis of high-performance liquid chromatography
(HPLC) in comparison with the literature data.[12] As illustrated
in Table 3, for the reactions of b-naphthol 2a, good results
were achieved with various a-bromonitroalkenes 3 bearing
various substitutions (Table 3, entries 1–12). It appeared
that the substituents’ electronics have a minimal impact on
enantioselectivities of the domino Friedel–Crafts alkylation.
Good enantioselectivities were obtained in the domino reaction
of 2a with an electron-withdrawing substituent on the aryl ring of
the a-bromonitroalkenes 3 (entries 2–9) as well as an electron-
donating substituent on the aryl ring of the a-bromonitroalkenes
3 (entries 10–12). a-Bromonitroalkenes 3 with electron-
withdrawing substituents in the ortho, meta, or para positions
afford thiochromanes with slightly inferior enantioselectivities
(entries 3–8). Subsequently, a few b-naphthol derivatives 2b
and 2c with different substitutions were investigated (entries
13–17). The domino reactions proceeded in high yields with
good to excellent enantioselectivities when b-naphthol 2b was
used as a Michael donor (entries 13, 15–17).
Conclusion
In summary, we have developed an organocatalytic asymmetric
domino Friedel–Crafts alkylation of various b-naphthols to
a-bromonitroalkenes with excellent chemo- and stereo-
selectivity. Chiral multiple catalysis is an efficient strategy for
the domino Friedel–Crafts alkylation. This novel and efficient
domino reaction affords chiral 1,2-dihydronaphtho[2,1-b]furans
in high yields and enantioselectivities. The use of chiral multiple
catalysts in asymmetric synthesis is a new emerging trend and
current studies are active and well underway to expand this
catalytic system in other asymmetric transformations.
Experimental
NMR spectra were recorded with tetramethylsilane as the
internal standard. TLC was performed on glass-backed silica
plates. Column chromatography was performed using silica
gel (160–200 mesh) eluting with ethyl acetate and petroleum

D
J.-Y. Pan et al.
ether. 1H NMR spectra were recorded at 400 MHz, and
13C NMR spectra were recorded at 100 MHz. Chemical shifts
(d) are reported in ppm downfield from CDCl3 (d ¼ 7.26 ppm)
77.0 ppm) for 13C NMR spectroscopy. Coupling constants (J)
are given in Hz. Electrospray ionization high-resolution mass
spectrometry (ESI-HRMS) was measured with a Finnigan
LCQDECA ion trap mass spectrometer. Enantiomeric excess (ee)
was determined by HPLC analysis on chiral Chiralpak columns.
Commercial grade solvents were dried and purified by standard
procedures as specified in the Purification of Laboratory
Chemicals.[19] Substrates were prepared according to literature
procedures.
General Procedure for the Synthesis
of Chiral 1,2-Dihydronaphtho[2,1-b]furans
Compounds 2a (44.0 mg, 0.3 mmol), 3a (22.8 mg, 0.1 mmol),
30 mol-% of 1a, and 10 mol-% of 1g were stirred in CHCl3
1
for H NMR and relative to the central CDCl3 resonance (d ¼
˚
(1 mL) at ꢁ408C under N2 and over 4 A molecular sieves for
96 h. Flash chromatography on silica gel (30 % ethyl acetate/
petroleum ether) then gave the product 4aa (23.3 mg) as a red
solid in 80 % yield.
(1R,2R)-2-Nitro-1-phenyl-1,2-dihydronaphtho[2,1-b]
furan (4aa)
Red solid, mp 108–1108C; 23.3 mg, yield 80 %; dH
(400 MHz, CDCl3) 7.93–7.86 (m, 2H), 7.45 (d, J 8.9, 1H),
7.37–7.30 (m, 6H), 7.20–7.18(m, J 1.8, 2H), 6.10 (d, J 1.7,
1H), 5.30 (d, J 10.2, 1H). dC (100 MHz, CDCl3) 156.2, 138.0,
131.5, 130.9, 129.6, 129.4, 129.1, 128.5, 127.7, 127.6, 124.5,
123.0, 118.3, 112.5, 111.9, 55.4; m/z Calc. for C18H13NO3 þ Na
314.0788, found 314.0775; nmax (KBr)/cmꢁ1 3067, 1566, 1368,
1092, 775, 745, 701; [a]D20 ¼ ꢁ156.7 (c 0.60, CHCl3), ee ¼ 85 %,
dr . 99 : 1; The enantiomeric ratio was determined by HPLC on
a Chiralpak IC column (15 % 2-propanol/hexane, 1 mL minꢁ1),
tmajor ¼ 4.88 min, tminor ¼ 5.44 min.
C16
C15
C14
C17
C13
Cl
Cl
O2
NO2
C11
C18
N
C4
C3
C12
O
C7
O1
(1R,2R)-1-(4-Fluorophenyl)-2-nitro-1,2-dihydronaphtho
[2,1-b]furan (4ab)
C2
C5
C6
O3
CI
C
C8
C9
O
H
N
Red solid, mp 138–1408C; 24.1mg, yield 78%; dH (400MHz,
CDCl3) 7.81–7.75 (m, 2H), 7.33 (d, J 8.9, 1H), 7.28–7.20 (m, 3H),
7.06–7.03 (m, 2H), 6.92–6.88 (m, 2H), 5.95 (d, J 1.8, 1H), 5.20
(s, 1H). dC (100MHz, CDCl3) 161.4, 156.2, 133.7, 131.7, 130.9,
129.5, 129.4, 129.3, 129.2, 127.8, 124.6, 122.9, 118.1, 116.5,
C1
4ad
C10
Fig. 2. X-ray analysis of compound 4ad.
Table 3. Scope of domino reaction of b-naphthols 2 with a-bromonitroalkenes 3A
Ar
NO2
OH
NO2
10 mol-% 1a, 30 mol-% 1g
O
ꢀ
R
Ar
CHCl3, ꢁ40ꢂC, N2, 96h, 4 Å molecular sieves
Br
R
3
2a R ꢃ H
4
2b R ꢃ 7-MeO
2c R ꢃ 6-Br
Entry
2
Ar
3
4/YieldB [%]
eeC [%]
1
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2b
2b
2b
Ph
3a
3b
3c
3d
3e
3f
4aa/80
4ab/78
4ac/86
4ad/82
4ae/76
4af/77
4ag/73
4ah/67
4ai/89
4aj/65
4ak/69
4al/60
4ba/93
4ca/79
4bb/84
4bg/86
4bk/80
85
84
80
85
81
84
85
80
85
80
76
76
91
72
85
89
84
2
p-F
3
p-Cl
m-Cl
o-Cl
p-Br
o-Br
2-Clꢁ4-Br
p-CF3
p-MeO
p-Me
2,5-(MeO)
Ph
4
5
6
7
3g
3h
3i
8
9
10
11
12
13
14
15
16
17
3j
3k
3l
3a
3a
3b
3g
3k
Ph
p-F
o-Br
p-Me
A
˚
Reaction conditions: 0.30 mmol of 2a, 0.10 mmol of 3a, 10 mol-% of 1g and 4 A molecular sieves in 1 mL solvent at ꢁ408C under N2 for 96 h.
BIsolated yields.
CEnantiomeric excess (ee) determined by chiral HPLC analysis.

Synthesis of Chiral 1,2-Dihydronaphtho[2,1-b]furans
E
116.3, 112.3, 111.9, 54.6. m/z Calc. for C18H12FNO3 þ Na
332.0693, found 332.0686; nmax (KBr)/cmꢁ1 2922, 1566, 1364,
1225, 1083, 817, 771; [a]D20 ¼ ꢁ87.3 (c 0.45, CHCl3), ee¼ 84%,
dr. 99 : 1; The enantiomeric ratio was determined by HPLC on a
Chiralpak IC column (10 % 2-propanol/hexane, 1 mLminꢁ1),
tmajor ¼ 5.35 min, tminor ¼ 6.57 min.
ee ¼ 84 %, dr . 99 : 1; The enantiomeric ratio was determined
by HPLC on a Chiralpak IC column (10 % 2-propanol/hexane,
1 mL minꢁ1), tmajor ¼ 5.56 min, tminor ¼ 7.66 min.
(1R,2R)-1-(2-Bromophenyl)-2-nitro-1,2-dihydronaphtho
[2,1-b]furan (4ag)
Black solid, mp 134–1368C; 27.1 mg, yield 73 %; dH
(400 MHz, CDCl3) 7.95–7.89 (m, 2H), 7.73 (d, J 7.8, 1H),
7.47–7.35 (m, 4H), 7.19–7.10 (m, 2H), 6.62 (s, 1H), 6.11
(s, 1H), 5.90 (s, 1H). dC (100 MHz, CDCl3) 156.5, 136.8,
133.6, 131.7, 130.9, 130.0, 129.4, 129.1, 128.4, 127.9, 124.7,
123.9, 123.1, 111.9, 111.8, 53.7. m/z Calc. for C18H12BrNO3 þ
Na 391.9893, found 391.9886; nmax (KBr)/cmꢁ1 2928, 1559,
1361, 1240, 1079, 739, 537; [a]2D0 ¼ ꢁ172.9 (c 0.45, CHCl3),
ee ¼ 85 %, dr . 99 : 1. The enantiomeric ratio was determined
by HPLC on a Chiralpak AS column (10 % 2-propanol/hexane,
1 mL minꢁ1), tmajor ¼ 8.63 min, tminor ¼ 6.79 min.
(1R,2R)-1-(4-Chlorophenyl)-2-nitro-1,2-dihydronaphtho
[2,1-b]furan (4ac)
Red solid, mp 118–1208C; 28.0 mg, yield 86 %; dH
(400 MHz, CDCl3) 7.94–7.87 (m, 2H), 7.44 (d, J 8.9, 1H),
7.39–7.37 (m, 2H), 7.31 (d, J 8.4, 3H), 7.13 (d, J 8.4, 2H),
6.05 (d, J 1.7, 1H), 5.29 (s, 1H). dC (100 MHz, CDCl3) 156.3,
136.4, 134.2, 131.8, 130.9, 129.6, 129.4, 129.2, 129.0, 127.8,
124.7, 122.8, 117.5, 112.1, 111.9, 54.7. m/z Calc. for
C18H12ClNO3 þ Na 348.0398, found 348.0398; nmax (KBr)/
cmꢁ1 2996, 1563, 1367, 1091, 804, 768, 742; [a]2D0 ¼ ꢁ116.1
(c 0.56, CHCl3), ee ¼ 80 %, dr . 99 : 1; The enantiomeric ratio
was determined by HPLC on a Chiralpak IC column (10 % 2-
propanol/hexane,
tminor ¼ 7.25 min.
1 mL minꢁ1),
tmajor ¼ 5.45 min,
(1R,2R)-1-(4-Bromo-2-chlorophenyl)-2-nitro-1,2-
dihydronaphtho[2,1-b]furan (4ah)
Black oil, 27.1 mg, yield 67 %; dH (400 MHz, CDCl3) 7.98–
7.88 (m, 2H), 7.73 (d, J 1.9, 1H), 7.47–7.37 (m, 3H), 7.33–7.29
(m, 1H), 7.22–7.19 (m, 1H), 6.48 (d, J 8.1, 1H), 6.08 (d, J 1.3,
1H), 5.80 (s, 1H). dC (100 MHz, CDCl3) 156.6, 134.5, 134.1,
132.8, 131.9, 131.0, 130.9, 130.3, 129.3, 129.2, 128.0, 124.8,
122.8, 122.7, 117.6, 111.8, 111.3, 110.0, 50.8. m/z Calc. for
C18H11BrClNO3 þ Na 425.9503, found 425.9494; nmax (KBr)/
cmꢁ1 2922, 1567, 1399, 1086, 769, 747, 555; [a]2D0 ¼ ꢁ98.9
(c 0.60, CHCl3), ee ¼ 80 %, dr . 99 : 1; The enantiomeric
ratio was determined by HPLC on a Chiralpak IC column
(10 % 2-propanol/hexane, 1 mL minꢁ1), tmajor ¼ 5.59 min,
tminor ¼ 6.17 min.
(1R,2R)-1-(3-Chlorophenyl)-2-nitro-1,2-dihydronaphtho
[2,1-b]furan (4ad)
Red solid, mp 126–1298C; 26.7 mg, yield 82 %; dH
(400 MHz, CDCl3) 7.95–7.88 (m, 2H), 7.45 (d, J 8.9, 1H),
7.41–7.38 (m, 2H), 7.37–7.31 (m, 1H), 7.30–7.29 (m, 2H),
7.19 (s, 1H), 7.09–7.07 (m, 1H), 6.07 (d, J 1.7, 1H), 5.29
(s, 1H). dC (100 MHz, CDCl3) 139.8, 135.2, 131.8, 130.9,
130.7, 129.4, 129.2, 128.8, 127.9, 127.7, 125.8, 124.7, 122.8,
117.5, 112.0, 1119, 54.9. m/z Calc. for C18H12ClNO3 þ Na
348.0398, found 398.0393; nmax (KBr)/cmꢁ1 2925, 1568,
1368, 1077, 863, 771, 740; [a]2D0 ¼ ꢁ110.7 (c 0.58, CHCl3),
ee ¼ 85 %, dr . 99 : 1; The enantiomeric ratio was determined
by HPLC on a Chiralpak IC column (10 % 2-propanol/hexane,
1 mL minꢁ1), tmajor ¼ 5.40 min, tminor ¼ 6.15 min.
(1R,2R)-2-Nitro-1-(4-(trifluoromethyl)phenyl)-1,2-
dihydronaphtho[2,1-b]furan (4ai)
Red solid, mp 142–1448C; 31.9 mg, yield 89 %; dH
(400 MHz, CDCl3) 7.99–7.87 (m, 2H), 7.61 (d, J 7.9, 2H),
7.47 (d, J 8.9, 1H), 7.41–7.39 (m, 2H), 7.32 (t, J 9.5, 3H), 6.07
(s, 1H), 5.38 (s, 1H). dC (100 MHz, CDCl3) 156.4, 132.0, 130.9,
129.4, 129.2, 128.1, 128.0, 126.5, 126.4, 124.8, 122.7, 117.4,
111.9, 111.8, 110.0 54.9. m/z Calc. for C19H12F3NO3 þ Na
382.0661, found 382.0658; nmax (KBr)/cmꢁ1 2924, 1569,
1323, 1231, 1109, 804, 770; [a]2D0 ¼ ꢁ39.5 (c 0.86, CHCl3),
ee ¼ 85 %, dr . 99 : 1; The enantiomeric ratio was determined
by HPLC on a Chiralpak AS column (30 % 2-propanol/hexane,
1 mL minꢁ1), tmajor ¼ 4.94 min, tminor ¼ 5.73 min.
(1R,2R)-1-(2-Chlorophenyl)-2-nitro-1,2-dihydronaphtho
[2,1-b]furan (4ae)
Red solid, mp 116–1188C; 24.7mg, yield 76 %; dH (400MHz,
CDCl3) 7.93–7.87 (m, 2H), 7.53 (d, J 8.0, 1H), 7.45–7.33 (m, 4H),
7.26–7.22 (m, 1H), 7.06 (t, J 7.6, 1H), 6.63 (d, J 7.5, 1H), 6.11
(s, 1H), 5.87 (s, 1H). dC (100 MHz, CDCl3) 156.6, 135.1, 133.7,
131.7, 131.0, 130.3, 129.8, 129.5, 129.2, 128.0, 127.8, 124.6,
123.0, 118.3, 111.9, 51.1. m/z Calc. for C18H12ClNO3 þ Na
348.0398, found 348.0395; nmax (KBr)/cmꢁ1 2925, 1568, 1368,
1077, 771, 740; [a]2D0 ¼ ꢁ172.2 (c 0.51, CHCl3), ee ¼ 81%,
dr. 99 : 1; The enantiomeric ratio was determined by HPLC
on a Chiralpak AS column (10 % 2-propanol/hexane, 1 mL
minꢁ1), tmajor ¼ 8.51 min, tminor ¼ 6.65 min.
(1R,2R)-1-(4-Methoxyphenyl)-2-nitro-1,2-
dihydronaphtho[2,1-b]furan (4aj)
Yellow solid, mp 108–1108C; 20.9 mg, yield 65 %; dH
(400MHz, CDCl3) 7.90 (d, J 8.9, 2H), 7.43 (d, J 8.9, 1H),
7.36–7.35 (m, 3H), 7.10–7.08 (m, 2H), 6.90–6.75 (m, 2H), 6.06
(d, J 1.7, 1H), 5.26 (s, 1H), 3.76 (s, 3H). dC (101 MHz, CDCl3)
159.6, 156.1, 131.4, 130.9, 130.0, 129.6, 129.1, 128.7, 127.6,
124.5, 123.0, 118.5, 114.7, 112.7, 111.8, 55.3, 54.8. m/z Calc. for
C19H15NO4 þ Na 344.0893, found 344.0890; nmax (KBr)/cmꢁ1
2961, 2934, 1567, 1370, 1093, 805, 771; [a]2D0 ¼ ꢁ144.7 (c 0.38,
CHCl3), ee¼ 80%, dr . 99 : 1; The enantiomeric ratio was deter-
mined by HPLC on a Chiralpak IC column (10 % 2-propanol/
hexane, 1 mL minꢁ1), tmajor ¼ 6.39 min, tminor ¼ 8.38min.
(1R,2R)-1-(4-bromophenyl)-2-nitro-1,2-dihydronaphtho
[2,1-b]furan (4af)
Red solid, mp 126–1288C; 28.5 mg, yield 77 %; dH
(400 MHz, CDCl3) 7.97–7.88 (m, 2H), 7.45 (t, J 7.7, 3H),
7.41–7.35 (m, 2H), 7.34–7.27 (m, 1H), 7.07 (d, J 8.3, 2H), 6.05
(d, J 1.4, 1H), 5.28 (s, 1H). dC (100 MHz, CDCl3) 156.3, 136.9,
132.6, 131.8, 130.9, 129.4, 129.3, 129.2, 127.9, 124.7, 122.8,
122.6, 117.7, 112.0, 111.9, 54.8. m/z Calc. for C18H12BrNO3 þ
Na 391.9893, found 391.9885; nmax (KBr) cmꢁ1 2923, 1566,
1368, 1092, 804, 740, 505; [a]2D0 ¼ ꢁ49.6 (c 0.50, CHCl3),

F
J.-Y. Pan et al.
(1R,2R)-2-Nitro-1-(p-tolyl)-1,2-dihydronaphtho[2,1-b]
furan (4ak)
7.12–7.08 (m, 2H), 6.98–6.93 (m, 3H), 6.46 (d, J 2.2, 1H), 5.98
(d, J 1.7, 1H), 5.17 (s, 1H), 3.62 (s, 3H). dC (100 MHz, CDCl3)
158.6, 156.4, 131.3, 130.9, 130.7, 129.3, 129.2, 126.3, 117.0,
116.5, 116.3, 112.3, 109.2, 101.5, 55.2, 54.6. m/z Calc. for
C19H14FNO4 þ Na 362.0799, found 362.0789; nmax (KBr)/cmꢁ1
2999, 2954, 1560, 1389, 1212, 1086, 808, 761; [a]2D0 ¼ ꢁ7.56
(c 0.79, CHCl3), ee ¼ 85 %, dr . 99 : 1; The enantiomeric ratio
was determined by HPLC on a Chiralpak IC column (10 % 2-
Red solid, mp 104–1068C; 21.1 mg, yield 69 %; dH
(400 MHz, CDCl3) 7.92 (d, 2H), 7.45 (d, 1H), 7.38 (d, 3H),
7.15 (d, 2H), 7.08 (d, 2H), 6.09 (s, 1H), 5.29 (s, 1H), 2.33 (s, 3H).
dC (100 MHz, CDCl3) 156.1, 138.3, 135.0, 131.4, 130.9, 130.1,
129.6, 129.0, 127.6, 127.4, 124.5, 123.0, 118.4, 112.7, 111.8,
55.1, 21.1. m/z Calc. for C19H15NO3 þ Na 328.0944, found
328.0932; nmax (KBr)/cmꢁ1 3068, 2925, 1563, 1366, 1089,
800, 768; [a]2D0 ¼ ꢁ34.1 (c 0.26, CHCl3), ee ¼ 76 %, dr . 99 : 1;
The enantiomeric ratio was determined by HPLC on a
Chiralpak IC column (10 % 2-propanol/hexane, 1 mL minꢁ1),
tmajor ¼ 5.12 min, tminor ¼ 5.78 min.
propanol/hexane,
tminor ¼ 8.02 min.
1 mL minꢁ1),
tmajor ¼ 6.12 min,
(1R,2R)-1-(2-Bromophenyl)-8-methoxy-2-nitro-1,2-
dihydronaphtho[2,1-b]furan (4bg)
Black solid, mp 158–1608C; 34.3 mg, yield 86 %; dH
(400 MHz, CDCl3) 7.81 (d, J 8.8, 1H), 7.74–7.69 (m, 2H),
7.28 (d, J 8.8, 1H), 7.16–7.13 (m, 2H), 7.01–6.98 (m, 1H),
6.73–6.67 (m, 2H), 6.12 (s, 1H), 5.85 (s, 1H), 3.74 (s, 3H). dC
(100 MHz, CDCl3) 159.1, 156.7, 137.0, 133.4, 131.2, 130.8,
130.6, 130.0, 129.2, 128.7, 126.2, 123.7, 117.4, 111.9, 110.0,
109.1, 101.5, 55.4, 53.5. m/z Calc. for C19H14BrNO4 þ Na
421.9998, found 421.9994; nmax (KBr)/cmꢁ1 2963, 2929,
1560, 1364, 1080, 759, 539; [a]2D0 ¼ 36.0 (c 0.50, CHCl3),
ee ¼ 89 %, dr . 99 : 1; The enantiomeric ratio was determined
by HPLC on a Chiralpak IC column (10 % 2-propanol/hexane,
1 mL minꢁ1), tmajor ¼ 6.31 min, tminor ¼ 6.91 min.
(1R,2R)-1-(2,5-Dimethoxyphenyl)-2-nitro-1,2-
dihydronaphtho[2,1-b]furan (4al)
White solid, mp 108–1108C; 21.0 mg, yield 60 %; dH
(400 MHz, CDCl3) 7.88–7.84 (m, 2H), 7.43–7.33 (m, 4H),
6.91 (d, J 8.9, 1H), 6.79–6.76 (m, 1H), 6.22 (d, J 2.9, 1H),
6.14 (d, J 1.8, 1H), 5.69 (s, 1H), 3.92 (s, 3H), 3.53 (s, 3H). dC
(100 MHz, CDCl3) 156.5, 153.8, 151.0, 131.2, 130.8, 129.9,
129.0, 127.6, 127.0, 124.4, 123.2, 118.2, 115.3, 113.2, 112.8,
111.8, 111.8, 56.2, 55.6, 48.7. m/z Calc. for C20H17NO5 þ Na
374.0999, found 374.0997; nmax (KBr)/cmꢁ1 2961, 2934, 2920,
1563, 1367, 1093, 800, 771; [a]2D0 ¼ ꢁ101.2 (c 0.61, CHCl3),
ee ¼ 76 %, dr . 99 : 1; The enantiomeric ratio was determined
by HPLC on a Chiralpak AS column (10 % 2-propanol/hexane,
1 mL minꢁ1), tmajor ¼ 7.39 min, tminor ¼ 6.48 min.
(1R,2R)-8-Methoxy-2-nitro-1-(p-tolyl)-1,2-
dihydronaphtho[2,1-b]furan (4bk)
White solid, mp 116–1208C; 26.8 mg, yield 80 %; dH
(400 MHz, CDCl3) 7.82–7.74 (m, 2H), 7.28–7.25 (m,1H),
7.17–7.05 (m, 4H), 7.01–6.99 (m, 1H), 6.60 (d, J 2.4, 1H),
6.08 (d, J 1.7, 1H), 5.21 (s, 1H), 3.70 (s, 3H), 2.32 (s, 3H). dC
(101 MHz, CDCl3) 158.8, 156.7, 138.2, 134.7, 131.0, 130.6,
130.0, 127.4, 126.2, 117.6, 116.9, 112.7, 109.1, 101.6, 55.2,
55.1, 21.1. m/z Calc. for C20H17NO4 þ Na 358.1050, found
358.1047; nmax (KBr)/cmꢁ1 2966, 2925, 1571, 1371, 1083,
834, 760; [a]2D0 ¼ 29.0 (c 0.65, CHCl3), ee ¼ 84 %, dr . 99 : 1;
The enantiomeric ratio was determined by HPLC on a Chiralpak
(1R,2R)-8-Methoxy-2-nitro-1-phenyl-1,2-
dihydronaphtho[2,1-b]furan (4ba)
Red solid, mp 124–1268C; 29.9 mg, yield 93 %; dH
(400 MHz, CDCl3) 7.83–7.74 (m, 2H), 7.36–7.28 (m, 4H),
7.22–7.20 (m, 2H), 7.02–6.99 (m, 1H), 6.58 (d, J 2.3, 1H),
6.11 (d, J 1.7, 1H), 5.25 (s, 1H), 3.68 (s, 3H). dC (100 MHz,
CDCl3) 158.8, 1568, 137.7, 131.1, 131.0, 130.6, 129.4, 128.4,
127.6, 126.2, 117.4, 117.0, 112.5, 109.1, 101.6, 55.4, 55.2. m/z
Calc. for C19H15NO4 þ Na 344.0893, found 344.0882; nmax
(KBr)/cmꢁ1 2998, 2923, 1570, 1366, 1080, 832, 755, 698;
[a]2D0 ¼ 1.57 (c 0.63, CHCl3), ee ¼ 91 %, dr . 99 : 1; The enan-
tiomeric ratio was determined by HPLC on a Chiralpak IC
IC column (10 % 2-propanol/hexane, 1 mL minꢁ1), tmajor
5.89 min, tminor ¼ 7.02 min.
¼
column (10 % 2-propanol/hexane, 1 mL minꢁ1), tmajor
6.05 min, tminor ¼ 7.21 min.
¼
Supplementary Material
NMR and HPLC spectra are available on the Journal’s website.
(1R,2R)-7-Bromo-2-nitro-1-phenyl-1,2-dihydronaphtho
[2,1-b]furan (4ca)
Acknowledgements
Red solid, mp 104–1068C; 29.2 mg, yield 79 %; dH
(400 MHz, CDCl3) 8.03 (s, 1H), 7.82 (d, J 8.9, 1H), 7.51–7.40
(m, 2H), 7.38–7.30 (m, 3H), 7.26–7.20 (m, 1H), 7.17–7.15 (m,
2H), 6.10 (d, J 1.7, 1H), 5.29 (s, 1H). dC (100 MHz, CDCl3)
156.5, 137.6, 132.0, 131.0, 131.0, 130.6, 129.5, 128.6, 128.0,
127.5, 124.6, 118.6, 118.3, 113.0, 112.4, 55.2. m/z Calc. for
C18H12BrNO3 þ Na 391.9893, found 391.9889; nmax (KBr)/
cmꢁ1 2962, 2361, 1568, 1401, 1088, 800, 703, 521; [a]2D0 ¼ 19.6
(c 0.56, CHCl3), ee ¼ 72 %, dr . 99 : 1; The enantiomeric
ratio was determined by HPLC on a Chiralpak IC column
(10 % 2-propanol/hexane, 1 mL minꢁ1), tmajor ¼ 5.65 min,
tminor ¼ 6.45 min.
The authors are grateful for the financial support by the Program for the
National Natural Science Foundation of China (21272214) and Zhejiang
Leading Team of Science and Technology Innovation (2009R50020).
References
[1] B. H. Lipshutz, Chem. Rev. 1986, 86, 795. doi:10.1021/CR00075A005
[2] R. Benassi, in Comprehensive Heterocyclic Chemistry II (Eds A. R.
Katritzky, C. W. Rees, E. F. V. Scriven) 1996, Vol. 2, pp. 259–295
(Pergamon Press: Oxford).
[3] B. A. Keay, P. W. Dibble, in Comprehensive Heterocyclic Chemistry II
(Eds A. R. Katritzky, C. W. Rees, E. F. V. Scriven) 1996, Vol. 4,
pp. 395–436 (Pergamon Press: Oxford).
[4] G. A. Kraus, N. Zhang, J. G. Verkade, M. Nagarajan, P. B. Kisanga,
Org. Lett. 2000, 2, 2409. doi:10.1021/OL0000758
[5] (a) H. Hagiwara, K. Sato, T. Suzuki, M. Ando, Heterocycles 1999, 51,
(1R,2R)-1-(4-Fluorophenyl)-8-methoxy-2-nitro-1,2-
dihydronaphtho[2,1-b]furan (4bb)
497. doi:10.3987/COM-98-8430
(b) H. Hagiwara, K. Sato, D. Nishino, T. Hoshi, T. Suzuki, M. J. Ando,
J. Chem. Soc., Perkin Trans. 1 2001, 1, 2946. doi:10.1039/B107180G
Brown solid, mp 132–1348C; 28.5 mg, yield 84 %; dH
(400 MHz, CDCl3) 7.76–7.68 (m, 2H), 7.21–7.18 (m, 1H),

Synthesis of Chiral 1,2-Dihydronaphtho[2,1-b]furans
G
[6] (a) J. J. Chambers, D. M. Kurrasch-Orbaugh, M. A. Parker,
D. E. Nichols, J. Med. Chem. 2001, 44, 1003. doi:10.1021/JM000491Y
(b) L. Rene, J.-P. Buisson, R. Royer, D. Averbeck, Eur. J. Med. Chem.
1977, 12, 31.
(d) J. N. Chatterjea, V. N. Mehrotra, S. K. Roy, Chem. Ber. 1963, 96,
1167. doi:10.1002/CBER.19630960432
(e) V. K. Mahesh, R. Sharma, M. Maheshwari, Indian J. Chem. 1979,
17, 528.
(c) C. Bilger, P. Demerseman, J. P. Buisson, R. Royer, P. Gayral,
J. Fourniat, Eur. J. Med. Chem. 1987, 22, 213. doi:10.1016/0223-5234
(87)90052-3
[12] C. Jarava-Barrera, F. Esteban, C. Navarro-Ranninger, A. Parra,
J. Alema´n, Chem. Commun. 2013, 49, 2001. doi:10.1039/
C2CC38534A
[7] G. A. Kraus, N. Zhang, J. G. Verkade, M. Nagarajan, P. B. Kisanga,
Org. Lett. 2000, 2, 2409. doi:10.1021/OL0000758
[8] (a) K. C. Nicolaou, S. A. Snyder, A. Bigot, J. A. Pfefferkora, Angew.
Chem. Int. Ed. 2000, 39, 1093. doi:10.1002/(SICI)1521-3773
(20000317)39:6,1093::AID-ANIE1093.3.0.CO;2-S
(b) J. Habermann, S. V. Ley, R. Smits, J. Chem. Soc., Perkin Trans. 1
1999, 1, 2421. doi:10.1039/A904384E
(c) H. M. Meshram, K. C. Sekhar, Y. S. S. Ganesh, J. S. Yadav, Synlett
2000, 1273.
(d) Z. Chen, X. Wang, W. Lu, J. Yu, Synlett 1991, 121. doi:10.1055/
S-1991-20651
[9] (a) K. K. Park, H. Seo, J.-G. Kim, I.-H. Suh, Tetrahedron Lett. 2000,
[13] (a) M. Abdul-Aziz, J. V. Auping, M. A. Meador, J. Org. Chem. 1995,
60, 1303. doi:10.1021/JO00110A038
(b) K. K. Park, H. Lim, S.-H. Kim, D. H. Bae, J. Chem. Soc., Perkin
Trans. 1 2002, 1, 310. doi:10.1039/B110312A
(c) K. K. Park, H. Lim, Heterocycles 2002, 57, 657. doi:10.3987/
COM-02-9446
(d) K. K. Park, S.-H. Kim, J. W. Park, J. Photochem. Photobiol. Chem.
2004, 163, 241. doi:10.1016/J.JPHOTOCHEM.2003.12.004
(e) P. K. Frederiksen, M. Jørgensen, P. R. Ogilby, J. Am. Chem. Soc.
2001, 123, 1215. doi:10.1021/JA003468A
(f) T. D. Poulsen, P. K. Frederiksen, M. Jørgensen, K. V. Mikkelsen,
P. R. Ogilby, J. Phys. Chem. A 2001, 105, 11488. doi:10.1021/
JP011974W
41, 1393. doi:10.1016/S0040-4039(99)02300-X
(b) K. K. Park, I. K. Han, J. W. Park, J. Org. Chem. 2001, 66, 6800.
doi:10.1021/JO0103165
[14] L.-P. Fan, X.-S. Li, D.-C. Xu, M.-M. Ge, W.-D. Zhu, J.-W. Xie, J. Org.
Chem. 2010, 75, 8716. doi:10.1021/JO101935K
(c) A. R. Katritzky, Y. Ji, Y. Fang, I. Prakash, J. Org. Chem. 2001, 66,
5613. doi:10.1021/JO010278P
[15] (a) S. H. McCooey, S. J. Connon, Angew. Chem. Int. Ed. 2005, 117,
6525. doi:10.1002/ANGE.200501721
(d) X. Xie, B. Chen, J. Lu, J. Han, X. She, X. Pan, Tetrahedron Lett.
2004, 45, 6235. doi:10.1016/J.TETLET.2004.06.110
(e) M. del Carmen Cruz, J. Tamariz, Tetrahedron Lett. 2004, 45, 2377.
doi:10.1016/J.TETLET.2004.01.073
(b) B. Vakulya, S. Varga, A. Csampai, T. Soos, Org. Lett. 2005, 7,
1967. doi:10.1021/OL050431S
[16] (a) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125,
12672. doi:10.1021/JA036972Z
[10] (a) H. Hagiwara, K. Sato, T. Suzuki, M. Ando, Heterocycles 1999, 51,
(b) T. Okino, Y. Hoashi, T. Furukawa, X. Xu, Y. Takemoto, J. Am.
Chem. Soc. 2005, 127, 119. doi:10.1021/JA044370P
[17] C.-L. Cao, M.-C. Ye, X.-L. Sun, Y. Tang, Org. Lett. 2006, 8, 2901.
doi:10.1021/OL060481C
[18] S. Piovesana, D. M. ScarpinoSchietroma, M. Bella, Angew. Chem. Int.
Ed. 2011, 50, 6216. doi:10.1002/ANIE.201005955
[19] W. L. F. Armarego, D. D. Perrin, Purification of Laboratory Chemi-
cals 1997, 4th edn (Butterworth Heinemann: Oxford).
497. doi:10.3987/COM-98-8430
(b) H. Hagiwara, K. Sato, D. Nishino, T. Hoshi, T. Suzuki, M. Ando,
J. Chem. Soc., Perkin Trans. 1 2001, 1, 2946. doi:10.1039/B107180G
[11] (a) I. Yavari, M. Anary-Abbasinejad, A. Alizadeh, Tetrahedron Lett.
2002, 43, 4503. doi:10.1016/S0040-4039(02)00821-3
(b) M. Jørgensen, F. C. Krebs, K. J. Bechgaard, J. Org. Chem. 2000, 65,
8783. doi:10.1021/JO005646O
(c) A. R. Katritzky, L. Serdyuk, L. Xie, J. Chem. Soc., Perkin Trans. 1
1998, 1, 1059. doi:10.1039/A708809D