Iridium-catalyzed asymmetric ring-opening of azabicyclic alkenes with alcohols

Article abstract of DOI:10.1039/c3ob40891d

A novel asymmetric ring-opening reaction of N-substituted azabenzonorbornadienes with a wide variety of substituted benzyl alcohols and the addition reaction of N-substituted azabenzonorbornadienes with thiols are reported, affording the corresponding 1,2-trans-alkoxyamino products in moderate yields with excellent enantioselectivities (up to 94% ee) and the corresponding thiol addition products in high yields with lower enantiomeric excesses (ee) in the presence of iridium catalyst, respectively. The effects of ligands, catalyst loading, solvents and additives, and temperature were also investigated. The anti-configuration of the product 3c was confirmed by X-ray crystal structure analysis. A possible mechanism for the present catalytic reaction is proposed.

Full text of DOI:10.1039/c3ob40891d

Organic &
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Iridium-catalyzed asymmetric ring-opening of
azabicyclic alkenes with alcohols†
Cite this: Org. Biomol. Chem., 2013, 11,
4871
Dingqiao Yang,*a Jiuyun Xia,a Yuhua Long,*a Zhongyi Zeng,a Xiongjun Zuo,a
Sanyong Wangb and Chunrong Lib
A novel asymmetric ring-opening reaction of N-substituted azabenzonorbornadienes with a wide variety
of substituted benzyl alcohols and the addition reaction of N-substituted azabenzonorbornadienes with
thiols are reported, affording the corresponding 1,2-trans-alkoxyamino products in moderate yields with
excellent enantioselectivities (up to 94% ee) and the corresponding thiol addition products in high yields
with lower enantiomeric excesses (ee) in the presence of iridium catalyst, respectively. The effects of
ligands, catalyst loading, solvents and additives, and temperature were also investigated. The anti-
configuration of the product 3c was confirmed by X-ray crystal structure analysis. A possible mechanism
for the present catalytic reaction is proposed.
Received 30th April 2013,
Accepted 22nd May 2013
DOI: 10.1039/c3ob40891d
www.rsc.org/obc
opening reaction of oxa- and azabicyclic alkenes with oxygen-
based nucleophiles such as phenols.19 However, limited
Introduction
It has been an attractive topic in organic synthesis to develop success has been achieved using methanol as nucleophile,4b
carbon–carbon bond and carbon–heteroatom bonds via tran- probably due to its poor nucleophilicity.20,21 To the best of our
sition metal asymmetric catalysis. These synthetic methods are knowledge, the use of substituted benzyl alcohols as the
important due to their potential to offer practical methods for nucleophile in asymmetric ring-opening has not been demon-
the synthesis of compounds with biological interest.1 For strated, and the stereochemical outcome (trans/cis) of the
example, transition-metal-catalyzed asymmetric ring-opening alkoxyamino ring-opened product is unknown. Herein we
reactions of oxa- and azabicyclic alkenes have been extensively report the full details of the catalytic asymmetric ring-opening
investigated.2 Many parameters had been investigated to opti- of N-substituted azabenzonorbornadienes 1a–1d with a wide
mize the ring-opening reactions, including the use of a variety variety of substituted benzyl alcohols in the presence of an
of metal catalysts, such as Pd,3 Rh,4 Cu,5 Ni,6 Fe,7 Ru8 etc., and iridium catalyst. The reactions afford the corresponding 1,2-
nucleophiles, such as dialkylzincs,3d–f,4b,c,5a,9 organoboronic trans-alkoxyamino products in moderate yields with excellent
acids,3b,c,10 alkynyl compounds,4d,5,11 organozinc halides,12 enantioselectivities (up to 94% ee). We subsequently investi-
amines,4b,c,f,13 Grignard reagents,5,7,14 carboxylates,15 sulfur,16 gated the effects of ligand, catalyst loading, the effects of sol-
phenols,4a methanol4b and others.5f,17 In recent years, our vents and additives, and reaction temperature on the yield and
group has demonstrated that iridium-catalyzed asymmetric enantioselectivity. Furthermore, we investigated the ring-
ring-opening of strained bicyclic alkenes is a highly efficient opening of N-substituted azabenzonorbornadienes 1a–1d with
and enantioselective process for generating a functionalized thiols. However, we did not obtain any desired ring-opened
dihydronaphthalene core. Chiral iridium(I) complexes cata- product, while the corresponding thiol addition products were
lyzed the ring-opening reaction of oxa- and azabicyclic alkenes obtained in high yields with lower enantiomeric excesses (ee),
with amines in high yield and enantioselectivity.18 Very demonstrating the impact of nucleophiles on the reaction
recently, we have reported an analogous asymmetric ring- types.
aKey Laboratory of Theoretical Chemistry of Environment, Ministry of Education,
Results and discussion
School of Chemistry and Environment, South China Normal University, Guangzhou
510006, People’s Republic of China. E-mail: yangdq@scnu.edu.cn,
The substrates 1a–1d were readily prepared by the Diels–Alder
reactions of benzynes with N-substituted pyrroles according to
longyh@scnu.edu.cn; Fax: +86 20 31040403; Tel: +86 20 31040403
bGuangdong Food Industry Institute, Guangzhou 510308, People’s Republic of China
the literature procedures.18 In order to explore the ring
†Electronic supplementary information (ESI) available. CCDC 918458. For
opening reactions, an achiral ligand 1,1′-bis(diphenyl-
phosphino)ferrocene (DPPF) was first chosen to validate the
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob40891d
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Table 1 Effect of ligand on the iridium-catalyzed asymmetric ring-opening of
N-Ts-azabenzonorbornadiene 1b with 4-bromophenylmethanola
Table 2 The optimization of solvents and additives for the iridium-catalyzed
asymmetric ring-opening of N-Ts-azabenzonorbornadiene 1b with 4-
bromophenylmethanola
Entry
Solvent
Additiveb
Time [h]
Yieldc [%]
eed [%]
1
2
3
4
5
6
7
8
THF
THP
13
13
15
15
9
55
25
27
42
22
37
nr
nr
92
79
80
91
8
Toluene
DCE
Dioxane
CH2Cl2
CH3CN
THF
THF
THF
THF
THF
9
92
40
24
24
18
36
15
12
NaH
9
DMAPf
NH4Br
NH4I
nr
10
11
12
13e
Trace
Trace
56
[Ir(COD)Cl]2
Entry [mol%]
Time Yieldb eec
Bu4NI
AgOTf/Bu4NI
5
19
Ligand [mol%]
[h]
[%]
[%]
THF
38
1
2
3
4
5
6
7
8
2.5
2.5
1.0
1.5
2.5
3.5
2.5
2.5
2.5
2.5
5.0 DPPF
13
13
12
12
12
12
13
13
52
Trace
27
45
55
34
11
34
32
0
a The reaction was carried out with 1b (0.2 mmol) and 5.0 equiv. of
4-bromophenylmethanol (1.0 mmol) in THF (2.0 mL) at 80 °C (oil bath
temperature) in the presence of [Ir(COD)Cl]2 (2.5 mol%) and (S)-BINAP
(5.0 mol%). b 1.0 equiv. of additive. c Isolated yield after silica gel
column chromatography (0.2 mmol). d Determined by HPLC with a
Chiralcel OD-H column. e AgOTf (10.0 mol%) and Bu4NI (20.0 mol%)
as additives. f 4-Dimethylaminopyridine (DMAP).
5.0 (R,S)-PPFPtBu2
2.0 (S)-BINAP
3.0 (S)-BINAP
5.0 (S)-BINAP
7.0 (S)-BINAP
5.0 (S)-p-Tol-BINAP
5.0 (R)-Segphos
10
84
92
52
16
1
9
5.0 (R)-DTBM-Segphos 13
5.0 (S)-BINAP 24
4
—
10d
—
a The reaction was carried out with 1b (0.2 mmol) and 5.0 equiv. of
4-bromophenylmethanol (1.0 mmol) in THF (2.0 mL) at 80 °C (oil bath
temperature). b Isolated yield after silica gel column chromatography.
c Determined by HPLC with a Chiralcel OD-H column. d The reaction
was carried out at room temperature.
was 2.5 : 5 (Table 1, entry 5). However, further increase of the
catalyst loading improved neither the yield nor the enantio-
selectivity (Table 1, entries 6–10). By examining the effect of
temperature, we observed that the enantioselectivity changed a
lot at different temperatures. Unexpectedly, room temperature
resulted in no reaction even after a prolonged reaction time
(Table 1, entry 10); when the reaction was carried out at 80 °C
(oil bath temperature), the product 3f was obtained in 55%
yield with 92% ee. Therefore, the optimum reaction tempera-
ture was identified as 80 °C in THF giving the desired product
3f in moderate yield (55%) with excellent enantioselectivity
(92% ee) in the presence of 2.5 mol% of [Ir(COD)Cl]2 and
5.0 mol% of (S)-BINAP (Table 1, entry 5).
We next investigated the effects of the solvents and addi-
tives on the reactivity and enantioselectivity (Table 2). Some
common solvents were initially tested without additives
(Table 2, entries 1–7). It was observed that the reaction in tetra-
hydrofuran (THF) afforded the corresponding ring-opening
product 3f in moderate yield with high ee value (92% ee)
(Table 2, entry 1). Other solvents, such as toluene, 1,2-dichloro-
ethane (DCE), tetrahydropyran (THP), and CH2Cl2 offered
high ee values with lower yields (Table 2, entries 2–4 and 6).
The same reaction in 1,4-dioxane afforded the expected
product 3f in low yield with low ee (Table 2, entry 5). Therefore,
the solvent effect study showed that THF was the best
one among the solvents tested. It was also particularly
noteworthy that a byproduct of 4-methyl-N-naphthalen-1-yl-
benzenesulfonamide 3fa was obtained in a 50% yield in THP.
catalytic activity of the iridium complex in the ring-opening
reactions of N-Ts-azabenzonorbornadiene 1b with 4-bromo-
phenylmethanol. The results were summarized in Table 1. The
use of ferrocenyl bisphosphine ligand, (R,S)-PPF-PtBu2, was
thus attempted. Unfortunately, we did not obtain any desired
ring-opening product 3f (Table 1, entry 2). However, the use of
(S)-BINAP18a,c,e,22 as ligand was observed to give moderate yield
and reasonable enantioselectivity (84% ee) (Table 1, entry 4).
Encouraged by this result, we carried out an asymmetric
version of the same reaction using different kinds of chiral
ligands commercially available. Among the chiral ligands
tested, (S)-BINAP was observed to give the best yield and excel-
lent enantioselectivity (up to 92% ee) (Table 1, entry 5). Other
chiral ligands, such as (S)-p-Tol-BINAP, (R)-Segphos, (R,S)-
PPFPtBu2, and (R)-DTBM-Segphos, gave unsatisfactory results
(Table 1, entries 7–9). Therefore, (S)-BINAP was chosen as the
best ligand for further optimization of reaction conditions. On
the other hand, when the amount of catalyst loading was
lowered to 1.0 mol% of [Ir(COD)Cl]2 and 2.0 mol% of (S)-
BINAP, the ring-opening products were obtained in a 27%
yield only with low ee (10%) (Table 1, entry 3). Better results
were observed when the molar ratio of [Ir(cod)Cl]2 to (S)-BINAP
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It was formed by ring-opening and dehydroalkoxylation from
substrate 1b.
Table 3 Ir-catalyzed asymmetric ring-opening of N-protected azabenzonor-
bornadienes 1a–1d with alcoholsa
Additives such as NaH and 4-dimethylaminopyridine
(DMAP) did not improve the yield and ee value (Table 2,
entries 8 and 9), presumably due to the poisoning of catalysts
by these additives. Lautens and co-workers23 previously
reported that the halide ions played an important role in Rh
transition-metal catalyzed ring-opening and improved the reac-
tivity and enantioselectivity of the desired products. Inspired
by their work, we further investigated ammonium halides
(NH4Br, NH4I and Bu4NI) as additives13a,16 (Table 2, entries
10–12). The results indicated that the halide ions and
ammonium ions were not playing any significant role or might
not be necessary. In some cases, the reaction obtained better
results without the addition of halide ions and ammonium
ions. We next investigated the impact of silver(I) salts on the
reaction. It was observed that silver salts, such as silver triflate
(AgOTf), might facilitate the reaction,4f,9c,24 but the use of
AgOTf and Bu4NI as additives did not improve the yield and ee
value (Table 2, entry 13). On the basis of these studies, the
optimal reaction conditions are 2.5 mol% of [Ir(COD)Cl]2 and
5 mol% of (S)-BINAP in THF at 80 °C.
With the optimized reaction conditions in hand (2.5 mol%
of [Ir(COD)Cl]2 and 5 mol% of (S)-BINAP in THF at 80 °C), we
attempted to expand the scope of this reaction to other N-pro-
tected (R1) azabenzonorbornadienes. All reactions of N-pro-
tected (R1) series (1a–1d) with alcohols proceeded smoothly to
give the expected products in moderate yields. These results
are summarized in Table 3, from which it can be seen that the
enantioselectivities of these reactions were largely dependent
on the N-protected (R1) groups. For example, the reaction of
N-Boc-azabenzonorbornadiene 1a with 4-bromophenylmethanol
afforded the corresponding ring-opened product 2b in 32%
yield with 75% ee (Table 3, entry 2). Excellent enantiomeric
excesses of up to 92% were observed for N-Ts-azabenzonor-
bornadiene 1b (Table 3, entry 3). However, N-Nos-azabenzonor-
bornadiene 1c and N-Bs-azabenzonorbornadiene 1d showed good
reactivity with very poor enantioselectivities (Table 3, entries
5–8). The experimental results indicated that the N-protected
group on the nitrogen atom of the azabicyclic alkenes has a
remarkable impact on both the reactivity and enantio-
selectivity. It is noteworthy that N-Ts-azabenzonorbornadiene
1b not only showed a remarkable reactivity, but also gave excel-
lent enantioselectivities (Table 3, entries 3 and 4).
eed
Entry R1 b R2OH
Time [h] Product Yieldc [%] [%]
1
2
Boc CH3OH
Boc
12
48
2a
2b
50
32
63
75
3
4
5
6
Ts
15
36
48
24
3f
55
45
75
65
92
88
10
16
Ts
3l
Nos
Nos
4a
4b
7
8
Nos
Bs
48
17
4c
5a
55
68
18
4
a The reaction was carried out with 1a–1d (0.2 mmol) and 5.0 equiv. of
alcohols (1.0 mmol) in THF (2.0 mL) at 80 °C (oil bath temperature) in
the presence of [Ir(COD)Cl]2 (2.5 mol%) and (S)-BINAP (5.0 mol%).
b R1: Boc
benzenesulfonyl, Nos
=
tert-butoxycarbonyl (COOC(CH3)3), Ts
4-nitro-benzenesulfonyl, Bs
=
4-methyl-
=
= 4-bromo-
benzenesulfonyl. c Isolated yield after silica gel column
chromatography. d Determined by HPLC with
column.
a Chiralcel OD-H
variety of steric and electronic properties of the aromatic
rings of the alcohols, the enantioselectivities of the reactions
were found to be more than 70% ee with moderate
yields (Table 4, entries 5–9 and 12). The reaction of 1b with
o-bromophenylmethanol resulted in product 3k with very poor
enantioselectivity, presumably due to the steric hindrance of
the ortho-bromo group (Table 4, entry 11). Due to the steric
bulkiness of triphenylmethanol as nucleophile, the substrate
1b did not afford any desired ring-opened product 3m
(Table 4, entry 13).
The impact of substituents on the aromatic ring on the
asymmetric ring-opening reactions of 1b were also investi-
gated. Nucleophiles bearing electron-rich groups on the
phenyl ring such as p-methoxyphenylmethanol offered moder-
ate yield with excellent enantioselectivity (up to 82% ee)
(Table 4, entry 9). When 4-chlorophenylmethanol bearing an
electron-withdrawing Cl group was present, the yield and
enantioselectivity was increased (Table 4, entry 8). On the
other hand, 4-nitrophenylmethanol bearing a strong electron-
withdrawing group (–NO2) as nucleophile was found not to be
favorable to enantioselectivity (Table 4, entry 10), and the ee
was decreased to 60%.
Having the optimized reaction conditions in hand, we then
examined the ring-opening with different alcohols as the
nucleophile. The results are summarized in Table 4. It was
found that the structure of the alcohol had a significant
impact on the yield and enantioselectivity for the catalytic
ring-opening reaction. The results demonstrated that aliphatic
alcohols offered high yields with poor enantioselectivities
(Table 4, entries 1–4), while substituted benzyl alcohols gave
moderate yields with satisfactory enantioselectivities (Table 4,
entries 6–10 and 12). For example, the reaction of N-Ts-azaben-
zonorbornadiene 1b with 4-bromophenylmethanol offered a
high enantioselectivity (92% ee) (Table 4, entry 6). Despite the
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Table 4 The scope of asymmetric ring-opening of N-Ts-azabenzonorborna-
diene 1b with various alcoholsa
Table 5 The scope of the iridium-catalyzed addition reaction of N-substituted
azabenzonorbornadienes 1a–1b with thiolsa
Entry
ROH
Time [h]
Product
Yieldb [%]
eec [%]
Entry
R1
R2
Product
Yieldb [%]
eec [%]
1
2
3
CH3OH
15
22
15
3a
3b
3c
85
90
75
4
1
12
CH3CH2OH
1
2
3
Boc
Boc
Ts
Cl
OCH3
Cl
OCH3
Cl
OCH3
Cl
6a
6b
6c
6d
6a
6b
6c
6d
80
82
85
88
6
48
29
46
9
8
1
5
0
0
0
0
iPrOH
4
24
3d
75
30
4
Ts
5d
6d
7d
8d
Boc
Boc
Ts
5
6
13
15
3e
3f
51
55
94
92
Ts
OCH3
a The reaction was carried out with 1a, 1b (0.2 mmol) and 5.0 equiv. of
thiol (1.0 mmol) in THF (2.0 mL) at 80 °C (oil bath temperature) in the
presence of [Ir(COD)Cl]2 (2.5 mol%) and (S)-BINAP (5.0 mol%).
b Isolated yield after silica gel column chromatography. c Determined
by HPLC with a Chiralcel OD-H column. d The reaction was carried out
with 1a, 1b (0.2 mmol) and 5.0 equiv. of thiol (1.0 mmol) in THF
(2.0 mL) at 80 °C (oil bath temperature) in the absence of iridium
catalyst.
7
8
17
36
3g
3h
45
65
78
73
9
36
36
3i
3j
32
60
82
60
10
(Table 5, entries 5–8). Thiols containing an electron-donating
group are beneficial for the addition reaction (Table 5, entries
6 and 8). It was proposed that hydrothiolations of strained
alkenes can be rapid processes via radical addition mecha-
nisms.25 But further study needs to be carried out to clarify the
ring-addition mechanism.
11
12
13
18
48
36
3k
3l
75
12
88
45
Ph3COH
3m
Trace
a The reaction was carried out with 1b (0.2 mmol) and 5.0 equiv. of
alcohol (1.0 mmol) in THF (2.0 mL) at 80 °C (oil bath temperature) in
the presence of [Ir(COD)Cl]2 (2.5 mol%) and (S)-BINAP (5.0 mol%).
b Isolated yield after silica gel column chromatography. c Determined
by HPLC with a Chiralcel OD-H column.
A single crystal of the ring-opened product 3c was obtained
by solvent evaporation from a solution consisting of dichloro-
methane, petroleum ether and chloroform. Its configuration
was assigned as (1R,2R) and confirmed as 1,2-trans-configu-
ration by X-ray crystal structure analysis as shown in Fig. 1.
Based on our findings and observations, a plausible mech-
anism has been proposed for the formation of the ring-opened
products 3 as shown in Scheme 1. When [Ir(COD)Cl]2 is used
as the iridium source, the chiral dimeric iridium complex A is
first formed. The nitrogen atom and the double bond of N-Ts-
azabenzonorbornadiene 1b are then reversibly coordinated to
the iridium center of the catalyst to give the intermediate B. In
this step, the intermediate B containing a smaller group (–Ts)
is more stable than the counterpart containing a relatively
larger group (–Boc). Oxidation insertion of the iridium into the
C–N bond of B forms C. Then, nucleophilic attack by the
alcohol with configuration inversion is proposed to occur in
an SN2′ nucleophilic displacement of the iridium catalyst. The
trans-1,2-alkoxyamino product 3 is subsequently released, and
the iridium complex A is regenerated.
Although the iridium catalyst system offered high enantio-
selectivity when substituted benzyl alcohols were used as
nucleophiles, the standard condition was not suitable for
thiols. While substituted benzyl alcohols offered ring-opening
products, thiols, on the contrary, gave addition products. Reac-
tions of 1a and 1b with aliphatic thiols, respectively, were
found to give the corresponding thiol addition products 6a–6d
in high yields with lower ee without giving any ring-opening
products. The results are summarized in Table 5. In light of
the very low enantioselectivities obtained, and the known reac-
tivity of strained azabicyclic alkenes with thiols, it is clear that
the iridium catalyst plays a role in the addition reaction, the
results indicate higher yields obtained in its presence than in
its absence (Table 5, entries 1–8). It may be that the iridium
catalyst as a Lewis acid promoted the addition reaction, but
low ee values were obtained. It is interesting that the extent of
the uncatalyzed reaction varies between substrates 1a and 1b.
1a and 1b reacted with (4-methoxy-phenyl)-methanethiol to
afford higher yields than that of (4-chloro-phenyl)-methane-
thiol in the absence of iridium catalyst, respectively
Conclusions
In summary, we have successfully developed the first enantio-
selective iridium-catalyzed ring-opening of N-protected
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Experimental
General procedures
All flasks were flame-dried under a stream of nitrogen and
cooled before use. Solvents and solutions were transferred
with syringes and cannulae using standard inert atmosphere
techniques. NMR spectra were recorded at 400 MHz using a
Varian INOVA NMR spectrometer with CDCl3 as reference stan-
dard (δ 7.27 ppm) for 1H NMR and (δ 77.23 ppm) for 13C NMR.
Spectral features are tabulated in the following order: chemical
shift (δ, ppm); number of protons; multiplicity (s, singlet, d,
doublet, t, triplet, m, complex multiplet, br, broad); coupling
constants (J, Hz). IR spectra were obtained using a Nicolet DX
FT-IR spectrometer as a KBr pellet or using a Perkin-Elmer
Spectrum 1000 FT-IR spectrometer as a neat film on a NaCl
plate. MS spectra were recorded on a Bruker esquire 6000 mass
spectrometer (ESI). Optical rotations were measured on a
Perkin-Elmer Model 243 Polarimeter using the sodium D line
with spectra-grade CHCl3 in a 1 dm cell. Melting points were
taken on an XT4 binocular micromelting point apparatus.
HPLC analysis was performed on an Agilent 1100 Series HPLC
with a Chiralcel AD column. Elemental analysis was conducted
on a Thermo. Flash EA. TM. 1112. Crystal structure determi-
nation was carried out on a Bruker SMART-1000 X-ray diffrac-
tion apparatus.
Fig. 1 ORTEP plot for 3ca. aCrystal data. C20H25NO3S, M = 359.47. Monoclinic,
a = 9.807(5), b = 13.026(6), c = 14.561(7), α = 90, β = 96.029(8), γ = 90, T =
293 K, space group P21/c, Z = 4. wR2 (reflections) = 0.1580 (3223). CCDC
918458.
Materials
DME was distilled from sodium benzophenone ketyl and
stored. THP, dioxane, toluene, and THF were distilled from
sodium benzophenone ketyl immediately prior to use. CH3CN
was distilled from calcium hydride. DMF was dried over
MgSO4 and stored over activated molecular sieves. The N-pro-
tected azabenzonorbornadienes 1a, 1b, 1c, 1d and [Ir(COD)Cl]2
were prepared according to the reported procedure.26
General procedure I for the asymmetric ring-opening of
azabicyclic alkenes with various alcohols
A 5.0 mL round-bottomed flask fitted with a reflux condenser
was flame-dried under a stream of nitrogen and cooled to
room temperature. [Ir(COD)Cl]2 (3.5 mg, 2.5 mol%) and (S)-
BINAP (6.5 mg, 5.0 mol%) were simultaneously added and fol-
lowed by the addition of anhydrous tetrahydrofuran (2.0 mL).
After the mixture was stirred for about 20 min, azabicyclic
alkene 1b (59.4 mg, 0.20 mmol) was added and the resulting
mixture was heated to reflux. On the first sign of reflux,
alcohol (5 equiv. to 1b) was added. Then the oil bath tempera-
ture was continuously increased to 80 °C and kept at reflux
until the reaction was completed as judged by thin layer
chromatography. The solvent was removed in vacuo and the
crude mixture was purified by column chromatography on
silica gel (ethyl acetate–petroleum ether = 1 : 10, v/v) to give the
target product.
Scheme 1 The proposed reaction mechanism for the asymmetric ring-opening
of N-Ts-azabenzonorbornadiene 1b with substituted benzyl alcohols.
azabicyclic alkenes with substituted benzyl alcohols. It may
provide an efficient and practical access to optically pure trans-
1,2-alkoxyamino derivatives in moderate yields with excellent
enantioselectivities. However, when thiols were used as the
nucleophiles, diastereoselective addition reactions of azabi-
cyclic alkenes with thiols were observed, and we obtained the
sulfide addition derivatives of N-protected azabenzonorborna-
dienes in good to excellent yield. Application of the iridium
catalyst to generate chiral compounds with high enantiomeric
excesses and further elaboration to asymmetric addition pro-
ducts are currently in progress.
(1R,2R)-[2-Methoxy-1,2-dihydro-naphthalen-1-yl]-carbamic acid
tert-butyl ester (2a). Following the general procedure I, 2a was
obtained as a white solid (25.0 mg, 50%). Rf = 0.31 on silica gel
(ethyl acetate–petroleum ether = 1 : 6, v/v). Mp 69–70 °C. The
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ee was determined to be 63% using HPLC analysis on a Chiral-
(1R,2R)-N-(2-Ethoxy-1,2-dihydronaphthalen-1-yl)-4-methyl-
benzenesulfonamide (3b). Following the general procedure
cel OD-H column (hexane–2-propanol = 95 : 5, 0.5 mL min−1
,
λ = 254 nm); retention times were 18.4 min (minor) and (I), 3b was obtained as a white solid (61.7 mg, 90%). Rf = 0.20
20.7 min (major). [α]2D0 = −100.5 (c 1.00, CHCl3). IR (film, on silica gel (ethyl acetate–petroleum ether = 1 : 5, v/v). Mp
cm−1): 3448(w), 2973(w), 2928(w), 1703(s), 1489(m), 1366(m), 146–148 °C. The ee was determined to be 1% using HPLC ana-
1274(w), 1160(w), 910(w), 750(w), 577(w). 1H NMR (400 MHz, lysis on a Chiralcel OD-H column (hexane–2-propanol = 90 : 10,
CDCl3): δ 7.35 (d, J = 2.4 Hz, 1H), 7.24–7.22 (m, 2H), 7.10 (d, J = 0.5 mL min−1, λ = 254 nm); retention times were 27.9 min
2.4 Hz, 1H), 6.59 (dd, J = 9.6 Hz, 2.8 Hz, 1H), 6.08 (dd, J = (major) and 39.4 min (minor). [α]2D0 = −10.2 (c 1.00, CHCl3). IR
9.6 Hz, 4.4 Hz, 1H), 4.98 (dd, J = 7.6 Hz, 4.8 Hz, 1H), 4.62 (d, (film, cm−1): 3273(w), 3040(w), 2967(w), 2924(m), 2853(w),
J = 8.0 Hz, 1H), 3.99 (t, J = 4.8 Hz, 1H), 3.46 (s, 3H), 1.44 (s, 1921(w), 1598(m), 1454(m), 1329(w), 1159(s), 1093(s), 968(m),
9H); 13C NMR (100 MHz, CDCl3): δ 155.3, 133.9, 131.9, 130.1, 923(w), 813(m), 780(m), 737(m), 666(m), 547(m). 1H NMR
129.0, 128.3, 127.1, 126.3, 125.8, 79.7, 76.6, 56.4, 51.1, 28.4. (400 MHz, CDCl3): δ 7.75 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.8 Hz,
MS (ESI) calcd for C16H21NO3 (M+): 275.15; Found: 298.30 2H), 7.21–7.15 (m, 1H), 7.08–7.03 (m, 2H), 6.85 (d, J = 7.6 Hz,
(M + Na)+. Anal. Calcd for C16H21NO3: C, 69.79; H, 7.69; N, 1H), 6.54 (d, J = 9.6 Hz, 1H), 6.00 (dd, J = 9.6 Hz, 4.8 Hz, 1H),
5.09. Found: C, 69.78; H, 7.71; N, 5.07.
(1R,2R)-[2-(4-Bromobenzyloxy)-1,2-dihydro-naphthalen-1-yl]-
4.74 (d, J = 7.6 Hz, 1H), 4.49 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 4.04
(t, J = 4.8 Hz, 1H), 3.49 (q, J = 7.2 Hz, 14 Hz, 2H), 2.44 (s, 3H),
carbamic acid tert-butyl ester (2b). Following the general pro- 1.03 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 143.5,
cedure (I), 2b was obtained as a white solid (27.5 mg, 32%). 137.8, 132.7, 131.8, 129.8, 129.6, 128.7, 128.3, 128.2, 127.3,
Rf = 0.31 on silica gel (ethyl acetate–petroleum ether = 1 : 6, 127.2, 125.8, 75.3, 64.5, 54.7, 21.6, 15.4. MS (ESI) calcd for
v/v). Mp 96–98 °C. The ee was determined to be 75% using C19H21NO3S (M+): 343.12; Found: 366.40 (M + Na)+. Anal.
HPLC analysis on a Chiralcel OD-H column (hexane–2-propa- Calcd for C19H21NO3S: C, 66.45; H, 6.16; N, 4.08; S, 9.34.
nol = 95 : 5, 0.5 mL min−1, λ = 254 nm); retention times were Found: C, 66.49; H, 6.14; N, 4.05; S, 9.30.
20.2 min (major) and 21.9 min (minor). [α]2D0 = −143.5 (c 1.00,
(1R,2R)-N-(2-Isopropoxy-1,2-dihydronaphthalen-1-yl)-4-methyl-
CHCl3). IR (film, cm−1): 3339(w), 2962(w), 2926(w), 1714(s), benzenesulfonamide (3c). Following the general procedure (I),
1488(m), 1366(w), 1248(w), 1170(s), 1081(w), 1012(w), 802(w), 3c was obtained as a white solid (53.6 mg, 75%). Rf = 0.16 on
747(w), 647(w). 1H NMR (400 MHz, CDCl3): δ 7.45 (d, J = silica gel (ethyl acetate–petroleum ether = 1 : 5, v/v). Mp
7.6 Hz, 2H), 7.38 (d, J = 5.6 Hz, 1H), 7.30–7.24 (m, 4H), 7.15 (d, 121–123 °C. The ee was determined to be 12% using HPLC
J = 6.4 Hz, 1H), 6.62 (d, J = 9.6 Hz, 1H), 6.05 (d, J = 9.6, 1H), analysis on a Chiralcel OD-H column (hexane–2-propanol =
5.09 (t, J = 5.6 Hz, 1H), 4.70–4.65 (m, 3H), 4.20 (s, 1H), 1.48 (s, 90 : 10, 0.5 mL min−1, λ = 254 nm); retention times were
9H); 13C NMR (100 MHz, CDCl3): δ 155.4, 137.5, 133.8, 132.0, 22.6 min (minor) and 28.3 min (major). [α]2D0 = −23.5 (c 1.00,
131.4, 130.2, 129.6, 128.4, 128.3, 127.1, 126.3, 125.9, 121.5, CHCl3). IR (film, cm−1): 3255(w), 3040(w), 2957(w), 2923(m),
79.8, 75.3, 69.7, 51.7, 28.4. MS (ESI) calcd for C22H24BrNO3 2852(w), 1727(w), 1598(w), 1495(m), 1462(w), 1288(w), 1185(w),
(M+): 429.09; Found: 452.37 (M + Na)+. Anal. Calcd for 1161(s), 968(m), 776(m), 666(m), 568(w). 1H NMR (400 MHz,
C22H24BrNO3: C, 61.40; H, 5.62; N, 3.25. Found: C, 61.36; H, CDCl3): δ 7.75 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8 Hz, 2H),
5.60; N, 3.25.
7.20–7.16 (m, 1H), 7.05–7.02 (m, 2H), 6.82 (d, J = 7.6 Hz, 1H),
(1R,2R)-N-(2-Methoxy-1,2-dihydronaphthalen-1-yl)-4-methyl- 6.54 (d, J = 9.6 Hz, 1H), 5.96 (dd, J = 9.6 Hz, 4.8 Hz, 1H), 4.68
benzenesulfonamide (3a). Following the general procedure (d, J = 7.6 Hz, 1H), 4.43 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 4.09 (t, J =
(I), 3a was obtained as a white solid (73.0 mg, 85%). Rf = 0.25 4.8 Hz, 1H), 3.75–3.72 (m, 1H), 2.44 (s, 3H), 1.02 (dd, J =
on silica gel (ethyl acetate–petroleum ether = 1 : 6, v/v). Mp 2.4 Hz, 8.8 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 143.5, 137.8,
71–72 °C. The ee was determined to be 4% using HPLC analy- 132.7, 131.9, 129.7, 129.5, 128.6, 128.4, 128.2, 127.3, 127.2,
sis on a Chiralcel OD-H column (hexane–2-propanol = 90 : 10, 126.4, 72.8, 70.3, 55.3, 22.5, 21.6. MS (ESI) calcd for
0.5 mL min−1, λ = 254 nm); retention times were 52.9 min C20H23NO3S (M+): 357.14; Found: 380.46 (M + Na)+. Anal.
(major) and 58.0 min (minor). [α]2D0 = 10.6 (c 1.00, CHCl3). IR Calcd for C20H23NO3S: C, 67.20; H, 6.49; N, 3.92; S, 8.97.
(film, cm−1): 3273(w), 3038(w), 2926(w), 2853(w), 1721(s), Found: C, 67.18; H, 6.50; N, 3.93; S, 8.95.
1598(m), 1493(m), 1454(w), 1329(m), 1159(s), 1093(m), 970(m),
(1R,2R)-N-(2-(4-Bromophenethoxy)-1,2-dihydronaphthalen-1-
916(w), 813(m), 666(m), 571(m). 1H NMR (400 MHz, CDCl3): yl)-4-methylbenzenesulfonamide (3d). Following the general
δ 7.75 (d, J = 8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 7.22–7.18 (m, procedure (I), 3d was obtained as a white solid (74.5 mg, 75%).
1H), 7.07–7.04 (m, 2H), 6.60 (d, J = 8 Hz, 1H), 6.57 (d, J = Rf = 0.27 on silica gel (ethyl acetate–petroleum ether = 1 : 4,
9.6 Hz, 1H), 6.03 (dd, J = 9.6 Hz, 4.8 Hz, 1H), 4.68 (d, J = v/v). Mp 163–164 °C. The ee was determined to be 30% using
7.6 Hz, 1H), 4.49 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 3.96 (t, J = 4.4 Hz, HPLC analysis on a Chiralcel OD-H column (hexane–2-propa-
1H), 3.25 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3): nol = 85 : 15, 0.5 mL min−1, λ = 254 nm); retention times were
δ 143.5, 137.7, 132.5, 131.7, 130.3, 129.6, 128.8, 128.3, 127.3, 24.4 min (minor) and 36.3 min (major). [α]2D0 = −62.7 (c 1.00,
125.0, 76.7, 56.5, 54.2, 21.6. MS (ESI) calcd for C18H19NO3S CHCl3). IR (film, cm−1): 3273(w), 3033(w), 2957(s), 2279(w),
(M+): 329.11; Found: 347.10 (M + Na)+. Anal. Calcd for 1727(m), 1598(w), 1488(m), 1455(w), 1331(m), 1160(s), 1093(s),
C18H19NO3S: C, 65.63; H, 5.81; N, 4.25; S, 9.73. Found: C, 962(w), 813(m), 666(m), 547(m). 1H NMR (400 MHz, CDCl3):
65.66; H, 5.78; N, 4.23; S, 9.69.
δ 7.72 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.0 Hz, 4H), 7.21 (t, J =
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7.6 Hz, 1H), 7.06 (d, J = 7.2 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 0.22, ethyl acetate–petroleum ether = 1 : 4, v/v). Mp 145–147 °C.
6.61 (d, J = 7.6 Hz, 1H), 6.56 (d, J = 9.6 Hz, 1H), 5.96 (dd, J = 1H NMR (400 MHz, CDCl3) δ 7.87–7.84 (m, 1H), 7.81–7.79 (m,
4.8 Hz, 9.6 Hz, 1H), 4.58 (d, J = 7.6 Hz, 1H), 4.31 (dd, J = 1H), 7.70 (dd, J = 2.4, 7.2 Hz, 1H), 7.65 (s, 1H), 7.63 (s, 1H),
4.0 Hz, 7.6 Hz, 1H), 4.07 (t, J = 4.4 Hz, 1H), 3.73–3.61 (m, 2H), 7.46–7.40 (m, 2H), 7.38–7.33 (m, 2H), 7.16 (s, 1H), 7.13 (s, 1H),
2.66 (t, J = 7.2 Hz, 2H), 2.46 (s, 3H); 13C NMR (100 MHz, 7.11 (s, 1H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.9,
CDCl3): δ 143.6, 137.9, 137.6, 132.3, 131.7, 131.3, 130.7, 130.3, 136.4, 134.3, 131.6, 129.7, 129.0, 128.5, 127.5, 127.3, 126.7,
129.7, 128.8, 128.5, 128.3, 172.3, 127.2, 125.1, 120.0, 75.3, 69.5, 126.4, 125.5, 122.8, 121.6, 21.6.
54.2, 35.7, 21.6. MS (ESI) calcd for C25H24BrNO3S (M+): 497.07;
(1R,2R)-N-(2-Benzyloxy-1,2-dihydronaphthalen-1-yl)-4-methyl-
Found: 520.16 (M + Na)+. Anal. Calcd for C25H24BrNO3S: C, benzenesulfonamide (3g). Following the general procedure (I),
60.24; H, 4.85; N, 2.81; S, 6.43. Found: C, 60.21; H, 4.87; N, 3g was obtained as a white solid (36.5 mg, 45%). Rf = 0.25 on
2.82; S, 6.40.
silica gel (ethyl acetate–petroleum ether = 1 : 4, v/v). Mp
(1R,2R)-N-(2-(Furan-2-ylmethoxy)-1,2-dihydronaphthalen-1-yl)- 113–114 °C. The ee was determined to be 78% using HPLC
4-methylbenzenesulfonamide (3e). Following the general pro- analysis on a Chiralcel OD-H column (hexane–2-propanol =
cedure (I), 3e was obtained as a white solid (40.5 mg, 51%). 85 : 15, 0.5 mL min−1, λ = 254 nm); retention times were
Rf = 0.30 on silica gel (ethyl acetate–petroleum ether = 1 : 3, 26.4 min (minor) and 29.2 min (major). [α]2D0 = −135 (c 1.00,
v/v). Mp 123–124 °C. The ee was determined to be 94% using CHCl3). IR (film, cm−1): 3280(w), 3061(w), 2920(w), 1723(m),
HPLC analysis on a Chiralcel OD-H column (hexane–2-propa- 1598(w), 1495(m), 1454(w), 1330(s), 1160(s), 1093(s), 966(w),
nol = 85 : 15, 0.5 mL min−1, λ = 254 nm); retention times were 918(w), 813(m), 750(w), 698(w), 666(m), 569(m). 1H NMR
29.1 min (minor) and 33.3 min (major). [α]2D0 = −165 (c 1.00, (400 MHz, CDCl3): δ 7.73 (d, J = 8.4 Hz, 2H), 7.33–1.21 (m, 8H),
CHCl3). IR (film, cm−1): 3269(w), 2926(w), 2854(w), 1715(m), 7.10 (d, J = 7.6 Hz, 2H), 6.79 (d, J = 7.2 Hz, 1H), 6.62 (d, J =
1598(w), 1503(w), 1454(m), 1331(m), 1159(s), 1069(m), 918(w), 9.6 Hz, 1H), 6.00 (dd, J = 4.8 Hz, 9.6 Hz, 1H), 4.59–4.55 (m,
815(m), 749(m), 665(m), 569(m). 1H NMR (400 MHz, CDCl3): 3H), 4.50 (t, J = 7.6 Hz, 1H), 4.18 (t, J = 4.8 Hz, 1H), 2.45 (s,
δ 7.75 (d, J = 8.0 Hz, 2H), 7.37 (s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 3H); 13C NMR (100 MHz, CDCl3): δ 143.5, 138.1, 137.6, 132.5,
7.18 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 7.2 Hz, 2H), 6.84 (d, J = 131.8, 130.3, 129.6, 128.8, 128.5, 128.4, 127.8, 127.7, 127.3,
7.6 Hz, 1H), 6.56 (d, J = 9.6 Hz, 1H), 6.32 (s, 1H), 6.27 (s, 1H), 127.2, 125.3, 74.5, 70.9, 54.5, 21.6. MS (ESI) calcd for
5.92 (dd, J = 4.8 Hz, 9.6 Hz, 1H), 4.51–4.46 (m, 2H), 4.43 (s, J = C24H23NO3S (M+): 405.14; Found: 428.64 (M + Na)+. Anal.
8.0 Hz, 2H), 4.18 (s, 1H), 2.46 (s, 3H); 13C NMR (100 MHz, Calcd for C24H23NO3S: C, 71.09; H, 5.72; N, 3.45; S, 7.91.
CDCl3): δ 151.3, 143.5, 142.9, 137.5, 132.5, 131.7, 130.2, 129.6 Found: C, 71.12; H, 5.74; N, 3.48; S, 7.89.
128.7, 128.4, 128.3, 127.4, 125.2, 110.3, 109.8, 74.4, 62.8, 54.7,
(1R,2R)-N-(2-(4-Chlorobenzyloxy)-1,2-dihydronaphthalen-1-yl)-
21.6. MS (ESI) calcd for C22H21NO4S (M+): 395.12; Found: 4-methylbenzenesulfonamide (3h). Following the general pro-
518.51 (M + Na)+. Anal. Calcd for C22H21NO4S: C, 66.82; H, cedure (I), 3h was obtained as a white solid (36.5 mg, 65%).
5.35; N, 3.54; S, 8.11. Found: C, 66.80; H, 5.34; N, 3.55; S, 8.08.
Rf = 0.22 on silica gel (ethyl acetate–petroleum ether = 1 : 4,
(1R,2R)-N-(2-(4-Bromobenzyloxy)-1,2-dihydronaphthalen-1-yl)- v/v). Mp 133–134 °C. The ee was determined to be 73% using
4-methylbenzenesulfonamide (3f). Following the general pro- HPLC analysis on a Chiralcel OD-H column (hexane–2-propa-
cedure (I), 3f was obtained as a white solid (53.5 mg, 55%). nol = 85 : 15, 0.5 mL min−1, λ = 254 nm); retention times were
Rf = 0.24 on silica gel (ethyl acetate–petroleum ether = 1 : 4, 25.4 min (minor) and 33.9 min (major). [α]2D0 = −135 (c 1.00,
v/v). Mp 132–134 °C. The ee was determined to be 92% using CHCl3). IR (film, cm−1): 3281(w), 2925(w), 1492(w), 1455(w),
HPLC analysis on a Chiralcel OD-H column (hexane–2-propa- 1328(m), 1454(w), 1330(s), 1159(s), 1093(s), 1014(w), 812(m),
1
nol = 85 : 15, 0.5 mL min−1, λ = 254 nm); retention times were 667(w), 666(m), 569(m). H NMR (400 MHz, CDCl3): δ 7.72 (d,
27.6 min (minor) and 38.6 min (major). [α]2D0 = −175 (c 1.00, J = 7.2 Hz, 2H), 7.30–7.27 (m, 4H), 7.24 (t, J = 7.2 Hz, 1H), 7.17
CHCl3). IR (film, cm−1): 3275(w), 3034(w), 2925(w), 1721(m), (d, J = 8.0 Hz, 2H), 7.12–7.08 (m, 2H), 6.73 (d, J = 7.6 Hz, 1H),
1597(w), 1487(m), 1454(w), 1330(m), 1159(s), 1093(s), 1070(s), 6.62 (d, J = 9.6 Hz, 1H), 6.00 (dd, J = 4.8 Hz, 9.6 Hz, 1H), 4.53
1011(m), 912(w), 811(m), 666(m), 570(m), 547(m). 1H NMR (d, J = 7.6 Hz, 2H), 4.49 (t, J = 7.6 Hz, 1H), 4.17 (t, J = 7.6 Hz,
(400 MHz, CDCl3): δ 7.71 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 1H), 2.46 (s, 3H), 2.18 (s, 1H); 13C NMR (100 MHz, CDCl3):
2H), 7.28 (d, J = 8.4 Hz, 2H), 7.24 (t, J = 7.6 Hz, 1H), 7.11 (d, J = δ 143.6, 137.6, 136.7, 133.4, 132.3, 131.7, 130.5, 129.7, 129.1,
8.0 Hz, 3H), 7.09–7.06 (m, 1H), 6.73 (d, J = 7.6 Hz, 1H), 6.63 (d, 128.9, 128.4, 128.5, 127.3, 127.2, 124.9, 74.7, 70.1, 54.4, 21.6.
J = 9.6 Hz, 1H), 6.00 (dd, J = 4.8 Hz, 9.6 Hz, 1H), 4.56–4.51 (m, MS (ESI) calcd for C24H22NO3ClS (M+): 439.10; Found: 462.58
3H), 4.46 (t, J = 8.0 Hz, 1H), 4.17 (t, J = 4.8 Hz, 1H), 2.46 (s, (M + Na)+. Anal. Calcd for C24H22NO3ClS: C, 65.52; H, 5.04; N,
3H); 13C NMR (100 MHz, CDCl3): δ 143.6, 137.6, 137.2, 132.3, 3.18; S, 7.29. Found: C, 65.53; H, 5.02; N, 3.19; S, 7.26.
131.7, 131.4, 130.5, 129.7 129.4, 129.0, 128.9, 128.5, 172.3,
(1R,2R)-N-(2-(4-Methoxybenzyloxy)-1,2-dihydronaphthalen-1-
127.2, 124.9, 121.6, 74.7, 70.1, 54.4, 21.6. MS (ESI) calcd for yl)-4-methylbenzenesulfonamide (3i). Following the general
C24H22BrNO3S (M+): 483.05; Found: 508.43 (M + Na)+. Anal. procedure (I), 3i was obtained as a white solid (27.9 mg, 32%).
Calcd for C24H22BrNO3S: C, 59.51; H, 4.58; N, 2.89; S, 6.62. Rf = 0.15 on silica gel (ethyl acetate–petroleum ether = 1 : 5,
Found: C, 59.53; H, 4.59; N, 2.89; S, 6.60.
v/v). Mp 83–84 °C. The ee was determined to be 82% using
1-Naphthyltosylamine (3fa). 3fa was obtained as a light- HPLC analysis on a Chiralcel OD-H column (hexane–2-propa-
brown solid and was purified by column chromatography (Rf = nol = 85 : 15, 0.5 mL min−1, λ = 254 nm); retention times were
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37.6 min (minor) and 40.8 min (major). [α]D20 = −143 (c 1.00, (M + Na)+. Anal. Calcd for C24H22NBrO3S: C, 59.51; H, 4.58; N,
CHCl3). IR (film, cm−1): 3276(w), 3035(w), 2925(w), 1724(w), 2.89; S, 6.62. Found: C, 59.54; H, 4.55; N, 2.88; S, 6.58.
1612(w), 1514(w), 1454(w), 1329(m), 1248(m), 1159(s), 1094(m),
(1R,2R)-N-(2-(Benzo[d][1,3]dioxol-5-ylmethoxy)-1,2-dihydro-
1
1034(m), 914(w), 8125(m), 664(m), 566(m). H NMR (400 MHz, naphthalen-1-yl)-4-methylbenzenesulfonamide (3l). Follow-
CDCl3): δ 7.73 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 9.6 Hz, 2H), 7.22 ing the general procedure (I), 3l was obtained as a white solid
(t, J = 7.2 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.8 Hz, (72.6 mg, 45%). Rf = 0.15 on silica gel (ethyl acetate–petroleum
2H), 6.85 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 7.2 Hz, 1H), 6.59 (d, J = ether = 1 : 5, v/v). Mp 63–64 °C. The ee was determined to be
9.6 Hz, 1H), 5.96 (dd, J = 4.4 Hz, 9.6 Hz, 1H), 4.55–4.51 (m, 88% using HPLC analysis on a Chiralcel OD-H column
1H), 4.50–4.47 (m, 3H), 4.16 (s, 1H), 3.82 (s, 3H), 2.46 (s, 3H); (hexane–2-propanol = 85 : 15, 0.5 mL min−1, λ = 254 nm); reten-
13C NMR (100 MHz, CDCl3): δ 159.2, 143.5, 137.7, 132.5, 131.8, tion times were 26.1 min (minor) and 35.5 min (major). [α]2D0
=
130.2, 130.1, 129.7, 129.5, 128.8, 128.5, 128.3, 127.3, 125.4, −128 (c 1.00, CHCl3). IR (film, cm−1): 3268(w), 3059(w), 2957(w),
113.7, 74.0, 70.6, 55.3, 54.4, 21.6. MS (ESI) calcd for 2924(w), 1597(w), 1454(w), 1329(m), 1161(s), 1093(s),
C25H25NO4S (M+): 435.15; Found: 458.45 (M + Na)+. Anal. 967(w), 916(w), 813(m), 752(m), 665(m), 548(m). 1H NMR
Calcd for C25H25NO4S: C, 68.94; H, 5.79; N, 3.22; S, 7.36. (400 MHz, CDCl3): δ 7.73 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz,
Found: C, 68.93; H, 5.77; N, 3.19; S, 7.34.
(1R,2R)-N-(2-(4-Nitrobenzyloxy)-1,2-dihydronaphthalen-1-yl)-
2H), 7.21 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 7.6 Hz, 2H), 6.77–6.73
(m, 4H), 6.59 (d, J = 9.6 Hz, 1H), 5.98 (d, J = 4.4 Hz, 1H), 5.95
4-methylbenzenesulfonamide (3j). Following the general pro- (s, 2H), 4.52 (s, 2H), 4.43 (s, 2H), 4.14 (s, 1H), 2.43 (s, 3H);
cedure (I), 3j was obtained as a white solid (54.1 mg, 60%). 13C NMR (100 MHz, CDCl3): δ 143.7, 143.2, 139.6, 133.7, 128.5,
Rf = 0.12 on silica gel (ethyl acetate–petroleum ether = 1 : 4, 127.9, 127.8, 126.4, 125.7, 124.9, 124.5, 124.4, 123.4, 123.3,
v/v). Mp 190–191 °C. The ee was determined to be 60% using 121.3, 117.6, 104.7, 104.1, 97.0, 70.1, 66.8, 50.5, 17.7. MS (ESI)
HPLC analysis on a Chiralcel OD-H column (hexane–2-propa- calcd for C25H23NO5S (M+): 449.13; Found: 472.33 (M + Na)+.
nol = 90 : 10, 1.0 mL min−1, λ = 254 nm); retention times were Anal. Calcd for C25H23NO5S: C, 66.80; H, 5.16; N, 3.12; S, 7.13.
47.3 min (minor) and 54.6 min (major). [α]2D0 = −121 (c 1.00, Found: C, 66.81; H, 5.15; N, 3.12; S, 7.16.
CHCl3). IR (film, cm−1): 3282(w), 3045(w), 2925(w), 2854(w),
(1R,2R)-N-(2-(4-Bromobenzyloxy)-1,2-dihydronaphthalen-1-yl)-
1958(w), 1519(w), 1397(w), 1344(s), 1161(s), 1092(m), 961(w), 4-nitrobenzenesulfonamide (4a). Following the general pro-
814(m), 775(m), 667(m), 569(m). 1H NMR (400 MHz, CDCl3): cedure (I), 4a was obtained as a white solid (77.3 mg, 75%).
δ 7.72 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.30–7.27 Rf = 0.18 on silica gel (ethyl acetate–petroleum ether = 1 : 4,
(m, 3H), 7.25 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 8.0 Hz, 3H), 6.70 v/v). Mp 166–167 °C. The ee was determined to be 10% using
(d, J = 7.6 Hz, 1H), 6.63 (d, J = 9.6 Hz, 1H), 5.98 (dd, J = 4.8 Hz, HPLC analysis on a Chiralcel OD-H column (hexane–2-propa-
9.6 Hz, 1H), 4.55–4.52 (m, 3H), 4.45 (t, J = 8.0 Hz, 1H), 4.16 nol = 80 : 20, 1.0 mL min−1, λ = 254 nm); retention times were
(t, J = 4.8 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3): 33.5 min (minor) and 50.1 min (major). [α]2D0 = −19 (c 1.00,
δ 145.6, 137.6, 136.7, 133.4, 132.3, 131.7, 130.5, 129.7, CHCl3). IR (film, cm−1): 3274(w), 3059(w), 2925(w), 2854(m),
129.1, 128.9, 128.4, 128.5, 127.3, 127.2, 124.9, 79.2, 71.9, 1724(m), 1605(w), 1530(s), 1487(w), 1455(w), 1348(s), 1288(m),
54.4, 24.3. MS (ESI) calcd for C24H22N2O5S (M+): 450.13; 1164(m), 1092(m), 1073(m), 853(w), 811(w), 736(m), 615(m),
1
Found: 473.52 (M + Na)+. Anal. Calcd for C24H22N2O5S: C, 503(m). H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 8.4 Hz, 2H),
63.98; H, 4.92; N, 6.22; S, 7.12. Found: C, 63.95; H, 4.94; N, 7.94 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.26 (s, 1H),
6.19; S, 7.08.
7.15–7.11 (m, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 7.6 Hz,
(1R,2R)-N-(2-(2-Bromobenzyloxy)-1,2-dihydronaphthalen-1-yl)- 1H), 6.60 (d, J = 9.6 Hz, 1H), 5.99 (dd, J = 4.0 Hz, 3.6 Hz, 1H),
4-methylbenzenesulfonamide (3k). Following the general pro- 4.96 (d, J = 7.6 Hz, 1H), 4.65 (t, J = 7.2 Hz, 1H), 4.52 (d, J =
cedure (I), 3k was obtained as a white solid (40.5 mg, 75%). 8.0 Hz, 1H), 4.36 (d, J = 9.6 Hz, 1H), 4.14 (t, J = 8.4 Hz, 1H);
Rf = 0.10 on silica gel (ethyl acetate–petroleum ether = 1 : 8, 13C NMR (100 MHz, CDCl3): δ 149.8, 146.5, 136.7, 132.1, 131.9,
v/v). Mp 134–135 °C. The ee was determined to be 12% using 131.5, 130.3, 129.3, 129.1, 128.5, 128.2, 127.7, 127.4, 125.1,
HPLC analysis on a Chiralcel OD-H column (hexane–2-propa- 124.1, 121.9, 75.5, 70.2, 55.8. MS (ESI) calcd for
nol = 85 : 15, 0.5 mL min−1, λ = 254 nm); retention times were C23H19N2O5BrS (M+): 514.02; Found: 538.34 (M + Na)+. Anal.
46.7 min (minor) and 50.3 min (major). [α]D20 = −23 (c 1.00, Calcd for C23H19N2O5BrS: C, 53.60; H, 3.72; N, 5.44; S, 6.22.
CHCl3). IR (film, cm−1): 3284(w), 3059(w), 2924(w), 1597(w), Found: C, 53.62; H, 3.71; N, 5.44; S, 6.19.
1491(w), 1444(m), 1332(m), 1159(s), 1094(m), 928(w), 812(w),
(1R,2R)-N-(2-(4-Chlorobenzyloxy)-1,2-dihydronaphthalen-1-yl)-
664(m), 547(m). 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 4-nitrobenzenesulfonamide (4b). Following the general pro-
8.4 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 4.8 Hz, 1H), cedure (I), 4b was obtained as a white solid (61.1 mg, 65%).
7.26–7.21 (m, 4H), 7.16–7.09 (m, 3H), 6.92 (d, J = 7.6 Hz, 1H), Rf = 0.18 on silica gel (ethyl acetate–petroleum ether = 1 : 4,
6.61 (d, J = 9.6 Hz, 1H), 6.05 (dd, J = 4.8 Hz, 9.6 Hz, 1H), 4.62 v/v). Mp 173–174 °C. The ee was determined to be 16% using
(s, 1H), 4.56 (s, 2H), 4.23 (t, J = 4.0 Hz, 1H), 2.40 (s, 3H), 2.34 HPLC analysis on a Chiralcel OD-H column (hexane–2-propa-
(s, 1H); 13C NMR (100 MHz, CDCl3): δ 143.3, 137.5, 137.3, nol = 80 : 20, 1.0 mL min−1, λ = 254 nm); retention times were
132.7, 132.4, 131.8, 130.4, 129.6, 129.4, 129.0, 128.7, 128.4, 31.0 min (minor) and 42.7 min (major). [α]2D0 = −32 (c 1.00,
128.3, 127.3, 127.2, 125.0, 122.8, 121.4, 75.5, 70.2, 54.7, 21.6. CHCl3). IR (film, cm−1) 3283(w), 3104(w), 2919(w), 2852(w),
MS (ESI) calcd for C24H22BrNO3S (M+): 485.05; Found: 506.33 1728(w), 1605(w), 1530(s), 1492(w), 1454(w), 1348(s), 1164(s),
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1091(m), 1014(w), 853(m), 813(m), 736(m), 558(m). 1H NMR the general procedure (I), 6a was obtained as a white solid
(400 MHz, CDCl3): δ 8.20 (d, J = 4.8 Hz, 2H), 7.94 (d, J = 8.8 Hz, (64.2 mg, 80%). Rf = 0.25 on silica gel (ethyl acetate–petroleum
2H), 7.36–7.24 (m, 4H), 7.14–1.10 (m, 3H), 6.97 (d, J = 7.6 Hz, ether = 1 : 15, v/v). Mp 91–93 °C. The ee was determined to
1H), 6.60 (d, J = 9.6 Hz, 1H), 6.00 (dd, J = 9.6 Hz, 4.0 Hz, 1H), be 9% using HPLC analysis on a Chiralcel OD-H column
4.85 (d, J = 8.4 Hz, 1H), 4.66 (t, J = 6.0 Hz, 1H), 4.53 (d, J = (hexane–2-propanol = 90 : 10, 0.5 mL min−1, λ = 254 nm);
12.0 Hz, 1H), 4.38 (d, J = 9.6 Hz, 1H), 4.15 (t, J = 8.4 Hz, 1H); retention times were 12.2 min (minor) and 16.2 min
13C NMR (100 MHz, CDCl3): δ 146.5, 136.1, 133.8, 132.1, 131.9, (major). [α]D20 = 9 (c 1.00, CHCl3). IR (film, cm−1): 3339(w),
130.3, 129.1, 128.9, 128.6, 128.5, 128.2, 127.7, 127.4, 125.1, 2962(w), 2926(w), 1714(m), 1488(w), 1366(m), 1248(s),
124.8, 124.1, 75.4, 70.1, 55.8. MS (ESI) calcd for C23H19N2O5ClS 1170(m), 1081(w), 802(s), 747(m), 693(w), 526(m). 1H NMR
(M+): 470.07; Found: 493.43 (M + Na)+. Anal. Calcd for (400 MHz, CDCl3): δ 7.30–7.26 (m, 4H), 7.20–7.12 (m, 4H),
C23H19N2O5ClS: C, 58.66; H, 4.07; N, 5.95; S, 6.81. Found: C, 5.14 (s, 1H), 4.76 (s, 1H), 3.88–3.78 (m, 2H), 2.60 (s, 1H),
58.67; H, 4.06; N, 5.94; S, 6.77.
(1R,2R)-N-(2-(Benzo[d][1,3]dioxol-5-ylmethoxy)-1,2-dihydro- (100 MHz, CDCl3):
naphthalen-1-yl)-4-nitrobenzenesulfonamide (4c). Following 128.8, 126.9, 126.7, 80.3, 65.6, 45.3, 36.4, 30.6, 29.7, 28.3.
1.87–1.84 (m, 1H), 1.78–1.75 (m, 1H), 1.40 (s, 9H); 13C NMR
167.7, 145.0, 132.9, 130.9, 130.2,
δ
the general procedure (I), 4c was obtained as a white solid MS (ESI) calcd for
C
22H24ClNO2S (M+): 401.12; Found:
(52.8 mg, 55%). Rf = 0.15 on silica gel (ethyl acetate–petroleum 424.23 (M + Na)+. Anal. Calcd for C22H24ClNO2S: C, 65.74;
ether = 1 : 5, v/v). Mp 173–175 °C. The ee was determined to be H, 6.02; N, 3.48; S, 7.98 Found: C, 65.75; H, 5.99; N, 3.44;
18% using HPLC analysis on a Chiralcel OD-H column S, 7.90.
(hexane–2-propanol = 75 : 25, 1.0 mL min−1, λ = 254 nm); reten-
tion times were 38.6 min (major) and 53.7 min (minor). [α]D20
2-(4-Methoxy-benzylsulfanyl)-1,2,3,4-tetrahydro-1,4-epiazano-
naphthalene-9-carboxylic acid tert-butyl ester (6b). Following
=
−28 (c 1.00, CHCl3). IR (film, cm−1): 3735(w), 3294(w), 2921(s), the general procedure (I), 6b was obtained as a white solid
1729(w), 1529(m), 1444(m), 1348(s), 1254(m), 1163(s), 1094(m), (65.1 mg, 82%). Rf = 0.25 on silica gel (ethyl acetate–petroleum
1039(m), 929(w), 737(w), 615(w), 503(m). 1H NMR (400 MHz, ether = 1 : 15, v/v). Mp 85–87 °C. The ee was determined to be
CDCl3): δ 8.21 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 8% using HPLC analysis on a Chiralcel OD-H column (hexane–
7.21–7.10 (m, 4H), 6.72 (d, J = 8.0 Hz, 1H), 6.63–6.56 (m, 3H), 2-propanol = 90 : 10, 0.5 mL min−1, λ = 254 nm); retention
6.00 (d, J = 3.6 Hz, 1H), 5.98 (d, J = 4.0 Hz, 2H), 4.75–4.68 (m, times were 13.4 min (minor) and 15.2 min (major). [α]2D0 = 8
2H), 4.46 (d, J = 12.0 Hz, 1H), 4.27 (d, J = 12.0 Hz, 1H), 4.10 (t, (c 1.00, CHCl3). IR (film, cm−1): 3339(w), 2962(w), 2926(w),
J = 3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 149.7, 147.7, 1714(m), 1488(w), 1366(m), 1248(s), 1170(m), 1081(w), 802(s),
147.3, 146.5, 132.6, 132.0, 131.2, 130.9, 129.9, 128.9, 128.5, 747(m), 693(w), 526(m). 1H NMR (400 MHz, CDCl3):
128.3, 127.5, 127.2, 125.6, 124.0, 121.3, 108.2, 101.2, 75.1, 70.6, δ 7.31–7.12 (m, 6H), 6.89–6.87 (m, 2H), 5.15–4.99 (m, 1H), 4.77
55.3. MS (ESI) calcd for C24H20N2O7S (M+): 480.10; Found: (s, 1H), 3.87–3.79 (m, 5H), 2.63 (s, 1H), 1.90–1.84 (m, 1H),
503.76 (M + Na)+. Anal. Calcd for C24H20N2O7S: C, 59.99; H, 1.80–1.73 (m, 1H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3):
4.20; N, 5.83; S, 6.67. Found: C, 59.95; H, 4.19; N, 5.80; S, 6.63.
δ 158.7, 145.1, 145.0, 130.0, 129.9, 126.8, 126.6, 114.0, 80.2,
(1R,2R)-N-(2-(4-Bromobenzyloxy)-1,2-dihydronaphthalen-1-yl)- 65.2, 60.0, 55.3, 45.2, 36.5, 35.9, 28.3. MS (ESI) calcd for
4-bromobenzenesulfonamide (5a). Following the general pro- C23H27NO3S (M+): 397.17; Found: 420.25 (M + Na)+. Anal.
cedure (I), 5a was obtained as a white solid (74.6 mg, 68%). Calcd for C23H27NO3S: C, 69.49; H, 6.85; N, 3.52; S, 8.07.
Rf = 0.15 on silica gel (ethyl acetate–petroleum ether = 1 : 5, Found: C, 69.45; H, 6.83; N, 3.50; S, 8.17.
v/v). Mp 136–137 °C. The ee was determined to be 4% using
2-(4-Chloro-benzylsulfanyl)-9-(toluene-4-sulfonyl)-1,2,3,4-tetra-
HPLC analysis on a Chiralcel OD-H column (hexane–2-propa- hydro-1,4-epiazano-naphthalene (6c). Following the general
nol = 85 : 15, 1.0 mL min−1, λ = 254 nm); retention times were procedure (I), 6c was obtained as a white solid (77.3 mg, 85%).
16.7 min (minor) and 27.1 min (major). [α]2D0 = −17 (c 1.00, Rf = 0.25 on silica gel (ethyl acetate–petroleum ether = 1 : 15,
CHCl3). IR (film, cm−1): 3565(w), 3270(w), 2924(s), 2028(w), v/v). Mp 94–96 °C. The ee was determined to be 1% using
1575(w), 1487(w), 1390(s), 1333(m), 1275(w), 1162(s), 1069(m), HPLC analysis on a Chiralcel OD-H column (hexane–2-propa-
1
1011(m), 819(m), 739(m), 610(m), 558(w). H NMR (400 MHz, nol = 85 : 15, 0.5 mL min−1, λ = 254 nm); retention times were
CDCl3): δ 7.65 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.45 35.4 min (major) and 41.9 min (minor). [α]2D0 = 1 (c 1.00,
(d, J = 8.0 Hz, 2H), 7.28–7.25 (m, 2H), 7.12–7.07 (m, 3H), 6.84 CHCl3). IR (film, cm−1): 2934(w), 2925(w), 1596(w), 1511(m),
(d, J = 8.0 Hz, 1H), 6.60 (d, J = 9.6 Hz, 1H), 5.98 (dd, J = 9.6 Hz, 1489(w), 1342(m), 1161(s), 1090(m), 1014(w), 971(s), 812(m),
4.4 Hz, 1H), 4.63 (d, J = 8.0 Hz, 1H), 4.56–4.51 (m, 2H), 4.43 (d, 693(w), 679(m), 604(m), 526(m). 1H NMR (400 MHz, CDCl3):
J = 9.6 Hz, 1H), 4.13 (d, J = 4.8 Hz, 1H); 13C NMR (100 MHz, δ 7.29–7.26 (m, 6H), 6.91 (d, J = 4.0 Hz, 2H), 6.86 (s, 3H), 6.73
CDCl3): δ 139.7, 136.9, 132.3, 132.2, 131.7, 131.5, 130.5, 129.4, (d, J = 4.4 Hz, 1H), 5.00 (d, J = 4.4 Hz, 1H), 4.52 (s, 1H), 3.84 (d,
129.0, 128.6, 128.5, 128.2, 127.7, 127.4, 124.9, 121.7, 74.9, 70.2, J = 4.8 Hz, 2H), 2.51 (dd, J = 3.6 Hz, 8.0 Hz, 1H), 2.25 (s, 3H),
54.9. MS (ESI) calcd for C23H19NO3Br2S (M+): 546.95; Found: 2.01–1.98 (m, 1H), 1.78–1.74 (m, 1H); 13C NMR (100 MHz,
569.93 (M + Na)+. Anal. Calcd for C23H19NO3Br2S: C, 50.29; H, CDCl3): δ 143.0, 142.9, 141.7, 136.9, 134.9, 132.9, 130.3, 128.9,
3.49; N, 2.55; S, 5.84. Found: C, 50.32; H, 3.48; N, 2.51; S, 5.80.
128.8, 127.9, 126.9, 126.7, 120.2, 120.1, 68.3, 63.1, 44.6, 36.7,
2-(4-Chloro-benzylsulfanyl)-1,2,3,4-tetrahydro-1,4-epiazano- 36.3, 21.4. MS (ESI) calcd for C24H22ClNO2S2 (M+): 455.08;
naphthalene-9-carboxylic acid tert-butyl ester (6a). Following Found: 478.43 (M + Na)+. Anal. Calcd for C24H22ClNO2S2: C,
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63.21; H, 4.86; N, 3.07; S, 14.06. Found: C, 63.23; H, 4.83; N,
3.08; S, 14.12.
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2-(4-Methoxy-benzylsulfanyl)-9-(toluene-4-sulfonyl)-1,2,3,4-
tetrahydro-1,4-epiazano-naphthalene (6d). Following the
general procedure (I), 6d was obtained as a white solid
(79.3 mg, 88%). Rf = 0.20 on silica gel (ethyl acetate–petroleum
ether = 1 : 15, v/v). Mp 102–103 °C. The ee was determined to
be 5% using HPLC analysis on a Chiralcel OD-H column
(hexane–2-propanol = 85 : 15, 0.5 mL min−1, λ = 254 nm); reten-
tion times were 39.0 min (minor) and 48.1 min (major). [α]D20
=
5 (c 1.00, CHCl3). IR (film, cm−1): 2933(w), 2925(w), 1669(w),
1511(m), 1460(w), 1342(m), 1161(s), 1089(m), 1031(w), 971(s),
1
813(m), 604(w), 558(m). H NMR (400 MHz, CDCl3): δ 7.31 (d,
J = 8.0 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H),
6.87–6.85 (m, 5H), 6.75 (d, J = 4.0 Hz, 1H), 4. 98 (d, J = 3.6 Hz,
1H), 4.50 (s, 1H), 3.83 (d, J = 4.8 Hz, 2H), 3.80 (s, 3H),
2.55–2.52 (m, 1H), 2.25 (s, 3H), 2.00–1.96 (m, 1H), 1.78–1.73
(m, 1H); 13C NMR (100 MHz, CDCl3): δ 154.7, 139.1, 138.9,
137.9, 131.0, 126.3, 126.1, 124.9, 123.9, 122.9, 122.7, 116.3,
116.2, 110.1, 64.4, 59.2, 51.4, 40.6, 32.7, 32.5, 17.5. MS (ESI)
calcd for C25H25NO3S2 (M+): 451.13; Found: 474.41 (M + Na)+.
Anal. Calcd for C25H25NO3S2: C, 66.49; H, 5.58; N, 3.10; 14.20.
Found: C, 66.55; H, 5.54; N, 3.12; 14.11.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (No. 21172081), Guangzhou Pearl River New Star Plan of
Science and Technology Program (2012J2200015) and Produce
and Learning and Research Project of Education Department
of Guangdong Province (No. 2011A090200039) for financial
support. We are also grateful to Dr Mahendra Chordia of Uni-
versity of Virginia at Charlottesville and Dr Qingqi Chen of
MedKoo Biosciences for critically reading and revising the
manuscript.
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