Condensation-ring expansion reaction of formyl[2.2.1]bicyclic carbinols with para-substituted phenyl amines: Application to the preparation of [3.2.1]bicyclic n-aryl-1,2,3-oxathiazolidine-2-oxide agents

Article abstract of DOI:10.1002/jccs.201100517

Individual reaction of camphene-derived endo-formyl[2.2.1]bicyclic carbinol and that of camphor-derived exo-formyl[2.2.1]bicyclic carbinol with parent and para-substituted phenyl amines gave regio- and stereospecific corresponding [3.2.1]bicyclic (para-su

Full text of DOI:10.1002/jccs.201100517

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Condensation-ring Expansion Reaction of Formyl[2.2.1]bicyclic Carbinols with
Para-substituted Phenyl Amines: Application to the Preparation of [3.2.1]bicyclic
N-aryl-1,2,3-oxathiazolidine-2-oxide Agents
Te-Fang Yang,a,* Li-Hsun Chen,b Li-Ta Kao,b Chih-Hsiang Chuanga and Yong-Yen Chena
aDepartment of Applied Chemistry, National Chi Nan University, Puli, 545, Nantou, Taiwan, R.O.C.
bDepartment of Applied Chemistry, Chaoyang University of Technology, Wufong, 413, Taichung, Taiwan, R.O.C.
(Received: Aug. 26, 2011; Accepted: Dec. 12, 2011; Published Online: Jan. 12, 2012; DOI: 10.1002/jccs.201100517)
Individual reaction of camphene-derived endo-formyl[2.2.1]bicyclic carbinol and that of camphor-de-
rived exo-formyl[2.2.1]bicyclic carbinol with parent and para-substituted phenyl amines gave regio- and
stereospecific corresponding [3.2.1]bicyclic (para-substituted) phenyl amino ketones. Mechanism of
each reaction was discussed. Some camphor-derived [3.2.1]bicyclic amino ketones were reduced to
[3.2.1]bicyclic (para-substituted) phenyl amino alcohols, which were then treated with mesyl chloride to
provide [3.2.1]bicyclic N-phenyl/aryl-1,2,3-oxathiazolidine-2-oxide agents. The mechanism of this final
reaction was discussed as well.
Keywords: Formyl bicyclic carbinols; Ring expansion; Bicyclic aryl amino ketone;
1,2,3-Oxathiazolidine-2-oxide.
INTRODUCTION
It has been known for several decades that the reac-
ketone agents could be selectively obtained from the treat-
ment of camphor-derived exo-formyl[2.2.1]bicyclic car-
binol with alkyl primary amines.5 Being encouraged by all
the above interesting works, we have further studied the
reaction of some formyl[2.2.1]bicyclic carbinols (3 and 4,
Fig. 1) with various para-substituted analines, which are
aryl amines and proved to be remarkable N-nucleophile
donors as well. For the study on the title reaction, car-
binols 3 and 4 were prepared using the known proce-
dures.4
tion of cyclopentyl phenyl epoxyether with para-substi-
tuted aniline afforded N-para-substituted-phenyl-1-(a-
phenyliminobenzyl)cyclopentol (1, Scheme I)1, which
could further undergo thermal rearrangement to give 2-
phenyl-2-para-substituted-phenyl-aminocyclohexanone
(2). The rearrangement was believed to proceed through a
concerted transition state, which was unlikely stabilized by
the resonance effect from the para-substituent. Neverthe-
less, the stereochemistry was not studied and discussed at
that time. An application of this thermal reaction to the
asymmetric synthesis of 2-chlorophenyl-2-methylamino
cyclohexanone from 1-(2-chlorophenylmethyliminometh-
yl)-cyclopentanol, using metal complexes as the catalysts,
was then reported by Brunner and co-workers.2 Further-
more, conversion of a-hydroxy imines to a-amino ketones
had been also carried out by utilizing thermal rearrange-
ment, which involved a conventional alkyl 1,2-carbon mi-
gration rather than a ring expansion.3 Recently, it has been
reported by our lab that reaction of formyl[2.2.1]bicyclic
carbinols with various C-nucleophiles provided corre-
sponding regio- and stereospecific alkyl/aryl [3.2.1]bi-
cyclic diols, whereas the solutions of the same substrate in
methanol furnished various [3.2.1]bicyclic hydroxyl ke-
tones.4 On the other hand, [3.2.1]bicyclic alkyl amino
Thermal rearrangement of phenyl-1-(a-
Scheme I
phenyl iminobenzyl)cyclopentol
RESULTS AND DISCUSSION
As demonstrated in Table 1, the reaction of carbinol 3
with parent aniline (entry 1) as well as with various para-
substituted phenyl amines (entries 2 ~ 10) correspondingly
furnished products 5a~5j. This reaction was individually
carried out in dichloromethane at room temperature (condi-
tion A) and in toluene at reflux (condition B). On the proton
NMR spectra of products 5, it was found that the chemical
Dedicated to the memory of Professor Yung-Son Hon (1955–2011).
* Corresponding author. Tel: +886-49-2910960; Fax: +886-49-2917956; E-mail: tfyang@ncnu.edu.tw
378
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JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Reaction of Formyl[2.2.1]bicyclic Carbinols
Table 1. Results of the reaction of carbinol 3 with aryl amines
para-bromo and para-iodo phenyl amines did not show
significant difference in their nucleophilicities under both
conditions (entries 7 and 8). Surprisingly, for the N-nucleo-
philes possessing nitro and acetyl groups at para-position,
dichloromethane was a better solvent than toluene (entries
9 and 10).
A plausible mechanism for the reaction of 3 is illus-
trated in Figure 2. In order to demonstrate how amino
ketone 5 was exclusively furnished from the reaction, the
structure of 3 is partially numbered. Based on the molecu-
lar model study,4c it is deduced that imino alcohol 6, the
condensation product, was formed at the beginning of reac-
tion. Then, the nitrogen atom captured the proton of hy-
droxyl group on C2, such that C2-C4 bond was forced to
break. Immediately, thus, C4 attacked C3 smoothly from
the si-face (route a), resulting in the formation of 5 (a 3C6
conformation), in which the aryl amino group on C3 is
equatorial.6 Alternatively, if the formation of 7 (a 2C6 con-
formation) occurred, then C1-C2 bond would have to
break. Thus, C2-C4 bond would rotate somewhat such that
C3 swung up and C2 flopped down, then, C1 could attack
C3 (route b). Accordingly, it is concluded that the process
for the formation of 7 was kinetically unfavorable due to
higher energy barrier, comparing with the process for the
formation of 5.
shifts of the signals of protons on the carbons which pos-
sess aryl amino groups ranged from 3.70 ppm to 4.04 ppm.
Furthermore, the signal of each of those protons turned out
to be either a singlet or a doublet, which was due to the cou-
pling of that corresponding proton with the proton on nitro-
gen atom, demonstrating that the aryl amino group is
bonded with exo-orientation to the ring-carbon atom which
is farthest from both bridgehead carbons. The exact struc-
tures of products 5 were confirmed with X-ray crystallog-
raphy. For each entry listed in Table 1, among all possible
regio- and stereoisomers of [3.2.1]bicyclic amino ketone
product, compound 5 was the only one observed and iso-
lated. As expected, carbinol 3 reacted with most of the
para-substituted phenylamines (entries 1~6) more effi-
ciently under condition B compared to that in A. However,
In order to assure that para-substituted phenyl amines
are indeed good N-nucleophiles for the title reaction, car-
binol 4 was adopted as the second substrate, and reaction
conditions A and B listed in Table 1 were employed. As
shown in Table 2, the outcome of reaction of 4 was analogi-
cal to that of reaction of 3. Obviously, compound 4 showed
higher reactivity under reaction condition B than under
condition A. Generally, under each condition, the para-
halogen-containing phenyl amines (entreis 6 ~ 8) are better
N-nucleophiles than parent and other para-substituted ani-
lines. That product 8i (entry 9) was obtained in low yield
Fig. 1. Formyl[2.2.1]bicyclic carbinols that react with
Fig. 2. Mechanism for the reaction of 3 with aryl
para-substituted analines.
amines.
J. Chin. Chem. Soc. 2012, 59, 378-388
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Table 2. Results of the reaction of carbinol 4 with aryl amines
group is bonded with endo-orientation to the ring-carbon
atom which is located between the bridgehead quaternary
carbon and the carbonyl group. On the other hand, the
ring-carbonyl group is located at the farthest position from
the bridgehead carbon atoms. The exact structures of prod-
ucts 8 were confirmed with X-ray crystallography. For
each entry, among all possible regio- and stereoisomers of
[3.2.1]bicyclic amino ketone product, compound 8 was the
only one observed and isolated. On the other hand, it was
found that there was no significant difference between the
reactivity of parent aniline (entry 1) and that of any aniline
possessing electron-donating group at para-position (en-
tries 2~5).
R
NH2
condition A or Ba
O
O
HO
NH
R
4
8
Entry
Aryl amine
Product
Yield (%)c
condition A condition B
b
1
2
3
4
5
6
7
8
9
p-H-PhNH2
8a (R = H)
58
54
38
42
45
68
74
83
89
87
65
90
95
92
93
95
p-Me-PhNH2
p-HO-PhNH2
p-MeO-PhNH2
8b (R = Me)
8c (R = OH)
8d (R = OMe)
A plausible mechanism for the reaction shown in Ta-
ble 2 is illustrated in Figure 3, and is similar to that of reac-
tion of 4 with alkyl primary amines.5 In order to demon-
strate how amino ketone 8 was exclusively furnished from
the reaction, the structure of 4 is partially numbered. Based
on the molecular model study,4c it is deduced that N-aryl
imino carbinol 9, the condensation product, was provided
first. Then, the nitrogen atom abstracted the proton of the
hydroxyl group on C2, such that C1-C2 bond was forced to
break. Immediately, thus, C1 attacked C3 from the re-face
(route a), resulting in the formation of 8 (a 2C6 conforma-
tion), in which the aryl amino group is equatorial. Alterna-
tively, if the formation of 10 (a 3C6 conformation) occurred,
then C2-C4 bond would have to break. Thus, C1-C2 bond
would rotate ~180o such that C3 swung down and C2 rela-
tively flopped up, then C4 could attack C3 (route b). Ac-
cordingly, it is speculated that the process for the formation
of 10 was kinetically unfavorable comparing with that for
the formation of 8. For the verification of existence of 9, the
reaction of 4 with aniline had also been carried out in di-
chloromethane, and the reaction mixture was worked up in
30 minutes. Then, the mixture of the crude products was
subject to the experiment for 1H-NMR spectroscopy. Evi-
dently, on the spectrum of the mixture, it was found that a
singlet signal appeared at 8.10 ppm, corresponding to the
proton of imino moiety on structure 9a. Presumably, the
structure of 9 was instantaneously stabilized by the conju-
gated double bond system, which was composed of the
imino group and aryl moiety. Such stabilization might be
the reason why the yields of products given from the reac-
tion of 4 with anilines are higher than those given from the
reaction with alkyl primary amines under the same condi-
tions.5
p-i-Pr-PhNH2
p-Cl-PhNH2
p-Br-PhNH2
p-I-PhNH2
8e (R = i-Pr)
8f (R = Cl)
8g (R = Br)
8h (R = I)
p-NO2-PhNH2
p-Ac-PhNH2
8i (R = NO2)
36
86
40
86
10
8j (R = Ac)
aCondition A: CH2Cl2, r.t., 30 min. Condition B: toluene, reflux, 3h.
bAniline.
cYield of isolated product.
was probably due to poor solubility of para-nitro-aniline.
Furthermore, it is noteworthy that the reaction under condi-
tion A provided bicyclic imino carbinol 9 (Fig. 3) as the in-
termediate, which could not be isolated with silica gel col-
umn chromatography. However, the existence of 9 was
1
proved with H-NMR spectroscopy (vide infra). On the
proton NMR spectra of products 8, it was found that the
chemical shifts of the signals of protons on the carbons
which possess aryl amino groups ranged from 3.88 ppm to
4.21 ppm. Furthermore, the signal of each of those protons
turned out to be a singlet, indicating that the aryl amino
Fig. 3. Mechanism for the reaction of 4 with aryl
amines.
380
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Reaction of Formyl[2.2.1]bicyclic Carbinols
For application of the title reaction, products 8a, 8d
and 8i shown in Table 2, were then reduced with sodium
borohydride to give [3.2.1]bicyclic aryl amino alcohols 11,
12 and 13, respectively (Scheme II). Our original plan in-
volved the utilization of 11 ~ 13 as the intermediates for the
preparation of some [3.2.1]bicyclic allyl aryl amines for
synthetic purposes. Therefore, compounds 11 ~ 13 were
then individually treated with mesyl chloride in order to ac-
tivate the hydroxyl group. This activation reaction was ex-
pected to efficiently provide compounds 14 ~ 16, which
perhaps further undergo an elimination reaction in the pres-
ence of appropriate basic agent. Surprisingly, however,
corresponding bicyclic 1,2,3-oxathiazolidine-2-oxide 17
was primarily obtained from the reaction of 11 with MsCl.
Furthermore, the reaction of aryl amino alcohol 13, which
possesses nitro group at para-position in the aryl moiety,
gave exclusively 19 in a good yield (94%). As shown in
Figure 4, the absolute structure of 19, a stereo-specific
compound, was confirmed with X-ray analysis.7
source of sulfoxide (S=O) moiety for 1,2,3-ozathiazoli-
dine-2-oxide system. The mechanism for this reaction,
which afforded the originally unexpected new product(s),
is illustrated in Figure 5. At the beginning of reaction, inter-
mediates 14 ~ 16 might be furnished, releasing triethyl am-
monium chloride. Structure 26 was then formed by abstrac-
tion of proton to sulfonate moiety from the aryl amino
group on 14 ~ 16 followed by cyclization via species 23, 24
or 25. Presumably, on species 25, the para-nitro group on
aryl moiety participated in through-resonance with nitro-
gen anion, such that compound 16 was completely con-
Reaction of [3.2.1]bicyclic aryl amino alco-
hol with mesyl chloride
Scheme II
Fig. 4. ORTEP drawing of [3.2.1]bicyclic 1,2,3-oxa-
thiazolidine-2-oxide 19.
It is known that chiral 1,2,3-oxathiazolidine-2-oxide
agents are useful intermediates for the syntheses of enantio-
pure sulfoxides, sulfinamides and sulfimines.8-12 Usually,
this heterocyclic 2-oxide system can be smoothly obtained
from the treatment of N-alkyl/aryl amino alcohol with
thionyl chloride.8-18 Thus, what has to be specially noted is
that the reaction of 11 ~ 13 shown in Scheme II demon-
strates, to the best of our knowledge, the first example of
using mesyl chloride instead of thionyl chloride as the re-
Fig. 5. Proposed mechanism for the reaction of 11, 12
and 13 with MsCl.
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Article
Yang et al.
sumed and not detected at all upon work-up. On the con-
trary, the para-methoxy group on aryl moiety might make
species 24 unstable, such that compound 15 was obtained
in a relatively significant yield (62%). The oxygen atom of
hydroxyl group bonded to sulfur on 26 was then protonated
in the presence of triethyl ammonium chloride to give spe-
cies 27. Finally, [3.2.1]bicyclic product 29, a new class of
N-aryl-1,2,3-oxathiazolidine-2-oxide agent, was produced
by release of water molecule from sulfur atom on 27 and
subsequent attack of the chloride ion to methyl group on
28.
EXPERIMENTAL
General information
Moisture-sensitive solvents were dried with standard
methods and, when necessary, transferred via a syringe.
Round bottom flasks were employed for carrying out all the
reactions. Solutions of crude product were dried on Na2SO4
or MgSO4. The dried solutions were then filtered and con-
centrated with a rotary evaporator below 40 oC at ~30 Torr.
Silica gel (230-400 mesh) was employed for flash column
chromatography. Rf values were obtained from thin layer
chromatography (TLC). TLC was performed on silica gel
sheets with organic binder and detected by 0.5% phos-
phor-molybdic acid solution in 95% ethanol. Melting
points were measured on a Fargo MP-1D apparatus and
were uncorrected. An FT/IR spectrophotometer (Perkin
Elmer-paragon 500) was used for obtaining the infrared
spectra, in which data were expressed as wave number of
absorption (cm-1). 1H NMR and 13C NMR spectra were ob-
tained using a 200 MHz (Varian) or 300 MHz (Bruker)
spectrometer. Chemical shifts (d scale) were expressed in
parts per million downfield from tetramethylsilane (TMS,
d = 0.00). 1H NMR data were presented as follows: chemi-
cal shift, multiplicity (s = singlet, br s = broad singlet, d =
doublet, dd = doublet of doublet, t = triplet, m = multiplet
and/or multiple resonances), coupling constant (J) in Hz
(Hertz), integration. Optical rotation ([a]) values were re-
corded at room temperature on a JASCO (P-1010), or
JASCO (P-2000) digital polarimeter.
For the comparison of mesyl chloride with thionyl
chloride in their functions, reaction of the latter with 11 ~
13 has also been carried out, as shown in Scheme III, under
the conditions reported by Senanayake and coworkers.9,10
As expected, for the reaction of 11 and 12, products 17 and
18 were predominantly obtained over 20 and 21, respec-
tively. Furthermore, the reaction of 13 with thionyl chlo-
ride was similar to that with mesyl chloride, giving exclu-
sive product 19 in good yield.
Reaction of [3.2.1]bicyclic aryl amino al-
cohol with thionyl chloride
Scheme III
General procedure for the reaction of carbinol 3 with
parent or para-substituted phenyl amines under con-
dition A
CONCLUSION
To a solution of carbinol 3 (0.5 g, 2.98 mmol) in
CH2Cl2 (20 mL) was added parent or p-substituted phenyl
amine (1.30 eq. 3.57 mmol) at room temperature. The reac-
tion mixture was stirred at room temperature for 30 min un-
der argon, then washed with water (30 mL´ 3). The organic
layers were combined, dried (Na2SO4), filtered and con-
centrated under reduced pressure. The residue was purified
with flash column chromatography (n-hexanes:EtOAc =
3:1) to give the corresponding camphene-derived [3.2.1]-
bicyclic a-amino ketone (5).
In conclusion, both the reaction of camphene-derived
exo-formyl[2.2.1]bicyclic carbinol and that of camphor-
derived endo-formyl[2.2.1]bicyclic carbinol with phenyl/
aryl amines proved to be regio- and stereoselective, fur-
nishing the corresponding [3.2.1]bicyclic N-phenyl/aryl
amino ketones. These reactions were individually com-
posed of consecutive condensation and ring-expansion.
Some of the camphor-derived products obtained from the
reaction were converted to [3.2.1]bicyclic N-phenyl/aryl
1,2,3-oxathiazolidine-2-oxide agents, which are new com-
pounds and expected to be used as chiral synthons for the
synthesis of enantiopure sulfinamides. One of the new
findings in this work is that mesyl chloride can be the re-
source of sulfoxide (S=O) moiety for 1,2,3-ozathiazoli-
dine-2-oxide system.
General procedure for the reaction of carbinol 3 with
parent or para-substituted phenyl amines under con-
dition B
To a solution of carbinol 3 (0.5 g, 2.98 mmol) in tolu-
ene (20 mL) was added parent or various p-substituted
phenyl amine (1.30 eq. 3.57 mmol) at room temperature.
382
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Reaction of Formyl[2.2.1]bicyclic Carbinols
The reaction mixture was heated at reflux for 3 hours under
argon, then cooled to room temperature, and washed with
water (30 mL´ 3). The organic layers were combined, dried
(Na2SO4), filtered and concentrated under reduced pres-
sure. The residue was purified with flash column chroma-
tography (n-hexanes:EtOAc = 3:1) to give the correspond-
ing camphene-derived [3.2.1]bicyclic a-amino ketone (5).
Data of camphene-derived [3.2.1]bicyclic (para-substi-
tuted) phenyl amino ketones
55.8, 49.6, 46.7, 45.1, 35.5, 26.7, 26.0, 25.0, 21.4. HRMS
calcd. for C17H23NO2: 273.1729; found: 273.1721.
Compound 5e
White solid, Rf = 0.86 (3:1, hexanes/EtOAc); 79%
yield; mp 69-70 oC; [a]D27 = +28.9 (0.2, CH2Cl2); IR (KBr):
3360, 3022, 2953, 2873, 1713, 1614, 1513 cm–1; 1H NMR
(200 MHz, CDCl3): d 7.06-6.60 (m, 4H), 4.26 (br s, 1H),
3.81 (s, 1H), 2.86-2.72 (m, 2H), 2.23-1.59 (m, 7H), 1.19 (s,
3H), 1.18 (d, J = 6.8 Hz, 6H), 0.82 (s, 3H); 13C NMR (50
MHz, CDCl3): d 212.4, 147.3, 138.5, 127.0, 113.9, 66.1,
49.5, 46.6, 45.2, 35.5, 33.1, 26.7, 26.0, 25.0, 24.2, 21.4.
HRMS calcd. for C19H27NO: 285.2093; found: 285.2097.
Compound 5f
Compound 5a
White solid, Rf = 0.74 (3:1, hexanes/EtOAc); 75%
yield, mp 93-94 oC; [a]D27 = +26.3 (0.2, CH2Cl2); IR (KBr):
3365, 3048, 2964, 2913, 1720, 1602, 1499 cm–1; 1H NMR
(200 MHz, CDCl3): d 7.25-6.66 (m, 5H), 4.20 (br s, 1H),
3.87 (s, 1H), 2.83 (m, 1H), 2.17-1.61 (m, 7H), 1.20 (s, 3H),
0.85 (s, 3H); 13C NMR (50 MHz, CDCl3): d 212.1, 149.0,
129.2, 118.2, 114.0, 65.9, 49.6, 46.7, 45.3, 35.51, 26.7,
26.1, 25.0, 21.4. HRMS calcd. for C16H21NO: 243.1623;
found: 243.1620.
White solid, Rf = 0.69 (3:1, hexanes/EtOAc); 95%
o
27
yield; mp 124-125 C; [a]D = +19.1 (0.2, CH2Cl2); IR
(KBr): 3361, 3031, 2958, 2924, 2874, 1715, 1591, 1504,
1491 cm–1; 1H NMR (200 MHz, CDCl3): d 7.09 (d, J = 8.8
Hz, 2H), 6.60 (d, J = 8.8 Hz, 2H), 3.89 (br s, 1H), 3.80 (s,
1H), 2.83 (m, 1H), 2.20-1.62 (m, 7H), 1.18 (s, 3H), 0.84 (s,
3H); 13C NMR (50 MHz, CDCl3): d 211.8, 147.5, 129.0,
122.7, 115.2, 66.0, 49.5, 46.6, 45.3, 35.5, 26.7, 26.0, 25.0,
21.4. HRMS calcd. for C16H20ClNO: 277.1233; found:
277.1232.
Compound 5b
White solid, Rf = 0.77 (3:1, hexanes/EtOAc); 88%
o
27
yield; mp 104-105 C; [a]D = +58.1 (0.2, CH2Cl2); IR
(KBr): 3356, 3014, 2964, 2913, 1715, 1608, 1522 cm–1; 1H
NMR (200 MHz, CDCl3): d 6.98-6.57 (m, 4H), 4.20 (br s,
1H), 3.81 (s, 1H), 2.81 (s, 1H), 2.22 (s, 3H), 2.18-1.60 (m,
7H), 1.19 (s, 3H), 0.83 (s, 3H); 13C NMR (50 MHz,
CDCl3): d 212.4, 147.1, 129.6, 127.2, 114.1, 66.2, 49.6,
46.6, 45.2, 35.5, 26.7, 26.0, 25.0, 21.4, 20.3. HRMS calcd.
for C17H23NO: 257.1780; found: 257.1784.
Compound 5g
White solid, Rf = 0.69 (3:1, hexanes/EtOAc); 66%
o
27
yield; mp 131-132 C; [a]D = +47.3 (0.2, CH2Cl2); IR
(KBr): 3378, 3070, 2958, 2908, 2880, 1720, 1589, 1488,
1311 cm–1; 1H NMR (200 MHz, CDCl3): d 7.26-7.18 (m,
2H), 6.58-6.51 (m, 2H), 3.90 (br s, 1H), 3.80 (s, 1H), 2.83
Compound 5c
(m, 1H), 2.15-1.62 (m, 7H), 1.16 (s, 3H), 0.83 (s, 3H); 13
C
Yellowish solid, Rf = 0.28 (3:1, hexanes/EtOAc);
73% yield; mp 129-130 oC; [a]D27 = +26.1 (0.2, CH2Cl2);
IR (KBr): 3378, 3227, 3020, 2958, 2874, 1710, 1614, 1519
cm–1; 1H NMR (200 MHz, CDCl3): d 6.68-6.54 (m, 4H),
4.43 (br s, 1H), 3.70 (s, 1H), 2.81 (s, 1H), 2.12-1.62 (m,
8H), 1.20 (s, 3H), 0.84 (s, 3H); 13C NMR (50 MHz,
CDCl3): d 213.7, 148.4, 143.1, 116.1, 115.9, 67.6, 49.6,
46.7, 45.1, 35.6, 26.7, 25.9, 25.0, 21.3. HRMS calcd. for
C16H21NO2: 259.1572; found: 259.1579.
NMR (50 MHz, CDCl3): d 211.8, 148.1, 131.8, 115.5,
109.6, 65.7, 49.5, 46.6, 45.3, 35.5, 26.7, 26.1, 25.0, 21.4.
HRMS calcd. for: C16H20BrNO: 321.0728; found: 321.0725.
Compound 5h
White solid, Rf = 0.69 (3:1, hexanes/EtOAc); 63%
o
27
yield; mp 172-173 C; [a]D = +27.3 (0.2, CH2Cl2); IR
(KBr): 3384, 3014, 2964, 2908, 1717, 1617, 1586, 1508,
1483, 1315 cm–1; 1H NMR (200 MHz, CDCl3): d 7.39 (d, J
= 9.0 Hz, 2H), 6.45 (d, J = 9.0 Hz, 2H), 4.32 (br s, 1H), 3.81
(d, J = 6.4 Hz, 1H), 2.83 (m, 1H), 2.16-1.62 (m, 7H), 1.16
(s, 3H), 0.83 (s, 3H); 13C NMR (50 MHz, CDCl3): d 211.7,
148.8, 137.7, 116.0, 78.5, 65.4, 49.5, 46.7, 45.4, 35.5, 26.8,
26.1, 25.0, 21.4. HRMS calcd. for: C16H20INO: 369.0590;
found: 369.0587.
Compound 5d
White solid, Rf = 0.63 (3:1, hexanes/EtOAc); 83%
o
27
yield; mp 103-104 C; [a]D = +22.0 (0.2, CH2Cl2); IR
(KBr): 3367, 3059, 3008, 2964, 2874, 1709, 1510, 1245
cm–1; 1H NMR (200 MHz, CDCl3): d 6.78-6.60 (m, 4H),
4.08 (br s, 1H), 3.73 (s, 3H), 3.72 (s, 1H), 2.81 (m, 1H),
2.20-1.60 (m, 7H), 1.20 (s, 3H), 0.84 (s, 3H); 13C NMR (50
MHz, CDCl3): d 212.8, 152.5, 143.6, 115.6, 114.8, 67.4,
Compound 5i
Yellowish solid, Rf = 0.34 (3:1, hexanes/EtOAc);
67% yield; mp 173-174 oC; [a]D27 = +12.7 (0.2, CH2Cl2);
J. Chin. Chem. Soc. 2012, 59, 378-388
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383

Article
Yang et al.
IR (KBr): 3373, 3087, 2952, 2913, 1717, 1600, 1314 cm–1;
1H NMR (200 MHz, CDCl3): d 8.50 (d, J = 9.2 Hz, 2H),
6.60 (d, J = 9.2 Hz, 2H), 5.03 (d, J = 8.2 Hz, 1H), 4.04 (d, J
= 8.2 Hz, 1H), 2.89 (m, 1H), 2.20-1.68 (m, 7H), 1.17 (s,
3H), 0.87 (s, 3H); 13C NMR (50 MHz, CDCl3): d 210.3,
154.0, 138.5, 126.2, 112.0, 64.0, 49.5, 46.7, 45.7, 35.4,
26.6, 26.2, 25.0, 21.3. HRMS calcd. for C16H20N2O3:
288.1474; found: 288.1465.
Data of camphor-derived [3.2.1]bicyclic (para-substi-
tuted) phenyl amino ketones
Compound 8a
White solid: Rf = 0.70 (3:1, hexanes/EtOAc); mp
o
28
76-78 C; [a]D = -14.9 (0.2, CH2Cl2); IR (KBr): 3367
(br), 3060, 2960, 1710, 1602, 1498 cm–1; 1H NMR (200
MHz, CDCl3): d 7.19-7.11 (m, 2H), 6.74-6.63 (m, 3H),
4,68 (br s, 1H), 4.04 (s, 1H), 2.79 (d, J = 14.9 Hz, 1H), 2.31
(dd, J = 3.2 Hz, J = 14.9 Hz, 1H), 2.06-1.89 (m, 2H),
1.64-1.23 (m, 3H), 1.37 (s, 3H), 1.04 (s, 3H), 1.03 (s, 3H);
13C NMR (50 MHz, CDCl3): d 209.3, 149.2, 129.1, 117.9,
113.8, 67.1, 53.0, 46.5, 45.6, 44.9, 30.9, 27.1, 24.5, 18,5,
18,2. HRMS calcd. for C17H23NO: 257.1780; found:
257.1782.
Compound 5j
Yellowish solid, Rf = 0.34 (3:1, hexanes/EtOAc);
82% yield; mp 123-125 oC; [a]D27 = +16.0 (0.2, CH2Cl2);
IR (KBr): 3361, 3053, 2964, 2930, 1715, 1664, 1600, 1533
cm–1; 1H NMR (200 MHz, CDCl3): d 7.80 (d, J = 9.0 Hz,
2H), 6.62 (d, J = 9.0 Hz, 2H), 4.77 (br s, 1H), 4.02 (s, 1H),
2.86 (m, 1H), 2.47 (s, 3H), 2.24-1.65 (m, 7H), 1.17 (s, 3H),
0.86 (s, 3H); 13C NMR (50 MHz, CDCl3): d 211.0, 196.2,
152.9, 130.7, 127.3, 112.3, 64.1, 49.5, 46.7, 45.6, 35.5,
26.7, 26.1, 26.0, 25.0, 21.3. HRMS calcd. for C18H23NO2:
285.1729; found: 285.1736.
Compound 8b
White solid: Rf = 0.70 (3:1, hexanes/EtOAc); mp
129-130 oC; [a]D28 = -117.7 (0.2, CH2Cl2); IR (KBr): 3383,
3037, 2955, 2850, 1708, 1607, 1456 cm–1; 1H NMR (200
MHz, CDCl3): d 6.96 (d, J = 8.2 Hz, 2H), 6.57 (d, J = 8.2
Hz, 2H), 4.60 (br s, 1H), 3.98 (s, 1H), 2.78 (m, 1H), 2.30
(dd, J = 3.4 Hz, 15.0 Hz, 1H), 2.22 (s, 3H), 2.06-1.23 (m,
5H), 1.36 (s, 3H), 1.04 (s, 3H), 1.03 (s, 3H); 13C NMR (50
MHz, CDCl3): d 209.4, 146.9, 129.5, 127.0, 113.9, 67.5,
52.9, 46.4, 45.5, 44.8, 30.9, 27.0, 24.5, 20.2, 18.4, 18.1.
HRMS calcd. for C18H25NO: 271.1936; found: 271.1939.
Compound 8c
General procedure for the reaction of carbinol 4 with
parent or para-substituted phenyl amines under con-
dition A
To a solution of carbinol 4 (0.5 g, 2.75 mmol) in
CH2Cl2 (20 mL) was added parent or p-substituted phenyl
amine (1.30 eq., 3.57 mmol) at room temperature. The re-
action mixture was stirred at room temperature for 30 min
under argon, then washed with water (30 mL ´ 3). The or-
ganic layers were combined, dried (Na2SO4), filtered and
concentrated under reduced pressure. The residue was pu-
rified with flash column chromatography (n-hexanes:
EtOAc = 3:1) to give the corresponding camphor-derived
[3.2.1]bicyclic a-amino ketone (8).
White solid: Rf = 0.56 (3:1, hexanes/EtOAc); mp
o
73-74 C; [a]D = -18.1 (0.2, CH2Cl2); IR (KBr): 3487
28
1
(br), 3054, 2972, 1708, 1601, 1455 cm–1; H NMR (200
MHz, CDCl3): d 6.69-6.53 (m, 4H), 4.63 (br s, 2H), 3.88 (s,
1H), 2.78 (d, J = 15.0 Hz, 1H), 2.30 (dd, J = 3.2 Hz, 15.0
Hz, 1H), 2.06-1.26 (m, 5H), 1.33 (s, 3H), 1.05 (s, 3H), 1.02
(s, 3H); 13C NMR (50 MHz, CDCl3): d 210.3, 148.0, 143.5,
116.0, 115.3, 68.6, 53.0, 46.5, 45.7, 44.9, 30.9, 27.1, 24.6,
18.5, 18.3. HRMS calcd. for C17H23NO2: 273.1729; found:
273.1734.
General procedure for the reaction of carbinol 4 with
parent or para-substituted phenyl amines under con-
dition B
To a solution of carbinol 4 (0.5 g, 2.75 mmol) in tolu-
ene (20 mL) was added parent or p-substituted phenyl
amine (1.30 eq., 3.57 mmol) at room temperature. The re-
action mixture was heated at reflux for 3 hours under argon,
then cooled to room temperature, and washed with water
(30 mL ´ 3). The organic layers were combined, dried
(Na2SO4), filtered and concentrated under reduced pres-
sure. The residue was purified with flash column chroma-
tography (n-hexanes:EtOAc = 3:1) to give the corre-
sponding camphor-derived [3.2.1]bicyclic a-amino ke-
tone (8).
Compound 8d
White solid: Rf = 0.70 (3:1, hexanes/EtOAc); mp
118-119 oC; [a]D28 = -65.8 (0.2, CH2Cl2); IR (KBr): 3330
(br), 3028, 2960, 2918, 2854, 1707, 1644, 1452 cm–1; 1H
NMR (200 MHz, CDCl3): d 6.79-6.58 (m, 4H), 4.49 (br s,
1H), 3.90 (s, 1H), 3.73 (s, 3H), 2.76 (d, J = 15.0 Hz, 1H),
2.29 (dd, J = 3.2 Hz, 15.0 Hz, 1H), 2.05-1.24 (m, 5H), 1.34
(s, 3H), 1.05 (s, 3H), 1.02 (s, 3H); 13C NMR (50 MHz,
CDCl3): d 209.8, 152.3, 143.6, 115.1, 114.7, 68.5, 55.7,
52.9, 46.5, 45.6, 44.9, 30.9, 27.0, 24.5, 18.5, 18.2. HRMS
calcd. for C18H25NO2: 287.1885; found: 287.1880.
384
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J. Chin. Chem. Soc. 2012, 59, 378-388

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Reaction of Formyl[2.2.1]bicyclic Carbinols
Compound 8e
150-151 oC; [a]D28 = -49.3 (0.2, CH2Cl2); IR (KBr): 3554,
3076, 2987, 1700, 1611, 1455 cm–1; 1H NMR (200 MHz,
CDCl3): d 8.06 (d, J = 9.4 Hz, 2H), 6.58 (d, J = 9.4 Hz, 2H),
4.21 (s, 1H), 2.84 (d, J = 15.0 Hz, 1H), 2.37 (dd, J = 3.2 Hz,
15.0 Hz, 1H), 2.13-1.22 (m, 6H), 1.40 (s, 3H), 1.05 (s, 3H),
0.99 (s, 3H); 13C NMR (50 MHz, CDCl3): d 207.7, 154.1,
138.6, 126.2, 112.1, 65.7, 53.4, 46.5, 45.6, 45.1, 30.8, 27.1,
24.5, 18.6, 18.1. HRMS calcd.for C17H22N2O3: 302.1630;
found: 302.1632.
White solid: Rf = 0.70 (3:1, hexanes/EtOAc); mp
129-130 oC; [a]D28 = -67.8 (0.2, CH2Cl2); IR (KBr): 3376
(br), 3073, 2963, 2915, 2854, 1708, 1644, 1453 cm–1; 1H
NMR (200 MHz, CDCl3): d 7.05 (d, J = 8.4 Hz, 2H), 6.65
(d, J = 8.4 Hz, 2H), 4.60 (br s, 1H), 4.00 (s, 1H), 2.85-2.75
(m, 2H), 2.32 (dd, J = 3.2, 14.8 Hz, 1H), 2.08-1.90 (m, 2H),
1.66 (m, 1H), 1.42-1.26 (m, 2H), 1.37 (s, 3H), 1.21 (d, J =
7.0 Hz, 6H), 1.08 (s, 3H), 1.05 (s, 3H); 13C NMR (50 MHz,
CDCl3): d 209.4, 147.2, 138.5, 126.9, 114.0, 67.9, 52.9,
46.5, 45.5, 44.9, 33.0, 30.9, 27.1, 24.5, 24.1, 18.5, 18.2.
HRMS calcd. for C20H29NO: 299.2249; found: 299.2251.
Compound 8f
Compound 8j
White solid: Rf = 0.65 (3:1, hexanes/EtOAc); mp
158-159 oC; [a]D28 = -55.2 (0.2, CH2Cl2); IR (KBr): 3324,
3063, 2958, 1722, 1705, 1698, 1615, 1450 cm–1; 1H NMR
(200 MHz, CDCl3): d 7.80-7.74 (m, 2H), 6.61-6.55 (m,
2H), 5.06 (br s, 1H), 4.19 (s, 1H), 2.66 (m, 1H), 2.37 (s,
3H), 2.32 (dd, J = 3.2 Hz, 15.0 Hz, 1H), 2.07-1.21 (m, 5H),
1.37 (s, 3H), 1.02 (s, 3H), 0.98 (s, 3H); 13C NMR (50 MHz,
CDCl3): d 208.3, 196.2, 153.0, 130.6, 127.2, 112.4, 65.7,
53.2, 46.5, 45.6, 45.0, 30.8, 27.0, 26.0, 24.4, 18.5, 18.0.
HRMS calcd. for C19H25NO2: 299.1885; found: 299.1894.
General procedure for the preparation of 11, 12 and
13
White solid: Rf = 0.62 (3:1, hexanes/EtOAc); mp
143-145 oC; [a]D28 = -61.5 (0.2, CH2Cl2); IR (KBr): 3383,
3077, 2964, 1708, 1590, 1499 cm–1; 1H NMR (200 MHz,
CDCl3): d 7.08 (d, J = 8.8 Hz, 2H), 6.56 (d, J = 8.8 Hz, 2H),
4.20 (br s, 1H), 3.97 (s, 1H), 2.79 (m, 1H), 2.32 (dd, J = 3.4
Hz, 15 Hz, 1H), 2.36-1.23 (m, 5H), 1.36 (s, 3H), 1.03 (s,
3H), 1.01 (s, 3H); 13C NMR (50 MHz, CDCl3): d 209.1,
147.7, 128.9, 122.4, 114.9, 67.2, 53.1, 46.5, 45.6, 44.9,
30.9, 27.1, 24.5, 18.5, 18.2. HRMS calcd. for C17H22ClNO:
291.1390; found: 291.1383.
To a solution of 8a, 8d or 8i (1.39 mmol) in methanol
(30 mL) was added sodium borohydride (0.21 g, 5.56
mmol). The reaction mixture was heated at reflux for 1
hour, then quenched with water (5 mL) and extracted with
ethyl acetate (20 mL ´ 3). The organic layers were com-
bined, dried (Na2SO4), and concentrated under reduced
pressure. The residue was purified with flash column chro-
matography (n-hexanes : EtOAc = 3:1) to give the corre-
sponding [3.2.1]bicyclic a-amino alcohol 11 (syrup, 86%),
12 (solid, 80%) or 13 (solid, 81%).
Compound 8g
White solid: Rf = 0.60 (3:1, hexanes/EtOAc); mp
147-148 oC; [a]D28 = -69.9 (0.2, CH2Cl2); IR (KBr): 3379,
3075, 2956, 1708, 1591, 1504 cm–1; 1H NMR (200 MHz,
CDCl3): d 7.21 (d, J = 9.0 Hz, 2H), 6.52 (d, J = 9.0 Hz, 2H),
4.67 (br s, 1H), 3.98 (s, 1H), 2.56 (d, J = 15 Hz, 1H), 2.32
(dd, J = 3.4 Hz, 15 Hz, 1H), 2.08-1.32 (m, 5H), 1.36 (s,
3H), 1.23 (s, 3H), 1.00 (s, 3H); 13C NMR (50 MHz, CDCl3):
d 209.0, 148.2, 131.8, 115.3, 109.4, 66.9, 53.1, 46.5, 45.6,
44.9, 30.9, 27.1, 24.5, 18.5, 18.2. HRMS calcd. for
C17H22BrNO: 335.0885; found: 335.0877.
Data of camphor-derived [3.2.1]bicyclic (para-substi-
tuted) phenyl amino alcohols
Compound 8h
Compound 11
28
White solid: Rf = 0.60 (3:1, hexanes/EtOAc); mp
155-157 oC; [a]D28 = -75.5 (0.2, CH2Cl2); IR (KBr): 3370,
3077, 2961, 1710, 1602, 1508 cm–1; 1H NMR (200 MHz,
CDCl3): d 7.37 (d, J = 9.0 Hz, 2H), 6.42 (d, J = 9.0 Hz, 2H),
4.66 (br s, 1H), 3.96 (s, 1H), 2.77 (d, J = 15 Hz, 1H), 2.30
(dd, J = 3.2 Hz, 15 Hz, 1H), 2.04-1.21 (m, 5H), 1.34 (s,
3H), 1.01 (s, 3H), 0.98 (s, 3H); 13C NMR (50 MHz, CDCl3):
d 208.9, 148.7, 137.7, 137.5, 117.2, 115.8, 66.6, 53.0, 46.4,
45.5, 44.8, 30.8, 27.0, 24.4, 18.5, 18.1. HRMS calcd. for
C17H22INO: 383.0746; found: 383.0741.
Syrup: Rf = 0.62 (5:1, hexanes/EtOAc); [a]D
=
-56.9 (0.2, CH2Cl2); IR (film): 3348, 3050, 2955, 1602,
1
1507, 1318, 1057 cm–1; H NMR (300 MHz, CDCl3): d
7.22-7.10 (m, 2H), 6.75-6.62 (m, 3H), 4.05 (t, J = 5.5 Hz,
1H), 3.86 (br s, 1H), 3.40 (d, J = 5.0 Hz, 1H), 2.59 (s, 1H),
2.16-1.62 (m, 6H), 1.46-1.26 (m, 1H), 0.96 (s, 3H), 0.90 (s,
3H), 0.87 (s, 3H); 13C NMR (75 MHz, CDCl3): d 148.8,
129.3, 117.8, 113.5, 66.1, 60.2, 47.1, 44.5, 43.8, 34.5, 29,8,
26.5, 24,9, 18.7, 17.4. HRMS calcd. for C17H25NO:
259.1936; found: 259.1934.
Compound 8i
Compound 12
White solid: Rf = 0.62 (3:1, hexanes/EtOAc); mp
White solid: Rf = 0.46 (5:1, hexanes/EtOAc); mp
J. Chin. Chem. Soc. 2012, 59, 378-388
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385

Article
Yang et al.
o
55-56 C; [a]D19 = +24.9 (0.2, CH2Cl2); IR (KBr): 3344,
+55.7 (0.2, CH2Cl2); IR (KBr): 065, 2919, 2890, 1515,
1337, 1233, 1175 cm–1; H NMR (300 MHz, CDCl3): d
3063, 2948, 2892, 1511, 1243, cm–1; 1H NMR (300 MHz,
CDCl3): d 6.77-6.60 (m, 4H), 4.02 (t, J = 5.7 Hz, 1H), 3.72
(s, 3H), 3.59 (br s, 1H), 3.26 (d, J = 5.1 Hz, 1H), 3.01 (br s,
1H), 2.10-1.78 (m, 5H), 1.63 (m, 1H), 1.37 (m, 1H), 0.94
(s, 3H), 0.88 (s, 3H), 0.87 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 152.2, 143.2, 115.2, 115.0, 66.1, 62.0, 55.8,
47.2, 44.6, 43.9, 34.5, 29.8, 26.6, 25.0, 18.9, 17.6. HRMS
calcd. for C18H27NO2: 289.2042; found: 289.2034.
Compound 13
1
6.75 (d, J = 9 Hz, 2H), 6.56 (d, J = 9 Hz, 2H), 4.93 (t, 1H),
3.78 (m, 1H), 3.72 (s, 3H), 3.63 (d, J = 5.1 Hz, 1H), 2.76 (s,
3H), 2.30-1.67 (m, 6H), 1.45 (m, 1H), 1.00 (s, 3H), 0.93 (s,
3H), 0.90 (s, 3H); 13C NMR (75 MHz, CDCl3): d 151.9,
141,9, 115.2, 113.9, 79.8, 56.8, 55.8, 47.8, 44.6, 43.3, 38.2,
34.2, 29.7, 26.3, 25.0, 18.6, 17.3. HRMS calcd. for
C19H29NSO4: 367.1817; found: 367.1810.
Data of compound 17
Yellow solid: Rf = 0.22 (5:1, hexanes/EtOAc); mp
201-203 oC; [a]D21 = +52.1 (0.2, CH2Cl2); IR (KBr): 3486,
3403, 3105, 2954, 2928, 2886, 1603, 1524, 1333, 1121,
833 cm–1; 1H NMR (300 MHz, CDCl3): d 8.02 (d, J = 9.2
Hz, 2H), 6.54 (d, J = 9.2 Hz, 2H), 5.29 (d, J = 9.0 Hz, 1H),
4.06 (s, 1H), 3.64 (m, 1H), 2.20 (m, 1H), 2.08 (m, 1H),
1.97-1.69 (m, 5H), 1.41 (m, 1H), 1.03 (s, 3H), 0.92 (s, 3H),
0.84 (s, 3H); 13C NMR (75 MHz, CDCl3): d 154.2, 137.5,
126.7, 111.6, 67.0, 57.6, 47.9, 44.7, 43.8, 36.1, 30.0, 26.7,
25.1, 18.7, 17.5. HRMS calcd. for C17H24N2O3: 304.1787;
found: 304.1797.
White sloid: Rf = 0.57 (5:1, hexanes/EtOAc); mp
128-129 oC; [a]D28 = -168.1 (0.2, CH2Cl2); IR (KBr): 3050,
2958, 2945, 2930, 2885, 1593, 1495, 1266, 1168, 1152
cm–1; 1H NMR (300 MHz, CDCl3): d 7.35-7.08 (m, 5H),
5.33 (t, J = 6.3 Hz, 1H), 4.23 (dd, J = 1.2 Hz, 6.3 Hz, 1H),
2.37 (m, 1H), 2.06 (dd, J = 2.7 Hz, 16.2 Hz, 1H), 1.94-1.55
(m, 4H), 1.32 (m, 1H), 0.96 (s, 3H), 0.87 (s, 3H), 0.65 (s,
3H); 13C NMR (75 MHz, CDCl3): d 141.1. 129.7, 125.0,
124.6, 78.5, 65.1, 48.0, 43.4, 42.8, 31.8, 30.3, 26.4, 24.6,
18.6, 18.5. HRMS calcd. for C17H23NSO2: 305.1449;
found: 305.1444. Anal Calcd. for C17H23NSO2: C, 66.85;
H, 7.59; N, 4.59; S, 10.50. Found: C, 66.78; H, 7.27; N,
4.47; S, 10.68.
General procedure for the reaction of 11, 12 and 13
with MsCl
To a solution of 11, 12 or 13 (0.35 mmol) in dichloro-
methane (7 mL) was added triethyl amine (1.75 mmol) at 0
oC. After the reaction mixture was stirred for 30 min,
methanesulfonyl chloride (MsCl, 1.75 mmol) was added.
Data of compound 18
White solid: Rf = 0.46 (5:1, hexanes/EtOAc); mp
143-145 oC; [a]D21 = -135.7 (0.2, CH2Cl2); IR (KBr): 3066,
2928, 2911, 2872, 1509, 1246, 1151 cm–1; 1H NMR (300
MHz, CDCl3): d 7.20 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7
Hz, 2H), 5.33 (t, J = 6.3 Hz, 1H), 4.00 (d, J = 5.7 Hz, 1H),
3.79 (s, 3H), 2.35 (m, 1H), 2.04 (dd, J = 2.1, 15.9 Hz, 1H),
1.93-1.54 (m, 4H), 1.36 (m, 1H), 0.92 (s, 3H), 0.87 (s, 3H),
0.65 (s, 3H); 13C NMR (75 MHz, CDCl3): d 157.9, 133.5,
128.2, 114.9, 78,2, 68.4, 55.6, 47.9, 43.4, 42.9, 31.9, 30.2,
26.5, 24,6, 18.6, 18.3. HRMS calcd. for C18H25NSO3:
335.1555; found: 335.1550.
o
The new reaction mixture was stirred at 0 C for 5 min,
then, quenched with water (3 mL). The organic layer was
washed with more water (3 ´ 5 mL), dried (Na2SO4), and
concentrated under reduced pressure. The residue was pu-
rified with flash column chromatography (n-hexanes :
EtOAc = 5:1) to give compounds 14, 15, 17 ~ 21.
Data of compound 14
White solid: Rf = 0.48 (5:1, hexanes/EtOAc); mp
99-100 oC; [a]D19 = +63.3 (0.2, CH2Cl2); IR (KBr): 3404,
3043, 2928, 2897, 1604, 1513, 1347, 1173, 909 cm–1; 1H
NMR (300 MHz, CDCl3): d 7.16-7.11 (m, 2H), 6.68-6.56
(m, 3H), 4.94 (t, J = 5.1 Hz, 1H), 3.96 (br s, 1H), 3.75 (d, J
= 4.5 Hz, 1H), 2.73 (s, 3H), 2.24 (m, 1H), 2.08 (ddd, J =
0.6, 3.3, 15.9 Hz, 1H), 2.03-1.41 (m, 5H), 1.02 (s, 3H), 0.94
(s, 3H), 0.90 (s, 3H); 13C NMR (75 MHz, CDCl3): d 147.6,
129.7, 117.5, 112.8, 79.8, 55.7, 47.8, 44.7, 43.4, 38.2, 34.4,
29.8, 26.4, 25.0, 18.7, 17.2. HRMS calcd. for C18H27NSO3:
337.1712; found: 337.1708.
Data of compound 19
Yellow solid: Rf = 0.28 (5:1, hexanes/EtOAc); mp
230-232 oC; [a]D19 = -172.7 (0.2, CH2Cl2); IR (KBr): 3116,
2956, 2916, 1594, 1505, 1339, 1288, 1177, 838 cm–1; 1H
NMR (300 MHz, CDCl3): d 8.18 (d, J = 9.0 Hz, 2H), 7.22
(d, J = 9.0 Hz, 2H), 5.33 (t, J = 6.0 Hz, 1H), 4.42 (d, J = 5.4
Hz, 1H), 2.40 (m, 1H), 2.11 (dd, J = 1.8, 16.2 Hz, 1H),
1.97-1.78 (m, 2H), 1.67-1.56 (m, 2H), 1.37 (m, 1H), 1.04
(s, 3H), 0.91 (s, 3H), 0.72 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 148.1, 142.5, 125.5, 120.2, 80.0, 63.3, 48.3,
43.7, 42.6, 31.5, 30.9, 26.3, 24.7, 19.1, 18.5. HRMS calcd.
for C17H22N2SO4: 350.1300; found: 350.1303.
Data of compound 15
22
Syrup: Rf = 0.28 (5:1, hexanes/EtOAc); [a]D
=
386
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© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2012, 59, 378-388

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Reaction of Formyl[2.2.1]bicyclic Carbinols
Data of compound 20
National Taiwan University for elemental analysis, high
resolution mass spectra and X-ray crystallography.
White solid: Rf = 0.70 (5:1, hexanes/EtOAc); mp
o
19
185-187 C; [a]D = +263.3 (0.2, CH2Cl2); IR (KBr):
3040, 2980, 2947, 2929, 2890, 1599, 1500, 1267, 1173,
1162 cm–1; 1H NMR (300 MHz, CDCl3): d 7.35-7.08 (m,
5H), 4.75 (t, J = 6.3 Hz, 1H), 4.18 (d, J = 6.3 Hz, 1H), 2.75
(m, 1H), 2.21 (m, 1H), 2.03 (dd, J = 2.4, 15.9 Hz, 1H), 1.91
(m, 1H), 1.82-1.73 (m, 2H), 1.46 (m, 1H), 0.98 (s, 3H),
0.94 (s, 3H), 0.75 (s, 3H); 13C NMR (75 MHz, CDCl3): d
142.2, 129.8, 124.3, 119.9, 80.7, 64.8, 47.3, 44.1, 43.3,
32.5, 30.3, 26.5, 24.8, 18.7, 18.6. HRMS calcd. for
C17H23NSO2: 305.1449; found: 305.1446. Anal Calcd. for
C17H23NSO2: C, 66.85; H, 7.59; N, 4.59; S, 10.50. Found:
C, 66.71; H, 7.60; N, 4.47; S, 10.35.
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Data of compound 21
White solid: Rf = 0.59 (5:1, hexanes/EtOAc); mp
o
19
172-174 C; [a]D = +256.5 (0.2, CH2Cl2); IR (KBr):
3065, 2951, 2900, 1509, 1461, 12490, 1157. 1037 cm–1;
1H-NMR (300 MHz, CDCl3): d 7.20 (d, J = 8.7 Hz, 2H),
6.86 (d, J = 8.7 Hz, 2H), 4.80 (t, J = 6.3 Hz, 1H), 3.95 (dd, J
= 1.5, 6.3 Hz, 1H), 3.79 (s, 3H), 2.75 (m, 1H), 2.20 (m, 1H),
2.03-1.87 (m, 2H), 1.81-1.71 (m, 2H), 1.46 (m, 1H), 0.92
(s, 6H), 0.72 (s, 3H); 13C-NMR (75 MHz, CDCl3): d 157.5,
153.0, 124.6, 115.0, 80.8, 67.8, 55.6, 47.2, 44.0, 43.2, 32.6,
30.2, 26.4, 24.7, 18.6, 18.4. HRMS calcd. for C18H25NSO3:
335.1555; found: 335.1554.
6. Cm is an abbreviation for a chair conformation, in which car-
n
bon-n is located at the lower-left corner, and carbon-m at the
upper-right corner. For example, 3C6 is an abbreviation for a
chair conformation, in which carbon-3 is located at the
lower-left corner, and catbon-6 at the upper-right corner.
7. Crystallographic data for structures 5a, 5b, 5i, 8a, 8b, 8j, 13,
19 and 21 in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary pub-
lication numbers CCDC 817964, CCDC 817965, CCDC
817966, CCDC 817967, CCDC 817968, CCDC 817969,
CCDC 817970, CCDC 817971, and CCDC 817972, respec-
tively. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.
com.ac.uk).
General procedure for the reaction of 11, 12 and 13
with SOCl2
To a solution of 11, 12 or 13 (0.35 mmol) in dichloro-
methane (7 mL) was added triethyl amine (0.53 mmol) at
o
-45 C. Thionyl chloride (SOCl2, 0.88 mmol) was then
dropwise added. The new reaction mixture was stirred at
-45 oC for 5 min, then, quenched with sodium bicarbonate
(pH = 7~8). The mixture was diluted with dichloromethane
(10 mL). Then, the organic layer was washed with water (3
´ 5 mL), dried (Na2SO4), and concentrated under reduced
pressure. The residue was purified with flash column chro-
matography (n-hexanes : EtOAc = 5:1) to give compounds
17 ~ 21.
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ACKNOWLEDGEMENTS
This work was supported by the National Science
Council (Grants NSC 96-2113-M-324-001 and NSC
98-2119-M-260-001), which is gratefully acknowledged.
The authors thank Regional Instruments Center at National
Chung-Hsing University and the Instrumental Center at
11. Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Su, X.;
Wilkinson, H. S.; Lu, Z.-H.; Magiera, D.; Senanayake, C. H.
J. Chin. Chem. Soc. 2012, 59, 378-388
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© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2012, 59, 378-388