Lewis acid catalyzed SN2-type ring opening of N -activated aziridines with electron-rich arenes/heteroarenes

Article abstract of DOI:10.1021/jo401028j

An efficient Lewis acid catalyzed S_N2-type ring opening of substituted aziridines with electron-rich arenes/heteroarenes to provide substituted 2,2-diaryl/heteroarylethylamines in excellent yields and stereoselectivity (er, dr >99:1) is describ

Full text of DOI:10.1021/jo401028j

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Article
Lewis acid Catalyzed SN2-type Ring Opening of N-
Activated Aziridines with Electron Rich Arenes/ Heteroarenes
Manas K. Ghorai, Deo Prakash Tiwari, and Nikita Jain
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401028j • Publication Date (Web): 24 Jun 2013
Downloaded from http://pubs.acs.org on June 28, 2013
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The Journal of Organic Chemistry
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Lewis acid Catalyzed SN2ꢀtype Ring Opening of Nꢀ
Activated Aziridines with Electron Rich Arenes/
Heteroarenes
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Manas K. Ghorai* Deo Prakash Tiwari and Nikita Jain
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
Fax: (+91)ꢀ512ꢀ2597436; Phone: (+91)ꢀ512ꢀ2597518; email: mkghorai@iitk.ac.in
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RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
An efficient Lewis acid catalyzed SN2ꢀtype ring opening of substituted aziridines with electron rich
arenes/heteroarenes to provide substituted 2,2ꢀdiaryl/heteroarylethylamines in excellent yields and
stereoselectivity (er, dr > 99:1) is described.
Keywords: 2,2ꢀdiaryl/heteroarylethylamine; aziridine; Lewis acid, enantioselective; nucleophilic ring
opening; arenes/heteroarenes.
INTRODUCTION
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In recent years aziridines have become one of the most useful substrates/building blocks for the
generation of a number of nitrogen containing compounds of contemporary interest.1 A large variety of
heteroatomic and carbon centered nucleophiles have been used for the nucleophilic ring opening of
aziridines.2,3 Although the ring opening chemistry of aziridines with heteroatomic nucleophiles is well
documented in the literature, the same with the carbon nucleophiles has not been much explored.4 It is
worth mentioning that mostly the carbanion based carbon nucleophiles have been employed for this
purpose compared to the neutral carbon nucleophiles like arenes/heteroarenes.5 There are very few
reports on interꢀ5 as well as intramolecular6 ring opening of aziridines with arenes/heteroarenes and
most of them suffer from poor regioselectivity and/or limited substrate scope. It is noteworthy that the
intermolecular ring opening of aziridines with arenes provides an easy access to 2ꢀarylethylamine
scaffolds7 which are biologically active compounds acting as drug molecules as well e. g.
phenylethylamines and serotonin, venlafaxine (antidepressive) and Salmeterol (antiasthmatic) (Figure
1). Many other synthetic routes are known for the synthesis of substituted 2ꢀarylethylamines.8,9 Although
the ring opening chemistry of aziridines has been utilized for the synthesis of phenylethylamines,5 to the
best of our knowledge, there is no report of stereoselective intermolecular ring opening reactions of
aziridines with arenes.10,5f Therefore, the development of an efficient pathway for the stereoselective
synthesis of such compounds is highly desirable. In continuation of our research activities in the area of
Lewis acid (LA) catalyzed SN2ꢀtype ring opening of activated aziridines/azetidines,11 we have
developed a diastereoꢀ as well as enantioselective route for the synthesis of 2ꢀarylethylamines via
intermolecular ring opening of substituted Nꢀactivated aziridines with electron rich arenes and
heteroarenes. Herein, we report our results in detail as an article.
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Figure 1. Some biologically active 2ꢀarylethylamine derivatives
RESULTS AND DISCUSSION
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Our study began with the reaction of 2ꢀphenylꢀNꢀnosylaziridine12 1a with 1,3,5ꢀtrimethoxybenzene 2a
(1.5 equiv.) in the presence of Sc(OTf)3 (20 mol%) as the LA catalyst (Table 1) in dichloromethane to
provide the corresponding phenylethylamine 3a in moderate yield (entry 1, Table 1). In order to find the
optimum reaction condition, we screened other Lewis acids as catalysts like Cu(OTf)2, Zn(OTf)2 and
solvents like dichloroethane, nitromethane etc. (entry 2 6). When the reaction was carried out in
dichloroethane using Sc(OTf)3 (20 mol%) as the LA catalyst 3a was obtained in good yield (62%) and
even with lesser amount (5 mol%) of the LA catalyst the reaction was found to be successful (entry 4
and 6). Based on a recent report by Wu et al.,5c employing AuCl3/AgOTf or Zn/Ag as the dual catalysts
for the nucleophilic ring opening of aziridines with arenes, when 1a was reacted with 2a, the
corresponding product 3a was produced in very poor yield (entry 8 and 9). Based on our success with
Sc(OTf)3 in dichloroethane solvent (entry 5), we intended to use a combination of Sc(OTf)3 and another
catalyst for this purpose. To our great pleasure, when reaction of 1a with 2a was carried out in the
presence of catalytic amount of Sc(OTf)3 (5 mol%) and Zn(OTf)2 (5 mol%) in dichloroethane, 3a was
obtained in excellent yield (entry 11). The yield of the product 3a could not be improved further using
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other combinations of LA catalysts such as Sc(OTf)3 (5 mol%) and Cu(OTf)2 (5 mol%) (entry 12) or
BF3.OEt2 (5 mol%) and Zn(OTf)2 (5 mol%) (entry 13). Unsatisfactory results in terms of yield and the
reaction time were obtained with less than 5 mol% of the catalysts.
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Table 1. Optimization Studya
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entry
1
LA catalyst
solvent
time
1.5 h
yieldb (%)
50
Sc(OTf)3 (20 mol%)
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
Dichloroethane
Nitromethane
2
Zn(OTf)2 (20 mol%)
30 h
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Cu(OTf)2 (20 mol%)
2.5 h
45
4
BF3.OEt2 (20 mol%)
1.5 h
45
5
Sc(OTf)3 (20 mol%)
1.5 h
62
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Sc(OTf)3 (20mol%)
1.5 h
20
7
Sc(OTf)3 (5 mol%)
Dichloroethane
Nitromethane
1.5 h
56
8
AuCl3 (5 mol%), AgOTf (15 mol%)
AuCl3 (5 mol%), AgSbF6 (15 mol%)
Zn(OTf)2 (5 mol%), AgOTf (15 mol%)
Sc(OTf)3 (5 mol%), Zn(OTf)2 (5 mol%)
Sc(OTf)3 (5 mol%), Cu(OTf)2 (5 mol%)
BF3.OEt2 (5 mol%), Zn(OTf)2 (5 mol%)
Sc(OTf)3 (5 mol%), Zn(OTf)2 (5 mol%)
Sc(OTf)3 (5 mol%), Zn(OTf)2 (5 mol%)
5 min
5 min
5 min
30 min
45 min
30 min
30 min
45 min
30
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Nitromethane
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Nitromethane
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Dichloroethane
Dichloroethane
Dichloroethane
Dichloromethane
Nitromethane
85
68
70
53
25
aReactions were performed using 1.0 equiv. of 1a and 1.5 equiv. of 2a. Products were obtained as a
single regioisomer.
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Using the optimized reaction condition, the strategy was applied for the synthesis of various
substituted 2,2ꢀdiarylethyl/2,2ꢀaryl/heteroarylethylamines (Table 2). A variety of functionalized 2,2ꢀ
diarylethylamines 3b, g, especially, fluoroꢀsubstituted product 3d could be synthesized in excellent
yields from the corresponding aziridines 1b, g with 2a following our protocol (entry 2 7). It is worth
mentioning that compounds with a fluoroꢀsubstituent on the aromatic ring e.g. 3d have found numerous
applications in pharmaceutical industry.13 When thiophene (2b) and 1ꢀmethylindole (2c) were reacted
with 1a, the corresponding products 3h and 3i, respectively, were obtained in high yields (entry 8 and
9). Product 3h was obtained as mixture of regioisomer (>3:1) probably due to attack of 2b on benzylic
and less substituted positions of the aziridine ring. It is interesting to note that 3i bears a tryptamine
motif which is present in pharmaceutical agents and natural products.14
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Table 2. Scope of the reaction with monosubstituted N-nosylaziridines
entry
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aziridine
nucleophile
product
yield
(%)
NO2
O
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O
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Ph
1a
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O
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NO2
OMe
H
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MeO
OMe
3g
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NO2
O
O
S
N
O
O
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75a
Ph
Ph
1a
NO2
S
N
N
Me
65b
2c
1a
aProduct was obtained as >3:1 mixture of regioisomers (via attack of thiophene on benzylic and
unsubstituted position of aziridine5e). Some uncharacterized compound was also produced along with
b
3i15.
Next, we extended the scope of the reaction with other aziridines 1h, k bearing other Nꢀprotecting
groups and the results are shown in Table 3.
Table 3. Scope of the reaction with other N-sulfonylaziridines
entry
aziridine
nucleophile
product
yield
(%)
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Me
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N
O
Ph
1h
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O
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N
O
1k
75a
O
S
O
N
1k
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N
O
1k
aProduct was obtained as 4:1 mixture of regioisomers (via attack of thiophene on benzylic and
unsubstituted position of aziridine5e).
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Reaction of 2ꢀphenylꢀNꢀtosylaziridine 1h with 2a provided 3j in quantitative yield as single
1
2
regioisomer (entry 1, Table 3). Haloarylꢀsubstituted aziridines 1i and 1j were also reacted with 2a in a
similar fashion to generate the corresponding products 3k and 3l, respectively, in excellent yields (entry
2 and 3). Nꢀ4ꢀtertꢀbutylphenylsulfonylꢀ2ꢀphenylaziridine 1k upon reaction with 2a, produced 3m in
excellent yield. However, the reaction of 1k with 2b and 2d led to the formation of the corresponding
products 3n and 3o, respectively, with comparatively reduced yields (entry 4 6).
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To broaden the scope of our strategy, it was extended further for the synthesis of chiral 2,2ꢀ
diarylethylamines (Table 4). When chiral aziridine (R)ꢀ1h (ee >99%) was reacted with 1,3,5ꢀ
trimethoxybenzene 2a under our optimized condition, to our great pleasure the corresponding product
(R)ꢀ3j was produced in excellent yield (97%) and high enantiomeric excess (83%) (entry 2, Table 4).
Reduced ee of the products were observed from other chiral aziridines (R)ꢀ1a, k (entry 1 and 3, Table
4).16
Table 4. Reaction of chiral monosubstituted aziridines with 1,3,5-trimethoxybenzene 2a
entry
1
aziridine
product
time (h)
1.0
yield (%)
85
ee (%)
43
NO2
O
S
O
N
Ph
(R)-1a
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Me
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O
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2.5
2.5
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88
83
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S
N
O
Ph
(R)-1h
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S
O
N
Ph
(R)-1k
To investigate the reason behind getting reduced enantiomeric excess of the products (R)ꢀ3a and (R)ꢀ3m
from the corresponding aziridines (R)ꢀ1a and (R)ꢀ1k, respectively, we performed a time dependent
study of reaction of (R)ꢀ1a with 2a under our developed condition at 30 °C. The aliquots were taken
from the reaction at a regular interval of 15 min. After purification, the ee of both the recovered
aziridine (R)ꢀ1a and the product (R)ꢀ3a was determined by chiral HPLC analysis and the results are
shown in Figure 2 (see supporting information for details).
Figure 2. Time dependent study for racemization process
From our studies (Figure 2) we could conclude that both the aziridine and the product were racemized
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during the reaction. Furthermore, the racemization of the product was found to be faster than that of the
substrate.
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Based on our earlier observation that the chiral transꢀdisubstituted aziridines do not undergo
racemization in the presence of Lewis acids,11d we studied the reaction of chiral trans disubstituted
aziridines 1l and 1m with arenes with a view to obtaining enantiomerically pure products (Table 5). To
our great delight, when transꢀ2ꢀphenylꢀ3ꢀnꢀpropylꢀNꢀtosylaziridine (2S,3S)ꢀ1l was reacted with 2a, the
corresponding ring opening product (1S,2S)ꢀ3p was obtained in excellent yield and in
diastereomerically pure form (entry 1, Table 5). A similar result was obtained with aziridine (2S,3S)ꢀ1m
(entry 2). Racemic trans disubstituted aziridine 1n with a synthetically modifiable appendage
(CH2OTBS) was converted into the corresponding products 3r and 3s using 2a and 2c, respectively, in
excellent yields as single diastereomer (entry 3 and 4). The structure and the relative stereochemistry of
3r were confirmed by Xꢀray crystallographic analysis (see supporting information for details).
Table 5. Scope of the reaction with chiral disubstituted aziridines.
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entry
1
aziridine
nucleophile
product
yield (%)
94
dr
OMe
>99:1
MeO
Ph
OMe
NHTs
(S,S)-3p
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OMe
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95
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>99:1
MeO
Ph
OMe
NHTs
(S,S)-3q
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3a
>99:1
>99:1
MeO
Ph
OMe
NHTs
OTBS
3r
Me
N
4a
NHTs
OTBS
Ph
N
Me
3s
2c
aRacemic aziridine was used.
CONCLUSION
In conclusion, we have developed an efficient protocol for the synthesis of highly functionalized 2,2ꢀ
diaryl/heteroarylethylamines from a variety of substituted aziridines. Both enantioꢀ and
diastereomerically pure products could be obtained when chiral disubstituted aziridines were employed
as the substrates.
Experimental Section
General experimental:
Thin Layer Chromatography (TLC) was used for monitoring progress of the reaction using silica gel 60
F254 preꢀcoated plates and the spots were visualized using UV lamp or I2 stain. Silica gel 230ꢀ400 mesh
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size was used for flash column chromatography using the combination of ethyl acetate and petroleum
ether as the eluent. Unless otherwise mentioned, all reactions were carried out in ovenꢀdried glassware
under nitrogen atmosphere using anhydrous solvents. Wherever appropriate, all the reagents were
purified prior to use following Perrin and Armarego guidelines.17 Monosubstituted NꢀNs aziridines18
Monosubstituted NꢀTs aziridines19 and disubstituted aziridines11d were prepared following earlier
reports. All the commercial reagents were used as received without further purification unless
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1
mentioned. H NMR spectra were recorded on 400 MHz or 500 MHz and the chemical shifts were
recorded in parts per million (ppm, δ) using tetramethyl silane (δ 0.00) as the internal standard. Splitting
patterns of 1H NMR are mentioned as singlet (s), doublet (d), doublet of doublet (dd), triplet (t), quartet
(q), multiplet (m) etc. 13C NMR spectra were recorded on 100 MHz or 125 MHz. HRMS were obtained
using (ESI) mass spectrometer (TOF). KBr plates were used for IR spectra of solid compounds whereas
liquid compounds were recorded as neat. Melting points measurements were made using hot stage
apparatus and were uncorrected. Chiral HPLC analysis using Chiralcel ODꢀH column (detection at 254
nm) was utilized for determining enantiomeric excess (ee). Optical rotations were measured using a 6.0
25
mL cell with a 1.0 dm path length and are reported as [
α]
D (c in gm per 100 mL solvent) at 25 ºC.
Experimental Procedure:
To a suspension of Zn(OTf)2 (5.0 mol%) and Sc(OTf)3 (5.0 mol%) in dichloroethane (2.0 mL)
arenes/heteroarenes (1.5 equiv.) (dissolved in dichloroethane (1.0 mL) if solid) was added at 0 °C under
the nitrogen atmosphere. Subsequently, a solution of Nꢀsulfonylaziridine (100 mg, 1.0 equiv.) in
dichloroethane was added to the reaction mixture. Then the reaction mixture was allowed to stir at room
temperature (25 °C) up to completion of the reaction. After complete consumption of the starting
compound (monitored by TLC), the reaction was quenched by adding water (2.0 mL). Organic phase
was separated and the aqueous phase was extracted with dichloromethane (3 × 3.0 mL). Combined
extracts were washed with brine and dried over anhydrous sodium sulphate. After removal of the
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solvent under the reduced pressure, the crude reaction mixture was purified by flash column
chromatography on silica gel (230ꢀ400 mesh) using ethyl acetate in petroleum ether as the eluent to give
pure 2ꢀaryl/heteroarylethylamines.
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4-Nitro-N-(2-phenyl-2-(2,4,6-trimethoxyphenyl)ethyl)benzenesulfonamide (3a). The general method
described above was followed when 1a (100 mg, 0.329 mmol) was reacted with 1,3,5ꢀtrimethoxy
benzene 2a (83 mg, 0.494 mmol) in the presence of Zn(OTf)2 (6 mg, 0.016 mmol) and Sc(OTf)3 (8 mg,
0.016 mmol) at 25 °C for 30 min to afford 3a (132 mg, 0.279 mmol) as a pale yellow solid in 85%
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41
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
yield: mp 108 110 °C; Rf 0.36 (25% ethyl acetate in petroleum ether); IR ν
max (KBr, cmꢀ1) 3310, 2949,
1742, 1603, 1494, 1453, 1402, 1335, 1226, 1205, 1165, 1152, 1126, 1062, 1035, 947, 854, 838, 815,
1
756, 746, 733, 700, 685, 625; H NMR (400 MHz, CDCl3)
δ 3.60 (s, 6H), 3.74 3.88 (m, 2H), 3.77 (s,
3H), 4.57 (dd, J = 8.8, 6.8 Hz, 1H), 4.77 (t, J = 5.4 Hz, 1H), 6.00 (s, 2H), 7.09 7.21 (m, 5H), 7.87 (d, J
13
= 8.8 Hz, 2H), 8.24 (d, J = 8.8 Hz, 2H); C NMR (125 MHz, CDCl3)
δ 39.8, 45.6, 55.4, 55.7, 91.2,
108.9, 124.1, 126.3, 127.6, 128.2 (2C), 141.5, 146.2, 149.8, 159.2, 160.6; HRMS (ESI) calcd for
C23H24N2O7S, (M + H)+ 473.1382, found 473.1385.
25
For (R)ꢀ3a: optical rotation [
α]
= +13.1 (c 0.228, CHCl3) for a 43% ee sample, enantiomeric excess
D
was determined by chiral HPLC analysis (Chiralcel ODꢀH column), hexane–isopropanol 90:10, flow
rate = 1.0 mL/min; tR (1) = 36.34 min (minor) , tR (2) = 57.06 min (major).
N-(2-(4-Chlorophenyl)-2-(2,4,6-trimethoxyphenyl)ethyl)-4-nitrobenzenesulfonamide (3b). The
general method described above was followed when 1b (100 mg, 0.295 mmol) was reacted with 1,3,5ꢀ
trimethoxy benzene 2a (74 mg, 0.443 mmol) in the presence of Zn(OTf)2 (5 mg, 0.015 mmol) and
Sc(OTf)3 (7 mg, 0.015 mmol) at 25 °C for 30 min to afford 3b (128 mg, 0.252 mmol) as a pale yellow
solid in 86% yield: mp 146 148 °C; Rf 0.33 (25% ethyl acetate in petroleum ether); IR ν
max (KBr, cm1)
3431, 3279, 2925, 2844, 1608, 1534, 1493, 1471, 1455, 1422, 1347, 1313, 1226, 1206, 1171, 1152,
1
1119, 1092, 1069, 1037, 1014, 946, 896, 854, 840, 818, 736; H NMR (400 MHz, CDCl3)
δ
3.54 (s,
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6H), 3.64 3.72 (m, 2H), 3.70 (s, 3H), 4.48 (dd J = 9.0, 6.8 Hz, 1H), 4.66 (t, J = 5.5 Hz, 1H), 5.93 (s,
1
2
3
2H), 6.97 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H), 7.79 (d, J = 8.8 Hz, 2H), 8.17 (d, J = 9.0 Hz,
4
5
6
13
2H); C NMR (125 MHz, CDCl3)
δ 39.3, 45.4, 55.4, 55.7, 91.2, 108.4, 124.1, 128.2, 128.3, 129.0,
7
8
9
131.9, 140.1, 146.2, 149.8, 159.1, 160.8; HRMS (ESI) calcd for C23H23ClN2O7S, (M H) 505.0836,
found 505.0837.
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18
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20
21
22
23
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55
56
57
58
59
60
N-(2-(4-Bromophenyl)-2-(2,4,6-trimethoxyphenyl)ethyl)-4-nitrobenzenesulfonamide (3c). The
general method described above was followed when 1c (100 mg, 0.261 mmol) was reacted with 1,3,5ꢀ
trimethoxybenzene 2a (66 mg, 0.392 mmol) in the presence of Zn(OTf)2 (5 mg, 0.013 mmol) and
Sc(OTf)3 (6 mg, 0.013 mmol) at 25 °C for 30 min to afford 3c (139 mg, 0.239 mmol) as a pale yellow
solid in 92% yield: mp 90–92 °C; Rf 0.40 (25% ethyl acetate in petroleum ether); IR ν
max (KBr, cmꢀ1)
3583, 3272, 2947, 2843, 1605, 1529, 1489, 1459, 1421, 1345, 1223, 1204, 1165, 1123, 1093, 1036,
1
1009, 948, 890, 836, 812, 738, 684; H NMR (400 MHz, CDCl3)
δ 3.61 (s, 6H), 3.69 3.83 (m, 2H),
3.77 (s, 3H), 4.54 (dd J = 9.2, 6.6 Hz, 1H), 4.78 (dd, J = 6.1, 5.3 Hz 1H), 5.99 (s, 2H), 6.99 (d, J = 8.6
13
Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 8.23 (d, J = 8.8 Hz, 2H); C NMR (125
MHz, CDCl3)
δ 39.3, 45.4, 55.4, 55.7, 91.2, 108.3, 120.0, 124.1, 128.2, 129.4, 131.2, 140.7, 146.2,
149.8, 159.1, 160.8; HRMS (ESI) calcd for C23H23BrN2O7S, (M H) 549.0331, found 549.0339.
N-(2-(4-Fluorophenyl)-2-(2,4,6-trimethoxyphenyl)ethyl)-4-nitrobenzenesulfonamide (3d). The
general method described above was followed when 1d (100 mg, 0.310 mmol) was reacted with 1,3,5ꢀ
trimethoxybenzene 2a (78 mg, 0.465 mmol) in the presence of Zn(OTf)2 (6 mg, 0.016 mmol) and
Sc(OTf)3 (8 mg, 0.016 mmol) at 25 °C for 30 min to afford 3d (157 mg, 0.285 mmol) as a pale yellow
solid in 92% yield: mp 146–148 °C; Rf 0.38 (25% ethyl acetate in petroleum ether); IR ν
max (KBr, cmꢀ1)
3270, 2947, 2873, 2843, 1608, 1534, 1506, 1474, 1456, 1424, 1349, 1223, 1171, 1153, 1119, 1038, 947,
1
903, 845, 820, 737, 682; H NMR (400 MHz, CDCl3)
δ 3.61 (s, 6H), 3.69 3.84 (m, 2H), 3.77 (s, 3H),
4.55 (dd, J = 9.5, 6.8 Hz, 1H), 4.76 (t, J = 5.8 Hz, 1H), 6.00 (s, 2H), 6.87 (dd, J = 8.8, 8.6 Hz, 2H),
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13
7.06 7.09 (m, 2H), 7.87 (d, J = 8.8 Hz, 2H), 8.24 (d, J = 8.8 Hz, 2H); C NMR (125 MHz, CDCl3)
1
2
3
4
5
δ
39.2, 45.6, 55.4, 55.7, 91.2, 108.6, 114.9, 115.0, 124.1, 128.2, 129.05, 129.11, 137.3, 146.2, 149.8,
159.1, 160.4, 160.7, 162.3; HRMS (ESI) calcd for C23H23FN2O7S, (M + H)+ 491.1288, found 491.1288.
6
7
8
9
4-Nitro-N-(2-p-tolyl-2-(2,4,6-trimethoxyphenyl)ethyl)benzenesulfonamide (3e). The general method
described above was followed when 1e (100 mg, 0.314 mmol) was reacted with 1,3,5ꢀ
trimethoxybenzene 2a (79 mg, 0.471 mmol) in the presence of Zn(OTf)2 (6 mg, 0.016 mmol) and
Sc(OTf)3 (8 mg, 0.016 mmol) at 25 °C for 45 min to afford 3e (134 mg, 0.275 mmol) as a pale yellow
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11
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40
41
42
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44
45
46
47
48
49
50
51
52
53
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55
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57
58
59
60
solid in 88% yield: mp 188–190 °C; Rf 0.44 (25% ethyl acetate in petroleum ether); IR ν
max (KBr, cmꢀ1)
3299, 3104, 2925, 2853, 1607, 1529, 1493, 1456, 1437, 1417, 1348, 1311, 1222, 1205, 1164, 1122,
1094, 1064, 1037, 1013, 950, 910, 855, 813, 735, 685; 1H NMR (400 MHz, CDCl3)
δ
2.26 (s, 3H), 3.61
(s, 6H), 3.71ꢀ3.86 (m, 2H), 3.77 (s, 3H), 4.53 (dd, J = 9.5, 6.8 Hz, 1H), 4.72 (t, J = 5.6 Hz, 1H), 6.00 (s,
13
2H), 6.98 7.02 (m, 4H), 7.87 (d, J = 8.6 Hz, 2H), 8.24 (d, J = 8.5 Hz, 2H); C NMR (125 MHz,
CDCl3)
δ 21.1, 39.5, 45.8, 55.4, 55.7, 91.2, 108.9, 124.1, 127.5, 128.2, 128.9, 135.9, 138.4, 146.3,
149.8, 159.2, 160.5; HRMS (ESI) calcd for C24H26N2O7S, (M + H)+ 487.1539, found 487.1536.
N-(2-(4-tert-Butylphenyl)-2-(2,4,6-trimethoxyphenyl)ethyl)-4-nitrobenzenesulfonamide (3f). The
general method described above was followed when 1f (100 mg, 0.277 mmol) was reacted with 1,3,5ꢀ
trimethoxybenzene 2a (70 mg, 0.416 mmol) in the presence of Zn(OTf)2 (5 mg, 0.014 mmol) and
Sc(OTf)3 (7 mg, 0.014 mmol) at 25 °C for 45 min to afford 3f (127 mg, 0.240 mmol) as a pale yellow
solid in 87% yield: mp 78–80 °C; Rf 0.40 (20% ethyl acetate in petroleum ether); IR ν
max (KBr, cmꢀ1)
3252, 2962, 2870, 1607, 1531, 1495, 1462, 1420, 1346, 1312, 1268, 1226, 1207, 1168, 1122, 1061,
1
1036, 952, 910, 850, 810, 736, 684, 612; H NMR (400 MHz, CDCl3)
δ 1.25 (s, 9H), 3.61 (s, 6H),
3.72 3.77 (m, 1H), 3.77 (s, 3H), 3.81 3.89 (m, 1H), 4.54 (dd, J = 9.3, 7.1 Hz, 1H), 4.73 (t, J = 5.6 Hz,
1H), 6.00 (s, 2H), 7.04 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 7.88 (d, J = 8.6 Hz, 2H), 8.25 (d, J
13
= 8.8 Hz, 2H); C NMR (125 MHz, CDCl3)
δ
31.4, 34.4, 39.5, 45.7, 55.4, 55.7, 91.2, 108.9, 124.1,
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125.1, 127.3, 128.3, 138.3, 146.3, 149.1, 149.8, 159.2, 160.5; HRMS (ESI) calcd for C27H32N2O7S, (M
+ Na)+ 551.1828, found 551.1827.
1
2
3
4
5
6
7
8
4-(2-(4-Nitrophenylsulfonamido)-1-(2,4,6-trimethoxyphenyl)ethyl)phenyl acetate (3g). The general
method described above was followed when 1g (100 mg, 0.276 mmol) was reacted with 1,3,5ꢀ
trimethoxybenzene 2a (70 mg, 0.414 mmol) in the presence of Zn(OTf)2 (5 mg, 0.014 mmol) and
Sc(OTf)3 (7 mg, 0.014 mmol) at 25 °C for 30 min to afford 3g (135 mg, 0.254 mmol) as a pale yellow
9
10
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13
14
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23
24
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29
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31
32
33
34
35
36
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
solid in 92% yield: mp 144–146 °C; Rf 0.22 (25% ethyl acetate in petroleum ether); IR ν
max (KBr, cmꢀ1)
3287, 2942, 2842, 1753, 1607, 1529, 1506, 1455, 1417, 1350, 1335, 1220, 1201, 1164, 1122, 1097,
1
1037, 1016, 948, 914, 854, 833, 808, 747, 735; H NMR (400 MHz, CDCl3)
δ 2.26 (s, 3H), 3.61 (s,
6H), 3.70ꢀ3.87 (m, 2H), 3.77 (s, 3H), 4.57 (dd, J = 9.0, 6.8 Hz, 1H), 4.78 (t, J = 5.6 Hz, 1H), 6.00 (s,
2H), 6.89 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 8.24 (d, J = 9.0 Hz,
13
2H); C NMR (125 MHz, CDCl3)
δ 21.2, 39.4, 45.7, 55.4, 55.7, 91.2, 108.6, 121.2, 124.1, 128.2,
128.7, 139.1, 146.2, 149.0, 149.8, 159.1, 160.7, 169.7; HRMS (ESI) calcd for C25H26N2O9S, (M + H)+
553.1257, found 553.1259.
4-Nitro-N-(2-phenyl-2-(thiophen-2-yl)ethyl)benzenesulfonamide (3h). The general method described
above was followed when 1a (100 mg, 0.329 mmol) was reacted with thiophene 2b (40 ꢁL, 0.494
mmol) in the presence of Zn(OTf)2 (6 mg, 0.016 mmol) and Sc(OTf)3 (8 mg, 0.016 mmol) at 25 °C for
30 min to afford 3h (96 mg, 0.247 mmol) as a white solid in 75% yield as regioisomeric mixture (>3:1):
Rf 0.44 (20% ethyl acetate in petroleum ether); IR
ν
max (KBr, cmꢀ1) 3316, 3103, 2925, 1605, 1529, 1496,
1
1454, 1417, 1351, 1335, 1307, 1159, 1110, 1090, 1076, 1008, 892, 858, 837, 775, 739; H NMR (500
MHz, CDCl3) (major regioisomer)
δ 3.51 3.66 (m, 2H), 4.33 (dd, J = 8.0, 7.7 Hz, 1H), 4.61 4.63 (m,
1H), 6.80 6.83 (m, 1H), 6.92 6.94 (m, 1H), 7.15 7.17 (m, 2H), 7.26 7.32 (m, 4H), 7.96 (d, J = 8.9
Hz, 2H), 8.33 (d, J = 8.9 Hz, 2H); 13C NMR (125 MHz, CDCl3)
δ
46.8, 48.7, 124.5, 125.0, 125.3, 127.2,
127.8, 127.9, 128.4, 129.2, 140.0, 143.8, 145.8, 150.2; HRMS (ESI) calcd for C24H26N2O7S, (M + H)+
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487.1539, found 487.1536.
1
2
3
4
5
6
7
8
9
N-(2-(1-Methyl-1H-indol-3-yl)-2-phenylethyl)-4-nitrobenzenesulfonamide (3i). The general method
described above was followed when 1a (100 mg, 0.329 mmol) was reacted with 1ꢀ Methylindole 2c (62
ꢁL, 0.494 mmol) in the presence of Zn(OTf)2 (6 mg, 0.016 mmol) and Sc(OTf)3 (8 mg, 0.016 mmol) at
25 °C for 30 min to afford 3i (93 mg, 0.214 mmol) as a thick liquid in 65% yield; Rf 0.38 (25% ethyl
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13
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23
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32
33
34
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42
43
44
45
46
47
48
49
50
51
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53
54
55
56
57
58
59
60
acetate in petroleum ether); IR
ν
max (neat, cmꢀ1) 3301, 3104, 3061, 2925, 1606, 1529, 1472, 1454, 1422,
1
1348, 1312, 1264, 1164, 1093, 1013, 855, 830, 737, 703, 685; H NMR (500 MHz, CDCl3)
δ
3.56 3.68 (m, 1H), 3.66 3.75 (m, 1H), 3.72 (s, 3H), 4.34 (dd, J = 7.7, 7.3 Hz, 1H), 4.60 4.65 (m,
1H), 6.79 (s, 1H), 6.94 6.98 (m, 1H), 7.14 7.26 (m, 8H), 7.83 (d, J = 8.8 Hz, 2H), 8.21 (d, J = 8.6 Hz,
13
2H); C NMR (125 MHz, CDCl3)
δ 32.9, 42.9, 47.6, 109.6, 113.5, 119.1, 119.4, 122.3, 124.3, 126.7,
126.9, 127.3, 127.9, 128.2, 129.0, 137.3, 140.7, 145.6, 150.0; HRMS (ESI) calcd for C23H21N3O4S, (M
H) 434.1175, found 434.1177.
4-Methyl-N-(2-phenyl-2-(2,4,6-trimethoxyphenyl)ethyl)benzenesulfonamide (3j).5b,d,i The general
method described above was followed when 1h (100 mg, 0.366 mmol) was reacted with 1,3,5ꢀ
trimethoxybenzene 2a (92 mg, 0.549 mmol) in the presence of Zn(OTf)2 (7 mg, 0.018 mmol) and
Sc(OTf)3 (9 mg, 0.018 mmol) at 25 °C for 1 h to afford 3j (157 mg, 0.356 mmol) as a white solid in
97% yield: mp 100–102 °C; Rf 0.42 (25% ethyl acetate in petroleum ether); IR ν
max (KBr, cmꢀ1) 3286,
3058, 2924, 2853, 1609, 1590, 1494, 1451, 1407, 1368, 1325, 1290, 1222, 1205, 1184, 1164, 1122,
1094, 1063, 1038, 949, 928, 911, 861, 841, 808, 785, 749, 729; 1H NMR (400 MHz, CDCl3)
δ
2.43 (s,
3H), 3.61 (s, 6H), 3.64 3.76 (m, 2H), 3.79 (s, 3H), 4.37 (dd, J = 6.8, 4.9 Hz, 1H), 4.66 (dd, J = 9.3, 7.3
Hz, 1H), 6.05 (s, 2H), 7.09 7.20 (m, 5H), 7.26 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H); 13C NMR
(125 MHz, CDCl3)
δ 21.6, 39.7, 45.3, 55.4, 55.6, 91.1, 108.9, 126.1, 127.2, 127.8, 128.1, 129.6, 137.1,
141.9, 143.0, 159.4, 160.5; HRMS (ESI) calcd for C24H27NO5S, (M + H)+ 442.1688, found 442.1689.
25
For (R)ꢀ3j: optical rotation [
α]
= +16.3 (c 0.256, CHCl3) for a 83% ee sample, enantiomeric excess
D
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was determined by chiral HPLC analysis (Chiralcel ODꢀH column), hexane–isopropanol 90:10, flow
1
2
3
rate = 1.0 mL/min; tR (1) = 29.27 min (minor), tR (2) = 34.56 min (major).
4
5
6
7
8
N-(2-(4-Chlorophenyl)-2-(2,4,6-trimethoxyphenyl)ethyl)-4-methylbenzenesulfonamide (3k).5b,i The
general method described above was followed when 1i (100 mg, 0.325 mmol) was reacted with 1,3,5ꢀ
trimethoxybenzene 2a (82 mg, 0.488 mmol) in the presence of Zn(OTf)2 (6 mg, 0.016 mmol) and
Sc(OTf)3 (8 mg, 0.016 mmol) at 25 °C for 1 h to afford 3k (139 mg, 0.292 mmol) as a white solid in
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10
11
12
13
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23
24
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27
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
90% yield: mp 120–122 °C; Rf 0.31 (25% ethyl acetate in petroleum ether); IR ν
max (KBr, cmꢀ1) 3256,
2946, 2871, 2845, 1592, 1492, 1467, 1418, 1327, 1304, 1287, 1222, 1208, 1180, 1157, 1119, 1091,
1
1070, 1038, 1013, 953, 910, 840, 814, 772, 751; H NMR (400 MHz, CDCl3)
δ 2.43 (s, 3H), 3.62 (s,
6H), 3.64 3.69 (m, 2H), 3.79 (s, 3H), 4.35 (dd, J = 6.8, 4.9 Hz, 1H), 4.62 (dd, J = 8.3, 7.8 Hz, 1H),
6.05 (s, 2H), 7.06 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.3
13
Hz, 2H); C NMR (125 MHz, CDCl3)
δ 21.6, 39.2, 45.2, 55.4, 55.6, 91.1, 108.5, 127.2, 128.2, 129.2,
129.6, 131.8, 137.1, 140.5, 143.1, 159.2, 160.6; HRMS (ESI) calcd for C24H26ClNO5S, (M + H)+
476.1298, found 476.1292.
N-(2-(4-Bromophenyl)-2-(2,4,6-trimethoxyphenyl)ethyl)-4-methylbenzenesulfonamide (3l). The
general method described above was followed when 1j (100 mg, 0.284 mmol) was reacted with 1,3,5ꢀ
trimethoxy benzene 2a (72 mg, 0.426 mmol) in the presence of Zn(OTf)2 (5 mg, 0.014 mmol) and
Sc(OTf)3 (7 mg, 0.014 mmol) at 25 °C for 1 h to afford 3l (136 mg, 0.261 mmol) as a white solid in
92% yield: mp 140–142 °C; Rf 0.31 (25% ethyl acetate in petroleum ether); IR ν
max (KBr, cmꢀ1) 3344,
3255, 2946, 2842, 1606, 1488, 1455, 1417, 1325, 1305, 1290, 1220, 1207, 1185, 1162, 1121, 1094,
1
1070, 1037, 1009, 952, 901, 879, 838, 814, 767, 730, 707, 669, 627; H NMR (400 MHz, CDCl3)
δ
2.43 (s, 3H), 3.62 (s, 6H), 3.63 3.68 (m, 2H), 3.79 (s, 3H), 4.35 (dd, J = 6.4, 5.4 Hz, 1H), 4.60 (dd, J =
8.3, 7.8 Hz, 1H), 6.04 (s, 2H), 7.00 (d, J = 8.3 Hz, 2H), 7.25 7.30 (m, 5H), 7.64 (d, J = 8.3 Hz, 2H);
13C NMR (125 MHz, CDCl3)
δ
21.6, 39.3, 45.1, 55.4, 55.6, 91.1, 108.4, 119.9, 127.2, 129.6 (2C),
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131.1, 137.0, 141.0, 143.1, 159.2, 160.6; HRMS (ESI) calcd for C24H26BrNO5S, (M + H)+ 520.0793,
found 520.0793.
1
2
3
4
5
6
7
8
4-tert-Butyl-N-(2-phenyl-2-(2,4,6-trimethoxyphenyl)ethyl)benzenesulfonamide (3m). The general
method described above was followed when 1k (100 mg, 0.317 mmol) was reacted with 1,3,5ꢀ
trimethoxybenzene 2a (80 mg, 0.476 mmol) in the presence of Zn(OTf)2 (6 mg, 0.016 mmol) and
Sc(OTf)3 (8 mg, 0.016 mmol) at 25 °C for 1 h to afford 3m (138 mg, 0.285 mmol) as a white solid in
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90% yield: mp 112–114 °C; Rf 0.31 (25% ethyl acetate in petroleum ether); IR ν
max (KBr, cmꢀ1) 3292,
2960, 2926, 2854, 1611, 1591, 1494, 1454, 1405, 1365, 1332, 1267, 1222, 1205, 1166, 1154, 1125,
1088, 1063, 1039, 950, 880, 831, 812, 753, 725, 702; 1H NMR (400 MHz, CDCl3)
δ
1.35 (s, 9H), 3.60
(s, 6H), 3.62 3.77 (m, 2H), 3.80 (s, 3H), 4.36 (dd, J = 6.6, 4.7 Hz, 1H), 4.71 (dd, J = 9.3, 6.8 Hz, 1H),
13
6.06 (s, 2H), 7.11 7.20 (m, 5H), 7.47 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H); C NMR (125
MHz, CDCl3)
δ 31.2, 35.2, 39.7, 45.3, 55.4, 55.6, 91.2, 108.9, 126.0, 126.1, 127.1, 127.8, 128.1, 136.9,
141.9, 156.1, 159.4, 160.5; HRMS (ESI) calcd for C27H33NO5S, (M + H)+484.2158, found 484.2161.
25
For (R)ꢀ3m: optical rotation [
α]
D = +10.0 (c 0.178, CHCl3) for a 53% ee sample, enantiomeric excess
was determined by chiral HPLC analysis (Chiralcel ODꢀH column), hexane–isopropanol 90:10, flow
rate = 1.0 mL/min; tR (1) = 24.88 min (minor), tR (2) = 29.60 min (major).
4-tert-Butyl-N-(2-phenyl-2-(thiophen-2-yl)ethyl)benzenesulfonamide (3n). The general method
described above was followed when 1k (100 mg, 0.317 mmol) was reacted with thiophene 2b (38 ꢁL,
0.476 mmol) in the presence of Zn(OTf)2 (6 mg, 0.016 mmol) and Sc(OTf)3 (8 mg, 0.016 mmol) at 25
°C for 1 h to afford 3n (95 mg, 0.238 mmol) as a white solid in 75% yield as regioisomeric mixture
(4:1): Rf 0.38 (15% ethyl acetate in petroleum ether); IR
ν
max (KBr, cmꢀ1) 3418, 3273, 2963, 2926, 1596,
1
1494, 1450, 1422, 1366, 1329, 1292, 1268, 1199, 1164, 1113, 1087, 833, 752, 700, 644, 629; H NMR
(500 MHz, CDCl3) (major regioisomer)
δ 1.36 (s, 9H), 3.48 3.63 (m, 2H), 4.29 (t, J = 7.8 Hz, 1H),
4.49 (t, J = 6.4 Hz, 1H), 6.79 (d, J = 3.4 Hz, 1H), 6.91 6.93 (m, 1H), 7.13 7.32 (m, 6H), 7.52 (d, J =
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8.8 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H); C NMR (125 MHz, CDCl3)
δ 31.2, 35.3, 46.6, 48.6, 124.8,
1
2
3
4
5
125.1, 126.3, 127.0 (2C), 127.7, 127.9, 129.1, 136.8, 140.4, 144.2, 156.7; HRMS (ESI) calcd for
C22H25NO2S2, (M + H)+ 400.1405, found 400.1406.
6
7
8
9
4-tert-Butyl-N-(2-phenyl-2-(2,3,4-trimethoxyphenyl)ethyl)benzenesulfonamide (3o). The general
method described above was followed when 1k (100 mg, 0.317 mmol) was reacted with 1,2,3ꢀ
trimethoxybenzene 2d (80 mg, 0.476 mmol) in the presence of Zn(OTf)2 (6 mg, 0.016 mmol) and
Sc(OTf)3 (8 mg, 0.016 mmol) at 25 °C for 1 h to afford 3o (110 mg, 0.227 mmol) as a white solid in
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72% yield: mp 90–92 °C; Rf 0.44 (25% ethyl acetate in petroleum ether); IR ν
max (KBr, cmꢀ1) 3286,
3062, 3028, 2963, 2872, 1737, 1598, 1495, 1465, 1417, 1364, 1330, 1275, 1199, 1164, 1098, 1015, 884,
1
832, 797, 752, 730, 700; H NMR (400 MHz, CDCl3)
δ 1.36 (s, 9H), 3.49 3.54 (m, 2H), 3.60 (s, 3H),
3.83 (s, 6H), 4.36 (t, J = 7.8 Hz, 1H), 4.42 (t, J = 6.1 Hz, 1H), 6.58 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 8.8
Hz, 1H), 7.08 7.10 (m, 2H), 7.19 7.27 (m, 3H), 7.50 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H); 13C
NMR (125 MHz, CDCl3)
δ 31.2, 35.2, 43.8, 46.8, 56.0, 60.8, 60.9, 107.2, 122.0, 126.2, 126.9, 127.0,
127.1, 128.1, 128.8, 136.8, 141.3, 142.6, 152.0, 152.9, 156.5; HRMS (ESI) calcd for C27H33NO5S, (M +
H)+ 484.2158, found 484.2156.
4-Methyl-N-((1S,2S)-1-phenyl-1-(2,4,6-trimethoxyphenyl)pentan-2-yl)benzenesulfonamide
(3p).
The general method described above was followed when (2S,3S)ꢀ1l (100 mg, 0.317 mmol) was reacted
with 1,3,5ꢀtrimethoxybenzene 2a (80 mg, 0.476 mmol) in the presence of Zn(OTf)2 (6 mg, 0.016 mmol)
and Sc(OTf)3 (8 mg, 0.016 mmol) at 25 °C for 3 h to afford 3p (144 mg, 0.298 mmol) as a white solid in
25
94% yield: mp 174–176 °C; Rf 0.46 (25% ethyl acetate in petroleum ether); [
CHCl3); IR
α]
= +8.9 (c 0.223,
D
ν
max (KBr, cmꢀ1) 3261, 2951, 2871, 2840, 1607, 1495, 1468, 1455, 1436, 1419, 1378, 1333,
1316, 1287, 1228, 1207, 1158, 1125, 1089, 1060, 1034, 970, 954, 910, 874, 813, 737, 696, 666, 647,
1
634; H NMR (400 MHz, CDCl3)
δ 0.74 (t, J = 7.1 Hz, 3H), 1.19 1.44 (m, 3H) , 1.69 1.76 (m, 1H),
2.41 (s, 3H), 3.71 (s, 6H), 3.74 (s, 3H), 4.35 (d, J = 5.8 Hz, 1H), 4.41 (d, J = 10.2 Hz, 1H), 4.45 4.51
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(m, 1H), 6.01 (s, 2H), 6.97 7.02 (m, 3H), 7.10 7.14 (m, 4H), 7.41 (d, J = 7.8 Hz, 2H); 13C NMR (125
MHz, CDCl3) 14.3, 16.7, 21.6, 35.2, 44.3, 55.3 (2C), 55.7, 91.2, 111.2, 126.0, 127.1, 128.1, 128.7,
1
2
3
4
δ
129.2, 137.5, 141.7, 142.5, 158.5, 159.9; HRMS (ESI) calcd for C27H33NO5S, (M + H)+ 484.2158,
found 484.2154.
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4-Methyl-N-((1S,2S)-1-phenyl-1-(2,4,6-trimethoxyphenyl)pent-4-en-2-yl)benzenesulfonamide (3q).
The general method described above was followed when (2S,3S)ꢀ1m (100 mg, 0.319 mmol) was reacted
with 1,3,5ꢀtrimethoxybenzene 2a (81mg, 0.479 mmol) in the presence of Zn(OTf)2 (6 mg, 0.016 mmol)
and Sc(OTf)3 (8 mg, 0.016 mmol) at 25 °C for 2 h to afford 3q (141 mg, 0.293 mmol) as a white solid in
25
92% yield: mp 156–158 °C; Rf 0.44 (25% ethyl acetate in petroleum ether); [
CHCl3); IR
1262, 1225, 1205, 1155, 1123, 1092, 1060, 1034, 953, 914, 810, 736, 699, 663; H NMR (400 MHz,
CDCl3) 2.10 2.16 (m, 1H), 2.41 (s, 3H), 2.43 2.50 (m, 1H), 3.74 (s, 3H), 3.76 (s, 6H), 4.33 4.36
α
]
= +16.3 (c 0.417,
D
ν
max (KBr, cmꢀ1) 3285, 3063, 3027, 2925, 2852, 1736, 1607, 1494, 1455, 1438, 1419, 1331,
1
δ
(m, 2H), 4.64 4.67 (m, 1H), 4.84 (d, J = 16.6 Hz, 1H), 5.06 (d, J = 10.2 Hz, 1H), 5.67 5.78 (m, 1H),
13
6.03 (s, 2H), 6.97 7.05 (m, 3H), 7.11 7.16 (m, 4H), 7.42 (d, J = 8.3 Hz, 2H); C NMR (125 MHz,
CDCl3)
δ 21.6, 37.3, 44.3, 54.5, 55.3, 55.7, 91.1, 110.1, 119.4, 126.0, 127.2, 128.1, 128.7, 129.3, 133.0,
137.6, 141.7, 142.6, 158.6, 160.1; HRMS (ESI) calcd for C27H31NO5S, (M + H)+ 482.2001, found
482.2007.
N-(3-(tert-Butyldimethylsilyloxy)-1-phenyl-1-(2,4,6-trimethoxyphenyl)propan-2-yl)-4-
methylbenzenesulfonamide (3r). The general method described above was followed when 1n (100 mg,
0.239 mmol) was reacted with 1,3,5ꢀtrimethoxybenzene 2a (60 mg, 0.359 mmol) in the presence of
Zn(OTf)2 (4 mg, 0.012 mmol) and Sc(OTf)3 (6 mg, 0.012 mmol) at 25 °C for 3 h to afford 3r (133 mg,
0.227 mmol) as a white solid in 95% yield: mp 160–162 °C; Rf 0.37 (15% ethyl acetate in petroleum
ether); IR
ν
max (KBr, cmꢀ1) 3486, 3281, 2954, 2927, 2855, 1602, 1495, 1466, 1417, 1361, 1324, 1254,
1
1219, 1203, 1185, 1158, 1120, 1096, 1081, 1064, 990, 953, 912, 837, 810, 782, 741, 699, 683, 665; H
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NMR (400 MHz, CDCl3)
δ
ꢀ0.22 (s, 3H), ꢀ0.19 (s, 3H), 0.82 (s, 9H), 2.38 (s, 3H), 3.40 (d, J = 9.8 Hz,
1
2
3
1H), 3.60 (d, J = 9.8 Hz, 1H), 3.74 (s, 9H), 4.60 4.69 (m, 2H), 4.85 (d, J = 8.3 Hz, 1H), 6.01 (s, 2H),
4
5
6
13
7.02 7.03 (m, 3H), 7.08 (d, J = 8.3 Hz, 2H), 7.26 7.28 (m, 2H), 7.42 (d, J = 8.3 Hz, 2H); C NMR
7
8
(125 MHz, CDCl3)
δ ꢀ6.0, ꢀ5.9, 18.3, 21.5, 25.8, 42.4, 55.3, 55.5, 56.4, 63.0, 90.9, 110.9, 125.7, 127.0,
9
127.9, 128.9, 129.4, 138.2, 142.5 (2C), 158.7, 159.9; HRMS (ESI) calcd for C31H43NO6SSi, (M + H)+
586.2659, found 586.2656.
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N-(3-(tert-Butyldimethylsilyloxy)-1-(1-methyl-1H-indol-3-yl)-1-phenylpropan-2-yl)-4-
methylbenzenesulfonamide (3s). The general method described above was followed when 1n (100 mg,
0.239 mmol) was reacted with 1ꢀ methylindole 2c (45 ꢁL, 0.359 mmol) ) in the presence of Zn(OTf)2 (4
mg, 0.012 mmol) and Sc(OTf)3 (6 mg, 0.012 mmol) at 25 °C for 3.5 h to afford 3s (100 mg, 0.182
mmol) as a thick liquid in 76% yield: Rf 0.45 (15% ethyl acetate in petroleum ether); IR ν
max (neat, cmꢀ
1) 3294, 2952, 2927, 2855, 1599, 1470, 1410, 1375, 1330, 1252, 1184, 1160, 1093, 1015, 984, 940, 836,
1
813, 779, 739, 703, 667; H NMR (400 MHz, CDCl3)
δ ꢀ0.12 (s, 3H), ꢀ0.11 (s, 3H), 0.86 (s, 9H), 2.40
(s, 3H), 3.40 (dd, J = 10.0, 6.3 Hz, 1H), 3.60 (dd, J = 10.0, 3.0 Hz, 1H), 3.70 (s, 3H), 4.08 4.16 (m,
1H), 4.56 (d, J = 9.3 Hz, 1H), 4.62 (d, J = 7.3 Hz, 1H), 6.95 7.00 (m, 1H), 7.02 (s, 1H), 7.14 7.35 (m,
13
12H), 7.53 (d, J = 8.3 Hz, 2H); C NMR (125 MHz, CDCl3)
δ ꢀ5.6, ꢀ5.5, 18.3, 21.6, 26.0, 32.8, 42.6,
57.8, 62.6, 109.2, 115.0, 118.9, 119.4, 121.7, 126.6, 126.8, 127.1, 127.5, 128.5, 129.1, 129.6, 136.9,
138.3, 140.7, 143.1; HRMS (ESI) calcd for C31H40N2O3SSi, (M + H)+ 549.2607, found 549.2609.
Acknowledgment: MKG is grateful to IITꢀKanpur and DST, India. DPT thanks UGC and IIT
Kanpur, India for a research fellowship and NJ thanks IITꢀKanpur for financial support.
Supporting Information Available: NMR spectra for all the new compounds, and HPLC
chromatograms. This material is available free of charge via the Internet at http://pubs.acs.org.
References
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X.; Huang, Z.ꢀT.; Wang, M.ꢀX. J. Org. Chem. 2008, 73, 1979. (d) Wang, J.ꢀY.; Hu, Y.; Wang, D.ꢀX.;
Pan, J.; Huang Z.ꢀT.; Wang, M.ꢀX. Chem. Commun. 2009, 422. (e) De Rycke, N.; David, O.; Couty, F.
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Komatsu, M. Org. Biomol. Chem. 2009, 7, 641. (f) Vicario, J. L.; Badía, D.; Carrillo, L. J. Org. Chem.
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2001, 66, 5801. (g) Moss, T. A.; Fenwick, D. R.; Dixon, D. J. J. Am. Chem. Soc. 2008, 130, 10076. (h)
Paixão, M. W.; Nielsen, M.; Jacobsen, C. B., Jørgensen, K. A. Org. Biomol. Chem. 2008, 6, 3467.
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