A Domino Aza-Prins/Friedel-Crafts Reaction for the Synthesis of Benzomorphans

Article abstract of DOI:10.1055/s-0036-1588071

A new domino sequence involving an aza-Prins cyclization and a Friedel-Crafts reaction is reported. The starting materials are N-tosylimines prepared in situ from N-tosylated homoallylamines and derivatives of phenylacetaldehyde. The domino reactions are

Full text of DOI:10.1055/s-0036-1588071

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–K
paper
A
J. Ploog et al.
Paper
Synthesis
A Domino Aza-Prins/Friedel–Crafts Reaction for the Synthesis of
Benzomorphans
Jasper Ploog
Tos
N
H
O
NHTos
Juliane Pongs
Stefan Weber
Wolfgang Maison*
BF3•OEt2
DCE, reflux
H
R2
R1
R3
R1
R3
R2
University of Hamburg, Department of Chemistry,
Pharmaceutical and Medicinal Chemistry,
Bundesstraße 45, 20146 Hamburg, Germany
maison@chemie.uni-hamburg.de
Received: 11.08.2016
Accepted: 18.08.2016
Published online: 14.09.2016
DOI: 10.1055/s-0036-1588071; Art ID: ss-2016-e0566-op
pain. Examples are pentazocine, phenazocine, metazocine
and eptazocine, which are all synthetic morphine ana-
logues. In addition, closely related morphan scaffolds can
be found in natural products such as strychnochromine and
aspernomine.2 Benzomorphans are therefore interesting
targets and several syntheses have been published.2,3
Abstract A new domino sequence involving an aza-Prins cyclization
and a Friedel–Crafts reaction is reported. The starting materials are N-
tosylimines prepared in situ from N-tosylated homoallylamines and de-
rivatives of phenylacetaldehyde. The domino reactions are mediated by
Brønsted and Lewis acids and give benzoannelated azabicyclononanes.
Many derivatives thereof contain the benzomorphan scaffold and are
thus of pharmaceutical interest as analgesics. The method provides a
one-step access to substituted benzomorphans from readily available
starting materials. The yields are generally good and various substitu-
ents are tolerated.
The Prins reaction is the acid-catalyzed addition of al-
dehydes to alkenes and was developed almost a century
ago.4 It allows the formation of C–C bonds and gives acetals,
diols, and allyl or homoallyl alcohols, depending on the re-
action conditions. Besides aldehydes, other carbonyl deriv-
atives can be used such as ketones, acetals and orthoesters.
Aza-Prins reactions involve the use of imines, iminium ions
or aminals.5 If the alkene (or alkyne) moiety is appended to
the carbonyl compound or imine, Prins-type cyclizations
are the result.6 These cyclizations have found numerous ap-
plications in organic synthesis and are particularly valuable
for natural product synthesis.5,7 The mechanism of the Prins
reaction involves a cationic intermediate, which may un-
dergo rearrangement, deprotonation or can be trapped
with a nucleophile. Prins-type domino sequences are there-
fore attractive for the synthesis of functionalized heterocy-
clic systems such as tetrahydropyrans.4,5,7,8 Examples of
these domino reactions are Prins/Friedel–Crafts sequences,
which have been described as intermolecular9 and intra-
molecular variants.5 In particular, the Reddy group has re-
ported a number of valuable intramolecular Prins/Friedel–
Crafts protocols for the synthesis of various heterocyclic
scaffolds.8c–l,10 We have recently reported a sequence of
Prins cyclization and intramolecular Friedel–Crafts reaction
with aryl acetones 1 and isoprenol derivatives 2 (Scheme
1).11 The first step of this sequence is a silyl-modified
Sakurai-type reaction that was developed by Marko for the
synthesis of dihydropyrans.12 A subsequent Friedel–Crafts
conversion gives benzoannelated oxabicyclo[3.3.1]nonanes
3 that cannot easily be prepared by other methods. In this
Key words arylation, cyclization, imines, aza-Prins reaction, Friedel–
Crafts reaction, morphine, pentazocine, domino reaction
The opium alkaloid (–)-morphine (Figure 1) remains
one of the most important narcotic analgesics, despite its
serious side effects including respiratory depression, low
blood pressure, anxiety, addiction and obstipation.1
OH
Me
N
HN
N
H
H
H
O
H
OH
(–)-morphine
OH
benzomorphan
(–)-pentazocine
Figure 1 The drugs morphine and pentazocine containing the benzo-
morphan scaffold
A number of structural analogues have been developed
with balanced pharmaceutical profiles. Many benzomor-
phan derivatives are partial agonists at opioid receptors and
are used as opioid analgesics to treat moderate and severe
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

B
J. Ploog et al.
Paper
Synthesis
paper, we report the extension of our method to an aza-
Prins version to give benzomorphans 6 in a one-step proto-
col starting from readily available aromatic aldehydes 4 and
tosylated homoallylamines 5.
newly generated double bond.15 In a first attempt toward
the synthesis of benzomorphans 6, according to Scheme 2,
we treated N-tosyl homoallylamine 5a with phenylacetone
(1a) and TMSOTf (20 mol%) in CH2Cl2 at reflux. These condi-
tions worked fine in our previous syntheses of oxabicyclo-
nonanes 3. However, no conversion of the starting materials
was observed in the corresponding aza-Prins variant. In-
creased amounts of Lewis acid and elevated temperatures
did not improve the reaction. The carbonyl compound was
therefore changed to the more reactive phenylacetaldehyde
(4a). In this case, the target benzomorphan 6a was obtained
in 47% yield along with tetrahydropyridine 9a, which was
obtained as a mixture of two regioisomers.
A screening of several Lewis and Brønsted acids and dif-
ferent solvents was performed to improve the yield of the
domino product 6a. Brønsted acids such as PTSA, phos-
phonoacetic acid and trifluoroacetic acid were found to be
less effective for this domino reaction (Table 1, entries 2–4)
and only CF3SO3H gave a substantial amount of the desired
product (Table 1, entry 23). Among different Lewis acids
such as Sc(OTf)3, CuCl, SiCl4, AlClEt2, AlCl3, InCl3 and TiCl4
a) Our previous work:
O
O
TMSO
TMSOTf
R1
R1
1
2
3
b) This work:
Tos
H
H
O
N
R2
R1
R3
TosHN
R3
BF3•OEt2
R1
R2
4
5
6
Scheme 1 Lewis acid mediated domino Prins/Friedel–Crafts reactions:
(a) synthesis of oxabicyclo[3.3.1]nonanes 3, and (b) the aza-Prins vari-
ant giving benzomorphans 6
In analogy to our previous route to oxabicycloalkanes 3,
it was anticipated that N-tosylated homoallylamines 5a
would undergo an acid-mediated reaction with carbonyl
compounds such as 1 or 4 to give the corresponding imini-
um species 7 (Scheme 2). These should cyclize in an aza-
Prins conversion to give heterocyclic carbocations of type 8,
which would then form benzomorphans 6 via intramolecu-
lar Friedel–Crafts alkylation. Alternatively, intermediate
cations 8 could eliminate a proton to give tetrahydropyri-
dines 9a. Examples of aza-Prins cyclizations are relatively
rare.13 However, tosylated iminium species similar to 7 have
been used for Prins cyclizations before to give tetrahydro-
pyridines (similar to 9a) as the major products.14 In most
cases, the starting materials contained silyl groups as leav-
ing groups or aromatic substituents in conjugation to the
Tos
N
H
O
TosHN
acid
4a
Tos
5a
7
N
Tos
N
9a
Tos
H
N
8
Scheme 3 Scope of the aza-Prins/Friedel–Crafts sequence. a Reaction
performed following procedure A. b Reaction performed following pro-
cedure B. c Ratio determined by 1H NMR spectroscopy after chromatog-
raphy. d Only the α-isomer is shown.
6a
Scheme 2 Acid-mediated aza-Prins reactions giving tetrahydropyri-
dines 9a and benzomorphans 6a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

C
J. Ploog et al.
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Synthesis
only BF3·OEt2 and TMSOTf led to good conversions of the
starting materials and gave the desired product 6a in good
yields. The cleanest conversions into benzomorphan 6a
were obtained with either BF3·OEt2 (Table 1, entries 20 and
22) or TMSOTf (Table 1, entry 12) in DCE at elevated tem-
perature or with microwave heating (Table 1, entry 21).
Similar results were obtained with CF3SO3H (Table 1, entry
23). The best yield was obtained by the sequential addition
of TMSOTf and CF3SO3H in a one-pot procedure in CH2Cl2 at
room temperature (Table 1, entry 24). At lower tempera-
tures (Table 1, entry 13) and with SiCl4 (Table 1, entry 7),
PTSA (Table 1, entry 2), TFA (Table 1, entry 4) or InCl3 (Table
1, entry 10), the aza-Prins intermediates were the major
products of the reaction and tetrahydropyridine 9a was ob-
tained in good yields. This parallels our observations in re-
cent Prins/Friedel–Crafts conversions into oxabicyclo-
nonanes 3.11
The scope of the reaction is quite general and a number
of different aromatic aldehydes and homoallylamines can
be converted into the corresponding benzomorphans 6. A
summary of the products is presented in Scheme 3 along
with the X-ray crystal structure of 6c as a representative
Table 1 Optimization of the Reaction Conditions
Tos
Tos
H
acid
solvent
N
N
H
O
TosHN
+
4a
5a
9a
6a
Entry
Acid
Solvent
Temp (°C)
Time (h)
Yield of 9a (%)
Yield of 6a (%)
1
2
TMSOTf (20 mol%)
PTSA (40 mol%)
CH2Cl2
DCE
40
85
85
85
85
85
85
85
85
85
85
85
25
25
40
60
40
80
110
85
85
85
25
25
21
20
20
20
20
20
22
20
18
18
20
20
20
20
20
20
20
2
46a
76a
–
47a
13a
3
phosphonoacetic acid (40 mol%)
TFA (40 mol%)
DCE
–
4
DCE
73a
63a
–
10a
5
ScOTf3 (40 mol%)
CuCl (40 mol%)
DCE
5a
6
DCE
–
7
SiCl4 (40 mol%)
DCE
83a
–
2a
8
AlClEt2 (40 mol%)
AlCl3 (40 mol%)
DCE
–
9
DCE
38a
79a
52a
–
3a
10
11
12
13
14
15
16
17
18
19
20
21c
22d
23
24e
InCl3 (40 mol%)
DCE
–
TiCl4 (40 mol%)
DCE
39a
TMSOTf (40 mol%)
TMSOTf (10 mol%)
BF3·OEt2 (1.2 equiv)
BF3·OEt2 (1.2 equiv)
BF3·OEt2 (1.2 equiv)
BF3·OEt2 (1.2 equiv)
BF3·OEt2 (1.2 equiv)
BF3·OEt2 (1.2 equiv)
BF3·OEt2 (40 mol%)
BF3·OEt2 (40 mol%)
BF3·OEt2 (1.2 equiv)
CF3SO3H (1.2 equiv)
DCE
90a (77b)
–
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DCE
100a (95b)
56a
34a
4a
22a
44a
72a
41a
18a
–
33a
benzene
toluene
DCE
53a (26b)
69a (24b)
90a (54b)
71a (76b)
100a (78b)
95a (76b)
92a (90b)
2
22
1
6a
DCE
29a
–
DCE
19
20
20
CH2Cl2
CH2Cl2
3a
(1) TMSOTf (10 mol%)
(2) CF3SO3H (1.2 equiv)
7a
a Yield as measured by GC–MS of the crude product.
b Yield of isolated product after chromatography.
c Reaction in a microwave system (20 W, 85 °C).
d Aldehyde 4a (2.5 equiv) was used instead of 1.2 equivalents.
e (1) TMSOTf, 3 h; (2) CF3SO3H, 19 h, r.t.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

D
J. Ploog et al.
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Synthesis
example. In a standard procedure, aromatic aldehyde 4 and
N-tosyl homoallylamine 5 were treated with BF3·OEt2 (40
mol%) in DCE at 85 °C. Unsubstituted and electron-rich aro-
matic aldehydes gave the expected benzomorphans 6a–c in
good yields. If the aromatic system was substituted with ac-
ceptors, Friedel–Crafts conversions under the standard con-
ditions (BF3·OEt2, 85 °C) were slowed and the benzomor-
phans such as 6f and 6g were obtained in lower yields along
with significant amounts of the intermediate tetrahydropy-
ridines 9. Increasing the reaction temperature did not im-
prove the yield of benzomorphans 6 in these cases, but led
to larger amounts of side products and thus to complex
product mixtures. Particularly for acceptor-substituted and
thus less reactive aromatic systems, the one-pot procedure
with sequential addition of TMSOTf followed by the addi-
tion of CF3SO3H in CH2Cl2 at room temperature turned out
to be the best method. Using this procedure, benzomor-
phan 6g with a bromo substituent was obtained in an im-
proved 46% yield compared to 35% for the standard proce-
dure with BF3·OEt2. The one-pot method also gave a higher
diastereoselectivity for the methyl-substituted benzomor-
phan 6i (α/β = 4:1, instead of 1:1).
dicated in Figure 2). The formation is complete in about 60
minutes with almost complete conversion of the starting
materials. After addition of CF3SO3H (after 65 min) the in-
tramolecular Friedel–Crafts conversion led to the formation
of the desired benzomorphan 6a. Full conversion was ob-
served after 24 hours and the resulting NMR spectrum of
the reaction mixture showed the characteristic signals of
benzomorphan 6a almost exclusively and was remarkably
clean.
The conversion of the α-disubstituted aldehyde 10
(Scheme 5) did not give the corresponding tetrahydropyri-
dine 11 or benzomorphan 12.
Tos
Tos
H
N
N
BF3•OEt2
DCE, 85 °C
H
O
TosHN
+
10
5a
11
12
Scheme 5 Attempted conversion of aldehyde 10
As mentioned before, tetrahydropyridines such as 9 are
obtained as mixtures of regioisomers in most cases. How-
ever, if substituents direct the elimination reaction, isomer-
ically pure tetrahydropyridines such as 9b and 9c are ob-
tained under thermodynamic control (Scheme 4).
This unexpected finding is due to a competing acid-cat-
alyzed rearrangement of 10 into phenyl isopropyl ketone,
which is too unreactive to form an intermediate iminium
species with 5a.16 We have applied the aza-Prins/Friedel–
Crafts sequence to the synthesis of the analgesic pentazo-
cine as depicted in Scheme 6.
TMSOTf or
BF3•OEt2
DCM
H
O
Tos
PPh3EtBr
KOt-Bu, THF
0 °C to rt, 18 h
N
TosNH2, Al2O3
CH2Cl2, 45 °C 4 d
TosHN
TosHN
TosHN
R2
R1
R2
O
65%
89%
O
R1
13
14
5b
4
5
9
TMSOTf (10 mol%)
3 h, then
CF3SO3H (1.2 equiv)
CH2Cl2, rt, 21 h
H
Tos
Tos
Tos
N
N
N
O
MeO
4b
49% α : β = 4.3 : 1
Tos
H
N
H
N
9b 64%[b]
9c 38%[c]
9a 95%[a]
OMe
3 steps
Scheme 4 Formation of tetrahydropyridines 9.a TMSOTf (0.1 equiv),
r.t. b BF3·OEt2 (40 mol%), r.t. c BF3·OEt2 (40 mol%), 40 °C.
OH
OMe
6k[a]
pentazocine
Scheme 6 Formal synthesis of pentazocine in six steps via key interme-
diate 6k. a Only the α-isomer is shown.
Prins reactions are often limited by the formation of
complex product mixtures. As mentioned before, this is a
consequence of various possible reaction pathways for the
intermediate carbocation. The reported aza-Prins/Friedel–
Crafts sequence, in contrast, is a quite clean reaction. We
have monitored the reaction by 1H NMR spectroscopy and a
collection of the resulting spectra are depicted in Figure 2.
The intermediate tetrahydropyrans 9aa and 9ab were
formed rapidly after addition of the Lewis acid (TMSOTf) in
a typical aza-Prins reaction. An additional isomer with an
exocyclic double bond is formed in minor amounts (not in-
A synthesis of pentazocine involving a Prins cyclization
has been reported by She and co-workers in 13 overall
steps.3d Our approach started from 3-buten-2-one (13),
which was transformed into α-aminoketone 14. Next, a
Wittig olefination gave homoallylamine 5b as a precursor.
The subsequent aza-Prins/Friedel–Crafts sequence was per-
formed using the one-pot procedure, as outlined before to
give benzomorphan 6k in 49% yield and a ratio of 4.3:1 in
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

E
J. Ploog et al.
Paper
Synthesis
Figure 2 Monitoring of the formation of benzomorphan 6a via 1H NMR spectroscopy. The reaction was performed in CDCl3 and spectra (600 MHz)
were taken regularly from the crude reaction mixture. TMSOTf (0.1 equiv) was added after 5 minutes and CF3SO3H (1.2 equiv) after 65 minutes. Repre-
sentative signals only have been highlighted with colored dots.
favor of the desired α-diastereoisomer.3l The stereochemis-
try of 6k was determined by 1D NMR NOE experiments and
the spectroscopic data are in agreement with the reported
data in the literature.3d Compound 6k is a known interme-
diate for the synthesis of pentazocine and can be converted
into the target compound in three steps according to litera-
ture protocols by removal of the tosyl group with sodium
and naphthalene17 followed by prenylation3d and final de-
methylation to give pentazocine.3m We have thus achieved
the formal synthesis of pentazocine in only six steps. To the
best of our knowledge, this is the shortest approach report-
ed so far.
The conversion of tosylamine 5c with aldehyde 4a
(Scheme 7) did not give the corresponding benzomorphan.
Instead, the formation of the hexahydro-1H-benz[f]indole
17 was observed in a good yield of 79%. Hexahydro-1H-
benz[f]indoles such as 17 are known 5-HT1A receptor antag-
onists and the conversion might thus be of special pharma-
ceutical interest.18 The regioselective cyclization to give 17
can be rationalized by the formation of a well-stabilized
benzylic carbocation intermediate 16 after Prins cyclization
to a pyrrolidine system. This intermediate carbocation is
then cyclized via a Friedel–Crafts reaction to give hexahy-
dro-1H-benz[f]indole 17.
In conclusion, we have reported a new acid-mediated
domino aza-Prins/Friedel–Crafts sequence. The method al-
lows the conversion of tosylated homoallylamines and aro-
matic aldehydes to give benzomorphan derivatives of phar-
maceutical relevance. Versatility is a major advantage of our
approach because both starting materials are readily avail-
able allowing the synthesis of benzomorphans with differ-
ent substitution patterns in only one step. We have applied
the method to the synthesis of pentazocine and achieved
the shortest formal synthesis with only six steps starting
from 3-buten-2-one. The stability of the intermediate car-
bocation determines the regioselectivity of the reaction and
stabilizing substituents, e.g., phenyl, allow the synthesis of
hexahydro-1H-benz[f]indoles such as 17, which have phar-
maceutical relevance as 5-HT1A receptor antagonists.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

F
J. Ploog et al.
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Synthesis
Scheme 7 Unexpected formation of hexahydro-1H-benz[f]indole 17
(3 × 100 mL). The combined organic layers were dried over Na2SO4.
Column chromatography over silica gel (pentane/EtOAc, 6:1) gave 4-
methyl-N-(3-methylpent-3-en-1-yl)benzenesulfonamide (5b) (E:Z =
2.5:1) as a colorless oil (4.48 g, 17.7 mmol, 89%).
All reactions were carried out under an N2 atmosphere. For the syn-
thesis of the starting materials, see the supporting information. Other
chemicals were obtained from commercial sources, and were used
without further purification. Yields refer to those of isolated com-
pounds. Flash column chromatography was performed on Macherey-
Nagel silica gel (40–60 μm). Melting points were obtained using a
Büchi M-560 apparatus. IR spectra were obtained with a JASCO FT/IR-
4100 spectrometer. Measurements were conducted on a diamond
ATR unit. NMR spectra were recorded on Bruker AVANCE III HD 600
MHz, Bruker AVANCE (I, II and III) 400 MHz or Bruker Fourier 300
MHz spectrometers. 1H NMR chemical shifts are referenced to residu-
al non-deuterated solvent (CDCl3, δH = 7.26). 13C NMR chemical shifts
are referenced to the solvent signal (CDCl3, δC = 77.16). Coupling con-
stants (J) are given in Hz. Chemical shifts (δ) are reported in ppm and
the signal patterns are indicated as s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), or combinations thereof. The NMR signals
are assigned on the basis of 2D NMR (HH-COSY, HMBC and HSQC) ex-
periments. The relative stereochemistry of the products has been as-
signed on the basis of 1D or 2D NOE experiments. The atom numbers
used for NMR peak assignments do not refer to IUPAC nomenclature
and are available from the structures provided with the NMR spectra
in the supporting information. ESI mass spectra were recorded in pos-
itive mode with an Agilent 6224 ESI-TOF system. Samples were dis-
solved in MeCN/H2O mixtures or pure MeOH. GC–MS analyses were
conducted with an Agilent Technologies GC system 7820A and 5977E
MSD by carrying a split sample with He gas through a 30 m po-
ly(methylphenylsiloxane) capillary column (95% dimethyl/5% diphe-
nyl, 0.25 mm i.d., and 0.25 μm film thickness) ending with an EI
mass-selective detector (70 eV). HPLC separations were performed
with a VWR Hitachi L-2130 pump and a VWR Hitachi UV Detector L-
2400 system.
Rf = 0.25 (pentane/EtOAc, 8:1, phosphomolybdic acid).
IR (ATR): 3278, 2924, 1739, 1598, 1322, 1155, 1092, 814, 660, 547 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.78–7.70 (m, 4 H, 9a-H, 9b-H), 7.34–
7.28 (m, 4 H, 10a-H, 10b-H), 5.41–5.29 (m, 1 H, 6b-H), 5.25–5.14 (m, 1
H, 6a-H), 4.29 (t, 3JH,H = 5.9 Hz, 2 H, 1a-H, 1b-H), 3.00 (td, 3JH,H = 6.8 Hz,
3JH,H = 5.8 Hz, 4 H, 2a-H, 2b-H), 2.43 (s, 6 H, 12a-H, 12b-H), 2.21 (t,
3JH,H = 7.0 Hz, 2 H, 3b-H), 2.09 (tt, 3JH,H = 6.4 Hz, 4JH,H = 1.2 Hz, 2 H, 3a-
H), 1.60–1.50 (m, 9 H, 5b-H, 7a-H, 7b-H), 1.46–1.41 (m, 3 H, 5a-H).
13C NMR (75 MHz, CDCl3): δ = 143.5, 137.0, 131.4, 129.8, 127.3, 123.1,
122.6, 53.6, 40.8, 40.6, 39.0, 31.2, 22.8, 21.7, 15.0, 13.6, 13.5.
HRMS (ESI): m/z [M + Na]+ calcd for C13H19NO2S + Na: 276.1029;
found: 276.1027.
6-Methyl-3-tosyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazo-
cine (6a)
To a mixture of 4-methyl-N-(3-methylbut-3-en-1-yl)benzenesulfon-
amide15c (5a) (120 mg, 0.50 mmol) and phenylacetaldehyde (4a) (72
mg, 0.60 mmol) in anhydrous DCE (3 mL) was added BF3·OEt2 (49 μL,
57 mg, 0.40 mmol). The resulting mixture was stirred in a microwave
at 85 °C for 1 h. Column chromatography (pentane/EtOAc, 13:1 → 9:1)
gave 6-methyl-3-tosyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benz-
azocine (6a) (130 mg, 0.38 mmol, 76%) as a colorless oil.
Mp 103–104 °C; Rf = 0.32 (pentane/EtOAc, 12:1, phosphomolybdic
acid).
IR (ATR): 2933, 1598, 1338, 1158, 1093, 728, 689 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.75–7.69 (m, 2 H, 16-H), 7.34–7.27
(m, 2 H, 17-H), 7.27–7.23 (m, 1 H, 3-H), 7.17–7.12 (m, 1 H, 4-H), 7.09
(td, 3JH,H = 7.4 Hz, 3JH,H = 1.5 Hz, 1 H, 5-H), 6.92 (d, 3JH,H = 7.3 Hz, 1 H, 6-
4-Methyl-N-(3-methylpent-3-en-1-yl)benzenesulfonamide (5b)
EtPPh3Br (7.80 g, 21.0 mmol) in abs THF (80 mL) was cooled to 0 °C
and KOt-Bu (4.60 g, 41.0 mmol) was added. The mixture was stirred
at 0 °C for 30 min. Next, a solution of 4-methyl-N-(3-oxobutyl)ben-
zenesulfonamide (14) (4.82 g, 20.0 mmol) in abs THF (40 mL) was
added dropwise over 30 min. The reaction mixture was stirred for 1 h
at 0 °C and then for 17 h at 25 °C. Sat. aq NH4Cl solution (100 mL) was
added to the solution and the aq layer was extracted with EtOAc
2
3
H), 4.55–4.43 (m, 1 H, 9-H), 3.66 (ddt, JH,H = 13.2 Hz, JH,H = 4.9 Hz,
3JH,H = 1.5 Hz, 1 H, 11-Ha), 3.03 (dd, 2JH,H = 18.3 Hz, 3JH,H = 6.1 Hz, 1 H, 8-
Ha), 2.70–2.59 (m, 2 H, 11-Hb, 8-Hb), 2.44 (s, 3 H, 19-H), 1.78 (dt, 2JH,H
12.7 Hz, JH,H = 2.5 Hz, 1 H, 13-Ha), 1.71–1.59 (m, 2 H, 13-Hb, 12-Ha),
=
2
1.42–1.33 (m, 4 H, 12-Hb, 14-H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

G
J. Ploog et al.
Paper
Synthesis
13C NMR (101 MHz, CDCl3): δ = 143.2 (C18), 142.1 (C2), 138.0 (C15),
135.6 (C7), 129.8 (C17), 128.0 (C6), 127.2 (C16), 126.5 (C5), 126.3
(C4), 124.9 (C3), 48.1 (C9), 40.2 (C12), 39.8 (C11), 38.9 (C13), 34.3
(C8), 32.2 (C1), 27.9 (C14), 21.6 (C19).
HRMS (ESI): m/z [M + H]+ calcd for C20H23NO2S + H: 342.1522; found:
342.1529.
IR (ATR): 2930, 2879, 1736, 1598, 1453, 1338, 1156, 1093, 815, 759,
549 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.71 (d, 3JH,H = 8.3 Hz, 2 H, 17-H), 7.29
3
(d, JH,H = 8.0 Hz, 2 H, 18-H), 7.19–7.11 (m, 2 H, 3-H, 4-H), 7.07 (ddd,
3JH,H = 8.6 Hz, 3JH,H = 6.5 Hz, 4JH,H = 2.2 Hz, 1 H, 5-H), 6.92 (d, 3JH,H = 7.6
Hz, 1 H, 6-H), 4.55–4.47 (m, 1 H, 9-H), 3.64 (ddt, 2JH,H = 13.0 Hz, 3JH,H
=
4.9 Hz, 3JH,H = 1.5 Hz, 1 H, 11-Ha), 3.01 (dd, 2JH,H = 18.2 Hz, 3JH,H = 5.9 Hz,
1 H, 8-Ha), 2.70–2.57 (m, 2 H, 8-Hb, 11-Hb), 2.44 (s, 3 H, 20-H), 2.06
(dq, 2JH,H = 14.8 Hz, 3JH,H = 7.5 Hz, 1 H, 14-Ha), 1.89 (dt, 2JH,H = 12.7 Hz,
3-Tosyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (6b)
Domino Procedure
To a mixture of N-(but-3-en-1-yl)-4-methylbenzenesulfonamide17
(223 mg, 1.00 mmol) and phenylacetaldehyde (4a) (144 mg, 1.20
mmol) in anhydrous DCE (3 mL) was added BF3·OEt2 (148 μL, 170 mg,
1.20 mmol). The resulting mixture was stirred at 85 °C for 5 d. Col-
umn chromatography (pentane/EtOAc, 14:1 → 12:1) gave 3-tosyl-
1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (6b) (120 mg,
0.37 mmol, 37%) as a yellow oil.
2
3
3JH,H = 2.6 Hz, 1 H, 13-Ha), 1.63 (td, JH,H = 12.8 Hz, JH,H = 5.1 Hz, 1 H,
2
12-Hb), 1.58–1.42 (m, 2 H, 13-Hb, 14-Hb), 1.28 (dq, JH,H = 12.9 Hz,
3JH,H = 2.5 Hz, 1 H, 12-Hb), 0.77 (t, 3JH,H = 7.4 Hz, 3 H, 15-H).
13C NMR (101 MHz, CDCl3): δ = 143.2 (C19), 140.0 (C2), 138.1 (C16),
136.6 (C7), 129.8 (C18), 128.3 (C6), 127.2 (C17), 126.4 (C5), 126.1
(C4), 125.3 (C3), 48.2 (C9), 40.2 (C12), 39.8 (C11), 35.9 (C1), 34.8, 34.5
(C13, C14), 32.3 (C8), 21.7 (C20), 7.9 (C15).
HRMS (ESI): m/z [M + H]+ calcd for C21H25NO2S + H: 356.1679; found:
356.1682.
One-Pot Procedure
To a mixture of N-(but-3-en-1-yl)-4-methylbenzenesulfonamide17
(225 mg, 1.00 mmol) and phenylacetaldehyde (4a) (144 mg, 1.20
mmol) in abs CH2Cl2 (3 mL) was added TMSOTf (18 μL, 22 mg, 0.10
mmol). The resulting mixture was stirred at 25 °C for 2 h. Afterwards,
CF3SO3H (105 μL, 180 mg, 1.2 mmol) was added and the mixture was
stirred at 25 °C for a further 36 h. Column chromatography (pen-
tane/EtOAc, 14:1) gave 3-tosyl-1,2,3,4,5,6-hexahydro-2,6-methano-
3-benzazocine (6b) (205 mg, 0.63 mmol, 63%) as a yellow oil.
6-Phenyl-3-tosyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazo-
cine (6d)
Domino Procedure
To a mixture of 4-methyl-N-(3-phenylbut-3-en-1-yl)benzenesulfon-
amide19 (151 mg, 0.50 mmol) and phenylacetaldehyde (4a) (77 mg,
0.60 mmol) in anhydrous DCE (3 mL) was added BF3·OEt2 (25 μL, 28
mg, 0.20 mmol). The resulting mixture was stirred at 85 °C for 24 h.
Column chromatography (pentane/EtOAc, 17:1 → 10:1) gave 6-phe-
nyl-3-tosyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (6d)
(89 mg, 0.22 mmol, 44%) as a yellow oil.
Rf = 0.21 (pentane/EtOAc, 14:1, phosphomolybdic acid).
IR (ATR): 2925, 2868, 1737, 1598, 1493, 1454, 1336, 1304, 1157, 1098,
986, 932, 815, 737, 688 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.76–7.68 (m, 2 H, 15-H), 7.30 (d,
3JH,H = 8.0 Hz, 2 H, 16-H), 7.14–7.07 (m, 2 H, Ar-H), 7.05–7.00 (m, 1 H,
Ar-H), 6.97–6.91 (m, 1 H, Ar-H), 4.52–4.45 (m, 1 H, 9-H), 3.63 (ddt,
One-Pot Procedure
To a mixture of 4-methyl-N-(3-phenylbut-3-en-1-yl)benzenesulfon-
amide19 (245 mg, 0.81 mmol) and phenylacetaldehyde (4a) (115 mg,
0.96 mmol) in anhydrous CH2Cl2 (3 mL) was added TMSOTf (29 μL, 36
mg, 0.16 mmol). The resulting mixture was stirred at r.t. for 2 h. After-
wards, CF3SO3H (96 μL, 144 mg, 0.96 mmol) was added and the mix-
ture was stirred at 25 °C for a further 36 h. Column chromatography
(pentane/EtOAc, 11:1) gave 6-phenyl-3-tosyl-1,2,3,4,5,6-hexahydro-
2,6-methano-3-benzazocine (6d) (254 mg, 0.63 mmol, 78%) as a yel-
low oil.
3
3
2JH,H = 13.0 Hz, JH,H = 5.1 Hz, JH,H = 1.5 Hz, 1 H, 11-Ha), 3.05 (quin,
3JH,H = 3.1 Hz, 1 H, 1-H), 2.99 (dd, 2JH,H = 18.4 Hz, 3JH,H = 6.2 Hz, 1 H, 8-
2
3
3
Ha), 2.75 (td, JH,H = 13.0 Hz, JH,H = 3.2 Hz, 1 H, 11-Hb), 2.64 (d, JH,H
=
18.4 Hz, 1 H, 8-Hb), 2.44 (s, 3 H, 18-H), 2.01–1.87 (m, 2 H, 12-Ha, 13-
Ha), 1.86–1.78 (m, 1 H, 13-Hb), 1.57–1.49 (m, 1 H, 12-Hb).
13C NMR (101 MHz, CDCl3): δ = 143.2 (C17), 139.0 (C14), 138.0 (C2),
135.8 (C7), 129.9 (C16), 128.4, 128.1, 127.2 (C15), 126.5, 126.2 (C3,
C4, C5, C6), 47.8 (C9), 38.2 (C11), 33.4 (C8), 32.7 (C12), 32.1 (C1), 30.8
(C13), 21.7 (C18).
Rf = 0.22 (pentane/EtOAc, 15:1, phosphomolybdic acid).
IR (ATR): 3027, 2926, 2359, 1739, 1598, 1494, 1446, 1338, 1155, 1095,
HRMS (ESI): m/z [M + Na]+ calcd for C19H21NO2S + Na: 350.1185;
found: 350.1190.
943, 753, 728, 689 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.77–7.69 (m, 2 H, 19-H), 7.37–7.20
(m, 7 H, 15-H, 16-H, 17-H, 20-H), 7.10–7.02 (m, 1 H, Ar-H), 6.99–6.91
(m, 2 H, Ar-H), 6.50 (dd, 3JH,H = 8.2 Hz, 4JH,H = 1.4 Hz, 1 H, Ar-H), 4.61–
4.51 (m, 1 H, 9-H), 3.90–3.80 (m, 1 H, 11-Ha), 3.20 (dd, 2JH,H = 18.1 Hz,
3JH,H = 5.7 Hz, 1 H, 8-Ha), 2.85–2.70 (m, 2 H, 8-Hb, 11-Hb), 2.43 (s, 3 H,
22-H), 2.35–2.21 (m, 2 H, 12-Ha, 13-Ha), 1.91–1.80 (m, 2 H, 12-Hb, 13-
Hb).
13C NMR (75 MHz, CDCl3): δ = 148.3 (C14), 143.3 (C21), 142.1 (C3),
137.9 (C18), 136.0 (C7), 129.9 (C20), 128.9 (Ar-C), 128.4 (C16), 127.8,
127.2 (C15, C19), 126.6, 126.5, 126.4 (C3, C4, C5, C6, C17), 48.4 (C9),
41.3 (C1), 40.3 (C11), 39.8 (C12), 36.3 (C13), 34.4 (C8), 21.7 (C22).
6-Ethyl-3-tosyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazo-
cine (6c)
To
a mixture of 4-methyl-N-(3-methylenepentyl)benzenesulfon-
amide (see the supporting information) (155 mg, 0.61 mmol) and
phenylacetaldehyde (4a) (80 mg, 0.66 mmol) in anhydrous DCE (3
mL) was added BF3·OEt2 (28 μL, 35 mg, 0.24 mmol). The resulting mix-
ture was stirred at 85 °C for 18 h. Column chromatography (pen-
tane/EtOAc, 14:1) gave 6-ethyl-3-tosyl-1,2,3,4,5,6-hexahydro-2,6-
methano-3-benzazocine (6c) (147 mg, 0.41 mmol, 68%) as a colorless
solid.
HRMS (ESI): m/z [M + Na]+ calcd for C25H25NO2S + Na: 426.1498;
Mp 132 °C; Rf = 0.33 (pentane/EtOAc, 14:1, phosphomolybdic acid).
found: 426.1493.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

H
J. Ploog et al.
Paper
Synthesis
6-Phenethyl-3-tosyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benz-
azocine (6e)
8-Bromo-6-methyl-3-tosyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-
benzazocine (6g)
To a mixture of 4-methyl-N-(3-methylene-5-phenylpentyl)benzene-
sulfonamide (see the supporting information) (171 mg, 0.52 mmol)
and phenylacetaldehyde (4a) (72 mg, 0.62 mmol) in anhydrous DCE
(3 mL) was added BF3·OEt2 (25 μL, 29 mg, 0.21 mmol). The resulting
mixture was stirred at 85 °C for 4 d. Column chromatography (pen-
tane/EtOAc, 16:1 → 9:1) gave 6-phenethyl-3-tosyl-1,2,3,4,5,6-hexa-
hydro-2,6-methano-3-benzazocine (6e) (142 mg, 0.33 mmol, 63%) as
a light yellow oil.
Domino Procedure
To a mixture of 4-methyl-N-(3-methylbut-3-en-1-yl)benzenesulfon-
amide (5a)15c (120 mg, 0.50 mmol) and (4-bromophenyl)acetalde-
hyde (109 mg, 0.55 mmol) in anhydrous DCE (3 mL) was added
BF3·OEt2 (25 μL, 28 mg, 0.20 mmol). The resulting mixture was stirred
at 85 °C for
5
d. Column chromatography (pentane/EtOAc,
19:1 → 14:1) gave 8-bromo-6-methyl-3-tosyl-1,2,3,4,5,6-hexahydro-
2,6-methano-3-benzazocine (6g) (74 mg, 0.18 mmol, 35%) as a yellow
solid.
Rf = 0.20 (pentane/EtOAc, 15:1, phosphomolybdic acid).
IR (ATR): 2927, 2362, 1738, 1600, 1495, 1453, 1340, 1155, 1091, 755,
689 cm–1
.
One-Pot Procedure
1H NMR (600 MHz, CDCl3): δ = 7.74–7.70 (m, 2 H, 21-H), 7.32–7.26
(m, 5 H, 22-H, 3 × Ph-H), 7.21–7.14 (m, 4 H, 3-H, 4-H, 2 × Ph-H), 7.11
(td, 3JH,H = 7.4, 1.3 Hz, 1 H, 7-H), 6.96 (d, 3JH,H = 7.6 Hz, 1 H, 6-H), 4.56–
4.52 (m, 1 H, 9-H), 3.65 (dt, 2JH,H = 13.0 Hz, 3JH,H = 3.2 Hz, 1 H, 11-Ha),
3.06 (dd, 2JH,H = 18.1 Hz, 3JH,H = 5.9 Hz, 1 H, 8-Ha), 2.72–2.62 (m, 2 H, 8-
To a mixture of 4-methyl-N-(3-methylbut-3-en-1-yl)benzenesulfon-
amide15c (5a) (239 mg, 1.00 mmol) and (4-bromophenyl)acetalde-
hyde (240 mg, 1.20 mmol) in anhydrous CH2Cl2 (3 mL) was added
TMSOTf (18 μL, 22 mg, 0.10 mmol). The resulting mixture was stirred
at 25 °C for 3 h. Afterwards, CF3SO3H (105 μL, 180 mg, 1.20 mmol)
was added and the mixture was stirred at 25 °C for a further 18 h. Col-
umn chromatography (pentane/EtOAc, 19:1 → 14:1) gave 8-bromo-6-
methyl-3-tosyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (6g)
(194 mg, 0.46 mmol, 46%) as a yellow solid.
2
Hb, 11-Hb), 2.55–2.41 (m, 5 H, 15-H, 24-H), 2.32 (dd, JH,H = 13.7 Hz,
2
3
3JH,H = 4.2 Hz, 1 H, 14-Ha), 2.02 (dt, JH,H = 12.6 Hz, JH,H = 2.6 Hz, 1 H,
13Ha), 1.76 (ddd, 2JH,H = 14.2, 12.5, 5.5 Hz , 1 H, 14-Hb), 1.71–1.64 (m, 2
H, 12-Ha, 13-Hb), 1.36–1.32 (m, 1 H, 12-Hb).
13C NMR (101 MHz, CDCl3): δ = 143.3 (C23), 142.7 (C16), 139.8 (C20),
138.0 (C2), 136.6 (C7), 129.9 (C22), 128.6, 128.5, 128.3 (C17, C18, C6),
127.2 (C21), 126.7 (C5), 126.4 (C4), 126.0 (C19), 125.1 (C3), 48.1 (C9),
42.2 (C14), 40.3 (C12), 39.7 (C11), 36.0 (C13), 35.5 (C1), 34.5 (C8), 29.9
(C15), 21.7 (C24).
HRMS (ESI): m/z [M + Na]+ calcd for C27H29NO2S + Na: 454.1811;
found: 454.1818.
Mp 157–159 °C; Rf = 0.26 (pentane/EtOAc, 14:1, phosphomolybdic
acid).
IR (ATR): 2969, 2360, 1739, 1215, 811, 709, 695, 682, 547, 533 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, 3JH,H = 8.3 Hz, 2 H, 16-H), 7.30
(d, 3JH,H = 8.0 Hz, 2 H, 17-H), 7.21 (d, 4JH,H = 2.3 Hz, 1 H, 3-H), 7.05 (dd,
3JH,H = 8.2 Hz, 3JH,H = 2.2 Hz, 1 H, 5-H), 6.85 (d, 3JH,H = 8.1 Hz, 1 H, 6-H),
4.52–4.44 (m, 1 H, 9-H), 3.65 (ddt, 2JH,H = 13.2 Hz, 3JH,H = 4.9 Hz, 3JH,H
=
1.5 Hz, 1 H, 11-Ha), 2.96 (ddd, 2JH,H = 18.3 Hz, 3JH,H = 6.0 Hz, 3JH,H = 1.1
Hz, 1 H, 8-Ha), 2.67–2.56 (m, 2 H, 11-Hb, 8-Hb), 2.44 (s, 3 H, 19-H),
1.77–1.57 (m, 3 H, 13-Ha, 13-Hb, 12-Ha), 1.41–1.30 (m, 4 H, 12-Hb, 14-
H).
13C NMR (101 MHz, CDCl3): δ = 144.5 (C18), 143.3 (C15), 137.9 (C2),
134.6 (C7), 129.9 (C17), 129.7, 129.5, 128.1 (C3, C5, C6), 127.2 (C16),
120.3 (C4), 47.8 (C9), 40.0 (C12), 39.6 (C11), 38.5 (C13), 34.0 (C8), 32.5
(C1), 27.8 (C14), 21.7 (C19).
8-Chloro-6-methyl-3-tosyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-
benzazocine (6f)
To a mixture of 4-methyl-N-(3-methylbut-3-en-1-yl)benzenesulfon-
amide15c (5a) (120 mg, 0.50 mmol) and (4-chlorophenyl)acetaldehyde
(85 mg, 0.55 mmol) in anhydrous DCE (3 mL) was added BF3·OEt2 (76
μL, 85 mg, 0.60 mmol). The resulting mixture was stirred at 85 °C for
5 d. Column chromatography (pentane/EtOAc, 14:1) gave 8-chloro-6-
methyl-3-tosyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (6f)
(65 mg, 0.17 mmol, 35%) as a yellow solid.
HRMS (ESI): m/z [M + H]+ calcd for C20H22BrNO2S + H: 420.0627;
found: 420.0628.
Mp 155–157 °C; Rf = 0.49 (pentane/EtOAc, 10:1, phosphomolybdic
acid).
6,8-Dimethyl-3-tosyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benz-
azocine (6h)
IR (ATR): 2969, 2919, 2359, 1739, 1338, 1321, 1215, 1165, 1145, 1094,
813, 682 cm–1
.
To a mixture of 4-methyl-N-(3-methylbut-3-en-1-yl)benzenesulfon-
amide15c (5a) (239 mg, 1.00 mmol) and (4-methylphenyl)acetalde-
hyde (161 mg, 1.20 mmol) in anhydrous DCE (3 mL) was added
BF3·OEt2 (49 μL, 57 mg, 0.40 mmol). The resulting mixture was stirred
at 85 °C for 21 h. Column chromatography (pentane/EtOAc, 14:1) gave
6,8-dimethyl-3-tosyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazo-
cine (6h) (224 mg, 0.63 mmol, 63%) as a yellow solid.
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, 3JH,H = 8.3 Hz, 2 H, 16-H), 7.30
(d, 3JH,H = 8.0 Hz, 2 H, 17-H), 7.21 (d, 4JH,H = 2.3 Hz, 1 H, 3-H), 7.05 (dd,
3JH,H = 8.2 Hz, 3JH,H = 2.2 Hz, 1 H, 5-H), 6.85 (d, 3JH,H = 8.1 Hz, 1 H, 6-H),
4.52–4.44 (m, 1 H, 9-H), 3.65 (ddt, 2JH,H = 13.2 Hz, 3JH,H = 4.9 Hz, 3JH,H
=
1.5 Hz, 1 H, 11-Ha), 2.96 (ddd, 2JH,H = 18.3 Hz, 3JH,H = 6.0 Hz, 3JH,H = 1.1
Hz, 1 H, 8-Ha), 2.67–2.56 (m, 2 H, 11-Hb, 8-Hb), 2.44 (s, 3 H, 19-H),
1.77–1.57 (m, 3 H, 13-Ha, 13-Hb, 12-Ha), 1.41–1.30 (m, 4 H, 12-Hb, 14-
H).
Mp 116–118 °C; Rf = 0.36 (pentane/EtOAc, 14:1, phosphomolybdic
acid).
13C NMR (101 MHz, CDCl3): δ = 144.1 (C18), 143.3 (C2), 137.9 (C15),
134.0 (C7), 132.2 (C4), 129.9 (C17), 129.4 (C6), 127.2 (C16), 126.5
(C5), 125.2 (C3), 47.8 (C9), 40.0 (C12), 39.6 (C11), 38.5 (C13), 33.9
(C8), 32.5 (C1), 27.8 (C14), 21.7 (C19).
HRMS (ESI): m/z [M + H]+ calcd for C20H22ClNO2S + H: 376.1133;
found: 376.1129.
IR (ATR): 2930, 1457, 1337, 1320, 1166, 1152, 1094, 823, 811, 686 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, 3JH,H = 8.2 Hz, 2 H, 16-H), 7.29
.
(d, 3JH,H = 8.0 Hz, 2 H, 17-H), 7.07–7.03 (m, 1 H, 3-H), 6.90 (dd, 3JH,H
=
7.8 Hz, 4JH,H = 1.7 Hz, 1 H, 5-H), 6.80 (d, 3JH,H = 7.7 Hz, 1 H, 6-H), 4.50–
4.43 (m, 1 H, 9-H), 3.70–3.60 (m, 1 H, 11-Ha), 2.97 (dd, 2JH,H = 18.1 Hz,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

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J. Ploog et al.
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Synthesis
3JH,H = 6.1 Hz, 1 H, 8-Ha), 2.68–2.55 (m, 2 H, 11-Hb, 8-Hb), 2.44 (s, 3 H,
19-H), 2.28 (s, 3 H, 20-H), 1.78–1.72 (m, 1 H, 13-Ha), 1.69–1.57 (m, 2
H, 13-Hb, 12-Ha), 1.41–1.32 (m, 4 H, 12-Hb, 14-H).
13C NMR (101 MHz, CDCl3): δ = 143.2 (C18), 142.0 (C2), 138.1 (C15),
135.9 (C7), 132.5 (C4), 129.8 (C17), 127.9 (C6), 127.21 (C16), 127.15
(C5), 125.5 (C3), 48.2 (C9), 40.2 (C12), 39.9 (C11), 39.0 (C13), 33.9
(C8), 32.1 (C1), 28.0 (C1), 21.7 (C14), 21.4 (C20).
8-Methoxy-6-methyl-3-tosyl-1,2,3,4,5,6-hexahydro-2,6-methano-
3-benzazocine (6j)
To a mixture of 4-methyl-N-(3-methylbut-3-en-1-yl)benzenesulfon-
amide15c (5a) (239 mg, 1.00 mmol) and (4-methoxyphenyl)acetalde-
hyde (180 mg, 1.20 mmol) in abs CH2Cl2 (3 mL) was added TMSOTf
(36 μL, 44 mg, 0.20 mmol). The resulting mixture was stirred in
CH2Cl2 at 40 °C for 21 h. Column chromatography (pentane/EtOAc,
10:1) gave 8-methoxy-6-methyl-3-tosyl-1,2,3,4,5,6-hexahydro-2,6-
methano-3-benzazocine (6j) (199 mg, 0.54 mmol, 54%) as a yellow
solid.
HRMS (ESI): m/z [M + H]+ calcd for C21H25NO2S + H: 356.1679; found:
356.1675.
Mp 114–117 °C; Rf = 0.16 (pentane/EtOAc, 10:1, phosphomolybdic
acid).
6,11-Dimethyl-3-tosyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benz-
azocine (6i)
IR (ATR): 2930, 2837, 2363, 1739, 1616, 1577, 1496, 1336, 1238, 1154,
1093, 1044, 811, 682 cm–1
.
Domino Procedure
1H NMR (400 MHz, CDCl3): δ = 7.71 (d, 3JH,H = 8.3 Hz, 2 H, 16-H), 7.29
(d, 3JH,H = 8.0 Hz, 2 H, 17-H), 6.84 (d, 3JH,H = 8.5 Hz, 1 H, 6-H), 6.79 (d,
4JH,H = 2.7 Hz, 1 H, 3-H), 6.66 (dd, 3JH,H = 8.4 Hz, 4JH,H = 2.7 Hz, 1 H, 5-H),
To a mixture of 4-methyl-N-(3-methylpent-3-en-1-yl)benzenesulfon-
amide (5b) (E:Z = 2.5:1) (254 mg, 1.00 mmol) and phenylacetalde-
hyde (4a) (144 mg, 1.20 mmol) in anhydrous DCE (3 mL) was added
BF3·OEt2 (49 μL, 57 mg, 0.40 mmol). The resulting mixture was stirred
at 85 °C for 4 d. Column chromatography (pentane/EtOAc, 12:1 → 9:1)
gave a mixture of two inseparable diastereomers (α/β = 1:1) of 6,11-
dimethyl-3-tosyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine
(6i) (247 mg, 0.70 mmol, 70%) as a light yellow solid.
2
4.50–4.43 (m, 1 H, 9-H), 3.76 (s, 3 H, 20-H), 3.65 (dd, JH,H = 12.6 Hz,
3JH,H = 3.9 Hz, 1 H, 11-Ha), 2.95 (dd, 2JH,H = 17.9 Hz, 3JH,H = 6.0 Hz, 1 H, 8-
Ha), 2.71–2.55 (m, 2 H, 11-Hb, 8-Hb), 2.43 (s, 3 H, 19-H), 1.79–1.55 (m,
3 H, 13-Ha, 13-Hb, 12-Ha), 1.43–1.29 (m, 4 H, 12-Hb, 14-H).
13C NMR (101 MHz, CDCl3): δ = 158.3 (C4), 143.4 (C18), 143.1 (C2),
138.1 (C15), 129.8 (C17), 128.9 (C6), 127.7 (C7), 127.2 (C16), 111.7
(C5), 110.7 (C3), 55.4 (C20), 48.2 (C9), 40.1 (C12), 39.9 (C11), 38.8
(C13), 33.6 (C8), 32.4 (C1), 28.0 (C14), 21.7 (C19).
HRMS (ESI): m/z [M + H]+ calcd for C21H25NO3S + H: 372.1628; found:
372.1642.
One-Pot Procedure
To a mixture of 4-methyl-N-(3-methylpent-3-en-1-yl)benzenesulfon-
amide (5b) (E:Z = 2.5:1) (253 mg, 1.00 mmol) and phenylacetaldehyde
(4a) (144 mg, 1.20 mmol) in abs CH2Cl2 (3 mL) was added TMSOTf (18
μL, 22 mg, 0.10 mmol). The resulting mixture was stirred at 25 °C for
2 h. Afterwards, CF3SO3H (105 μL, 180 mg, 1.2 mmol) was added and
the mixture was stirred at 25 °C for a further 36 h. Column chroma-
tography (pentane/EtOAc, 15:1) gave a mixture of two inseparable di-
astereomers (α/β = 1:4) of 6,11-dimethyl-3-tosyl-1,2,3,4,5,6-hexahy-
dro-2,6-methano-3-benzazocine (6i) (274 mg, 0.77 mmol, 77%) as a
light yellow solid. The isomers were separated by HPLC (CHIRALPAK
IA 10 mm × 250 mm, 5 μ, 5 mL/min, n-hexane/EtOAc, 93:7).
2-Benzyl-4-methyl-1-tosyl-1,2,3,6-tetrahydropyridine (9aa) and
6-Benzyl-4-methyl-1-tosyl-1,2,3,6-tetrahydropyridine (9ab)
To a mixture of 4-methyl-N-(3-methylbut-3-en-1-yl)benzenesulfon-
amide15c (5a) (239 mg, 1.00 mmol) and phenylacetaldehyde (4a) (144
mg, 1.20 mmol) in abs CH2Cl2 (3 mL) was added TMSOTf (18 μL, 22
mg, 0.10 mmol). The resulting mixture was stirred at 25 °C for 18 h.
Column chromatography (pentane/EtOAc, 16:1) gave the two regio-
isomers 9aa and 9ab (326 mg, 0.95 mmol, 95%) as a colorless oil. The
isomers were separated by HPLC (Nucleodur 100-5, 21 mm × 250
mm, 7 mL/min, n-hexane/EtOAc, 93:7).
(2R/S,6R/S,11R/S)-6,11-Dimethyl-3-tosyl-1,2,3,4,5,6-hexahydro-
2,6-methano-3-benzazocine
Mp 121–123 °C; Rf = 0.26 (pentane/EtOAc, 15:1, phosphomolybdic
acid).
2-Benzyl-4-methyl-1-tosyl-1,2,3,6-tetrahydropyridine (9aa)
Rf = 0.42 (pentane/EtOAc, 16:1, phosphomolybdic acid).
IR (ATR): 2967, 1598, 1335, 1316, 1157, 1094, 971, 817, 655 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, 3JH,H = 8.2 Hz, 2 H, 18-H), 7.30
IR (ATR): 3023, 2926, 1599, 1337, 1151, 1095, 1031, 936, 814, 753,
(d, 3JH,H = 8.0 Hz, 2 H, 17-H), 7.21 (dd, 3JH,H = 7.8 Hz, 4JH,H = 1.2 Hz, 1 H,
728, 673 cm–1
.
3
3
4
Ar-H), 7.14 (t, JH,H = 7.5 Hz, 1 H, Ar-H), 7.07 (td, JH,H = 7.3 Hz, JH,H
=
1H NMR (600 MHz, CDCl3): δ = 7.65–7.61 (m, 2 H, 13-H), 7.29–7.25
(m, 2 H, 9-H), 7.24–7.19 (m, 3 H, 10-H, 14-H), 7.13–7.08 (m, 2 H, 8-H),
5.40 (dq, 3JH,H = 3.9 Hz, 3JH,H = 1.8 Hz, 1 H, 2-H), 4.38–4.31 (m, 1 H, 5-
1.5 Hz, 1 H, Ar-H), 6.89 (d, 3JH,H = 7.6 Hz, 1 H, Ar-H), 4.19–4.13 (m, 1 H,
2
3
9-H), 3.60 (dd, JH,H = 13.1 Hz, JH,H = 5.1 Hz, 1 H, 11-Ha), 3.01 (dd,
2JH,H = 18.7 Hz, 3JH,H = 6.2 Hz, 1 H, 8-Ha), 2.63 (td, 2JH,H = 13.0 Hz, 3JH,H
3.2 Hz, 1 H, 11-Hb), 2.54–2.41 (m, 4 H, 8-Hb, 20-H), 1.88–1.77 (m, 1 H,
13-H), 1.72 (td, 3JH,H = 12.9 Hz, 3JH,H = 5.1 Hz, 1 H, 12-Ha), 1.40–1.32 (m,
4 H, 12-Hb, 14-H), 0.83 (d, 3JH,H = 7.1 Hz, 3 H, 15-H).
13C NMR (151 MHz, CDCl3): δ = 143.2 (C16), 140.3 (C2), 138.1 (C19),
135.0 (C7), 129.8 (C18), 127.6, 127.2 (C17), 126.7, 126.1, 125.9 (C3,
C4, C5, C6), 53.1 (C9), 41.8 (C12), 41.4 (C13), 39.7 (C11), 36.2 (C1),
30.0 (C8), 25.4 (C14), 21.7 (C20), 13.8 (C15).
=
2
3
H), 4.14–4.06 (m, 1 H, 1-Ha), 3.63 (ddq, JH,H = 17.4 Hz, JH,H = 4.4 Hz,
3JH,H = 2.3 Hz, 1 H, 1-Hb), 2.69–2.60 (m, 2 H, 6-H), 2.39 (s, 3 H, 16-H),
2.10–2.02 (m, 1 H, 4-Ha), 1.71–1.65 (m, 1 H, 4-Hb), 1.63 (t, JH,H = 1.7
4
Hz, 3 H, 11-H).
13C NMR (151 MHz, CDCl3): δ = 143.2 (C15), 138.7, 137.7 (C7, C12),
131.0 (C3), 129.7 (C9), 129.4 (C14), 128.7 (C8), 127.2 (C13), 126.6
(C10), 116.4 (C2), 52.5 (C5), 40.9 (C1), 37.2 (C6), 31.5 (C4), 23.6 (C11),
21.6 (C16).
HRMS (ESI): m/z [M + Na]+ calcd for C20H23NO2S + Na: 364.1342;
found: 364.1340.
HRMS (ESI): m/z [M + H]+ calcd for C21H25NO2S + H: 356.1679; found:
356.1682.
6-Benzyl-4-methyl-1-tosyl-1,2,3,6-tetrahydropyridine (9ab)
Rf = 0.42 (pentane/EtOAc, 16:1, phosphomolybdic acid).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

J
J. Ploog et al.
Paper
Synthesis
IR (ATR): 3023, 2926, 1599, 1337, 1151, 1095, 1031, 936, 814, 753,
728, 673 cm–1
1H NMR (600 MHz, CDCl3): δ = 7.62–7.56 (m, 2 H, 13-H), 7.30–7.25
2.95 (dd, 2JH,H = 14.2 Hz, 3JH,H = 4.5 Hz, 1 H, 6-Ha), 2.72 (dd, 2JH,H = 14.3
Hz, 3JH,H = 8.2 Hz, 1 H, 6H-b), 2.37 (s, 3 H, 17-H), 2.00–1.86 (m, 1 H, 2-
Ha), 1.67 (s, 3 H, 12-H), 1.61–1.51 (m, 1 H, 2-Hb), 1.46 (s, 3 H, 11-H).
.
(m, 2 H, 8-H), 7.24–7.16 (m, 5 H, 9-H, 10-H, 14-H), 5.27–5.21 (m, 1 H,
13C NMR (101 MHz, CDCl3): δ = 158.3 (C10), 142.7 (C16), 138.1 (C13),
130.6 (C8), 129.8 (C7), 129.2 (C15), 127.2 (C14), 126.2, 125.9 (C3, C4),
113.8 (C9), 59.3 (C5), 55.3 (C19), 38.7 (C1), 38.2 (C6), 29.3 (C2), 21.6
(C17), 19.0, 17.0 (C11, C12).
HRMS (ESI): m/z [M + Na]+ calcd for C22H27NO3S + Na: 408.1604;
found: 408.1615.
4-H), 4.51 (dd, 3JH,H = 5.8 Hz, 3JH,H = 4.2 Hz, 1 H, 5-H), 3.77 (ddt, 2JH,H
=
14.3 Hz, 3JH,H = 6.3 Hz, 3JH,H = 1.0 Hz, 1 H, 1-Ha), 3.03–2.91 (m, 2 H, 1-
Hb, 6-Ha), 2.82 (dd, 2JH,H = 13.0 Hz, 3JH,H = 8.5 Hz, 1 H, 6-Hb), 2.39 (s, 3 H,
16-H), 1.88–1.77 (m, 1 H, 2-Ha), 1.59 (dd, J = 17.2, 4.2 Hz, 1 H, 2-Hb),
1.56–1.53 (m, 3 H, 11-H).
13C NMR (151 MHz, CDCl3): δ = 143.0 (C15), 138.5 (C12), 137.9 (C7),
133.2 (C3), 129.8 (C8), 129.6 (C13), 128.5 (C9), 127.1 (C14), 126.5
(C19), 121.0 (C4), 54.9 (C5), 42.2 (C1), 38.9 (C6), 28.2 (C2), 23.5 (C11),
21.6 (C16).
HRMS (ESI): m/z [M + Na]+ calcd for C20H23NO2S + Na: 364.1342;
found: 364.1340.
8-Methoxy-6,11-dimethyl-3-tosyl-1,2,3,4,5,6-hexahydro-2,6-
methano-3-benzazocine (6k)
To a mixture of 4-methyl-N-(3-methylpent-3-en-1-yl)benzenesulfon-
amide (5b) (E/Z = 2.5:1) (255 mg, 1.01 mmol) and 4-methoxyphenyl-
acetaldehyde (180 mg, 1.20 mmol) in abs CH2Cl2 (3 mL) was added
TMSOTf (18 μL, 22 mg, 0.10 mmol). The resulting mixture was stirred
at 25 °C for 3 h. Afterwards, CF3SO3H (106 μL, 180 mg, 1.20 mmol)
was added and the mixture was stirred at 25 °C for a further 21 h. Sat.
aq NaHCO3 solution (10 mL) was added and the aq layer was extract-
ed with CH2Cl2 (3 × 10 mL). The combined organic layers were dried
over Na2SO4, filtered and concentrated in vacuo. Purification of the
crude mixture by column chromatography (pentane/EtOAc, 12:1)
gave a mixture of two inseparable diastereomers of 6k (α/β = 4.3:1)
(189 mg, 0.49 mmol, 49%) as a yellow oil. The isomers were separated
for analytical probes by HPLC (CHIRALPAK IA, 10 mm × 250 mm, 5 μ,
5 mL/min, n-hexane/EtOAc, 90:10). Mp 112–113 °C.
6-Benzyl-4,5-dimethyl-1-tosyl-1,2,3,6-tetrahydropyridine (9b)
To a mixture of 4-methyl-N-(3-methylpent-3-en-1-yl)benzenesulfon-
amide (5b) (E/Z = 2.5:1) (253 mg, 1.00 mmol) and phenylacetalde-
hyde (4a) (144 mg, 1.20 mmol) in abs CH2Cl2 (3 mL) was added
BF3·OEt2 (49 μL, 57 mg, 0.40 mmol). The resulting mixture was stirred
at 25 °C for 60 min. Column chromatography (pentane/EtOAc, 16:1)
gave 6-benzyl-4,5-dimethyl-1-tosyl-1,2,3,6-tetrahydropyridine (9b)
(227 mg, 0.64 mmol, 64%) as a colorless oil.
Rf = 0.27 (pentane/EtOAc, 20:1, phosphomolybdic acid).
IR (ATR): 2923, 1738, 1598, 1454, 1336, 1155, 1090, 1033, 934, 814,
720, 697, 661, 546 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.40–7.35 (m, 2 H, 14-H), 7.28–7.18
.
(2R/S,6R/S,11R/S)-8-Methoxy-6,11-dimethyl-3-tosyl-1,2,3,4,5,6-
hexahydro-2,6-methano-3-benzazocine
3
4
(m, 3 H, 9-H, 10-H), 7.15 (dd, JH,H = 7.8 Hz, JH,H = 1.8 Hz, 2 H, 8-H),
7.11 (d, 3JH,H = 8.0 Hz, 2 H, 15-H), 4.37 (dd, 3JH,H = 8.5 Hz, 3JH,H = 4.5 Hz,
1 H, 5-H), 3.57 (ddt, 2JH,H = 14.6 Hz, 3JH,H = 7.0 Hz, 3JH,H = 1.4 Hz, 1 H, 1-
Ha), 3.12–2.96 (m, 2 H, 1-Hb, 6-Ha), 2.78 (dd, 2JH,H = 14.1 Hz, 3JH,H = 8.4
Hz, 1 H, 6-Hb), 2.36 (s, 3 H, 17-H), 2.02–1.87 (m, 1 H, 2-Ha), 1.67 (s, 3
H, 12-H), 1.61–1.53 (m, 1 H, 2-Hb), 1.47 (s, 3 H, 11-H).
13C NMR (101 MHz, CDCl3): δ = 142.8 (C16), 138.5 (C13), 138.0 (C7),
129.7, 129.3, 128.4, 127.3, 126.4 (C8, C9, C19, C14, C15), 126.2, 126.0
(C3, C4), 59.1 (C5), 39.2 (C1), 38.6 (C6), 29.3 (C2), 21.6 (C17), 19.0,
17.4 (C11, C12).
Rf = 0.27 (pentane/EtOAc,10:1, phosphomolybdic acid).
IR (ATR): 2967, 1598, 1491, 1453, 1316, 1157, 1094, 971, 903, 849,
817, 760, 655 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, 3JH,H = 8.3 Hz, 2 H, 18-H), 7.29
(d, 3JH,H = 8.1 Hz, 2 H, 19-H), 6.81 (d, 3JH,H = 8.4 Hz, 1 H, 6-H), 6.75 (d,
4JH,H = 2.7 Hz, 1 H, 3-H), 6.65 (dd, 3JH,H = 8.4 Hz, 4JH,H = 2.7 Hz, 1 H, 5-H),
4.14 (dd, 3JH,H = 6.1 Hz, 3JH,H = 3.3 Hz, 1 H, 9-H), 3.76 (s, 3 H, 16-H), 3.59
(ddt, 2JH,H = 13.2 Hz, 3JH,H = 5.1 Hz, 3JH,H = 1.6 Hz, 1 H, 11-Ha), 2.94 (dd,
2JH,H = 18.0 Hz, 3JH,H = 6.0 Hz, 1 H, 8-Ha), 2.65 (td, 2JH,H = 12.9 Hz, 3JH,H
=
3.2 Hz, 1 H, 11-Hb), 2.49–2.40 (m, 4 H, 8-Hb, 21-H), 1.79 (dq, 3JH,H = 7.0
Hz, 3JH,H = 3.4 Hz, 1 H, 13-H), 1.70 (td, 2JH,H = 12.9 Hz, 3JH,H = 5.1 Hz, 1 H,
12-Ha), 1.37 (ddd, 2JH,H = 12.9 Hz, 3JH,H = 3.1 Hz, 3JH,H = 1.7 Hz, 1 H, 12-
Hb), 1.32 (s, 3 H, 14-H), 0.82 (d, 3JH,H = 7.1 Hz, 3 H, 15-H).
HRMS (ESI): m/z [M + H]+ calcd for C21H25NO2S + H: 356.1679; found:
356.1681.
6-(4-Methoxybenzyl)-4,5-dimethyl-1-tosyl-1,2,3,6-tetrahydropyr-
idine (9c)
13C NMR (151 MHz, CDCl3): δ = 158.5 (C4), 143.1 (C17), 141.7 (C2),
138.1 (C20), 129.8 (C19), 128.5 (C6), 127.2 (C18), 127.1 (C7), 111.6
(C3), 111.4 (C5), 55.3 (C16), 53.1 (C9), 41.7 (C12), 41.2 (C13), 39.8
(C11), 36.4 (C1), 29.3 (C8), 25.4 (C14), 21.7 (C21), 13.8 (C15).
HRMS (ESI): m/z [M + H]+ calcd for C22H27NO3S + H: 386.1784; found:
386.1793.
To a mixture of 4-methyl-N-(3-methylpent-3-en-1-yl)benzenesulfon-
amide (5b) (E/Z = 2.5:1) (254 mg, 1.00 mmol) and 4-methoxyphenyl-
acetaldehyde (180 mg, 1.20 mmol) in abs CH2Cl2 (3 mL) was added
BF3·OEt2 (49 μL, 57 mg, 0.40 mmol). The resulting mixture was stirred
at 40 °C for 21 h. Column chromatography (pentane/EtOAc, 11:1) gave
6-(4-methoxybenzyl)-4,5-dimethyl-1-tosyl-1,2,3,6-tetrahydropyri-
dine (9c) (148 mg, 0.38 mmol, 38%) as a yellow oil.
4-Phenyl-1-tosyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]indole (17)
To a mixture of 4-methyl-N-(4-phenylbut-3-en-1-yl)benzenesulfon-
amide20 (5c) (301 mg, 1.00 mmol) and phenylacetaldehyde (4a) (144
mg, 1.20 mmol) in abs CH2Cl2 (3 mL) was added TMSOTf (18 μL, 22
mg, 0.10 mmol). The resulting mixture was stirred at 25 °C for 3 h.
Afterwards, CF3SO3H (106 μL, 180 mg, 1.20 mmol) was added and the
mixture was stirred at 25 °C for a further 19 h. Column chromatogra-
phy (pentane/EtOAc, 13:1) gave 17 (310 mg, 0.79 mmol, 79%) as a col-
orless solid.
Rf = 0.41 (pentane/EtOAc, 10:1, phosphomolybdic acid).
IR (ATR): 2930, 2360, 1739, 1512, 1335, 1244, 1155, 1091, 1035, 814,
729, 661 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.44–7.38 (m, 2 H, 14-H), 7.11 (d,
3JH,H = 8.0 Hz, 2 H, 15-H), 7.07–7.02 (m, 2 H, 8-H), 6.80–6.74 (m, 2 H,
9-H), 4.34–4.27 (m, 1 H, 5-H), 3.80 (s, 3 H, 19-H), 3.62–3.54 (m, 1 H, 1-
Ha), 3.04 (ddd, 3JH,H = 14.5 Hz, 3JH,H = 11.7 Hz, 3JH,H = 5.1 Hz, 1 H, 1-Hb),
Mp 234 °C; Rf = 0.23 (pentane/EtOAc, 13:1, phosphomolybdic acid).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

K
J. Ploog et al.
Paper
Synthesis
IR (ATR): 2358, 1598, 1449, 1339, 1163, 1108, 1035, 815, 762, 702 cm–1
.
(8) (a) Han, X.; Peh, G.; Floreancig, P. E. Eur. J. Org. Chem. 2013,
1193. (b) Hinkle, R. J.; Lewis, S. E. Org. Lett. 2013, 15, 4070.
(c) Reddy, B. V. S.; Borkar, P.; Yadav, J. S.; Sridhar, B.; Grée, R.
J. Org. Chem. 2011, 76, 7677. (d) Reddy, B. V. S.; Reddy, M. R.;
Reddy, S. G.; Sridhar, B.; Kumar, S. K. Eur. J. Org. Chem. 2015,
3103. (e) Subba Reddy, B. V.; Borkar, P.; Yadav, J. S.;
Purushotham Reddy, P.; Kunwar, A. C.; Sridhar, B.; Grée, R. Org.
Biomol. Chem. 2012, 10, 1349. (f) Subba Reddy, B. V.; Kumar, H.;
Borkar, P.; Yadav, J. S.; Sridhar, B. Eur. J. Org. Chem. 2013, 1993.
(g) Subba Reddy, B. V.; Medaboina, D.; Sridhar, B. J. Org. Chem.
2014, 80, 653. (h) Subba Reddy, B. V.; Medaboina, D.; Sridhar,
B.; Singarapu, K. K. J. Org. Chem. 2013, 78, 8161. (i) Subba Reddy,
B. V.; Medaboina, D.; Sridhar, B.; Singarapu, K. K. J. Org. Chem.
2014, 79, 2289. (j) Subba Reddy, B. V.; Prudhvi Raju, N.;
Someswarao, B.; Mohan Reddy, B. J.; Sridhar, B.; Marumudi, K.;
Kunwar, A. C. Org. Biomol. Chem. 2015, 13, 4733. (k) Subba
Reddy, B. V.; Swathi, V.; Swain, M.; Bhadra, M. P.; Sridhar, B.;
Satyanarayana, D.; Jagadeesh, B. Org. Lett. 2014, 16, 6267.
(l) Subba Reddy, B. V.; Venkateswarlu, A.; Sridevi, B.; Marumudi,
K.; Kunwar, A. C.; Gayatri, G. Org. Biomol. Chem. 2015, 13, 2669.
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74, 2605. (b) Tian, X.; Jaber, J. J.; Rychnovsky, S. D. J. Org. Chem.
2006, 71, 3176.
1H NMR (400 MHz, CDCl3): δ = 7.77–7.72 (m, 2 H, 18-H), 7.33 (d,
3JH,H = 8.0 Hz, 2 H, 19-H), 7.31–7.21 (m, 4 H, Ar-H), 7.18 (tt, 3JH,H = 7.6
Hz, 4JH,H = 1.1 Hz, 1 H, 16-H), 7.09–7.01 (m, 3 H, Ar-H), 6.73 (dt, 3JH,H
=
7.9 Hz, 4JH,H = 1.2 Hz, 1 H, Ar-H), 3.75 (dd, 2JH,H = 16.0 Hz, 3JH,H = 4.8 Hz,
1 H, 11-Ha), 3.67 (d, 3JH,H = 11.5 Hz, 1 H, 4-H), 3.50–3.38 (m, 2 H, 1-H),
3.27–3.18 (m, 1 H, 11-Hb), 3.07 (td, 3JH,H = 10.9 Hz, 3JH,H = 4.8 Hz, 1 H,
3
3
12-H), 2.45 (s, 3 H, 21-H), 2.23 (tdd, JH,H = 11.9 Hz, JH,H = 10.6 Hz,
3JH,H = 5.8 Hz, 1 H, 3-H), 1.63 (dtd, 2JH,H = 12.0 Hz, 3JH,H = 6.0 Hz, 3JH,H
=
1.8 Hz, 1 H, 2-Ha), 1.21–1.09 (m, 1 H, 2-Hb).
13C NMR (101 MHz, CDCl3): δ = 144.0 (C13), 143.7 (C17), 139.2 (C10),
135.5 (C5), 133.6 (C20), 130.1, 129.9, 129.7, 128.9, 128.8, 127.9, 127.0,
126.7, 126.5 (C6, C7, C8, C9, C14, C15, C16), 61.7 (C12), 52.1 (C4), 50.7
(C3), 49.1 (C1), 38.0 (C11), 28.6 (C2), 21.7 (C21).
HRMS (ESI): m/z [M + H]+ calcd for C25H25NO2S + H: 404.1679; found:
404.1683.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588071.
S
u
p
p
ortiInfogrmoaitn
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u
p
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(10) Subba Reddy, B. V.; Medaboina, D.; Sridhar, B. J. Org. Chem.
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