Stereoselective synthesis of hexahydroindoles and octahydrocyclohepta[b]pyrroles via gold(I)-catalyzed intramolecular 1,4-hydroamination of cyclic 1,3-dienes

Article abstract of DOI:10.1016/j.tet.2009.04.064

The gold(I)-catalyzed intramolecular hydroamination of cyclohexa-1,3-dienes bearing an arylsulfonamide at the C-5 position proceeds in a 1,4-addition manner to afford hexahydroindole derivatives in a diastereoselective fashion and in good yields, whereas

Full text of DOI:10.1016/j.tet.2009.04.064

Tetrahedron 65 (2009) 4789–4794
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of hexahydroindoles and octahydrocyclohepta-
[b]pyrroles via gold(I)-catalyzed intramolecular 1,4-hydroamination
of cyclic 1,3-dienes
*
Ming-Chang P. Yeh , Hui-Fen Pai, Zao-Jun Lin, Bo-Ren Lee
Department of Chemistry, National Taiwan Normal University, 88 Ding-Jou Road, Section 4, Taipei 11677, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
The gold(I)-catalyzed intramolecular hydroamination of cyclohexa-1,3-dienes bearing an aryl-
sulfonamide at the C-5 position proceeds in a 1,4-addition manner to afford hexahydroindole derivatives
in a diastereoselective fashion and in good yields, whereas octahydrocyclohepta[b]pyrrole derivatives
can be obtained from seven-membered ring substrates under the same reaction conditions. Coordination
of the gold(I) species to the 1,3-diene at the double bond adjacent to the arylsulfonamide tether gave an
Received 18 February 2009
Received in revised form 17 April 2009
Accepted 17 April 2009
Available online 24 April 2009
h
2-alkene gold complex. The anti-attack of the sulfonamide to the
minal position of the 1,3-diene resulted in the formation of the fused bicyclic ring with a newly formed
Au–C bond at the allylic position. Allylic rearrangement of the
1-allylgold complex followed by proto-
demetalation provided the fused heterobicyclic skeletons and regenerated the catalyst.
Ó 2009 Published by Elsevier Ltd.
h
2-alkene gold complex at the ter-
Keywords:
Hydroamination
Sulfonamide
Hexahydroindoles
Octahydrocyclohepta[b]pyrroles
Intramolecular
h
Gold-catalyzed
Cyclohexadiene
Cycloheptadiene
1. Introduction
efficient catalysts for intermolecular hydroamination of 1,3-dienes
with benzyl carbamates or sulfonamides to produce allylic
amines.14 It has been shown that coordination of electrophilic
gold(I) complexes to the 1,3-diene group at the less substituted
The hexahydroindole and octahydrocyclohepta[b]pyrrole ring
skeletons are present in numerous natural products of biological
interest.1,2 Because the availability of these building blocks could
greatly facilitate the elaboration of more complex target molecules,
the design of expedient synthetic routes to such intermediates has
been actively pursued. Recently, transition metal-promoted
intramolecular hydroamination of C–C multiple bonds has been
a convenient process for the synthesis of nitrogen heterocycles.
Metals such as Hg(II),3 Ag(I),4 Pd(0 or II),5 and Au(I or III)6 as well as
organolanthanides7 were used for intramolecular cyclization of
aminoallenes, whereas in the case of cyclization of aminoalkenes
and alkynes the reactions were performed using alkali metals,8 rare
earth metals,9 early transition metals,9b,10 and late transition met-
als.9b,11 However, only few examples are known for hydroamination
of dienes. Hartwig and co-workers reported palladium- and nickel-
catalyzed intermolecular hydroamination reactions of 1,3-dienes
with amines,12 while Shibasaki and co-workers reported the bis-
muth-catalyzed intermolecular hydroamination of 1,3-dienes with
amides.13 Recently, Au(I) and Au(III) complexes have emerged as
double bond of the diene afforded an h
2-alkene gold complex. At-
tack of the N-nucleophile at the internal position of the alkene li-
gand generated an Au–C bond. Proton transfer from NH2 group to
the carbon atom provided allylic amines. Concerning the gold-
catalyzed hydroamination of dienes, the intermolecular reaction is
well-known in comparison with the intramolecular reaction.14
Herein, we report for the first time that the gold(I)-catalyzed
intramolecular hydroamination of cyclic 1,3-dienes containing an
arylsulfonamide tether at C-5 proceeds in a 1,4-addition manner in
refluxing toluene to afford hexahydroindole and octahydro-
cyclohepta[b]pyrrole ring systems in a diastereoselective fashion
and in high yields.
2. Results and discussion
2.1. Synthesis of cyclic 1,3-dienes bearing an arylsulfonamide
tether at C-5
The requisite cyclohexadienic sulfonamides 1a–f were prepared
by addition of lithium diphenylacetonitrile to the
hexadienyl)tricarbonyliron cation salt in THF according to literature
(h
5-cyclo-
* Corresponding author. Tel.: þ886 2 29309080.
E-mail address: cheyeh@scc.ntnu.edu.tw (M.-C.P. Yeh).
0040-4020/$ – see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tet.2009.04.064

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M.-C.P. Yeh et al. / Tetrahedron 65 (2009) 4789–4794
a
Treatment of 1a with 5 mol % of Ph3PAuCl/AgOTf in toluene at 85 ꢀC
NHSO2Ar
NSO2Ar
Ph
for 18 h produced 2,3,3a,4,5,7a-hexahydro-3,3-diphenyl-1-tosyl-
1H-indole (3a) in 88% isolated yield (Scheme 1). The 1,4-addition
product of the relative stereochemistry as depicted was obtained as
a single diastereomer, which is derived from addition of the aryl-
sulfonamide and proton across the conjugated diene. The cis ste-
reochemistry of 3a was determined by 1H NMR spectroscopy, with
5% Ph3PAuCl,5% AgOTf
toluene,85 °C,18 h
b
n
n
Ph Ph
Ph
1
3
a: n = 1, Ar = phenyl 88%
b: n = 1, Ar = 4-methylphenyl 88%
c: n = 1, Ar = 4-methoxyphenyl 85%
d: n = 1, Ar = 4-fluorophenyl 80%
e: n = 1, Ar = 3-nitrophenyl 84%
f: n = 1, Ar = 2,4,6-trimethylphenyl 0%
g: n = 2, Ar = phenyl 86%
h: n = 2, Ar = 4-methylphenyl 83%
i: n = 2, Ar = 4-methoxyphenyl 84%
j: n = 2, Ar = 4-nitrophenyl 78%
assignments deriving from coupling constants. The proton at d 4.16
as a triplet, J¼4.6 Hz was assigned to Ha. The coupling constant of
Ha–Hb (Jab) of 4.6 Hz agrees with the coupling constants for similar
cis hydrogens compared to the 10–12 Hz observed when these
protons are trans.16 The structure elucidation of 3a was further
accomplished by X-ray diffraction analysis. The syn relative ste-
reochemistry between two hydrogen atoms at fused carbon cen-
ters further supports the proposed reaction path suggested for the
formation of the hexahydroindole 3a (vide infra). It is important to
mention that similar cis hexahydroindole rings were available by
palladium-catalyzed intramolecular 1,4-oxyamidation of cyclic 1,3-
dienes.17 The reaction pathway leading to 3a was suggested as
follows (Fig. 1). In the known experimental work Ph3PAuOTf was
proposed as the catalytically reactive species, which is generated in
situ from Ph3PAuCl and AgOTf in toluene.14c Coordination of the
gold(I) species to 1a at the double bond adjacent to the arylsulfo-
Scheme 1. Intramolecular gold(I)-catalyzed hydroamination of cyclohexa-1,3-dienes.
procedures.15 Decomplexation of the resulting complex with cerium
ammonium nitrate (CAN) in acetone at 0 ꢀC afforded 2-(cyclohexa-
2,4-dienyl)-2,2-diphenylacetonitrile 2. Treatment of 2 with lithium
aluminumhydride followed by reaction with corresponding aryl-
sulfonyl chlorides furnished 1a–f in 72–88% overall yields. The
seven-membered ring substrates 1g–k were prepared in good yields
(78–87%) starting from addition of lithium diphenylacetonitrile to
namide tether gave an
the arylsulfonamide from the opposite face of the gold center at the
terminal position of the diene would generate the
1-allylgold
h
2-alkene gold complex 4 (Fig. 1). Attack of
the (h
5-cycloheptadienyl)-tricarbonyliron cation salt following the
h
intermediate 5a with the newly formed carbon–nitrogen bond. The
cis relative stereochemistry of the two fused protons at the ring
juncture of 5a was fixed by arylsulfonamide moiety aligned with
the face of the cyclic diene in which the tethering chain resides.
Allylic isomerization of 5a led to 5b. The triflate-assisted tauto-
merization of 5b gave 5c, as suggested in the literature.14b,c Proton
transfer from either NH (5b) or OH (5c) to the carbon atom fol-
lowed by recoordination of the remaining double bond to the gold
same procedure as described above for synthesis of 1a–f.
CN
Ph Ph
2
center afforded the h
2-alkene gold intermediate 5d. Replacement
2.2. Synthesis of hexahydroindoles via gold(I)-catalyzed
intramolecular 1,4-hydroamination of cyclohexa-1,3-dienes
of the double bond of 5d with triflate produced the hexahy-
droindole derivative 3a and regenerated the reactive species
Ph3PAuOTf in the catalytic cycle. It must be mentioned that the
current result is contrast to the regioselectivity of gold-catalyzed
intermolecular addition of N-nucleophiles to 1,3-dienes.14a In
Our study of intramolecular gold(I)-catalyzed hydroamination
of cyclohexa-1,3-dienes began with compound 1a (Scheme 1).
AuPPh3
AuPPh3
Ph3PAu
NHSO2Ph
NHSO2Ph
NHSO2Ph
Ph3PAuOTf
NHSO2Ph
Ph
Ph
5b
OTf
Ph Ph
Ph Ph
OTf
Ph
OTf
Ph
1a
5a
4
X
Ph
Ph3PAu
H
Ph3PAu
S
N
O
AuPPh3
NSO2Ph
OH
NSO2Ph
Ph
Ph
Ph
5c
OTf
Ph
OTf
Ph
OTf
Ph
5d
6
not formed
Ph3PAuOTf
-
3a
Figure 1. A plausible reaction path for the formation of hexahydroindole 3a.

M.-C.P. Yeh et al. / Tetrahedron 65 (2009) 4789–4794
Ts
4791
stereochemistry of cycloaddition products 3a–e was assigned as the
same all-syn relationship between two fused protons on the basis of
their close chemical shift values and similar coupling patterns of the
fused protons in their 1H NMR spectra. Furthermore, the structure
elucidations of hexahydroindole derivatives 3a–e were accom-
plished by X-ray diffraction analysis. Electron-neutral and -rich
phenylsulfonamides were proven to be good substrates, as the
yields of desired hexahydroindole products 3a–c ranged from 85%
to 88% (Scheme 1). In addition, the substrate with a fluoro atom, for
example,1d, did not inhibit the catalytic activity of the gold species,
as evidenced by a good yield of the cyclized product 3d (80%,
Scheme 1). An electron-withdrawing group on the benzene ring
also provided the desired product. For example, substrate 1e, pos-
sessing a meta nitro group at the phenyl ring, was effective and
afforded 3e in 84% isolated yield. However, substrate 1f, bearing
three methyl groups at the phenyl ring, failed to give any cyclized
products. Compound 1f was recovered quantitatively after treat-
ment of 1f with the catalytic species in refluxing toluene for 2 days.
The failure of cyclization may be due to the steric hindrance of the
two ortho methyl groups at the phenyl ring.
N
NHTs
5% HOTf
Toluene, 110 °C, 4 h, 65%
7
1b
Scheme 2. Intramolecular HOTf-catalyzed hydroamination of 1b.
Ts
5% Ph3PAuCl, 5% AgOTf
N
NHTs
toluene, 110 °C, 15 h, 60%
9
8
Scheme 3. Intramolecular gold(I)-catalyzed 1,2-hydroamination of 8.
general, gold-catalyzed intermolecular addition of N-nucleophiles,
such as carbamates and sulfonamides occurred at the internal
position of 1,3-dienes to give 1,2-hydroamination products.
Therefore, it is reasonable to state that the arylsulfonamide may
add initially to the transient intermediate 4 at the internal position
of the diene to produce the steric congested bridged bicyclic
skeleton 6. The nucleophile reversed and added at the terminal
position of the diene to generate the thermally more stable fused
bicyclic intermediate 5a. The transient intermediate 5a led to the
hexahydroindole derivative 3a as stated above.
NHSO2Ar
Ph
NHSO2Ar
NSO2Ar
Ph
1k
Ph Ph
1l
Ph
3k
Ph
Ar = 4-fluorophenyl
It is also known that TfOH-catalyzed hydroamination of alkenes
and 1,3-dienes to afford amine products in good yields.18 Thus,
TfOH generated from sulfonamide and AgOTf may catalyze the
hydroamination of cyclohexadienic sulfonamide 1 to afford hexa-
hydroindole 3 (Scheme 1). To examine this possibility, cyclo-
hexadienic sulfonamide 1b was treated with TfOH in refluxing
toluene for 4 h. The nitrogen heterotricyclic compound 7 was iso-
lated in 65% yield (Scheme 2). The product of the relative stereo-
chemistry as depicted was obtained as a single diastereomer, which
is derived from hydroamination and hydroarylation of the conju-
gated diene. The structure elucidation of 7 was established by X-ray
diffraction analysis.
In order to examine the scope and limitation of the intra-
molecular 1,4-hydroamination, the parent compound 8 was treated
with 5 mol % of Ph3PAuCl/AgOTf in refluxing toluene for 15 h to
generate 2-toluenesulfonyl-2-azabicyclo[3.3.1]non-7-ene (9) in
60% isolated yield (Scheme 3). The morphan derivative 919 was
resulted from addition of the sulfonamide at the internal position of
the cyclohexadiene ring and is consistent with the regioselectivity
of gold-catalyzed intermolecular addition of N-nucleophiles to 1,3-
dienes.14 However, two phenyl groups presenting on the tether of
intermediate 6 (Fig.1) may increase steric congestion of the bridged
skeleton, the sulfonamide reverses and adds at the terminal posi-
tion of the diene to afford hexahydroindole derivatives. Moreover,
treatment of the cyclohexadienic sulfonamide 8 with TfOH in tol-
uene at room temperature for 5 h produce both 1,2-hydro-
amination product 9 and 1,4-hydroamination product 1017c in
a ratio of 1:1 and in 60% total isolated yield (Scheme 4).
2.3. Synthesis of octahydrocylohepta[b]pyrroles via gold(I)-
catalyzed intramolecular 1,4-hydroamination of cyclo-
hepta-1,3-dienes
The chemistry can be applied to synthesis of octahy-
drocyclohepta[b]pyrroles from seven-membered ring substrates.
As shown in Scheme 1, cycloheptadienic arylsulfonamides 1g–j
underwent 1,4-hydroamination using the same reaction protocols
to provide octahydrocyclohepta[b]pyrrole derivatives 3g–j, re-
spectively, as the only stereoisomer in each case and in good yields
(78–86%). NOESY (nuclear Overhauser enhancement spectroscopy)
experiments provided the initial evidence for support of all-syn
relationship between two hydrogen atoms at the fused carbons of
3g–j. The structure elucidations of 3g–j were further confirmed by
X-ray diffraction analysis.
Interestingly, substrate 1k, possessing a para fluoro atom at the
phenyl ring, generated the octahydrocyclohepta[b]pyrrole de-
rivative 3k in 82% yield under the same reaction conditions. Com-
pound 1k may undergo double bond rearrangement assisted by the
catalytic gold species to give 1l, which underwent gold(I)-catalyzed
1,4-hydroamination as those found for 3g–j to produce the octa-
hydrocyclohepta[b]pyrrole derivative 3k. The structure of 3k was
proved by X-ray diffraction analysis.
3. Conclusions
Results of gold(I)-catalyzed intramolecular 1,4-hydroamination
of cyclohexa-1,3-dienes 1a–f are listed in Scheme 1. The relative
In conclusion, a gold(I)-catalyzed intramolecular regio- and
stereoselective hydroamination of cyclic dienes containing a ger-
minal diphenyl group has been successfully developed. Intra-
molecular addition of the arylsulfonamide occurred at the terminal
position of the cyclohexa-1,3-diene in the presence of a catalytic
Ts
5% TfOH
Toluene, r.t., 5 h, 60 %
Ts
N
+
NHTs
N
amount of Ph3PAuCl/AgOTf to generate an
termediate. Allylic rearrangement of the
1-allylgold species fol-
lowed by triflate-assisted proton transfer followed by replacement
h
1-allylgold in-
9
10
8
h
Scheme 4. Intramolecular TfOH-catalyzed 1,2- and 1,4-hydroamination of 8.

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M.-C.P. Yeh et al. / Tetrahedron 65 (2009) 4789–4794
of the double bond of the
h
2-alkene gold intermediate with triflate
calcd for C26H25NO2S 415.1606, found 415.1601. Crystals suitable for
X-ray diffraction analysis were grown from methylenechloride and
hexanes.
afforded hexahydroindoles. Under the same reaction conditions,
intramolecular 1,4-hydroamination of cycloheptadienic arylsulfo-
namides furnished octahydrocyclohepta[b]pyrroles in high ster-
eoselective fashion and in good yields. Hydroamination of the
parent cyclohexadienic sulfonamide without a germinal diphenyl
group proceeds in a 1,2-addition fashion to afford a bridged aza-
bicyclic ring system.
4.2.2. (ꢁ)-(3aS,8aR)-3,3-Diphenyl-1-(4-methylphenylsulfonyl)-
1,3,3a,4,5,7a-hexahydro-1H-indole (3b)
The crude mixture obtained from intramolecular 1,4-hydra-
mination of 1b (429.6 mg, 1.0 mmol) was purified by flash column
chromatography (silica gel, gradient elution: 10–30% ethyl acetate/
hexanes) to give 3b (378 mg, 0.88 mmol, 88%) as a yellow solid:
mp 188–190 ꢀC; IR (CH2Cl2) 3432, 2372, 2092, 1654, 1340,
4. Experimental section
4.1. General experimental information
1159 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.39 (d, J¼8.1 Hz, 2H), 7.20
(t, J¼8.1 Hz, 2H), 7.13–6.94 (m, 10H), 6.23–6.20 (m, 1H), 5.96 (m,
1H), 4.39 (d, J¼10.8 Hz, 1H), 4.26 (d, J¼10.8 Hz, 1H), 4.14 (br s, 1H),
3.08 (dt, J¼12.6, 4.4 Hz, 1H), 2.31 (s, 3H), 2.02–1.85 (m, 2H), 1.40–
1.37 (m, 1H), 1.28–1.15 (m, 1H); 13C NMR(100 MHz, CDCl3)
All reactions were conducted in oven-dried glassware under
a nitrogen atmosphere unless otherwise indicated. Anhydrous
solvents or reaction mixtures were transferred via an oven-dried
syringe or cannula. Toluene was predried by molecular sieves and
then by passing through an Al2O3 column.20 Flash column chro-
matography, following the method of Still, was carried out with E.
Merck silica gel (Kieselgel 60, 230–400 mesh) using the indicated
solvents.21 1H nuclear magnetic resonance (NMR) spectra were
obtained with Bruker-AC 400 (400 MHz) and 500 (500 MHz)
spectrometers. The chemical shifts are reported in parts per million
with either tetramethylsilane (0.00 ppm) or CDCl3 (7.26 ppm) as
internal standard. 13C NMR spectra were recorded with Bruker-AC
400 (100 MHz) and 500 (125 MHz) spectrometers with CDCl3
(77.0 ppm) as the internal standard. Infrared (IR) spectra were
recorded with a JASCO IR-700 spectrometer. Mass spectra were
acquired on a JEOL JMS-D 100 spectrometer at an ionization po-
tential of 70 eV and were reported as mass/charge (m/e) with
percent relative abundance. High-resolution mass spectra were
obtained with an AEI MS-9 double-focusing mass spectrometer and
a JEOL JMS-HX 110 spectrometer at the Department of Chemistry,
Central Instrument Center, Taichung, Taiwan.
d
144.86, 143.57, 142.47, 134.98, 130.39, 129.23, 128.47, 128.42,
127.40, 126.88, 126.66, 126.29, 126.14, 125.81, 56.73, 56.66, 56.02,
43.62, 24.32, 21.65, 21.38; MS (EI) m/z (rel intensity) 429.0 (Mþ,
69), 274.1 (67), 246.1 (49), 245.0 (40), 193.0 (70), 180.0 (38), 167.0
(64), 165.0 (38), 115.0 (42), 91.0 (100); HRMS (EI) m/z calcd for
C27H27NO2S 429.1763, found 429.1765. Crystals suitable for X-ray
diffraction analysis were grown from methylenechloride and
hexanes.
4.2.3. (ꢁ)-(3aS,8aR)-3,3-Diphenyl-1-(4-methoxyphenylsulfonyl)-
1,3,3a,4,5,7a-hexahydro-1H-indole (3c)
The crude mixture obtained from intramolecular 1,4-hydrami-
nation of 1c (445.6 mg, 1.0 mmol) was purified by flash column
chromatography (silica gel, gradient elution: 10–30% ethyl acetate/
hexanes) to give 3c (380 mg, 0.85 mmol, 85%) as a yellow solid: mp
195–197 ꢀC; IR (CH2Cl2) 3422, 3090, 1654, 1498, 1339, 1257,
1154 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.44 (d, J¼8.8 Hz, 2H), 7.21
(t, J¼7.4 Hz, 2H), 7.14–7.07 (m, 3H), 7.05–6.98 (m, 5H), 6.63 (d,
J¼8.8 Hz, 2H), 6.22–6.19 (m, 1H), 5.97–5.95 (m, 1H), 4.40 (d,
J¼10.8 Hz, 1H), 4.25 (d, J¼10.8 Hz, 1H), 4.14 (t, J¼4.7 Hz, 1H), 3.81 (s,
3H), 3.08 (dt, J¼12.6, 4.6 Hz, 1H),1.98–1.89 (m, 2H), 1.41–1.37 (m,
4.2. Representative procedure for gold(I)-catalyzed
intramolecular 1,4-hydroamination of cyclic-1,3-dienes
1H), 1.27–1.16 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 162.21, 145.00,
To an oven-dried 50 mL round-bottom flask equipped with
a stirrer bar and capped with a rubber septa were added cyclohexa-
1,3-diene sulfonamide 1a (415.5 mg,1.0 mmol) and AgOTf (12.5 mg,
0.05 mmol). The apparatus was evacuated (oil pump) and filled
with nitrogen three times. To the reaction mixture was then added
via syringe Ph3PAuCl (24.7 mg, 0.05 mmol) in 20 mL of toluene. The
resulting mixture was stirred at 80 ꢀC until all 1a was consumed
(typically 18 h). The reaction mixture was filtered through a bed of
Celite. The filtrate was concentrated in vacuo to give the crude
mixture.
143.61, 130.35, 129.85, 128.93, 128.54, 128.43, 127.43, 126.73, 126.37,
126.16, 126.10, 113.81, 56.74, 56.06, 55.39, 43.68, 24.33, 21.69; MS
(EI) m/z (rel intensity) 445.2 (Mþ, 100), 274.2 (83), 246.2 (49), 193.1
(72), 171.0 (43), 167.1 (82), 165.1 (54), 115.1 (55), 91.1 (71), 77.0 (54);
HRMS (EI) m/z calcd for C27H27NO3S 445.1711, found 445.1717.
Crystals suitable for X-ray diffraction analysis were grown from
methylenechloride and hexanes.
4.2.4. (ꢁ)-(3aS,8aR)-3,3-Diphenyl-1-(4-fluorophenylsulfonyl)-
1,3,3a,4,5,7a-hexahydro-1H-indole (3d)
The crude mixture obtained from intramolecular 1,4-hydrami-
nation of 1d (433.5 mg, 1.0 mmol) was purified by flash column
chromatography (silica gel, gradient elution: 10–30% ethyl acetate/
hexanes) to give 3d (347 mg, 0.80 mmol, 80%) as a yellow solid: mp
189–193 ꢀC; IR (CH2Cl2) 3429, 2360, 2104, 1642, 1592, 1492,
4.2.1. (ꢁ)-(3aS,8aR)-3,3-Diphenyl-1-(phenylsulfonyl)-
1,3,3a,4,5,7a-hexahydro-1H-indole (3a)
The crude mixture obtained from intramolecular 1,4-hydrami-
nation of 1a (415.5 mg, 1.0 mmol) was purified by flash column
chromatography (silica gel, gradient elution: 10– 30% ethyl acetate/
hexanes) to give 3a (370 mg, 0.89 mmol, 89%) as a yellow solid: mp
172–174 ꢀC; IR (CH2Cl2) 3433, 2093, 1638, 1445, 1341, 1160 cmꢂ1; 1H
1164 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.49 (dd, J¼8.6, 5.2 Hz, 2H),
7.21 (t, J¼7.5 Hz, 2H), 7.14–6.99 (m, 8H), 6.82 (t, J¼8.6 Hz, 2H), 6.19
(m, 1H,), 6.01–5.99 (m, 1H), 4.42 (d, J¼10.9 Hz, 1H), 4.26 (d,
J¼10.9 Hz, 1H), 4.15 (m, 1H), 3.13–3.09 (m, 1H), 2.06–1.91 (m, 2H),
1.39–1.36 (m, 1H), 1.19 (qd, J¼12. 6, 5.2 Hz, 1H); 13C NMR (100 MHz,
NMR (400 MHz, CDCl3)
d
7.53 (d, J¼7.5 Hz, 2H), 7.34 (t, J¼7.5 Hz,
1H), 7.23–7.18 (m, 4H), 7.13–7.10 (m, 3H), 7.04–6.99 (m, 5H), 6.21
(dt, J¼9.9, 2.0 Hz, 1H), 5.97–5.95 (m, 1H), 4.35 (q, J¼10.8 Hz, 2H),
4.16 (t, J¼4.6 Hz, 1H), 3.09 (dt, J¼12.8, 4.5 Hz, 1H), 2.02–1.89 (m,
2H), 1.43–1.39 (m, 1H), 1.19 (qd, J¼12.7, 5.9 Hz, 1H); 13C NMR
CDCl3)
d 165.81, 163.29, 144.76, 143.33, 134.17, 134.14, 130.70,
129.48, 129.39, 128.61, 128.50, 127.31, 126.67, 126.30, 126.25, 126.07,
115.86, 115.64, 56.89, 56.75, 56.13, 43.63, 24.34, 21.71; MS (EI) m/z
(rel intensity) 433.2 (Mþ, 46), 274.2 (66), 243.1 (57), 205.1 (60),
180.1 (34), 167.1 (87), 165.1 (96), 159.0 (59), 95.0 (100), 91.1 (53);
HRMS (EI) m/z calcd for C26H24NO2SF 433.1511, found 433.1508.
Crystals suitable for X-ray diffraction analysis were grown from
methylenechloride and hexanes.
(100 MHz, CDCl3)
d 144.74, 143.45, 138.38, 131.99, 130.55, 128.60,
128.58, 128.45, 127.43, 126.90, 126.58, 126.41, 126.20, 126.05, 56.73,
56.62, 56.02, 43.80, 24.31, 21.65; MS (EI) m/z (rel intensity) 415.1
(Mþ, 58), 274.1 (87), 248.1 (100), 205.1 (59), 193.1 (87), 178.0 (68),
167.0 (92), 165.0 (74), 115.0 (82), 91.0 (85), 77.0 (79); HRMS (EI) m/z

M.-C.P. Yeh et al. / Tetrahedron 65 (2009) 4789–4794
4793
4.2.5. (ꢁ)-(3aS,8aR)-3,3-Diphenyl-1-(3-nitrophenylsulfonyl)-
4.2.8. (ꢁ)-(3aS,8aR)-3,3-Diphenyl-1-(4-methoxysulfonyl)-
1,2,3,3a,4,5,6,8a-octahydrocyclohepta[b]pyrrole (3i)
1,3,3a,4,5,7a-hexahydro-1H-indole (3e)
The crude mixture obtained from intramolecular 1,4-hydra-
mination of 1e (460.5 mg, 1.0 mmol) was purified by flash column
chromatography (silica gel, gradient elution: 10–30% ethyl acetate/
hexanes) to give 3e (387 mg, 0.84 mmol, 84%) as a yellow solid:
mp 202–204 ꢀC; IR (CH2Cl2) 3433, 2091, 1735, 1637, 1528,
The crude mixture obtained from intramolecular 1,4-hydrami-
nation of 1i (459.2 mg, 1.0 mmol) was purified by flash column
chromatography (silica gel, gradient elution: 10–30% ethyl acetate/
hexanes) to give 3i (386 mg, 0.84 mmol, 84%) as a yellow solid: mp
152–154 ꢀC; IR (CH2Cl2) 2943, 2066, 1637, 1596, 1497, 1444, 1345,
1350 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d
8.29 (t, J¼1.8 Hz, 1H),
1261, 1159, 1026, 702 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 7.76 (d,
8.16–8.14 (m, 1H), 7.88 (d, J¼7.8 Hz, 1H), 7.41 (t, J¼8.0 Hz, 1H), 7.22
(t, J¼7.3 Hz, 2H), 7.12 (t, J¼7.4 Hz, 1H), 7.03 (d, J¼7.4 Hz, 2H), 6.96
(d, J¼7.3 Hz, 2H), 6.93–6.84 (m, 3H), 6.28–6.24 (m, 1H), 6.08–6.04
(m, 1H), 4.49 (d, J¼14.4 Hz, 1H), 4.29–4.24 (m, 2H), 3.13 (dt,
J¼13.5, 4.2 Hz, 1H), 2.11–2.07 (m, 1H), 2.01–1.93 (m, 1H), 1.36–1.33
(m, 1H), 1.16 (qd, J¼12.8, 5.1 Hz, 1H); 13C NMR (100 MHz, CDCl3)
J¼6.8 Hz, 2H), 7.25–7.13 (m, 8H), 7.05 (d, J¼10.7 Hz, 2H), 6.96 (d,
J¼8.8 Hz, 2H), 5.64 (ddd, J¼10.9, 3.6, 2.6 Hz, 1H), 5.26–5.19 (m, 1H),
4.58 (d, J¼9.8 Hz, 1H), 4.38 (d, J¼9.7 Hz, 1H), 3.86 (s, 3H), 3.10 (d,
J¼9.7 Hz, 1H), 2.84 (ddd, J¼12.2, 10.2, 4.4 Hz, 1H), 2.18–2.12 (m, 1H),
2.00–1.94 (m, 1H), 1.78–1.72 (m, 1H), 1.57–1.50 (m, 2H), 1.05–1.00
(m, 1H); 13C NMR (100 MHz, CDCl3)
d 162.99, 145.52, 143.28, 131.99,
d
147.96, 144.38, 142.85, 139.93, 132.38, 131.15, 129.50, 128.54,
129.96, 129.68,128.34, 127.46,127.25, 126.97, 126.59, 126.39, 124.70,
114.22, 61.00, 60.02, 55.51, 55.19, 48.86, 26.56, 24.95, 21.11; MS (EI)
m/z (rel intensity) 459.3 (Mþ, 41), 395.3 (26), 366.2 (29), 288.2
(100), 261.2 (14), 205.1 (12), 193.1 (30), 180.1 (29), 171.0 (44), 91.1
(40); HRMS (EI) m/z calcd for C28H29NO3S 459.1863, found
459.1868. Crystals suitable for X-ray diffraction analysis were
grown from ethyl acetate and hexanes.
128.48, 127.08, 126.57, 126.50, 126.31, 125.77, 121.97, 57.22, 56.90,
56.26, 43.33, 24.24, 21.75; MS (EI) m/z (rel intensity) 460.0 (Mþ,
25), 274.1 (96), 245.0 (84), 193.0 (51), 180.0 (52), 178.0 (50), 167.0
(100), 165.0 (99), 122.0 (58), 115.0 (61), 91.0 (63); HRMS (EI) m/z
calcd for C26H24N2O4S 460.1457, found 460.1461. Crystals suitable
for X-ray diffraction analysis were grown from methylenechloride
and hexanes.
4.2.9. (ꢁ)-(3aS,8aR)-3,3-Diphenyl-1-(4-nitrophenylsulfonyl)-
1,2,3,3a,4,5,6,8a-octahydrocyclohepta[b]pyrrole (3j)
4.2.6. (ꢁ)-(3aS,8aR)-3,3-Diphenyl-1-(phenylsulfonyl)-
1,2,3,3a,4,5,6,8a-octahydrocyclohepta[b]pyrrole (3g)
The crude mixture obtained from intramolecular 1,4-hydrami-
nation of 1j (474.2 mg, 1.0 mmol) was purified by flash column
chromatography (silica gel, gradient elution: 10–30% ethyl acetate/
hexanes) to give 3j (370 mg, 0.78 mmol, 78%) as a yellow solid: mp
The crude mixture obtained from intramolecular 1,4-hydrami-
nation of 1g (429.2 mg, 1.0 mmol) was purified by flash column
chromatography (silica gel, gradient elution: 10–30% ethyl acetate/
hexanes) to give 3g (370 mg, 0.86 mmol, 86%) as a yellow solid: mp
234–237 ꢀC; IR (CH2Cl2) 2092, 1654, 1499, 1458, 1350, 1165 cmꢂ1
;
174–176 ꢀC; IR (CH2Cl2) 2093, 1638 cmꢂ1
CDCl3)
;
1H NMR (400 MHz,
1H NMR (400 MHz, CDCl3)
d
8.32 (d, J¼8.8 Hz, 2H), 7.97 (d, J¼8.8 Hz,
d
7.84 (d, J¼7.4 Hz, 2H), 7.62–7.58 (m, 1H), 7.54–7.50 (m, 2H),
2H), 7.26–7.02 (m, 10H), 5.66 (ddd, J¼11.0, 3.5, 2.5 Hz, 1H), 5.33–
5.27 (m, 1H), 4.62 (br d, J¼9.1 Hz, 1H), 4.44 (d, J¼9.9 Hz, 1H), 3.21 (d,
J¼9.9 Hz, 1H), 3.12–3.09 (m, 1H), 2.92 (ddd, J¼11.9, 9.7, 4.1 Hz, 1H),
2.20–2.14 (m, 1H), 2.03–1.98 (m, 1H), 1.76–1.71 (m, 1H), 1.53–1.49
(m, 1H), 1.41 (t, J¼7.2 Hz, 1H), 1.15–1.09 (m, 1H); 13C NMR (100 MHz,
7.26–7.16 (m, 8H), 7.04 (d, J¼7.0 Hz, 2H), 5.65 (dt, J¼10.9, 3.0 Hz,
1H), 5.27–5.21 (m, 1H), 4.62 (br d, J¼9.4 Hz, 1H), 4.41 (d, J¼9.7 Hz,
1H), 3.12 (d, J¼9.7 Hz, 1H), 2.84 (td, J¼11.1, 4.4 Hz, 1H), 2.19–2.11
(m, 1H), 2.03–1.94 (m, 1H), 1.79–1.73 (m, 1H), 1.58–1.47 (m, 2H),
1.09–0.99 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
145.45, 143.20,
CDCl3) d 150.19, 144.99, 142.91, 141.89, 130.96, 129.29, 128.93,
135.86, 132.85, 131.80, 129.69, 129.10, 128.39, 127.89, 127.31, 126.99,
126.67,126.48,124.85, 61.00, 60.16, 55.22, 48.98, 26.62, 24.94, 21.13;
MS (EI) m/z (rel intensity) 429.3 (Mþ, 13), 336.2 (14), 260.2 (19),
194.1 (19),193.1 (100),178.1 (13),167.1 (19),115.1 (20), 91.1 (18), 77.0
(21); HRMS (EI) m/z calcd for C27H27NO2S 429.1749, found 429.1756.
Crystals suitable for X-ray diffraction analysis were grown from
ethyl acetate and hexanes.
128.54, 127.58, 126.90, 126.68, 125.65, 124.33, 60.95, 60.75, 55.44,
48.89, 26.44, 24.73, 21.37; MS (EI) m/z (rel intensity) 474.1 (Mþ, 15),
409.1 (24), 381.0 (25), 288.1 (100), 210.1 (19), 180.0 (27), 178.0 (34),
167.0 (27), 165.0 (37), 91.0 (40); HRMS (EI) m/z calcd for
C27H26N2O4S 474.1613, found 474.1622. Crystals suitable for X-ray
diffraction analysis were grown from ethyl acetate and hexanes.
4.2.10. Azatricyclic compound (7)
4.2.7. (ꢁ)-(3aS,8aR)-3,3-Diphenyl-1-(4-methylsulfonyl)-
To a solution of 1b (429 mg, 1.0 mmol) in 30 ml of toluene was
added 0.005 ml of HOTf. The mixture was refluxed under a nitrogen
untill no 1b was detected on TLC (ca. 4 h). Removal of the solvent on
rotary evaporator gave the crude mixture. The crude mixture was
purified by flash column chromatography (silica gel, gradient elu-
tion: 10–20% ethyl acetate/hexanes) to give 7 (270 mg, 0.63 mmol,
65%) as a white solid: mp 209–211 ꢀC; IR (CH2Cl2) 2930, 2863, 1598,
1,2,3,3a,4,5,6,8a-octahydrocyclohepta[b]pyrrole (3h)
The crude mixture obtained from intramolecular 1,4-hydra-
mination of 1h (443.2 mg, 1.0 mmol) was purified by flash column
chromatography (silica gel, gradient elution: 10–30% ethyl ace-
tate/hexanes) to give 3h (368 mg, 0.83 mmol, 83%) as a yellow
solid: mp 173–175 ꢀC, IR (CH2Cl2) 3088, 3059, 2861, 2104, 1638,
1599, 1495, 1477, 1445, 1346, 1163 cmꢂ1
CDCl3)
;
1H NMR (400 MHz,
1343,1155,1104 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.82 (d, J¼8.1 Hz,
d
7.71 (d, J¼8.2 Hz, 2H), 7.35–7.15 (m, 10H), 7.04 (d,
2H), 7.34 (d, J¼8.1 Hz, 2H), 7.23–7.18 (m, 2H), 7.15–7.09 (m, 3H),
7.08–7.05 (m, 1H), 7.00–6.97 (m, 1H), 6.75–6.71 (m, 2H), 4.42 (d,
J¼11.3 Hz, 1H), 4.23 (dt, J¼9.8, 7.4 Hz, 1H), 4.04 (d, J¼11.3 Hz, 1H),
2.97 (m,1H), 2.45 (s, 3H), 2.30–2.24 (m,1H),1.90–1.84 (m,1H),1.75–
1.71 (m, 1H), 1.70–1.57 (m, 3H), 1.14–1.02 (m, 1H); 13C
J¼8.0 Hz, 2H), 5.65 (ddd, J¼10.8, 3.52, 2.64 Hz, 1H), 5.26–5.20 (m,
1H), 4.59 (br.d, J¼9.9 Hz, 1H), 4.38 (d, J¼9.7 Hz, 1H), 3.09 (d,
J¼9.7 Hz, 1H), 3.83 (ddd, J¼10.2, 12.1, 4.6 Hz, 1H), 2.42 (s, 3H),
2.18–2.12 (m, 1H), 2.01–1.95 (m, 1H), 1.77–1.72 (m, 1H), 1.56–1.41
(m, 2H), 1.08–0.98 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
145.51,
NMR(100 MHz, CDCl3) d 147.64, 143.28, 142.69, 140.17, 136.90,
143.60, 143.26, 132.82, 131.95, 129.99, 129.70, 129.68, 128.72,
128.34, 127.91, 127.55, 127.27, 126.98, 126.59, 126.41, 124.71, 60.97,
60.07, 55.19, 48.89, 26.57, 24.96, 21.50, 21.12; MS (EI) m/z (rel
intensity) 443.1 (Mþ, 29), 379.2 (26), 378.1 (17), 350.0 (19), 288.1
(79), 178.0 (21), 165.0 (20), 101.1 (24), 91.0 (61), 86.1 (100); HRMS
(EI) m/z calcd for C28H29NO2S 443.1919, found 443.1917. Crystals
suitable for X-ray diffraction analysis were grown from ethyl
acetate and hexanes.
129.89, 129.73, 128.09, 127.87, 127.65, 127.34, 126.95, 126.82, 126.09,
62.63, 60.37, 54.62, 49.43, 33.13, 30.51, 24.91, 24.63, 21.50; MS (EI)
m/z (rel intensity) 429.3 (Mþ, 20), 274.2 (88), 247.2 (59), 246.2 (30),
245.2 (30), 217.1 (53), 205.1 (30), 203.1 (30), 202.1 (31), 91.0 (100);
HRMS (EI) m/z calcd for C27H27NO2S 429.1764, found 429.1763. Anal.
Calcd for C27H27NO2S: C, 75.49; H, 6.34; N, 3.26; S, 7.46. Found: C,
75.19; H, 6.15; N, 3.26; S, 7.74. Crystals suitable for X-ray diffraction
analysis were grown from methylenechloride and hexanes.

4794
M.-C.P. Yeh et al. / Tetrahedron 65 (2009) 4789–4794
4. (a) Amombo, M. O.; Hausherr, A.; Reissig, H. U. Synlett 1999, 1871; (b) Davis, I.
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4.2.11. 2-Toluenesulfonyl-2-azabicyclo[3.3.1]non-7-ene (9)
The crude mixture obtained from the gold-catalyzed intra-
molecular 1,4-hydramination of 8 (277 mg, 1 mmol) was purified
by flash column chromatography (silica gel, gradient elution: 5–10%
ethyl acetate/hexanes) to give 9 (167 mg, 0.6 mmol, 60%) as a light
yellow oil: IR (CH2Cl2) 3026, 2937, 1598, 1344, 1159, 1093 cmꢂ1; 1H
6. (a) Krause, N.; Morita, N. Org. Lett. 2004, 6, 4121; (b) Yamamoto, Y.; Patil, N. T.;
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NMR (400 MHz, CDCl3)
d
7.67 (d, J¼8.1 Hz, 2H), 7.27 (d, J¼8.1 Hz,
2H), 5.88 (dt, J¼9.65, 3.16 Hz, 1H), 5.22 (m, 1H), 4.39 (m, 1H), 3.60
(dd, J¼12.2, 5.6 Hz, 1H), 2.95 (td, J¼12.8, 3.3 Hz, 1H), 2.41 (s, 3H),
2.33–2.25 (m, 1H), 2.08 (m, 1H), 1.87–1.78 (m, 3H), 1.71–1.66 (m,
1H), 1.53–1.49 (m, 1H); 13C NMR(100 MHz, CDCl3)
d 142.85, 137.36,
133.43, 129.45, 127.09, 122.37, 46.84, 38.48, 32.19, 31.24, 30.93,
24.16, 21.40; MS (EI) m/z (rel intensity) 277.1 (Mþ, 44), 269.0 (8),
255.0 (5), 243.5 (16), 236.1 (100), 234.1 (27), 231.0 (38), 223.1 (27);
HRMS (EI) m/z calcd for C15H19NO2S 277.1135, found 277.1133.
10. (a) Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2003, 935; (b) Doye, S. Synlett 2004,
1653; (c) Odom, A. L. Dalton Trans. 2005, 225; (d) Ackermann, L.; Bergman, R.
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Takaya, J.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 5756; (c) Field, L. D.; Mes-
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2004, 43, 4099; (i) Carreira, E. M.; Waser, J. J. Am. Chem. Soc. 2004, 126, 5676; (j)
Yamamoto, Y.; Patil, N. T.; Huo, Z.; Bajracharya, G. B. J. Org. Chem. 2006, 71, 3612.
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Acknowledgements
This work was supported by grants from the National Science
Council (NSC 95-2113-M-003-003).
Supplementary data
1H and 13C NMR spectra of compounds 3a–e, 3g–k, and 7 and
X-ray crystallographic information files for compounds 3a–e, 3g–k,
and 7 are provided, Supplementary data associated with this article
can be found in the online version at doi:10.1016/j.tet.2009.04.064.
13. Shibasaki, M.; Qin, H.; Yamagiwa, N.; Matsunage, S.; Kawatsura, M. J. Am. Chem.
Soc. 2006, 128, 1611.
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