Synthesis of 2,3-dihydro-1: H -pyrroles by intramolecular cyclization of N -(3-butynyl)-sulfonamides

Article abstract of DOI:10.1039/c7ob00528h

Hydroamination of 3-butynamine derivatives to give non-aromatic 2,3-dihydropyrroles was achieved by using PdCl₂ or AuCl as the catalyst. With microwave-assisted heating, up to 92% isolated yield was obtained from this intramolecular 5-endo-dig

Full text of DOI:10.1039/c7ob00528h

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Synthesis of 2,3-dihydro-1H-pyrroles by intramolecular cyclization
of N-(3-butynyl)- sulfonamides
Min-Ching Chung,a Yung-Hsiang Chan,a Wen-Jung Changa and Duen-Ren Hou a,*
Received 00th January 20xx,
Accepted 00th January 20xx
Hydroamination of 3-butynamine derivatives to give non-aromatic 2,3-dihydropyrroles was achieved by using PdCl2 or
AuCl as the catalysts. With microwave-assisted heating, up to 92% isolated yield was obtained from this intramolecular 5-
endo-dig cyclisation. The cyclopentane- and cyclohexane-fused 2,3-dihydropyrroles were transformed into the
corresponding N-tosyl-pyrrolidine-2-carboxylic acids.
DOI: 10.1039/x0xx00000x
www.rsc.org/
This wor k
R
Introduction
PdCl2 or AuCl
Pyrrole, dihydropyrrole and pyrrolidine are five membered N-
heterocycles, widely found in dye, drug and biological
molecules.1 The development of new synthetic methods to
access these compounds has attracted the attentions of
organic chemists.2 Metal catalyzed, intramolecular 5-endo-dig
cyclisation of 2-ethynylanilines has been widely applied to
generate the corresponding indoles and their derivatives,3-6
since the stability of the products increased by the conjugation
of the aromatic system. This intramolecular cyclisation
reaction could be also facilitated by the formation of aromatic
pyrroles.7 Without the conjugation or formation of an aromatic
system, the corresponding hydroamination of 3-butynamine or
its derivatives is difficult and less explored.8 Recently, gold and
platinum complexes were found to be active in catalysing the
intramolecular hydroaminations of non-aromatic compounds.9
We found that under microwave irradiation, PdCl2 and AuCl
catalysed the intramolecular cyclisation of N-(3-alkynyl)-
R
(CH2)n
(CH2)n
microwave, CH3CN
85 °C, 20 min
N
Ts
NHTs
n = 0, 3, 4; R = alkyl, aryl
yield up to 92%
CO2H
(CH2)n
N
Ts
n = 4, perhydroindolic acid
n = 3, 2-azabicyclo[3.3.0]octane-3-carboxylic acid
Scheme 1 Metal catalyzed cyclization to give 5-membered N-heterocycles
The derivatives of cycloalkane-fused pyrrolidine, such as
perhydroindolic
acid
and
2-azabicyclo[3.3.0]octane-3-
carboxylic acid, are found in medicines and natural products
with biological activities (Figure 1). For example, tradolapril
and rampiril are angiotensin-converting enzyme (ACE)
inhibitors to treat hypertension.10,11 S-17092 is a prolyl
endopeptidase inhibitor with therapeutic potential to treat
cognitive deficits associated with aging or neurodegenerative
sulfonamides to give 2,3-dihydropyrroles (Scheme 1).
Cy clization with aromatic system
R'
diseases.12 Aeruginosins are
a family of marine natural
Cu(II), Ag (I), Au(I)
Pd(II), Rh(I) and Pt (IV)
products showing serine protease inhibition activity.13 Here,
we report that the intramolecular cyclisation of N-(3-alkynyl)-
sulfonamides and the following two transformations afforded
the cyclopentane and cyclohexane-fused pyrrolidine-2-
carboxylic acids with good efficiency and diastereoselctivity.
R'
N
R
NR1R2
R = H, Ts, Boc, Ac, etc.
R1= H, R2 = Ts, Boc, Ac, etc.
or R1 = R2 = N
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Scheme 2. Preparation of N-substituted 3-heptynamines
Table 1. Formation of 2,3-dihydro-1H-pyrrole from 3
entry
1
substrate, R
3a, Ts
solvent
CH3OH
EtOH
product
yield (%)a
4a
4a
5a
4b
-
61
27
53
36
0 b
28
8
2
3a, Ts
3
3a, Ts
CH2Cl2
CH3OH
CH3OH
CH2Cl2
CH3OH
CH3OH
CH3OH
CH3OH
4
3b, Ms
3c, Boc
3c, Boc
3a, Ts
5
6
5c
4a
-
7c
8d
9e
10f
3a, Ts
0b
Figure 1. Bioactive molecules exhibiting the cycloalkane-fused pyrrolidine motif
.
3a, Ts
5a
85
3a, Ts
5a
85
aIsolated yields. bStarting material recovered. cPdCl2(CH3CN)2, 5 mol%.
dPdCl2(PPh3)2, 5 mol%. emicrowave-assisted heating, 70 °C, 20 min. fAuCl,
5 mol%.
Results and discussion
Starting from commercially available 3-heptynol (1), various N-
substituted 3-heptynamine derivatives (3a–3g) were prepared
(Scheme 2). In addition to the mesylation and sulfonamidation
to yield 3a, other substrates were prepared by the sequence of
mesylation, azidation and Staudinger reduction to give the
To further explore and optimize this reaction, cis-2-(1-alkynyl)-
cyclohexanamines and cyclopentanamines were prepared
from the corresponding cycloalkene oxides by the sequence of
the epoxide ring opening, Mitsunobu reaction and hydrolysis
of phthalimides (Scheme 3).16 The amino groups were then
amine,14 which was then capped as sulfonamide
carbamates (3c 3e 3g) and amides (3d 3f).
(3b),
,
,
,
converted to the N-tosyl and N-mesyl sulfonamides,
8 and 9,
The results of 3a–3g in palladium catalyzed cyclization are
summarized in Table 1. The desired 2,3-dihydropyrrole
derivative 4a was produced in anhydrous, alcoholic solvents
(entry 1 and 2). In dichloromethane, 3-heptanone 5a was
harvested (entry 3), which should be due to the hydration of
the alkyne group directed by the neighboring sulfonamide
respectively, for further cyclization study.
group.15
A lower yield (36% yield) was obtained when
methanesulfonamide 3b (entry 4) was the substrate. tert-Butyl
carbamate 3c did not yield the corresponding dihydropyrrole
in methanol but provided the ketone 5c in CH2Cl2 (entry 5 and
6, respectively). All the other amides and carbamates, 3d–3g
,
did not undergo the cyclization or hydration reactions and the
corresponding starting materials were recovered. Replacing
PdCl2 with bis(acetonitrile)dichloropalladium(II) gave a poor
yield of 4a (entry 7). Other palladium complexes containing
phosphine ligands, such as PdCl2(PPh3)2, did not promote this
cyclization (entry 8). Microwave-assisted heating or the gold (I)
catalyzed reaction provided the ketone 5a with good yields
(entries 9 and 10). We were not able to obtain better yields of
Scheme 3. Preparation of cis-1- sulfonamido-2-alkynyl-cycloalkanes.
dihydropyrroles from the linear substrates
numerous attempts.
3 in spite of
The cyclopentyl and cyclohexyl trimethylsilylacetylene (7pc
and 7hc) were also utilized to prepare aryl alkynes (Scheme 4).
Thus, the TMS group was removed to give terminal alkynes 10
,
which were converted to the required substrates by the
sequence of Sonogashira reaction,17 hydrolysis of phthalimides
and formation of sulfonamides.
2 | J. Name., 2012, 00, 1-3
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ARTICLE
entry
reactant
R2
solvent
methoda;
product
A; 12pa
A; 12pa
Bc; 12pa
B; 12pa
B; 12pa
B; 12pa
A; 13pa
B; 13pa
B; 12pb
B; 13pb
B; 12pc
B; 13pc
B; 13pd
B; 13pe
B; 13pg
B; 13ph
B; 12pi
B; 12pj
B; 12pk
yield
(%)b
8
1
2
8pa
8pa
8pa
8pa
8pa
8pa
9pa
9pa
8pb
9pb
8pc
9pc
9pd
9pe
9pg
9ph
8pi
Ph
Ph
CH3OH
CH3CN
CH3OH
CH3CN
DMF
26
48
77
67
0 d
3
Ph
4
Ph
5
Ph
6
Ph
THF
C6H4R
C6H4R
7
Ph
CH3OH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
27
71
53
37
87
84
76
70
78
65e
92
83
74
(1) H2NNH2
8
Ph
(CH2)n
n = 4
(CH2)n
(2) TsCl or MsCl
Et3N
9
n-Bu
NHTs
NHMs
10
11
12
13
14
15
16
17
18
19
n-Bu
n = 3
n = 3
4-NO2C6H4
4-NO2C6H4
4-CO2MeC6H4
4-ClC6H4
4-t-BuC6H4
4-OMe-C6H4
3-Cl-C6H4
2-Cl-C6H4
2-F-C6H4
8pc, R = 4-NO2, 77% 8hc, R = 4-NO2, 70%
8pi, R = 3-Cl, 76% 8hd, R = 4-CO2Me, 55%
8pj, R = 2-Cl, 79% 8he, R = 4-Cl, 64%
9pc, R = 4-NO2, 60%
9pd, R = 4-CO2Me, 45%
9pe, R = 4-Cl, 67%
8pk, R = 2-F, 77%
8hf, R = 4-Me, 72%
8hg, R = 4-t-Bu, 71%
8hh, R = 4-OMe, 53%
9pg, R = 4-t-Bu, 40%
9ph, R = 4-OMe, 78%
Scheme 4. Preparation of aryl alkynes.
8pj
8pk
The results for the cyclization using cylopentane derivatives 8p
and 9p were summarized in Table 2. Initially, only 8% and 26%
yields of 12pa were obtained by the conventional heating in
methanol or acetonitrile (entry 1 and 2, respectively). We
found that microwave-assisted heating was helpful to improve
the yields to 48% and 77% for the reactions in CH3OH and
CH3CN (entry 3 and 4). Although the yields varied with the
solvents (entries 3–6), acetonitrile turned out to be the choice
for this reaction (77%, entry 4). The advantages of using
microwave heating and acetonitrile were also observed in the
conversion of 9pa to 13pa (entry 7 versus 8). Alkyl substituted
alkynes 8pb and 9pb gave lower yields than the aryl-alkyl
counterparts (entries 9 and 10). The difference in yields was
insignificant for the substrates carrying a Ts or Ms group (entry
4 versus 8 and entry 11 versus 12). Good yields, up to 87%
(entry 11, 12pc), were obtained from the substrates bearing an
electron withdrawing group (entries 11–14). On the other
hand, the substrates bearing an electron donating group (4-t-
butyl, 9pg and 4-OMe, 9ph) gave moderate yields (78% and
65%, entries 15 and 16, respectively). In the reaction of 9ph to
13ph (entry 16), 10% of the starting material 9ph was
recovered, which could be contributed to the reduced
electrophilicity of the intermediate alkyne-Pd complex by the
electron donating, 4-OMe group.15a Good to excellent yields
were also observed for the 2-chloro-, 3-chloro- and 2-fluoro-
substituted aryl alkynes (entries 17–19).
aMethod A: reaction conducted in the refluxing solvent, 14 h; method B:
microwave-assisted heating, 85 °C, 20 min. bIsolated yields. cMicrowave-
assisted heating, 70 °C, 20 min. dStarting material recovered. e10%
starting material recovered.
The results using cyclohexyl alkynes 8ha-8hh are summarized
in Table 3. Conventional heating did not yield any product
(entry 1), and only 39% yield was obtained with microwave-
assisted heating (entry 2). Further attempts using PdCl2 did not
make progress. Fortunately, the combination of microwave
heating and gold(I) chloride improved the yield to 60%. Dialkyl
alkyne 8hb remained a challenging substrate (47%, entry 4),
which is consistent with the results derived from the five-
membered analogues in Table 2. Other aryl alkynes 8hc-8hg
provided moderate yields (50–64%, entries 5–9) and the
electron-rich, 4-methoxyphenyl substituted alkyne 8hh gave
the lowest yield (42%, entry 10) as expected. In general, the
yields in forming the cyclohexane-fused dihydropyrroles (Table
3) are lower than that of the cyclopentane analogues (Table 2),
which should reflect their conformational differences during
the ring-formation and is consistent with the trend observed in
radical cyclisations to generare the cycloalkane-fused furan
derivatives.18 Our studies showed that bicyclic 2,3-dihydro-
pyrroles could be prepared via the palladium or gold catalyzed,
intramolecular hydroaminations and better yields were
obtained with the alkynes conjugated with the electron
deficient aryl groups.
Table 2. Intramolecular cyclisation of 8p and 9p
Table 3. Intramolecular cyclization of 8h
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Journal Name
entry
reactant
R1
catalyst
product
yield
(%)a
0c
achieved with the Pd(II) or Au(I) catalysts, which are
commercially available and convenient to apply. Microwave-
assisted heating also benefited this disfavored 5-endo-dig
cyclization. This method has been applied to generate
cyclopentane- or cyclohexane-fused pyrrolidine-2-carboxylic
acids.
1b
2
8ha
8ha
8ha
8hb
8hc
8hd
8he
8hf
Ph
Ph
PdCl2
PdCl2
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
12ha
12ha
12ha
12hb
12hc
12hd
12he
12hf
12hg
12hh
39
3
Ph
60
4
n-Bu
47
5
4-NO2C6H4
4-CO2MeC6H4
4-ClC6H4
4-MeC6H4
4-t-BuC6H4
4-OMe-C6H4
51
6
50
7
57
Acknowledgements
8
64
9
8hg
8hh
55
This research was supported by the Ministry of Science and
Technology (NSC 101-2113-M-008-003, MOST 104-2113-
M008-003), Taiwan. We thank Ms. Ping-Yu Lin at the Institute
of Chemistry, Academia Sinica, Taiwan, and the Valuable
Instrument Center at National Central University, Taiwan, for
mass analysis.
10
42
aIsolated yields. bReaction conducted in a sealed tube, methanol, 100 °C,
14 h. cStarting material recovered.
This method was applied to the synthesis of cyclopentane- or
cyclohexane-fused N-tosyl-pyrrolidine-2-carboxylic acid 15p
and 15h, found in the structures of ramipril and S-17092
(Scheme 5). Both 12pa and 12ha were reduced to give 14p and
Experimental sections
14 h as
a
single diastereomer, respectively.19 The cis-
General information
stereochemical assignment of 14p and 14h was based on their
NOE spectra and consistent with the X-ray crystallography of
14h (Figure 2).20 The oxidation of the phenyl group with
ruthenium (III) chloride and sodium periodate provided the
All reactions involving air- or moisture-sensitive reagents or
intermediates were performed under an inert atmosphere of
nitrogen in oven-dried glassware. All reagents and solvents
were obtained from commercial suppliers and used without
further purification, if not mentioned otherwise. THF and
diethyl ether were dried over sodium, monitored with
benzophenone ketyl radical and distilled prior to use.
Dichloromethane (DCM) and toluene were dried over CaH2
desired carboxylic acids 15p and 15h 21
.
Et3SiH, TFA
(CF3CO)2O
Ph
(CH2)n
Ph
(CH2)n
N
Ts
N
Ts
and distilled prior to use. Thin layer chromatography (TLC) was
n = 3, 14p, 96%
n = 4, 14h, 98%
n = 3, 12pa
n = 4, 12ha
done using pre-coated silica gel 60 F254 plates containing a
fluorescent indicator; purification by chromatography was
done using silica gel (230-400 mesh). 1H and 13C chemical shifts
are reported in parts per million and referenced to residual
RuCl3, NaIO4
CO2H
(CH2)n
n = 3, 15p, 72%
n = 4, 15h, 67%
CCl4/MeCN/H2O
N
Ts
solvent. All spectra were obtained at 25 °C.
Microwave-assisted reactions were performed in
a
CEM
Discover single mode microwave reactor, equipped with
vertically-focused IR temperature sensor, and controlled
temperature, power and time settings were used for all
reactions.
Scheme 5 Synthesis of pyrrolidine-2-carboxylic acid.
Hept-3-yn-1-yl methanesulfonate
Methanesulfonyl chloride (164 µL, 2.14 mmol) was added
solution of 3-heptyn-1-ol (200.0 mg, 1.78 mmol),
trimethylamine (0.5 mL, 3.59 mmol) and dichloromethane (
(2)
to
a
6
mL) at -10 ºC. The reaction mixture was stirred for 1 h at -10
ºC, added with water (5 mL) and extracted with
dichloromethane (12 mL × 3). The combined organic layers
were washed with HCl(aq) (1 N, 10 mL), sat. NaHCO3(aq) (15 mL),
sat. NaCl(aq) (10 mL), dried over Na2SO4, filtered and
concentrated to give
2 as a light yellow oil (336.3 mg, 1.77
1
mmol, 99%). H NMR (CDCl3, 500 MHz) δ 0.94 (t, J = 7.4 Hz,
3H), 1.47 (q, J = 7.3 Hz, 2H), 2.08–2.11 (m, 2H), 2.58–2.62 (m,
2H), 3.01 (s, 3H), 4.24 (t, J = 6.9 Hz, 2H); 13C NMR (CDCl3, 125
MHz) δ 13.4, 20.0, 20.6, 22.1, 37.6, 67.9, 74.2, 82.9; HRMS-FAB
(m/z) calcd for [M+H]+ (C8H15O3S) 191.0742, found 191.0747.
Figure 2. ORTEP of 14h.
Conclusions
(N-(Hept-3-yn-1-yl)-4-methylbenzenesulfonamide
(3a)
A reaction mixture of compound 2 (168.1 mg, 0.88 mmol),
In summary, the hydroamination of 3-butynamine
derivatives to yield non-aromatic, 2,3-dihydropyrroles was
p-toluenesulfonamide (302.6 mg, 1.77 mmol), potassium
4 | J. Name., 2012, 00, 1-3
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carbonate (244.3 mg, 1.77 mmol) and acetonitrile (4 mL) was (t, J = 8.6 Hz, 2H), 4.93 (t, J = 1.2 Hz, 1H), 7.27 (d, J = 8.1 Hz,
heated to reflux for 15 h and concentrated. The residue was 2H), 7.66 (d, J = 8.3 Hz, 2H); 13C NMR (CDCl3, 75MHz) δ 13.8,
added with water (5 mL) and extracted with dichloromethane 20.8, 21.5, 27.1, 31.2, 50.7, 111.4, 127.4, 129.6, 134.6, 143.4,
(12 mL × 3). The combined organic layers were washed with 144.5；
HRMS-APCI (m/z) calcd for [M+Na]+ (C14H19NO2SNa)
NaOH(aq) (1.5 N, 5 mL), sat. NaCl(aq) (7 mL), dried over Na2SO4, 288.1034, found, 288.1027.
filtered and concentrated. The crude product was further 4-Methyl-N-(4-oxoheptyl)benzenesulfonamide (5a)
purified by column chromatography (SiO2,
ethyl
A reaction mixture of 3a (113.9 mg, 0.43 mmol), palladium
acetate/hexanes, 1:3; Rf 0.50) to give 3a (203.1 mg, 0.76 mmol, chloride (3.8 mg, 21 µmol) and dichloromethane (6 mL) was
87%) as a viscous liquid. 1H NMR (CDCl3, 500 MHz) δ 0.92 (t, J heated to reflux for 16 h under an atmosphere of nitrogen,
= 7.3 Hz, 3H), 1.45 (q, J = 7.3 Hz, 2H), 2.05–2.08 (m, 2H), 2.26– filtered and concentrated. The crude product was purified by
2.30 (m, 2H), 2.41 (s, 3H), 3.03 (q, J = 6.4 Hz, 2H), 4.70 (d, J = column chromatography (SiO2, ethyl acetate/hexanes, 1:2; Rf
5.6 Hz, 1H), 7.29 (d, J = 8.4Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H); 13C 0.68) to give 5a (64.8 mg, 0.23 mmol, 53%) as a colorless oil. 1H
NMR (CDCl3, 125 MHz) δ 13.5, 19.9, 20.6, 21.5, 22.2, 42.1, NMR (CDCl3, 300 MHz) δ 0.87 (t, J = 7.4 Hz, 3H), 1.48–1.61 (m,
75.8, 83.1, 127.1, 129.7, 137.0, 143.5; HRMS-ESI (m/z) calcd for 2H), 1.66–1.75 (m, 2H), 2.33 (t, J = 7.4 Hz, 2H), 2.40 (s, 3H),
[M-H]- (C14H18NO2S) 264.1058, found 264.1059.
N-(Hept-3-yn-1-yl)methanesulfonamide (3b
A reaction mixture of
2.45 (t, J = 6.9 Hz, 2H), 2.91 (q, J = 6.5 Hz, 2H), 4.67 (t, J = 6.2
Hz, 1H), 7.28 (d, J = 8.2 Hz, 2H), 7.70 (d, J=8.2 Hz, 2H); 13C NMR
)
2
(166.5 mg, 0.87 mmol), sodium (CDCl3, 75MHz) δ 13.7, 17.2, 21.5, 23.1, 39.3, 42.7, 44.8, 127.0,
azide (170.6 mg, 2.62 mmol) and DMF (6 mL) was stirred at 129.7, 136.8, 143.4, 210.7; HRMS-ESI (m/z) calcd for [M+Na]+
100 ºC for 16 h, cooled to rt, added with water (5 mL) and (C14H21NO3SNa) 306.1140, found, 306.1131.
extracted with diethyl ether (15 mL × 3). The combined organic 1-(Methylsulfonyl)-5-propyl-2,3-dihydro-1H-pyrrole
(4b)
layers were washed with sat. NaCl(aq) (20 mL), dried over A reaction mixture of 3b (28.7 mg, 0.15 mmol), palladium
Na2SO4, filtered and concentrated to yield 1-azido-3-heptyne chloride (1.3 mg, 7.3 µmol) and anhydrous methanol (5 mL)
(105.8 mg, 0.77 mmol, 88%) as a light yellow oil. 1H NMR was heated to reflux for 17 h under an atmosphere of
(CDCl3, 500 MHz) δ 0.94 (t, J = 7.3 Hz, 3H), 1.48 (q, J = 7.3 Hz, nitrogen, filtered and concentrated. The crude product was
2H), 2.08–2.12 (m, 2H), 2.41–2.44 (m, 2H), 3.32 (t, J = 6.8 Hz, purified by column chromatography
(SiO2,
ethyl
2H); 13C NMR (CDCl3, 125 MHz) δ 13.4, 19.8, 20.7, 22.1, 50.4, acetate/hexanes/Et3N; 32%, 63%, 5%, respectively; Rf 0.47) to
1
76.1, 82.6. The solution of the azide (105.8 mg, 0.77 mmol), give 4b (10.4 mg, 0.055 mmol, 36%) as a colorless oil; H NMR
triphenylphosphine (303.6 mg, 1.16 mmol) water (0.15 mL) (CDCl3, 300 MHz) δ 0.93 (t, J = 7.4 Hz, 3H), 1.50–1.63 (m, 2H),
and THF (5m L) was stirred at rt for 12 h and concentrated. The 2.28–2.33 (m, 2H), 2.44–2.52 (m, 2H), 2.83 (s, 3H), 3.81 (t, J =
crude amine was purified by column chromatography (SiO2, 8.6 Hz, 2H), 5.03–5.06 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ
ethyl acetate/hexanes, 5:1; then methanol; Rf 0.60) to give 3- 13.8, 20.6, 27.3, 30.8, 35.6, 50.8, 110.0, 144.3; HRMS-APCI
heptynamine (64.5 mg, 0.58 mmol, 75%) as a light yellow oil. (m/z) calcd for [M+H]+ (C8H16NO2S) 190.0902, found, 190.0898.
Methanesulfonyl chloride (43 µL, 0.55 mmol) was added to a (tert-Butyl (4-oxoheptyl)carbamate
(5c)
solution of 3-heptynamine (47.3 mg, 0.42 mmol), triethylamine A reaction mixture of 3c (37.2 mg, 0.18 mmol), palladium
(120 µL, 0.85 mmol) and CH2Cl2 (5 mL) at 0 ºC. The resulting chloride (1.6 mg, 9 µmol) and dichloromethane (6 mL) was
mixture was stirred at rt for 16 h, added with water (7 mL) and heated to reflux for 16 h under an atmosphere of nitrogen,
extracted with CH2Cl2 (12 mL × 3). The combined organic filtered and concentrated. The crude product was purified by
layers were washed with HCl(aq) (1.0 N, 5 mL), sat. NaCl(aq) (10 column chromatography (SiO2, ethyl acetate/hexanes, 1:3; Rf
mL), dried over Na2SO4, filtered and concentrated. The crude 0.89) to give 5c (11.0 mg, 0.048 mmol, 28%) as a colorless oil.
product was further purified by column chromatography (SiO2, 1H NMR (CDCl3, 300 MHz) δ 0.86 (t, J = 7.4 Hz, 3H), 1.41 (s, 9H),
ethyl acetate/hexanes, 1:2; Rf 0.32) to give 3b (57.4 mg, 0.30 1.51–1.61 (m, 2H), 1.69–1.78 (m, 2H), 2.36 (t, J = 7.3 Hz, 2H),
1
mmol, 72%) as a colorless oil. H NMR (CDCl3, 300MHz) δ 0.94 2.42 (t, J = 7.1 Hz, 2H), 3.09 (m, 2H), 4.55 (br, 1H); 13C NMR
(t, J = 7.2 Hz, 3H), 1.48 (q, J = 7.2 Hz, 2H), 2.08–2.13 (m, 2H), (CDCl3, 75MHz) δ 13.7, 17.3, 24.0, 28.4, 39.8, 40.1, 44.8, 77.2,
2.41–2.45 (m, 2H), 2.96 (s, 3H), 3.21 (q, J = 6.3Hz, 2H), 4.62 (br, 156.0, 210.7; HRMS-ESI (m/z) calcd for [M+Na]+
1H); 13C NMR (CDCl3, 75 MHz) δ 13.5, 20.5, 20.6, 22.4, 40.7, (C12H23NO3SNa) 252.1576, found, 252.1578.
42.3, 75.8, 83.2; HRMS-EI (m/z) calcd for [M]+ (C8H15NO2S) cis-2-Phenyl-1-tosyl-1,3a,4,5,6,6a-
189.0824, found 189.0826.
hexahydrocyclopenta[b]pyrrole
(12pa)
5-Propyl-1-tosyl-2,3-dihydro-1H-pyrrole (4a)
A suspension of 8pa (72.5 mg, 0.21 mmol), PdCl2 (2.1 mg,
A reaction mixture of 3a (184.2 mg, 0.69 mmol), palladium 10.5 µmol) and acetonitrile (2 mL) was heated to 85 ºC by the
chloride (6.1 mg, 34 µmol) and anhydrous methanol (6 mL) microwave reactor and maintained at 85 ºC for 20 min. After
was heated to reflux for 16 h under an atmosphere of cooled to rt, the solvent was remove, and the crude product
nitrogen, filtered and concentrated. The crude product was was purified by column chromatography (SiO2, ethyl
purified by column chromatography
(SiO2,
ethyl acetate/hexanes, 1:6; Rf 0.55) to give 12pa (55.8 mg, 0.16
1
acetate/hexanes/Et3N; 22.5%, 72.5%, 5%, respectively; Rf 0.60) mmol, 77% ) as a colorless solid. M.p. 93.0–93.5 ºC; H NMR
to give 4a (111.7 mg, 0.42 mmol, 61%) as a colorless oil. 1H (CDCl3, 500 MHz) δ 1.48–1.54 (m, 3H), 1.58–1.63 (m, 1H),
NMR (CDCl3, 300 MHz) δ 0.93 (t, J = 7.3 Hz, 3H), 1.52–1.64 (m, 1.95–2.06 (m, 2H), 2.40 (s, 3H), 2.85–2.89 (m, 1H), 4.47 (td, J =
2H), 2.07 (dt, J = 8.6 Hz, J = 2.3 Hz, 2H), 2.38–2.45 (m, 5H), 3.75 7.8 Hz, J = 3.8 Hz, 1H), 5.02 (d, J = 2.1 Hz, 1H), 7.24 (d, J = 8.0
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Hz, 2H), 7.30–7.35 (m, 3H), 7.47–7.50 (m, 4H); 13C NMR (CDCl3,
A solution of 12ha (52.1 mg, 0.15 mmol) and CH2Cl2 (4 mL)
125 MHz) δ 21.5, 23.2, 31.7, 35.9, 45.1, 67.8, 121.5, 127.7, was added with trifluoroacetic acid (56 µL, 0.74 mmol),
128.0, 128.4, 129.2, 133.3, 133.5, 143.4, 144.0; HRMS-ESI trifluoroacetic anhydride (104 µL, 0.74 mmol) and
(m/z) calcd for [M+Na]+ (C20H21NO2SNa) 362.1191, found triethylsilane (118 µL, 0.74 mmol) sequentially at 0 ºC. The
362.1183.
reaction mixture was stirred at rt for 13 h and concentrated.
The crude product was purified by column chromatography
(SiO2, ethyl acetate/hexanes, 1:6; Rf 0.30) to give 14h (51.4 mg,
cis-1-(Methylsulfonyl)-2-phenyl-1,3a,4,5,6,6a-
hexahydrocyclopenta[b]pyrrole (13pa)
A suspension of 9pa (31.7 mg, 0.12 mmol), PdCl2 (1.1 mg, 0.14 mmol, 98%) as a white solid. M.p. 114.0–116.0 ºC; 1H
5.8 µmol) and acetonitrile (1 mL) was heated to 85 ºC by the NMR (CDCl3, 500 MHz) δ 1.14–1.24 (m, 2H), 1.38–1.42 (m, 1H),
microwave reactor and maintained at 85 ºC for 20 min. After 1.44–1.52 (m, 1H), 1.53–1.60 (m, 2H), 1.67–1.70 (m, 1H), 1.75–
cooled to rt, the solvent was remove, and the crude product 1.82 (m, 1H), 1.92 (td, J = 13.1 Hz, J = 10.0 Hz, 1H), 2.03–2.10
was purified by column chromatography (SiO2, ethyl (m, 2H), 2.40 (s, 3H), 3.84 (dt, J = 11.4 Hz, J = 6.4 Hz, 1H), 4.59
acetate/hexanes, 1:2; Rf 0.45) to give 13pa (22.9 mg, 0.09 (dd, J = 9.8 Hz, J = 7.3 Hz, 1H), 7.19–7.23 (m, 1H), 7.24–7.31 (m,
1
mmol, 71% ) as a viscous liquid. H NMR (CDCl3, 300 MHz) δ 4H), 7.35–7.37 (m 2H), 7.64–7.66 (m, 2H); 13C NMR (CDCl3, 125
1.53–1.69 (m, 3H), 1.73–1.85 (m, 1H), 1.96–2.03 (m, 2H), 2.75 MHz) δ 20.4, 21.5, 24.3, 25.9, 30.9, 37.0, 39.0, 61.0, 64.3,
(s, 3H), 3.53 (tt, J = 8.4 Hz, J = 2.4 Hz, 1H), 4.58–4.64 (m, 1H), 126.1, 126.9, 127.5, 128.3, 129.5, 135.7, 143.1, 143.2; HRMS-
5.23 (d, J = 2.2 Hz, 1H), 7.27–7.32 (m, 3H), 7.42–7.47 (m, 2H); ESI (m/z) calcd for [M+H]+ (C21H26NO2S) 356.1684, found
13C NMR (CDCl3, 75 MHz) δ 23.1, 32.2, 35.7, 36.4, 45.5, 68.3, 356.1685.
109.4, 120.0, 127.8, 128.7, 132.6, 144.1. HRMS-APCI (m/z) cis-1-Tosyl-octahydro-cyclopenta[b]pyrrole-2-carboxylic acid
calcd for [M+H]+ (C14H18NO2S) 264.1058, found, 264.1063.
(
15p
A solution of 14p (77.0 mg, 0.23 mmol ), CCl4 (1.4 mL),
acetonitrile (1.4 mL) and water (2.1 mL) was added with
)
cis-2-Phenyl-1-tosyl-3a,4,5,6,7,7a-hexahydro-1H-indole
7b
(
12ha)
A suspension of 8ha (167.5 mg, 0.47 mmol), AuCl (5.5 mg, sodium periodate (737.9 mg, 3.45 mmol) at rt and stirred for
23.6 µmol) and acetonitrile (3 mL) was heated to 85 ºC by the 15 min. The reaction mixture was added with ruthenium(III)
microwave reactor and maintained at 85 ºC for 20 min. After chloride (2.4 mg, 0.011 mmol), stirred at rt for 10 h, added
cooled to rt, the solvent was remove, and the crude product with water (7 mL), filtered and extracted with CH2Cl2 (5 mL ×
was purified by column chromatography (SiO2 basified with 3). The combined organic layers were extracted with NaOH(aq)
NEt3, ethyl acetate/hexanes, 1:5; Rf 0.45) to give 12ha1 (101.0 (1.5 N, 10 mL × 3). The collected aqueous layers were acidified
mg, 0.29 mmol, 60%) as a colorless solid. M.p. 143.0–144.0 ºC; with conc. HCl(aq) (6 mL) and extracted with CH2Cl2 (30 mL × 3).
1H NMR (CDCl3, 500 MHz) δ 1.12–1.26 (m, 2H), 1.31–1.38 (m, The combined organic layers were dried over Na2SO4, filtered
1H), 1.42–1.44 (m, 1H), 1.56–1.66 (m, 3H), 2.05–2.09 (m, 1H), and concentrated to give 15p (50.6 mg, 0.16 mmol, 72%) as a
2.34–2.36 (m, 1H), 2.41 (s, 3H), 4.24 (dt, J = 10.1 Hz, J = 6.9 Hz, white solid. 1H NMR (CDCl3, 500 MHz) δ 1.40–1.45 (m, 1H),
1H), 5.36 (d, J = 1.8 Hz, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.31–7.37 1.49–1.55 (m, 1H), 1.60–1.67 (m, 1H), 1.71–1.83 (m, 2H), 1.97–
(m, 3H), 7.55–7.57 (m, 2H), 7.60 (d, J = 8.1 Hz, 1H); 13C NMR 2.08 (m, 3H), 2.43 (s, 3H), 2.46–2.52 (m, 1H), 3.98–4.01 (m,
(CDCl3, 125 MHz) δ 21.2, 21.6, 22.2, 26.0, 28.8, 40.1, 63.7, 1H), 4.14 (dd, J = 5.9 Hz, J = 8.7 Hz, 1H), 7.33 (d, J = 8.1 Hz, 2H),
123.5, 127.2, 127.4, 127.9, 128.6, 129.4, 133.6, 135.9, 143.4; 7.75 (d, J = 8.1 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 21.6, 24.5,
HRMS-APCI (m/z) calcd for [M+H]+ (C21H24NO2S) 354.1528, 31.3, 34.6, 34.8, 43.1, 63.0, 67.6, 127.9, 129.9, 133.9, 144.3,
found 354.1527.
174.1; HRMS-ESI (m/z) calcd for [M+Na]+ (C15H19NO4SNa)
cis-2-Phenyl-1-tosyloctahydrocyclopenta[b]pyrrole
(
14p
)
332.0932, found, 332.0932.
21a,22
A solution of 12pa (79.5 mg, 0.23 mmol) and CH2Cl2 (4 mL) cis-1-Tosyloctahydro-1H-indole-2-carboxylic acid (15h)
was added with trifluoroacetic acid (88 µL, 1.2 mmol), A solution of 14h (38.2 mg, 0.11 mmol), CCl4 (0.7 mL),
trifluoroacetic anhydride (160 µL, 1.2 mmol) and triethylsilane acetonitrile (0.7 mL) and water (1.4 mL) was added with
(184 µL, 1.2 mmol) sequentially at 0 ºC. The reaction mixture sodium periodate (343.3 mg, 1.60 mmol) at rt and stirred for
was stirred at rt for 12 h and concentrated. The crude product 15 min. The reaction mixture was added with ruthenium(III)
was purified by column chromatography (SiO2, ethyl chloride (1.1 mg, 5.6 µmol), stirred at rt for 13 h, added with
acetate/hexanes, 1:5; Rf 0.58) to give 14p (75.6 mg, 0.22 water (7 mL), filtered and extracted with ethyl acetate (20 mL
mmol, 96%) as a white solid. M.p. 120.0–121.5 ºC; 1H NMR × 3). The combined organic layers were extracted with
(CDCl3, 500 MHz) δ 1.34–1.40 (m, 1H), 1.51–1.67 (m, 3H), NaOH(aq) (1.5 N, 30 mL × 3). The collected aqueous layers were
1.71–1.81 (m, 1H), 1.90–1.97 (m, 1H), 2.09–2.15 (m, 1H), 2.19– acidified with conc. HCl(aq) (15 mL) and extracted with CH2Cl2
2.25 (m, 1H), 2.39 (s, 3H), 2.41–2.49 (m, 1H), 4.17 (td, J = 7.9 (25 mL × 3). The combined organic layers were dried over
Hz, J = 3.6 Hz, 1H), 4.37 (dd, J = 9.2 Hz, J = 7.2 Hz, 1H), 7.18– Na2SO4, filtered and concentrated to give 15h5 (23.2 mg, 0.067
7.26 (m, 5H), 7.30–7.32 (m, 2H), 7.57 (d, J = 8.3 Hz, 2H); 13C mmol, 67%) as a white solid. M.p. 176.0–178.0 ºC; 1H NMR
NMR (CDCl3, 125 MHz) δ 21.4, 24.0, 31.3, 34.9, 41.4, 42.8, (CDCl3, 500 MHz) δ 1.08–1.16 (m, 1H), 1.26–1.40 (m, 2H),
66.5, 67.0, 126.5, 127.1, 127.9, 128.1, 129.3, 134.5, 141.9, 1.44–1.64 (m, 4H), 1.73–1.74 (m, 1H), 1.83–1.86 (m, 1H), 2.03–
143.1; HRMS-ESI (m/z) calcd for [M+Na]+ (C20H23NO2SNa) 2.19 (m, 3H), 2.40 (br, 1H), 2.42 (s, 3H), 3.64 (dt, J = 10.6 Hz, J =
364.1347, found 364.1352.
6.4 Hz, 1H), 4.17 (t, J = 8.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.75
(d, J = 8.0 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 20.3, 21.5, 23.7,
cis-2-Phenyl-1-tosyloctahydro-1H-indole (14h)
6 | J. Name., 2012, 00, 1-3
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15
, 2616; (f) J. E. Perea-Buceta, T. Wirtanen, O.-V.
25.6, 29.6, 32.5, 37.3, 60.6, 60.8, 127.6, 129.9, 134.8, 144.0,
176.0; HRMS-ESI (m/z) calcd for [M+Na]+ (C16H21NO4SNa)
346.1089, found 346.1090.
Laukkanen, M. K. Mäkelä, M. Nieger, M. Melchionna, N.
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