Concise [4+3] cycloaddition reaction of pyrroles leading to tropinone derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.07.130

A concise [4+3] cycloaddition reaction of pyrroles with 2-(silyloxy)allyl cations has been developed. The oxyallyl cations stabilized with a methylthio group or geminal methyl groups were generated from the corresponding allylic alcohols under the influence of a Br?nsted acid (Tf₂NH), respectively. The use of N-nosyl-protected pyrroles as the four-carbon unit was found to give tropinone derivatives in high yield.

Full text of DOI:10.1016/j.tetlet.2012.07.130

Tetrahedron Letters 53 (2012) 5725–5728
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise [4+3] cycloaddition reaction of pyrroles leading to tropinone derivatives
Ryuichi Fuchigami a, Kosuke Namba b, , Keiji Tanino b,
⇑
⇑
a Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0810, Japan
b Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise [4+3] cycloaddition reaction of pyrroles with 2-(silyloxy)allyl cations has been developed. The
oxyallyl cations stabilized with a methylthio group or geminal methyl groups were generated from the
corresponding allylic alcohols under the influence of a Brönsted acid (Tf2NH), respectively. The use of
N-nosyl-protected pyrroles as the four-carbon unit was found to give tropinone derivatives in high yield.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 9 June 2012
Revised 25 July 2012
Accepted 30 July 2012
Available online 19 August 2012
Keywords:
Tropinone
[4+3] Cycloaddition reaction
Pyrroles
Oxyallyl cation
Sulfur-stabilized cation
Tropane alkaloids, which comprise a large family of natural
products, have received a great deal of attention due to their vari-
ety of pharmacological activities and structural diversities.1 In par-
ticular, atropine, cocaine, and scopolamine are famous lead
compounds of pharmaceuticals,2 stemofoline3 and himandrine4
are also known as a class of challenging synthetic targets. One of
the most powerful synthetic approaches to tropane scaffold may
be a [4+3] cycloaddition reaction of pyrroles with oxyallyl cations,
giving rise to tropinones (Scheme 1).5
methylthio group or gem-dialkyl groups with pyrroles having var-
ious substituents.
The 2-nitrobenzenesulfonyl (nosyl, Ns) group,11 which can be
removed under mild conditions, was chosen for protection of the
R3
Me
N
N
R3
N
O–
+
R1
+
R1
While there are a number of reports concerning the [4+3] cyclo-
addition reactions of furans or cyclopentadienes,5 the use of pyr-
roles as four-carbon units is generally difficult due to
competition with the Friedel–Crafts type reaction.6 The oxyallyl
cation species applicable to pyrroles thus far have been confined
R2
O
R2
Tropinones
Tropane
OH
oxyallyl cation
Scheme 1. The [4+3] cycloaddition reaction of oxyallyl cation with pyrrole
derivative.
to those generated from
a,
a0-dihaloketones7 or allenamides.8 On
the other hand, one of the authors reported the regio- and stereo-
selective [3+2] cycloaddition reactions using allyl acetates 1a and
1b as a three-carbon unit (Scheme 2).9 Under the influence of EtAl-
Cl2, allyl acetate 1 reacted with alkene 2 to afford cyclopentanone 3
in good yield. In this reaction, the methylthio group of 1 plays an
important role in stabilizing the allyl cation species A as well as
controlling the regioselectivity of the cycloadducts.10
O
OSiiPr3
MeS
R
Ph
Ph
EtAlCl2
CH2Cl2
Ph
Ph
MeS
OAc
+
R
2
1a: R = H
1b: R = Me
3a: 77%
3b: 99%
These results led us to examine the [4+3] cycloaddition reaction
of 1 with pyrrole derivatives. Herein, we describe concise [4+3]
cycloaddition reactions of 2-(silyloxy)allyl cations stabilized by a
OSiiPr3
OSiiPr3
+
MeS
MeS
R
+
R
⇑
Corresponding authors. Tel.: +81 11 706 2703; fax: +81 11 706 4920 (K.N.); tel.:
A
+81 11 706 2705; fax: +81 11 706 4920 (K.T.).
E-mail addresses: namba@mail.sci.hokudai.ac.jp (K. Namba), ktanino@sci.hoku-
dai.ac.jp (K. Tanino).
Scheme 2. The [3+2] cycloaddition reaction using sulfur-stabilized siloxyallyl
cations.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.130

5726
R. Fuchigami et al. / Tetrahedron Letters 53 (2012) 5725–5728
Table 1
Table 2
The reactions of 4 with three-carbon units 1 promoted by an acida
Comparison of the protecting group on pyrrolea
OSiiPr3
OSiiPr3
MeS
O
Ns
N
O
MeS
acid
X
OH
X
N
Ns
N
X
N
MeS
MeS
1
Ns
N
1d
Tf2NH
CH2Cl2
R
X
N
R
+
+
CH2Cl2,
–78 °C, 1 h
4
-78 °C, 1 h
6
5
X-4
X-5
X-6
Entry
1:X
Acid
Yieldb (%)
Entry
X
Yieldb (%)
5
6
X-5
X-6
1
2
3
4
5
1a:OAc
1a:OAc
1c:OCO2Me
1d:OH
EtAlCl2
15
34
54
85
41
0
27
0
5
38
1
2
3
4
5
6
7
Ns
Ms
Ts
Cbz
Ac
Bn
H
85
33
46
0
0
0
5
Tf2NH
Tf2NH
Tf2NH
TfOH
30
23
9c
23
0
1d:OH
R = CH2C(O)CH2SMe.
Conditions: N-nosyl pyrrole (0.10 mmol),
CH2Cl2 (0.2 M).
0
0
a
1 (0.30 mmol), acid (0.60 mmol),
R = CH2C(O)CH2SMe.
b
Isolated yield.
a
Conditions: pyrrole X-4 (0.10 mmol), 1d (0.30 mmol), Tf2NH (0.60 mmol),
CH2Cl2 (0.2 M).
b
c
Isolated yield.
NMR yield using CHBr3 as an internal standard.
nitrogen atom. The reactions of N-nosyl pyrrole (4) with 1a or its
derivatives under acidic conditions are summarized in Table 1.
While the reaction of 4 with 1a promoted by EtAlCl2 led to the
formation of cycloadduct 5 in 15% yield (entry 1),12 the use of a
Brönsted acid was found to be more effective for the desired trans-
formation. Thus, under the influence of trifluoromethanesulfoni-
mide (Tf2NH), tropinone 5 was obtained in 34% yield along with
27% of 6 (entry 2). Interestingly, the Tf2NH-promoted reaction of
4 with carbonate 1c gave 54% of 5 (entry 3), and the yield increased
to 85% with alcohol 1d9 (entry 4).13 On the other hand, the use of
trifluoromethanesulfonic acid (TfOH) instead of Tf2NH in the reac-
tion of 4 and 1d resulted in decrease of 5 (entry 5), probably be-
cause of the low solubility of TfOH in dichloromethane.
It is noteworthy that tropinone 5 was produced as a single dia-
stereomer which underwent partial isomerization to afford epi-5
by chromatography on silica gel. The stereostructure of these com-
pounds was determined by the NOE experiments, indicating that 5
possesses the methylthio group and the nitrogen atom on the
opposite face of the seven-membered ring (endo-type stereochem-
istry). The methylthio group of 5 was easily removed by treating
with PPh3 and p-toluenesulfonic acid (TsOH) to give tropinone 7
in good yield, according to the desulfurization protocol of Durst
(Scheme 3).14 Thus, the [4+3] cycloaddition reaction using sulfur-
stabilized 2-(silyloxy)allyl cation is proven to be a concise and
effective method for the preparation of tropinone derivatives.15
Next, the [4+3] cycloaddition reaction of pyrroles possessing
various protecting groups (X) with allyl alcohol 1d was examined
(Table 2). While N-(p-toluenesulfonyl) and N-methanesulfonyl
pyrroles Ts-4 and Ms-4 afforded the corresponding tropinones
Ts-5 and Ms-5 in low yields, respectively (entries 2 and 3), N-ben-
zyloxycarbonyl (Cbz), N-acetyl (Ac), N-benzyl (Bn), and unsubsti-
tuted pyrroles failed to undergo the cycloaddition reaction
(entries 4–7). These results suggest that the electron-withdrawing
inductive effect of the protecting group (Ns > Ts, Ms > Ac, Cbz) is of
more significance than the steric bulkiness.16
Having established the suitable conditions of the [4+3] cycload-
dition reaction, the scope of the tropinone synthesis was examined
(Table 3). Although the reaction of N-nosyl-2-methylpyrrole (8) led
to the formation of the Friedel–Crafts product 13 (entry 1),
3-methylpyrrole (9) underwent the desired [4+3] cycloaddition
reaction at ꢀ60 °C to afford tropinone 14 in 71% yield as a single
product (entry 2). The configuration of 14 and the stereochemical
relationship between the methyl group and the methylthio group
were determined by the 1H–1H COSY and the NOE experiments.
Similarly, tropinone 15 was obtained from the corresponding
pyrrole 10 in a regio- and stereoselective manner, albeit in low
yield due to the instability of the vinyl bromide moiety.17
The reaction of methyl-substituted three-carbon unit 11 with
pyrrole 4 at 0 °C afforded the desired cycloadduct 16 in 55% yield.
The three-carbon unit 12 having a methyl group at the other side
also gave cycloadduct 17 as a single regio- and stereoisomer, while
the yield was low.
Next, the stabilizing effect of a methylthio group on the 2-
(silyloxy)allyl cation was compared with that of an alkyl group
(Table 4). The reaction of allyl alcohol 18 with 4 under the influ-
ence of Tf2NH gave neither cycloadduct 7 nor a Friedel–Crafts
type product (entry 1), and allyl alcohol 19 possessing a methyl
group instead of the methylthio group of 1d also failed to under-
go the [4+3] cycloaddition reaction (entry 2). On the other hand,
the use of gem-dimethyl-substituted derivative 20 led to the for-
mation of the desired cycloadduct 22 in 54% yield (entry 3). These
results indicate that a gem-dimethyl group is as effective as a
methylthio group in stabilizing a 2-(silyloxy)allyl cation, while a
single methyl group of 19 is not sufficient for this purpose. Fur-
thermore, we later found that 1,1,1,3,3,3-hexafluoro-2-propanol
(HFIP) is a better solvent for the reaction of gem-dimethyl-substi-
tuted analog 20, and the yield of 22 was increased to 67% (entry
3).18 In contrast to the reaction of 2-methylpyrrole 8 with alcohol
1d which gave only substituted pyrrole 13 (entry 1 in Table 3),
cycloadduct 23 was obtained by the use of 20 as the three-carbon
unit (entry 4). It is noteworthy that the regiochemical outcome of
the reaction of alcohol 20 is also different from that of the
sulfur-containing alcohol 1d. Thus, for the reactions with 3-meth-
ylpyrrole 9, alcohol 20 afforded a 1:1 regioisomeric mixture of
cycloadducts 24a and 24b in 65% yield (entry 5), while the use
of 1d resulted in the formation of cycloadduct 14 as a single
regioisomer (entry 2 in Table 3).
O
O
O
PPh3
MeS
MeS
silica gel
TsOH
Ns
N
Ns
N
Ns
N
CHCl3
60 °C, 36 h
5
5, epi-5
7
83%
Scheme 3. Desulfurization of cycloadduct 5.

R. Fuchigami et al. / Tetrahedron Letters 53 (2012) 5725–5728
5727
Table 3
Table 4
Substrate scope in the [4+3] cycloaddition reactions
The [4+3] cycloaddition reactions of N-nosyl pyrroles with siloxyallyl alcohol
derivatives having no methylthio group
Entry Pyrrole Alcohol Conditions
Product
Yielda
(%)
Entry
Pyrrole
Alcohol
Product
Yielda (%)
SMe
O
O
Ns
N
ꢀ78 °C
1
2
8
9
1d
1d
64
71
Ns
N
1
4
18
0
60 min
Me
13
7
O
O
MeS
Me
Ns
ꢀ60 °C
Ns
N
2
3
4
4
19
20
0
N
120 min
14
21
22
Me
MeS
O
Me
Me
O
67 (54)b
Ns
N
Ns
N
ꢀ40 °C
3
10
1d
30
10 min
O
15
Me
16
Me
Me
Br
Ns
N
48(20)b
O
4
5
8
9
20
Me
23
MeS
Ns
N
4
5
4
4
11
12
0 °C 3 min
0 °C 5 min
55
25
O
Me
Me
O
Ns
N
MeS
Me
Ns
N
20
65 (47)b
R1
R2
17
24a: R1=Me, R2=H
24b: R1=H, R2=Me
Ns
N
Ns
N
Ns
N
OSiiPr3
OH
OSiiPr3
OH
Me
Ns
Ns
N
MeS
MeS
OSiiPr3
OH
OSiiPr3
OSiiPr3
OH
N
Me
Me
Me
Me
Me
Br
OH Me
8
9
10
11
12
Me
Me
8
9
18
19
20
Conditions: N-nosyl pyrrole (0.10 mmol), allyl alcohol (0.30 mmol), Tf2NH
(0.60 mmol), CH2Cl2 (0.2 M).
Reaction conditions: N-nosyl pyrrole (0.10 mmol), allyl alcohol (0.30 mmol), Tf2NH
(0.60 mmol), HFIP (0.2 M), 0 °C, 30 min.
a
Isolated yield.
a
Isolated yield.
b
The reaction was conducted in dichloromethane at 0 °C.
Finally, the utility of the present [4+3] cycloaddition reaction
was demonstrated through the synthesis of tricyclic compound
28, possessing a common framework with biologically active nat-
ural products such as Daphniphyllum alkaloids.19 Ketone 26,
which was prepared from pyrrole 25 and alcohol 20 via a [4+3]
cycloaddition reaction, was converted to the corresponding enol
silyl ether 27. Treatment of 27 with silver (I) trifluoroacetate20 ef-
fected the intramolecular alkylation reaction to provide the de-
sired tricyclic compound 28 in 46% yield from ketone 26
(Scheme 4).
In conclusion, the [4+3] cycloaddition reaction of pyrroles lead-
ing to various tropinones was developed.20 The use of N-nosyl pyr-
role derivatives was found to afford the desired cycloadducts in
good yields. The 2-(silyloxy)allyl cation was generated by treating
the corresponding allyl alcohol with Tf2NH, while the cation-
stabilizing effect of a methylthio group or a gem-dimethyl group
was essential for generation of the reactive species. The present
[4+3] cycloaddition protocol provides a powerful method for con-
structing substituted tropane skeleton, and the applications to
the synthesis of complex natural products are currently underway
in our laboratory.
O
I
Me
Me
Ns
N
I
OSiiPr3
OH
Ns
N
Tf2NH
HFIP
33%
Me
+
Me
20
25
26
I
OTMS
O
H
Me
Me
Me
Me
TMSI
Ns
N
TMS2NH
CF3CO2Ag
Ns
N
CH2Cl2
CH2Cl2
27
2 steps, 46%
28
Scheme 4. Synthesis of tricyclic ketone 28 via a [4+3] cycloaddition reaction.
Acknowledgments
This work was partially supported by the Global COE program
(Project No. B01: Catalysis as the Basis for Innovation in Material
Science) and Grant-in-Aid for Scientific Research on Innovative
Areas (Project No. 2105: Organic Synthesis Based on Reaction Inte-
gration and No. 2301: Chemical Biology of Natural Products) from
the Ministry of Education, Culture, Sports, Science, and Technology,
Japan.
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R. Fuchigami et al. / Tetrahedron Letters 53 (2012) 5725–5728
9. Masuya, K.; Domon, K.; Tanino, K.; Kuwajima, I. J. Am. Chem. Soc. 1998, 120,
Supplementary data
1724–1731.
10. For recent reviews on the [4+3] cycloaddition reaction using heteroatom-
substituted oxyallyl cations, see (a) Harmata, M. Adv. Synth. Catal. 2006, 348,
2297–2306; (b) Harmata, M. Chem. Commun. 2010, 46, 8904–8922.
11. For review, see: Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353–359.
12. The yield of 5 was substantially increased up to 66% when the reaction
temperature was elevated to ꢀ40 °C.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
07.130.
13. The reaction using catalytic amount of Tf2NH (10 mol %) did not proceeded at
ꢀ78 °C, and the nosylpyrrole 4 (quant) and three carbon unit 1d (90%) were
recovered after 1 h. The similar reaction with increasing temperature induced
only decomposition of 1d.
References and notes
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(0.25 mL) was added a mixture of 1d (83 mg, 0.30 mmol) and 4 (25.2 mg,
0.1 mmol) in CH2Cl2 (0.25 mL) at ꢀ78 °C. After the mixture was stirred at
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group was considered to suppress the retro-Mannich reaction leading to
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