Highly selective FeCl3-catalyzed cyclization of β-sulfonamidoallenes or β-allenols and aldehydes

Article abstract of DOI:10.1021/cs300838k

A FeCl₃-catalyzed Prins cyclization reaction of β-sulfonamidoallenes or β-allenols with aldehydes has been developed for the synthesis of 3-chloromethyl-1,2,5,6-tetrahydro-1H-pyridine or 3-chloromethyl-5,6-dihydro-2H-pyran. The reaction is highly selective due to the stability of the allyl cation intermediate.

Full text of DOI:10.1021/cs300838k

Letter
pubs.acs.org/acscatalysis
Highly Selective FeCl3‑Catalyzed Cyclization of β‑Sulfonamidoallenes
or β‑Allenols and Aldehydes
Jiajia Cheng,† Xinjun Tang,† and Shengming Ma*,†,‡
†State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, People’s Republic of China
‡Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of Chemistry, East China Normal University,
3663 North Zhongshan Road, Shanghai 200062, People’s Republic of China
S
* Supporting Information
ABSTRACT: A FeCl3-catalyzed Prins cyclization reaction of
β-sulfonamidoallenes or β-allenols with aldehydes has been
developed for the synthesis of 3-chloromethyl-1,2,5,6-tetrahy-
dro-1H-pyridine or 3-chloromethyl-5,6-dihydro-2H-pyran. The
reaction is highly selective due to the stability of the allyl cation
intermediate.
KEYWORDS: β-sulfonamidoallenes, β-allenols, Prins cyclization, catalysis, 3-chloromethyl-1,2,5,6-tetrahydro-1H-pyridine,
3-chloromethyl-5,6-dihydro-2H-pyran
etrahydropyridines and dihydropyran compounds, espe-
cially 3-chloromethyl-1,2,5,6-tetrahydropyridines and 3-
Herein, we report an efficient synthesis of 3-chloromethyl-
1,2,5,6-tetrahydropyridine or 3-chloromethyl-5,6-dihydro-2H-
pyran derivatives via FeCl3-catalyzed cyclization reactions of β-
sulfonamidoallenes38 or β-allenols39 in the presence of
aldehydes and TMSCl under mild conditions.40−42
T
chloromethyl-5,6-dihydro-2H-pyran derivatives, are important
structural units of broad interest and have been extensively
utilized as synthetic intermediates.1−8 However, there are only
scattered synthetic reports, such as by chlorination of the
corresponding alcohols,9−11 which indicated the challenge for
synthesizing such compounds.9−12
During the last 20 years, cyclization reactions of allenes have
been extensively developed as an efficient methodology for the
synthesis of cyclic products.13−22 On the other hand, Prins
cyclization utilizing alkenes and alkynes as substrates has
emerged as a powerful tool for the synthesis of hetero-
cycles.23−31 We envisioned that 3-chloromethyl-1,2,5,6-tetrahy-
dropyridine derivatives may be efficiently constructed by using
β-sulfonamidoallenes, aldehydes, and TMSCl in an atom-
economic manner (X = NTs, Scheme 1). In principle, the
Our initial work began with N-(3,4-pentadienyl)-4-tolylsul-
fonamide 1a, 4-chlorobenzaldehyde 2a, and TMSCl under the
catalysis of Fe(III). As a first try, we were happy to notice that
the reaction of 1a (1 equiv), 2a (1.2 equiv), FeCl3 (5 mol %),
and TMSCl (1.5 equiv) in DCM with stirring at 30 °C for 10 h
afforded the A-type cyclized product 3a in 24% yield (Table 1,
entry 1).43 Increasing the amount of catalyst improved the yield
greatly (Table 1, entries 2−3); however, applying 30 mol % of
FeCl3 decreased the yield of 3a (Table 1, entry 4). Increasing
the amount of 2a did not help (Table 1, entry 5). Interestingly,
when we reduced the amount of TMSCl, the reaction became
higher yielding, with 1 equiv of TMSCl being the best (Table 1,
entry 6). Studies on the solvent effect (Table 1, entries 7−9)
revealed that DCM is the best. No product was obtained in the
absence of FeCl3 (Table 1, entry 10). Only a trace amount of
product was afforded if TMSCl was not added (Table 1, entry
11). The reaction also did not happen if LiCl was used instead
of TMSCl (Table 1, entry 12). Furthermore, Fe(acac)3 and
FeSO4·7H2O were less efficient than FeCl3 (Table 1, entries 13
and 14).
Scheme 1. Possible Reaction Pathways
Having the optimized reaction conditions in hand, we next
set out to examine the generality of this cyclization reaction of
various substituted β-sulfonamidoallenes 1 with aldehydes. As
for benzaldehyde 2b, the corresponding product 3b was
obtained in 70% yield (Table 2, entry 1). The reactions were
reaction of β-sulfonamidoallenes or β-allenols with aldehydes
under the catalysis of acid might provide intermediate Int-
1.27,28 Sequential cyclization and nucleophilic attack may
provide products A and B. What is more interesting to us is
the possibility of highly selective formation of A-type 3-
chloromethyl-5,6-dihydropyran derivatives (X = O, Scheme
1).32−37
Received: December 22, 2012
Revised: February 25, 2013
Published: March 11, 2013
© 2013 American Chemical Society
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ACS Catalysis
Letter
(Table 2, entry 8), primary- (Table 2, entry 9), and secondary-
alkyl aldehydes (Table 2, entries 10−11), the reaction also
afforded the corresponding products in 40−71% yields. When
N-(3-allyl-3,4-pentadienyl)-4-tolylsulfonamide, 1b, was used as
substrate, the corresponding product 3m was obtained in 60%
yield. The structure of the product was unambiguously
established by the X-ray diffraction study of 3h and 3k (Figure
1).44,45
Table 1. Optimization of the Reaction Conditions for the
Fe(III)-Catalyzed Prins Cyclization of 1a with 2a
a
TMSCl
(equiv)
yield of 3a
b
entry
cat. (mol %)
solvent
t (h)
(%)
1
2
3
4
FeCl3 (5)
FeCl3 (10)
FeCl3 (25)
FeCl3 (30)
FeCl3 (25)
FeCl3 (25)
FeCl3 (25)
FeCl3 (25)
FeCl3 (25)
−
1.5
1.5
1.5
1.5
1.5
1.0
1.0
1.0
1.0
1.0
−
DCM
DCM
DCM
DCM
DCM
DCM
DCE
10
9
24
54
70
64
68
8.5
9
c
5
16
8
j
6
7
8
78 (71 )
10
10
15.5
16.5
16.5
23
10
12
59
15
−
−
6
toluene
THF
d
9
e
10
DCM
DCM
DCM
DCM
DCM
f
11
FeCl3 (25)
FeCl3 (25)
Fe(acac)3
FeSO4·7H2O
g
12
−
1.0
−
33
h
13
h,i
14
1.0
−
a
The reaction was conducted using 1a (0.1 M), aldehyde (1.2 equiv),
b
1
catalyst, and TMSCl in CH2Cl2 at 30 °C. Determined by H NMR
analysis with 1,3,5-trimethyl benzene as the internal standard. 1.5
equiv of 2a was applied. The recovery of 1a is 93%. The recovery of
1a is 94%. The recovery of 1a is 45%. 1.0 equiv of LiCl was used
instead of TMSCl. The conversion of the reaction is 11%. 25 mol %
catalyst was applied. The recovery of 1a is 84%. Isolated yield.
c
d
e
f
g
h
i
j
Table 2. FeCl3-Catalyzed Prins Cyclization of 1a with
a
Aldehydes 2 under Standard Conditions
Figure 1. ORTEP drawings of (a) 3h and (b) 3k.
It is easy to conduct the reaction of 1a and 2a to afford 3a in
65% yield in 1 g scale (eq 1).
b
entry
R1
R2
Ph (2b)
t (h)
yield of 3 (%)
1
2
3
4
5
6
7
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
allyl (1b)
8
8
70 (3b)
68 (3c)
52 (3d)
66 (3e)
66 (3f)
64 (3g)
65 (3h)
40 (3i)
71 (3j)
64 (3k)
61 (3l)
60 (3m)
4-BrC6H4 (2c)
4-FC6H4 (2d)
3-BrC6H4 (2e)
3-NO2C6H4 (2f)
2-BrC6H4 (2g)
2-ClC6H4 (2h)
H (2i)
9
8
8
8
8
Excitingly, when 3,4-pentadien-1-ol 4a was applied as
substrate, 3-chloromethyl-5,6-dihydro-2H-pyran derivative 5a
was also obtained in high yield and selectivity.46,47 Only 5 mol
% FeCl3 was used at 40 °C due to the higher reactivity of β-
allenol than β-sulfonamidoallene. As can be seen from Table 3,
the cyclization of 3,4-pentadien-1-ol 4a (R1 = H) and various
substituted aromatic aldehydes all proceeded smoothly to give
the desired products 5 in excellent yields (Table 3, entries 1−
9). Moreover, when R1 was n-butyl or allyl, the corresponding
products 5j and 5k were also formed in excellent yields (Table
3, entries 10 and 11). 3-Phenyl-3,4-pentadien-1-ol 4d (R1 = Ph)
was also a suitable substrate for this reaction, although the yield
was somewhat lower (Table 3, entry 12).
c
8
d
8
9
n-C3H7 (2j)
19
10
10
9.5
d
10
i-C3H7 (2k)
11
12
c-hexyl (2l)
4-ClC6H4 (2a)
a
The reaction was carried out at 30 °C in CH2Cl2 using 1 (c = 0.1 M),
aldehyde (1.2 equiv), FeCl3 (25 mol %), and TMSCl (1.0 equiv) at the
b
c
indicated time. Yield of isolated product. p-Formaldehyde was used.
d
FeCl3 (30 mol %), aldehyde (2.0 equiv), and TMSCl (1.5 equiv)
were used in this reaction.
also suitable when the phenyl ring in the aromatic aldehydes
was substituted with p/m/o-Br (Table 2, entries 2, 4, and 6), p-
F (Table 2, entry 3), m-NO2 (Table 2, entry 5), or o-Cl (Table
2, entry 7). For aliphatic aldehydes, including paraformaldehyde
In conclusion, we have demonstrated a highly regioselective
FeCl3-catalyzed cyclization reaction of 3,4-allenyl amines or
alcohols with aldehydes in the presence of TMSCl. This
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ACS Catalysis
Letter
results presented in entry 5 of Table 2 and entries 3 and 10 in
Table 3.
Table 3. FeCl3-catalyzed Prins-cyclization of 4 with
Aldehydes 2 under Standard Conditions
a
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures; characterization data; and copies of
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available free of charge via the Internet at http://pubs.acs.org.
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Corresponding Author
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666
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