FeCl3-catalyzed cyclization of α-sulfonamido-allenes with aldehydes - The substituent effect

Article abstract of DOI:10.1039/c2cc36941a

FeCl₃-catalyzed aza-Prins-cyclization reaction of α-sulfonamido-allenes with aldehydes afforded 1,2,3,6-tetrahydropyridine or 2,5-dihydro-1H-pyrrole derivatives efficiently and highly selectively. The different regioselectivity is probably caus

Full text of DOI:10.1039/c2cc36941a

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COMMUNICATION
FeCl3-catalyzed cyclization of a-sulfonamido-allenes with aldehydes—the
substituent effectw
Jiajia Cheng,a Xinjun Tang,a Yihua Yub and Shengming Ma*ac
Received 25th September 2012, Accepted 19th October 2012
DOI: 10.1039/c2cc36941a
FeCl3-catalyzed aza-Prins-cyclization reaction of a-sulfonamido-
allenes with aldehydes afforded 1,2,3,6-tetrahydropyridine or 2,5-
dihydro-1H-pyrrole derivatives efficiently and highly selectively.
The different regioselectivity is probably caused by the stabilizing
effect of the phenyl group on the positively charged allylic
intermediate.
principle, provide three types of products A–C. Herein, we report
a mild and highly selective aza-Prins-cyclization for efficient
assembly of 1,2,3,6-tetrahydropyridine or 2,5-dihydro-1H-pyrrole
skeletons from a-sulfonamido-allenes and aldehydes, depending on
the nature of the R1 substituent on the allene unit.
Functionalized 1,2,3,6-tetrahydropyridines1 are versatile
building blocks widely utilized in the total synthesis of natural
products2 and this important structural motif widely exists in
compounds displaying significant pharmacological and biological
activities.3 The cyclic double bonds are not only responsible for
their interesting biological properties but also serve as a functional
group for further manipulations in organic synthesis. Various
methodologies have been developed toward the construction of
1,2,3,6-tetrahydropyridine derivatives, including Ru-catalyzed
olefin metathesis,4 palladium-,5 silver-catalyzed6 cyclization
reactions and various multistep syntheses.7 However, these types
of reactions usually require expensive transition-metal catalysts or
strict reaction conditions such as anhydrous and anaerobic
conditions, which restrict their applications. Thus, the develop-
ment for highly efficient synthesis of 1,2,3,6-tetrahydropyridine
derivatives under mild conditions are still in great demand.
Prins cyclization utilizing alkenes and alkynes as substrates has
now emerged as a powerful tool for the synthesis of heterocycles.8
On the other hand, the cyclization reaction of allenes has been
extensively developed as an efficient methodology for the
synthesis of cyclic products.9 Based on these facts, we envisioned
that the reaction of a-sulfonamido-allenes with aldehydes10 under
acid catalysis would provide imine intermediates Int-1 or Int-2
(Scheme 1). Sequential cyclization and nucleophilic attack may, in
Scheme 1 Possible reaction pathways.
Our initial work began with N-(buta-2,3-dienyl)-4-tolyl-
sulfonamide 1a and 1-naphthaldehyde 2a under the catalysis
of Fe(III) and TMSCl.11 As a first attempt, we were happy to
notice that the reaction of 1a (1 equiv.), 2a (1.5 equiv.), FeCl3
(20 mol%) and TMSCl (1.5 equiv.) in CH2Cl2 with stirring at
30 1C for 16 h afforded the cyclized product 3a in 38% yield
(Table 1, entry 1). Increasing the amount of catalyst improved
the yield greatly (Table 1, entries 2 and 3). The yield was
improved to 71% when reducing the loading of the aldehyde
to 1.2 equiv. However, when we reduced the amount of
aldehyde further, the yield dropped (Table 1, entries 4 and
5). Addition of anhydrous MgSO4 led to no improvement
(Table 1, entry 6). Then, the reaction was tested with different
Fe(III) salts which showed that other Fe(III) salts were not as
efficient as FeCl3 (Table 1, entries 7 and 8). Efforts trying to
reduce the loading of TMSCl were also not successful (Table 1,
entries 9 and 10). The reaction did not take place if FeCl3 was
not added or using CH3CN as the solvent (Table 1, entries
11–13). Thus, FeCl3 (45 mol%), aldehyde (1.2 equiv.) and
TMSCl (1.5 equiv.) in CH2Cl2 at 30 1C were defined as the
optimized reaction conditions for further study.
a State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, P. R. China.
E-mail: masm@sioc.ac.cn; Fax: (+86)-21-6260-9305
b Shanghai Key Laboratory of Magnetic Resonance, Department of
Physics, East China Normal University, 3663 North Zhongshan Lu,
Shanghai 200062, P. R. China
With the optimized conditions in hand, we turned to examine
the substrate scope of the reaction. Benzaldehyde (Table 2, entry 1)
and aromatic aldehydes substituted by o-Cl, p-NO2, o-Br groups
on the phenyl ring all afforded good yields of the products (Table 2,
entries 2–4). The reaction may also be extended to a variety of
aliphatic aldehydes. In addition to primary- (Table 2, entries 5 and
6) and secondary-alkyl aldehydes (Table 2, entry 7), pivaldehyde
c Shanghai Key Laboratory of Green Chemistry and Chemical
Process, Department of Chemistry, East China Normal University,
3663 North Zhongshan Road, Shanghai 200062, P.R. China
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, and copies of 1H and 13C NMR
spectra for all products. CCDC 880541 and 880542. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c2cc36941a
c
12074 Chem. Commun., 2012, 48, 12074–12076
This journal is The Royal Society of Chemistry 2012

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Table 1 Optimization of the reaction conditions for Fe(III)-catalyzed
aza-Prins-cyclization of 1a with 2aa
Then, N-(2-phenylbuta-2,3-dienyl)-4-tolylsulfonamide 1b
was applied as substrate to investigate a substituent effect.
However, the Prins-type cyclization afforded the five-
membered 2,5-dihydro-1H-pyrrole derivative 4a exclusively.
The structure was unambiguously established by X-ray
diffraction (see ESIw).13 As is well known, functionalized 2,5-
dihydropyrrole is a commonly observed structural unit in
various biologically active natural compounds.14 Thus, we
demonstrated that the FeCl3-catalyzed aza-Prins-cyclization
reaction of N-(2-phenylbuta-2,3-dienyl)-4-tolylsulfonamide 1b
and p-Br/F-benzaldehydes all proceeded smoothly to afford 4b
and 4c in 66 and 74% yields, respectively (Table 3, entries
2 and 3). Aromatic aldehydes with electron-donating groups
such as p-Me, p-MeO on the phenyl ring gave the products in
excellent yields (Table 3, entries 4 and 5). Furthermore,
m-MeO and o-F substituted aromatic aldehydes may also be
used as substrates, although the yields are somewhat lower
(Table 3, entries 6–7). The reaction may also be extended to
aliphatic aldehydes such as 2q which affords 4h in 46% yield.
Cat.
(mol%)
2a/TMCl
(equiv.)
Yield of
3ab (%)
Recovery of
1ab (%)
Entry
t/h
1
2
3
4
FeCl3 (20)
FeCl3 (30)
FeCl3 (45)
FeCl3 (45)
FeCl3 (45)
FeCl3 (45)
1.5/1.5
1.5/1.5
1.5/1.5
1.2/1.5
1.0/1.5
1.2/1.5
1.2/1.5
1.2/1.5
1.2/—
1.2/0.5
1.2/1.5
1.2/1.5
1.2/—
21
17
21
21
21
22
22
18
21
21
12
18.5
12.5
38
50
60
78 (71c)
19
13
10
8
9
0
62
89
35
24
95
98
96
5
67
73
8
6d
7
e
Fe(acac)3
8
9
10
11
12g
13g
Fe(III)f
FeCl3 (45)
FeCl3 (45)
—
7
48
57
—
—
—
—
FeCl3 (45)
a
The reaction was conducted using 1a (0.1 M), 2a (1.2 equiv.), Fe(III) and
b
Table 3 FeCl3-catalyzed aza-Prins-cyclization of 1b with aldehydes 2
under standard conditionsa
1
TMSCl at 30 1C. Determined by H NMR analysis with mesitylene as
the internal standard. Isolated yield. 1.0 equiv. MgSO4 was used in this
c
d
e
f
reaction. 45 mol% of catalyst was used. 45 mol% of Fe(NO3)3ꢀ9H2O
g
was used. CH3CN was used as solvent.
(Table 2, entry 8) and paraformaldehyde (Table 2, entry 9) may all
used to afford the corresponding 1,2,3,6-tetrahydropyridine
derivatives with excellent yields. The structure of 3j was further
confirmed by X-ray diffraction (see ESIw).12
Entry
R2
Yield of 4b (%)
1
2
3
4
4-ClC6H4 (2c)
4-BrC6H4 (2k)
4-FC6H4 (2l)
4-MeC6H4 (2m)
4-MeOC6H4 (2n)
3-MeOC6H4 (2o)
2-FC6H4 (2p)
n-C3H7 (2q)
67 (4a)
66 (4b)
74 (4c)
81 (4d)
67 (4e)
66 (4f)
53 (4g)
46 (4h)
Table 2 FeCl3-catalyzed aza-Prins-cyclization of 1 with different
aldehydes 2 under standard conditionsa
5
6c
7
8d
a
The reaction was carried out at 30 1C in CH2Cl2 using aldehyde (c =
0.1 M), 1b (1.5 equiv.), FeCl3 (30 mol%) and TMSCl (1.5 equiv.).
b
c
Yield of isolated product. The reaction was stirred for 14 h. The
d
Entry
R1CHO
t/h
Yield of 3b (%)
reaction was stirred for 36 h.
1
2
3
4
5
6
C6H5 (2b)
13
13
11
11
7
10
8
12.5
11
78 (3b)
80 (3c)
79 (3d)
83 (3e)
83 (3f)
86 (3g)
84 (3h)
58 (3i)e
74 (3j)
2-ClC6H4 (2c)
4-NO2C6H4 (2d)
2-BrC6H4 (2e)
n-C7H15 (2f)
3-PhC3H6 (2g)
c-C6H11 (2h)
t-Bu (2i)
The 4-phenyl-1,2,3,6-tetrahydropyridine skeleton is a key
structural motif in a series of bioactive molecules, such as
Parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP).15 In order to show the potential
of our method, the Suzuki coupling reactions of 1,2,3,6-
tetrahydropyridine derivatives 3 with boronic acid were rea-
lized using the LB-Phos recently developed in this group as the
ligand (Scheme 2).16 The coupling of 1,2,3,6-tetrahydro-
pyridine derivative 3j with phenyl- and 2-furyl-boronic acid
both afforded the cross-coupling products in excellent yields.
This coupling is also suitable for 3b to form the corresponding
Suzuki coupling product 6c in 85% yield.
7c
8d
9
H (2j)
a
The reaction was conducted at 30 1C in CH2Cl2 using 1a (c = 0.1 M),
aldehyde (1.2 equiv.), FeCl3 (45 mol%) and TMSCl (1.5 equiv.). b Yield
c
of isolated product. 1.5 equiv. aldehyde was used. 2.0 equiv. aldehyde
d
was used. The conversion of 1a was 89% based on 1H NMR analysis
of the crude product with mesitylene as internal standard.
e
The reaction of 1a and 2j to afford 3j in 70% yield can be
readily carried out on a one gram scale (eqn (1)).
ð1Þ
Scheme 2 Pd(OAc)2/LB-Phos-catalyzed Suzuki coupling of 3.
Chem. Commun., 2012, 48, 12074–12076 12075
c
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The high regioselectivity of this reaction may be explained as
follows: the combination of FeCl3 and TMSCl would work
together to promote the condensation of the a-sulfonamido-allenes
with aldehydes to afford the intermediate 7. When R1 = H, the
regioselective cyclization of 7 occurs to afford the intermediate 8
which would finally lead to the formation of 3. When R1 = Ph, the
positive charge of the intermediate 9 is stabilized and five-
membered cyclic products 4 are formed exclusively (Scheme 3).
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Scheme 3 Rationale for the selectivity observed.
In conclusion, we have demonstrated FeCl3-catalyzed
highly regioselective aza-Prins-cyclization reactions of
a-sulfonamido-allenes with aldehydes. This reaction may pro-
duce 1,2,3,6-tetrahydropyridine or 2,5-dihydro-1H-pyrrole
derivatives efficiently and highly selectively depending on the
R1 substituent on the allene unit. In view of the ready
availability of the starting materials from terminal alkynes17
and the mediators, this type of transformations may be useful
in organic synthesis and medicinal chemistry. Further studies
including mechanistic studies and the asymmetric variants of
the cyclization reactions are being conducted in our laboratory.
Financial support from National Basic Research Program
of China (Grant Nos. 21232006 and 2011CB808700) and
National Natural Science Foundation of China (21172192) is
greatly appreciated. We thank Mr Shangze Wu in our group
for reproducing the results presented in entries 3, 6 of Table 2
and entry 3 in Table 3.
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M. A. Ramı
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12 Crystal data for 3j. C12H14ClNO2S, Mr = 271.75, monoclinic,
space group P21/c, final R indices [I 4 2(I)], R1 = 0.0401,
wR2 = 0.1023, R indices (all data) R1 = 0.0439, wR2 = 0.1062,
a = 7.7348(5), b = 8.2950(5), c = 20.1342(13) A, b = 98.598(1)1,
V = 1277.3(14) A3, T = 293 K, Z = 4, reflections collected/
unique: 7493/2511 (Rint = 0.0285), number of observations [I 4 2(I)],
parameters: 156. CCDC 880541w.
13 Crystal data for 4a. C24H21Cl2NO2S, Mr = 458.38, monoclinic,
space group P21/n, final R indices [I 4 2(I)], R1 = 0.0536,
wR2 = 0.1300, R indices (all data) R1 = 0.0759, wR2 = 0.1405,
a = 17.918(2), b = 5.8464(8), c = 21.295(3) A, b = 99.577(4)1,
V = 2199.7(5) A3, T = 296 K, Z = 4, reflections collected/unique:
24225/3857 (Rint = 0.0603), number of observations [I 4 2(I)],
parameters: 271. CCDC 880542w.
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c
12076 Chem. Commun., 2012, 48, 12074–12076
This journal is The Royal Society of Chemistry 2012