Nucleophilic 5-endo-trig cyclizations of N-homoallylic sulfonamides: A facile method for the construction of pyrrolidine rings

Article abstract of DOI:10.1039/b618251h

Normally disfavored 5-endo-trig cyclizations proceed in N-homoallylsulfonamides bearing a CF₃, CCl₃, CO ₂Et or CN group at the C-3 position, via an intramolecular S _N2′-type or addition reaction to construct pyr

Full text of DOI:10.1039/b618251h

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Nucleophilic 5-endo-trig cyclizations of N-homoallylic sulfonamides: a
facile method for the construction of pyrrolidine rings{
Junji Ichikawa,* Guillaume Lapointe and Yu Iwai
Received (in Cambridge, UK) 13th December 2006, Accepted 6th February 2007
First published as an Advance Article on the web 11th April 2007
DOI: 10.1039/b618251h
to possess an SN29-type reactivity similar to that of 2-trifluoro-
methyl-1-alkenes. Their reaction with nucleophiles would occur at
the terminal vinylic carbon, followed by elimination. Before
investigating other 2-halomethyl-1-alkene systems, we confirmed
that the substituent (R) at the homoallylic position did not affect
the course of the reaction, because substrate 1b gave the 5-endo-trig
product, pyrrolidine 2b, albeit in diminished yield (entry 2). When
trichloromethyl-substituted alkene 1c was treated with NaH in
DMF (N,N-dimethylformamide), cyclization readily proceeded in
a 5-endo-trig fashion at 80 uC, a lower temperature than that of
the trifluoromethyl counterpart, affording dichloromethylene-
substituted pyrrolidine 2c in 89% yield (entry 3). To evaluate the
advantage of trihalomethyl (CX3) groups in the 5-endo-trig
process, we employed alkene substrates with a 2-monohalomethyl
(CHDX) group, whose deuterium atom was introduced to
differentiate between the 5-endo-trig and the 5-exo-tet products.
In contrast to the trihalomethylated substrates, fluoromethyl-,
chloromethyl- and bromomethyl-1-alkenes 1d–f underwent direct
substitution without allylic rearrangement, leading to the 5-exo-tet
product 3d exclusively (Table 1, entries 4–6).
Normally disfavored 5-endo-trig cyclizations proceed in
N-homoallylsulfonamides bearing a CF3, CCl3, CO2Et or CN
group at the C-3 position, via an intramolecular SN29-type or
addition reaction to construct pyrrolidine rings, even though
the system allows a more favorable 5-exo-trig pathway.
It has long been considered, following Baldwin’s rules,1 that the
5-endo-trig cyclization is a geometrically disfavored process. These
ring closures can be classified into three categories: nucleophile-
driven,2 electrophile-driven,3 and radical-initiated4 cyclizations.
Among them, the nucleophile-driven 5-endo-trig cyclization has
rarely been observed in synthetic chemistry and is still a challenge
in organic synthesis.
Recently, we have accomplished the disfavored 5-endo-trig
cyclization in 2-trifluoromethyl-1-alkenes 1 bearing a 4-methyl-
benzenesulfonamide (tosylamide: TsNH–) moiety as an intramo-
lecular nucleophile (Scheme 1).5 The nitrogen anion attacked the
alkene in an SN29 fashion with elimination of a fluoride ion to
afford difluoromethylene-substituted pyrrolidines 2. In this
cyclization, the 5-endo-trig products were obtained without any
products of the favored 5-exo-tet ring closure. These results show
that (i) the trifluoromethyl group activates the C–C double bond in
1 to allow the normally disfavored 5-endo-trig cyclization and (ii)
this reaction has a high potential in the synthesis of substituted
pyrrolidines.6
The preference in 1a–c for the 5-endo-trig cyclization over the
normally favored 5-exo-tet cyclization can be explained as follows.
The sulfonamidate, in the 5-exo-tet approach, meets severe
electrostatic and steric repulsions from the halogens present on
the trihalomethyl group, which consequently retards the normally
favored 5-exo-trig process. On the other hand, the 5-endo-trig
approach, while geometrically disfavored, has no such repulsions.
Because the steric and electrostatic repulsions dominate over the
geometric distortion, only the 5-endo-trig cyclization proceeds in
the trihalomethyl substrates.
To expand the scope of this synthetic method for functionalized
pyrrolidines, the reactions of other types of electrophilic moieties
with intramolecular N-nucleophiles have been investigated. Herein,
we wish to report the nucleophilic 5-endo-trig cyclization of
N-homoallylic sulfonamides containing an electron-withdrawing
group at the C-3 position.
We first set our goal on 3-halomethyl-substituted analogs of
N-homoallylsulfonamides (Table 1). Such substrates were expected
Table 1 Nucleophilic cyclization of N-(3-halomethylhomoallyl)-
sulfonamides 1
Scheme 1 Nucleophilic 5-endo-trig cyclization of N-(3-trifluoromethyl-
homoallyl)sulfonamides 1.
Entry
1
CYZ
X
R
Conditions
2 (%)
3 (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
CF2
CF2
CCl2
CHD
CHD
CHD
F
F
Cl
F
Cl
Br
Ph
H
Ph
Ph
Ph
Ph
130 uC, 3 h
130 uC, 4 h
80 uC, 1 h
110 uC, 2 h
50 uC, 1 h
rt, 0.25 h
91
67
89
—
—
—
—
—
—
91
86
89
Department of Chemistry, Graduate School of Science, The University
of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan.
E-mail: junji@chem.s.u-tokyo.ac.jp; Fax: +81-3-5841-4345;
Tel: +81-3-5841-4345
{ Electronic supplementary information (ESI) available: Spectroscopic
data. See DOI: 10.1039/b618251h
2698 | Chem. Commun., 2007, 2698–2700
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Scheme 2 Nucleophilic 5-endo-trig cyclization of N-(3-trichlororo-
methylhomoallyl)sulfonamide 1g.
(Trichloromethyl)alkene 1g bearing
a nosyl group (Ns:
o-NO2C6H4SO2–)7 on the nitrogen instead of a tosyl group also
underwent the 5-endo-trig cyclization to afford pyrrolidine 2g
(Scheme 2). However, other examined (trichloromethyl)alkenes
with an intramolecular nitrogen nucleophile failed to cyclize. The
substrates with
a free amine (NH2–) or a benzylamine
Scheme 3 Nucleophilic 5-endo-trig and 5-exo-trig cyclizations of
a,b-unsaturated esters 4.
(PhCH2NH–) moiety resulted in decomposition upon heating,
probably due to the strongly basic conditions. The cyclization of
the substrates with a benzamide (PhCONH–) or a carbamate
(t-BuOCONH–) moiety gave poor results. This fact might be due
to the partial pyramidalization of the sulfonamidate in the
transition state,8 which could help the geometrically unfavorable
cyclization, when compared with the planar amide and carbamate
nitrogen anions. The relative stability of the N-sulfonamide
nitrogen anions may also prevent decomposition prior to the
cyclization.
Thus, not only trihalomethyl groups (CF3 and CCl3) but other
electron-withdrawing groups (CO2Et and CN) also promote the
5-endo-trig cyclization. Moreover, both 5-endo-trig and 5-exo-trig
cyclization products can be obtained by choosing an appropriate
alkoxy group in the starting esters (CO2Et or CO2Ph).
In the a,b-unsaturated ester system, both preferences can be
interpreted as follows (Scheme 3). The 5-exo-trig cyclization of A
preferentially proceeds up to intermediate B, which has two leaving
groups, a sulfonamidate and an alkoxide. Because 4-methylbenze-
nesulfonamidate is a better leaving group than ethoxide, the
reaction of ethyl esters 4a and 4b (R9 = Et) goes back to
intermediate A. Once the disfavored 5-endo-trig cyclization
proceeds, further protonation of intermediate C with the starting
sulfonamide 4 occurs to give pyrrolidines 5. On the other hand,
phenyl esters 4d and 4e (R9 = Ph) undergo elimination of
phenoxide, a better leaving group than sulfonamidate, via
intermediate B to give lactams 6, the 5-exo-trig products.
In conclusion, we have shown that sulfonamides are good
intramolecular nucleophiles for the nucleophilic 5-endo-trig
cyclization of electron-deficient alkenes. The normally disfavored
5-endo-trig cyclization is effected in N-homoallylsulfonamides
bearing a CF3, CCl3, CO2Et or CN group at the C-3 position,
which provides an easy access to functionalized pyrrolidines. Thus,
the nucleophilic 5-endo-trig cyclization can be achieved by
choosing the right combination of nucleophile, electrophile, and
reaction conditions.
Then, taking into account the relative electrophilicity of the
trihalomethyl-substituted alkene moiety, we examined different
electrophiles, such as a,b-unsaturated esters and nitriles (Table 2).
Baldwin et al. previously reported that the 5-exo-trig cyclization
proceeded more favorably than the 5-endo-trig pathway in an
a,b-unsaturated ester bearing an amino group.1 Pursuing the goal
of 5-endo-trig cyclization, we adopted the aforementioned
sulfonamide moiety as an N-nucleophile. Whereas treatment of
ethyl ester 4a with 1 equiv. of NaH gave the expected 5-endo-trig
product 5a only in 12% yield (entry 1), a catalytic amount
(0.1 equiv.) of NaH2d raised the yield to 87% (entry 2).{ When
ethyl ester 4b and nitrile 4c were subjected to similar reaction
conditions, the 5-endo-trig products 5b and 5c were obtained in
high yield (entries 3 and 4). In contrast to ethyl esters, phenyl esters
4d and 4e afforded the 5-exo-trig cyclization products 6d and 6e
exclusively (entries 5 and 6).§
Table 2 Nucleophilic cyclization of 2-functionalized 1-alkenes 4
The present research is supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology of Japan.
Notes and references
{ Representative procedure: To a solution of N-(1-phenyl-3-ethoxycarbonyl-
3-buten-1-yl)-4-methylbenzenesulfonamide (4a, 234 mg, 0.62 mmol) in
DMF (6 mL) was added NaH (1.5 mg, 0.06 mmol) under argon. After the
reaction mixture was stirred at 110 uC for 3 h, phosphate buffer (pH 7) was
added to quench the reaction. The mixture was then extracted twice with
AcOEt and the combined organic extracts were washed with water twice,
brine and dried over Na2SO4. The solution was filtered and concentrated
under reduced pressure. The residue was purified by column chromato-
graphy on silica gel (AcOEt–hexane–Et3N 20 : 79 : 1), affording 5a (203 mg,
Entry
4
EWG
R
Conditions 5 (%) (anti:syn)b 6 (%)
1a
2
3
4
5
6
a
4a CO2Et Ph 110 uC, 3 h 12
—
—
—
—
90
76
4a CO2Et Ph 110 uC, 3 h 87 (59 : 41)c
4b CO2Et
4c CN
4d CO2Ph Ph 100 uC, 1 h
4e CO2Ph 100 uC, 1 h
H
110 uC, 4 h 72
Ph 50 uC, 4 h
88 (37 : 63)c
—
—
H
b
c
NaH (1.0 eq.) was used.
Determined by 1H NMR. See
1
87%, anti : syn = 59 : 41) as a white solid. H NMR (500 MHz, CDCl3):
anti isomer: d 1.18 (3H, t, J = 7.1 Hz), 2.06 (1H, ddd, J = 12.5, 6.7, 3.0 Hz),
footnote."
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2.13–2.20 (1H, m), 2.41 (3H, s), 3.08 (1H, dddd, J = 6.3, 6.3, 6.3, 6.3 Hz),
3.57 (1H, dd, J = 10.1, 8.7 Hz), 3.89 (1H, dd, J = 10.1, 7.9 Hz), 4.00–4.05
(2H, m), 4.90 (1H, dd, J = 8.1, 3.0 Hz), 7.20–7.31 (7H, m), 7.69 (2H, d, J =
8.4 Hz); syn isomer: d 1.15 (3H, t, J = 7.1 Hz), 2.13–2.20 (1H, m), 2.43 (3H,
s), 2.49 (1H, ddd, J = 13.0, 7.7, 7.7 Hz), 2.71 (1H, dddd, J = 6.0, 6.0, 6.0,
6.0 Hz), 3.77 (1H, dd, J = 11.3, 8.9 Hz), 3.91 (1H, dd, J = 11.3, 8.0 Hz),
4.00–4.05 (2H, m), 4.74 (1H, dd, J = 7.7, 7.7 Hz), 7.22–7.31 (7H, m), 7.60
(2H, d, J = 8.4 Hz). 13C NMR (126 MHz, CDCl3): anti isomer: d 14.0, 21.5,
38.3, 41.3, 50.8, 61.0, 62.8, 125.9, 126.4, 127.4, 127.5, 128.4, 134.5, 142.0,
143.5, 171.8; syn isomer: d 14.0, 21.5, 39.4, 42.6, 51.1, 61.0, 63.6, 125.9,
126.3, 127.3, 127.5, 128.3, 135.1, 141.5, 143.5, 171.4. IR (neat) 3032, 2920,
2850, 1732, 1348, 1219, 1161, 914 cm21. Anal. Calcd. for C20H23NO4S; C,
64.32; H, 6.21; N, 3.75. Found: C, 64.07; H, 6.17; N, 3.55%.
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§ The 5-exo-trig cyclization was easily effected also in other active
carboxylic acid derivatives, such as acyl chlorides and mixed anhydrides.
3 For a recent review, see: (a) D. W. Knight, Progress in Heterocyclic
Chemistry, ed. G. W. Gribble and T. L. Gilchrist, Pergamon,
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NOESY experiment. A cross peak between the 2- and 4-protons was not
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2- and 4-protons in the anti-isomer were observed at lower field (d 4.90 and
3.08) than those in the syn-isomer (d 4.74 and 2.71). The configuration of 5c
was determined by analogy with 5a by comparing the C2- and C4-proton
chemical shifts of each isomer.
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O. Dogan, H. Koyuncu, P. Garner, A. Bulut, W. J. Youngs and
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2700 | Chem. Commun., 2007, 2698–2700
This journal is ß The Royal Society of Chemistry 2007