Stereoisomeric Styryl-substituted Pyrrolidines, 3,7-Diazobicyclo[3.3.0]octanes and 2-Styrylpyrroles from Cinnamaldehyde Iminium-N-methanide 1,3-Dipoles

Article abstract of DOI:10.1039/a706737b

The reaction of cinnamaldehyde N-aryliminium methanide 1,3-dipoles with dimethyl maleate, dimethyl fumarate and some N-arylmaleimides gives equal mixtures of stereoisomeric substituted pyrrolidines and a route to 2-styrylpyrroles with dimethyl acetylene-d

Full text of DOI:10.1039/a706737b

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82 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 82±83
Stereoisomeric Styryl-substituted Pyrrolidines, 3,7-
Diazobicyclo[3.3.0]octanes and 2-Styrylpyrroles from
Cinnamaldehyde Iminium-N-methanide 1,3-Dipoles{
Richard N. Butler* and Derval M. Farrell
Chemistry Department, University College Galway, Ireland
The reaction of cinnamaldehyde N-aryliminium methanide 1,3-dipoles with dimethyl maleate, dimethyl fumarate and some N-aryl-
maleimides gives equal mixtures of stereoisomeric substituted pyrrolidines and a route to 2-styrylpyrroles with dimethyl acetylene-
dicarboxylate.
Azomethine methanide (ylide) 1,3-dipoles have proved to be
important synthons for the pyrrole system.1±3 Routes to
these dipoles include thermal ring-opening of aziridines,1±4
reactions of a-amino esters with carbonyl compounds,5±6
reactions of amines with aldehydes7 and desilylation of tri-
methylsilylmethyliminium salts.8,9 We have recently exam-
ined10 the stereochemistry of the cycloadducts of the
phthalazinium-2-methanide 1,3-dipole 1. This contains a
more rigid structural component than the analogous cin-
namaldehyde iminium±methanide dipole 3 and we wished
to compare the behaviour of 1 with this more ¯exible
structure 3.
All the compounds gave the expected microanalyses and
1
IR and H and 13C NMR spectra with the required splitting
patterns (Scheme 1 and Experimental section). The stereo-
isomers were distinguished by the NOE e€ects of the pyrro-
lidine 2- and 3-H atoms when these were cis and the
absence of this NOE e€ect when these H atoms were trans
(5-H and 6-H in products 6, 7, 12±15). In the exo cyclo-
adducts 7, 13 and 15 the 6-CH was also signi®cantly more
shielded when cis to the imido p-electrons, a feature we
have also noted10 for the C-10a bridgehead hydrogen in
cycloadducts from the dipole 1. Varying and unequal
endo:exo ratios were formed10 in the cycloadditions of the
dipole 1. The consistent 1:1 ratio of stereoisomers observed
herein with the dipole 3 probably re¯ects the lower steric
Ar
N+
N
N+
Ph
–
CH2
CH2
1
3 (EZ)
X
In the generation of 1,3-dipoles from iminium salts the
possible EZ stereochemistry of the trimethylsilylmethyl
iminium tri¯ate salts has not been commented on, since
these salts were generally not isolated in earlier studies.
In the present work with cinnamaldehyde imines the salts
2 were readily isolated by stirring cinnamaldehyde N-aryl-
imines with trimethylsilylmethyl tri¯uoromethanesulfonate
in diethyl ether and varying mixtures of the EZ and EE
forms were obtained (Scheme 1; Table 1, entries 1±5).
The ratios were readily established by the 1H NMR
spectra which showed the styryl a-CH (a doublet of
doublets) more up®eld when in the shielding region of
the N-aryl ring in the EZ form (Scheme 1). When the
salts 2 were desilylated in the presence of the dipolaro-
philes dimethyl acetylenedicarboxylate (DMAD), N-( p-
substituted phenyl)maleimides, dimethyl fumarate and
dimethyl maleate, the respective products 4, stereoisomer
pairs 6,7, 12,13, 14,15 (all 1:1 ratio) and 10,11 (1:1 ratio)
were obtained in high yields (Table 1). Interestingly the
ratio of EZ and EE isomers in the dipole precursor 2
did not in¯uence the stereoisomer ratio of the cyclo-
adducts, suggesting that the same dipole 3 (EE or EZ)
enters the cycloaddition from either precursor. The 2,5-
dihydropyrrole derivatives 4 and the pyrrolidine derivatives
8±11 could be readily oxidised to 2-styrylpyrroles 5 with
PbO2 in CH2Cl2. The product series 6, 7, 12±15 are new
6-styryl-substituted 3,7-diazabicyclo[3.3.0]octane-2,4-diones.
In all cases the isomeric pairs were readily separated by
column chromatography.
6.51
7.23
CH2SiMe3•TfO–
N+
H
H
α
Ph
N+
Ph
β
CH2SiMe3•TfO–
+
8.23
8.33
H
H
H
H
9.20
8.82
X
i
2 (EZ)
2 (EE)
3
ii
iii
CO2Me
CO2Me
6.10
Ph
C6H4X-p
H
Ph
4.63
3.68 3.75
N
H
H
7
N
H
6
8
4.39
6.68
4.02
H
H
2
5.13
5
1
5.44
C6H4X-p
H
H
O
4
4
3 N
3.54
C6H4Y-p
O
iv or v
vi
6 Y = H
12 Y = OMe
14 Y = Br
CO2Me
CO2Me
+
Ph
Ph
C6H4X-p
N
4.19
N
C6H4X-p
H
H
5
vi
H
H
H
4.72
3.54 3.72
3.91
X
Z
3
4
5
Y
H
W
O
Ph
2
O
N
1
N
C6H4Y-p
C6H4Br-p
7 Y = H
13 Y = OMe
15 Y = Br
8 X = W = CO2Me; Y = Z = H
9 X = W = H; Y = Z = CO2Me
10 X = Z = H; Y = W = CO2Me
11 X = Z = CO2Me; Y = W = H
X = a, MeO; b, Me; c, H; d, Br; e, Cl
To receive any correspondence.
± = ±
Fig. 1 Reagents: i. CsF; (ii) MeO C C C CO Me; iii, p-substituted
This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
=
2
2
phenylmaleimide; iv, dimethyl fumarate; v, dimethyl maleate; vi, PbO2
in CH2Cl2; some key1HNMR shifts (CDCl3) are shown for X = Br

View Article Online
J. CHEM. RESEARCH (S), 1998 83
Ta bl e 1 Substrates and cycloadducts
Mpa
(T 8/C)
Yield
(%)
Mpa
(T 8/C)
Yield
(%)
Entry
Compd.
dH
Compd.
dH
1
2
2a
2b
2c
2d
2e
6d
6c
158^159b
163^164b
135^137b
156^158b
146^148b
99^100
95(4:1)d
93(1.5:1)
92(1:3)
90(1.2:1)
90(1:1)
40
^
^
4ah
4b
143^145
104^106
99^100
88
63
60
80
80
40
40
30
46
35
20
5.38g
5.41g
5.45g
5.44g
5.40g
4.72e
4.75e
4.71e
4.70e
4.66g
4.62f,g
3
^
4c
4
^
^
4dh
4e
7d
7c
164^166
154^155
174^175
173^174c
190^192
152^154
88^89
5
6
5.13e,f
5.19e,f
5.10e,f
5.09e,f
4.58f,g
4.59g
7
198^200c
120^122
178^180
84^85
40
8
12d
14d
8
30
13d
15d
9h
9
46
10
11
35
10
124^126
20
11
130^132
e
f
aFrom EtOH unless stated otherwise. bWashed with Et2O. cFrom MeOH. dParentheses contain EZ:EE ratio.
from adjacent cis H. g H for H-2. hOxidation gave compounds 5a and 5d.
for H-6. NOE enhancement
H
(Found C, 59.5; H, 4.7; N, 3.1. C22H20BrNO4 requires C, 59.7; H,
4.5; N, 3.1.1%); max/cm (mull) 1725, 1730 (ester C1O); dH
strain and greater ¯exibility in the cycloaddition transition
state.
1
(CDCl3) 3.81 (s, 3 H, CO2Me), 3.85 (s, 3 H, CO2Me), 4.39 (dd, 1 H,
H-5 trans relative to styryl), 4.63 (dd, 1 H, H-5 cis), 5.44 (m, 1 H,
H-2), 6.10 (dd, 1 H, styryl, H-a), 6.49±6.53 (m, 2 H, N-ArBr), 6.68
(d, J 16.1 Hz, 1 H, styryl, H-b), 7.27±7.32 (m, 7 H, Ar); dC (CDCl3)
(o€-res) 52.6 (q, OMe), 55.9 (t, C-5), 69.3 (d, C-2), 144.6, 113.9,
132.0, 109.5 (N-1-p-BrC6H4,C-1', C-2', C-3', C-4' resp.), 139.9,
126.8, 128.2, 126.2 (styryl phenyl, C-1', C-2', C-3', C-4' resp.), 132.4
(s, C-4), 135.9 (s, C-3), 128.1 (d, styryl C-a), 135.9 (d, styryl, C-b),
162.9, 163.5 (s, C1O).
Experimental
Mps were measured on an Electrothermal apparatus. IR spectra
were measured with a Perkin Elmer 983G spectrophotometer. NMR
spectra were measured on JEOL GX FT270 and GXFT400 spec-
trometers using CDCl3 as solvent. Cinnamaldehyde N-arylimines
separated on cooling after a dry EtOH solution of the aldehyde and
the p-substituted aniline (1:1 mol) was heated under re¯ux for 1 h.
The salts 2 were obtained in 90±95% yields when equimolar quan-
tities of the imine and trimethylsilylmethyl tri¯ate were stirred in
dry Et2O at ambient temperature for 12 h.
Oxidation of 4d (0.45 mmol) with PbO2 (4.5 mmol) in CH2Cl2
(20 cm3) for 48 h at ambient temperate gave the pyrrole 5d (50%),
mp 94±95 8C (from EtOH) (isolated by elution from a ¯ash column
of silica gel 230±400 mesh ASTM with petroleum spirit (bp 40±
60 8C±CH2Cl2 (20:1 v/v) (Found: C, 59.7; H, 4.0; N, 3.2. C22
Cycloadditions
(Typical
Examples).Ð3,7-Diphenyl-6-exo-[(E)-
styryl]-3,7-diazabicyclo[3.3.0]octane-2,4-dione 7c and the endo isomer
6c (Table 1, entry 7). A solution of the tri¯ate salt 2c (0.50 g, 1.38
mmol) in dry CH2Cl2 (20 cm3) was treated with N-phenylmaleimide
(0.48 g, 2.76 mmol) followed by an excess of CsF. The mixture was
stirred under anhydrous conditions at ambient temperatures for 24
h and then ®ltered. The ®ltrate (together with the CH2Cl2 ®lter-cake
washings) was evaporated under reduced pressure to 4 cm3, placed
on a column of silica gel (230±400 mesh) and eluted slowly with
CH2Cl2. First eluted was the endo isomer 6c (40%) mp 198±200 8C
(from MeOH) (Found: C, 79.0; H, 5.5; N, 7.0. C27H22NO2 requires
1
H18BrNO4 requires C, 60.0; H, 4.1; N, 3.2%); max/cm (mull),
1724, 1710 (ester C1O); dH (CDCl3) 3.85 (s, 3 H, OMe), 3.93 (s,
3 H, OMe), 6.79 (dd, 2 H, N-1-p-BrC6H4, H-2'), 7.23±7.35 (m, 9 H,
aromatic protons, styryl, Ha, Hb), 7.64 (m, 1 H, H-5); dC (CDCl3)
(o€-res.), 51.7, 52.4 (q, OMe), 137.5, 115.3, 132.9, 116.3 (N-1-p-
BrC6H4, C-1', C-2', C-3', C-4' resp.), 136.5, 127.8, 128.7, 126.5
(styryl phenyl, C-1', C-2', C-3', C-4' resp.), 122.6 (s,C-4), 127.9 (s,
C-3), 128.0 (d, styryl, C-a), 128.5 (d, styryl, C-b), 132.7 (C-2), 133.5
(d, -5), 163.8, 166.3 (s, C1O).
1
C, 79.2; H, 5.6; N, 7.1%) max/cm (mull) 1709 br (amido C1O;
The 1-(p-methoxyphenyl) pyrrole 5a, mp 104±106 8C (from
EtOH), was similarly obtained.
dH(CDCl3) 3.54 (d, J 7.3 Hz, H-5), 3.64±3.79 (m, 2 H, H-1,
H-8endo), 4.08 (d, J 9.5 Hz, H-8exo), 5.19 (d, J 6.6 Hz, 1 H, H-6),
6.08±6.16 (dd, 1 H, styryl, Ha), 6.62 (d, J 15.4 Hz, 1 H, styryl, Hb),
6.74±6.8 (m, 3 H, Ar), 7.21±7.49 (m, 12 H, Ar); dC (CDCl3) (o€-res)
43.6 (d, C-1), 49.6 (t, C-8), 51.5 (d, C-5), 63.3 (d, C-6), 145.1, 115.1,
128.5, 118.7 (N-7-Ph, C-1', C-2', C-3', C-4' resp.), 135.9, 126.6,
129.3, 125.7 (styryl phenyl, C-1', C-2', C-3', C-4' resp.), 131.5, 126.5,
128.7, 128.2 (N-3-Ph, C-1', C-3', C-4' resp.), 128.9 (d, styryl C-a),
133.2 (d, styryl C-b), 176.8, 177.9 (s, C1O).
Received, 16th September 1997; Accepted, 8th October 1997
Paper E/7/06737B
References
1 I. Coldham, A. J. Collis, R. J. Mould and D. E. Robinson,
Synthesis, 1995, 1147.
Next eluted was the exo isomer 7c (40%), 173±174 8C (from
MeOH) (Found: C, 79.1; H, 5.4; N, 6.9. C27H22NO2 requires C,
79.2; H, 5.6; N, 7.1%); max/cm (mull) 1712 br (amido C1O); dH
2 For a review see, J. W. Lown, in 1,3-Dipolar Cycloaddition
Chemistry, ed. A. Padwa, Wiley, New York, 1984, vol. 1, p. 653.
3 A. Padwa and L. Hamilton, Tetrahedron Lett., 1965, 4363;
C. Wittland, M. Arend and N. Risch, Synthesis, 1996, 367.
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1982, 60, 2830; R. Grigg, J. Montgomery and A.
Somasunderam, Tetrahedron, 1992, 48, 10431.
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K. Ueno, Bull. Chem. Soc. Jpn., 1987, 4067; O. Tsuge, S.
Kanemasa, M. Ohe and S. Takenaka, Chem. Lett., 1986, 973.
6 J. Mortier and M. Joucla, Tetrahedron Lett., 1987, 27, 2973;
J. E. Baldwin, S. C. MacKenzie Turner and M. G. Moloney,
Synlett., 1994, 925.
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Montgomery, V. Sridharan and S. Surendrakumar, Tetrahedron,
1990, 46, 6449.
8 E. Vedejs, S. Larsen and F. G. West, J. Org. Chem., 1985, 50,
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1
(CDCl3) 3.68±3.76 (m, 2 H, H-8endo, H-1), 3.85±3.92 (m, 1 H, H-5),
4.23±4.26 (m, 1 H, H-8exo), 4.75 (m, 1 H, H-6), 6.17±6.26 (dd, J
16.1, 5.9 Hz, 1 H, styryl, H-a), 6.56 (d, 1 H, styryl, Hb), 6.78±6.86
(m, 3 H, Ar), 7.03±7.07 (2 H, m, Ar), 7.22±7.30 (10 H, m, Ar); dC
(CDCl3) (o€-res). 44.9 (d, C-1), 49.9 (d, C-5) 50.9 (t, C-8), 62.3 (d,
C-6), 146.4, 115.3, 128.6, 119.1 (N-7-Ph, C-1', C-2', C-3', C-4' resp.),
135.9, 126.6, 129.2, 126.8 (styryl phenyl C-1', C-2', C-3', C-4' resp.),
131.6, 124.9, 129.2, 128.1 (N-3-Ph, -1', C-2', C-3', C-4' resp.), 128.7
(d, styryl C-a) 133.1 (d, styryl, C-b), 174.8, 177.3 (s, C1O).
1-(p-Bromophenyl)-3,4-bis(methoxycarbonyl)-2-[(E)-styryl]-2,5-dihy-
dropyrrole 4d and -pyrrole 5d (Table 1, entry 4).±A solution of the
tri¯ate salt 2d (0.50 g, 1.13 mmol) in dry CH2Cl2 (20 cm3) was
treated with dimethyl acetylenedicarboxylate (0.28 ml, 2.6 mmol)
followed by an excess of CsF. The mixture was stirred under anhy-
drous conditions at ambient temperatures for 24 h and then ®ltered.
The ®ltrate (together with the CH2Cl2 ®lter-cake washings) was
evaporated under reduced pressure to 4 cm3, placed on a ¯ash col-
umn of silica gel (230±400 mesh ASTM) and eluted with gradient
mixtures of petroleum spirit (bp 40±60 8C)±CH2Cl2 (1:0 to 1:1) to
give the dihydropyrrole 4d (80%), mp 164±166 8C (from EtOH)
10 R. N. Butler, D. M. Farrell and C. S. Pyne, J. Chem. Res. (S),
1996, 418.