An efficient synthesis of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3- dihydro-lh-pyrrolizine, a key intermediate in the licofelone synthesis

Article abstract of DOI:10.1135/cccc2009026

An efficient synthesis of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3- dihydro-1H-pyrrolizine, a key intermediate for the synthesis of licofelone, an anti-inflammatory drug currently undergoing evaluation of the phase-III clinical studies, is described. The method is based on a novel synthesis of unstable 5-benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole, which is then treated with 2-bromo-1-(4-chlorophenyl)ethan-1-one. 2,2-Dimethyl-5-phenylpent-4-ynal with benzylamines provides the corresponding Schiff bases. Migration of the C=N double bond in these N-(2,2-dimethyl-5-phenylpent-4-yn-1-ylidene)benzylamines into conjugation with the aromatic ring using various base/solvent systems was studied. Acid hydrolysis of the formed Schiff bases then provided 2,2-dimethyl-5-phenylpent-4-yn-1-amine and 2,2-dimethyl-5-phenylpenta-3,4-dien- 1-amine; their ratio was influenced mainly by the reaction conditions. Cyclization of these amines using Ag or Au catalysts then led to 5-benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole.

Full text of DOI:10.1135/cccc2009026

Synthesis of 6-(4-Chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine
1011
AN EFFICIENT SYNTHESIS OF 6-(4-CHLOROPHENYL)-
2,2-DIMETHYL-7-PHENYL-2,3-DIHYDRO-1H-PYRROLIZINE,
A KEY INTERMEDIATE IN THE LICOFELONE SYNTHESIS
1,
2
3
4
Stanislav RÁDL *, Jan STACH , Josef ČERNÝ and Ondřej KLECÁN
Zentiva, U kabelovny 130, 102 37 Prague 10, Czech Republic;
1
2
3
e-mail: stanislav.radl@zentiva.cz, jan.stach@zentiva.cz, josef.cerny@zentiva.cz,
4
ondrej.klecan@zentiva.cz
Received March 3, 2009
Accepted April 21, 2009
Publish ed on lin e Jun e 23, 2009
Dedicated to Dr. Alfred Bader, a friend and an exceptional human being, on the occasion of his 85th
birthday in recognition of his outstanding contributions to the science of chemistry.
An efficien t syn th esis of 6-(4-ch loroph en yl)-2,2-dim eth yl-7-ph en yl-2,3-dih ydro-1H-pyrrolizin e,
a key in term ediate for th e syn th esis of licofelon e, an an ti-in flam m atory drug curren tly un -
dergoin g evaluation of th e ph ase-III clin ical studies, is described. Th e m eth od is based on a
n ovel syn th esis of un stable 5-ben zyl-3,3-dim eth yl-3,4-dih ydro-2H-pyrrole, wh ich is th en
treated with 2-brom o-1-(4-ch loroph en yl)eth an -1-on e. 2,2-Dim eth yl-5-ph en ylpen t-4-yn al
with ben zylam in es provides th e correspon din g Sch iff bases. Migration of th e C=N double
bon d in th ese N-(2,2-dim eth yl-5-ph en ylpen t-4-yn -1-yliden e)ben zylam in es in to con jugation
with th e arom atic rin g usin g various base/solven t system s was studied. Acid h ydrolysis of
th e form ed Sch iff bases th en provided 2,2-dim eth yl-5-ph en ylpen t-4-yn -1-am in e an d 2,2-
dim eth yl-5-ph en ylpen ta-3,4-dien -1-am in e; th eir ratio was in fluen ced m ain ly by th e reaction
con dition s. Cyclization of th ese am in es usin g Ag or Au catalysts th en led to 5-ben zyl-
3,3-dim eth yl-3,4-dih ydro-2H-pyrrole.
Keyw ord s: Licofelon e; Sch iff bases; Cyclization ; Double bon d m igration ; Isom erization ;
Pyrroles; Pyrrolizin es; Au catalysis; Am in es; Alkyn es; Allen es.
Licofelon e (ML3000)1, a dual cyclooxygen ase/5-lipoxygen ase in h ibitor de-
veloped by Merckle, is th e first m em ber of th is n ew class of an algesic an d
an ti-in flam m atory drugs curren tly un dergoin g evaluation of th e ph ase-III
clin ical studies for treatm en t of osteoarth ritis2.
Th ere are several m eth ods for con struction of th e paren t m oiety of th e
drug; it is usually form ed by con den sation of rath er un stable 5-ben zyl-
3,3-dim eth yl-3,4-dih ydro-2H-pyrrole (1) with 2-brom o-1-(4-ch loroph en yl)-
eth an -1-on e (2) providin g 2,3-dih ydro-1H-pyrrolizin e 3 (refs3–5). Th ough ,
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 1011–1022
© 2009 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc2009026

1012
Rádl, Stach, Černý, Klecán:
a differen t syn th esis of 3 based on th e Suzuki cross-couplin g reaction h as
been publish ed6–8, th e origin al m eth od usin g th e in term ediacy of 1 seem s
to be m ore efficien t. Com poun d 3 wh en treated with eth yl diazoacetate
gives ester 4a an d its h ydrolysis gives licofelon e. Altern atively, com poun d 3
treated with oxalyl ch loride gives acyl ch loride 5, wh ich un der th e con di-
tion s of Wolff–Kish n er reduction th en provides licofelon e (Sch em e 1)3–5
.
Recen tly we h ave reported a n ew efficien t syn th esis of 4a an d its an alogs
based on Fen ton -type radical alkylation of com poun d 3 with iodoacetates9.
SCHEME 1
Syn th esis of licofelon e
Several m eth ods of syn th esis of 1 h ave been described (Sch em e 2), but
n on e of th em seem s to be efficien t en ough for in dustrial production . Th e
first described syn th esis3 leadin g to low yields of 1 is based on treatm en t of
4-ch loro-3,3-dim eth ylbutan en itrile (6), obtain ed in th ree steps from com -
m ercially available 2,2-dim eth ylpropan e-1,3-diol, with ben zylm agn esium
ch loride. Better yields can be obtain ed by syn th esis4 based on cyan oh ydrin
reaction of ch loroacetaldeh yde an d N-m eth ylan ilin e followed by elim in a-
tion of h ydrogen ch loride un der PTC con dition s. Th e form ed 2-(N-m eth yl-
an ilin o)acrylon itrile (7) is tran sform ed in to n itrile 8 an d its reduction on
Ran ey n ickel leads directly to required com poun d 1. Recen tly, a syn th esis
based on th e Mich ael addition of n itrom eth an e to 9 an d subsequen t
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Synthesis of 6-(4-Chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine
1013
reductive cyclization of th e prim arily form ed n itro derivative 10 h as been
described10; h owever, n o yields are given th rough out th e paten t. Th e last
described syn th etic route to 1 is based on th e alkylation of isobutyron itrile
with cin n am yl brom ide providin g n itrile 11 (ref.11), wh ich is th en reduced
with LiAlH4 to un saturated am in e 12 (ref.12). Th e fin al cyclization 13 of 12
in to 1 is catalyzed with [RuCl2(CO)3]2-1,3-bis(diph en ylph osph an yl)pro-
pan e.
SCHEME 2
Th e kn own m eth ods of syn th esis of 1
Syn th esis of 6-(4-ch loroph en yl)-2,2-dim eth yl-7-ph en yl-2,3-dih ydro-
1H-pyrrolizin e (3) via 2,3-dih ydro-1H-pyrrolizin e 16 described by Cossy et
al.7,8 is sh own in Sch em e 3. Startin g 1-ch loro-3-ph en ylprop-2-yn e (13)
treated with isobutyraldeh yde provides aldeh yde 14. Reductive am in ation
of 14 with m eth yl glycin ate gives a good yield of 15 an d its th erm al
cyclization yields 2,3-dih ydro-1H-pyrrolizin -6(5H)-on e 16. Suzuki cross-
couplin g of th e correspon din g triflate provides on ly low yields of 3.
Th ere are several reports14–16 describin g base-catalyzed carbon -n itrogen
double bon d m igration in Sch iff bases derived from aliph atic aldeh ydes an d
ben zylam in e. Acid h ydrolysis of th e resultin g rearran ged Sch iff bases pro-
vided an en try to m ake am in es from aldeh ydes. We decided to utilize th is
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1014
Rádl, Stach, Černý, Klecán:
SCHEME 3
Syn th esis of 3 by Suzuki cross-couplin g
approach in th e syn th esis of 1 (see retrosyn th etic an alysis in Sch em e 4). We
assum ed th at un der th e con dition s used for th e isom erization , th e triple
bon d in 19 could rem ain un touch ed to give 20 or could un dergo isom er-
ization to th e correspon din g allen e 21. In both cases am in es 22 an d 23
form ed in th e followin g step were con sidered to be poten tial in term ediates
in th e syn th esis of 1.
SCHEME 4
Retrosyn th esis of 1
RESULTS AND DISCUSSION
Aldeh yde 14, wh ich was prepared in good yields by a kn own procedure7,8
,
treated with ben zylam in e un der stan dard con dition s15, provided Sch iff
base 19a. Its base-catalyzed isom erization provided m ixtures of both pos-
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Synthesis of 6-(4-Chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine
1015
sible products 20a an d 21a. Sim ilarly, usin g th e respective ben zylam in es,
Sch iff bases 19b, 19c were obtain ed an d th eir isom erization was also stud-
ied. Th e ratio 20/21 was in fluen ced m ain ly by th e used base/solven t sys-
tem s, th e in fluen ce of th e R was n egligible an d th erefore com poun d 19a
was m ostly used (Table I). Mixtures of 20 an d 21 were th en h ydrolyzed with
aqueous oxalic acid to get th e correspon din g m ixtures of oxalates of am in es
22 an d 23.
TABLE I
Base-catalyzed isom erization of com poun ds 19
Startin g com poun d Con dition s
Ratio of 22/23
Notes
19a
19a
19a
19a
19a
19a
19a
19a
19a
19b
19c
t-BuOK, DMSO, 20 °C, 1 h
2:1
7:1
Im purities form ed
t-BuOK, THF, 20 °C, 1 h
t-BuOK, THF, reflux, 1 h
t-BuOK, toluen e, reflux, 1 h
t-BuOK, MeCN, reflux, 1 h
KDMO, THF, reflux, 1 h
KDMO, THF, 0 °C, 1 h
4:1
5:1
6:1
Im purities form ed
6:1
8:1
KDMO, THF, –30 °C, 2 h
KDMO, THF, –50 °C, 20 h
t-BuOK, THF, reflux, 1 h
t-BuOK, THF, reflux, 1 h
25:1
>99:1
3.5:1
3:1
Wh en th e isom erization with potassium 3,7-dim eth yl-3-octan -3-olate
(KDMO) was perform ed at –50 °C, acetylen ic com poun d 20a stron gly pre-
vailed so th at after h ydrolysis on ly am in e 22 was obtain ed as oxalate salt.
On th e oth er h an d, we failed to get on ly allen ic com poun d 21a.
Successful cyclization of am in o derivative 22 or its m ixtures with 23 can
be ach ieved by catalysis of various silver salts (Table II). Th e best results
were ach ieved with AgBF4. Sim ilar results were obtain ed also with AgClO4
or Ph COOAg. A rath er slower reaction was observed usin g Ag2CO3. Th e
cyclization s were usually perform ed in refluxin g dich lorom eth an e, but sim -
ilar results were also observed in THF or toluen e. Th e reaction m ixture after
com plete con version (GC) was sim ply worked-up by pourin g in to a brin e
solution , filterin g off th e in soluble portion an d evaporatin g th e filtrate.
Due to th e kn own in stability of 5-ben zyl-3,3-dim eth yl-3,4-dih ydro-2H-
pyrrole (1), th e form ed residue was directly used in th e preparation of 3. In
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 1011–1022

1016
Rádl, Stach, Černý, Klecán:
th is com poun d, th e Ag con ten t was foun d below th e m easurem en t lim its
usin g in ductively coupled plasm a atom ic em ission spectroscopy (ICP AES)
an alysis.
TABLE II
Catalytic cyclization of com poun ds 22 an d 23 to 5-ben zyl-3,3-dim eth yl-3,4-dih ydro-2H-
pyrrole (1)
Molar ratio
22/23
Con dition s
Con version , (yield) Notes
4:1
>99:1
4:1
AgBF4, CH2Cl2, 40 °C, 6 h
AgBF4, CH2Cl2, 40 °C, 4 h
AgClO4, CH2Cl2, 40 °C, 6 h
Ph CO2Ag, CH2Cl2, 40 °C, 24 h
Ag2CO3, CH2Cl2, 40 °C, 24 h
AuCl3, CH2Cl2, 40 °C, 4 h
PdCl2, CH2Cl2, 40 °C, 24 h
Pd/C, CH2Cl2, 40 °C, 24 h
CHCl3, reflux, 24 h
100% (quan t.)
100% (quan t.)
100% (quan t.)
4:1
100%
98%
100%
70%
18%
18%
96% after 6 h
4:1
55% after 6 h
4:1
9:1
4:1
all allen e disappeared
all allen e disappeared
4:1
We h ave n ot exten sively studied th e cyclization usin g gold catalysts for
th eir h igh er price wh ich could preven t th eir in dustrial application . AuCl3,
th e on ly gold catalyst tested, provided virtually iden tical results as AgBF4.
Our attem pts to use oth er catalysts were successful on ly with PdCl2, but th e
reaction was rath er slow (70% con version after 24 h ). Due to th e lon ger re-
action tim e also som e im purities were form ed. Th e oth er catalysts tested,
e.g. Pd/C, Sm I2, Ni(II) acetylaceton ate or NaF, failed to give an y cyclization
products. Durin g th ese studies we foun d, th at un der som e con dition s, e.g.
Pd/C, usin g a 4:1 m ixture of 22 an d 23, allen ic com poun d 23 cyclized
wh ile th e acetylen ic com poun d 22 did n ot ch an ge. However, we foun d
later th at sim ilar results can be ach ieved with out an y catalyst, e.g. in re-
fluxin g ch loroform (Sch em e 5).
Com poun d 21a can be obtain ed also by isom erization of Sch iff base 24,
wh ich is form ed from th e correspon din g aldeh yde 25 (Sch em e 6).
Black an d Lan dor17 prepared on ly low yields (10–30%) of 2,2-dim eth yl-
pen ta-3,4-dien al (27a) an d 2,2-dim eth ylh exa-3,4-dien al (27b) by th erm ally
in duced Claisen rearran gem en t of 2-m eth yl-1-(prop-2-yn -1-yloxy)prop-
1-en e (26a) an d 3-(2-m eth ylprop-1-en -1-yloxy)but-1-yn e (26b ), respec-
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Synthesis of 6-(4-Chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine
1017
SCHEME 5
Syn th esis of 1
SCHEME 6
Retrosyn th esis of 21a
tively. Th ere are several papers18–21 describin g con den sation of propargylic
alcoh ols 28 an d isobutyraldeh yde catalyzed with p-toluen esulfon ic acid
affordin g low to m oderate yields of 3-(un )substituted 2,2-dim eth ylpen ta-
3,4-dien al derivatives 27. However, n o reaction occurred with 1-ph en yl-
prop-2-yn -1-ol 28 (R = Ph ). A good yield of 32 was obtain ed by th e Claisen
rearran gem en t of th e correspon din g 2-m eth ylprop-1-en -1-yl 3-ph en yl-
prop-2-yn -1-yl eth er (31) form ed in situ from 1-ch loro-2-m eth ylpropyl
3-ph en ylprop-2-yn -1-yl eth er 30 (ref.22) (Sch em e 7). We h ave tried to apply
th is m eth odology to th e syn th esis of aldeh yde 25, but on ly a com plex m ix-
ture was obtain ed.
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1018
Rádl, Stach, Černý, Klecán:
SCHEME 7
Preparation of allen ic aldeh ydes 27 an d 32
EXPERIMENTAL
Meltin g poin ts were m easured on a Kofler block an d are un corrected. Th e IR spectra were
m easured on a Perkin –Elm er Spectrum BX FT-IR in strum en t by th e diffuse reflectan ce
m eth od (KBr), an d FT-Ram an spectra on a Bruker RFS 100/S in strum en t; waven um bers are
given in cm –1. UV spectra were recorded on a Hewlett–Packard 8452A spectroph otom eter
(eth an ol) in th e ran ge 190–400 n m . NMR experim en ts (δ, ppm ; J, Hz) were carried out on a
Bruker Avan ce 500 in strum en t at 500.13 MHz (1H), 125.77 MHz (13C) usin g residual
deuterated solven t sign als as in tern al stan dards (for 1H δ 7.26 ppm , for 13C δ 77.0 ppm , both
in CDCl3). All experim en ts were perform ed in CDCl3 at 298 K, un less oth erwise stated. Mass
spectra (MS/MS; ion ization m ode APCI(+)) were m easured on an API 3000 PE spectrom eter
(Sciex In strum en ts, Applied Biosystem s). GC was perform ed on a Fin n igan Focus GC in stru-
m en t usin g Restek RTX-5 am in e colum n . Th e purity of th e prepared substan ces was evalu-
ated by TLC on silica gel (FP KG F 254, Merck). 2,2-Dim eth yl-5-ph en ylpen t-4-yn al (14) vas
prepared accordin g to th e literature procedure7,8; Potassium 3,7-dim eth yl-3-octan -3-olate
(KDMO) was obtain ed from BASF. Oth er ch em icals used in th e syn th esis were purch ased
from Sigm a–Aldrich an d were used with out purification .
Preparation of (E)-N-(2,2-dim eth yl-5-ph en ylpen t-4-yn -1-yliden e)ben zylam in es (19).
Gen eral Procedure
2,2-Dim eth yl-5-ph en ylpen t-4-yn al (14; 21.3 g, 114 m m ol) an d appropriate ben zylam in e
(114 m m ol) was added to a stirred suspen sion of an h ydrous MgSO4 (20 g, 167 m m ol) in
tetrah ydrofuran (150 m l) an d th e m ixture was stirred at room tem perature for 6 h . Th e in -
soluble portion was filtered off an d th e filtrate was evaporated un der reduced pressure to
give th e desired product, wh ich was used with out purification in th e n ext step.
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 1011–1022

Synthesis of 6-(4-Chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine
1019
(E)-N-(2,2-Dimethyl-5-phenylpent-4-yn-1-ylidene)benzylamine (19a). Colorless oil. 1H NMR
(CDCl3): 1.26 (s, 6 H, 2 × CH3), 2.57 (s, 2 H, CH2), 4.62 (s, 2 H, CH2), 7.19–7.38 (m , 10 H,
Ar), 7.75–7.79 (m , 1 H, Ar). 13C NMR (CDCl3): 21.5, 24.9, 30.9, 39.8, 64.7, 82.8, 87.5, 124.0,
126.9, 127.7, 127.8, 128.3, 128.5, 131.7, 139.6, 171.5. ATR-IR: ν(CH) 3029, ν(CH) 2964,
ν(CH) 2826, ν(C≡C) 2225, ν(C=N) 1666, ν(C=C) 1490, δ(CH)Ar 755. FT-Ram an : ν(CH) 3061,
ν(CH) 2904, ν(C≡C) 2221, ν(C=N) 1667, ν(C=C) 1598, δ(CH) 1258, δ(CH)Ar 1002. UV (EtOH),
λm ax (log ε): 204 (4.60), 240 (4.35), 250 (4.30). HRMS, m/z: calculated for C20H22N (M + H)
276.1752, foun d 276.1746. EI MS (m/z, %): 276.1 (M+, 95), 234.2 (25), 161.4 (20), 91.2 (100).
(E)-N-(2,2-Dimethyl-5-phenylpent-4-ynylidene)-4-chlorobenzylamine (19b ). Yellowish oil.
1H NMR (CDCl3): 1.28 (s, 6 H, 2 × CH3), 2.57 (s, 2 H, CH2), 4.58 (s, 2 H, CH2), 7.21 (s, 4 H,
Ar), 7.26–7.39 (m , 5 H, Ar), 7.75–7.78 (m , 1 H, Ar). 13C NMR (CDCl3): 24.9, 30.8, 39.8, 63.9,
82.9, 87.39, 123.9, 127.8, 128.3, 128.6, 129.1, 131.7, 132.6, 138.1, 171.8. ATR-IR: ν(CH)
2961, ν(CH) 2826, ν(C≡C) 2223, ν(C=N) 1665, ν(C=C) 1189, ν(CCl) 1088, ν(CCl) 1014,
δ(CC)Ar 755. FT-Ram an : ν(CH) 3060, 2907, ν(C≡C) 2221, ν(C=N) 1666, ν(C=C) 1596, δ(CH)
1061, ν(CCl) 1089, δ(CH)Ar 1001. UV (EtOH), λm ax (log ε): 204 (4.48), 224 (4.24), 240 (4.27).
HRMS, m/z: calculated for C20H21ClN (M + H) 310.1363, foun d 310.1356. EI MS (m/z, %):
310.4 (M + H+, 65), 268.3 (15), 184.1 (10), 124.9 (100).
(E)-N-(2,2-Dimethyl-5-phenylpent-4-ynylidene)-4-methoxybenzylamine (19c). Yellowish oil.
1H NMR (CDCl3): 1.24 (s, 6 H, 2 × CH3), 2.56 (s, 2 H, CH2), 3.74 (s, 3 H, CH3), 4.55 (s, 2 H,
CH2), 6.75–6.78 (m , 2 H, Ar), 7.14–7.17 (m , 2 H, Ar), 7.24–7.38 (m , 5 H, Ar), 7.73–7.75 (m ,
1 H, Ar). 13C NMR (CDCl3): 24.9, 30.9, 39.7, 55.4, 64.2, 82.8, 87.6, 113.9, 124.0, 127.7,
128.0, 128.9, 131.7, 131.8, 158.6, 171.1. ATR-IR: ν(CH) 3009, 2985, 2820, ν(C≡N) 2231,
ν(C=N) 1662, ν(C=C) 1511, ν(CO) 1241, ν(CC)Ar 757. FT-Ram an : ν(CH) 3066, 2918, 2895,
ν(C≡C) 2236, 2220, ν(C=N) 1662, ν(C=C) 1597, ν(CO) 1257, δ(CH)Ar 1001. UV (EtOH), λm ax
(log ε): 204 (4.55), 230 (4.36), 240 (4.35). HRMS, m/z: calculated for C21H24NO (M + H)
306.1858, foun d 306.1852. EI MS (m/z, %): 306.4 (M + H+, 100), 121.1 (85).
2,2-Dim eth yl-5-ph en ylpen t-4-yn -1-am in e Oxalate (22)
A solution of potassium 3,7-dim eth yloctan -3-olate (50 wt.% solution in h eptan e; 3.6 m l,
7.3 m m ol) was added dropwise to a stirred solution of th e Sch iff base (19a; 1 g, 3.6 m m ol)
in tetrah ydrofuran (40 m l) at –50 °C an d th e solution was stirred at th is tem perature for
20 h . Water (10 m l) was added an d th e stirred solution was allowed to warm up to room
tem perature an d th en extracted with dieth yl eth er (3 × 20 m l). Th e com bin ed extracts were
dried with an h ydrous MgSO4 an d evaporated un der reduced pressure. Th e residue was dis-
solved in toluen e an d added to a stirred solution of oxalic acid dih ydrate (0.45 g, 3.6 m m ol)
in water (25 m l). Th is solution was refluxed for 1 h an d th e h ot aqueous layer was separated
an d cooled (10 °C). Th e form ed crystals were isolated by filtration an d dried at 40 °C to give
0.6 g (70%) of wh ite crystals of oxalate 22; m .p. 168–170 °C. For C15H19NO4 (277.32) calcu-
lated: 64.97% C, 6.91% H, 5.05% N; foun d: 65.35% C, 7.09% H, 5.23% N. 1H NMR
(DMSO-d6): 1.09 (s, 6 H, 2 × CH3), 2.49 (s, 2 H, CH2), 2.83 (s, 2 H, CH2), 6.99–7.61 (m , 8 H,
Ar + NH3). 13C NMR (DMSO-d6): 24.2, 29.7, 33.4, 47.7, 82.8, 87.2, 122.9, 128.1, 128.6,
131.3, 164.2. ATR-IR: ν(NH) 3361, ν(CH) 3054, ν(CH) 2966, ν(C=O) 1721, ν(C=0) 1699,
ν(CC)Ar + δ(NH+) 1602, ν(CH) + δ(NH+) 1211. FT-Ram an : ν(CH) 3061, 2969. ν(C≡C) 2251,
2222, ν(C=O) 1718, ν(C=C) 1598, δ(CH) 1429, δ(CH) 1029, 1001. UV (EtOH), λm ax (log ε):
204 (4.57), 240 (4.34), 250 (4.32). HRMS, m/z: calculated for C13H18N (M + H) 188.1439,
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Rádl, Stach, Černý, Klecán:
foun d 188.1434. EI MS (m/z, %): 188.2 (M+, 5), 186.3 (M–, 10), 172.2 (75), 170.1 (35), 155.2
(100), 141.3 (35), 128.2 (30), 115.2 (50), 91.2 (30).
Preparation of 2,2-Dim eth yl-5-ph en ylpen t-4-yn -1-am in e Oxalate (22) an d
2,2-Dim eth yl-5-ph en ylpen ta-3,4-dien -1-am in e Oxalate (23)
Method A. To a stirred solution of Sch iff base (19; 114 m m ol) in toluen e (150 m l) was
added t-BuOK (12.8 g, 114 m m ol) an d th e solution was refluxed for 1 h . Th e solution was
cooled to room tem perature an d diluted with water (200 m l). Th e toluen e layer was sepa-
rated an d wash ed with water (100 m l). A solution of oxalic acid dih ydrate (14.5 g,
114 m m ol) in water (500 m l) was added to th e stirred toluen e layer an d th e m ixture was
refluxed for 30 m in . Th e h ot layers were separated an d th e aqueous layer was wash ed with
h ot toluen e (100 m l) an d cooled (10 °C). Th e form ed crystals were filtered off an d dried at
40 °C to give th e desired m ixture of oxalates 22 an d 23 (22/23 5:1). Th e ratio was deter-
m in ed by 1H NMR (DMSO) an d th e results are sum m arized in Table I. For C15H19NO4
(277.32) calculated: 64.97% C, 6.91% H, 5.05% N; foun d: 65.27% C, 7.14% H, 5.30% N.
Method B. To a stirred solution of Sch iff base (19; 114 m m ol) in THF (150 m l) was added
t-BuOK (12.8 g, 114 m m ol) an d th e solution was refluxed for 1 h . Th e solution was cooled
to room tem perature, diluted with water (200 m l) an d th en extracted with dieth yl eth er (3 ×
150 m l). Th e com bin ed extracts were wash ed with brin e (100 m l) an d dried with an h ydrous
MgSO4. Th e residue after evaporation was dissolved in toluen e (100 m l), a solution of oxalic
acid dih ydrate (14.5 g, 114 m m ol) in water (500 m l) was added an d th e m ixture was
refluxed for 30 m in . Th e h ot layers were separated, th e aqueous layer was wash ed with h ot
toluen e (50 m l) an d cooled (10 °C). Th e form ed crystals were filtered off an d dried at 40 °C
to give 24 g (76%) of th e desired m ixture of oxalates 22 an d 23 (22/23 4:1). Com parison of
th e NMR an d FT-Ram an spectra with th e correspon din g spectra of 22 led to th e followin g
spectral ch aracteristics of 2,2-dim eth yl-5-ph en ylpen ta-3,4-dien -1-am in e oxalate (23):
1H NMR (DMSO-d6): 1.10 (s, 3 H, CH3), 1.16 (s, 3 H, CH3), 2.84 (s, 2 H, CH2), 5.75 (d, 1 H,
J = 6.55, CH=C), 6.42 (d, 1 H, J = 6.55, CH=C), 6.20–7.48 (m , 8 H, Ar + NH3). 13C NMR
(DMSO-d6): 24.1, 25.5, 35.0, 48.8, 96.9, 102.1, 126.5, 127.1, 128.7, 133.9, 163.3, 203.1.
FT-Ram an : ν(CH) 3068, ν(C=C) 1952, 1600, δ(CH) 1495, δ(CH) 1003. HRMS, m/z: calculated
for C13H18N (M + H) 188.1439, foun d 188.1433. EI MS (m/z, %): 187.2 (M, 100), 172.2 (40),
143.2 (80), 128.2 (45), 115.2 (30), 91.2 (25).
Meth od B was also used for preparation of 22 an d 23 from (E)-N-(2,2-dim eth yl-5-ph en yl-
pen t-4-yn yliden e)-4-ch loroben zylam in e (19b) an d (E)-N-(2,2-dim eth yl-5-ph en ylpen t-4-yn -
1-yliden e)-4-m eth oxyben zylam in e (19c) providin g com poun ds 22 an d 23 in ratios of 3.5:1
an d 3:1, respectively.
5-Ben zyl-3,3-dim eth yl-3,4-dih ydro-2H-pyrrole (1)
Method A. Catalyst screen in g. To a stirred solution of th e m ixture of am in es 22 an d 23
(200 m g, 0.72 m m ol) in dich lorom eth an e (5 m l) was added th e relevan t catalyst (3 m ole %)
an d th e solution was refluxed for appropriate tim e. Th e solution was cooled to room tem -
perature an d diluted with brin e (2 m l). Th e black precipitate was rem oved by filtration , th e
dich lorom eth an e layer was separated an d dried with an h ydrous MgSO4. Th e solution after
rem oval of MgSO4 was evaporated un der reduced pressure to give th e desired product as un -
stable yellow oil, wh ich was an alyzed by GC (RTX-5 am in e colum n ). Th e results are given in
Table II.
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Synthesis of 6-(4-Chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine
1021
Method B. To a stirred solution of am in e 22 (2 g, 11 m m ol) in dich lorom eth an e (15 m l)
was added AgBF4 (40 m g, 0.2 m m ol) an d th e solution was refluxed for 6 h . Th e solution was
cooled to room tem perature an d diluted with brin e (5 m l). Th e black precipitate was re-
m oved, th e dich lorom eth an e layer was separated an d dried with an h ydrous MgSO4. Th e
solution after rem oval of MgSO4 was evaporated un der reduced pressure to give 2 g (quan ti-
tative yield) of th e desired product as un stable yellow oil wh ich was im m ediately used in
th e n ext step.
Method C. To a stirred suspen sion of oxalates 22 an d 23 (4:1; 23 g, 83 m m ol) in dich loro-
m eth an e (150 m l) was added a solution of NaHCO3 (200 m l, 10%). Th e aqueous layer was
extracted with dich lorom eth an e (100 m l), th e com bin ed extracts were wash ed with brin e
(100 m l) an d dried with an h ydrous MgSO4. After its rem oval, AgBF4 (325 m g, 1.7 m m ol) was
added an d th e solution was refluxed for 6 h . Th e reaction m ixture was th en cooled to room
tem perature, diluted with brin e (50 m l) an d th e form ed black precipitate was rem oved by
filtration th rough a Celite pad. Th e dich lorom eth an e layer was separated an d dried with an -
h ydrous MgSO4. Th e yellow oily residue (15.5 g, quan titative yield) obtain ed after evapora-
tion un der reduced pressure was im m ediately used in th e n ext step.
6-(4-Ch loroph en yl)-2,2-dim eth yl-7-ph en yl-2,3-dih ydro-1H-pyrrolizin e (3)
Sodium h ydrogen carbon ate (14.5 g, 1.7 m ol) was added to a stirred solution of 5-ben zyl-
3,3-dim eth yl-3,4-dih ydro-2H-pyrrole (1; 15.3 g, 82 m m ol) in m eth an ol (210 m l) an d, after
sh ort stirrin g, solid 2-brom o-1-(4-ch loroph en yl)eth an -1-on e (2; 23.9 g, 102 m m ol) was
added. Th e m ixture was stirred for 20 h , th e solid portion was filtered off, wash ed with
sm all am oun t of m eth an ol, in troduced in to vigorously stirred water (150 m l) an d stirred at
40 °C for 1 h . Th e product was filtered off, wash ed with water an d dried at 40 °C to give
22.2 g (84%) of yellow crystals of 3; m .p. 104–106 °C. 1H NMR (CDCl3): 1.28 (s, 6 H, CH3),
2.78 (s, 2 H, CH2), 3.71 (s, 2 H, CH2N), 6.69 (s, 1 H, pyrrole CH), 6.97–7.51 (m , 9 H, Ar).
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