Changing stereoselectivity and regioselectivity in copper(i)-catalyzed 5-: Exo cyclization by chelation and rigidity in aminoalkyl radicals: Synthesis towards diverse bioactive N-heterocycles

Article abstract of DOI:10.1039/c9nj05166j

The work reveals that a chelate-Type interaction in the transition state of a β-Aminoalkyl radical in a copper(i)-catalyzed 5-exo-Trig radical cyclization step changes the usual stereochemistry of the NH-pyrrolidine ring predicted by the Beckwith-Houk transition state model. In contrast, the rigidity in the fused β-Aminoalkyl radical changes the Baldwin's predicted 5-exo to 6-endo cyclization mode, preferentially forming a piperidine ring over a pyrrolidine ring via a geometrically constrained transition state. The resultant diverse NH-pyrrolidines, pyrrolines and piperidines are sources of the bioactive natural product roseophilin and the drug Ritalin among others.

Full text of DOI:10.1039/c9nj05166j

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Changing Stereo- And Regioselectivity In Copper(I)-Catalyzed 5-
Exo Cyclization By Chelation And Rigidity In Aminoalkyl Radicals:
Synthesis Towards Diverse Bioactive N-heterocycles
Received 00th January 20xx,
Accepted 00th January 20xx
Sandhya Sadanandan*a and Dharmendra Kumar Gupta*b
DOI: 10.1039/x0xx00000x
The work reveals that chelate-type interaction in the transition state of a β-aminoalkyl radicals in copper(I)-
catalyzed 5-exo-trig radical cyclization step changes the usual stereochemistry of the NH-pyrrolidine ring
predicted by Beckwith-Houk transition state model. Whereas, the rigidity in the fused β-aminoalkyl radical
changes the Baldwin’s predicted 5-exo to 6-endo cyclization mode preferentially forming piperidine ring over
pyrrolidine ring via geometrically constraint transition state. The resultant diverse NH-pyrrolidines, pyrrolines
and piperidines are sources for bioactive natural product Roseophilin and a drug Ritalin among others.
operate, cost-effective, high yielding and environmentally
benign protocol which retains the valuable halogen atom(s) of
a radical precursor in the cyclized product for further chemical
Introduction
Steric and stereoelectronic factors in a cyclizing alkenyl
radical govern the Baldwin’s rules for 5-exo and 6-endo
cyclization modes to produce five- and/ or six-membered cyclic
products including pyrrolidines and piperidines, respectively.1
The conformational and steric factors in the cyclizing radical
further control the stereochemical outcomes in the cyclized
product(s) including N-heterocycles via Beckwith-Houk
transformations and biological applications. Our previous
experiences in Cu(I)-catalyzed ATRC reactions with halo-alkenyl
substrates led us to investigate the changes in usual regio- and
stereoselectivity during 5-exo ATRC reactions of bidentate
aminoalkyl radical precursors(capable of forming chelate ring
with Cu-catalyst) and the fused-α/β-aminoalkyl radical
precursors having different degrees of rigidities. A suitable Cu
(I)-catalytic system capable of radical generation and
complexation with aminoalkyl radical precursors, particularly
at catalytic level, viable at industrial level, was explored. Short-
methods to transform resultant N-heterocycles towards
bioactive natural products and medicines were also devised.
transition state model.1 However,
a suitably positioned
substituent or a functionality in the cyclizing aminyl N-radical
can change the 5-exo mode to 6-endo mode to give piperidine
preferentially over pyrrolidine against Baldwin’s rules.1i-j
Similarly, an intramolecular hydrogen bonding2 and lewis-acid
(BF3 and AlMe3) coordinated quartenary-nitrogen3 in the
cyclizing aminoalkyl C-radical can change the usual
conformation in the Beckwith-Houk transition state model to
change the usual stereochemistry of the pyrrolidine ring.
However, these radical cyclzation methods are reductive in
nature and require excess of radical initiator nBu3SnH and
Lewis acids for N-coordination.3 The ability of a catalytic
copper complex to generate a radical and form a chelate ring
in the transition state of the cyclising aminoalkyl radical4 to
change the usual stereoselectivity in NH-pyrrolidine ring5-6 is
not explored so far. Also, the ability of a fused aminoalkyl C-
radical to change the regioselectivity from 5-exo- to 6-endo
mode through a persistent radical rather than the usual
carbocation (oxidized C-radical), is scarcely explored.4-5,6i
Results and Discussions
First, a pyridine-substituted β-chloroethyl allyl amine 2a
(Scheme1), an aminoalkyl radical precursor with two
coordinating centers capable of forming a chelate ring with
Cu(I)-catalyst in the transition state, was synthesized by simple
addition of CCl3CO2H-DMSO solution to a solution of N-allyl
aldimine 1a in DMSO at ambient temperature.5a Next, the
ATRC reactions of NH-amine 2a
(Table 1) were performed with
varying amount of CuCl (5 %, to begin with) and commercially
available
tetramethylethylenediamine
ligands
[2,2’-bipyridine
(bpy),
and
(TMEDA),
pentamethyldiethylenetriamine (PMDETA) usually employed in
Cu(I)-catalyzed ATRC protocols6b,d] in different solvents at
different temperatures under a nitrogen atmosphere, to
explore a suitable catalyst. The progress of the reaction was
monitored by thin layer chromatography (TLC) and was further
Copper(I)-catalyzed atom transfer radical cyclization
(ATRC)6-7 method is a catalytic, atom-economic, easy to
a.Department of chemistry, Amrita Vishwa Vidyapeetham, Amritapuri, India-690525
b.Department of chemistry, Indian Institute of Technology, Delhi, India-110016
Electronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx00000x
1
confirmed by H NMR of the aliquots taken directly from the
reaction mass.
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Scheme 1. Synthesis and Copper(I)-catalyzed ATRC reactions of 2a a
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Table 1. Optimization of the reaction conditions in Cu(I)-catalyzed ATRC of 2a
Mol % CuCl / Ligand (mol ratio) / additive
(eq)
Solvent
Temp.
Time
4a-a′
Yield c
4a-a′
Entry
Trans : Cis b
1
2
3
4
5
100 % CuCl / bpy (1:1)
80 % CuCl / TMEDA (1:2)
40 % CuCl / PMDETA (1:1)
40 % CuCl / PMDETA (1:1)
40 % CuCl / PMDETA (1:1)
DCE
DCE
DCE
MeCN
MeCN
reflux
reflux
reflux
reflux
RT
8 h
6 h
4 h
3 h
5 h
58 %
72 %
74 %
78 %
80 %
--
--
--
50:50
55:45
6
7
40 % CuCl / PMDETA (1:1)
MeCN
MeCN
0 ˚C
6 h
3 h
82 %
60:40
50:50
5 % CuCl / PMDETA (1:1) / AIBN (0.250)
reflux
52 % d
a All the reactions were performed with 1 mmol of 2a under a nitrogen atmosphere. b Mixture of diastereomers in 1H NMR of the crude product.
c Isolated yield after purification by column chromatography on basic alumina. d Not a clean reaction due to decompositions oftheradical precursor
PMDETA was the most effective ligand in terms of product pyrrolidine 3a-a′ (Scheme 1) could not be detected or isolated.
yield and catalyst loading (Table 1, entry 1-3). The reaction in a A considerable amount of the product 4a-a′ was also
coordinating solvent acetonitrile (MeCN) was slightly better recovered from the aqueous phase during the work up by
than chlorinated solvent 1,2-dichloroethane (DCE) in terms of treating it with aqueous ammonia solution and extracting with
product yield and reaction time due to higher solubility of the ethyl acetate. This was due to the pyrrolines 4a-a′ being
Cu-catalyst in acetonitrile (Table 1, entry 3-4).5a,8 Due to the bidentate ligands like N-alkyl pyridinemethanimines (N-
tendency of a β-haloalkyl-NH-amine to decompose at high RPMI)6b,d which could form a 5-membered C-N-Cu-N-C chelate
reaction temperature (SI Fig. S25-S28),9 the ATRC reactions of ring10 and went into the aqueous solution. The 3,4-trans and
2a were performed at lower temperatures. The 1H NMR of the 3,4-cis stereochemistry was assigned unambiguously to the
crude product obtained at 0° C was cleaner and had higher major 4a and minor 4a′ diastereomers, respectively on the
percentage of 3,4-trans
at 25 °C and reflux though a longer reaction time was required 1H NMR of 4a-a′ mixture.
to complete this reaction (Table 1, entry 5-6). An attempt was The preferential formation of major 3,4-trans diastereomer
made to lower the catalyst loading to minimum (Table 1 entry 4a over 3,4-cis 4a′ might occur via 5-exo ATRC of 2a (2,4-trans-
SI Fig 29) by using AIBN7 as a reducing agent for catalyst- 3a> 2,4-cis-3a’) followed by their dehydrochlorination and
-diastereomer 4a (SI Fig. S27-28) than basis of dihedral angle between protons at C-3 and C-4 in the
,
7
,
regeneration, a method successfully employed in our previous tautomerization. This assumption was experimentally studied
work.7b However, this method was found ineffective in this by undertaking a DBU-mediated dehydrochlorination and
case due to the presence of pyridine substituent (internal base) tautomerization of NH-pyrrolidines 3c-d5a
(
Scheme 2) having
known 2,4-trans geometry which were previously synthesized
The cyclization of 1-pyridyl NH-amine 2a furnished the by us under the same reaction condition (Table 1, entry-6). The
pyrrolines 4a-a′ directly as a 3:2 (4a Trans : Cis 4a′, SI Fig S27- reaction of crude 2,4-trans pyrrolidines 3c-d with DBU at 25-
28) diastereomeric mixture under the optimized reaction 30 °C and subsequent purification of crude products by column
in 2a causing the decomposition of 2a 7b
.
.
conditions (Table1 entry-6). The intermediate 2-pyridyl-NH- chromatography afforded 3,4-trans-pyrrolines 4c-d (SI Fig.
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S32-35). The corresponding minor 3,4-cis-diastereomers were
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3-chloro-pyrrolines of type (4a-a′
,
c-d) aromatize easily to β-
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perhaps too little, to be isolated by column chromatography. chloro-NH-pyrroles under basic conditioDnOtI:o10g.1i0v3e9/vCa9rNiaJn05ts166oJf
The higher acidity of the hydrogen at C-2 in 4-NO2-phenyl Pyrrolnitrin, an antifungal and antibiotic extracted from
derivative 3c than 3d probably facilitated a quick elimination of Pseudomonas
HCl. Slight basic reaction condition possibly tautomerized the species.11 These pyrrolines also give useful chiral 3-chloro-NH-
2,3-dihydro-1H-pyrrole intermediates to stable 3,4-dihydro- pyrrolidines on simple reduction with sodium borohydride, as
2H-pyrrole (or pyrrolines 4c-d), also reported by kempe et al.11 thoroughly demonstrated by Kimpe et al.11
Pyrrocinia
and
other
Pseudomonas
9
Disappearance of CCl2 peak, appearance of an olefinic carbon
A weak coordinative interaction of sulphur(thiophene) with
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in 13C NMR and no disappearance of any peak belonging to copper has been reported by Li and co-workers,5b and was also
NH-proton in the 1H NMR of the compound in CDCl3 on shaking observed by us in Cu(I)-promoted radical cyclization of β-
with D2O confirmed the formation of pyrrolines 4a-a′
,
c-d
.
haloethyl allyl thioethers to tetrahydrothiophenes.9b Thus an
insignificant change in the usual 2,4-trans stereochemistry in
the thiophene-(α) substituted NH-pyrrolidine was expected.
The Cu(I)-catalyzed radical cyclization of 2b led to the
formation of usual major 2,4-trans-NH-pyrrolidine 3b and
negligible amount of minor 2,4-cis-NH-pyrrolidine 3b′ (SI Fig.
S30-31) under the optimized reaction condition of 2a (Table 1,
entry-6). Considerably high change in the 2,4-trans geometry
to 2,4-cis geometry in the cyclization of 2a (Scheme 1) than 2b
(Scheme 2) might be due to stronger chelate type interaction
in the transition state of pyridine substitutedpyrrolidine (of
5c-e
5b
type
5
)
than a weaker one (of type
6
2
)
in thiophene
. The recovery of
substituted pyrrolidine as shown in Scheme
more pyridine substituted pyrrolidine 3a-a‘ (or 4a-a‘≈40%)
than thiophene pyrrolidine 3b-b‘ (≈5%) from aqueous phases
during work up by addition of aqueous ammonia and
extraction with ethyl acetate (experimental section), proved
the presence of greater chelate type interactions in the
transition state of cyclizing aminoalkyl radical of 2a than 2b
.
Stereocontrol Studies
The effect of chelate type interaction of type 5 (scheme 2
)
in changing the usual 2,4-trans-stereochemistry of the NH-
pyrrolidine was further extended by performing Cu(I)-
catalyzed ATRC reaction on bidentate 2,2,2-trichloroethyl allyl
NH-amines
8 having coordinating keto, amide and nitro group
in a side chain at C-2 (Table 2). The functionalized precursors
8a-e were prepared by Aza-Michael addition of allyl amines to
Michael acceptors 7a-d with slight modifications of our
previous method on Thio-Michael addition reactions.9b
Treatment of NH-amines 8a-e with CuCl/PMDETA (60
mol %) at 0 ˚C for 6-8 h followed by purification by column
chromatography (basic alumina) furnished the side chain
functionalized 3,3-dichloro-NH-pyrrolidines 9a-e in high
isolated yields (Table 2, 79-85 %). Ratio of diastereomers was
1
determined from the H NMR of the aliquots taken from the
reaction mass after completion of the reactions as indicated by
TLC. The structures of unknown NH-pyrrolidines were
supported by 1H NMR, 13C NMR, IR spectroscopy and mass
spectrometry. With expected carbonyl group-dependent
minor differences in the structures, the gross NMR spectral
Scheme 2: Comparision of impacts of co-coordinative interaction
between (pyridine)N—Cu--NH and (Thiophene)S—Cu--NH on 2,4-
transstereochemistry of NH-pyrrolidine rings
features of 9a-b,d (SI Fig. S36-43) were largely similar to those
of the phenyl ketone-substituted 2,4-trans-NH-pyrrolidine 9c5a
which was previously synthesized by us using the same
reaction conditions (Table 2).
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Table 2. Copper(I)-catalyzed radical cyclization of side chain functionalized radical precursors for stereocontDroOlI:s1t0u.1d0ie39s/C9NJ05166J
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2,2,2-trichloroethyl allylamines a
Halogenated NH-Pyrrolidines b
Entry
Structure
Yield % (time)
Stereochemistry c
Yield d
%
(Time)
1
80 % (6 h)
83 % (6 h)
2
80 % (6 h)
80 % (7 h)
3
4
82 % (5 h)
85 % (6 h)
76 % (24 h)
81 % (8 h)
79 % (8 h)
5
83 % (4 h)
aThe reactions were performed with 10 mmol of the Michael acceptor 7a-d with allyl amines for 8a-e and were purified by column
chromatography using neutral alumina.
b The reactions were performed with CuCl/PMDETA (60 mol %) at 0˚C in MeCN using 1 mmol of radical precursorsunder a N2 atm.
c 1H NMR spectrum of crude mass was used for the determination of diastereomeric ratio in NH-pyrrolidines.
d The products 9a-ewere purified by column chromatography using basic alumina.
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Table 3. Copper (I)-catalyzed radical cyclization of radical precursors for regiocontrol studies
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Entry
2,2,2-trichloroethyl allylamines a
Halogenated N-protected pyrrolidines/piperidines b
Structure
Yield %
(time)
Stereochemistry/Regioselectivity c,e
Yield d
%
(time)
1
80 % (5 h)
88 % (12 h)
2
3
45 % (7 h)
70 % (12 h)
75 % (3 h)
68 % (12 h)
4
5
58 % (3 h)
80 % (6 h)
46 % (4 h)
75 % (6 h)
a The reactions were performed with 10 mmol of the starting materials and products were purified by column chromatography using
neutral alumina. 10a was prepared by reaction of 2,2,2-trichloroethyl allyl NH-amine5a with methyl chloroformate (1 eq) in DCM in
the presence of triethyl amine. b The reactions were performed with CuCl/TMEDA/PMDETA (25-60 mol %) at RT/reflux in DCE/MeCN
using 1 mmol of 10a-e under a N2 atm. c 1H NMR spectrum of crude mass was used for the determination of stereochemistry and
pyrrolidine-piperidine ratio in cyclization products. d The products 11a-e were purified by column chromatography using neutral
alumina. e Previously known structurally different α-carbon radical precursors 10b6h and 10c6h were reacted with 25 mol %
CuCl/PMDETA at RT in DCE. under N2 atmosphere to compare their regioselectivity with that of β-carbon radical precursors 10a and
10d-e, respectively.
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The formation of minor 2,4-cis diastereomers in undetected in 1H NMR of crude products) diVaisewteArreticolemOenlrinice
pyrrolidines 9a-b than 9c (Table 1) suggests some effective 6- mixtures of 9a-a′,b-b′,d-d′ were assigned 2,4-cis geometry. The
membered C=O--Cu(I/II)-NH chelate type interaction with major isomers were assigned 2,4-trans geometry on the basis
MeC=O than the bulky PhC=O group possibly due to high steric of 2,4-trans geometry of 9c5a due t o structural similarity and
hindrance posed by the bulky phenyl group in the transition use of same radical reaction conditions (Table 2).
state. Methyl substituents at the terminal double bond in 8b
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DOI: 10.1039/C9NJ05166J
seemed not to affect this NH-Cu-O=C interaction. The amide
group in the side chain of 8d interacted with Cu-catalyst to
produce the minor diastereomer. The minor isomers detected
Regiocontrol Studies
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No 6-endo radical cyclization products (piperidine ring) could
be detected in 1H NMR of the crude products 3a-d or 9a-e and
could not be isolated by column chromatography also. This
indicated an occurrence of a regioselective cyclization of
precursors 2a-d and 8a-e by 5-exo mode which is widely
accepted in the cyclization of 3-aza-5-hexenyl (β-carbon)
radicals in the allyl NH-amines.1,5a In order to study the
changes in the known regioselectivity from 5-exo to 6-endo
modes in N-heterocycles synthesis, different carbon radical
centered α/β-haloalkyl alkenyl amines, and the fused-α/β-
haloalkyl alkenyl amines having different degrees of rigidities
in the rings, were synthesized (Table 3).
1
in H NMR of the crude products had almost similar Rf with
major products, thus could not be isolated by simple column
chromatography. The impact of this interaction was most
prominent in the precursor 8e due to the presence of nitro
group in the side chain arguably due to its anionic nature (O--
N+-O-) resulting into relatively stronger O=N-O--Cu—NH
interaction in the transition state (SI Fig. S44-45).
First, a comparison in the regioselectivity was done by
performing Cu(I)-catalyzed ATRC reactions on 3-aza-5-hexenyl
(β-carbon) radical precursor 10a and 2-aza-5-hexenyl (α-
carbon) radical precursor 10bunder the same reaction
conditions using relatively stronger catalyst CuCl/PMDETA (25
mol %) and milder reaction condition (at room temperature) in
a coordinating solvent MeCN. The ATRC reaction of precursor
Scheme 3. Tosylation product 12 of NH-pyrrolidines 9e
10a led to the formation of pyrrolidine 11a (SI Fig. S46-47)
exclusively whereas precursor 10b afforded a mixture of
pyrrolidine 11b and piperidine 11b* in 70:30 ratio. A less
regioselectivity in the 5-exo cyclization of acyclic 2-aza-5-
hexenyl (α-carbon) radical of precursor 10b giving a mixture of
pyrrolidine 11b and piperidine 11b* in similar ratiois
documented in the Cu(I)/bpy-catalyzed ATRC reaction in DCE
at reflux.6h This insignificant impact on regioselectivity is
possibly due to the independent nature of cyclizing 2-aza-5-
hexenyl (α-carbon) radical of 10b and its MeOCO-protected
nitrogen atom could not interact with the Cu-catalyst to alter
this 5-exo mode.
Figure 1. ORTEP diagram of N-tosyl-NO2-pyrrolidine 12
Determination of the stereochemistry of the major
products 9a-d by 2D NOE or NOESY-spectroscopy was not
unambiguous because the relevant proton signals were not
An increase in ratio of 6-endo cyclization mode 11c* over
5-exo mode 11c was observed when 2-aza-5-alken-l-y1 radical
precursor 10c was fused with pyrrolidinone ring.6h Thus,
cyclization reaction of 10c was performed with CuCl/PMDETA
(25 mol %) at room temperature in acetonitrile and compared
well separated
(SI).
A
method to determine the
stereochemistry of NH-pyrrolidines through corresponding N-
tosyl-pyrrolidines has been employed in many halogenated
and functionalized NH-pyrrolidines without affecting their
the changes in regio- and stereoselectivity of 11c-
c* obtained
chiral centers.5a Thus, the stereochemistry in 9e was confirmed with Cu(I)/bpy catalyst at reflux in DCE.6h The reaction led to
the formation of a mixture of fused-pyrrolidine 11c and fused-
piperidine 11c* in almost similar ratio (20:80).
from X-ray single crystal structure of its N-tosyl-pyrrolidine 12
(
(
1
SI Fig. S54-55) prepared under milder reaction conditions
Scheme 3). The ORTEP diagram of tosylation product 12 Fig.
) of nitro-functionalized NH-pyrrolidine 9e showed it has 2,4-
An Ineffective role of the Cu-catalyst and the protected-
nitrogen atom of the radical precursors 10a-c in deciding the
regioselectivity indicated towards the dominant role of cyclic
template in changing the regioselectivity. Thus, an exclusive 6-
endo mode of cyclization to piperidine ring in the small ring
fused-3-aza-5-alkenyl radical using a highly strained β-lactam
(
cis geometry of nitro-methylene substituent at C-2 position
and chloromethyl substituent at C-4. On the basis of single
crystal data of 12 and NMR measurements, the
stereochemistry of minor isomers in the inseparable (or
template 10d-e (Table 3) was envisaged.
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Scheme 4. Probable mechanism for pyrrolidine and piperidine synthesis
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Radical cyclization of precursor 10d occurred completely
with 80 mol % CuCl/bpy, 40 mol % of CuCl/TMEDA and 25
mol % CuCl/PMDETA in DCE solvent in 6, 6 and 5 h, next ATRC reaction with another radical precursor.12
Cu(II)Cl2-complex to produce the final ATRC products (
along with active Cu(I)Cl-catalyst which participate again in the
I, L,O, R)
Stereoselective formation of 2,4-trans-diastereomers in 1-
substituted-NH-pyrrolidines were speculated on the basis of
Beckwith–Houk transition state model.1 The bulky copper-
complex bonded to nitrogen atom is expected to occupy
preferably sterically less demanding position in chair like
transition state4b thus the formation of a chair-equatorial
conformation(C) in the transition state was anticipated.
However, a high A1,2-strain arising due to steric-repulsion
between bulky copper-complex and α-substituent in
respectively at reflux. However, a trace of reduced starting
material of 10d in 1H NMR of the crude product of 11d-d* was
observed in MeCN solvent with 25 mol % CuCl/PMDETA at
reflux. The TMEDA and PMDETA showed similar results and
thus, the use of cheaper and easily accessible TMEDA over
PMDETA and DCE over MeCN were preferred.
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1H NMR of the crude product 11d-d* showed an
occurrence of almost exclusive 6-endo radical cyclization (≈
96 %, SI Fig. S48-49) in precursor 10d with TMEDA ligand in
DCE at reflux to afford major β-lactam fused piperidines 11d*
along with minor pyrrolidine product 11d. Piperidine moieties
conformation (
C
) may cause its conformational change to a
). This
energetically more favorable boat-axial conformation (
D
conformational change may occur as the boat-axial
conformation is nearly ca.1 kcal/ mol higher in energy than its
11d*-e* were obtained in high yield (75-80 %, SI Fig. S50-53
)
after purification of the crude product by column
chromatography. Both the Cu(I)Cl/TMEDA and Cu(I)Cl/PMDETA
catalysts showed similar regioselectivity indicates towards no
participation of Cu-catalyst in determining the regioselectivity
due to the absence of an effective Cu-O=C-N interaction in
10d-e (like 10a-c). Thus, the change in the regioselectivity was
mainly due to the inclusion of a rigid β-lactam template in
precursors 10d-e.
corresponding chair-equatorial conformation (
C
).1b The change
) is
in this conformation ( ) to chair-equatorial conformation (
C
E
another possiblity, however, it is energetically unfavourable
due to the stronger 1,3-axial interaction (A1,3 strain) between
bulky axial copper-complex and a halogen atom. Thus it is
hard to predict whether the chair-equatorial (
conformation ( ) contributes the most to the preferential
formation of the 2,4-trans-NH-pyrrolidines ( ) at present.
C) or boat-axial
D
I
Pyridyl(N), NO2, CONMe2 or CH3CO groups in the side chain at
C-2 position, together with NH-group of the cyclizing radical,
may act as a bidentate ligand and interact with Cu-catalyst to
form a chelate (
these groups in an equatorial orientation in a boat-like
conformation ( J→K) leading to a development of 2,4-cis-
stereochemistry in the corresponding NH-pyrrolidine ( ).
J) in transition state. This interaction may bring
C
→
L
Coordinative interaction of a copper complex with a NH- and
other functionality of a molecule forming a chelate ring in the
cyclizing radical is well known.5d Complexing agents-mediated
conversion of one conformation to another leading to a
stereoselective synthesis of pyrrolidines and other
heterocycles, is not uncommon.13
A rigid β-lactam ring in the radical precursor arguably
restrains double bond and dichloromethyl radical group to
attain a energetically favorable chair like conformation (P) in
Figure 2. ORTEP diagram of β-lactam fused piperidine11d*
1
The structures of 11d*-e* were supported by H NMR, 13C
NMR, IR and HRMS, and the stereochemistry of the major
piperidines 11d*-e* was determined from X-ray single crystal
structure of 11d*. The ORTEP diagram of piperidine 11d* is
the transition state. This angle strain results into the formation
of a more favoured chair like (piperidine type) conformation
(M)
14 resulting into preferential formation of β-lactam fused
shown in figure 2
.
piperidine (
atom transfer from CuCl2-complex to 6-endo-trig (
exo-trig ( ) cyclized radicals, respectively. Such preferential
O
) than corresponding pyrrolidine (
R
) after chlorine
Mechanistic Pathways to Stereo- and Regiocontrol
N) and 5-
Q
Mechanistically, first the Cu(I)Cl-catalyst reversibly
regioselectivity of 6-endo over the 5-exo mode of cyclization
has also been observed by Alabugin et al.14a-b They found that
the 6-endo cyclization is kinetically favored in smaller (and
strained) cycles and thus, a smaller cycle changes the
regioselectivity of closure and such effects are known for a
number of cyclizations.
abstracts
allylamine precursor
dichloroethyl allylamine radical
via concerted inner-sphere electron transfer (ET)
process.7a,6b,d The radical
undergoes 5-exo-trig and/or 6-
endo-trig radical cyclization to form 5-exo pyrrolidine radical
F-H ) and 6-endo piperidine radical ( ), respectively.
a
chlorine atom from
a
2,2,2-trichloroethyl
A
(Scheme
4) to generate 2,2-
B
along with Cu(II)Cl2 complex
a
B
(
,
K,
Q
N
Synthetic Applications
These cyclized radicals then abstract chlorine atom from
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A very low catalyst loading is always preferred in any (I)Cl/PMDETA catalyst to 10 mol % at reflux to affoVriedw3AbrticalenOdnl1in7e
synthetic chemical reactions particularly for Industrial On treatment with DBU, the chlorinated NH-pyrrolidine 3b and
applications to incur lesser-cost and lesser-operational issues. 17 underwent double dehydrochlorinations-isomerization in
Thus, an attempt was made to reduce the Cu(I)-catalyst by single operation to give NH-pyrrole 15 and 18, respectively.
using AIBN as a reducing agent.7 Use of 0.2 equivalent of AIBN
.
DOI: 10.1039/C9NJ05166J
in ATRC reaction of 10e, reduced the amount of Cu
(I)Cl/TMEDA catalyst to 5 mol % at reflux to afford 11e*. The
treatment of 6-endo ATRC product 11e* with nBu3SnH using a
frequently used method for dehalogenative reduction of
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halogenated N-heterocycles15 afforded
bicyclo[4.2.0]octan-8-one 13 Scheme 5) in good yield. Further
a known 1-aza-
(
reaction of 13 with methanolic hydrochloric acid at room
temperature using a reported method generally employed for
the hydrolysis of the same 1316 afforded
a D-threo-
methylphenidate hydrochloride 1417, marketed under the
name Ritalin.
Figure 3. Examples of bioactive halogen- and heteroaryl-
substituted and functionalized N-heterocycles and their
derivatives
Close similarity in structures of functionalized NH-
pyrrolidines
make them direct variants of existing natural products19 such
as cyclochlorotine,19a islanditoxin,19b and Astin A-C 19 19c
pharmaceuticals20 20 and materials.21 Further, such 3-chloro-
3 and 9 (Table 2-3) with molecules shown in figure
3
,
Scheme
5. Synthetic applications of halogenated and pyrrolidines are constant sources for structure activity
functionalized pyrrolidines and piperidine
relaionship (SAR) studies,22 inter- and intra-molecular
substitution reactions,23 selective dehalogenation24 and
Synthetic application of halogenated NH-pyrrolidines was functional group transformations25 to give pyrrolidine-based
demonstrated by converting 3,3-dichloro-NH-pyrrolidines 3b drug Derifenacin,23a natural product Ioline alkaloid23d and (-)-
and 17 into a corresponding β-chloro-NH-pyrrole 15 and 18
respectively. This unit of type 18 is present in some bioactive reported the antibiotic activity β-chloropiperidine based 593A
pyrroles such as antileukemic Roseophilin 2918 Figure 3). drug substance 21 26
Side chain functionalized pyrrolidines
,
Trechelanthamidine.25 Gatto, Göttlich and co-workers
(
.
Again, an attempt was made to reduce the catalyst loading (to with their NH and/or side chain functionalities undergo inter-
begin with 1 mol %) and use the ATRC product as such in the and intra-molecular reactions to give natural products (22-24
27
next step (after simple work up) to produce highly useful β- in Fig. 3
)
and pharmaceuticals.28 Tilve and co-workers
chloro-NH-pyrrole unit 15 and 18 in single operation. Use of exploited pyrrolidine 25 in the synthesis of (-)-hygrine, (-)-non-
0.3 equivalent of AIBN, reduced the amount of Cu hygrine, (-)-pseutohygroline and (-)-hygroline via Nef reaction
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of nitro-group in the side chain.29 An intramolecular cyclization and n-hexane-ethyl acetate mixtures were used as the mobile
View Article Online
DOI: 10.1039/C9NJ05166J
of methyl ketone in norhygrine 23 gives alkaloid ipalbidine phase. Solvents were evaporated on a rotary evaporator under
26 30
Ruspoline 24 converts to alkaloid 27 with simple reduced pressure using an aspirator. Aliphatic, aromatic and
.
reduction of ketone group and subsequent dehydration heteroaromatic
aldehydes,
chloral
hydrates,K2CO3,
forming olefinic bond.31 Reduction of ketone group of 23 to trichloroacetic acid, DMSO and MgSO4 were commercially
alcohol followed by its coupling with sugar moiety gives available and were used as received. THF was dried over KOH
hygroline 28 30
.
pellets overnight and distilled over stored over sodium wires.
DCM was dried by distilling over anhydrous P2O5.
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Conclusions
Preparation of α-substituted 2,2,2-trichloroethyl allyl NH-
amines 2a-b:
In conclusion, present work describes a mild and general
method for the synthesis of 1-hetero-aryl substituted and
functionalized NH-pyrrolidines. With the introduction of a
heteroaryls or side chain functionality at C-2, bidentate NH-
precursors may interact with copper-catalyst to change the
usual 2,4-trans-conformation in the Beckwith-Houk transition
state leading to the formation of a 2,4-cis diastereomer. This
conformational shift was not noticeable with the introduction
of S-heterocycles and became considerable with N-heteroaryl
(pyridyl) due to strong (py)N--Cu--NH chelate type interaction.
Side chain methyl-ketone, amide and nitro groups at C-2 in the
NH-radical precursor changed the usual 2,4-trans geometry to
2,4-cis via =O--Cu--NH chelate type interaction in the transition
state than the hindered ketone-functionality. β-lactam
template in the precursors alters the 5-exo cyclization mode to
6-endo cyclization mode to form pharmaceutically important
piperidine ring against Baldwin’s rule. Difficult to prepare in
single operation, hetero-aryl substituted, halogenated and
functionalized NH-pyrrolidines and piperidine rings are
potential building blocks for carbapenam, pyrroline and β-
chloropyrrole units useful in natural products synthesis and
SAR studies for drug development. Decrease in cheap and
recyclable Cu (I)-catalyst loading even to 5-10 mol % was easily
achievable in the synthesis of drug (Ritalin) and a sub-unit of
natural product (Roseophilin), establishes potential industrial
applications of this methodology.
General procedure: Schiff's bases 1a-b were prepared by
stirring mole equivalents of aldehydes and amine in DCM in
the presence of anhydrous MgSO4 at room temperature for 6-
8 h, which on filtration and subsequent concentration on
rotary evaporator,32 was used as such in the next step. To a
solution of freshly prepared aldimine 1a-b (10 mmol) in DMSO
(10 mL) was added portion wise a solution of trichloroacetic
acid (3.268 g, 20 mmol) in DMSO (20 mL) at 40 ˚C (4.902 g, 30
mmol at 50˚C for 1a) with stirring during 1 h. After the
disappearance of the imine as indicated by TLC (1 h), the
solution was poured into ice-cold water and extracted with
ethyl acetate/n-hexane mixture (50:50 v:v). The combined
organic extract was washed with brine (3x50 mL), dried
(Na2SO4) and filtered. The solvent of the filtrate was
evaporated under reduced pressure. The crude product thus
obtained was purified by column chromatography on small
pad of neutral alumina using n-hexane (or mixture of ethyl
acetate in n-hexane 0-3 %, v/v in case of 2a) as the solvent for
elution to obtain 2,2,2-trichloroethyl allyl NH-amines 2a-b in
good to high yields.
N-(2,2,2-trichloro-1-(pyridin-2-yl)ethyl)prop-2-en-1-amine 2a:
Light red liquid, 52 % yield; 1H NMR (CDCl3, 300 MHz): δ 3.13 (s,
br, 1H, NH, D2O-exchangeable merged with dd at δ 3.16), 3.16
(dd, 1H, J = 13.8, 6.3 Hz, allylic CH2), 3.35 (dd, 1H, J = 13.8, 5.7
Hz, allylic CH2), 4.41 (s, 1H, NCH), 5.07-5.15 (m, 2H, allylic
=CH2), 5.77-5.87 (m, 1H, allylic =CH), 7.27 (t, 1H, J = 6.3 Hz,
pyridyl CH), 7.48 (d, 1H, J = 7.8 Hz, pyridyl CH), 7.68 (t, 1H, J =
7.6 Hz, pyridyl CH ), 8.62 (d, 1H, J = 4.2 Hz, pyridyl CH) ppm; 13
C
Experimental
General Information:
NMR (CDCl3, 75 MHz); δ 50.9 (CH2), 75.9 (CH), 102.3 (C), 117.0
(CH2), 123.5 (CH), 126.1 (CH), 135.8 (CH), 135.9 (CH), 149.0
(CH), 155.2 (C) ppm; IR (KBr): νmax 3323(m, br), 3076(m),
2924(m), 1644(w), 1583(s), 1468(s), 1432(s), 1299(w), 1148(m),
1119(m), 995(s), 921(s), 799(s), 752(s) cm-1; HRMS (ESI+): m/z
[M + Na]+ calcd for C10H11Cl3N2Na 286.9880, found 286.9875.
N-(2,2,2-trichloro-1-(thiophen-2-yl)ethyl)prop-2-en-1-amine
IR spectra were recorded on an FT-IR spectrometer by taking
solid samples as KBr pellets and liquids as thin films on KBr
disks. NMR spectra were recorded on a 300 MHz FT NMR
spectrometer in CDCl3 with TMS as internal standard.
Multiplicities are indicated by the following abbreviations: s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and
dd (doublet of doublet). DEPT spectra were routinely recorded
to identify different types of carbons. Mass spectra were
recorded on a high-resolution mass spectrometer (ESI-TOF) in
positive-ion mode. Melting points were determined on an
electrically heated apparatus by taking the samples in a glass
capillary sealed at one end and are uncorrected. The progress
of the reaction was monitored by TLC using a glass plate
coated with a TLC grade silica gel. Iodine was used for
visualizing the spots. For column chromatography, silica gel,
basic and neutral alumina was used as the stationary phase
1
2b: Colorless liquid, 82 % yield; H NMR (CDCl3, 300 MHz): δ
2.24 (s, br, 1H, NH, D2O-exchangeable), 3.08 (dd, 1H, J = 14.1,
6.9 Hz, allylic CH2), 3.29 (dd, 1H, J = 14.1, 4.5 Hz, allylic CH2),
4.54 (s, 1H, NCH), 5.09-5.15 (m, 2H, allylic =CH2), 5.75-5.87 (m,
1H, allylic =CH), 6.95 (dd, 1H, J = 5.1, 1.8 Hz, thienyl CH), 7.19 (s,
br, 1H, thienyl CH), 7.26 (d, 1H, J = 1.8 Hz, thienyl CH) ppm; 13
C
NMR (CDCl3, 75 MHz): δ 50.9 (CH2), 75.9 (CH), 102.3 (C), 117.0
(CH2), 126.07 (CH), 126.09 (CH), 128.5 (CH), 132.9 (CH), 138.2
(C) ppm; IR (KBr): νmax 3345(m, br), 3080(m), 2923(m), 1685(m),
1642(w), 1610(m), 1505(w), 1462(s), 1325(m), 1292(m),
1230(s), 112(s), 1014(s), 925(s), 806(s), 709(s) cm-1; HRMS
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(ESI+): m/z [M + H]+ calcd for C9H11Cl3NS 269.9672, found J = 14.4 Hz, CH) ppm; 13C NMR (CDCl3, 75 MHz): δ 37.0 (CH3),
View Article Online
DOI: 10.1039/C9NJ05166J
269.9675.
37.3 (CH3), 90.1 (C), 120.1 (CH), 136.2 (CH), 164.4 (C) ppm; IR
(KBr): νmax 3063(w), 2938(m), 1695(s), 1591(m), 957(s), 850(s),
Preparation of the functionalized trichloroethyl allyl NH- 750(s), 692(s) cm-1; HRMS (ESI+): m/z [M + Na]+ calcd for
amines 8a-e: First the required Michael acceptors 7a-d were C6H8Cl3NONa 237.9564, found 237.9570.
synthesized using methods reported in our previous works 4-(Allylamino)-5,5,5-trichloropentan-2-one8a: Colorless liquid,
1
with slight modifications.5a,9b 5 mol% CuCl/PMDETA-catalyzed 80 % yield; H NMR (CDCl3, 300 MHz): δ 1.76 (s, br, 1H, NH,
atom transfer radical addition of CCl4 to 1-phenylprop-2-en-1- D2O-exchangeable), 2.23 (s, 3H, CH3), 3.03 (dd, 1H, J = 17.4,
one in the presence of AIBN (20 mol %) followed by DBU- 9.6 Hz, CH2CO), 3.26 (dd, 1H, J = 17.4, 2.4 Hz, CH2CO), 3.45 (dd,
mediated dehydrochlorination furnished previously known 1H, J = 12.9, 6.9 Hz, allylic CH2), 3.56 (dd, 1H, J = 12.9, 7.8 Hz,
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Michael acceptor 7b 33
Use of NEt3 as a base to allylic CH2), 4.01 (dd, 1H, J = 9.6, 2.4 Hz, CHN), 5.12-5.25 (m, 2H,
.
dehydrochlorinate similar ATRA adducts at reflux in toluene =CH2), 5.76-5.90 (m, 1H, =CH-) ppm; 13C NMR (CDCl3, 75 MHz):
has been reported earlier also.34 Previously known (E)-4,4,4- δ 30.8 (CH3), 38.5 (CH2), 47.6 (CH2), 59.3 (CH), 104.3 (C), 118.8
trichlorobut-2-enoic acid33 gives (E)-4,4,4-trichlorobut-2-enoyl (CH2), 132.9 (CH), 203.4 (C) ppm; IR (KBr): νmax 3377(m, br),
chloride on treatment with oxalyl chloride in DCM at 0 °C 3080(w), 2952(m), 1741(s), 1644(w), 1439(m), 1358(m),
which on subsequent treatment with one equivalent of 1175(s), 923(m), 795(s) cm-1; HRMS (ESI+): m/z [M + H]+ calcd
dimethyl amine (anhydrous) in DCM in the presence of triethyl for C8 H13Cl3NO 244.0057, found 244.0050.
amine furnished previously known (E)-4,4,4-trichloro-N,N- 5,5,5-trichloro-4-((3-methylbut-2-en-1-yl)amino)pentan-2-
dimethylbut-2-enamide 7c35 in 45 % yield. The Michael one 8b: Colorless liquid, 80 % yield; 1H NMR (CDCl3, 300 MHz);
addition of allyl amines with different Michael acceptors δ 1.70 (s, 3H, CH3), 1.75 (s, 3H, CH3), 2.25 (s, 3H, CH3CO), 2.30
occurred under slightly different reaction conditions due to (s, br, 1H, NH, D2O-exchangeable), 3.04 (dd, 1H, J = 16.8, 9.9 Hz,
their differential reactivity.9b The Michael acceptor 7a-b9b and CH2CO), 3.25 (1H, J = 17.1, 2.4 Hz, CH2CO), 3.48-3.63 (m, 2H,
7d9b containing the keto and nitro groups, respectively were allylic CH2 ), 3.96 (dd, 1H, J = 9.9, 2.7 Hz, NCH), 5.22-5.25 (m,
found to react smoothly with allyl amine in THF solvent 1H, =CH) ppm; 13C NMR (CDCl3, 75 MHz): δ 18.8 (CH3), 26.7
whereas the Michael acceptor 7c containing the amide group (CH3), 31.8 (CH3), 39.6 (CH2), 48.6 (CH2), 60.2 (CH), 102.9 (C),
required a protic solvent methanol and a mild base to react.
116.8 (CH), 138.2 (C), 201.2 (CO) ppm; IR (KBr): νmax3365 (m,
General method: A solution of allyl amine (or 3-methylbut-2- br), 2971(m), 2924(s), 1720(s), 1668(w), 1418(m), 1362(s),
en-1-amine, 10 mmol) and the Michael acceptor 7a-b,
d9b(10 1243(m), 1149(m), 845(m), 768(s) cm-1; HRMS (ESI+): m/z
mmol) in dry THF (30 mL) was stirred at room temperature [M+H]+ calcd for C10H17Cl3NO 272.0370, found 272.0262.
(25-30 ˚C). After completion of the reaction (4-6 h) as indicated 3-(Allylamino)-4,4,4-trichloro-1-phenylbutan-1-one 8c5a
:
by TLC, the solvent was removed on a rotary evaporator to Colorless liquid, 82% yield; 1H NMR (CDCl3, 300 MHz): δ 1.93 (s,
obtain almost pure products in quantitative yields. The crude br, 1H, NH, D2O-exchangeable), 3.26 (dd, 1H, J = 18.0, 9.0 Hz,
products were further purified by column chromatography on allylic CH2), 3.49-3.63 {m, 2H, (1H, CH2CO and 1H, allylic CH2)},
a small pad of neutral alumina using a mixture of ethyl acetate 3.76 (dd, 1H, J = 18.0, 3.0 Hz, CH2CO), 4.13 (dd, 1H, J = 18.0, 3.0
in n-hexane (0-3%, v:v) as the solvent for elution to obtain the Hz, CHN), 4.99-5.15 (m, 2H, =CH2), 5.74-5.87 (m, 1H, =CH-),
functionalized acyclic precursor 8a-c,e. The amide precursor 7.51 (t, 2H, J = 7.5 Hz, aromatic CH), 7.62 (t, 1H, J = 7.5 Hz,
8d was prepared as above by taking t-butanol (30 mL) as the aromatic CH), 7.99 (d, 2H, J = 6.0 Hz, aromatic CH) ppm; 13C
solvent and triethyl amine (0.42 mL, 0.336 g, 3 mmol) as the NMR (CDCl3, 75 MHz): δ 42.4 (CH2), 52.0 (CH2), 69.6 (CH), 105.4
catalyst and stirring the solution at room temperature (25-30 (C), 116.3 (CH2), 128.2 (CH), 128.7 (CH), 133.5 (CH), 136.2 (CH),
˚C) for 24 h. Purification of the crude product by column 136.4 (C), 196.4 (C) ppm; IR (KBr): νmax 3375(m, br), 2921(m),
chromatography on a small pad of neutral alumina gave 8d
These precursors were obtained in high yields 80-83 % as 755(m) cm-1; HRMS (ESI+): m/z [M
mentioned in Table 2 C13H14Cl3NONa 328.0020, found 328.0033.
2,4,4,4-Tetrachloro-1-phenylbutan-1-one: Yellow liquid, 81% 3-(Allylamino)-4,4,4-trichloro-N,N-dimethylbutanamide8d
.
1686(s), 1590(w), 1449(w), 1352(w), 1272(m), 993(m), 795(m),
+
Na]+ calcd for
.
:
yield; 1H NMR (CDCl3, 300 MHz): δ 3.33 (d, 1H, J = 15.3, 2.7 Hz, Colorless liquid, 76 % yield; 1H NMR (CDCl3, 300 MHz): δ 1.89 (s,
CH2), 4.17 (dd, 1H, J = 15.3, 6.9 Hz, CH2), 5.50 (t, 1H, J = 6.9, br, 1H, NH, D2O-exchangeable), 2.65 (dd, 1H, J = 15.0, 9.9 Hz,
2.7 Hz, CH), 7.52 (t, 2H, J = 6.9 Hz, aryl CH), 7.63 (t, 1H, J = 7.1 CH2CO), 3.20 (dd, 1H, J = 15.6, 9.3 Hz, CH2CO), 3.21 (s, 6H, CH3),
Hz, aryl CH), 8.06 (d, 2H, J = 7.8 Hz, aryl CH) ppm; 13C NMR 3.58-3.72 (m, 2H, allylic CH2), 3.88-3.95 (m, 1H, CHN). 5.13-
(CDCl3, 75 MHz): δ 50.7 (CH2), 56.7 (CH), 96.1 (C), 128.9 (CH), 5.33 (m, 2H, =CH2), 5.87-5.96 (m, 1H, =CH-) ppm; 13C NMR
129.1 (CH), 133.7 (C), 134.2 (CH), 190.9 (C) ppm; IR (KBr): νmax (CDCl3, 75 MHz): δ 39.3 (CH3), 39.4 (CH3), 42.4 (CH2), 52.0 (CH2),
3063(w), 2938(m), 1695(s), 1591(m), 1449(m), 1419(w), 69.5 (CH), 105.5 (C), 116.3 (CH2), 136.2 (CH) 166.4 (CO) ppm; IR
1367(w), 1312(m), 1245(m), 1179(m), 1046(m), 957(s), 850(s), (KBr): νmax 3377(m, br), 3080(w), 2952(m), 1705(s), 1604(w),
750(s), 692(s) cm-1; HRMS (ESI+): m/z [M + Na]+ calcd for 1439(m), 1358(m), 1274(s), 1175(s), 1024(m), 923(m), 795(s)
C10H8Cl4ONa 306.9221, found 306.9213.
cm-1; HRMS (ESI+): m/z [M + H]+ calcd for C10 H16Cl3N2O
Yellow 273.0323, found 273.0328.
(E)-4,4,4-trichloro-N,N-dimethylbut-2-enamide 7c
:
1
liquid, 80 % yield; H NMR (CDCl3, 300 MHz): δ 2.91 (s, 3H, N-(1,1,1-trichloro-3-nitropropan-2-yl)prop-2-en-1-amine 8e:
1
CH3), 2.96 (s, 3H, CH3), 6.30 (d, 1H, J = 14.4 Hz, CH), 7.25 (d, 1H, Light yellow liquid, 83 % yield; H NMR (CDCl3, 300 MHz): δ
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1.82 (s, br, 1H, NH, D2O-exchangeable), 3.53 (dd, 1H, J = 14.1, = 3.9 Hz, CH), 5.23-5.32 (m, 3H, =CH2), 5.70-5.83 (m, 1H, =CH-),
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6.0 Hz, allylic CH), 3.70 (dd, 1H, J = 14.1, 5.7 Hz, CH), 4.26 (dd, 7.30-7.35 (m, 3H, aryl CH), 7.45-7.56 (m,D2OHI,: 1a0r.y10l 3C9H/C)9pNpJm05;16136CJ
1H, J = 9.6, 3.3 Hz, CHN), 4.51 (dd, 1H, J = 13.2, 9.6 Hz, CH2NO2), NMR (CDCl3, 75 MHz):δ 42.9 (CH2), 58.9 (CH), 70.7 (CH), 97.8
5.06 (dd. 1H, J = 13.2, 3.3 Hz, CHNO2 partially overlapped (C), 119.7 (CH2), 127.6 (CH), 128.2 (CH), 128.6 (CH), 132.2 (CH),
multiplet at δ 5.11-5.24), 5.11-5.24 (m, 2H, olefinic CH2), 5.72- 137.2 (C), 163.5 (C) ppm; IR(KBr):νmax 3033(s), 2959(s), 2921(s),
5.85 (m, 1H, olefinic CH) ppm; 13C NMR (CDCl3, 75 MHz): δ 1720(s), 1413(m), 1360(s), 1175(m), 816(s), 772(s) ppm. HRMS
51.2 (CH2), 71.0 (CH2), 77.4 (CH), 101.7 (C), 117.1 (CH2), 135.5 (ESI+):m/z [M + Na]+calcd for C13H12Cl3NONa(M+Na)+ 325.9877,
(CH) ppm; IR (KBr): νmax 3382(m, br), 3081(w), 2926(m), found 325.9890.
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1643(w), 1561(s), 1472(w), 1425(m), 1379(s), 1162(m), 996(m),
926(m), 802(m ), 636(s) cm-1; HRMS (ESI+): m/z [M + H]+ calcd Halogen atom transfer radical cyclization of 2,2,2-
for C6H10Cl3N2O2 246.9808, found 246.9802.
trichloroethyl allyl amines 2a-b: General method: A flame-
dried two-neck round-bottom flask was charged with CuCl (40
Preparation of Methyl
allyl(2,2,2- mg, 0.40 mmol) and degassed acetonitrile (20 mL) under a N2
trichloroethyl)carbamate10a: This precursor was prepared by atmosphere using Schlenk technique. The suspension was
acylation reaction of 2,2,2-trichloroethyl allyl NH-amine with cooled to 0 ˚C and PMDETA (0.070 g, 0.8 mL, 0.4 mmol) was
methyl chloroformate (1 eq) in DCM solvent in the presence of injected into it. The mixture was stirred for 10 minutes at the
triethyl amine base ( 1 eq).5a
same temperature. N-(2,2,2-trichloroethyl)prop-2-en-1-amine
Colorless liquid, 80 % yield; 1H NMR (CDCl3, 300 MHz): δ 3.78 (s, 2a-b (1 mmol) was added to this mixture and stirring was
3H, CH3), 4.32-4.48 (m, 4H, CH2), 5.07-5.20 (m, 2H, allylic =CH2), continued further at the same temperature. After the
5.76-5.90 (m, 1H, allylic =CH-) ppm; 13C NMR (CDCl3, 75 MHz): disappearance of the starting material as indicated by TLC
1
d 52.7 (CH2), 53.8 (CH2), 57.7 (CH3), 100.3 (C), 117.5 (CH2), monitoring and confirmed by H NMR (4-6 h) of the aliquots
137.1 (CH), 155.5 (C) ppm; IR (KBr): νmax 3079 (w), 2924(m), taken directly from the reaction mass. The solvent was
1645(w), 1462(m), 1294(m), 1232(s), 1150(m), 1112(s), 1012(s), removed under reduced pressure. Ethyl acetate (100 mL) was
924(s), 802(s), 745(s) cm-1; HRMS (ESI+): m/z [M + Na]+ calcd added to the residual mass. The organic phase was washed
for C7H10Cl3NO2Na 267.9669, found 267.9665.
with brine (3x25 mL). [In case of low yield, the combined
Preparation of β-lactam fused 2,2,2-trichloroethyl allylamines aqueous layer was treated with dilute aqueous ammonia (20
9a-b. These precursors were prepared by reaction of aldimine mL) and extracted with ethyl acetate (2x20 mL) to recover the
and in situ generated ketene by a reported procedure with product from the aqueous layer went with copper complex].
slight modification.36
mixture of N-(2,2,2-trichloroethylidene)prop-2-en-1- filtered and concentrated under reduced pressure. The crude
The combined organic layer was dried (Anhydrous Na2SO4),
A
amine36(Schiff's base, 10 mmol) with triethylamine (20 mmol) product was purified by column chromatography on a small
in DCM at 0°C (at 10°C in case of 10b), is added drop wise a basic alumina column using different mixture of ethyl acetate
solution of phenoxyacetyl chloride (2-phenylacetyl chloride in in n-hexane (10-40 %, v:v) as eluent. The 1-substituted NH-
case of 10b) (20 mmol) in DCM and stirred at room pyrrolidines 3b andpyrroline4a-a′ were obtained in high yields.
temperature for 2-3 h. Solvent was removed under vacuum 2-(3-Chloro-4-(chloromethyl)-4,5-dihydro-3H-pyrrol-2-
and ethylacetate (200 mL) was taken into the residue. Washed yl)pyridine 4a-a′: obtained as a light red liquid in 78 % yield as
organic layer with water (2x50 mL), concentrated the organic diastereomeric mixture (Trans: Cis = 3:2). 1H NMR (CDCl3, 300
layer under vacuum and the purified the crude product on MHz): δ [2.92-2.97 (m) (minor isomer) + 3.05-3.11 (m) (major
column chromatography using alumina (neutral) andn-hexane: isomer), 1H, CHCH2], [3.41 (dd, J = 11.1, 7.5 Hz) (minor isomer)
ethylacetate (3 %, v:v) as eluent to obtain the precursor 10a-b + 3.53 (dd, J = 11.1, 6.6 Hz)(major isomer), 1H, NCH2], [3.69-
in good isolated yields.
3.80 (m) (major isomer + minor isomer), 1H, NCH2], [3.87 (dd, J
1-Allyl-3-phenoxy-4-(trichloromethy)azetidin-2-one
11d: = 10.8, 8.4 Hz) (minor isomer) + 4.05 (d, J = 17.7 Hz)(major
pinkish crystals, mp 93 °C (n-hexane/DCM), 58 % yield;1H NMR isomer), 1H, CH2Cl], 4.27-4.42 [(m)(minor isomer)(major
(CDCl3, 300 MHz) δ 3.90 (dd, 1H, J = 15.6, 7.5 Hz, CH2), 4.41 isomer), 1H, CH2Cl,], [5.43 (s) (major isomer) + 5.60 (d, J = 6.3
(dd, 1H, J = 15.6, 7.5 Hz, CH2), 4.73 (d, 1H, J = 4.8, CH), 5.30- Hz) (minor isomer), 1H, CHCl], 7.32 (t, 1H, J = 4.8 Hz, CH), 7.73
5.34 (m, 3H, olefinic CH2), 5.39 (d, 1H, J = 4.8 Hz, OCH), 5.77- (t, 1H, J = 7.5 Hz, CH), 8.16 (d, 1H, J = 6.6 Hz, CH), 8.64 (d, 1H, J
5.88 (m, 1H, olefinic CH), 7.02-7.10 (m, 3H, aryl CH), 7.26- = 4.2 Hz, CH) ppm; 13C NMR (CDCl3, 75 MHz): δ 42.1 (CH2),
7.31(m, 2H, aryl CH) ppm; 13C NMR (CDCl3, 75 MHz) δ 43.9 45.0 (CH2), 46.9 (CH), 50.1 (CH), 60.6 (CH), 61.1 (CH), 62.8 (CH2),
(CH2), 71.8 (CH), 84.7 (OCH), 96.8 (C), 116.7 (CH), 119.8 (CH2), 63.5 (CH2), 122.6 (CH), 122.9 (CH), 125.3 (CH), 125.4 (CH),
123.1 (CH), 129.6 (CH), 130.2 (CH), 157.01 (C), 164.5 (C) ppm. 136.59 (CH), 136.62 (CH), 149.3 (CH), 149.4 (CH), 150.4 (C),
IR(KBr) νmax 3033(s), 2959(s), 2921(s), 1720(s), 1413(m), 171.4 (C), 173.0 (C) ppm: IR (KBr);νmax3064(m), 2953(s), 2855(s),
1360(s), 1175(m), 816(s), 772(s) ppm. HRMS (ESI+):m/z [M + 1620(s), 1579(s), 1467(s), 1440(s), 1344(s), 1294(m), 1042(m),
H]+calcd for C13H13Cl3NO2 320.0006, found 320.001
1-allyl-3-phenyl-4-(trichloromethy)azetidin-2-one 11e: pinkish calcd for C10H10Cl2N2H 229.0294, found 229.0294.
crystals, mp 48 °C, (n-hexane/DCM), 46 % yield;1H NMR (CDCl3, 3,3-Dichloro-4-(chloromethyl)-2-(thien-2-yl)pyrrolidine
300 MHz):δ 3.82 (dd, 1H, J = 15.6, 7.8 Hz, CH2), 4.31 (dd, 1H, J Colorless liquid, 83 % yield; H NMR (CDCl3, 300 MHz): δ 1.84
= 15.36, 4.2 Hz, CH2), 4.32 (d, 1H, J = 3.6 Hz, CH), 4.66 (d, 1H, J (s, br, 1H, NH, D2O-exchangeable), 3.15-3.18 (m, 2H, NCH2 and
981(m), 987(m), 799(s), 742(s) cm-1; HRMS (ESI+): m/z [M + H]+
3b:
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CHCH2), 3.63-3.75 {m, 2H, (1H, CH2N and 1H, CH2Cl)}, 3.96-3.99 7.60 (t, 1H, J = 7.5 Hz, aromatic CH), 8.00 (d, 2H, J = 7.2 Hz,
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(m, 1H, CH2Cl), 4.63 (s, 1H, CH), 7.00 (t, 1H, J = 4.5 Hz, CH), 7.27 aromatic CH) ppm; C NMR (CDCl3, 75DMOIH: 1z0):.10δ39/3C99.N3J0(C51H626)J,
(d, 1H, J = 4.5 Hz, CH), 7.34 (d, 1H, J = 4.8 Hz, CH) ppm; 13C 42.4 (CH2), 47.9 (CH2), 56.1 (CH), 67.7 (CH), 93.2 (C), 128.1 (CH),
NMR (CDCl3, 75 MHz): δ 43.5 (CH2), 48.8 (CH2), 54.9 (CH), 75.3 128.2 (CH), 133.5 (CH), 136.3 (C), 197.3 (C) ppm; IR (KBr): νmax
(CH), 94.3 (C), 127.0 (CH), 127.1 (CH), 128.5 (CH), 137.3 (C) 3326 (m, br), 2924(s), 2854(s), 1682(s), 1627(s), 1580(s),
ppm; IR (KBr): νmax 3353(br, m), 2962(s), 1610(m), 1503(w), 1398(s), 1283(s), 1072(s), 1005(m), 827(s), 756(s) cm-1;HRMS
1430(s), 1252(m), 1152(s), 1070(m), 1011(s), 927(m), 807(s), (ESI+): m/z [M + H]+ calcd for C13H14Cl3NONa 328.0038, found
709(s) cm-1;HRMS (ESI+): m/z [M + H]+ calcd for C9H11Cl3NS 328.0033.
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269.9672, found 269.9682.
2-(3,3-dichloro-4-(chloromethyl)pyrrolidin-2-yl)-N,N-
dimethylacetamide 9d-d′: Reddish liquid, 81 % yield as
1
The side chain functionalized NH-pyrrolidines 9a-e were diastereomeric mixture (74:26); H NMR (CDCl3, 300 MHz): δ
prepared from the corresponding amines 8a-e as above, 2.0 (br, s, 1.25 H, NH, D2O-exchangeable), 2.47-2.58 (m, 1.25 H,
except that 60 mol % each of CuCl and PMDETA were taken CH2CON, major and minor isomer), 2.86-2.93 (m, 1.25H,
and the reaction mixture was stirred at 0˚C for 6-10 h.
1-(3,3-dichloro-4-(chloromethyl)pyrrolidin-2-yl)propan-2-one
CH2CON, major and minor isomer), 3.0-3.11 (m, 10H 2xCH3,
CHCH2 andNCH2, major and minor isomer), 3.45-3.61 (m, 2.5H,
9a-a′: Reddish liquid, 83 % yield as diastereomeric mixture NCH2 and CH2Cl)(major + minor isomer}], 3.64-3.72 (m, 1.25H,
1
(70:30); H NMR (CDCl3, 300 MHz): δ 2.19 (s, 4.5H, CH3, major ClCH2 major and minor isomers), 3.82 (dd, 1H, J = 16.8, 5.7 Hz,
and minor isomers), 2.30 (br, s, 1.5 H, NH, D2O-exchangeable), NCH major isomer), 4.00 (dd, 0.25H, J = 12.9, 4.8 Hz, NCH
2.60 (dd, 0.5H, J = 9.0, 1.5 Hz, CH2CO, minor isomer), 2.69 (dd, (minor isomer) ppm; 13C NMR (CDCl3, 75 MHz): δ 30.2 (CH2),
1H, J = 7.8, 1.2 Hz, CH2CO, major isomer), 2.80-2.92 (m, 1.5H, 30.4 (CH2), 38.7 (CH3), 38.9 (CH3), 41.9 (CH2), 51.17 (CH2),
COCH2, major and minor isomer), 2.94-3.01(m, 3H, (1.5H, 51.20 (CH2), 54.3 (CH), 54.6 (CH), 57.8 (CH), 58.8 (CH), 95.3 (C),
CHCH2 and 1.5H, NCH2)(major + minor isomer}], 3.38-3.50 (m, 95.4 (C), 164.7 (C), 164.9 (C) ppm; IR (KBr): νmax 3367 (m, br),
1.5H, CH2Cl(major + minor isomer)}, 3.59 (t, 1H, J = 10.4 Hz, 2923(m), 1705 (s), 921(s), 832(s), 764(m) cm-1; HRMS (ESI+):
NCH2 major isomer), 3.76 (dd, 0.5H, J = 9.6, 3.0 Hz, NCH2 minor m/z [M + H]+ calcd for C9H16Cl3N2O 273.0323, found 273.0330.
isomer), 3.82-3.95 [(m, 3H, NCH (major and minor isomer) 3,3-dichloro-4-(chloromethyl)-2-(nitromethyl)pyrrolidine 9e-
and CH2Cl (major and minor isomer)] ppm; 13C NMR (CDCl3, 75 e′: Reddish liquid as diastereomeric mixture of diastereomers
MHz): δ 30.2 (CH3), 30.4 (CH3), 42.0 (CH2), 43.4 (CH2), 44.0 (22:78), 79 % yield; 1H NMR (CDCl3, 300 MHz): δ 2.08 (s, br, 1H,
(CH2), 44.6 (CH2), 47.6 (CH2), 48.4 (CH2), 55.4 (CH), 55.8 (CH), NH, D2O-exchangeable), 2.97-3.13 [m, 2H, (1H, CHCH2 and 1H,
67.1 (CH), 67.3 (CH), 92.6 (C), 93.9 (C), 205.6 (C), 205.8 (C) ppm; NCH2)(major and minor isomer}], 3.49-3.68 [m, 2H, (1H, NCH2
IR (KBr): νmax 3367 (m, br), 2923(m), 1715 (s), 1558(s), 1421(m), and 1H, CH2Cl)(major and minor isomer)], 3.95 (m, 1H,
1377(s), 921(s), 832(s), 764(m) cm-1; HRMS (ESI+): m/z [M + H]+ CH2Cl)(major and minor isomer), 4.29-4.47 (m, 1H, NCH)(major
calcd for C8H13Cl3NO 244.0057, found 244.0047.
and minor isomer), [4.38-4.46 (m, CH2NO2)(minor isomer) +
1-(3,3-dichloro-4-(2-chloropropan-2-yl)pyrrolidin-2-yl)propan- 4.56 (dd, 1H, J = 13.5, 9.3 Hz)(major isomer), 1H, CH2NO2)],
2-one 9b-b′: Reddish liquid, 80 % yield as diastereomeric [4.79-4.90 (m)(major isomer) + 4.90-5.02 (m)(minor isomer),
mixture (72:28); H NMR (CDCl3, 300 MHz): δ 1.94 (s, 7.5H, 1H, CH2NO2) ppm; 13C NMR (CDCl3, 75 MHz): δ 41.5 (CH2), 42.8
1
CH3, major and minor isomers), 2.22 (br, s, 1.25H, NH, D2O- (CH2), 48.1 (CH2), 48.3 (CH2), 55.3 (CH), 56.4 (CH), 68.7 (CH),
exchangeable, major and minor isomers), 2.25 (s, 3.75H, CH3, 69.2 (CH), 76.1 (CH2), 77.1 (CH2), 90.1 (C), 90.9 (C) ppm; IR
major and minor isomers), 2.80 (dd, 0.25H, J = 10.8, 2.4 Hz, (KBr): νmax 3367 (m, br), 2923(m), 1558(s), 1421(m), 1377(s),
CH2CO minor isomer), 2.88 (dd, 1H, J = 17.1, 8.1 Hz, CH2CO 921(s), 832(s), 764(m) cm-1; HRMS (ESI+): m/z [M + H]+ calcd
major isomer), 2.92-3.11 (m, 1.25H, CH2CO major and minor for C6H10Cl3N2O2 246.9802, found 246.9806.
isomer), 3.17-3.40 (m, 3.75H, (1.25H, CHCH2 and 2.50H,
NCH2)(major + minor isomer}], 4.12 (dd, 0.25H, J = 10.8, 4.8 Hz, N-protected Pyrrolidine 11a: The amine precursor 10a was
NCH, minor isomer), 4.18 (dd, 1H, J = 13.2, 7.8 Hz, NCH, major cyclized with 25 mol % CuCl/PMDETA at RT in MeCN under N2
isomer) ppm; 13C NMR (CDCl3, 75 MHz): δ 29.2 (CH2), 29.9 atmosphere for 12 hrs.9b
(CH2), 30.2 (CH3), 30.3 (CH3), 30.6 (CH3), 34.3 (CH3), 34.5 (CH3), Methyl
3,3-dichloro-4-(chloromethyl)pyrrolidine-1-
1
44.9 (CH2), 49.8 (CH2), 55.6 (CH), 57.6 (CH), 63.9 (CH), 64.3 (CH), carboxylate 11a: Colorless liquid, 88% yield; H NMR (CDCl3,
71.2 (C), 71.5 (C), 93.3 (C), 93.6 (C), 202.7 (C), 202.8 (C) ppm; IR 300 MHz): δ 3.02-3.29 (m, 1H, CH), 3.32-3.51 (m, 1H, CH2),
(KBr): νmax 3367 (m, br), 2923(m), 17.16 (s), 1558(s), 1421(m), 3.55-3.60 (m, 1H, CH2), 3.82-3.86 (2xs, 5H, CH2 & CH3), 3.96-
1377(s), 921(s), 832(s), 764(m) cm-1; HRMS (ESI+): m/z [M + H]+ 4.03 (m, 1H, CH2), 4.04-4.10 (m, 1H, CH2) ppm; 13CNMR (CDCl3,
calcd for C10H17Cl3NO 272.0370, found 272.0380.
2-(3,3-Dichloro-4-(chloromethyl)pyrrolidin-2-yl)-1-
75 MHz): δ 43.0 (CH2), 51.2 (CH2), 56.1 (CH), 56.2 (CH3), 67.1
(CH2), 90.7 (C) 156.0 (CO) ppm; IR (KBr): νmax 2976(s), 1690(s),
phenylethanone 9c5a
:
Colorless liquid, 85%; H NMR (CDCl3, 1368(m), 1150(s), 1070(s), 807(s), 718(s) cm.-1; HRMS (ESI+):
1
300 MHz): δ 2.24 (s, br, 1H, NH, D2O-exchangeable), 2.92 (d, m/z (M+ Na)+calcd for C7H10Cl3NO2 267.9669, found 267.9675.
1H, J = 10.5, 9.6 Hz, COCH2), 3.02-3.13 (m, 1H, CHCH2), 3.20- Preparation of Pyrrolines 4c-d: These were obtained by
3.32 (m, 1H, COCH2), 3.48-3.62 (m, 2H, NCH2), 3.68 (t, 1H, J = stirring an equimolar mixture of crude NH-pyrrolidines 3c-d5a
10.4 Hz, CH2Cl), 4.01 (dd, 1H, J = 11.1, 4.2 Hz, CH2Cl), 4.11 (dd, (1 mmol) with DBU (1 mmol) base at room temperature in
1H , J = 9.6, 1.8 Hz, CHN), 7.49 (t, 2H, J = 7.5 Hz, aromatic CH), toluene (30 mL) for 3-6 h, followed by filtration, washing the
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filtrate with brine (2x25 mL) and purification by column 753(s)cm-1.HRMS(ESI+): m/z (M+ Na)+calcd for C13H12Cl3NO2
chromatography on small pad of neutral alumina using 10-20 % 341.9826, found 341.9832
View Article Online
DOI: 10.1039/C9NJ05166J
ethyl acetate/n-hexane (v:v) as eluent.
X-ray crystal structure data of lactam 11d*
4-Chloro-3-(chloromethyl)-5-(4-nitrophenyl)-3,4-dihydro-2H-
pyrrole 4c:Yellow solid, 78 % yield; mp 84 ˚C (n-hexane): H Crystal system: monoclinic; Space group: P 21/c; Unit cell
Formula sum:C13H12Cl3NO2,Formula weight:110.54 g/mol;
1
NMR (CDCl3, 300 MHz):
 3.09-3.11 (m, 1H, methine CH), 3.51 dimensions: a = 12.302(3) Å b = 13.884(3) Å c = 8.368(2) Å, α =
(dd, 1H, J = 11.4, 7.5 Hz, NCH2), 3.71 (dd, 1H, J = 11.4, 5.4 Hz, 90.00(0)°β = 101.188(4)°γ = 90.00(0)°; Cell volume = 1402.1(6)
NCH2), 4.07 (dd, 1H, J = 17.7, 2.1 Hz, CH2Cl), 4.45 (dd, 1H, 17.7, Å3, Z = 4; Density calculated = 1.519 g/cm3; RAll = 0.086.
7.2 Hz, CH2Cl), 5.19 (s, 1H, CHCl), 8.09 (d, 2H, J = 8.4 Hz, Detailed X-ray crystallographic data is available from the
aromatic CH), 8.28 (d, 2H, J = 8.4 Hz, aromatic CH) ppm; 13C Cambridge Crystallographic Data Centre, 12 Union Road,
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NMR (CDCl3, 75 MHz):
 44.8 (CH2), 50.4 (CH), 61.1 (CH), 63.1 Cambridge CB2 1EZ, UK (CCDC 1504483).
(CH2), 123.7 (CH), 129.2 (CH), 137.0 (C), 149.1 (C), 168.2 (C) 3,5,5-trichloro-7-phenyl-1-aza-bicyclo[4.2.0]octan-8-one 11e*
ppm; IR (KBr): νmax2962(w), 1591(m), 1521(s), 1441(w), 1347(s), LightPink crystal (n-hexane-DCM), mp 58.5 °C, 75 % yield; H
:
1
1108(w), 1012(m), 973(w), 864(m), 844(w), 713(m), 713(m) NMR (CDCl3, 300MHz):
 2.47-2.55 (m, 1H, CH2), 2.94-3.02 (m,
cm-1;HRMS (ESI+): m/z [M + H]+ calcd for C11H11Cl2N2O2 1H, CH2CCl2), 3.01-3.18 (m, 1H, CH2CCl2), 3.71 (s, 1H, NCH),
273.0196, found 273.0200.
4-Chloro-3-(chloromethyl)-5-phenyl-3,4-dihydro-2H-pyrrole
4d:yellow solid, 62 % yield, mp 48-49 ˚C (n-hexane); H NMR (CDCl3, 75 MHz):
4.19-4.33 (m, 2H, CHCl+NCH2), 4.27 (s, 1H, CHCO), 7.25-7.38
(m, 3H, aryl CH), 7.48-7.57 (m, 2H, aryl CH) ppm;13C NMR
1
 44.7 (CH2), 48.3 (CH), 52.9 (CH2), 59.0 (CH),
(CDCl3, 300 MHz):
 3.01-3.10 (m, 1H, CHCH2), 3.35 (dd, 1H, J 65.9 (CH), 83.4 (C), 128.3 (CH), 129.1 (CH), 129.3 (CH), 161.6 (C)
= 11.7, 7.5 Hz, NCH2), 3.56 (dd, 1H, J = 11.7, 5.7 Hz, NCH2), 3.83 ppm; IR(KBr):νmax 2974(s), 1775(s), 1595(s), 1491(s), 1446(s),
(dd, 1H, J = 15.0, 3.0 Hz, CH2Cl), 4.25 (dd, 1H, J = 15.0, 7.2 Hz, 1398(s), 1284(s), 1237(s), 892(s), 753(s)cm.-1 HRMS(ESI+): m/z
CH2Cl), 5.27 (s, 1H, CHCl), 7.26-7.38 (m, 5H, phenyl CH) ppm; [M + Na]+ calcd for C13H12Cl3NO2 325.9877, found 325.9880.
13C NMR (CDCl3, 75 MHz):
 43.8 (CH2), 49.5 (CH), 60.1 (CH), Preparation of 3,3-dichloro-4-(chloromethyl)-2-(nitromethyl)-
62.1 (CH2), 126.3 (CH), 128.3 (CH), 130.3 (CH), 132.8 (C), 162.2 1-tosylpyrrolidine 12: Tosylation of the crude product 9e was
(C) ppm; IR (KBr): νmax2962(w), 2955(m), 2924(m), 1520(s), done using a method reported in the literature5a for tosylation
1440(w), 1346(s), 1010(w), 973(w), 865(m), 700(m), 670(m) of 2-cyanomethylene–NH-pyrrolidine under a mild condition. A
cm-1;HRMS (ESI+): m/z [M + H]+ calcd for C11H12Cl2N 228.0241, mixture of pyrrolidines (1 mmol), Tosyl chloride (1 mmol) and
found 228.0250.
K2CO3 (1.5 equiv) in dry THF (50 mL) was stirred for 16 hrs at
10-15 ˚C. After disappearance of starting material as indicated
Halogen atom transfer radical cyclization (ATRC) of β-lactam by TLC, the reaction mixture was concentrated under rotary
fused
precursor
10d-e:
Preparation
of
1-aza- evaporator. Ethylacetate (100 mL) was added to the reaction
bicyclo[4.2.0]octan-8-one 11d*-e*
mixture and washed with brine (2x25 mL), dried (anhydrous
A flame-dried, two-necked, round-bottom flask was charged Na2SO4), concentrated and recrystallized (DCM: n-hexane) to
with CuCl (40 mg, 0.4 mmol), and degassed DCE (30 mL) under obtain tosylatedpyrrolidine12 (58 %).
a
N2 atmosphere using Schlenk techniques. Into this 3,3-Dichloro-4-(chloromethyl)-2-(nitromethyl)-1-
suspension were injected TMEDA (0.093 g, 0.8 mmol), starting tosylpyrrolidine 12: White crystals, 58 % yield, mp 78 ˚C (DCM:
material 10d-e (0.320 g, 1 mmol) was added and the mixture n-hexane); 1H NMR (CDCl3, 300 MHz):
2.40-2.47 (m, 1H,

was stirred at reflux. After completion of reaction as indicated CHCH2), 2.49 (s, 3H, CH3), 3.40 (t, 1H, J = 11.4 Hz, CHCl), 3.50-
by TLC monitoring after 6 hrs, the reaction mixture was 3.58 (m, 1H, CH2Cl), 3.78-3.87 (m, 2H, CH2N), 4.70 (dd, 1H, J =
evaporated under reduced pressure and the residual mass was 4.8, 3.2 Hz, CHN), 4.93-5.11 (m, 2H, CH2NO2), 7.44 (d, 2H, J =
added ethyl acetate(100 mL) and washed with brine (2x20 7.8 Hz, CH), 7.76 (d, 2H, J = 7.8 Hz, CH) ppm; 13C NMR (CDCl3,
mL), dried (anhydrous Na2SO4), concentrated under reduced 75 MHz): 21.6 (CH3), 39.6 (CH2), 50.9 (CH2), 54.4 (CH), 69.9
pressure and purified by column chromatography (neutral (CH2), 75.3 (CH), 88.9 (C), 127.9 (C), 130.4 (CH), 131.8 (CH),
alumina, n-hexane / Ethylacetate = 70:30 v/v) followed by 145.4 (C) ppm; IR (KBr): νmax 3049(m), 2996(m), 15976(w),
recrystallization from n-hexane-DCM gave β-lactam fused 1552(s), 1420(m), 1358(s), 1164(s), 1099(s), 1048(m), 999(m),
piperidines11d*-e* in high isolated yields (75-80 %).
778(m), 665(s), 559(s) cm-1;HRMS (ESI+): m/z [M + Na]+ calcd
for C13H15Cl3N2O4SNa 422.9710, found 422.9715.
X-ray crystal structure data of 12
3,5,5-trichloro-7-phenoxy-1-aza-bicyclo[4.2.0]octan-8-one
11d*: Light pink crystal(n-hexane-DCM), Mp 78.5 °C, 80 % yield; Formula sum: C13H15Cl3N2O4S, Formula weight:401.69 g/mol;
1H NMR (CDCl3, 300MHz):
2.51 (dd, 1H, J = 14.1, 11.7 Hz, CH2), Crystal system: triclinic; Space group: P-1; Unit cell dimensions:

2.98 ( dd, 1H, J = 13.8, 11.4 Hz, CH2), 3.13-3.18 (m, 1H, NCH2), a = 8.1177(13) Å b = 13.574(2) Å c = 16.277(3) Å α = 107.443(3)°
3.93 (s,1H, CHCCl2), 4.19-4.33 (m, 2H, CHCl+NCH2), 5.51 (s,1H, β = 90.128(3)° γ = 90.166(3)°; Cell volume = 1711.1(5) Å3, Z = 4;
CH-O), 7.05-7.11 (m, 3H, CH), 7.27-7.36 (m, 2H, CH) ppm;13C Density calculated = 1.559 g/cm3; RAll = 0.085. Detailed X-ray
NMR (CDCl3, 75 MHz): 44.8 (CH2), 48.3 (CH), 52.1 (CH2), 66.0 crystallographic data is available from the Cambridge
(CH), 83.2 (C), 84.5 (CH), 115.6 (CH), 122.8 (CH), 129.7 (CH), Crystallographic Data Centre, 12 Union Road, Cambridge CB2
156.9 (C.), 162.1 (C) ppm. IR(KBr) νmax 2974(s), 1775(s), 1EZ, UK (CCDC 1504482).
1595(s), 1491(s), 1446(s), 1398(s), 1284(s), 1237(s), 892(s),
14 | J. Name., 2012, 00, 1-3
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Synthesis of β-lactam fused piperidine 11e* in the presence of each of CuCl and PMDETA were taken along with 30 mol%
View Article Online
AIBN and its Synthetic application towards Ritalin 14. The NH- AIBN and the reaction mixture was stirreDdOaIt: 1r0e.1fl0u3x9/6C9hNrJs0. 5N16e6xJt
pyrrolidines11e*was prepared from the corresponding amines the crude product after usual work up was taken up as such for
10e using general ATRC procedure as above for 10d-e, except next step of aromatization step. This reaction was performed
that 5 mol % each of CuCl and 10 mol% of TMEDA were taken by following a method reported in our previous work9h-I in
in DCE along with 20 mol % AIBN and the reaction mixture was which 3,3-dichloro-4-chloromethyl-tetrahydrofurans were
stirred at reflux 6 hrs. The reaction mixture was evaporated aromatized by DBU. A solution of the chlorinated pyrrolidine
under reduced pressure and to the residual mass was added 3b or 175a (1mmol) and DBU (0.38 mL, 2.5 mmol) in dry
ethyl acetate (100 mL), washed with brine (2x20 mL), dried toluene (30 mL) was heated at reflux for 24 h. The reaction
(anhydrous Na2SO4), concentrated under reduced pressure mass was cooled to room temperature and ethyl acetate (100
and purified by column chromatography (neutral alumina, n- mL) was added. The solution was washed successively with
hexane / Ethylacetate = 70:30 v/v) to obtain 11e* in high saturated solution of NH4Cl (20 mL) and with brine (2x20 mL).
isolated yields (75%) which was used in the next step as such The organic phase was dried (anhydrous Na2SO4), filtered and
for dehalogenative reduction. Dehalogenative reduction evaporated to obtain the crude product. The purification of
of11e* to 13 was done using a reported method for reduction the crude product by column chromatography on a neutral
of trichlorinated N-heterocycles.15 Bu3SnH (1.32 g, 1.22 mL, 4.5 alumina column using a mixture of ethyl acetate and n-hexane
mmol) and AIBN (80 mg, 0.5 mmol) were added to a stirred (10-20 %, v:v) as the mobile phase gave the pure product 15
solution of piperidine 11e* (0.305 g, 1 mmol) in dry, degassed and 18 in good yield (45-46 %).
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toluene (40 mL) under nitrogen atmosphere. The reaction was 3-Chloro-4-(chloromethyl)-2-(thiophen-2-yl)-1H-pyrrole 15:
heated to reflux and then maintained the temperature for 1 h. Viscous liquid, 45 % yield; 1H NMR (CDCl3, 300 MHz):
 2.21 (s.
The reaction mass was cooled to room temperature. The 3H, CH3), 6.51 (d, 1H, J = 1.2 Hz, pyrrolic CH), 7.20 (t, 1H, J =
solvent was removed in vacuum on rotary evaporator. The 4.5 Hz, thienyl CH), 7.39 (d, 1H, J = 5.1 Hz, thienyl CH), 7.49 (s,
resultant residue was triturated with diethyl ether (40x2 mL) 1H, thienyl CH), 8.67 (br, s, 1H, NH, D2O-exchangeable) ppm;
and stirred vigorously with an aqueous potassium fluoride 13C NMR (CDCl3, 75 MHz):
 9.9 (CH3), 109.8 (C), 118.2 (CH),
solution (10 % by weight, 50 mL) for 12 hours. The organic and 124.3 (C), 126.3 (CH), 126.7 (CH), 127.7 (C), 128.3 (C), 138.5 (C)
aqueous layers were then separated. The aqueous layer was ppm; IR (KBr): νmax 3363(s, br), 2927(m), 1697(s), 1576(m),
then extracted with ethyl acetate (60 mL). The combined 1526(s), 1451(s), 1248(s), 1097(m), 1027(s), 830(s), 723(m) cm-
organic layer was washed with water (30 mL), brine (30 mL), 1; HRMS (ESI+): m/z [M + H]+ calcd for C9H8Cl1N1ONa 219.9958,
dried (anhydrous Na2SO4) and concentrated in vacuum. The found 219.9970.
purification of the crude product with silica gel column 3-Chloro-4-(chloromethyl)-2-(furan-2-yl)-1H-pyrrole
18:
2.11
1
chromatography using n-hexane-ethylacetate) gave
a
Viscous liquid in 46 % yield; H NMR (CDCl3, 300 MHz):

previously known compound 13 (80 mg, 40 %) as solid, m.p. (s. 3H, CH3), 6.42 (s, 1H, pyrrole CH), 6.54-6.57 (m, 2H, furyl
88 °C. This compound on reaction with methanolic CH), 7.08 (br, s, 1H, NH, D2O-exchangeable), 7.38-7.39 (m, 1H,
hydrochloric acid is known in literature to give Ritalin 14in furyl CH) ppm; 13C NMR (CDCl3, 75 MHz):
 10.3 (CH3), 108.8
single step, was used as such in the next step for preparation (C), 111.2 (CH), 112.2 (CH), 116.5 (CH), 124.3 (C), 126.3 (C),
of 14 with slight modifications.16-17 A solution of β-lactam 13 140.0 (CH), 150.3 (C) ppm; IR (KBr): νmax 3363(s, br), 2927(m),
(80 mg) in MeOH (20 mL) was cooled to 0 °C. Then anhydrous 1697(s), 1576(m), 1526(s), 1451(s), 1248(s), 1097(m), 1027(s),
HCl gas was purged into the solution for 10 minutes till its 830(s), 723(m) cm-1; HRMS (ESI+): m/z [M + H]+ calcd for
saturation. The reaction mass was then stirred at 0-5 °C for 15 C9H8Cl1NNa 204.0187, found 204.0190.
min. The temperature of the reaction mixture was raised to
room temperature and stirred further till the complete
disappearance of starting material on TLC plate in 6hrs. The
Conflicts of interest
solvent was removed under vacuum to obtain the solid
hydrochloride salt. This was triturated twice with diethyl ether
(25 mL). The solid was filtered and washed with diethyl ether
(10 mL). This solid was further recrystallized in MeOH-diethyl
ether to obtain previously known compound 14 as white
There are no conflicts of interests to declare.
Acknowledgements
1
crystals in 80 % yield having mp 220 °C matching with H NMR
spectrum reported in literature.16-17
Financial assistance to Dharmendra Kumar Gupta by CSIR New Delhi
is gratefully acknowledged
Synthesis of 1-heteroarylsubstituted NH-pyrrolidine 3b and
17 in the presence of AIBN and their synthetic application in
the preparation of 3-chloro-NH-pyrroles 15 and 18.
The NH-pyrrolidines 3band 17 was prepared from the
corresponding amines 2bor 165a which was previously
synthesized by us using same route for 2a, respectively using
general ATRC procedure as above for 3a-b, except that 10 mol %
Notes and References
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1
2
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4
Table of Contents
5
6
7
8
R4
R3
R4
R3
Cl
R4
Cl
Cl
Cl
CuCl/TMEDA/PMDETA
(5-60 mol %)/AIBN
Cl
R1
R3
Cl
R1
CCl3
+
9
MeCN/DCE, 0 °C-reflux,
5-24 h, N2 atm.
N
R2
R1
N
R2
N
R2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
75-88 %
R1 = N & S-heteroaryls, CO2Me, CH2EWG (EWG = CONMe2, COR, NO2), H
R1-R2 = RCHCO, R2 = H, CO2Me, R3 & R4 = H, alkyl
Chelation, rigidity and carbon-radical positions in aminoalkyl precursors disturb the usual 2,4-
trans diastereoselectivity and 5-exo mode in Cu(I)-catalyzed ATRC