β,β,β-Trichloroethyl-NH-Enamine as Viable System for 5-Endo-trig Radical Cyclization via Multifaceted CuI?CuII Redox Catalysis: Single Step Synthesis of Multi-Functionalized NH-Pyrroles

Article abstract of DOI:10.1002/adsc.201900938

Here we report a mild and regioselective copper-catalyzed direct synthesis of multi-substituted and functionalized NH-pyrroles in high yields from diverse β,β,β-trichloroethyl-NH-enamines via a novel 5-endo-trig radical cyclization mode, previously known to be unviable in the enamine system. An approach to transform a geometrically ‘disfavored to favored’ 5-endo-trig radical cyclization mode in NH-enamine systems via multifaceted Cu^I?Cu^II redox catalysis generating radicals, preventing dehalogenative reduction of radical precursors and dehydrohalogenating the 5-endo-trig cyclized products have been demonstrated experimentally. With wider substrate scope, this method incorporates halo-, NH- and carbonyl functionalities besides alkyl, aryl and heteroaryl substituents in the pyrrole unit easily. These difficult to prepare 3-halo-NH-pyrroles are potential sources for natural products, agrochemicals, pharmaceuticals and organometallic chemistry.

Full text of DOI:10.1002/adsc.201900938

Title: β,β,β-Trichloroethyl-NH-Enamine As Viable System For 5-
Endo-trig Radical Cyclization Via Multifaceted CuI-CuII Redox
Catalysis: Single Step Synthesis of Multi-Functionalized NH-
pyrroles
Authors: Ram Ram, sandhya sadanandan, and Dharmendra Gupta
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900938
Link to VoR: http://dx.doi.org/10.1002/adsc.201900938

10.1002/adsc.201900938
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
β,β,β-Trichloroethyl-NH-Enamine as Viable System for 5-Endo-trig
Radical Cyclization via Multifaceted CuI-CuII Redox Catalysis: Single
Step Synthesis of Multi-Functionalized NH-Pyrroles
Ram N. Ram,a Sandhya Sadanandanb and Dharmendra Kumar Gupta*a
a Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
b Department of Chemistry, Amrita Vishwa Vidyapeetham, Amritapuri, Kerala 690525, India.
Received:((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Here we report a mild and regioselective copper- 5-endo-trig cyclized products have been demonstrated
catalyzed direct synthesis of multi-substituted and experimentally. With wider substrate scope, this method
functionalized NH-pyrroles in high yields from diverse β,β, incorporates halo-, NH- and carbonyl functionalities
β-trichloroethyl-NH-enamines via a novel 5-endo-trig radical besides alkyl, aryl and heteroaryl substituents in the
cyclization mode, previously known to be unviable in the pyrrole unit easily. These difficult to prepare 3-halo-NH-
enamine system. An approach to transform a geometrically pyrroles are potential sources for natural products,
‘disfavored to favored’ 5-endo-trig radical cyclization mode agrochemicals, pharmaceuticals and organometallic
in NH-enamine systems via multifaceted CuI-CuII redox chemistry.
catalysis generating radicals, preventing dehalogenative
Keywords: 5-Endo-trig radical cyclization; NH-Pyrrole;
reduction of radical precursors and dehydrohalogenating the
NH-enamine; Cu(I)-catalyst; captodative-stabilization
effective and high yielding strategy to synthesize
Introduction
various heterocycles with wider substrate scope,
100 % atom efficiency and functional group tolerance
including halogens.[6] AIBN and ascorbic acid
(ARGET), and platinum electrode surface (eATRC)
regenerate an active Cu(I)-catalyst by reducing a
Cu(II)-complex to decrease the catalyst loading
drastically even below 1 mol %.[6a-b] However, there
is a scarcity of radical cyclization approaches to
access an aromatic ring in single step.[6] Quayle and
co-workers reported an efficient benzannulation
reaction to access chloronaphthalenes using
trichloroacetates.[6e] However, to the best of our
knowledge, synthesis of a NH-pyrrole unit via the
cyclization of a NH-enamine system under a radical
condition is undiscovered so far.[5-6]
The structure-activity relationship (SAR) studies
of a large number of bioactive pyrrole derivatives
reveal the pharmacophoric properties of various
substiuents, functionalities and halogen(s) present at
specific position on the pyrrole ring.[1] NH-, halogen-,
carbonyl and related functionalities of a pyrrole
ring[2] are reaction centers to construct natural and
artificial
bioactive
pyrrole
derivatives,[2a-c]
agrochemicals and pharmaceuticals,[2d-f] advance
materials[2g] and catalysts.[2h] In recent times, the
development of direct, regioselective, cost-effective
and
industry-oriented
methods
capable
of
incorporating diverse functionalities and substituents
on the NH-pyrrole ring while using a cheap catalyst
and easily accessible raw materials are in great
demands.[3] In this regard, the NH-enamine system is
such a synthetically simple, easily diversifiable and
an economical building block for N-heterocycles.[4]
However, the synthetic potential of such NH-enamine
systems in the formation of diversely substituted- and
The pioneers Ikeda, Ishibashi and co-workers[7]
found that an internal C=O group in the cyclizing 5-
membered transition state 2 (Scheme 1) assists in the
realization of 5-endo-trig radical cyclization in an
enamide 1 to furnish a γ-lactam 3. Whereas the N-
substituted enamine 4 with an external C=O group 5
fails to give the pyrrolidine 7 via 5-endo radical
cyclization 6[7] due to high geometrical constraints in
the 5-endo-trig transition state,[5] as reported by
Baldwin et al.[8] in other systems. Unlike
geometrically favored vinyl ether[8a-b] and N-protected
enamide 1,[8a,c] and disfavored N-substituted enamine
4,[7] 5-endo-trig radical cyclization of a geometrically
disfavored NH-enamine of type 8 is further a bigger
challenge for a radical chemist due to three reasons.[9-
10] First, a NH-enamine is sensitive to both acidic and
basic conditions,[9a] needs a neutral reaction condition.
functionalized
3-halo-NH-pyrroles
using
a
regioselective intramolecular cyclization reaction in a
single operation has been scarcely exploited so far.[3h]
Among various types of cyclization protocols,[3]
free radical cyclization reaction is a powerful tool to
construct cyclic frameworks from acyclic unsaturated
radical precursors via carbon-carbon bond formation
in the fewest and concise steps.[5] Over the years,
Copper(I)-catalyzed halogen atom transfer radical
cyclization (HATRC) of unsaturated polyhalomethyl
substrates has emerged as a mild, catalytic, cost-
1
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10.1002/adsc.201900938
Advanced Synthesis & Catalysis
Scheme 1. a) Viable 5-endo-trig radical cyclizations in N-substituted enamide, b) unviable 5-endo-trig radical
cyclizations in N-substituted enamine and c) transformation of unviable to viable mode in present work
Secondly, there is a greater geometric constraint in
the transition state of the NH-enamine 8 than N-
substituted enamine 4 as the nitrogen atom in 8 is not
pre-substituted with any group or functionality acting
as a cyclization auxillary.[9b] Thirdly, a free NH-group
in an enamine can bind to a Cu(I)-catalyst to form an
inactive Cu(I)-NH complex[9d] causing the loss of
catalyst-redox activity essential to perform the radical
reactions.[10b] Despite all these challenges, a single
step synthesis of a NH-pyrrole from a NH-enamine is
advantageous over multisteps N-preprotection post
deprotection dependent protocols usually suffering
with the loss of the yields.[9c]
16,[12] functionalized materials,[13] and agrochemicals
12.[14] Carbonyl and NH-functionalities in a 3-
chloropyrrole unit are well-established centers for its
intra- and intermolecular chemical transformations to
obtain complex pyrroles and natural products,[2a-b,e-
f,11b,15]
agrochemicals,[14] medicines 17,[16] and
aromatic compounds.[3g] The β-chlorine atom
modulates the physical and biological properties of
the pyrrole moity, thus they find frequent applications
in SAR studies[17,1-2,11b,16] for drug development.[18,12]
This chlorine atom on a pyrrole ring is a center for
substitution[2g] and transition metal-catalyzed cross-
coupling[19] reactions, and acts as a reductively
removable blocking group for a regioselective
substitution on its adjacent position[20] to furnish
natural products, drugs and materials.
Our previous experiences with substrate-[10a] and
catalyst-controlled[10b] radical cyclization reactions
prompted us to investigate roles of enamine-
structures, radical initiators, additives and reaction
conditions in a “disfavored” 5-endo-mode of radical
cyclization in an enamine system. This led to a
discovery of an efficient approach to convert a
“disfavored mode 5 to a favored mode 9” of a 5-
endo-trig radical cyclization to form pyrrolidine
radical 10 which spontaneously converts to NH-
pyrrole 11 having a 4-halo-and the carbonyl
functionalities at 2- and 3-positions (Scheme 1). This
functionalized 3-chloro-NH-pyrrole unit of type 11 is
frequently encountered in several bioactive natural
products 12-13,[11,2e] (figure 1) pharmaceuticals 13-
A few methods to synthesize functionalized 3-
chloro-pyrroles are known.[21] They are not typically
general and suffer from the problems of non regio-
selectivity, over-halogenation, multi-steps synthesis,
low to moderate yield, high cost, inaccessibility of
starting materials and are mostly limited to the
synthesis of simple N-protected pyrroles.[21] Here we
report a first, single step, general and an efficient
cyclization protocol to access tri- and tetrasubstituted
multi-functionalized 3-chloro-NH-pyrroles in good to
high yields from cheaper and diversely accessible β-
haloalkyl-NH-enamines
using
environmentally
2
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10.1002/adsc.201900938
Advanced Synthesis & Catalysis
benign and cost-effective Cu(I)-catalyst via a novel
5−endo−trig radical cyclization in NH-enamine
systems.
(Table 1, entry1-4). Only the Cu(I)/PMDETA
complex could effectively retain its redox activity,
unaffected by deactivating NH-groups of the enamine
20a and/or pyrroles 21a formed during progress of
the radical reaction.[10b]
In order to reduce the catalyst loading, easily
accessible and cheap reducing agents AIBN and
ascorbic acid were chosen to regenerate the active
Cu(I)-catalyst from the inactive Cu(II)-complex
accumulated over the long reaction time[22] (Table 1,
entry3-4). However, a catalytic amount of AIBN (10
mol % to begin with) did not give satisfactory result.
Finally, by using one equivalent of AIBN from the
beginning of the reaction, the amount of the catalyst
CuCl/PMDETA was almost halved from 130 mol %
to 70 mol % and the time of the reaction was
dramatically reduced from 24 h to 6 h (Table 1,
entry-5). The slow rate of reaction in entry-3 as
compared to entry-5 was due to low solubility of
CuCl2/PMDETA in the reaction medium. The high
concentration of soluble and reactive IBN radicals
(produced on decomposition of AIBN) efficiently
reduced the CuCl2/PMDETA to CuCl/PMDETA
leading to higher solubility of the reaction mass. The
IBN radicals acted as soluble halogen carriers to
promote the HATRC reaction further.[22b] An attempt
to lower the catalyst loading using ascorbic acid-
Na2CO3 combination in ethanol by employing a
method reported in literature[22e-f] was ineffective due
to the heterogeneous nature of the reaction mass
(Table 1, entry-6). Reaction of enamine 20a (Table
1, entry-5) with CuCl/PMDETA (0.7 eq) and AIBN
(1 eq) in the presence of two equivalents of insoluble
NaCl salt prolonged the reaction time from 6 h to 8h,
suggests towards low solubility of the reaction mass
retarding the rate of reaction in entry 3-4,6 Table 1.
Easy to handle AIBN whose by-products were
volatile was selected for further study. Dropwise
addition of a solution of one equivalent of AIBN in
DCE took a longer time (8 h) for the completion of
the reaction. Further an attempt to lower the catalyst
loading gave inferior results even with higher amount
of AIBN (Table 1, entry-7). Although AIBN is a
well-known radical initiator, it has been reported to
be ineffective in the absence of Cu(I)-catalyst in the
HATRC of bromoacetamides,[22d] so was in this case
also (Table 1, entry-8).
Fig. 1 Some selective examples of functionalized 3-
chloro-NH-pyrrole unit occuring in natural products,
drug molecules, agrochemicals and their synthetic
intermediates
Results and Discussion
More reactive 2,2,2-trichloroethyl amines 19
(Scheme 2) than 2-monochloro- or 2,2,-dichloroethyl
amines were chosen to produce NH-enamine
precursors
20.
Aza-Michael
addition
of
1−phenyl−2,2,2−trichloroethyl amine 19a to dimethyl
acetylenedicarboxylate(DMAD) afforded dimethyl 2-
(2,2,2-trichloro-1-phenyl-ethylamino)fumerate 20a as
the representative precursor. The reactions of
enamine 20a were performed with redox active CuCl-
and CuCl2-[complexes with 2,2′−bipyridine (bpy),
The necessity of higher amount of the copper-
complex (Table 1, entry 3-4) might be due to
catalyst-deactivation via protonation of nitrogenous-
ligands by liberated HCl produced during the
dehydrohalogenations of pyrrolidine ring.[23] This
possibility was supported by the fact that the reaction
proceeded to completion even with a lower (40
mol %) catalyst loading in the presence of additional
bases pyridine and PMDETA to give the product 21a
(Table 1, entry 9-10). However, the use of only base
was rather detrimental to the enamine substrate 20a
(Table 1, entry-11) as several spots were obtained on
TLC plate. No cyclization product was formed on
TLC plate when the reaction of 20a was performed at
room temperature for 24 h (Table 1, entry-12).
tetramethylethylenediamine
(TMEDA),
pentamethyldiethylenetriamine (PMDETA) and
tris(2-pyridylmethyl)amine (TPMA) ligands[6a-b]],
Ni(OAc)3,
Mn/AcOH,
and
reductive
nBu3SnH/AIBN[7] radical initiators using various
solvents and additives under a nitrogen atmosphere
(Table 1) to explore the suitable catalytic system.
The reaction of enamine 20a with varying amounts
of CuCl (30-140 mol %) in 1,2-dichloroethane (DCE)
was first performed in the presence of bpy, TMEDA,
PMDETA and TPMA ligands at reflux under a
nitrogen atmosphere. PMDETA was the most
effective ligand in terms of the product yield (74 %)
3
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10.1002/adsc.201900938
Advanced Synthesis & Catalysis
Scheme 2. Synthesis of 3-chloro-NH-pyrroles 21 by Cu(I)/PMDETA-catalyzed 5-endo-trig radical cyclization-
aromatization of NH-enamines 20
Table 1. Optimization of reaction conditions for cyclization of 20aa
4
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10.1002/adsc.201900938
Advanced Synthesis & Catalysis
Radical initiator (mol eq)/Ligand
Solvent Time
20a (%) 21a (%)
Entry
(hrs) Recovered Isolated
yield
(mol eq)/Additive (mol eq)
1
2
CuCl(1.3)/bpy (1.3)
DCE
DCE
24
24
90
75
-
CuCl(1.3)/TMEDA (2.6)
15
3
4
5
6
CuCl(1.3)/PMDETA (1.3)
CuCl(1.4)/TPMA(1.4)
DCE
DCE
DCE
EtOH
24
24
6
-
-
74b
72b
84c
10b
CuCl(0.7)/PMDETA(0.7)/AIBN(1.0)
-
CuCl(0.7)/PMDETA(0.7)/Ascorbic
acid (1.0)/Na2CO3(1.5)
12
15d
7
8
CuCl(0.4)/PMDETA(0.4)/AIBN(2.0)
AIBN (1.0)
DCE
DCE
12
6
25
92
52
-
9
10
11
12
CuCl(0.4)/PMDETA(0.4)/Pyridine(1.0)
DCE
DCE
DCE
DCE
24
20
6d
-
-
-
65
74
--
CuCl(0.4)/PMDETA(0.4+0.5)/AIBN
(0.5)
PMDETA (1.0)
CuCl(0.7)/PMDETA(0.7)/AIBN (1.0)
24
90e
--
--
13
14
CuCl2(0.8)/PMDETA(0.8)/AIBN (1.2)
DCE
9
6
70
--
nBu3SnH(1.1)/AIBN (0.2)
benzene
10
-
15
CuCl(0.4)/PMDETA(0.4)/AIBN (1.0)
+ CuCl(0.3)/PMDETA(0.3)
DCE
7
80
16
17
Ni(30.0)/acetic acid(20.0)/NaOAc(3.0) i-PrOH
6
8
--
--
--d
--d
Mn(OAc)3.2H2O(4.0)
MeOH
a All the reactions were performed with 1 mmol of 20a at reflux temperature (except entry 6 at 60 °C &
entry 12 at RT) under N2 atmosphere. b Formation of insoluble reaction mass was observed. c Better
soluble than the reaction masses in entry 3-4. d Formation of inseparable decomposed side products. e No
product formation at room temperature, as observed on TLC plate.
Scheme 3. Fate of 5-endo-trig cyclization of 20a with reductive radical agent
5
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10.1002/adsc.201900938
Advanced Synthesis & Catalysis
CuCl-PMDETA-AIBN combination was found to be
more efficient catalyst system than CuCl2-PMDETA-
AIBN complex in terms of yield, catalyst loading and
reaction time (Table 1, entry 5 & 13).
trig radical cyclization of trichloroacetamides, a
kinetically
‘favored’
system,
to
2-
azabicyclo[3.3.1]nonane rings, was reported by
Bonjoch, Belderrain and co-workers[24c]. Thus, an
increase in quantity of AIBN and CuCl/PMDETA
(entry-5 table-1) in the cyclization of 20a is
reasonable due to two reasons. First, a very high
geometrical constraint in the occurrence of 5-endo
radical cyclization step of enamine 20a necessitates a
continuous regeneration of active Cu(I)-catalyst by
continuous supply of IBN radicals. Second, the Cu(I)-
catalyst performs the radical generation in enamine
20a and the double dehydrohalogenation reactions in
the 5-endo-trig product (pyrrolidine intermediate) to
give an aromatic product (Scheme 5) while
undergoing HCl-catalyst-deactivation.[6a-b,23,24]
Like Ikeda, Ishibashi and co-workers,[7a] we also
obtained a mixture containing major reduced starting
material 22 (Table 1, entry-14 and Scheme 3) when
20a was treated with nBu3SnH/AIBN by their general
reaction procedure reported in the literature[7a] for the
attempted 5-endo cyclization of enamine 4 (Scheme
1). No isolation of expected 5-endo trig cyclization
product 23 or its dimer 24 by column
chromatography of the crude product suggests a less
possibility for 5-endo radical cyclization for NH-
enamines 20 under reductive radical conditions.
The cyclization of enamine 20a was under taken
with two lots of the catalyst to understand its roles in
5-endo-cyclization and aromatization processes.
Reaction of 20a was performed first with catalytic 40
mol % CuCl/PMDETA at reflux for 2 hours,
followed by addition of a pre-prepared solution of 30
mol % CuCl/PMDETA in DCE into the reaction
mass at 50 °C (Table 1, entry-15) and then heating at
reflux for 5 hours. This afforded a better yield of the
product 21a than with 40 mol% catalyst along with
pyridine and PMDETA bases (Table 1, entry 9-10).
This comparison suggests 40 mol % catalyst performs
the 5-endo-trig HATRC reaction and remaining 30
mol % catalyst (using its internal tert-amine centers
in PMDETA ligands) performs the in situ
dehydrohalogenation reactions of the NH-pyrrolidine
intermediate to produce NH-pyrrole. Further,
PMDETA in coordination with CuCl, constitutes a
milder basic catalyst system suitable for sensitive
substrates like 20a (Table 1, entry 9-10, 15) where
free bases like PMDETA/pyridine decompose them.
Thus, use of additional 30 mol % CuCl/PMDETA
over 1 equivalent pyridine or 50 mol % PMDETA for
in-situ dehydrochlorinations of HATRC intermediate
to pyrrole ring was prefered.
30-40 mol % is a generally used catalytic amount
of Cu(I)-complex in the HATRC reactions in the
synthesis of halogenated O- and N-heterocycles.[10b,e-f]
The double dehydrohalogenations-isomerization of
these heterocycles to corresponding aromatic
compounds require an excess amount of strong base
(DBU 2.5 eq.) and longer reaction time (24 hrs)[10b] in
the next step of the synthesis protocols.[10b,e-f,,21c,g]
Advantageously, this Cu(I)/PMDETA-catalyst uses
overall lesser amount of PMDETA and lesser
reaction time (Table 1, entry-5) than required for the
aromatization of an isolated halogenated pyrrolidine
in the next aromatization reaction. Thus, it shortens
the synthetic operations and reaction time for,
otherwise a multi-step synthetic protocol.[10b,3g,,21c,g]
An increase in the amount of Cu(I)/tert-amine
catalyst over the catalytic 40 mol %, due to HCl-
mediated catalyst-deactivation, even with stronger
tetradentate TMPA ligand in the 5-endo cyclization
of α-halo-enamide systems to unsaturated γ-lactam, is
well-known.[24] Similarly, a high consumption of the
AIBN (50 mol %) in Cu(I)/TPMA-catalyzed 6-exo-
Cu(I)-catalyst is a cheap, recyclable, easily
available, easy to use and remove from the reaction
mass. In addition, it has unique in situ
dehydrohalogenation ability. Thus, this is preferable
over other transition metals,[25] 30 equivalents of
Ni/acetic acid/NaOAc[25a] or
4
equivalents of
where the
Mn(OAc)3.2H2O/methanol25b]
decomposition of enamine 20a was observed (Table
1, entry 16-17) under the reported procedure therein.
The use of very costly RuCl2(PPh3)3 more than 0.5
equivalent of radical precursor is least preferable in
view of bulk scale synthesis and industrial
applications.[25c-d]
After selecting CuCl as radical initiator, PMDETA
as ligand, AIBN as reducing agent and reflux as
reaction temperature, screening of solvents for the
cyclization of 20a was done at reflux to select the
most suitable solvent (Table 2). The reaction mixture
blackened in complexing solvent acetonitrile (Table
2, entry-2) against the gradual colour change in
chlorinated solvent DCE from green to orange to red
(Table 2, entry-1). Though the reaction was
observed to be complete in a slightly shorter time (5
h) due to better solubility of the copper-catalyst,[10b-c]
the very same solubility characteristic made the
removal of the copper complex difficult during work
up. This led to greater loss of the product (75 %).
Replacing DCE with non polar benzene lead to
incompletion of reaction due to insolubility of the
copper complex (Table 2, entry-3). Raising of
reaction temperature using a high boiling toluene
went in vain (Table 2, entry-4). The use of high
solublizing protic bio-solvent ethanol and DCE-
ethanol mixture lead to the decomposition of enamine
(Table 2, entry-5-6).
After having the optimized radical conditions (Table
1, entry-5), the conformational role of substituents
and functionalities of a NH-enamine system in the 5-
endo-trig radical cyclization was investigated by
comparing the radical reactions of α-substituted 20a
and α-unsubstituted 20n having an α′-ester group
attached to the radical acceptor C=C with that of
trichloroethyl enamine 28 and 33 having a α′-methyl
and α′-phenyl group, respectively under the usual
optimized reaction conditions for 12 h (Scheme 4).
6
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10.1002/adsc.201900938
Advanced Synthesis & Catalysis
Table 2.Screening of solvents in the cyclization of 20aa
Entry
Solvents
Reaction
20a (%)
21a (%)
Nature of reaction mass
Time (h) Recovered Isolated yield
1
2
DCE
MeCN
6
5
-
-
84
75
Initially soluble
Highly soluble
3
4
5
6
Benzeneb
Tolueneb
Ethanolb
24
24
5
16
10
-
58
60
10
12
Highly insoluble
Insoluble
Highly soluble
DCE/Ethanolb(4:1 v/v)
12
-
Soluble
aAll the reactions were performed with 1 mmol of 20a and with CuCl(0.7)/PMDETA(0.7)/AIBN (1.0) at reflux
temperature under N2 atmosphere. b Formation of decomposition side products was observed on TLC plate.
Scheme 4. Study of the conformational role of substituents and functionalities of NH-enamines in the
5-endo-trig radical cyclization process
7
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10.1002/adsc.201900938
Advanced Synthesis & Catalysis
Figure 2. Chemical structures and yields of 5-Endo-Trig radical cyclization products 21 of enamines 20 and
ORTEP diagrams of 3-chloro-NH-pyrrole 21f and 21j
No pyrrole moiety of type 32 could be isolated by
column chromatography of the crude product, formed
expectedly through dehydrochlorinations[26,10b] of
HATRC product 31. A trace of pyrrole 37 was
obtained on the purification of the crude product by
column chromatography whereas enamines 20a,n
underwent the cyclization smoothly.
A radical approaches an α-unfunctionalized double
bond above and directly behind the p-orbitals
generating great angle strain in the 5-endo-trig
transition state. An attached carbonyl group to this
double bond modifies this trajectory in accordance
with Baldwin’s approach vector analysis whereby the
radical approaches the double bond above and behind
the p-orbitals, but also away from the carbonyl group
resulting into the formation of a less strained 5-endo
transition state.[27] Thus, clearly in the absence of this
α′-ester group, generation of comparatively greater
angle strain in the 5-endo conformation 29 and 34
than 25 can be expected in these cases also. Further,
5-Endo
radical
cyclization
is
not
only
thermodynamically but also kinetically favored when
the transition state is stabilized by the delocalization
of the unpaired electrons, was theoretically
anticipated by Chatgilialoglu, Gimisis and co-
workers [8c] in enamides. Thus, easier formation of 5-
endo cyclic radical 26 than 30 and 35 might have
been further facilitated in the enamine 20n due to an
effective stabilization of the transition state 25 than
29 and 34 by relatively a stronger stabilizing
captodative effect (of type 27).[28] An attempt to
perform the 5-endo radical cyclization of cyclic NH-
enamine 38 under the optimized conditions failed to
deliver 39, although its structural analog aceto-
enamide is known to give 5-endo radical cyclization
product easily under same Cu(I)-catalyzed radical
conditions.[25c] This indicates towards no involvement
of a β-carbonyl group at C=C bond in the 5-endo
radical cyclization. This was further vindicated by the
smooth 5-endo-trig cyclization-aromatization of 20O
8
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10.1002/adsc.201900938
Advanced Synthesis & Catalysis
to mono-functionalized NH-pyrrole 21O under the
same reaction condition via less strained transition
state 40 and captodative stabilization 41due to the
presence of a carbonyl group at α-carbon (not at β-
carbon to the olefinic bond as in 28 and 38).
formation of the 5-endo products at higher
temperatures has been observed earlier.[29]
Further, participation of the α′-carbonyl group
attached to the C=C bond in the easing of the angle
strain in the 5-endo transition state 44 and its further
transformation to the cyclic radical 45 by kinetic
stabilization of the transition state through a stronger
stabilizing captodative effect[28] might be reason for
successful cyclization of all enamines 20a-q as
observed in Scheme 4.
After successful cyclization of enamine 20a under
the optimized condition (Table 1, entry-5), diversely
substituted and functionalized enamines 20b−q were
synthesized, their structures were established using
NMR, IR, HRMS and their stereochemistry was
confirmed by single crystal X-ray diffraction
spectroscopy of 20f (Fig. S1, refer SI). This
methodology was successfully extended to
2,2,2−trichloroethyl-NH-enamines 20b−q (Scheme
2) to obtain functionalized 3-chloro-NH-pyrroles
21b−q (Figure 2) in high yields with complete
regioselectivity. This method successfully cyclized
NH-enamine 20O-p containing an α′-ketone and α′-
ester group to 21O-p in good isolated yields in single
step. They are potential bioactive molecules like 12-
17 (fig 1).[11-18] The method is suitable for synthesis
of synthetic intermediate 15 for glycine site
antagonists,[12e] obtained simply by condensing
methyl amine (19, R1: Me) with ethyl 3-cyano-2-
oxopropanoate to give β-cyano-NH-enamine (20 R3:
CN) precursor and its subsequent 5-endo radical
cyclization (Scheme 2). The structures of 3-chloro-
NH-pyrroles 21a−q were established by 1H NMR, 13C
NMR, IR spectroscopy and mass spectrometry. The
formation of the 3-chloro-NH-pyrroles 21a-q was
further supported by single crystal X-ray diffraction
spectroscopy of the 2-thienyl derivative 21f and 2-(4-
methoxyphenyl) derivative 21j. The ORTEP
diagrams of 21f and 21j are shown in Figure 2.
No isolation of a 5-endo cyclization product 23
except reduced enamine 22 (Scheme 3) arising due
to nBu3SnH-mediated reduction of dichloroethyl-NH-
enamine radicals of type 43 before their 5-endo-trig
cyclization to 23 could occur, suggests very slow
occurrence of 5-endo-trig cyclization step (43 to 44).
Advantageously in Cu(I)-catalyzed HATRC, the
radical 43 abstracts readily and reversibly the
chlorine atom from CuCl2/PMDETA to regenerate
the active CuCl/PMDETA and enamine 20 which,
with longer life time, could attempt repeatedly in 5-
endo-trig cyclization step to eventually give 45. Thus,
CuCl2-complex prevents wasteful reduction of
enamines 20, was equally important in the cyclization
of such geometrically constraints systems. It was
therefore concluded that the presence of an α′-
carbonyl group on the radical acceptor alkenic bond,
high reaction temperature and the reversible CuI-CuII
catalyst system might have contributed in realizing
the 5-endo cyclization in these geometrically
constraint enamines 20a-q to form the 5-endo
cyclization radical 45 exclusively.
The captodative stabilization in the radical
intermediate 45 (Scheme 5) might also promote the
reaction by reducing the reversibility of the 5-endo-
cyclization product. At the same time, it may also
reduce the reactivity of the radical in abstracting a
chlorine atom from CuCl2/PMDETA complex in the
next step leading to the formation of α-
chloropyrrolidine intermediate 46. This would result
in accumulation of the CuCl2/PMDETA complex and
disruption of the catalytic cycle. Thus, the role of
AIBN appears to restore the catalytic cycle by
continuously reducing CuCl2/PMDETA to the active
CuCl2/PMDETAcatalyst and promote the formation
of HATRC product 46.[22b]
Mechanistic Study
A plausible mechanism involving the 5-endo-trig
cyclization of 2,2-dichloroethyl-NH-enamine radical
43 (Scheme 5) to α-pyrrolidine radical intermediate
45 and subsequent chlorine atom abstraction from
Cu(II)Cl2/PMDETA to form mainly the α-
chloropyrrolidine intermediate 46 followed by
copper/ligand-promoted
successive
This α-chloropyrrolidine 46 was expected to
spontaneously eliminate a molecule of HCl to form
the pyrroline intermediate 47 due to basic
Cu(I/II)/PMDETA complex as reported by Stevens et
al.[26] However, when the reaction of 20a under the
optimized reaction condition was intercepted after 4 h,
2 h before the completion of the reaction, no
pyrroline derivative (of type 47 or isopyrazole 48)
except the pyrrole 21a and the unreacted starting
dehydrochlorinations to 47-48 and isomerization by
concerted [1,5]-sigmatropic H-shift to aromatic 3-
chloro-NH-pyrroles 21 has been proposed.
No 4-exo cyclization product 42 except the 5-endo
1
cyclization product 21 was detected in the H NMR
of the crude products and isolated by the column
chromatography in the cyclization of the enamines
20a-q. It might be due to high ring strain and more
steric congestion in the 4-exo transition state.[8a,c] The
relatively high reaction temperature in the present
cyclization reactions (refluxing DCE) might have
enforced the equilibrating reaction conditions
material 20a
were obtained by column
chromatography of the crude product. Probably the
pyrroline 47 had high propensity to spontaneously
dehydrohalogenate and isomerize to pyrrole ring in
the presence of basic Cu(I/II)/PMDETA complex and
high reaction temperature condition.
arguably
towards
the
formation
of
the
thermodynamically controlled 5-endo cyclization
product 45 exclusively. The preference for the
9
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10.1002/adsc.201900938
Advanced Synthesis & Catalysis
Scheme 5. Plausible mechanism for 5-endo-trig radical cyclization-aromatization of NH-enamines 20
The precise mechanism for the transformation of
cyclic captodative radical 45 (Scheme 5) to pyrroline
47 occuring via either α-chloropyrrolidine
intermediate (path A) or carbocation-deprotonation
(Path B) or hydrogen atom abstraction (Path C) or
carbocation-addition (Path D) routes, might be
debatable. Cu(II)-mediated oxidation of an acyclic
captodative radical center bearing an NH and an ester
group, and subsequent addition of the anion of the
Cu(II) salt to the corresponding carbocation giving an
adduct is known.[30] In the present case also,
Cu(II)Cl2/PMDETA-complex produced in the first
step may oxidize radical 45 to carbocation 49 which
might reversibly combine with chloride ion of the
Cu(II)Cl2/PMDETA to give α-chloropyrrolidine
46(Path D) or might eliminate a proton to give
pyrroline 47(Path B) directly without involving α-
chloropyrrolidine intermediate 46(Path A), cannot be
ruled out entirely. However, in both of these
processes, the chlorine atom transfer from
CuCl2/PMDETA to the radical 45 and oxidation of 45
to carbocation 49 by single electron transfer to
CuCl2/PMDETA, appear to be slow probably due to
low solubility of the CuCl2/PMDETA complex in the
reaction medium. This was indicated by the reaction
of 20a with CuCl/PMDETA in the absence of AIBN
(Table 1, entry-3), where the reaction required long
time (24 h) and large amount of the catalyst (1.3 eq)
10
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10.1002/adsc.201900938
Advanced Synthesis & Catalysis
to complete the reaction. However, In the presence of
a reasonably good amount of AIBN used in the
present reactions (Table 1, entry-5), the chlorine
atom transfer mechanism (path A) appear to be
preferentially promoted. The high concentration of
soluble and more reactive IBN radicals would more
efficiently reduce the CuCl2/PMDETA to regenerate
the active soluble catalyst CuCl/PMDETA.
Presumably, an IBN radical might also serve as a
soluble halogen carrier in the chlorine atom transfer
step[22b] leading to the formation of the α-
chloropyrrolidine intermediate 46. Further due to
continuous consumption of the CuCl2/PMDETA by
the IBN radicals, the concentration of the former
would considerably decrease in the solution, thus
disfavoring the oxidation of the captodatively
stabilized radical 45 to the carbocationic intermediate
49. An attempt to cyclize enamine 20a with oxidizing
The captodative radical of type 45 might be
expected to disproportionate to a pyrroline of type 47
and a pyrrolidine of type 23, and dimerize to 2,2’-
bipyrrolidine (of type 24).[23,28c-d] However, in none of
the cyclization reactions of enamines 20 in the
present study, the conceivable products derived from
it was isolated or detected, thus ruling out this
possibility in the formation of 47 and 21 through
disproportionation route.
[32-33]
Attempts to intramolecularly
(Scheme S1)
and inter-molecularly (Scheme S2) trap the possible
captodative radical 45 and carbocation 49 with
internal alkene,[32-33]
external alkenes and an
alcohol[34] failed. No IBN-captodative radical coupled
product[34] (Scheme S2) was isolated or detected in
any of the cyclization reactions of 20a-q carried out
under the optimized conditions even though all these
experiments were performed in the presence of
CuCl2/PMDETA (1.5 eq) failed to give 21a. However, relatively excess amount of AIBN. Failure to trap
this cyclization reaction occured completely when
enamine 20a was heated at reflux with 0.8 equivalent
of CuCl2/PMDETA in the presence of 1.2 equivalent
of AIBN in the reaction mass (Table 1, entry-13).
This indicates that the Cu(I)/PMDETA complex is
an active catalyst for the present 5-endo-trig radical
cyclization and the extent of oxidation of the radical
45 to cation 49 due to Cu(II)/PMDETA complex
(Path B) appears to be insignificant.
captodative radical 45 and carbocation 49 may be
understood in terms of faster rate of the chlorine atom
transfer (path A) and hydrogen atom abstraction (path
C) or it could be also due to faster rate of its
oxidation-deprotonation (path B) in the (NH)amino
ester radicals due to basic nature of copper catalyst
(Table 1, entry-15) as compared to radical addition
to alkenes, coupling to IBN radicals and alcohol
addition to carbocation in the present case.
Further, the possibility of IBN radical-mediated
oxidation of captodatively stabilized radical 45 to the
carbocationic intermediate 49 followed by
deprotonation to 47 seems to be arguably less. In
nBu3SnH/AIBN-mediated 5-endo cyclization of
acetamides, Miranda and co-workers [31] reported that,
unlike peroxide radicals, an IBN-radical hardly
involves in the oxidation of a carbon radical and
subsequent deprotonation of the carbocation to form
an olefinic bond. Experimentally, upon treatment of a
deuterated NH-enamine (ND instead of NH in 20a)
under the optimized reaction conditions, HRMS of
the reaction mixture showed no m/z value
corresponding to Me2CDCN. Moreover, Cu(I)-
diamine/tri-amine ligand complex-mediated hydrogen
abstraction (oxidation) from the cyclic mono- and
dienes to give diene and benzene ring, respectively
has been noticed by parsons,[23] Clark[6b] and co-
workers also. It is further evident from experiments
(Table 1, entry-7,9-10 and 15), despite excess of
AIBN, enamine 20a did not undergo complete 5-endo
cyclization reaction and the reaction completed on
addition of pyridine and PMDETA bases or
CuCl/PMDETA catalyst to the same amount of
catalyst (0.4 equivalent) in each case. Furthermore, in
the absence of AIBN also, Cu(I)-complexes alone
were able to cyclize enamine 20a and aromatize the
pyrrolidine intermediate to pyrrole (Table 1, entry 3-
4). These experimental and literature evidences
suggest higher possiblity of Cu-PMDETA than IBN
radical mediated dehydrohalogenation (Path A) and
hydrogen atom abstraction (path C) reactions to 47,
although the involvement of IBN radicals in path C
cannot be completely ignored.
From the foregoing account, the conversion of
captodative radical 45 (Scheme 5) to the cationic
intermediate 49 appears less likely to occur in these
reactions. Even in the case of the reported Cu(I)-
catalyzed 5-endo cyclizations of haloenamides, only
the electron rich tertiary carbon-radicals, which are
prone to oxidation, have been reported to be oxidized
by Cu(II) species.[6a-b] For example, Hiemstra,
Speckamp and co-workers[36] reported that a carbon
radical center bonded to an amino group and an ester
group hardly oxidizes to carbocation in CuCl/bpy-
catalyzed radical reaction due to its captodative
stabilization, gives the pyrrolidine only via 5-exo
radical cyclization. Whereas, in the absence of an
ester group, the α-amino carbon radical undergoes
Cu(II)-mediated oxidation to a carbocation to give a
piperidine via 6-endo cationic cyclization. Due to
similarities in the structure of α-aminoester
captodative radicals 45 and Cu(I)-catalyzed reaction
conditions in the present study and this literature,[36]
the retention of radical character at the captodative
radical 45 is expected in the present case as well.
Thus, a mechanism involving a persistent 5-endo-
captodative
radical
and
subsequent
dehydrochlorinations of HATRC product (path A)
appears to be more favorable. However, the
intermediacy of carbocation due to oxidation of the
captodative radical by Cu(II) species (Path B)
followed by deprotonation to pyrroline could not be
ruled out completely.
CONCLUSION
11
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10.1002/adsc.201900938
Advanced Synthesis & Catalysis
by taking the sample 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, basic and neutral alumina
was used as the stationary phase, and n-hexane−ethyl
acetate mixtures were used as the mobile phase. Solvents
were evaporated on a rotary evaporator under reduced
pressure using an aspirator. N-(2,2,2-trichloro-1-
hydroxy)ethyl acetamide was obtained by condensation of
chloral hydrate and acetamide by a method reported in the
CuCl/PMDTA-complex acts as both a radical
initiator and a mild base, catalyzes 5-endo-trig radical
cyclization of NH-enamine precursors and doubly
dehydrohalogenates the 5-endo-pyrrolidine product in
single step to give polysubstituted and multi-
functionalized 3-chloro-NH-pyrroles with high
degree of functional groups tolerance and
regioselectivity. The success of the kinetically
‘disfavored’ 5−endo cyclization was attributed to the
availability of a radical acceptor α′-carbonyl group
bonded to olefinic bond (causing the formation a less
strained transition state and its further stabilization by
captodative effect), high reaction temperature, copper
(I)-catalyst homolysing the C-X bond and CuCl2-
complex prolonging the life time of radical precursor
suitable for slow 5-endo cyclization step. This
reaction experimentally proves that the 5-Endo
radical cyclization is not only thermodynamically but
also kinetically favored due to stabilization of the 5-
endo transition state by delocalization/captodative
stabilization of the unpaired electrons. A mechanism
through a preferentially cyclic captodative radical
over the carbocation has been anticipated. Transition
metals Ni and Mn, reductive and Irreversible
nBu3SnH or similar radical initiators, are ineffective
in the 5-endo cyclization of these geometrically
constraint systems due to a very slow cyclization step
leading to reductive dehalogenation of amine
precursor. Besides keto and ester groups, this method
can introduceother electron withdrawing groups
particularly at α-positions in NH-pyrrole ring by
virtue of their participation in captodative radical
stabilizationof a carbon radicalalong with a NH
group[28] (Scheme 4). CF2Br or CFBr2 unit in starting
material trihaloamines is a potential source for the
preparation of 3-fluoropyrroles. This shows method
has wider substrate scope. This method further
provides a synergistic approach to attain a cyclisable
5-endo transition state in other geometrically
constraint or partially successful vinylic systems in
the literature,[8a] by their structural modifications
while employing reversible redox active transition
metal catalysts under suitable reaction conditions.
With halogens, NH and carbonyl functionalities, such
pyrroles are valuable source for halogen effect[10e]
and SAR studies, halogen based organometallic
reactions besides functional group elaborations
towards bioactive and pharmaceutically important
molecules.
literature.[37] Ethyl acetopyruvate
was prepared by
condensation of acetone and diethyl oxalate.[38]Dimethyl
acetylenedicarboxylate (DMAD), para-toluene sulphonic
acid monohydrate (PTSA) and AIBN was commercially
available and used as received. THF was dried over KOH
pellets overnight, distilled over and stored over sodium
wires. Benzene was distilled and stored over sodium wires.
DCE was dried by distilling over anhydrous P2O5. The
commercial nitrogen gas was used after passing
successively through traps containing solutions of alkaline
anthraquinone-sodium dithionite, alkaline pyrogallol, conc.
H2SO4 and KOH pellets. Nitrogen atmosphere was created
by Schlenk technique in all the experiments carried out
under a nitrogen atmosphere.
1.2 Preparation of starting materials
1.2.1.
N-(1-substituted-2,2,2-trichloroethyl)
acetamides 18a-f
N-(1-substituted-2,2,2-trichloroethyl)acetamides18a-f
(Table S1) were synthesized using an one pot strategy.
Simple chlorination of N-(2,2,2-trichloro-1-hydroxy)ethyl
acetamide,[39] subsequent dehydrochlorination of N-
(1,2,2,2-tetrachloroethyl)acetamide
to
N-
acetylchloralimine[40] and addition of Grignard reagents[41]
furnished acetamides 18a-f.
General procedure: To a stirred suspension of N-(2,2,2-
trichloro-1-hydroxy)ethyl acetamide (4.13 g, 20 mmol) in
dry chloroform (100 mL), a suspension of phosphorus
pentachloride (4.165 g, 20 mmol) in dry chloroform (60
mL) was slowly added with stirring over a period of 10
min. The temperature of the reaction was carefully
controlled and was not allowed to rise above 20 ˚C. The
stirring was continued for another 30 min. During this time
the evolution of HCl and a progressive loss of turbidness
of the reaction mixture were perceptible and the mixture
became totally transparent. Then chloroform was removed
under reduced pressure at the optimum temperature to get
N-(1,2,2,2-tetrachloroethyl) acetamide as a white solid. To
this solid, dry THF (60 mL) was added, the reaction mass
was stirred to dissolve and cooled to 0 °C. To this solution
of the N-(1,2,2,2-tetrachloroethyl)acetamide in THF, NaH
(0.800 g, 60 % as dispersion in mineral oil, 20 mmol) was
added with stirring at 0 ˚C. The stirring was continued for
0.5 h at the same temperature to obtain N-acetylchloral
imine. This solution was cooled to -15 ˚C under a nitrogen
atmosphere and was added with a solution of Grignard
reagent (20 mmol, 1 equiv) [prepared by a reaction of
alkyl or aryl or heteroaryl bromides (20 mmol) with
magnesium (0. 486 g, 20 mmol) activated by iodine (cat.)
in THF by usual procedure]. The reaction mixture was
stirred for 2 h at the same temperature and then the
temperature was allowed to slowly rise to 0 ˚C. The
stirring was continued for further 30 min duration. The
reaction mixture was then quenched at 10 ˚C by addition of
a saturated aq. solution of NH4Cl (20 mL) slowly and
extracted with ethyl acetate (3x50 mL). The combined
organic layer was dried (anhydrous Na2SO4) and filtered.
The solvent from the filtrate was removed under reduced
pressure and the residue was purified by column
chromatography on a basic alumina column using a
mixture n-hexane/ethyl acetate (9:1, v/v) as the solvent for
EXPERIMENTAL SECTION
1.1. General Remarks. 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 DMSO
(D6) and CDCl3 with TMS as internal standard.
Multiplicities are indicated by the following abbreviations:
s (singlet), d (doublet), t (triplet), q (quartet), sext (sextet),
m (multiplet), dd (doublet doublet), ddd (doublet of a
doublet of adoublet). DEPT spectra were routinely
recorded to identify different types of carbons.
Massspectra were recorded on a high-resolution mass
spectrometer (ESI-TOF) in positive-ion mode. Melting
points were determined on an electrically heated apparatus
elution
to
obtain
N-(1-substituted-2,2,2-
trichloroethyl)acetamides 18a-f in high yields (80-83 % ).
12
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10.1002/adsc.201900938
Advanced Synthesis & Catalysis
acetate in n-hexane (1%, v/v) as the solvent for elution
furnished the enamine 20h-n in 63-78 % yield.
1.2.2. 1-Substituted 2,2,2-trichloroethyl amines 19a-f:
Hydrolysis of 18a-f
(Z)-ethyl
2-((2,2,2-trichloroethyl)amino)but-2-enoate
2,2,2-Trichloroethyl amines 19a-f (Table S2) were
prepared by acid hydrolysis of N-(1-substituted-2,2,2-
trichloroethyl)acetamides 18a-f by using methods reported
in the literature[42] for acid-catalyzed hydrolysis of N-
substituted acetamide derivatives.
20O: It was prepared by acid-catalyzed condensation
reaction between 2,2,2-trichloroethyl amine 19g (1.485 g,
10 mmol)of ethyl 2-oxobutanoate (1.30 g, 10 mmol) for 7
h in same manner as other enamines 20h-n.
(Z)-1-phenyl-2-(2,2,2-trichloroethylamino)but-2-en-1-
one 20p: It was prepared by acid-catalyzed condensation
reaction between 2,2,2-trichloroethyl amine 19g (1.485 g,
10 mmol)of 1-phenylbutane-1,2-dione (1.62 g, 10 mmol)
for 8 h in same manner as other enamines 20h-n.
General procedure: A mixture of N-(1-substituted-2,2,2-
trichloroethyl)acetamide 18 (10 mmol), 5N H2SO4 (or 4N
HCl in the case of 18c) (50 mL) and methanol (50 mL)
was heated at reflux. After completion of the reaction as
indicated by disappearance of the starting acetamide on
TLC monitoring (8-16 h), the reaction mixture was
allowed to cool to room temperature (25-30 ˚C). It was
washed with benzene (2x20 mL) to remove any organic
residue. The aqueous phase was cooled at 0 ˚C and NaOH
(aq. 2N) was added to it with stirring. The solution became
gradually turbid in this process. The addition of NaOH
solution was stopped when the pH of the turbid suspension
rose to 9-10. The suspension was further stirred for 15 min
and extracted with ethyl acetate (3x30 mL). The combined
extract was dried (anhydrous Na2SO4), filtered and
evaporated under reduced pressure to obtain 1-substituted
2,2,2-trichloroethylamines 19a-f in good yield (66-81 %).
The amines were directly used in the next step without
further purification.
2-(2,2,2-Trichloro-1-phenylethoxy)naphthalene-1,4-
dione 20q:This was prepared by a procedure reported in
the literature with a slight modification.[42, 4c] A mixture of
2-bromo-1,4-naphthoquinone (10 mmol), 2,2,2-trichloro-1-
phenylamine 19a, (12 mmol) and Na2CO3 (15 mmol) in
abs. EtOH (40 mL) was stirred at 40-45 °C for 14 h. The
resulting mixture was filtered and the filtrate was removed
under reduced pressure and water (100 mL) was added to
the residual mass. The resulting suspension was extracted
with ethylacetate (2×50 mL) and the combined solvent
extract was washed with brine (2×20 mL), dried (Na2SO4),
filtered and evaporated under reduced pressure.
Purification of the residual mass by column
chromatography on a small pad of neutral alumina using n-
hexane/ethyl acetate mixture (90:10 %, v/v) afforded the
pure enamine 20q.
This previously known 2,2,2-trichloroethylamine 19g was
prepared by reduction of trichloroacetonitrile with LiAlH4
according to a method reported as reported in our previous
article.[10b]
(Z)-4-(2,2,2-Trichloroethylamino)pent-3-en-2-one 28: It
was prepared by acid-catalyzed condensation reaction
between 2,2,2-trichloroethyl amine 19g (1.485 g, 10
mmol)of acetyl acetone (1.002 g, 1.02 mL, 10 mmol) for 8
h in same manner as other enamines 20h-n.
1.2.3. Preparation of N-2,2,2-trichloroethylenamines
20a-g
The previously unknown enamines 20a-g (Table S3)were
prepared by Michael addition of trichloroethyl amines 19
to DMAD following a procedure reported in the literature
with slight modification.[4e]
(Z)-Ethyl
3-phenyl-3-((2,2,2-trichloroethyl)amino)
acrylate33: It was prepared by acid-catalyzed
condensation reaction between trichloroethyl amine 2g
(1.485 g, 10 mmol)and ethyl 3-oxo-3-phenylpropanoate
(1.92 g, 10 mmol) for 8 h in same manner as other
enamines 20h-n.
General procedure:
A
solution
of the 2,2,2-
trichloroethylamine 19 (10 mmol) and dimethyl
acetylenedicarboxylate (DMAD) (1.23 mL, 1.421 g, 10
mmol) in THF was stirred at room temperature (25-30 ˚C)
for 6-8 h. After the completion of the reactions as indicated
by TLC, the THF was evaporated under reduced pressure
and the residual mass was purified by column
chromatography using basic alumina column. The column
was run through initially by n-hexane then by a solution of
ethyl acetate in n-hexane (1%, v:v). The enamines 20a-g
were obtained in 72-80 % yields as mentioned in Table S3.
(Z)-4-(2,2,2-Trichloroethylamino)pent-3-en-2-one 38: It
was prepared by acid-catalyzed condensation reaction
between 2,2,2-trichloroethyl amine 19g (1.485 g, 10
mmol)of 3-acetyl-dihydrofuran-2(3H)-one (1.28 g, 10
mmol) for 8 h in same manner as other enamines 20h-n.
(Z)-Allyl
4-oxo-2-(2,2,2-trichloro-1-(4-chlorophenyl)
ethylamino)pent-2-enoate50: It was also prepared by
acid-catalyzed condensation reaction between amine 19d
(2.590 g, 10 mmol) and allyl acetopyruvate (1.72 g, 10
1.2.4. Preparation of N-(2,2,2-trichloroethyl)enamines
20h-n derived from ethyl acetopyruvate
mmol) for
8
h
in same manner as other
enaminoketoesters20h-n under reflux condition in benzene
using Dean-Stork apparatus.
The previously unknown enamines 20h-n (Table S4)were
prepared by using a method reported in the literature,[4d] in
which similar enamines were prepared by acid-catalyzed
azeotopic condensation reaction of various 2,4-dioxoester
derivatives with non-chlorinated primary amines.
Cu(I)/PMDETA-catalyzed
5-endo
HATRC-
Aromatization of NH-enamines 20. General procedure:
A flame-dried two-neck round-bottom flask was charged
with CuCl (70 mg, 0.7 mmol) and degassed DCE (30 mL)
under a N2 atmosphere using Schlenk technique. PMDETA
(0.146 mL, 0.121g, 0.7 mmol) was injected to the
suspension and the suspension was stirred magnetically for
10 min. Next, the 2,2,2-trichloroethyl enamine 20a-q(1
mmol) and solid AIBN (0.137g, 1 mmol) were added. The
reaction mixture was degassed again by applying vacuum
and refilled with the N2 gas. The solution was then heated
at reflux with stirring. After completion of reaction (6-12
h) as indicated by TLC monitoring, the reaction mixture
was cooled and the solvent was evaporated. Ethyl acetate
(150 mL) was added to the residual mass and the resulting
solution was washed with brine (3x25 mL) till the color of
the solution became reddish or yellowish. The combined
aqueous layer was treated with ammonium chloride
General procedure:
trichloroethylamine
A
19
solution of the 2,2,2-
(10 mmol), ethyl
acetopyruvate(1.582 g, 10 mmol) and a catalytic amount of
PTSA (0.344 g, 2 mmol) in benzene was heated at reflux in
a Dean Stark apparatus. The progress of the reaction was
monitored by TLC as well as by 1H NMR of aliquots taken
from the reaction mixture from time to time. After
completion of the reaction (4-5 h), the reaction mixture
was cooled to room temperature (25-30 ˚C). The benzene
was evaporated under reduced pressure. The purification of
the residual mass on basic alumina column by running
through with n-hexane followed by a solution of ethyl
13
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10.1002/adsc.201900938
Advanced Synthesis & Catalysis
solution and extracted with ethyl acetate to ascertain that
there is no loss of the product into the aqueous layer along
with copper complexes. All the organic extract was
combined and dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated under reduced pressure and
the residual mass was purified by column chromatography
using neutral alumina column using a mixtures n-hexane/
ethyl acetate (9:1-8:2, v/v) as the solvents for elution. The
product thus obtained was further purified by
recrystallization from n-hexane-chloroform or n-hexane-
DCM to obtain the 2,3-difunctionalized 5-substituted 3-
chloropyrroles 21a-qin (50-84 %) good to high yields.
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Advanced Synthesis & Catalysis
FULL PAPER
β,β,β,-Trichloroethyl-NH-Enamine As Viable
System For 5-Endo-trig Radical Cyclization Via
Multifaceted CuI-CuII Redox Catalysis: Single
Step Synthesis of Multi-Functionalized NH-
pyrroles
Adv. Synth. Catal. Year, Volume, Page – Page
Ram N. Ram,a Sandhya Sadanandanb and
Dharmendra Kumar Gupta*a
17
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