Direct and Stereoselective Synthesis of Diversely Substituted 2,4-trans-(NH)-Pyrrolidines by Copper(I)-Catalyzed Radical Cyclization at Low Temperature

Article abstract of DOI:10.1002/adsc.201600844

This work describes a successful copper(I)-catalyzed radical cyclization of β-haloethylallylamines bearing an unprotected NH-group while retaining catalyst-redox activity. The cyclization occurs regio- and diastereoselectively at 0 °C and furnishes diversely substituted 1,3-trans-(NH)-pyrrolidines directly in high isolated yields. An involvement of the bulky copper complex in the cyclization step as the possible reason for the diastereoselectivity was proposed. Synthetic applications of the products in the preparation of useful 4-chloro-NH-pyrrole in a single step, has also been demonstrated. A quick, mild and general method involving simple addition of trichloroacetic acid/dimethyl sulfoxide (CCl₃CO₂H-DMSO) solution to readily accessible N-allylaldimines and ketimines tolerating acid-sensitive and highly deactivating substituents was developed to access the amine precursors. (Figure presented.).

Full text of DOI:10.1002/adsc.201600844

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DOI: 10.1002/adsc.201600844
Direct and Stereoselective Synthesis of Diversely Substituted
2,4-trans-(NH)-Pyrrolidines by Copper(I)-Catalyzed Radical
Cyclization at Low Temperature
Ram N. Rama and Dharmendra Kumar Guptaa,*
a
Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi – 110016, India
Fax : (+91)-11-2658-1102; phone: (+91)-11-2659-1501; e-mail: dkgiitd@gmail.com or cyz068237@chemistry.iitd.ac.in
Received: July 29, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600844.
Abstract: This work describes a successful copper(I)- general method involving simple addition of tri-
catalyzed radical cyclization of b-haloethylallyla- chloroacetic acid/dimethyl sulfoxide (CCl3CO2H-
mines bearing an unprotected NH-group while re- DMSO) solution to readily accessible N-allylaldi-
taining catalyst-redox activity. The cyclization occurs mines and ketimines tolerating acid-sensitive and
regio- and diastereoselectively at 08C and furnishes highly deactivating substituents was developed to
diversely substituted 1,3-trans-(NH)-pyrrolidines di- access the amine precursors.
rectly in high isolated yields. An involvement of the
bulky copper complex in the cyclization step as the
possible reason for the diastereoselectivity was pro- Keywords: copper(I) chloride; diastereoselectivity;
posed. Synthetic applications of the products in the pentamethyldiethylenetriamine (PMDETA); 1,3-
preparation of useful 4-chloro-NH-pyrrole in a single trans-(NH)-pyrrolidines;
2,2,2-trichloroethylallyl-
step, has also been demonstrated. A quick, mild and NH-amines
Introduction
pyrrolidines using alkenyl NH-amine substrates di-
rectly.
The radical cyclization reaction is an attractive and
Over the years, Cu(I)-catalyzed halogen atom
milder route for the synthesis of a variety of pyrroli- transfer radical cyclization (ATRC) of unsaturated
dines.[1] A few reports describe the successful stereo- polyhalomethyl substrates has emerged as a mild, cat-
selective synthesis of NH-pyrrolidines directly from alytic, cost-effective and high yielding strategy to syn-
the NH-substrates,[2] bypassing N-protection–depro- thesize various heterocycles.[1,10] It possesses a high
tection routes.[3] The chair-like transition-state model degree of functional group tolerance[10a,11] and pre-
proposed by Beckwith and Houk successfully predicts serves all the halogen atoms in the cyclization prod-
the stereochemistry in pyrrolidine rings also where ucts which is useful in performing halogen-dependent
the conformational and the steric factors in the cycliz- transformations. Activators regenerated by the elec-
ing 3-azaalkenyl radical govern the stereochemical tron transfer (ARGET)[12] process using reducing
outcomes in the products.[4] However, intramolecular agents (AIBN, ascorbic acid, etc)[12b,c] and a platinum
hydrogen bonding,[5] pre-existing chiral auxillaries[6] electrode surface (eATRC),[12a] represent a powerful
and complexing agent (Lewis acid additives)[7] control technique in ATRC to reduce the catalyst loading
the cyclization step and perturb these usual stereo- drastically even below 1 mol%. Various nitrogenous
chemical outcomes. Unlike complexing Lewis acids, ligands, in the complexation with Cu(I) halides, en-
where an additional radical initiator is required,[7] the hance the catalytic efficiency and regioselectivity in
redox-active copper(I) catalyst[8] is both a radical ini- the cyclization step.[1] Despite versatility, to date,
tiator[8a,b] and a complexing agent[8c,d] to the nitrogen Cu(I)-catalyzed radical cyclization of the 3-aza-5-hex-
atom in the transition state leading to a stereoselective enyl moiety bearing a free NH-group and its stereo-
formation of the final product.[8d] The Cu(I) catalyst chemical outcome is not documented so far.[1,10] It
can complex with the NH-group of the secondary could be possibly for NH-species to bind to Cu(I)-cat-
amines[9] but to date, its complexing property has not alyst to form an inactive copper-amine complex which
been exploited in the stereoselective synthesis of NH- loses the redox activity that is essential to perform
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the radical reaction.[11b] Thus, Cu(I)-catalyzed ATRC
in the synthesis of pyrrolidines was confined to the
cyclization of a few alkenylamine precursors whose
nitrogen was pre-protected.[13,14] For example, Pinta-
uer and co-workers[14] reported the synthesis of N-
protected pyrrolidine by CuCl/TPMA-catalyzed radi-
cal cyclization of diallylamine bearing a nitrogen pro-
tected with a 2,2,2-trifluoroacetyl group.
Our interest in the synthesis of polyhaloalkyl sub-
strates[15] and copper(I)-catalyzed ATRC[10c,f,i,15a,16] led
us to develop a mild and an efficient method for the
synthesis of sensitive b-haloethylalkenyl-NH-amines
2a–k (Scheme 1) followed by their Cu(I)-catalyzed
radical cyclization reaction to afford b-chloro-NH-
pyrrolidines 3a–k having 2,4-trans-selectivity almost
exclusively. Synthesis of the b-chloropyrrolidine ring
as a key structural unit continues to be of considera-
ble interest in recent times due to its presence in
many naturally occurring compounds[17] such as cyclo-
chlorotine,[17c] islanditoxin,[17d] and astins A–C (1),[17e]
pharmaceuticals[18] (2) (Figure 1) and materials.[19]
A
Figure 1. Chemical structures of some bioactive halogenat-
ed/functionalized pyrrolidines and their derivatives.
b-chlorine atom modulates the biological property of
the pyrrolidine ring, which is vital to study structure-
activity relationships and thus drug design.[20] Inter-
and intramolecular substitution[21] reactions at these
b-chlorines give pyrrolidine-based pharmaceuticals
(3)[21a] and natural products (4).[21d] The dehalogena-
tion,[22] dehydrochlorination/aromatization[23] and
functional group transformations[24] of these b-chlor-
ines of the pyrrolidine rings (also chlorine atoms in
the side chain) furnish synthetically and pharmaceuti-
cally important molecules and natural products (5).
Furthermore, the unprotected NH-group in the pyrro-
lidine ring and functionalities (keto, ester and cyano)
in its side chain are the centers for further inter- and
intramolecular reactions to prepare natural products
(6 and 7)[25] and pharmaceuticals.[17a,b] An NH-group
and a side chain functionality together form chiral
auxiliaries and organocatalysts useful in asymmetric
synthesis.[26]
Despite these diverse synthetic applications, there
are few methods for the preparation of diversely sub-
stituted b-chlorinated pyrrolidines.[2d,e,27,23] Most of
these methods are applicable in the synthesis of N-
substituted b-chloropyrrolidines with less sensitive
Scheme 1. Synthesis of 1-substituted 2,2,2-trichloroethylallyl
NH-amines 2a–k and 3,3-dichloro-NH-pyrrolidines 3a–k.
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substituents and functional groups. One radical cycli- of unidentifiable decomposition products due to the
zation method[2d,e] realizes the synthesis of b-chloro- use of reflux conditions (Table 1, entry 3; Supporting
NH-pyrrolidines.[2e] However, it uses excess of Information, Figure S31). AIBN and ascorbic acid
Bu3SnH/AIBN as reagent and the purification of cy- mediated ARGET-ATRC[12b,c] is highly successful in
ACHTUNGTRENNUNGclization products was done under strong acidic condi- N-allyl-a-halo-amides, a highly activated precursor
tions, harmful to acid-sensitive groups.[2e] The product with a pre-protected nitrogen. However, in the cycli-
lost one halogen functionality useful in further halo- zation of constitutionally different 2a, a less active
gen-dependent transformations. Moreover, this haloalkyl precursor with free NH-group, the amount
method relied on b-haloethylallylamines as starting of CuCl/PMDETA (1 mol%, to begin with) could be
materials, however their preparation is still a methodo- changed up to 10 mol%, only with AIBN[12c] (Table 1,
logical challenge.[2e,28]
entry 4; Supporting Information, Figure S32). The
cyclization of 2a did not occur completely (85%)
using 10 mol% of CuCl2/PMDETA:ascorbic Acid/
Na2CO3(1/1:5/10) in AcOEt/EtOH (3:1) at 35–408C
even after 16 h,[12b] possibly due to lower solubility of
Results and Discussion
First, a mild and a general method for the synthesis of copper complexes (isolated yield 68%; Supporting In-
b-haloethylallyl-NH-amines was devised. Simple addi- formation, Figure S33) among other factors. The pres-
tion of CCl3CO2H-DMSO solution to the solution of ence of reactive NH-groups in 2a, and 3a and acidity
N-allylaldimine/ketimine 1a–g in DMSO under mild (also generated during the progress of the reaction)
conditions (40–508C) furnished 1-alkyl/aryl/heteroar- probably deactivated the Cu(I)/(II)-species. The sensi-
yl-2,2,2-trichloroethylallyl-NH-amine
2a–g tivity of both the precursor 2a and product 3a under
(Scheme 1). This quick reaction also tolerated the acidic and basic conditions particularly at higher tem-
acid-sensitive furyl and highly deactivating 4-nitro- perature, possibly led to the formation of some un-
phenyl substituents in aldimines 1d and 1f, respective- identifiable side products, complicating the purifica-
ly. The crucial Cu(I)-catalyzed ATRC reaction tion of 3a by column chromatography, leading to
was first performed with representative NH-substrate a low yield of 3a. Interestingly, the cyclization reac-
2a (R1 =Ph) with varying amounts of CuCl (20 mol%, tion at relatively lower temperatures suppressed the
to begin with) using commercially available ligands decomposition considerably, and the product yield
2,2’-bipyridine (bpy), tetramethylethylenediamine was also marginally increased (Table 1, entries 5 and
(TMEDA),
pentamethyldiethylenetriamine 6), although a longer reaction time was required to
1
(PMDETA) in DCE at reflux under a nitrogen at- complete this reaction. The H NMR spectrum of the
mosphere. The progress of the reactions was moni- crude products showed the occurrence of a cleaner re-
tored by TLC and further confirmed by H NMR of action and the presence of almost a single diastereo-
1
the aliquots taken directly from the reaction mass.
mer. An increase in the yield, cleanliness and diaster-
PMDETA was the most effective ligand[15a,29] in eoselctivity of the cyclization products due to lower-
terms of the product yield and amount of the catalyst ing of the reaction temperature, was also observed re-
1
loading (Table 1, entries 1–3). H NMR analysis of the cently in the Cu(I)/PMDETA-promoted cyclization of
crude product showed formation of a major single b-haloethyl allyl sulfides also.[15a] The reaction in the
diastereomer (nearly 92%) along with small amounts coordinating solvent acetonitrile (MeCN) at 08C
Table 1. Optimization of the reaction conditions for Cu(I)-catalyzed radical cyclizations of representative 1-phenyl-2,2,2-tri-
chloroethyl allyl amine 2a under different conditions.[a]
Entry CuCl [mol%]
Ligand (mol%)
Solvent Temp.
Time [h] 3a Yield [%][b] 2a Recovered [%][b]
1
2
3
4
5
6
7
8
9
10
100
100
40
10
40
40
40
30
40
bpy (100)
TMEDA (200)
PMDETA (40)
DCE
DCE
DCE
reflux
reflux
reflux
reflux
258C
08C
6[c]
4[c]
3[c]
6[c]
5[c]
6
55
71
74
75
78
81
83
79
65
82
35
–
–
–
–
–
–
5
25
–
PMDETA(10)/AIBN(25) DCE
PMDETA (40)
PMDETA (40)
PMDETA (40)
PMDETA (30)
PMDETA (40)
TPMA (40)
DCE
DCE
MeCN
MeCN
MeCN
MeCN
08C
08C
5
12
À108C 12
40
08C
5
[a]
[b]
[c]
All the reactions were performed with 1 mmol of 2a under a nitrogen atmosphere.
Isolated yield after purification by column chromatography on basic alumina.
1
The presence of unidentifiable side products was seen in the H NMR spectra of the crude products.
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proved to be slightly better than the reaction in 1,2-
dichloroethane (DCE) in terms of product yield
(83%) and reaction time (5 h) (Table 1, entry 7; Sup-
porting Information, Figure S34). It might be due to
the relatively higher solubility of the copper complex
in acetonitrile.[15a,29] However, neither with lower cata-
lyst loading (30 mol%) nor at À108C, could the reac-
tion proceed to completion even after a longer reac-
tion time of 12 h (Table 1, entries 8 and 9). The reac-
tion of precursor 2a with TPMA [tris(2-pyridylme-
thyl)amine] in acetonitrile at 08C was found to be
equally effective in terms of yield of 3a, diastereose-
lectivity and reaction time (Table 1, entry 10).
Scheme 2. Tosylation of NH-pyrrolidines 3a, b, h, k.
Thus, 40 mol% CuCl/PMDETA (1:1 mol ratio) in diagram of pyrrolidine 4a (Figure 2) showed 1,3-trans
acetonitrile at 08C (Table 1, entry 7) were found to be geometry of 1-phenyl and chloromethyl substituents
the best optimized reaction conditions for ATRC of in the NH-pyrrolidine 3a.
2a in terms of product yield, cost of the ligand,
Subsequently NH-precursors 2b–g (Scheme 1,
amount of the catalyst, reaction time, cleanliness and Table 2) were successfully cyclized under the opti-
diastereoselectivity of the reaction. Purification of the mized conditions. However, the side chain functional-
crude product (Table 1, entry 3) by column chroma- ized NH-substrates 2h–j (Scheme 1, Table 2) and cy-
tography on basic alumina afforded a major product clohex-2-ene NH-amine 2k were less reactive than
3a, the common product in Table 1, entries 1–10 and 2a–g and required 60 mol% of the catalyst for com-
a trace amount of minor cyclized product 3a’ whose pletion in comparable reaction times. In all the cases,
NOESY spectrum showed it to be 2,4-cis-NH-pyrroli- the radical cyclization step was observed to be highly
dine (Supporting Information, Figure S37).
regio- and diastereoselective as only a single diaste-
1
Thus, the stereochemistry of major isolated NH- reomer could be detected by H NMR of the crude
pyrrolidine 3a was expected to be 1,3-trans. Determi- product and column chromatographic isolation. The
nation of the stereochemistry of the major product 3a amounts of the minor 2,4-cis-isomers were perhaps
1
by NOE or NOESY-spectroscopy was not unambigu- too little to be detected in the H NMR of the crude
ous because the relevant proton signals were not well products. The structures of all NH-pyrrolidines 3a–k
1
separated. Alternatively, its stereochemistry was con- were supported by H NMR, 13C NMR, IR spectros-
firmed from an X-ray single crystal structure analysis copy and mass spectrometry. The interpretation of
of its N-tosylpyrrolidine 4a (Scheme 2). The ORTEP 1H NMR and 13C NMR was further supported by
Figure 2. ORTEP diagram of N-tosylpyrrolidines a) 4a, and b) 4h.
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Table 2. Preparation of 1-substituted 2,2,2-trichloroethyl allyl NH-amines 2a–k and 3,3-dichloro-NH-pyrrolidines 3a–k.
En-
try
2,2,2-Trichloroethyl allyl NH-amine 2[a]
3,3-Dichloro-NH-pyrrolidine 3[b]
Structure
Yield [%]
Time [h]
1
Stereochemistry
Yield [%]
Time [h]
5
1
2a
77
3a
83
2
3
4
5
6
2b
2c
2d
2e
2f
80
76
68
78
52
1
1
1
1
1
3b
3c
3d
3e
3f
84
80
83
81
79
5
5
6
6
5
7
2g
2h
2i
60
76
83
80
76
1
3g
3h
3i
85
87
82
85
84
5
8
24
4
7
9
8
10
2j
5
3j
6
11
2k
6
3k
10
[a]
The reactions were performed with 10 mmol of the aldimines/ketimine 1a–g, Michael acceptors 1h–j and trichloroethyl-
ACHTUNGTRENNUNGamine 1k.
The reactions were performed with 40 mol% (or 60 mol% in the case of 2h–k) of CuCl/PMDETA and 1 mmol of 2a–k in
acetonitrile at 08C under a nitrogen atmosphere. The products 2 and 3 were purified by column chromatography using
neutral and basic alumina, respectively.
[b]
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HSQC spectra (Supporting Information, Figure S40 chair-equatorial conformations.[4b] Another chair-
for NH-pyrrolidines 3a and Figure S59 for 3h) and equatorial conformation (C) facing an 1,3-axial inter-
a COSY spectrum (Supporting Information, Fig- action (A1,3 strain) between bulky axial copper com-
ure S60 for 3h). The spectral features of single diaste- plex and halogen atom, is energetically unfavourable.
reomers 3b–j were found to be almost similar to Thus it is hard to predict whether the chair-equatorial
those of 3a with substituent-dependent minor differ- (A) or boat-axial conformation (B) contributes the
ences and, therefore, the 1,3-trans geometry was as- most to the preferential formation of the 2,4-trans-
signed to these pyrrolidines also. Single crystal struc- NH-pyrrolidines at present. A complexing agent-
tures of N-tosyl products of two other NH-pyrroli- mediated conversion of one conformation to another
dines, 4b and functionalized NH-pyrrolidine 4h leading to stereoselective synthesis of pyrrolidines[7]
(ORTEP diagram, Figure 2b) further supported the and other heterocycles,[33] is not uncommon.
1,3-trans stereochemistry in NH-pyrrolidines 3a–j. A
We observed in our previous work that the 1-
method of determining the stereochemistry of NH- phenyl-b-trichloroethyl allyl ether undergoes CuCl/
pyrrolidines through tosylation products (N-tosylpyr- bpy-catalyzed radical cyclization to give correspond-
rolidines) has been employed in several similar halo- ing tetrahydrofuran product as a diastereomeric mix-
genated and functionalized NH-pyrrolidines where to- ture[10f,i] whereas its NH-analogue 2a, in the present
sylation occurs without affecting their chiral center- case, cyclizes stereoselectively to furnish the 2,4-trans-
s.[2c,e,21a] The ORTEP diagram of N-tosyl-fused pyrroli- diastereomer 3a under the same reaction conditions
dine 4k (Supporting Information, Figure S79) showed (Table 1, entry 1). This stereoselectivity in 3a resulted
cis-ring fusion in 3k.[30]
probably due to interaction of Cu (I/II) complex with
Mechanistically, the reaction followed a general the NH-group of the cyclizing radical in a rigid transi-
form of atom transfer radical cyclization (ATRC) tion state (Figure 3) whereas interaction between Cu
where an activator, the Cu(I)L complex reversibly ab- (I/II) complex with the ethereal oxygen of b-haloethyl
stracts a halogen atom from the halide substrates and allyl ether is unknown so far.[10f,i]
generates a radical along with a deactivator the X–
Cyclization of substrate 2a (1 mmol) in the pres-
Cu(II)L complex via a concerted inner-sphere elec- ence of the product 3a (0.5 mmol) under the opti-
tron transfer (ET). The deactivator then transfers mized reaction conditions (Table 1, entry 7) could not
a halogen atom to a 5-exo cyclized radical giving the proceed to its completion (nearly 60%) even after
final product and the activator.[1a, 8a,b,31] Amine ligands, 12 h, this indicates potential product-inhibition of the
solvents and other experimental conditions (tempera- copper catalyst. This catalyst-inhibition might have
tures) influence the redox properties of the copper(I) occurred with bpy and TMEDA more than PMDETA
catalyst which is strongly related to inner sphere ET and TPMA (ligand-effect) in the cyclization reaction
as reported by Pintauer and Matyjaszewski.[8b,32]
At present, the reason for the highly stereoselective
of 2a (Table 1) and 5a (Scheme 3).
Furthermore, an investigation of cyclization reac-
formation of 2,4-trans-diastereomers may only be tions on NH-substrates
5
(Scheme 3) and 7a
speculated (Figure 3, A–C) on the basis of the Beck- (Scheme 4) suggest substrate-inhibition of the copper
with–Houk transition state model.[4] The bulky catalyst also, which varies with the ligands. Even a sto-
copper-ligand complex is known to occupy preferably ichiometric amount of CuCl/bpy could not cyclize 5a
a sterically less demanding position in a chair-like (Scheme 3). The cyclization required CuCl/TMEDA
transition state[8d] thus the formation of a chair-equa- (100 mol%) or CuCl/PMDETA (40 mol%) at reflux
torial conformation (A) may be expected in the pres- in acetonitrile for 3 h and 2 h, respectively. The cycli-
ent case also. However, high A1,2-strain arising due to zation with CuCl/PMDETA (40 mol%) did not occur
steric interaction between bulky copper complex and at 08C under the optimized conditions. High catalyst
a-substituent in conformation (A) may lead to the loading (1 equiv.) of an even stronger complex (CuCl/
formation of an energetically more favourable boat-
axial conformation (B). This conformational change
may occur as the boat-axial conformations are ca.1 k-
calmolÀ1 higher in energy than their corresponding
Scheme 3. Synthesis of a,a’-unsubstituted NH-pyrrolidines
6a, b.
Figure 3. Probable transition states (A-C) in cyclization step
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spectrum of the crude sample also. These reactions
suggest that CuCl/PMDETA is an inefficient catalyst
to perform a radical generation at C–Cl centers in 3a
at 08C to promote further dimerization or other side
reactions of 3a, which might be a reason for the clean-
er cyclization reaction.
Synthetic application of these halogenated NH-pyr-
rolidines was demonstrated by converting one of the
3,3-dichloro-NH-pyrrolidines into a b-chloro-NH-pyr-
role, a unit present in many bioactive pyrroles.[23b] On
treatment with DBU,[10f] the chlorinated NH-pyrroli-
dine 3b (Scheme 5) underwent dehydrochlorination–
isomerization in a single step to give b-chloro-NH-
pyrrole 13.
Scheme 4. Effect of NH, N-Ts and O in Cu(I)-catalyzed rad-
ical cyclization reactions.
PMDETA), longer reaction time (12 h) and relatively
higher reaction temperature (30–358C) were required
for complete cyclization of 5a. It occurs probably due
to catalyst-deactivation by the NH-group present in
the precursors 5a and the product 6a formed during
course of the reaction.[11b]
An attempt to synthesize NH-pyrrolidine
8
Scheme 5. Aromatization of chlorinated NH-pyrrolidine 3b.
(Scheme 4) by CuCl/TPMA-catalyzed cascade-inter-
molecular radical addition of CCl4 to diallylamine 7a
(X=H) under the reported reaction conditions[14] and Conclusions
also by CuCl/PMDETA (40 mol%) in acetonitrile
(Scheme 4) at reflux was unsuccessful. On the other In conclusion, a mild, general, regio- and stereoselec-
hand the cyclization of N-protected N,N-diallylamine tive protocol for the synthesis of diversely substituted
7b with CCl4 is reported to be highly successful.[14] 2,4-trans-NH-pyrrolidines from unprotected b-halo-
This points towards deactivation of the copper cata-
ACHTUNGTRENeNUNG thyl NH-amines has been developed. This new pro-
lysts more with the increase in basicity of the NH- tocol illustrates a scarcely known catalyst-influenced
group of the substrate (7a as compared to 5a).[11b] N- stereoselectivity in the radical reaction in the synthe-
(Boc-protected) amine 10a underwent cyclization re- sis of NH-pyrrolidine moities. It is a direct route to
action even with a moderate catalyst (CuCl/bpy), access 2,4-trans-NH-pyrrolidines whereas most of
under similar radical conditions employed for the cyc- other radical methods produce 2,4-cis-NH-pyrroli-
lization of b-trichloroethyl ether 10b.[10f,i] This indi- dines from similar NH-substrates. NH-Pyrrolidine
cates that the protecting group in 7b and 10a inhibits rings having no substituent or alkyl, aryl, heteroaryl
the co-ordination of basic nitrogen to the copper cata- and halogen atoms in the pyrrolidine ring as well as
lyst and thus the catalyst retains its redox activity to ester, cyano, keto and halogen functionalities in the
cyclize the substrates similar to 10b. On the contrary, side chain are potential building blocks for the ad-
when the substrate/product has a coordinating NH- vanced synthesis of natural products and medicines.
functionality, a stronger multidentate ligand like These NH-pyrrolidines have considerable synthetic
PMDETA and TPMA is required to preserve the potential as illustrated by aromatizing one of them to
redox activity of the catalyst so as to perform its radi- the b-chloro-NH-pyrrole. A mild and general method
cal reaction smoothly. Selective formation of 2,4- for preparation of a-substituted b-haloethyl alkenyl
trans-diastereomer 3a at 08C, room temperature and amines from easily available aldimines and ketimine
at reflux indicates that there is very little effect of re- widens the scope of this radical methodology further.
action temperature in the determination of the stereo-
chemistry in the cyclization step.
Stirring of isolated NH-pyrrolidine 3a with CuCl/
Experimental Section
PMDETA (40 mol%) under the optimized conditions
(Table 1, entry 7) showed the absence of any other
1
General Information
product except 3a in its H NMR spectrum. Further-
more, a reaction of 3a with 1-hexene (1.2 equiv.)
IR spectra were recorded on an FT-IR spectrometer by
taking solid samples as KBr pellets and liquids as thin films
under the same optimized conditions, showed no for-
1
mation of any ATRA mono-adduct in the H NMR on KBr disks. NMR spectra were recorded on a 300 MHz
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FT NMR spectrometer in CDCl3 with TMS as internal stan-
dard. Multiplicities are indicated by the following abbrevia-
tions: s (singlet), d (doublet), t (triplet), q (quartet), m (mul-
tiplet) and dd (doublet of doublet). DEPT spectra were rou-
tinely recorded to identify different types of carbons. Mass
spectra were recorded on a high-resolution mass spectrome-
ter (ESI-TOF) in the 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 glass plates coated with TLC grade silica gel.
Iodine was used for visualizing the spots. For column chro-
matography, silica gel, basic and neutral alumina were 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 aspira-
tor. Acrylonitrile, methyl acrylate, chloral, para-toluenesul-
fonyl chloride, trichloroacetonitrile and K2CO3 were com-
mercially available and were used as received. Benzene and
THF were dried over KOH pellets overnight and distilled
and stored over sodium wire. DCE and acetonitrile were
dried by distilling over anhydrous P2O5. The commercial ni-
trogen gas was used after passing it successively through
traps containing solutions of alkaline anthraquinone-sodium
dithionite, alkaline pyrogallol, concentrated H2SO4 and
KOH pellets. Nitrogen atmospheres were created by
Schlenk technique in all the experiments carried out under
a nitrogen atmosphere.
dry THF (or MeOH in the case of the ester derivative 1i)
(30 mL) was stirred at room temperature (25–308C). After
completion of the reaction (1i: 4 h, 1j: 5 h) as indicated by
TLC, the solvent was removed on a rotavapor to obtain
almost pure products in quantitative yields. The crude prod-
ucts were further purified by column chromatography on
a small pad of neutral alumina using a mixture of ethyl ace-
tate in n-hexane (0–3%, v:v) as the solvent for elution to
obtain the functionalized acyclic precursor 2j and 2i. The
cyano derivative 2h was prepared as above by taking tert-
butyl alcohol (30 mL) as the solvent and triethylamine
(0.42 mL, 0.336 g, 3 mmol) as the catalyst and stirring the so-
lution at room temperature (25–308C) for 24 h. Purification
of the crude product by column chromatography on a small
pad of neutral alumina gave 2h. These precursors 2h–j were
obtained in high yields: 76–83%.
Preparation of N-(2,2,2-trichloroethyl)cyclohex-2-enyl
NH-amine 2k: The previously known trichloroethylamine
1k was obtained by reduction of trichloroacetonitrile with
LiAlH4 according to a method reported in the literature.[37]
The light red crude product (40% yield) was almost pure
and was used as such in the next step. A mixture of 2,2,2-tri-
chloroethylamine 1k (1.484 g, 10 mmol), cyclohexyl bromide
(1.485 g, 10 mmol) and K2CO3 (2.073 g, 1.5 mmol) in THF
(30 mL) was stirred at room temperature (25–308C) for 6 h.
The solvent was removed under reduced pressure. The re-
sidual mass thus obtained was purified by column chroma-
tography on a small pad of neutral alumina column using n-
hexane as the eluent to obtain 2,2,2-trichloroethyl cyclohex-
3-enyl NH-amine 2k as a colourless liquid; yield: 1.875 g
(82%).
Preparation of a-Substituted 2,2,2-Trichloroethyl
Allyl NH-Amines 2a–g
Preparation of a,a’-Unsubstituted N-2,2,2-
Trichloroethyl Allylic NH-Amines 5a, b
These were prepared by azeotropic condensation[38a] of chlo-
ral with allylic amines followed by reduction[38b] according to
the methods reported in the literatures with slight modifica-
tions.
General procedure: To a solution of freshly prepared aldi-
mine[34a] 1a–f (10 mmol) or the ketimine[34b] 1g (10 mmol) in
DMSO (10 mL) was added portionwise a solution of tri-
chloroacetic acid (3.268 g, 20 mmol) in DMSO (20 mL) at
408C (4.902 g, 30 mmol at 508C for 1f) with stirring during
0.5 h. The stirring was continued at the same temperature
and the progress of the reaction was monitored by TLC.
After the disappearance of the imine as indicated by TLC
(1 h), the solution was poured into ice-cold water and ex-
tracted with diethyl ether (for aliphatic products) or ethyl
acetate/n-hexane mixture (50:50 v:v, for aromatic deriva-
tives). The combined organic extract was washed with brine
(3ꢁ50 mL), dried (Na2SO4) and filtered. The solvent of the
filtrate was evaporated under reduced pressure. The crude
product thus obtained was purified by column chromatogra-
phy on a small pad of neutral alumina using n-hexane (or
mixture of ethyl acetate in n-hexane 0–3%, v/v in the case
of 2f) as the solvent for elution to obtain 2,2,2-trichloroethyl
allyl NH-amines 2a–g; yields: 52–80%.
General method: A solution of chloral (0.98 mL, 1.47 g,
10 mmol) and allylamine (0.75 mL, 0.570 g, 10 mmol) or cin-
namylamine (1.33 g, 10 mmol) in the benzene was heated at
reflux in a Dean–Stark apparatus for 3 or 4 h, respectively.
Benzene was removed under reduced pressure to obtain the
Schiff bases as orange viscous liquids which were used as
such in the next step. To the solution of the Schiff base in
absolute ethanol (30 mL), NaBH4 (0.756 g, 20 mmol) was
added portionwise at 108C and the reaction mixture stirred
until completion of the reaction as indicated by TLC moni-
toring (2 h). The ethanol was removed on a rotavapor, the
residue was taken up in water (10 mL) and extracted with
diethyl ether (3ꢁ50 mL). The combined organic extract was
dried (Na2SO4), filtered and evaporated. The residual mass
was purified by column chromatography on a small pad of
neutral alumina column using n-hexane as eluent to obtain
the pure products 5a (57%) and 5b (64%) as colourless liq-
uids.
Preparation of the functionalized trichloroethyl allyl NH-
amines 2h–j: Michael acceptors 1h, i[35] were obtained in
84% and 87% yields from previously known 2,4,4,4-tetra-
chlorobutanenitrile and methyl 2,4,4,4-tetrachlorobutano-
ACHTUNGTRENNUNG
ate,[14a] respectively on treatment with DBU (1 equivalent)
in benzene at 208C for 7–8 h followed by purification of the
crude products by column chromatography (silica gel). Use
of Et3N as a base to dehydrochlorinate similar ATRA ad-
ducts at reflux in toluene has been reported earlier also.[36]
General method: A solution of allylamine (0.78 mL,
0.57 g, 10 mmol) and the Michael acceptor 1j (10 mmol) in
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phy (on a small pad of alumina-neutral, n-hexane/EtOAc=
70:30 v/v) gave N-Boc pyrrolidine 11; yield: 0.317 g (86.8%).
tert-Butylcinnamyl (2,2,2-Trichloroethyl)carbamate
10a
A mixture of amine 5b (2.646 g, 10 mmol), Boc-anhydride
(2.4 g, 11 mmol) and triethylamine (1.4 mL, 10 mmol) in the
presence of catalytic amount of DMAP (40 mg) in acetoni-
trile (40 mL) was stirred at 508C for 6 h. After the disap-
pearance of starting material as indicated by TLC, acetoni-
trile was evaporated on a rotavapor. Diethyl ether (200 mL)
was added to the residue followed by its washing with brine
(50ꢁ2 mL), drying (Na2SO4), removal of solvent and purifi-
cation by column chromatography n-hexane/EtOAc (1%,
v:v) to furnish 10a; yield: 2.972 g, (82%).
Preparation of N-Tosylpyrrolidines 4a, 4b, 4h and 4k
These were prepared under further milder conditions using
a method reported in the literature[2e] for the tosylation of
b-chlorinated 1-substituted NH-pyrrolidines with slight
modification.
General method: A mixture of the NH-pyrrolidine 3a, 3b,
3h or 3k (1 mmol), tosyl chloride (0.190 g, 1 mmol) and
K2CO3 (0.207 g, 1.5 mmol) in dry THF was stirred at low
temperature (15–208C). After the disappearance of the
starting material as indicated by TLC (12 h for 3a, b and
14 h for 3h, k), the reaction mixture was concentrated on
a rotavapor and diluted with ethyl acetate. It was washed
with brine (2ꢁ20 mL), dried (Na2SO4) and filtered. The fil-
trate was evaporated and the crude solid thus obtained was
recrystalized from DCM/n-hexane to obtain the tosylated
products 4a, 4b, 4h and 4k.
Halogen Atom Transfer Radical Cyclization of 2,2,2-
Trichloroethyl Allyl Amines 2a–k and 5 Preparation
of the Chlorinated NH-Pyrrolidines 3a–k and 6
General method: A flame-dried two-neck round-bottom
flask was charged with CuCl (40 mg, 40 mol%) and de-
gassed acetonitrile (20 mL) under an N2 atmosphere using
Schlenk technique. The suspension was cooled to 08C and
PMDETA (0.070 g, 0.8 mL, 0.4 mmol) was injected into it.
The mixture was stirred for 10 min at the same temperature.
N-(2,2,2-Trichloroethyl)prop-2-en-1-amine 2a–g (1 mmol)
was added to this mixture and stirring was continued further
at the same temperature. After the disappearance of the
starting material as indicated by TLC monitoring and con-
firmed by 1H NMR (4–6 h) of the aliquots taken directly
from the reaction mass, the solvent was removed under re-
duced pressure. Diethyl ether or ethyl acetate (100 mL) was
added to the residual mass. The organic phase was washed
with brine (3ꢁ25 mL). [In the case of low yields, the com-
bined aqueous layer was treated with dilute aqueous ammo-
nia (20 mL) and extracted with same organic solvent to re-
cover the product from the aqueous layer went with copper
complex]. The combined organic layer was dried (Na2SO4),
filtered and concentrated under reduced pressure. The crude
product was purified by column chromatography on a small
basic alumina column using different mixture of ethyl ace-
tate in n-hexane (10–40%, v:v) as the solvent for elution.
The 1-substituted NH-pyrrolidines 3a–g were obtained in
high yields: 79–85%.
Dehydrochlorination of Pyrrolidine 3b: Chloro-2-(4-
methoxyphenyl)-4-methyl-1H-pyrrole 13
The reaction was performed by following a method reported
in our previous work[10f,i] in which 3,3-dichloro-4-chlorome-
thyltetrahydrofurans were aromatized by DBU. A solution
of the chlorinated pyrrolidine 3b (0.195 g, 1 mmol) and
DBU (0.38 mL, 2.5 mmol) in dry benzene (30 mL) was
heated at reflux. After completion of the reaction as indicat-
ed by disappearance of the starting material 3b on TLC
monitoring (24 h), ethyl acetate (100 mL) was added to the
reaction mixture. The solution was washed successively with
saturated solution of NH4Cl (20 mL) and with brine (2ꢁ
20 mL). The organic phase was dried (Na2SO4), filtered and
evaporated to obtain the crude product. The purification of
the crude product by column chromatography on a neutral
alumina column using a mixture of ethyl acetate in n-
hexane (10–20%, v:v) as the mobile phase gave the pure
product 13 as a yellow solid; yield: 0.101 g (46%).
CCDC 989262, CCDC 989264, and CCDC 989286 contain
the supplementary crystallographic data for compounds 4a,
4h and 4k, respectively. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
The side chain functionalized NH-pyrrolidines 3h–j and
fused pyrrolidine 3k were prepared from the corresponding
amines 2h–j and 2k purified as above, except that 60 mol%
each of CuCl and PMDETA were taken and the reaction
mixture was stirred at 08C for 6–10 h.
The unsubstituted NH-pyrrolidines 6a and 6b were pre-
pared from the corresponding amines 5a and 5b and purified
as above except that 40 mol% each of CuCl and PMDETA
were taken and the reaction mixture was heated under
reflux conditions for 2 h.
Acknowledgements
Financial assistance by CSIR, New Delhi, and IIT Delhi, is
gratefully acknowledged.
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Adv. Synth. Catal. 0000, 000, 0 – 0
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ÞÞ
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FULL PAPERS
12 Direct and Stereoselective Synthesis of Diversely
Substituted 2,4-trans-(NH)-Pyrrolidines by Copper(I)-
Catalyzed Radical Cyclization at Low Temperature
Adv. Synth. Catal. 2016, 358, 1 – 12
Ram N. Ram, Dharmendra Kumar Gupta*
Adv. Synth. Catal. 0000, 000, 0 – 0
12
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!