One-pot nitro-Mannich/hydroamination cascades for the direct synthesis of 2,5-disubstituted pyrroles using base and gold catalysis

Article abstract of DOI:10.1039/c1cc10751h

An efficient, easy to perform, one-pot reaction cascade for the synthesis of 2,5-disubstituted pyrroles from p-toluenesulfonyl protected imines and 4-nitrobut-1-yne under a combination of base and gold(iii) catalysis is reported.

Full text of DOI:10.1039/c1cc10751h

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COMMUNICATION
One-pot nitro-Mannich/hydroamination cascades for the direct synthesis
of 2,5-disubstituted pyrroles using base and gold catalysisw
David M. Barber,a Hitesh Sanganeeb and Darren J. Dixon*a
Received 8th February 2011, Accepted 15th February 2011
DOI: 10.1039/c1cc10751h
An efficient, easy to perform, one-pot reaction cascade for the
synthesis of 2,5-disubstituted pyrroles from p-toluenesulfonyl
protected imines and 4-nitrobut-1-yne under a combination of
base and gold(III) catalysis is reported.
The continuing drive for practically simple and efficient
organic transformations has resulted in the development of
many novel concepts and methodologies. Of particular
importance is the field of cascade reactions. These multi-step,
often multi-component reaction sequences offer a powerful
method to gain molecular complexity, whilst also improving
resource efficiency and significantly enhancing the overall
yields compared to their step-wise counterparts.1 As a result,
numerous elegant cascade sequences catalysed by single
chemical entities or by a compatible combination of catalysts
have been reported.2 To this end, our group recently reported a
one-pot, multi-step reaction cascade to 2-methylenepyrrolidines
from p-toluenesulfonyl protected imines and propargylated
carbon acids using a combination of base and copper ion
catalysis.3 As part of our ongoing research into reaction
cascades using the powerful and atom efficient nitro-Mannich
reaction,4 we envisaged that the combination of a nitro-Mannich
reaction followed by an alkyne hydroamination reaction5
would result in a highly efficient protocol for the direct
synthesis of pyrroles. Herein we report our findings.
Scheme 1 Concept of the nitro-Mannich/hydroamination cascade for
the direct synthesis of disubstituted pyrroles.
Having previous experience with nitro-Mannich and hydro-
amination reactions,3,4i,j we were confident of the reactivity
match between the nitro alkyne substrates and the imine
components. The challenge that remained was finding a
metal ion complex to facilitate the hydroamination reaction
whilst also complementing the base catalysed nitro-Mannich
reaction.
In our proposed concept (Scheme 1) it was envisaged that
the activated a-position of nitro alkyne substrate II would
undergo addition to a protected imine I under base catalysis,
leading to the formation of nitro-Mannich adduct III. This
adduct would then be poised to react with the pendant alkyne
functionality when activated by a suitably alkynophilic metal
ion complex, with the resulting protodemetallation forming
pyrrolidine VI. We further postulated that under the conditions
employed, exo/endo-alkene isomerisation3,6 was possible
and a subsequent elimination of the nitro group (reminiscent
of Barton–Zard pyrrole synthesis)7 would afford the desired
pyrrole product VIII.
The addition of nitro alkanes to p-toluenesulfonyl imines is
well-precedented.8 Relevant studies conducted using 1a and 2a
identified that methanol, used in conjuction with KOtBu
(10 mol%) at room temperature were optimal conditions for
this nitro-Mannich reaction, affording 3 in a high yield
as a mixture of diastereoiosmers (Table 1, entry 5, 90%,
dr = 83 : 17 syn : anti). For complete optimisation data see
ESIw for details.
The isolated nitro-Mannich adduct 3 (mixture of syn : anti
diastereoisomers) was then treated with a range of alkynophilic
metal ion complexes to determine which would facilitate the
cyclisation reaction (Table 2). Pleasingly, the use of gold(I) and
gold(III) catalysts9 in toluene, indeed resulted in the formation
of the desired pyrrole10 4a in 48–68% yield after 24 hours at
room temperature (entries 2–4). In contrast, the employment
a Department of Chemistry, Chemistry Research Laboratory,
University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
E-mail: Darren.Dixon@chem.ox.ac.uk
b AstraZeneca R&D Charnwood, Bakewell Road, Loughborough,
Leicestershire, LE11 5RH, UK
1
of Cu(OTf)Á /2 PhCH3 required much harsher reaction conditions
w Electronic supplementary information (ESI) available: See DOI:
10.1039/c1cc10751h
(refluxing toluene), affording pyrrole 4a in a significantly
Chem. Commun., 2011, 47, 4379–4381 4379
c
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Table 1 Nitro-Mannich optimisation studies
pyrrole 4a was produced. However, using stoichiometric
KOtBu (1.0 eq.) and AuCl3 (10 mol%), 4a was furnished in
a promising 26% yield (entry 2). This demonstrated that a
one-pot procedure was viable, however, in an effort to under-
stand the low yield of 4a, a control experiment was conducted.
4-Nitrobut-1-yne 2a was treated with KOtBu (10 mol%) and
AuCl3 (10 mol%) in methanol at room temperature. Analysis
of the reaction mixture showed that extensive polymerisation/
degradation of 2a had occurred. As a result, sequential addition
of KOtBu and AuCl3 was adopted over the simultaneous
addition method. Pleasingly, it was observed that addition of
KOtBu (10 mol%) to a solution of 1a and 2a in methanol at
room temperature, followed by AuCl3 (10 mol%) in methanol
at 70 1C significantly improved the reaction, with pyrrole 4a
being afforded in 81% yield (entry 5). Reduction of the
catalyst loading [AuCl3 (5 mol%)] was found to have no
significant detrimental effect on the reaction sequence, with
pyrrole 4a being afforded in 78% yield (entry 11).
Entry
Solvent
Base (10 mol%)
dra (syn : anti)
Yieldb (%)
1
2
3
4
5
6
7
8
9c
MeCN
CH2Cl2
PhCH3
THF
MeOH
MeOH
MeOH
MeOH
MeOH
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
Et3N
DBU
TMG
—
77 : 23
63 : 37
54 : 46
52 : 48
83 : 17
73 : 27
82 : 18
82 : 18
64 : 36
75
63
47
35
90
93
73
78
56
a
b
Determined by crude 1H NMR. Isolated yield after flash column
c
chromatography. Reaction time of 9 days.
With optimal conditions identified, a range of electron-rich
and electron-poor aromatic p-toluenesulfonyl protected imines
were used in the nitro-Mannich/hydroamination cascade using
the sequential addition of base and gold (Table 4). The cascade
reaction was found to tolerate ortho-, meta- and para-
methoxyphenyl derived imines (entries 2–4), furnishing the
desired disubstituted pyrroles in moderate to good yields after
heating in methanol at 70 1C for 36 hours. Several electron-
poor p-toluenesulfonyl protected imines were also found to be
good components for the reaction cascade. Ortho-, meta- and
para-substituted fluorophenyl derived imines were all tolerated
and afforded the desired pyrroles in moderate to good yields
(entries 6–8). The electron-withdrawing para-trifluoromethyl-
phenyl (entry 10) and ortho-nitrophenyl (entry 11) derived
imines both resulted in good yields (71 and 63%). A hetero-
aromatic 2-thienyl derived imine was also found to tolerate
the reaction sequence, affording pyrrole 4n in 71% yield
(entry 14). An analogous phenyl N-Boc protected imine
reduced 29% yield (entry 7). In light of the success of the base
catalysed nitro-Mannich reaction conducted in methanol, and,
from the point of view of developing a one-pot reaction
sequence, ideally we desired the hydroamination reaction to
proceed in the same solvent under basic conditions. Pleasingly,
employment of methanol with AuCl3 (entry 11) afforded
pyrrole 4a in 41% yield after 24 hours at room temperature.
Increasing the reaction time to 36 hours and the temperature
of the sealed reaction vial to 70 1C (entry 12) resulted in an
improved 58% yield of 4a. The addition of 10 mol% KOtBu
(entry 13) further increased the yield of 4a to 87%.
With success obtained in both the nitro-Mannich and
hydroamination reactions, our focus turned to the development
of
a
one-pot nitro-Mannich/hydroamination cascade
(Table 3). Initial studies were conducted with the simultaneous
addition of KOtBu and AuCl3 to imine 1a and 4-nitrobut-1-yne
2a (entries 1–3). With KOtBu (0.5 eq.) and AuCl3 (10 mol%)
in methanol at room temperature none of the desired
Table 2 Hydroamination catalyst identification and optimisation
Table 3 One-pot nitro-Mannich/hydroamination cascade optimisation
Temp/ Time/ Yielda
Entry [M] (10 mol%)
(i) Time/h (ii) Time/h Yielda (%)
Entry Solvent [M] (5 mol%)
1C
h
(%)
1b,c
2b,d
3b,e
4
AuCl3
AuCl3
AuCl3
AuCl3
AuCl3
AuCl3
24
1
2
4
4
4
4
4
4
4
4
—
—
—
4
36
36
36
36
36
36
36
0
26
21
51
81
48
48
57
41
0
1
PhCH3 Au(PPh3)Cl
PhCH3 Au(PPh3)Cl
PhCH3 Au[P(t-Bu)2(o-biphenyl)]Cl rt
rt
rt
48
24
24
24
6
24
24
24
24
24
24
36
36
0
48
59
68
35
65
29
32
58
64
41
58
87
2b
3b
4
PhCH3 AuCl3
PhCH3 AuCl3
PhCH3 AuCl3
rt
rt
rt
110
rt
rt
rt
rt
70
70
5
5
6f
6c
7
7f,g
8g
Au[P(t-Bu)2(o-biphenyl)]Cl
Au[P(t-Bu)2(o-biphenyl)]Cl
AuCl3
—
AuCl3
1
PhCH3 Cu(OTf)Á /2 PhCH3
8
9
10
11
12
13d
CH2Cl2 AuCl3
THF
9h
AuCl3
10
11i
MeCN AuCl3
MeOH AuCl3
MeOH AuCl3
MeOH AuCl3
78
a
b
Isolated yield after flash column chromatography. Simultaneous
addition of base and gold catalysts. KOtBu (0.5 eq.). KOtBu
c
d
a
b
Isolated yield after flash column chromatography. With AgOTf
(1.0 eq.). KOtBu (1.5 eq.). MeCN used as solvent. With AgOTf
e
f
g
(5 mol%). With KOtBu (25 mol%). With KOtBu (10 mol%).
c
d
h
(10 mol%). Et3N used as base (10 mol%). AuCl3 (5 mol%).
i
c
4380 Chem. Commun., 2011, 47, 4379–4381
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Table
cascade
4 Scope of the one-pot nitro-Mannich/hydroamination
Notes and references
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Yielda
(%)
Entry R1
R2 R3 (i) Time/h (ii) Time/h
4
1
Ph
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4
4
4
4
4
6
6
4
8
4
6
8
4
5
5
216
6
36
36
36
36
24
36
36
36
36
24
36
48
36
36
36
36
72
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
76
68
86
55
64
76
61
74
66
71
63
60
61
71
56
35
21
2
3
4
5
o-MeOC6H4
m-MeOC6H4
p-MeOC6H4
Piperonal
o-FC6H4
3 H.-F. Wang, T. Yang, P.-F. Xu and D. J. Dixon, Chem. Commun.,
2009, 3916.
6
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7
8
m-FC6H4
p-FC6H4
9
3,5-F2C6H3
p-CF3C6H4
o-NO2C6H4
10
11
12b
13
14
15
16c
17d
p-MeOOCC6H4 Ts
p-MeC6H4
2-Thienyl
Ph
Ph
Ph
Ts
Ts
Ns
Boc
Ts Me
a
b
Isolated yield after flash column chromatography. THF used as
c
d
co-solvent (3.0 mL). MeCN used as solvent. Au(PPh3)Cl (5 mol%)
and AgOTf (5 mol%).
yielded the desired pyrrole 4p, albeit in a lower 35% yield
(entry 16) and after a nitro-Mannich reaction time of 9 days.
To further extend the scope of our methodology, the methyl
substituted nitro alkyne 2b was investigated. Unfortunately,
using our previously optimised conditions none of the desired
pyrrole 4q was afforded. Accordingly, a selection of gold(I)
catalysts was screened to probe the reactivity of 2b towards the
nitro-Mannich/hydroamination cascade. Pleasingly, using
Au(PPh3)Cl (5 mol%) with AgOTf (5 mol%) was found to
facilitate the cascade reaction affording pyrrole 4q in an
unoptimised 21% yield after heating in methanol at 70 1C
for 72 hours (entry 17).
To highlight the synthetic potential of the pyrrole products
4, their deprotection was demonstrated. KOH in refluxing
methanol gave the deprotected pyrroles in good yields
(62–84%).11
In summary, we have developed an efficient, one-pot
synthesis of 2,5-disubstituted pyrroles starting from readily
available p-toluenesulfonyl protected imines and 4-nitrobut-1-
yne using a mutually compatible combination of KOtBu and
AuCl3. The reaction cascade is initiated through a base
catalysed nitro-Mannich reaction. Following a gold(III) catalysed
cyclisation, an exo/endo-alkene isomerisation and nitro group
elimination sequence afforded the desired disubstituted pyrroles
in good yields for a range of substituted aryl p-toluenesulfonyl
imines. Further work to probe the mechanism and extend this
methodology to other chemical entities is under investigation.
The results will be reported in due course.
10 For selected examples, see: (a) A. I. Siriwardana, K. K. A. D. S.
Kathriarachchi, I. Nakamura, I. D. Gridnev and Y. Yamamoto,
J. Am. Chem. Soc., 2004, 126, 13898; (b) S. Kamijo, C. Kanazawa
and Y. Yamamoto, J. Am. Chem. Soc., 2005, 127, 9260; (c) W. Liu,
H. Jiang and L. Huang, Org. Lett., 2010, 12, 312; (d) H.-Y. Wang,
D. S. Mueller, R. M. Sachwani, H. N. Londino and L. L. Anderson,
Org. Lett., 2010, 12, 2290; (e) D. J. Gorin, N. R. Davis and
F. D. Toste, J. Am. Chem. Soc., 2005, 127, 11260; (f) N. Martin and
P. W. Davies, Org. Lett., 2009, 11, 2293; (g) M. Egi, K. Azechi and
S. Akai, Org. Lett., 2009, 11, 5002; (h) M. Blangetti, A. Deagostino,
C. Prandi, S. Tabasso and P. Venturello, Org. Lett., 2009, 11,
3914.
We thank the EPSRC (for a studentship to DMB and for a
Leadership Fellowship to DJD) and AstraZeneca (studentship
to DMB) for support.
11 Pyrroles 4 were deprotected using a modified literature procedure,
A. V. Samet, A. N. Yamskov, Y. A. Strelenko and V. Semernov,
Tetrahedron, 2009, 65, 6868; see ESIw for details.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 4379–4381 4381