Copper-catalyzed condensation of imines and α-diazo-β-dicarbonyl compounds: modular and regiocontrolled synthesis of multisubstituted pyrroles

Article abstract of DOI:10.1039/c5sc02322j

In the presence of a copper(ii) catalyst, enolizable imines bearing various N-substituents and α-diazo-β-ketoesters undergo denitrogenative and dehydrative condensation to afford highly substituted pyrroles in moderate to good yields with exclusive regioselectivity. The reaction likely involves nucleophilic addition of the imine nitrogen to a copper carbenoid, tautomerization of the resulting azomethine ylide to an α-enaminoketone, and a subsequent enamine-ketone cyclocondensation. With Yb(OTf)₃ as a unique cocatalyst, α-diazo-β-diketones also participate in the same condensation reaction. The present reaction is applicable to acyclic, exocyclic, and endocyclic imines with tolerance of a broad range of functional groups and heterocyclic moieties, thus opening a new convenient route for the synthesis of the lamellarin family of natural products.

Full text of DOI:10.1039/c5sc02322j

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Journal Name
ARTICLE
Copper-Catalyzed Condensation of Imines and α-Diazo-β-
dicarbonyl Compounds: Modular and Regiocontrolled Synthesis of
Multisubstituted Pyrroles
Received 00th January 20xx,
Accepted 00th January 20xx
Wei Wen Tan and Naohiko Yoshikai*
DOI: 10.1039/x0xx00000x
In the presence of a copper(II) catalyst, enolizable imines bearing various N-substituents and α-diazo-β-ketoesters undergo
denitrogenative and dehydrative condensation to afford highly substituted pyrroles in moderate to good yields with
exclusive regioselectivity. The reaction likely involves nucleophilic addition of the imine nitrogen to a copper carbenoid,
tautomerization of the resulting azomethine ylide to α-enaminoketone, and subsequent enamine–ketone
cyclocondensation. With Yb(OTf)3 as a unique cocatalyst, α-diazo-β-diketones also participate in the same condensation
reaction. The present reaction is applicable to acyclic, exocyclic, and endocyclic imines with tolerance of a broad range of
functional groups and heterocyclic moieties, thus opening a new convenient route for the synthesis of the lamellarin
family of natural products.
www.rsc.org/
R2
H
R3
CO2R4
(a)
Introduction
N
R1
R3
R2
MLn
– N2
Transition metal carbenoids generated through decomposition
of diazocarbonyl compounds have proven to serve as
extremely versatile electrophilic intermediates for organic
synthesis.1 Among various carbenoid transformations,
reactions using aldimines bearing N-aryl or N-alkyl substituents
as nucleophilic reaction partners have been extensively
explored as they offer useful methods for the synthesis of
+
NR1
N2
CO2R4
H
X
Y
R2
H
R3
CO2R4
X
Y
N
R1
M = Rh, Cu, Ru
LnM–
R2
R2 R3
R3
CO2R4
–
via:
H
N+
R1
H
N+ CO2R4
R1
– MLn
nitrogen-containing heterocycles (Scheme 1a). In
a
prototypical reaction pattern, nucleophilic addition of the
aldimine nitrogen atom to the carbenoid gives rise to a metal-
bound or a free azomethine ylide.2 The azomethine ylide then
undergoes intramolecular cyclization to afford an aziridine
derivative—a process that can be made enantioselective using
a chiral metal catalyst.3 The azomethine ylide can also be
intercepted by an appropriate dipolarophile such as an
(b)
R3
R4
R3
R2
R4
O
cat. CuII
O
+
R2
N
O
N
N2
toluene
80–110 °C
– N2, – H2O
R5
R1
R1
R5
R3 R4
O
R3 R4
O
–
O
O
electron-deficient alkene or alkyne, thus affording
a
via:
R2 N+
R1
R2
N
R5
R5
pyrrolidine or related heterocycle through [3
+
2]
R1
cycloaddition.4,5
• Regiocontrolled access to highly substituted pyrroles
• Broad scope of imines and diazodicarbonyl compounds
• Applicable to Lamellarin synthesis
Scheme 1 Transition metal-catalyzed condensation of imines and diazocarbonyl
compounds.
In contrast to the extensive studies on the carbenoid
reactions with aldimines, reports on transition metal-catalyzed
reactions of ketimines with diazocarbonyl compounds are very
rare. While isatin-derived ketimines were reported to react
with a rhodium carbenoid derived from diazomalonate to
generate azomethine ylides for [3 + 2] cycloaddition,6 in other
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examples, ketimines do not directly react with a metal
carbenoid but undergo [2 + 2] cycloaddition with a ketene
generated through Wolff rearrangement of the carbenoid.7 To
our knowledge, reactions of other types of ketimines, including
those bearing α-protons, with metal carbenoids have not been
documented in the literature. In pursuit of heterocycle
synthesis through transition metal catalysis of ketimines,8 we
have found that a ketimine derived from an enolizable ketone
participates in the reaction with an α-diazo-β-ketoester (or
diketone) under copper catalysis to afford a multisubstituted
pyrrole with concomitant loss of dinitrogen and water (Scheme
1b), which is reported herein. The reaction is considered to
involve nucleophilic addition of the ketimine nitrogen to a
copper carbenoid and tautomerization of the resulting
azomethine ylide to an α-enamino-β-dicarbonyl intermediate,
which then undergoes dehydrative cyclocondensation to give
the pyrrole product. The reaction is applicable to ketimines
with various skeletons and N-substituents, and features simple
catalytic system and operation.
Multisubstituted pyrroles are present in many natural
products, pharmaceutically relevant compounds, and other
functional molecules (Chart 1).9 While a number of new
synthetic methods for multisubstituted pyrroles, those
catalyzed by transition metals in particular, have been
developed in the last decades,10,11 the demand for simple,
robust, and sustainable methods remains high. Notably, in
many of the recent transition metal-catalyzed methods, the
Results and Discussion
View Article Online
DOI: 10.1039/C5SC02322J
The present study commenced with attempts on the
condensation of imine 1a derived from acetophenone and p-
anisidine with α-diazo-β-ketoester 2a derived from ethyl
isobutyrylacetate (Table 1). Upon screening of various reaction
conditions, the desired condensation was found to proceed
efficiently in the presence of catalytic copper(II)
trifluoroacetylacetonate (Cu(tfacac)2, 10 mol%) and 4Å
molecular sieves (MS) in toluene at 110 °C to afford
tetrasubstituted pyrrole 3aa as the exclusive regioisomer in
88% yield (entry 1). The regiochemistry of 3aa was confirmed
by two-dimensional NMR (HMQC and HMBC) analysis. While
copper(II) hexafluoroacetylacetonate (Cu(hfacac)2) showed a
comparable catalytic activity as Cu(tfacac)2 did (entry 2), other
copper salts such as Cu(acac)2 and Cu(OAc)2 were much less
effective (entries 3 and 4). The use of Rh2(OAc)4 resulted in the
formation of an intractable mixture of products, in which the
desired product 3aa was not detected (entry 5). The yield of
3aa diminished substantially in the absence of 4Å MS (entry 6).
Reduction of the catalyst loading (to 5 mol%) or the reaction
temperature (to 90 °C) resulted in slightly lower yields (entries
7 and 8). 1,2-Dichloroethane (DCE) can be used as an
alternative solvent (entry 9), while the reaction was
completely shut down in DMSO (entry 10). Note that
formation of an aziridine product was not observed during the
optimization study.3a-e
Table 1 Screening of reaction conditionsa
catalyst plays
a key role in the formation of linear
intermediates such as α-enaminoketone,12 γ-ketoimine (or its
tautomers),13 and 1,4-diimine,14 which undergo dehydrative or
deaminative cyclocondensation to afford the pyrrole products.
In this context, the present reaction represents a useful
addition to the synthetic repertoire for pyrroles, because the
substitution patterns of the key α-enamino-β-dicarbonyl
intermediates are otherwise not readily accessible.15 As such,
the present reaction enables modular and expeditious
preparation of dozens of new multisubstituted pyrroles and
also opens a new alternative route for the synthesis of the
lamellarin family of natural products.
Cu(tfacac)2 (10 mol %)
4Å MS
O
+
Ph
NPMP
Ph
CO2Et
N
toluene, 110 °C, 12 h
N2
CO2Et
PMP
3aa
standard conditions
1a
2a
Entry
Deviation from the standard conditions
none
Yield (%)b
1
2
3
4
5
6
7
8
9
88c
87
7
Cu(hfacac)2 instead of Cu(tfacac)2
Cu(acac)2 instead of Cu(tfacac)2
Cu(OAc)2 instead of Cu(tfacac)2
Rh2(OAc)4 instead of Cu(tfacac)2
Without 4Å MS
21
0
MeO
HO
MeO
MeO
HO
52
76
82
81
0
OH
5 mol% of Cu(tfacac)2
O
Me
T = 90 °C
DCE instead of toluene
DMSO instead of toluene
N
H
H
N
O
N
N
H
10
O
O
a The reaction was performed using 0.2 mmol of 1a and 0.3 mmol of 2a. PMP = p-
methoxyphenyl. Cu(tfacac)2 = copper(II) trifluoroacetylacetonate. Cu(hfacac)2 =
copper(II) hexafluoroacetylacetonate. b Determined by GC. c Isolated yield.
lamellarin D
(HIV-1 integrase inhibitor etc.)
kendine 91
(HDAC inhibitor)
N
N Me
OH OH
O
O
To explore the scope of the present pyrrole synthesis, we
first subjected various N-PMP ketimines 1a–1u to the reaction
with the diazoester 2a (Table 2). Imines 1a–1o derived from a
wide variety of (hetero)aryl methyl ketones could be
condensed with 2a, affording tetrasubstituted pyrroles 3aa–
3oa in moderate to good yields. X-ray diffraction analysis of
single crystals of 3ja unambiguously confirmed its
regiochemistry. The reaction of the parent acetophenone
N
OH
Me
N
Cl
F
Cl
atorvastatin
BM212
(antimycobacterial)
(HMG-CoA reductase inhibitor)
Chart 1 Examples of pyrrole-containing bioactive molecules.
2 | J. Name., 2012, 00, 1-3
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imine 1a could be performed on a gram (5 mmol) scale Napieralski reaction, was also amenable to the condensation
View Article Online
DOI: 10.1039/C5SC02322J
without problem (see 3aa). Various functional groups such as with 2a to afford a 5,6-dihydropyrrolo[2,1-a]isoquinoline
halogen (F, Cl, Br, I), trifluoromethyl, cyano, and nitro groups derivative 3aaa, implying potential applicability of the present
as well as heteroaryl moieties such as furyl, benzofuryl, thienyl, method to the synthesis of lamellarin family of natural
and indolyl groups were tolerated. Imines 1p–1t derived from products (vide infra).9b-c Interestingly, benzyl-substituted
propiophenone, 2-phenylacetophenone, cyclopropyl methyl dihydroisoquinoline 1ab afforded
a
mixture of 5,6-
ketone, and cycloalkanones also participated in the reaction dihydropyrrolo[2,1-a]isoquinoline 3aba and unexpected
with 2a to afford the corresponding penta- or tetrasubstituted dihydrobenz[g]indolizinone derivative 3aba'.16 The latter
pyrroles 3pa–3ta in moderate to good yields.
product features migration of the phenyl group of 1ab from
the β-position of the nitrogen atom to the α-position as well as
concomitant oxidation of the β-position. We consider that
these structural changes occur on the reaction pathway
leading to the pyrrole product 3aba rather than after the
formation of 3aba, because the ratio of 3aba and 3aba' was
not affected by the reaction time (see Scheme S1 in the
Supplementary Information for a possible mechanism).
Table 2 Condensation of various N-PMP imines with diazoketoester 2aa
R2
R2
standard
conditions
O
+
R1 NPMP
R1
CO2Et
N
N2
CO2Et
PMP
1a–1t
2a
3aa–3ta
Table 3 Condensation of other imines with diazoketoester 2aa
CO2Et
CO2Et
standard
conditions
R3
R2
N
N
R3
O
X
PMP
PMP
+
Me
CO2Et
R2 NR1
1u–1ab
N
R1
N2
CO2Et
3aa (X = H), 92% [5 mmol]
3ba (X = OMe), 84%
3ca (X = F), 85%
3ja, 88%
(X-ray)
CO2Et
2a
3ua–3aba
3da (X = Cl), 80%
3ea (X = Br), 72%
3fa (X = I), 71%
3ga (X = CF3), 72%
3ha (X = CN), 74%
3ia (X = NO2), 52%
O
CO2Et
N
N
PMP
PMP
Ph
CO2Et
CO2Et
Ph
N
CO2Et
N
N
X
3ka, 87%
3la, 83%
R
Ph
3ya (R = PMB), 73%b
3ya' (R = H), 90%
3va (X = H), 72%
3wa (X = F), 68%
3xa (X = Cl), 72%
c
Cl
O
S
3ua, 42%
CO2Et
N
CO2Et
CO2Et
N
N
MeN
PMP
PMP
PMP
R
O
3ma, 87%
3na, 73%
3oa, 70%
Ph
Ph
CO2Et
N
CO2Et
CO2Et
N
N
R
Ph
CO2Et
CO2Et
CO2Et
n
N
N
N
3za, 57%
3aaa (R = H), 73%
3aba (R = Ph), 48%
+
3aba', 50%
PMP
PMP
PMP
3pa (R = Me), 77%
3qa (R = Ph), 76%
3ra, 84%
3sa (n = 1), 73%
3ta (n = 2), 68%
a The reaction was performed on a 0.2 mmol scale according to the standard
conditions described in Table 1. b Performed on a 0.5 mmol scale. c TFA, anisole,
CH2Cl2, 37 °C, 40 h.
a The reaction was performed on a 0.2 mmol scale according to the standard
conditions described in Table 1.
Besides isolable imines described above, we also examined
the viability of unstable imines as reactants for the present
pyrrole synthesis (Scheme 2). First, an N-H imine of
acetophenone 1ac, prepared from benzonitrile and
methyllithium with minimal workup, was subjected to the
reaction with ethyl acetyldiazoacetate 2b, which afforded the
desired N-H pyrrole 3acb in a modest yield (Scheme 4a).
Interestingly, the reaction was accompanied by the formation
of a 2H-1,4-oxazine derivative 4 as a byproduct. Next,
condensation of 4-methoxyphenylacetaldehyde and p-
anisidine and subsequent reaction of the resulting aldimine
1ad and 2b were performed in a one-pot manner. Although
the first condensation step was inevitably complicated by side
reactions such as enamine aldol reaction, the desired
tetrasubstituted pyrrole 3adb was obtained in a modest yield
(Scheme 4b).
The present condensation reaction is applicable to imines
bearing N-substituents other than the PMP group, as
illustrated in Table 3. The reaction of acetophenone imine
bearing N-4-chlorophenyl group (1u) with 2a afforded the
desired product 3ua in 42% yield, which was markedly lower
than obtained with the N-PMP imine 1a. This suggests the
relevance of the electron-richness of the nitrogen atom to the
reactivity of the imine. Imines 1v–1z bearing removable
benzyl, 4-methoxybenzyl (PMB), and allyl groups smoothly
participated in the reaction with 2a to afford pyrroles 3va–3za
in respectable yields of 57–73%, thus making the preparation
of N-H pyrroles feasible. For example, the removal of the PMB
group of 3ya was achieved in 90% yield with the aid of
trifluoroacetic acid and anisole. Methyl-substituted
dihydroisoquinoline 1aa, readily prepared by Bischler–
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entry
R1
Me
c-C3H5
c-C6H11
Bn
R2
Et
product View AyrtiieclledO(%nl)ine
(a) N-H Imine
DOI: 10.1039/C5SC02322J
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
3ap
81
80
88
94
77
77
86
80
67
60
74
70
79
41
47
PhCN
1) MeLi
2) MeOH
Et
Me
N2
O
Me
Me
Et
Et
Et
Et
Et
Et
Me
Me
Et
Et
Et
Me
CO2Et
3acb, 35%
O
Me
CO2Et
2b
+
Ph
Ph
Ph
N
CO2Et
Ph
NH
N
H
standard
conditions
4-MeOC6H4
4-BrC6H4
4-NO2C6H4
2-MeC6H4
2-BrC6H4
1-naphthyl
2-furyl
CO2Et
1ac
4, 22%
(b) Aldimine (one-pot)
Me
N2
O
MeO
CO2Et
Ar
Me
PMPNH2
Ar
2b
standard
conditions
CHO
Ar = 4-MeOC6H4
H
NPMP
1ad
CO2Et
CF3
H
N
PMP
3adb, 32%
a The reaction was performed on a 0.2 mmol scale according to the standard
conditions described in Table 1.
Scheme 2 Condensation of unstable imines with diazoketoester 2b.
During the exploration of the scope of imines, we
encountered a few cases of an unexpected mode of cyclization
(Scheme 3). The reaction of pinacolone-derived imine 1ae with
2a cleanly furnished a 2,3-dihydrooxazole derivative 5a rather
than the expected pyrrole. The same reaction was also
observed using trifluoroacetone-derived imine 1af.
The reaction of 1a with 3-diazopentane-2,4-dione 2q under
the standard conditions with Cu(tfacac)2 did not give the
desired pyrrole product. The use of Cu(hfacac)2 instead of
Cu(tfacac)2 promoted the reaction, but produced a ca. 1:1
mixture of the expected pyrrole 3aq and its positional isomer
3aq' in a low overall yield (Scheme 4a). The latter isomer
would be formed through formal C–H insertion of a copper
carbenoid into the α-position of 1a. Interestingly, the
efficiency and the chemoselectivity of this reaction were
substantially improved by adding Yb(OTf)3 (10 mol %) and
lowering the temperature to 80 °C.17 Thus, the 2-acetylpyrrole
isomer 3aq was obtained almost exclusively in a respectable
yield of 57%. The Cu/Yb cocatalytic system also effected the
condensation of 1a with 1-diazo-1-benzoylacetone 2r in the
same mode of cyclization, in favor of the 2-benzoylpyrrole
isomer 3ar over the 2-acetylpyrrole isomer 3ar' (Scheme 4b).
Note that the same reaction in the absence of Yb(OTf)3
produced a mixture of four isomers including 3ar and 3ar' in a
low overall yield, as suggested by GC analysis of the crude
product. While the role of Yb(OTf)3 is not clear, we speculate
that it serves as a Lewis acid to the diketo moiety to enhance
the electrophilicity of the copper carbenoid. Note that α-
standard
conditions
O
O
+
Me
R
NPMP
CO2Et
N
R
N2
CO2Et
PMP
1ae (R = tBu)
1af (R = CF3)
2a
5a (R = tBu), 95%
5b (R = CF3), 70%
Scheme 3 Formation of dihydrooxazole derivatives.
We next explored the reaction of imine 1a with various α-
diazo-β-ketoesters 2b–2p (Table 4). The reaction allowed facile
preparation of tetrasubstituted pyrroles bearing alkyl (entries
1–3), benzyl (entry 4), and (hetero)aryl (entries 5–12) groups in
moderate to good yields with tolerance of functional groups
such as bromo and nitro groups (entries 7, 8, and 10). Diazo
compounds derived from diethyl 2-oxosuccinate and ethyl
4,4,4-trifluoroacetoacetate could also be condensed with 1a,
thus furnishing 2,3-diethoxycarbonylpyrrole 3an and 2-
ethoxycarbonyl-3-trifluoromethylpyrrole 3ao, respectively
(entries 13 and 14). In addition to the 1,2,3,5-tetrasubstituted
pyrroles 3ab–3ao, 1,2,5-trisubstituted pyrrole 3ap was also
diazoketones
such
as
2-diazo-1,2-diphenylethanone
decomposed too quickly not only under the standard
conditions but also under conditions employing less reactive
Cu(acac)2 at a lower temperature, hence producing none of
the desired pyrrole product.
successfully prepared in
a moderate yield using ethyl
formyldiazoacetate 2p as the reactant (entry 15).
Table 4 Condensation of imine 1a with various α-diazo-β-ketoestersa
standard
conditions
R1
CO2R2
R1
N2
O
+
Ph
Ph
NPMP
N
CO2R2
PMP
3ab–3ap
1a
2b–2p
4 | J. Name., 2012, 00, 1-3
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Scheme 5 Model reactions of dihydroisoquinolines 1aa and 1ab with ethyl
View Article Online
(a)
benzoyldiazoacetate 2f.
DOI: 10.1039/C5SC02322J
Me
Cu(hfacac)2 (10%)
cocatalyst (10%)
4Å MS
Me
O
Me
N2
O
While the above results suggest that the present method
may not be suitable for direct assembly of the
pentasubstituted pyrrole core of lamellarins, attempts using
ethyl formyldiazoacetate 2p have proven its utility in the
preparation of building blocks for modular synthesis of
O
+
+
1a
O
Ph
Ph
Me
N
N
toluene
temp, 12 h
Me
PMP
PMP
Me
2q
3aq
3aq'
cocatalyst, temp
none, 110 °C
11%
12%
lamellarins
(Scheme
6).
The
reaction
of
Yb(OTf)3, 80 °C
57%
< 1%
methyldihydroisoquinoline with two methoxy groups (1ag) and
2p cleanly afforded 3-ethoxycarbonyl-5,6-dihydropyrrolo[2,1-
a]isoquinoline derivative 3agp (Scheme 6a). An analogous
compound of 3agp was previously synthesized through a
sequence of pyrrole N-alkylation and intramolecular Heck
reaction, and used as an intermediate to lamellarin D and its
(b)
Cu(hfacac)2 (10%)
Yb(OTf)3 (10%)
4Å MS
Me
Ph
Me
N2
O
O
O
+
+
1a
O
Ph
Ph
N
N
toluene
80 °C, 12 h
Ph
Me
PMP
PMP
Ph
analogues.19b,20
Furthermore,
benzyldihydroisoquinoline
2r
3ar, 50%
3ar', 13%
bearing four methoxy groups (1ah) also underwent
condensation with 2p to afford 1-aryl-3-ethoxycarbonyl-5,6-
dihydropyrrolo[2,1-a]isoquinoline derivative 3ahp (Scheme
6b). In a previous study by Handy et al., 3ahp was prepared
through six-step manipulation of a pyrrole-based starting
material, and was then converted to lamellarin G trimethyl
ether in two steps.19a
Scheme 4 Condensation of 1a with α-diazo-β-diketones using Yb(OTf)3 cocatalyst.
Having established the scope and limitation with respect to
imines and diazo compounds, we became interested in the
applicability of the present condensation reaction to the
synthesis of bioactive natural or unnatural products. In this
connection, the successful reactions of dihydroisoquinolines
1aa and 1ab (Table 3) turned our attention to the lamellarin
family of natural products, many members of which contain a
(5,6-dihydro)pyrrolo[2,1-a]isoquinoline skeleton. Since the
early studies of Steglich, Ishibashi/Iwao, and Banwell,18
lamellarins have been popular synthetic targets due to the
broad spectrum of their biological activities, and also have
served as touchstones for new methods of the construction
and the functionalization of pyrrole rings.9b-c,19 As some of the
completed lamellarin syntheses involve 3-alkoxycarbonyl-5,6-
(a) 3-Alkoxycarbonyl derivative
standard
conditions
H
O
MeO
MeO
MeO
MeO
+
CO2Et
N
N
N2
CO2Et
1ag
2p
3agp, 68%
cf. Álvarez et al. (ref 19b)
MeO
Br
MeO
OTs
CO2Me
+
N
CO2Me
N
H
i-PrO
dihydropyrrolo[2,1-a]isoquinoline
derivatives
as
key
i-PrO
precursor to Lamellarin D
and its analogues
intermediates, we wondered whether the present reaction
offers an alternative and efficient route to such intermediates.
Aiming at a straightforward access to the polyarylated
pyrrole structure of lamellarins, we first tested model
reactions of methyl- and benzyldihydroisoquinolines 1aa and
1ab with ethyl benzoyldiazoacetate 2f (Scheme 5). The
reaction of the former imine successfully furnished the desired
pyrrole scaffold 3aaf in 62% yield (Scheme 5a). By contrast, the
(b) 1-Aryl-3-alkoxycarbonyl derivative
MeO
MeO
standard
conditions
MeO
MeO
MeO
H
O
MeO
MeO
+
N2
CO2Et
N
CO2Et
OMe
N
2p
MeO
1ah
3ahp, 48%
latter exclusively afforded
a
dihydrobenz[g]indolizinone
derivative 6,16 the structure of which was unambiguously
MeO
MeO
MeO
MeO
cf. Handy et al. (ref 19a)
6 steps
confirmed by X-ray crystallographic analysis (Scheme 5b).
2 steps
Br
3ahp
(a)
O
Ph
N2
O
CO2Et
N
H
Ph
CO2Et
N
O
MeO
CO2Et
2f
N
N
Lamellarin G trimethyl ether
standard
conditions
Scheme 6 Construction of 5,6-dihydropyrrolo[2,1-a]isoquinolines scaffolds for
lamellarin synthesis.
1aa
3aaf, 62%
(b)
O
Ph
CO2Et
On the basis of the regiochemistry of the pyrrole products
as well as common reaction patterns in transition metal
catalysis of diazo compounds, the present reaction is
considered to involve the addition of the imine nitrogen to a
copper carbenoid.2-3,4g To probe the nature of this putative
Ph
2f
Ph
N
N
standard
conditions
1ab
6, 63%
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step, competition experiments using imines bearing different
substituents were performed. The reaction of a mixture of
imines 1b and 1h derived from electron-rich and electron-poor
acetophenones, respectively, with 2a afforded the product of
the former (3ba) as the dominant product (Scheme 7a).
Likewise, the reaction of a mixture of imines 1a and 1u derived
from electron-rich and electron-poor anilines, respectively,
preferentially produced the product of the former (Scheme
7b). Thus, the nucleophilicity of the imine nitrogen atom would
play a critical role in its reaction with the copper carbenoid.
View Article Online
DOI: 10.1039/C5SC02322J
R3 R4
O
R3 –O
R4
[Cu]
–
R2 N+ CO2R5
R2 N+ CO2R5
2
R1
R1
I
I'
cf. Scheme 3
1
N2
R4
R4
[Cu]
O
R3 R4
O
R3
O
CO2R5
CO2R5
R2
N
CO2R5
N
R1
R2
R1
5
II
R1 = H
[O]
–H2O
R3
R3
R2
O
N
R4
R4
CO2R5
(a)
i-Pr
CO2R5
III
R2
NPMP
N
CO2Et
N
2a (1.5 equiv)
R1
cf. Scheme 2a
MeO
MeO
PMP
standard
conditions
3
1b
3ba, 63%
R3
R2
O
N
R4
+
+
2 h
i-Pr
CO2R5
4
NPMP
CO2Et
N
Scheme 8 Plausible reaction pathways leading to pyrrole and other byproducts.
NC
NC
PMP
1h
3ha, 14%
(b)
CO2Et
N
Conclusions
OMe
i-Pr
OMe
In conclusion, we have developed
condensation reaction of imines and α-diazo-β-dicarbonyl
compounds to afford multisubstituted pyrroles in
a copper-catalyzed
2a (1.5 equiv)
Ph
N
standard
conditions
1a
Ph
3aa, 55%
a
+
+
2 h
CO2Et
regiocontrolled manner. The reaction features broad scope
and ready availability of the starting materials and simple
operation, thus enabling modular and quick preparation of a
variety of densely functionalized pyrroles. Given the extensive
previous studies on carbenoid reactions with imines,2-6 it is
rather surprising that the present condensation of enolizable
imines has not been documented. The reaction opens concise
preparative routes to lamellarin scaffolds, and may find further
applications in the synthesis of pyrrole alkaloids. The
cooperative effect of the carbene transfer catalyst
(Cu(hfacac)2) and the Lewis acid catalyst (Yb(OTf)3), observed
in the reaction of α-diazo-β-diketones, also deserves
mechanistic and synthetic explorations. Further studies on
heterocycle synthesis using imines as starting materials8
and/or based on carbenoid chemistry are currently in progress
in our laboratory.
Cl
i-Pr
N
Cl
Ph
N
1u
Ph
3ua, 8%
Scheme 7 Competition experiments.
Scheme 8 shows plausible reaction pathways of the
present pyrrole synthesis. Decomposition of the diazo
compound
2 with the copper catalyst generates an
electrophilic copper carbenoid. Nucleophilic attack of the
imine 1 to the carbenoid gives azomethine ylide I2-6 and
regenerates the copper catalyst. Tautomerization of I to α-
enaminoketone II via proton transfer is followed by
cyclocondensation to afford the pyrrole product 3. Attempts to
intercept the azomethine ylide I with typical dipolarophiles
such as dimethyl acetylenedicarboxylate, dimethyl maleate,
and N-phenylphthalimide failed to give the corresponding [3 +
2] cycloadducts but exclusively afforded the pyrrole product,
presumably because of rapid tautomerization of I to II.
Nevertheless, the intermediacy of I and II rationalizes not only
the formation of the pyrrole 3 but also the side reactions
observed in the present study. In the reaction of N-H imine
(Scheme 2), the intermediate II may be oxidized to 1-acyl-2-
azadiene III, which would then undergo 6π electrocyclization
to afford 2H-1,4-oxazine derivative 4.21 The azomethine ylide I
may also behave as an enolate/iminium bifunctional species I',
which undergoes intramolecular attack of the enolate oxygen
to the iminium moiety to afford 2,3-dihydrooxazole 5. This side
reaction would be operative in the cases shown in Scheme 3,
possibly because of lower acidity of the α-proton of the
iminium moiety (for 1ae) or increased electrophilicity of the
iminium moiety (for 1af).
Acknowledgements
This work was supported by the Singapore National Research
Foundation (NRF-RF2009-05) and Nanyang Technological
University. We thank Dr. Malleswara Rao Kuram for his early
study and Drs. Yongxin Li and Rakesh Ganguly for assistance
with the X-ray crystallographic analysis.
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