Copper(II)-Catalyzed [4+1] annulation of propargylamines with N,O-acetals: Entry to the synthesis of polysubstituted pyrrole derivatives

Article abstract of DOI:10.1002/ejoc.201500098

Described herein is the CuCl₂-catalyzed [4+1] annulation of a variety of propargylamines with N,O-acetals that function as a C1 unit, leading to the production of polysubstituted pyrrole derivatives. Three important features of the N,O-acetal during the [4+1] annulation series via 5-endo-dig cyclization are described: an enolizable substituent adjacent to the central sp³-carbon is required, the central sp³-carbon displays the functions of both an electrophile and a nucleophile, and liberation of the secondary amine smoothly leads to the aromatization. A CuCl₂-catalyzed [4+1] annulation of propargylamines with N,O-acetals having an ester, a ketone, and an amide moiety, leading to the facile preparation of polysubstituted pyrrole derivatives is presented. This annulation series was achieved through 5-endo-dig cyclization and subsequent aromatization in one pot.

Full text of DOI:10.1002/ejoc.201500098

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500098
Copper(II)-Catalyzed [4+1] Annulation of Propargylamines with N,O-Acetals:
Entry to the Synthesis of Polysubstituted Pyrrole Derivatives
Norio Sakai,*[a] Hiroaki Hori,[a] and Yohei Ogiwara[a]
Keywords: Annulation / Pyrroles / Acetals / Copper / Propargylamines / Cyclization
Described herein is the CuCl2-catalyzed [4+1] annulation of
a variety of propargylamines with N,O-acetals that function
as a C1 unit, leading to the production of polysubstituted pyr-
role derivatives. Three important features of the N,O-acetal
during the [4+1] annulation series via 5-endo-dig cyclization
are described: an enolizable substituent adjacent to the cen-
tral sp3-carbon is required, the central sp3-carbon displays
the functions of both an electrophile and a nucleophile, and
liberation of the secondary amine smoothly leads to the aro-
matization.
Introduction
The preparation of polysubstituted pyrrole derivatives
has attracted considerable attention in organic and pharma-
ceutical chemistry, because the main framework of the
nitrogen-containing five-membered rings occurs in many
natural products, biologically active substances, and func-
tional materials.[1] Hence, a number of approaches involving
Hantzsch synthesis ([2+2+1] annulation),[2] Piloty–Robin-
son synthesis ([2+2+1] annulation),[3] and Barton–Zard
synthesis ([3+2] annulation)[4] have been developed for the
preparation of this unique skeleton.
Two well-known representative methods for the prepara-
tion of substituted pyrrole derivatives through [4+1]
annulation (path A in Scheme 1) are the Parr–Knorr pyr-
role method by the cyclocondensation of a 1,4-diketone
with a primary amine or ammonia under acidic condi-
tions[5] and the Clauson–Kaas reaction through the acid-
promoted condensation of 2,5-dimethoxytetrahydrofuran
and a primary amine.[6] In both [4+1] approaches, one of
the five constituent atoms is constructed from a primary
amine (or ammonia) as an N1 unit, and the remaining four
atoms are derived from a carbon atom. On the basis of
these approaches, a number of modified [4+1] preparations
leading to the preparation of a pyrrole skeleton have been
disclosed (path A in Scheme 1).[7]
Scheme 1. Divergent approaches to a pyrrole framework via a [4+1]
annulation.
In contrast to the above examples, an effective construc-
tion of a pyrrole framework by a combination of com-
pounds composed of a [C–C–C–N] unit with a carbon-
source compound as a C1 unit has not been investigated
extensively and is limited to only a few methods (path B
in Scheme 1). For example, Pedersen et al. reported that
NbCl3(DME) promoted the annulation of 1-azadine deriva-
tives with esters or N,N-dimethylformamide (DMF), pro-
ducing the pyrrole derivatives (path B1 in Scheme 1).[8]
Iwasawa and co-workers also disclosed a catalytic prepa-
ration of pyrrole derivatives via the RhI-catalyzed [4+1]
annulation of 1-azadines with terminal alkynes (path B1 in
Scheme 1).[9] Moreover, a phosphine-mediated annulation
of 1-azadines with acid chlorides has been reported by
[a] Department of Pure and Applied Chemistry,
Faculty of Science and Technology,
Tokyo University of Science (RIKADAI),
Noda, Chiba 278-8510, Japan
E-mail: sakachem@rs.noda.tus.ac.jp
http://www.rs.tus.ac.jp/sakaigroup
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500098.
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SHORT COMMUNICATION
Arndtsen et al. (path B1 in Scheme 1).[10] In other ap- perature to 100 °C shortened the reaction time to 2 h and
proaches to [4+1] annulation, Müller has reported that a decreased the equivalent of CuCl2 to 5 mol-% (entries 18
coupling of propargylamines and acid chlorides and subse- and 19). When annulation was carried out by using a
quent intramolecular cyclocondensation of the alkynone in- Brønsted acid, HCl, instead of CuCl2, the corresponding
termediate leads to the preparation of pyrrole derivatives,[11] pyrrole was not obtained, which definitively showed that
and the Rh-catalyzed hydroformylation of propargylamines copper(II) chloride effectively promoted the annulation
with H2/CO gas has been reported by Campi (path B2 in series (entry 20).
Scheme 1).[12] In both cases with a propargylamine, the
terminal alkyne carbon is initially bonded to a C1 unit,
Table 1. Examination of the reaction conditions.
followed by the intramolecular formation of a C–N bond
to construct a pyrrole ring.
As a preliminary result, however, we developed the
copper-catalyzed [5+1] annulation of 2-ethynylanilines with
an N,O-acetal with an ester group, which functions as a
glycine cation equivalent,[13] leading to the preparation of
2-ester-substituted quinoline derivatives, although the N,O-
acetal used in this transformation was limited to a single
substrate with the ester group.[14] Herein we report the
Entry
Catalyst
Solvent
Yield [%][a]
1
2
3
4
5
6
7
8
MgCl2
Yb(OTf)3
HfCl4
FeCl2
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,2-DCE[g]
toluene
ND[b]
ND
ND
ND
ND
trace (19)[c]
ND
trace
ND
ND
64
(67)
53
48
trace
65
72
unprecedented example of
a copper-catalyzed [4+1]
annulation of propargylamines with N,O-acetals, wherein
the central sp3-carbon functions as both an electrophile and
a nucleophile, leading to the preparation of polysubstituted
pyrrole derivatives via 5-endo-dig cyclization (path B3 in
Scheme 1). The single-step preparation of nitrogen-contain-
ing aromatic heterocycles, such as pyrrole, via 5-endo-dig
intramolecular cyclization is extremely rare compared with
FeCl3
CoCl2
NiCl2
ZnCl2
GaCl3
InCl3
CuCl
CuCl2
CuBr
CuBr2
Cu(OTf)2
CuCl2
CuCl2
CuCl2
CuCl2
HCl[f]
9
10
11
12
that of carbocycles through a Conia-ene-type cycliza- 13
tion.[15–17] The present method permits the unique prepara-
14
15
16
tion of a variety of polysubstituted pyrrole derivatives.
17
18[d]
toluene
toluene
toluene
80
(86)
ND
19[e]
20
Results and Discussion
[a] NMR (Isolated) yield. [b] ND: not determined. [c] CoBr2
(10 mol-%). [d] 100 °C, 2 h. [e] 1a (0.4 mmol), 2a (0.44 mmol),
CuCl2 (5 mol-%), 100 °C, 2 h. [f] HCl in MeOH (2 m). [g] 1,2-
Dichloroethane.
Initially, as
a model reaction, the intermolecular
annulation of N-phenylpropargylamine (1a) with N,O-
acetal 2a, which was prepared from methyl 2-bromo-2-
methoxyacetate and piperidine,[18] was examined in the
presence of a variety of metal catalysts in 1,4-dioxane
To expand the scope of this annulation, the reaction of
(Table 1). For instance, when the reaction was carried out propargylamines 1, possessing a variety of aryl groups, with
with group 2, 3, and 4 metals such as MgCl2, Yb(OTf)3, N,O-acetal 2a was examined under the optimized condi-
and HfCl4 as catalysts, the expected annulation did not tions (Table 2). With no relationship to the electronic effect
occur, and only decomposition of the N,O-acetal was ob- of an aryl group on propargylamines, most reactions were
served (entries 1–3). Although late transition metals such completed within 2 h to give the N-arylated 2-substituted
as FeCl2, FeCl3, and NiCl2 did not function as Lewis acids pyrrole derivatives 3ba–3ma in moderate to good yields.
for the annulation, CoCl2 gave a trace amount of the ex- Also, the steric effect of an o-substituted methyl group did
pected pyrrole derivative 3aa (entries 4–7). ZnCl2 also pro- not have a strong effect on the chemical yield. However,
duced a small amount of the pyrrole, but group 13 metals, when the reaction of propargylamine 1g, which had a
such as GaCl3 and InCl3, led to a complex mixture (entries hydroxy group on the benzene ring, with N,O-acetal 2a was
8–10). It is noteworthy that when the reaction was con- treated under the optimized conditions, the expected pyr-
ducted with CuCl, the yield of the pyrrole was dramatically role was not obtained. In this context, the use of prop-
improved to 64% yield (entry 11). Also, the use of CuCl2 argylamine (1n) did not give the expected N-unsubstituted
increased the yield slightly (entry 12). However, CuBr and pyrrole (entry 13).
CuBr2 led to a decrease in the product yield; in particular,
The preparation of 1,2-di- or 1,2,5-trisubstituted pyrrole
a strong Lewis acidic Cu(OTf)2 did not give the product derivatives was then examined with several prop-
(entries 13–15). Then, upon examination of several solvents argylamines 1 that possessed a substituent group next to an
such as THF, CH3CN, and DMF, besides 1,4-dioxane, the amino group (Table 3). In most cases, when prop-
most effective ones were found to be toluene and 1,2-di- argylamines possess either an aliphatic or an aromatic
chloroethane (entries 16 and 17). Raising the reaction tem- group, the corresponding 1,2,5-trisubstituted pyrrole
2
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[4+1] Annulation of Propargylamines with N,O-Acetals
Table 2. The synthesis of N-arylated pyrrole derivatives using a amine 1a with several other N,O-acetals was carried out
variety of N-arylpropargylamines.
under our optimized conditions (Table 4). Any type of
amine moiety on N,O-acetal 2b that functioned as a leaving
group had no significant effect on the subsequent annu-
lation (entry 1). The use of N,O-acetals with a ketone or an
amide group produced the corresponding pyrrole deriva-
tives 3ac and 3ad in moderate to good yields (entries 2 and
3). In contrast, when using N,O-acetals with a phenyl group
or without a substituent, the desired annulation did not
occur (entries 4 and 5). These results strongly implied that
the enolization of an ester, a ketone, or an amide portion
of an N,O-acetal is key in the [4 +1] annulation series.
Entry Propargylamine 1
Yield of 3 [%][a]
Ar
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
o-MeC6H4
m-MeC6H4
p-MeC6H4
p-Me2NC6H4
p-MeOC6H4
o-HOC6H4
p-FC6H4
p-ClC6H4
p-BrC6H4
p-CF3C6H4
p-AcC6H4
p-NCC6H4
H
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
86
80
80
81
Table 4. Scope and limitations of an N,O-acetal.
90
1g
1h
1i
CM[b]
81
87
83
84
77
9
1j
3ja
10
11
12
13
1k
1l
1m
1n
3ka
3la
Yield of 3 [%][a]
3ma
3na
70
Entry
N,O-Acetal 2
ND[c]
R
E
[a] Isolated yield. [b] CM: complex mixture. [c] ND: not deter-
mined.
1
2b
2c
2d
2e
2f
Et
CO2Me
COPh
CONR2
Ph
3aa
3ac
3ad
3ae
3af
85
43
2[b]
3[b]
4
–(CH2)5-
–(CH2)5-
–(CH2)5-
–(CH2)5-
[c]
58
ND[d]
ND
derivatives 3pa–3ta are produced in relatively good to
excellent yields (entries 1–5). When the reaction was carried
out with N-tert-butyl-substituted propargylamine 1o, how-
ever, the yield of the corresponding 1,2-disubstituted pyr-
role derivative 3ta was 31% (entry 6). However, when
several substituents, such as a phenyl, an n-butyl, an ester,
and a trimethylsilyl group, were introduced into the ter-
minal alkyne moiety on a propargylamine, the expected
[4+1] annulation unfortunately did not occur to produce
the corresponding pyrrole derivative with a decomposition
of both starting materials. These results were probably due
to the fact that a steric effect of the introduced substituent
hindered the intramolecular cyclization of the expected
intermediate.
5
H
[a] Isolated yield. [b] Unpurified N,O-acetal was used, because of
decomposition during a common purification. [c] NR2 = a piperidi-
nyl group. [d] ND: not determined.
The direct preparation of a pyrrole derivative by the
CuCl2-catalyzed coupling of a propargylamine with a
glyoxylate ester in the presence of a secondary amine was
attempted (Scheme 2). First, when the reaction mixture of
N-phenylpropargylamine (1a), ethyl glyoxylate, and piper-
idine was treated under our optimized conditions, the ex-
pected pyrrole derivative 4 was obtained in 50% yield.
Without piperidine, however, the same conditions would
not yield pyrrole 4. These results definitely showed that an
in situ formation of an N,O-hemiacetal intermediate from
piperidine and ethyl glyoxylate initially occurs, then an
intermolecular substitution of the hemiacetal intermediate
with a propargylamine proceeds to produce the correspond-
ing N,N-aminal intermediate.
Table 3. The synthesis of 1,2-di- or 1,2,5-trisubstituted pyrrole de-
rivatives using a variety of propargylamines.
Entry
Propargylamine 1
Yield of 3 [%][a]
R1
R2
1
2
3
4
5
6
1o
1p
1q
1r
1s
1t
PhCH2CH2
c-hexyl
Ph
p-MeC6H4
p-ClC6H4
H
Ph
Ph
Ph
Ph
Ph
tBu
3oa
3pa
3qa
3ra
3sa
3ta
70
60
90
91
77
31
Scheme 2. Copper(II)-catalyzed direct coupling reaction of N-
phenylpropargylamine with ethyl glyoxylate.
On the basis of these results, a plausible mechanism for
the [4+1] annulation of propargylamines with N,O-acetals
is shown in Scheme 3. First, the copper catalyst activates an
[a] Isolated yield.
To expand on the scope and overcome the limitations of oxygen atom of N,O-acetal 2 to generate iminium interme-
N,O-acetal 2 as a substrate, the annulation of propargyl- diate A. Second, the nitrogen atom on propargylamine 1
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N. Sakai, H. Hori, Y. Ogiwara
SHORT COMMUNICATION
nucleophilically attacks the iminium, which leads to the
production of N,N-aminal intermediate B. Third, the reac-
tion of the intermediate with the copper catalyst generates
copper enolate intermediate C, and the intermediate un-
dergoes 5-endo-dig intramolecular cyclization to construct
the nitrogen-containing five-membered ring skeleton D.
This mechanism also implies that the copper catalyst would
simultaneously activate a relatively soft electrophile, a
carbon–carbon triple bond moiety on intermediate C,
facilitating intramolecular cyclization. This discussion is
supported by the fact that an N,O-acetal either with a non-
enolizable group, such as a phenyl or a nitrile group, or
without a substituted group did not yield the expected pyr-
role derivative (see Table 4) and that the expected [4+1] an-
nulation did not proceed without the copper catalyst.
Finally, both protonation and aromatization through the
liberation of a secondary amine of ring product D occurred
to produce the corresponding pyrrole derivative 3, along
with a regeneration of the copper(II) catalyst.
Experimental Section
General Procedure for the Synthesis of Pyrrole Derivatives with 1
and 2: In a glove box, CuCl2 (0.0200 mmol, 2.69 mg) was weighed
directly into a screw-glass vial. The vial was sealed with a PTFE
sealed screw cap under a N2 atmosphere and was removed from
the glove box. To the vial were successively added a magnetic
stirring bar, distilled toluene (1 mL), propargylamine
1
(0.400 mmol), and N,O-acetal 2 (0.440 mmol). The solution was
stirred at 100 °C for 2 h. After the reaction, the resultant mixture
was filtered through a pad of silica gel. The filtrate was purified by
silica gel chromatography (hexane/AcOEt = 9:1) to give the corre-
sponding pyrrole derivative 3.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures and characterization data
for the products obtained by this method and copies of the 1H and
13C NMR spectra of the products.
Acknowledgments
This work was partially supported by the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) through a
Grant-in-Aid for Scientific Research (C) (No. 25410120). We
deeply thank Shin-Etsu Chemical Co., Ltd., for the gift of hydro-
silanes.
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In summary, we have demonstrated the copper(II)-
catalyzed [4+1] annulation of propargylamines with N,O-
acetals that possess an ester, a ketone, and an amide unit,
leading to the facile production of polysubstituted pyrrole
derivatives. The key to this [4+1] annulation series is the
use of an N,O-acetal that can be enolizable. Also, we have
disclosed significant results: (1) with the copper catalyst,
these N,O-acetals effectively function as a C1 unit of a pyr-
role skeleton; (2) the central sp3-carbon displays the func-
tions of both an electrophile and a nucleophile; and (3) the
annulation series was achieved through both 5-endo-dig
cyclization and a subsequent aromatization. Furthermore,
we have demonstrated the copper(II)-catalyzed direct cou-
pling reaction of a propargylamine and ethyl glyoxylate in
the presence of a secondary amine, leading to the pro-
duction of a pyrrole derivative.
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[4+1] Annulation of Propargylamines with N,O-Acetals
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Received: January 21, 2015
Published Online: ᭿
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Job/Unit: O50098
/KAP1
Date: 16-02-15 14:36:19
Pages: 6
N. Sakai, H. Hori, Y. Ogiwara
SHORT COMMUNICATION
Pyrrole Synthesis
N. Sakai,* H. Hori, Y. Ogiwara ....... 1–6
Copper(II)-Catalyzed [4+1] Annulation of
Propargylamines with N,O-Acetals: Entry
to the Synthesis of Polysubstituted Pyrrole
Derivatives
A
CuCl2-catalyzed [4+1] annulation of
substituted pyrrole derivatives is presented.
This annulation series was achieved
through 5-endo-dig cyclization and sub-
sequent aromatization in one pot.
propargylamines with N,O-acetals having
an ester, a ketone, and an amide moiety,
leading to the facile preparation of poly-
Keywords: Annulation / Pyrroles / Acetals /
Copper / Propargylamines / Cyclization
6
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