One-pot preparation of pyrrole derivatives via the copper-catalyzed [4+1] annulation of propargylic amines with ethyl glyoxylate and phenylglyoxal in the presence of piperidine

Article abstract of DOI:10.1016/j.tetlet.2016.11.097

We describe how copper(II) chloride efficiently catalyzes the [4+1] annulation of propargylamines with either ethyl glyoxylate or phenylglyoxal functioning as a C1 unit, in the presence of piperidine, which leads to a straightforward and one-pot preparati

Full text of DOI:10.1016/j.tetlet.2016.11.097

Accepted Manuscript
One-Pot Preparation of Pyrrole Derivatives via the Copper-Catalyzed [4+1]
Annulation of Propargylic Amines with Ethyl Glyoxylate and Phenylglyoxal in
the Presence of Piperidine
Norio Sakai, Hiroki Suzuki, Hiroaki Hori, Yohei Ogiwara
PII:
S0040-4039(16)31578-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.097
TETL 48383
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
24 October 2016
17 November 2016
22 November 2016
Please cite this article as: Sakai, N., Suzuki, H., Hori, H., Ogiwara, Y., One-Pot Preparation of Pyrrole Derivatives
via the Copper-Catalyzed [4+1] Annulation of Propargylic Amines with Ethyl Glyoxylate and Phenylglyoxal in the
Presence of Piperidine, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.11.097
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Graphical Abstract
One-Pot Preparation of Pyrrole Derivatives
via the Copper-Catalyzed [4+1] Annulation of
Propargylic Amines with Ethyl Glyoxylate and
Phenylglyoxal in the Presence of Piperidine
Leave this area blank for abstract info.
Norio Sakai,* Hiroki Suzuki, Hiroaki Hori, and Yohei Ogiwara

1
Tetrahedron Letters
One-Pot Preparation of Pyrrole Derivatives via the Copper-Catalyzed [4+1]
Annulation of Propargylic Amines with Ethyl Glyoxylate and Phenylglyoxal in
the Presence of Piperidine
Norio Sakai,* Hiroki Suzuki, Hiroaki Hori, and Yohei Ogiwara
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We describe how copper(II) chloride efficiently catalyzes the [4+1] annulation of
propargylamines with either ethyl glyoxylate or phenylglyoxal functioning as a C1 unit, in the
presence of piperidine, which leads to a straightforward and one-pot preparation of pyrrole
derivatives. The key feature in this annulation is the in-situ generation of an N,O-hemiacetal
intermediate from either the glyoxylate or the glyoxal and a secondary amine.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Copper
[4+1] Annulation
Pyrrole
Propargylamine
Acetal
Introduction
and we have already demonstrated how the CuCl2-catalyzed
[4+1] annulation of propargylamines with an N,O-acetal leads to
the preparation of pyrrole derivatives (Eq 1 in Scheme 1).12,13,14
However, the annulation required preparing an N,O-acetal, which
is relatively sensitive to hydrolysis, that was obtained via a four-
step preparation. In addition, a trial examination of the direct
preparation of the pyrrole derivative by using a propargylamine
and ethyl glyoxylate in the presence of a secondary amine
resulted in only a moderate yield, and was limited to only one
example. During further improvement of this annulation,
however, we re-examined the reaction in greater detail and found
Pyrrole derivatives have assumed a central and important role
in nitrogen-containing heterocycles. This five-membered ring
framework has sustained the interest of organic and
pharmaceutical chemists, and it appears in a number of natural
products and biologically active substances.1 Thus far, many
approaches to a pyrrole skeleton via cyclization and annulation
have been developed. As classic examples, Parr-Knorr2 and
Clauson-Kass syntheses3 proceeded through an association with a
moiety of four carbons and one nitrogen amine. In addition to
those venerable examples, a variety of synthetic approaches have
been described: the Hantzsch,4 the Piloty-Robinsons,5 and the
Barton-Zard.6
However, there are only a few examples of synthetic methods
for the [4+1] preparation of pyrrole derivatives via the
combination of a [C-C-C-N] part and one carbon source. For
example, treatments of 1-azadienes with one carbon sources
involving esters,7 N,N-dimethylformamide (DMF),7 terminal
alkynes8 and acid chlorides,9 in the presence of either a metal
catalyst, such as niobium and rhodium, or a phosphine, can
achieve
a
pyrrole skeleton. Also, examples employing
propargylamines and either acid chlorides10 or H2/CO11 with a
rhodium catalyst, have enabled the production of pyrrole
derivatives.
In this context, our groups has pursued the development of a
facile and straightforward preparation of the pyrrole skeleton,
Scheme 1. The [4+1] annulation of propargylamines with either
ethyl glyoxylate or phenylglyoxal in the presence of a secondary
amine leading to pyrroles
 Corresponding author. Tel.: +81-4-7122-1092; fax: +81-4-
7123-9890; e-mail: sakachem@rs.noda.tus.ac.jp (N. Sakai).

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Tetrahedron Letters
a one-pot preparation of substituted pyrrole derivatives that led
a catalytic amount (0.2 equiv to the glyoxylate) of the secondary
amine did not promote the annulation, which led to a decrease in
the product yield (41%).
to the in-situ generation of an N,O-hemiacetal from ethyl
glyoxylate (or phenylglyoxal) and a secondary amine with a
subsequent copper-catalyzed [4+1] annulation (Eq 2 in Scheme
1). In this letter, we report the scope and limitations of this
process.
With the optimal conditions in hand, the substituent effect of
an aryl group on the propargylamine was then examined (Table
2). Most N-arylated propargylamines yielded the corresponding
pyrroles 2-11 in relatively good yields (entries 1-10). These
contained either an electron-withdrawing group, such as
halogens, a CF3 and an acetyl group, or an electron-donating
group, such as a methoxy and an alkyl group. Also, regardless of
the location of the alkyl group on the benzene ring, the expected
[4+1] annulation proceeded cleanly (entries 8-10). Moreover, a
propargylamine with a naphthyl ring also led to the production of
pyrrole 12 (entry 11). Unfortunately, this reaction system could
not be applied to substrates with a pyridine ring, which resulted
in the complicated mixture, probably due to a strongly basic
nitrogen atom (entry 12). Also, [4+1] annulation using an N-
alkyl-propargylamine with a phenethyl group hardly proceeded
(entry 13). Moreover, the use of N-unsubstituted propargylamine
resulted in the formation of a complex mixture (entry 14).
Results and discussion
Examinations of the detailed reaction conditions for the [4+1]
annulation of N-phenylpropargylamine with ethyl glyoxylate
leading to pyrrole 1 were reinvestigated (Table 1).15 On the basis
of our previous work, an annulation of the propargylic amine and
ethyl glyoxylate in the presence of CuCl2 and piperidine was
initially examined in several solvents (entries 1-4). Consequently,
toluene and 1,2-dichloroethane showed the better results. Also,
increasing the reaction temperature (100 ˚C) in toluene slightly
improved the yield (entry 5). To prevent decomposition of the
glyoxylate ester at high temperature, an equivalent amount of
ethyl glyoxylate was increased to 4 equiv per the amine, and the
product was yielded in an 82% GC yield. Then, pyrrole 1 was
finally isolated in a 60% yield after common column purification
(entries 6 and 7). There was no clear reason for the significant
decrease in the isolation step. Other copper(II) catalysts, such as
CuBr2 and Cu(OAc)2, were ineffective in this annulation process
(entries 8 and 9). The use of copper(I) catalysts also led to a
decrease in the product yield (entries 10-12).16 Because the
annulation without a secondary amine did not form a pyrrole
derivative,12 we speculated that the role of piperidine was to form
an N,O-hemiacetal intermediate with the glyoxylate ester in-situ.
Indeed, the addition of a secondary amine to the reaction system
was indispensable to the series of annulations. When several
secondary amines were examined, instead of piperidine,
pyrrolidine showed a moderate effect (1: 53%), but morpholine
and diisopropylamine were ineffective. On the other hand,
Table 2. Scope of N-aryl-, N-alkyl- or N-unsubstituted
propargylamines
entry
product
yield
(%)a
Ar or R
1
2
4-Cl-C6H4
4-Br-C6H4
4-I-C6H4
2
3
54 (70)
48 (74)
56 (76)
54 (74)
53 (75)
50 (62)
54 (60)
52 (66)
54 (77)
56 (59)
50 (60)
CMb
3
4
Table 1. Examination of the reaction conditionsa
4
4-CF3-C6H4
4-Ac-C6H4
4-MeO-C6H4
2-MeO-C6H4
4-Me-C6H4
3-Me-C6H4
2-Me-C6H4
1-naphthyl
4-pyridinyl
PhCH2CH2
H
5
5
6
6
7
7
8
8
9
9
10
11
12
13
14
15
entry
[Cu] catalyst
solv
temp
(˚C)
80
yield
(%)b
56
10
11
12
13
14
1
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuBr2
Cu(OAc)2
CuCl
toluene
1,2-DCEc
DMF
2
80
58
trace
CMb
3
80
14
4
NMPd
80
20
5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
100
100
100
100
100
100
100
100
63
a Isolated (NMR) yield. b A complex mixture.
6e
7f
8
70
82g (60)
Annulations with a propargylamine, which has a branched
structure adjacent to a nitrogen atom, were then performed under
the optimal conditions (Scheme 2). When using a substrate with
an N-phenyl substituent, the expected trisubstituted pyrrole
33
9
27
10
11
12
38
CuBr
34
CuI
32
a
Standard conditions;
a copper catalyst (0.020 mmol), N-
phenylpropargylamine (0.40 mmol), ethyl glyoxylate (0.44 mmol),
solvent (1 mL), 2 h. b GC (Isolated) yield. c 1,2-Dichloroethane. d N-
e
Methylpyrrolidone. Ethyl glyoxylate and piperidine (2 equiv per
f
Scheme 2. Scope of branched propargylaminesa
propargylamine). Ethyl glyoxylate and piperidine (4 equiv per
propargylamine). g Average of two runs.

3
derivative 16 was obtained in a 50% yield. In contrast, the
substrate with an N-phenethyl group finally led to the
complicated mixture.
an N,O-hemiacetal intermediate and
a
subsequent
intramolecular cyclization between an alkyne moiety and a
formed enolate species in a 5-endo-dig manner.
Gratifyingly, the copper catalytic system could be applied to
the [4+1] annulation of propargylamines with a glyoxal that had a
ketone moiety instead of an ester portion (Scheme 3). For
example, when phenylglyoxal was treated with three types of N-
arylated propargylic amines under the optimal conditions, the
annulation of all substrates proceeded to produce the
corresponding pyrrole derivative 18, 19 and 20 in 67, 48, and
54% yields, respectively.
Acknowledgement
We deeply thank Shin-Etsu Chemical Co., Ltd., for the gift of
chlorotrimethylsilane and trimethylsilylacetylene.
References and notes
1.
2.
(a) Estevez, V.; Villacampa, M.; Menendez, J. C. Chem. Soc. Rev.
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L. F.; Sega, A.; Taddei, M. Eur. J. Org. Chem. 2005, 5277-5288.
(c) Banik, B. K.; Banik, I.; Renteria, M.; Dasgupta, S. K.
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Jothilingam, S.; Scheeren, H. W. Tetrahedron 2004, 60, 1625-
1630. (e) Paal, C. Ber. Dtsch. Chem. Ges. 1885, 18, 367-371. (f)
Knorr, L. Ber. Dtsch. Chem. Ges. 1884, 17, 1635-1642.
For example; (a) Mahmoudi, H.; Jafari, A. A. ChemCatChem
2013, 5, 3743-3749. (b) Azizi, N.; Khajeh-Amiri, A.; Ghafuri, H.;
Bolourtchian, M.; Saidi, M. R. Synlett 2009, 2245-2248. (c)
Gourlay, B. S.; Molesworth, P. P.; Ryan, J. H.; Smith, J. A.
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L. J. Org. Chem. 1962, 27, 2466-2470. (e) Clauson-Kass, N.;
Tyle, Z. Acta Chem. Scand. 1952, 6, 667-670.
3.
Scheme 3. Application to [4+1] annulation with phenylglyoxal
Scheme 4 shows the plausible reaction mechanism for the
[4+1] annulation. The first key step was that both the in-situ
generation of N,O-hemiacetal A from a glyoxylate ester (or
phenylglyoxal) and a secondary amine (piperidine), and a
subsequent conversion to iminium intermediate B proceeded in
the presence of a copper(II) catalyst. The second key step
involved the enolization from intermediate C, which was formed
through a nucleophilic addition of a propargylamine to B, to
intermediate D and the subsequent intramolecular nucleophilic
addition of the enol part to an alkyne moiety activated by a
copper(II) catalyst.12,13 The final step proceeded through 5-endo-
dig cyclization and protonation to yield the 5-membered ring
skeleton E.17 We assumed that unlike a copper(I) catalyst, a
copper (II) catalyst generally shows borderline Lewis acidity to
function as a dual activator of a carbonyl group and an triple
bond, which successfully led to a smooth [4+1] annulation.18
4.
5.
For example; (a) Estevez, V.; Villacampa, M.; Menendez, J. C.
Chem. Commun. 2013, 49, 591-593. (b) Hantzsch, A. Ber. Dtsch.
Chem. Ges. 1890, 23, 1474-1476.
For example; (a) Milgram, B. C.; Eskildsen, K.; Richter, S. M.;
Scheidt, W. R.; Scheidt, K. A. J. Org. Chem. 2007, 72, 3941-
3944. (b) Posvic, H.; Dombro, R.; Ito, H.; Telinski, T. J. Org.
Chem. 1974, 39, 2575-2580. (c) Robinson, G. M.; Robinson, R. J.
Chem. Soc., Trans. 1918, 113, 639-645. (d) Piloty, O. Ber. Dtsch.
Chem. Ges. 1910, 43, 489-498.
6.
For example; (a) Banala, S.; Wurst, K.; Kräutler, B. Helv. Chim.
Acta 2010, 93, 1192-1198. (b) Coffin, A. R.; Roussell, M. A.;
Tserlin, E.; Pelkey, E. T. J. Org. Chem. 2006, 71, 6678-6681. (c)
Bhattacharya, A.; Cherukuri, S.; Plata, R. E.; Patel, N.; Tamez Jr,
V.; Grosso, J. A.; Peddicord, M.; Palaniswamy, V. A. Tetrahedron
Lett. 2006, 47, 5481-5484. (d) Barton, D. H. R.; Kervagoret, J.;
Zard, S. Z. Tetrahedron 1990, 46, 7587-7598. (e) Barton, D. H.
R.; Zard, S. Z. J. Chem. Soc., Chem. Commun. 1985, 1098-1100.
Roskamp, E. J.; Dragovich, P. S.; Hartung, J. B.; Pedersen, S. F. J.
Org. Chem. 1989, 54, 4736-4737.
7.
8.
9.
Mizuno, A.; Kusama, H.; Iwasawa, N. Angew. Chem. Int. Ed.
2009, 48, 8318-8320.
Lu, Y.; Arndtsen, B. A. Org. Lett. 2009, 11, 1369-1372.
10. Merkul, E.; Boersch, C.; Frank, W.; Müller, T. J. J. Org. Lett.
2009, 11, 2269-2272.
11. Campi, E. M.; Roy Jackson, W.; Nilsson, Y. Tetrahedron Lett.
1991, 32, 1093-1094.
12. Sakai, N.; Hori, H.; Ogiwara, Y. Eur. J. Org. Chem. 2015, 1905-
1909.
13. For the paper of a 6-member ring construction with an N,O-acetal,
see: Sakai, N.; Tamura, K.; Shimamura, K.; Ikeda, R.;
Konakahara, T. Org. Lett. 2012, 14, 836-839.
14. For selected recent papers using N,O-acetals, which function as a
C1 carbon source, see: (a) Aliyenne, A.; Pin, F.; Nimbarte, V. D.;
Lawson, A. M.; Comesse, S.; Sanselme, M.; Tognetti, V.; Joubert,
L.; Daïch, A. Eur. J. Org. Chem. 2016, 3592-3602. (b) Wunder,
S.; Deutsch, A.; Deutsch, C.; Hoffmann-Röder, A. Synthesis 2016,
48, 1167-1176. (c) Chen, Q.; Liu, C.; Guo, F.; Li, L. Tetrahedron
2015, 71, 5337-5340. (d) Sakai, N.; Hori, H.; Yoshida, Y.;
Konakahara, T.; Ogiwara, Y. Tetrahedron 2015, 71, 4722-4729.
(e) Michalska, M.; Songis, O.; Taillier, C.; Bew, S. P.; Dalla, V.
Adv. Synth. Catal. 2014, 356, 2040-2050. (f) Hamon, M.;
Dickinson, N.; Devineau, A.; Bolien, D.; Tranchant, M.-J.;
Taillier, C.; Jabin, I.; Harrowven, D. C.; Whitby, R. J.; Ganesan,
A.; Dalla, V. J. Org. Chem. 2014, 79, 1900-1912.
Scheme 4. A plausible reaction path for the [4+1] annulation
Conclusions
We demonstrated a one-pot and straightforward preparation of
pyrrole derivatives with an ester or a ketone group at the 2-
postion via the copper(II)-catalyzed [4+1] annulation of
propargylamines with ethyl glyoxylate or phenylglyoxal in the
presence of a secondary amine, piperidine. We found that the key
steps in the series of annulations included an in-situ formation of
15. General procedure for Cu-catalyzed an [4+1] annulation of
propargylamines and ethyl glyoxylate in the presence of
piperidine: In a glove box, CuCl2 (0.0200 mmol, 2.68 mg) was

4
Tetrahedron Letters
weighed directly into a screw glass vial. The vial was sealed
Miura, T.; Iwasawa, N. J. Am. Chem. Soc. 2002, 124, 518-519. (e)
Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem.
Int. Ed. 2004, 43, 5350-5352. (f) Barluenga, J.; Palomas, D.;
Rubio, E.; González, J. M. Org. Lett. 2007, 9, 2823-2826. (g) Gou,
F.-R.; Bi, H.-P.; Guo, L.-N.; Guan, Z.-H.; Liu, X.-Y.; Liang, Y.-
M. J. Org. Chem. 2008, 73, 3837-3841. (h) Fujino, D.; Yorimitsu,
H.; Osuka, A. Org. Lett. 2012, 14, 2914-2917. (i) Chan, L. Y.;
Kim, S.; Park, Y.; Lee, P. H. J. Org. Chem. 2012, 77, 5239-5244.
(j) Brazeau, J.-F.; Zhang, S.; Colomer, I.; Corkey, B. K.; Toste, F.
D. J. Am. Chem. Soc. 2012, 134, 2742-2749.
with a PTFE sealed screw cap under a N2 atmosphere. To the vial
was successively added a magnetic stirring bar, distilled toluene (1
mL), propargylamine (0.400 mmol), an ethyl glyoxylate 50%
toluene solution (0.440 mmol, 81.7 mg), and piperidine (0.440
mmol, 37.5 mg). The solution was stirred at 100 ˚C for 2 h. After
the reaction, the mixture was directly subjected to
a
chromatography column filled with silica gel without the usual
work-up, and was then purified with an eluent (hexane : AcOEt =
9 : 1) to isolate the corresponding pyrrole. Ethyl 1-phenyl-1H-
pyrrole-2-carboxylate (1): 60% (52 mg); a brown oil; 1H NMR
(500 MHz, CDCl3)  1.20 (t, 3 H, J = 7.0 Hz), 4.15 (q, 2 H, J = 7.0
Hz), 6.28 (dd, 1 H, J = 2.5 and 3.5 Hz), 6.93 (dd, 1 H, J = 2.0 and
2.5 Hz), 7.11 (dd, 1 H, J = 2.0 and 3.5 Hz), 7.30−7.42 (m, 5 H);
13C NMR (125 MHz, CDCl3)  14.2, 59.8, 109.0, 118.7, 123.6,
126.3, 127.7, 128.5, 129.6, 140.5, 160.4; MS (FAB): m/z 216
[M+H]+.
18. Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533-3539.
Supplementary Material
Copies of the 1H and 13C NMR spectra of the pyrrole
derivatives that were produced by this procedure were supplied.
16. When several Brønsted acids were examined in this annulation, no
improvement of the product yield was observed.
17. For selected papers of carbocycles via 5-endo-dig cyclization, see:
(a) McDonald, F. E.; Olson, T. C. Tetrahedron Lett. 1997, 38,
7691-7692. (b) Maeyama, K.; Iwasawa, N. J. Am. Chem. Soc.
1998, 120, 1928-1929. (c) Iwasawa, N.; Miura, T.; Kiyota, K.;
Kusama, H.; Lee, K.; Lee, P. H. Org. Lett. 2002, 4, 4463-4466. (d)
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[Highlights]
Copper(II) chloride catalyzes [4+1] annulation.
Pyrroles are constructed from propargylamines and
either a glyoxylate or a glyoxal.
An N,O-Hemiacetal is formed from either a
Glyoxylate or a glyoxal and piperidine.