Unusual domino Michael/aldol condensation reactions employing oximes as N-selective nucleophiles: Synthesis of N-hydroxypyrroles

Article abstract of DOI:10.1002/anie.200805205

(Figure Presented) A facile synthesis of N-hydroxypyrroles has been developed using readily available α-carbonyl oximes and α,β-unsaturated aldehydes. The domino reaction proceeds through iminium activation of α,β-unsaturated aldehydes, Michael addition u

Full text of DOI:10.1002/anie.200805205

Communications
DOI: 10.1002/anie.200805205
Pyrrole Synthesis
Unusual Domino Michael/Aldol Condensation Reactions
Employing Oximes as N-Selective Nucleophiles: Synthesis of
N-Hydroxypyrroles**
Bin Tan, Zugui Shi, Pei Juan Chua, Yongxin Li, and Guofu Zhong*
Dedicated to Professor Li-Xin Dai on the occasion of his 85th birthday
As one of the most important classes of heterocycles, pyrroles
are not only important building blocks in the synthesis of
natural products,[1] but also key structural units in compounds
with interesting biological activities.[2] Pyrroles have also
found broad application in materials chemistry.[3] Accord-
ingly, substantial attention has been paid to develop efficient
methods for their synthesis. One of the common approaches
to pyrrole synthesis is the Paal–Knorr reaction, in which 1,4-
dicarbonyl compounds are converted into pyrroles by acid-
mediated dehydrative cyclization.[4] However, this approach
is usually subject to significant limitations in terms of
substituents introduced, substitution patterns, or regioselec-
tivities.
derivatives through this simple and mild domino strategy has
not been reported to date.
Amine catalysts perform efficient iminium activation by
lowering the LUMO of a,b-unsaturated aldehydes.[7a,10] Thus,
we set out to investigate the use of IV as a catalyst for a
domino reaction involving sequential Michael addition and
intramolecular aldol condensation (Scheme 1, Table 1). Ini-
Although several novel synthetic strategies have been
described in recent years,[5,6] a general facile and regioselec-
tive approach to generate pyrroles with a wide functional-
group tolerance from readily available precursors is still
lacking. Over the past few years, organocatalytic domino
reactions have emerged as a powerful synthetic paradigm to
make diverse molecules.[7] The operational simplicity, readily
available catalysts, and low toxicity associated with organo-
catalysis make it an attractive method in organic synthesis.
Herein, we report a catalytic synthesis of multisubstituted
N-hydroxypyrroles by the domino reaction of a-carbonyl
oxime compounds[8] and a,b-unsaturated aldehydes in the
presence of secondary amine catalysts through the iminium
activation strategy.[8a,9] This approach is differs from previ-
ously reported strategies, as oximes were employed as N-
selective nucleophiles in the Michael addition step instead of
the more commonly used O-selective nucleophiles in organo-
catalysis.[8a,b] To our knowledge, the formation of pyrrole
Scheme 1. Proposed mechanism of the domino Michael addition/aldol
condensation reaction by iminium activation in pyrrole synthesis.
tially, we used ethyl 2-(hydroxyimino)-3-oxobutanoate (1a)
and (E)-hex-2-enal (2a) as reactants to test the reaction.
Pleasingly, the reaction led smoothly to the formation of N-
hydroxypyrrole in good yield. After optimizing the reaction
conditions by changing the amount of the aldehyde and
studying solvent effects, the yield was improved to 82%
(Table 1, entry 4). With these encouraging results at hand, we
explored other secondary amine catalysts (I–VII, Table 1).
The results were influenced by both amine catalysts and
solvents. Surprisingly, no product was obtained when DMSO
or DMF was used as solvent. Eventually, we decided to use
diisopropylamine (VII) as a catalyst for this study, owing to its
cheap price, ready availability, and higher catalytic efficiency
in the reaction (Table 1, entry 7). After the optimal conditions
have been established with catalyst VII, the generality of the
domino process was investigated (Table 2). Good yields were
achieved with many substrates (Table 2, entries 1–19) and
several types of R1 group, such as Me, MeO, EtO, tBuO, and
BnO, did not significantly affect the reaction (Table 2,
entries 1–9). If R2 was changed from methyl to ethyl, the
yields were almost the same even when different aldehydes
were used (Table 2, entries 10–13). When a less reactive
substrate was used, a higher catalytic loading and longer
reaction time were required to obtain pyrrole 3u in 58% yield
(entry 21). To our delight, the above reaction proceeded well
[*] B. Tan, Z. Shi, P. J. Chua, Dr. Y. Li, Prof. Dr. G. Zhong
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences
Nanyang Technological University
21 Nanyang Link, Singapore 637371 (Singapore)
Fax: (+65)6791-1961
E-mail: guofu@ntu.edu.sg
[**] Research support from the Ministry of Education in Singapore
(ARC12/07 #T206B3225) and Nanyang Technological University
(URC RG53/07 and SEP RG140/06) is gratefully acknowledged. We
are very grateful to Prof. K. Narasaka and Dr. S. Chiba for helpful
discussions.
Supporting Information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805205.
758
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 758 –761

Angewandte
Chemie
Table 1: Screening of catalysts and solvents for the domino reaction[a]
with a variety of different functional groups R3, such as
phenylethyl, benzoxypropyl, and 2-(tert-butoxycarbonylami-
no)ethyl, attached to the a,b-unsaturated aldehydes (Table 2,
entries 5, 6, 18–20). However, the reaction did not proceed
when the a,b-unsaturated aldehydes possessed beta aromatic
substituents, such as phenyl. We believe that this domino
reaction could find potential use in synthetic chemistry
laboratories and in industry, despite its limitations, since R3
bearing many different functionalities could be tolerated.
When oxime compound 4 was subjected to the above
reaction conditions, the two theoretically predicted pyrroles
(5 and 6, Scheme 2) were isolated (Table 3, entries 2 and 3).
Interestingly, the use of different substituted aldehydes could
Entry
Catalyst
Solvent
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
9
I
II
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
Et2O
10
12
12
10
18
18
18
24
24
24
58
61
63
82
66
67
83
79
33
0
III
IV
V
VI
VII
VII
VII
VII
10
DMSO
Scheme 2. Regioselectivity of the domino reaction.
[a] Reactions were carried out using 1a (0.2 mmol, 1.0 equivalents) and
2a (0.5 mmol, 2.5 equivalents) with catalyst (20 mol%) in solvent
(1.0 mL) at room temperature. [b] Yield of isolated product.
Table 3: Regioselectivity in the domino reaction of diketone oximes 4
and a,b-unsaturated aldehydes.[a]
Entry
R
Cat Solvent Yield of 5 [%][b] Yield of 6 [%][b]
Table 2: Synthesis of N-hydroxypyrroles by the domino Michael addi-
1
2
3
4
5
6
7
Me
nPr
VII toluene 5a, 76
VII toluene 5b (62)
6a, trace[c]
6b, 13
6c, 16
tion/aldol condensation reaction.[a]
Me(CH2)4 VII toluene 5c, 60
Me(CH2)4 VII CH2Cl2 5c, 64
Me(CH2)4
Me(CH2)4
nPr
6c, 13
IV
V
toluene 5c, 71
toluene 5c, 61
toluene 5b, 78
6c, trace
6c, trace
6b, trace
IV
Entry
Oxime 1
Enal 2
Time [h] Yield of 3 [%][b]
[a] Reactions were carried out using 4 (0.3 mmol, 1.0 equivalents) and
aldehyde (0.6 mmol, 2.0 equivalents) in the presence of catalyst
(20 mol%) in solvent (1.0 mL) at room temperature. [b] Yield of isolated
product. [c] Almost undetectable.
R1
R2
R3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21[c]
EtO
EtO
EtO
EtO
EtO
EtO
MeO
tBuO
BnO
MeO
MeO
MeO
MeO
Me
Me
Me
Me
Me
Me
Me
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
nPr
Me
Et
18
18
18
18
24
24
18
24
18
24
24
24
24
18
18
18
18
18
18
24
48
3a, 83
3b, 83
3c, 81
3d, 76
3e, 82
3 f, 78
3g, 73
3h, 72
3i, 75
3j, 77
3k, 67
3l, 79
3m, 66
3n, 79
3o, 81
3p, 83
3q, 77
3r, 82
3s, 73
3t, 61
3u, 58
Me(CH2)4
PhCH2CH2
BnOCH2CH2CH2
influence the results significantly. For example, when R3 was a
methyl group, only one product (5a) was isolated, prompting
us to investigate the reaction further by changing other
conditions in order to achieve higher regioselectivity.
Although changing the solvent did not improve the results,
changing the catalyst to IVor V (Table 3, 5–7) surprisingly led
to the formation of only one major product. The excellent
regioselectivity may be attributed to the bulky group in
catalyst IV and hydrogen bonding in catalyst V.
Transforming product 3a into 1H-pyrrole under mild
conditions with good yield illustrated the synthetic usefulness
of these polyfunctionalized N-hydroxypyrroles. Furthermore,
the methyl group can be facilely converted into an aldehyde
(Scheme 3).[11]
Me
Me
Me
Me
Et
Et
Et
nPr
Et
Me(CH2)4
Me
Me
Me
Me
Me
Me
Me
Me
Ph
nPr
Et
Me(CH2)4
PhCH2CH2
BnOCH2CH2CH2
BocNHCH2CH2
Me
X-ray crystallographic analysis (Figure 1)[12] of the
domino product 3r further confirmed the structure of the
product established by NMR spectroscopy.
One-pot multicomponent reactions have recently gained
considerable and steadily increasing academic, economic, and
ecological attention owing to their improved efficiency,
reduced waste, and rapid access of structural diversity.[10]
[a] Unless otherwise specified, reactions were carried out using 1
(0.2 mmol, 1.0 equivalents) and 2 (0.5 mmol, 2.5 equivalents) in the
presence of VII (20 mol%) in toluene (1.0 mL) at room temperature.
[b] Yield of isolated product. [c] 30 mol% catalyst was used. Boc=tert-
butoxycarbonyl.
Angew. Chem. Int. Ed. 2009, 48, 758 –761
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
759

Communications
Scheme 3. Transformation into 1H-pyrrole 7.
Figure 2. Preliminary conjecture of mechanism: the effect of intra-
molecular hydrogen bonding (see Scheme 5).
exclusively the O-selective Michael adduct, which supported
our hypothesis as 8 was unable to form intramolecular
hydrogen bonds. Furthermore, when acetyl or methyl-pro-
tected oxime 11 or 13 was used in this reaction, the reaction
did not proceed at all (Scheme 5), further strengthening our
conjecture that the intramolecular hydrogen bond is the main
driving force for producing N-selective products.
Figure 1. Molecular structure of 3r determined by X-ray diffraction
crystallography.
Such reactions carried out in water[13] would be ideal reactions
from a green chemistry perspective. Considering these
advantages, we carried out these reactions in water, leading
to N-hydroxypyrroles isolated as major products in moderate
yields (Scheme 4). Notably, lower yields were obtained from
Scheme 5. Control reactions for investigation of O/N-selectivity.
In summary, a facile and efficient one-pot synthesis of
polyfunctionalized N-hydroxypyrroles has been developed,
using readily available carbonyl oximes and a,b-unsaturated
aldehydes. This synthesis involves sequential Michael addi-
tion, intramolecular aldol condensation, and aromatization
reactions through iminium activation of a,b-unsaturated
aldehydes by diisopropylamine. In the domino synthesis,
carbonyl oximes acted as unusual N-selective nucleophiles in
the Michael addition reaction. This method employed readily
available starting materials and mild conditions, and pro-
ceeded in good yields with wide substrate scope, high
regioselectivity, and flexible substitution patterns, affording
products with great synthetic potential. Our future studies will
entail expansion of the scope and applications of these
powerful domino processes.
Scheme 4. One-pot synthesis of N-hydroxypyrrole in water.
the one-pot synthesis of pyrrole when compared with that
from two separate steps with carbonyl compounds, possibly as
a result of the significant influence of solvent in these
reactions.
Experimental Section
A possible explanation as to why the unusual N-selective
Michael products were obtained from the above reaction
protocol is attributed to the different substrate structures. The
ability of the dicarbonyl oxime to form an intramolecular
hydrogen bond (Figure 2). The intramolecular hydrogen bond
could decrease the nucleophilicity of the oxime oxygen, thus
increasing the nucleophilicity of the oxime nitrogen and
resulting in N-selectivity. Based on the above deduction, we
carried out some control experiments. (E)-Oxime 8 afforded
Typical Procedure for N-Hydroxypyrrole Synthesis (Table 2, entry 1):
Catalyst VII (0.04 mmol, 0.2 equivalents)was added to a solution of
oxime 1a (0.2 mmol, 1.0 equivalents) and (E)-hex-2-enal 2a
(0.5 mmol, 2.5 equivalents) in toluene (1.0 mL) at room temperature.
The resulting mixture was stirred vigorously. After the reaction was
completed (monitored by thin-layer chromatography), the mixture
was quenched with saturated ammonium chloride, extracted with
dichloromethane (8 mL) three times, dried over anhydrous Na2SO4,
and concentrated under reduced pressure. Flash column chromatog-
raphy on silica gel (gradient elution, EtOAc/Hexane = 1:15–1:10)
760
www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 758 –761

Angewandte
Chemie
afforded the pure product 3a in 81% yield. 1H NMR (400 MHz,
CDCl3): d = 12.37 (s, 1H), 9.96 (s, 1H), 4.44 (q, J = 7.2 Hz, 2H), 2.96
(t, J = 7.6 Hz, 2H), 2.57 (s, 3H), 1.74–1.66 (m, 2H), 1.44 (t, J = 7.6 Hz,
3H), 0.99 ppm (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d =
184.8, 165.5, 137.9, 127.8, 115.1, 112.4, 61.6, 24.7, 21.7, 14.3, 13.7,
10.6 ppm. HRMS (ESI) [M + H]+ calcd for C12H18NO4: 240.1236;
found: 240.1238 (see the Supporting Information for full experimen-
tal details).
D. H. Huang, N. D. P. Cosford, Org. Lett. 2002, 4, 3537; d) L. Lu,
G. Chen, S. Ma, Org. Lett. 2006, 8, 835; e) M. Shimizu, A.
Takahashi, S. Kawai, Org. Lett. 2006, 8, 3585; f) M. Shindo, Y.
Yoshimura, M. Hayashi, H. Soejima, T. Yoshikawa, K. Matsu-
moto, K. Shishido, Org. Lett. 2007, 9, 1963; g) M. R. Rivero, S. L.
Buchwald, Org. Lett. 2007, 9, 973; h) D. J. St. Cyr, B. A.
Arndtsen, J. Am. Chem. Soc. 2007, 129, 12366; i) S. Chiba, Y.
Wang, G. Lapointe, K. Narasaka, Org. Lett. 2008, 10, 313; j) B.
Alcaide, P. Almendros, R. Carrascosa, M. C. Redondo, Chem.
Eur. J. 2008, 14, 637.
Received: October 24, 2008
Revised: November 16, 2008
[7] For a review, see: a) D. Enders, C. Grondal, M. R. M. Hꢂttl,
Angew. Chem. 2007, 119, 1590; Angew. Chem. Int. Ed. 2007, 46,
1570. For selected recent examples: b) B. Tan, Z. Shi, P. J. Chua,
G. Zhong, Org. Lett. 2008, 10, 3425; c) B. Tan, P. J. Chua, X.
Zeng, M. Lu, G. Zhong, Org. Lett. 2008, 10, 3489; d) D. Zhu, M.
Lu, P. J. Chua, B. Tan, F. Wang, G. Zhong, Org. Lett. 2008, 10,
4585; e) D. Enders, M. R. M. Hꢂttl, C. Grondal, G. Raabe,
Nature 2006, 441, 861; f) Y. Yamamoto, N. Momiyama, H.
Yamamoto, J. Am. Chem. Soc. 2004, 126, 5962; g) D. B.
Ramachary, N. S. Chowdari, C. F. Barbas III, Angew. Chem.
2003, 115, 4365; Angew. Chem. Int. Ed. 2003, 42, 4233; h) M. Lu,
D. Zhu, Y. Lu, Y. Hou, B. Tan, G. Zhong, Angew. Chem. 2008,
120, 10341; Angew. Chem. Int. Ed. 2008, 47, 10187.
[8] For the O-selective organocatalytic Michael addition of oximes
to enals: a) S. Bertelsen, P. Dinꢄr, R. L. Johansen, K. A.
Jørgensen, J. Am. Chem. Soc. 2007, 129, 1536; b) A. Carlone,
G. Bartoli, M. Bosco, F. Pesciaioli, P. Ricci, L. Sambri, P.
Melchiorre, Eur. J. Org. Chem. 2007, 5492. For a review on
amination with oximes: c) K. Narasaka, M. Kitamura, Eur. J.
Org. Chem. 2005, 4505.
[9] For reviews: a) C. F. Barbas III, Angew. Chem. 2008, 120, 44;
Angew. Chem. Int. Ed. 2008, 47, 42; b) S. Mukherjee, J. W. Yang,
S. Hoffmann, B. List, Chem. Rev. 2007, 107, 5471; c) G. Lelais,
D. W. C. A. MacMillan, Aldrichimica Acta 2006, 39, 79; d) I.
Erkkila, P. Majander, M. Pihko, Chem. Rev. 2007, 107, 5416;
e) G. Bartoli, P. Melchiorre, Synlett 2008, 1759. Examples of
iminium activation of conjugated aldehydes: f) D. Enders, M. H.
Bonten, G. Raabe, Synlett 2007, 0885; g) C. Palomo, A. Landa,
A. Mielgo, M. P. A. Oiarbide, S. Vera, Angew. Chem. 2007, 119,
8583; Angew. Chem. Int. Ed. 2007, 46, 8431; h) A. Mielgo, C.
Palomo, Chem. Asian J. 2008, 3, 922; i) P. Melchiorre, M. Marigo,
A. Carlone, G. Bartoli, Angew. Chem. 2008, 120, 6232; Angew.
Chem. Int. Ed. 2008, 47, 6138.
Keywords: aldehydes · aldol reaction · domino reactions ·
.
Michael addition · N heterocycles
[1] a) G. W. Gribble in Comprehensive Heterocyclic Chemistry II,
Vol. 2 (Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven),
Elsevier, Oxford, 1996, p. 207; b) C. T. Walsh, S. Garneau-
Tsodikova, A. Howard-Jones, Nat. Prod. Rep. 2006, 23, 517;
c) H. Hoffmann, T. Lindel, Synthesis 2003, 1753; d) D. L. Boger,
C. W. Boyce, M. A. Labroli, C. A. Sehon, Q. Jin, J. Am. Chem.
Soc. 1999, 121, 54.
[2] a) J. W. Huffman, Curr. Med. Chem. 1999, 6, 705; b) S. Agarwal,
S. Cꢀmmerer, S. Filali, W. Frꢁhner, J. Knꢁll, M. P. Krahl, K. R.
Reddy, H. J. Knꢁlker, Curr. Org. Chem. 2005, 9, 1601.
[3] a) C. F. Lee, L. M. Yang, T. Y. Hwu, A. S. Feng, J. C. Tseng, T. Y.
Luh, J. Am. Chem. Soc. 2000, 122, 4992; b) P. Novak, K. Mꢂller,
K. S. V. Santhanam, O. Haas, Chem. Rev. 1997, 97, 207; c) N. J. L.
Guernion, W. Hayes, Curr. Org. Chem. 2004, 8, 637.
[4] a) C. Paal, Ber. Dtsch. Chem. Ges. 1885, 18, 367; b) L. Knorr, Ber.
Dtsch. Chem. Ges. 1885, 18, 299. For recent examples: c) J. Chen,
H. Wu, Z. Zheng, C. Jin, X. Zhang, W. Su, Tetrahedron Lett.
2006, 47, 5383; d) G. Minetto, L. F. Raveglia, A. Sega, M. Taddei,
Eur. J. Org. Chem. 2005, 5277; e) B. K. Banik, I. Banik, M.
Renteria, S. K. Dasgupta, Tetrahedron Lett. 2005, 46, 2643; f) G.
Minetto, L. F. Raveglia, M. Taddei, Org. Lett. 2004, 6, 389;
g) A. R. Bharadwaj, K. A. Scheidt, Org. Lett. 2004, 6, 2465; h) B.
Khalili, P. Jajarmi, B. Eftekhari-Sis, M. M. Hashemi, J. Org.
Chem. 2008, 73, 2090.
[5] Examples of metal-catalyzed pyrrole syntheses: a) J. T. Kim,
A. V. Kelꢃin, V. Gevorgyan, Angew. Chem. 2003, 115, 102;
Angew. Chem. Int. Ed. 2003, 42, 98; b) G. Balme, Angew. Chem.
2004, 116, 6396; Angew. Chem. Int. Ed. 2004, 43, 6238; c) A. V.
Kelꢃin, A. W. Sromek, V. Gevorgyan, J. Am. Chem. Soc. 2001,
123, 2074; d) D. J. St. Cyr, N. Martin, B. A. Arndtsen, Org. Lett.
2007, 9, 449; e) J. T. Binder, S. F. Kirsch, Org. Lett. 2006, 8, 2151;
f) D. J. Gorin, N. R. Davis, F. D. Toste, J. Am. Chem. Soc. 2005,
127, 11260; g) R. Dhawan, B. A. Arndtsen, J. Am. Chem. Soc.
2004, 126, 468; h) S. Su, J. A. Porco, Jr., J. Am. Chem. Soc. 2007,
129, 7744; i) L. Peng, X. Zhang, J. Ma, Z. Zhong, J. Wang, Org.
Lett. 2007, 9, 1445; j) Y. Yamamoto, H. Hayashi, T. Saigoku, H.
Nishiyama, J. Am. Chem. Soc. 2005, 127, 10804; k) Y. Wang,
K. K. Toh, S. Chiba, K. Narasaka, Org. Lett. 2008, 10, 5019.
[6] Examples of metal-free pyrrole syntheses: a) J. L. Bullington,
R. R. Wolff, P. F. Jackson, J. Org. Chem. 2002, 67, 9439; b) O. A.
Attanasi, L. De Crescentini, G. Favi, P. Filippone, F. Mantellini,
S. Santeusanio, J. Org. Chem. 2002, 67, 8178; c) N. D. Smith,
[10] D. J. Ramꢅn, M. Yus, Angew. Chem. 2005, 117, 1628; Angew.
Chem. Int. Ed. 2005, 44, 1602.
[11] a) L. Syper, Tetrahedron Lett. 1966, 7, 4493; b) E. Baciocchi, E.
Muraglia, G. Sleiter, J. Org. Chem. 1992, 57, 2486.
[12] CCDC 703858 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[13] a) S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb,
K. B. Sharpless, Angew. Chem. 2005, 117, 3339; Angew. Chem.
Int. Ed. 2005, 44, 3275; b) Y. Hayashi, Angew. Chem. 2006, 118,
8281; Angew. Chem. Int. Ed. 2006, 45, 8103; c) D. G. Blackmond,
A. Armstrong, V. Coombe, A. Wells, Angew. Chem. 2007, 119,
3872; Angew. Chem. Int. Ed. 2007, 46, 3798; d) F. Wang, H. Fu, Y.
Jiang, Y. Zhao, Adv. Synth. Catal. 2008, 350, 1830.
Angew. Chem. Int. Ed. 2009, 48, 758 –761
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
761