Multifunctionalized 3-hydroxypyrroles in a three-step, one-pot cascade process from methyl 3-TBSO-2-diazo-3-butenoate and nitrones

Article abstract of DOI:10.1021/ol2026125

The synthesis of N-aryl-2-carboxyl-3-hydroxy-5-arylpyrroles has been achieved in high yield by the combination of a TBSO-substituted vinyldiazoacetate and nitrones in a one-pot cascade process involving copper-catalyzed Mannich addition, dirhodium-catalyz

Full text of DOI:10.1021/ol2026125

ORGANIC
LETTERS
2011
Vol. 13, No. 22
6122–6125
Multifunctionalized 3-Hydroxypyrroles in
a Three-Step, One-Pot Cascade Process
from Methyl 3-TBSO-2-diazo-3-butenoate
and Nitrones
Xinfang Xu, Maxim O. Ratnikov, Peter Y. Zavalij, and Michael P. Doyle*
Department of Chemistry and Biochemistry, University of Maryland, College Park,
Maryland 20742, United States
mdoyle3@umd.edu
Received September 29, 2011
ABSTRACT
The synthesis of N-aryl-2-carboxyl-3-hydroxy-5-arylpyrroles has been achieved in high yield by the combination of a TBSO-substituted
vinyldiazoacetate and nitrones in a one-pot cascade process involving copper-catalyzed Mannich addition, dirhodium-catalyzed dinitrogen
extrusion and N-OTBS insertion, and acid-promoted aromatization (elimination).
Pyrroles are found in a broad range of bioactive
molecules1 and have multiple applications in materials
science.2,3 Efficient methods for their synthesis continue to
be a topic of intense interest,4 especially for complex
systems, and recent reports have focused on polysubstituted
pyrroles.5 However, none of these methods have been
designed for or are applicable to the synthesis of substituted
3-hydroxypyrroles, and there is only one recent example
specific to the preparation of 3-hydroxypyrroles,6,7 despite
their well-known applications.8 Herein we report a novel
(1) (a) Seiple, I. B.; Su, S.; Young, I. S.; Nakamura, A.; Yamaguchi,
A.; Jørgensen, L.; Rodriguez, R. A.; O’Malley, D. P.; Gaich, T.; Kck,
M.; Baran, P. S. J. Am. Chem. Soc. 2011, 133, 14710. (b) Fan, H.; Peng,
J.; Hamann, M.; Hu, J.-F. Chem. Rev. 2008, 108, 264.
(2) Kim, S. K.; Sessler, J. L.; Gross, D. E.; Lee, C.-H.; Kim, J. S.;
Lynch, V. M.; Delmau, L. H.; Hay, B. P. J. Am. Chem. Soc. 2010, 132,
5827.
(3) Zhang, X.; Richter, L. J.; DeLongchamp, D. M.; Kline, R. J.;
Hammond, M. R.; McCulloch, I.; Heeney, M.; Ashraf, R. S.; Smith,
J. N.; Anthopoulos, T. D.; Schroeder, B. C.; Geerts, Y. H.; Fischer,
D. A.; Toney, M. F. J. Am. Chem. Soc. 2011, 133, 15073.
(6) Attanasi, O. A.; Berretta, S.; De Crescentini, L.; Favi, G.; Giorgi,
G.; Mantellini, F.; Nicolini, S. Adv. Synth. Catal. 2011, 353, 595.
(7) Synthesis of 3-alkoxy- or 3-acetoxypyrroles: (a) Lubriks, D.;
Sokolovs, I.; Suna, E. Org. Lett. 2011, 13, 4324. (b) Sasada, T.; Sawada,
T.; Ikeda, R.; Sakai, N.; Konakahara, T. Eur. J. Org. Chem. 2010, 4237.
(c) Dieker, J.; Frohlich, R.; Wurthwein, E.-U. Eur. J. Org. Chem. 2006,
5339. (d) Merz, A.; Anikin, S.; Lieser, B.; Heinze, J.; John, H. Chem.;
Eur. J. 2003, 9, 449.
(8) (a) Mcnab, H.; Monahan, L. C. In Chemistry of Heterocyclic
Compounds: Pyrroles, Part 2: The Synthesis, Reactivity, and Physical
Properties of Substituted Pyrroles; Jones, R. A., Eds.; John Wiley & Sons,
Inc.: Hoboken, New Jesery, 2008; Vol. 48. (b) Baughman, R. H. Science
2005, 308, 63. (c) Urbach, A. R.; Szewczyk, J. W.; White, S.; Turner,
J. M.; Baird, E. E.; Dervan, P. B. J. Am. Chem. Soc. 1999, 121, 11621.
(4) D’Ischia, M.; Napolitano, A. In Comprehensive Heterocyclic
Chemistry III; Katrisky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor,
R. J. K., Eds.; Pergamon-Elsevier Science: Amsterdam, 2008; Vol. 4.
(5) (a) Hong, D.; Zhu, Y.; Li, Y.; Lin, X.; Lu, P.; Wang, Y. Org. Lett.
2011, 13, 4668. (b) Yamagishi, M.; Nishigai, K.; Hata, T.; Urabe, H.
Org. Lett. 2011, 13, 4873. (c) Thompson, B. B.; Montgomery, J. Org.
Lett. 2011, 13, 3289. (d) Wang, H.-Y.; Mueller, D. S.; Sachwani, R. M.;
Kapadia, R.; Londino, H. N.; Anderson, L. L. J. Org. Chem. 2011, 76,
3203. (e) Attanasi, O. A.; Favi, G.; Mantellini, F.; Moscatelli, G.;
Santeusanio, S. J. Org. Chem. 2011, 76, 2860. (f) Trost, B. M.; Lumb,
J.-P.; Azzarelli, J. M. J. Am. Chem. Soc. 2011, 133, 740. (g) Rakshit, S.;
Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9585.
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10.1021/ol2026125
Published on Web 10/27/2011
2011 American Chemical Society

and efficient one-pot reaction for the construction of multi-
functionalized 3-hydroxylpyrrole derivatives.
When TBSO-substituted vinyldiazoacetate 1 is treated
with N,R-diphenylnitrone (2a, R = Ph) in dichloro-
methane at 0 °C in the presence of a catalytic amount of
dirhodium tetraacetate, formal [3 þ 3] addition occurs
to form methyl N,3-diphenyl-3,6-dihydro-1,2-oxazine 6
in >95% yield (eq 1).16 Under the same conditions, however,
only Mannich addition occurs between these substrates in
the presence of catalytic copper(I) hexafluorophosphate.
By warming the reaction mixture containing CuPF6 to
100 °C or by adding Rh2(OAc)4 at room temperature, 3a
underwent formal N-OTBS insertion to produce pyrroli-
din-3-one 4 as a single diastereoisomer in moderate yield
(Scheme 2). The structure of the pyrrolidine product was
confirmed by single-crystal X-ray diffraction analysis of its
p-bromo-substituted derivative (Figure 1).
The Lewis acid catalyzed MukaiyamaꢀMannich addition
of a TBSO-substituted vinyldiazoacetate to imines9 coupled
with dirhodium(II)-catalyzed NꢀH insertion of δ-amido-β-
keto-R-diazo esters10 is a convenient methodology for the
synthesis of 3-ketopyrrolidine derivatives. However, rela-
tively harsh conditions are required to convert pyrrolidine
derivatives to pyrroles.11 Based on the success of the
Mannich/NꢀH insertion process, we considered this com-
bination of steps together with mild dehydration as a com-
bined methodology for the synthesis of 3-hydroxypyrroles
(Scheme 1). To accomplish this transformation we adopted
nitrones, instead of imines, as Mannich addition acceptors.
Nitrones have been used in Mannich-type reactions with
keteneacetals catalyzed by Lewis acids.12 Hydroxylamines 3
Scheme 2. Access to Pyrrolidin-3-one 4a by a Two-Step Process
Scheme 1
were anticipated from reactions of nitrones with 1 that, fol-
lowing unprecedented dirhodium catalyzed N-OTBS inser-
tion, would produce 2-hydroxy-3-oxopyrrolidines 4. Dehy-
dration of 4 to the multifunctionalized pyrrole 5 is known to
occur under acidic conditions.13 Although insertion into the
NꢀO bond of a hydroxylamine is unprecedented,14 insertion
into the isoxazole NꢀO bond has recently been reported.15
Figure 1. Crystal structure of compound 4d. The p-bromophe-
nyl and OTBS functionalities are on the same side of the five-
membered ring.
(9) Doyle, M. P.; Kundu, K.; Russell, A. E. Org. Lett. 2005, 7, 5171.
(10) Davis, F. A.; Wu, Y.; Xu, H.; Zhang, J. Org. Lett. 2004, 6, 4523.
(11) (a) Xu, T.; Mu, X.; Peng, H.; Liu, G. Angew. Chem., Int. Ed.
2011, 50, 8176. (b) Wang, Y.; Zhu, S. Org. Lett. 2003, 5, 745.
(12) Merino, P.; Jimenez, P.; Tejero, T. J. Org. Chem. 2006, 71, 4685.
(13) (a) Wasserman, H. H.; Cook, J. D.; Fukuyama, J. M.; Rotello,
V. M. Tetrahedron Lett. 1989, 30, 1721. (b) Truong, P.; Xu, X.; Doyle,
M. P. Tetrahedron Lett. 2011, 52, 2093–2096.
(14) A diazoacetoacetate of an N-benzyloxy-β-lactam underwent
ylide formation with hydride transfer to form a carbapenam and
benzaldehyde: Williams, M. A.; Hsiao, C.-N.; Miller, M. J. Tetrahedron
1991, 56, 2688. Diazoacetamides derived from hydroxylamines undergo
CꢀH insertion into the CꢀH bond adjacent to the hydroxylamide
oxygen: Wang, J.; Stefane, B.; Jaber, D.; Smith, J. A. I.; Vickery, C.;
Diop, M.; Sintim, H. O. Angew. Chem., Int. Ed. 2010, 49, 3964.
(15) Manning, J. R.; Davies, H. M. L. Tetrahedron 2008, 64, 6901.
Carbene insertion into a saturated NꢀO bond is un-
precedented, so efforts were undertaken to further under-
stand this process. As a first experiment, we investigated
the outcome of the reaction with the TBS group of 3a
replaced by hydrogen. In this case there is potential
competition between NꢀOH insertion and OꢀH insertion
and, indeed, both are observed (eq 2), with OꢀH insertion
being the preferred process. However, the lower stereo-
selectivity in this case (9:1 with 10a versus >20:1 for 4a) ledus
(16) Wang, X.; Xu, X.; Zavalij, P. Y.; Doyle, M. P. J. Am. Chem. Soc.
2011, 133, 16402.
Org. Lett., Vol. 13, No. 22, 2011
6123

Table 1. Optimization of Reaction Conditions for the Synthesis
of 4aa
Scheme 3. NOꢀH versus NꢀOH Insertion via Ylide Inter-
mediates
entry
Lewis acid
3a:4a:6b
yield (%)c
1
2
3
4
5
6
7
8
CuPF6
0:98:2
0:95:5
47:50:3
0:71:29
0:96:4
0:55:45
0:67:33
0:98:2
76
78
92
80
77
88
86
72d
CuPF6 (5 mol %)
CuPF6 (10 mol %)
Zn(OTf)2
Sc(OTf)3
Cu(OTf)2
Yb(OTf)3
CuPF6
a Reactions were carried out on a 0.25 mol scale: 1 (0.30 mmol), 2
˚
(0.25 mmol), 4 A MS (0.10 g), Rh2(OAc)4 (2.0 mol %), Lewis acid
cocatalyst (2.0 mol %), in DCM (2.0 mL) at 0 °C. b Determined by 1H
NMR of the crude reaction mixture. c Isolated yield of 3a, 4a, and 6.
d Yield of the corresponding pyrrole 5a after 3 N HCl was treated with
the crude reaction mixture of entry 1.
to the conclusion that the TBS attachment is critical for
high stereocontrol in product formation. The mechanism
of these processes probably involves ylide intermediates,
either as an oxonium ylide leading to 9 or as an ammonium
ylide leading to 10 (Scheme 3).17 Why the six-membered
ring OꢀH insertion product is preferred over the five-
membered ring NꢀOH insertion product is uncertain, but
this competition and selectivity may be related to the rate
of hydrogen versus hydroxyl shift, which would be asso-
ciatedwitha commonintermediateorequilibriumbetween
the oxonium and ammonium ylides.
Rh2(OAc)4 showed that a lower Lewis acid catalyst
loading was advantageous. The use of alternative Lewis
acid cocatalysts in combination with dirhodium acetate
was also explored. An outcome comparable to that from
the use of CuPF6 could be obtained with Sc(OTf)3 (entry
5). However, use of other Lewis acids, including copper-
(II) triflate, led to a decrease in the relative percentage of
pyrrolidine 4a (entries 4,6ꢀ7). In the absence of Rh2(OAc)4
all Lewis acids employed catalyze the Mannich reaction of
1 with 2 to form 3 at various rates.
Table 2. Substrate Generality of the One-Pot Cascade Reaction
for the Pyrrole Synthesisa
With the assumption that copper and rhodium cata-
lysts act independently, so that the combination of
TBSO-substituted vinyldiazoacetate 1 and nitrone could
achieve the formation of 4 under one set of reaction
conditions, we treated 1 with N,R-diphenylnitrone (2a)
in the presence of catalytic amounts of rhodium acetate
and copper(I) hexafluorophosphate at room tempera-
ture. As anticipated, pyrrolidine 4a was formed with only
a trace amount of 6 and was isolated as a pure product in
76% yield (Table 1, entry 1). Obviously, the role of CuPF6
as a Lewis acid in these reactions is pronounced, and the
possibility exists that coordination of CuPF6 with 1 or 3
inhibits its use as a catalyst for dinitrogen extrusion,17
which is successfully compensated with the addition of
Rh2(OAc)4 that is not inhibited by reactant or product.
Further attempted optimization in the amount of Lewis
acid employed (entries 1ꢀ3) with a constant 2 mol % of
entry
Ar1/ Ar2
C6H5/C6H5
product
5:7b
yieldc
1
5a
5b
5c
<98:2
<98:2
<98:2
<98:2
<98:2
<98:2
<98:2
<98:2
<98:2
67:33
10:90
72
79
76
77
85
75
80
85
87
88
90d
2
4-BrC6H4/4-ClC6H4
4-MeOC6H4/C6H5
C6H5/4-BrC6H4
C6H5/4-CF3C6H4
C6H5/4-FC6H4
3
4
5d
5e
5
6
5f
7
C6H5/4-ClC6H4
C6H5/3-ClC6H4
C6H5/2-ClC6H4
C6H5/4-MeC6H4
C6H5/4-MeOC6H4
5g
5h
5i
8
9
10
11
5jþ7j
6k
a The reaction was carried out in 0.25 mol scale: 1 (0.30 mmol),
˚
2 (0.25 mmol), 4 A MS(0.10g),Rh2(OAc)4 (2.0mol%),CuPF6 (5.0mol%),
in DCM (2.0 mL) at 0 °C for 1 h with stirring another 2 h at room
temperature; then the solvent was replaced with THF (5 mL) followed by
3 N HCl (5 mL), and the mixture was warmed to 70 °C for another 3 h.
b Determined by 1H NMR of the crude reaction mixture. c Isolated yield
of 5 and 7 based on 2. d Isolated yield of 6 (skip the step with HCl) based
on 2.
(17) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; Wiley: New York,
1998; Chapter 3.
6124
Org. Lett., Vol. 13, No. 22, 2011

The aromatization step for pyrrole synthesis was con-
veniently achieved by refluxing 4a in THF with 3 N HCl
for 3ꢀ5 h to give 100% conversion.13 A one-pot three-step
pyrrole synthesis was achieved by performing the catalytic
Mannich addition and N-OTBS insertion in dichloro-
methane, replacing that solvent with THF, adding 3 N HCl,
and heating at 70 °C for 3 h to give pyrrole product 5a in
72% isolated yield (Table 1, entry 8).
Substrate generality for the one-pot synthesis of 3-hydro-
xypyrroles with various arylnitrones was determined from
the yields and selectivities that are reported in Table 2. All
substrates gave high to excellent product yields from reac-
tions using moderate amounts of the combined catalysts
and subsequent aromatization. Pyrrole 5 was the only
product observed with all N-arylnitrones having electron-
withdrawing substituents on the R-aryl group. In contrast,
nitrones with electron-donating substituents on the R-aryl
group formed both six- and five-membered ring products
with moderate chemoselectivity but also in high yield
(entries 10ꢀ11). The N-OTBS insertion product 4 was
formed with high diastereoselectivity; in the case of entry
3 (Ar1 = p-MeOC6H4) and entry 4 (Ar2 = p-BrC6H4) the
pyrrolidin-3-one products were single diastereoisomers with
the aryl and OTBS functionalities on the same side of the
five-membered ring.
In conclusion, we have developed a general and efficient
three-step, one-pot methodology for the construction of
N-aryl-2-carboxyl-3-hydroxy-5-arylpyrroles from TBSO-
substituted vinyldiazoacetate 1 and nitrones in high yield.
This cascade reaction involves Lewis acid catalyzed Man-
nich addition, a novel dirhodium tetraacetate catalyzed
N-OTBS insertion, and acid-promoted aromatization
(elimination). Efforts are underway to assess the generality
of methodology for the synthesis of heterocycles and to gen-
eralize NꢀO and related bis-heteroatom insertion reactions.
Acknowledgment. Support for this research from the
National Institutes of Health (GM 46503) and the
National Science Foundation (CHE-0748121) is gratefully
acknowledged.
Supporting Information Available. General experimen-
tal procedures, X-ray structures of 4d and 5g, and spectro-
scopic data for all new compounds. This material is
available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 13, No. 22, 2011
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