Convergent approach to nonsymmetrical 2,5-diester pyrroles

Article abstract of DOI:10.1055/s-0030-1259074

A convergent approach towards nonsymmetrical 2,5-diester pyrroles is described. The building blocks can be easily assembled in less than four steps allowing for facile construction of diversity. The synthesis uses a rhodium-catalyzed NH insertion, followe

Full text of DOI:10.1055/s-0030-1259074

3086
LETTER
Convergent Approach to Nonsymmetrical 2,5-Diester Pyrroles
Preparation of
2
r
,5-Diest
i
er Pyrr
c
oles Lévesque, Louis-Charles Campeau, Danny Gauvreau*
Merck Frosst, Centre for Therapeutic Research, Department of Process Research, 16711 Trans Canada Highway, Kirkland,
Québec, H9H 3L1, Canada
Fax +1(514)4284939; E-mail: danny_gauvreau@merck.com
Received 6 October 2010
Early on, we realized that the choice of protecting group
(PG) on 2 was crucial, since its removal under mild con-
ditions was required during the cyclization. The very acid-
ic conditions required for Boc deprotection led to
Abstract: A convergent approach towards nonsymmetrical 2,5-di-
ester pyrroles is described. The building blocks can be easily assem-
bled in less than four steps allowing for facile construction of
diversity. The synthesis uses a rhodium-catalyzed NH insertion, fol-
lowed by a one-pot deprotection–condensation to yield the desired decomposition and the acetate protecting group proved
pyrroles.
difficult to remove. The sensitive nature of the enamine 2
led us to consider the use of the Troc group which could
be deprotected under buffered conditions. Another key
consideration was the nature of R4. Our original intent was
to have R4 = H which would provide the trisubstituted
pyrrole 1. The general synthesis of the enamine fragments
3 is outlined in Scheme 2.
Key words: pyrrole, rhodium catalysis, NH insertion, zinc depro-
tection, enamine
Given their importance in natural and pharmaceutical
products,1 extensive efforts have been targeted to the
preparation of pyrroles.2 However, very few methods al-
low access to pyrroles bearing two electron-withdrawing
groups at the 2- and 5-positions. In most cases, these ap-
proaches lead to symmetrical pyrroles.3 Therefore, the de-
sign of a synthesis to access unsymmetrical pyrroles
bearing electron-withdrawing groups at the 2- and 5-posi-
tions would be of great value.
OH
a, b
H2N
CO2Me
TrocHN
CO2Me
5a
6
SPh
Br
c
d
TrocHN
CO2Me
TrocHN
CO2Me
We envisioned access to 2,5-diester pyrroles bearing a
substituent at the 3-position (1) via a one-pot deprotec-
tion–cyclization of keto enamine 2. We expected that the
deprotection of the enamine would facilitate its cycliza-
tion by increasing the electron density on the system.4 To
maximize convergence, 2 would be obtained via a rhodi-
um-catalyzed N–H insertion between readily prepared
enamine 3 and diazo 4 (Scheme 1).5 Enamine 3 can con-
veniently be prepared from serine.
7
8
Scheme 2 Preparation of the Troc-protected enamines substrates.
Reagents and conditions: a) TrocCl, Et3N, CH2Cl2, 0 °C, 16 h, 93%;
b) MsCl, Et3N, CH2Cl2, –30 °C, 16 h, 72%; c) NBS, 16 h, then Et3N,
2 h, CH2Cl2, 20 °C, 68%; d) PhSH, K2CO3, MeCN, 20 °C, 1 h, 57%.
Conveniently, DL-serine methyl ester is initially protected
with a Troc protecting group, followed by a one-pot me-
sylation–elimination sequence to yield enamine 6. From
this key enamine, we could prepare bromo-substituted
enamines 7 and thiophenyl ether 8 to evaluate the effect of
substitution pattern on the pyrrole formation chemistry.6
Literature precedents led us to believe that both these sub-
stituents could be removed to access our desired trisubsti-
tuted pyrrole 1.7 The desired cyclization precursors 2
having R4 = H, Br, and SPh were prepared via rhodium-
catalyzed N–H insertion. However, initial attempts at af-
fecting cyclization upon Troc deprotection conditions re-
sulted in decomposition except when using the enamine
2a (R4 = SPh). Treating 2a with excess zinc in THF and 1
N HCl at 60 °C, led to a promising 26% yield of 1a. Sur-
prisingly, the thiophenol was removed during cyclization.
At this moment, we have no direct mechanistic evidence
to explain the lost of this moiety, however, literature pre-
cedents suggest that it may play a role in the dehydration
required to afford the pyrrole.8
R2
H
R2
O
R4
R1O2C
CO2R3
R1O2C
N
CO2R3
N
H
PG
1
2
R4
O
O
OH
CO2R3
R2
+
R1O
PGHN
CO2R3
H2N
N2
5
3
4
Scheme 1 Retrosynthetic approach towards pyrroles bearing 2,5-
esters
SYNLETT 2010, No. 20, pp 3086–3088
x
x
.x
x
.2
0
1
0
We then focused our efforts on the optimization of our
protocol. The best conditions for the rhodium-catalyzed
Advanced online publication: 25.11.2010
DOI: 10.1055/s-0030-1259074; Art ID: S07110ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Preparation of 2,5-Diester Pyrroles
3087
N–H insertion use 5 mol% of Rh2(oct)4 in dichlo- where the nitrogroup is reduced, in respectable yield
romethane at 20 °C in the presence of 1.5 equivalents of (Table 1, entry 4). Lower yields were obtained for alkyl-
diazo 4. Table 1 outlines the substrate scope of this trans- substitued keto enamines (Table 1, entries 7 and 8). How-
formation.
ever, good yield was achieved for the bulkier isopropyl
derived substrate (Table 1, entry 9).
Both electron-rich and electron-poor aryl substituents (en-
tries 1–6), as well as alkyl substituents (entries 7–9) were Evaluation of the scope at the 2-position is subject of cur-
all well tolerated. Highly stabilized diazo 4h proved less rent evaluation and will be reported in due course. How-
reactive (entry 8). Extensive development was required to ever, we have demonstrated that tert-butyl ester at the 2-
optimize the deprotection–cyclization step.9 Ultimately, position can be prepared (in place of the ethyl ester), thus
we found that the use of 10 equivalents of zinc, in 2-pro- facilitating the differentiation of the two esters on the pyr-
panol–water (8:1 ratio), at 60 °C for 24 hours was optimal. role (Equation 1).
Under these conditions, pyrrole 1a10 was obtained in 60%
In conclusion, we have designed and developed a conver-
yield. Submitting other keto-enamines bearing aryl sub-
gent approach to access nonsymmetrical 2,5-diester pyr-
stituents showed that the electron density on the aryl did
roles. The key steps of the synthesis involved a rhodium-
not have a significant impact upon cyclization efficiency
catalyzed N–H insertion and a one-pot, zinc-mediated
(Table 1, entries 2–6). Even the strongly withdrawing 4-
deprotection–cyclization.
nitro-substituted keto enamine afforded the pyrrole 1d,
Table 1 Scope for the Rhodium-Catalyzed NH Insertion and Zinc-Mediated Deprotection–Cyclization Sequence
R
SPh
R
O
SPh
O
O
Rh2(oct)4 (5 mol%)
CH2Cl2, 20 °C
Zn, H2O
R
+ EtO
EtO2C
CO2Me
TrocHN
CO2Me
EtO2C
N
CO2Me
N
H
i-PrOH, 60 °C
Troc
N2
8
4 (1.5 equiv)
2a–i
1a–i
Entry
1
Diazo 4
Isolated yield insertion (%)
Isolated yield cyclization (%)
4a
4b
2a
2b
74
1a
1b
60
58
2
3
4
61a
OMe
CF3
4c
2c
69
88
1c
54
4d
2d
1d
47b
NO2
5
6
4e
4f
2e
2f
74
79
1e
1f
54
59
Br
O
Me
7
8
9
4g
4h
4i
2g
2h
2i
92
1g
1h
1i
24
33
52
CF3
i-Pr
58a
85a
a Conditions: 3 equiv of diazo were used.
b The pyrrole-aniline was obtained (reduction of the nitro).
Synlett 2010, No. 20, 3086–3088 © Thieme Stuttgart · New York

3088
É. Lévesque et al.
LETTER
(7) (a) Thiophenol removal: Hamel, P.; Girard, Y.; Atkinson,
J. G. J. Chem. Soc., Chem. Commun. 1989, 63. (b)Bromide
removal: Chang, M. N.; Biftu, T.; Boulton, D. A.; Finke,
P. E.; Hammond, M. L.; Pessolano, A. A.; Zambias, R. A.;
Bailey, P.; Goldenberg, M.; Rackham, A. Eur. J. Med.
Chem. 1986, 363.
(8) (a) Sowerby, R. L.; Coates, R. M. J. Am. Chem. Soc. 1972,
4758. (b) Kuwajima, I.; Sato, S.-J.; Kurata, Y. Tetrahedron
Lett. 1972, 737.
(9) Optimization of the deprotection–cyclization involved
screening for organic solvents, aqueous solvent (pH 1–14
buffer), metal used, quantity of zinc, temperature, and
reaction time.
O
O
Ph
t-BuO
Ph
H
N2
SPh
1) Rh2(oct)4
2) Zn
32%
t-BuO2C
CO2Me
N
H
TrocHN
CO2Me
8
1j
Equation 1 Preparation of the pyrrole bearing a tert-butyl ester at
2-position
(10) General Procedure for the Synthesis of Compounds 2a–i
To a stirred solution of 8 (1.70 mmol) and Rh2(oct)4 (0.085
mmol) in CH2Cl2 (4 mL) at 20 °C was added a solution of 4
(3.40 mmol) in CH2Cl2 (2 mL) over a period of 20 min. The
mixture was stirred for 1 h; gas evolution was observed. The
reaction mixture was partitioned between CH2Cl2 and a sat.
NaHCO3 solution, back extracted with CH2Cl2. Combined
organic layers were washed with brine, dried over MgSO4,
and concentrated under vacuum. Purification by flash
chromatography (silica gel, 230–400 mesh; Merck) using
hexanes–EtOAc yielded 2 as a pure product.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
References and Notes
(1) (a) For examples of natural products bearing a pyrrole:
Gupton, J. T. Topics in Heterocyclic Chemistry, Vol. 2; Lee,
M., Ed.; Springer: Berlin, 2006, 53. (b) For drugs
containing a pyrrole, one of the best-known examples is
Lipitor®: Roth, B. D. US Patent 4681893, 1987.
(2) For a recent review on pyrrole synthesis: (a) Schmuck, C.;
Rupprecht, D. Synthesis 2007, 3095. (b) Ferreira, V. F.;
De Souza, M. C.; Cunha, A. C.; Pereira, L. O. R.; Ferreira,
M. L. G. Org. Prep. Proced. Int. 2001, 33, 411.
Methyl 2-{(1-Ethoxy-1,3-dioxo-3-phenylpropan-2-
yl)[(2,2,2-trichloroethoxy)carbonyl]amino}-3-
(phenylthio)acrylate (2a)
1H NMR (400 MHz, acetone-d6): d = 8.12 (br, 1 H), 7.58–
7.51 (m, 2 H), 7.53–7.45 (m, 3 H), 7.45–7.39 (m, 2 H), 7.38–
7.30 (m, 2 H), 7.30–7.24 (m, 2 H), 4.83 (s, 2 H), 3.78 (q,
J = 7.1 Hz, 2 H), 3.60 (s, 3 H), 0.79 (t, J = 7.1 Hz, 3 H) ppm.
13C NMR (101 MHz, acetone-d6): d = 165.9, 165.0, 159.8,
153.3, 149.7, 134.7, 133.7, 131.6, 131.1, 130.0, 129.7,
129.6, 128.1, 114.9, 112.3, 96.7, 75.2, 61.9, 52.1, 13.8 ppm.
IR (neat): 3311 (br), 2982, 1715, 1439, 1268, 1179, 1128,
1034, 732. ESI-HRMS: m/z calcd for C24H22Cl3NNaO7S
[M + Na]: 598.0049; found: 598.0044.
(3) (a) Schmuck, C.; Geiger, L. J. Am. Chem. Soc. 2004, 126,
8898. (b) Hekmatshoar, R.; Nouri, R.; Beheshtiha, S.
Heteroat. Chem. 2008, 19, 100. (c) Beckert, R.; Buehrdel,
G.; Herzigova, P.; Petrlikova, E.; Schuch, D.; Birckner, E.;
Goerls, H. Eur. J. Org. Chem. 2009, 3404. (d) Gupton, J.
T.; Giglio, B. C.; Eaton, J. E.; Rieck, E. A.; Smith, K. L.;
Keough, M. J.; Barelli, P. J.; Firich, L. T.; Hempel, J. E.;
Smith, T. M.; Kanters, R. P. F. Tetrahedron 2009, 65, 4283.
(e) Takamura, N.; Yasui, E.; Mada, M. Tetrahedron Lett.
2009, 50, 4762. (f) Ciez, D. Org. Lett. 2009, 11, 4282.
(g) Jiang, H.; Lui, W.; Huang, L. Org. Lett. 2010, 12, 312.
(4) No pyrrole was observed when the keto enamine 2a was
submitted under thermal or dehydrating conditions in the
absence of zinc.
General Procedure for the Synthesis of Compounds 1a–i
To a stirred solution 2 (0.35 mmol) in 2-PrOH (3.5 mL) and
H2O (0.627 mL, 35 mmol) was added zinc (228 mg, 3.5
mmol). Mixture was heated to 60 °C and stirred for 24 h. The
suspension was filtered on Celite, then concentrated under
vacuum. Purification by flash chromatography (silica gel,
230–400 mesh; Merck) using hexanes–EtOAc yielded 1 as a
pure product.
(5) Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D.
Synth. Commun. 1987, 17, 1709.
(6) The stereochemistry of compounds 7 and 8 was not
determined since it is irrelevant for the later chemistry.
Opposite stereochemistry have been assigned to analogous
enamines in literature: (a) Yamada, M.; Nakao, K.; Fukui,
T.; Nunami, K. Tetrahedron 1996, 52, 5751. (b) Das, J.;
Reid, J. A.; Kronenthal, D. R.; Singh, J.; Pansegrau, P. D.;
Mueller, R. H. Tetrahedron Lett. 1992, 33, 7835. (c) Singh,
J.; Kronenthal, D. R.; Schwinden, M.; Godfrey, J. D.; Fox,
R.; Vawter, E. J.; Zhang, B.; Kissick, T. P.; Patel, B.;
Mneimne, O.; Humora, M.; Papaioannou, C. G.; Szymanski,
W.; Wong, M. K. Y.; Chen, C. K.; Heikes, J. E.; DiMarco,
J. D.; Qiu, J.; Deshpande, R. P.; Gougoutas, J. Z.; Mueller,
R. H. Org. Lett. 2003, 3155. (d) Queiroz, M.-J.; Monteiro,
L. S.; Silva, N. O.; Abreu, A. S.; Ferreira, P. M. T. Eur.
J. Org. Chem. 2002, 2524.
2-Ethyl 5-Methyl 3-Phenyl-1H-pyrrole-2,5-
dicarboxylate (1a)
1H NMR (400 MHz, acetone-d6): d = 11.43 (br, 1 H), 7.69–
7.65 (m, 2 H), 7.42–7.39 (m, 3 H), 7.30 (s, 1 H), 4.16 (q,
J = 7.1 Hz, 2 H), 3.81 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H) ppm.
13C NMR (101 MHz, acetone-d6): d = 164.2, 161.3, 141.7,
131.9, 130.6, 129.5, 128.5, 123.3, 118.8, 114.7, 60.2, 51.8,
14.5 ppm. IR (neat): 3706 (br), 3306, 2973, 1692, 1467,
1249, 1143, 1035, 757, 687. ESI-HRMS: m/z calcd for
C15H16NO4 [M + H]: 274.1074; found: 274.1077.
Synlett 2010, No. 20, 3086–3088 © Thieme Stuttgart · New York

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