One-step continuous flow synthesis of highly substituted pyrrole-3-carboxylic acid derivatives via in situ hydrolysis of tert-butyl esters

Article abstract of DOI:10.1021/ol102216x

The first one-step, continuous flow synthesis of pyrrole-3-carboxylic acids directly from tert-butyl acetoacetates, amines, and 2-bromoketones is reported. The HBr generated as a byproduct in the Hantzsch reaction was utilized in the flow method to hydrolyze the t-butyl esters in situ to provide the corresponding acids in a single microreactor. The protocol was used in the multistep synthesis of pyrrole-3-carboxamides, including two CB1 inverse agonists, directly from commercially available starting materials in a single continuous process.

Full text of DOI:10.1021/ol102216x

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5182-5185
One-Step Continuous Flow Synthesis of
Highly Substituted Pyrrole-3-carboxylic
Acid Derivatives via in Situ Hydrolysis
of tert-Butyl Esters
Ananda Herath and Nicholas D. P. Cosford*
Apoptosis and Cell Death Research Program & Conrad Prebys Center for Chemical
Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines
Road, La Jolla, California 92037, United States
ncosford@sanfordburnham.org
Received September 15, 2010
ABSTRACT
The first one-step, continuous flow synthesis of pyrrole-3-carboxylic acids directly from tert-butyl acetoacetates, amines, and 2-bromoketones
is reported. The HBr generated as a byproduct in the Hantzsch reaction was utilized in the flow method to hydrolyze the t-butyl esters in situ
to provide the corresponding acids in a single microreactor. The protocol was used in the multistep synthesis of pyrrole-3-carboxamides,
including two CB1 inverse agonists, directly from commercially available starting materials in a single continuous process.
Automated microreactor-based (microfluidic chip) continuous
flow chemistry is emerging as a powerful technology for the
synthesis of small molecule compounds.1a,b The application
of continuous flow methods to the production of libraries of
druglike structures (primarily heterocycles) has the potential
to greatly accelerate the drug discovery process.1c Continuous
flow synthetic methods have the advantage of being highly
efficient, atom economical,2a,b environmentally friendly
(reduction of waste streams), and cost-effective.2a-f More-
over, the potential to run multistep reactions in a single,
uninterrupted microreactor sequence using continuous flow
chemistry is particularly beneficial for the rapid and efficient
generation of large numbers of compounds with high purity
and minimal byproducts.2c-h Our research is focused on
developing flow chemistry methods for multistep transforma-
tions that are either not possible or highly inefficient using
in-flask chemistry. We have previously reported general
methods for the preparation of 1,2,4-oxadiazoles and imi-
dazo[1,2-a]pyridine-2-carboxamides in uninterrupted con-
tinuous flow sequences.2c,d We now report an efficient
continuous flow procedure for the synthesis of functionalized,
(2) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew.
Chem., Int. Ed. 1995, 34, 259. (c) Herath, A.; Dahl, R.; Cosford, N. D. P.
Org. Lett. 2010, 12, 412. (d) Grant, D.; Dahl, R.; Cosford, N. D. P. J. Org.
Chem. 2008, 73, 7219. (e) Baxendale, I. R.; Ley, S. V.; Mansfield, A. C.;
Smith, C. D. Angew. Chem., Int. Ed. 2009, 48, 4017. (f) Usutani, H.; Tomida,
Y.; Nagaki, A.; Okamoto, H.; Nokami, T.; Yoshida, J. J. Am. Chem. Soc.
2007, 129, 3046. (g) Sahoo, H. R.; Kralj, J. G.; Jensen, K. F. Angew. Chem.,
Int. Ed. 2007, 46, 5704. (h) Bogdan, A. R.; Poe, S. L.; Kubis, D. C.;
Broadwater, S. J.; McQuade, D. T. Angew. Chem., Int. Ed. 2009, 48, 8547.
(1) (a) Kappe, C. O.; Van der Eycken, E. Chem. Soc. ReV. 2010, 39,
1280. (b) Razzaq, T.; Kappe, C. O. Chem. Asian J. 2010, 5, 1274. (c) Kang,
L.; Chung, B. G.; Langer, R.; Khademhosseini, A. Drug DiscoVery Today
2008, 13, 1.
10.1021/ol102216x  2010 American Chemical Society
Published on Web 10/21/2010

highly diverse derivatives of the pyrrole-3-carboxylic acid
scaffold.
Our investigations initially focused on the direct synthesis
of pyrroles from commercially available ethyl acetoacetate
(2.2 equiv), benzylamine (1.0 equiv), and R-bromoacetophe-
none (1.0 equiv). A variety of bases such as N,N-diisopro-
pylethylamine (DIPEA), triethylamine, 2,6-lutidine, pyridine,
and 2,6-di-tert-butylpyridine were screened at different
temperatures using a single microreactor. It was found that
the use of DIPEA (1.0 equiv) in dimethylformamide (DMF)
at 200 °C was most efficient for this process. A solution of
ethyl acetoacetate/benzylamine/DIPEA (2.2:1:1, 0.5 M,
DMF) and R-bromoacetophenone (1.0 equiv, 0.5 M, DMF)
was introduced into a preheated microreactor at 200 °C and
5.0 bar (Table 1). Analysis of the reactions by LC-MS
showed that the conversion of R-bromoacetophenone to the
The pyrrole framework is a ubiquitous structural motif
found in a wide range of biologically active natural products
and pharmaceutically active agents.3 Members of this
important class of heterocyclic compounds display a variety
of pharmacological properties including antibacterial, anti-
viral, anti-inflammatory, anticancer, and antioxidant activity.4
A prime example is atorvastatin calcium (Lipitor), the
world’s leading cholesterol-lowering drug.5 Consequently,
there is significant interest in the development of efficient
methods for the synthesis of pyrrole derivatives bearing
diverse substitution patterns. There are several classical
methods for the synthesis of pyrroles, including the
Hantzsch,6 Paal-Knorr,7 and Knorr, in addition to a variety
of cycloadditions8 and transition-metal-catalyzed cyclization
reactions.9 Although these methods have proven effective
for the preparation of pyrrole derivatives, they involve
multistep in-flask (batch) syntheses that limit scope and
efficiency, especially with respect to analogue library syn-
thesis.
Table 1. Scope of ꢀ-Ketoesters
The Hantzsch pyrrole synthesis involves the reaction of
ꢀ-ketoesters with ammonia (or primary amines) and
R-haloketones.6a Although the Hantzsch method produces
N-substituted pyrroles, the yields are often low, and this may
be why the procedure has been somewhat under utilized
historically.6c,10a Furthermore, the “one-pot” synthesis of
pyrrole-3-carboxylic acids has not been reported, and thus
stepwise, in-flask (batch) protocols are necessary.10b Herein,
we describe the first direct continuous flow synthesis of
pyrrole-3-carboxylic acids. In addition, we have applied the
method to the synthesis of pyrrole-3-carboxamide derivatives
in an uninterrupted sequence.
entry
R1
yield (%)a
1
2
3
4
Me
Et
Bn
tBu
82
81
78
76
a Isolated yield based on benzylamine after purification of the crude
reaction mixture.
(3) (a) Boger, D. L.; Boyce, C. W.; Labrili, M. A.; Sehon, C. A.; Jin,
Q. J. Am. Chem. Soc. 1999, 121, 54. (b) Groenendaal, L.; Meijer, E.-W.;
Vekemans, J. A. J. M. Electronic Materials: The Oligomer Approach;
Mu¨llen, K.,; Wegner, G., Eds.; WILEY-VCH: Weinheim, 1997. (c)
Domingo, V. M.; Aleman, C.; Brillas, E.; Julia, L. J. Org. Chem. 2001, 66,
4058. (d) Loya, S.; Rudi, A.; Kashman, Y.; Hizi, A. Biochem. J. 1999,
344, 85.
corresponding pyrrole derivatives was complete within 8 min.
This reaction tolerated a variety of ꢀ-ketoesters including
ethyl, benzyl, methyl, and tert-butyl acetoacetates (Table 1).
tert-Butyl esters are versatile protecting groups for car-
boxylic acids which are stable under basic conditions but
can be removed using acid.11 Typically strong protic acids,
such as HCl, H2SO4, HNO3, or TFA, are employed for tert-
butyl ester hydrolysis in aqueous or organic solvents.12
During the Hantzsch pyrrole synthesis, HBr is generated as
a side product, and in our procedure DIPEA is used as a
neutralizing agent. We hypothesized that we could take
advantage of the strong acid generated in the Hantzsch
reaction to hydrolyze the tert-butyl ester formed in the initial
product. With this in mind, we varied the reaction conditions
(4) (a) Jacobi, P. A.; Coutts, L. D.; Guo, J.; Hauck, S. I.; Leung, S. H.
J. Org. Chem. 2000, 65, 205. (b) Martinez, G. R.; Hirschfeld, D. R.;
Maloney, P. J.; Yang, D. S.; Rosenkranz, R. P.; Walker, K. A. M. J. Med.
Chem. 1989, 32, 890. (c) Khanna, I. K.; Weier, R. M.; Yu, Y.; Collins,
P. W.; Miyashiro, J. M.; Koboldt, C. M.; Veenhuizen, A. W.; Currie, J. L.;
Seibert, K.; Isakson, P. C. J. Med. Chem. 1997, 40, 1619.
(5) Thompson, R. B. FASEB J. 2001, 15, 1671.
(6) (a) Hantzsch, A. Ber. 1890, 23, 1474. (b) Trautwein, A. W.;
Sussmuth, R. D.; Jung, G. Bioorg. Med. Chem. Lett. 1998, 8, 2381. (c)
Roomi, M. W.; MacDonald, S. F. Can. J. Chem. 1970, 48, 1689. (d)
Palacios, F.; Aparico, D.; Santos, J. M.; Vicario, J. Tetrahedron 2001, 57,
1961.
(7) (a) Chen, J. X.; Wu, H. Y.; Zheng, Z. G.; Jin, C.; Zhang, X. X.; Su,
W. K. Tetrahedron Lett. 2006, 47, 5383. (b) Trost, B. M.; Doherty, G. A.
J. Am. Chem. Soc. 2000, 122, 3801. (c) Quiclet-Sire, B.; Quintero, L.;
Sanchez-Jimenez, G.; Zard, S. Z. Synlett 2003, 75. (d) Tracey, M. R.; Hsung,
R. P.; Lambeth, R. H. Synthesis 2004, 918. (e) Knorr, L. Chem. Ber. 1885,
18, 299. (f) Paal, C. Chem. Ber. 1885, 18, 367.
(10) (a) Agosta, W. C. J. Org. Chem. 1961, 26, 1724. (b) LoVerme, J.;
Duranti, A.; Tontini, A.; Spadoni, G.; Mor, M.; Rivara, S.; Stella, N.; Xu,
C.; Tarzia, G.; Piomelli, D. Bioorg. Med. Chem. Lett. 2009, 19, 639.
(11) (a) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis; John Wiley and Sons: New York, 1999. (b) Kocienski, P. G. P. J.
Protecting Groups: Thieme: Stuttgart, 1994.
(8) (a) Katritzky, A. R.; Zhang, S.; Wang, M.; Kolb, H. C.; Steel, P. J.
J. Heterocycl. Chem. 2002, 39, 759. (b) Bullington, J. L.; Wolff, R. R.;
Jackson, P. F. J. Org. Chem. 2002, 67, 9439. (c) Washizuka, K. I.; Minakata,
S.; Ryu, I.; Komatsu, M. Tetrahedron 1999, 55, 12969. (d) Kim, Y.; Kim,
J.; Park, S. B. Org. Lett. 2009, 11, 17.
(12) (a) Strazzolini, P.; Misuri, N.; Polese, P. Tetrahedron Lett. 2005,
46, 2075. (b) Strazzolini, P.; Scuccato, M.; Giumanini, A. G. Tetrahedron
2000, 56, 3625. (c) Strazzolini, P.; Melloni, T.; Giumanini, A. G.
Tetrahedron 2001, 57, 9033. (d) Lin, L. S.; Lanza Jr., T.; de Laszlo, S. E.;
Truong, Q.; Kamenecka, T.; Hagmann, W. K. Tetrahedron Lett. 2000, 41,
7013. (e) Gibson, F. S.; Bergmeier, S. C.; Rapoport, H. J. Org. Chem. 1994,
59, 3216.
(9) (a) Egi, M.; Azechi, K.; Akai, S. Org. Lett. 2009, 11, 5002. (b) Kel’in,
A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074.
(c) Gabriele, B.; Salerno, G.; Fazio, A. J. Org. Chem. 2003, 68, 7853. (d)
Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260.
(e) Rivero, M. R.; Buchwald, S. L. Org. Lett. 2007, 9, 973.
Org. Lett., Vol. 12, No. 22, 2010
5183

using different equivalents of DIPEA (Table 2) and found
that the use of 0.5 equiv of DIPEA was optimal to efficiently
6) or electron-withdrawing groups (Table 3, entries 3-5)
proceeded efficiently with moderate to good yields. The product
in Table 3, entry 8, is notable since it is a dicarboxylic acid
that is monoprotected as the ester, allowing selective function-
alization of the free acid in subsequent synthetic transformations.
Additionally, the reaction can tolerate a variety of primary
amines such as allyl, cyclic, linear, and branched alkylamines
to provide N-substituted pyrroles (Table 4). One intriguing
Table 2. Optimization of the Synthesis of Pyrrole-3-carboxylic
Acids
Table 4. Scope of Amines
entry
1a:1b:DIPEA
products 2a:2b:2ca
1
2
3
4
5
6
7
3:1:0.25
3:1:0.5
3:1:0.6
3:1:0.7
3:1:0.8
3:1:0.9
3:1:1
44:56b
14:75:11
15:68:17
14:62:24
13:47:40
10:10:80
4:2:94
a Isolated yield based on amine after purification of the crude reaction
mixture.
a Compound ratios were determined using LC-MS. b Compound 2c
was not observed.
observation was that this new method can be employed
to generate free hydroxyl group-containing pyrrole car-
boxylic acids in an efficient manner, without the use of a
protecting group (Table 4, entry 6).
convert the tert-butyl ester pyrroles to the corresponding
acids in situ (Table 2, entry 2).
A variety of substrates were amenable to the reaction
conditions, and good to high yields of the corresponding pyrrole-
3-acids were obtained (Table 3). Reactions of R-bromoac-
etophenones having electron-donating (Table 3, entries 1 and
We were also able to extend the methodology to the synthesis
of N-H pyrrole acids. Thus, the required starting material, tert-
butyl 3-aminobut-2-enoate, was obtained by simply mixing 3
equiv of ammonium carbamate (NH4OOCNH2) and tert-
butylacetoactate in methanol for 15 min.13 As shown in Table
5, the preparation of N-unsubstituted pyrrole-3-acids proceeds
in uniformly good yields. To demonstrate the utility of the newly
developed methodology, our next goal was to develop a
continuous flow method to access pyrrole-3-carboxamides in a
single, uninterrupted process directly from readily available
starting materials.
Table 3. Scope of R-Bromoketones
Previously, we demonstrated that the conversion of
heterocyclic acids to amides was efficient using a solution
of EDC/HOBt and amine/DIPEA in a second microreactor
at 75 °C for 10 min.2c However, the use of the same
conditions provided a low conversion of pyrrole-3-carboxylic
acids to the corresponding amides. Several attempts were
made to generate amides using a second microfluidic chip.
entry
R2
yield (%)a
1
2
3
4
5
6
7
8
Ph
65
61
60
48
61
57
64
40
4-OMeC6H4
4-FC6H4
4-CNC6H4
4-NO2C6H4
3-OHC6H4
4-BrC6H4
CO2Et
(13) Litvic, M.; Filipan, M.; Pogorelic, I.; Cepanec, I. Green Chem. 2005,
7, 771.
(14) (a) Mayweg, A.; Marty, H. P.; Mueller, W.; Narquizian, R.;
Neidhart, W.; Pflieger, P.; Roever, S. U.S. Patent 7294644B2, Nov. 13,
2007. (b) Mayweg, A.; Marty, H. P.; Mueller, W.; Narquizian, R.; Neidhart,
W.; Pflieger, P.; Roever, S. WO2004060870, Jul. 22, 2004. (c) Jagerovic,
N.; Fernandez-Fernandez, C.; Goya, P. Curr. Top. Med. Chem. 2008, 8,
205.
a Isolated yield based on 1b after purification of the crude reaction
mixture.
5184
Org. Lett., Vol. 12, No. 22, 2010

Finally, to demonstrate the utility of the new method we
synthesized compounds 3d and 3e which were recently
disclosed as cannabinoid receptor subtype 1 (CB1R) inverse
agonists.14a,b There is significant interest in small molecule
CB1R inverse agonists within the pharmaceutical sector
because of their potential to treat various CNS disorders
including obesity and drug dependence.14c The reported in-
flask synthesis of 3d and 3e required three separate steps,
while the same compounds were prepared very efficiently
using our flow method in a single step (Scheme 1).
Table 5. Synthesis of 1H-Pyrrole-3-carboxylic Acids
Several aspects of this new continuous flow process are
noteworthy. For example, this is the first instance of the
synthesis of pyrrole-3-carboxylic acids and pyrrole-3-car-
boxamides directly from inexpensive commercially available
starting materials in a single continuous process without
isolating intermediates. As noted previously, the standard in-
flask synthesis of these compounds involves multiple reaction
steps requiring workup and purification of several intermedi-
ates. Second, the HBr generated as a byproduct in the
Hantzsch reaction is employed in the flow method to
hydrolyze the t-butyl esters in situ to provide the corre-
sponding acids in a one-chip reaction. By way of comparison,
we performed the in-flask (batch) synthesis of 1-benzyl-2-
methyl-5-phenyl-1H-pyrrole-3-carboxylic acid (Table 3, entry
1) using the optimized conditions we developed for our
continuous flow method (see Supporting Information for
experimental details). Interestingly, the reaction proceeded
as expected to provide the product but in significantly lower
yield (40%) than the flow process (65%). Finally, the
products can be further manipulated in the final step by
coupling diverse amines to generate a variety of amides
allowing the introduction of additional structural complexity.
To demonstrate the utility of the flow method to generate
useful quantities of material for further synthetic manipula-
tion, we scaled up the flow synthesis of 1-benzyl-2-methyl-
5-phenyl-1H-pyrrole-3-carboxylic acid (Table 3, entry 1) by
approximately 17-fold. Gratifyingly, using the flow method,
850 mg (63% yield) of the compound was efficiently
produced in 2.5 h flow time.
entry
R2
yield (%)a
1
2
3
4
Ph
60
60
62
48
4-OMeC6H4
4-FC6H4
4-CNC6H4
a Isolated yield based on R-bromoketone after purification of the crude
reaction mixture.
All flow reaction conditions attempted led to low conversion
to product. To overcome this obstacle, the stream containing
the pyrrole-3-carboxylic acid exiting the first microreactor
was combined first with EDC/HOBt (1:1, 1.2 equiv) and then
with amine/DIPEA (1:1, 1.5 equiv) in a collecting vial and
stirred overnight at room temperature (Scheme 1). This
Scheme 1. Direct Synthesis of Pyrrole-3-carboxamides
In summary, we have developed the first general method
for the synthesis of diversely substituted pyrrole-3-carboxylic
acids and amides directly from commercial tert-butyl ac-
etoacetates, amines, and R-bromoketones. We anticipate that
these advances will facilitate the rapid synthesis of these
biologically important compounds. Further exploration of the
reactivity features of this methodology and applications to
the synthesis of complex molecules and the drug discovery
process are in progress.
Acknowledgment. This work was supported by National
Institutes of Health grant nos. HG005033, GM079590, and
GM081261.
a 0.25 equiv of DIPEA was used.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds including
1H and 13C NMR spectra and MS data. This material is
available free of charge via the Internet at http://pubs.acs.org.
process tolerates a range of amines including primary
(Scheme 1, 3c-3e) and secondary (Scheme 1, 3a). Addition-
ally, amino acid derivatives can directly couple efficiently
to introduce further complexity to the final compounds
(Scheme 1, 3b).
OL102216X
Org. Lett., Vol. 12, No. 22, 2010
5185