Modular approach to substituted Boc-protected 4-(Aminomethyl)pyrroles

Article abstract of DOI:10.1021/ol500544u

The radical addition of various α-xanthyl ketones to Boc-protected azetine gives adducts which, when treated with ammonia or primary amines, furnish 2,4-disubstituted, 2,3,4-trisubstituted, and polycyclic pyrroles having a protected aminomethyl group at position 4. An unusual ring-opening was observed in the case of a cyclobutanone precursor.

Full text of DOI:10.1021/ol500544u

Letter
pubs.acs.org/OrgLett
Modular Approach to Substituted Boc-Protected
4‑(Aminomethyl)pyrroles
Songzhe Han and Samir Z. Zard*
Laboratoire de Synthes
̀
e Organique, UMR 7652 CNRS/Ecole Polytechnique, 91128 Palaiseau Cedex, France
S
* Supporting Information
ABSTRACT: The radical addition of various α-xanthyl ketones to Boc-protected azetine gives adducts which, when treated with
ammonia or primary amines, furnish 2,4-disubstituted, 2,3,4-trisubstituted, and polycyclic pyrroles having a protected
aminomethyl group at position 4. An unusual ring-opening was observed in the case of a cyclobutanone precursor.
We were, however, intrigued by TAK-438, an unusual pyrrole
he pyrrole ring is one of the basic heteroaromatic motifs
Tfound as a structural element in numerous biologically developed by Takeda, where the introduction of a methyl-
aminomethyl group at the 4-position of the ring greatly
improved its potential as a gastric antisecretory agent.4 Indeed,
this compound was selected as a drug candidate for the
treatment of gastresophageal reflux disease (GERD), peptic
ulcer, and other gastric acid-related diseases.
active alkaloids, pharmaceutical products, or even in such
materials as conducting polymers.1 For instance, Lipitor, a
pyrrole-based statin, was for many years the largest selling drug,
with yearly sales in excess of 10 billion U.S. dollars.2 2,4-
Disubstituted pyrroles are especially interesting since they are
useful intermediates for the synthesis of more highly substituted
derivatives and are present in a few pharmacologically
significant products.3 Three examples of 2,4-disubstituted
pyrrole natural products are displayed in Figure 1: Hymenidin
is an antagonist of serotonergic receptors,3b,c pyrrolostatin is a
potent inhibitor of lipid peroxidation,3d and heronapyrroles A
and B display antibiotic activity against Gram-positive bacteria
such as Staphylococcus aureus and Bacillus subtilis.3e
There are a plethora of methods for the synthesis of pyrroles,
such as the classical Hantzsch, Knorr, and Paal−Knorr
reactions, and metal-based or 1,3-dipolar cycloadditions
strategies;5,6 however, only a limited number of examples
dealing with metal-free, modular, and direct construction of the
more unusual 2,4-disubstituted pyrroles have been reported
(the Hantzsch reaction being most prominent).7 In particular,
the current methods to obtain 4-(aminomethyl)-substituted
pyrroles are mainly based on reductive amination of the
corresponding pyrrole 4-carboxaldehydes.4,8 Recently, Huestis
et al. reported a rhodium-catalyzed approach to unsymmetrical
2,3-aliphatic-substituted indoles and pyrroles, but only one
example had a tert-butyl carbamate-protected aminomethyl
group on position 3 of the pyrrole ring.9
The need for modular and direct synthetic protocols
encouraged us to examine the applicability of xanthate
chemistry to design flexible routes to pyrroles related to
TAK-438. Xanthates allow many otherwise difficult inter- or
intramolecular additions to olefins to occur,10 and the ability to
add to various strained alkanes such as cyclopropenes,
cyclobutenes, and azetines opens numerous possibilities to
access unusual structures.11 In the present context, the addition
of an α-ketonyl xanthates 1 to Boc-protected azetine 2 would
give adducts 3. These compounds represent in principle
Received: February 19, 2014
Published: March 19, 2014
Figure 1. Examples of biologically active pyrroles.
© 2014 American Chemical Society
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dx.doi.org/10.1021/ol500544u | Org. Lett. 2014, 16, 1992−1995

Organic Letters
Letter
compact synthetic equivalents of 1,4-ketoaldehydes 4, which
would be extremely difficult to access. The reaction of adducts
3 with ammonia or a primary amine in the presence of acid
should therefore lead to the desired pyrroles 5 (Scheme 1). We
Table 1. Formation of 2,4-Disubstituted Pyrroles
Scheme 1. Route to Aminomethyl-Substituted Pyrroles
had in the past tested successfully a conceptually related
approach involving addition to vinyl pivalate.12 By this route, 2-
substituted or 2,3-disubstituted pyrroles are readily available,
but not 2,4-di- or 2,3,4-trisubstituted derivatives 5.
N-Protected azetine 2 is easily prepared from cheap
commercially available N-Boc-3-hydroxyazetidine by sulfonyla-
tion and elimination (Scheme 1).13 In the event, the lauroyl
peroxide (DLP) mediated radical addition of various xanthates
to azetine 2 proceeded in generally good yield, and exposure of
the resulting adducts 3 to the action of a range of primary
amines or ammonia and p-TsOH (0.5 equiv with respect to the
adduct 3) in hot dioxane (80 °C) indeed furnished the
corresponding pyrroles 5 very efficiently within a short reaction
time (ca. 1 h).
A plausible mechanism for the pyrrole formation is outlined
in Scheme 2. Aminolysis of the xanthate group results in the
Scheme 2. Mechanism for the Formation of Pyrroles
formation of thiol 6, which must readily undergo ring-opening
to thioaldehyde 8 to relieve the strain of the azetidine ring.
Finally, condensation of the amine with both the reactive
thioaldehyde and the ketone provides the pyrrole. The last step
is analogous to the chemical condensation of primary amines or
ammonia with 1,4-diketones or 1,4-ketoaldehydes (Paal−Knorr
reaction).
Our results are compiled in Tables 1 and 2. The two steps
could be performed without purification of the intermediate
adducts and with the same overall efficiency. This is illustrated
by the synthesis of pyrroles 5m and 5n in Table 1 and by all the
pyrroles compiled in Table 2. While the pyrroles in Table 1 are
2,4-disubtituted, those in Table 2 are 2,3,4-trisubstituted
derivatives.
a
The dr was measured by NMR spectroscopy after purification by
b
column chromatography. Overall yield for the two steps.
The radical addition to azetine 2 to give the intermediate
adducts 3 is regioselective in part because of polar effects: the
ketonyl radicals derived from xanthates 1 are electrophilic in
nature and prefer to add to the most nucleophilic terminus of
the alkene. Steric hindrance by the Boc- group also favors the
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Organic Letters
Letter
We made an unexpected observation in the case of
cyclobutanone adduct 3m derived by addition of xanthate 1m
to azetine 2 (Scheme 3).14 Upon treatment with benzylamine
Table 2. Synthesis of 2,3,4-Trisubstituted Pyrroles
Scheme 3. Ring-Opening of a Cyclobutane Intermediate
or allylamine and toluenesulfonic acid, a pyrrole was indeed
obtained but the 4-membered ring ruptured under the reaction
conditions to afford derivatives 5v and 5w in moderate yield.
Presumably, the strain inherent in a pyrrolocyclobutanone 10
forces the reaction to proceed by ring-opening of the
cyclobutanone in the final aromatization steps, as shown in
intermediate 9. No products arising from a thermal electro-
cyclic ring-opening to diene 11 were observed.15
In summary, we have accomplished a flexible synthesis of
diversely substituted pyrroles related to TAK-438. Most of the
compounds described herein would be exceedingly tedious to
prepare by traditional routes based on ionic or organometallic
pathways. The possibility of placing almost any side chain on
the nitrogen atom of the pyrrole ring by simply modifying the
amine partner is another valuable feature for building libraries.
Normally, such side chains are introduced by alkylation, after
pyrrole formation, and this often constitutes a serious
limitation. Our approach will hopefully allow a better
exploration of the pharmacological profile of this class of
pyrroles. An ancillary benefit may further be derived from
intermediates 3, since reductive removal of the xanthate group
would deliver variously functionalized azetidines scaffolds.
a
The crude adduct was used directly in the second step after a quick
b
purification on silica gel. Overall yield for the two steps.
observed regiochemistry. Furthermore, it is clear from the
transformations in both tables that numerous functional groups
may be introduced, either through the xanthate partner or
through the amine moiety. Thus, functionality in the xanthate
allows the incorporation of an aryl, a cyclopropyl, or a
trifluoromethyl group (examples 5a−f,m,n,t), an ethoxycarbo-
nylmethyl, or a phosphonomethyl group as in pyrroles 5k and
5l. In the former case, it was necessary to use a full equivalent of
p-TsOH to avoid aminolysis of the ester group. This, however,
came at a small cost since some acid-catalyzed de-
ethoxycarboxylation leading to 5k′ was also observed.
Perhaps more interesting is the synthesis of pyrroles
containing differentially protected aminomethyl motifs such
as 5o−q and 5j (Tables 1 and 2). In the former, the second
aminomethyl moiety is embedded in a fused six-membered
ring. The ease of access to polycyclic pyrroles by this approach
is also worthy of note. The acetal in intermediate 3l did not
withstand the acidic conditions and directly furnished
pyrrolecarboxaldehyde 5u. This compound could in principle
be subjected to reductive amination reactions leading to more
elaborate 3,4-bis-(aminomethyl)pyrroles. Finally, pyrrole 5t is
in fact a masked 3-aminopyrrole, since the phthalimido group is
directly linked to the pyrrole nucleus. Routes to amino pyrroles
are very scarce, and rely essentially on reduction of the
corresponding nitropyrroles.5 Furthermore, free amino-pyrroles
are labile entities that are highly sensitive to air oxidation and
the presence of the electron-withdrawing phthalimide is
essential in stabilizing the structure.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, full spectroscopic data, and copies of
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: samir.zard@polytechnique.edu.
Notes
The authors declare no competing financial interest.
1994
dx.doi.org/10.1021/ol500544u | Org. Lett. 2014, 16, 1992−1995

Organic Letters
Letter
(7) See, for example: (a) Zhao, M.-N.; Ren, Z. H.; Wang, Y. Y.;
ACKNOWLEDGMENTS
We thank the China Scholarship Council for a grant to one of
us (S.H.).
■
Guan, Z.-H. Org. Lett. 2014, 16, 608. (b) Estev
Menendez, J. C. Chem. Commun. 2013, 49, 591. (c) Chen, F.; Shen,
T.; Cui, Y.; Jiao, N. Org. Lett. 2012, 14, 4926.
́
ez, V.; Villacampa, M.;
́
(8) Direct aminoalkylation of pyrroles usually takes place on position
2; see: (a) Korakas, D.; Varvounis, G. Synthesis 1994, 2, 164.
(b) Katritzky, A. R.; Wang, J.; Yang, B. Synth. Commun. 1995, 17,
2631.
DEDICATION
■
This paper is dedicated with respect to the memory of Prof.
Alan R. Katritzky (University of Florida).
(9) (a) Huestis, M. P.; Chan, L.; Stuart, D. R.; Fagnou, K. Angew.
Chem., Int. Ed. 2011, 50, 1338. The synthesis of cyclic 3-aminoalkyl
pyrroles has been recently disclosed: (b) Zhuo, C. K.; Wu, Q. -F.;
Zhao, Q.; Xu, Q. L.; You, S.-L. J. Am. Chem. Soc. 2013, 135, 8169.
Note that position 3 can become position 4 because the presence of
other substituents can modify the numbering around the pyrrole ring.
(10) For reviews on the xanthate radical addition-transfer process,
see: (a) Zard, S. Z. Angew. Chem., Int. Ed. 1997, 36, 672. (b) Quiclet-
Sire, B.; Zard, S. Z. Top. Curr. Chem. 2006, 264, 201. (c) Zard, S. Z.
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5, 205. (e) Quiclet-Sire, B.; Zard, S. Z. Pure Appl. Chem. 2011, 83, 519.
For a review on its application to the synthesis of heteroaromatics, see:
(f) El Qacemi, M.; Petit, L.; Quiclet-Sire, B.; Zard, S. Z. Org. Biomol.
Chem. 2012, 10, 5707.
(11) (a) Ferjancic, Z.; Cekovic, Z.; Saicicc, R. N. Tetrahedron Lett.
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(12) Quiclet-Sire, B.; Quintero, L.; Sanchez-Jimenez, G.; Zard, S. Z.
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