New synthesis of unsymmetrically-substituted 2,5-diarylpyrroles from homopropargyl sulfonamides

Article abstract of DOI:10.1039/c3ra46579a

Unsymmetrically-substituted 2,5-diarylpyrroles were prepared by 5-endo-dig cyclization with consecutive deprotection of homopropargyl sulfonamides. Stepwise elaboration of an aldehyde allows the introduction of a variety of functional aryl moieties at the

Full text of DOI:10.1039/c3ra46579a

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New synthesis of unsymmetrically-substituted 2,5-
diarylpyrroles from homopropargyl sulfonamides†
Cite this: RSC Adv., 2014, 4, 4897
*
*
Wim Van Rossom, Yoshitaka Matsushita, Katsuhiko Ariga and Jonathan P. Hill
Received 11th November 2013
Accepted 2nd December 2013
DOI: 10.1039/c3ra46579a
www.rsc.org/advances
Unsymmetrically-substituted 2,5-diarylpyrroles were prepared by 5- their H+/Clꢀ binding and transmembrane transport properties.6
endo-dig cyclization with consecutive deprotection of homo- Preorganization of a polarized hydrogen-bond about the pyrrole
propargyl sulfonamides. Stepwise elaboration of an aldehyde allows ring, forming a central binding pocket, is of great importance
the introduction of a variety of functional aryl moieties at the for the operation of macrocycles and transmembrane trans-
pyrrole ring.
porter systems.
Prior to this work, we had envisioned synthesis of a variety of
anion receptors based on an oligomeric aryl-pyrrole framework.
Thus, we set out to explore the potential synthetic methodolo-
gies towards pyrroles bearing aryl groups only at the 2,5-posi-
tions. Maintaining the 3,4-positions substituent-free allows for
the preparation of systems with lower molecular weights
(<500 Da), which is one of the requirements stipulated by the
Lipinski rules for pharmaceuticals, supposed to increase
membrane permeability in biological systems.7 Various routes
for the synthesis of multi-substituted pyrrole moieties have
been investigated.8 There also exist methods for the preparation
of 2,5-diarylpyrrole derivatives usually containing an additional
electrophilic substituent other than a hydrogen atom at the 3 or
4 positions.9 Other known methods involve azides,10a boronic
acid/esters,10b toxic stannyl compounds,11 or unstable interme-
diates requiring glovebox conditions are available.12 Other
useful methods involve 1,4-butanediones13 but these are less
exible for syntheses of unsymmetrical derivatives.
Heterocyclic compounds are of great importance since they are
widely distributed in nature and have shown great potential as
components in the design of macromolecules.1 The introduc-
tion of heteroatoms such as nitrogen into macromolecular
systems introduces particular physical and chemical properties
compared to the carbon-only systems.2 Pyrrole rings are espe-
cially well known as p-conjugated aromatic heterocyclic moie-
ties and have been used extensively as building blocks of a
broad range of macrocycles including porphyrins,3 corroles,4
and calixpyrroles.5 In addition, pyrrole groups have been
demonstrated to be indispensable to the functions of naturally
occurring and synthetic prodigiosin and tambjamine deriva-
tives (Fig. 1), which are known to possess substantial antima-
larial, immunosuppressive and anticancer potencies due to
A recent development in indole synthesis describes the tetra-
n-butylammonium uoride (TBAF)-promoted cyclization of 1-
acetyl-2-tosylaminophenyl derivatives leading to unprotected
indole compounds.14 There are three aspects to the function of
TBAF in this reaction: the strongly basic character of the uo-
ride ion results in deprotonation of the sulfonamide with
subsequent reaction of the nitrogen at the acetylene forming an
N-tosylindole ring; nucleophilic uoride ions lead directly to
detosylation giving the 1H-indole moiety; nally, tetra-n-buty-
lammonium counterions promote the solubility of the uoride
ion in the appropriate solvent. To investigate the potency of
TBAF in the synthesis of 2,5-diarylpyrroles a series of homo-
propargyl sulfonamides was prepared (Scheme 1). Acid-cata-
lyzed condensation reaction on p-methoxybenzaldehyde (1)
with p-toluenesulfonamide yielded the corresponding
Fig. 1 Natural compounds prodigiosin and tambjamine C.
World Premier International (WPI) Research Center for Materials Nanoarchitectonics
(MANA), National Institute for Materials Science (NIMS), 1-1 Namiki, Tsukuba
305-0044, Japan. E-mail: wimvanrossom@gmail.com; jonathan.hill@nims.go.jp
† Electronic supplementary information (ESI) available: Experimental procedures
and data for all novel compounds, and CIF le for 5c. CCDC 962821. For
crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ra46579a
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Scheme 1 Synthesis of homopropargyl sulfonamides 4a–e, 2,5-diarylpyrroles 5a–c and 2-pyrroline 6.
N-tosylimine 2 in 89% yield. Subsequently, Barbier reaction of
the N-tosylimine 2 with excess propargylzinc bromide yielded
homopropargyl sulfonamide 3 in quantitative yield. Sonoga-
shira reactions of the terminal acetylene of sulfonamide 3 with
various aryl halides gave sulfonamide derivatives 4a–e in
excellent yields (65–86%; Scheme 1).
Treating CF3-substituted propargyl sulfonamides 4a and 4b
with an excess of TBAF$3H2O (5 equiv.) in DMF at 80 ꢁC for 48 h
resulted in the formation of 2,5-diarylpyrroles 5a and 5b in
excellent yields (74% and 68%, respectively; Scheme 1). The
ease with which the CF3-substituted aryl groups can be intro-
Scheme 2 Proposed reaction sequence from sulfonamide to pyrrole.
duced onto the pyrrole ring is very useful for tuning the lip-
ophilicity and acidity of molecular receptors. In addition,
formation of the pyrrole ring starting from a benzaldehyde cyclization upon deprotonation of the N-tosylamide, followed by
allows for the smooth introduction of an electron rich aryl- deprotection through elimination of sulnic acid, and nally
group without the formation of instable intermediates, making tautomerization leads to formation of the pyrrole ring
this methodology suitable for various applications.
(Scheme 2).
To extend the scope of applicable aryl groups the introduc-
Under the same reaction conditions (TBAF$3H2O, DMF,
80 ꢁC, 48 h) only 20% yield of pyrrole 5c was derived from tion of a transition metal catalyst to promote the 5-endo-dig
sulfonamide 4c while for 4d only trace amounts of pyrrole 5d cyclization was investigated. Catalytic amounts of various
were obtained, leaving most of the starting material 4d intact transition metal salts including AuCl3, AgOAc, AgNO3, and
(Scheme 1). A potential explanation for this lies in the lower Ag2CO3 have been reported to promote 5-endo-dig cyclization of
electron withdrawing character of pyridinyl and phenyl groups terminal alkyne homopropargyl sulfonamides.8c,d,15 Unfortu-
relative to CF3-substituted phenyl groups. This results in a nately, upon reaction of aryl substituted sulfonamide 4a with Au
weaker induced d+ charge on the acetylene moiety making or Ag salts no cyclization occurred and mostly the starting
nitrogen atom insertion at the sp-hybridized carbon atom more material was recovered. Furthermore, the palladium-catalyzed
difficult. Even at higher temperatures (stirring at 160 ꢁC) no intramolecular hydroamination of o-alkynylaniline and homo-
noteworthy changes were observed and again 18% and trace propargyl amide derivatives has proven extremely useful for the
amounts of pyrrole 5c and 5d, respectively, were obtained.
synthesis of indoles and multisubstituted pyrrole rings.8b,16
Reaction of a more electron decient pyridinyl derivative 4e, Here, activation of the carbon–carbon triple bond towards
containing a methyl ester in the 6-position, resulted solely in the nucleophilic attack by p-coordination to a Pd species leads to an
hydrolysis of the ester function without any cyclization. Inter- increase in the electrophilicity of the triple bond, and is fol-
estingly, upon exposure of the aryl-free sulfonamide 3 to these lowed by 5-endo-dig cyclization with migratory insertion and
cyclization/deprotection reaction conditions (TBAF$3H2O, consecutive elimination of the Pd species.
DMF, 80 ꢁC, 48 h) the reaction terminated upon completion of
When sulfonamide 4c was subjected to the earlier estab-
the 5-endo-dig cyclization without deprotection occurring lished reaction conditions (TBAF$3H2O, DMF, 80 ꢁC, 48 h) with
resulting in the N-tosyl protected 2-pyrroline 6 in excellent yield the addition of a catalytic amount of Pd(PPh3)2Cl2 (10 mol%) no
(69%; Scheme 1).
signicant improvement of the reaction outcome was observed
When the cyclization/deprotection reaction on a sulfon- (23%). Therefore, we set out to investigate the use of a palla-
amide was neutralized aer 24 h a mixture of N-tosyl-2-pyrroline dium catalyst to induce 2,5-diaryl-2-pyrroline formation.
and 1H-pyrrole was obtained. Therefore, the reaction sequence Homopropargyl sulfonamide 4c was stirred with Pd(PPh3)2Cl2
ꢁ
can be considered to commence with an initial 5-endo-dig as catalyst and K2CO3 (5 equiv.) as a base in DMF at 80 C for
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assisted cyclization with a consecutive deprotection step opens
up the route to pyrrolopyridine derivatives. Currently, we are
applying these synthetic techniques in the development of the
relatively unexplored molecular receptors consisting of carefully
arranged pyrrole rings forming a highly preorganized hydrogen-
bonding pocket with potentially interesting supramolecular
properties. Further investigation of the effect of substituents is
required for a more profound understanding of the reaction
involved here and will establish these new approaches towards
2,5-diarylpyrroles and N-tosyl-2,5-diaryl-2-pyrrolines allowing for
the 2,5-diarylpyrrole sequence to be explored more intensively.
The authors gratefully acknowledge the Japan Society for the
Promotion of Science (JSPS) for nancial support and a post-
doctoral fellowship for W.VR. The World Premier International
(WPI) Research Center for Materials Nanoarchitectonics
(MANA) and National Institute for Materials Science (NIMS) are
also thanked for nancial support.
Scheme
lpyrroles 5c and d.
3 Synthesis of 2,5-diarylpyrrolines 7b–d and 2,5-diary-
24 h leading to a 60% yield of N-tosyl-2-pyrroline 7c (Scheme 3).
Consecutive addition of an excess of NaOH (20 equiv.; 80 C, 3
ꢁ
h) resulted in the deprotected pyrrole 5c in 48% overall yield
(2 steps; Scheme 3). From this outcome the yield for the
deprotection of the pyrroline 7c can be deduced to be 80%.
Interestingly, while for 4b the TBAF-assisted cyclization/depro-
tection reaction gave an excellent conversion to pyrrole 5b, the
palladium-assisted cyclization afforded N-tosylpyrroline 7b in a
modest 27%. Under the same conditions phenyl derivative 4d
resulted in only traces of pyrroline 7d. Fortunately, increasing
the temperature (100 ꢁC) and extending the reaction time (48 h)
resulted in an improved conversion to the N-tosyl-2-pyrroline 7d
(33%). Further elevation of the temperature (120 ꢁC) and
extension of the reaction time (72 h) did not further improve the
reaction outcome (30%). Deprotection of 7d by reaction with an
excess of NaOH in wet DMF at 80 ꢁC for 72 h nally yielded
pyrrole 5d in a modest 18% yield (77% of the starting material
7d was recovered).
Single crystals of 5c suitable for X-ray diffraction were grown by
vapour diffusion of hexane into a CHCl3 solution of 5c stored
under a nitrogen atmosphere and shielded from light (Fig. 2). The
structure appears almost completely planar with the aryl groups
maintained at an angle of approximately 137ꢁ. Nitrogen atoms of
both pyrrole and pyridine rings are oriented to the same side,
presumably due to a weak N–H–N hydrogen bonding interaction.‡
In conclusion, we present new approaches towards unsym-
metrical-substituted 2,5-diarylpyrroles by 5-endo-dig cyclization
and simultaneous deprotection of readily available homo-
Notes and references
‡ X-ray data for 5c: Rigaku Varimax Saturn; T ¼ 100(2) K. monoclinic, space group
ꢁ
ꢁ
˚
˚
˚
P21, a ¼ 5.6181(4) A, b ¼ 21.2320(19) A, c ¼ 10.8628(9) A, a ¼ 90 , b ¼ 98.103(2) , g
¼ 90 , V ¼ 1282.82(18) A , Z ¼ 4, rcalc ¼ 1.291 g cmꢀ3, m ¼ 0.082 mmꢀ1. 3938
reections, 3256 independent. Final wR2 ¼ 0.1152, R1 ¼ 0.0414 and Rint ¼ 0.0335.
GoF ¼ 1.031.
3
ꢁ
˚
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