Polysubstituted pyrrole derivatives via 1,2-alkenyl migration of novel γ-amino-α,β-unsaturated aldehydes and α-diazocarbonyls

Article abstract of DOI:10.1039/c3ra47020b

Tri-substituted pyrrole derivatives were successfully synthesized from aminoaldehyde and α-diazocarbonyl, using a TiCl₄ catalyst. The reactions proceeded via 1,2-migration and condensation, leading to the corresponding pyrroles in moderate to excellent yields. Reaction susceptibility was subsequently demonstrated by the variation in substrates. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3ra47020b

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Polysubstituted pyrrole derivatives via 1,2-alkenyl
migration of novel g-amino-a,b-unsaturated
aldehydes and a-diazocarbonyls†
Cite this: RSC Adv., 2014, 4, 7275
Received 26th November 2013
Accepted 7th January 2014
*
Shuting Cai, Jing Zeng, Yongxin Li and Xue-Wei Liu
DOI: 10.1039/c3ra47020b
www.rsc.org/advances
Tri-substituted pyrrole derivatives were successfully synthesized from
aminoaldehyde and a-diazocarbonyl, using a TiCl4 catalyst. The
reactions proceeded via 1,2-migration and condensation, leading to
the corresponding pyrroles in moderate to excellent yields. Reaction
susceptibility was subsequently demonstrated by the variation in
substrates.
In the eld of pyrrole synthesis, the continuous efforts to
develop competent strategies emphasize the inadequacy of the
currently available methods. Probing into the existing methods
provided an insight to the inefficacy as well as substantiated the
need to rene and surpass current approaches. The use of non-
environmental catalysts,1 harsh reaction conditions and
deprived yields2 contributed to the general consensus that there
is still a huge underlying potential in pyrrole synthesis. Not only
are pyrroles omnipresent in natural products3,4 and drugs5,6
(Fig. 1), they also exhibit a wide range of biological activities
(anti-inammatory,7 antibiotic8 and anti-tumour9 activities),
provide an excellent choice in catalytic systems10 and adopt a
leading spot over other aromatic heterocycles in drug
discovery.11 With such compelling benets, it is not surprising
that their synthesis has engaged the chemical society over the
past century.
Classical approaches to the synthesis of substituted pyrroles
oen revolve around the concept of Paal–Knorr synthesis in
1884.12,13 This work, involving the reaction between an amine
and a 1,4-dicarbonyl compound, has brought great expansion to
the otherwise limited synthesis of pyrroles. Noteworthy, other
conventional methods such as Huisgen12 and Hantzsch13
pyrrole synthesis have also contributed signicantly to the
development of pyrrole derivatives. Over the past decades,
Fig. 1 Pyrrole-containing natural products/drugs.
various strategies which attempted to improve on these tradi-
tional approaches have emerged and produced remarkable
results, such as multi-component one-pot reactions14 and
palladium catalyzed C–H activation.15 They served as alterna-
tives to synthesize poly-functionalized pyrrole derivatives and
have created excellent opportunities for researchers. Inspired by
the abundant benets and possibilities, our group has decided
to develop new methodologies in the synthesis of pyrrole
derivatives,16 continuing our constant efforts in the construc-
tion of heterocyclic compounds.17–20 Successful representations
of transition metal-catalyzed 1,2-migration in the assembly of
heterocycles21,22 sparked off our interests in adopting this
method for the synthesis of pyrroles. A widely used and highly
efficient strategy in organic synthesis, 1,2-migration can be
generally classied into 1,2-hydride,23 alkyl,24 aryl and alkenyl
migration.25,26 Although the reactions involving 1,2 migrations
generally produce promising results, 1,2-alkenyl migration
seems to be less prevalent in contrast to the other categories.
Therefore, due to the increasing popularity of diazo compounds
at the same time, we envisioned the possibility of using diazo
compounds to participate in a 1,2-alkenyl migration, forming
pyrrole derivatives simultaneously.27,28 The generation of metal
carbene species through the diazo compounds provides diverse
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371. E-mail: xuewei@ntu.
edu.sg
† Electronic supplementary information (ESI) available: All relevant synthetic
details as well as 1H and 13C spectra for all compounds. See DOI:
10.1039/c3ra47020b
This journal is © The Royal Society of Chemistry 2014
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reactivities, which in turn helps to induce 1,2-shi formations, several unsuccessful tries involving ZnBr2, ZnCl2 and AlCl3,
cyclopropanations and bond insertions.29,30 With the integra- TiCl4 was nally located as an efficient catalyst which could
tion of both aspects, herein, we report an efficient synthesis of catalyze the reaction with a reasonably good yield of 63%.34
polysubstituted pyrrole derivatives through the addition of
Having identied the suitable catalyst, other factors such as
diazocarbonyl compounds to various g-amino-a,b-unsaturated solvent and temperature were then taken into consideration
aldehydes. We envisioned that the successful execution of such and varied. When the reaction was subjected to reux condition
a system will provide an interesting insight through the instead of normal room temperature, the yield was exponen-
implementation of 1,2-alkenyl shi from novel g-amino-a,b- tially increased to 78%. In addition, aer some analysis, it was
unsaturated aldehydes (Table 1).
found that CH2Cl2 remains the most appropriate solvent in
Preliminary studies focus on the optimization of a suitable contrast to other common solvents such as toluene, DMF,
and efficient set of conditions for the reaction between ethyl MeCN and THF. Finally, the catalyst loading was modied and
diazoacetate 2a and N-Boc-g-amino-a,b-unsaturated aldehyde 10 mol% of the catalyst proves to be the best loading (similar
1a.The search began with the identication of an appropriate results were produced at 20 mol% and less yield was obtained
catalyst to encourage this reaction. Based on earlier reports, it when the catalyst loading was decreased to 5 mol%). Consoli-
could be observed that successful 1,2-migration oen involves dating the above mentioned experiment results; the optimal
the incorporation of BF3$Et2O as the Lewis acid catalyst.25,31 condition was elucidated as 10 mol% of TiCl4 in CH2Cl2 at
With this noticable trend, BF3$Et2O naturally became the rst reux temperature.
choice of catalyst for the initial optimization. Although
BF3$Et2O appears to be a promising catalyst at the outset, no of the reaction's versatility through modication of the
desired product was obtained when it was employed in this protecting group on g-amino-a,b-unsaturated aldehyde
Acquirement of the ideal condition permitted investigation
1
reaction. Therefore, the change in focus towards other possible (Scheme 1). Although several protecting groups were screened,
catalyst was essential and further review of past literatures only the tert-butyloxycarbonyl (Boc) and the benzyl protecting
revealed Rh2(OAc)4 (ref. 32) and SnCl4 (ref. 33) as highly efficient groups were suitable for the reaction, obtaining yields of 78%
catalysts for 1,2-shis. While Rh2(OAc)4 did not manage to and 55% respectively. Since the Boc protecting group proved
induce the reaction, SnCl4 successfully produced the desired superior over others, we carried out the screening of the
product, albeit a relatively low yield (35%) was obtained with substrates using N-Boc-g-amino-a,b-unsaturated aldehyde 1a.
long reaction time. Despite the success of SnCl4 in obtaining the
As the initial results amplied the suitability of diphenyl
desired product, the search for an optimal catalyst continued as aldehydes, a range of electron donating and electron withdrawing
attempts to raise the yields through changing the solvent, substituents on the phenyl group was introduced (Scheme 2).
reaction times and temperature were unproductive. Aer Beginning from symmetrical diarylaminoaldehydes, the electron
donating methyl-substituted 1b was able to produce the pyrrole
derivative 3b in outstanding yield of 85%. Subjecting the reaction
Table 1 Optimization of the synthesisa
to electron withdrawing uoro-substituted 3c proved to be
successful as well, obtaining a yield comparable to electron
donating substituents (83%). To ensure that the reaction works on
non-symmetrical diarylaminoaldehydes, single substituted
methyl- and methoxy-1d and 1e were synthesized and excellent
yields were obtained for both compounds 3d (83%) and 3e (85%).
However, when attempts to increase the scope were made by
employing aliphatic aminoaldehyde, the reaction did not proceed
as desired and no product was obtained.
Entry
Catalyst
Solvent
Temp (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
BF3$Et2O
Rh2(OAc)4
SnCl4
ZnBr2
ZnCl2
AlCl3
TiCl4
TiCl4
TiCl4
TiCl4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
r.t
r.t
r.t
r.t
r.t
r.t
r.t
Reux
60
Reux
r.t
Reux
Reux
Reux
—
n.r
35
n.r
n.r
n.r
63
78
55
28
20
—
9
10
11
12
13c
14d
TiCl4
TiCl4
TiCl4
TiCl4
MeCN
DMF
CH2Cl2
CH2Cl2
64
79
Scheme 1 Investigation of the amine protecting group in the synthesis
of polysubstituted pyrrole derivatives. All reactions were conducted in
CH2Cl2 with 2.0 equiv. of N-protected-g-amino-a,b-unsaturated
aldehyde 1 and 1.0 equiv. of a-diazocarbonyl 2a in the presence of
10 mol% TiCl4. Isolated yield after chromatography.
a
All reactions were conducted in CH2Cl2 with 2.0 equiv. of aldehyde 1a
and 1.0 equiv. of a-diazocarbonyl 2a in the presence of 10 mol% TiCl4.
b
Isolated yield. c Reaction was conducted with 5 mol% TiCl4. d Reaction
was conducted with 20 mol% TiCl4.
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Fig. 2 X-ray structure of compound 3c.
The crystal structure of the g-amino-a,b-unsaturated alde-
hyde (ESI†) conrms with our theory that during the synthesis
of this aldehyde, the ring opening of the non-symmetrical
cyclopropenone occurs in a manner whereby the amine will
attack the more electron decient carbon site. This preference is
largely inuenced by the substituents on the phenyl ring (elec-
tron donating or withdrawing). Although the crystal structure
shows a trans-form of the g-amino-a,b-unsaturated aldehyde (1f
without protecting group), it can be expected that such
compounds are present in an equilibrium mixture of trans- and
cis-isomers.35,36 However, it is worthy of note that the cis-isomer
might predominate aer protection due to stabilization
through intramolecular hydrogen bonding and steric
hindrance.37 Subsequently, conrmation of the structure of the
polysubstituted pyrrole product was further done by obtaining
the X-ray crystallography data of 3c (Fig. 2).
With this product conrmation, a plausible mechanism can
be deduced. Through a Lewis acid-catalyzed addition of diazo-
acetates with N-protected-g-amino-a,b-unsaturated aldehyde 1,
an alkoxide intermediate Int-1 could be formed. A 1,2-alkenyl
shi would then produce Int-2. Following which, cyclization
would then result in the desired pyrroles 3 (Scheme 3).
Scheme 2 Pyrrole derivatives from 1,2-migration of N-protected-g-
amino-a,b-unsaturated aldehyde 1 and a-diazocarbonyl 2. Reactions
were conducted in CH2Cl2 with 1.0 equiv. of N-protected-g-amino-
a,b-unsaturated aldehyde 1 and 2.0 equiv. of a-diazocarbonyl 2 in the
presence of 10 mol% TiCl4. Isolated yield.
Having investigated the aminoaldehydes component, the
investigation was then drawn towards modifying the a-diazo-
carbonyls. Fixing on diazocarbonyl ester, branched ester
substituents such as isopropyl ester 3g and 2-methylbutyl ester
3h were examined and the reactions were able to give good to
moderate yields of 76% and 58% respectively. Finally, the
successful application of diazopentan-2-one on both g-amino-
a,b-unsaturated aldehyde 3j and diuoro-3k further indicated
the tolerance of the reaction to an array of a-diazocarbonyls. To
round up on our investigation of the substrate scope, the pro-
tecting group of the g-amino-a,b-unsaturated aldehyde was
changed to benzyl group. Although the reaction was generally
less satisfactory and slower as compared to using Boc protecting
group, the pyrrole derivative 3l was still obtained in a moderate
yield of 55%.
Scheme 3 Plausible synthetic pathway of 2,3-diaryl pyrroles.
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In conclusion, successful reactions between g-amino-a,b-
unsaturated aldehydes and a-diazocarbonyls were established.
Polysubstituted pyrrole derivatives were obtained, using TiCl4
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Acknowledgements
Financial supports from Nanyang Technological University 19 K. K. Pasunooti, H. Chai, C. N. Jensen, B. K. Gorityala,
(NTU RG50/08), the Ministry of Education, Singapore (MOE S. Wang and X.-W. Liu, Tetrahedron Lett., 2011, 52, 80–84.
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Science, Technology and Research (A*STAR) are gratefully
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