From conjugated tertiary skipped diynes to chain-functionalized tetrasubstituted pyrroles

Article abstract of DOI:10.1002/chem.200802262

A novel and metal-free method for the synthesis of chain-functionalized tetrasubstituted pyrroles from easily accessible tertiary skipped diynes, was reported. The method involved modular synthesis of chain functionalized tetrasubstituted pyrroles from ea

Full text of DOI:10.1002/chem.200802262

DOI: 10.1002/chem.200802262
From Conjugated Tertiary Skipped Diynes to Chain-Functionalized
Tetrasubstituted Pyrroles
David Tejedor,*[a, b] Sara Lꢀpez-Tosco,[a, b] Javier Gonzꢁlez-Platas,[c] and
Fernando Garcꢂa-Tellado*[a, b]
Among the most appreciated chemical complexity-gener-
ating reactions, domino processes[1] maintain a privileged
status. They generate molecular complexity in a fast and ef-
ficient manner, accumulating important “green chemistry”
values such as atom, time, and labor economies, resource
management, and minimal chemical waste generation.[2] An
appealing subclass of domino processes comprises the reac-
tion of a densely and conveniently functionalized acyclic
scaffold with simple and readily accessible chemical reac-
tants, such as amines, alcohols, or C-nucleophiles.[3] The
design and synthesis of these scaffolds constitutes a sought-
after challenge in current organic synthesis and, more specif-
ically, in drug discovery research.[4] These densely function-
alized structural units must be designed to accommodate
three main practical requirements: a short synthesis (effi-
ciency principle), a modular origin (diversity principle) and
a defined interrelationship between functional groups (reac-
tivity principle). Tertiary skipped diynes 1 fulfil these
requirements. They are modularly assembled according to
the four-component A2BB’ synthetic manifold (Figure 1).[5,6]
Moreover, these C5 linear scaffolds feature an interconnect-
Figure 1. Synthesis and reactivity patterns of tertiary skipped diynes 1.
ed reactivity frame defined by the quaternary sp3-center and
the two conjugated alkyne units. Whereas the quaternary
center favors alkyne-mediated cyclization processes
(Thorpe–Ingold effect),[7] the ester group at this center and
one of the two alkynoate units are conveniently oriented for
a [3,3]-sigmatropic rearrangement.[8] In addition, each alky-
noate group holds a polyvalent reactivity profile which is ex-
pressed as d0, a1, a2, a3, d2, or [a3 +d2] (letters refer to accept-
or/donor properties, numbers refer to position).[9] Each nota-
tion (ai, di) codifies for a particular chemical transformation
at this specific position, that is, a1 codifies for 1,2-addition,
a3 for 1,4-addition, and so on. We hypothesized that this
rich arsenal of chemical transformations could be used as a
convenient chemical toolbox for the design and implementa-
tion of a different domino-based complexity-generating pro-
cess involving these 1,4-diynic scaffolds (Figure 1).
[a] Dr. D. Tejedor, S. Lꢀpez-Tosco, Dr. F. Garcꢁa-Tellado
Instituto de Productos Naturales y Agrobiologꢁa-CSIC
Avda. Astrofꢁsico Francisco Sꢂnchez 3
38206 La Laguna, Tenerife (Spain)
Fax : (+34)922-260135
E-mail: dtejedor@ipna.csic.es
fgarcia@ipna.csic.es
[b] Dr. D. Tejedor, S. Lꢀpez-Tosco, Dr. F. Garcꢁa-Tellado
Instituto Canario de Investigaciꢀn del Cꢂncer
http://www.icic.es
[c] Dr. J. Gonzꢂlez-Platas
Servicio de Difracciꢀn de Rayos X
Departamento de Fꢁsica Fundamental II
Universidad de La Laguna
Avda. Astrofꢁsico Francisco Sꢂnchez 2,
38204 La Laguna, Tenerife (Spain)
As a proof of concept, we report herein our preliminary
results on the design and implementation of an efficient and
novel metal-free domino-based synthetic manifold for the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802262.
838
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Chem. Eur. J. 2009, 15, 838 – 842

COMMUNICATION
transformation of tertiary skipped diynes 1 into chain-func-
tionalized tetrasubstituted pyrroles 5 (Scheme 1). The chem-
ical key to this domino process relies on the excellent
Figure 2. Five points of diversity and two points for generation of com-
plexity in pyrrole 5.
These hybrid structures are usually synthesized by Frie-
del–Crafts reaction between the substituted pyrrole and the
corresponding alkyl glyoxylate.[18,19] In recent years,
a
number of important organometallic methodologies for the
synthesis of pyrroles from alkyne-containing materials have
been developed.[20] Paradoxically, the number of metal-free
homologous methodologies remains scarce.[21] This scarcity
offers a challenge for the design and implementation of
novel synthetic methodologies in line with recent progress
in organic synthesis[22] and drug discovery research.[4]
Herein, we report our preliminary contribution to this chal-
lenge with the design and implementation of a novel, metal-
free, modular, and direct synthetic manifold to gain access
to this important structural motif. This strategy was imple-
mented studying the reaction of 1,4-diyne 1a (R=Ph) with
benzylamine 2a [Eq. (1) in Table 1]. Diyne 1a reacted with
amine 2a in refluxing dichloroethane (5 h) to afford pyrrole
5aa in 74% yield. Exchanging conventional heating for
microwave heating (100 watt, 1008C, closed vessel)[23] deliv-
ered pyrrole 5aa in a shorter period of time (30 min) but
with a slight decrease in the reaction efficiency (70% yield).
Having established these satisfactory experimental condi-
tions, we next studied the reaction scope with regard to both
components (Table 1). As a general tendency, conventional
Scheme 1. Domino reaction leading to chain-functionalized tetrasubsti-
tuted pyrroles 5 [Z=CO2R2].
Michael-acceptor character of the alkynoate functionality
(a3-reactivity).[10] The synthetic manifold operates in the ab-
sence of metals and it is triggered by the nucleophilic addi-
tion of a primary amine on the alkynoate function (aza-Mi-
chael addition). An anti-Michael[11] ring-closing hydroamina-
tion[12] followed by a [3,3]-sigmatropic rearrangement com-
pletes the process to generate the pyrrole 5. The strategical-
ly placed oxygenated functionality at the quaternary sp3-
center accomplishes two important tasks: it favors the 5-
endo-dig cyclization (gem-dimethyl effect), and once the
ring forms, it drives the process to completion by an aroma-
tization-driven [3,3]-sigmatropic rearrangement.[13] Overall
the process comprises a novel, two-step modular synthesis
of chain-functionalized tetrasubstituted pyrroles from readi-
ly available alkyl propiolates, acid chlorides and primary
amines. Whereas the multicomponent nature of the A2BB’
manifold ensures a convenient grade of functional diversity
in the 1,4-diyne, the subsequent bimolecular domino reac-
tion generates a significant grade of structural complexity
(one aromatic ring, one functionalized chain and four differ-
ent substituents). To our knowledge, this method represents
the first example of a metal-free, two-step synthesis of these
pyrroles from readily accessible starting materials.[14]
Table 1. Domino synthesis of pyrroles 5 from tertiary skipped diynes 1
and primary amines 2.[a]
Entry Diyne
R
Amine R1
Pyrrole
Yield [%][b]
D
MW
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1e
1e
1a
1 f
1 f
1g
1g
Ph
2a
Bn
Bn
Bn
Bn
5aa
5ba
5ca
5da
5ea
5eb
5ec
5ad
5 fa
5 fa
5ga
5ga
74
66
61
74
72
73
65
43[d]
69
–
70
54
59
72
84
71
Chain-functionalized pyrroles constitute a structural motif
of particular interest in synthetic and medicinal chemistry,
as it is the foundation of important medicines, natural prod-
ucts and synthetic materials.[15] In particular, tetrasubstituted
pyrroles 5 can be considered as hybrid scaffolds[16] compris-
ing a structurally privileged pyrrole ring and a naturally
occurring a-hydroxy acid motif.[17] The hybrid features five
4-MeC6H4 2a
4,4’-Biph
2-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
cHex
cHex
iPr
iPr
2a
2a
2a
2b
2c
2d
2a
2a
2a
2a
Bn
nBu
allyl
PEA[c]
Bn
Bn
Bn
67
28[c]
54
10
11
12
64[f]
66
points of diversity (two chemodifferentiated ester groups,
68
–
1
À
71[g]
two chemodifferentiated R groups and one N R group)
Bn
and two differentiated points for complexity generation, one
[a] See experimental section; [b] yields of isolated products; [c] PEA=
(S)-1-phenylethylamine; [d] heated at reflux for 48 h; [e] 5 h; [f] amine
(1.7 equiv), 1 h; [g] amine (1.7 equiv), 45 min. MW=microwave heating.
in the ring (sp2-linking point; C4-H) and the other in the
chain (sp3-linking point; CH
ACTHNUTRGNEUNG(OCOR)Z, Figure 2).
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839

D. Tejedor et al.
heating proved to be slightly more effective than microwave
heating (Table 1, entries 1–4, 6, 8, 9, and 11). With regard to
the substituents of the 1,4-diyne component, the reaction
proved tolerant to both aromatic and aliphatic groups. As
expected, the electronic nature of the aromatic ring did not
have
a definitive influence on the reaction efficiency
(Table 1, entries 1, 2, and 5). Aliphatic substituents were
limited to secondary or tertiary by the 1,4-diyneꢄs own con-
struction manifold.[5] Whereas 1,4-diynes bearing secondary
alkyl substituents were incorporated with similar chemical
efficiency to the aromatic homologues (Table 1, entries 1–5
and 9–12), those bearing tertiary alkyl groups
afforded mixtures of unidentified compounds. Finally, the
reaction required a sufficiently nucleophilic amine. Whereas
benzyl, n-butyl or allyl amines afforded the corresponding
pyrroles in good yields, aromatic amines did not react under
these experimental conditions (data not shown). Likewise,
substitution at the a-position of the aliphatic chain of the
primary amine reduced its reactivity and, therefore, the effi-
ciency of the domino reaction (Table 1, entry 8). In this case,
although the amine is chiral, the pyrrole derivative 5ad is
obtained as a 1:1 mixture of diastereoisomers. Overall, the
manifold constructs densely functionalized pyrroles 5 using
a wide range of primary amines and diyne substituents.
The pyrrole structure was unambiguously confirmed by
X-ray crystallographic analysis of the carboxylic acid deriva-
tive 6 [Eq. (2)].[24] The synthesis of this derivative highlight-
ed the synthetic advantages associated with the breaking of
symmetry enabled by this synthetic manifold. The two iden-
tical ester functionalities of the starting 1,4-diyne are incor-
porated as two chemodifferentiated functionalities into the
final pyrrole structure, allowing the chemoselective hydroly-
sis of pyrrole 5aa to acid 6 under standard conditions
(LiOH/THF–H2O)and without special chemical care.
Scheme 2. Three-step synthesis of pyrrole 5aa from 1,4-diyne 7.
a) BnNH2 (1.4 equiv), ClCH2CH2Cl, reflux, 3 days, 64%; b) tetrabutylam-
monium fluoride, THF, room temperature, 1 h, 47% (E-isomer);
c) nBuLi, À788C, THF, then BzCl, room temperature, 1 h, 68% (unopti-
mized yields).
nary center does not have an electronic influence on the
course of the 5-endo-dig cyclization step; and secondly, it
stresses the importance of an ester group to drive the pro-
cess towards pyrrole ring formation (aromatization).
3) Reaction of alcohol 9 with nBuLi and benzoyl chloride
afforded pyrrole 5aa. This result confirms the liability of the
tertiary ester group allocated on the 5-member ring and the
postulated [3+3]-sigmatropic rearrangement (Scheme 2).
In summary, we have developed a novel and efficient
metal-free method for the synthesis of chain-functionalized
tetrasubstituted pyrroles from easily accessible tertiary
skipped diynes. The reaction utilizes a primary amine as the
nitrogen source and the particular reactivity profile of the
tertiary 1,4-diyne scaffolds to undergo an efficient domino
reaction involving an allowed 5-endo-digonal ring-cycliza-
tion step and a complexity-generating [3,3]-sigmatropic rear-
rangement. The resultant tetrasubstituted pyrroles 5 are
densely functionalized hybrid scaffolds, featuring five points
of diversity and two points for generation of further com-
plexity. In addition, the synthetic manifold is atom and labor
economical, and the reaction processing is safe and environ-
mentally benign. The reaction can be performed under con-
ventional or microwave heating conditions; whereas the
latter is faster (30 min), the former is slightly more efficient,
leading to higher yields. Further studies in our group into
the use of these hybrid motifs as polyfunctionalized scaffolds
for the development of building, coupling, and pairing strat-
egies[4a] are underway.
With regard to the reaction mechanism, the following ex-
perimental results support the participation of the reactive
intermediates 3 and 4 (Scheme 1) and their postulated
chemical transformations:
Experimental Section
1) Reduction of the reaction time afforded variable mix-
tures of enamine 3 and pyrrole 5.[25] This fact indicates that
enamine formation is faster than the enamine cyclization,
and that the latter constitutes the rate-determining step of
this process (anti-Michael addition).
2) Reaction of skipped diyne 7 with excess of benzylamine
delivered the 5-membered ring compound 8 in 64% yield as
a 2:1 mixture of E and Z isomers (Scheme 2). The formation
of this product indicates two important mechanistic features.
Firstly, it reveals that the oxygenated group at the quarter-
Representative procedures (Table 1, entry 1):
5aa (conventional heating): A solution of 1,4-diyne 1a (1.0 mmol) and
benzylamine (1.4 mmol) in dichloroethane (10 mL) was heated under
reflux for 5 h. Solvent was removed under reduced pressure and the resi-
due was purified by flash column chromatography on silica gel. Elution
with a 15:85 mixture of ethyl acetate and hexanes afforded pure pyrrole
5aa in 74% yield.
5aa (microwave heating): A solution of 1,4-diyne 1a (1.0 mmol) and ben-
zylamine (1.4 mmol) in dichloroethane (4 mL) was placed in a sealed mi-
crowave vial and the solution was irradiated for 30 min in a single-mode
microwave oven (100 Watt, 1008C). Purification (as above) afforded pure
840
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Chem. Eur. J. 2009, 15, 838 – 842

Chain-Functionalized Tetrasubstituted Pyrroles
COMMUNICATION
1
pyrrole 5aa in 70% yield. m.p. 59.4–60.38C; H NMR (400 MHz, CDCl3):
[12] For a review: R. Severin, S. Doye, Chem. Soc. Rev. 2007, 36, 1407–
1420.
3
3
d=3.42 (s, 3H), 3.75 (s, 3H), 5.89 (d, J
(H,H)=17.2 Hz, 1H), 6.69 (s, 1H), 6.89 (d, 3J
7.20 (m, 1H), 7.18 (s, 1H), 7.24–7.30 (m, 4H), 7.34 (tt, 3J
7.2 Hz, 1H), 7.39–7.45 (m, 2H), 7.47–7.52 (m, 3H), 7.65 ppm (d, 3J-
(H,H)=7.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) d=49.5, 51.4, 52.8,
66.2, 118.1, 124.1, 125.2, 126.8, 127.3, 128.1, 128.3, 128.5, 128.6, 128.7,
129.1, 130.0, 133.4, 134.3, 138.7, 160.9, 165.1, 167.8 ppm;[26] IR (CHCl3):
n˜ =3030.0, 1757.4, 1720.6, 1452.1, 1256.4, 1222.1, 1167.1, 1092.9 cmÀ1; MS
(70 eV): m/z (%): 483 (9.6) [M+], 318 (3.7), 302 (5.1), 105 (100), 91 (28),
77 (12); elemental analysis calcd (%) for C29H25NO6: C 72.04; H 5.21;
N 2.90; found: C 72.17; H 5.37; N 2.96.
ACHTUNGTRENNUNG
A
U
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favors the ring-cyclization step, but inhibits the aromatization of the
ring. V. Lavallo, G. D. Frey, B. Donnadieu, M. Soleilhavoup, G. Ber-
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2008, 47, 5224–5228.
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
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Acknowledgements
Authors thank the Spanish Ministerio de Educaciꢀn y Ciencia and the
European Regional Development Fund (CTQ2005-09074-C02-02), the
Spanish MSC ISCIII (RETICS RD06/0020/1046), CSIC (Proyecto Intra-
mural Especial 200719) and Fundaciꢀn Instituto Canario de Investigaciꢀn
del Cꢂncer (FICI-G.I. No. 08/2007) for financial support. S.L.-T. Thanks
MEC for a FPU grant. The authors thank technicians Sonia Rodriguez
Dꢁaz and Aida Sꢂnchez Lꢀpez for preparation of starting materials.
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Keywords: alkynes
nitrogen heterocycles · nucleophilic addition
· cyclization · domino reactions ·
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data_request/cif.
[25] Spectroscopic evidence shows that compound 3 is an intermediate
of the reaction and leads to the final product (see the Supporting In-
formation).
1978, Chapter 19, pp. 813–855; c) E. Winterfeldt, Angew. Chem.
1967, 79, 389–400; Angew. Chem. Int. Ed. Engl. 1967, 6, 423–434.
[22] Special issue: “Frontiers in organic synthesis” Chem. Rev. 1996, 96,
1–600, edited by P. A. Wender
[23] Microwave heating was performed in a commercial single-mode mi-
crowave CEM Discover oven.
[26] A peak corresponding to the quaternary carbon is buried under a
large peak in the aromatic region.
[24] CCDC 695860 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Received: October 31, 2008
Published online: December 10, 2008
842
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