Tertiary skipped diynes: A pluripotent building block for the modular and diversity-oriented synthesis of nitrogen heterocycles

Article abstract of DOI:10.1002/chem.200903577

Dominos! The multivalent reactivity profile of tertiary skipped diynes has been conveniently exploited in the domino and diversity-oriented synthesis of fully substituted pyrazoles and 1, 4-diazepane derivatives (see scheme). The developed manifold is chemically efficient and simple to operate. In addition, the resulting Ncontaining heterocycles are obtained in a regio- and chemoselective manner. (Chemical Equation Presented)

Full text of DOI:10.1002/chem.200903577

DOI: 10.1002/chem.200903577
Tertiary Skipped Diynes: A Pluripotent Building Block for the Modular and
Diversity-Oriented Synthesis of Nitrogen Heterocycles
David Tejedor,*[a, b] Sara Lꢀpez-Tosco,[a, b] Javier Gonzꢁlez-Platas,[c] and
Fernando Garcꢂa-Tellado*[a, b]
The development of diversity-oriented synthetic (DOS)
methodologies to construct libraries of small molecules to
explore chemical space is a current topic in modern organic
synthesis.[1] An important challenge for these methodologies
is the generation of skeletal diversity. This can be generated
by using the so-called reagent-based DOS methodology,
which utilises different reagents to transform a substrate
into an array of products with distinct molecular skeletons.[2]
In practice, two main reagent-based strategies are currently
used: the densely functionalised molecule (different func-
tionalities in the same molecule are sequentially trans-
formed by different reagents) and the pluripotent functional
group (the same functional group in the molecule is trans-
formed by different reagents in different reactions).[3] The
latter approach requires the use of building blocks contain-
ing a functional group, or an array of interconnected func-
tional groups, featuring a polyvalent reactivity profile. Skip-
ped diynes 1[4] with a quaternary sp3 centre and two conju-
gated alkyne units constitute an example of such building
blocks (Scheme 1; ai/di refer to acceptor/donor properties of
Scheme 1. Reactivity profile of tertiary skipped diynes 1.
position i).[5] A recent report from this lab has shown that
these diynes are efficient precursors of chain-functionalised,
tetrasubstituted pyrroles 2 by an efficient microwave-assist-
ed domino reaction with primary amines (Scheme 2).[6] The
necessary pyrrole connectivity is generated from the enam-
ine intermediate I by a selective 5-endo-dig cyclisation reac-
tion (a2 reactivity; anti-aza-Michael addition) via a transient
pyrrolidine intermediate II that rearranges into the final pyr-
role 2 by a sigmatropic [3,3]-Claisen rearrangement ([d0 +
a2] reactivity). Herein, we report our preliminary results on
the use of this C7 pluripotent array of organic functionalities
for the generation of other important N-containing hetero-
cycles. As a proof of concept, we describe a convenient ap-
proach to the regioselective domino synthesis of chain-func-
tionalised, fully substituted pyrazoles 4 by using N-substitut-
ed hydrazine derivatives (R4NHNH2) as nucleophiles
(Scheme 2). As an extension of this concept, we have also
synthesised 1,4-diazepane derivatives 6 by using ethane-1,2-
diamine derivatives as N-centred nucleophiles (Scheme 2).
We first focused our efforts on pyrazoles because these
heterocycles constitute an important structural motif[7] pres-
ent in a large number of bioactive molecules spanning a
wide array of biological and pharmaceutical properties.[8]
Traditionally, these heterocyclic units have been assembled
by condensation reactions of 1,3-dicarbonyl compounds and
hydrazines,[9] or by cycloaddition reactions between alkynes
and electron-rich diazo compounds.[10] However, regioselec-
[a] Dr. D. Tejedor, S. Lꢀpez-Tosco, Dr. F. Garcꢁa-Tellado
Departmento de Quꢁmica Biolꢀgica y Biotecnologꢁa
Instituto de Productos Naturales y Agrobiologꢁa
Consejo Superior de Investigaciones Cientꢁficas
Astrofꢁsico Francisco Sꢂnchez 3
38206 La Laguna, Tenerife (Spain)
Fax : (+34)922-260135
E-mail: fgarcia@ipna.csic.es
dtejedor@ipna.csic.es
[b] Dr. D. Tejedor, S. Lꢀpez-Tosco, Dr. F. Garcꢁa-Tellado
Instituto Canario de Investigaciꢀn del Cꢂncer (Spain)
[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)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903577.
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Chem. Eur. J. 2010, 16, 3276 – 3280

COMMUNICATION
Table 1. Reaction of skipped diyne 1a and hydrazine 7a.
Solvent
D/MW[a]
t
4aa [%]
Solv. [%]
1
2
3
4
5
5
6
7
8
ClCH2CH2Cl
ClCH2CH2Cl
EtOH
iPrOH
tBuOH
tBuOH
tBuOH
tBuOH
F3CCH2OH
reflux
MW
reflux
reflux
reflux
MW
MW
MW
MW
4 h
30 min
4 h
4 h
8 h
30 min
15 min
1 h
77
79
87
91
88
92
81
91
86
nd[b]
nd[b]
14
8
nd[b]
4
nd[b]
3
30 min
8
[a] Microwave irradiation: 100 W, 1008C, closed vessel. [b] Not detected.
hydrazine and just one of the two acetylenic esters present
in the skipped diyne[16] are observed and 4) diversity/com-
plexity: pyrazoles are assembled with five points of diversity
and one a-acyloxy ester chain placed ortho to the substitut-
ed N atom of the ring; this arrangement should allow the
development of selective complexity-generating reactions in-
volving both functionalities (e.g., ring formation).
Scheme 2. Pluripotent functional array approach to the diversity-oriented
synthesis of pyrroles 2, pyrazoles 4 and 1,4-diazepanes 6 from tertiary
skipped diynes 1. Z=CO2R5.
Once the reaction had been standardised, we studied the
scope of this domino reaction with regard to the hydrazine
and the diyne (Table 2). In general, the reaction displayed a
wide scope with regard to both components. Although the
reaction was tolerant of the nature of the substituent at the
tivity has been a recurrent problem with many of these reac-
tions. In recent years, efficient new processes involving
alkyne-containing materials have emerged; these include,
À
among others, Cu-catalysed domino C N coupling/hydro-
A
complex substrates.[13] In spite of these advances, the devel-
opment of general, highly efficient, metal-free domino
methodologies for regioselective access to polysubstituted
pyrazoles in a modular and diversity-oriented manner from
easily accessible starting materials remains a challenge.[14,15]
We initiated our studies with the reaction of commercially
available N-methyl hydrazine (7a; 1.1 equiv) and skipped
diyne 1a (1 equiv) under different experimental conditions
(Table 1). We were pleased to observe that the microwave
irradiation of a solution of 7a and 1a in tert-butanol (techni-
cal grade; 100 W, 1008C, closed vessel) delivered pyrazole
4aa in a short time and excellent yield (30 min, 92%;
Table 1, entry 5) accompanied by a small amount (4%) of
the solvolysis product (Solv.; R6 =tBuO). Other assayed
conditions also afforded product 4aa, but with lower effi-
ciency and/or longer reaction times (Table 1).
Four properties of this reaction deserve to be highlighted:
1) efficiency: the domino reaction constructs the pyrazole
topology, placing a different substituent at each available
ring position, in excellent yield and under bench-friendly
conditions; 2) regioselectivity: pyrazole 4aa is obtained as
the only regioisomer (pyrazole 5 is not detected; see the
Supporting Information for details); 3) chemoselectivity:
neither products coming from the double attack of the same
nitrogen atom on the diyne system (5-endo-dig cyclisation)[6]
nor those from a cyclocondensation reaction between the
Table 2. Microwave-assisted synthesis of pyrazoles 4.
R
R4
t [min] Product 4 Yield [%]
1
2
3
4
5
6
7
8
9
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Me (7a)
30
45
60
30
30
30
30
180
4aa
4ab
4ac
4ad
4ae
4ae
4ag
4ah
4ai
92
80
80
73
75
85
63
47
74
95
99
90
97
88
95
97
Ph (7b)
Bn[b,c] (7c)
NCCH2CH2 (7d)
HOCH2CH2 (7e)
cHex[b,c] (7 f)
H[d] (7g)
4-BrC6H4 (7h)
4-MeOC6H4 (7i) 45
[b]
[b]
10 p-ClC6H4 (1b)
11 p-tolyl (1c)
12 p-biphenyl (1d) Me (7a)
13 p-MeOC6H4 (1e) Me (7a)
14 o-ClC6H4 (1 f)
15 iPr (1g)
16 cHex (1h)
Me (7a)
Me (7a)
30
30
30
30
4ba
4ca
4da
4ea
4 fa
4ga
4ha
Me (7a)
Me (7a)
Me (7a)
30
60[e]
60[e]
[a] Diyne (0.5 mmol), hydrazine (0.55 mmol), tBuOH (5 mL), MW
(100 W, 1008C), closed vessel. [b] Hydrazine was used in the form of its
hydrochloride salt. The reaction was performed in the presence of
NaOAc (3.3 equiv). [c] Bn=benzyl, cHex=cyclohexyl. [d] 1.0m in THF.
[e] 300 W; 1508C.
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3277

D. Tejedor, F. Garcꢁa-Tellado et al.
hydrazine nitrogen, it was observed that aliphatic substitu-
ents afforded the corresponding pyrazoles 4 in better yields
than those with aromatic ones (compare entries 1, 3–6 with
entries 2, 8 and 9 in Table 2). Whereas N-(4-bromophenyl)-
hydrazine (7h) gave the corresponding pyrazole 4ah in
modest yield (47%, entry 8), N-phenylhydrazine (7b) and
the electron-rich substituted hydrazine 7i afforded the cor-
responding pyrazoles 4ab and 4ai in good yields (80 and
74%, respectively; Table 2, entries 2 and 9). Conversely, hy-
It should be noted that the final [3,3]-Claisen rearrange-
ment distinguishes the two ester functionalities by placing
an oxygen functionality in the alpha position to one of
them. This electronically differentiated ester group should
be expected to be hydrolysed more easily and faster than
the other ester group. Hence, controlled hydrolysis of pyra-
zole derivative 4aa (LiOH, THF/H2O, 0 8C, 6 h) (Scheme 4)
proved to be chemoselective, generating monoacid 8 in
good yield (72%; see the Supporting Information for de-
tails). The free carboxylic acid functionality in pyrazole 8
gives rise to another position for the generation of diversity
and/or complexity (it can be used as a convenient chemical
handle).
drazines
with
electron-poor
aromatic
rings
(p-
CF3C6H4NNH2 and p-NO2C6H4NNH2) or a sulfonate group
(TsNNH2) were not reactive enough to participate in this re-
action (data not shown). Hydrazines 7d and 7e, featuring a
reactive functionality at the end of the alkyl chain, reacted
with diyne 1a in a chemoselective and efficient manner to
yield pyrazoles 4ad and 4ae in very good yields, with the
extra functionality untouched (Table 2, entries 4 and 5).
These extra functionalities could be convenient handles for
further generation of molecular complexity. Remarkably,
simple hydrazine 7g reacted with diyne 1a in a very efficient
manner to construct the trisubstituted pyrazole 4ag in good
yield (63%; Table 2, entry 7). The diyne scope was studied
by using N-methylhydrazine 7a and a set of substituted ter-
tiary skipped diynes 1a–h (Table 2, entries 10–16). In gener-
al, the reaction was tolerant of the nature of the substituent
at the tertiary sp3 centre. Although both aliphatic and aro-
matic derivatives generated the corresponding pyrazoles in
excellent yields, aliphatic derivatives needed more energetic
conditions than their aromatic homologues to deliver the
corresponding pyrazoles in good yields (compare entries 10–
14 with entries 15 and 16 in Table 2).
A proposed mechanism for this domino reaction is out-
lined in Scheme 3. Remarkably, advanced intermediate III
could be isolated when reactions were performed at room
temperature. Further transformation of this ring into pyra-
zole 4 through a [3,3]-Claisen rearrangement required heat-
ing (microwave activation) to proceed in a reasonable time
(see the Supporting Information for details). As expected,
this transformation constitutes the rate-determining step of
the domino process.
Scheme 4. Controlled hydrolysis of pyrazole 4aa.
Once the transformation of skipped diynes 1 into pyra-
zoles was successfully achieved, we studied the reaction of
these diynes with other diamines to gain access to different
N-heterocycles. Thus, the reaction of diyne 1a with 1,2-sub-
stituted ethane-1,2-diamines 9a–c afforded 1,4-diazepane
derivatives 6a–c in good yield and stereoselectivity (Z,Z
isomer;[17] see the Supporting Information for details),
through two consecutive and energetically favoured aza-Mi-
chael additions, the latter being a 7-exo-dig cyclisation pro-
cess (Scheme 5). The 1,4-diazepane core[18] constitutes a bio-
logically valuable scaffold[19] with interesting applications as
a surrogate of the biologically relevant piperazine ring (ho-
mopiperazines).[20] Surprisingly, benzene-1,2-diamine (9d),
featuring two aromatic amines, did not give the correspond-
Scheme 3. Mechanistic proposal for the synthesis of pyrazoles 4. Z=
CO2R5.
Scheme 5. Reaction of skipped diyne 1a and alkane 1,n-diamines.
3278
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Chem. Eur. J. 2010, 16, 3276 – 3280

Tertiary Skipped Diynes
COMMUNICATION
(63), 315 (50), 283 (37), 105 (100), 77 (35); elemental analysis calcd (%)
for C24H24N2O6: C 66.04, H 5.54, N 6.42; found: C 66.13, H 5.66, N 6.43.
ing bicyclic 1,4-diazepane 6d, affording a mixture of uniden-
tified products. Remarkably, the reaction of propane-1,3-di-
ACHTUNGTRENNUNGamine (10a) with diyne 1a under these conditions did not
afford the corresponding 1,5-diazocane 11a, but instead it
generated the N-substituted pyrrole 12a (12%; not opti-
mised yield). This result mirrors the inherent energy differ-
ences between 5-endo-dig (favoured) and 8-exo-dig (unfav-
oured) cyclisations. A similar result was obtained when
butane-1,4-diamine (10b) was treated with diyne 1a under
the same reaction conditions (Scheme 5). Instead of the ex-
pected 1,5-diazepane derivative 11b resulting from an al-
lowed 9-exo-dig cyclisation process, pyrrole 12b was ob-
tained as the major compound (21%; not optimised yield).
These studies show that the length of the alkyl chain of the
diamine determines the fate of the cyclisation reaction and,
therefore, the outcome of the process. Only 1,2-diamines
react with diyne 1a using their two nitrogen atoms to afford
1,4-diazepane derivatives 6 through two kinetically allowed
aza-Michael additions. The rest of the 1,n-diamines react as
simple monoamines, affording the corresponding N-(amino-
alkyl)pyrrole derivatives 12 by a well-established domino
mechanism.[6]
Acknowledgements
This research was supported by the Spanish Ministerio de Ciencia e Inno-
vaciꢀn, the European Regional Development Fund (CTQ2008-06806-
C02-02), the Spanish MSC ISCIII (RETICS RD06/0020/1046), FUNCIS
(REDESFAC PI01/06) and the Fundaciꢀn Instituto Canario de Investiga-
ciꢀn del Cancer (FICI-G.I.N808/2007). S.L.-T. thanks the Spanish MEC
for an FPU grant. The authors thank technician Anna Jurado Varona for
her experimental assistance.
Keywords: alkynes · cyclization · diazepanes · domino
reactions · pyrazoles
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In summary, we have shown that the tertiary skipped
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conveniently used to generate skeletal diversity. An array of
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Experimental Section
[5] Each alkynoate group holds a polyvalent reactivity profile, which is
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of diyne 1a (0.50 mmol) in tert-butanol (4 mL). The reaction mixture was
placed in a special microwave closed vial and the solution was irradiated
for 30 min in a single-mode microwave oven (100 W, 1008C). After re-
moving the solvent at reduced pressure, the products were purified by
flash column chromatography (silica gel, n-hexane/EtOAc 40/60) to yield
4aa (92%); 1H NMR (400 MHz, CDCl3, 258C): d=3.61 (d, 3J
16.9 Hz, 1H), 3.63 (s, 3H), 3.66 (d, 3J
(H,H)=16.4 Hz, 1H), 3.71 (s, 3H),
4.04 (s, 3H), 6.38 (s, 1H), 7.32–7.45 (m, 7H), 7.55–7.60 (m, 1H),
7.99 ppm (d, 3J(H,H)=7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3, 258C):
ACHTUNGTRNE(NUNG H,H)=
AHCTUNGTRENNUNG
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ACHTUNGTRENNUNG
d=32.5, 38.0, 52.0, 53.0, 65.5, 123.7, 127.6, 128.5, 128.6, 128.7, 129.9,
130.0, 131.3, 132.4, 133.7, 142.7, 165.0, 167.2, 171.0 ppm; IR (CHCl3): n=
3000.3, 3028.2, 2955.9, 1733.3, 1445.8, 1334.9, 1266.5, 1237.7, 1175.0,
1099.0 cmÀ1; MS (70 eV): m/z (%): 422 (30) [M+], 317 (20), 259 (6.3), 241
(11), 105 (100), 77 (15); elemental analysis calcd (%) for C23H22N2O6: C
65.39, H 5.25, N 6.63; found: C 65.38, H 5.28, N 6.43.
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a solution of diyne 1a
(0.5 mmol) in dry CH2Cl2 (13 mL) at room temperature. The reaction
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ACHTUNGTRENNUNG(H,H)=7.4, 1.3 Hz, 1H), 7.68–7.70 (m, 2H), 8.09–8.12 (m,
2H), 9.59 ppm (brs, 2H); 13C NMR (100 MHz, CDCl3, 258C): d=45.0,
50.3, 84.1, 84.5, 126.3, 128.3, 128.65, 128.69, 129.8, 129.9, 133.7, 141.5,
164.3, 164.9, 171.3 ppm; IR (CHCl3): n=1091.2, 1192.8, 1262.6, 1497.3,
1603.8, 1655.3, 1733.7 cmÀ1; MS (70 eV): m/z (%): 436 (23) [M+], 331
Chem. Eur. J. 2010, 16, 3276 – 3280
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D. Tejedor, F. Garcꢁa-Tellado et al.
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Received: December 30, 2009
Published online: February 19, 2010
3280
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