Reactivity control in the addition of N,N′-dialkylated 1,n-diamines to activated skipped diynes: Synthesis of fused bicyclic 1,4-diazepanes and 1,5-diazocanes

Article abstract of DOI:10.1002/ejoc.201101368

A metal-free domino reaction for the synthesis of a new family of fused bicyclic 1,4-diazepanes and 1,5-diazocanes has been developed. The reaction involves the use of N,N′-dialkylated 1,n-diamines as the nitrogen source, through-space orbital interactions between the two nitrogen atoms as the reactivity director element, and an activated skipped diyne as the reactive platform. A key Morita-Baylis-Hillman-like reaction allows the formation of 1,4-diazepanes and 1,5-diazocanes (medium-sized diazoheterocycles). These structures incorporate a 1,n-diazocycle fused to a I3-butenolide ring and different functionalities to be used as convenient handles for further complexity generation. The good efficiency of this reaction and its simple experimental protocol make this process an excellent candidate for the fast construction of structure-focused libraries based on this fused bicyclic motif.

Full text of DOI:10.1002/ejoc.201101368

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101368
Reactivity Control in the Addition of N,NЈ-Dialkylated 1,n-Diamines to
Activated Skipped Diynes: Synthesis of Fused Bicyclic 1,4-Diazepanes and
1,5-Diazocanes
Sara López-Tosco,[a] David Tejedor,*[a] Javier González-Platas,[b] and
Fernando García-Tellado*[a]
Keywords: Through-space interactions / Domino reactions / Fused-ring systems / Michael addition / Heterocycles
A metal-free domino reaction for the synthesis of a new fam-
ily of fused bicyclic 1,4-diazepanes and 1,5-diazocanes has
been developed. The reaction involves the use of N,NЈ-di-
alkylated 1,n-diamines as the nitrogen source, through-space
orbital interactions between the two nitrogen atoms as the
reactivity director element, and an activated skipped diyne
as the reactive platform. A key Morita–Baylis–Hillman-like
reaction allows the formation of 1,4-diazepanes and 1,5-di-
azocanes (medium-sized diazoheterocycles). These struc-
tures incorporate a 1,n-diazocycle fused to a γ-butenolide
ring and different functionalities to be used as convenient
handles for further complexity generation. The good effi-
ciency of this reaction and its simple experimental protocol
make this process an excellent candidate for the fast con-
struction of structure-focused libraries based on this fused bi-
cyclic motif.
hexadienones 5,[9] and aromatic scaffolds 6[9] when they are
made to react with primary amines, hydrazines, 1,2-di-
amines, and secondary amines, respectively. In this com-
munication, we report on the synthesis of a novel family of
fused bicyclic compounds 8 featuring a 1,n-diazocyclic core
joined to a biologically relevant butenolide motif by an un-
precedented reaction of N,NЈ-dialkyldiamines 7 with terti-
ary skipped diynes 1. The mechanism of this reaction in-
volves a Morita–Baylis–Hillman-like reaction, which is
based on through-space nitrogen–nitrogen orbital interac-
tions.
Introduction
The direct aza-Michael addition of amines (primary and
secondary) onto activated alkynes in the absence of a cata-
lyst is a favored reaction.[1] In this context, it would be pos-
sible to react 1,n-diamines with double Michael acceptors
to generate diazoheterocycles with a size that would depend
on the nature of the diamine. 1,4-Diazepanes constitute
valuable chemical scaffolds[2] and they are usually synthe-
sized by the reaction of 1,2-diamines or 1,2-bis(sulfon-
amide)s (or their anions) with 1,3-dihalides,[3] 1,3-dicarb-
onyl compounds and derivatives,[4] and α,β-unsaturated (or
β-halogenated) carbonyl compounds.[5] Activated skipped
diynes 1[6] constitute an exceptional example of densely
functionalized scaffolds with a pluripotent reactivity profile
(pluripotency refers to the property of expressing more than
one chemical outcome) (Figure 1). Recent reports from our
group have shown how these platforms can be selectively
transformed into polysubstituted pyrroles 2,[7] pyrazoles
3,[8] 1,4-diazepane derivatives 4,[8] polyfunctionalized cyclo-
[a] Instituto de Productos Naturales y Agrobiología,
Departamento de Química Biológica y Biotecnología, Consejo
Superior de Investigaciones Científicas,
Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tenerife,
Spain
Fax: +34-922260135
Figure 1. Nucleophilic addition vs. reactivity profile of activated
skipped diynes1.
E-mail: dtejedor@ipna.csic.es
fgarcia@ipna.csic.es
[b] (Crystallographer) Servicio de Difracción de Rayos X,
Departamento de Física Fundamental II. Universidad de La
Laguna
Results and Discussion
Avda. Astrofísico Francisco Sánchez 2, 38204 La Laguna,
Tenerife, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101368.
In our earlier report,[8] we showed that the reaction of
N,NЈ-dimethylethane-1,2-diamine (7a) with skipped diyne
Eur. J. Org. Chem. 2011, 6847–6850
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6847

S. López-Tosco, D. Tejedor, J. González-Platas, F. García-Tellado
SHORT COMMUNICATION
1a afforded expected polysubstituted 1,4-diazepane 4aa Table 1. Reaction of activated skipped diynes 1 and monosubsti-
tuted 1,n-diamines 7.[a]
(Z,Z isomer, 54% yield), accompanied by a significant
amount of a secondary product, which has now been iden-
tified as fused bicyclic 1,4-diazepane 8aa (31%; Scheme 1;
Table 1, Entry 1). The structure of this secondary com-
pound, which reveals a higher structural complexity than
that expected for a sequential double aza-Michael addition
onto the diyne, represents an unexpected and novel chemi-
cal outcome for the array of functionalities present in
skipped diyne 1a. From a biological (pharmacological)
point of view, this novel structure incorporates relevant
pharmacophore motifs; that is, a butenolide ring,[10] a 4-
aminotetronic acid,[11] and a 1,4-diazepane ring.[12] On the
other hand, from a chemical point of view, the structure
accommodates a high functional density on a minimal skel-
etal connectivity, supporting a reactivity profile steered by
the α-benzoyl-substituted butenolide ring and the two
chemically differentiated conjugated N-methyl enamines.
Prompted by the attractive pharmacological and chemical
profile of this structure and its unprecedented chemical ori-
gin, we undertook the study of this novel reaction and its
possible preparative use (Table 1).
Entry
Ar
n
R
Yield [%][b]
4
8
1
2
3
4
5
6
7
Ph
Ph
Ph
1a
1a
1a
1a
1b
1c
1a
1
1
2
2
2
2
3
Me
Bn
Me
Bn
Me
Me
Bn
7a
7b
7c
7d
7c
7c
7e
4aa (54) 8aa (31)
4ab (34) 8ab (47)
4ac (0)
4ad (0)
4bc (0)
4cc (0)
4ae (0)
8ac (61)
8ad (10)
8bc (59)
8cc (60)
8ae (3)
Ph
4-ClPh
4-MePh
Ph
[a] See the Experimental Section for reaction conditions. [b] Iso-
lated yield.
ronment surrounding the two amine atoms showed a large
influence on the efficiency of the reaction. Thus, whereas
N,NЈ-dimethylpropane-1,3-diamine (7c) afforded corre-
sponding product 8ac[14] in 61% yield (Table 1, Entry 3),
homologous diamine 7d delivered corresponding product
8ad in a low 10% yield (Table 1, Entry 4). Further increase
in the diamine chain resulted in a severe drop in the yield
of corresponding fused derivative 8ae (3% yield; Table 1,
Entry 7).
The scope with regard to the diyne derivative was
screened by using derivatives 1a–c, which feature three elec-
tronically different aromatic rings at the diyne tertiary posi-
tion and on the ester functionality. As expected, all of them
expressed the same reactivity pattern with similar chemical
efficiencies (Table 1, Entries 3, 5, and 6).
The mechanism for the formation of these fused bicycles
is not straightforward. Our proposed mechanism is outlined
in Scheme 2. The aza-Michael addition of one amine onto
the diyne unit affords enamine intermediate 9 (step i), which
cyclizes to give intermediate azetidinium cation 10 (step iii).
Scheme 1. Reaction of activated skipped diyne 1a and N,NЈ-di-
methylethane-1,2-diamine (7a). Structure and properties of fused
bicycle 8aa.
With regard to the diamine component, the chemical This cyclization is assisted by through-space orbital interac-
outcome of the reaction was sensitive to steric and elec- tions with the second nitrogen atom (in the same manner
tronic factors. Thus, whereas 7a afforded a mixture of prod- as the two nitrogen atoms interact in the 1,4-diazabicy-
ucts 4aa/8aa in a ratio of 1.75:1.0 in a good combined yield clo[2.2.2]octane molecule).[15] This cyclization follows a
(85%), the more sterically demanding N,NЈ-dibenzylethane- Morita–Baylis–Hillman (MBH)-type reactivity pattern,[16]
1,2-diamine (7b) rendered a mixture of 4ab/8ab in a re- delivering MBH-adduct-like intermediate 10,[17,18] which
versed ratio of 0.72:1.0 while maintaining the efficiency serves as a convenient template for the next cyclization step
(81% combined yield; Table 1, Entries 1 & 2). On the other (step iv). Observe that the formation of 10 allows the gener-
hand, electron-poor amines (aromatic or amides) did not ation of eight-membered cycle 11 (n = 2), which is not pos-
give the desired compounds (data not shown). Because the sible from a direct double aza-Michael reaction of the di-
reaction constructs fused bicycles, we expected an entropic amine and the diyne. Likewise, the formation of seven-
influence from the size of the diamine linker on the effi- membered cycle 11 (n = 1) competes with the formation of
ciency and chemical outcome of the reaction.[13] Indeed, corresponding 1,4-diazepane derivative 4, which is kinet-
when the chain linking the two nitrogen atoms was in- ically favored (step ii). This fact outlines the strong elec-
creased by one unit (1,3-diamines), the reaction exclusively tronic influence that the amine nitrogen atom exercises on
afforded the corresponding fused bicyclic 1,5-diazocane de- the reactivity of the enamine nitrogen atom. It is able to
rivatives (Table 1, Entries 3–6). Remarkably, the steric envi- competitively overcome the low kinetic barrier needed for
6848
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6847–6850

Synthesis of Fused Bicyclic 1,4-Diazepanes and 1,5-Diazocanes
the direct double aza-Michael addition. It should also be
noted that, as a consequence of the reduction on the molec-
ular volume produced when enamine 9 forms azetidinium
cation 10, the steric effects exercised by the two amine sub-
stituents bring out the reactivity restraints of the molecular
system. It is clearly reflected in the data of Table 1, which
shows a drop in the yield of fused bicyclic derivative 8 when
the methyl substituents are changed by the more sterically
demanding benzyl groups. This fact also explains the ob-
served reversed ratio of monocycle 4 to bicycle 8 in the reac-
tion of 7b with diyne 1a (Table 1, Entries 1 & 2). Finally,
the lactone ring is generated from the intramolecular reac-
tion of the alkoxide ion and the methyl ester with the loss
of MeOH (step v).
Figure 2. 13C NMR spectrum of 8ac13C.
Conclusions
In summary, we have developed a novel metal-free proto-
col for the synthesis of a new family of fused bicyclic struc-
tures featuring a skeletal connectivity based on 3,4,5,5a-
tetrahydro-1H-furo[3,2-e][1,4]diazepin-7(2H)-one (8, n = 1)
or a 5,6,7,8,9,9a-hexahydrofuro[3,2-b][1,5]diazocin-2(4H)-
one (8, n = 2). These structures incorporate a fused 1,n-
diazocycle to a γ-butenolide ring and different chemical
functionalities to be used as convenient handles for further
complexity generation (one aroyl group attached to the α-
position of the butenolide ring and two chemically differen-
tiated conjugated enamine units). In addition, these struc-
tures feature an array of pharmacologically relevant struc-
tural motives (γ-butenolide ring, 1,n-diazocycle, and 4-aza-
tetronic acid). They are fast and directly assembled from
tertiary skipped diynes and N,NЈ-dialkylated 1,n-diamines
by a domino reaction involving a MBH-like reaction. This
procedure uses N,NЈ-dialkylated 1,n-diamines as the nitro-
gen source, through-space orbital interactions between the
two nitrogen atoms as the reactivity director element, and
a diversely functionalized activated skipped diyne as the re-
active platform. The length of the alkyl chain of the di-
amine determines the fate of the cyclization reaction and,
therefore, the outcome of the process. The good efficiency
of this reaction and its simple experimental protocol make
this process an excellent candidate for the fast construction
of structure-focused libraries based on this fused bicyclic
motif. These libraries will be used in our ongoing drug-dis-
covery research program.[19] These studies are in progress
in our laboratory and they will be reported in due course.
Scheme 2. Mechanistic proposal for the formation of fused bicyclic
structure 8. Reactions: (i,ii) aza-Michael; (iii) aza-Michael/Baylis–
Hillman-like; (iii) aza-addition/elimination, and (iv) lactonization.
The mechanistic hypothesis was further confirmed by
13C-isotopic enrichment NMR experiments (Scheme 3).
When skipped diyne 1a marked with 13C (1a13C) was
treated with diamine 7c, corresponding doubly labeled
product 8ac13C was obtained (64% yield). The 13C NMR
spectrum showed an increased singlet for the ketone signal
(Figure 2), information that corroborates that this carbonyl
group comes from the tertiary benzoate group, which con-
firms the proposed reaction pathway outlined in Scheme 2.
Scheme 3. 13C-isotopic enrichment NMR experiment.
Experimental Section
The formation of these fused bicyclic structures expresses
a new reactivity profile of skipped diynes 1 when they are
made to react with N,NЈ-dialkylated 1,n-diamines. This re-
active profile is elicited by secondary diamines that can ex-
ercise a measurable 1–4, 1–5, or 1–6 NǞN through-space
electronic interaction, which allows a template effect that
biases the formation of the otherwise kinetically disfavored
eight-membered ring of fused 1,5-diazocanes 8 (n = 2).
Representative Procedure for the Synthesis of Fused Bicyclic 1,n-
Diazocycles: 1,n-Diamine 7 (0.55 mmol) was added to a solution of
skipped diyne 1 (0.50 mmol) in CH2Cl2 (13 mL) at room tempera-
ture, and the mixture was stirred overnight. The solvent was re-
moved under reduced pressure, and the products were purified by
flash column chromatography (silica gel; EtOAc/CH2Cl2, 10:90) to
give fused bicyclic 1,n-diazocycle 8 and, in cases where there are
mixtures, 1,4-diazepanes 4.
Eur. J. Org. Chem. 2011, 6847–6850
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6849

S. López-Tosco, D. Tejedor, J. González-Platas, F. García-Tellado
SHORT COMMUNICATION
[10] C. R. Carreras, C. E. Tonn, J. I. Padrón, M. A. Ramírez, D. D.
Díaz, F. García-Tellado, V. S. Martín, Synlett 2005, 1575–1578
and references cited therein.
[11] a) For a review, see: D. Tejedor, F. García-Tellado, Org. Prep.
Proced. Int. 2004, 36, 33–59 and references cited therein; b) H.
Bühler, A. Bayer, F. Effenberger, Chem. Eur. J. 2000, 6, 2564–
2571.
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis and characterization of fused bicyclic 1,n-diazocy-
cles 8, procedure for the synthesis of 8ac13C, 1H and 13C NMR
spectra of selected compounds, and X-ray crystal structure of 8ac.
[12] T. Tanaka, T. Muto, H. Maruoka, S. Imajo, H. Fukami, Y.
Tomimori, Y. Fukuda, T. Nakatsuka, Bioorg. Med. Chem. Lett.
2007, 17, 3431–3434.
Acknowledgments
This research was supported by the Spanish Spanish Ministerio de
Ciencia e Innovación (MICINN), the European Regional Develop-
ment Fund (RDF) (CTQ2008-06806-C02-02), and the Spanish
Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III
(MSC ISCIII) (RETICS RD06/0020/1046) and the Fundación
Canaria de Investigación y Salud (FUNCIS) (PI 43/09).
[13] J. E. Baldwin, J. Chem. Soc., Chem. Commun. 1976, 734–736.
[14] The bicyclic 1,5-diazocane structure was unambiguously con-
firmed by X-ray crystallographic analysis of derivative 8ac (see
the Supporting Information). CCDC-843724 contains the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[15] For a review of through-space and through-bonds orbital inter-
actions, see: R. Hoffmann, Acc. Chem. Res. 1971, 4, 1–9.
[16] a) A. B. Baylis, M. E. D. Hillman, German Patent 2155113,
1972 [Chem. Abstr. 1972, 77, 34174q]; for selected recent re-
views, see: b) J. Mansilla, J. M. Saá, Molecules 2010, 15, 709–
734; c) Y. Wei, M. Shi, Acc. Chem. Res. 2010, 43, 1005–1018;
d) D. Basavaiah, B. S. Reddy, S. S. Badsara, Chem. Rev. 2010,
110, 5447–5674.
[17] We refer to intermediate 10 as MBH-adduct-like because it is
formed by a MBH-like reaction that uses esters instead of alde-
hydes as electrophiles, tertiary enamines as the Lewis base, and
alkynoates instead of the corresponding alkenoates.
[18] For an excellent discussion on the differences between tandem
Michael aldol reactions on terminal conjugated alkynes and
the Morita–Baylis–Hillman reaction, see: T. Kataoka, H. Ki-
noshita, Eur. J. Org. Chem. 2005, 45–58 and references cited
therein.
[1]
[2]
[3]
[4]
P. Perlmutter in Conjugate Addition Reactions in Organic Syn-
thesis, Pergamon, Oxford, 1992, pp. 339–357.
A. R. Katritzky, C. W. Rees in Comprehensive Heterocyclic
Chemistry, Pergamon, 1984, vol. 7, pp. 608–620.
F. D. Popp, A. C. Noble, Adv. Heterocycl. Chem. 1967, 8, 21–
82.
D. Lloyd, H. P. Cleghorn, D. R. Marshall, Adv. Heterocycl.
Chem. 1974, 17, 1–26.
[5] a) G. A. Archer, L. H. Sternbach, Chem. Rev. 1968, 680, 747–
784; b) D. Nardi, R. Pennini, A. Tajana, J. Heterocycl. Chem.
1975, 12, 825–828; c) J. S. Walia, L. A. Heidl, A. S. Walia, P. S.
Walia, J. Chem. Soc., Chem. Commun. 1972, 962.
[6] D. Tejedor, S. López-Tosco, J. González-Platas, F. García-Tel-
lado, J. Org. Chem. 2007, 72, 5454–5456.
[7] D. Tejedor, S. López-Tosco, J. González-Platas, F. García-Tel-
lado, Chem. Eur. J. 2009, 15, 838–842.
[8] D. Tejedor, S. López-Tosco, J. González-Platas, F. García-Tel-
lado, Chem. Eur. J. 2010, 16, 3276–3280.
[19] L. G. León, C. Ríos-Luci, D. Tejedor, E. Pérez-Roth, J. C.
Montero, A. Pandiella, F. García-Tellado, J. M. Padrón, J.
Med. Chem. 2010, 53, 3835–3839.
[9] D. Tejedor, S. López-Tosco, J. González-Platas, F. García-Tel-
lado, Chem. Eur. J. 2011, 17, 9571–9575.
Received: September 19, 2011
Published Online: October 19, 2011
6850
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6847–6850