The spontaneous activation of a nonaromatic enediynyl azide under ambient conditions has been demonstrated. The aromatic enediyne followed the expected cycloaddition with the alkene in the neighbouring arm to form a stable bridged bicyclic enediyne

Basak, Amit

Das, Sanket

Ghosh, Subhash C.

Hazra, Amrita B.

Jha, Shailendra

Roy, Sandip K.

English

Publications of the IAS Fellows

Chemistry of enediynyl azides: activation through a novel pathway{
Amit Basak,*a Sandip K. Roy,a Sanket Das,a Amrita B. Hazra,a Subhash C. Ghosha and Shailendra Jhab
Received (in Cambridge, UK) 22nd August 2006, Accepted 2nd October 2006
First published as an Advance Article on the web 1st November 2006
DOI: 10.1039/b612114d
The spontaneous activation of a nonaromatic enediynyl azide
under ambient conditions has been demonstrated. The
aromatic enediyne followed the expected cycloaddition with
the alkene in the neighbouring arm to form a stable bridged
bicyclic enediyne.
Enediynes usually undergo Bergman cyclization (BC)1 under
ambient conditions when they are cyclic2 or are capable of forming
a pseudo cyclic network mediated by ligand–metal3 or H-bond4 or
charge transfer5 interactions. The inherent strain6 in a cyclic
framework coupled with the close proximity7 of the acetylenic
carbons undergoing covalent connection is responsible for such
behaviour. Since the spontaneity of BC of monocyclic enediynes
can be controlled by fusion of an extra ring on to the parent
molecule, bicyclic enediynes continue to be attractive targets. One
can fine tune their reactivity by perturbing the size of the ring8 or
by changing the hybridization of the ring atom.9 Recently, we have
reported an intramolecular cycloaddition route to isooxazoline10
and b-lactam fused enediynes11 in a single step starting from an
acyclic enediyne precursor. In this communication, we describe a
similar approach, this time involving an alkene and an azide.
During the course of our work, we observed many interesting
results which are presented here. One particularly important
observation is the activation of an enediyne through a novel
pathway.
1,3-Dipolar cycloaddition of an azide with alkene/alkyne is well-
known to lead to the formation of fused ring heterocycles.12 A
variety of heterocycles like imines, aziridines, pyrrolidines formed
using an alkene as the dipolarophile by the loss of molecular
nitrogen from the initial adduct which is usually a mixture of
regioisomeric 1,2,3-triazolines. For inducing an intramolecular
cycloaddition, the azide and the dienophile should be placed in the
two arms of an acyclic enediyne. Accordingly, we have designed
the enediyne scaffolds 1–4 containing the required functionalities
(Fig. 1). These are classified into two groups, one having the alkene
functionality conjugated to the enediyne (1 and 2) while the other
having an isolated alkene (3 and 4).
As an initial study, compound 1 was taken up for synthesis.
Thus the bromoalkene 5, made by our published procedure,10 was
coupled to 3-butyn-1-ol under Sonogashira conditions.13 The
resulting alcohol 6 was mesylated and then converted to the azide
(Scheme 1). The azide 114 was, however, found to be stable and
reluctant to undergo cycloaddition even when refluxed in toluene
or xylene for 35–40 h. Initially, we thought that the acetylene arm
containing the azide was too short to come within reacting distance
with the alkene. However, the homologous azide 2,14 prepared in a
similar manner, also failed to react thus ruling out the above logic.
It appears that the alkene being conjugated to the benzene ring is
deactivated and the HOMO–LUMO energy difference is perhaps
too large for the reaction between the partners to occur. This
argument was supported by the fact that an attempted
intermolecular reaction between the alkene 5 and the 3-phenyl
propyl azide 10 also did not go through (Scheme 2).
We then synthesized the nonconjugated enediynes 3 and 414 to
find out whether deconjugation facilitates the reaction or not. The
synthesis of 3 and 4 was achieved by two Sonogashira coupling
steps followed by a Cu(I)-mediated alkylation of the terminal
alkyne15 and subsequent conversion of the alcohol to azide. The
entire synthesis is shown in Schemes 3 and 4.
Both the aromatic and nonaromatic enediynes were found to be
unstable even under ambient conditions. Upon refluxing in
benzene in the presence of 1,4-CHD for 5 h, the aromatic
enediyne 3 underwent intramolecular cycloaddition to give mainly
one triazoline fused enediyne 22 (yield y42%) (Scheme 5). The
occurrence of cycloaddition was indicated by the disappearance of
the characteristic absorption band for the azide at 2120 cm21 and
aBioorganic Laboratory, Department of Chemistry, Indian Institute of
Technology, Kharagpur, India. E-mail: absk@chem.iitkgp.ernet.in;
Fax: 91 3222 282252; Tel: 91 3222 283300
bDepartment of Chemistry, Jadvapur University, Kolkata, 700 032, India
{ The HTML version of this article has been enhanced with colour
images.
Fig. 1 Structure of 1–4. Scheme 1 Synthesis of 1 and 2.
Scheme 2 Attempted intermolecular 1,3-dipolar cycloaddition.
COMMUNICATION www.rsc.org/chemcomm | ChemComm
622 | Chem. Commun., 2007, 622–624 This journal is  The Royal Society of Chemistry 2007
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also by the absence of the signals for the vinyl group in the
1H-NMR spectrum. The 13C-NMR spectrum showed the
characteristic signals for the four acetylenic carbons between d
80–100 thus ruling out any cycloaromatization during the azide–
alkene cycloaddition. Between the two possible regioisomeric
triazolines, the one with a bridgehead was favoured due to the
following reasons: (i) the non-occurrence of BC which was
expected for the other isomer 21 containing a 10-membered ring;
and (ii) the absence of any 1,4-cross peak in the NOESY spectrum.
A cross peak between H-2 and H-13 was expected for structure 21.
The nonaromatic enediyne 4, upon similar refluxing in benzene
in presence of 1,4-CHD for 5 h also produced only one major
product, characterized as the benzotriazine derivative 27 (yield
y35%). The structure elucidation was based upon the following:
(i) disappearance of the peak for the azide at 2107 cm21 in the FT-
IR spectrum; (ii) presence of allyl group as revealed in the 1H-
NMR; (iii) appearance of three aromatic protons characteristic of
a 1,2,3-trisubstituted benzene; (iv) a D2O-exchangeable peak at d
8.06 due to NH and appearance of a peak at m/z 146 (MH+–N2) in
the ESI mass spectrum. Structure 27 was favoured over structure
26 because of the low chemical shift of NH proton.16 Interestingly,
the same product could also be obtained (in lower yield y15%) if
the solution was kept at room temperature for 7 d. The mesylate
20 could be converted into the azide (y30% yield) if it was stirred
in water under similar concentrations at room temperature and the
resulting azide 4 has also been shown to undergo slow
decomposition in aqueous medium thus opening the possibility
of DNA-cleavage under aqueous conditions. The low yield was
due to the competing hydrolysis back to the starting alcohol 19.
The probable mechanism of formation of the product is shown
in Scheme 6. It is based on the initial dipolar cycloaddition with
the alkyne12a,17 followed by rearrangement to form the eneyne-
allene 24. Myers–Saito cyclization18 and subsequent abstraction
of hydrogen atoms lead to the final product 27. Similar cascade of
reactions is not possible in the aromatic system because of
deactivation of the alkynes which is conjugated to the benzene
ring. Since the mechanism involves the formation of diradicals
under ambient conditions, radical-mediated cleavage of ds-DNA
can be expected. In fact, azide showed DNA-cleavage under
ambient conditions. Thus, supercoiled plasmid DNA (pBR 322)
underwent single strand cuts when incubated with the enediyne 4
at 37 uC for 48 h (Fig. 2).
In conclusion, we have demonstrated the spontaneous activa-
tion of a nonaromatic enediynyl azide under ambient conditions.
The aromatic enediyne followed the expected cycloaddition with
the alkene in the neighbouring arm to form a bridged bicyclic
enediyne. Current studies are aimed towards exploring the novel
rearrangement in other nonaromatic analogues.
SKR and SD are grateful to CSIR, Government of India for
research fellowships. AB thanks DST, Government of India for a
research grant.
Notes and references
1 (a) R. G. Bergman, Acc. Chem. Res., 1973, 6, 25; (b) T. P. Lockhart and
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5 A. Basak, S. S. Bag and A. K. Das, Eur. J. Org. Chem., 2005, 1239.
6 (a) K. C. Nicolaou, G. Zuccarello, Y. Oogawa, E. J. Schweiger and
T. Kumazawa, J. Am. Chem. Soc., 1988, 10, 4866; (b) P. R. Schreiner,
J. Am. Chem. Soc., 1998, 120, 4184.
Scheme 4 Synthesis of 4.
Scheme 3 Synthesis of 3.
Scheme 5 Reactivity of 3.
Fig. 2 Picture of DNA cleavage. Lanes: 1. DNA in TAE buffer (pH 8)
(5 mL) + acetonitrile (15 mL) at 37 uC; 2. DNA in TAE buffer (pH 8) (5 mL)
+ azide 4 (40 mM, 48 h) in acetonitrile (15 mL) at 37 uC.
Scheme 6 Reactivity of 4.
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14 Selected spectral data: For 1: dH (200 MHz, CDCl3) 8.25 (dd,
3J (H,H) =
1.6, 7.8 Hz, 1H; Ar–H), 7.60 (dd, 3J (H,H) = 1.4, 7.8 Hz, 1H; Ar–H),
7.43-7.12 (m, 2H; Ar–H), 6.62–6.48 (m, 1H; CHCH2), 5.87–5.54 (m, 1H;
CHCH2), 5.34 (dd,
3J (H,H) = 2.2, 10.4 Hz, 1H; CHCH2), 3.54–3.44 (m,
2H; CH2N), 2.80–2.63 (m, 2H; CH2CH2N); HRMS (ES+) calcd for
C14H11N3 (MH
+) 222.1029, found 222.1046; For 2: dH (200 MHz,
CDCl3) 7.45–7.35 (m, 2H; Ar–H), 7.29–7.20 (m, 2H; Ar–H), 6.07 (dd,
3J
(H,H) = 11.0, 17.5 Hz, 1H; CHCH2), 5.75 (dd,
3J (H,H) = 2.2, 17.5 Hz,
1H; CHCH2), 5.58 (dd,
3J (H,H) = 2.2, 11.0 Hz, 1H; CHCH2), 3.54 (t,
3J (H,H) = 6.7 Hz, 2H; CH2N), 2.59 (t,
3J (H,H) = 6.8 Hz, 2H;
CCH2CH2), 1.95–1.82 (m, 2H; CH2CH2N); HRMS (ES+) calcd for
C15H13N3 (MH
+) 236.1185, found 236.1201; For 3: dH (200 MHz,
CDCl3) 7.47–7.38 (m, 2H; Ar–H), 7.31–7.20 (m, 2H; Ar–H), 5.96–5.85
(m, 1H; CH2CH), 5.48 (dd,
3J (H,H) = 1.8, 16.9 Hz, 1H; CH2CHCH2),
5.18 (dd, 3J (H,H) = 1.8, 10.0 Hz, 1H; CH2CHCH2), 4.17 (s, 2H;
CH2N), 3.25 (t,
3J (H,H) = 2.4 Hz, 2H; CCH2CH); HRMS (ES+) calcd
for C14H11N3 (MH
+) 222.1029, found 222.1011; For 4: dH (200 MHz,
CDCl3) 5.94–5.74 (m, 1H; CHCH2), 5.38 (qd,
3J (H,H) = 1.8, 18.6 Hz,
1H; CH2CHCH2), 5.13 (qd,
3J (H,H) = 1.8, 10.0 Hz, 1H; CH2CHCH2),
4.09 (d, 3J (H,H) = 1.4 Hz, 2H; CH2N), 3.19–3.15 (m, 2H; CCH2CH);
HRMS (ES+) calcd for C10H9N3 (MH
+) 172.0873, found 172.0880; For
22: dH (500 MHz, CDCl3) 7.46 (d,
3J (H,H) = 8.5 Hz, 1H; Ar–H), 7.28–
7.06 (m, 2H; Ar–H), 7.05 (d, 3J (H,H) = 6.4 Hz, 1H; Ar–H), 5.05 (d, 3J
(H,H) = 18.3 Hz, 1H; CCH2N), 4.72–4.66 (m, 1H; NCH2CH), 4.06 (d,
3J (H,H) = 18.3 Hz, 1H; CCH2N), 3.61 (t,
3J (H,H) = 9.2 Hz, 1H;
NCH2CH), 3.36 (dd,
3J (H,H) = 2.4, 18.0 Hz, 1H; CCH2CH), 3.27 (t,
3J
(H,H) = 9.2 Hz, 1H; NCH2CH), 2.79 (dd,
3J (H,H) = 4.4, 18.0 Hz, 1H;
CCH2CH); HRMS (ES+) calcd for C14H11N (MH
+) 194.0967, found
194.1044; For 27: dH (200 MHz, CDCl3) 8.06 (s, 1H; NH), 7.34 (d,
3J
(H,H) = 8.0 Hz, 1H; Ar–H), 7.07 (d, 3J (H,H) = 8.0 Hz, 1H; Ar–H),
7.01 (d, 3J (H,H) = 8.0 Hz, 1H; Ar–H), 6.03–5.86 (m, 1H; CHCH2), 5.10
(s, 2H; CH2N), 5.05–5.00 (m, 1H; CHCH2), 4.92 (d,
3J (H,H) = 1.6 Hz,
1H; CHCH2), 3.52 (d,
3J (H,H) = 6.2 Hz, 2H; CCH2CH); HRMS
(ES+) calcd for C10H11N (MH
+) 146.0967, found 146.1026.
15 Synthesis of allylacetylenes from terminal acetylenes and allyl halides.
N. A. Bumagin, A. B. Ponomarev and I. P. Beletskaya, Izv. Akad. Nauk
SSSR, Ser. Khim., 1987, 7, 1565 (in Russian).
16 The chemical shift of NH proton for naphtho[1,8-de][1,2,3]triazine has
been reported to be d 13.29 in d6-DMSO see H. Al-Awadi,
M. R. Ibrahim, H. H. Dib, N. A. Al-Awadi and Y. A. Ibrahim,
Tetrahedron, 2005, 61, 10507.
17 (a) S. Roper, M. H. Franz, R. Wartchow and H. M. R. Hoffman, Org.
Lett., 2003, 5, 2773; (b) C. von Riesen and H. M. R. Hoffman, Chem.–
Eur. J., 1996, 2, 680.
18 (a) R. Nagata, H. Yamanaka, E. Okazaki and I. Saito, Tetrahedron
Lett., 1989, 30, 4995; (b) A. G. Myers, E. Y. Kuo and N. S. Finnney,
J. Am. Chem. Soc., 1989, 111, 8057; (c) A. G. Myers and P. S. Dragovich,
J. Am. Chem. Soc., 1989, 111, 9130; (d) R. Nagata, H. Yamanaka,
E. Murahashi and I. Saito, Tetrahedron Lett., 1990, 31, 2907.
624 | Chem. Commun., 2007, 622–624 This journal is  The Royal Society of Chemistry 2007
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Chemistry of enediynyl azides: activation through a novel pathway

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Chemistry of enediynyl azides: activation through a novel pathway

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