Aza Hopf cyclization: synthesis and reactivity of cyclic azadieneynes

Article abstract of DOI:10.1016/j.tetlet.2009.03.168

Nine- and 10-membered azadieneynes have been synthesized for the first time via an intramolecular aza Wittig reaction. The compounds undergo Hopf cyclization under ambient conditions to the hydroxy dihydroisoquinoline derivatives.

Full text of DOI:10.1016/j.tetlet.2009.03.168

Tetrahedron Letters 50 (2009) 3641–3644
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Tetrahedron Letters
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Aza Hopf cyclization: synthesis and reactivity of cyclic azadieneynes
*
Sayantan Mandal, Amit Basak
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Nine- and 10-membered azadieneynes have been synthesized for the first time via an intramolecular aza
Wittig reaction. The compounds undergo Hopf cyclization under ambient conditions to the hydroxy dihy-
droisoquinoline derivatives.
Received 5 January 2009
Revised 6 March 2009
Accepted 14 March 2009
Available online 28 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The study of generation of diradicals and their chemical as well
as biological reactivity has become an area of intense research in
the past two decades.1 Primarily there are three reasons behind
such an interest. The first and foremost is their ability to simulta-
neously pull off hydrogens from the sugar moiety of opposite
strands of a ds-DNA resulting in its cleavage,2 a process important
for cancer chemotherapy.3 Additionally, these diradicals are useful
intermediates for the synthesis of various aromatic compounds4
including conducting polymers.5 Their synthesis and methods of
generation under ambient conditions are some of the important
challenges in this area. The Bergman cyclization6 of (Z)-3-hex-
ene-1,5-diynes (enediynes) to 1,4-didehydrobenzene diradicals
and the Myers–Saito cyclization7 of (Z)-1,2,4-heptatriene-6-ynes
Like BC, Hopf cyclization can also be speeded up by keeping the
dieneyne constrained in a cyclic framework which also aides the
reaction. Like our earlier work on N-substituted enediyne13 and
also Kerwin’s work on azaenediynes,14 we decided to incorporate
a nitrogen atom at the terminal ethylenic carbon and to constrain
the moiety in a nine-membered cyclic network and to study its
reactivity. Another motivation was to explore the possibility of
DNA cleavage by the intermediate for aza Hopf cyclization. It
may be pointed out that amongst the various diradical forming
processes, Hopf cyclization has a rapid self-quenching mechanism
which prevents the intermediate to pull out H from external
source. Thus, abstraction of H from sugar phosphate backbone is
almost ruled out. In this Letter, we have successfully demonstrated
that the nine-membered azadieneyne can cause DNA damage via
Hopf cyclization, possibly via a nucleophilic addition.
(enyne-allenes) to a,3-didehydrotoluene diradicals under thermal
conditions provide easy entry to a variety of carbon-centered
diradicals. Similarly, the Moore cyclization8 of eneyne–ketenes in
which a ketene moiety replaces the allene moiety in the eneyne–
allene system leads to a diradical having an aryl and a phenoxy
radical. Schmittel9a,b has developed several variations of Myers–
Saito cyclization using the eneyne carbodiimide in addition to
the formation of fulvene diradical9c,d from suitably substituted
eneyne allenes. Nicolaou et al.10 in a seminal paper used the chem-
istry of bisallenic sulfone. These molecules also undergo cycliza-
tion to generate diradicals, the reaction is known as the Garatt–
Braverman cyclization (GBC).11 All these cyclization processes
leading to diradicals are shown in Scheme 1. In 1969, Hopf and
Musso12 showed that hexa-1,3-dien-5-yne undergoes a thermal
cycloisomerization to give rise to benzene. The reaction needs high
temperature (>274 °C) and is believed to proceed through the
intermediacy of the diradical. A H-shift resulted in the formation
of benzene. In this Letter, we have synthesized the nine-membered
cyclo 1-aza-1,3-dien-5-yne via an intermolecular aza Wittig reac-
tion. The compound undergoes Hopf cyclization spontaneously at
room temperature in CDCl3 solution to a dihydroisoquinoline
derivative.
Before embarking upon the synthesis of the target molecule, we
analyzed the possible outcome of a nine-membered azadieneyne
system. In case of acyclic systems with a t-butyl group attached
to imino nitrogen, the molecule undergoes an electrophile-induced
intramolecular cyclization to isoquinoline derivative, as demon-
strated by Larock and co-workers15 Similarly, Asao et al.16a have
also reported the synthesis of 1,2-dihydroisoquinoline derivatives
by AgOTf-catalyzed addition of pronucleophiles to o-alkynylaryl
aldimine. The same reaction has also been carried via a three-com-
ponent reaction16b using o-alkynylbenzaldehyde, primary amine,
and pronucleophiles.16c The reaction proceeded in the absence of
a catalyst and an ionic mechanism was proposed as shown in
Scheme 2. We argued that with an appropriately sized cyclic dien-
eyne, instead of an electrophile or nucleophile-induced cyclization,
Hopf cyclization can take place to form a diradical as the first step.
Intramolecular electron transfer then leads to a zwitter ion similar
to that proposed by Asao et al.16 Subsequent protonation followed
by the addition of a nucleophile will generate the dihydro isoquin-
oline derivative (Scheme 2). If the reaction is performed in the
presence of DNA, then that will act as a nucleophile, and its addi-
tion will certainly cause its damage via Maxam–Gilbert pathway.
The synthesis (Scheme 3) started with the protection of 2-iodob-
enzyl alcohol, prepared from the corresponding acid. Sonogashira
* Corresponding author. Tel.: +91 3222283300; fax: +91 3222282252.
E-mail address: absk@chem.iitkgp.ernet.in (A. Basak).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.168

3642
S. Mandal, A. Basak / Tetrahedron Letters 50 (2009) 3641–3644
R
R
.
R
BC
GBC
C
C
O
O
O
O
.
S
S
.
R
.
.
R
R
.
MC
R
R
MSC
O
.
C
.
O
C
R
.
SC
.
.
H
HC
.
H
BC = Bergman Cyclization, MSC = Myers Saito Cyclization, SC = Schmittel
Cyclization, GBC = Garratt Braverman Cyclization, MC = Moore Cyclization,
HC = Hopf Cyclization
Scheme 1. Diradical generating processes.
E
R1
R = tBu
Larrock
E+
N
E
R1
R
R1
R
a
. .
N
E
N
Asao
R1
NuH
N
R
Nu
R1
R1
.
R1
. .
N
N
N
R
R
.
R
H
H
R1
R
R1
DNA Cleavage
N
N
R
DNA
Nu
Scheme 2. Electrophile-induced reactivity of ene-yne-imine and predicted reactivity of cyclic systems.
I
I
c
a
b
N3
OH
95%
95%
80%
CH2OTHP
CH2OTHP
10
CH2OTHP
CO2H
11
9
d
98%
e
f
N
N
90%
60%
CHO
N3
OH
2
1
3
Scheme 3. Synthesis of imine 1 and formation of cyclization product 2. Reagents and conditions: (i) BH3–THF, rt, 6 h; (ii) DHP, PPTS, CH2Cl2, 12 h; (b) 4-pentyn-1-ol,
Pd(PPh3)4, CuI, n-BuNH2, rt, 9 h; (c) (i) MsCl, Et3N, 0 °C, 10 min; (ii) NaN3, DMF, rt, 6 h; (d) (i) PPTS, EtOH, rt, 12 h; (ii) Dess–Martin Periodinate, CH2Cl2, rt, 3 h; (e) PPh3, CHCl3,
3days, rt; (f) incubatation at 37 °C for 3 days.
coupling17 with 4-pentyn-1-ol followed by standard functional
group transformations produced the azide. Deprotection followed
by oxidation with Dess–Martin reagent18 gave azido aldehyde 3.
In order to follow the outcome of the intramolecular aza Wittig

S. Mandal, A. Basak / Tetrahedron Letters 50 (2009) 3641–3644
3643
reaction, the azido aldehyde was dissolved in CDCl3 and 1H NMR
was recorded at different time points after adding 1 equiv of PPh3
in order to determine the course of aza Wittig reaction.19 The forma-
tion of the ylide could be seen within half hour as evidenced from
the appearance of a new aldehyde peak at d 10.45 along with con-
comitant decrease in the signal for the aldehyde peak.
The conversion to the ylide was complete in 1 h after which an-
other new peak started to appear at d 9.05 which grew in intensity
at the expense of the aldehyde peak of the ylide. The product cor-
responding to this new peak was assigned the imine structure. This
is the first example of an aza analogue of nine-membered dieneyne
and the conversion was almost complete within 3 days with an
estimated yield of ꢀ80%. The various time-dependent NMRs are
shown in Figure 1.
spectral data. A solution of the imine in CDCl3 was kept at 37 °C
in an incubator. It was smoothly converted to the dihydroisoquin-
oline derivative 2 with a half-life of ꢀ27 h in near quantitative
yield (1H NMR is shown in Fig. 2). The structure of the imine as well
as the final cyclization product has been confirmed by 1H, 13C, and
COSY NMR as well as by mass spectral analysis. Thus, the two sing-
lets in the 1H NMR spectrum at d 5.61 and d 5.06 were assigned to
be due to the H-1 and H-4, respectively. The 13C NMR spectrum
showed the presence of three methylenes and six methine carbons.
Mass spectra showed the peak at m/z 171 corresponding to
[MÀOH+H]+. In case of the higher homologue (synthesis shown
in Scheme 4), the azide 13 upon PPh3 reduction gave the mono-
imine 4 (formed by intramolecular condensation) which was
mixed with the intermolecular product, namely, bis-imine 5. These
could not be separated even by HPLC thus prompting us to carry
out the Hopf cyclization on the mixture. However unlike in the
case of 1, the temperature had to be raised to 50 °C for mono-imine
The imine 1 was, however, unstable to Silica gel chromato-
graphic conditions. It was purified by HPLC (100% methanol, flow
rate 0.8 mL/min) and was fully characterized by NMR and mass
I
b
c
OH
N3
80%
95%
CH2OTHP
CH2OTHP
12
CH2OTHP
9
13
98%
d
N
e
N3
N
CHO
60%
(Combined)
5
7
+
f
N
N
For b-f, refer to Scheme 3
90%
4
6
OH
Scheme 4. Synthesis of imine 4 and the formation of cyclization product.
T = 78 h
T = 75 h
T = 51h
T = 68 h
T = 58.5 h
T = 38.5 h
T = 22.5 h
T = 42 h
T=27 h
T = 6.5 h
T = 4 h
T = 18 h
T = 3 h
T = 0 h
T = 1.5 h
T = 0.5 h
1
2
Figures 1 and 2. (1) 1H NMR at different time points after the addition of PPh3 to the azido aldehyde 3. (2) 1H NMR at different time points upon incubation of imine 1.

3644
S. Mandal, A. Basak / Tetrahedron Letters 50 (2009) 3641–3644
1
2
3
4
5
Acknowledgments
The author S.M. is grateful to CSIR, Government of India, for a
fellowship. DST is thanked for providing funds for 400 MHz NMR
facility under the IRPHA program.
Figure 3. DNA cleavage experiment with compound 1 at 37 °C: Lanes 5: DNA (7
in TAE buffer (pH 7.5) (5 L) + acetonitrile (6 L), 4: DNA (7 L) in TAE buffer (pH
7.5) (5 L) + 1 in acetonitrile (6 L, 2 mM) for 24 h, 3: DNA (7 L) in TAE buffer
L) + 1 in acetonitrile (6 L, 2 mM) for 48 h, 2: DNA (7 L) in TAE buffer
L) + 1 in acetonitrile (6 L, 2 mM) for 72 h, 1: DNA (7 L) in TAE buffer
L) + 1 in acetonitrile (6 L, 2 mM) for 96 h.
lL)
l
l
l
l
l
l
l
l
(pH7.5) (5
(pH 7.5) (5
(pH 7.5) (5
l
l
l
l
l
l
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.03.168.
4 to undergo cyclization to the dihydro isoquinoline derivative 6 in
about 45% yield; bis-imine 5 remained intact during the process.
Having accomplished the synthesis and the chemical reactivity
study of azadieneyne toward Hopf cyclization, we checked its DNA
cleavage activity. Thus incubation of compound 1 in acetonitrile
(6 lL) and ds-plasmid DNA in aqueous buffer (7 lL) at 37 °C led
to the moderate cleavage of DNA after 48 and 72 h (Fig. 3) in mil-
limolar concentrations.
In conclusion, we have synthesized the aza analogue of the 9-
and 10-membered dieneyne for the first time. The compounds
showed cyclization to form dihydroisoquinoline derivatives. The
nine-membered imine showed moderate DNA cleaving activity.
Selected spectral data: All 1H and 13C NMR spectra were recorded
in CDCl3 at 400 MHz and 100 MHz, respectively.
For3: State: Oily liquid; yield: 95%: dY 10.51 (1H, s), 7.89 (1H, d,
J = 7.6 Hz), 7.53–7.50 (2H, m), 7.43–7.39 (1H, m), 3.50 (2H, t,
J = 6.8 Hz), 2.62 (2H, t, J = 6.8 Hz), 1.95–1.88 (2H, m); dC 191.8,
135.9, 133.7, 133.4, 128.1, 127.2, 127.1, 95.7, 77.30, 50.2, 27.7,
16.9; MS (ESI) m/z 213 (M+).
References and notes
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For compound 1: State: Oily liquid; yield: 60%: dY 9.04 (1H, s),
8.07–8.05 (1H, m), 7.46–7.43 (1H, m), 7.37–7.26 (2H, m), 3.94
(2H, t, J = 6.4 Hz), 2.50 (2H, t, J = 6.0 Hz), 2.10–2.04 (2H, m); dC
160.6, 136.3, 132.7, 130.3, 127.9, 125.8, 125.0, 95.0, 78.4, 60.0,
28.5, 16.5; MS (ESI) m/z 170 (MH+).
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For compound 2: State: Oily liquid; yield: 98%: dY 7.39 (1H, d,
J = 7.6 Hz), 7.36–7.31 (1H, m), 7.17 (1H, t, J = 7.6), 7.07 (1H, d,
J = 7.6 Hz), 5.61 (1H, s), 5.06 (1H, s), 4.29–4.22 (1H, m), 3.40 (1H,
d, J = 16.0 Hz), 2.48–2.43 (1H, m), 2.20 (1H, d, J = 12.8 Hz), 1.86–
1.83 (1H, m), 1.77–1.74 (1H, m): dC 144.2, 134.7, 129.7, 128.9,
124.4, 123.1, 121.4, 100.7, 76.8, 49.4, 27.0, 23.2; MS (ESI) m/z
171 (MH+ÀOH).
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For compound 7: State: Oily liquid; yield: 95%: dY 10.52 (1H, s),
7.89 (1H, d, J = 8.0 Hz), 7.53–7.51 (2H, m), 7.43–7.39 (1H, m), 3.36
(2H, t, J = 6.4 Hz), 2.55 (2H, t, J = 6.4 Hz), 1.80–1.73 (4H, m): dC
191.9, 135.9, 133.7, 133.3, 128.0, 127.4, 127.0, 96.9, 76.9, 50.9,
28.0, 25.6, 19.1; MS (ESI) m/z 227 (M+).
For 1:1 mixture of compounds 5 and 6: State: Oily liquid; dY 8.80
(1H, s), 7.98–7.95 (1H, m), 7.36–7.30 (4H, m), 7.26–7.23 (1H, m),
7.12–7.09 (1H, m), 6.99 (1H, d, J = 7.6 Hz), 5.62 (1H, s), 4.93 (1H,
s), 4.01–3.89 (2H, m), 3.60–3.54 (1H, m), 3.32–3.25 (1H, m),
2.60–2.54 (1H, m), 2.42–2.30 (3H, m), 2.12–2.08 (1H, m), 1.90–
1.85 (1H, m), 1.73–1.43 (6H, m); dC 160.7, 144.0, 136.6, 135.0,
132.1, 130.2, 129.7, 128.8, 128.0, 126.1, 124.6, 124.2, 122.1,
106.2, 103.7, 95.6, 59.9, 55.0, 30.7, 28.9, 28.3, 25.6, 23.4, 19.4.
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