Nitrogen substituted cyclic enediynes: Synthesis, thermal reactivity and coniplexation with metal ions

Article abstract of DOI:10.1039/b000963f

A number of N-substituted cyclic enediynes (azaenediynes) have been synthesized via Pd(0)-catalysed ene-yne coupling followed by N-alkylation. The simplest of them, a 10-membered monocyclic enediyrie 1, underwent Bergman cyclization (BC) at 23°C with a half-life of 72 h. The kinetics of BC slowed down considerably by fusing a benzene ring onto the enediyne. Several novel bis(azaenediyne)s and bis(diazaenediyne)s 3-6 have been synthesized. Their onset temperatures for BC were lowered under metal ion complexation conditions. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b000963f

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Nitrogen substituted cyclic enediynes: synthesis, thermal reactivity
and complexation with metal ions
Amit Basak,*a Jagadish Chandra Shain,a Uttam Kumar Khamrai,a Kakali Rani Rudraa
and Ajoy Basakb
1
a Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
b Loeb Research Institute, Ottawa Civic Hospital, University of Ottawa, 725 Parkdale Avenue,
Ottawa, ON, Canada, K1Y 4K9
Received (in Cambridge, UK) 3rd February 2000, Accepted 5th April 2000
Published on the Web 31st May 2000
A number of N-substituted cyclic enediynes (azaenediynes) have been synthesized via Pd(0)-catalysed ene–yne
coupling followed by N-alkylation. The simplest of them, a 10-membered monocyclic enediyne 1, underwent
Bergman cyclization (BC) at 23 ЊC with a half-life of 72 h. The kinetics of BC slowed down considerably by
fusing a benzene ring onto the enediyne. Several novel bis(azaenediyne)s and bis(diazaenediyne)s 3–6 have
been synthesized. Their onset temperatures for BC were lowered under metal ion complexation conditions.
Table 1 MM2 results for enediynes 1–6
Introduction
The enediyne class of natural products,1 discovered more than
Molecule
‘Calculated’ c,d-distance/Å
a decade ago, continues to draw the attention of chemists
working in various fields. One important aspect of the chem-
istry of the enediynes is the design and synthesis of simple
model systems.2 Several of these possess antitumour activity by
virtue of their DNA-cleaving ability and have shown promise as
anticancer agents.3 Over the past few years we have been trying
to understand the behaviour of cyclic enediynes with one or
more nitrogen atoms constituting a part of the ring. The
rationale behind such an interest involves the following: 1) the
shorter C–N bond length may help in speeding up the kinetics
of BC4 compared to the C or S analogs,5,6 2) the ease of attach-
ment of DNA binding agents7 onto the nitrogen atom, 3) the
possible decrease of torsional strain8 compared to the all
carbon analogs, thus reducing the activation barrier for BC and
4) probable perturbation of the kinetics of BC upon complex-
ation to metal ions9 via chelation through N. At the very outset
it is pertinent to mention that although the synthesis and
reactivity of the bicyclic azaenediyne core related to dynemicin
were previously described prior to this work,10 the synthesis
of simple monocyclic azaenediynes and the influence of the
nitrogen atom on the reactivity towards cycloaromatization had
not been investigated. In fact, we are one of the first groups to
report the synthesis of such analogs.11,12 In the present article,
we wish to report in detail the synthesis of these molecules,
their comparative thermal reactivities under neat and metal
complexation conditions.
1
2
3
4
5
6
3.22
3.24
4.08
3.68
3.86
4.0, 4.17
In our design, two types of enediynes were considered: (a)
systems with a single N-atom (monoaza) and (b) systems with
multiple N-atoms. In the latter category we have concentrated
on molecules with either two (diaza) or four (tetraaza) N-
atoms. In order to get an idea about the distances between the
reacting acetylenic atoms (c,d distance), molecular mechanics
calculations were carried out on all these systems using the
MM2 force field (Table 1). The energy minimised conform-
ations of the pertinent species are shown in Fig. 1. The c,d-
distance for the monocyclic enediyne 1 came out to be 3.22 Å
which is within the critical range of 3.31–3.20 Å proposed
by Nicolaou et al.13 for spontaneous cyclization at ambient
temperature. The aromatic fused analog 2, like the carbocyclic
counterparts,14 is expected to exhibit better stability. However, a
c,d-distance of 3.24 Å based on MM2 calculations would
predict similar behaviour to 1. For the other enediynes 3–6, the
c,d-distance expectedly came out much higher (>3.6 Å)
because of the presence of larger rings (18, 12, 13 and 24
DOI: 10.1039/b000963f
J. Chem. Soc., Perkin Trans. 1, 2000, 1955–1964
This journal is © The Royal Society of Chemistry 2000
1955

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Fig. 1 Energy minimized conformations of azaenediynes.
respectively) and these should undergo BC at a much higher
M) proceeded smoothly to produce the 10-membered azaene-
temperature. Complexation to metal ions, however, would lead
to a change of ring size and should alter the kinetics of BC.
diyne 1. Carrying out the reaction at a higher concentration
(e.g. >0.06 M) produced a substantial amount of the dimer
11a. The benzene-fused enediyne 2 was synthesized in a similar
fashion (Scheme 2). However, in this case the Pd(0)-based coup-
Synthesis of the azaenediynes 1–6
Zerovalent Pd-catalysed Sonogashira coupling15 is the key
reaction used to synthesize the target enediynes 1–6. For the
construction of the simple 10-membered azaenediyne 1, (z)-1,2-
dichloroethylene was first monocoupled with homopropargyl†
alcohol (Scheme 1). The resulting 6-chlorohex-5-en-3-ynol 7
Scheme 2 Reagents and conditions: a, But-3-yn-1-ol, Pd(PPh3)4, n-
BuNH2, 80 ЊC; b, MsCl, NEt3; c, NaN3, DMF; d, PPh3–H2O; e, TsCl,
DMAP; f, propargyl alcohol, Pd(PPh3)4, n-BuNH2, 80 ЊC; g, MsCl,
NEt3; h, K2CO3, DMF.
ling had to be carried out in the absence of CuI, addition of
which led to extensive oxidative dimerization of the acetylene in
our hands. An attempt to prepare a 9-membered analog failed;
the initial intermolecular N-alkylation product 26a underwent
intramolecular cyclization leading to the 18-membered bis-
(azaenediyne) 3 (Scheme 3). Just and Singh16a and Konig
et al.16b had previously reported the formation of a similar mol-
ecule starting from the dimesylate 28 or dibromide 29 and
a primary amine. The other bis(azaenediyne)s 4 and 5 were
prepared in a single step from the dimesylate 28 by double
N-alkylation with N,NЈ-dibenzylethylenediamine and N,NЈ-
bis(p-tolylsulfonyl)-m-phenylenediamine respectively (Scheme
4). It must be pointed out here that in both the cases we ended
up getting only the 1:1 adducts. We did not see the formation
of any higher adducts; the dilute conditions employed might be
responsible for this observation. The mass spectra of both the
adducts are in accord with the proposed structures (appearance
Scheme 1 Reagents and conditions: a, Pd(PPh3)4, n-BuNH2, CuI, PhH,
rt; b, MsCl, NEt3; c, NaN3, DMF; d, PPh3–H2O; e, TsCl, DMAP;
f, propargyl tert-butyldimethylsilyl ether, Pd(PPh3)4, n-BuNH2, Cul,
PhH, rt; g, CsF, MeCN; h, MsCl, NEt3; i, K2CO3, DMF.
was converted to the azide 9, which upon reduction with PPh3–
H2O produced the amine, isolated as the toluene-p-sulfonamide
10. Another round of Pd(0)-catalysed coupling with propargyl†
tert-butylsilyl ether gave the acyclic enediyne 11 which was
deprotected to the alcohol 12. Intramolecular N-alkylation of
the mesylate 13 using K2CO3–DMF under high dilution (0.006
† IUPAC name for homopropargyl is but-3-ynyl; IUPAC name for
propargyl is prop-2-ynyl.
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enediamine failed. Gratifyingly, however, 6 could be prepared in
moderate yield in a single step from the diyne 35 by a novel
Pd(0)-catalyzed macrocyclization (Scheme 5).
Results and discussion
The enediyne 1 was found to be sufficiently stable at ambient
1
temperature to allow us to record its H, 13C and correlation
NMR spectra. The molecule, however, slowly underwent
cycloaromatization (BC) in CDCl3 at room temperature result-
ing in the formation of a tetrahydroisoquinoline system 39a.
₁
The t at 23 ЊC for such a cyclization was found to be around
₂

72 h (Ea ~ 18 kcal molϪ1). The Bergman cyclization could be
monitored by keeping a solution of the sample in CDCl3 at a
1
constant temperature and checking the H-NMR at different
points in time. Interestingly, the characteristic peaks at δ 5.84,
4.09, 3.53 and 2.77 for 1 diminished while new peaks at δ 4.22,
3.33 and 2.91 appeared, corresponding to the tetrahydroisoqui-
noline system. Differential scanning calorimetric (DSC)17
measurements on 1 in the neat liquid state showed the onset
temperature for BC to be around 50 ЊC. The benzene-fused
enediyne 2, on the other hand, is stable at room temperature.
The cyclized product, a tetrahydrobenzoisoquinoline derivative
40a, could be isolated by refluxing a chloroform solution of 2
₁
for 3 days followed by chromatography. The t for the cyclo-
₂
aromatization was found to be ~ 52 h at 65 ЊC. The molecule
showed an onset temperature for BC of ~110 ЊC when checked
by DSC. Thus, fusion of an aromatic ring on to the 10-
membered azaenediyne caused a significant elevation of the
activation barrier to cycloaromatization. A similar slowing
down of kinetics has been observed by Semmelhack et al.14a and
by Nicolaou et al.14b for carbocyclic systems. One would expect
that the larger ene bond length (1.39 Å) possibly led to an
increase in the distance between the reacting acetylenic carbons
in 2 thereby slowing down the kinetics of BC. However, as
indicated earlier, MM2 calculations showed the c,d-distance in
2 to be 3.24 Å, well within Nicolaou’s proposed critical range
for spontaneous cyclization at room temperature thus possibly
ruling out the above proposition. A more plausible explanation
is based on the lower gain of resonance energy in the
naphthalene-like transition state (TS) for the BC of 2, acting as
weaker driving force compared to an isolated benzenoid TS for
cyclization of 1.
The onset temperature for BC in the case of bis(azaene-
diyne)s 3, 4 and 5 were, as expected, quite high, 130, 210 and
275 ЊC respectively. We failed to prepare any well-defined metal
complex from 3 probably because of the weak ligation by
NHSO2Ar, which has a delocalized N-lone pair. However, when
an acetonitrile solution containing equimolar quantities of 3
and AgOAc was evaporated and the resulting brown solid was
checked for DSC measurement, the exothermic rise now started
Scheme 3 Reagents and conditions: a, MsCl, NEt3; b, NaN3, DMF; c,
PPh3–H2O; d, TsCl, DMAP; e, propargyl tert-butyldimethylsilyl ether,
Pd(PPh3)4, Cul, n-BuNH2; f, CsF, MeOH; g, MsCl, NEt3; h, K2CO3,
DMF.
of molecular ion peaks at 390 and 566). No peak corresponding
to a higher mass was observed in the mass spectrum. Single
crystal X-ray diffraction data on the enediyne 4 confirmed the
formation of a 1:1 coupling product.‡ Our initial attempt to
prepare the bis(diazaenediyne) 6 from the dibromo dienediyne
35 via Pd(0)-catalyzed coupling with propargyl alcohol followed
by mesylation and bis-N-alkylation with N,NЈ-dibenzylethyl-
‡ The X-ray structure along with all the parameters are, as yet,
unpublished results.
Scheme 4 Reagents and conditions: a, MsCl, NEt3; b, K2CO3, DMF; c, Cu(OAc)2 MeOH, reflux; d, chlorobenzene, cyclohexa-1,4-diene, 240 ЊC.
J. Chem. Soc., Perkin Trans. 1, 2000, 1955–1964
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Fig. 2 DSC curve of i) tetraazaenediyne (6) and ii) its Ni()-complex
(38).
the solvent was evaporated. Like all the other Cu()-complexes,
compound 31 also exhibited extremely broad signals in its
1H-NMR spectrum due to the paramagnetism of Cu(). DSC
measurements on the complex showed an onset temperature
for BC at 110 ЊC, indicating a considerable reduction of the
activation barrier for BC upon complexation, attributable to
the formation of a smaller 11-membered metallocycle in the
complex compared to the 12-membered parent enediyne 4. The
cycloaromatization of 4 to the diazacyclooctene 41 could be
followed by heating a degassed chlorobenzene solution of 4 in
the presence of a large excess of cyclohexa-1,4-diene (1,4-CHD)
to 240 ЊC for 24 h. The presence of an equivalent amount of
copper acetate enhanced the rate of disappearance of starting
enediyne 4 probably due to complexation.
For the tetraazaenediyne, in addition to the Cu()-complex,
the Ni()-complex was also prepared as a brown solid from
Ni() perchlorate and methanol. The 1H-NMR spectrum of the
Ni() complex taken in d6-DMSO showed three broad singlets
corresponding to the three sets of methylenes at δ 3.24
(NCH2CH2), 3.94 (NCH2CC) and 4.09 (CH2Ph); each meth-
ylene undergoing a downfield shift of ~ δ 0.4 upon complex-
ation. As expected, DSC measurements on the two complexes
showed considerable reduction in the activation barrier for BC,
exemplified by a lowering of onset temperature for the cycliz-
ation in both the cases (Fig. 2). Presumably, complexation with
Scheme 5 Reagents and conditions: a, MsCl, NEt3; b, K2CO3, DMF; c,
Pd(PPh3)4, n-BuNH2, 80 ЊC; d, Cu(OAc)2 or Ni(ClO4)2, MeOH, reflux.
at a temperature of 110 ЊC, a decrease of about 20 ЊC from the
parent enediyne 3, probably induced by a weakly complexing
Agϩ which lowers the transannular repulsion between the N-
lone pairs. The other bis(azaenediyne) 4 formed a brown solid,
possibly containing the complex 31, when a methanolic solution
of 4 and Cu(OAc)2 in a 2:1 molar ratio was refluxed for 10 h and
Scheme 6
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Fig. 3 Emission spectra of (A) cyclic azaenediyne 6, (B) its Ni()-
complex and (C) DMSO at excitation wavelength λ 360 nm. Slit widths
used are: excitation, 5 mm and emission, 3 mm.
Fig. 5 Excitation spectra of (A) enediyne 6 and (B) its Ni()-complex
at λems = 426 nm.
Fig. 4 Emission spectra of the Ni()-complex of 6 at λexc = 360 nm at
various concentrations. (A) The topmost spectrum is for 9.0
mM concentration with each successive spectrum representing two-fold
dilutions. The lowest spectrum is that of the solvent DMSO.
Fig. 6 Emission spectra of 6 in the presence of various metal ions at
identical concentration levels.
show any detectable fluorescence maximum at identical concen-
trations (Fig. 5). Again, a dose-dependent increase in intensity
of excitation maximum was observed for the Ni-complex
(Figure not shown). These fluorescence data clearly suggested
that the enediyne 6 does indeed form a complex with Ni2ϩ. In
fact, 6 is capable of forming complexes with various other tran-
sition and alkaline-earth metal ions. These metal ions showed a
major maximum peak at anywhere ranging from 418 to 435 nm
in their emission spectra with the excitation wavelength fixed at
360 nm (Fig. 6). This observation of a shift to higher or lower
wavelengths or an increase in fluorescence intensity in either
excitation or emission spectra, upon treatment with metal
ions,19 also suggests complex formation.
metal ions brings the reacting acetylenic carbon atoms closer,
thus making the BC more favourable. Heating a solution of 6
in chlorobenzene in the presence of 1,4-CHD led to disappear-
ance of the starting material leading to a complex mixture of
cyclization products. Again the disappearance of 6 was faster in
the presence of Cu2ϩ or Ni2ϩ ions.
Fluorescence studies
Fluorescence measurements18 also showed that the enediyne 6
was able to form complexes with divalent metal ions. Thus the
fluorescence spectra of the parent enediyne 6 in DMSO showed
extremely weak excitation and emission at λmax 360 and 426 nm
respectively (Fig. 3). However, the Ni()-complex of 6 displayed
a broad but intense maximum at λ 426 nm in the emission
spectrum when the excitation λ was fixed at 360 nm (Fig. 3) at a
concentration at which neither the starting enediyne nor pure
DMSO showed any detectable maxima. In this and in all the
other fluorescence studies, DMSO was selected as the solvent
because of its high polarity and low background fluorescence
intensity at the above mentioned λ for excitation and emission
spectra. Increasing the concentration of 6 by up to ten times
failed to show any detectable maxima in the emission spectrum
at a fixed excitation λ of 360 nm. Also the intensity of the
maximum of the Ni-complex of 6 was enhanced gradually as
the concentration of the complex was increased (Fig. 4). Thus,
there is a modest (more than two-fold) increase in intensity as
the concentration of the Ni-complex is raised from 0.45 to 9
mM. Moreover, the complex also exhibited a maximum at 360
nm in the excitation spectrum, when the λ for emission was kept
fixed at its maximum value of 426 nm. However the intensity of
this fluorescence was much less pronounced compared to the
emission spectrum. Here again the starting material 6 did not
Conclusion
We have successfully synthesized several novel and interesting
azaenediynes. The monocyclic enediyne 1 has the ability to
undergo spontaneous cyclization at room temperature, thus
making it a logical target for elaboration into a selective DNA-
cleaving agent. The effect of existing aromaticity is to slow
down the rate of BC, while complexation with metal ions tends
to accelerate the cyclization rate. The DNA-cleaving properties
of the bis(azaenediyne)s and bis(diazaenediyne)s, complexed to
various metal ions are now being studied in our laboratory.
Because of the ability of the azaenediyne 6 to bind alkaline-
earth as well as transition metal ions (many of which are known
to regulate the proteolytic activity of enzymes like proprotein
convertases (PC’s), subtilisin/kexin-like serine proteases,20 we
are currently conducting studies to examine the potential
enzyme inhibitory properties of these molecules. The develop-
ment of selective inhibitors of PC’s are of prime importance
in view of the clinical relevance of these proteases.21 Studies
pertaining to these results will be presented in the near future.
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Synthesis of 1-azido-6-chlorohex-5-en-3-yne (9)
Experimental
To a solution of the mesylate 8 (500 mg, 2.4 mmol) in dry DMF
(20 ml), NaN3 (625 mg, 4 equiv.) was added and stirred for 4 h
at room temperature. The mixture was then partitioned
between EtOAc and water (50 ml each). The organic layer was
thoroughly washed with water (3 × 50 ml), dried, filtered and
then evaporated. The title compound 9 was isolated by chrom-
atography (Si-gel, hexane–EtOAc 1:1) as a pale brown oil (220
mg, 80%); δH 2.37 (2H, dt, J = 2.0, 6.8 Hz), 3.14 (2H, t, J = 6.8
Hz), 5.54 (1H, dt, J = 2.1, 7.4 Hz), 5.89 (1H, dd, J = 1.8, 7.3
Hz), 6.36 (1H, d, J = 7.3 Hz); δC 20.54, 49.53, 94.34, 96.04,
111.76, 127.92; MS (EI) 157, 155 (Mϩ); HRMS: calcd for
C6H635ClN3 155.0250, found 155.0252.
General
All solvents were dried prior to use. Methylene chloride,
triethylamine and DMF were distilled from calcium hydride.
All reactions were carried out under nitrogen. IR spectra were
1
recorded on a Perkin-Elmer model 883 spectrometer. H- and
13C-NMR spectra were recorded in CDCl3 (unless mentioned
otherwise) on a Bruker AC 200 spectrometer. Melting points
were determined in open capillaries and are uncorrected.
Anhydrous Na2SO4 was used for drying organic extracts after
reaction workup. DSC measurements were done using a
NETZSCH 40 Thermal Analyzer Instrument.
Synthesis of 1-(4-methylphenylsulfonamido)-6-chlorohex-5-en-3-
yne (10)
Fluorescence studies
All fluorescence studies were conducted in 96-well plate format;
typical sample volume is 100 µl. DMSO was used as the solvent
and the fluorescence measurements were carried out using a
Perkin-Elmer MPF-3L spectrofluorimeter. The slit widths used
were 5 and 3 mm for the excitation and emission spectra
respectively. All experiments were performed in duplicate. For
all metal ion binding studies, a 4.2 mM stock solution of 6 in
DMSO was prepared and 95 µl of this solution was treated with
5 µl of the solution of the metal salt in a well plate. The solution
was shaken vigorously at ambient temperature for times
ranging from 6 h to overnight, depending upon the nature
of cation used. The following metal salts were employed for
the study: CoCl2, NiCl2ؒ6H2O, CaCl2, CuCl2, ZnSO4 and
Hg(OAc)2. A stock solution of 100 mM of each salt in an aque-
ous medium of pH 7.0 was used. Thus the final concentration
of 6 and each metal salt was kept very near to 5 mM. For
fluorescence measurements of 6 and its Ni-complex, a 100 µl
solution was used with the fluorescence parameters as described
earlier.
To a solution of the azide 9 (200 mg, 1.28 mmol) in THF (15
ml), PPh3 (370 mg, 1.4 mmol) and water (200 µl) were added
and stirred at room temperature for 20 h. It was then par-
titioned between EtOAc and water (50 ml each). The organic
layer was dried, filtered and evaporated. The oily residue was
dissolved in CH2Cl2 (15 ml) and toluene-p-sulfonyl chloride
(267 mg, 1.4 mmol) and DMAP (172 mg, 1.4 mmol) were
added. The mixture was stirred for 3 h. After partitioning
between CH2Cl2 and water (50 ml each), the organic layer was
dried (Na2SO4), filtered and evaporated. From the oily residue,
the title compound 10 was isolated in pure form by chrom-
atography (Si-gel, hexane–EtOAc 1:1) as a pale brown oil (200
mg, 55%); δH 2.38 (3H, s), 2.94 (2H, t, J = 6.6 Hz), 3.08 (2H, dd,
J = 6.6, 13.2 Hz), 5.46 (1H, br s), 5.74 (1H, dd, J = 2.0, 5.7 Hz),
6.27 (1H, d, J = 7.4 Hz), 7.25 (2H, d, J = 8.1 Hz), 7.72 (2H, d,
J = 8.1 Hz); δC 20.83, 21.38, 41.57, 76.70, 96.0, 111.89, 126.95,
127.74, 129.58, 137.03, 143.14; MS (EI) 285, 283 (Mϩ); HRMS:
calcd for C13H1435ClNO2S 283.0435, found 283.0436.
Synthesis of 1-tert-butyldimethylsilyloxy-9-(4-methylphenyl-
sulfonamido)non-4-ene-2,6-diyne (11)
Synthesis of (Z)-6-chlorohex-5-en-3-yn-1-ol (7)
To a dry degassed benzene (15 ml) solution of (z)-1,2-dichloro-
ethylene (305 µl, 4 mmol), Pd(PPh3)4 (185 mg, 0.16 mmol) and
n-butylamine (1.75 ml, 16 mmol) were added and stirred for
5 min under argon. CuI (152 mg, 0.8 mmol) was added and
stirred for 20 min followed by addition of but-3-yn-1-ol (330 µl,
4.4 mmol). Stirring was continued for 3 h at room temperature.
A mixture of EtOAc and saturated NH4Cl (15 ml each) was
added and stirred for a further 10 min. The organic layer was
washed with water (3 × 20 ml), dried and filtered. Evaporation
afforded an oil from which the title compound 7 was isolated
by column chromatography (Si-gel, hexane–EtOAc 1:1) as an
orange–yellow oil (418 mg, 80%); νmax (CHCl3) 3340, 1800,
1340, 1060, 850 cmϪ1; δH 2.15 (1H, br s), 2.67 (2H, dt, J = 1.8,
6.0 Hz), 3.79 (2H, t, J = 6.0 Hz), 5.88 (1H, dd, J = 1.8, 7.4 Hz),
6.35 (1H, d, J = 7.4 Hz); δC 23.8, 60.7, 76.2, 90.9, 112.0, 127.6;
MS (EI) 132, 130 (Mϩ); HRMS: calcd for C6H735ClO 130.0185,
found 130.0186.
To a degassed solution of the chlorosulfonamide 10 (200 mg,
0.71 mmol) in benzene (10 ml), Pd(PPh3)4 (33 mg, 0.0284 mmol)
and n-butylamine (310 µl, 2.84 mmol) were added and stirred
for 5 min. CuI (27 mg, 0.142 mmol) was added and stirred for
20 min after which tert-butyldimethylsilyl propargyl ether (140
mg, 0.82 mmol) dissolved in degassed benzene (1 ml) was added
and the reaction mixture was stirred at 40 ЊC for 3 h. EtOAc
(20 ml) and saturated. NH4Cl (10 ml) were added and stirred for
a further 10 min. The organic layer was washed with water,
dried and evaporated. The title compound 11 was isolated by
chromatography (Si-gel, hexane–EtOAc 4:1) and isolated as a
yellow oil (210 mg, 70%); δH 0.05 (6H, s), 0.83 (9H, s), 2.36 (3H,
s), 2.42 (2H, t, J = 6.6 Hz), 3.06 (2H, dd, J = 6.6, 13.6 Hz), 4.46
(2H, s), 5.05 (1H, t, J = 6.2 Hz), 5.68–5.87 (2H, m), 7.22 (2H, d,
J = 8.2 Hz), 7.69 (2H, d, J = 8.2 Hz); δC 5.08, 18.29, 21.05,
21.51, 25.86, 41.58, 52.22, 80.45, 82.21, 93.49, 95.63, 119.13,
119.20, 127.08, 129.60, 137.44, 143.10; MS (CI) 418 (MHϩ);
HRMS: calcd for C22H31NO3SSiϩHϩ 418.1872, found
418.1874.
Synthesis of 6-chlorohex-5-en-3-ynyl methanesulfonate (8)
To a solution of 7 (400 mg, 3.1 mmol) in CH2Cl2 (20 ml), meth-
anesulfonyl chloride (265 µl, 3.3 mmol) and triethylamine (470
µl, 3.37 mmol) were added at 0 ЊC. The mixture was stirred for
15 min at room temperature after which it was poured into
water and CH2Cl2 (50 ml each). The organic layer was washed
with water (2 × 50 ml), dried and then evaporated. Chrom-
atography of the residue over Si-gel, furnished the title com-
pound 8 as a pale brown oil (540 mg, 85%); δH 2.16 (1H, br s),
2.49 (3H, s), 2.69 (2H, dt, J = 1.8, 6.0 Hz), 4.82 (2H, t, J = 6.0
Hz), 5.89 (1H, dd, J = 1.8, 7.3 Hz), 6.36 (1H, d, J = 7.3 Hz); MS
(EI) 210, 208 (Mϩ); HRMS: calcd for C7H935ClO3S 207.9961,
found 207.9965.
Synthesis of 9-(4-methylphenylsulfonamido)non-4-ene-2,6-diyn-
1-ol (12)
Caesium fluoride (152 mg, 1 mmol) was added to a solution of
11 (250 mg, 0.92 mmol) in CH3CN (10 ml) and the mixture was
stirred for 4 h at room temperature. The mixture was filtered
through Si-gel and evaporated. The title compound 12 was
isolated in pure form by chromatography (Si-gel, hexane–
EtOAc 1:1) as a pale brown oil (160 mg, 90%); δH 2.41 (3H, s),
2.49 (2H, t, J = 6.6 Hz), 3.12 (2H, dd, J = 6.3, 12.2 Hz), 4.49
(2H, s), 5.80 (3H, m), 7.30 (2H, d, J = 8.2 Hz), 7.75 (2H, d,
J = 8.2 Hz); δC 20.96, 21.58, 41.43, 51.19, 80.88, 82.62, 93.93,
1960
J. Chem. Soc., Perkin Trans. 1, 2000, 1955–1964

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95.94, 119.51, 119.63, 127.18, 129.73, 137.21, 143.37; MS (EI)
303 (Mϩ); HRMS: calcd for C16H17NO3S 303.0930, found
303.0935.
Synthesis of 2-bromo-1-[4-azidobut-1-yn-1-yl)]benzene (16)
The title compound 16 was prepared following the same
procedure as described for 9. Isolated as a pale brown oil (78%);
δH 2.76 (2H, t, J = 6.9 Hz), 3.51 (2H, t, J = 6.9 Hz), 7.08–7.27
(2H, m), 7.43 (1H, d, J = 7.5 Hz), 7.55 (1H, d, J = 7.8 Hz); MS
(EI) 251, 249 (Mϩ); HRMS: calcd for C10H879BrN3 248.9902,
found 248.9905.
Synthesis of 1-Methylsulfonyloxy-9-(4-methylphenylsulfon-
amido)non-4-ene-2,6-diyne (13)
To a solution of 12 (150 mg, 0.5 mmol) in CH2Cl2 (10 ml),
methanesulfonyl chloride (43 µl, 0.55 mmol) and triethylamine
(76 µl, 0.55 mmol) were added and stirred at rt for 15 min. After
partitioning between water and CH2Cl2, the organic layer was
dried and evaporated. The title compound 13 was isolated by
chromatography (Si-gel, hexane–EtOAc 1:1) as an oil (160 mg,
85%); δH 2.44 (3H, s), 2.56 (2H, t, J = 6.2 Hz), 3.11–3.17 (5H, br
m), 5.08 (2H, s), 5.14 (1H, t, J = 8.4 Hz), 5.80–5.92 (2H, m),
7.30 (2H, d, J = 8.2 Hz), 7.76 (2H, d, J = 8.2 Hz); δC 21.27,
21.59, 38.92, 41.45, 58.19, 80.13, 82.62, 89.50, 95.44, 117.82,
122.27, 127.20, 129.75, 137.36, 143.33; MS (EI) 381 (Mϩ);
HRMS: calcd for C17H19NO5S2 381.0705, found 381.0709.
Synthesis of 2-bromo-1-[4-(4-methylphenylsulfonamido)but-1-
yn-1-yl]benzene (17)
The title compound was prepared from the azide 16 (120 mg,
0.48 mmol) via reduction with Ph3P (126 mg, 0.45 mmol) and
water (200 µl), followed by protection with toluene-p-sulfonyl
chloride and Et3N (each 1.2 equiv.); isolated as a pale brown oil
(90 mg, 52%); δH 2.42 (3H, s), 2.61 (2H, t, J = 6.4 Hz), 3.23 (2H,
dd, J = 6.4, 12.8 Hz), 5.25 (1H, t, J = 6.2 Hz), 7.09–7.23 (2H,
m), 7.28 (2H, d, J = 8.0 Hz), 7.38 (1H, dd, J = 1.4, 7.5 Hz), 7.55
(1H, dd, J = 1.4, 7.8 Hz), 7.79 (2H, d, J = 8.0 Hz); MS (EI) 379,
377 (Mϩ); HRMS: calcd for C17H1679BrNO2S 377.0086, found
377.0088.
Synthesis of 1-(4-Methylphenylsulfonyl)-1-azacyclodec-5-ene-
3,7-diyne (1)
Synthesis of 2-(3-hydroxyprop-1-yn-1-yl)-1-[4-(4-methylphenyl-
sulfonamido)but-1-yn-1-yl]benzene (18)
To a solution of the mesylate 13 (50 mg, 0.13 mmol) in DMF
(20 ml), K2CO3 (90 mg, 0.66 mmol) was added and stirred at rt
for 3 h. EtOAc was added and the organic layer was washed
with water (3 × 25 ml), dried and evaporated. Si-gel chrom-
atography (hexane–EtOAc 2:1) furnished the title compound 1
as an oil (30 mg, 85%); δH 2.45 (3H, s), 2.77 (2H, t, J = 5 Hz),
3.53 (2H, t, J = 5 Hz), 4.09 (2H, s), 5.84 (2H, br s), 7.30 (2H, d,
J = 8.1 Hz), 7.76 (2H, d, J = 8.1 Hz); δC 21.58, 22.45, 42.16,
51.15, 83.82, 89.53, 94.39, 96.54, 122.18, 124.48, 127.39, 129.75,
136.11, 143.46; MS (EI, CHCl3) 321 (MHClϩ), 287 (MH2ϩ), 286
(MHϩ), 285 (Mϩ), 155, 130 (Mϩ Ϫ CH3C6H4SO2), 104, 102;
HRMS: calcd for C16H15NO2S 285.0824, found 285.0828.
The bromotosylate 17 (80 mg, 0.22 mmol), dissolved in
degassed n-butylamine (8 ml), was treated with Pd(PPh3)4 (10
mg, 0.009 mmol) and propargyl alcohol (10 µl, 0.27 mmol). The
mixture was refluxed for 20 h after which it was partitioned
between EtOAc and 0.1 M HCl (30 ml each). The organic layer
was dried, filtered and evaporated. The title compound was
isolated by chromatography (Si-gel, hexane–EtOAc 1:1) as a
pale yellow oil (60 mg, 80%); δH 2.41 (3H, s), 2.59 (2H, t, J = 5.8
Hz), 3.21 (2H, t, J = 5.8 Hz), 4.56 (2H, s), 5.52 (1H, t, J = 1.5
Hz), 7.33–7.36 (2H, d, J = 8.3 Hz), 7.44–7.48 (2H, m), 7.80 (2H,
d, J = 8.3 Hz); MS (EI) 353 (Mϩ); HRMS: calcd for
C20H19NO3S 353.1086, found 353.1088.
Spectral data for 1,11-bis(4-methylphenylsulfonyl)-1,11-diaza-
cycloicosa-5,15-diene-3,7,13,17-tetrayne (11a)
Synthesis of 2-(1-methylsulfonyloxyprop-1-yn-1-yl)-1-[4-(4-
methylphenylsulfonamido)but-1-yn-1-yl]benzene (19)
The title compound was obtained when the previous reaction
was carried out at a concentration of 0.06 M. Isolated as a
pale brown oil (30%); δH 2.40 (3H, s), 2.67 (2H, dt, J = 2.0,
7.5 Hz), 3.27 (2H, t, J = 7.5 Hz), 4.40 (2H, s), 5.48 (2H, s), 5.70
(1H, d), 7.30 (2H, d, J = 8.2 Hz), 7.72 (2H, d); MS (EI) 570
(Mϩ); HRMS: calcd for C32H30N2O4S2 570.1648, found
570.1651.
The title compound was prepared from the alcohol 18 following
the same procedure as described for 7. Isolated as a brown oil
(85%); δH 2.40 (3H, s), 2.63 (2H, t, J = 5.9 Hz), 3.10 (3H, s), 3.17
(2H, t, J = 5.9 Hz), 5.17 (2H, s), 5.75 (1H, t, J = 1.5 Hz), 7.20–
7.40 (5H, m), 7.43–7.53 (1H, m), 7.78 (2H, d, J = 8.1 Hz); MS
(EI) 431 (Mϩ); HRMS: calcd for C21H21NO5S2 431.0861, found
431.0863.
Synthesis of 2-bromo-1-(4-hydroxybut-1-yn-1-yl)benzene (14)
Synthesis of 5-(4-methylphenylsulfonyl)-5-azabicyclo[8.4.0]-
tetradeca-1(10),11,13-triene-2,8-diyne (2)
1,2-Dibromobenzene (500 µl, 4.2 mmol), homopropargyl alco-
hol (350 µl, 4.62 mmol) and Pd(PPh3)4 (194 mg, 0.169 mmol)
were added to degassed n-butylamine (15 ml) and the solution
was refluxed for 10 h. It was then poured into EtOAc (50 ml)
and the organic layer was washed with 0.1 M HCl, then with
water (50 ml each) and dried. Evaporation in vacuo gave an oil
from which the title compound 15 was isolated by chroma-
tography (Si-gel, hexane–EtOAc 1:1) as a brown oil (850 mg,
90%); δH 2.90 (2H, t, J = 6.1 Hz), 4.01 (2H, t, J = 6.1 Hz), 7.26–
7.44 (2H, m), 7.60 (1H, dd, J = 1.8, 7.7 Hz), 7.73 (1H, dd,
J = 1.3, 7.9 Hz); MS (EI) 226, 224 (Mϩ); HRMS: calcd for
C10H979BrO 223.9837, found 223.9840.
The mesylate 19 (50 mg, 0.12 mmol), dissolved in dry DMF
(20 ml) was treated with K2CO3 (85 mg, 0.61 mmol) and the
mixture was stirred for 3 h at room temperature. It was then
partitioned between EtOAc and water (50 ml each). The
organic layer was further washed with water (3 × 50 ml), dried
and evaporated. From the residue the title compound was
isolated by chromatography (Si gel, hexane–EtOAc 4:1) as a
pale brown oil (30 mg, 80%); δH 2.40 (3H, s), 2.80 (2H, t, J = 5
Hz), 3.58 (2H, t, J = 5 Hz), 4.15 (2H, s), 7.24–7.29 (6H, m), 7.75
(2H, d, J = 8.3 Hz); MS (EI) 335 (Mϩ); HRMS: calcd for
C20H17NO2S 335.0981, found 335.0982.
Synthesis of 2-bromo-1-(4-methylsulfonyloxybut-1-yn-1-yl)-
benzene (15)
Synthesis of 5-chloropent-4-en-2-yn-1-ol (20)
Prepared from the corresponding alcohol 14 (200 mg, 0.89
mmol) following the procedure as described for the preparation
of 8. Isolated as a brown oil (230 mg, 85%); δH 2.95 (2H, t,
J = 6.8 Hz), 3.06 (3H, s), 4.42 (2H, t, J = 6.8 Hz), 7.14–7.28 (2H,
m), 7.43 (1H, dd, J = 1.9, 7.6 Hz), 7.56 (1H, dd, J = 1.4, 9.3 Hz);
MS (EI) 304, 302 (Mϩ); HRMS: calcd for C11H1179BrO3S
301.9612, found 301.9614.
The title compound 20 was prepared from (Z)-1,2-dichloro-
ethylene and propargyl alcohol via a Pd(0)-catalysed coupling
following the same procedure as described for the preparation
of 7. Isolated as a brown oil (yield 65%); δH 2.22 (1H, br s), 4.23
(2H, s), 5.89 (1H, dt, J = 2, 7.5 Hz), 6.37 (1H, d, J = 7.5 Hz);
MS (EI) 118, 116 (Mϩ); HRMS: calcd for C5H535ClO 116.0029,
found 116.0031.
J. Chem. Soc., Perkin Trans. 1, 2000, 1955–1964
1961

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Synthesis of 5-chloropent-4-en-2-ynyl methanesulfonate (21)
143.99; MS (EI) 542 (Mϩ); HRMS: calcd for C30H26N2O4S2
542.1335, found 542.1339.
Prepared from the corresponding alcohol 20 (232 mg, 2 mmol)
following the procedure as described for the preparation of 8.
Isolated as a brown oil (310 mg, 80%); δH 3.13 (3H, s), 5.01
(2H, d, J = 2 Hz), 5.91 (1H, dt, J = 1.8, 7.5 Hz), 6.49 (1H,
d, J = 7.5 Hz); MS (EI) 196, 194 (Mϩ); HRMS: calcd for
C6H735ClO3S 194.1234, found 194.1236.
Synthesis of 1,2-bis(3-hydroxyprop-1-yn-1-yl) benzene (27)
To a degassed solution of 1,2-dibromobenzene (500 µl, 4.2
mmol) and propargyl alcohol (513 µl, 8.83 mmol) in
n-butylamine (5 ml), Pd(PPh3)4 was added and refluxed for 20 h.
It was then partitioned between EtOAc and 0.1 M HCl (50 ml
each). The organic layer was dried and evaporated to leave a
residue from which 27 was isolated by chromatography (Si-gel,
hexane–EtOAc 1:2) as a brown oil (625 mg, 80%); νmax (CHCl3)
Synthesis of 5-chloro-1-azidopent-4-en-2-yne (22)
The title compound 22 was prepared from the mesylate 21 (194
mg, 1 mmol) following the same procedure as described for 9.
Isolated as a pale brown oil (127 mg, 90%); δH 4.10 (2H, s), 5.92
(1H, dt, J = 2, 7.5 Hz), 6.45 (1H, d, J = 7.5 Hz); MS (EI) 143,
141 (Mϩ): HRMS: calcd for C5H435ClN3 141.0094, found
141.0097.
3413, 3022, 2929, 2858, 1642, 1450, 1215, 1025, 910, 758 cmϪ1
;
δH 4.54 (4H, s), 7.24–7.29 (2H, m), 7.37–7.44 (2H, m); HRMS:
calcd for C12H10O2 186.0681, found 186.0683.
Synthesis of 1,2-bis-(1-methylsulfonyloxyprop-1-yn-1-yl)
benzene (28)
Synthesis of 5-chloro-1-(4-methylphenylsulfonamido)pent-4-en-
2-yne (23)
The title compound was prepared via mesylation following the
same procedure as described for 8 (yield 85%); νmax 3448, 2927,
2857, 2244, 1742, 1646, 1449, 1359, 1171, 999, 934, 803, 762
cmϪ1; δH 3.15 (6H, s), 5.13 (4H, s), 7.33–7.40 (2H, m), 7.44–7.51
(2H, m); MS (EI) 342 (Mϩ); HRMS: calcd for C14H14O6S2
342.0232, found 342.0234.
The title compound 22 was prepared from the corresponding
azide 22 via reduction with PPh3–H2O followed by protection as
the sulfonamide (55%); δH 2.42 (3H, s), 4.04 (2H, dd, J = 2, 6.1
Hz), 4.60 (1H, t, J = 5.6 Hz), 5.64 (1H, dt, J = 2, 7.4 Hz), 6.32
(1H, d, J = 7.4 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.78 (2H, d, J = 8.1
Hz); MS (EI) 271, 269 (Mϩ); HRMS: calcd for C12H1235ClNSO2
269.0277, found 269.0279.
Synthesis of 5,8-dibenzyl-5,8-diazabicyclo[10.4.0]hexadeca-
1(12),13,15-triene-2,10-diyne (4)
To a solution of the mesylate 28 (117 mg, 0.44 mmol) in DMF
(30 ml), N,NЈ-dibenzylethylenediamine 30 (104 µl, 0.44 mmol)
and K2CO3 (243 mg, 1.76 mmol) were added and stirred at
room temperature for 3 h. The solution was then partitioned
between EtOAc and water (50 ml each). The organic layer was
further washed with water (3 × 50 ml), dried and evaporated.
The residue, on chromatography (Si-gel, hexane–EtOAc 1:1)
furnished 4 as a white solid, crystallized from hexane–CH2Cl2 as
needles (125 mg, 72%); mp 123 ЊC, νmax 3445, 3030, 2916, 2846,
Synthesis of 1-tert-butyldimethylsilyloxy-8-(4-methylphenyl-
sulfonamido)oct-4-ene-2,6-diyne (24)
The title compound 23 was synthesized from the chloroenyne
23 via Pd(0)-mediated coupling as described for 11 (yellow oil,
72%); δH 0.13 (6H, s), 0.91 (9H, s), 2.42 (3H, s), 4.01 (2H, dd,
J = 2, 6 Hz), 4.48 (2H, d, J = 2 Hz), 4.49 (1H, t, J = 5.6 Hz), 5.54
(1H, d, J = 10.9 Hz), 5.78 (1H, d, J = 10.9 Hz), 7.30 (2H, d,
J = 8.1 Hz), 7.77 (2H, d, J = 8.1 Hz); MS (EI) 403 (Mϩ); calcd
for C21H29NO3SSi 403.1637, found 403.1639.
2360, 1704, 1479, 1440, 1372, 1332, 1131, 1072, 736, 696 cmϪ1
;
δH 3.04 (2H, s), 3.56 (2H, s), 3.68 (2H, s), 7.22–7.42 (14H, m); δC
43.22, 51.77, 60.66, 84.81, 89.95, 126.99, 127.10, 127.63, 128.24,
128.95, 130.45, 138.5; MS (CI) 391 (MHϩ), 300, 299, 152, 91;
HRMS calcd. for C28H26N2 ϩ Hϩ 391.2176, found 391.2180.
Synthesis of 1-hydroxy-8-(4-methylphenylsulfonamido)oct-4-
ene-2,6-diyne (25)
The title compound 25 was synthesized from the silyl protected
compound 24 by deprotection with CsF (nearly colourless
oil, 90%); δH 2.41 (3H, s), 3.39 (1H, t, J = 6.8 Hz), 3.96 (2H, s),
4.45 (2H, s), 5.62 (1H, d, J = 10 Hz), 5.72 (1H, d, J = 10 Hz),
7.28 (2H, d, J = 8.1 Hz), 7.78 (2H, d, J = 8.1 Hz); HRMS: calcd
for C15H15NO3S 289.0773, found 289.0775.
Synthesis of the copper(II) complex (31)
To a solution of 4 (80 mg, 0.2 mmol) in MeOH (4 ml), a meth-
anolic solution of Cu(OAc)2ؒ2H2O (20 mg, 0.1 mmol) was
added dropwise and then refluxed for 10 h. The Cu()-complex
31 was collected as a brown precipitate and dried under vacuum
(75 mg, 80%); νmax 3425, 3061, 2927, 1567, 1435, 1082, 1030,
746, 696 cmϪ1; MS (ES) 453 (Mϩ).
Synthesis of 1-methylsulfonyloxy-8-(4-methylphenylsulfon-
amido)oct-4-ene-2,6-diyne (26)
The title compound 26 was prepared from the alcohol following
the same procedure as described for 8; isolated as a pale brown
oil (81%); δH 2.41 (3H, s), 3.14 (3H, s), 3.99 (1H, dd, J = 1.3, 6.0
Hz), 5.12 (1H, t, J = 5.6 Hz), 5.76 (2H, m ), 7.29 (2H, d, J = 7.5
Hz), 7.78 (2H, d, J = 7.5 Hz); MS (EI) 367 (Mϩ); HRMS: calcd
for C16H17NO5S2 367.0548, found 367.0549.
Synthesis of bisazaenediyne (5)
To a solution of the mesylate 28 (100 mg, 0.37 mmol) in DMF
(5 ml), N,NЈ-bis(p-tolylsulfonyl)-1,3-phenylenediamine 32 (158
mg, 0.37 mmol) and K2CO3 (207 mg, 1.50 mmol) were added
and stirred at room temperature for 3 h. It was then partitioned
between EtOAc and water (50 ml each). The organic layer was
further washed with water (3 × 50 ml), dried and evaporated.
The residue, on chromatography (Si-gel, hexane–EtOAc 1:1)
furnished 5 as a white solid, crystallized from hexane–CH2Cl2
as needles (125 mg, 60%); mp 142 ЊC, νmax 3445, 3030, 2916,
2846, 2360, 1704, 1479, 1440, 1372, 1332, 1131, 1072, 736, 696
cmϪ1; δH 3.04 (2H, s), 3.56 (2H, s), 3.68 (2H, s), 7.22–7.42 (14H,
m); MS (EI) 566 (Mϩ); HRMS: calcd for C32H26N2O4S2
566.1335, found 566.1336.
Synthesis of 1,10-bis(4-methylphenylsulfonyl)-1,10-diaza-
cyclooctadeca-5,14-diene-3,7,12,16-tetrayne (3)
To a solution of 26 (50 mg, 0.14 mmol) in dry DMF (5 ml),
K2CO3 (95 mg, 0.68 mmol) was added and the mixture was
stirred for 3 h at room temperature. It was then partitioned
between EtOAc and water (50 ml each). The organic layer was
washed with water (3 × 50 ml), dried and evaporated. The resi-
due on chromatography (Si-gel, hexane–EtOAc 2:1) furnished
the title compound 3 as a viscous oil (35 mg, 90%); νmax (KBr)
3438, 2925, 1633, 1162, 670 cmϪ1; δH 2.41 (6H, s), 4.34 (8H, s),
5.58 (4H, s),7.29 (4H, d, J = 8.3 Hz), 7.69 (4H, d, J = 8.3 Hz);
δC 21.51, 36.85, 83.10, 88.93, 120.25, 127.94, 129.51, 135.10,
Synthesis of 2-bromo-1-(3-hydroxyprop-1-yn-1-yl) benzene (33)
The title compound was prepared from 1,2-dibromobenzene
(500 µl, 4.2 mmol), propargyl alcohol (270 µl, 4.62 mmol)
1962
J. Chem. Soc., Perkin Trans. 1, 2000, 1955–1964

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following the procedure as described for 14. Isolated as a light
brown oil (90%); νmax 3379, 3021 2929, 2860, 1676, 1470, 1435,
1343, 1216, 1151, 1027, 910, 851, 758, 651 cmϪ1; δH 4.53 (2H, s),
7.15–7.29 (2H, m), 7.46 (1H, dd, J = 7.5, 1.9 Hz), 7.57 (1H, dd,
J = 7.5, 1.9 Hz); MS (EI) 212, 210 (Mϩ); HRMS: calcd for
C9H779BrO 209.9680, found 209.9682.
Bergman cyclization of the enediynes
For enediyne 1. A solution of 1 (10 mg) in CDCl3 (0.5 ml)
was kept at a constant temperature of 23 ЊC with occasional
shaking. The 1H-NMR was checked at different points in time.
After 7 days, the solution was evaporated and the cyclized
product,
N-(4-methylphenylsulfonyl)-5,8-dideuterio-1,2,3,4-
tetrahydroisoquinoline 39a was isolated by chromatography
(6 mg); δH 2.40 (3H, s), 2.91 (2H, t), 3.33 (2H, t, J = 6.0 Hz),
4.22 (2H, s), 7.30 (2H, d, J = 8.0 Hz), 7.39 (1H, d, J = 8.0 Hz),
7.70 (2H, d, J = 8.0 Hz), 7.92 (1H, d, J = 8.0 Hz); MS (EI) 289
(Mϩ); HRMS: calcd for C16H15D2NO2S 289.1103, found
289.1105.
Synthesis of 2-bromo-1-(3-methylsulfonyloxyprop-1-yn-1-yl)
benzene (34)
The title compound was prepared from the corresponding
alcohol following the same procedure as described for 8.
Isolated as a pale brown oil (85%); νmax 3026, 2932, 2861, 2236,
1742, 1633, 1467, 1360, 1177, 1054, 990, 936, 805, 758, 655
cmϪ1; δH 3.19 (3H, s), 5.13 (2H, s), 7.35–7.18 (2H, m), 7.49 (1H,
dd, J = 2.0, 7.4 Hz), 7.60 (1H, dd, J = 1.9, 7.4 Hz); δC 38.5, 57.9,
85.7, 88.0, 122.85, 124.2, 128.1, 130.2, 132.0, 133.9; MS (EI)
290, 288 (Mϩ); HRMS: calcd for C10H979BrO3S 287.9455, found
287.9458.
For enediyne 2. A solution of 2 (20 mg) in CHCl3 (2 ml) was
refluxed under argon. Aliquots (200 µl) were taken at different
points in time and the extent of conversion was checked by
1H-NMR. When the reaction was almost complete (96 h), the
solution was cooled, evaporated and then chromatographed to
give the N-(4-methylphenylsulfonyl)-1,2,3,4-tetrahydrobenzo-
[g]isoquinoline 40a; δH 2.39 (3H, s), 3.11 (2H, t, J = 6.2 Hz), 3.49
(2H, t, J = 6.1 Hz), 4.43 (2H, s), 7.29 (2H, d, J = 8.0 Hz), 7.38
(2H, m), 7.51 (1H, br s), 7.54 (1H, br s), 7.70 (2H, m), 7.73 (2H,
d, J = 8.2 Hz); MS (EI) 337 (Mϩ); HRMS calcd for C20H19NO2S
337.1138, found 337.1142.
Synthesis of N,NЈ-dibenzyl-N,NЈ-bis[3-(2-bromophenyl)prop-2-
ynyl]ethylene diamine (35)
To a solution of 34 (333 mg, 0.735 mmol) in DMF, N,NЈ-dibenz-
ylethylenediamine (86 µl, 0.38 mmol) and K2CO3 were added
and stirred at room temperature for 3 h. It was then poured into
EtOAc (50 ml) and washed with water (3 × 50 ml). The organic
layer was dried and evaporated to leave a brown solid from
which the title compound 35 was isolated by chromatography
(Si-gel, hexane–EtOAc 10:1) as a brown solid (550 mg, 80%);
νmax (KBr) 3448, 3032, 2922, 2840, 1632, 1498, 1457, 1374,
1235, 1078, 938, 833, 746, 694 cmϪ1; δH 2.93 (4H, s), 3.67 (4H,
s), 3.80 (4H, s), 7.14–7.56 (18H, m); δC 42.4, 51.4, 58.3, 84.1,
89.7, 125.4, 126.8, 127.0, 128.2, 129.2, 132.2, 133.4, 138.6;
HRMS: calcd for C34H3079Br2N2 624.0777, found 624.0779.
For enediyne 4. A degassed solution of 4 (20 mg) and
cyclohexa-1,4-diene (10 equiv.) in chlorobenzene (2 ml) was
heated in a sealed tube in a sand bath kept at 240 ЊC for 24
hours. After cooling, the solution was evaporated in vacuo and
the residue, upon chromatography, furnished 5,8-dibenzyl-5,8-
diazatricyclo[10.4.0.03,10]hexadeca-1(12),2,10,13,15-pentaene
41 in 85% yield; δH 2.76 (2H, s), 3.65 (2H, s), 4.15 (2H, s), 7.28–
7.38 (10H, m), 7.45 (2H, dd, J = 3.2, 6.2 Hz), 7.57 (2H, m), 7.79
(2H, dd, J = 3.2, 6.2 Hz); MS (EI) 392 (Mϩ), 301, 155; HRMS:
calcd for C28H28N2 392.2255, found 392.2257.
Synthesis of bis(diazaenediyne) (6)
To a solution of 33 in degassed n-butylamine, N,NЈ-dibenzyl-
N,NЈ-di(prop-2-yn-1-yl)ethylenediamine (36) (34 mg, 0.17
mmol) and Pd(PPh3)4 (10 mg, 0.0085 mmol) were added and
refluxed for 24 h. The mixture was then poured into EtOAc (30
ml) and the organic layer was washed with 0.1 M HCl (50 ml),
then water (2 × 50 ml) and dried. Filtration followed by evap-
oration gave a residue from which the title compound 6 was
isolated by chromatography (Si-gel, hexane–EtOAc 10:1) as a
solid (40 mg, 50%); νmax (KBr) 3069, 3025, 2921, 2830, 1969,
1603, 1545, 1442, 1318, 1112, 1075, 983 cmϪ1; δH 2.87 (8H, s),
3.65 (8H, s), 3.74 (8H, s), 7.21–7.49 (28H, m); δH (d6-DMSO)
2.77 (8H, s), 3.59 (8H, s), 3.68 (8H, s), 7.21–7.54 (28H, m);
δC 42.5, 51.3, 58.3, 84.8, 88.3, 125.7, 127.1, 127.7, 128.2, 129.2,
132.3, 138.7; MS (EI) 780 (Mϩ); HRMS calcd. for C56H52N4
780.4196, found 780.4195.
Acknowledgements
A. B. thanks Council of Scientific and Industrial Research
(CSIR), Government of India, for partially financing this
project. We are grateful to Professor Craig A. Townsend, Johns
Hopkins University, Baltimore, USA, for providing spectral
and computer facilities and for helpful discussions. We also
thank Professor Michel Chretien for his interest in the work.
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J. Chem. Soc., Perkin Trans. 1, 2000, 1955–1964
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