Synthesis and characterization of novel acyclic enediynes

Article abstract of DOI:10.1080/00397911.2012.698355

A novel group of symmetrical and asymmetrical acyclic enediynes has been synthesized by using Sonogashira coupling conditions and characterized spectroscopically. Copyright

Full text of DOI:10.1080/00397911.2012.698355

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Synthesis and Characterization of Novel
Acyclic Enediynes
Mukesh C. Joshi a
a Department of Chemistry , University of Delhi , Delhi , India
Published online: 03 Jun 2013.
To cite this article: Mukesh C. Joshi (2013): Synthesis and Characterization of Novel Acyclic
Enediynes, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 43:16, 2246-2255
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Synthetic Communications1, 43: 2246–2255, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.698355
SYNTHESIS AND CHARACTERIZATION
OF NOVEL ACYCLIC ENEDIYNES
Mukesh C. Joshi
Department of Chemistry, University of Delhi, Delhi, India
GRAPHICAL ABSTRACT
Abstract A novel group of symmetrical and asymmetrical acyclic enediynes has been
synthesized by using Sonogashira coupling conditions and characterized spectroscopically.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Acyclic enediynes; Bergman cyclization; Sonogashira coupling
INTRODUCTION
Ever since the initial reports of enediyne anticancer antibiotics in the late 1980s,
researchers from a number of disciplines have been devoting increasing attention to
their chemistry, biology, and potential medical applications. Origins of enediynes
have come from various marine and terrestrial plant sources, and they are a potent
class of antitumor and antimicrobial agents and high cytotoxic activity. Natural pro-
duct enediynes (viz., calichemicin,[1] esperamicins,[2] dynemicin,[3] neocarzinostatin,[4]
kedarcidin,[5] uncialamycin,[6] etc.) are known for spectacular biological profiles and
proven clinical efficacy.[7,8] The antitumor activity of these compounds is due to the
presence of the highly unsaturated 1,5-diyne-3-ene unit, which undergoes Bergman
cyclization (BC) under physiological conditions to generate a benzene-1,4-diradical
intermediate. This radical intermediate abstracts hydrogen atom from the DNA
backbone and causes cell death.[9,10] To control BC, different approaches have been
explored and used.[11–14] Furthermore, recent studies revealed that even thermally
stable enediynes exert biological activities,[15] which indicates that enediynes can
Received July 6, 2011.
Address correspondence to Mukesh C. Joshi, Department of Chemistry, University of Delhi, Delhi
110007, India. E-mail: mukeshjoshi21@gmail.com
2246

NOVEL ACYCLIC ENEDIYNES
2247
have potential in the treatment of many infectious diseases apart from their role in
anticancer drug discovery.[16,17] Therefore, the aim is to synthesize enediynes and
evaluate their biological activities. To this end, we have already explored the syn-
thesis and biological activity of enediynes,[18,19] and this article deals with the synth-
eses and characterization of novel groups of O-, N-, and S-substituted symmetrical
and asymmetrical acyclic enediynes.
RESULTS AND DISCUSSION
Intermediate (7-bromohept-3-ene-1,5-diynyl)benzene (4) was synthesized using
two standard Sonogashira coupling reactions followed by bromination of
2-(7-phenylhept-4-ene-2,6-diynyloxy)tetrahydropyran 3[20] in the presence of PPh3=
Br2. Then intermediate 4 (1.0 equiv) reacted with various substituted phenol deriva-
tives (1.0 equiv), in the presence of K2CO3 (dry, 5.0 equiv) and dimethylformamide
(DMF) (dry) as a solvent, leading to the formation of asymmetrical acyclic enediynes
(5–11, Scheme 1).
At the same time intermediate 1,8-dibromo-oct-4-ene-2,6-diyne (13)[21] was
synthesized by using one standard Sonogashira coupling reaction followed by bro-
mination in the presence of PPh3=Br2. Intermediate 13 (1.0 equiv) reacted with vari-
ous substituted phenol, thiophenol, and aromatic amines (2.1 equiv) in the presence
of K2CO3 (dry, 10.0 equiv) and DMF (dry) as a solvent, leading to the formation of
symmetrical acyclic enediynes (14–18, Scheme 2). Oxidation of 1,10-[(4Z)-oct-
4-ene-2,6-diyne-1,8-diylbis(thio)]dibenzene (18, 1.0 equiv) in the presence of KMnO4
(4.0 equiv), 2 mL of H2O2 (30%), and glacial acetic acid as a solvent led to the for-
mation of 1,10-[(4Z)-oct-4-ene-2,6-diyne-1,8-diyldisulfonyl]dibenzene (19, Scheme 4).
The overall yields of all the enediynes are very good to excellent.
These all enediynes were characterized spectroscopically. Asymmetrical acyclic
enediyne 1-nitro-4-(7-phenylhept-4-ene-2,6-diynyloxy) benzene (5) shows six signals
1
in the H NMR spectrum. The peak appears at d 5.01 as a singlet and was assigned
to two -OCH2 proton, whereas the peaks at d 5.86 (J ¼ 10.8 Hz) and d 6.09
(J ¼ 10.8 Hz) as doublets were assigned to two vinylic protons. The aromatic peak
Scheme 1. Synthesis of asymmetrical enediynes.

2248
M. C. JOSHI
Scheme 2. Synthesis of symmetrical enediynes.
downfield at d 7.29–7.33 as a multiplet was assigned to acetylenic linked aryl five
protons, whereas peaks at d 7.05 (J ¼ 9.0 Hz) and d 8.08 (J ¼ 9.0 Hz) as doublets were
assigned to two set of protons (2H each) attached to the nitrobenzene ring. The 13C
NMR spectrum of enediynes 5 showed 15 signals in the spectrum. Asymmetry in the
enediyne can be easily seen for all the four acetylenic carbon atoms separately, at d
85.72, 86.40, 90.03, and 97.78, whereas peak at d 57.16 was assigned to the OCH2
carbon. The peaks at d 128.41, 128.99 were assigned to two asymmetric alkene car-
bon atoms. All the aromatic carbons at d 115.00, 117.85, 121.57, 122.57, and 131.65,
whereas the peaks appeared at d 125.83, 142.20, and 162.55 were assigned to three
quaternary carbon atoms. On the other hand symmetrical acyclic enediyne 1,10-
[(4Z)-oct-4-ene-2,6-diyne-1,8-diylbis(oxy)]bis(4-nitrobenzene) (16) shows only four
signals in the 1H NMR spectrum. The peak at d 4.98 as a singlet was assigned to four
protons of -OCH2, whereas peak the at d 5.90 as a singlet was assigned to two sym-
metrical alkene protons. The two sets of aromatic protons (4H each) appeared at d
7.07 and 8.23 as a doublet each. The 13C NMR spectrum of enediyne 16 showed
eight signals in the spectrum. The peaks at d 84.88 and 90.25 were assigned to the
two set of acetylenic carbon atoms, while peak appear at d 56.88 was assigned for
two symmetrical -OCH2 carbon atoms. The peak at d 125.77 was assigned to two
symmetric alkene carbon atoms. The peaks at d 114.98, 119.91 were assigned to
two sets of phenyl carbon atoms, whereas the peaks at d 142.07 and 162.34 were
assigned to two sets of quaternary carbon atoms.
EXPERIMENTAL
All of the chemicals used in the synthesis were purchased from Sigma-Aldrich
and were used as such. Thin-layer chromatography (TLC) was used to monitor
the progress of the reactions. All of the compounds were purified over a silica-gel
column (60–120 mesh). Solvents were distilled prior to use. Melting points (mp) were

NOVEL ACYCLIC ENEDIYNES
2249
determined on a Glassco melting-point apparatus (Cat. No. 514.303.01). Infrared
Infrared (IR) (KBr) spectra were recorded using a Perkin-Elmer Fourier transform
(FT)–IR spectrophotometer and the values are expressed as nmax cmꢀ1. Mass spec-
tral data were recorded on a Jeol (Japan) JMS-DX303 and micromass LCT, mass
1
spectrometer=data system. The H NMR and 13C NMR spectra were recorded on
a Bruker Spectrospin spectrometer at 300 and 75.5 MHz, tetramethylsilane respect-
ively using (TMS) as an internal standard. The chemical shift values are recorded on
d (ppm) scale and the coupling constants (J) are in hertz (Hz). Elemental analysis for
all compounds were performed on a Carlo Erba model EA-1108 elemental analyzer
and data of C, H, and N are within ꢁ0.4% of calculated values. Differential scanning
calorimetry (DSC) traces were recorded on a Pyris 6 differential ꢀsc1anning calorimeter
of Perkin-Elmer as a peak value at a heating rate of 10 ꢂC min
.
General Procedure for the Synthesis of Compounds 2 and 12
2-Prop-2-ynyloxy-tetrahydro-pyran (1.0 equiv) was added dropwise to a stirred
solution of Pd(PPh3)4 (0.04 equiv), CuI (0.02 equiv), and n-butylamine (5.0 equiv) in
benzene at 40 ꢂC. Then, cis-dichloroethylene (1, 1.0=0.5 equiv) was added to the reac-
tion mixture after 15 min, and the reaction mixture continued to stir for 13 h at the
same temperature. The progress of the reaction was monitored by TLC. The excess
solvent was evaporated under vacuo. Residue was purified over SiO2 column using
ethyl acetate=hexane as an eluent.
2-(5-Chloro-pent-4-en-2-ynyloxy)-tetrahydro-pyran (2).[22] Yellow liquid;
1
yield 60%; IR (KBr, cmꢀ1): 2933, 2852, 2207, 1428, 1341, 1195, 1062, 1019. H
NMR (300 MHz, CDCl3) d 6.34 (d, J ¼ 10.3 Hz, 1H), 5.85 (d, J ¼ 10.3 Hz, 1H),
4.81–4.78 (t, J ¼ 3.4 Hz, 1H), 4.37 (s, 2H), 3.80–3.74 (m, 1H), 3.48–3.44 (m, 1H),
1.70–1.35 (m, 6H); MS m=z (%) 202 (M þ 2, 31), 200 (Mþ, 99), 117 (48), 115 (13).
1,8-Bis-(tetrahydropyran-2-yloxy)-oct-4-ene-2,6-diyne
(12).[21] Yellow
liquid; yield 62%; DSC 151.57 ꢂC; (peak value); IR (KBr, cmꢀ1): 2942, 2870, 2210,
1
1440, 1389, 1344, 1201, 1119, 1078, 1023. H NMR (300 MHz, CDCl3) d 5.85 (s,
2H), 4.88–4.86 (t, J ¼ 3.4 Hz, 2H), 4.45 (s, 4H), 3.88–3.81 (m, 2H), 3.56–3.52 (m,
13
=
2H) 1.85–1.42 (m, 12H); C NMR (75.5 MHz, CDCl3) d 119.00 (C C), 96.30
(CꢃC), 92.60 (CꢃC), 82.60 (OꢀCꢀO), 61.60 (OꢀCH2), 54.30 (OꢀCH2), 30.00
(ꢀCH2), 25.10 (ꢀCH2), 18.60 (ꢀCH2); MS m=z (%) 304 (Mþ, 100), 136 (56), 104 (32).
Synthesis of 2-(7-Phenyl-hept-4-ene-2,6-diynyloxy)-tetrahydro-
pyran (3)[20]
Phenylacetylene (1.1 equiv) was added dropwise to a stirred solution of
Pd(PPh3)4 (0.05 equiv), CuI (0.02 equiv), and n-butylamine (5.0 equiv) in benzene
(40 mL) at 40 ꢂC. Then 2-(5-chloro-pent-4-en-2-ynyloxy)-tetrahydro-pyran (2, 1.0
equiv) was added to the reaction mixture after 15 min, and the reaction mixture
was stirred for 13 h at the same temperature. The progress of the reaction was mon-
itored by TLC. The excess solvent was evaporated in vacuo. Residue was purified
over an SiO2 column using ethyl acetate=hexane as an eluent. Yellow oil; yield

2250
M. C. JOSHI
70%; DSC: 158.56 ꢂC (peak value); IR (KBr, cmꢀ1): 3054, 2943, 2852, 2190, 1598,
1489, 1441, 1344, 1201, 1116, 1054, 1023.1H NMR (CDCl3, 200 MHz) d 7.50–7.46
(m, 2H), 7.33–7.30 (m, 3H), 6.06 (d, 1H, J ¼ 10.8 Hz), 5.91 (d, 1H, J ¼ 10.8 Hz),
4.92–4.90 (t, J ¼ 3.3 Hz, 1H), 4.50 (s, 2H), 3.87–3.80 (m, 1H), 3.54–3.50 (m, 1H),
1.73–1.47 (m, 6H); 13C NMR (CDCl3, 75.5 MHz) d 131.72 (Cquart), 128.51 (C C),
=
=
128.23 (C C), 122.90 (CAr), 119.82 (CAr), 118.94 (CAr), 96.67 (CꢃC), 94.67
(CꢃC), 93.39 (CꢃC), 86.81 (CꢃC), 83.33 (OꢀCꢀO), 54.70 (ꢀCH2O), 30.63
(ꢀOCH2), 30.29 (ꢀCH2), 25.40 (ꢀCH2), 25.33(ꢀCH2); MS m=z (%) 266 (Mþ,
99), 190 (22), 182 (29), 166 (54), 106 (21).
Synthesis of (7-Bromohept-3-ene-1,5-diynyl)benzene (4)
PPh3 (1.6 equiv) was added to a mixture of 2-(7-phenylhept-4-ene-2,6-
diynyloxy)tetrahydropyran (3) in dichloromethane (40 mL) and stirred for 10 min.
Then the reaction mixture was cooled to 10 ꢂC, followed by the slow addition of bro-
mine (1.6 equiv) for 20 min. Then the reaction was allowed to stir at 10 ꢂC for 4 h.
The progress of the reaction was monitored by TLC. After completion of the reac-
tion, excess solvent was removed under high vacuum. Then the crude mixture was
washed several times with cold hexane. The solvent was removed again under high
vacuum. Then the crude mixture was purified using SiO2 column chromatography
with 5% ethyl acetate=hexane as an eluent. Yellow liquid; yield 98%; IR (KBr,
cmꢀ1): 2952, 2878, 2209; 1H NMR (300 MHz, CDCl3) d 7.52–7.49 (m, 2H),
7.34–7.32 (m, 3H), 6.10 (d, J ¼ 10.8 Hz, 1H), 5.91 (d, J ¼ 10.8 Hz, 1H), 4.16 (s, 2H);
MS m=z (%) 246, 244 (Mþ, 70, 100), 166 (45).
General Procedure for the Syntheses of Asymmetrical Acyclic
Enediynes (5–11)
A solution of (7-bromohept-3-ene-1,5-diynyl)benzene (4) (1.0 equiv) in 5 mL
DMF to a stirred solution of substituted phenols (1.0 equiv), K2CO3 (5.0 equiv)
in dry DMF (20 mL), was added dropwise. The reaction mixture was stirred at ambi-
ent temperature for 13 h under a nitrogen atmosphere. The reaction mixture was
extracted with CHCl3 (6 ꢄ 25 mL), and the combined organic layer was washed with
water (6 ꢄ 250 mL). The organic layer was dried over anhydrous Na2SO4, and the
solvent was removed under high vacuum. The crude product was purified over
SiO2 column using ethyl acetate=hexane as an eluent.
1-Nitro-4-(7-phenylhept-4-ene-2,6-diynyloxy)benzene (5). Yellow solid
powder; yield 90%; mp 74–78 ꢂC; DSC 134.39 ꢂC (peak value); IR (KBr, cmꢀ1):
3081, 2924, 2190, 1592, 1513, 1494, 1342, 1262, 1228, 1111, 1005; 1H NMR
(300 MHz, CDCl3) d 8.11 (d, J ¼ 8.9 Hz, 2H), 7.32–7.26 (m, 5H), 7.08 (d, J ¼ 8.9 Hz,
2H), 6.13 (d, J ¼ 10.8 Hz, 1H), 5.89 (d, J ¼ 10.8 Hz, 1H), 5.01 (s, 2H); 13C NMR
=
(75.5 MHz, CDCl3) d 162.55 (Cquart), 142.00 (Cquart), 131.65 (CAr), 128.99 (C C),
=
128.41 (C C), 125.83 (CAr), 122.57 (CAr), 121.57 (CAr), 117.85 (CAr), 115.00 (Cquart),
97.78 (CꢃC), 90.03 (CꢃC), 86.40 (CꢃC), 85.72 (CꢃC), 57.16 (ꢀCH2); MS m=z (%)
303 (Mþ, 100), 258 (32), 182 (27), 166 (35). Anal. calcd. for C19H13NO3: C, 75.24; H,
4.32; N, 4.62; O, 15.82. Found: C, 75.29; H, 4.34; N, 4.58.

NOVEL ACYCLIC ENEDIYNES
2251
4-(7-Phenylhept-4-ene-2,6-diynyloxy)benzaldehyde (6). Yellow liquid;
yield 77%; DSC 138.52 ꢂC (peak value); IR (KBr, cmꢀ1): 3052, 2922, 2851, 2194,
1
1693, 1599, 1507, 1222, 1161, 1007; H NMR (300 MHz, CDCl3) d 9.81 (s, 1H),
7.77 (d, J ¼ 8.5 Hz, 2H), 7.35–7.26 (m, 5H), 7.13 (d, J ¼ 8.5 Hz, 2H), 6.12
(d, J ¼ 10.8 Hz, 1H), 5.90 (d, J ¼ 10.8 Hz, 1H), 5.01 (s, 2H); 13C NMR (400 MHz,
CDCl3) d 190.73 (CHO), 162.49 (Cquart), 131.82 (CAr), 131.64 (CAr), 130.30 (Cquart),
=
=
128.76 (C C), 128.29 (C C), 122.00 (Cquart), 121.14 (CAr), 117.92 (CAr), 115.10
(CAr), 97.56 (CꢃC), 90.50 (CꢃC), 86.41 (CꢃC), 85.23 (CꢃC), 56.69 (ꢀCH2); MS
m=z (%) 286 (Mþ, 100), 258 (54), 182 (21), 166 (28). Anal. calcd. for C20H14O2: C,
83.90; H, 4.93; O, 11.18. Found: C, 83.87; H, 4.99.
1-Chloro-4-(7-phenylhept-4-ene-2,6-diynyloxy)benzene (7). Yellow liquid;
yield 85%; IR (KBr, cmꢀ1): 3055, 2919, 2865, 2191, 1596, 1489, 1288, 1220, 1171,
1
1093, 1008; H NMR (300 MHz, CDCl3) d 7.38–7.30 (m, 5H), 7.19 (d, J ¼ 9.0 Hz,
2H), 6.95 (d, J ¼ 9.0 Hz, 2H), 6.09 (d, J ¼ 10.8 Hz, 1H), 5.89 (d, J ¼ 10.8 Hz, 1H),
4.89 (s, 2H); 13C NMR (400 MHz, CDCl3) d 156.14 (Cquart), 131.63 (CAr), 129.20
=
=
(C C), 128.67 (CAr), 128.24 (C C), 126.13 (Cquart), 122.54 (Cquart), 120.71 (CAr),
118.08 (CAr), 116.08 (CAr), 97.45 (CꢃC), 91.33 (CꢃC), 86.52 (CꢃC), 84.73 (CꢃC),
56.67 (ꢀCH2); MS m=z (%) 295, 292 (Mþ, 88, 100), 258 (41), 182 (30), 166 (44).
Anal. calcd. for C19H13ClO: C, 77.95; H, 4.48; Cl, 12.11; O, 5.47. Found: C,
77.99; H, 4.45.
1-Bromo-4-(7-phenylhept-4-ene-2,6-diynyloxy)benzene
(8). Yellow
liquid; yield 85%; IR (KBr, cmꢀ1): 3055, 2921, 2851, 2190, 1579, 1487, 1287, 1221,
1173, 1072, 1014; 1H NMR (300 MHz, CDCl3) d 7.35–7.25 (m, 7H), 6.91 (m,
J ¼ 8.6 Hz, 2H), 6.10 (d, J ¼ 10.8 Hz, 1H), 5.89 (d, J ¼ 10.8 Hz, 1H), 4.89 (s, 2H);
13C NMR (400 MHz, CDCl3) d 156.79 (Cquart), 132.41 (Cquart), 132.27 (CAr
)
=
=
131.75 (CAr), 128.77 (C C), 128.36 (C C), 122.68 (Cquart), 120.89 (CAr), 118.15
(CAr), 116.73 (CAr), 113.67 (CAr), 97.53 (CꢃC), 91.23 (CꢃC), 86.51 (CꢃC), 84.86
(CꢃC), 56.78 (ꢀCH2); MS m=z (%) 339, 337 (Mþ, 94, 100), 258 (32), 182 (18),
166 (38). Anal. Calcd. for C19H13BrO: C, 67.67; H, 3.89; Br, 23.70; O, 4.74. Found:
C, 67.63; H, 3.93.
2,4-Dichloro-1-(7-phenylhept-4-ene-2,6-diynyloxymethyl)benzene (9).
Dark brown liquid; yield 79%; IR (KBr, cmꢀ1): 3057, 2921, 2851, 2191, 1582,
1478, 1439, 1024; 1H NMR (300 MHz, CDCl3) d 7.60–7.16 (m, 8H), 6.11 (d,
J ¼ 10.8 Hz, 1H), 5.93 (d, J ¼ 10.8 Hz, 1H), 4.71 (s, 2H), 4.49 (s, 2H); 13C NMR
(400 MHz, CDCl3) d 151.28 (Cquart), 150.99 (Cquart), 131.63 (CAr), 128.60 (Cquart
)
=
=
128.26 (C C), 128.21 (C C), 126.93 (CAr), 122.68 (Cquart), 120.26 (CAr), 118.52
(CAr), 97.74 (CꢃC), 92.61 (CꢃC), 86.68 (CꢃC), 84.42 (CꢃC), 67.97 (ꢀCH2Ph),
58.60 (ꢀCH2); MS m=z (%) 344, 341 (Mþ, 96, 100), 306 (17), 272 (25), 182 (30),
166 (46). Anal. calcd. for C20H14Cl2O: C, 70.40; H, 4.14; Cl, 20.78; O, 4.69. Found:
C, 70.43; H, 4.19.
f[(4Z)-7-Phenylhept-4-ene-2,6-diyne-1-yl]thiogbenzene
(10).[20] Dark
brown liquid; yield 75%; IR (KBr, cmꢀ1): 3057, 2921, 2851, 2191, 1582, 1478,
1
1439, 1024; H NMR (300 MHz, CDCl3) d 7.57–7.49 (m, 4H), 7.44–7.27 (m, 6H),
5.98 (d, J ¼ 10.8 Hz, 1H), 5.83 (d, J ¼ 10.8 Hz, 1H), 3.65 (s, 2H); 13C NMR
(400 MHz, CDCl3) d 141.21 (Cquart), 132.41 (CAr), 132.27 (CAr), 130.75 (CAr),

2252
M. C. JOSHI
=
=
128.77 (C C) 128.36 (C C), 122.68 (Cquart), 120.89 (CAr), 118.15 (CAr), 116.73
(CAr), 113.67 (CAr), 97.53 (CꢃC), 91.23 (CꢃC), 86.51 (CꢃC), 80.99 (CꢃC), 56.78
(ꢀCH2); MS m=z (%) 275 (Mþ, 100), 198 (52), 166 (31). Anal. calcd. for C19H14S:
C, 83.17; H, 5.14; S, 11.69. Found: C, 83.11; H, 5.18.
1-Methyl-4-(7-phenylhept-4-ene-2,6-diynylsulfanyl)benzene (11). Dark
brown liquid; yield 66%; IR (KBr, cmꢀ1): 3022, 2920, 2851, 2190, 1597, 1478,
1490, 1232, 1017; 1H NMR (300 MHz, CDCl3) d 7.45 (d, J ¼ 8.2 Hz, 2H),
7.40–7.23 (m, 5H), 7.06 (m, J ¼ 7.9 Hz, 2H), 6.03 (d, J ¼ 10.8 Hz, 1H), 5.87 (d,
J ¼ 10.8 Hz, 1H), 3.80 (s, 2H), 2.26 (s, 3H); 13C NMR (400 MHz, CDCl3) d 136.99
=
(Cquart), 131.67 (CAr), 131.26 (CAr), 130.83 (CAr), 129.57 (CAr), 128.41 (C C)
=
128.12 (C C), 122.12 (Cquart), 119.50 (CAr), 118.99 (CAr), 96.78 (CꢃC), 93.89
(CꢃC), 86.86 (CꢃC), 80.90 (CꢃC), 53.36 (ꢀCH2); MS m=z (%) 288 (Mþ, 99), 274
(59), 198 (52), 166 (31). Anal. calcd. for C20H16S: C, 83.29; H, 5.59; S, 11.12. Found:
C, 83.33; H, 5.64.
Synthesis of 1,8-Dibromooct-4-ene-2,6-diyne (13)[20]
PPh3 (1.6 equiv) was added to a stirred solution of 1,8-bis-(tetrahydropyran-
2-yloxy)-oct-4-ene-2,6-diyne (12, 1.0 equiv) in dichloromethane (40 mL) and stirred
for 10 min. Then the reaction mixture was cooled to 10 ꢂC, followed by the slow
addition of bromine (1.6 equiv) for 20 min. Then the reaction was allowed to stir
at 10 ꢂC for 4 h. The progress of the reaction was monitored by TLC. After com-
pletion of reaction, excess solvent was removed under high vacuum. Then the crude
mixture was washed several times with cold hexane. The solvent was removed again
under high vacuum. Then the crude mixture was purified over SiO2 column chroma-
tography using 5–10% ethyl acetate=hexane as an eluent. Light yellow liquid; yield
82%; IR (KBr, cmꢀ1): 3400, 3051, 2924, 2854, 2211, 2161, 2172, 1602, 1504, 1436,
1
1314, 1259, 1154, 1059. H NMR (300 MHz, CDCl3) d 5.91 (s, 2H), 4.14 (s, 4H);
MS m=z (%) 266 (M þ 4, 58), 264 (M þ 2, 94), 262 (Mþ, 37), 104 (29).
General Proceedure for the Synthesis of Symmetrical Acyclic
Enediynes (14–18)
A solution of 1,8-dibromooct-4-ene-1,6-diyne (13, 1.0 equiv) in 5 mL of DMF
was added to a stirred solution of substituted phenols (2.1 equiv) and K2CO3 (10.0
equiv) in dry DMF (25 mL), dropwise. The reaction mixture was stirred at ambient
temperature for 13 h under nitrogen atmosphere. The reaction mixture was extracted
with CHCl3 (6 ꢄ 25 mL), and the combined organic layer was washed with water
(6 ꢄ 250 mL). The organic layer was dried over anhydrous. Na2SO4, and the solvent
was removed under high vacuum. The crude product was purified over a silica-gel
column using 10% ethyl acetate=hexanes as an eluent.
(4Z)-N,N’-Diphenyloct-4-ene-2,6-diyne-1,8-diamine (14). Dark red crys-
tal; yield 85%; mp 128–135 ꢂC; DSC 155.31 ꢂC (peak value); IR (KBr, cmꢀ1):
1
3400, 3051, 2924, 2854, 2211, 1602, 1504, 1436, 1314, 1259, 1154, 1059; H NMR
(300 MHz, CDCl3) d 7.25–7.15 (m, 4H), 6.77–6.66 (m, 6H), 5.76 (s, 2H), 4.02 (s,
4H), 3.89 (brs, 2H); 13C NMR (400 MHz, CDCl3) d 146.81 (Cquart), 129.07 (CAr),

NOVEL ACYCLIC ENEDIYNES
2253
=
119.28 (CAr), 118.25 (C C) 114.89 (CAr), 113.34 (CAr), 94.23 (CꢃC), 80.05 (CꢃC),
53.38 (ꢀCH2); MS m=z (%) 286 (Mþ, 100), 134 (39), 104 (19). Anal. calcd. for
C20H18N2: C, 83.88; H, 6.34; N, 9.78. Found: C, 83.91; H, 6.30; N, 9.71.
(4Z)-N,N’-Tetraphenyloct-4-ene-2,6-diyne-1,8-diamine (15). Brown solid;
yield 90%; mp 158–163 ꢂC; IR (KBr, cmꢀ1): 2926, 2857, 2208, 1611, 1517, 1448,
1
1341, 1165, 1042; H NMR (300 MHz, CDCl3) d 7.23–7.10 (m, 12H), 6.99–6.94
(m, 8H), 5.96 (s, 2H), 4.30 (s, 4H); 13C NMR (400 MHz, CDCl3) d 146.98 (Cquart),
=
142.49 (Cquart), 129.17 (CAr), 123.57 (CAr), 119.28 (C C) 118.25 (CAr), 114.99
(CAr), 113.14 (CAr), 95.21 (CꢃC), 82.05 (CꢃC), 54.33 (ꢀCH2); MS m=z (%) 439
(Mþ, 100), 286 (35), 134 (39), 104 (19). Anal. calcd. for C32H26N2: C, 87.64; H,
5.98; N, 6.39. Found: C, 87.60; H, 5.92; N, 6.33.
1,1’-[(4Z)-Oct-4-ene-2,6-diyne-1,8-diylbis(oxy)]bis(4-nitrobenzene) (16).
White solid powder; yield 88%; mp 119–122 ꢂC; IR (KBr, cmꢀ1): 2923, 2123, 1589,
1
1493, 1339, 1109; H NMR (300 MHz, CDCl3) d 8.23 (m, J ¼ 10.8 Hz, 4H), 7.07
(m, J ¼ 10.8 Hz, 4H), 5.90 (s, 2H), 4.89 (s, 4H); 13C NMR (300 MHz, CDCl3) d
=
162.34 (Cquart), 142.07 (Cquart), 125.77 (CAr), 119.91 (C C), 114.98 (CAr), 90.25
(CꢃC), 84.88 (CꢃC), 56.88 (ꢀCH2); MS m=z (%) 378 (Mþ, 100), 288 (51), 136
(65), 104 (17). Anal. calcd. for C20H14N2O6: C, 63.49; H, 3.73; N, 7.40; O, 25.37.
Found: C, 63.44; H, 3.70; N, 7.44.
1,1’-[(4Z)-Oct-4-ene-2,6-diyne-1,8-diylbis(oxy-7)]bis(4-methyl-chromen-
2-one) (17). Brown solid powder; yield 78%; mp 140–145 ꢂC; IR (KBr, cmꢀ1): 2924,
1
2854, 2211, 1722, 1612, 1462, 1376, 1278, 1138, 1069, 1013; H NMR (300 MHz,
CDCl3) d 7.53 (d, J ¼ 8.6 Hz, 2H), 6.97–6.90 (m, 4H), 6.13 (s, J ¼ 1.0 Hz, 2H), 5.90
(s, 2H), 4.92 (s, 4H), 2.39 (d, J ¼ 1.0 Hz, 6H); 13C NMR (400 MHz, CDCl3) d
161.10 (Cquart), 160.51 (Cquart), 154.94 (Cquart), 152.49 (Cquart), 125.57 (CAr),
=
119.98 (C C), 114.99 (Cquart), 112.84 (CAr), 112.23 (CAr), 102.03 (CAr), 90.71
(CꢃC), 84.67 (CꢃC), 56.89 (ꢀCH2), 18.63 (ꢀCH3); MS m=z (%) 452 (Mþ, 100),
424 (13), 368 (11), 288 (47), 136 (27), 104 (52). Anal. calcd. for C28H20O6: C,
74.33; H, 4.46; O, 21.22. Found: C, 74.38; H, 4.53.
1,1’-[(4Z)-Oct-4-ene-2,6-diyne-1,8-diylbis(thio)]dibenzene (18). Yellow
liquid; yield 60%; DSC 169.78 ꢂC (peak value); IR (KBr, cmꢀ1): 3056, 2960, 2925,
1
2854, 2202, 1582, 1479, 1439, 1260, 1089, 1024; H NMR (400 MHz, CDCl3) d
7.40–7.36 (m, 3H), 7.24–7.14 (m, 7H), 5.75 (s, 2H), 3.73 (s, 4H); 13C NMR
=
(400 MHz, CDCl3) d 142.80 (Cquart), 129.07 (CAr), 120.29 (CAr), 118.23 (C C),
113.11 (CAr), 95.21 (CꢃC), 81.09 (CꢃC), 52.29 (ꢀCH2); MS m=z (%) 321 (Mþ,
100), 168 (56), 104 (18). Anal. calcd. for C20H16S2: C, 74.96; H, 5.03; S, 20.01.
Found: C, 75.00; H, 5.05.
Synthesis of 1,1’-[(4Z)-Oct-4-ene-2,6-diyne-1,8-diyldisulfonyl]
dibenzene (19)
KMnO4 (610 mg, 0.38 mmol) was added to a mixture of 1,10-[(4Z)-oct-
4-ene-2,6-diyne-1,8-diylbis(thio)]dibenzene (18) (310 mg, 0.09 mmol) in glacial acetic
acid (15 mL) and stirred at room temperature for 45 min. Excess of KMnO4 was
decomposed by addition of 2 mL of H2O2 (30%). The crude product was then

2254
M. C. JOSHI
extracted with CHCl3 (4 ꢄ 25 mL) and washed with H2O (5 ꢄ 30 mL), and then the
resulting solution was dried over anhydrous Na2SO4 and excess solvent was removed
under high vacuum. The crude product was then purified by SiO2 column chroma-
tography using 40% ethyl acetate=hexane as an eluent. Yellow liquid; yield 78%;
DSC 221.57 ꢂC (peak value); IR (KBr, cmꢀ1): 2956, 2872, 2211, 1732, 1455, 1442,
1251, 1122, 1077, 1027; 1H NMR (400 MHz, CDCl3) d 7.91–7.89 (m, 4H),
7.63–7.60 (m, 4H), 7.52–7.48 (m, 2H), 5.76 (s, 2H), 4.06 (s, 4H); 13C NMR
=
(400 MHz, CDCl3) d 148.67 (Cquart), 130.10 (CAr), 122.26 (CAr), 118.93 (C C),
114.71 (CAr), 98.67 (CꢃC), 84.73 (CꢃC), 60.20 (ꢀCH2); MS m=z (%) 384 (M,
100), 230 (12), 104 (22). Anal. calcd. for C20H16O4S2: C, 62.48; H, 4.19; O, 16.65;
S, 16.68. Found: C, 62.45; H, 4.22.
Further details are available online in the Supplemental Materials.
CONCLUSIONS
Thus, a novel group of symmetrical and asymmetrical acyclic enediynes has
been synthesized and characterized spectroscopically, using standard Sonogashira
coupling conditions.
ACKNOWLEDGMENTS
The author thanks Diwan S. Rawat for the valuable support during his labora-
tory work the Department of Science and Technology, New Delhi, India, for finan-
cial support, and the Department of Chemistry and University Science
Instrumentation Center, University of Delhi, for their kind organizational and
instrumentation support.
REFERENCES
1. Lee, M. D.; Dunne, T. S.; Chang, C. C.; Ellestad, G. A.; Siegel, M. M.; Morton, G. O.;
McGahren, W. J.; Border, D. B. Calichemicins, a novel family of antitumor antibiotics, 2:
Chemistry and structure of chelichemicin k. J. Am. Chem. Soc. 1987, 109, 3466–3468.
2. Golik, J.; Clardy, J.; Dubay, G.; Groenewold, G.; Kawaguchi, H.; Konishi, M.; Krishnan,
B.; Ohkuma, H.; Saitoh, K.; Doyle, T. W. Esperamicins, a novel class of potent antitmor
antibiotics, 2: Structure of esperamicin X. J. Am. Chem. Soc. 1987, 109, 3461–3462.
3. Konishi, M.; Ohkuma, H.; Tsuno, T.; van Duyne, G. D.; Clardy, J. Crystal and molecular
structure of dynemicin A: A novel 1,5-diyne-3-ene antitumor antibiotic. J. Am. Chem. Soc.
1990, 112, 3715–3716.
4. Ishida, N.; Miyazaki, K.; Kumagai, K.; Rikimaru, M. Neocarzinostatin, an antitumor
antibiotic of high molecular weight. J. Antibiot. 1965, 18, 68–76.
5. Lam, K. S.; Hesler, G. A.; Gustavson, D. R.; Crosswell, A. R.; Veitch, J. M.; Forenza, S.;
Tomita, K. Kedarcidin, a new chromoprotein antitumor antibiotic, I: Taxonomy of pro-
ducing organism, fermentation, and biological activity. J. Antibiot. 1991, 44, 472–478.
6. Davies, J. E.; Wang, H.; Taylor, T.; Warabi, K.; Huang, X.-H.; Andersen, R. J. Unciala-
micin, a new enediyne antitumor antibiotic. Org. Lett. 2005, 7, 5233–5236.
7. Smith, A. L.; Nicolaou, K. C. The enediyne antibiotics. J. Med. Chem. 1996, 39,
2103–217.

NOVEL ACYCLIC ENEDIYNES
2255
8. Xi, Z.; Goldberg, I. H. DNA damaging enediyne compounds. In Comprehensive Natural
Products Chemistry; D. S. Barton and K. Nakanishi (Eds.); Elsevier: New York, 1999;
pp. 553–592.
9. Bergman, R. G. Reactive 1,4-dehydroaromatics. Acc. Chem. Res. 1973, 6, 25–31.
10. Jones, R.; Bergman, R. G. p-Benzyne: Generation as an intermediate in a thermal isomer-
ization reaction and trapping evidence for the 1,4-benzenediyl structure. J. Am. Chem.
Soc. 1972, 94, 660–661.
11. Rawat, D. S.; Zaleski, J. M. Geometric and electronic control of thermal bergman cycliza-
tion. Synlett 2004, 3, 393–421.
12. Nicolaou, K. C.; Dai, W.-M. Chemistry and biology of the enediyne anticancer antibio-
tics. Angew. Chem., Int. Ed. Engl. 1991, 30, 1387–1416.
13. Konig, B.; Pitsch, W.; Thondorf, I. Synthesis, structure, and reactivity of enediyne macro-
cycles. J. Org. Chem. 1996, 61, 4258–4261.
14. Basak, A.; Shain, J. C.; Khamari, U. K.; Rudra, K. R.; Basak, A. Nitrogen substituted
cyclic enediynes: Synthesis, thermal reactivity, and complexation with metal ions. J. Chem.
Soc., Perkin Trans. 1 2000, 12, 1955–1964.
15. Lu, Y.-J.; Yang, S.-H.; Chien, C.-M.; Lin, Y.-H.; Hu, X.-W.; Wu, Z.-Z.; Wu, M.-J.; Lin,
S.-R. Induction of G2=M phase arrest and apoptosis by a novel enediyne derivative,
THDB, in chronic myeloid leukemia (HL-60) cells. Toxicol. in Vitro 2007, 21, 90–98.
16. Liu, X.; He, H.; Feng, Y.; Zhang, M.; Ren, K.; Shao, R. Difference of cell cycle arrests
induced by lidamycin in human breast cancer cells. Anti-Cancer Drugs 2006, 17, 173–179.
17. Lin, C.-F.; Hsieh, P.-C.; Lu, W.-D.; Chiu, H.-F.; Wu, M.-J. A series of enediynes as novel
inhibitors of topoisomerase I. Bioorg. Med. Chem. 2001, 9, 1707–1711.
18. Joshi, M. C.; Bisht, G. S.; Rawat, D. S. Syntheses and antibacterial activity of phendioxy
substituted cyclic enediynes. Bioorg. Med. Chem. Lett. 2007, 17, 3226–3230.
19. Sharma, M.; Joshi, M. C.; Kumar, V.; Malhotra, S. V.; Rawat, D. S. Synthesis and antic-
ancer activity of 13-membered cyclic enediynes. Archiv Pharma. Chem. Life Sci. 2011, 344,
564–571.
20. Wu, H.-J.; Lin, C.-F.; Lee, J.-L.; Lu, W.-D.; Lee, C.-Y.; Chen, C.-C.; Wu, M.-J. Sub-
stituent effects on the cyclization mode of 7-sulfonyl-3-hepten-1,5-diynes and 11-
sulfonylundeca-3,7-dien-1,5,9-triynes. Tetrahedron 2004, 60, 3927–3934.
21. Konig, B.; Pitsch, W.; Dix, I.; Jones, P. G. Synthesis of macrocyclic enediynes by twofold
C-alkylation. Syntheis 1996, 4, 446–448.
22. Erdelyi, M.; Gogoll, A. Rapid homogeneous-phase Sonogashira coupling reactions using
controlled microwave heating. J. Org. Chem. 2001, 66, 4165–4169.