Exploring the scope of Bergman Cyclization mediated cascade reaction of alkenyl enediynes: Synthesis of [5]helicene and amino acid appended [4]helicenes

Article abstract of DOI:10.1016/j.tet.2012.12.064

Bergman Cyclization mediated cascade radical process is employed for the synthesis of [5]helicenes as well as diastereoselective mixtures of chiral amino acid appended [4]helicenes. Maximum selectivity (2.5:1) was found in case of l-leucine attached cyclic enediyne. Mechanistic considerations for this tandem radical reaction revealed that the major pathway probably involved quenching of the biradical, formed after aryl radical addition to pendant aromatic ring, by the solvent followed by aromatization. Intramolecular H-abstraction by the sp²-hybridized radical in the central ring or a 1,5-H shift followed by self-quenching could be the other possible ways to lead to the helicenes.

Full text of DOI:10.1016/j.tet.2012.12.064

Tetrahedron 69 (2013) 2184e2192
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Exploring the scope of Bergman Cyclization mediated cascade
reaction of alkenyl enediynes: synthesis of [5]helicene and
amino acid appended [4]helicenes
*
Snigdha Roy, 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:
Received 11 October 2012
Received in revised form 21 December 2012
Accepted 26 December 2012
Available online 4 January 2013
Bergman Cyclization mediated cascade radical process is employed for the synthesis of [5]helicenes as
well as diastereoselective mixtures of chiral amino acid appended [4]helicenes. Maximum selectivity
(2.5:1) was found in case of L-leucine attached cyclic enediyne. Mechanistic considerations for this
tandem radical reaction revealed that the major pathway probably involved quenching of the biradical,
formed after aryl radical addition to pendant aromatic ring, by the solvent followed by aromatization.
Intramolecular H-abstraction by the sp2-hybridized radical in the central ring or a 1,5-H shift followed by
self-quenching could be the other possible ways to lead to the helicenes.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
H
H
Recently, we have reported1 a general method for the synthesis
of [4]helicenes via a novel cascade radical reaction initiated by
Bergman Cyclization2 starting from alkenyl aromatic enediynes
(Scheme 1). Helicenes have attracted lot of attention in materials
chemistry3 as well as catalysts for asymmetric synthesis.4 All these
applications originated from their helical chirality, which arises due
to the non-planarity of the aryl rings caused mainly by the steric
repulsion between protruding/proximal hydrogens in smaller hel-
icene and inner axial terminal carbon-carbon nonbonded in-
teractions in higher helicenes as shown (Fig. 1). The extent of non-
NNs
[4]Helicene
[6]Helicene
[7]Helicene
Fig. 1. Different helicenes.
planarity of the aryl groups will be more in higher helicenes as well
as for helicenes with bulky substituents replacing the concerned
hydrogen(s). Racemization barrier for [4]helicene is calculated5 to
be around 8 kcal/mol at 27 ꢀC whereas in case of the next higher
benzologue, i.e., [5]helicene, the barrier rises up to 23 kcal/mol.
Incorporation of a simple methyl group at the terminal position can
also enhance the barrier energy by about 8e14 kcal/mol.6 In this
paper we wish to report that the method of cascade radical reaction
can be extended for the synthesis of [5]helicenes as well as [4]
helicenes appended with chiral amino acid substituents at one of
the proximal positions (Fig. 2). The diastereoselctivity shown in the
latter case is also reported.
NNs
NNs
Alkenyl enediyne
[4]Helicene
2. Results and discussions
Scheme 1. Synthesis of [4]helicene.
For the synthesis of [5]helicene, 2-naphthaldehyde was taken as
the starting substrate. Halo-Wittig7 reaction followed by DIBAL
reduction produced the allyl alcohol 5 (Scheme 2). This was
mesylated, substituted with sodium azide and then reduced with
triphenylphosphine. Product 7, an unsaturated amine, was
* Corresponding author. Fax: þ91 3222 283300; e-mail address: absk@chem.
iitkgp.ernet.in (A. Basak).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.064

S. Roy, A. Basak / Tetrahedron 69 (2013) 2184e2192
2185
diastereoselectivity of the cascade reaction. All these five chiral
enediynes were characterized by NMR and mass spectral data.
With all the required cyclic enediynes in hand, the final tandem
cyclization was attempted. At first, compound 1 was subjected to
the cyclization condition as described for [4]helicene,1 which in-
volved heating at 90 ꢀC in dry DMSO (Scheme 4). The reaction was
found to be complete in 8 h. Column purification of the crude re-
action mixture gave a gummy liquid whose 1H and 2H NMR spectra
(Fig. 3) clearly proves the formation of [5]helicene, 21. In case of
chiral amino acid tagged cyclic enediyne, temperature had to be
raised to induce the cyclization. Thus, each of these chiral enediyne
was heated at 120 ꢀC in dry DMF for 7e9 h (Scheme 5). 1H NMR
spectrum of the crude reaction mixture indicated the formation of
R1
NR
Amino acyl [4]helicenes
NR
[5]Helicene
R = Tosyl, R1= N-Boc amino acyl
Fig. 2. [5]Helicene and chiral amino acid tagged [4]helicene.
CO2Et
CHO
a
b
OH
I
I
76%
80%
5
4
c
3
58%
NHTs
e
d
NH2
N3
I
72%
I
80%
I
8
7
6
60%
f
H
H
H
H
NHTs
g
NHTs
h, i
OTHP
38%
11
62%
NTs
OTHP
OH
9
10
1
Reagents and conditions: a) i) Ph3P+CH2CO2Et.Br-, I2, K2CO3, CH3OH, 0 °- 5 °C, 1.5 h, ii) 3, Tetrabutyl
ammonium bromide, K2CO3, 40 °C, 18 h; b) DIBAL-H, CH2Cl2, -78 °C, 3 h; c) i) MsCl, Et3N, CH2Cl2, 0
°C, 15 min, ii) NaN3, DMF, r.t., 2 h; d) PPh3, THF-H2O, r.t., 7 h; e) TsCl, Et3N, CH2Cl2, 0 °C, 1.5 h; f)
Pd(PPh3)4, CuI, 11, Et3N, THF, r.t., 10 h; g) Pyridinium p-toluene sulfonate, EtOH, r.t., 6 h; h) MsCl, Et3N,
CH2Cl2, 0 °C, 5 min; i) K2CO3, DMF, r.t., 4 h.
Scheme 2. Synthesis of cyclic enediyne 1.
protected as tosyl to form the sulfonamide 8. Final Sonogashira
coupling8 between this sulfonamide and the previously prepared9
enediyne 11 provided the intermediate 9, which on deprotection,
mesylation followed by intramolecular cyclization under high di-
lution10 produced the desired cyclic enediyne 1. NMR and mass
spectral analysis were in full agreement with its structure.
Fordiastereoselective synthesis of aminoacidappended chiral[4]
helicenes, 2,3-diiodotoluene (Scheme 3) was first subjected to ben-
zylic bromination with NBS and benzoyl peroxide in carbon tetra-
chloride. Reactionwith N-Boc protected amino acids with potassium
carbonate in dry acetone produced the N-Boc aminoacyl methyl 2,3-
diiodobenzene 14(aee). Sequential Sonogashira coupling with THP-
protected propargyl alcohol and then with TMS-acetylene followed
by silyl deprotection produced the terminal alkyne derivatives
17(aee). The latter on Sonogashira coupling with iodo alkene 20
(prepared from benzaldehyde following procedure similar to that of
8) followed by a sequence of steps (Supplementary data) finally
provided the cyclic enediynes appended with N-Boc protected chiral
amino acids 2(aee).11 Five different amino acids were incorporated
to see the effect of different amino acid side chains on the
two diastereomers in unequal proportions. Unfortunately, the di-
astereomers could not be separated by column chromatography.
The formation of helicenes was confirmed on the basis of NMR and
mass spectral analysis.
Based on the 1H NMR [Fig. 4(AeD)], the diastereomeric ratio for
each set of chiral amino acid attached [4]helicenes was calculated.
These are compiled in Table 1. For leucine attached diastereomers
22c and 23c, 1H NMR failed to resolve any signal. In this case, the
diastereomeric ratio was calculated from the corresponding HPLC
profile using CHIRALCEL OD-H column (250 mmꢁ4.6 mm) (Fig. 4E).
The fact that there was no equilibration between the diastereomers
via rotation around the chiral axis under ambient conditions was
confirmed by recording the VT-NMR on valine based [4]helicenes. It
clearly showed that the signals did not coalesce even after heating
up to 60 ꢀC thus pointing to a much slower equilibration as com-
pared to NMR time scale (Fig. 5).
From these results, it is quite evident that although the synthesis
of the aminoacyl helicenes was successful, the diastereoselectivityof
the reaction was rather poor in spite of the variation in steric bulk of
the amino acid side-chain. The maximum selectivity with the dr

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S. Roy, A. Basak / Tetrahedron 69 (2013) 2184e2192
R
R
Br
O
BocHN
O
BocHN
I
O
I
I
I
I
c
I
a
b
O
74%
80-85%
70-74%
OTHP
I
15(a-d)
13
12
14(a-d)
58-60%
O
R
R
O
d
R
H
O
HN
Boc O
BocHN
H
O
BocHN
TMS
O
O
e
NTs
68-70%
OTHP
OTHP
17(a-d)
16(a-d)
2(a-d)
H
O
H
O
H
O
Br
H
N
N
N
H
Boc
Boc
Boc
O
I
I
O
I
I
c, d and e
f
NTs
78%
25%
OTHP
13
14e
2e
17e
NHTs
a, R = CH3
R
H
b, R = CH(CH3)2
c, R = CH2CH(CH3)2
d, R = CH2Ph
OH
OH
BocHN
OTHP
19
N
I
O
Boc
O
18e
18(a-d)
20
Reagents and conditions: a) N-Bromosuccinimide, Benzoyl peroxide, CCl4, 80 °C, 4 h;b)
18(a/b/c/d), K2CO3, CH3COCH3, 70 °C, 0.5 h; c) Pd(PPh3)4, CuI, 19, Et3N, r.t., 0.5 h; d)Pd(PPh3)4,
CuI, TMS-acetylene, Et3N, r.t., 16 h; e) KF, CH3OH, r.t., 1 h; f) 18e, K2CO3,CH3COCH3,70 °C,0.5 h.
Scheme 3. Synthesis of aminoacyl enediynes 2(aee).
considerably labile hydrogen atom at the D/E ring junction proba-
bly in an intramolecular fashion (Step IIIb).15 This particular CeH
bond dissociation energy should be lower than that of the 1,4-CHD
or DMF. So, a direct aromatization of rings E and D may easily take
place along with quenching of B ring sp2 radical to lead to the final
product. An alternate way to view this process is to have a 1,5H-
shift (Step IIIc) followed by self-quenching. However, such 1,5 H-
shift is unlikely to be concerted due to geometric constraint.16 The
possibility of abstracting the benzylic hydrogen in case of amino
acid appended helicenes was ruled out by lack of deuterium in-
corporation at the benzylic carbon when the reaction was carried
out in a mixed solvent system of MeOH-d4 (20%) in dry DMF.
In conclusion, we have successfully demonstrated the versatility
of our previously reported ring annulations by tandem radical pro-
cess initiated by Bergman Cyclization in synthesizing [5]helicene as
well as various amino acid based diastereomeric [4]helicenes in
good yields. The diastereoselectivity, however, was far less than
satisfactory. Only leucine based helicenes were obtained as a mix-
ture diastereomers with moderate diastereoselectivity. Further
studies are currently in progress to improve the diastereoselectivity
by directly attaching the stereogenic centre to the ring A carbon.
H
Dry DMSO, 90 °C, 8 h
80%
NTs
NTs
21
1
(rac)-[5]helicene
Scheme 4. Synthesis of [5]helicene.
value of 2.5:1.0 was obtained in case of leucine attached cyclic
enediyne (22cþ23c). The reason for poor stereoselectivity may
possibly be due to the quite remote positioning of the stereogenic
centre.
The proposed mechanism of the cascade radical reaction leading
to the formation of [5]helicene and also the substituted [4]heli-
cenes is somewhat different from the earlier one.1,12 In these cases,
the radical formed via addition of the aryl radical to the naphtha-
lene or benzene moiety13,14 is not in a position to abstract H from
the benzene ring A because of either steric constraint or absence of
such hydrogen. Thus the biradical in either case is quenched by H-
abstraction from the solvent (Step IIIa) followed by aromatization
under the reaction condition to provide the final product
(Scheme 6). An alternative mechanism has also been shown where,
after the intramolecular radical addition in Step II, the sp2-carbon
based radical in the newly generated biradical, can abstract the
3. Experimental
3.1. General
All reactions were conducted with oven-dried glassware under
an atmosphere of argon (Ar) or nitrogen (N2). All common reagents

S. Roy, A. Basak / Tetrahedron 69 (2013) 2184e2192
2187
Fig. 3. 1H-1H COSY spectrum (400 MHz, CD3COCD3) of [5]helicene 21 (
d
9.2e4.5).
R
R
R
H
H
O
H
O
H
O
O
HN
Boc
dry DMF
S
HN
Boc
S
HN
Boc
S
O
O
NTs
NTs
NTs
+
120-125 °C,
7-9 h
22(a-d)
23(a-d)
2(a-d)
Combined Yield = 75-80% (M,S)
(P,S)
H
O
S
N
H
H
H
S
S
N
O
O
O
N
Boc
Boc
O
Boc
O
dry DMF
NTs
NTs
NTs
+
120-125 °C,
8 h
23e
22e
(P,S)
2e
Combined Yield = 76%
(M,S)
a: R = CH3, b: R = CH(CH3)2, c: R = CH2CH(CH3)2, d: R = CH2Ph
Scheme 5. Synthesis of diastereomeric mixture of chiral amino acid attached [4]helicenes.
were commercial grade reagents and used without further purifi-
cation. The solvents were dried by standard methods and purified
by distillation before use. All crude products were purified by silica
gel column chromatography (60e120 mesh) with petroleum ether/
ethyl acetate (PE/EA) as eluent and characterized by IR, NMR, and
mass spectrometry unless otherwise mentioned. 1H and 13C NMR
spectra of all compounds were recorded at 400 and 100 MHz, re-
spectively, using CDCl3 solvent unless otherwise noted. Infrared
(FTIR) spectra were recorded as thin films on potassium bromide
plates (solid sample), or in chloroform solvent (liquid sample) using
Perkin Elmer Spectrum Rx1 spectrometer and are expressed as
%-transmission (cmꢂ1). ESI-MS and HRMS were recorded using
a Waters LCT mass spectrometer.
3.2. General synthesis of
Halo-Wittig reaction
a,b-unsaturated ester (4, 20b) via
(Ethoxycarbonylmethyl)triphenylphosphonium bromide salt
(1.3 g, 3.0 mmol) was first dissolved in dry MeOH (50 mL) and
cooled to ꢂ5 ꢀC. Molecular iodine (1.5 g, 6.0 mmol) and freshly

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S. Roy, A. Basak / Tetrahedron 69 (2013) 2184e2192
Fig. 4. 1H NMR of pair of doublets for one of the CH2 protons of 22a and 23a (A), 22b and 23b (B), two singlets for tosyl methyl protons of 22d and 23d (C), 22e and 23e (D); HPLC
profile of 22c and 23c (E) (solvent system¼1% CH3CN in 99% MeOH, flow rate¼1 mL/min).
Table 1
Diastereomeric ratio for the amino acid based helicenes
Starting enediyne
Diastereomers
L-Amino acid used
Reaction time (h)
Combined yield (%)
Diastereomeric ratio (dr) from NMR
2a
2b
2c
2d
2e
22aþ23a
22bþ23b
22cþ23c
22dþ23d
22eþ23e
Alanine
Valine
Leucine
Phenyl alanine
Proline
7
75
80
77
78
76
1.3:1.0
1.2:1.0
2.5:1 (from HPLC)
1.4:1.0
1.6:1.0
7.5
8.5
8
9
activated K2CO3 (414 mg, 3.0 mmol) were successively added to it
and stirred for 1.5 h strictly maintaining the temperature between
ꢂ5 and 5 ꢀC. A brown colored suspension was obtained into
which aldehyde 3/20a (2.6 mmol), tetrabutyl ammonium bromide
(TBAB) (0.13 mmol,) and K2CO3 (0.42 mmol) were added con-
secutively. The reaction pot was removed from the low temper-
ature immersion bath (set at ꢂ5 ꢀC) and heated in an oil bath kept
at 40 ꢀC. After every 2 h of heating, K2CO3 (0.42 mmol) was added
for another two times and the heating was continued for next
10e16 h. On completion, MeOH was evaporated under vacuum
and the crude reaction mass was subjected to column
purification.
3.3. General synthesis a,b-unsaturated alcohol (5, 20c)
The unsaturated ester 4/20b (1.5 mmol) was dissolved in dry
DCM (25 mL) and cooled at ꢂ78 ꢀC. DIBAL (3 equiv) was added to
this solution drop wise and stirred for 3e4 h at the same
Fig. 5. VT-NMR (400 MHz, CDCl3) of diastereomeric mixture of L-valine amino acid attached [4]helicenes (22bþ23b).

S. Roy, A. Basak / Tetrahedron 69 (2013) 2184e2192
2189
Scheme 6. Mechanism of formation of helicenes.
temperature under nitrogen. The reaction was quenched with
a saturated Rochelle salt solution (15 mL) and diluted with DCM
(20 mL). Resultant thick reaction mixture was filtered through
a Celite bed to have a clear biphasic layer from which the organic
layer was separated, washed with water and brine solution, dried
over Na2SO4, and concentrated.
and 25 were subjected to the next reaction condition without fur-
ther column purification.
3.5. Synthesis of azide (6, 20e)
To a dry DMF (10e15 mL) solution of the mesylate 5a/20d
(0.32 mmol), NaN3 (1.5 or 3.0 equiv, depending on mono or di
substitution) was added and stirred for 6e8 h at room temperature.
Afterward, it was quenched with water and extracted with EtOAc
(3ꢁ10 mL). The combined organic layers were washed with water
and brine solution, dried over Na2SO4, and concentrated.
3.4. Mesylation of primary alcohol (5a, 10a, 20d, and 26)
Dry DCM (20 mL) solution of compound 5/10/20c/25
(0.30 mmol) was first cooled to 0 ꢀC. MsCl (1 equiv) and dry Et3N
(1.2 equiv) were added successively to the solution drop wise and
stirred for 5 min. Progress of the reaction was carefully monitored
by TLC and on completion, rapid quenching was done with addition
of water to avoid over mesylation. The organic layer was washed
with a dilute solution of NaHCO3 (10 mL) to remove excess MsCl.
Due to the stability problem, the crude mesylates of compounds 10
3.6. Synthesis of 2-iodo-3-naphthalen-2-yl-allylamine (7, 20f)
Azide derivative 6/20e (700 mg, 2.26 mmol) was dissolved in
THF (25 mL). PPh3 (1.18 gm, 4.51 mmol) and 3e4 drops of water
were added to the solution and stirred for 6 h at room temperature.

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S. Roy, A. Basak / Tetrahedron 69 (2013) 2184e2192
After THF evaporation, the crude reaction mass was subjected to
column purification (8% MeOH in DCM).
0.23 mmol) was added. After 10 min of stirring, CuI (145 mg,
0.76 mmol) and THP-protected propargyl alcohol (1 mL, 7.65 mmol)
were added successively with 5 min interval. The whole mixture
was stirred for 0.5 h at room temperature under nitrogen atmo-
sphere. On completion, a saturated NH4Cl solution (10 mL) was
poured into the reaction pot and extracted with EtOAc (3ꢁ10 mL).
The combined organic layers were washed with water and brine
solution, dried over Na2SO4, and concentrated.
3.7. Tosylation of primary amine (8, 20)
Primary amine (7/20f) (7.72 mmol) was first dissolved in dry
DCM (20 mL) at 0 ꢀC under nitrogen atmosphere and then TsCl
(1.0 equiv) and Et3N (1.2 equiv) were added successively at this
same temperature. The reaction mixture was stirred for next
1.5e2.0 h while the temperature increased up to room tempera-
ture. Progress of the reaction was monitored by TLC. On completion,
it was quenched with water and diluted with more DCM (10 mL).
The organic layer was separated, washed with water and brine
solution, dried over Na2SO4, and concentrated.
3.12. Sonogashira coupling with TMS-acetylene [16(aee)]
Same procedure as described for the synthesis of 15(aee). The
reaction mixture was stirred for a longer time of 16 h at room
temperature.
3.7.1. N-(2-Iodo-3-naphthalen-2-yl-allyl)-4-methyl-benzenesulfona-
mide (8). Light browncolored solid; Rf (PE/EA¼4:1) 0.50; yield: 72%;
mp: 90e92 ꢀC; dH (200 MHz): 7.84e7.75 (m, 7H), 7.53e7.46 (m, 2H),
7.29e7.25 (m, 2H), 7.00 (s, 1H), 5.30 (t, J¼6.4 Hz, 1H), 4.17 (dd, J¼6.5,
1.2 Hz, 2H), 2.37 (s, 3H); dC (50 MHz): 143.8,137.7,136.9,134.3,133.1,
129.9, 128.3, 127.9, 127.6, 126.7, 126.5, 126.2, 101.4, 56.6, 21.7.
3.13. Removal of TMS group [17(aee)]
To a dry MeOH (15 mL) solution of compound 16(aee) (600 mg,
1.44 mmol), KF (440 mg, 7.2 mmol) was added and stirred for 1 h at
room temperature under nitrogen atmosphere. On completion, the
solvent was evaporated under reduced pressure and subjected to
column purification.
3.7.2. N-(2-Iodo-3-phenyl-allyl)-4-methyl-benzenesulfonamide
(20). White solid; Rf (PE/EA¼5:1) 0.60; yield: 76%; mp: 55e56 ꢀC;
dH (200 MHz): 7.79 (d, J¼8.0 Hz, 2H), 7.33e7.28 (m, 6H), 6.85 (s, 1H),
5.29 (t, J¼6.5 Hz, 1H), 4.10 (dd, J¼6.0, 1.2 Hz, 2H), 2.38 (s, 3H); dC
(50 MHz): 143.8, 137.6, 136.9, 129.9, 128.6, 128.5, 128.2, 127.5, 101.1,
56.5, 21.7.
3.14. Deprotection of THP group [10, 25(aee)]
The THP-protected alcohol [9/24(aee)] (0.37 mmol) was dis-
solved in commercial grade EtOH (10e20 mL) and PPTS (0.1 equiv)
was added. Resulting reaction mixture was stirred for 6 h at room
temperature. The solvent was removed under vacuum and the
crude reaction mass was subjected to column purification without
any further washing.
3.8. Sonogashira coupling of iodo alkene with terminal
alkyne (9, 24)
Iodo alkene 8/20 (0.9 mmol) was dissolved in dry THF (15 mL)
followed by the addition of dry Et3N (10 mL). After degasification of
the solution for 0.5 h, Pd(PPh3)4 (0.03 equiv) was added to it and
stirred for 5 min under nitrogen atmosphere. CuI (0.1 equiv) and
alkyne 11/17 (1.2 equiv) were added to it with 5 min interval and
stirred for 8e12 h at room temperature. On completion, it was
quenched with a saturated NH4Cl solution (15 mL) and extracted
with EtOAc (3ꢁ15 mL). The combined organic layers were washed
with water and brine solution, dried over Na2SO4, and
concentrated.
3.15. General synthesis of cyclic enediyne [1, 2(aee)]
Mesylate 10a/26(aee) (w0.18 mmol), in its crude form, was
dissolved in perfectly dry DMF (w65 mL) maintaining a high di-
lution of the solution (w3.0ꢁ10ꢂ3 mmol/mL) and freshly activated
K2CO3 (3 equiv) was added to it. The whole mixture was stirred for
next 4 h at room temperature. On completion, the reaction mixture
was diluted with water (20 mL) and extracted with EtOAc
(4ꢁ15 mL). The combined organic layers were thoroughly washed
with water and brine solution, dried over Na2SO4, and
concentrated.
3.9. Synthesis of 1-bromomethyl-2,3-diiodobenzene (13)
2,3-Diiodotoluene (12) (800 mg, 2.33 mmol), NBS (500 mg,
2.79 mmol), and benzoyl peroxide (670 mg, 2.34 mmol) were taken
in distilled CCl4 (40 mL) and refluxed for 4 h. On completion, the
reactionmixturewas evaporated to dryness andsubjected to column
chromatography without any further washing (purification: PE).
3.15.1. Compound 1. White solid; Rf (PE/EA¼4:1) 0.40; yield: 80%;
mp: 135 ꢀC; dH: 8.20 (s, 1H), 7.98e7.97 (m, 1H), 7.96e7.82 (m, 3H),
7.70 (d, J¼8.0 Hz, 2H), 7.52e7.50 (m, 2H), 7.39e7.33 (m, 2H),
7.30e7.28 (m, 2H), 6.98e6.93 (m, 3H), 4.52 (s, 2H), 4.41 (s, 2H), 2.15
(s, 3H); dC: 143.1, 138.4, 138.0, 133.6, 133.5, 133.4, 129.3, 129.2, 128.9,
128.6, 128.4, 128.2, 128.0, 127.9, 127.8, 127.7, 126.8, 126.5, 126.3,
3.10. General synthesis of ester [14(aee)]
116.7, 98.3, 96.8, 94.3, 86.7, 59.3, 42.3, 21.5; FTIR (KBr, cmꢂ1):
n
3446,
N-Boc protected amino acid 18 (a/b/c/d/e) (3.50 mmol) and the
bromide 13 (3.50 mmol) were dissolved in dry acetone (30 mL) and
freshly dried K2CO3 (1.2 equiv) was added to it. Total solution was
refluxed for 0.5 h. On completion, acetone was evaporated and the
crude mass was taken in EtOAc (25 mL). The resultant solution was
washed with water and brine solution, dried over Na2SO4, and
concentrated.
2923, 2366, 2340, 1750, 1718, 1653, 1622, 1543, 1354, 1335, 1265,
1153, 1122, 1091, 813, 752; HRMS: found 474.1525. C31H23NO2SþHþ
requires 474.1528.
3.15.2. Cyclic enediyne 2a. White solid; Rf (PE/EA¼7:1) 0.50; yield:
57%; mp: 126 ꢀC; dH: 7.79 (d, J¼7.6 Hz, 2H), 7.66 (d, J¼8.0 Hz, 2H),
7.43e7.39 (m, 2H), 7.36e7.33 (m, 2H), 7.30e7.26 (m, 2H), 6.94 (d,
J¼8.0 Hz, 2H), 6.84 (s,1H), 5.21 (ABq, J¼31.0,13.0 Hz, 2H), 5.02e5.00
(m, 1H), 4.47 (ABq, J¼27.0, 18.6 Hz, 2H), 4.39e4.30 (m, 3H), 2.16 (s,
3H), 1.43 (s, 9H), 1.32 (d, J¼7.2 Hz, 3H); dC: 173.2, 155.3, 143.2, 138.9,
138.6, 137.8, 135.7, 135.6, 129.3, 129.2, 129.0, 128.6, 128.5, 128.4,
127.9, 127.8, 127.7, 116.3, 100.9, 95.7, 94.7, 86.5, 80.1, 65.7, 59.1, 49.5,
3.11. Sonogashira coupling with THP-protected propargyl
alcohol [15(aee)]
In a dry degassed Et3N (15 mL) solution of compound 14, tet-
rakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] (264 mg,
42.3, 28.5, 21.4, 18.7; FTIR (KBr, cmꢂ1):
n
3399, 2927, 2856, 2363,

S. Roy, A. Basak / Tetrahedron 69 (2013) 2184e2192
2191
2342, 1899, 1740, 1708, 1597, 1496, 1449, 1345, 1261, 1159, 1091,
3.16.1. Compound 21. Colorless viscous oil; Rf (PE/EA¼5:1) 0.45;
yield: 80%; dH (acetone-d6): 8.30e8.28 (m, 2H), 8.06e8.03 (m, 2H),
8.00 (d, J¼8.4 Hz, 1H), 7.95e7.93 (m, 1H), 7.86 (s, 1H), 7.85 (s, 1H),
7.60e7.55 (m, 2H), 7.50 (d, J¼8.4 Hz, 2H), 7.34e7.29 (m, 2H), 6.76 (d,
J¼8.0 Hz, 2H), 5.01e4.91 (m, 4H), 1.84 (s, 3H); dC: 147.3, 143.6, 134.1,
132.6, 132.0, 131.7, 130.8, 129.2, 129.0, 128.9, 128.3, 128.1, 127.8,
127.6, 127.0, 126.8, 126.4, 126.0, 124.8, 124.6, 124.2, 119.3, 50.2, 50.0,
1068; HRMS: found 625.2369. C36H36N2O6SþHþ requires 625.2372.
3.15.3. Cyclic enediyne 2b. Cream colored solid; Rf (PE/EA¼5:1)
0.45; yield: 60%; mp: decomposed at 175e177 ꢀC; dH: 7.80 (d,
J¼7.6 Hz, 2H), 7.66 (d, J¼8.4 Hz, 2H), 7.43e7.39 (m, 2H), 7.37e7.32
(m, 2H), 7.28e7.26 (m, 2H), 6.93 (d, J¼8.0 Hz, 2H), 6.84 (s, 1H),
5.26e5.18 (m, 2H), 5.05e5.03 (m, 1H), 4.52e4.41 (m, 2H),
4.38e4.28 (m, 3H), 2.15 (s, 4H), 1.43 (s, 9H), 0.92 (d, J¼6.8 Hz, 3H),
0.83 (d, J¼6.8 Hz, 3H); dC: 172.3, 155.8, 143.1, 138.9, 137.8, 135.6,
129.2, 129.1, 129.0, 128.5, 128.3, 128.0, 127.8, 127.7, 127.6, 116.3,
100.9, 95.6, 94.7, 86.5, 80.0, 65.3, 59.1, 58.8, 42.3, 31.4, 28.5, 21.4,
22.9; FTIR (KBr, cmꢂ1):
n
3450, 2934, 1754, 1684, 1653, 1524, 1362,
1238, 1135, 1091, 752; HRMS: found 474.1520. C31H23NO2SþHþ
require 474.1528.
3.17. General synthesis of chiral amino acid tagged [4]heli-
cene [(22D23)(aee)]
19.2, 17.7; FTIR (KBr, cmꢂ1):
n
3394, 2968, 2928, 2364, 2341, 1740,
1714, 1597, 1497, 1451, 1349, 1158, 1092, 1015, 918, 749; HRMS:
found 675.2488. C38H40N2O6SþNaþ requires 675.2505.
Cyclic enediyne [2(a/b/c/d/e)] (0.04 mmol) was dissolved in dry
DMF (10 mL) maintaining a high dilution of the reaction mixture
(3e4ꢁ10ꢂ3 mmol/mL). It was then heated at 125 ꢀC for 7e9 h
(different times were required for different substrates, which were
monitored by TLC). On completion, the reaction mixture was
extracted with EtOAc (4ꢁ10 mL). Combined organic layers were
washed with water and brine solution, dried over Na2SO4 and
concentrated.
3.15.4. Cyclic enediyne 2c. White solid; Rf (PE/EA¼5:1) 0.50; yield:
60%; mp: 160e162 ꢀC; dH: 7.80 (d, J¼7.6 Hz, 2H), 7.67 (d, J¼8.0 Hz,
2H), 7.44e7.40 (m, 2H), 7.36e7.34 (m, 2H), 7.29e7.26 (m, 2H), 6.94
(d, J¼8.0 Hz, 2H), 6.84 (s, 1H), 5.26e5.16 (m, 2H), 4.87e4.85 (m,
1H), 4.54e4.46 (m, 2H), 4.42e4.31 (m, 3H), 2.17 (s, 3H), 1.68e1.54
(m, 3H), 1.43 (s, 9H), 0.87e0.86 (m, 6H); dC: 173.3, 155.6, 143.1,
139.3, 138.8, 137.7, 135.6, 129.4, 129.2, 129.1, 129.0, 128.6, 128.5,
128.4, 127.8, 127.7, 127.6, 116.2, 100.9, 95.7, 94.6, 86.6, 80.1, 65.5,
3.17.1. Amino acid tagged [4]helicene (22aþ23a). Yellow solid; Rf
(PE/EA¼5:1) 0.50; yield: 58%; mp: 125e127 ꢀC; dH: 7.97e7.84 (m,
3H), 7.70e7.67 (m, 3H), 7.61e7.52 (m, 5H), 6.82e6.80 (m, 2H),
5.65e5.57 (m, 1H), 4.91e4.70 (m, 6H), 4.15e4.11 (m, 1H), 2.04e2.02
59.1, 52.3, 42.3, 41.7, 28.5, 24.9, 23.0, 22.0, 21.4; FTIR (KBr, cmꢂ1):
3390, 2959, 2925, 2363, 2341, 1742, 1706, 1347, 1274, 1261, 1159,
1091, 750; HRMS: found 667.2840. C39H42N2O6SþHþ requires
667.2842.
n
(m, 3H), 1.39e1.37 (m, 9H), 1.25e1.23 (m, 3H), 1.11e1.10 (m, 2H); dC
:
173.1, 155.1, 143.9, 143.7, 133.9, 133.7, 132.9, 131.7, 130.8, 130.5, 130.3,
129.9, 129.3, 127.8, 127.3, 126.8, 126.6, 126.0, 125.0, 124.7, 124.5,
124.2, 119.3, 80.1, 66.9, 66.8, 50.0, 49.9, 49.3, 49.2, 28.5, 24.9, 22.9,
3.15.5. Cyclic enediyne 2d. Light yellow solid; Rf (PE/EA¼7:1) 0.50;
yield: 58%; mp: 143e145 ꢀC; dH: 7.82 (d, J¼7.2 Hz, 2H), 7.66 (d,
J¼8.4 Hz, 2H), 7.43e7.39 (m, 2H), 7.36e7.34 (m, 1H), 7.33e7.18 (m,
6H), 7.02e7.01 (m, 2H), 6.91 (d, J¼7.6 Hz, 2H), 6.86 (s,1H), 5.21 (ABq,
J¼27.2, 12.8 Hz, 2H), 4.98e4.96 (m, 1H), 4.66e4.64 (m, 1H),
4.54e4.41 (m, 2H), 4.37e4.31 (m, 2H), 3.09, 3.00 (ABq of d, J¼13.6,
5.8 Hz, 2H), 2.12 (s, 3H), 1.41 (s, 9H); dC: 171.8, 155.3, 143.2, 139.0,
137.8, 136.0, 135.7, 135.5, 129.5, 129.3, 129.2, 129.0, 128.8, 128.6,
128.5, 128.4, 128.2, 128.1, 127.8, 127.7, 127.2, 116.3, 101.0, 95.7, 94.8,
18.7, 18.6; FTIR (KBr, cmꢂ1):
n
3384, 2925, 2854, 1738, 1708, 1597,
1448, 1346, 1219, 1163, 1065, 772; HRMS: found 625.2365.
C36H36N2O6SþHþ requires 625.2372.
3.17.2. Amino acid tagged [4]helicene (22bþ23b). Light orange
solid; Rf (PE/EA¼5:1) 0.60; yield: 58%; mp: 128e130 ꢀC; dH
:
7.99e7.94 (m, 1H), 7.92e7.88 (m, 2H), 7.73e7.67 (m, 4H), 7.61e7.52
(m, 4H), 6.81 (m, 2H), 5.62 (d, J¼13.2 Hz, 0.5H), 5.53 (d, J¼12.4 Hz,
0.5H), 4.92e4.87 (m, 3H), 4.82e4.70 (m, 3H), 4.08e4.07 (m, 0.5H),
4.00e3.98 (m, 0.5H), 2.03e2.02 (m, 3H), 1.93 (m, 0.5H), 1.87e1.86
(m, 0.5H), 1.38e1.36 (m, 9H), 0.84e0.83 (m, 1.5H), 0.77e0.73 (m,
3H), 0.57e0.55 (m, 1.5H); dC: 172.2, 155.8, 155.7, 143.7, 134.0, 133.9,
133.7,133.6,132.9,132.8, 131.7,130.5, 130.4, 129.1,128.0, 127.9, 127.8,
127.7, 127.6, 127.4, 127.3, 127.1, 127.0, 126.8, 126.7, 126.6, 126.5, 126.4,
126.3, 126.0, 125.9, 124.8, 124.5, 79.9, 66.7, 58.6, 58.4, 50.0, 49.9,
86.6, 80.2, 65.6, 59.1, 54.7, 42.3, 38.4, 28.5, 21.4; FTIR (KBr, cmꢂ1):
n
3389, 2945, 2364, 2342, 1745, 1695, 1492, 1398, 1342, 1244, 1219,
1165, 1095, 956, 770; HRMS: found 701.2680. C42H40N2O6SþHþ
requires 701.2685.
3.15.6. Cyclic enediyne 2e. Light brown solid; Rf (PE/EA¼5:1) 0.40;
yield: 55%; mp: 126e128 ꢀC; dH: 7.81e7.78 (m, 2H), 7.66e7.63 (m,
2H), 7.42e7.39 (m, 2H), 7.37e7.32 (m, 2H), 7.27e7.23 (m, 2H),
6.94e6.90 (m, 2H), 6.82e6.81 (m, 1H), 5.28e5.11 (m, 2H), 4.44 (s,
2H), 4.39e4.25 (m, 3H), 3.54e3.33 (m, 2H), 2.14 (s, 4H), 1.89e1.77
(m, 3H), 1.44 (s, 4H), 1.33 (s, 5H); dC: 172.9, 172.7, 154.6, 153.9, 143.1,
143.0, 138.6, 137.7, 136.1, 135.8, 135.6, 135.5, 129.3, 129.2, 129.1,
129.0, 128.9, 128.6, 128.5, 128.4, 128.3, 128.2, 127.7, 127.6, 127.5,
127.3, 116.3, 116.2, 100.9, 100.7, 95.8, 95.7, 94.7, 94.6, 86.6, 86.5,
80.0, 65.1, 59.2, 59.0, 58.9, 46.7, 46.4, 42.2, 30.9, 28.5, 28.4, 24.4,
31.2, 31.1, 28.5, 21.4, 21.3, 19.2, 17.5, 17.3; FTIR (KBr, cmꢂ1):
n
3381,
2965, 2927, 1737, 1712, 1597, 1498, 1346, 1257, 1161, 1091, 957, 758;
HRMS: found 675.2530. C38H40N2O6SþNaþ requires 675.2505.
3.17.3. Amino acid tagged [4]helicene (22cþ23c). Yellow solid; Rf
(PE/EA¼7:1) 0.45; yield: 58%; mp: 115e117 ꢀC; dH: 7.96e7.95 (m,
1H), 7.92e7.88 (m, 2H), 7.71e7.67 (m, 3H), 7.61 (s, 1H), 7.59e7.52
(m, 4H), 6.81e6.80 (m, 2H), 5.64e5.56 (m, 1H), 4.92e4.67 (m, 6H),
4.13e4.09 (m, 1H), 2.02e2.01 (m, 3H), 1.45e1.33 (m, 9H), 0.89e0.77
(m, 8H); dC: 173.3, 173.2, 155.5, 147.9, 147.3, 143.7, 138.7, 138.6, 133.9,
133.7, 133.6, 132.9, 131.7, 130.5, 129.1, 127.9, 127.8, 127.7, 127.5, 126.8,
126.7, 126.0, 124.8, 124.7, 124.5, 124.2, 119.3, 80.0, 66.8, 66.7, 52.2,
52.1, 50.0, 49.9, 41.8, 41.6, 28.5, 24.9, 24.8, 23.0, 22.9, 22.0, 21.9, 21.4;
23.7, 21.3; FTIR (KBr, cmꢂ1):
n
3398, 2943, 2845, 2365, 2335,
1765, 1698, 1578, 1476, 1365, 1187, 960; HRMS: found
673.2344. C38H38N2O6SþNaþ requires 673.2348. found 651.2528.
C38H38N2O6SþHþ requires 651.2529.
3.16. Synthesis of [5]helicene
FTIR (KBr, cmꢂ1):
n
3389, 2957, 2942, 1755, 1702, 1364, 1258, 1159,
Cyclic enediyne 1 (w0.08 mmol) was dissolved in perfectly dry
DMSO (w15 mL) maintaining the whole solution concentration
around 5ꢁ10ꢂ3 mmol/mL. It was heated at 90 ꢀC for 8 h. On com-
pletion, the reaction mixture was extracted with EtOAc (3ꢁ10 mL).
The combined organic layers were washed with water and brine
solution, dried over Na2SO4, and concentrated.
1091, 774; HRMS: found 667.2837. C39H42N2O6SþHþ requires
667.2842.
3.17.4. Amino acid tagged [4]helicene (22dþ23d). Yellow solid; Rf
(PE/EA¼5:1) 0.45; yield: 58%; mp: 118e119 ꢀC; dH: 8.00e7.87 (m,
3H), 7.69e7.53 (m, 7H), 7.48e7.46 (m, 1H), 7.26e7.24 (m, 1H),

2192
S. Roy, A. Basak / Tetrahedron 69 (2013) 2184e2192
Katz, T. J. J. Am. Chem. Soc. 1998, 120, 9541; (c) Nuckolls, C.; Katz, T. J.; Katz, G.;
Collings, P. J.; Castellanos, L. J. Am. Chem. Soc. 1999, 121, 79; (d) Katz, T. J. Angew.
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Lapkowski, M.; Rajca, A. J. Am. Chem. Soc. 2010, 132, 3246; (j) Rahe, P.; Nimmrich,
7.17e7.09 (m, 2H), 7.02e6.99 (m, 1H), 6.85e6.77 (m, 3H), 5.59e5.51
(m, 1H), 4.98e4.87 (m, 3H), 4.79e4.69 (m, 3H), 4.44e4.42 (m,
0.5H), 4.37e4.35 (m, 0.5H), 2.93e2.75 (m, 2H), 2.05e2.03 (m, 3H),
1.37e1.28 (m, 9H); dC: 171.8, 171.6, 155.2, 155.1, 143.7, 143.6, 136.1,
135.9, 133.7, 133.6, 133.5, 132.9, 131.7, 130.5, 129.4, 129.3, 129.1,
129.0, 128.7,128.6,128.3,128.0,127.9,127.7,127.6,127.4,127.2,127.0,
126.9, 126.8, 126.6, 126.4, 126.0, 124.9, 124.8, 124.5, 80.1, 67.0, 66.9,
54.5, 54.3, 50.0, 49.9, 49.8, 38.4, 38.1, 28.4, 21.4, 21.3; FTIR (KBr,
€
ꢀ
ꢀꢁ
ꢀ
M.; Grueling, A.; Schutte, J.; Stara, I. G.; Rybacek, J.; Huerta-Angeles, G.; Stary, I.;
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cmꢂ1):
n
3380, 2959, 2925, 2854, 1738, 1712, 1496, 1453, 1364, 1347,
1250, 1219, 1164, 1091, 1052, 958, 770; HRMS: found 701.2681.
4. (a) Ben Hassine, B.; Gorsane, M.; Geerts-Evrard, F.; Pecher, J.; Martin, R. H.;
Castelet, D. Bull. Soc. Chim. Belg. 1986, 95, 547; (b) Ben Hassine, B.; Gorsane, M.;
Pecher, J.; Martin, R. H. Bull. Soc. Chim. Belg. 1986, 95, 557; (c) Weix, D. J.;
Dreher, S. D.; Katz, T. J. J. Am. Chem. Soc. 2000, 122, 10027; (d) Sato, I.;
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Int. Ed. 2001, 40, 1096; (e) Reetz, M. T.; Sostmann, S. Tetrahedron 2001, 57, 2515;
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C42H40N2O6SþHþ requires 701.2685.
3.17.5. Amino acid tagged [4]helicene (22eþ23e). Light orange
solid; Rf (PE/EA¼5:1) 0.40; yield: 58%; mp: 170e172 ꢀC; dH
:
8.00e7.89 (m, 3H), 7.68e7.66 (m, 3H), 7.60e7.50 (m, 5H), 6.85e6.80
(m, 2H), 5.81e5.77 (m, 0.3H), 5.66e5.61 (m, 0.6H), 5.55e5.52 (m,
0.3H), 4.95e4.63 (m, 5H), 4.19e4.04 (m, 2H), 3.34e3.28 (m, 2H),
2.04e2.00 (m, 4H), 1.79e1.63 (m, 6H), 1.41e1.40 (m, 5H), 1.33e1.25
(m, 19H); dC: 172.8, 172.6, 154.5, 154.4, 153.9, 143.7, 143.6, 134.2,
134.1, 133.6,133.5, 132.9, 132.8, 131.7, 131.6,130.5, 130.4, 129.1, 129.0,
127.9, 127.8, 127.7, 127.6, 127.4, 127.3, 127.1, 126.9, 126.8, 126.7, 126.6,
126.5, 126.4, 126.3, 126.1, 126.0, 124.8, 124.7, 124.5, 80.0, 79.9, 66.6,
66.5, 66.4, 59.2, 59.1, 58.8, 50.0, 49.9, 46.6, 46.4, 46.3, 31.8,
30.8, 30.7, 28.6, 28.4, 28.3, 24.4, 24.3, 23.6, 23.5, 22.9, 21.4; FTIR
€
5. (a) Janke, R. H.; Haufe, G.; Wurthwein, E.-U.; Borkent, J. H. J. Am. Chem. Soc.
1996, 118, 6031; (b) Grimme, S.; Peyerimhoff, S. D. Chem. Phys. 1996, 204, 411.
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Marchant, M.-J. Tetrahedron Lett. 1972, 35, 3707; (c) Martin, R. H.; Marchant, M.-J.
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8. Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
9. Two sequential Sonogashira coupling of diiodobenzene with THP-protected
propargyl alcohol and TMSeacetylene followed by desilylation provides com-
pound 11.
(KBr, cmꢂ1):
n
3408, 2958, 2925, 2854, 1740, 1689, 1598, 1458, 1401,
1346, 1218, 1161, 1089, 962, 772; HRMS: found 651.2523.
C38H38N2O6SþHþ requires 651.2529.
10. Basak, A.; Shain, J. C.; Khamrai, U. K.; Rudra, K. R.; Basak, A. J. Chem. Soc., Perkin
Trans. 1 2000, 1955.
11. Breiner, B.; Kaya, K.; Roy, S.; Yang, W.-Y.; Alabugin, I. V. Org. Biomol. Chem. 2012,
10, 3974.
Acknowledgements
12. This alternative mechanism induced us to think about the energetics of the
mechanism proposed earlier. We also thank Professor Igor Alabugin, Florida
State University, for drawing our attention to this aspect. The activation barrier
for the H-atom abstraction by the radical in structure X has been calculated to
be a 45.1 kcal/mol at the uB3LYP/6-31G** level of theory and the reaction is
endothermic by 36.7 kcal/mol (personal communication from Professor Ala-
bugin and Mr. Paul Peterson who have most kindly allowed us to use their
result). Presently, we are carrying out a detailed mechanistic reinvestigation on
the formation of unsubstituted [4]helicenes. The results will be published in
due course.
Author A.B. expresses his sincere thanks to Professor I. Alabugin
for drawing our attention to the high endothermicity of the aryleH
abstraction and for many other helpful suggestions regarding the
mechanism. The authors are also grateful to CSIR, Govt. of India, for
research funding and a fellowship (to S.R.) respectively. DST is
thanked for the funds for a 400 MHz facility under the IRPHA
program and for a JC Bose fellowship (to A.B.). We also thank Pro-
fessor U. Maitra, IISc, Bangalore, for useful suggestions on the
equilibration between the diastereomeric helicenes.
H
H
H
H atom
Supplementary data
abstraction
Full synthetic schemes, detail experimental procedures, spectral
data of all new compounds, COSY, NOESY spectra of selected
compounds, and copies of 1H and 13C NMR spectra. Supplementary
data associated with this article can be found in the online version,
at http://dx.doi.org/10.1016/j.tet.2012.12.064.
N
N
H
H
X
Y
13. Radical addition to benzene or quinoline leading to the formation of helicene or
azahelicene has been demonstrated: see Harrowven, D. C.; Guy, I. L.; Nanson, L.
Angew. Chem., Int. Ed. 2006, 45, 2242.
14. For some recent work on radical addition to aromatic rings see: (a) Baroudi, A.;
Alicea, J.; Flack, P.; Kirincich, J.; Alabugin, I. V. J. Org. Chem. 2011, 76, 1521; (b)
Baroudi, A.; Flack, P.; Alabugin, I. V. Chem.dEur. J. 2010, 16, 12316.
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Soc. 2006, 128, 13706; (c) Clive, D. L. J.; Peng, J.; Fletcher, S. P.; Ziffle, V. E.;
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References and notes
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