Experiment and Computational Study on the Regioselectivity of Nucleophilic Addition to Unsymmetrical p-Benzynes Derived from Bergman Cyclization of Enediynes

Article abstract of DOI:10.1021/acs.joc.8b00624

The regioselectivity in addition of nucleophiles to the p-benzyne intermediates derived from unsymmetrical aza-substituted enediynes via Bergman cyclization was studied. Computational studies [using UB3LYP/6-31G(d,p) level of theory] suggest that the p-benzyne intermediate retains its similar electrophilic character at the two radical centers even under unsymmetrical electronic perturbation, thus supporting the predicted model of nucleophilic addition to p-benzyne proposed by Perrin and co-workers (Perrin et al. J. Am. Chem. Soc. 2007, 129, 4795-4799) and later by Alabugin and co-workers (Peterson et al. Eur. J. Org. Chem. 2013, 2013, 2505-2527). However, observed experimental results suggest that there was small but definite regioselectivity (～5-25%), the extent varying with the electronic nature of the substituents. Differential solvated halide ion concentrations around the vicinity of two radical centers arising due to surrounding surface electrostatic potential (computationally calculated) may be one of the possible factors for such selectivity in some of the examined p-benzynes. However, other complicated dynamical issues like the trajectory of the attacking nucleophile to the radical center which can be influenced by electronic and/or steric perturbation of starting enediyne conformation cannot be ruled out. The overall yield of the anionic addition was in the range of 80-99%.

Full text of DOI:10.1021/acs.joc.8b00624

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Article
An Experiment cum Computational Study on the
Regioselectivity of Nucleophilic Addition to Unsymmetrical p-
Benzynes Derived from Bergman Cyclization of Enediynes
Eshani Das, Shyam Basak, Anakuthil Anoop, and Amit Basak
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00624 • Publication Date (Web): 23 May 2018
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Page 1 of 23
The Journal of Organic Chemistry
An Experiment cum Computational Study on the Regioselectivity of Nucleophilic
Addition to Unsymmetrical p-Benzynes Derived from Bergman Cyclization of
Enediynes
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Eshani Dasa*, Shyam Basaka, Anakuthil Anoopa*, and Amit Basak*a,b
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aDepartment of Chemistry, bSchool of Bioscience,
Indian Institute of Technology Kharagpur 721 302, India
* Corresponding authors
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daseshani69@gmail.com;
anoop@chem.iitkgp.ernet.in; absk@chem.iitkgp.ernet.in
Abstract
The regioselectivity in addition of nucleophiles to the p-benzyne intermediates derived from unsymmetrical aza-
substituted enediynes via Bergman Cyclization was studied. Computational studies [using UB3LYP/6-31G(d,p) level
of theory] suggest that the p-benzyne intermediate retains its similar electrophilic character at the two radical centres
even under unsymmetrical electronic perturbation, thus supporting the predicted model of nucleophilic addition to p-
benzyne proposed by Perrin and O’Connor (JACS 2007) and later by Alabugin et al. (EJOC 2013). However,
observed experimental results suggest that there was small but definite regioselectivity (~5–25%), the extent varying
with the electronic nature of the substituents. Differential solvated halide ion concentrations around the vicinity of two
radical centres arising due to surrounding surface electrostatic potential (computationally calculated) may be one of
the possible factors for such selectivity in some of the examined p-benzynes. However, other complicated dynamical
issues like the trajectory of the attacking nucleophile to the radical centre which can be influenced by electronic and/or
steric perturbation of starting enediyne conformation cannot be ruled out. The overall yield of the anionic addition was
in the range of 80–99%.
Key Words: Enediynes, Bergman Cyclization, p-Benzyne, Diradical, Zwitterion.
Introduction
Ever since their discovery1 in the late 80’s as natural products with potent antitumor and antibiotic activity, the
enediynes have aroused much interest amongst the scientific community.2 They show their biological activity by
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cyclizing to a p-benzyne (supposed to exist as benzene 1,4-diradical), a reaction first observed by Masamune3 and the
mechanism proposed by Bergman4 in simpler enediynes. These diradicals quench their unpaired electron character by
abstracting either hydrogen or halogen atoms from suitable organic molecules such as cyclohexadiene or CCl4. If the
H-donor happens to be a DNA molecule, the latter undergoes cleavage causing the strand to break. This is the basis
for the action of Gemtuzumab ozogamicin (Mylotarg™)5, which has been re-approved for treatment of acute myeloid
leukemia.
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However, there was no known case where one halogen and one hydrogen are introduced into the molecule after
cyclization till Perrin and O’Connor et al.6 have shown the addition of both halide and hydrogen ion when an enediyne
was treated with lithium halide in the presence of pivalic acid. This anionic addition to p-benzyne was inspired by the
isolation of marine natural products7 where there is incorporation of both hydrogen and chlorine. The authors
proposed a mechanism which involves a rate-limiting cycloaromatization that leads to a p-benzyne (B) diradical. This
is followed by attack of a halide to generate a haloaryl anion (F) that is then trapped in situ by a proton donor (Figure
1). The most obvious way to explain the addition of halide and hydrogen ion to the p-benzyne is to invoke a
zwitterionic form of the p-benzyne derived by a so called “zwitterionic Bergman cyclization”, but that is a process
disfavoured due to coulombic separation of charges and the intrinsic instability of aryl cation.8 Based upon a series of
kinetic studies involving various halides as well as deuterium incorporation from labelled solvents9, the mechanism
involving addition of anion to the diradical was proposed ruling out the involvement of a formal zwitterion.
Another novel approach as proposed by Alabugin et al.8 to explain the ionic addition to p-benzyne is to invoke a
closed-shell diradicaloid structure of the p-benzyne and not an open-shell pure diradical form. This is due to the
existence of a weak coupling between the two radical centres through the * orbitals forming a weak 1,4-C-C bridge
in the diradicaloid, represented by structure E. The anionic addition then becomes an SN2 attack by the nucleophile to
one of the bridged carbon with the opposite carbon becoming the leaving group (Figure 1). The diradicaloid structure
of p-benzyne which may also be considered as a resonance hybrid of three canonicals, namely, the pure diradical B
and the two zwitterionic forms, C and D, gives rise to the prospect of having non-radical reactions like the anionic
additions. Beside this, in an earlier paper10 Salem and Rowland had provided wave-function based calculation to
understand the actual electronic properties of diradical and according to their explanation the contribution of two
atomic orbital coefficients actually define the diradical (singlet/triplet)/ diradicaloid/ zwitterionic state of any diradical
intermediates and/or p-benzyne.
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Therefore the real scenario in an unsymmetrical p-benzyne is very complex regarding two odd electron atomic orbital
overlap and their relative energy. Without going into such complications, in simple terms one can assume that if there
is any significant inequality in partial charge distribution or in atomic orbital overlapping, some degree of preferential
attack of the nucleophile may give rise to regioselectivity. Again having said that, as the addition of the anion has been
shown to be barrier-less,11 no regioselectivity is expected in halide addition to any p-benzyne, symmetrical or
unsymmetrical. The isolation of the natural marine products as a 1:1 mixture of halogenated regio-isomers
strengthened this assertion.7
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A
B
C
D
Diradical
Zwitterion
Valence Bond Approach
Diradicals
Diradicaloid
Diradicaloid
E
MO Approach
X
X
X
X
H
Diradical
B
H
G
F
1-halotetrahydro
naphthalene
Diradicaloid
E
Addition Products
Addition of nucleophile to an unsymmetrical
p-benzyne (diradical/ diradicaloid/ zwitterionic form)
intermediate.
ii)
i)
H
X
R1
R2
R1
R1
R2
N
N
N
R3
R2
R3
R3
J
H
I
i)
X
H
ii)
Addition Products
Figure 1: Possible intermediates involved in Anionic addition to p-benzyne
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Results and Discussion
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To test this aspect of regioselectivity in anionic addition, several N-substituted 10-membered unsymmetrical aryl-
fused enediynes 1a-1g were synthesized (see Scheme 1) and subjected to Bergman cyclization conditions (see
Scheme 2) in presence of metal halides. The results were quite interesting. Except for the unsubstituted N-tosyl
enediyne 1a, all other enediynes 1b-1g showed varying degree of regioselectivity with the regiomeric excess (re)
ranging from 5–25%. Although the extent of regioselectivity was small but certainly not ignorable, the results
apparently indicated some degree of polarization in p-benzyne diradical, especially in case of enediynes showing
selectivity. The differential charge density, however, was marginal from the Broken-Symmetry Density Functional
Theory calculations. Further computational analysis suggests the existence of differential electrostatic potential nearby
the two radical centres in p-benzynes, which may be one of the possible factors for the observed selectivity in some
enediynes. But the reason behind the diradical 4f (derived from nosyl enediyne) giving highest selectivity, is not
clearly understood from electrostatic potential surface alone. This discrepancy points out that other complicated issues
besides electrostatic potential, may be playing a significant role which actually need a more detail study. Herein we
have presented and discussed the experimental results and also included the analysis of computational outcome on
charge density and surface electrostatic potential.
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Synthesis of target enediynes
The target nitrogen substituted enediynes along with various substitutions in the aromatic ring were synthesized
following our published procedure12 with minor changes in the strategy depending upon the substituents. Two distinct
routes A and B were followed. Route A provided the enediynes 1a, 1b and 1e while the remaining enediynes 1c, 1d,
1f and 1g were synthesized following route B. The final cyclization of the acyclic enediynes is same for all enediynes
and was accomplished by stirring a dilute solution of the mesylate in dry DMF in presence of anhydrous K2CO3 for 3
h followed by chromatographic isolation (Scheme 1). The structures of the already reported enediynes12a,b were
1
confirmed by comparing the H and 13C NMR. The newly synthesized methoxy, carbomethoxy and naphthylsulfonyl
substituted enediynes were characterized by NMR and HRMS studies.
Bergman Cyclization in presence of lithium halides
The enediynes were next subjected to Bergman cyclization under anionic condition (Scheme 2) by heating a DMSO
solution in a sealed tube in presence of a large excess of lithium halide (138 eq) and pivalic acid (3 eq) for ~72 h
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following the reported procedure by Perrin and O’Connor et al.6 However, as the enediynes were benzo fused
systems, the temperature of the reaction had to be kept at 65 0C. After removal of DMSO by lyophilisation, the residue
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was extracted into ethyl acetate which was then evaporated off. The H NMR of the crude reaction products was
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recorded to know the ratio of the two haloaromatic regioiosomers (see SI) which were then separated in each case by
column chromatography and their structures were elucidated by NOESY spectral analysis. For compounds 2a, 3a, 2b,
3b, 3c, 2d, 2f, 3f, 3j single crystal X-ray crystallography13 further confirmed the assigned structure (included in SI).
As a representative example, the NOESY spectra and ORTEP diagram of 2b and 3b are shown in Figure 2. The NOE
cross peaks between Hc and Hd in the NOESY spectrum of 2b and between Ha and He for 3b confirmed their assigned
structures. The results of anionic addition to p-benzyne are shown in Table 1. The combined yields are very
impressive and were in the range 80–99%.
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Route A
Br
OH
OH
MeO
I
MeO
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3
4
5
6
7
8
i
ii
Br
Br
Br
78%
Br
5a
5b
6a:
OH
iii
6b:
92%
N3
iv
NHR'
R
R
R
OH
A=
B=
Br
Br
Br
OH
OTHP
6a, 6b
7a:
7b:
77%;
78%
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8a:
8b:
88%; 89%;
8e: 65%
C=
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For 6a, 7a, R= H; 6b, 7b, R= OMe
v
NHR'
R
vi
R
NR'
For 1a, 8a, 9a, R= H, R'= tosyl;
1b, 8b, 9b, R= OMe, R'= tosyl;
1e, 8e, 9e, R= H, R'= 2-naphthyl
sulfonyl
OH
1a:
1e: 50%
1b:
58%;
54%;
9a:
9e: 44%
9b:
50%;
60%;
Route B
OH
Br
vii
Br
Br
Br
viii
i
R
I
R
R
OTHP
OTHP
6d':
57%
5b, 5d
5a
6c:
6d:
97%
92%
6c':
6f':
56%;
55%
iii
For 5b, 6c-c', R= OMe;
5d, 6d-d', R= CO Me; For 6f', R= H
For
2
N3
NHR'
iv/ ix
NHR'
x
vi
NR'
R
R
R
R
OTHP
OTHP
OH
7c:
7d:
74%
65%
8c:
8f:
8d:
8g:
9c:
9f:
9d:
9g:
79%;
85%;
92%
80%
1c:
1f:
1d:
1g:
80%;
84%;
86%
81%
60%;
45%;
65%
40%
7f: 77%
For 7c, R= OMe; 7d, R= CO2M
7f, R= H
For 1c, 8c, 9c, R= OMe, R'= tosyl; 1d, 8d, 9d, R= CO2Me, R'= tosyl;
1f, 8f, 9f, R= H, R'= nosyl; 1g, 8g, 9g, R= H, R'= 2,4-dinitrobenzenesulfonyl
tosyl = 4-methylbenzenesulfonyl;
nosyl = 4-nitrobenzenesulfonyl
i. PdCl2(PPh3)2, n-BuNH2, A, 80 °C, 18 h; ii. PdCl2(PPh3)2, CuI, Et3N, A, r.t., 10 h; iii. a) MsCl, Et3N, DCM, 0
8a-8d
°C, 0.5 h; b) NaN3, DMF, r.t., 12 h; iv. a) PPh3, THF, H2O, r.t., 24 h; b) TsCl (for
)/ 2-naphthylsulfonyl
chloride (for 8e), Et3N, DCM, 0 °C-r.t., 4 h; v. PdCl2(PPh3)2, n-BuNH2, B, 80 °C, 24-36 h; vi. a) MsCl, Et3N,
C
DCM, 0 °C, 0.5 h; b) K2CO3, DMF, r.t., 3h; vii. PdCl2(PPh3)2, CuI, Et3N, , r.t., 10 h; viii. a) PdCl2(PPh3)2, n-
BuNH2, A, 80 °C, 18 h; b) PdCl2(PPh3)2, n-BuNH2, C, 80 °C, 24 h; ix. a) PPh3, THF, H2O, r.t., 24 h; b) NsCl
8f
(for )/ 2,4-dinitrosulfonylchloride (for
8g
), Et3N, DCM, 0 °C-r.t., 40 min; x. PPTS, EtOH, 55 °C, 12 h.
Scheme 1: synthesis of substituted enediynes 1a-1g
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1
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Ha, He
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Figure 2: NOESY spectrum and ORTEP diagram of compound 2b and 3b
X
H
R1
R2
R1
R2
R1
R2
LiX
NR3
NR3
NR3
pivalic acid, DMSO
65 °C, ~3 days, 80-99%
H
X
1a-1g
3a-3k
2a-2k
X = Cl, Br, I
For compounds 1a-1g, a: R1 = R2 = H, R3 = tosyl; b: R1 = OMe, R2 = H, R3 = tosyl; c: R1 = H, R2 = OMe, R3 = tosyl; d:
e: f: g:
R1 = H, R2 = CO2Me, R3 = tosyl; R1 = R2 = H, R3 = 2-naphthylsulfonyl; R1 = R2 = H, R3 = nosyl;
R1 = R2 = H, R3
= 2, 4-dinitrobenzenesulfonyl: For compounds 2a-2k and 3a-3k, a: R1 = R2 = H, R3 = tosyl, X = Br; b: R1 = OMe, R2
H, R3 = tosyl, X = Br; c: R1 = H, R2 = OMe, R3 = tosyl, X = Br; d: R1 = H, R2 = CO2Me, R3 = tosy, X = Br; e: R1 = R2
=
=
f:
h
i
H, R3 = 2-naphthylsulfonyl, X = Br; R1 = R2 = H, R3 = nosyl, X = Br; : R1 = R2 = H, R3 = tosyl, X = Cl; : R1 = R2 = H,
R3 = tosyl, X = I; j: R1 = R2 = H, R3 = nosyl, X = Cl; k: R1 = R2 = H, R3 = nosyl, X = I.
Scheme 2: Reaction of Lithium halide with enediynes
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1
2
Isomeric
products
Combined
yield
Enediynes
Substituents
Reagent
Ratio
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5
6
7
8
9
1a
1a
1a
1a
1b
1c
1d
R1= R2 = H, R3= tosyl
R1 = R2 = H, R3 = tosyl
LiBr
LiCl
LiI
2a
2h
2i
3a
1 : 1
99%
97%
94%
95%
92%
96%
95%
3h
3i
0.97 : 1
0.99 : 1
0.99 : 1
1 : 0.89
0.79 : 1
1 : 0.71
R1 = R2 = H, R3 = tosyl
R1 = R2 = H, R3 = tosyl
NaBr
LiBr
LiBr
LiBr
2a
2b
2c
2d
3a
3b
3c
3d
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R1 = OMe, R2 = H, R3 = tosyl
R1 = H, R2 = OMe, R3 = tosyl
R1 = H, R2 = CO2Me, R3 = tosyl
R1 = H, R2 = H, R3 = 2-
naphthylsulfonyl
1e
LiBr
2e
3e
0.87 : 1
80%
1f
1f
1f
R1 = R2 = H, R3 = nosyl
R1 = R2 = H, R3 = nosyl
R1 = R2 = H, R3 = nosyl
LiBr
LiCl
LiI
2f
2j
3f
3j
0.61 : 1
0.76 : 1
0.91 : 1
85%
98%
90%
2k
3k
Table 1: Experimental Results
Inspection of the results depicted in Table 1 shows that for unsubstituted N-tosyl enediyne 1a, there was virtually no
regioselectivity (the ratio of the two isomers is ~1:1) irrespective of the nature of halide. This was in accordance with
studies by Perrin and O’Connor et al.6 which indicated that addition of a nucleophile to a diradical does not need any
extra thermodynamic assistance. When the fused aromatic ring in the N-tosyl enediyne is substituted with electron
donor methoxy or electron withdrawing carbomethoxy group, some extent of selectivity (re ~5–17%) started to
appear. The most striking selectivity was obtained for the N-nosyl enediyne 1f (re ~25%). We expected even higher
regioselectivity in case of 2,4-dinitrobenzenesulfoyl enediyne 1g. Unfortunately, the situation in this case was
complicated by accompanying decomposition of the starting enediyne under the reaction condition and the extent of
regioselectivity (re ~15%) may not be reliable. For the selectivity to arise at this stage of nucleophilic addition, an
difference in activation energy between two regioselective addition pathways was expected. But as found
computationally (see SI) the nucleophilic addition to unsymmetrical p-benzyne being barrier-less in gas phase as well
as in the solution phase (disregarding solvation/desolvation parameter), similar to earlier observation in symmetrical
p-benzyne,6,9 the mechanism is outside the scope of transition state theory 11b. At the same time, it is true that a number
enediynes with substituents of varying electronic nature underwent cyclization followed by anionic addition with
some degree of selectivity, the origin of which cannot be apparently explained by relative ease of
solvation/desolvation alone (which has been proposed to explain the variation of rate of addition of different halides
with same enediyne11a). This prompted us to look at other scenarios and as a first attempt, we checked the possibility
of preferential existence of a particular partially polarized diradical. This was presently done for the unsymmetrical p-
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benzynes by calculating the partial charges (see SI) from natural population analysis (NPA) at the two radical centres
using Gaussian 09 software [UB3LYP(D)/6-31G(d,p)].14,15 For all the diradical intermediates, the difference in partial
charge was marginal and was also inconsistent with experimental selectivity. Therefore direct correlation of the
electronic effect with selectivity is ruled out and we are trying to attribute the selectivity to the “ease” of ions to reach
the active centre. We believe that this is atleast partly governed by the differential electrostatic potential near the
vicinity of radical centres arising due to the unsymmetrical nature of enediynes.
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View from C1 side
View from C4 side
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Figure 3: Electrostatic potential mapped over electron density (isovalue: 0.0004 e/Å3) at the [UB3LYP/6-31G(d,p)] level of
theory for the diradical (4a-4f) originating from 1a-1f. The red surface indicates the electron-rich regions (negative electrostatic
potential), and the blue part indicates the electron-deficient regions (positive electrostatic potential) of the molecule.
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Interestingly, for the diradical generated from enediynes with substitution in the fused aryl ring, the charge distribution
is a little different around the two radical centres, creating a scenario in which the concentration of solvated
nucleophile is more in the surface of less electrostatic potential. This coupled with other forces like dipolar/induced
dipolar interactions may force the nucleophile to approach preferentially from the surface of lower electronic charge
density. The electrostatic potential around the radical centres (C1 and C4) of corresponding diradical (4a–4f) from
each of the compounds 1a–1f are shown in Figure 3. The overall experimental results can be qualitatively explained
with the help of electrostatic potential map for enediynes where substituents are present in the fused benzene ring. The
electrostatic potential near the C1 and C4 radical centre of diradical 4a is qualitatively not much different from each
other thus giving rise to almost zero selectivity as shown in the ratio of the corresponding products (2a:3a :: 1:1) of N-
tosylated enediyne 1a. For other enediynes like the diradical 4b (generated from 1b), the OMe group16 creates an
electropositive environment (blue zone; high electrostatic potential) besides the C1 centre which can drive more
solvated nucleophile to come along C1 side relative to C4 side. This is also reflected in experimental results greater
selectivity for 2b). The same argument can explain the selectivity behaviour as shown by the other OMe substituted
diradical 4c. In case of CO2Me substituted diradical 4d generated from 1d, a negative potential nearby C4 radical
centre [generated due to carbony (-C=O) of carbomethoxy (CO2Me) group] obstruct the nucleophile to attack at C4
centre. Thus the product 2d corresponds to the preferential attack of bromide from C1 side. One important point to be
mentioned here is that we have chosen the conformations (for energy minimization) of each diradical, inspired by the
crystal structure of final halogenated compound (for detail see SI). This model of electrostatic potential, however,
failed to explain the selectivity shown by the napthylsulfonyl enediyne 4e and nosyl enediyne 4f. This means that
other electronic and/or steric factors influencing the trajectory of the approaching nucleophile also play a complex role
that need to be taken into consideration.
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Regarding the unusual trend of regioselectivity observed in halide addition (Brˉ > Clˉ > Iˉ) to nosyl enediyne (1f), it
appears that two opposing factors are involved: the solvation energy and the kinetics of approaching nucleophile
towards reactive radical centre. Solvation energy decreases from Clˉ to Brˉ to Iˉ. As solvation energy is decreased, the
ions would more available to act as nucleophile. Therefore, the reactivity is increased (Clˉ < Brˉ < Iˉ) and selectivity is
decreased (Clˉ > Brˉ > Iˉ). On the other hand, considering the kinetics of the halide’s approach (trajectory) to the
reactive centre, the larger ions will be slower to reach the centre, and therefore less reactive, and in turn more
selective. So bulky Iˉ is slower than Brˉ followed by Clˉ and the reactivity follows the order Clˉ > Brˉ > Iˉ.
Accordingly, the selectivity should follow the order Clˉ < Brˉ < Iˉ. These two opposing effects probably have
combined effect and the result becomes optimum for Brˉ (shows highest selectivity).
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We have also carried out kinetic experiments on some of the enediynes to find out the relative rates of anionic
additions. The reactions were found to follow a 1st order kinetics and dependent only on the concentration of enediyne
(see SI).
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Conclusion
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We have for the first time carried out the anionic addition to p-benzynes generated from unsymmetrical enediynes via
Bergman cyclization and evaluated the regioselectivity. The combined yield of the two regioisomeric products were
impressive (~80–90%) with the regioselectivity varying from (~5–25%). Computational results suggest similar
electrophilicity at two radical centres (found from charge density analysis), which cannot explain the regioselectivity.
We have also shown that the differential concentration of solvated halide ions around the vicinity of the two radical
centres (due to difference in surface electrostatic potential) can qualitatively explain the observed selectivity for
enediynes with substitution in the fused benzene ring. Future studies will aim at a multi-reference approach to come
out with a unified model to explain the origin of regioselectivity17 and also increasing the regioselectivity to make the
reaction synthetically more useful.
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Experimental section:
All reactions were performed under a nitrogen atmosphere unless otherwise stated. Glassware used in reactions was
thoroughly oven-dried. All commercial grade reagents were used without further purification and solvents were dried
prior to use following standard protocol. TLC was carried out on precoated plates (silica gel 60 F254), and the spots
were visualized by exposure to UV light and/or by staining with iodine. All crude products were purified by silica gel
flash column chromatography (230–400 mesh) with petroleum ether/ethyl acetate as eluent and characterized by NMR
and mass spectrometry unless otherwise mentioned. Melting points were determined in open capillary tubes and are
1
reported as uncorrected. H and 13C NMR spectra for all the compounds were recorded at 400/500/600 and
100/125/150 MHz (Bruker UltrashieldTM 400, AscendTM 500, AscendTM 600), respectively. The spectra were recorded
in deuterochloroform (CDCl3) as solvent at room temperature. Chemical shifts are reported in ppm from
1
tetramethylsilane with the solvent resonance as internal standard (CDCl3: δH = 7.26, δC = 77.16 ppm). Data for H
NMR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet,
dd = doublet of doublet), coupling constant (Hz), integration. Data for 13C NMR are reported as chemical shift. HRMS
spectra using ESI were recorded on an ESI-FTMS mass spectrometer.
General experimental Procedure:
Sonogashira coupling of iodo arene with terminal alkyne for synthesis of compound 6b, 6c, 6d: PdCl2(PPh3)2 (1
mol%), CuI (2 mol%), and iodo arene (5b/5d) (1 equiv) were dissolved in dry Et3N. After degasification of the
solution for 20 min, the terminal alkyne (A/C) (1.2 equiv) was added and the reaction was stirred at room temperature
for 10 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined
organic layers were washed with water and brine solution, dried over Na2SO4 and subjected for column
chromatography for further purification.
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Sonogashira coupling of bromo arene with terminal alkyne for synthesis of compound 6a, 6c’, 6d’, 6f’, 9a, 9b,
9e: PdCl2(PPh3)2 (1 mol%) and bromo arene (5a/6c/6d/8a/8b/8e) (1 equiv) were dissolved in dry n-BuNH2. After
degasification of the solution for 20 min, the terminal alkyne (A/B) was added and the reaction was stirred at 80 ˚C
until the completion of reaction. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with
EtOAc. The combined organic layers were washed with water and brine solution, dried over Na2SO4 and subjected for
column chromatography for further purification.
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General procedure for mesylation of primary alcohol: To a solution of compound 6a/6b/6c’-6f’/9a-9g (l equiv) in
dry DCM at 0 ˚C, MsCl (1.1 equiv) and dry Et3N (1.1 equiv) were added. Progress of the reaction was carefully
monitored by TLC and on completion, rapid quenching was done with addition of water. Due to the stability problem,
after usual workup the crude mesylates were subjected to the next reaction without further column purification.
General procedure for synthesis of azide (7a-7d, 7f): To a dry DMF solution of the mesylate, NaN3 (1.5 equiv) was
added and stirred for ~12 h at room temperature. Afterwards, it was quenched by water and extracted with EtOAc.
The combined organic layers were washed with water and brine solution, dried over Na2SO4 and subjected for column
chromatography.
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General procedure for primary amine formation: To the solution of azide (7a-7d, 7f) (1equiv) in THF, PPh3
(1equiv) and 3-4 drops of water were added and the reaction was stirred for ~24 h at room temperature. After
evaporating the solvent, the crude reaction mass was subjected to the next reaction without further purification.
General procedure for N-protection (with TsCl/ Naphthalene-2-sulfonylchloride/ NsCl/ 2,4-
dinitrosulfonylchloride) for synthesis of compound 8a-8g: The free amine was dissolved in dry DCM at 0 °C,
followed by the addition of triethylamine (1.5 equiv) and tosyl chloride/2-naphthalenesulfonylchloride (1.2 equiv) [or
nosyl chloride/ 2,4-dinitrobenzenesulfonyl chloride (1 equiv)]. The reaction was monitored by TLC. After completion,
the reaction was quenched with water and extracted with DCM. The combined organic layer was washed with water
and brine. It was then dried, concentrated and subjected to column chromatography for purification.
4-(2-bromo-5-methoxyphenyl)but-3-yn-1-ol (6b): Purification was done by flash column chromatography using
hexane/EtOAc (4/1) as solvent to afford light brown liquid product (990 mg, 3.88 mmol) in 92% yield. Rf 0.20
(hexane/EtOAc, 4/1); 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.9 Hz, 1H), 6.97 (d, J = 2.9 Hz, 1H), 6.73 (dd, J =
8.9, 2.9 Hz, 1H), 3.85 – 3.84 (m, 2H), 3.77 (s, 3H), 2.73 (t, J = 6.0 Hz, 2H), 2.11 (br s, 1H); 13C NMR (100 MHz,
CDCl3) δ 158.6, 133.0, 125.9, 118.0, 116.4, 116.3, 91.6, 81.6, 61.1, 55.7, 24.2. MALDI (m/z) 253.433.
2-(4-azidobut-1-yn-1-yl)-1-bromo-4-methoxybenzene (7b): Purification was done by flash column
chromatography using hexane/EtOAc (19/1) as solvent to afford yellow liquid product (834 mg, 2.98 mmol) in 78%
yield. Rf 0.22 (hexane/EtOAc, 19/1); 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.9 Hz, 1H), 6.98 (d, J = 2.9 Hz, 1H),
6.73 (dd, J = 8.9, 2.9 Hz, 1H), 3.77 (s, 3H), 3.52 (t, J = 6.8 Hz, 2H), 2.77 (t, J = 6.8 Hz, 2H); 13C NMR (125 MHz,
CDCl3) δ 158.6, 133.1, 125.8, 118.2, 116.5, 116.2, 90.7, 81.3, 55.7, 50.0, 20.8. MALDI (m/z) 279.578.
N-(4-(2-bromo-5-methoxyphenyl)but-3-yn-1-yl)-4-methylbenzenesulfonamide (8b): Purification was done by
flash column chromatography using hexane/EtOAc (4/1) as solvent to afford brown viscous liquid product (760 mg,
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1.86 mmol) in 89% yield. Rf 0.28 (hexane/EtOAc, 4/1); H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz, 2H), 7.41
(d, J = 8.8 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 6.91 (d, J = 3.0 Hz, 1H), 6.73 (dd, J = 8.8, 3.0 Hz, 1H), 5.12 (t, J = 6.2
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Hz, 1H), 3.76 (s, 3H), 3.24 – 3.20 (m, 2H), 2.60 (t, J = 6.3 Hz, 2H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
158.6, 143.7, 137.1, 133.0, 129.9, 127.2, 125.6, 118.0, 116.5, 116.3, 90.6, 81.9, 55.7, 41.9, 21.6, 20.9; HRMS [ESI-
TOF] calcd for C18H18BrNO3SNa [M+Na]+ 430.0088, found 430.0085.
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N-(4-(2-(3-hydroxyprop-1-yn-1-yl)-5-methoxyphenyl)but-3-yn-1-yl)-4-methylbenzenesulfonamide
(9b):
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Purification was done by flash column chromatography using hexane/EtOAc (4/1) as solvent to afford brown gummy
liquid product (243 mg, 0.634 mmol) in 50% yield. Rf 0.20 (hexane/EtOAc, 4/1); 1H NMR (400 MHz, CDCl3) δ 7.79
(d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 6.87 – 6.80 (m, 2H), 5.55 (t, J = 5.1 Hz, 1H),
4.58 (s, 2H), 3.79 (s, 3H), 3.23 – 3.18 (m, 2H), 2.56 (t, J = 5.9 Hz, 2H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
159.3, 143.7, 137.0, 133.7, 129.9, 127.2, 126.7, 117.8, 116.4, 114.9, 90.5, 89.9, 84.1, 82.1, 55.5, 51.5, 41.7, 21.6, 20.8;
HRMS [ESI-TOF] calcd for C21H21NO4SNa [M+Na]+ 406.1089, found 406.1090.
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1-[4-Methylphenylsulfonyl]-[5,6]-[benz-(4-methoxy)]-1-azacyclodec-3,7-diyne (1b): Purification was done by
flash column chromatography using hexane/EtOAc (4/1) as solvent to afford white semisolid product (98 mg, 0.27
mmol) in 54% yield. Rf 0.30 (hexane/EtOAc, 4/1); 1H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 8.4 Hz, 2H), 7.29 (d, J =
8.4 Hz, 2H), 7.22 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 2.5 Hz, 1H), 6.77 (dd, J = 8.6, 2.5 Hz, 1H), 4.14 (s, 2H), 3.79 (s,
3H), 3.57 (t, J = 5.1 Hz, 2H), 2.82 (t, J = 5.1 Hz, 2H), 2.40 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 159.4, 143.9,
136.0, 130.9, 130.0, 129.0, 127.5, 120.7, 113.8, 113.8, 98.5, 91.1, 86.9, 83.5, 55.6, 51.2, 42.4, 22.4, 21.6; HRMS [ESI-
TOF] calcd for C21H19NO3SNa [M+Na]+ 388.0983, found 388.0982.
2-((3-(2-bromo-5-methoxyphenyl)prop-2-yn-1-yl)oxy)tetrahydro-2H-pyran (6c): Purification was done by flash
column chromatography using hexane/EtOAc (19/1) as solvent to afford yellow viscous liquid product (1543 mg, 4.74
mmol) in 97% yield. Rf 0.20 (hexane/EtOAc, 19/1); 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.8 Hz, 1H), 7.00 (d, J
= 3.0 Hz, 1H), 6.74 (dd, J = 8.8, 3.0 Hz, 1H), 4.98 (t, J = 3.3 Hz, 1H), 4.54 (s, 2H), 3.93 – 3.87 (m, 1H), 3.77 (s, 3H),
3.59 – 3.55 (m, 1H), 1.89 – 1.52 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 158.5, 133.1, 125.5, 118.3, 116.8, 116.3,
96.9, 89.8, 84.5, 62.3, 55.7, 54.7, 30.4, 25.5, 19.3; MS [ESI] calcd for C15H16O3 [M-HBr]+ 244, found 244.
4-(4-methoxy-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)phenyl)but-3-yn-1-ol (6c’): Purification was
done by flash column chromatography using hexane/EtOAc (4/1) as solvent to afford brown liquid product (970 mg,
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3.09 mmol) in 56% yield. Rf 0.20 (hexane/EtOAc, 4/1); H NMR (400 MHz,CDCl3) δ 7.31 (d, J = 8.6 Hz, 1H), 6.96
(d, J = 2.6 Hz, 1H), 6.80 (dd, J = 8.6, 2.6 Hz, 1H), 4.98 (t, J = 3.1 Hz, 1H), 4.53 (ABq, J = 25.2, 16.0 Hz, 2H), 3.92 –
3.79 (m, 3H), 3.79 (s, 3H), 3.61 – 3.55 (m, 1H), 2.70 (t, J = 5.9 Hz, 2H), 2.55 (br s, 1H), 1.90 – 1.55 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 158.9, 133.0, 126.6, 118.8, 116.7, 115.3, 96.8, 89.5, 88.7, 85.0, 81.1, 62.0, 61.2, 55.5,
54.9, 30.3, 25.5, 24.3, 19.0; HRMS [ESI-TOF] calcd for C19H22O4Na [M+Na]+ 337.1416, found 337.1418.
2-((3-(2-(4-azidobut-1-yn-1-yl)-5-methoxyphenyl)prop-2-yn-1-yl)oxy)tetrahydro-2H-pyran (7c): Purification
was done by flash column chromatography using hexane/EtOAc (19/1) as solvent to afford yellow liquid product (337
mg, 0.99 mmol) in 74% yield. Rf 0.16 (hexane/EtOAc, 19/1); 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.6 Hz, 1H),
6.95 (d, J = 2.7 Hz, 1H), 6.80 (dd, J = 8.6, 2.7 Hz, 1H), 4.98 (t, J = 3.2 Hz, 1H), 4.53 (ABq, J = 22.0, 16.0 Hz, 2H),
3.92 – 3.84 (m, 1H), 3.78 (s, 3H), 3.60 – 3.57 (m, 1H), 3.50 (t, J = 7.0 Hz, 2H), 2.74 (t, J = 7.0 Hz, 2H), 1.91 – 1.52
(m, 6H); 13C NMR (100 MHz, CDCl3) δ 159.0, 133.3, 126.6, 118.4, 116.8, 115.3, 96.6, 88.8, 88.3, 84.6, 81.0, 62.0,
55.5, 54.8, 50.2, 30.4, 25.5, 20.8, 19.1; HRMS [ESI-TOF] calcd for C19H21N3O3Na [M+Na]+ 362.1481, found
362.1481.
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N-(4-(4-methoxy-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)phenyl)but-3-yn-1-yl)-4-
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methylbenzenesulfonamide (8c): Purification was done by flash column chromatography using hexane/EtOAc
(4/1) as solvent to afford yellow gummy liquid product (310 mg, 0.66 mmol) in79% yield. Rf 0.20 (hexane/EtOAc,
4/1); 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz, 2H), 7.26 – 7.22 (m, 3H), 6.96 (d, J = 2.5 Hz, 1H), 6.80 (dd, J
= 8.6, 2.5 Hz, 1H), 5.37 (t, J = 6.0 Hz, 1H), 5.00 (t, J = 2.9 Hz, 1H), 4.54 (ABq, J = 18.8, 16.0, 2H), 3.91 – 3.84 (m,
1H), 3.79 (s, 3H), 3.61 – 3.54 (m, 1H), 3.22 –31.7 (m, 2H), 2.56 (t, J = 6.2 Hz, 2H), 2.37 (s, 3H), 1.88 – 1.53 (m, 6H);
13C NMR (100 MHz, CDCl3) δ 159.0, 143.4, 137.5, 133.1, 129.8, 127.2, 126.6, 118.3, 116.8, 115.3, 96.6, 89.0, 88.4,
84.9, 81.4, 61.9, 55.6, 54.8, 42.0, 30.3, 25.5, 21.6, 20.9, 18.9; HRMS [ESI-TOF] calcd for C26H29NO5SNa [M+Na]+
490.1664, found 490.1664.
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N-(4-(2-(3-hydroxyprop-1-yn-1-yl)-4-methoxyphenyl)but-3-yn-1-yl)-4-methylbenzenesulfonamide
(9c):
Purification was done by flash column chromatography using hexane/EtOAc (7/3) as solvent to afford yellow
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semisolid product (122 mg, 0.32 mmol) in 80% yield. Rf 0.20 (hexane/EtOAc, 7/3); H NMR (400 MHz, CDCl3) δ
7.79 (d, J = 8.2 Hz, 2H), 7.27 – 7.24 (m, 3H), 6.99 (d, J = 2.6 Hz, 1H), 6.81 (dd, J = 8.6, 2.6 Hz, 1H), 5.48 (t, J = 6.1
Hz, 1H), 4.60 (d, J = 6.5 Hz, 2H), 3.81 (s, 3H), 3.21 – 3.10 (m, 3H), 2.55 (t, J = 5.8 Hz, 2H), 2.40 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 159.1, 143.8, 136.9, 132.9, 129.9, 127.3, 126.8, 117.8, 117.0, 115.4, 92.1, 88.1, 84.1, 82.2, 55.6,
51.5, 41.7, 21.7, 20.7; HRMS [ESI-TOF] calcd for C21H21NO4SNa [M+Na]+ 406.1089, found 406.1086.
1-[4-Methylphenylsulfonyl]-[5,6]-[benz-(5-methoxy)]-1-azacyclodec-3,7-diyne (1c): Purification was done by
flash column chromatography using hexane/EtOAc (9/1) as solvent to afford white semisolid product (49 mg, 0.13
mmol) in 60% yield. Rf 0.12 (hexane/EtOAc, 9/1); 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 2H), 7.29 (d, J =
8.3 Hz, 2H), 7.23 (d, J = 8.6 Hz, 1H), 6.85 (d, J = 2.6 Hz, 1H), 6.79 (dd, J = 8.6, 2.6 Hz, 1H), 4.16 (s, 2H), 3.79 (s,
3H), 3.57 (t, J = 5.0 Hz, 2H), 2.80 (t, J = 5.0 Hz, 2H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.9, 143.9,
135.9, 130.0, 129.7, 129.3, 127.4, 121.8, 114.3, 113.6, 96.4, 92.9, 87.0, 83.3, 55.6, 51.4, 42.3, 22.4, 21.6; HRMS [ESI-
TOF] calcd for C21H19NO3SNa [M+Na]+ 388.0983, found 388.0981.
methyl 4-bromo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl) benzoate (6d): Purification was done by
flash column chromatography using hexane/EtOAc (19/1) as solvent to afford colourless gummy liquid product (570
mg, 1.61 mmol) in 92% yield. Rf 0.20 (hexane/EtOAc, 19/1); 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 2.0 Hz, 1H),
7.80 (dd, J = 8.4, 2.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 4.98 (t, J = 3.3 Hz, 1H), 4.55 (s, 2H), 3.91 (s, 3H), 3.90 – 3.86
(m, 1H), 3.61 – 3.55 (m, 1H), 1.89 – 1.53 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 165.9, 134.7, 132.8, 130.9, 130.3,
129.4, 125.5, 97.0, 91.2, 83.6, 62.3, 54.7, 52.6, 30.4, 25.5, 19.2; HRMS [ESI-TOF] calcd for C16H17BrO4Na [M+Na]+
375.0208, found 375.0204.
methyl
4-(4-hydroxybut-1-yn-1-yl)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)benzoate
(6d’):
Purification was done by flash column chromatography using hexane/EtOAc (9/1) as solvent to afford colourless
gummy liquid product (354 mg, 1.03 mmol) in 57% yield. Rf 0.14 (hexane/EtOAc, 9/1); 1H NMR (400 MHz, CDCl3)
δ 8.10 (s, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 4.97 (t, J = 3.0 Hz, 1H), 4.53 (ABq, J = 25.2, 16.0
Hz, 2H), 3.90 (s, 3H), 3.88 – 3.81 (m, 3H), 3.59 – 3.56 (m, 1H), 2.74 (t, J = 5.9 Hz, 2H), 2.67 (br s, 1H), 1.86 – 1.54
(m, 6H); 13C NMR (100 MHz, CDCl3) δ 166.1, 133.2, 131.7, 130.7, 129.3, 129.1, 125.7, 96.8, 94.9, 89.7, 84.2, 80.8,
62.0, 60.9, 54.8, 52.5, 30.3, 25.5, 24.3, 18.9; HRMS [ESI-TOF] calcd for C20H22O5Na [M+Na]+ 365.1365, found
365.1363.
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methyl
The Journal of Organic Chemistry
4-(4-azidobut-1-yn-1-yl)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)benzoate
(7d):
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Purification was done by flash column chromatography using hexane/EtOAc (19/1) as solvent to afford yellow liquid
product (209 mg, 0.57 mmol) in 65% yield. Rf 0.16 (hexane/EtOAc, 19/1); 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J =
1.6 Hz, 1H), 7.89 (dd, J = 8.1, 1.6 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 4.97 (t, J = 3.0 Hz, 1H), 4.54 (ABq, J = 21.6,
16.0 Hz, 2H), 3.90 (s, 3H), 3.89 – 3.84 (m, 1H), 3.61 – 3.56 (m, 1H), 3.53 (t, J = 6.9 Hz, 2H), 2.78 (t, J = 6.9 Hz, 2H),
1.87 – 1.56 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 166.1, 133.3, 132.0, 130.2, 129.4, 129.0, 125.7, 96.7, 93.3, 89.9,
83.8, 80.9, 62.0, 54.7, 52.5, 49.9, 30.4, 25.5, 20.9, 19.1; HRMS [ESI-TOF] calcd for C20H21N3O4Na [M+Na]+
390.1430, found 390.1434.
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methyl 4-(4-((4-methylphenyl)sulfonamido)but-1-yn-1-yl)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-
yl)benzoate (8d): Purification was done by flash column chromatography using hexane/EtOAc (4/1) as solvent to
afford yellow semisolid product (237 mg, 0.48 mmol) in 92% yield. Rf 0.20 (hexane/EtOAc, 4/1); 1H NMR (400 MHz,
CDCl3) δ 8.12 (s, 1H), 7.89 (dd, J = 8.2, 1.2 Hz, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.2 Hz, 1H), 7.23 (d, J =
8.1 Hz, 2H), 5.40 (t, J = 6.0 Hz, 1H), 5.00 (t, J = 2.8 Hz, 1H), 4.56 (ABq, J = 18.0, 16.4 Hz, 2H), 3.92 (s, 3H), 3.90 –
3.84 (m, 1H), 3.62 – 3.56 (m, 1H), 3.26 – 3.21 (m, 2H), 2.63 (t, J = 6.2 Hz, 2H), 2.37 (s, 3H), 1.88 – 1.53 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 166.0, 143.5, 137.6, 133.4, 131.9, 130.2, 129.8, 129.5, 129.1, 127.2, 125.8, 96.7, 93.6,
90.1, 84.1, 81.2, 61.9, 54.8, 52.5, 41.8, 30.3, 25.5, 21.6, 21.2, 18.9; HRMS [ESI-TOF] calcd for C27H29NO6SNa
[M+Na]+ 518.1613, found 518.1612.
methyl
3-(3-hydroxyprop-1-yn-1-yl)-4-(4-((4-methylphenyl)sulfonamido)but-1-yn-1-yl)benzoate
(9d):
Purification was done by flash column chromatography using hexane/EtOAc (7/3) as solvent to afford white solid
1
product (62 mg, 0.15 mmol) in 86% yield. m.p. 118–119 ˚C; Rf 0.16 (hexane/EtOAc, 7/3); H NMR (400 MHz,
CDCl3) δ 8.11 (s, 1H), 7.91 – 7.87 (dd, J = 8.2, 1.4 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.2 Hz, 1H), 7.25 (d,
J = 8.2 Hz, 2H), 5.58 (t, J = 6.1 Hz, 1H), 4.60 (d, J = 5.4 Hz, 2H), 3.92 (s, 3H), 3.24 – 3.19 (m, 2H), 3.16 (t, J = 5.4
Hz, 1H), 2.61 (t, J = 5.9 Hz, 2H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.0, 143.8, 137.0, 133.4, 131.8,
129.9, 129.7, 129.6, 129.1, 127.2, 125.8, 93.3, 92.9, 83.4, 81.7, 52.5, 51.5, 41.6, 21.6, 21.1; HRMS [ESI-TOF] calcd
for C22H21NO5SNa [M+Na]+ 434.1038, found 434.1038.
1-[4-Methylphenylsulfonyl]-[5,6]-[benz-(5-carbomethoxy)]-1-azacyclodec-3,7-diyne (1d): Purification was
done by flash column chromatography using hexane/EtOAc (4/1) as solvent to afford white solid product (34 mg, 0.09
1
mmol) in 65% yield. m.p. decomposition over 150 ˚C; Rf 0.34 (hexane/EtOAc, 4/1); H NMR (400 MHz, CDCl3) δ
7.96 (d, J = 1.4 Hz, 1H), 7.92 (dd, J = 8.0, 1.4 Hz, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.29 (d, J =
8.2 Hz, 2H), 4.17 (s, 2H), 3.91 (s, 3H), 3.56 (t, J = 5.0 Hz, 2H), 2.86 (t, J = 5.0 Hz, 2H), 2.39 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 166.2, 144.1, 135.7, 133.8, 130.0, 129.3, 129.2, 128.9, 128.7, 128.1, 127.4, 101.7, 93.7, 86.3, 83.2,
52.5, 51.1, 42.3, 22.6, 21.7; HRMS [ESI-TOF] calcd for C22H20NO4S [M+H]+ 394.1113, found 394.1100.
N-(4-(2-bromophenyl)but-3-yn-1-yl)naphthalene-2-sulfonamide (8e): Purification was done by flash column
chromatography using hexane/EtOAc (4/1) as solvent to afford white gummy liquid product (522 mg, 1.26 mmol) in
65% yield. Rf 0.36 (hexane/EtOAc, 4/1); 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.99 – 7.85 (m, 4H), 7.68 – 7.53
(m, 3H), 7.37 – 7.32 (m, 1H), 7.25 – 7.12 (m, 2H), 5.18 (t, J = 6.2 Hz, 1H), 3.31 – 3.26 (m, 2H), 2.61 (t, J = 6.2 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 136.8, 134.9, 133.3, 132.3, 132.2, 129.7, 129.4, 129.3, 128.9, 128.5, 128.0, 127.6,
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127.1, 125.6, 125.0, 122.4, 90.8, 81.9, 41.9, 20.9; HRMS [ESI-TOF] calcd for C20H17BrNO2S [M+H]+ 414.0163,
found 414.0149.
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N-(4-(2-(3-hydroxyprop-1-yn-1-yl)phenyl)but-3-yn-1-yl)naphthalene-2-sulfonamide (9e): Purification was done
by flash column chromatography using hexane/EtOAc (7/3) as solvent to afford brown liquid product (407 mg, 1.05
1
mmol) in 44% yield. Rf 0.20 (hexane/EtOAc, 7/3); H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.89 – 7.86 (m, 4H),
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8
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7.64 – 7.55 (m, 2H), 7.48 (d, J = 6.8 Hz, 1H), 7.30 – 7.22 (m, 4H), 5.73 (t, J = 5.9 Hz, 1H), 4.63 (d, J = 5.6 Hz, 2H),
3.28 – 3.23 (m, 2H), 3.13 (t, J = 5.6 Hz, 1H), 2.57 (t, J = 5.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 136.8, 135.0,
132.4, 132.2, 131.7, 129.7, 129.3, 128.9, 128.6, 128.3, 128.0, 128.0, 127.7, 125.5, 125.4, 122.4, 92.1, 90.0, 84.3, 82.2,
51.5, 41.7, 20.9; HRMS [ESI-TOF] calcd for C23H19NO3SNa [M+Na]+ 412.0983, found 412.0982.
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1-[naphthalene-2-sulfonyl]-[5,6]-benz-1-azacyclodec-3,7-diyne (1e): Purification was done by flash column
chromatography using hexane/EtOAc (4/1) as solvent to afford white solid product (44 mg, 0.12 mmol) in 50% yield.
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m.p. decomposition over 160 ˚C; Rf 0.44 (hexane/EtOAc, 4/1); H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.94 (d, J
= 8.7 Hz, 1H), 7.90 – 7.83 (m, 3H), 7.66 – 7.54 (m, 2H), 7.31 – 7.28 (m, 2H), 7.26 – 7.19 (m, 2H), 4.27 (s, 2H), 3.66
(t, J = 5.0 Hz, 2H), 2.86 (t, J = 5.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 135.9, 135.0, 132.3, 129.7, 129.4, 129.0,
128.8, 128.3, 128.2, 128.2, 128.0, 127.9, 127.7, 127.6, 122.5, 98.2, 92.8, 87.2, 83.6, 51.4, 42.5, 22.3; HRMS [ESI-
TOF] calcd for C23H17NO2SNa [M+Na]+ 394.0878, found 394.0882.
5-bromo-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline (2a): Purification was done by flash column
chromatography using hexane/EtOAc (19/1) as solvent to afford white solid product (19 mg, 0.046 mmol) in 49.5%
yield. m.p. 161–162 ˚C; Rf 0.60 (hexane/EtOAc, 7.8/2.2); 1H NMR (600 MHz, CDCl3) δ 8.22 (d, J = 8.5 Hz, 1H), 7.74
(d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.1 Hz, 1H), 7.54 – 7.45 (m, 3H), 7.31 (d, J = 8.1 Hz, 2H), 4.41 (s, 2H), 3.44 (t, J =
6.2 Hz, 2H), 3.15 (t, J = 6.2 Hz, 2H), 2.41 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 144.0, 133.4, 132.9, 131.9, 131.6,
131.4, 129.9, 128.0, 127.8, 127.4, 127.0, 126.6, 125.0, 125.0, 48.4, 44.3, 31.1, 21.7; HRMS [ESI-TOF] calcd for
C20H18BrNO2SNa [M+Na]+ 438.0139, found 438.0136.
10-bromo-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline (3a): Purification was done by flash column
chromatography using hexane/EtOAc (19/1) as solvent to afford white solid product (19 mg, 0.046 mmol) in 49.5%
yield. m.p. 200–201 ˚C; Rf 0.53 (hexane/EtOAc, 7.8/2.2); 1H NMR (600 MHz, CDCl3) δ 8.21 (d, J = 8.5 Hz, 1H), 7.78
(d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.55 – 7.46 (m, 3H), 7.34 (d, J = 8.2 Hz, 2H), 4.48 (s, 2H), 3.42 (t, J =
5.9 Hz, 2H), 3.14 (t, J = 5.9 Hz, 2H), 2.41 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 143.9, 133.6, 133.2, 132.8, 131.1,
130.5, 130.0, 127.9, 127.7, 127.2, 127.1, 126.8, 126.7, 122.5, 49.9, 43.6, 29.8, 21.7; HRMS [ESI-TOF] calcd for
C20H18BrNO2SNa [M+Na]+ 438.0139, found 438.0139.
5-chloro-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline (2h): Purification was done by flash column
chromatography using hexane/EtOAc (19/1) as solvent to afford white solid product (21.3 mg, 0.057 mmol) in 47.8%
yield. m.p. 147–148 ˚C; Rf 0.57 (hexane/EtOAc, 7.8/2.2); 1H NMR (600 MHz, CDCl3) δ 8.21 (d, J = 8.5 Hz, 1H), 7.75
– 7.72 (m, 3H), 7.55 – 7.52 (m, 1H), 7.49 – 7.46 (m, 2H), 7.31 (d, J = 8.0 Hz, 2H), 4.42 (s, 2H), 3.46 (t, J = 6.1 Hz,
2H), 3.17 (t, J = 6.1 Hz, 2H), 2.41 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 144.0, 133.4, 132.7, 131.3, 131.0, 130.2,
129.9, 129.6, 128.0, 127.8, 127.1, 126.6, 124.2, 124.1, 48.4, 44.1, 28.0, 21.7; HRMS [ESI-TOF] calcd for
C20H18ClNO2SNa [M+Na]+ 394.0644, found 394.0647.
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The Journal of Organic Chemistry
10-chloro-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline (3h): Purification was done by flash column
chromatography using hexane/EtOAc (19/1) as solvent to afford white solid product (22 mg, 0.059 mmol) in 49.2%
yield. m.p. 135–136 ˚C; Rf 0.50 (hexane/EtOAc, 7.8/2.2); 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.4 Hz, 1H), 7.78
(d, J = 8.2 Hz, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.55 – 7.46 (m, 3H), 7.34 (d, J = 8.2 Hz, 2H), 4.50 (s, 2H), 3.43 (t, J =
5.9 Hz, 2H), 3.14 (t, J = 5.9 Hz, 2H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.0, 133.6, 133.0, 132.4, 130.0,
129.7, 129.3, 128.4, 127.9, 127.6, 126.9, 126.8, 126.2, 124.0, 47.0, 43.6, 29.7, 21.7; HRMS [ESI-TOF] calcd for
C20H18ClNO2SNa [M+Na]+ 394.0644, found 394.0646.
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5-iodo-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline (2i): Purification was done by flash column
chromatography using hexane/EtOAc (9.2/0.8) as solvent to afford white solid product (19.5 mg, 0.042 mmol) in
46.8% yield. m.p. 156–157 ˚C; Rf 0.57 (hexane/EtOAc, 7.8/2.2); 1H NMR (600 MHz, CDCl3) δ 8.15 (d, J = 8.5 Hz,
1H), 7.73 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.51 – 7.49 (m, 2H), 7.45 (t, J = 7.2 Hz, 1H), 7.30 (d, J = 8.1
Hz, 2H), 4.41 (s, 2H), 3.44 (t, J = 6.0 Hz, 2H), 3.12 (t, J = 6.0 Hz, 2H), 2.40 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
144.0, 136.1, 134.3, 133.4, 132.6, 132.3, 131.4, 129.9, 128.0, 128.0, 127.8, 126.7, 126.3, 107.4, 48.5, 44.9, 37.3, 21.7;
HRMS [ESI-TOF] calcd for C20H18INO2SNa [M+Na]+ 486.0001, found 486.0009.
10-iodo-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline (3i): Purification was done by flash column
chromatography using hexane/EtOAc (9.2/0.8) as solvent to afford white solid product (19.9 mg, 0.043 mmol) in
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47.2% yield. m.p. 160–161 ˚C; Rf 0.50 (hexane/EtOAc, 7.8/2.2); H NMR (600 MHz, CDCl3) δ 8.15 (d, J = 8.5 Hz,
1H), 7.79 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.53 – 7.48 (m, 1H), 7.47 – 7.44 (m, 1H), 7.34 (d,
J = 8.2 Hz, 2H), 4.43 (s, 2H), 3.41 (t, J = 5.9 Hz, 2H), 3.13 (t, J = 5.9 Hz, 2H), 2.41 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 144.0, 134.4, 133.8, 133.6, 133.1, 132.9, 131.9, 130.0, 128.4, 127.9, 127.9, 127.6, 126.9, 104.0, 55.8, 43.7,
29.9, 21.7; HRMS [ESI-TOF] calcd for C20H18INO2SNa [M+Na]+ 486.0001, found 486.0009.
5-bromo-7-methoxy-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline (2b): Purification was done by flash column
chromatography using hexane/EtOAc (19/1) as solvent to afford white solid product (24.1 mg, 0.054 mmol) in 48.7%
yield. m.p. 173–175 ˚C; Rf 0.53 (hexane/EtOAc, 7.8/2.2); 1H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H), 7.62
(d, J = 8.9 Hz, 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.44 (s, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.12 (dd, J = 8.9, 2.3 Hz, 1H), 4.38
(s, 2H), 3.95 (s, 3H), 3.44 (t, J = 6.2 Hz, 2H), 3.15 (t, J = 6.2 Hz, 2H), 2.41 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
159.1, 144.0, 133.5, 132.9, 132.3, 129.9, 129.5, 128.9, 128.4, 128.0, 124.8, 123.6, 119.7, 105.3, 55.6, 48.3, 44.3, 31.3,
21.7; HRMS [ESI-TOF] calcd for C21H20BrNO3SNa [M+Na]+ 468.0245, found 468.0245.
10-bromo-7-methoxy-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline (3b): Purification was done by flash
column chromatography using hexane/EtOAc (19/1) as solvent to afford white solid product (21.4 mg, 0.048 mmol) in
43.3% yield. m.p. 154–156 ˚C; Rf 0.37 (hexane/EtOAc, 7.8/2.2); 1H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 9.3 Hz,
1H), 7.78 (d, J = 8.1 Hz, 2H), 7.43 (s, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.17 (dd, J = 9.3, 2.5 Hz, 1H), 6.99 (d, J = 2.5 Hz,
1H), 4.44 (s, 2H), 3.90 (s, 3H), 3.41 (t, J = 5.9 Hz, 2H), 3.10 (t, J = 5.9 Hz, 2H), 2.41 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 158.4, 143.9, 134.4, 133.7, 133.4, 129.9, 128.4, 128.0, 127.9, 126.7, 126.0, 122.4, 120.0, 105.3, 55.5, 49.6,
43.6, 29.8, 21.7; HRMS [ESI-TOF] calcd for C21H20BrNO3SNa [M+Na]+ 468.0245, found 468.0248.
5-bromo-8-methoxy-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline (2c): Purification was done by flash column
chromatography using hexane/EtOAc (19/1) as solvent to afford white solid product (25.4 mg, 0.057 mmol) in 42.4%
yield. m.p. 189–191 ˚C; Rf 0.40 (hexane/EtOAc, 7.8/2.2); 1H NMR (600 MHz, CDCl3) δ 8.13 (d, J = 9.3 Hz, 1H), 7.74
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(d, J = 8.1 Hz, 2H), 7.40 (s, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.18 (dd, J = 9.3, 2.5 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 4.40
(s, 2H), 3.91 (s, 3H), 3.44 (t, J = 6.2 Hz, 2H), 3.11 (t, J = 6.2 Hz, 2H), 2.41 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
158.2, 144.0, 134.1, 133.5, 131.9, 129.9, 129.4, 128.7, 128.0, 127.2, 124.9, 123.8, 120.2, 105.5, 55.6, 48.4, 44.4, 30.8,
21.7; HRMS [ESI-TOF] calcd for C21H20BrNO3SNa [M+Na]+ 468.0245, found 468.0244.
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10-bromo-8-methoxy-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline (3c): Purification was done by flash
column chromatography using hexane/EtOAc (19/1) as solvent to afford white solid product (32.1 mg, 0.072 mmol) in
53.6% yield. m.p. 153–156 ˚C; Rf 0.47 (hexane/EtOAc, 7.8/2.2); 1H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 8.1 Hz,
2H), 7.60 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.47 (s, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.13 (dd, J = 8.9, 2.4 Hz,
1H), 4.47 (s, 2H), 3.96 (s, 3H), 3.41 (t, J = 5.8 Hz, 2H), 3.10 (t, J = 5.8 Hz, 2H), 2.41 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 158.9, 143.9, 133.6, 132.3, 130.8, 130.3, 130.0, 129.4, 128.7, 127.9, 126.9, 121.1, 119.9, 104.9, 55.6, 50.0,
43.7, 29.6, 21.7; HRMS [ESI-TOF] calcd for C21H20BrNO3SNa [M+Na]+ 468.0245, found 468.0247.
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methyl 5-bromo-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline-8-carboxylate (2d): Purification was done by
flash column chromatography using hexane/EtOAc (9.2/0.8) as solvent to afford white solid product (17.9 mg, 0.038
mmol) in 55.6% yield. m.p. 206–207 ˚C; Rf 0.43 (hexane/EtOAc, 7.8/2.2); 1H NMR (600 MHz, CDCl3) δ 8.47 (s, 1H),
8.27 (d, J = 8.9 Hz, 1H), 8.09 (d, J = 8.9 Hz, 1H), 7.75 (d, J = 8.1 Hz, 2H), 7.62 (s, 1H), 7.32 (d, J = 8.1 Hz, 2H), 4.43
(s, 2H), 3.99 (s, 3H), 3.46 (t, J = 6.1 Hz, 2H), 3.18 (t, J = 6.1 Hz, 2H), 2.41 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
166.9, 144.2, 134.7, 133.6, 133.3, 132.5, 132.0, 130.8, 130.0, 128.3, 128.0, 127.5, 126.7, 126.3, 125.0, 52.5, 48.4,
44.2, 31.4, 21.7; HRMS [ESI-TOF] calcd for C22H21BrNO4S [M+H]+ 474.0375, found 474.0375.
methyl 10-bromo-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline-8-carboxylate (3d): Purification was done by
flash column chromatography using hexane/EtOAc (9.2/0.8) as solvent to afford white solid product (12.7 mg, 0.027
mmol) in 39.4% yield. m.p. 150–151 ˚C; Rf 0.33 (hexane/EtOAc, 7.8/2.2); 1H NMR (500 MHz, CDCl3) δ 8.97 (s, 1H),
8.05 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 7.7 Hz, 2H), 7.75 (d, J = 8.7 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J = 7.7 Hz, 2H), 4.47
(s, 2H), 3.99 (s, 3H), 3.43 (t, J = 5.7 Hz, 2H), 3.17 (t, J = 5.7 Hz, 2H), 2.42 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
167.0, 144.1, 135.6, 135.2, 133.4, 131.6, 130.4, 130.0, 129.8, 128.7, 128.1, 127.9, 127.0, 126.3, 123.9, 52.6, 49.9,
43.4, 30.0, 21.7; HRMS [ESI-TOF] calcd for C22H20BrNO4SNa [M+Na]+ 496.0194, found 496.0198.
5-bromo-2-(naphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydrobenzo[g]isoquinoline (2e): Purification was done by
flash column chromatography using hexane/EtOAc (9/1) as solvent to afford white solid product (27.1 mg, 0.060
1
mmol) in 37.2% yield. m.p. decomposition over 180 ˚C; Rf 0.57 (hexane/EtOAc, 7.8/2.2); H NMR (600 MHz,
CDCl3) δ 8.44 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.98 – 7.94 (m, 2H), 7.90 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.5 Hz,
1H), 7.70 (d, J = 8.1 Hz, 1H), 7.65 – 7.61 (m, 2H), 7.52 – 7.50 (m, 2H), 7.47 – 7.44 (m, 1H), 4.50 (s, 2H), 3.54 (t, J =
6.1 Hz, 2H), 3.17 (t, J = 6.1 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 135.1, 133.6, 132.9, 132.4, 131.9, 131.6, 131.3,
129.5, 129.4, 129.4, 129.1, 128.1, 127.8, 127.8, 127.4, 127.0, 126.7, 125.0, 123.0, 48.4, 44.4, 31.2; HRMS [ESI-TOF]
calcd for C23H18BrNO2SNa [M+Na]+ 474.0139, found 474.0136.
10-bromo-2-(naphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydrobenzo[g]isoquinoline (3e): Purification was done by
flash column chromatography using hexane/EtOAc (9/1) as solvent to afford white solid product (31.6 mg, 0.070
mmol) in 42.8% yield. m.p. 126–127 ˚C; Rf 0.48 (hexane/EtOAc, 7.8/2.2); 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H),
8.20 (d, J = 8.5 Hz, 1H), 8.04 – 7.94 (m, 2H), 7.93 – 7.83 (m, 2H), 7.72 – 7.58 (m, 3H), 7.55 – 7.42 (m, 3H), 4.58 (s,
2H), 3.52 (t, J = 5.8 Hz, 2H), 3.14 (t, J = 5.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 135.1, 133.9, 133.1, 132.8,
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132.4, 131.1, 130.4, 129.6, 129.4, 129.2, 129.0, 128.1, 127.8, 127.7, 127.2, 127.2, 126.8, 126.7, 122.9, 122.5, 49.8,
43.7, 29.8; HRMS [ESI-TOF] calcd for C23H18BrNO2SNa [M+Na]+ 474.0139, found 474.0136.
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5-bromo-2-((4-nitrophenyl)sulfonyl)-1,2,3,4-tetrahydrobenzo[g]isoquinoline (2f): Purification was done by flash
column chromatography using hexane/EtOAc (9.2/0.8) as solvent to afford yellow solid product (11.6 mg, 0.026
1
mmol) in 32.2% yield. m.p. decomposition over 200 ˚C; Rf 0.57 (hexane/EtOAc, 7.8/2.2); H NMR (400 MHz,
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CDCl3) δ 8.34 (d, J = 8.6 Hz, 2H), 8.23 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.74 (d, J = 7.9 Hz, 1H), 7.58 –
7.48 (m, 3H), 4.54 (s, 2H), 3.58 (t, J = 6.1 Hz, 2H), 3.18 (t, J = 6.1 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 150.4,
143.1, 132.9, 131.7, 131.4, 130.5, 128.9, 127.8, 127.4, 127.1, 127.0, 125.2, 125.0, 124.5, 48.2, 44.3, 30.9; MALDI
(m/z) 445.649.
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10-bromo-2-((4-nitrophenyl)sulfonyl)-1,2,3,4-tetrahydrobenzo[g]isoquinoline (3f): Purification was done by
flash column chromatography using hexane/EtOAc (9.2/0.8) as solvent to afford yellow solid product (19.4 mg, 0.043
mmol) in 52.8% yield. m.p. 185–186 ˚C; Rf 0.43 (hexane/EtOAc, 7.8/2.2); 1H NMR (600 MHz, CDCl3) δ 8.36 (d, J =
8.8 Hz, 2H), 8.22 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.1 Hz, 1H), 7.59 – 7.52 (m, 2H), 7.50 –
7.48 (m, 1H), 4.60 (s, 2H), 3.54 (t, J = 6.0 Hz, 2H), 3.14 (t, J = 6.0 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 150.4,
143.3, 133.3, 132.3, 131.2, 129.7, 128.8, 127.7, 127.5, 127.4, 127.1, 126.7, 124.6, 122.5, 49.5, 43.7, 29.5; MALDI
(m/z) 445.601.
5-chloro-2-((4-nitrophenyl)sulfonyl)-1,2,3,4-tetrahydrobenzo[g]isoquinoline (2j): Purification was done by flash
column chromatography using hexane/EtOAc (9.2/0.8) as solvent to afford white solid product (13.9 mg, 0.035 mmol)
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in 42.3% yield. m.p. >200 ˚C; Rf 0.57 (hexane/EtOAc, 7.8/2.2); H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.3 Hz,
2H), 8.22 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.58 – 7.50 (m, 3H), 4.53 (s, 2H),
3.58 (t, J = 6.1 Hz, 2H), 3.19 (t, J = 6.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 150.4, 143.1, 132.7, 131.5, 130.3,
130.2, 129.1, 128.9, 127.8, 127.4, 126.9, 124.5, 124.3, 124.1, 48.2, 44.1, 27.7; MALDI (m/z) 402.507; HRMS [ESI-
TOF] calcd for C19H15ClN2O4SNa [M+Na]+ 425.0339, found 425.0339.
10-chloro-2-((4-nitrophenyl)sulfonyl)-1,2,3,4-tetrahydrobenzo[g]isoquinoline (3j): Purification was done by
flash column chromatography using hexane/EtOAc (9.2/0.8) as solvent to afford white solid product (18.5 mg, 0.046
mmol) in 55.7% yield. m.p. 141–143 ˚C; Rf 0.44 (hexane/EtOAc, 7.8/2.2); 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J =
8.4 Hz, 2H), 8.21 (d, J = 8.3 Hz, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.59 – 7.46 (m, 3H), 4.61 (s,
2H), 3.54 (t, J = 5.8 Hz, 2H), 3.14 (t, J = 5.8 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 150.4, 143.2, 133.1, 131.8,
129.4, 128.8, 127.7, 127.5, 127.2, 127.1, 126.5, 124.6, 124.0, 46.7, 43.7, 29.5; MALDI (m/z) 402.533; HRMS [ESI-
TOF] calcd for C19H15ClN2O4SNa [M+Na]+ 425.0339, found 425.0337.
5-iodo-2-((4-nitrophenyl)sulfonyl)-1,2,3,4-tetrahydrobenzo[g]isoquinoline (2k): Purification was done by flash
column chromatography using hexane/EtOAc (9.2/0.8) as solvent to afford white solid product (13.3 mg, 0.027 mmol)
1
in 42.9% yield. m.p. >200 ˚C; Rf 0.57 (hexane/EtOAc, 7.8/2.2); H NMR (500 MHz, CDCl3) δ 8.33 (d, J = 7.4 Hz,
2H), 8.16 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 7.4 Hz, 2H), 7.68 (d, J = 8.2 Hz, 1H), 7.50 – 7.47 (m, 3H), 4.53 (s, 2H),
3.57 (t, J = 6.2 Hz, 2H), 3.15 (t, J = 6.2 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 150.4, 143.0, 135.5, 134.5, 132.6,
132.4, 130.5, 128.9, 128.2, 128.0, 127.0, 126.3, 124.5, 107.6, 48.3, 44.9, 37.0; MALDI (m/z) 493.556; HRMS [ESI-
TOF] calcd for C19H14IN2O2 [M-SO2-H]+ 429.0094, found 429.0146.
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10-iodo-2-((4-nitrophenyl)sulfonyl)-1,2,3,4-tetrahydrobenzo[g]isoquinoline (3k): Purification was done by flash
column chromatography using hexane/EtOAc (9.2/0.8) as solvent to afford white solid product (14.3 mg, 0.029 mmol)
in 47.1% yield. m.p. 180–181 ˚C; Rf 0.46 (hexane/EtOAc, 7.8/2.2); 1H NMR (500 MHz, CDCl3) δ 8.36 (d, J = 8.2 Hz,
2H), 8.15 (d, J = 9.0 Hz, 1H), 8.08 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 7.7 Hz, 1H), 7.57 (s, 1H), 7.55 – 7.52 (m, 1H),
7.50 – 7.45 (m, 1H), 4.55 (s, 2H), 3.53 (t, J = 5.6 Hz, 2H), 3.13 (t, J = 5.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
150.4, 143.2, 133.8, 133.6, 133.0, 132.6, 131.9, 128.9, 128.6, 127.9, 127.2, 124.6, 103.9, 55.4, 43.8, 29.6; MALDI
(m/z) 493.553; HRMS [ESI-TOF] calcd for C19H15IN2O4SNa [M+Na]+ 516.9695, found 516.9694.
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ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
* E-mail for A.B.: absk@chem.iitkgp.ernet.in
* E-mail for A.A.: anoop@chem.iitkgp.ernet.in
* E-mail for E.D.: daseshani69@gmail.com
Notes
The authors declare no competing financial interest.
Acknowledgement
DST is acknowledged for an SERB grant (SB/S1/OC-94/2013) and for the JC Bose Fellowship to AB which
supported this research. We are thankful to Mr. Santanu Chand for solving X-ray crystal structure. ED is grateful to
IIT Kharagpur for a senior research fellowship.
Supporting Information
1H, 13C, 2D (NOESY) NMR spectra of the synthesized compounds and X-ray crystallographic data,
Cartesian coordinates of optimized geometry and other computational details
References and Notes
1. (a) Border, D. B., Doyle, T. W. Eds. Enediyne Antibiotics as Antitumor Agents, Marcel Dekker: New York, 1995.
(b) Nicolaou, K. C.; Smith, A. L. Modern Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH: Weinheim,
Germany, 1995; p 203. (c) DNA and RNA Cleavers and Chemotherapy of Cancer and Viral Diseases; Meunier, B.,
Ed.; Kluwer Publishers: Dordrecht, The Netherlands, 1996; p 1.
2. (a) Nicolaou, K. C.; Dai, W. M. Chemistry and Biology of the Enediyne Anticancer Antibiotics. Angew. Chem. Int.
Ed. Engl. 1991, 30, 1387–1530. (b) Basak, A.; Mandal, S.; Bag, S. S. Chelation-Controlled Bergman Cyclization:
Synthesis and Reactivity of Enediynyl Ligands. Chem. Rev. 2003, 103, 4077–4094. (c) Saito, I.; Nakatani, K. Design
of DNA-Cleaving Agents. Bull. Chem. Soc. Jpn. 1996, 69, 3007–3019. (d) Wenk, H. H.; Winkler, M.; Sander, W. One
Century of Aryne Chemistry. Angew. Chem. Int. Ed. 2003, 42, 502–528. (e) Maier, M. E. Design of Enediyne
Prodrugs. Synlett 1995, 13–26. (f) Grisom, J. W.; Gunawardena, G. U.; Klingberg, D.; Huang, D. The Chemistry of
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Enediynes, Enyne Allenes and Related Compounds. Tetrahedron 1996, 52, 6453–6518. (g) Rawat, D. S.; Zaleski, J.
M. Geometric and Electronic Control of Thermal Bergman Cyclization. Synlett 2004, 393–421. (h) Klein, M.;
Walenzyk, T.; Ko¨nig, B. Electronic effects on the Bergman cyclisation of enediynes. A review. Collect. Czech.
Chem. Commun. 2004, 69, 945–965.
1
2
3
4
5
6
7
8
3. Darby, N.; Kim, C. U.; Salaun, J. A.; Shelton, K. W.; Takada, S.; Masamune, S. Concerning the 1,5 -
Didehydro[10]annulene System. J. Chem. Soc., Chem. Commun. 1971, 1516–1517.
9
4. (a) Jones, R. R.; Bergman, R. G. p-Benzyne. Generation as an intermediate in a thermal isomerization reaction and
trapping evidence for the 1,4-benzenediyl structure. J. Am. Chem. Soc. 1972, 94, 660–661. (b) Bergman, R. G.
Reactive 1,4-dehydroaromatics. Acc. Chem. Res. 1973, 6, 25–31. (c) Lockhart, T. P.; Bergman, R. G. Evidence for the
reactive spin state of 1,4-dehydrobenzenes J. Am. Chem. Soc. 1981, 103, 4091–4096.
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44
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50
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53
54
55
56
57
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60
5. Damle, N. K.; Frost, P. Antibody-targeted chemotherapy with immunoconjugates of calicheamicin. Current
Opinion in Pharmacology 2003, 3, 386–390.
6. Perrin, C. L.; Rodgers, B. L.; O’Connor, J. M. Nucleophilic Addition to a p-Benzyne Derived from an Enediyne: A
New Mechanism for Halide Incorporation into Biomolecules. J. Am. Chem. Soc. 2007, 129, 4795–4799.
7. (a) Buchanan, G. O.; Williams, P. G.; Feling, R. H.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. Sporolides A and
B: Structurally Unprecedented Halogenated Macrolides from the Marine Actinomycete Salinispora tropica. Org. Lett.
2005, 7, 2731–2734. (b) Oh, D. C.; Williams, P. G.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. Cyanosporasides A
and B, Chloro- and Cyano-cyclopenta[a]indene Glycosides from the Marine Actinomycete “Salinispora pacifica”.
Org. Lett. 2006, 8, 1021–1024.
8. (a) Mohamed, R. K.; Peterson, P. W.; Alabugin, I. V. Concerted Reactions That Produce Diradicals and
Zwitterions: Electronic, Steric, Conformational, and Kinetic Control of Cycloaromatization Processes. Chem. Rev.
2013, 113, 7089–7129. (b) Peterson, P. W.; Mohamed, R. K.; Alabugin, I. V. How to Lose a Bond in Two Ways –
The Diradical/Zwitterion Dichotomy in Cycloaromatization Reactions. Eur. J. Org. Chem. 2013, 2505–2527. (c)
Recently, Alabugin group has shown zwitterionic assistance of p-benzyne in Au(I) catalyzed Bergman cyclization.
Gomes, G. P.; Alabugin, I. V. Drawing Catalytic Power from Charge Separation: Stereoelectronic and Zwitterionic
Assistance in the Au(I)-Catalyzed Bergman Cyclization. J. Am. Chem. Soc. 2017, 139, 3406–3416.
9. Perrin, C. L.; Reyes-Rodríguez, G. J. Reactivity of nucleophiles toward a p-benzyne derived from an enediyne. J.
Phys. Org. Chem. 2013, 26, 206–210.
10. Salem, L.; Rowland, C. The Electronic Properties of Diradicals. Angew. Chem. Int. Ed. 1972, 11, 92–111.
11. (a) Reyes-Rodríguez, G. J. Nucleophilic additions to a p-benzyne derived from an enediyne: Exploring the
nonradical reactivity of a diradical, Ph D Thesis, University of California, San Diego 2013. (b) Sedenkova, K. N.;
Averina, E. B.; Grishin, Y. K.; Kolodyazhnaya, J. V.; Rybakov, V. B.; Kuznetsova, T. S.; Hughes, A.; Gomes, G. P.;
Alabugin, I. V.; Zefirov, N. S. Substituent effects on stereoselectivity of dihalocarbene reactions with cyclohexadiene
and on the reactivity of bis-dihalocyclopropanes in electrophilic nitrations en route to pyrimidine N-oxides. Org.
Biomol. Chem. 2017, 15, 9433–9441.
12. (a) Basak, A.; Mandal, S.; Das, A. K.; Bertolasi, V. Benzene fused monocyclic enediynyl amides: synthesis,
reactivity and DNA-Cleavage activity in comparison to the corresponding sulphonamides. Bioorg. Med. Chem. Lett.
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2002, 12, 873–877. (b) Basak, A.; Shain, J. C.; Khamrai, U. K.; Rudra, K. R.; Basak, A. Nitrogen substituted cyclic
enediynes: synthesis, thermal reactivity and complexation with metal ions. J. Chem. Soc., Perken Trans. 1, 2000,
1955–1964. (c) Basak, A.; Khamrai, U. K.; Shain, J. C. Synthesis and reactivity of a novel 10-membered azaenediyne.
Tetrahedron Lett. 1997, 38, 6067–6070. (d) Basak, A.; Khamrai, U. K.; Mallik, U. The synthesis and reactivity of
novel azetidinyl enediynes. Chem. Commun. 1996, 749–750.
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13. CCDC no. of 2a=1819044; 3a=1819053; 2b=1819048; 3b=1819049; 3c=1819051; 2d=1819050; 2f=1819052;
3f=1823835; 3j=1823834.
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14. Frisch, M. J.; et al. Gaussian 09, revision C.01; Gaussian, Inc.: Wallingford, CT, 2010.
15. (a) Becke, A. D. Density-functional thermochemistry. III. The role of exact exchange. J. Chem.Phys. 1993, 98,
5648–5652. (b) Becke, A. D. Density-functional exchange-energy approximation with correct asymptotic behaviour.
Phys. Rev. A 1988, 38, 3098–3100. (c) Lee, C.; Yang, W.; Parr, R. G. Development of the Colic-Salvetti correlation-
energy formula into a functional of the electron density. Phys. Rev. B 1988, 37, 785–789. (d) Vosko, S. H.; Wilk, L.;
Nusair, M. Accurate spin-dependent electron liquid correlation energies for local spin density calculations: a critical
analysis. Can J. Phys. 1980, 58, 1200–1211.
16. One interesting point to be noted here is that the electron donating OMe group is creating a positive surface charge
density in the vicinity of the nearest radical centre (C1 or C4 depending upon the location of OMe), instead of
showing its usual donor nature. It may be pertinent to mention that Alabugin et al. in a recent paper has deliberated
upon such type of donor-acceptor dichotomy on the basis of relative conformational changes. Vatsadze, S. Z.;
Loginova, Y. D.; Gomes, G. P.; Alabugin, I. V. Stereoelectronic Chameleons: The Donor–Acceptor Dichotomy of
Functional Groups. Chem. Eur. J. 2017, 23, 3225–3245.
17. The origin of regioselectivity is governed by many factors. It may be argued that the main difference between the
two regioselective pathways lies in the energy difference of the products. Since there is no barrier for addition to either
end, there should not be much of difference between them. Some selectivity may arise due to the actual exothermicity
of the reaction, but there are also dynamical issues that come into play at long distances which can go either way,
depending on the trajectory. We thank the reviewers for their suggestion in this regard.
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1
2
R1
3
4
NR3
R2
5
6
7
8
pivalic acid, DMSO
LiX
65 °C, ~3 days
X
H
R1
R2
view from C1 side
view from C4 side
R1
R2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NR3
NR3
H
X
1
4
X = Cl, Br, I
O2
S
Regioselctivity ranged from 5-25% (re)
N
MeO2C
Combined yield 80-99%
CH3
Differential surface charge density around
the vicinity of the reacting centre (C1 & C4)
is the origin of regioselectivity
?
Diradical
Diradicaloid Zwitterion
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