How to Achieve High Regioselectivity in Barrier-less Nucleophilic Addition to p-Benzynes Generated via Bergman Cyclization of Unsymmetrical Cyclic Azaenediyne?

Article abstract of DOI:10.1021/acs.joc.9b00060

Inducing high regioselectivity in nucleophilic addition to p-benzynes, first reported by Perrin and O'Connor et al. (J. Am. Chem. Soc. 2007, 129, 4795-4799) has been a challenge as the reaction involves a very fast barrier-less addition of nucleophile. On

Full text of DOI:10.1021/acs.joc.9b00060

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Article
How to achieve high regioselectivity in barrier-less
nucleophilic addition to p-benzynes generated via Bergman
Cyclization of unsymmetrical cyclic azaenediyne?
Eshani Das, Shyam Basak, Anakuthil Anoop, Santanu Chand, and Amit Basak
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00060 • Publication Date (Web): 28 Jan 2019
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How to achieve high regioselectivity in barrier-less nucleophilic addition to p-benzynes
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generated via Bergman Cyclization of unsymmetrical cyclic azaenediyne?
†
†
Eshani Das* , Shyam Basak* , Anakuthil Anoop*, Santanu Chand, and Amit Basak*
Department of Chemistry
Indian Institute of Technology Kharagpur 721 302, India
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† equal contribution
*
Corresponding authors
Abstract
Inducing high regioselectivity in nucleophilic addition to p-benzynes, first reported by Perrin and O’Connor et al. (J.
Am. Chem. Soc. 2007, 129, 4795−4799) has been a challenge as the reaction involves a very fast barrier-less addition
of nucleophile. On the other hand, achieving a high degree of regioselectivity is important as that will make the
reaction synthetically useful. Recently, a study has been reported from our group (J. Org. Chem. 2018, 83,
7
730−7740) whereby it was shown that nucleophilic addition to p-benzynes derived from unsymmetrical N-substituted
cyclic enediynes proceeds with low extent of selectivity by incorporation of groups with divergent electronic
characters. Herein, we report that excellent regioselectivity (>99%) can be achieved keeping an ortho alkoxy group in
unsymmetrical 1,2-dialkynylbenzene in the form of a cyclic enediyne in quantitative yields. High regioselectivity
(84%) is also shown by pyridine based enediynes where the pyridine nitrogen is in a 1,3-relationship with impending
radical center, expanding the synthetic scope of this nucleophilic addition. The regioselectivity can be explained in
terms of computed electrostatic potentials which are substantially different around two radical centers arising due to
“
ortho effect” (conformational alignment of lone pair of the ortho alkoxy oxygen or the nitrogen in pyridine systems).
Key Words: Enediynes, Bergman Cyclization, p-Benzyne, Nucleophilic Addition, Regioselectivity,
Diradical
INTRODUCTION
1
Enediynes, discovered in the late 80’s as a group of natural products , have been drawing considerable attention
2
amongst the scientific community because of their potent biological activities which originate from their ability to
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3
generate p-benzyne (believed to exist as a 1,4-benzene diradical) via a process known as cycloaromatization . The
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reaction of enediynes was originally observed by Masamune and the diradical mechanism was established by
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Bergman. The reaction is now popularly known as Bergman cyclization (BC) . The diradical nature of p-benzyne is
responsible for abstracting H or halogen atom from suitable small molecule donors e.g. cyclohexadiene and
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haloalkanes . Large biomolecules DNA and proteins can also act as H-donors which ultimately results in their
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cleavage . In 2007, Perrin and O’Connor reported for the first time that p-benzyne can also undergo nucleophilic
addition. Based on various kinetic studies as well as isotope labelling experiments, they have proposed a mechanism
involving initial rate determining formation of p-benzyne which then undergoes rapid attack by the nucleophile
followed by protonation of the carbanion (Scheme 1). Their results have provided a new dimension to the diradical
chemistry and have indicated a dual nature of reactivity of the p-benzyne intermediate.9
8
Scheme 1: Proposed mechanism for nucleophilic addition to a p-benzyne derived from an enediyne
Recently, we have reported10 the results of nucleophilic addition to p-benzynes (Scheme 2) generated from
unsymmetrical N-substituted enediynes attached with electron donor or acceptor moieties to influence the attack of the
nucleophile from one side of the p-benzyne. The observed selectivity, although small, was explained on the basis of
electrostatic potential difference in the vicinity of radical centers which causes differential concentration of the
solvated nucleophile. This ultimately leads to some degree of selectivity.
H
X
R1
R1
R1
LiX
+
N
pivalic acid
SO2R3 DMSO, 65 °C
N
N
R2
SO2R3
R2
SO2R3
R2
X
H
X= Cl, Br, I
R1 = R2 = H, R3 = C6H4-CH3
R1 = R2 = H, R3 = C6H4-NO2
R1 = R2 = H, R3 = 2-Naph
R1 = OMe, R2 = H, R3 = C6H4-CH3
R1 = H, R2 = OMe, R3 = C6H4-CH3
R1 = H, R2 = CO2Me, R3 = C6H4-CH3
Scheme 2: Previous studies by Das et al.10
Taking a cue from our earlier work, it was realized that incorporation of a group (withdrawing or donating) at the meta
or para position with respect to the impending radical centers would not produce high degree of selectivity indicating
that through-bond electronic effects will be marginal to make any substantial difference in the electrophilic character
between the two radical centers. So in order to achieve high degree of selectivity in the nucleophilic addition, an
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electron rich group at the ortho position could be ideal as that might provide substantial difference in surface charge
density near the immediate vicinity of the radical centers along with the possibility of offering steric hindrance to the
approach of the nucleophile from the side of the ortho group (Figure 1). Our idea to induce selectivity via ortho
substitution was also inspired by the seminal work of Alabugin et al. to perturb the reactivity of enediynes via “ortho
effect” 11 (tuning Bergman cyclization rate by ortho substitution). In this paper we report the synthesis of a series of o-
alkoxy substituted unsymmetrical 1,2 dialkynylbenzene in the form of cyclic enediynes 1a-d and the results of
nucleophilic addition LiX (X = Cl, Br, I) to the p-benzynes derived from them. We are happy to disclose that in all
cases, we obtained only one regioisomeric halogenated derivative in excellent yields with regioselectivity > 99%. We
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didn’t observe the formation of the other regioisomer in the crude H and C NMR (included in SI). In our studies we
have included pyridine based enediynes 1e-f which also showed high regioselectivity (~84%). The origin of such high
degree of selectivity has also been assessed through computational studies.
Figure 1: Possible scenario of approach of nucleophile to ortho substituted p-benzyne
RESULTS AND DISCUSSION
To test this aspect of regioselectivity in nucleophilic addition, several N-substituted 10-membered unsymmetrical aryl-
fused enediynes 1a-d with various alkoxy substituents at the ortho position were synthesized starting from a common
12a
intermediate 2-bromo-3-iodophenol which was prepared following a literature protocol . This was first O-alkylated
to the 2-bromo-1-iodo-3-alkoxy benzene derivatives. For the synthesis of enediynes of type I, two successive
Sonogashira coupling12b,c, first with THP-protected propargyl alcohol and then with homopropargyl alcohol, were
carried out. The resulting acyclic enediynes were converted into target cyclic ones by functional group modification
and finally intramolecular cyclization. For the synthesis of type II enediynes, the sequence of Sonogashira couplings
was reversed. The pyridine based enediyne 1e was similarly prepared starting from commercially available 2-bromo-
3-iodo pyridine. The entire synthetic protocol is shown in Scheme 3. An alternative approach which could provide
1
3
rapid access to the precursor for the cyclic enediynes was to employ the tosyl protected homopropargyl amine as the
nd
alkyne partner for Sonogashira coupling followed a 2 coupling with propargyl alcohol. The success of this strategy
has been demonstrated in case of synthesis of the isomeric pyridine based enediyne 1f (Scheme 4). The structures of
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all the synthesized enediynes were confirmed by extensive NMR including NOESY and HRMS studies as well as by
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single crystal X-ray structure obtained for one of the starting enediyne (as shown in Figure 2).
OR
Br
OR
5
a; 90%
v
v
OR
5b; 94%
Br
I
Br
5c; 92%
5d; 91%
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4a; 70%
4b; 68%
4c; 71%
vi
OH
OTHP
vi
OR
OH
OR
for a and d, R = Me; b, R = Et; c, R = Bn
OTHP
6a; 44%
6d; 41%
OTHP
vii
OH
vii
7
a; 68%
7b; 66%
c; 50%
yield over
OR
N3
O
O
OH
O
NEt2
O
NEt2
7
(
OR
OTHP
Br
i
ii
two steps
for 7b and
OTHP
7d; 59%
I
I
I
viii
OR
7c)
N3
OH
OR
viii
NHTs
Br
I
Br
iii
iv
8a; 79%
OR
OTHP
8b; 80%
I
8c; 68%
8d; 96%
OTHP
ix
NHTs
OR
NHTs
ix
9
9
9
a; 80%
b; 85%
c; 76%
OR
OH
OH
9d; 80%
Ts = 4-methylbenzenesulfonyl;
THP = Tetrahydropyran
x
NHTs
x
OR
OR
1
a; 81%
NTs
1b; 70%
1d; 82%
NTs
1c; 75%
Type I
a, R = Me; 1b, R = Et;
1c, R = Bn
Type II
1
1d; R = Me
OTHP
OTHP
OTHP
N3
I
xi
xii
vii
N
Br
N
Br
N
N
OH
5
e; 85%
6e; 82%
7e; 58%
viii
OH
OTHP
NTs
x
ix
N
N
N
NHTs
NHTs
1e; 65%
9e; 75%
8e; 90%
i) diethylcarbamoyl chloride, NaH, THF, rt, 10 h; ii) LDA, C H Br , THF, -78 °C-rt, 14 h; iii) NaOH, EtOH, 80
2
4
2
°
C, 7 h; iv) alkyl/aryl halide, base, solvent; v) 3-butyn-1-ol/THP-protected propargyl alcohol, PdCl (PPh ) ,
2 3 2
CuI, Et N, rt, 10 h; vi) THP-protected propargyl alcohol/ 3-butyn-1-ol, Pd(PPh ) , n-BuNH , 80 °C, 24-36h;
3
3 4
2
vii) a) MsCl, Et N, DCM, 0 °C, 0.5 h; b) NaN , DMF, rt, 24h; viii) a) PPh , THF, H O, rt, 24 h; b) TsCl, Et N,
3
3
3
2
3
DCM, 0 °C-rt, 4 h; ix) PPTS, EtOH, 55 °C, 12 h; x) a) MsCl, Et N, DCM, 0 °C, 0.5 h; b) K CO , DMF, rt, 3 h;
3
2
3
xi) THP-protected propargyl alcohol, PdCl (PPh ) , CuI, Et N, rt, 2 h; xii) 3-butyn-1-ol, Pd(PPh ) , CuI,
2
3 2
3
3 4
Et N, 90 °C, 24h.
3
Scheme 3: Synthesis of o-substituted and pyridine based enediynes (1a-e)
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NHTs
NHTs
iii
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2
3
4
5
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7
8
9
I
A
=
i
ii
NTs
NHTs
N
N
Br
N
Br
N
OH
9
f; 83%
9f'; 50%
1f; 77%
i) A, PdCl (PPh ) , CuI, Et N, THF, rt, 3.5 h; ii) propargyl alcohol, Pd(PPh ) , CuI, Et N-THF (4:1), 80 C, 12 h; iii)
2
3 2
3
3 4
3
a) MsCl, Et N, DCM, 0 C, 0.5 h; b) K CO , DMF, rt, 3 h.
3
2
3
Scheme 4: Synthesis of pyridine based enediyne 1f
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Bergman Cyclization in presence of lithium halide
The enediynes were next subjected to Bergman cyclization 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 following our earlier reported procedure10
Scheme 5). Here also, the temperature of the reaction was kept at 65 C as the enediynes were benzo fused systems15

(
known to undergo BC at comparatively higher temperature. After removal of DMSO under cold condition, the residue
1
was extracted into ethyl acetate which was then evaporated off. The H NMR of the crude reaction products showed
the formation of only one isomer in each case. Even for the pyridine based enediynes 1e and 1f, high regioselectivity
(~84%) was observed; in this case, the two regioisomers were isolated in a ratio of 1:0.19. All the cyclized products
1
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were isolated in pure form by column chromatography and their structures were elucidated by H, C and NOESY
spectral analysis. As a representative example, the NOESY spectrum and X-ray crystal structure of one halogenated
product is shown in Figure 2. The results of nucleophilic addition to p-benzyne are shown in Table 1. Apart from
excellent regioselectivity, the yields were nearly quantitative except for the benzyloxy enediyne 1e for which the
isolated yield was 76% (may be due to participation of benzylic hydrogen into alternate radical initiated pathway).
Ha
Hb
a
Me
O
CH3
H
b
N
S
O
2
NOESY spectrum of enediyne 1a
ORTEP diagram of enediyne 1a
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Hc
Ha
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Hb
Hd
c
Me
O
O2
b
a
S
d
N
Me
Br
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NOESY spectrum of cyclised product 2d
ORTEP diagram of cyclised product 2d
Figure 2: NOESY spectra and ORTEP diagram of enediyne 1a and cyclised product 2d
Scheme 5: Reaction of enediynes with lithium halides
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Enediynes
Reagent
Isomeric
products
Product
Combined
yield
1
2
3
4
5
6
7
8
9
1
1
a
a
LiBr
LiCl
LiI
2a
3a
3a’
3a”
3b
3c
Only 2a
Only 2a’
99%
95%
96%
90%
76%
99%
93%
96%
2a’
2a”
2b
2c
1a
1b
Only 2a”
LiBr
LiBr
LiBr
LiBr
LiBr
Only 2b
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
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7
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9
0
1
2
3
4
5
6
7
8
9
0
1
c
Only 2c
1
d
2d
2e
3d
3e
Only 2d
1
e
2e : 3e :: 1 : 0.19
2f : 3f :: 1 : 0.19
1
f
2f
3f
Table 1: Experimental Results
Inspection of the results depicted in Table 1 shows that unlike the previously reported examples, all the enediynes 1a-
d reacted with lithium bromide to give exclusively one halogenated product in very high yields. The nucleophilic
addition also worked with other halides LiCl and LiI. These are the first examples of complete regioselectivity in
nucleophilic addition to p-benzynes generated via Bergman Cyclization and make such addition reactions to lead to
16
synthetically useful halo functionalized arenes . When we switch over to a heterosystem like pyridine based
enediynes 1e and 1f, high selectivity was also observed (84%). This type of regioselective nucleophilic addition leads
to useful synthetic intermediates. The benzotetrahydroisoquinoline as well as the corresponding pyridine fused
1
7
analogues with a halogen atom at the peri position offers a route to different natural and non-natural skeletons via
cross-coupling reactions. Literature survey reveals the existence of several medicinally important natural products
1
8
with similar skeleton (benzo tetrahydroisoquinoline). The high regioselectivity observed by incorporation of an o-
substituent certainly expands the scope of this reaction.
The approach of the halide ion was also according to our proposed hypothesis (Figure 1). As suggested by Perrin et
8
al., the barrier-less nature of nucleophilic addition to p-benzyne, was found to be true in our previous cases of
unsymmetrical cyclic enediyne. Just to make sure that ortho substitution does not alter the barrier-less nature, we have
carried out similar calculations and found that the nucleophilic addition remains barrier-less (computation results
1
0
included in SI). Thus this observation of exclusive regioselectivity is striking. Earlier, we have also shown that the
N-tosyl group has no role in inducing any selectivity to halide addition. This indicates that the regioselectivity in these
present systems must be originating due to the presence of the alkoxy group at the ortho position.
C1 radical center
C4 radical center
C1 radical center
C4 radical center
a
b
c
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Figure 3: Electrostatic potential mapped over electron density (isovalue: 0.0004 e/Å3) at the [BS-B3LYP/6-31G(d,p)]
level of theory for the diradical originating from 1a. 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. (a) view from C1 side; (b) front view; (c) view from C4 side.
To understand such high degree of regioselectivity we looked at the surface electrostatic potential adjacent to two
radical centers. Unlike the previously reported examples (where the difference in surface charge density causing
selectivity was marginal), here the electrostatic potential significantly differs in the vicinity of two reactive radical
center (C1 and C4 as shown in Figure 3). For an example if we consider p-benzyne generated from the ortho-methoxy
enediyne 1a, the conformation of methoxy group (as shown in Figure 4) is such that the methyl is away from the
radical center thus keeping the lone pair of oxygen in syn orientation with respect to C1 radical center. Such spatial
disposition of lone pair creates highly negative electrostatic potential close to C1 center thus creating a substantial and
clear difference in electrostatic potential in the other side (C4 center). This fact compels the negatively charged
bromide or other nucleophiles to come from opposite side (C4 side) with respect to the ortho-methoxy group. The
conformation of other p-benzynes from alkoxy substituted enediynes (1b-d) being similar, the resulting electrostatic
potential map is also nearly the same (see SI). Thus the explanation is applicable to all other p-benzynes generated
from enediynes 1b-d (results included in SI). One interesting point to be noted here is that the crystal structure,
computation and NOESY spectral analysis of respective enediynes and halogenated products suggest that the
conformations (Figure 4) we are talking about is all anti (wrt alkoxy alkyl group) and syn (wrt oxygen lone pair) with
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nearby radical center. Next in case of pyridine fused enediyne, the electrostatic potential difference also supports the
observation. The nitrogen lone pair acted as a repulsive factor (negative electrostatic potential, see SI) to force the
nucleophile to approach from the opposite side. However, unlike the previous cases (>99% regioselectivity), here
besides the exclusive product another regioisomer is formed as minor product (ratio 2e : 3e :: 1 : 0.19 and 2f : 3f :: 1 :
0
.19 ). This may be attributed to the geometric disposition of nitrogen lone pair of pyridine which is actually parallel
with the trajectory of attacking nucleophile, whereas in alkoxy substituted cases the oxygen lone pair is bent towards
the nucleophile’s trajectory.
syn (OMe wrt C1 radical center)
anti (OMe wrt C1 radical center)
Figure 4: optimized syn and anti-conformations of p-benzyne generated from enediyne 1a
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CONCLUSION
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In summary, we have for the first time reported excellent regioselectivity in barrier-less nucleophilic addition20, 21 to p-
benzyne leading to the formation of mostly one regioisomer in near quantitative yields. This was achieved via
incorporation of various alkoxy substitutions at the ortho position of a cyclic N-substituted enediyne. High
regioselectivity was also obtained in pyridine based system, which further broadens the scope of such reaction in
heterocyclic systems. This observed selectivity has been successfully explained on the basis of electrostatic potential.
Currently we are exploring other ways to induce similar selectivity and the synthetic utility of the halo functionalised
cyclised products.
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EXPERIMENTAL SECTION
General experimental details
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 F ), and the spots
2
54
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
reported as uncorrected. H and 13C NMR spectra for all the compounds were recorded at 400/500/600 and
1
1
00/125/150 MHz (Bruker UltrashieldTM 400, AscendTM 500, AscendTM 600), respectively. The spectra were recorded
in deuterochloroform (CDCl ) and deuterated dimethyl sulfoxide (DMSO-d ) as solvent at room temperature.
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Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as internal standard (CDCl : δ
3
H
1
= 7.26, δ = 77.16 ppm). Data for H NMR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet,
C
brs = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet), coupling constant
13
(Hz), integration. Data for C NMR are reported as chemical shift. HRMS spectra using ESI were recorded on an
ESI-FTMS mass spectrometer.
General experimental Procedure
1
0
All the compounds were synthesized using our earlier reported procedure . The starting materials (4a-c) were
synthesized using literature known procedure12a,22
.
[2-((3-(2-bromo-3-methoxyphenyl)prop-2-yn-1-yl)oxy)tetrahydro-2H-pyran] (5a)
The compound 5a was synthesized by Sonogashira coupling between 2-bromo-3-iodoanisole (4a) and THP-protected
1
propargyl alcohol in 90% yield (1.2 g). Brown gummy liquid; R 0.66 (hexane/EtOAc, 7.8/2.2); H NMR (600 MHz,
f
CDCl ) δ 7.20 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.99 (t, J = 3 Hz, 1H), 4.54 (s,
3
1
3
1
2H), 3.92–3.86 (m, 4H), 3.59–3.56 (m, 1H), 1.86–1.60 (m, 6H); C{ H} NMR (100 MHz, CDCl ) δ 156.3, 127.9,
3
1
26.5, 125.7, 115.2, 111.9, 96.8, 90.1, 84.5, 62.3, 56.5, 54.7, 30.4, 25.5, 19.2; HRMS [ESI-TOF] calcd for
+
C H BrO H [M+H] 325.0439, found 325.0436.
1
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17
3
[4-(2-methoxy-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)phenyl)but-3-yn-1-ol] (6a)
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The compound 6a was synthesized by Sonogashira coupling between 5a and 3-butyn-1-ol in 44% yield (450 mg).
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Brown gummy liquid; R 0.17 (hexane/EtOAc, 7.8/2.2); H NMR (400 MHz, CDCl ) δ 7.18 (t, J = 8.0 Hz, 1H), 7.06
f
3
(d, J = 7.6 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 4.97 (s, 1H), 4.53 (ABq, J = 24.8, 16.0 Hz, 2H), 3.93–3.82 (m, 6H),
1
3
1
3.55–3.58 (m, 1H), 2.78 (s, 2H), 1.84–1.55 (m, 6H); C{ H} NMR (100 MHz, CDCl ) δ 160.0, 128.6, 126.9, 124.6,
3
1
15.5, 110.7, 96.8, 95.9, 88.9, 84.9, 77.9, 62.0, 61.0, 56.2, 54.9, 30.3, 25.5, 24.7, 19.0; HRMS [ESI-TOF] calcd for
+
C H O H [M+H] 315.1596, found 315.1595.
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[2-((3-(2-(4-azidobut-1-yn-1-yl)-3-methoxyphenyl)prop-2-yn-1-yl)oxy)tetrahydro-2H-pyran] (7a)
The compound 7a was synthesized from 6a via mesylation followed by nucleophilic substitution (with NaN ) in 68%
3
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yield (290 mg). Yellow liquid; R 0.57 (hexane/EtOAc, 7.8/2.2); H NMR (500 MHz, CDCl ) δ 7.18 (t, J = 7.9 Hz,
f
3
1H), 7.05 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 4.97 (t, J = 3 Hz, 1H), 4.53 (ABq, J = 25.5, 15.5 Hz, 2H),
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3
.90–3.86 (m, 4H), 3.58–3.53 (m, 3H), 2.81 (t, J = 7.0 Hz, 2H), 1.90–1.53 (m, 6H); C{ H} NMR (125 MHz, CDCl )
3
δ 160.1, 128.7, 127.2, 124.5, 115.2, 110.7, 96.7, 94.5, 89.02, 84.6, 62.0, 56.1, 54.8, 50.2, 30.4, 25.5, 21.1, 19.1;
+
HRMS [ESI-TOF] calcd for C H N O Na [M+Na] 362.1481, found 362.1482.
19 21
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[N-(4-(2-methoxy-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)phenyl)but-3-yn-1-yl)-4-
methylbenzenesulfonamide] (8a)
The compound 8a was synthesized from 7a via reduction to amine followed by N-protection (with TsCl) in 79% yield
1
(
270 mg). White gummy solid; R 0.20 (hexane/EtOAc, 7.8/2.2); H NMR (600 MHz, CDCl ) δ 7.78 (d, J = 7.9 Hz,
f
3
2
H), 7.25–7.20 (m, 3H), 7.07 (d, J = 7.7 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 5.64 (s, 1H), 4.98 (s, 1H), 4.57–4.51 (m,
2H), 3.93 (s, 3H), 3.87 (t, J = 10.4 Hz, 1H), 3.56 (d, J = 11.2 Hz, 1H), 3.24–3.21 (m, 2H), 2.58 (t, J = 5.6 Hz, 2H),
1
3
1
2
.38 (s, 3H), 1.84–1.55 (m, 6H); C{ H} NMR (150 MHz, CDCl ) δ 160.3, 143.4, 137.6, 129.8, 128.8, 127.2, 126.5,
3
124.7, 115.0, 110.7, 96.7, 94.8, 89.3, 84.6, 78.7, 62.0, 56.2, 54.9, 41.8, 30.4, 25.5, 21.6, 21.0, 19.0; HRMS [ESI-TOF]
+
calcd for C H NO SNa [M+Na] 490.1664, found 490.1665.
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[N-(4-(2-(3-hydroxyprop-1-yn-1-yl)-6-methoxyphenyl)but-3-yn-1-yl)-4-methylbenzenesulfonamide] (9a)
The compound 9a was synthesized from 8a via OTHP deprotection in 80% yield (150 mg). Light yellow gummy
1
liquid; R 0.08 (hexane/EtOAc, 7.8/2.2); H NMR (600 MHz, CDCl ) δ 7.78 (d, J = 7.8 Hz, 2H), 7.26–7.20 (m, 3H),
f
3
7
1
1
.08 (d, J = 7.7 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 5.64 (t, J = 5.6 Hz, 1H), 4.58 (s, 2H), 3.89 (s, 3H), 3.21 (dd, J =
1
3
1
1.7, 5.9 Hz, 2H), 2.61 (t, J = 5.9 Hz, 2H), 2.38 (s, 3H); C{ H} NMR (150 MHz, CDCl ) δ 160.0, 143.7, 136.9,
3
29.9, 129.0, 127.2, 126.9, 124.9, 114.5, 110.7, 94.4, 92.2, 84.0, 78.7, 56.2, 51.5, 41.7, 21.6, 21.0; HRMS [ESI-TOF]
+
calcd for C H NNaO S [M+Na] 406.1089, found 406.1087.
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[1-[4-Methylphenylsulfonyl]-[5,6]-[benz-(3-methoxy)]-1-azacyclodec-3,7-diyne] (1a)
The compound 1a was synthesized from 9a via mesylation followed by cyclization in 81% yield (80 mg). White solid;
1
m.p. decomposition over 120 ˚C; R 0.40 (hexane/EtOAc, 7.8/2.2); H NMR (400 MHz, CDCl ) δ 7.75 (d, J = 7.8 Hz,
f
3
2
H), 7.30–7.25 (m, 2H), 7.19 (t, J = 8.0 Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.15 (s, 2H), 3.89
1
3
1
(
s, 3H), 3.58 (t, J = 4.8 Hz, 2H), 2.87 (t, J = 4.8 Hz, 2H), 2.39 (s, 3H); C{ H} NMR (150 MHz, CDCl ) δ 158.1,
3
1
43.9, 135.8, 130.0, 129.7, 128.6, 127.4, 120.6, 118.3, 111.0, 102.0, 92.7, 86.8, 80.4, 56.1, 51.2, 42.2, 22.9, 21.6.
+
HRMS [ESI-TOF] calcd for C H NO SH [M+H] 366.1164, found 366.1160.
2
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19
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The Journal of Organic Chemistry
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[2-bromo-1-ethoxy-3-iodobenzene] (4b)
The compound 4b was synthesized from corresponding alcohol in 68% yield (694 mg). White gummy liquid; R 0.77
f
1
(hexane/EtOAc, 7.8/2.2); H NMR (600 MHz, CDCl ) δ 7.47 (dd, J = 8.1, 1.1 Hz, 1H), 6.97 (t, J = 8.1 Hz, 1H), 6.85–
3
1
3
1
6
1
.82 (m, 1H), 4.08 (q, J = 7.0 Hz, 2H), 1.47 (t, J = 7.0 Hz, 3H); C{ H} NMR (150 MHz, CDCl ) δ 156.4, 132.1,
3
29.5, 120.1, 112.6, 103.1, 65.5, 14.8.
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[2-((3-(2-bromo-3-ethoxyphenyl)prop-2-yn-1-yl)oxy)tetrahydro-2H-pyran] (5b)
The compound 5b was synthesized by Sonogashira coupling between 4b and THP-protected propargyl alcohol in 94%
1
yield (700 mg). Brown gummy liquid; R 0.68 (hexane/EtOAc, 7.8/2.2); H NMR (400 MHz, CDCl ) δ 7.17 (t, J = 7.3
f
3
Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 4.99 (s, 1H), 4.54 (s, 2H), 4.11–4.06 (m, 2H), 3.92–3.87
1
3
1
(
m, 1H), 3.60–3.55 (m, 1H), 1.91–1.50 (m, 6H), 1.48–1.44 (m, 3H); C{ H} NMR (100 MHz, CDCl ) δ 155.9, 127.8,
3
1
26.5, 125.7, 115.9, 113.3, 96.9, 89.9, 84.7, 65.2, 62.3, 54.8, 30.4, 25.5, 19.3, 14.8; HRMS [ESI-TOF] calcd for
+
C H BrO Na [M+Na] 361.0415, found 361.0413.
16 19
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[2-((3-(2-(4-azidobut-1-yn-1-yl)-3-ethoxyphenyl)prop-2-yn-1-yl)oxy)tetrahydro-2H-pyran] (7b)
The compound 7b was synthesized first by Sonogashira coupling between 5b and 3-butyn-1-ol and then mesylation
followed by nucleophilic substitution (with NaN ) in 66% yield (255 mg). Brown gummy liquid; R 0.63
3
f
1
(
hexane/EtOAc, 7.8/2.2); H NMR (600 MHz, CDCl ) δ 7.14 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.81 (d, J =
3
8
.3 Hz, 1H), 4.97 (t, J = 3.1 Hz, 1H), 4.53 (ABq, J = 23.7, 16.2 Hz, 2H), 4.08 (q, J = 6.9 Hz, 2H), 3.91–3.86 (m, 1H),
1
3
1
3.59–3.52 (m, 3H), 2.80 (t, J = 7.2 Hz, 2H), 1.86–1.56 (m, 6H), 1.44 (t, J = 6.9 Hz, 3H); C{ H} NMR (150 MHz,
CDCl ) δ 159.7, 128.6, 127.1, 124.5, 115.8, 112.3, 96.7, 94.3, 88.9, 84.7, 77.6, 64.7, 62.0, 54.9, 50.3, 30.5, 25.6, 21.0,
3
+
19.2, 14.8; HRMS [ESI-TOF] calcd for C H N O Na [M+Na] 376.1637, found 376.1641.
2
0
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[N-(4-(2-ethoxy-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)phenyl)but-3-yn-1-yl)-4-
methylbenzenesulfonamide] (8b)
The compound 8b was synthesized from 7b via reduction to amine followed by N-protection (with TsCl) in 80% yield
1
(300 mg). White gummy liquid; R 0.27 (hexane/EtOAc, 7.8/2.2); H NMR (600 MHz, CDCl ) δ 7.78 (d, J = 8.1 Hz,
f
3
2H), 7.24 (d, J = 8.1 Hz, 2H), 7.18 (t, J = 8.1 Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 5.45 (t, J =
6.0 Hz, 1H), 4.98 (t, J = 3.1 Hz, 1H), 4.56–4.50 (m, 2H), 4.13 (q, J = 6.9 Hz, 2H), 3.90–3.85 (m, 1H), 3.58–3.55 (m,
1H), 3.24 (q, J = 6.0 Hz, 2H), 2.59 (t, J = 6.0 Hz, 2H), 2.39 (s, 3H), 1.87–1.50 (m, 6H), 1.45 (t, J = 6.9 Hz, 3H);
13
1
C{ H} NMR (150 MHz, CDCl ) δ 159.6, 143.4, 137.7, 129.8, 128.7, 127.2, 126.7, 124.5, 115.4, 112.0, 96.6, 94.4,
3
89.2, 84.8, 78.5, 64.7, 62.0, 54.9, 42.0, 30.4, 25.5, 21.6, 21.2, 19.0, 14.8; HRMS [ESI-TOF] calcd for C H NO SNa
2
7
31
5
+
[
M+Na] 504.1821, found 504.1820.
[N-(4-(2-ethoxy-6-(3-hydroxyprop-1-yn-1-yl)phenyl)but-3-yn-1-yl)-4-methylbenzenesulfonamide] (9b)
The compound 9b was synthesized from 8b via OTHP deprotection in 85% yield (200 mg). White gummy liquid; Rf
1
0
.08 (hexane/EtOAc, 7.8/2.2); H NMR (600 MHz, CDCl ) δ 7.78 (d, J = 7.2 Hz, 2H), 7.25 (m, 2H), 7.19 (t, J = 8.0
3
Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 5.55 (s, 1H), 4.59 (s, 2H), 4.10 (q, J = 6.8 Hz, 2H), 3.22–
1
3
1
3
.20 (m, 2H), 2.62 (t, J = 5.6 Hz, 2H), 2.39 (s, 3H), 1.43 (t, J = 6.8 Hz, 3H); C{ H} NMR (150 MHz, CDCl ) δ
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59.4, 143.7, 137.0, 129.9, 128.9, 127.3, 127.0, 124.8, 114.9, 112.1, 94.0, 92.1, 84.2, 78.7, 64.7, 51.5, 41.7, 21.6, 21.1,
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+
14.8; HRMS [ESI-TOF] calcd for C H NO SNa [M+Na] 420.1245, found 420.1247.
2
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[1-[4-Methylphenylsulfonyl]-[5,6]-[benz-(3-ethoxy)]-1-azacyclodec-3,7-diyne] (1b)
The compound 1b was synthesized from 9b via mesylation followed by cyclization in 70% yield (152 mg). White
1
solid; m.p. 107–109 ˚C; R 0.43 (hexane/EtOAc, 7.8/2.2) H NMR (400 MHz, CDCl ) δ 7.75 (d, J = 7.8 Hz, 2H), 7.29
f
3
(d, J = 7.8 Hz, 2H), 7.16 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 4.16–4.11 (m, 4H),
0
1
2
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4
5
6
7
8
9
0
1
2
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7
8
9
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8
9
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7
8
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7
8
9
0
13
1
3
.60–3.55 (m, 3H), 2.90–2.84 (m, 3H), 2.39 (s, 3H), 1.45 (t, J = 6.9 Hz, 3H); C{ H} NMR (150 MHz, CDCl ) δ
3
157.4, 143.9, 135.8, 130.0, 129.7, 128.4, 127.4, 120.5, 118.7, 112.4, 101.7, 92.4, 87.0, 80.6, 64.6, 51.2, 42.2, 23.0,
+
2
1.6, 14.8; HRMS [ESI-TOF] calcd for C H NO SH [M+H] 380.1320, found 380.1319.
2
2
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[1-(benzyloxy)-2-bromo-3-iodobenzene] (4c)
The compound 4c was synthesized from corresponding alcohol in 71% yield (1 g). White gummy liquid; R 0.80
f
1
(hexane/EtOAc, 7.8/2.2); H NMR (600 MHz, CDCl ) δ 7.50–7.45 (m, 3H), 7.40 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.1
3
1
3
1
Hz, 1H), 6.97 (t, J = 8.1 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 5.14 (s, 2H); C{ H} NMR (150 MHz, CDCl ) δ 156.0,
3
136.2, 132.6, 129.5, 128.8, 128.2, 127.1, 120.4, 113.1, 103.2, 71.3.
[2-((3-(3-(benzyloxy)-2-bromophenyl)prop-2-yn-1-yl)oxy)tetrahydro-2H-pyran] (5c)
The compound 5c was synthesized by Sonogashira coupling between 4c and THP-protected propargyl alcohol in 92%
1
yield (900 mg). Brown gummy liquid; R 0.66 (hexane/EtOAc, 7.8/2.2); H NMR (400 MHz, CDCl ) δ 7.48–7.46 (m,
f
3
2H), 7.41–7.30 (m, 2H), 7.32 (t, J = 7.1 Hz, 1H), 7.20–7.10 (m, 2H), 6.89 (d, J = 7.8 Hz, 1H), 5.16 (s, 2H), 5.00 (s,
1
3
1
1
H), 4.56 (s, 2H), 3.91 (t, J = 9.9 Hz, 1H), 3.60–3.56 (m, 1H), 1.87–1.60 (m, 6H); C{ H} NMR (125 MHz, CDCl ) δ
3
155.6, 136.5, 128.7, 128.1, 127.8, 127.1, 126.7, 126.2, 116.2, 113.9, 97.0, 90.2, 84.6, 71.2, 62.3, 54.8, 30.5, 25.6, 19.3;
+
HRMS [ESI-TOF] calcd for C H BrO Na [M+Na] 423.0572, found 423.0575.
2
1
21
3
[2-((3-(2-(4-azidobut-1-yn-1-yl)-3-(benzyloxy)phenyl)prop-2-yn-1-yl)oxy)tetrahydro-2H-pyran] (7c)
The compound 7c was synthesized first by Sonogashira coupling between 5c and 3-butyn-1-ol and then mesylation
followed by nucleophilic substitution (with NaN ) in 50% yield (145 mg). Yellow liquid; R 0.63 (hexane/EtOAc,
3
f
1
7
4
.8/2.2); H NMR (400 MHz, CDCl ) δ 7.50–7.30 (m, 5H), 7.15–7.05 (m, 2H), 6.85 (d, J = 8.1 Hz, 1H), 5.15 (s, 2H),
3
.99 (s, 1H), 4.60–4.50 (m, 2H), 3.88 (t, J = 10.0 Hz, 1H), 3.59–3.56 (m, 1H), 3.52 (t, J = 7.3 Hz, 2H), 2.81 (t, J = 7.3
1
3
1
Hz, 2H), 1.87–1.57 (m, 6H); C{ H} NMR (150 MHz, CDCl ) δ 159.4, 136.9, 128.6, 128.6, 128.0, 127.1, 127.1,
3
1
24.9, 116.1, 113.0, 96.6, 94.6, 89.0, 84.6, 77.5, 70.7, 62.0, 54.8, 50.2, 30.4, 25.5, 21.0, 19.1; HRMS [ESI-TOF] calcd
+
for C H N O K [M+K] 454.1533, found 454.1530.
2
5
25
3
3
[N-(4-(2-(benzyloxy)-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)phenyl)but-3-yn-1-yl)-4-
methylbenzenesulfonamide] (8c)
The compound 8c was synthesized from 7c via reduction to amine followed by N-protection (with TsCl) in 68% yield
1
(111 mg). Yellow gummy liquid; R 0.27 (hexane/EtOAc, 7.8/2.2); H NMR (600 MHz, CDCl ) δ 7.74 (d, J = 8.2 Hz,
f
3
2
H), 7.40–7.30 (m, 5H), 7.20 (d, J = 8.1 Hz, 2H), 7.13 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 8.3
Hz, 1H), 5.48 (t, J = 6.0 Hz, 1H), 5.21 (s, 2H), 4.99 (t, J = 3.1 Hz, 1H), 4.58–4.51 (m, 2H), 3.90–3.85 (m, 1H), 3.59–
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1
3
1
3
.56(m, 1H), 3.22 (q, J = 6.3 Hz, 2H), 2.61 (t, J = 6.1 Hz, 2H), 2.36 (s, 3H), 1.86–1.54 (m, 6H); C{ H} NMR (150
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
MHz, CDCl ) δ 159.3, 143.4, 137.6, 136.8, 129.8, 128.8, 128.0, 127.2, 127.0, 125.0, 115.9, 113.0, 96.6, 94.8, 89.3,
3
+
8
4.7, 78.3, 70.7, 61.9, 54.9, 41.9, 30.4, 25.5, 21.6, 21.2, 19.0; HRMS [ESI-TOF] calcd for C H NO SNa [M+Na]
32 33 5
566.1977, found 566.1981.
[N-(4-(2-(benzyloxy)-6-(3-hydroxyprop-1-yn-1-yl)phenyl)but-3-yn-1-yl)-4-methylbenzenesulfonamide] (9c)
The compound 9c was synthesized from 8c via OTHP deprotection in 76% yield (60 mg). Yellow gummy liquid; Rf
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
0
.07 (hexane/EtOAc, 7.8/2.2); H NMR (400 MHz, CDCl ) δ 7.78 (d, J = 7.9 Hz, 2H), 7.41–7.01 (m, 9H), 6.86 (d, J =
3
1
3
1
8.0 Hz, 1H), 5.54 (s, 1H), 5.17 (s, 2H), 4.60 (s, 2H), 3.22–3.21 (m, 2H), 2.63 (t, J = 5.7 Hz, 2H), 2.39 (s, 3H); C{ H}
NMR (150 MHz, CDCl ) δ 159.3, 143.7, 137.0, 136.8, 129.9, 128.8, 128.7, 128.1, 127.3, 127.1, 127.0, 125.3, 115.6,
3
+
113.1, 94.4, 92.3, 84.1, 78.7, 70.8, 51.6, 41.8, 21.6, 21.1; HRMS [ESI-TOF] calcd for C H NO SNa [M+Na]
2
7
25
4
4
82.1402, found 482.1401.
[1-[4-Methylphenylsulfonyl]-[5,6]-[benz-(3-benzyloxy)]-1-azacyclodec-3,7-diyne] (1c)
The compound 1c was synthesized from 9c via mesylation followed by cyclization in 75% yield (41 mg). Yellow
1
gummy liquid; R 0.60 (hexane/EtOAc, 7.8/2.2); H NMR (400 MHz, CDCl ) δ 7.76 (d, J = 7.9 Hz, 2H), 7.44–7.28
f
3
(m, 7H), 7.10 (t, J = 8.0 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 5.21 (s, 2H), 4.15 (s, 2H), 3.62–
13
1
3
.55 (m, 2H), 2.92–2.85 (m, 2H), 2.39 (s, 3H); C{ H} NMR (150 MHz, CDCl ) δ 157.2, 143.9, 136.8, 135.8, 130.0,
3
1
29.8, 128.8, 128.4, 128.0, 127.4, 127.1, 120.9, 119.1, 113.3, 102.0, 92.6, 86.9, 80.5, 70.8, 51.2, 42.2, 23.0, 21.6;
+
HRMS [ESI-TOF] calcd for C H NO SH [M+H] 442.1477, found 442.1476.
2
7
23
3
[4-(2-bromo-3-methoxyphenyl)but-3-yn-1-ol] (5d)
The compound 5d was synthesized by Sonogashira coupling between 2-bromo-3-iodo anisole (4a) and 3-butyn-1-ol in
1
9
1% yield (519 mg). Brown gummy liquid; R 0.31 (hexane/EtOAc, 7.8/2.2); H NMR (400 MHz, CDCl ) δ 7.20 (t, J
f
3
=
8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 3.89 (s, 3H), 3.85 (t, J = 6.0 Hz, 2H), 2.74 (t, J = 6.0
1
3
1
Hz, 2H); C{ H} NMR (150 MHz, CDCl ) δ 156.3, 127.9, 127.0, 125.4, 115.3, 111.5, 91.8, 81.7, 61.1, 56.5, 24.2;
3
+
HRMS [ESI-TOF] calcd for C H BrO H [M+H] 255.0021, found 255.0022.
1
1
11
2
[4-(3-methoxy-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)phenyl)but-3-yn-1-ol] (6d)
The compound 6d was synthesized by Sonogashira coupling between 5d and THP-protected propargyl alcohol in 41%
1
yield (360 mg). Brown gummy liquid; R 0.17 (hexane/EtOAc, 7.8/2.2); H NMR (400 MHz, CDCl ) δ 7.19 (t, J = 8.1
f
3
Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 5.03 (s, 1H), 4.58 (ABq, J = 22.8, 15.6, 2H), 3.91–3.84 (m,
1
3
1
4H), 3.82 (t, J = 5.8 Hz, 2H), 3.58–3.55 (m, 1H), 2.71 (t, J = 5.8 Hz, 2H), 1.86–1.53 (m, 6H); C{ H} NMR (150
MHz, CDCl ) δ 160.3, 129.2, 128.1, 124.1, 114.6, 110.3, 96.5, 93.1, 91.6, 81.4, 81.2, 61.9, 61.0, 56.1, 55.2, 30.3, 25.5,
3
+
24.3, 19.0; HRMS [ESI-TOF] calcd for C H O H [M+H] 315.1596, found 315.1598.
1
9
22
4
[2-((3-(2-(4-azidobut-1-yn-1-yl)-6-methoxyphenyl)prop-2-yn-1-yl)oxy)tetrahydro-2H-pyran] (7d)
The compound 7d was synthesized from 6d via mesylation followed by nucleophilic substitution (with NaN ) in 59%
3
1
yield (210 mg). Brown liquid; R 0.54 (hexane/EtOAc, 7.8/2.2); H NMR (400 MHz, CDCl ) δ 7.19 (t, J = 8 Hz, 1H),
f
3
7
.02 (d, J = 7.6 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 5.04 (s, 1H), 4.64–4.54 (m, 2H), 3.91–3.86 (m, 4H), 3.58–3.50 (m,
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1
3
1
3
H), 2.76 (t, J = 7.1 Hz, 2H), 1.87–1.55 (m, 6H); C{ H} NMR (150 MHz, CDCl ) δ 160.3, 129.1, 127.7, 124.3,
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
114.7, 110.5, 96.4, 93.4, 90.1, 81.2, 81.0, 61.9, 56.1, 55.0, 50.0, 30.5, 25.6, 20.8, 19.1; HRMS [ESI-TOF] calcd for
+
C H N O Na [M+Na] 362.1481, found 362.1481.
1
9
21
3
3
[N-(4-(3-methoxy-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)phenyl)but-3-yn-1-yl)-4-
methylbenzenesulfonamide] (8d)
The compound 8d was synthesized from 7d via reduction to amine followed by N-protection (with TsCl) in 96% yield
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
(
245 mg). Yellow gummy liquid; R 0.20 (hexane/EtOAc, 7.8/2.2); H NMR (400 MHz, CDCl ) δ 7.78 (d, J = 8.1 Hz,
f
3
2H), 7.23–7.17 (m, 3H), 6.93 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 5.45 (t, J = 5.1 Hz, 1H), 5.06 (s, 1H), 4.60
s, 2H), 3.88–3.85 (m, 4H), 3.59–3.56 (m, 1H), 3.23–3.20 (m, 2H), 2.59 (t, J = 6.0 Hz, 2H), 2.36 (s, 3H), 1.84–1.57
(
1
3
1
(m, 6H); C{ H} NMR (100 MHz, CDCl ) δ 160.4, 143.4, 137.6, 129.8, 129.2, 127.7, 127.3, 124.1, 114.7, 110.5,
3
9
6.3, 93.5, 90.4, 81.5, 81.3, 61.8, 56.1, 55.1, 41.9, 30.4, 29.8, 25.6, 21.0, 18.9; HRMS [ESI-TOF] calcd for
+
C H NO SNa [M+Na] 490.1664, found 490.1664.
2
6
29
5
[N-(4-(2-(3-hydroxyprop-1-yn-1-yl)-3-methoxyphenyl)but-3-yn-1-yl)-4-methylbenzenesulfonamide] (9d)
The compound 9d was synthesized from 8d via OTHP deprotection in 80% yield (150 mg). White gummy liquid; Rf
1
0
7
=
.07 (hexane/EtOAc, 7.8/2.2); H NMR (400 MHz, CDCl ) δ 7.79 (d, J = 7.9 Hz, 2H), 7.24–7.18 (m, 3H), 6.95 (d, J =
3
.7 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 5.61 (t, J = 5.2 Hz, 1H), 4.65 (s, 2H), 3.89 (s, 3H), 3.23–3.18 (m, 2H), 2.58 (t, J
1
3
1
5.8 Hz, 2H), 2.39 (s, 3H); C{ H} NMR (150 MHz, CDCl ) δ 160.4, 143.7, 137.1, 129.9, 129.2, 127.3, 124.0,
3
+
1
14.6, 110.5, 96.4, 90.1, 82.0, 80.5, 56.1, 51.8, 41.7, 21.6, 20.9; HRMS [ESI-TOF] calcd for C H NO SNa [M+Na]
21 21 4
406.1089, found 406.1086.
[1-[4-Methylphenylsulfonyl]-[5,6]-[benz-(6-methoxy)]-1-azacyclodec-3,7-diyne] (1d)
The compound 1d was synthesized from 9d via mesylation followed by cyclization in 82% yield (91 mg). White
1
solid; m.p. decomposition over 164 ˚C; R 0.37 (hexane/EtOAc, 7.8/2.2); H NMR (600 MHz, CDCl ) δ 7.75 (d, J =
f
3
8
.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 7.21 (t, J = 8.1 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.20
13
1
(
s, 2H), 3.88 (s, 3H), 3.59 (t, J = 5.1 Hz, 2H), 2.81 (t, J = 5.1 Hz, 2H), 2.39 (s, 3H); C{ H} NMR (150 MHz, CDCl )
3
δ 158.1, 143.9, 136.0, 130.8, 130.0, 129.2, 127.5, 120.9, 117.4, 110.5, 98.3, 96.3, 84.1, 83.4, 56.1, 51.1, 42.6, 22.4,
+
2
1.6; HRMS [ESI-TOF] calcd for C H NO SH [M+H] 366.1164, found 366.1161.
2
1
19
3
[2-bromo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine] (5e)
The compound 5e was synthesized by Sonogashira coupling between 2-bromo-3-iodo pyridine (commercially
available) and THP-protected propargyl alcohol in 85% yield (1.09 g). Brown gummy liquid; R 0.80 (hexane/EtOAc,
f
1
3
/2); H NMR (400 MHz, CDCl ) δ 8.30–8.28 (m, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.24–7.21 (m, 1H), 4.96 (s, 1H), 4.54
3
1
3
1
(
s, 2H), 3.89 (t, J = 9.2 Hz, 1H), 3.59–3.56 (m, 1H), 1.86–1.60 (m, 6H); C{ H} NMR (100 MHz, CDCl ) δ 148.8,
3
1
44.6, 141.3, 123.3, 122.2, 97.1, 93.1, 82.4, 62.3, 54.7, 30.4, 25.5, 19.2.; HRMS [ESI-TOF] calcd for C H BrNO H
13 14 2
+
[
M+H] 296.0286, found 296.0288.
[4-(3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-2-yl)but-3-yn-1-ol] (6e)
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1
The compound 6e was synthesized by Sonogashira coupling between 5e and 3-butyn-1-ol in 82% yield (891 mg). H
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NMR (600 MHz, CDCl ) δ 8.47 (dd, J = 4.8, 1.6 Hz, 1H), 7.72 (dd, J = 7.9, 1.6 Hz, 1H), 7.17 (dd, J = 7.9, 4.8 Hz,
3
1
H), 4.97 (t, J = 3.2 Hz, 1H), 4.54 (ABq, J = 30.6, 16.0 Hz, 2H), 3.89–3.84 (m, 3H), 3.60–3.56 (m, 1H), 2.91 (s, 1H),
1
3
1
2.76 (t, J = 5.9 Hz, 2H), 1.86–1.56 (m, 6H); C{ H} NMR (150 MHz, CDCl ) δ 148.9, 145.4, 139.4, 122.3, 122.0,
3
+
9
2
6.8, 92.3, 91.7, 82.6, 81.0, 62.0, 60.8, 54.8, 30.3, 25.5, 24.2, 18.9; HRMS [ESI-TOF] calcd for C H NO H [M+H]
17 19 3
86.1443, found 286.1443.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
[2-(4-azidobut-1-yn-1-yl)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine] (7e)
The compound 7e was synthesized from 6e via mesylation followed by nucleophilic substitution (with NaN ) in 58%
3
1
yield (402 mg). Yellow liquid; R 0.60 (hexane/EtOAc, 3/2); H NMR (600 MHz, CDCl ) δ 8.48 (dd, J = 4.8, 1.5 Hz,
f
3
1H), 7.73 (dd, J = 7.9, 1.5 Hz, 1H), 7.17 (dd, J = 7.9, 4.8 Hz, 1H), 4.96 (t, J = 3.2 Hz, 1H), 4.55 (q, J = 16.0 Hz, 2H),
1
3
1
3
.90–3.86 (m, 1H), 3.60–3.55 (m, 3H), 2.79 (t, J = 7.1 Hz, 2H), 1.81–1.55 (m, 6H); C{ H} NMR (150 MHz, CDCl )
3
δ 148.9, 145.0, 139.4, 122.5, 122.1, 96.8, 91.9, 90.4, 82.3, 81.1, 62.0, 54.7, 49.7, 30.4, 25.5, 20.6, 19.0; HRMS [ESI-
+
TOF] calcd for C H N O H [M+H] 311.1508, found 311.1505.
17 18
4
2
[4-methyl-N-(4-(3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-2-yl)but-3-yn-1-
yl)benzenesulfonamide] (8e)
The compound 8e was synthesized from 7e via reduction to amine followed by N-protection (with TsCl) in 90% yield
1
(
356 mg). White gummy liquid; R 0.29 (hexane/EtOAc, 3/2); H NMR (600 MHz, CDCl ) δ 8.46 (dd, J = 4.8, 1.1 Hz,
f
3
1
H), 7.77 (d, J = 8.1 Hz, 2H), 7.74 (dd, J = 7.9, 1.1 Hz, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.19 (dd, J = 7.9, 4.8 Hz, 1H),
5.65 (t, J = 6.1 Hz, 1H), 4.99 (t, J = 3.1 Hz, 1H), 4.57 (ABq, J = 21.0, 16.2 Hz, 2H), 3.90–3.86 (m, 1H), 3.60–3.58 (m,
1
3
1
1
H), 3.24 (q, J = 6.3 Hz, 2H), 2.63 (t, J = 6.3 Hz, 2H), 2.37 (s, 3H), 1.86–1.54 (m, 6H); C{ H} NMR (150 MHz,
CDCl ) δ 148.9, 145.0, 143.5, 139.5, 137.5, 129.8, 127.2, 122.4, 122.2, 96.8, 92.1, 90.9, 82.5, 81.3, 61.9, 54.8, 41.6,
3
+
3
0.3, 25.5, 21.6, 21.1, 18.9; HRMS [ESI-TOF] calcd for C H N O SH [M+H] 439.1692, found 439.1691.
2
4
26
2
4
[N-(4-(3-(3-hydroxyprop-1-yn-1-yl)pyridin-2-yl)but-3-yn-1-yl)-4-methylbenzenesulfonamide] (9e)
The compound 9e was synthesized from 8e via OTHP deprotection in 75% yield (191 mg). Yellow liquid; R 0.11
f
1
(hexane/EtOAc, 3/2); H NMR (600 MHz, CDCl ) δ 8.47 (d, J = 4.3 Hz, 1H), 7.78 (d, J = 7.8 Hz, 2H), 7.74 (d, J = 7.9
3
Hz, 1H), 7.27–7.19 (m, 3H), 5.67 (t, J = 5.5 Hz, 1H), 4.62 (s, 2H), 3.31 (brs, 1H), 3.24–3.20 (m, 2H), 2.63 (t, J = 5.7
1
3
1
Hz, 2H), 2.39 (s, 3H); C{ H} NMR (150 MHz, CDCl ) δ 149.0, 144.6, 143.9, 139.6, 136.9, 130.0, 127.2, 122.5,
3
+
1
22.3, 95.0, 90.6, 81.8, 81.7, 51.4, 41.4, 21.7, 21.0; HRMS [ESI-TOF] calcd for C H N O SH [M+H] 355.1116,
1
9
18
2
3
found 355.1117.
[1-[4-Methylphenylsulfonyl]-[5,6]-[N-3-pyridinyl]-1-azacyclodec-3,7-diyne] (1e)
The compound 1e was synthesized from 9e via mesylation followed by cyclization in 65% yield (36 mg). Colourless
1
gummy solid; R 0.46 (hexane/EtOAc, 3/2); H NMR (400 MHz, CDCl ) δ 8.45 (d, J = 4.1 Hz, 1H), 7.75 (d, J = 7.9
f
3
Hz, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.9 Hz, 2H), 7.17–7.11 (m, 1H), 4.18 (s, 2H), 3.58 (t, J = 4.6 Hz, 2H),
1
3
1
2
1
.86 (t, J = 4.6 Hz, 2H), 2.39 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 149.1, 148.3, 144.1, 135.7, 134.8, 130.1,
3
27.4, 125.4, 121.6, 100.2, 94.8, 85.3, 82.8, 51.0, 42.3, 22.4, 21.7; HRMS [ESI-TOF] calcd for C H N O SH
1
9
16
2
2
+
[
M+H] 337.1011, found 337.1011.
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
[N-(4-(2-bromopyridin-3-yl)but-3-yn-1-yl)-4-methylbenzenesulfonamide] (9f)
The compound 9f was synthesized by Sonogashira coupling between 2-bromo-3-iodo pyridine (commercially
available) and tosyl-protected homopropargylamine (A) in 83% yield (300 mg). light brown gummy liquid; R 0.20
f
1
(
hexane/EtOAc, 4/1); H NMR (600 MHz, CDCl ) δ 8.28 (dd, J = 4.8, 1.9 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.64 (dd,
3
J = 7.6, 1.9 Hz, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.21 (dd, J = 7.6, 4.8 Hz, 1H), 5.08 (t, J = 6.2 Hz, 1H), 3.24 (q, J = 6.4
1
3
1
Hz, 2H), 2.64 (t, J = 6.4 Hz, 2H), 2.41 (s, 3H). C{ H} NMR (150 MHz, CDCl ) δ 148.6, 144.6, 143.8, 141.0, 137.1,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
+
1
29.9, 127.2, 123.3, 122.3, 94.0, 79.8, 41.7, 21.7, 21.1; HRMS [ESI-TOF] calcd for C H BrN O SH [M+H]
16 15 2 2
379.0116, found 379.0114.
[N-(4-(2-(3-hydroxyprop-1-yn-1-yl)pyridin-3-yl)but-3-yn-1-yl)-4-methylbenzenesulfonamide] (9f’)
The compound 9f’ was synthesized by Sonogashira coupling between 9f and propargylalcohol in 50% yield (130 mg).
1
brown gummy liquid; R 0.11 (hexane/EtOAc, 1/1); H NMR (600 MHz, CDCl ) δ 8.49 (s, 1H), 7.79 (d, J = 8.1 Hz,
f
3
2
3
H), 7.64 (d, J = 7.9 Hz, 1H), 7.28–7.26 (m, 2H), 7.18 (dd, J = 7.9, 4.8 Hz, 1H), 5.56 (t, J = 6.0 Hz, 1H), 4.62 (s, 2H),
1
3
1
.24–3.21 (m, 2H), 3.15 (brs, 1H), 2.64 (t, J = 5.9 Hz, 2H), 2.40 (s, 3H); C{ H} NMR (150 MHz, CDCl ) δ 148.7,
3
144.7, 143.8, 139.0, 137.1, 129.9, 127.2, 122.6, 122.4, 93.4, 92.0, 83.8, 79.5, 51.4, 41.6, 21.6, 21.2; HRMS [ESI-TOF]
+
calcd for C H N O SH [M+H] 355.1116, found 355.1118.
1
9
18
2
3
[1-[4-Methylphenylsulfonyl]-[5,6]-[N-6-pyridinyl]-1-azacyclodec-3,7-diyne] (1f)
The compound 1f was synthesized from 9f’ via mesylation followed by cyclization in 77% yield (30 mg). Colourless
1
gummy solid; R 0.14 (hexane/EtOAc, 4/1); H NMR (600 MHz, CDCl ) δ 8.43 (d, J = 4.9 Hz, 1H), 7.75 (d, J = 8.2
f
3
Hz, 2H), 7.59 (dd, J = 7.8, 1.5 Hz, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.17 (dd, J = 7.8, 4.9 Hz, 1H), 4.18 (s, 2H), 3.59–
1
3
1
3.56 (m, 2H), 2.88–2.84 (m, 2H), 2.40 (s, 3H); C{ H} NMR (150 MHz, CDCl ) δ 148.3, 147.7, 144.2, 135.5, 135.1,
3
1
30.1, 127.5, 126.6, 122.2, 100.5, 94.3, 85.9, 81.7, 51.1, 42.1, 22.6, 21.7; HRMS [ESI-TOF] calcd for C H N O SH
19 16 2 2
+
[
M+H] 337.1011, found 337.1009.
[10-bromo-6-methoxy-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline] (2a)
The compound 2a was synthesized from 1a in presence of LiBr, under Bergman cyclization condition in 99% yield
1
(
23 mg). White semi-solid; R 0.41 (hexane/EtOAc, 4/1) H NMR (600 MHz, CDCl ) δ 8.00 (s, 1H), 7.80–7.77 (m,
f
3
3
H), 7.42 (t, J = 8.2 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.81 (d, J = 7.6 Hz, 1H), 4.46 (s, 2H), 3.98 (s, 3H), 3.41 (t, J =
1
3
1
5.8 Hz, 2H), 3.14 (t, J = 5.8 Hz, 2H), 2.41 (s, 3H); C{ H} NMR (150 MHz, CDCl ) δ 155.0, 143.9, 133.5, 132.1,
3
1
32.1, 131.0, 130.0, 127.9, 127.1, 125.4, 122.2, 121.3, 118.9, 104.4, 55.8, 49.9, 43.7, 30.0, 21.7; HRMS [ESI-TOF]
+
calcd for C H BrNO SH [M+H] 446.0426, found 446.0406.
2
1
20
3
[10-chloro-6-methoxy-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline] (2a’)
The compound 2a’ was synthesized from 1a in presence of LiCl, under Bergman cyclization condition in 95% yield
1
(
18 mg). White solid; m.p. 193–195 ˚C; R 0.40 (hexane/EtOAc, 4/1); H NMR (400 MHz, CDCl ) δ 7.95 (s, 1H),
f
3
7.79–7.76 (m, 3H), 7.42 (t, J = 8.1 Hz, 1H), 7.34 (d, J = 7.8 Hz, 2H), 6.81 (d, J = 7.6 Hz, 1H), 4.48 (s, 2H), 3.98 (s,
1
3
1
3
H), 3.42 (t, J = 5.6 Hz, 2H), 3.14 (t, J = 5.6 Hz, 2H), 2.41 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 155.1, 143.9,
3
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33.5, 131.6, 130.8, 130.0, 129.1, 128.9, 127.9, 126.9, 125.3, 120.5, 116.2, 104.5, 55.8, 47.0, 43.7, 29.9, 21.7; HRMS
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
[ESI-TOF] calcd for C H ClNO SH [M+H] 402.0931, found 402.0931.
2
1
20
3
[10-iodo-6-methoxy-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline] (2a’’)
The compound 2a’’ was synthesized from 1a in presence of LiI, under Bergman cyclization condition in 96% yield
1
(24 mg). White solid; m.p. 201–203 ˚C; R 0.40 (hexane/EtOAc, 4/1); H NMR (400 MHz, CDCl ) δ 8.02 (s, 1H), 7.79
f
3
(d, J = 7.9 Hz, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 8.2 Hz, 1H), 7.34 (d, J = 7.9 Hz, 2H), 6.82 (d, J = 7.7 Hz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
1
H), 4.41 (s, 2H), 3.99 (s, 3H), 3.40 (t, J = 5.7 Hz, 2H), 3.13 (t, J = 5.7 Hz, 2H), 2.41 (s, 3H); C{ H} NMR (100
MHz, CDCl ) δ 154.9, 143.9, 134.9, 134.7, 133.6, 132.4, 130.0, 127.9, 127.3, 125.0, 124.2, 122.6, 104.4, 103.4, 55.9,
3
+
5
5.9, 43.8, 30.0, 21.7; HRMS [ESI-TOF] calcd for C H INOK [M+K] 468.0227, found 468.0244.
2
1
20
[10-bromo-6-ethoxy-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline] (2b)
The compound 2b was synthesized from 1b in presence of LiBr, under Bergman cyclization condition in 90% yield
1
(28 mg). White solid; m.p. 200–202 ˚C; R 0.44 (hexane/EtOAc, 4/1); H NMR (600 MHz, CDCl ) δ 8.02 (s, 1H),
f
3
7
.79–7.76 (m, 3H), 7.40 (t, J = 8.1 Hz, 1H), 7.34 (d, J = 7.8 Hz, 2H), 6.79 (d, J = 7.8 Hz, 1H), 4.46 (s, 2H), 4.19 (q, J
1
3
1
= 6.9 Hz, 2H), 3.41 (t, J = 5.8 Hz, 2H), 3.16 (t, J = 5.8 Hz, 2H), 2.41 (s, 3H), 1.54 (t, J = 6.9 Hz, 3H); C{ H} NMR
(150 MHz, CDCl ) δ 154.3, 143.9, 133.7, 132.2, 132.0, 130.9, 130.0, 127.9, 127.2, 125.6, 122.2, 121.5, 118.7, 105.2,
3
+
6
4.2, 49.9, 43.7, 30.0, 21.7, 14.9; HRMS [ESI-TOF] calcd for C H BrNO SH [M+H] 460.0582, found 460.0580.
2
2
22
3
[
6-(benzyloxy)-10-bromo-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline] (2c)
The compound 2c was synthesized from 1c in presence of LiBr, under Bergman cyclization condition in 76% yield
1
(14 mg). White semi-solid; R 0.46 (hexane/EtOAc, 4/1) H NMR (600 MHz, CDCl ) δ 8.06 (s, 1H), 7.82 (d, J = 8.6
f
3
Hz, 1H), 7.78 (d, J = 7.5 Hz, 2H), 7.50 (d, J = 7.3 Hz, 2H), 7.44–7.32 (m, 6H), 6.89 (d, J = 7.5 Hz, 1H), 5.23 (s, 2H),
1
3
1
4
1
7
.46 (s, 2H), 3.41 (t, J = 5.4 Hz, 2H), 3.14 (t, J = 5.4 Hz, 2H), 2.41 (s, 3H); C{ H} NMR (150 MHz, CDCl ) δ 154.1,
3
43.9, 136.8, 133.5, 132.2, 132.2, 131.1, 130.0, 128.8, 128.3, 127.9, 127.7, 127.1, 125.6, 122.2, 121.5, 119.2, 105.8,
+
0.6, 49.9, 43.7, 30.0, 21.7; HRMS [ESI-TOF] calcd for C H BrNO SH [M+H] 522.0739, found 522.0734.
27 24
3
[5-bromo-9-methoxy-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline] (2d)
The compound 2d was synthesized from 1d in presence of LiBr, under Bergman cyclization condition in 99% yield
1
(19 mg). White solid; m.p. 197–199 ˚C; R 0.37 (hexane/EtOAc, 4/1); H NMR (600 MHz, CDCl ) δ 7.98 (s, 1H), 7.80
f
3
(d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.42 (t, J = 8.2 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 7.6 Hz,
13
1
1
H), 4.43 (s, 2H), 3.99 (s, 3H), 3.45 (t, J = 6.2 Hz, 2H), 3.14 (t, J = 6.2 Hz, 2H), 2.40 (s, 3H); C{ H} NMR (150
MHz, CDCl ) δ 155.2, 144.0, 133.6, 132.6, 132.5, 130.6, 129.9, 128.0, 127.3, 125.3, 124.6, 119.3, 119.3, 104.3, 55.9,
3
+
4
8.6, 44.3, 31.2, 21.6; HRMS [ESI-TOF] calcd for C H BrNO SH [M+H] 446.0426, found 446.0424.
2
1
20
3
[5-bromo-7-tosyl-6,7,8,9-tetrahydropyrido[3,4-g]quinolone] (2e)
The compound 2e was synthesized from 1e in presence of LiBr, under Bergman cyclization condition in 82% yield
1
(10.9 mg). White semisolid; R 0.43 (hexane/EtOAc, 3.4/1.6); H NMR (600 MHz, CDCl ) δ 8.87 (dd, J = 4.1, 1.4 Hz,
f
3
1
2
H), 8.53 (d, J = 8.5 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.45 (dd, J = 8.5, 4.1 Hz, 1H), 7.34 (d, J = 8.3 Hz,
1
3
1
H), 4.48 (s, 2H), 3.44 (t, J = 5.9 Hz, 2H), 3.21 (t, J = 5.9 Hz, 2H), 2.42 (s, 3H); C{ H} NMR (150 MHz, CDCl ) δ
3
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51.4, 147.4, 144.1, 136.8, 135.1, 133.4, 131.3, 130.0, 128.6, 127.9, 126.7, 122.2, 121.6, 49.6, 43.4, 29.9, 21.7;
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
HRMS [ESI-TOF] calcd for C H BrN O SH [M+H] 417.0272, found 417.0273.
1
9
17
2
2
[10-bromo-7-tosyl-6,7,8,9-tetrahydropyrido[3,4-g]quinolone] (3e)
The compound 3e was synthesized from 1e in presence of LiBr, under Bergman cyclization condition in 14% yield
1
(2.1 mg). White semisolid; R 0.24 (hexane/EtOAc, 3.4/1.6); H NMR (600 MHz, CDCl ) δ 9.00 (dd, J = 4.2, 1.5 Hz,
f
3
1
H), 8.08 (dd, J = 8.3, 1.5 Hz, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.52 (s, 1H), 7.43 (dd, J = 8.3, 4.2 Hz, 1H), 7.32 (d, J =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
8
.3 Hz, 2H), 4.45 (s, 2H), 3.47 (t, J = 6.2 Hz, 2H), 3.24 (t, J = 6.2 Hz, 2H), 2.41 (s, 3H); C{ H} NMR (150 MHz,
CDCl ) δ 151.4, 144.6, 144.2, 136.1, 136.0, 133.2, 132.4, 130.0, 128.0, 127.7, 127.0, 124.4, 122.0, 48.2, 44.0, 31.3,
3
+
2
1.7; HRMS [ESI-TOF] calcd for C H BrN O SH [M+H] 417.0272, found 417.0268.
1
9
17
2
2
[5-bromo-8-tosyl-6,7,8,9-tetrahydropyrido[4,3-g]quinolone] (2f)
The compound 2f was synthesized from 1f in presence of LiBr, under Bergman cyclization condition in 83% yield
1
(22.4 mg). White semisolid; R 0.20 (DCM/EtOAc, 9.7/0.3); H NMR (600 MHz, CDCl ) δ 8.87 (d, J = 4.1 Hz, 1H),
f
3
8
.53 (d, J = 8.6 Hz, 1H), 7.79 (s, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.45 (dd, J = 8.6, 4.1 Hz, 1H), 7.33 (d, J = 8.2 Hz, 2H),
1
3
1
4.46 (s, 2H), 3.46 (t, J = 6.2 Hz, 2H), 3.17 (t, J = 6.2 Hz, 2H), 2.41 (s, 3H); C{ H} NMR (150 MHz, CDCl ) δ 151.2,
3
1
47.2, 144.2, 135.3, 135.1, 133.1, 132.8, 130.0, 128.0, 127.1, 126.4, 124.0, 122.3, 48.4, 44.1, 31.0, 21.7; HRMS [ESI-
+
TOF] calcd for C H BrN O SH [M+H] 417.0272, found 417.0276.
1
9
17
2
2
[10-bromo-8-tosyl-6,7,8,9-tetrahydropyrido[4,3-g]quinolone] (3f)
The compound 3f was synthesized from 1f in presence of LiBr, under Bergman cyclization condition in 16% yield
1
(4.3 mg). White semisolid; R 0.54 (DCM/EtOAc, 9.7/0.3); H NMR (600 MHz, CDCl ) δ 9.03–8.99 (m, 1H), 8.09 (d,
f
3
J = 8.2 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.57 (s, 1H), 7.45 (dd, J = 8.2, 4.1 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 4.55 (s,
1
3
1
2
1
H), 3.47 (t, J = 5.9 Hz, 2H), 3.21 (t, J = 5.9 Hz, 2H), 2.44 (s, 3H). C{ H} NMR (150 MHz, CDCl ) δ 151.2, 144.2,
3
44.1, 136.0, 134.4, 133.9, 133.4, 130.0, 127.9, 126.6, 124.5, 122.1, 50.0, 43.4, 29.7, 21.7; HRMS [ESI-TOF] calcd
+
for C H BrN O SH [M+H] 417.0272, found 417.0271.
19 17
2
2
Supporting Information
1H, 13C, 2D (NOESY) NMR spectra of the synthesized compounds and X-ray crystallographic data, Cartesian co-
ordinates of optimized geometry and other computational details.
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. ED is grateful to IIT Kharagpur for a senior research fellowship.
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References
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9. Alabugin et al. have earlier reported intramolecular H-atom transfer from methoxy during Bergman cyclization of
o-methoxy acyclic enediyne thereby slowing down the retro BC. The driving force for such abstraction is the stability
of resultant alkoxy methyl radical. In our case, such a possibility can be ruled out as in nucleophilic addition, the
+
intramolecular abstraction of H will lead to an unstable alkoxy methyl anion. Moreover, the molecule prefers the anti
geometry as revealed by X-ray structure.(for reference see: Zeidan, T. A; Manoharan, M.; Alabugin I. V. Ortho Effect
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Chem. 2006, 71, 954-961.)
2
0. We have tried other nucleophiles like azide for which preliminary data suggests that the ratio of two regiomeric
azides is ~1:0.5. The reaction is complicated by the appearance of other products, presumably via dealkylation due to
the presence of pivalic acid and azide as nucleophile. We need to do further experiments to come out with precise
results on the ratio of regiomeric azides.
2
1. The reaction works in other polar aprotic solvents like acetonitrile. Non-polar solvents could not be used because
of solubility problems. Moreover, some these are good H or halogen atom donor thus making the radical pathway
predominant. Polar protic solvent like methanol is also a good H-atom donor as well as a nucleophile which further
complicates the reaction.
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