Thermal and Photoinduced Copper-Promoted C-Se Bond Formation: Synthesis of 2-Alkyl-1,2-benzisoselenazol-3(2H)-ones and Evaluation against Mycobacterium tuberculosis

Article abstract of DOI:10.1021/acs.joc.7b00440

2-Alkyl-1,2-benzisoselenazol-3(2H)-ones, represented by ebselen (1a), are being studied intensively for a range of medicinal applications. We describe both a new thermal and photoinduced copper-mediated cross-coupling between potassium selenocyanate (KSeCN) and N-substituted ortho-halobenzamides to form 2-alkyl-1,2-benzisoselenazol-3(2H)-ones containing a C-Se-N bond. The copper ligand (1,10-phenanthroline) facilitates C-Se bond formation during heating via a mechanism that likely involves atom transfer (AT), whereas, in the absence of ligand, photoinduced activation likely proceeds through a single electron transfer (SET) mechanism. A library of 15 2-alkyl-1,2-benzisoselenazol-3(2H)-ones was prepared. One member of the library was azide-containing derivative 1j that was competent to undergo a strain-promoted azide-alkyne cycloaddition. The library was evaluated for inhibition of Mycobacterium tuberculosis (Mtb) growth and Mtb Antigen 85C (Mtb Ag85C) activity. Compound 1f was most potent with a minimal inhibitory concentration (MIC) of 12.5 μg/mL and an Mtb Ag85C apparent IC₅₀ of 8.8 μM.

Full text of DOI:10.1021/acs.joc.7b00440

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Article
Thermal and photoinduced copper-promoted C-Se bond
formation: Synthesis of 2-alkyl-1,2-benzisoselenazol-3(2H)-
ones and evaluation against Mycobacterium tuberculosis
Sandeep Thanna, Christopher M Goins, Susan E Knudson,
Richard A. Slayden, Donald R Ronning, and Steven J. Sucheck
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00440 • Publication Date (Web): 08 Mar 2017
Downloaded from http://pubs.acs.org on March 9, 2017
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Thermal and photoinduced copperꢀpromoted CꢀSe bond
formation: Synthesis of 2ꢀalkylꢀ1,2ꢀbenzisoselenazolꢀ3(2H)ꢀones
and evaluation against Mycobacterium tuberculosis
a
a
b
b
Sandeep Thanna, Christopher M. Goins, Susan E. Knudson, Richard A. Slayden, Donald R.
a
a
Ronning, and Steven J. Sucheck *
a
Department of Chemistry and Biochemistry, The University of Toledo, 2801 W. Bancroft
Street, Toledo, OH, USA 43606
b
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and
Pathology, Colorado State University, Fort Collins, CO 80523
Supporting Information Placeholder
Abstract
2ꢀAlkylꢀ1,2ꢀbenzisoselenazolꢀ3(2H)ꢀones, represented by the ebselen (1a), are being studied
intensively for a range of medicinal applications. We describe both a new thermal and
photoinduced copperꢀmediated crossꢀcoupling between potassium selenocyanate (KSeCN) and
Nꢀsubstituted orthoꢀhalobenzamides to form 2ꢀalkylꢀ1,2ꢀbenzisoselenazolꢀ3(2H)ꢀones containing
a CꢀSeꢀN bond. The copper ligand (1,10ꢀphenanthroline) facilitates CꢀSe bond formation during
heating via a mechanism that likely involves atom transfer (AT); whereas, in the absence of
ligand, photoinduced activation likely proceeds through a single electron transfer (SET)
mechanism. A library of fifteen 2ꢀalkylꢀ1,2ꢀbenzisoselenazolꢀ3(2H)ꢀones was prepared. One
member of the library was azideꢀcontaining derivative 1j that was competent to undergo a strainꢀ
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promoted azideꢀalkyne cycloaddition. The library was evaluated for inhibition of Mycobacterium
tuberculosis (Mtb) growth and Mtb Antigen 85C (Mtb Ag85C) activity. Compound 1f was most
potent with a minimal inhibitory concentration (MIC) of 12.5 µg/mL and an Mtb Ag85C
apparent IC of 8.8 µM.
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Keywords: Cuꢀpromoted CꢀSe crossꢀcoupling, photoinduced, ebselen, 1,2ꢀbenzisoselenazolꢀ
(2H)ꢀones, Mycobacterium tuberculosis (Mtb), Antigen 85C (Ag85C)
3
Introduction
ꢀPhenylꢀ1,2ꢀbenzisoselenazolꢀ3(2H)ꢀone (1a), also called ebselen, EBS, PZ51, and DR3305
(Figure 1), is a lipid soluble organoꢀselenium compound that mimics glutathione peroxidase
2
(GPx) activity and has the ability to inhibit some bacterial thioredoxin reductase systems (Figure
1
ꢀ3
4ꢀ8
9
1
). EBS is being studied as a possible therapeutic agent for cancer, bipolar disorder, and for
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0ꢀ14
a rapidly expanding list of other indications.
Our interest was drawn to EBS due to our own
15ꢀ19
efforts to identifying new Mycobacterium tuberculosis (Mtb) Ag85 inhibitors,
by reports of
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its activity against Mtb Ag85C and drugꢀresistant Mtb. In this work we develop a convenient
method to prepare libraries of 2ꢀalkylꢀ1,2ꢀbenzisoselenazolꢀ3(2H)ꢀones in order to identify a lead
candidate to for the treatment of Mtb infection.
Our efforts lead us to evaluate the contributions of a number of groups with regard to the
preparation of EBS and its derivatives. The first report was in 1924 by Lesser and Weiss who
2
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started from 2ꢀ(hydroxyselanyl)cyclohexaneꢀ1ꢀcarbonyl chloride. Later, Welter et al. converted
23ꢀ32
to anthranilic acid to 2,2'ꢀdiselanediyldibenzoic acid followed by elaboration to EBS.
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Further, Nꢀsubstituted benzamides have been treated with nꢀbutyl lithium, Se powder, and CuBr
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3ꢀ35
to produce this chemotype.
Kumar et al., accessed EBS using Nꢀsubstituted orthoꢀ
halobenzamides catalytic CuI, 1,10ꢀphenanthroline (2), Se powder, base, and heating for 8ꢀ36
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t
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h.
The same group later accessed EBS using KSeO Bu while Schinowski et al. used lithium
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diselenide and Nꢀsubstituted orthoꢀiodobenzamides. In this work, we report that EBS and its
derivatives can be prepared in as little as one hour using CuI, 1,10ꢀphenanthroline (2), KSeCN
(
3), and Nꢀsubstituted orthoꢀhalobenzamides (4aꢀc) (Figure 1, eq. 1). In addition, we report a
second method which represents the first example of a low temperature photoinduced copperꢀ
mediated cross coupling of (4bꢀc) with KSeCN (3) to form a CꢀSe bond leading to the formation
of EBS (Figure 1, eq. 2).
Figure 1. Thermal (eq. 1) and photoinduced (eq. 2) preparation of ebselen (1a).
The discovery of a photoinduced copperꢀmediated cross coupling for CꢀSe bonds also lead us to
evaluate some of the key contributions to copperꢀmediated cross coupling chemistry. The origins
of this chemistry can be traced back to the early 1900’s where Ullmann and Goldberg introduced
copper as a catalyst for CꢀC and CꢀN bond formation. Within the last twenty years, there has
been a resurgence in the use of copper with the development of new methods to allow the
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formation of other types CꢀN, CꢀO, CꢀS and CꢀSe bonds.
The crossꢀcoupling reactions
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reported toꢀdate for CꢀSe bond formation require temperatures of greater than 100 °C.
However, we took note of the work of Fu and Peters who reported photoinduced Cuꢀcatalyzed
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crossꢀcouplings to form CꢀS and CꢀN
bonds at temperatures as low as 0 °C in seminal work
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which expanded the scope of Ullmannꢀtype chemistry to thermally sensitive compounds.
Herein, we introduce ligandꢀdirected thermal and photoinduced Cuꢀpromoted crossꢀcoupling
methods to form CꢀSe bonds in which the presence of ligand favors thermal activation via a
putative atom transfer (AT) mechanism, whereas the absence of ligand favors photoinduced
activation, which proceeds through a putative single electron transfer (SET) mechanism (Scheme
1
). In this work, the CꢀSe bond formation results in a putative selenoscyanate 6 which cyclizes to
the medicinally important ebselen (1a) and its congeners in a single step.
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Scheme 1. Proposed Cuꢀpromoted Mechanisms for Thermal and Photoinduced Synthesis of 2ꢀ
a
Alkylꢀ1,2ꢀbenzisoselenazolꢀ3(2H)ꢀones
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a
AT = Atom transfer, SET = Single electron transfer.
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Results
Thermal activation. We initially explored synthesis of 2ꢀalkylꢀ1,2ꢀbenzisoselenazolꢀ3(2H)ꢀones
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using reported conditions requiring 1,10ꢀphenanthroline(phen)ꢀCuI Seꢀpowder, potassium
,
carbonate in combination with 4a to afford 1a; however, yields were modest in our hands after
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30 h of heating (Table 1, entry 1).
We noted that diaryl selenides have been successfully
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synthesized using phenꢀCuI in combination with KSeCN. Based on this observation, we
surmised that the substitution of insoluble selenium power with KSeCN would produce an
intermediate selenoscyanate 6 that would cyclize to a selenazolꢀ3(2H)ꢀone under base promoted
conditions. Indeed, when we used aryl bromide 4b, KSeCN, 0.2 equivalents of phenꢀCuI and 2.5
,
equivalents of Cs CO we obtained similar yields to entry 1 (Table 1) with a significantly
2
3
reduced reaction time (Table 1, entry 2). Furthermore, the reaction was homogenous and
convenient to workup. Increasing the phenꢀCuI to 0.30 equivalents improved the yield to 34%
and 53% at 1 and 12 hour reaction times, respectively (Table 1, entry 3 and 4), while increasing
the catalyst loading to 1.0 equivalents resulted in a 71% yield in one hour (Table 1, entry 5). The
chloride 4a was less reactive producing a 33% yield in 1.5 hours under the same conditions
(
Table 1, entry 6), while the iodide 4c reacted quickly to produce 1a in 75% yield (Table 1, entry
). Improved yields for the 4a were obtained by switching the solvent to acetonitrile (Table 1,
entry 8). Aryl bromide 4b and aryl iodide 4c were converted to 1a using acetonitrile in 89% and
1% yields (Table 1, entry 9 and 10), respectively. DMSO could also be used as a solvent;
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however, yields were reduced (Table 1, entry 11). Further we noted that 1,10ꢀphenathroline could
be removed from the reaction to produce 1a; however, the yields were reduced (Table 1, entry
12).
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Table 1. Optimization of Thermal Method to Produce 2ꢀPhenylꢀ1,2ꢀbenzisoselenazolꢀ3(2H)ꢀone
a
(1a)
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Entry
Aryl
PhenꢀCuI
Solvent
Temp (°C)
Time (h)
Yield (%)
Halide
(Equiv)
b
1
4a
4b
4b
4b
4b
4a
4c
4a
4b
4c
4b
4b
0.25
DMF
DMF
DMF
DMF
DMF
DMF
DMF
110
100
100
100
100
100
100
80
30
12
1
20
30
34
53
71
33
75
48
89
91
44
41
2
0.2
0.3
0.3
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
3
4
5
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7
8
9
12
1
1.5
0.6
1
CH CN
3
CH CN
82
12
12
1.5
12
3
1
0
CH CN
80
3
1
1
DMSO
100
82
c
1
2
CH CN
3
a
Unless otherwise stated 1.2 equivalents of KSeCN, and 2.5 equivalents of Cs CO were used
2
3
b
Condition used for comparison = Se powder, K CO (3.0 equiv), CuI (25 mol%), phen (25
2
3
3
6 c
mol%). No phen, ambient light. The temperatures reported were measured outside the reaction
vessel.
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A library of fourteen 1,2ꢀbenzisoselenazolꢀ3(2H)ꢀones was synthesized using this thermal
method. The members of the library differ from each other at the nitrogen substituent (Table 2).
Compounds 1a, 1d, 1h, 1i, and 1j were prepared with a phenyl group or an orthoꢀ or paraꢀ
substituted phenyl group (i.e., substituents = fluoro, methoxy, or azide) as the nitrogen
substituent. Compounds 1b, 1c, and 1e contained a benzyl substituent while compound 1f
possessed an allyl substituent. Aliphatic substituents were also tolerated as demonstrated by the
preparation of compounds 1g, 1m, and 1n, which contain aliphatic rings. Larger substituents
were tolerated such as tertꢀbutyl and adamantyl, as shown by the preparation of compounds 1k
and 1l, respectively.
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Table 2. Thermal Synthesis of a 1,2ꢀBenzisoselenazolꢀ3(2H)ꢀone Library
O
O
1
.0 eqiv phen-CuI
NHR
NR
Se
1
.2 equiv KSeCN
I
2
.5 equiv Cs CO , 0.4-1.5 h
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o
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1
00-110 C
1
a-n
4c, 5b-n
product,
yield (%)
product,
yield (%)
entry substrate
R
entry substrate
R
F
1
2
4c
5b
1a, 91
1b, 63
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9
5h
5i
1h, 52
1i, 35
OCH3
F
N3
3
5c
1c, 44
10
5j
1j, 23
H CO
3
OCH3
4
5
5d
5e
1d, 67
1e, 39
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5k
5l
1k, 75
1l, 72
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5f
1f, 39
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5m
5n
1m, 78
1n, 85
5g
1g, 63
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Photoinduced activation. We were intrigued by a report from Fu et al., that shows
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Ullmannꢀtype reactions occur under photoinduced conditions in the absence of a copper ligand.
Therefore, we explored this possibility with KSCN and aryl halides (4aꢀc) to form ebselen (1a).
Table 3 shows our results using aryl bromide (4b) which affords 1a in 87% using thermal
conditions (entry 1). Replacing the heating with a 22ꢀWatt (combined) Hg lamp (Figure S1) and
cooling with ice for two hours following by warming to room temperature afforded 1a in 31%
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(
Table 3, entry 2). A significant improvement in the yield to 82% occurred when the 1,10ꢀ
phenanthroline ligand was removed from the reaction (Table 3, entry 3). This data supports a
proposed mechanism in which a [(phen)CuI(SeCN)] (C) complex is needed in the thermal
activation method; however, not needed in the light activated case. The yield of the photoinduced
reaction dropped to 60% and 0% when 10 mol% and 0 mol% CuI were used (Table 3, entry 4
and 5, respectively). These results illustrate the requirement for copper (I). When the phenꢀfree
reaction was placed in the dark a 6% yield was observed (Table 3, entry 6) indicating the
importance of light. Removal of the base (Table 3, entry 7) resulted in no reaction. Ambient light
was sufficient to generate a 21% yield (Table 3, entry 8). Use of a 250ꢀWatt IR lamp produced a
63% yield; however, moderate heating (65ꢀ70 °C) was also involved (Table 3, entry 9). Finally,
t
the combination of 10 mol% CuI and NaO Bu as afforded a yield of 81%; however, the reaction
time was extended to 48 h (Table 3, entry 10). Iodide 4c was a superior substrate in the reaction;
however, chloride 4a was unreactive (Table 3, entry 11 and 12, respectively). The chemistry was
also successful for alkyl amide 5o which afforded ebselen derivative 1o in 85% yield. An
additional reaction was conducted using only the shortwave U.V. light (RPRꢀ3000A lamp, 250 to
3
60 nm) indicating that the BLEꢀ8T365 lamp (320 to 400 nm) was not needed for the reaction
(
Table 3, entry 14). In summary, the combination of light, a phenꢀfree Cu(I) source, and base
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promoted efficient formation of ebselen (1a). This is first report of a photoinduced copperꢀ
promoted CꢀSeꢀN bond forming reaction.
0
1
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8
9
0
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3
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9
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Table 3. Optimization of Photoinduced Method to Produce 2ꢀPhenylꢀ1,2ꢀbenzisoselenazolꢀ
a
3(2H)ꢀones
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
Entry
Equiv.,
Halogen
Energy
Yield (%)
Catalyst
b
1
2
3
4
5
6
7
8
9
1.0, phenꢀCuI
1.0, phenꢀCuI
1.0, CuI
0.1, CuI
ꢀ
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4c
Thermal reaction
22ꢀWatt Hg lamp
22 Watt Hg lamp
22 Watt Hg lamp
22ꢀWatt Hg lamp
dark
1a: 89
1a: 31
1a:82
c
1a:60
1a: N.R.
1a:6
1.0, CuI
1.0, CuI
1.0, CuI
1.0, CuI
0.1, CuI
1.0, CuI
1.0, CuI
1.0, CuI
1.0, CuI
22ꢀWatt Hg lamp
ambient light
1a: N.R.
1a:21
d
250ꢀWatt infrared lamp
22ꢀWatt Hg lamp
22ꢀWatt Hg lamp
22ꢀWatt Hg lamp
22ꢀWatt Hg lamp
14ꢀWatt Hg lamp
1a:63
c,e
1
0
1
1a:81
1
1a:92
12
4a
5o
4b
1a: N.R.
13
1o: 85
f
14
1a: 77
a
Unless otherwise stated, KSeCN (2.5 equiv.) and Cs CO (1.2 equiv.) 24 h, and acetonitrile
2
3
were used. Reactions were cooled for about 2 h and allowed to warm to room temperature (20
b
°
C). Thermal activation = phenꢀCuI (1.0 equiv.), KSeCN (1.2 equiv.), Cs CO (2.5 equiv), 12 h,
2
3
c
d
e
100ꢀ110 °C. 48 h. reaction reached 65ꢀ70 °C. NaOtBu (0.1 equiv). N.R. = no reaction. 22
f
Watts is a combined wattage of two lamps. reaction performed without BLEꢀ8T365 (320 to 400
nm) lamp, only the 14 Watt Rayonet RPRꢀ3000A lamp was used.
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Copper species study. We investigated the identity of possible copper complexes that might be
present under thermal conditions by electrospray ionization mass spectrometry (ESIꢀMS). For
the thermal case a mixture of CuI, phen, KSeCN and Cs CO (1.0:1.0:1.2:2.5) in acetonitrile was
2
3
0
1
2
3
4
5
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0
heated to 70ꢀ80 °C for 1 hour followed by ESIꢀMS. Major cationic species were detected at m/z:
63 +
65 +
423.2 and 425.1, which correspond to [(phen) Cu ] and [(phen) Cu ] (A), respectively
2
2
(Supporting Information, Figure S2). ESIꢀMS in the negative ion mode was inconclusive. For the
photoinduced case, a mixture of CuI, KSeCN and Cs CO (1.0:2.2:1.2) in acetonitrile, which
2
3
lacks phen, was irradiated with a 22ꢀWatt (combined) Hg lamp at room temperature for 1 h. ESIꢀ
MS was inconclusive in the positive ion mode; however, the negative ion mode revealed major
ꢀ
masses at m/z: 272, 274 and 276 that were assigned to the isotope envelope of [Cu(SeCN) ] ,
2
63
80
ꢀ
63
80
78
ꢀ
65
80
ꢀ
i.e., [Cu (Se CN) ] , [Cu (Se CN)(Se CN)] and [Cu (Se CN) ] (B), respectively,
2
2
(
Supporting Information, Figure S3). The absorption spectrum of the CuI, KSeCN and Cs CO3
2
(1.0:2.2:1.2) mixture was recorded after irradiation. The sample had a strong absorption band at
242 nm and the sample exhibited a strong fluorescence emission at 338 nm after excitation at
242 nm (Supporting Information, Figure S4). The absorption spectra of a mixture of complex B
(0.91 ꢁM) + 4b (0.91 ꢁM) and compound 4b (0.91 ꢁM) alone were obtained for characterization
purposes (Supporting Information, Figure S5). To provide evidence of that photoexcited
complex B can transfer energy to the substrate, substrate 4b was titrated into complex B and the
luminescence recorded revealing strong concentrationꢀdependent fluorescence quenching.
(Supporting Information, Figure S6)
Synthesis of biotinylated 1,2ꢀbenzisoselenazolꢀ3(2H)ꢀones. Our interest in 1,2ꢀ
benzisoselenazolꢀ3(2H)ꢀones was sparked by the cysteineꢀreactive nature of ebselen (1a) against
20
49
a Mtb Ag85C as well as reports of activity against other cysteineꢀcontaining enzymes. New
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tools are needed to identify other possible cysteineꢀreactive targets within Mtb and other
organisms. Our method development was driven in part by a desire to access 1j which could
potentially be used in combination with click chemistry as part of a longꢀterm goal to identify
cysteineꢀreactive enzymes and proteins. Once in hand, we investigated whether azide 1j would
undergo the copperꢀpromoted azideꢀalkyne Huisgen cycloaddition (CuAAC). Thus, azide 1j was
treated with to phenylacetylene (7) under standard CuAAC conditions. However, instead of
forming the 1,2,3ꢀtriazole, phenylacetylene opened the selenazolꢀ3(2H)ꢀone ring to afford the
isobaric dialkyl selenide (8). The formation of compound 8 was is confirmed by Xꢀray
crystallography (Scheme 2). In retrospect, the identification of adduct 8 is not surprising since
10
11
12
13
14
15
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17
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51
52
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57
58
59
60
5
0
Cu(I) is known to form Cuꢀacetylides. These intermediates can attack the Se atom in 1,2ꢀ
benzisoselenazolꢀ3(2H)ꢀones. To circumvent this problem 1j was treated with
dibenzocyclooctyneꢀPEG ꢀbiotin (9) in THF to afford triazole 10 in 79% yield. Compound 10
3
may serve as a useful affinityꢀbased tool for identification of enzymes with solvent exposed
cysteines.
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Scheme 2. Synthesis of 2ꢀPhenylbiotinylꢀ1,2ꢀbenzisoselenazolꢀ3(2H)ꢀone 10 and Xꢀray Crystal
Structure of Nꢀ(4ꢀAzidophenyl)ꢀ2ꢀ((phenylethynyl)selanyl)benzamide (8).
0
1
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9
0
Mtb growth and enzyme inhibition studies. The library of sixteen 1,2ꢀbenzisoselenazolꢀ3(2H)ꢀ
ones was screened against Mtb H Rv using a modified 96ꢀwell microplate Alamar blue assay
3
7
(MABA) to determine minimal inhibitory concentrations (MICs). The MICs ranged from 12.5ꢀ
00 µg/mL with the exception of compound 10 which was less active (Table 4). The library was
1
screened at 5 µM for the ability to covalently inhibit the activity of Mtb Ag85C using a
20
previously reported fluorometric assay. Mtb Ag85C is involved in the biosynthesis of the Mtb
5
1
cell wall and EBS has been shown to inhibit Mtb Ag85C by forming a selenenylsulfide bond at
2
0
Cys209. Based on the activity EBS it was expected that some members of this library would
behave similarly. The percent of Mtb Ag85C activity remaining after 40 minutes of incubation
ranged from 15ꢀ80% for the library (Table 4, Supporting Information Figure S7). The same
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assay was used to determine the apparent IC50 (appIC ) for each compound against Mtb
50
Ag85C after 15 minutes of incubation. This assay revealed appIC in the range of 0.54 to greater
50
than 100 µM (Table 4, Supporting Information Figure S8A and Figure S8B).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
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38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Activity of 2ꢀAlkylꢀ1,2ꢀbenzisoselenazolꢀ3(2H)ꢀones against Mtb H Rv and Mtb
3
7
Ag85C
a
b
Compound No.
cLogP
MIC (µg/ml)
Mtb Ag85C
Ag85C appIC50
activity (%)
(µM)
1a
3.70
3.65
3.65
3.62
3.73
2.73
4.60
3.85
3.85
4.15
3.20
4.62
3.43
3.99
5.76
5.26
12.5
25
17 ± 3
5.12
0.54
28.6
1.2
1
b
24 ± 17
36 ± 4
1c
12.5
25
1
d
20 ± 4
1e
25
20 ± 10
15 ± 2.0
30 ± 16
19 ± 2
6.5
1
f
12.5
50
8.8
1g
5.3
1
h
25
0.72
1.0
1
i
25
21 ± 7
1
j
25
20 ± 4
1.1
1
k
25
31 ± 12
59 ± 14
40 ± 17
44 ± 15
80 ± 7
1.5
1
l
50
25
1
m
25
4.1
1
n
25
3.7
8
100
N/A
> 100
2.02
1
0
61 ± 11
a
b
clogP was calculated using ChemBioDraw Ultra 13. The percent activity of Mtb Ag85C was
determined after treatment with 5 µM inhibitor and 40 min of preincubation. The activity was
normalized to an untreated (uninhibited) control reaction. The error was calculated by
performing each reaction in triplicate.
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Discussion
Chemistry. Different mechanisms have been proposed for the copperꢀcatalyzed Ullmannꢀtype
5
2ꢀ62
reactions.
These include
: i) oxidative additionꢀreductive elimination (OAꢀRE,
0
1
2
3
4
5
6
7
8
9
0
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2
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9
0
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2
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4
5
6
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9
0
57,63
2
56
Cu(I)/(III)),
ii) singleꢀelectron transfer (SET, Cu(I)/(II)), and iii) atom transfer (AT,
6
I
Cu(I)/(II)). An OAꢀRE cycle involves oxidative addition of ArꢀX on LCu (SeCN) to generate a
III
LCu (SeCN)ArX intermediate, which undergoes RE to form a CꢀSe coupled product. The work
64
65
66
67
of Mitani, Bethell, Hartwig, and Huffman suggested the possible occurrence of Cu(III)
species. However, more recent computational studies by Jones et al., suggest the energies
required to access the Cu(III) species in the OA step are prohibitively high in comparison to
68
energies required for key intermediates in SET and AT mechanisms. We propose AT and SET
mechanisms for the arylselenocyanate formation in Scheme 1. The AT mechanism involves
I
transfer of the halide atom from aryl halide to a (phen)Cu (SeCN) (C) complex forming caged
II
aryl radical (Ar·) and (phen)Cu (SeCN)X complex (D). Complex (D) would couple to afford a
I
arylselenocyanate 6 and (phen)Cu X (E). Intermediate E can undergo ligand exchange to
regenerated C completing the cycle. Arylselenocyanate 6 can cyclize to form 1. A photoinduced
SET mechanism requires a radicalꢀnucleophilic aromatic substitution (S 1) and involves
RN
I
ꢀ
I
ꢀ*
photoexcitation of [Cu (SeCN) ] (B) to afford excited species [Cu (SeCN) ] (F) which can
2
2
ꢀ
II
68
undergoes SET to form a putative caged radical pair comprising [Ar· and Cu (SeCN) X] (G).
2
I
ꢀ
Intermediate G can couple to form arylselenocyanate 6 and [Cu (SeCN)X] (H). Intermediate H
can undergo ligand exchange to regenerate B completing the catalytic cycle. The radicals
generated in SET and AT are proposed to exist as caged radical pairs which rapidly convert to
6
9,70
product; hence, are not affected in presence of radical quenchers.
EPR spectroscopy studies
by Hida and coꢀworkers on the reaction of haloanthraquinones and aminoethanol observed the
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69,70
short lived radical species and Cu(II) species.
Similarly, Fu and Peters observed copper(II)ꢀ
thiolate complexes during studies on photoinduced crossꢀcoupling between aryl thiols and aryl
7
1
halides. We also note the order of reactivity of aryl halides for CꢀSe crossꢀcoupling under the
thermal and photoinduced conditions was I > Br > Cl, which parallels the reduction potentials of
10
11
12
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15
16
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2,73
aryl halides (e.g. PhI ꢀ1.91 V, PhBr ꢀ2.43 V, PhCl ꢀ2.76)
and is opposite to the reactivity of
aromatic nucleophilic substitution reaction. This also infers the thermal reaction proceeds
through a radical reaction.
The observed and proposed intermediates parallel what has been observed for the Cuꢀcatalyzed
crossꢀcoupling of aryl halides with thiols both thermally and photoinduced. For the thermal case,
Hartwig, et al. used Xꢀray diffraction and solution phase characterization to observe copper
I
complexes that exist as neutral threeꢀcoordinate trigonal planar complexes of [(phen)Cu (phth)]
I +
ꢀ
in the solid state and as ionic complexes consisting of [(phen) Cu ] and [Cu(phth) ] in
2
2
66
+
ꢀ
solution. Hartwig, et al. also isolated ionic complexes (e.g., [(Me phen) Cu] and [Cu(OPh) ] )
2
2
2
in the copperꢀcatalyzed etherification of aryl halides and observed that the concentration of ionic
74
complexes is higher in polar solvents. We postulate the presence of a related neutral
I
[
(phen)Cu (SeCN)] (C) intermediate in the thermally activated copperꢀpromoted crossꢀcoupling
I +
to form CꢀSe bonds. This adduct can form from the disproportionation reaction of [(phen) Cu ]
2
I
ꢀ
(
A) and [Cu (SeCN) ] (B) complexes. Our evidence for this intermediate is indirectly supported
2
by the observation that addition of ligand increases the yield from 42% to 91% (Table 1, entry 11
I
and 9). Only the addition of ligand would allow for formation of a [(phen)Cu (SeCN)] (C) or a
related neutral (phen) complex. For the photoinduced case, Peters and Fu extensively
investigated the crossꢀcoupling between and thiols and aryl halides. They concluded that the
ꢀ
71
[
Cu(SAr) ] anion is the lone and active intermediate. Similarly, we observed the related
2
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2
2
2
2
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3
3
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3
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3
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6
ꢀ
[
Cu(SeCN) ] (B) anion. EPR studies by Hida and coꢀworkers on the photoinduced Cuꢀcatalyzed
2
crossꢀcoupling of haloanthraquinones and aminoethanol identified short lived radical species and
6
9,70
Cu(II) species.
Similarly, Fu and Peters observed copper(II)ꢀthiolate complexes (analogous to
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
complex G) during studies on photoinduced crossꢀcoupling between and thiols and aryl
7
1
halides. We set up experiments with and without 1,10ꢀphenanthroline ligand. Under
photoinduced activation, addition of ligand decreases yield from 82% to 31% (Table 3, entry 3
I
ꢀ
and 2), which is likely a result of a decrease in [Cu (SeCN) ] concentration indicating
2
I
ꢀ
[Cu (SeCN) ] as active catalyst. Our observations combined with the cited prior work suggests
2
that the photoinduced Cuꢀpromoted crossꢀcoupling of arylhalides and KSeCN proceeds through
a SET mechanism.
Biological. Among the library, compound 1a, 1c, and 1f showed the lowest MICs = 12.5 µg/mL
against Mtb H37Rv and shared calculated LogP (cLogP) values in the range of 2.73ꢀ3.70.
Compounds 1g, 8 and 10 showed MIC ≥ 50 µg/mL and shared clogP values ≥4.60. The
remainder of the compounds shared intermediate MICs and cLogP values. We suspect the most
active compounds had cLogP values ideal for cell wall diffusion. Compounds 1a, 1c, and 1f
reduced Mtb Ag85C activity to 17%, 36%, and 15%, respectively, after 40 minutes of enzyme
incubation (Table 4). Compounds 1g, 1l, 1m, 1n, 10 reduced Mtb Ag85C activity to 30%, 59%,
4
0%, 44%, and 61%, respectively. This reduction in compound activity between the two groups
loosely correlates with the replacement of the phenyl group with an alkyl or the large biotinyl
moiety in the case of 10. The data suggest all the compounds were reacting with the exposed
cysteine 209 on Mtb Ag85C; however, the phenyl containing compounds accessed the reactive
site better. This conclusion is supported by the appIC data which shows all the compounds with
5
0
the exception of 8 rapidly inactivate the enzyme at low concentrations.
The
results
are
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significant in light of limited progress that has been made identifying inhibitors of Ag85s. The
7
5
few classes of compounds have been described which inhibit the Ag85s have been reviewed
1
7,76
77
78
51,79,80
and include thiophenes,
phosphonates, sulfonates, and derivatives of trehalose
and
10
11
12
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1
9,81
arabinosides.
these earlier inhibitors demonstrated IC50s in the mid to low µM range;
whereas, in the current this study we identified inhibitors in the nM range.
Conclusions
An efficient Cuꢀpromoted synthesis of 2ꢀalkylꢀ1,2ꢀbenzisoselenazolꢀ3(2H)ꢀones was discovered
that involves the use of 1,10ꢀphenanthroline, KSeCN and orthoꢀhalobenzamides. The method
affords the products in as little as one hour, which is significantly faster than similar chemistry
using Se powder. As part of this study, the first example of a photoinduced Cuꢀpromoted CꢀSe
bond forming reaction was discovered that enabled the synthesis of ebselen (1a) at low
temperatures upon irradiation with a 22ꢀWatt (combined) Hg lamp. An atom transfer step and a
1
,10ꢀphenanthrolineꢀCu complex is proposed in the thermal mechanism and single electron
transfer step is proposed for the photoinduced mechanism. The mechanisms are supported by the
+
ꢀ
ESIꢀMS detection of [(phen) CuI] (A) and [CuI(SeCN) ] (B) complexes. A library of fourteen
2
2
1
,2ꢀbenzisoselenazolꢀ3(2H)ꢀones was prepared in good yield using the thermal method. The
library was evaluated for antiꢀMtb H Rv activity and the ability to inhibit a cysteine containing
3
7
Mtb Ag85C demonstrating different aspects of utility for the chemotype. As a result, new Mtb
growth and enzyme inhibitors were identified. Due to the rapidly expanding medical applications
for 2ꢀalkylꢀ1,2ꢀbenzisoselenazolꢀ3(2H)ꢀones these methods are expected to facilitate the
synthesis of new therapeutics.
EXPERIMENTAL SECTION
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General Information. All the starting materials were obtained from Acros Organics or
SigmaꢀAldrich. Unless specified all the reactions are carried out under an atmosphere of nitrogen
using a nitrogen balloon. All solvents were purchased form Fisher Scientific or SigmaꢀAldrich.
The solvents were purified by distillation and other standard methods. Reaction were monitored
using Thinꢀlayer chromatography (TLC silica gel 62 F ) and spots were observed by UV light.
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All photochemical reactions were carried out in a handmade cardboard box fitted with two bulbs
with combined output of 22 Watts (14 watts Rayonet RPRꢀ3000A lamp (spectral energy
distribution wavelength range: 250ꢀ360 nm) + 8 watts Spectronics Corp. BLEꢀ8T365 (365nm)).
1
An Aminco Bowman II luminescence spectrometer was used for fluorimetry experiments. Hꢀ
1
3
NMR and CꢀNMR and GꢀCOSY were carried out using a Bruker Avance III 600 MHz or
1
13
Varian Inova. 600 MHz spectrometers. HꢀNMR and CꢀNMR were referenced to CDCl peak
3
at 7.27 and 77.16 respectively. High resolution mass spectroscopy (HRMS) was performed on a
micro mass QꢀTOF2 instrument.
General procedure for thermal activated synthesis of benzoꢀ1,2ꢀselenazolꢀ3(2H)ꢀone
compounds, Table 1. The starting benzamide (1 equiv), copper (I) iodide (1 equiv), 1,10ꢀ
phenanthroline (1 equiv), cesium carbonate (2.5 equiv), potassium selenocyanate (1.2 equiv),
were suspended in solvent N,Nꢀdimethylmethanamide or acetonitrile. The resulting red colored
mixture was heated to 95ꢀ100 °C for 0.6ꢀ12 h. The reaction was cooled, diluted with 20.0 mL of
ethyl acetate, filtered, and the residue washed with ethyl acetate. To the filtrate was added cold
H O (20.0 mL) followed by extraction with 20.0 mL of ethyl acetate. This process was repeated
2
thrice. The combined ethyl acetate extracts were dried over anhydrous Na SO , filtered, and
2
4
concentrated to obtain a solid which was purified by flash column chromatography on silica gel
ethyl acetateꢀhexane) to obtain product 1,2ꢀbenzisoselenazolꢀ3(2H)ꢀone derivative.
(
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Synthesis
of
2ꢀphenylbenzo[d][1,2]selenazolꢀ3(2H)ꢀone
(1a).
2ꢀIodoꢀNꢀ
phenylbenzamide (400 mg, 1.24 mmol), copper (I) iodide (236 mg, 1.24 mmol), 1,10ꢀ
phenanthroline (223 mg, 1.24 mmol), cesium carbonate (1011 mg, 3.10 mmol), potassium
selenocyanate (214 mg, 1.49 mmol), and N,Nꢀdimethylmethanamide (4.0 mL), 45 mins, 100 °C.
Purified by flash column chromatography on silica gel (35% ethyl acetateꢀhexanes) to obtained
pure 2ꢀphenylbenzo[d][1,2]selenazolꢀ3(2H)ꢀone 1a. Yield 75% (256.2 mg), white solide; silica
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59
60
1
gel TLC R = 0.37 (3:7 ethyl acetateꢀhexanes); mp 182−183 °C; H NMR (600MHz ,CDCl ) δ
f
3
8.13 (d, J = 7.7 Hz, 1 H), 7.70 ꢀ 7.62 (m, 4 H), 7.49 (ddd, J = 2.3, 5.8, 7.9 Hz, 1 H), 7.47 ꢀ 7.42
13
(
m, 2 H), 7.32 ꢀ 7.28 (m, J = 1.0, 1.0 Hz, 1 H) ; CꢀNMR (150.2 MHz, MeoD) δ 166.6, 139.7,
+
1
39.0, 132.2, 129.0, 128.0, 127.9, 126.7, 126.1, 125.5, 124.8; HRMS (ESIꢀTOF) m/z: [M + Na]
Calcd for C H NO Na 297.9747; Found 297.9748.
1
3
17
3
Synthesis of 2ꢀ(4ꢀmethoxybenzyl)benzo[d][1,2]selenazolꢀ3(2H)ꢀone (1b). 2ꢀIodoꢀNꢀ(4ꢀ
methoxybenzyl)benzamide (400 mg, 1.08 mmol), copper (I) iodide (207 mg, 1.08 mmol), 1,10ꢀ
phenanthroline (196 mg, 1.08 mmol), cesium carbonate (888 mg, 2.72 mmol), potassium
selenocyanate (188mg, 1.30 mmol), and N,Nꢀdimethylmethanamide (4.0 mL), 1 h, 100 °C.
Purified by flash column chromatography on silica gel (35% ethyl acetateꢀhexane) to obtain
pure 2ꢀ(4ꢀmethoxybenzyl)benzo[d][1,2]selenazolꢀ3(2H)ꢀone (1b). Yield 63% (220.5 mg), white
1
solid; silica gel TLC R = 0.1 (3:7 ethyl acetateꢀhexanes); mp 139ꢀ141 °C; HꢀNMR (600 MHz,
f
CDCl ) δ 8.08 (d, J = 7.9 Hz, 1 H), 7.59 ꢀ 7.54 (m, 9 H), 7.43 (ddd, J = 2.6, 5.6, 7.9 Hz, 1 H),
3
1
3
7
.33 ꢀ 7.30 (m, J = 8.6 Hz, 8 H), 6.92 ꢀ 6.89 (m, 2 H), 4.96 (s, 2 H), 3.82 (s, 3 H); CꢀNMR
(
150.2 MHz, CDCl ) δ 167.1, 159.8, 139.3, 132.0, 130.3, 129.5, 129.0, 127.9, 126.3, 124.1,
3
+
114.3, 55.5, 48.4; HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for C H NO SeNa 342.0004;
15
13
2
Found 342.0016.
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ꢀ(2ꢀmethoxybenzyl)benzo[d][1,2]selenazolꢀ3(2H)ꢀone
(1c).
2ꢀIodoꢀNꢀ(2ꢀ
methoxybenzyl)benzamide (370 mg, 1.01 mmol), copper (I) iodide (192 mg, 1.01 mmol), 1,10ꢀ
phenanthroline (182 mg, 1.01 mmol), cesium carbonate (821 mg, 2.52 mmol), potassium
selenocyanate (174 mg, 1.20 mmol), and N,Nꢀdimethylmethanamide (4.0 mL), 1 h, 100 °C.
Purified by flash column chromatography on silica gel (25% ethyl acetateꢀhexane) to obtain pure
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product 2ꢀ(2ꢀmethoxybenzyl)benzo[d][1,2]selenazolꢀ3(2H)ꢀone (1c). Yield 44% (141 mg), white
1
solid; silica gel TLC R = 0.24 (3:7 ethyl acetateꢀhexanes); mp 169ꢀ170 °C; H NMR (600 MHz,
f
CDCl ) δ 8.08 (d, J = 7.9 Hz, 5 H), 7.58 ꢀ 7.56 (m, 10 H), 7.44 ꢀ 7.40 (m, J = 1.7 Hz, 11 H), 7.34
3
(
dt, J = 1.7, 7.8 Hz, 6 H), 6.99 ꢀ 6.91 (m, J = 0.9, 7.4, 7.4 Hz, 11 H), 5.07 (s, 2 H), 3.93 (s, 3 H);
1
3
CꢀNMR (150.2 MHz, CDCl ) δ 167.3, 157.6, 138.6, 131.9, 131.0, 130.0, 128.9, 127.6, 126.1,
3
+
125.7, 123.9, 121.0, 110.6, 55.4, 43.6; HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for
C H NO SeNa 342.0009; Found 342.0017.
1
5
13
2
3
9
Synthesis of 2ꢀ(4ꢀmethoxyphenyl)benzo[d][1,2]selenazolꢀ3(2H)ꢀone (1d). 2ꢀIodoꢀNꢀ
(4ꢀmethoxyphenyl) benzamide (400 mg, 1.13 mmol), copper (I) iodide (216 mg, 1.13 mmol),
,10ꢀphenanthroline (204 mg, 1.33 mmol), cesium carbonate (922 mg, 2.83 mmol), potassium
1
selenocyanate (196 mg, 1.30 mmol) and N,Nꢀdimethylmethanamide (4.0 mL), 1 h, 100 °C.
Purified by flash column chromatography on silica gel (35% ethyl acetateꢀhexane) to obtain pure
product 2ꢀ(4ꢀmethoxyphenyl)benzo[d][1,2]selenazolꢀ3(2H)ꢀone (1d). Yield 67% (231 mg), pale
1
yellow solid; silica gel TLC R = 0.25 (3:7 ethyl acetateꢀhexanes); mp 170ꢀ171 °C; H NMR (600
f
MHz, CDCl ) δ 8.12 (td, J = 0.9, 7.7 Hz, 1H), 7.65 ꢀ 7.68 (m, 2H), 7.46 ꢀ 7.53 (m, 3H), 6.94 ꢀ
3
1
3
6
.98 (m, 2H), 3.85 (s, 3H); CꢀNMR (150.2 MHz, CDCl ) δ 166.1, 158.6, 137.9, 132.5, 131.7,
3
+
129.5, 127.6, 127.4, 126.6, 132.9, 114.7, 55.7; HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for
C H NO SeNa 327.9847; Found 327.9858.
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Synthesis
of
2ꢀbenzylbenzo[d][1,2]selenazolꢀ3(2H)ꢀone
(1e).
Nꢀbenzylꢀ2ꢀ
iodobenzamide (276 mg, 0.88 mmol), copper (I) iodide (156 mg, 0.82 mmol), 1,10ꢀ
phenanthroline (148 mg, 0.82 mmol), cesium carbonate (667 mg, 2.04 mmol), potassium
selenocyanate (142 mg, 1.20 mmol), N,Nꢀdimethylmethanamide (4.0 mL) 1 h, 100 °C. Purified
by flash column chromatography on silica gel (25% ethyl acetateꢀhexane) to obtain pure product
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ꢀbenzylbenzo[d][1,2]selenazolꢀ3(2H)ꢀone (1e). Yield 39% (90 mg), white solid; silica gel TLC
1
R = 0.28 (3:7 ethyl acetateꢀhexanes); mp 130ꢀ132 °C; H NMR (600 MHz, CDCl ) δ 8.10 (d, J =
f
3
7.9 Hz, 1H), 7.56 ꢀ 7.60 (m, J = 0.7 Hz, 2H), 7.44 (ddd, J = 2.7, 5.4, 7.9 Hz, 1H), 7.33 ꢀ 7.39 (m,
13
5
H), 5.03 (s, 2H); CꢀNMR (150.2 MHz, CDCl ) δ 167.2, 138.0, 137.2, 132.0, 129.0, 128.9,
3
+
1
28.6, 128.4, 127.4, 126.3, 124.0, 49.0; HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for
C H NOSeNa 311.9898; Found 311.9914.
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4
11
Synthesis of 2ꢀallylbenzo[d][1,2]selenazolꢀ3(2H)ꢀone (1f). 2ꢀiodoꢀNꢀallylbenzamide
400 mg, 1.39 mmol), copper (I) iodide (267 mg, 1.39 mmol), 1,10ꢀphenanthroline (251 mg, 1.39
(
mmol), cesium carbonate (1.135 g, 3.48 mmol) and potassium selenocyanate (241 mg, 1.67
mmol), N,Nꢀdimethylmethanamide (4.0 mL), 1.5 h, 100 °C. Purified by flash column
chromatography on silica gel (25% ethyl acetateꢀhexane) to obtain pure product 2ꢀ
allylbenzo[d][1,2]selenazolꢀ3(2H)ꢀone (1f). Yield 39% (90 mg), white solid; silica gel TLC R =
f
1
0
.28 (3:7 ethyl acetateꢀhexanes); mp 124ꢀ126 °C; H NMR (600 MHz, CDCl ) δ 8.08 (qd, J =
3
0.7, 7.9 Hz, 1 H), 7.67 ꢀ 7.64 (m, 1 H), 7.63 ꢀ 7.59 (m, 1 H), 7.45 (ddd, J = 1.0, 7.0, 7.9 Hz, 1 H),
13
5
.99 (tdd, J = 6.3, 10.2, 16.9 Hz, 1 H), 5.44 ꢀ 5.31 (m, 2 H), 4.50 (td, J = 1.3, 6.4 Hz, 2 H); Cꢀ
NMR (150.2 MHz, CDCl ) δ 167.1, 138.0, 133.7, 132.1, 129.0, 127.8, 126.3, 124.1, 119.5, 47.3;
3
+
HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for C H NOSeNa 261.9742; Found 261.9755.
1
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Synthesis of 2ꢀ(cyclohexylmethyl)benzo[d][1,2]selenazolꢀ3(2H)ꢀone (1g). Nꢀ
(
cyclohexylmethyl)ꢀ2ꢀiodobenzamide (200 mg, 0.58 mmol), copper (I) iodide (110 mg, 0.58
mmol), 1,10ꢀphenanthroline (105 mg, 0.58 mmol), cesium carbonate (474.66 mg, 1.45 mmol),
potassium selenocyanate (100 mg, 0.70 mmol) and N,Nꢀdimethylmethanamide (4.0 mL), 1.5 h,
100 °C. After flash column chromatography on silica gel using 20% ethyl acetate in hexanes as
mobile phase obtained pure product 2ꢀ(cyclohexylmethyl)benzo[d][1,2]selenazolꢀ3(2H)ꢀone
0
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3
4
5
6
7
8
9
0
(
1g). Yield 63% (110 mg), off white solid; silica gel TLC R = 0.59 (1:1 ethyl acetateꢀhexanes);
f
1
mp 151ꢀ152 °C; H NMR (600 MHz, CDCl ) δ 8.07 (d, J = 7.9 Hz, 1 H), 7.66 ꢀ 7.59 (m, 2 H),
3
7
.47 ꢀ 7.43 (m, 1 H), 3.73 (d, J = 7.0 Hz, 2 H), 1.82 ꢀ 1.73 (m, 5 H), 1.69 (d, J = 9.0 Hz, 1 H),
1
3
1
.31 ꢀ 1.18 (m, 3 H), 1.12 ꢀ 1.03 (m, 2 H); CꢀNMR (150.2 MHz, CDCl ) δ 167.4, 137.8, 131.9,
3
128.9, 127.5, 126.2, 123.9, 59.5, 50.9, 39.1, 31.3, 30.6, 26.3, 25.7; HRMS (ESIꢀTOF) m/z: [M +
+
Na] Calcd for C H NOSeNa 318.0368; Found 318.0381.
1
4
17
Synthesis of 2ꢀ(4ꢀfluorophenyl)benzo[d][1,2]selenazolꢀ3(2H)ꢀone (1h). Nꢀ(4ꢀ
fluorophenyl)ꢀ2ꢀiodobenzamide (400 mg, 1.17 mmol), copper (I) iodide (335 mg, 1.76 mmol),
1
,10ꢀphenanthroline (317 mg, 1.79 mmol), cesium carbonate (995.56 mg, 2.93 mmol), potassium
selenocyanate (203 mg, 1.40 mmol), N,Nꢀdimethylmethanamide (4.0 mL), 1 h, 100 °C. After
flash column chromatography on silica gel using 20% ethyl acetate in hexanes as mobile phase
obtained pure product 2ꢀ(4ꢀfluorophenyl)benzo[d][1,2]selenazolꢀ3(2H)ꢀone (1h). Yield 52%
1
(180 mg), white solid; silica gel TLC R = 0.15 (3:7 ethyl acetateꢀhexanes); mp 176ꢀ177 °C; H
f
NMR (600 MHz, CDCl ) δ 8.13 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 3.7 Hz, 2H), 7.56 ꢀ 7.61 (m,
3
1
3
2
H), 7.46 ꢀ 7.52 (m, 1H), 7.11 ꢀ 7.18 (m, J = 8.6 Hz, 1H); C NMR (151 MHz, CDCl ) δ 165.8,
3
160.94 (d, J = 247.6 Hz), 137.47, 134.77 (d, J =3.30 Hz), 132.6, 129.4, 127.49 (d, J =7.7 Hz),
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27.0, 126.6, 123.7, 116.2 (d, J =22.0 Hz); HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for
C H FNOSeNa 315.9647; Found 315.9657.
13
8
Synthesis of 2ꢀ(2ꢀfluorophenyl)benzo[d][1,2]selenazolꢀ3(2H)ꢀone (1i).
fluorophenyl)ꢀ2ꢀiodobenzamide (400 mg, 1.17 mmol), copper (I) iodide (335 mg, 1.76 mmol),
,10ꢀphenanthroline (317 mg, 1.79 mmol), cesium carbonate (995.56 mg, 2.93 mmol), potassium
Nꢀ(2ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
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29
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31
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36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
selenocyanate (203 mg, 1.40 mmol) and N,Nꢀdimethylmethanamide (4.0 mL), 1 h, 100 °C. After
flash column chromatography on silica gel using 20% ethyl acetate in hexanes as mobile phase
obtained pure product 2ꢀ(2ꢀfluorophenyl)benzo[d][1,2]selenazolꢀ3(2H)ꢀone (1i). Yield 35% (120
1
mg), off white solid; silica gel TLC R = 0.24 (3:7 ethyl acetateꢀhexanes); mp 156ꢀ158 °C; H
f
NMR (600 MHz, CDCl ) δ 8.04 ꢀ 7.97 (m, J = 7.3 Hz, 2 H), 7.82 ꢀ 7.73 (m, 2 H), 7.54 ꢀ 7.49 (m,
3
1
3
J = 1.7 Hz, 1 H), 7.43 ꢀ 7.39 (m, J = 1.7 Hz, 1 H), 7.38 ꢀ 7.31 (m, J = 1.2, 7.6 Hz, 2 H); C NMR
(
151 MHz, CDCl ) δ 117.18 (d, J =19.8 Hz), 122.1, 123.9, 125.11 (d, J =3.3 Hz), 130.7, 130.9,
3
1
31.13 (d, J =6.6 Hz), 132.7, 133.7, 158.44 (dd, J =250.8, 1.0 Hz), 166.4; HRMS (ESIꢀTOF)
+
m/z: [M + Na] Calcd for C H FNOSeNa 315.9647; Found 315.9657.
13
8
Synthesis of 2ꢀ(4ꢀazidophenyl)benzo[d][1,2]selenazolꢀ3(2H)ꢀone (1j). Nꢀ(4ꢀ
azidophenyl)ꢀ2ꢀiodobenzamide (500 mg, 1.37 mmol), copper (I) iodide (262 mg, 1.37 mmol),
1,10ꢀphenanthroline (247 mg, 1.37 mmol), cesium carbonate (1118 mg, 3.43 mmol), potassium
selenocyanate (237 mg, 1.40 mmol) and N,Nꢀdimethylmethanamide (5.0 mL) 1 h, 90 °C. After
flash column chromatography on silica gel using 20% ethyl acetate in hexanes as mobile phase
obtained pure product 2ꢀ(4ꢀazidophenyl)benzo[d][1,2]selenazolꢀ3(2H)ꢀone (1j). Yield 20% (90
1
mg), brown solid; silica gel TLC R = 0.24 (3:7 ethyl acetateꢀhexanes); mp 169ꢀ170°C; H NMR
f
(
600 MHz, CDCl ) δ 8.14 (td, J = 0.9, 7.9 Hz, 1 H), 7.71 ꢀ 7.67 (m, 2 H), 7.66 ꢀ 7.63 (m, J = 8.8
3
1
3
Hz, 2 H), 7.51 (ddd, J = 3.7, 4.5, 7.9 Hz, 1 H), 7.14 ꢀ 7.09 (m, J = 8.8 Hz, 2 H); CꢀNMR (150.2
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6
MHz, CDCl ) δ 165.8, 138.4, 137.4, 135.9, 132.7, 129.5, 127.2, 127.0, 126.7, 123.8, 119.8;
3
+
HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for C H N OSeNa 338.9756; Found 338.9763.
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Synthesis of 2ꢀ(tertꢀbutyl)benzo[d][1,2] selenazolꢀ3(2H)ꢀone (1k). Nꢀ(tertꢀbutyl)ꢀ2ꢀ
iodobenzamide (200.0 mg, 0.66 mmol), copper (I) iodide (126 mg, 0.66 mmol), 1,10ꢀ
phenanthroline (119 mg, 0.66 mmol), cesium carbonate (538 mg, 1.65 mmol), potassium
selenocyanate (114 mg, 0.79 mmol) and N,Nꢀdimethylmethanamide (2.0 mL) 1 h, 90 °C. After
flash column chromatography on silica gel using 20% ethyl acetate in hexanes as mobile phase
0
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obtained pure product 2ꢀ(tertꢀbutyl)benzo[d][1,2] selenazolꢀ3(2H)ꢀone (1k). Yield 75% (125
1
mg), white solid; silica gel TLC R = 0.43 (3:7 ethyl acetateꢀhexanes); mp 137ꢀ139 °C; H NMR
f
(
600 MHz, CDCl ) δ 7.97 (td, J = 1.1, 7.8 Hz, 1H), 7.56 ꢀ 7.60 (m, 2H), 7.40 (ddd, J = 1.7, 6.3,
3
1
3
8.0 Hz, 1H), 1.69 (s, 9H); C NMR (151 MHz, CDCl ) δ 167.1, 137.0, 131.7, 130.2, 128.5,
3
+
1
26.1, 123.3, 59.0, 29.2; HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H NOSe 256.0235;
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14
Found 256.0233.
Synthesis of 2ꢀ((3R,5S)ꢀadamantanꢀ1ꢀyl)benzo[d][1,2]selenazolꢀ3(2H)ꢀone (1l). Nꢀ
(3R,5S)ꢀadamantanꢀ1ꢀyl)ꢀ2ꢀiodobenzamide (400.0 mg, 1.04 mmol), copper (I) iodide (200 mg,
(
1
.04 mmol), 1,10ꢀphenanthroline (189 mg, 1.04 mmol), cesium carbonate (855 mg, 2.62 mmol),
potassium selenocyanate (182 mg, 1.26 mmol) and N,Nꢀdimethylmethanamide (4.0 mL) 1 h, 90
C. After flash column chromatography on silica gel using 20% ethyl acetate in hexanes as
°
mobile phase obtained pure product 2ꢀ((3R,5S)ꢀadamantanꢀ1ꢀyl)benzo[d][1,2]selenazolꢀ3(2H)ꢀ
one (1l). Yield 72% (250 mg), white solid; silica gel TLC R = 0.51 (3:7 ethyl acetateꢀhexanes);
f
1
mp 215ꢀ217 °C; H NMR (600 MHz, CDCl ) δ 7.97 (d, J = 7.9 Hz, 1H), 7.59ꢀ7.58 (m, 1H),
3
7.57ꢀ7.54 (m, 1H), 7.41ꢀ7.38 (m, 1H), 2.43 (d, J = 2.4 Hz, 6H), 2.19 (s, 3H), 1.81ꢀ1.79 (m, 3H),
1
3
1
.75ꢀ1.73 (m, 3H); CꢀNMR (150.2 MHz, CDCl ) δ 166.8, 137.5, 131.5, 130.5, 128.5, 126.0,
3
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The Journal of Organic Chemistry
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+
1
23.4, 60.1, 41.7, 36.4, 30.3; HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H NOSe 334.0705;
17
20
Found 334.0722.
Synthesis of 2ꢀcyclopentylbenzo[d][1,2]selenazolꢀ3(2H)ꢀone (1m). Nꢀcyclopentylꢀ2ꢀ
iodobenzamide (350.0 mg, 1.11 mmol), copper (I) iodide (211.6 mg, 1.11 mmol), 1,10ꢀ
phenanthroline (200.2 mg, 1.11 mmol), cesium carbonate (905 mg, 2.77 mmol), potassium
selenocyanate (192.1 mg, 1.33 mmol) and N,Nꢀdimethylmethanamide (3.0 mL) 1 h, 90 °C. After
flash column chromatography on silica gel using 20% ethyl acetate in hexanes as mobile phase
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59
60
obtained pure product 2ꢀcyclopentylbenzo[d][1,2]selenazolꢀ3(2H)ꢀone (1m). Yield 78% (232
1
mg), white solid; silica gel TLC R = 0.23 (3:7 ethyl acetateꢀhexanes); mp 119ꢀ120 °C; H NMR
f
(
600 MHz, CDCl ) δ 8.03 ꢀ 8.05 (m, 1H), 7.62 ꢀ 7.64 (m, 1H), 7.57 (dt, J = 1.4, 7.6 Hz, 1H), 7.42
3
(ddd, J = 1.0, 7.1, 7.9 Hz, 1H), 4.98 (quin, J = 7.8 Hz, 1H), 2.17 ꢀ 2.27 (m, J = 1.6, 2.8 Hz, 2H),
1
3
1
.81 ꢀ 1.90 (m, 1H), 1.69 ꢀ 1.75 (m, 2H), 1.61 ꢀ 1.68 (m, 2H); C NMR (151 MHz, CDCl ) δ
3
1
67.2, 137.5, 133.2, 131.7, 128.6, 126.2, 123.8, 55.9, 33.5, 24.2; HRMS (ESIꢀTOF) m/z: [M +
+
Na] Calcd for C H NOSeNa 290.0055; Found 290.0058.
1
2
13
3
9
Synthesis of 2ꢀcyclohexylbenzo[d][1,2]selenazolꢀ3(2H)ꢀone (1n). Nꢀcyclohexylꢀ2ꢀ
iodobenzamide (400.0 mg, 1.21 mmol), copper (I) iodide (231.6 mg, 1.22 mmol), 1,10ꢀ
phenanthroline (219.1 mg, 1.21 mmol), cesium carbonate (990.3 mg, 3.04 mmol), potassium
selenocyanate (210.2 mg, 1.45 mmol) and N,Nꢀdimethylmethanamide (4.0 mL) 1 h, 90 °C. After
flash column chromatography on silica gel using 20% ethyl acetate in hexanes as mobile phase
obtained pure product 2ꢀcyclohexylbenzo[d][1,2]selenazolꢀ3(2H)ꢀone (1n). Yield 85% (290 mg),
1
white solid; silica gel TLC R = 0.27 (3:7 ethyl acetateꢀhexanes); mp 157ꢀ158 °C; H NMR (600
f
MHz, CDCl ) δ 8.10 ꢀ 7.99 (m, 1 H), 7.64 (d, J = 7.9 Hz, 1 H), 7.57 (s, 1 H), 7.42 (s, 1 H), 4.53 ꢀ
3
4
.45 (m, 1 H), 2.11 (dd, J = 2.0, 12.7 Hz, 2 H), 1.87 (d, J = 13.9 Hz, 2 H), 1.77 ꢀ 1.70 (m, 1 H),
29
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