Application of thio-Ugi adducts for the preparation of benzo[ b ]thiophene and S-heterocycle library via copper catalyzed intramolecular C-S bond formation

Article abstract of DOI:10.1021/acscombsci.5b00034

Fused heterocycles, such as benzo[b]thiophene, thiochroman, benzo[b][1,4]thiazine, and 1,4-benzothiazepine were generated from thio-Ugi adducts containing a thioamide group through copper-catalyzed intramolecular C-S bond formation under microwave irradiation.

Full text of DOI:10.1021/acscombsci.5b00034

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Article
Application of Thio-Ugi Adducts for the Preparation
of Benzo[b]thiophene and S-Heterocycle Library via
Copper Catalyzed Intramolecular C-S Bond Formation
Yong-Sang Kim, Se Hun Kwak, and Young-Dae Gong
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.5b00034 • Publication Date (Web): 11 May 2015
Downloaded from http://pubs.acs.org on May 15, 2015
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Application of Thio-Ugi Adducts for the Preparation of
Benzo[b]thiophene and S-Heterocycle Library via Copper
Catalyzed Intramolecular C-S Bond Formation
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†
†
YongꢀSang Kim, Se Hun Kwak, and YoungꢀDae Gong*
Innovative Drug Library Research Center, Department of Chemistry, College of Science,
Dongguk University, 26, 3-ga, Pil-dong Jung-gu, Seoul 100-715, Korea
Fax: +82-2-2290-1351
E-mail: ydgong@dongguk.edu
KEYWORDS
thio-Ugi, copper, benzothiophene, thiochroman, benzothiazine, benzothiazepine
ABSTRACT
Fused heterocycles such as benzo[b]thiophene, thiochroman, benzo[b][1,4]thiazine and 1,4-
benzothiazepine were generated from thio-Ugi adducts containing a thioamide group through
copper catalyzed intramolecular C-S bond formation under microwave irradiation.
INTRODUCTION
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Various strategies have been harnessed to quickly and efficiently achieve the construction of
chemical libraries for drug discovery. Among them, multicomponent reactions (MCRs) play a
pivotal role in solution phase synthesis to easily and quickly generate a large number of
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compounds using simple starting materials. The merits have driven many research groups to
devise entirely novel MCRs. However, the accumulated MCRs released to date are not enough to
fill chemical space with peculiar and unconventional compounds, which emphasizes the
difficulty in designing new MCRs. Therefore, in order to complement existing MCRs, variations
2
,3
4
of them and either further transformations or pairing strategies after conducting MCRs have
been continuously reported.
The Ugi reaction is a four-components reaction that incorporates an aldehyde or ketone, an
5
isocyanide, an amine and a carboxylic acid or thioacid. Generally, the Ugi adduct obtained from
the reaction is more popular as the substrate for rendering new scaffolds because they could not
be easily accessed from other routes in many cases. Diverse heterocycles have been generated
2
via the adducts in combination with either classical protocols or transition metal catalyzed
3
reactions .
Figure 1. Examples of bioactive molecules containing benzo[b]thiophenes
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Synthetic efforts toward the synthesis of heterocycles via intramolecular C-S bond formation,
emerged by development of catalysts and ligands, have mainly focused on thiazoles fused with
3
b, 6
6b
7
8
9
aryls such as benzene,
pyridine, pyrimidine, pyridazine and pyrazine. As far as we know,
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application of the transformation is rare with other heterocycles containing a sulfur atom and
even with the prominent bicyclic core benzo[b]thiophene found in biologically active
1
0
compounds (Figure 1). For the purpose of library production, we envisioned that the Ugi
adducts 5 containing a thioamide could be elegant substrates for the study of intramolecular C-S
coupling reactions to produce the fused heterocyclic compounds 8, 9, 10, 11 (Scheme 1). In this
report, we will discuss the synthesis of these heterocycles.
Scheme 1. Synthetic Strategy for Heterocycles from Thio-Ugi Adducts
A
n=0,1
Br
O
R
O
R
O
H
R
N
R
N
N
R
N
R
A
S
A
NH
S
9
N
R
n=0,1
B
S
R
Br
8
5
O
R
O
R
R
N
R
N
B
B
S
N
R
S
N
R
10
11
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a
Table 1. Optimization of Thio-Ugi Reaction
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b
yields (%)
entry
solvent
addictive
5
6
21
7
1
2
3
4
MeOH
TFE
25
63
65
50
48
23
16
10
9
TFE
MgSO (1 equiv)
trace
trace
4
TFE
Molecular sieve (4Å)
a
Reaction conditions: 1{1} (1 mmol), 2{1} (1 equiv.), 3{1} (1 equiv.), 4{1} (1 equiv.) and solvent (2 mL) under at
b
2
5 °C. Isolated yield.
RESULTS AND DISCUSSION
Initially, we conducted Ugi reactions in methanol and identified that there were two other
1
1
products 6 and 7 with the desired product 5a,; the two byproducts had not been reported in
2
b, 2e, 2h, 3b
papers pertinent to thio-Ugi synthesis (Table 1).
By substituting methanol with 2,2,2-
trifluroroethanol (TFE), the yield of 5a significantly increased while that of the two byproducts
declined. A more acidic character of TFE than methanol seemed to drive the formation of the
adduct. We speculated that water emanating from imine formation could be responsible for the
3
a, 12
undesired products and partly succeeded in reducing them with drying agents.
But we did not
use MgSO , because it did not always afford positive results in yields with other amines. Also,
4
the isolation of Ugi adducts in the absence of MgSO was more convenient when the product
4
precipitated in the reaction mixture.
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a
Table 2. Optimization for C-S Bond Formation
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cat.
(mol %)
-
ligand
(mol %)
-
Temp/Time
(h)
110 ºC/1
Yield b
entry
R
base
solvent
toluene
(5/8) (%)
1
2
3
4
5
6
7
8
9
H
Cs
Cs
2
2
CO
3
3
-/90
Trace
50/44
45/33
31/50
-/80
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
-
-
CO
Toluene
110 ºC/12
110 ºC/20
110 ºC/6
80 ºC/4
-
-
K
3
PO
4
Toluene
CuI (10)
CuI (10)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
-
K
3
PO
PO
PO
PO
PO
PO
4
4
4
4
4
4
toluene
1,10-phen (10)
1,10-phen (20)
1,10-phen (20)
1,10-phen (20)
1,10-phen (20)
K
K
K
K
K
3
THF
3
3
3
3
THF
80 ºC/3
THF (MW)
THF/water (MW)
100 ºC/1
100 ºC/1
80 ºC/6
56/42
-/94
c
c
THF/water
70
a
b
c
Reaction conditions: 5 (0.4 mmol), base (2 equiv.). Isolated yield. THF (4.75 mL) and water (0.25 mL)
The C-S bond formation from 5a was achieved without the aid of transition metals such as
6e
palladium or copper as reported by Liu et al. Interestingly, we obtained the desired product
with only Cs CO (Table 2, entry 1). However, when implementing the Cs CO conditions with
2
3
2
3
other substrates, the yield of 8 was not satisfactory despite prolonged reaction times. Therefore,
we changed the model compound 5a to 5b which was almost unreactive under the Cs CO3
2
conditions (Table 2, entry 2). Addition of copper iodide and 1,10-phenanthroline (1,10-phen)
was effective in completing the reaction (Table 2, entry 6). In order to reduce the reaction time,
microwave irradiation (MW) was introduced which tends to give better yields in a shorter time
than conventional heating. It is noteworthy that while microwave heating afforded no benefits
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with only THF (Table 2, entry 7), the addition of water to the THF resulted in excellent yields
(Table 2, entry 8).
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Figure 2. A List of Four Components Used for Thio-Ugi Reaction
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Table 3. Synthesis of Thio-Ugi Adducts and Their Corresponding Heterocycles
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a,b
b,c
a,b
b,c
a,b
b,c
No
1
Ugi adducts
Products
No
2
Ugi adducts
Products
No
3
Ugi adducts
Products
5{1,1,1,1}, 5a
3%
8{1,1,1,1}, 8a
5{1,1,1,2}, 5b
8{1,1,1,2}, 8b
5{1,1,1,3}, 5c
8{1,1,1,3}, 8c
6
90%
42%
94%
56%
85%
CF3
O
4
N
5
6
NH
S
5
{1,1,1,4}, 5d
0%
8{1,1,1,4}, 8d
5{1,1,1,5}, 5e
8{1,1,1,5}, 8e
5{1,1,1,6}, 5f
8{1,1,1,6}, 8f
4
80%
55%
86%
47%
65%
7
8
9
5
{1,1,1,7}, 5g
8{1,1,1,7}, 8g
5{1,1,1,8}, 5h
8{1,1,1,8}, 8h
5{1,1,1,9}, 5i
8{1,1,1,9}, 8i
45%
74%
40%
70%
44%
82%
O
N
CO2Me
10
11
12
NH
S
5{1,1,1,11}, 5j
0%
8{1,1,1,10}, 8j
5{1,1,1,11}, 5k
8{1,1,1,11}, 8k
5{1,1,1,12}, 5l
8{1,1,1,12}, 8l
4
70%
31%
84%
26%
75%
1
1
1
3
6
9
14
17
20
15
18
21
5
{1,1,1,13}, 5m
8{1,1,1,13}, 8m
5{1,1,1,14}, 5n
8{1,1,1,14}, 8n
5{1,1,1,15}, 5o
8{1,1,1,15}, 8o
7%
62%
22%
67%
25%
80%
5
{2,1,1,1}, 5p
8{2,1,1,1}, 8p
5{2,1,1,3}, 5q
8{2,1,1,3}, 8q
5{2,1,1,4}, 5r
8{2,1,1,4}, 8r
44%
91%
58%
81%
37%
74%
O
N
NH
Br S
5
{2,1,1,8}, 5s
8{2,1,1,8}, 8s
5{2,1,1,10}, 5t
8{2,1,1,10}, 8t
5{1,2,1,1},5u
8{1,2,1,1}, 8u
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5
5
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5
5
5
5
5
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48%
80%
43%
74%
61%
76%
2
2
23
24
5
{1,2,1,2}, 5v
8{1,2,1,2}, 8v
5{1,2,1,3}, 5w
8{1,2,1,3}, 8w
5{1,2,1,4}, 5x
8{1,2,1,4}, 8x
0
1
2
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4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
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8
9
0
1
2
3
4
5
6
7
8
9
0
35%
71%
67%
96%
47%
63%
O
N
25
26
27
NH
Br S
5
{1,2,1,6}, 5y
3%
8{1,2,1,6}, 8y
5{1,2,1,7}, 5z
8{1,2,1,7}, 8z
5{1,2,1,8}, 5aa
8{1,2,1,8}, 8aa
4
65%
55%
77%
40%
67%
O
N
28
29
30
NH
S
5
{1,1,2,1}, 5ab
7%
8{1,1,2,1}, 8ab
5{1,1,2,4}, 5ac
8{1,1,2,4}, 8ac
5{1,1,2,8}, 5ad
8{1,1,2,8}, 8ad
5
64%
42%
87%
41%
62%
31
32
9{12,1,2,1}, 9a
5
{1,2,2,1}, 5ae
8{1,2,2,1}, 8ae
5{12,1,2,1}, 5ag
d
70%
87%
49%
52%
a
Reaction conditions: 1{1} (3 mmol), 2{2} (1 equiv.), 3{1} (1 equiv.), 4{1} (1 equiv.) and solvent (6 mL) at 25 °C.
Isolated yield. Reaction conditions : 5 (0.4 mmol), Cs CO (2 equiv.), CuI (20 mol%), 1,10-phenanthroline (20
mol%) and solvent (THF: water, v/v=95:5) under microwave irradiation at 100 °C. Cs CO (4 equiv.), CuI (40
mol%), 1,10-phenanthroline (40 mol%).
b
c
2
3
d
2
3
A range of amines 1, two types of isocyanides 2 and thioacids 3, as well as various aldehydes 4
were used to prepare thio-Ugi adducts 5 which were subsequently transformed into fused cyclic
derivatives 8, 9, 10, and 11. The confirmation of thio-Ugi adducts synthesized with thiobenzoic
acid 3{1} was accomplished by NMR and LC/MS. However, structure elucidation of adducts
from thioacetic acid 3{2} was difficult using NMR spectra due to the restricted C-N amide
2
c
bond. Thus, purity and structural identification of the adducts were confirmed by LC/MS.
Compared to the known yields of Ugi adducts with carboxylic acid, those of thio-Ugi adducts 5
with thioacids 3 tended to be lower. Although a limited number of thio-Ugi adducts 5 were
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prepared, we observed some evidences from the results (Table 3 and Table 4) suggesting that the
yields of thio-Ugi 5 are affected by both electronic and steric effects. The bar graphs are attached
to illustrate and help with understanding the trends at a glance (Figure 3). Figure 3a and 3b show
that amines bearing electron donating groups (EDG) are better than those with electron
withdrawing groups (EWG), and also that alkyl amines are superior to aryl amines which is in
accord with the former conclusion. From Figure 3c, it is clear that steric factors are closely
related to the production of Ugi adducts.
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40
20
EWG
EDG
EWG
EDG
60
40
20
4-CF3
4-Cl
2,4-diOMe 4-OMe
H
3-CN
4-Cl
2-F 4-COOMe
H
3,5-diMe 4-Me
1
2
R
R
a)
b)
80
R = CH3
R = Phenyl
60
40
20
0
1
2
n
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c)
Figure 3. Comparisons of thio-Ugi Adducts' yields
With these thio-Ugi substrates in hand, we set out to prepare benzo[b]thiophenes 8 under the
optimized condition described above (Table 3). During the process, no negative events arose and
the yields of 8 were good to moderate. When the thio-Ugi adduct 5af obtained from an optically
pure amino ester 4{16} was used, two inseparable (silica gel chromatography) tautomers 8af and
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9
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1
2
3
4
5
6
7
8
9
0
8ag were observed. However, the optical purity of 8af could be determined by HPLC using a
chiral column (Scheme 2), verifying that a little racemization had occurred. Thiochroman 9a was
also produced but we failed to eliminate the byproduct suspected to be 2H-thiochromene which
would be derived from oxidation of the product.
a
Scheme 2. Application of an Optically Pure Amino Ester
a
Reaction conditions : 5 (0.4 mmol), Cs CO (2 equiv.), CuI (20 mol%), 1,10-phenanthroline (20 mol%) and
solvent (THF: water, v/v=95:5) under microwave irradiation at 100 °C.
2
3
Table 4. Synthesis of Thio-Ugi Adducts and Their Corresponding Heterocycles
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a,b
b,c
a,b
b,c
a,b
b,c
No
1
Ugi adducts
Products
No
2
Ugi adducts
Products
No
3
Ugi adducts
Products
O
N
O
N
OMe
S
N
S
NH
Br
1
0{5,1,1,17}, 10c
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
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59
60
5{3,1,1,17}, 5ba
7%
10{3,1,1,17}, 10a
5{4,1,1,17}, 5bb
10{4,1,1,17}, 10b
5{5,1,1,17}, 5bc
g
d
1
64%
20%
53%
26%
64%
4
5
6
1
0{9,2,2,17}, 10d
5
{6,1,1,17}, 5bd
5{7,1,1,17}, 5be
5{9,2,2,17}, 5bf
d
-
-
57%
-
-
13%
e
(E/Z ratio = 24:76)
7
8
9
1
0{8,1,2,17}, 10g
d
1
0{3,1,2,17}, 10e
10{6,1,2,17}, 10f
5
{3,1,2,17}, 5bg
9%
5{6,1,2,17}, 5bh
5{8,1,2,17}, 5bi
64%
d
d
2
68%
15%
83%
24%
e
(E/Z ratio = 16:84)
O
N
O
N
S
10
11
12
S
NH
N
Br
10{9,1,2,17}, 10h
10{10,1,2,17}, 10j
1
0{5,2,2,17}, 10i
5
{9,1,2,17}, 5bj
7%
d,h
5{5,2,2,17}, 5bk
5{10,1,2,17}, 5bl
d
4
0%
d
23%
1
23%
80%
20%
e
e
(E/Z ratio = 23:77)
(E/Z ratio = 17:83)
13
14
15
1
0{8,2,2,17}, 10k
10{4,2,1,17}, 10l
5
{11,1,1,17}, 5bm
5{8,2,2,17}, 5bn
d
5{4,2,1,17}, 5bo
-
57%
d
-
26%
14%
63%
e
(
E/Z ratio = 16:84)
O
N
16
17
18
S
Br
NH
1
1{3,1,2,18}, 11a
11{7,1,2,18}, 11b
5{3,1,1,18}, 5bp
2%
5{3,1,2,18}, 5bq
5{7,1,2,18}, 5br
-
i
k
3
54%
28%
49%
9%
N
O
N
19
S
5
{3,1,2,19}, 5bs
-
62%
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5
5
5
5
5
5
5
5
6
a
Reaction conditions: 1{1} (3 mmol), 2{2} (1 equiv.), 3{1} (1 equiv.), 4{1} (1 equiv.) and solvent (6 mL) at 25 °C.
b
c
Isolated yield. Reaction conditions : 5 (0.4 mmol), Cs CO (2 equiv.), CuI (20 mol%), 1,10-phenanthroline (20
2
3
d
mol%) and solvent (THF: water, v/v=95:5) under microwave irradiation at 100 °C. Reaction conditions : 5 (0.4
mmol), Cs CO (4 equiv.), CuI (40 mol%), 1,10-phenanthroline (40 mol%) and solvent (THF: water, v/v=95:5)
under microwave irradiation at 100 °C. Ratio determined by H NMR analysis. 15% Ugi adducts recovered. 42%
2
3
e
1
g
h
i
j
k
Ugi adducts recovered. 53% Ugi adducts recovered. 28% Ugi adducts recovered. 20% Ugi adducts recovered.
0
1
2
3
4
5
6
7
8
9
0
1
2
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5
6
7
8
9
0
1
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8
9
0
Next, we turned our attention to the construction of thiazines 10 and thiazepine 11 (Table 4).
The yields of thio-Ugi adducts for condensed thiazine 10 was inferior compared to the thio-Ugi
for 8 and 9 because o-bromoaniline creates a more sterically hindered circumstance. Also, we
were unable to synthesize 5bd and 5be which use an aldehyde with an EWG group, revealing
that the electronic nature of the imine should be adjusted for the successful formation of Ugi
adducts. Unfortunately, due to the failure of imine formation between 1{11} and 4{17}, we were
also unable to synthesize 5bm. Under identical conditions to those used for the fused
benzo[b]thiophenes 8, the starting materials for the synthesis of thiazine were remained except
for 5ba. The problem was simply solved by increasing the amount of CuI and the ligand. When
1
R (10d, 10g, 10h, 10j, 10k) consisted of alkyl groups that were less bulky than aromatics, the
corresponding products existed as a mixture of E and Z stereoisomers whereas the other products
contained only the Z- isomer (10a, 10c, 10e, 10f, 10i, 10l).
For the synthesis of thiazepines 11, adding more catalyst and ligand was ineffective in
improving yields, although the starting materials were consumed. Attempts to develop better
conditions ended in failure. Additionally, the reaction did not proceed with 5bp possessing a
benzoyl moiety. Eventually, we applied the conditions used for the benzo[b]thiophenes 8. 5bq
and 5br respectively gave an enamine tautomer 11a and imine form 11b confirmed by NMR
3
(
Table 4, entry 17 and 18). The difference in the number of sp hybridized carbons between 11a
1
(or 11b) and their corresponding tautomer, and coupling patterns of H-NMR in 11b permitted
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the determination of the structure. Finally, the attempts to produce 8-membered rings were
disappointing (Table 4, entry 19).
Scheme 3. N-de-tert-butylation of 8b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Only two commercial isocyanides were used for producing the heterocycles. Instead of
introducing a variety of isocyanides in the first step for Ugi adducts, deprotection of tert-butyl
group of the benzo[b]thiophene 8b was carried out with trifluoroacetic acid (TFA) to make the
primary arylamine that could be further diversified with electrophiles (Scheme 3). However, the
1
3
obtained product was the amide 12 which we had not expected. Hydrolysis of the amide 12
under the basic conditions gave the desired product 14. In the literature, we found another
condition for N-detertbutylation using BF complex but it also gave the corresponding amide
3
2g
13.
CONCLUSION
In summary, we have described the synthesis of fused heterocycles by intramolecularly creating
a C-S bond between thioamides generated from an Ugi reaction and aryl halides.
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5
5
5
5
5
5
5
6
Furthermore, in the preparation of thio-Ugi adducts, electronic and steric effects on the reaction
efficiency were briefly discussed. Biologically important derivatives of benzo[b]thiophenes,
benzo[b][1,4]thiazines and thiochroman were successfully synthesized in two synthetic steps in
good to excellent yields but 1,4-benzothiazepines were obtained in low yields. Although we
employed inexpensive copper(I) iodide and a ligand for the C-S bond formation, it is necessary
to seek better catalysts and ligands because constructing rings larger than five-membered rings
requires high loading of catalysts and ligands.
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
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7
8
9
0
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9
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8
9
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0
EXPERIMENTAL PROCEDURES
General Preocedure for Preparation of thio-Ugi Adducts 5. The aldehyde 1{1} (3 mmol) was
added to the amine 4{1} (1 equiv). The reaction mixture was stirred at room temperature for the
imine formation for 1-2 h. Then, TFE (6 mL), the isocyanide 2{1} (1 equiv) and the thio acid
3
{1} (1 equiv) was added slowly to the reaction mixture and the mixture was stirred overnight at
room temperature. The reaction mixture was concentrated under reduced pressure. Water was
added to the crude mixture, and extracted with ethyl acetate. The combined organic layer was
dried over MgSO and filtered. After removal of the solvent in vacuum, the residue was purified
4
by column chromatography on silica gel with an ethyl acetate/hexanes mixture as eluents to give
1
thio-Ugi adducts 5{1,1,1,1}, 5a (63%). White solid; H NMR (500 MHz, CDCl ) δ 8.80 (s, 1H),
3
7.62 – 7.52 (m, 3H), 7.47 – 7.37 (m, 4H), 7.28 (t, J = 7.2 Hz, 1H), 7.20 – 7.14 (m, 3H), 7.12 –
1
3
7.04 (m, 3H), 5.86 (s, 1H), 5.20 – 4.54 (m, 2H), 1.40 (s, 9H); C NMR (126 MHz, CDCl ) δ
3
198.09, 173.62, 136.96, 135.91, 135.86, 133.05, 131.45, 130.23, 129.93, 128.49, 128.45, 128.44,
+
1
27.61, 127.50, 127.36, 125.50, 76.67, 56.94, 55.81, 27.16; LC/MS (ESI) m/z 495 [M+H] .
General Procedure for Preparation of benzo[b]thiophene 8 and S-heterocycles 9, 10 and
1
1. K PO (2 quiv), CuI (20 mol%) and 1,10-phenanthroline (20 mol%) was added to a stirred
3
4
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solution of Ugi adduct 5{1,1,1,2} (0.40 mmol) in 4.75 mL of THF and 0.25 mL of H O
2
o
(
THF:H O = 95:5, v:v). The reaction mixture was subjected to microwave heating (100 C) for 1
2
h and then the reaction mixture were concentrated under reduced pressure. Water was added to
the crude mixture, and extracted with ethyl acetate. The combined organic layer was dried over
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
MgSO and filtered. After removal of the solvent in vacuum, the residue was purified by column
4
chromatography using ethyl acetate and hexanes as eluents to give the desired products
o
1
8
{1,1,1,2}, 8b (94%). Pale yellow solid; mp 140-141 C; H NMR (500 MHz, CDCl ) δ 7.51 (d,
3
J = 7.9 Hz, 1H), 7.35 – 7.29 (m, 6H), 7.25 (d, J = 8.2 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.10 (ddd,
J = 8.1, 5.1, 3.3 Hz, 1H), 7.05 (t, J = 7.7 Hz, 2H), 5.68 (d, J = 13.5 Hz, 1H), 4.17 (d, J = 13.5 Hz,
1
3
1
H), 3.40 (s, 1H), 0.92 (s, 9H) C NMR (126 MHz, CDCl ) δ 172.30, 146.59, 136.75, 135.52,
3
135.32, 133.91, 131.20, 130.11, 129.21, 128.73, 127.35, 126.91, 125.10, 121.95, 121.27, 117.07,
+
1
10.96, 51.92, 50.19, 28.89; HRMS (ESI) m/z calcd for C H ClN OS [M+H] 449.1449, found
2
6
26
2
449.1449.
(Z)-(2-(tert-butylimino)-3-phenyl-2H-benzo[b][1,4]thiazin-4(3H)-yl)(phenyl)methanone 10a.
1
Isolated yield: 64%; Colorless oil; H NMR (500 MHz, CDCl ) δ 7.43 (d, J = 7.7 Hz, 2H), 7.35
3
(t, J = 7.4 Hz, 1H), 7.26 (t, J = 7.0 Hz, 4H), 7.20 – 7.13 (m, 3H), 7.10 (t, J = 7.2 Hz, 1H), 6.90 (t,
1
3
J = 7.6 Hz, 2H), 6.71 (t, J = 6.5 Hz, 1H), 6.51 (s, 1H), 1.52 (s, 9H); C NMR (126 MHz, CDCl )
3
δ 169.97, 152.27, 136.80, 136.61, 134.81, 130.82, 129.13, 128.44, 128.19, 128.10, 127.45,
127.03, 126.90, 126.85, 126.02, 125.77, 62.15, 57.21, 28.98; HRMS (ESI) m/z calcd for
+
C H N OS [M+H] 401.1682, found 401.1683.
25
25
2
1-(2-(tert-butylamino)-3-phenylbenzo[f][1,4]thiazepin-4(5H)-yl)ethan-1-one 11a. Isolated
1
yield: 28%; Pale yellow oil; H NMR (500 MHz, CDCl ) δ 7.55 (d, J = 7.5 Hz, 2H), 7.37 (dd, J
3
=
15.3, 7.5 Hz, 3H), 7.26 – 7.18 (m, 2H), 7.17 – 7.09 (m, 2H), 5.84 – 5.54 (m, 1H), 4.12 (s, 1H),
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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
13
4
1
4
.07 – 3.85 (m, 1H), 2.19 (s, 3H), 1.41 (s, 9H); C NMR (126 MHz, CDCl ) δ 172.67, 146.70,
3
36.13, 135.52, 131.21, 129.28, 129.19, 129.03, 127.49, 126.83, 126.56, 126.11, 122.48, 53.83,
+
6.91, 31.31, 21.48; HRMS (ESI) m/z calcd for C H N OS [M+H] 353.1682, found 353.1682.
2
1
25
2
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
ACKNOWLEDGMENTS
Funding Sources
This research was financially supported by the Ministry of Trade, Industry & Energy
MOTIE), and the Korea Institute for Advancement of Technology (KIAT) through the Inter-ER
(
Cooperation Projects (Grant Number R0002016) and the industrial infrastructure program for
fundamental technologies (Grant Number M0000338).
AUTHOR INFORMATION
Corresponding Author
*
Fax: 82-2-2290-1351. E-mail: ydgong@dongguk.edu
Author Contributions
†
These authors contributed equally to this work as the first author.
ASSOCIATED CONTENT
Supporting Information
1
13
Experimental procedures, H NMR and C NMR data and spectra for products 5-14. This
information is available free of charge via the Internet at http://pubs.acs.org.
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0
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007, 48, 9030–9034. (c) El Kaim, L.; Gizzi, M.; Grimaud, L. New MCR-Heck-Isomerization
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Cascade toward Indoles. Org. Lett. 2008, 10, 3417–3419. (d) Erb, W.; Neuville, L.; Zhu, J. Ugi-
Post Functionalization, from a Single Set of Ugi-Adducts to Two Distinct Heterocycles by
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Zheng, M.; Zhao, F.; Zhai, Y.; Liu, H. Rapid Generation of Privileged Substructure-Based
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(4) (a) Spiegel, D. A; Schroeder, F. C.; Duvall, J. R.; Schreiber, S. L. An Oligomer-Based
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