Reinvestigation of ortho-amidoacetophenones' cyclization mediated by trimethylsilyl trifluoromethanesulfonate. the Lewis-acid-assisted and Br?nsted-acid-catalyzed reaction

Article abstract of DOI:10.1016/j.tet.2016.02.068

Reinvestigation the synthesis of quinolones from ortho-amidoacetophenones by trimethylsilyl trifluoromethanesulfonate (TMSOTf) mediated reaction is reported. In addition to receiving the expected quinolones, an unexpected intermolecular self-condensation adduct was also isolated. The detailed mechanism of its formation is discussed.

Full text of DOI:10.1016/j.tet.2016.02.068

Tetrahedron 72 (2016) 2006e2011
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Reinvestigation of ortho-amidoacetophenones’ cyclization mediated
by trimethylsilyl trifluoromethanesulfonate. The Lewis-acid-assisted
and Brønsted-acid-catalyzed reaction
Yi-Ru Chen, Yu Cheng Cho, Tzenge-Lien Shih *
Department of Chemistry, Tamkang University, Tamsui Dist., 25137 New Taipei City, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Reinvestigation the synthesis of quinolones from ortho-amidoacetophenones by trimethylsilyl tri-
fluoromethanesulfonate (TMSOTf) mediated reaction is reported. In addition to receiving the expected
quinolones, an unexpected intermolecular self-condensation adduct was also isolated. The detailed
mechanism of its formation is discussed.
Received 3 November 2015
Received in revised form 22 February 2016
Accepted 29 February 2016
Available online 2 March 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Methylquinoline
Quinolone
Trifluoromethanesulfonic acid
Trimethylsilyl trifluoromethanesulfonate
Lewis-acid-assisted and Brønsted-acid-
catalyzed reaction
1. Introduction
isolated as a white solid by column chromatography. Its X-ray
crystallography and HRMS data confirmed the structure 3 (vide
The quinolone derivatives are an important class of nitrogen-
containing heterocycles because of the wide spectrum of bi-
infra). However, compound 3 was not discussed in that report and
its formation arose our interests.
1
2
3
ological activities, such as anti-malarial, anti-cancer, anti-viral
4
and anti-bacterial properties. Owing to their pharmaceutical im-
2. Results and discussion
portance, many synthetic strategies have been demonstrated, such
5
6
7
as by Camps, ConradeLimpach, GouldeJacobs, and Nie-
8
To a flame-dried under vacuum, two-necked round-bottomed
mentowski, respectively. Among these strategies, the Camps cy-
glassware equipped with a condenser was charged with 1, 1,2-
clization was most widely employed. However, all the above-
mentioned methods were required the strong basic and harsh
conditions and the less functional groups compatibility limited
1
1
dichloroethane (1,2-DCE), Et
3
N (3 equiv) and ‘TMSOTf’ (6 equiv).
ꢀ
This mixture was heated at 95 C for 6 h (Table 1, Entry 1). The
desired compound 2 was received as the major component (48%)
along with a red spot observed on TLC, which was then isolated as 3
their applications. Therefore, several improved methods have been
reported in the synthesis of 4-quinolones.9
(38%). The structure of compound 3, a methylquinoline framework,
We have noticed the condition of a Lewis acid, trimethylsilyl
was confirmed by X-ray crystallography (Fig. 1). Compound 3 was
most likely derived from the intermolecular self condensation of 1.
The earliest and recent reports regarding to the synthesis of 3 were
trifluoromethanesulfonate (TMSOTf) mediated ortho-amidoaceto-
1
0
phenones’ cyclization to synthesize 4-quinolone 2 and derivatives
Scheme 1). The mechanism in formation of 2 has been addressed
(
12
13
by Camps and Molina, respectively. Especially, the later applied
ortho-substituted arylazide by the Staudinger reduction and fol-
lowed by condensation with ortho-azido acetophenone. When
compound 1 was then treated with various equivalents of ‘TMSOTf’
by the same condition, respectively, the yields of both 2 and 3 were
gradually declined till 3 equiv of ‘TMSOTf’ were used. The reaction
was not complete by treating with 2 equiv of ‘TMSOTf‘. No com-
pound 2 was isolated but trace of 3 was obtained when the
in that article. The authors claimed this strategy was a modified
method of Camps cyclization to avoid a harsh condition. When we
repeated this procedure recently, beside the desired product 2, we
observed a certain amount of a red pot on TLC. This red spot was
*
Corresponding author. Tel./fax: þ886 2 86315024; e-mail address: tlshih@mail.
tku.edu.tw (T.-L. Shih).
http://dx.doi.org/10.1016/j.tet.2016.02.068
0
040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

Y.-R. Chen et al. / Tetrahedron 72 (2016) 2006e2011
2007
Scheme 1. The TMSOTf mediated cyclization of 1. Intramolecular cyclization versus intermolecular self condensation.
reactions were used one and 0.3 equiv of ‘TMSOTf’, respectively.
Most of compound 1 was recovered.
Table 1
We were aware that our results in Table 1 were different from
Optimized conditions of cyclization reaction of 1 by ‘TMSOTf’
10
3
literature (Et N, 3 equiv; TMSOTf, 6 equiv; 83% of 2). We as-
Entry
1
‘TMSOT’ (equiv)
Time (h)
2 (Yield%)
3 (Yield%)
sumed that the ‘TMSOTf’ used in reaction might contain certain
amount of moisture. It has been reported that TfOH served as
6
48
38
6
6
6
6
þ
14
a super proton (H ) donor to facilitate the ring cyclization. The
reaction mixture containing TMSOTf and moist TfOH might cause
a different mechanism from the literature proposed.1 In order to
2
3
4
5
6
7
5
32
28
25
18
0
4
19
15
prove our assumption, a new bottle of anhydrous TMSOTf was
used and the glassware system was flame-dried under vacuum. A
dramatically improved yield of 2 was obtained by using 6 equiv of
TMSOTf (Table 2, Entry 1). The yield of 2 (91%) was comparable
3
21
2
20 (22)a
24 (27)a
3 (4)a
2 (3)a
26
26
30
10
1
0
0
with the literature results. However, a small quantity of com-
pound 3 (2%) was also received. Compound 2 was isolated as
major instead of compound 3 when compound 1 was treated with
anhydrous TMSOTf (5e2 equiv). However, the longer reaction time
was required (48 h) to compare with in Table 1. When the reaction
was separately treated with one or 0.3 equiv of TMSOTf, no
compound 2 was obtained and far low yields of compound 3 was
received. In light of the results from Tables 1 and 2, we might
conclude that not only TMS group but also moist TfOH were es-
sential in affording 3.
0.3
ꢀ
Condition: Et
3
N (3 equiv), ‘TMSOTf’ (6e0.3 equiv), 1,2-DCE (0.20 M), 95 C and
flame-dried glassware.
a
Yields based on the recovery of starting material 1.
Conditions were used the non-flame-dried glassware and
‘TMSOTf’ (6e0.3 equiv) system to compare with the results of
Tables 1e3. However, the data were in contrast to the results in
Tables 1 and 2. The yields of compound 3 was slightly dominant
over than 2. This confirmed that the resulting moist TfOH from
decomposition of TMSOTf by moisture was pertaining to the for-
mation of 3. The yields of 3 decreased gradually with reducing
amounts of ‘TMSOTf’. We also found two or less equivalents of
TMSOTf would not drive the reaction in completion. Since we had
no clue how much amount of moist content in TMSOTf was nec-
essary to obtain 3, therefore, the reaction mixture was added
2
TMSOTf (6 equiv) along with 1% H O (relative to the equivalents of
Table 2
Conditions and yields of cyclization reaction of 1 by anhydrous TMSOTf
Entry
TMSOTf (equiv)
6
5
4
3
2
1
0.3
Time (h)
48
48
48
48
48
48
48
2 (Yield%)
3 (Yield%)
2
22
22
1
2
3
4
5
6
7
91
76
57
29
22
a
20 (22)a
22 (24)
a
Trace
0
11 (16)
2 (3)a
ꢀ
3
Condition: Et N (3 equiv), TMSOTf (6e0.3 equiv), 1,2-DCE (0.20 M), 95 C and flame-
dried glassware.
a
Fig. 1. Single crystal X-ray structure of 3.
Yields based on the recovery of starting material 1.

2008
Y.-R. Chen et al. / Tetrahedron 72 (2016) 2006e2011
Table 3
Yields of cyclization reaction of 1 by ’TMSOTf’ under moist condition
Entry
‘TMSOTf’ (equiv)
Time (h)
2 (Yield%)
3 (Yield%)
1
2
3
4
5
6
7
6
5
4
3
2
1
0.3
48
48
48
48
48
48
48
18
23
20
21
20 (20)
Trace
0
47
27
34
19
15 (16)
6 (15)
a
a
a
a
2 (9)
ꢀ
Condition: Et
3
N (3 equiv), ‘TMSOTf’ (6e0.3 equiv), 1,2-DCE (0.20 M), 95 C and non-
flame-dried glassware.
a
Yields based on the recovery of starting material 1.
TMSOTf) and heated for 30 h. At this stage, part of the TMSOTf was
decomposed to afford TMSOH and TfOH. Compounds 2 and 3 were
isolated with 17% and 29% yields, respectively. Although the com-
bined yields was slightly lower, this indeed demonstrated that
TfOH was essentially needed for 1 in favor of formation of 3.
In order to discern the role of TMS group during the reaction
course, we used anhydrous TfOH as the only source of Brønsted acid
in reaction (Table 4). No compound 2 was isolated throughout the
reactions at any event. We observed that the extended reaction
time (72 h) was needed and relatively lower yields of 3 were ob-
tained in comparison to the data of Table 3. When analogous 4 was
treated with anhydrous TfOH (Scheme 2) in the same condition as
in Table 4, the intermolecular condensation adduct 6 (Fig. 2)was
received in comparable yields (Table 5). However, these reactions
also required longer reaction time and did not complete in the
absence of TMS group. Again, no intramolecular cyclization com-
pound 5 was detected through the studies. In addition, when
methanesulfonic acid (MsOH, 6e0.3 equiv) was replaced for TfOH
in Table 4, neither 2 nor 3 were formed and 1 was fully recovered.
We assumed that the acidity of MsOH was not strong enough to
mediate intermolecular self condensation of 1 to furnish 3.
Fig. 2. Single crystal X-ray structure of 6.
Table 5
Conditions and yields of cyclization reaction of 4 by anhydrous TfOH
Entry
TfOH (equiv)
Time (h)
5 (Yield%)
6 (Yield%)
50 (57)a
1
2
3
4
5
6
7
6
5
4
3
2
1
0.3
72
72
72
72
72
72
72
0
0
0
0
0
0
0
a
38 (49)
19 (41)a
10 (28)a
11 (30)a
13 (22)a
10 (22)a
ꢀ
3
Condition: Et N (3 equiv), TfOH (6e0.3 equiv), 1,2-DCE (0.20 M), 95 C and flame-
dried glassware.
a
Yields based on the recovery of starting material 4.
Table 4
Conditions and yields of cyclization reaction of 1 by anhydrous TfOH
Entry
TfOH (equiv)
Time (h)
2 (Yield%)
3 (Yield%)
We found two or less equivalents of TMSOTf were not enough to
complete reactions in Table 1e3. Therefore, it was more reasonable
that the reaction required at least 3 equiv of TMSOTf because the
same equivalent amounts of Et N were used. The plausible mech-
3
anism of formation 3 from 1 by treating with ‘TMSOTf’ (3 equiv) is
a
1
2
3
4
5
6
7
6
5
4
3
2
1
0.3
72
72
72
72
72
72
72
0
0
0
0
0
0
0
40 (53)
34 (45)
15 (17)
a
a
a
19 (46)
a
5 (9)
3 (4)
a
depicted in Fig. 3. Two equivalents of TMS groups complexed with
a
3 (13)
0
both oxygens of amide and ketone to form either TMS-enol 7 or 7 .
ꢀ
3
Condition: Et N (3 equiv), TfOH (6e0.3 equiv), 1,2-DCE (0.20 M), 95 C and flame-
The resulting TfOH (cat) arose from the partial decomposition of
the rest 1 equiv of TMSOTf by the moisture. Equilibrium occurred
dried glassware.
a
Yields based on the recovery of starting material 1.
Scheme 2. Cyclization reaction of 4 by anhydrous TfOH to lead to the intermolecular self-condensation compound 6.

Y.-R. Chen et al. / Tetrahedron 72 (2016) 2006e2011
2009
Fig. 3. Plausible mechanism of cyclization reaction of 1 mediated by ‘TMSOTf’. The intermolecular self-condensation reaction of 1 facilitated by TfOH (cat.) to furnish 3.
0
e
between 7 and 7 while TfOH presented. The presence of OTf se-
The reaction concentration used throughout these studies
were 0.2 M instead of those in the literature (0.1 M) based on
starting materials 1. A question might arise from the higher
concentration media leading to higher yields of 3. Therefore, the
conditions in Tables 1e3 (Entry 1) were repeated except the re-
0
quentially removed TMS of 7 to trigger the intramolecular self
condensation of 1 to lead to compound 3. The similar mechanism is
also applicable to the cyclization of 4 to provide 6 while the TMS
þ
group(s) in Fig. 3 were replaced with H .
action concentrations were reduced to 0.05
M (Table 6,
Entry1ꢁ3). In presence of moisture of ‘TMSOTf’ (Entry 3), yields of
2 were dominated over 3 of which yield was slightly increased
and less reaction time was needed to compare with Entry1ꢁ2.
When the concentration was 0.5 M, compounds 2 and 3 were
received almost equivalent yields (Entry 4). The above-mentioned
results and in Table 3 (Entry 1) clearly demonstrated that the
reaction was most likely concentration dependent to form 3.
Especially, the moist TfOH along with TMS group and higher
concentration (0.2e0.5 M) were without doubt in favor of
compound 3.
Table 6
Conditions and yields of cyclization reaction of 1 by TMSOTf or moist ‘TMSOTf’ under
different concentrations
Entry
Condition
Time (h)
2 (Yield%)
3 (Yield%)
1
2
3
4
a
b
c
24
24
18
4
63
53
49
47
8
11
18
43
d
ꢀ
Condition: a. Et
dried glassware. b. Et
flame-dried glassware. c. Et
and non-flame-dried glassware. d. Et
3
N (3 equiv), TMSOTf (6 equiv), 1,2-DCE (0.05 M), 95 C and flame-
ꢀ
3
N (3 equiv), ‘TMSOTf’ (6 equiv), 1,2-DCE (0.05 M), 95 C and
In order to determine whether cyclization reaction could occur
for 16 by TMSOTf, compound 16 was treated with the same con-
ditions as in Tables 1 and 2 (Scheme 3). The cyclized adduct 17 was
ꢀ
3
N (3 equiv), ‘TMSOTf’ (6 equiv), 1,2-DCE (0.05 M), 95
C
3
N (3 equiv), ‘TMSOTf’ (6 equiv), 1,2-DCE
ꢀ
(
0.5 M), 95 C and non-flame-dried glassware.
Scheme 3. Intramolecular cyclization of 16 by TMSOTf.

2010
Y.-R. Chen et al. / Tetrahedron 72 (2016) 2006e2011
formed while TMSOTf was used (6e0.3 equiv) for 16 (Table 7). The
yields of 17 declined as the equivalents of TMSOTf reduced. We
observed 16 also gradually decomposed during 17 was forming that
accounted for its lower yields in prolonged reaction time. When
determined on Fargo MP-2D and not corrected. Column chroma-
tography was conducted under flash pressure and the silica gel was
used 230e400 mesh (MachereyeNagel, MN Kiesegel 60) except
otherwise stated. The chemical shifts were reported in parts per
million (ppm) and referenced to the residual protonated solvent:
‘TMSOTf’ was used, the relatively lower yields of 17 were received
1
13
1
13
(Table 8). It was probably the resulting TfOH in reaction mixture to
3 2 2
CD OD ( H: 3.31 ppm; C: 49.2 ppm) or CD Cl ( H: 5.32 ppm; C:
decompose compound 16. That explained why we observed com-
pound 16 immediately decomposed by TLC monitoring when TfOH
54.0 ppm). The HRMS (FAB) data were recorded on Finnigan MAT-
95S.
(
6e0.3 equiv) was added. We suspected that the ester moiety of 16
might be too labile to survive under strong Brønsted acid condi-
tions. Unlike the cyclization reactions of 1 and 4, we have to point
out that the intermolecular self condensation of 16 did not oc-
curred. When MsOH was used as the only proton source
4
.1. N-(2-(4-Methylquinolin-2-yl)phenyl)benzamide (3)
A set of two-necked round-bottom flask equipped with a con-
denser was flame-dried under vacuum then charged with 1
132 mg, 0.55 mmol). After the flask was evacuated and purged
with N for three times, anhydrous 1,2-dichloroethane (2.8 mL),
anhydrous triethylamine (0.24 mL, 1.66 mmol), and TMSOTf
(
6e0.3 equiv), compound 16 was fully recovered and no cyclized
(
adduct 17 was received.
2
3
. Conclusion
(0.60 mL, 3.32 mmol) were added sequentially. This mixture was
ꢀ
heated at 95 C for 48 h. At the end of reaction time, MeOH (5 mL)
was added to quench the reaction. The solvent was removed under
reduced pressure, diluted with EtOAc (20 mL), and washed with
In conclusion, we have investigated in details the mechanism of
formation of 3 from ortho-amidoacetophenone 1 by moist TMSOTf.
It is noteworthy that the TMS group, catalytic moist TfOH and
higher concentration media (0.2e0.5 M) play essential roles to fa-
cilitate the formation of 3. The combined yields of 2 and 3 were
moderate to good with at least 3 equiv of TMSOTf (Tables 1e3). The
yields of compound 3 and 6 were moderate to low and required
longer reaction times by using TfOH as the only proton source
2
M NaOH(aq) (3ꢂ10 mL). The organic layer was separated and the
aqueous layer was extracted with EtOAc (3ꢂ10 mL). The combined
organic layer was dried with MgSO , filtered, and concentrated
under reduced pressure. The residue was purified by flash column
4
chromatography (CH
2
Cl
2
:Hexane¼1:2e19:1) to afford 3 as a white
ꢀ
solid (4 mg, 2%); Mp¼132e134 C. Then the eluent was changed
(Tables 4 and 5). We found the only TfOH could not drive the re-
(CH
2
Cl
2
:MeOH¼20:1) to afford 2 as a yellow solid (112 mg, 91%);
actions in completion without the TMS group’s assistance. This is an
example of Lewis-acid-assisted and Brønsted-acid-catalyzed
cyclization.
ꢀ
10 1
ꢀ
Mp¼251e253 C (lit. >230 C). For 3: H NMR (600 MHz, CD
3
OD)
8.61 (d, J¼8.3 Hz, 1H), 8.07 (d, J¼8.3 Hz, 1H), 7.45 (dd, J¼7.4, 1.6 Hz,
H), 7.84 (s, 1H), 7.72 (t, J¼8.0 Hz, 1H), 7.57e7.62 (m, 2H), 7.51 (t,
d
4
J¼7.7 Hz, 2H), 7.47 (t, J¼8.2 Hz, 1H), 7.28 (t, J¼7.7 Hz, 1H), 5.47 (s,
13
1
1
1
H), 2.75 (s, 3H). C NMR (150 MHz, CD
47.4, 139.3, 136.9, 133.3, 131.3 (ꢂ2), 131.1, 130.9 (ꢂ2), 129.8 (ꢂ2),
27.9, 125.5, 125.4, 123.1, 122.6, 19.2. HRMS (ESI) calcd for
3
OD) d 168.2, 159.1, 148.3,
4
. Experimental section
All chemicals were purchased from either Aldrich Chemical Co.
þ
1
2
C23H18N O [M] 339.1497; found: 339.1490.
or Arcos companies and used without further purification. H NMR
(
600 MHz) and 13C NMR (150 MHz) spectra were recorded on
Bruker Advance 600 spectrometer. The melting points were
4.2. 4-Bromo-N-(2-(4-methylquinolin-2-yl)phenyl)benza-
mide (6)
Table 7
Conditions and yields of cyclization reaction of 16 by anhydrous TMSOTf
Purification
(Hexane:CH Cl
CD Cl
by
flash
column
chromatography
¼2:1e0:1). Mp¼135e136 C. 1H NMR (600 MHz,
ꢀ
Time (h)a
2
2
Entry
TMSOTf (equiv)
17 (Yield%)
2
2
)
d
13.69 (s, 1H), 8.79 (d, J¼8.3 Hz, 1H), 8.08 (d, J¼8.3 Hz, 1H),
1
2
3
4
5
6
7
6
5
4
3
2
1
0.3
6
8
7
10
13
14
24
53
49
36
22
16
10
1
8
.04 (d, J¼8.3 Hz, 1H), 7.93 (d, J¼8.5 Hz, 3H), 7.80 (t, J¼8.7 Hz, 2H),
7.66e7.62 (m, 3H), 7.51 (t, J¼7.5 Hz, 1H), 7.28 (t, J¼7.5 Hz, 1H), 2.80
13
(s, 3H). C NMR (150 MHz, CD
2 2
Cl ) d 165.0,158.2,147.0,146.3,138.9,
1
35.4, 132.2 (ꢂ2), 130.7, 130.5, 129.9 (ꢂ2), 129.6 (ꢂ2), 128.9, 127.1,
126.5, 126.2, 124.5, 124.0, 122.0, 121.9, 19.31. HRMS (FAB) calcd for
C
23
H18BrN
2
O [Mþ1]þ 417.0603; Found: 417.0605.
ꢀ
3
Condition: Et N (3 equiv), TMSOTf (6e0.3 equiv), 1,2-DCE (0.20 M), 95 C and flame-
dried glassware.
a
Reaction was terminated until compound 16 was consumed by TLC detection.
Acknowledgements
The authors gratefully acknowledge the Ministry of Science
Council (MOST 103-2113-M-032-008) and Tamkang University for
financial support. We thank the National Tsing Hua University, the
National Chung Hsing University for LRMS/HRMS and the National
Taiwan Normal University for X-ray experiments.
Table 8
Conditions and yields of cyclization reaction of 16 by ’TMSOTf’
Entry
‘TMSOTf’ (equiv)
Time (h)a
17 (Yield%)
1
2
3
4
5
6
7
6
5
4
3
2
1
0.3
8
9
9
10
11
15
26
27
23
22
18
15
8
Supplementary data
Supplementary data (Copies of 1H, 13C NMR spectra and X-ray
data of compounds 3 and 6) associated with this article can be
found in the online version, at http://dx.doi.org/10.1016/
j.tet.2016.02.068.
Trace
ꢀ
Condition: Et
3
N (3 equiv), ‘TMSOTf’ (6e0.3 equiv), 1,2-DCE (0.20 M), 95 C and
flame-dried glassware.
a
Reaction was terminated until compound 16 was consumed by TLC detection.

Y.-R. Chen et al. / Tetrahedron 72 (2016) 2006e2011
2011
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6
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