Two birds with one stone: One-pot simultaneous synthesis of 2,2,2-trifluoroethylphenanthridines and benzochromenones featuring the utilization of the byproduct of Togni's reagent

Article abstract of DOI:10.1039/c9gc02001b

In this paper, a novel and efficient one-pot synthesis of 2,2,2-trifluoroethylphenanthridines (4) and benzochromenones (5) through three-component reactions of vinyl azides (1) with cyclic α-diazo carbonyl compounds (2) and Togni's reagent (3) is presente

Full text of DOI:10.1039/c9gc02001b

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DOI: 10.1039/C9GC02001B
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Two birds with one stone: One-pot simultaneous synthesis of
2,2,2-trifluoroethylphenanthridines and benzochromenones
featuring with utilization of the byproduct of Togni’s reagent
Received 00th January 20xx,
Accepted 00th January 20xx
Cai Gao, Bin Li, Xueyang Geng, Qianting Zhou, Xinying Zhang*, and Xuesen Fan*
DOI: 10.1039/x0xx00000x
www.rsc.org/
functional materials. Accordingly, extensive efforts have been
made in developing reliable methods for the introduction of a
CF3 unit into the target molecules.5,6 Meanwhile, vinyl azide is
recently emerging as an important three-atom synthon for the
construction of the synthetically and biologically valuable N-
containing compounds (Scheme 1, (1)).7-9 Under this
background and as part of our continuing efforts in exploring
α-diazo carbonyl compounds as an efficient coupling partner
for Rh(III)-catalyzed inert C−H bond functionalizations,10 we
have studied the three-component reaction of (1-azidovinyl)
benzene with 2-diazocyclohexane-1,3-dione and Togni’s
reagent. During this study, we serendipitously found that this
reaction could not only provide a novel access toward the
envisioned 2,2,2-trifluoroethylphenanthridine derivative, but
also result in the formation of benzochromenone as an
unexpected yet highly rewarding product through the in situ
trapping of the decomposition product of Togni’s reagent, o-
iodobenzoic acid, with the cyclic α-diazo carbonyl substrate
(Scheme 1, (2)). Herein, we would like to report the detailed
results of our study in this regard.
In this paper, a novel and efficient one-pot synthesis of 2,2,2-
trifluoroethylphenanthridines (4) and benzochromenones (5)
through the three-component reactions of vinyl azides (1)
with cyclic α-diazo carbonyl compounds (2) and Togni’s
reagent (3) is presented. In these cascade reactions, 3 acted
as not only the source of CF3 radical to react with 1 and 2 to
afford 4, but also the pool of o-iodobenzoic acid to couple
with 2 to afford 5. To our knowledge, this is the first example
in which 4 and 5 were obtained in a one-pot manner, and the
byproduct of Togni’s reagent, o-iodobenzoic acid, was
trapped in situ by another substrate to give valuable product
instead of being abandoned as a waste.
It is well known that phenanthridine derivatives present
ubiquitously in natural products and man-made compounds
possessing diverse pharmacological activities and unique
functional properties.1,2 Due to their importance, a number of
methods for the preparation of functionalized phenanthridine
derivatives have been developed based on different synthetic
strategies.3,4 While these elegant literature protocols are
generally reliable, some of them still suffered from limitations
such as necessitating the use of difficult-to-obtain ortho-
functionalized biaryls as substrates and the production of
halides or boronic acids as non reusable byproducts. In view of
green and sustainable chemistry, there is an urgent need to
develop novel approaches toward phenanthridine derivatives
starting from easily accessible substrates and accomplished in
a more sustainable and atom-economic manner.
CF3
9a
N3
fac-Ir(ppy)3
N
+
(1)
Na2HPO4, DMF
white LEDs, rt
S
BF4
CF3
CF3
N
O
this work
CF3
I
O
N2
O
O
[RhCp*Cl2]2, Cu(OAc)2
N3
+
(2)
+
+
HOAc, 100 o
C
O
O
O
O
The trifluoromethyl (CF3) group is a valuable structural motif
embedded in numerous pharmaceuticals, agrochemicals, and
Scheme 1 Syntheses of 2,2,2-trifluoroethyl phenanthridines
from vinyl azide and trifluoromethylation reagent.
a. Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Key
Laboratory of Green Chemical Media and Reactions, Ministry of Education,
Collaborative Innovation Center of Henan Province for Green Manufacturing of
Fine Chemicals, School of Chemistry and Chemical Engineering, School of
Environment, Henan Normal University, Xinxiang, Henan 453007, China.
b. E-mail: xinyingzhang@htu.cn; xuesen.fan@htu.cn
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Results and discussion
Our study was initiated by treating a mixture of (1-
azidovinyl)benzene (1a), 2-diazocyclohexane-1,3-dione (2a)
and Togni’s reagent (3a) with [RhCp*Cl2]2 and AgOAc in CH3CN
at 80 °C for 3 h. From this reaction, 6-(2,2,2-trifluoroethyl)-3,4-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2019, 00, 1-5 | 1
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dihydrophenanthridin-1(2H)-one (4a) was obtained in a yield reaction as 4l is structurally similar to Papaverine and might
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12
of 23%. Meanwhile, 3,4-dihydro-1H-benzo[c]chromene-1,6(2H) possess promising biological activities.DOMI: 1e0a.1n0w39h/Cil9eG,C50a20w0a1Bs
-dione (5a) was obtained in 16% yield (Table 1, entry 1). We
deduced that the unexpected formation of 5a should involve
Table 1 Optimization studies for the formation of 4a and 5aa
the coupling of 2a with o-iodobenzoic acid, generated in situ
via the decomposition of 3a. It occurred to us that the
simultaneous formation of 4a and 5a is synthetically highly
attractive due to the following reasons: 1) to the best of our
knowledge, this is the first example in which the byproduct of
Togni’s reagent was trapped in situ to afford valuable product
instead of being abandoned as a waste; 2) benzochromenone
derivatives like 5a have been found widely in nature, and
many of them are highly effective antifungal and
antiproliferation reagents, thus holding great potential in the
development of new drugs.11 To develop this novel reaction
into an efficient and reliable one-pot synthesis of
CF3
N
O
CF3
I
O
N2
O
O
conditions
N3
+
+
+
O
O
3a
1a
2a
O
5a
O
4a
Yield (%)b
4a
Entry
Solvent
Additive
T (oC)
5a
16
1c
2d
3e
CH3CN
CH3CN
AgOAc
AgOAc
80
80
23
29
17
CH3CN
AgOAc
80
35
27
4
CH3CN
AgOAc
80
40
32
5
DCE
AgOAc
80
34
29
6
CH3OH
AgOAc
80
45
32
7
toluene
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
AgOAc
80
18
20
trifluoroethylphenanthridine
and
benzochromenone
8
AgOAc
80
48
35
derivatives, and to make a better and greener use of Togni’s
reagent, various reaction conditions were then screened. It
was firstly found that increasing the molar ratio of 2a to 1a
and 3a improved the yields of 4a and 5a obviously (entries 1-4).
In specific, when 3 equiv of 2a was used, 4a and 5a could be
obtained in yields of 40% and 32%, respectively (entry 4).
Following study on the effect of different solvents including
DCE, CH3OH, toluene and acetone revealed that acetone is the
most effective medium for this reaction (entries 4-8). Next,
AgSbF6, CsOAc, Cu(OAc)2, HOAc or PivOH was tried to replace
AgOAc as the additive (entries 9-13). Among them, Cu(OAc)2
was found to be the most effective (entry 11). In further
screening on the effect of mixed additive, we were pleased to
find that using a combination of Cu(OAc)2 and HOAc as the
additive improved the reaction efficiency significantly (entry
15). In addition, a slightly better result was obtained when the
reaction was carried out at 100 °C compared with those run at
80 °C, 60 °C or 120 °C (entry 17 vs 15, 16 and 18). Finally,
control experiments indicated that the presence of catalyst
and additive is indispensable for the formation of 4a and 5a
(entries 19-20).
With the establishment of the optimum conditions, the
substrate scope of this novel reaction was explored, and the
results are listed in Table 2. First, by using 2a and 3a as model
substrates, the reaction of different vinyl azides 1 was studied.
It turned out that phenyl substituted vinyl azides with either
electron-donating groups (EDG) such as methyl, tert-butyl,
methoxy and acetoxyl, or electron-withdrawing groups (EWG)
such as fluoro, chloro and bromo attached on the phenyl ring
took part in this reaction smoothly to give 4a-4i in moderate to
good yields. Notably, various functional groups were tolerated
well under the reaction conditions. In the case of meta-
substituted substrate, the reaction took place efficiently and
regioselectively on the less hindered site to give 4i.
Furthermore, 2-naphthylvinyl azide reacted with 2a and 3a to
give a benzo[j]phenanthridine derivative 4j in a yield of 57%.
Interestingly, vinyl azide 1 bearing a phenyl unit at the -
position could also participate in this reaction to give 4k. Of
particular interest was the successful synthesis of 4l via this
9
AgSbF6
CsOAc
80
ND
trace
50
ND
trace
38
10
11
12
13
14f
15g
16g
17g
18g
19g,h
20
80
Cu(OAc)2
HOAc
80
80
trace
trace
31
trace
trace
15
PivOH
80
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
none
80
80
68
46
60
45
30
100
120
100
100
72
52
70
51
ND
ND
ND
ND
a
Conditions: 1a (0.3 mmol), 2a (0.6 mmol), 3a (0.2 mmol), [RhCp*Cl2]2 (0.01
mmol), additive (0.4 mmol), solvent (2 mL), 3 h. b Isolated yield. c 1a (0.3 mmol),
2a (0.2 mmol), 3a (0.2 mmol). d 1a (0.3 mmol), 2a (0.3 mmol), 3a (0.2 mmol). e 1a
f
g
(0.3 mmol), 2a (0.4 mmol), 3a (0.2 mmol). With 0.2 mmol of CsOAc. With 0.2
mmol of HOAc. h Without [RhCp*Cl2]2.
Table 2 Substrate scope for the synthesis of 4 and 5 (I)a
R2 CF3
R2
O
CF3
I
O
N2
[RhCp*Cl2
]
2
O
O
Cu(OAc)2, HOAc
acetone, 100 oC, 3 h
N
N3
R1
R1
+
+
+
O
O
1
2a
3a
O
O
5a
4
CF3
N
CF3
N
CF3
O
O
O
N
+
+
+
H3
C
O
O
tBu
O
O
O
O
O
O
O
4b, 68%; 5a, 50%
4a, 72%; 5a, 52%
4c, 63%; 5a, 50%
CF3
CF3
CF3
O
O
O
N
+
N
+
N
+
MeO
O
AcO
O
F
O
O
O
O
O
O
O
4d, 55%; 5a, 48%
4e, 51%; 5a, 45%
4f, 58%; 5a, 48%
CF3
CF3
CF3
O
O
O
Cl
N
+
N
+
N
+
Cl
O
Br
O
O
O
O
O
O
O
O
4h, 69%; 5a, 51%
4i, 60%; 5a, 49%
4g, 72%; 5a, 56%
OMe
CF3
Ph
CF3
O
O
F3
C
O
OMe
+
N
+
N
MeO
MeO
O
+
N
O
O
O
O
O
O
O
O
4k, 48%; 5a, 46%
4l, 48%; 5a, 46%
4j, 57%; 5a, 50%
2 | J. Name., 2019, 00, 1-5
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CF3
a Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), 3a (0.2 mmol), [RhCp*Cl2]2
(0.01 mmol), Cu(OAc)2 (0.4 mmol), HOAc (0.2 mmol), acetone (2 mL), 100 °C, 3
h. b Isolated yield.
CF3
I
O
N2
O
[RhCp*Cl2]2
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O
O
N3
N
Cu(OAc)2, HOAc
acetone, 100 oC, 3 h
DOI: 10.1039/C9GC02001B
+
+
+
O
O
3a
1a
6
O
O
8
7
, 48%
, 62%
successfully obtained along with 4 in all these cases in yields
ranging from 45-56%. Finally, it is worth to be noted that the
structure of 4j was unambiguously confirmed by its single
crystal X-ray diffraction analysis.13
Scheme 2 Reaction of 6 with 1a and 3a to give 7 and 8.
To gain some insight into the mechanism of this reaction, several
control experiments were conducted. First, 2,2,6,6-tetramethyl-1-
piperidinyloxyl (TEMPO) as a radical scavenger was added to the
reaction of 1a with 2a and 3a under standard conditions. From this
reaction, 4a was formed only in trace amount. Meanwhile, 5a was
obtained in a yield of 50% (Scheme 3, (1)). These results showed
that the formation of 4a might involve a radical process, and the
formation of 5a, on the other hand, might be free of radical
intermediate. Second, 2-iodobenzoic acid and 2a was subjected to
standard conditions for 3 h to afford 5a in a yield of 48% (Scheme 3,
(2)). Third, 2a was treated with benzoic acid under standard
conditions, from which 5a was obtained in a yield of 65% (Scheme
3, (3)). These results indicated that either 2-iodobenzoic acid or
benzoic acid might be an intermediate to react with 2a to give 5a.
Next, the suitability of different diazo substrates 2 was
studied. The results listed in Table 3 showed that in addition to
2a, 2-diazo-5,5-dimethylcyclohexane-1,3-dione (2b) and 2-
diazo-4,4-dimethylcyclohexane-1,3-dione (2c) were also
suitable for this reaction to give the corresponding products
4m, 4n and 5b, 5c smoothly. Next, a series of 5-phenyl
substituted 2-diazocyclohexane-1,3-diones with either EDG
such as methoxy or EWGs such as fluoro, chloro or bromo
attached on the phenyl ring were reacted with 1a and 3a. It
turned out that these reactions took place effectively to give
4o-4s and 5d-5h in moderate to good yields without showing
obvious electronic effect. Finally, functional group (R4)
variations (from H to methyl, fluoro, chloro or bromo) on the
phenyl ring of Togni’s reagent turned out to be equally
successful to afford 4a and 5i-5l.
CF3
O
TEMPO (2 equiv)
CF3
N2
[RhCp*Cl2]2
Cu(OAc)2, HOAc
I
O
O
N
N3
+
O
+
(1)
+
acetone, 100 oC, 3 h
O
O
1a
2a
3a
O
O
4a
5a, 50%
, trace
Table 3 Substrate scope for the synthesis of 4 and 5 (II)a
O
N2
I
[RhCp*Cl2]2
Cu(OAc)2, HOAc
O
O
+
+
CF3
R3
(2)
O
acetone, 100 oC, 3 h
CO2H
CF3
N2
[RhCp*Cl2
]
2
O
O
I
O
O
Cu(OAc)2, HOAc
acetone, 100 oC, 3 h
5a
5a
2a
, 48%
N
N3
R4
+
O
O
O
+
+
R4
O
R3
O
O
N2
1a
3
2
O
R3
O
[RhCp*Cl2]2
Cu(OAc)2, HOAc
5
4
O
O
(3)
CF3
N
CF3
N
CF3
acetone, 100 oC, 3 h
CO2H
O
O
Ph
O
, 65%
2a
N
+
+
+
O
O
O
O
Scheme 3 Control experiments.
O
O
O
O
Ph
O
4n, 41%; 5c, 22%
4m, 56%; 5b, 55%
4o, 68%; 5d, 59%
CF3
CF3
CF3
O
Ph(4-F)
O
Ph(4-Cl)
O
Ph(4-Br)
N
N
N
Based on the above described experimental results and literature
reports,6,8,14 plausible mechanisms accounting for the formation of
4a and 5a from the reaction of 1a with 2a and 3a were proposed in
Scheme 4. Initially, decomposition of 3a under the assistance of
Cu(II) generates CF3 radical and 2-iodobenzoic acid (H). Addition of
+
+
+
O
O
O
O
Ph(4-Br)
O
O
Ph(4-F)
O
Ph(4-Cl)
O
O
4r, 66%; 5g, 53%
4p, 61%; 5e, 53%
4q, 69%; 5f, 52%
CF3
CF3
CF3
O
O
O
Ph(4-OMe)
N
N
+
N
+
+
O
O
O
F
H3
C
O
Ph(4-OMe)
O
O
O
O
O
the CF3 radical onto 1a gives A, which then undergoes
a
4s, 59%; 5h, 56%
4a, 68%; 5j, 36%
4a, 71%; 5i, 43%
coordination with Cu(II) to give B. Metal transfer of Cu(III) with
Rh(III) occurs with B followed by an ortho-C(sp2)–H metallation to
afford a five-membered rhodacyclic intermediate C. C then reacts
with 2a to give Rh-carbene species D. Next, migratory insertion of
the carbene unit into the Rh–C bond in D affords E. Protonation of E
gives F and releases the Rh(III) complex to start a new catalytic
cycle. In the second stage of this cascade process, F undergoes an
intramolecular N-nucleophilic addition to afford G, from which
product 4a is formed through an aromatization-driven elimination
of water. As for the formation of 5a, it should firstly involve the
generation of a rhodacyclic species I through reaction of Rh(III) with
benzoic acid, formed in situ through the deiodination of H under
the reaction conditions.15 Next, coordination of I with 2a gives a Rh-
carbene species J followed by migratory insertion of the carbene
unit into the Rh–C bond in J to give intermediate K. Protonation of K
CF3
CF3
O
O
N
+
N
+
O
O
Cl
Br
O
O
O
O
4a, 69%; 5k, 44%
4a, 66%; 5l, 48%
a Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), 3 (0.2 mmol), [RhCp*Cl2]2
(0.01 mmol), Cu(OAc)2 (0.4 mmol), HOAc (0.2 mmol), acetone (2 mL), 100 °C,
3 h. b Isolated yield.
Interestingly, 2-diazocycloheptane-1,3-dione (6) having a seven-
membered ring was found to be also suitable for this reaction to
give 5-(2,2,2-trifluoroethyl)-7,8,9,10-tetrahydro-11H-cyclohepta[c]-
isoquinolin-11-one (7) and 7,8,9,10-tetrahydrocyclohepta[c]iso-
chromene-5,11-dione (8) in moderate to good yields (Scheme 2).
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leads to the formation of L and releases the Rh(III) catalyst. Finally, L and its decomposition product were utilized simultaneously to
View Article Online
DOI: 10.1039/C9GC02001B
undergoes an intramolecular esterification to give 5a. Meanwhile, it afford two different kinds of highly valuable products in a one-pot
is worth to be noted that Li and Ribas have independently described manner. With notable features such as easily obtainable substrates,
the in situ generation of Ag(III) from Ag(I).16 These precedent high efficiency, broad substrate scope, excellent functional group
reports might explain our observation that with AgOAc as the tolerance and high atom-economy, this new method is expected to
additive, 4a and 5a could also be formed albeit in lower yields find wide applications in related areas.
compared with that with Cu(OAc)2 (Table 1, entries 1-8). In another
example, Qing et al reported a hydrotrifluoromethylation of alkenes
with CF3 radical generated from the in situ formed AgCF3 promoted
by PhI(OAc)2 working as an oxidant.17 We thus deduced that the
Conflicts of interest
There are no conflicts to declare.
formation of 4a in the presence of AgOAc might alternatively
involve the in situ formation and spontaneously collapse of AgCF3 to
form CF3 radical required for the trifluoromethylation process, in
which Togni’s reagent may serve as an oxidant. Further study is still
We are grateful to the National Natural Science Foundation of China
required to elucidate the exact nature of this cascade reaction.
Acknowledgements
(21572047), Plan for Scientific Innovation Talents of Henan Province
(184200510012), Program for Innovative Research Team in Science
N2
and Technology in Universities of Henan Province (20IRTSTHN005)
and 111 Project (D17007) for financial support.
O
O
O
O
O
O
Cp*
Cp*
L
Rh
N
Rh
O
CF3
OH
Cp*
Rh
*Cp
2a
D
Rh
N
J
O
Cp*
L
L
O
O
Cp*
OH
Rh
O
Rh
CF3
O
N
O
K
C
I
Notes and references
[Rh(III)]
CF3
OH
E
H+
H+
(1) (a) C.-H. Yang, M.-J. Cheng, M.-Y. Chiang, Y.-H. Kuo, C.-J. Wang
and I.-S. Chen, J. Nat. Prod., 2008, 71, 669; (b) D.-Z. Chen, C.-X.
Jing, J.-Y. Cai, J.-B. Wu, S. Wang, J.-L. Yin, X.-N. Li, L. Li and X.-J.
Hao, J. Nat. Prod., 2016, 79, 180.
CF3
CF3
O
F3
C
[Cu(III)]
CO2
O
H
OH
OH
NH
OH
NH2
O
N
O
H
Ph
O
B
Cu(II)
OH
O
O
L
O
O
G
F3C
F
N
O
A
CF3
N
O
3
a
Ph
N2
I
(2) (a) I. Kock, D. Heber, M. Weide, U. Wolschendorf and B.
Clement, J. Med. Chem., 2005, 48, 2772; (b) P. H. Bernardo, K.-
F. Wan, T. Sivaraman, J. Xu, F. K. Moore, A. W. Hung, H. Y. K.
Mok, V. C. Yu and C. L. L. Chai, J. Med. Chem., 2008, 51, 6699.
(3) (a) B. Zhang and A. Studer, Chem. Soc. Rev., 2015, 44, 3505; (b)
J. Lei, J. Huang and Q. Zhu, Org. Biomol. Chem., 2016, 14, 2593.
(4) (a) M. Blanchot, D. A. Candito, F. Larnaud and M. Lautens, Org.
Lett., 2011, 13, 1486; (b) Y, Wu, S. M. Wong, F, Mao, T. L. Chan
and F. Y. Kwong, Org. Lett., 2012, 14, 5306; (c) T.-H. Zhu, S.-Y.
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CF3
O
H2
O
H2
O
Cu(II)
O
I
Cu(III)
CF3
N3
OH
1a
H+
O
O
Ph
5a
4a
H
Scheme 4 Plausible reaction mechanisms accounting for the
formation of 4a and 5a.
Finally, to see whether this newly developed synthesis of
phenanthridine and benzochromenone derivatives is suitable for
more practical applications, the reaction of 1a with 2a and 3a was
tried in an enlarged scale of 5 mmol. From this reaction, 4a and 5a
were obtained in yields of 68% and 50%, respectively (Scheme 5).
CF3
O
CF3
I
N2
[RhCp*Cl2]2
Cu(OAc)2, HOAc
acetone, 100 oC, 3 h
O
O
N
N3
O
+
+
+
O
O
O
1a
2a
O
, 7.5 mmol
, 15 mmol
3a
, 5 mmol
4a
5a
, 0.535 g, 50%
, 0.949 g, 68%
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Conclusions
In summary, an unprecedented one pot synthesis of 2,2,2-
trifluoroethylphenanthridines and benzochromenones from the
cascade reactions of vinyl azides with cyclic α-diazo carbonyl
compounds and Togni’s reagent has been established. To the best
of our knowledge, this is the first example in which Togni’s reagent
4 | J. Name., 2019, 00, 1-5
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Journal Name
COMMUNICATION
Li, B. Wang and L. Wang, Green Chem., 2019, doi: 10.1039/
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DOI: 10.1039/C9GC02001B
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DOI: 10.1039/C9GC02001B
A table of contents entry
R2
CF3
CF3
R3
R2
I
O
R4
O
N2
N
R1
O
O
N3
+
R4
+
R1
O
O
R3
Rh(III)/Cu(II)
solvent
O
O
R3
Dual role of Togni's reagent & diazo carbonyl compounds with high efficiency
First reuse of the byproduct of Togni's reagent with remarkable sustainability
A one-pot simultaneous synthesis of 2,2,2-trifluoroethylphenanthridines and benzochromenones
featuring with utilization of the byproduct of Togni’s reagent is presented.