Reaction of Cycloalkene-1-carboxamides with Aryl Boronates via Rhodium(III)-Catalyzed C?H Activation: A Versatile Route to 3,4-Cycloalkaquinolin-2(1H)-ones

Article abstract of DOI:10.1002/adsc.201901047

Under rhodium(III) catalysis, substituted N-methoxycycloalkene-1-carboxamides successfully reacted with aryl boronic acid pinacol esters to provide 3,4-cycloalkaquinolin-2(1H)-ones via direct functionalization of the β-alkenyl C?H bond and form C?C/C?N bond in one pot. The gram-scale synthesis of the title compound demonstrated the great synthetic utility of this methodology. (Figure presented.).

Full text of DOI:10.1002/adsc.201901047

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DOI: 10.1002/adsc.201901047
Reaction of Cycloalkene-1-carboxamides with Aryl Boronates via
Rhodium(III)-Catalyzed CÀ H Activation: AVersatile Route to 3,4-
Cycloalkaquinolin-2(1H)-ones
You-Quan Zhu,a,* Li-Wen Hui,a Yun-Xia Niu,a Lin-Ge Lv,a and Kun Zhua
a
State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, People’s
Republic of China
E-mail: zyq8165@nankai.edu.cn
Manuscript received: August 21, 2019; Revised manuscript received: September 20, 2019;
Version of record online: ■■■, ■■■■
This research work is dedicated to 100th anniversary of Nankai University
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201901047
Abstract: Under rhodium(III) catalysis, substituted N-methoxycycloalkene-1-carboxamides successfully
reacted with aryl boronic acid pinacol esters to provide 3,4-cycloalkaquinolin-2(1H)-ones via direct
functionalization of the β-alkenyl CÀ H bond and form CÀ C/CÀ N bond in one pot. The gram-scale synthesis of
the title compound demonstrated the great synthetic utility of this methodology.
Keywords: 3,4-cycloalkaquinolin-2(1H)-ones; Rhodium; CÀ H activation; aryl boronates; cyclohexene-1-carbox-
amides
Introduction
(Scheme 1b).[4] Hashimoto and Harayama prepared
cycloalkaquinolinones through cyclization of 2-bromo-
Cycloalkaquinolinones are widespread in natural oc- N-arylcyclohex-1-enecarboxamide at the presence of
curring and synthetic bioactive compounds and exhibit Pb(OAc)2 (Scheme 1c).[5,6] Zhang and Xu reported
biological and pharmacological properties, such as transformed acrylamides with 2-(trimethylsilyl) phenyl
Orixalone D, Meloscine and FK389 (Figure 1).[1] trifluoromethanesulfonate to 2-quinolinones through
Hence, much effort has been foused on how to obtain copper-mediated bidentate carboxamide- directed cas-
them rapidly under mild reaction conditions with cade CÀ H/NÀ H annulation (Scheme 1d).[7–8] In addi-
simple and readily available starting materials. For tion, this kind of compounds can also be obtained with
instance, Knochel and Wang developed routes to the aid of microwave or strong acid (Scheme 1e).[9–12]
access unsaturated tricyclic derivatives of quinolin-2 Although a variety of methods above have been
(1H)-ones through an intermolecular Suzuki cross- documented, the very limited availability of prefunc-
coupling reaction (Scheme 1a).[2,3] Wang successfully tionalized β-substituted cyclohexene-1-carboxamides
synthesized the target molecules with 2-vinyl-phenyl (or esters) and 2-substituted phenyltrifluoromethane
oxamic acid via a hypervalent iodine(III)-mediated sulfonate calls for a more straightforward alternative
intramolecular decarboxylative Heck-type reaction method with wide scope under mild conditions for the
synthesis of cycloalkaquinolinones. Herein, we wish to
report a new rhodium(III)-catalyzed CÀ H activation
reaction for the synthesis of cycloalkaquinolinones
through the direct cross-coupling reaction of different
readily available N-methoxycycloalkene-1-carboxa-
mides with aryl boronic acid pinacol esters
(Scheme 1).
Figure 1. Selected bioactive cycloalkaquinolinones.
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Table 1. Optimization of the Reaction Conditions.[a]
entry catalyst
oxidant
solvent
Yield
(%)[b,c]
40
trace
19
1
2
3
[RhCp*Cl2]2
[IrCp*Cl2]2
Cp*Rh(CH3CN)3
(SbF6)2
Ag2O
Ag2O
Ag2O
MeOH
MeOH
MeOH
4
5
6
7
[CyRuCl2]2
Pd(PPh3)4
Pd(OAc)2
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DCE
THF
1,4-diox- 26
ane
trace
trace
trace
trace
32
21
trace
23
Pd2(dba)3
8[d] [RhCp*Cl2]2
9[e] [RhCp*Cl2]2
10
11
12
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
13
14
15
16
17
18
19
20
21
22
23
24
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
Ag2O
Ag2O
Ag2O
Ag2O
toluene
DMF
H2O
trace
27
12
34
trace
9
17
trace
10
trace
7
9
trace
55
63
93(89)
59
HFIP
Cu(OAc)2 MeOH
Scheme 1. Strategies for the synthesis of cycloalkaquinoli-
nones.
Ag2CO3
AgOAc
AgOTf
MeOH
MeOH
MeOH
CF3CO2Ag MeOH
Results and Discussion
AgSbF6
MnO2
TBHP
K2S2O8
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
Our study commenced from the model reaction of N-
methoxycyclohex-1-enecarboxamide (1a) and phenyl
boronic acid pinacol ester (2a) in the presence of 25 [RhCp*Cl2]2
26[f] [RhCp*Cl2]2
Ag2O as the oxidant (Table 1). Initially, the model
27[g] [RhCp*Cl2]2
°
reaction was carried out at 40 C in methanol with
28[h] [RhCp*Cl2]2
different catalysts (Table 1, entries 1–7). To our
29[i] [RhCp*Cl2]2
surprise, when [RhCp*Cl2]2 was used as catalyst, 3a
30[j] [RhCp*Cl2]2
70
was formed in 40% yield (Table 1, entry 1). When the
[a] 1a (0.2 mmol), 2a (0.4 mmol), catalyst (2 mol%), oxidant
°
reaction temperature was raised to 60 C or lowered to
°
35 C, both of 3a’s yields were decreased, which
°
(0.8 mmol), solvent (0.5 mL), 40 C, 20 h, air;
[b] the yields were determined by the 1H NMR integration
method using trimethoxybenzene as the internal standard;
[c] value in parentheses indicates isolated yield with respect to
°
indicated 40 C was the optimum temperature (Table 1,
entries 8–9). When the reaction was conducted in
different solvents, the yields of 3a fallen in 0–34%
(Table 1, entries 10–16). In order to ameliorate the
reaction efficiency, various oxidants were used. Un-
fortunately, no improvement was observed and the best
yield was only 17% at the presence of AgOAc
(Table 1, entries 17–25). To our delight, when the
solvent volume was increased from 0.5 to 2 mL, the
yield was significantly improved (55%) (Table 1,
entry 26). In further, the reaction time was reduced to
12 h, the yield was increased to 63% (Table 1,
entry 27). When the ammount of catalyst was in-
1a;
60 C;
[d]
°
[e]
°
35 C;
[f] MeOH 2 mL;
[g] MeOH 2 mL, 12 h;
[h] MeOH 2 mL, 12 h, [RhCp*Cl2]2(5 mol%);
[i] MeOH 2 mL, 12 h, [RhCp*Cl2]2(5 mol%), N2;
[j] MeOH 2 mL, 12 h, [RhCp*Cl2]2(5 mol%), O2.
creased to 5 mol% and compound 3a was afforded in was decreased sharply to 59% and 70% (Table 1,
93% yield and this result was the best (Table 1, entries 29–30).
entry 28). Finally, when the reaction was performed in
In order to make this reaction more practical,
nitrogen or oxygen atmosphere respectively, the yield phenyl boronic acid pinacol ester was replaced by
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Table 2. Scope of the Cyclization Reactiona.[a]
Scheme 2. Reactions between 1a and phenylboronic acid or
iodobenzene.
phenylboronic acid and iodobenzene respectively.
Unfortunately, no product (3a) was detected
(Scheme 2).
Under the optimized conditions, the scope of the
reaction of 1a–1c with aryl boronic acid pinacol esters
2a–2m was firstly explored (Table 2).
As listed in table 2, the following could be
concluded:
1) When R2 was an electron-donating group or a
halo atom, compound 3 was always afforded with
higher yields, such as 3a (89%), 3b (84%), 3c (80%),
3e (78%), 3t (92%); when R2 was an electron-
withdrawing group (such as 4-CHO, 3-CF3), the yields
of 3g, 3j and 3u were decreased significantly (3g
52%; 3j 58%; 3u 45%). In particular, When R2 was 4-
nitro group, no product (3h) was detected (Table 2),
suggesting that the electron-withdrawing group made
the transmetalation of 2a difficult.
2) When 1a was reacted with 2-methoxyphenyl
boronic acid pinacol ester, the 3n’s yield was only
47%, which may be resulted from steric effect
(Table 2). However, when 2-methoxy group was
replaced with 2-nitro group, no product (3o) was
detected, suggesting that an electron-donating group
was preferred.
3) Traditionally, when 3-substituted aryl boronic
acid pinacol esters 2 reacted with 1, two products
should be produced (Scheme 3). For example, when 3-
methlphenyl boronic acid pinacol ester (2k) was
reacted with 1a two products were obtained (3l 39%
and 3m 36%) (Table 2). 2D NOESY spectra of 3l and
3m confirmed the position of methyl group. Some of
the major long-range correlations observed in the 2D
NOESY contour plots of compounds 3l and 3m were
outlined in the structure (Figure 2). However, when R2
was 3-F, 3-CF3 or 3-OCH3, only compound 3–b was
isolated, such as 3i, 3j, 3k, 3u, 3v, and 3x.
[a] 1 (0.2 mmol), 2 (0.4 mmol), [Cp*RhCl2]2 (5 mol%), Ag2O
(0.8 mmol), CH3OH (2 mL). Isolated yields were calculated
with respect to 1.
4) When R1 was a (S)-prop-1-en-2-yl group (1b)
instead of hydrogen, no remarkable effect was ob-
served. However, when 4-methoxyphenyl boronic acid
pinacol ester was reacted with 1b, the yield of product
3t was upto 92% (Table 2).
[b] The value in brackets had been reported in reference 8.
5) When 1a was replaced by N-methoxycyclopen-
tene -1-carboxamide (1c), the yields of corresponding
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Table 3. Scope of the Cyclization Reactiona.[a]
Scheme 3. Reactions between 1 and 3-substituted arylboronic
acid pinacol esters 2.
Figure 2. Selected long-range 2D NOESY correlations found in
the corresponding contour plots of compounds 3l and 3m.
compounds 3 were decreased significantly (3y 51% vs
3b 84%; 3z 41% vs 3c 80%; 3aa 40% vs 3f 72%),
presumably due to the detrimental effect of the tension
of cyclopentene (Table 2).
However, when N-methoxy-4-methylcyclohexa-
1,4-dienecarboxamide 4 was reacted with arylboronic
acid pinacol esters (such as 2b and 2d), normal
product 5a–1 or 5b–1 was not detected. Interestingly,
compounds 5a–2 and 5b–2 were isolated with 51%
and 55% yield respectively, suggesting that an oxida-
tive dehydrogenation reaction might be involved from
5a–1/5b–1 to 5a–2/5b–2 (Scheme 4).
[a] 6 (0.2 mmol), 2 (0.4 mmol), [Cp*RhCl2]2 (5 mol%), Ag2O
(0.8 mmol), CH3OH (2 mL). Isolated yields were calculated
with respect to 6.
To further explore the scope of the reaction, we optimized conditions (Scheme 5). Through the reaction
investigated the reaction of various arylboronic acid of N-methoxycyclohexene-1-carboxamide 1a with
pinacol esters 2 with 6a and 6b under the optimized phenylboronic acid pinacol ester 2a, the pure product
conditions. Thus, the treatment of 6a with 4-methox- 3a was obtained in 85% yield after 12 h.
ylphenyl-, 4-fluorophenyl-, 3-fluorophenyl-, 4-phenox-
To gain further understanding of the mechanistic
yphenyl-, 4-benzyloxyphenyl- and phenylboronic acid details of this catalytic reaction, a series of control
pinacol esters 2 provided target products 7a–7g in 55– experiments were performed (Scheme 6). Firstly, in
86% yield (Table 3). The reactions of 6b with 2 absence of the catalyst [Cp*RhCl2]2 or the oxidant
suggested that, at the presence of transitional metals Ag2O, no product 3a was detected, suggesting that
and methanol, the protecting group (N-Boc) was stable both of them were crucial to this reaction (Scheme 6a).
(Table 3).
Secondly, a radical trapping experiment with TEMPO
To probe the synthetic utility of this method, a was carried out under the optimized conditions and
scale-up reaction of 10 mmol was carried out under the compound 3a was obtained in 73% yield, suggesting
that a radical reaction was not involved in this
transformation (Scheme 6b). Thirdly, H/D exchange of
Scheme 4. Reactions between 4 and 2.
Scheme 5. Gram scale reaction.
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Scheme 7. A proposed mechanism for the catalytic reaction.
Scheme 8. Strategies for the synthesis of compound 3a. (i)
Scheme 6. Control Experiments.
2.5 mol%[Cp*IrCl2]2, 15 mol %AgNTf2,
3 equiv. PivOH,
[15]
°
200 mg 4ÅMS, cylcohexane, 100 C,12 h, Ar;
(ii) EDCI
(1.2 equiv.), DMAP(1.2 equiv.); (iii) 2 mol% [Cp*RhCl2]2, 1.5
1a at the C2-position (21% D) indicated that a
reversible deprotonative CÀ H bond activation step
might be involved in this reaction (Scheme 6c).
°
equiv. Ag2O, MeOH, 40 C, 1 h.
Finally, the kinetic isotope effect studies (KIE1 and 10 in 91% yield also support compound 10 as a
KIE2) were conducted (Scheme 6d). The KIE1 value catalytic intermediate (Scheme 8).
(6.7) suggested that the cleavage of the CÀ H bond of
1a was involved in the rate-determining step. The
Conclusion
KIE2 value (1.5) indicated that the CÀ H bond cleavage
of the benzene ring of 2a is not the product- We have developed a direct and efficient Rh(III)-
determining step.
catalyzed amide-directed CÀ H functionalizations of
Based on the above experiments and the relevant cycloalkenes with aryl boronates. The present reaction
reports,[13–14] a plausible mechanism is proposed enables the synthesis of cycloalkaquinolinones in high
(Scheme 7). With the help of Ag2O, [Cp*RhCl2]2 yield through the direct cross-coupling reaction of
readily coordinates to the nitrogen atom and subse- readily available N-methoxycycloalkene carboxamides
quent C(sp2)À H bond activation leads to a five- with aryl boronates, while tolerating many sensitive
membered rhodacycle 8. Transmetalation with 2a then functional groups. Therefore, this method supplies an
forms intermediate 9, which undergoes reductive efficient and convenient approach for modification of
elimination to give the N-methoxy-2-phenylcyclohex- interesting molecules. Mechanistic studies revealed
1-enecarboxamide 10 and a RhI species. Subsequent that the present reaction might involve a rhodium-
deprotonative coordination of the nitrogen atom in 10 catalyzed dual CÀ H activation process.
to RhIII and CÀ H activation give rhodacycle 11. Further
reductive elimination of 11 affords 3a and RhI species,
Experimental Section
which is oxidized by Ag2O or Ag+ to regenerate the
active RhIII species for the next cycle. Other proof
which 3a could be synthesized by heating compound
To an oven-dried 15 mL sealed tube was added substrate 1, 4 or
6 (0.2 mmol), 2 (0.4 mmol), [Cp*RhCl2]2 (5 mol%,), Ag2O
(0.8 mmol) and CH3OH (2.0 mL) were added to the vial. The
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°
mixture was stirred at 40 C (oil bath temperature) for 12 h.
After this time, the resulting mixture was cooled down to room
temperature, filtered through a short pad of silica gel. The silica
gel was eluted with ethyl acetate (5 mL). After concentrated
under vacuum, the residue was purified by preparative TLC, to
afford the desired product 3, 5 and 7 (eluent: PE/EA=4/1).
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Acknowledgements
We are grateful for the support from Natural Science
Foundation of Tianjin City (No. 18JCYBJC21300), the National
Key R&D Program (2017YFD0200507), and the National
Natural Science Foundation of China (No. 21372134). We also
thank Prof. Chao-Jun Li (McGill University) for helpful
discussions.
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Reaction of Cycloalkene-1-carboxamides with Aryl
Boronates via Rhodium(III)-Catalyzed CÀ H Activation: A
Versatile Route to 3,4-Cycloalkaquinolin-2(1H)-ones
Adv. Synth. Catal. 2019, 361, 1–7
Y.-Q. Zhu*, L.-W. Hui, Y.-X. Niu, L.-G. Lv, K. Zhu