Intramolecular cyclization of alkynyl α-ketoanilide utilizing [1,2]-phospha-brook rearrangement catalyzed by phosphazene base

Article abstract of DOI:10.1021/ol501479t

A novel catalytic cyclization reaction of alkynyl α-ketoanilide was developed by utilizing the [1,2]-phospha-Brook rearrangement. This reaction involves the generation of an amide enolate via the umpolung process, that is the addition of dialkyl phosphite to a keto moiety followed by the [1,2]-phospha-Brook rearrangement, and the subsequent intramolecular addition of the enolate to an alkyne to afford 3,4-dihydro-2-quinolone derivatives. Under high-temperature reaction conditions, further rearrangement of the allylic phosphate moiety occurs to provide 2-quinolone derivatives.

Full text of DOI:10.1021/ol501479t

Letter
pubs.acs.org/OrgLett
Intramolecular Cyclization of Alkynyl α‑Ketoanilide Utilizing [1,2]-
Phospha-Brook Rearrangement Catalyzed by Phosphazene Base
Azusa Kondoh,‡ Takuma Aoki,† and Masahiro Terada*,†,‡
‡
†Department of Chemistry and Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku
University, Aoba-ku, Sendai 980-8578, Japan
S
* Supporting Information
ABSTRACT: A novel catalytic cyclization reaction of alkynyl α-ketoanilide was developed by utilizing the [1,2]-phospha-Brook
rearrangement. This reaction involves the generation of an amide enolate via the umpolung process, that is the addition of dialkyl
phosphite to a keto moiety followed by the [1,2]-phospha-Brook rearrangement, and the subsequent intramolecular addition of
the enolate to an alkyne to afford 3,4-dihydro-2-quinolone derivatives. Under high-temperature reaction conditions, further
rearrangement of the allylic phosphate moiety occurs to provide 2-quinolone derivatives.
Scheme 1. Proposed Catalytic System
he [1,2]-phosphonate−phosphate rearrangement, the so-
called [1,2]-phospha-Brook rearrangement, involves the
T
migration of a dialkoxyphosphoryl moiety of an α-hydroxy
phosphonate from carbon to oxygen under the influence of a
Brønsted base to generate an α-oxygenated carbanion.1,2 The
resulting carbanion, which requires several steps to generate by
other methods, is potentially useful for new bond formation.
However, the carbon−carbon bond-forming reactions that
utilize this rearrangement are limited to the benzoin-type
condensation of acyl phosphonates3 and the aldol-type reaction
of α-hydroxy phosphonates.4 Meanwhile, the intramolecular
addition of enols or enolates to alkynes is a useful method for the
construction of cyclic frameworks.5 In this transformation, the
substrates are mainly limited to compounds possessing relatively
high acidity at the nucleophilic site, such as 1,3-dicarbonyl
compounds, which facilitate the generation of enols and
enolates6,7 or silyl enol ethers generated by a cumbersome
prefunctionalization of carbonyl compounds.8 On the other
hand, reactions involving the direct generation of enolates of the
substrates having a less acidic nucleophilic site are rare.9 In this
context, during the course of our studies of novel reactions
utilizing the [1,2]-phospha-Brook rearrangement10 as well as the
intramolecular cyclization reactions of substrates bearing less
acidic pro-nucleophiles,9 we designed a novel intramolecular
cyclization reaction of alkynyl α-ketoamide with dialkyl
phosphite under Brønsted base catalysis. We envisioned that
an amide enolate would be directly generated from an α-
ketoamide via the umpolung process, that is, the addition of a
dialkyl phosphite to a keto moiety followed by the [1,2]-
phospha-Brook rearrangement under the influence of a Brønsted
base catalyst, and the amide enolate would be utilized for
intramolecular cyclization. Our proposed reaction system is
shown in Scheme 1. At first, the deprotonation of dialkyl
phosphite 2 by a Brønsted base and the following chemoselective
addition of the resulting anion to a keto moiety of α-ketoamide 1
provide alkoxide A. Subsequently, the [1,2]-phospha-Brook
rearrangement proceeds to generate amide enolate B. Finally, the
addition of the enolate to an alkyne followed by protonation by
the conjugated acid of the Brønsted base or dialkyl phosphite
affords product 3 along with the regeneration of the Brønsted
base or the anion of 2. The key to the success of this tandem
reaction is the addition of amide enolate B to an alkyne in
preference to the protonation of enolate B, which is a competing
side reaction arising from the basicity of B. Once B is protonated
to form the corresponding acyclic amide, re-entering the catalytic
cycle, or regeneration of B, would be difficult because of the low
acidity of the amide. We were able to resolve this challenging
issue and report herein the phosphazene base-catalyzed
Received: May 22, 2014
Published: June 23, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
cyclization reaction of alkynyl α-ketoanilide with dialkyl
phosphite to provide 3,4-dihydro-2-quinolone derivatives.
even after 16 h, which indicated that the cyclization occurred
directly from the enolate generated via the [1,2]-phospha-Brook
rearrangement. Considering that the acidity of dialkyl phosphite
lies between that of the conjugated acid of P1-t-Bu and that of P2-
t-Bu (dimethyl phosphite, pKa = 18.4 in DMSO, estimated),14
the results of the initial study implied that the acidity of a proton
source in the reaction system, as well as the basicity of a Brønsted
base catalyst, strongly affected the outcome, that is, the ratio of
3aa to 4aa.
a
Table 1. Initial Screening of Reaction Conditions
b
b
entry
base
solvent
yield of 3aa (%)
yield of 4aa (%)
1
DBU
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
0
0
90
98
35
3
With the optimum reaction conditions in hand, the scope of
alkynyl α-ketoanilide 1 and phosphite 2 was investigated (Table
2). At first, some phosphites were tested (entries 1 and 2). Bulky
diisopropyl phosphite (2b) provided the corresponding product
3ab in good yield. In contrast, diphenyl phosphite (2c) did not
provide any products, and 1a was recovered. Next, a variety of
alkynyl α-ketoanilides were subjected to the reaction conditions.
In this reaction, an alkyl substituent on nitrogen was crucial.
Whereas methyl-substituted 1b provided the product in good
yield, N-H 1c afforded not 3ca but 4ca as the main product.15
Various substituents on a keto moiety were then investigated. In
regard to aryl substituents, an electron-donating group as well as
an electron-withdrawing group at the para or meta position was
favorable for this reaction, and the corresponding products were
obtained in good yields (entries 5−8).16 In contrast, the reaction
of an ortho-substituted substrate, such as 1h, was sluggish, and
cyclized product 3ha was obtained in low yield (entry 9). In the
case of 1i and 1j, which are substrates possessing an alkyl
substituent on a keto moiety, the desired products 3 were formed
in moderate yields along with considerable amounts of side
products 4 (entries 10 and 12). Decreasing of the concentration
of 1 and 2 from 0.25 to 0.05 M improved the yield of 3, and 3ia
and 3ja were obtained in 59 and 82% yield, respectively (entries
11 and 13). The presence of a bromo group on the benzene ring
of an anilide moiety did not affect the reaction, and the product
was obtained in high yield (entry 14). The halo moieties allow for
the further transformation of 3ea and 3ka. Then, substrates
bearing an internal alkyne moiety were also examined (eqs 2 and
3). Interestingly, phenyl-substituted 1l provided tricyclic product
5 as a diastereo mixture, which should be formed by the
nucleophilic attack of a vinyl anion on the phosphorus center and
the concomitant elimination of one of the ethoxides on the
phosphorus after the cyclization.17 On the other hand, alkyl-
substituted 1m did not provide any cyclized products, and 4ma
was obtained in high yield.
2
TBD
3
P1-t-Bu
P2-t-Bu
P4-t-Bu
t-BuOK
Cs2CO3
P2-t-Bu
P2-t-Bu
P2-t-Bu
P2-t-Bu
P2-t-Bu
P2-t-Bu
52
c
4
88
5
81
79
49
86
79
30
69
8
11
11
36
9
6
7
8
9
CH3CN
THF
12
68
25
89
62
10
11
12
13
CH2Cl2
toluene
EtOH
0
a
Reaction conditions: 1a (0.25 mmol), 2a (0.25 mmol), base (0.025
b
mmol), solvent (1.0 mL), rt, 4 h. NMR yields. Bn2O was used as the
c
internal standard. Determined by 1H NMR measurement after
column chromatography. See the Supporting Information for details.
To ascertain the viability of the proposed tandem reaction
system, we started our investigation by screening for the reaction
conditions using alkynyl α-ketoanilide 1a as the primary
substrate (Table 1). First, 1a was treated with diethyl phosphite
(2a) in the presence of a number of organic bases in DMSO at
+
room temperature (entries 1−5). DBU (pKBH = 13.9 in
DMSO)11 and TBD12 provided only amide 4aa, which was
formed via the expected side reaction, namely, the protonation of
the amide enolate generated by the [1,2]-phospha-Brook
rearrangement (entries 1 and 2). In contrast, phosphazene P1-
t-Bu (pKBH+ = 15.7), to our delight, afforded the desired product
3aa as the major product (entry 3).13 Two stronger phosphazene
+
+
bases, P2-t-Bu (pKBH = 21.5) and P4-t-Bu (pKBH = 30.3),
dramatically improved the yield of 3aa, and P2-t-Bu gave the best
among the organic bases tested, affording the product in 88%
yield (entries 4 and 5). For comparison, such inorganic bases as t-
BuOK and Cs2CO3 were also examined (entries 6 and 7).
However, they were less effective than P2-t-Bu and provided 3aa
in 79% and 49% yield, respectively. Next, several solvents were
screened (entries 8−13). The results showed that the solvent
effect was also significant, and aprotic polar solvents, such as
DMSO and DMF, were the solvents of choice (entries 4 and 8).
In order to clarify whether amide 4aa was the appropriate
intermediate to form 3aa, 4aa was treated with P2-t-Bu in DMSO
at room temperature (eq 1). Low conversion of 4aa was observed
In the course of investigations of this reaction, we found that 2-
quinolone derivatives 6 were formed when the reaction was
conducted at elevated temperatures (Scheme 2). Specifically,
when the reaction of 1a with diethyl phosphite was carried out in
DMSO at 90 °C, 6aa was obtained in 82% isolated yield (Scheme
2a). As a control experiment, 3aa was heated in DMSO at 90 °C.
As a result, 3aa was completely converted into 6aa, which clearly
indicated that 6aa was formed via the thermal rearrangement of
the allylic phosphate moiety of 3aa (Scheme 2c).18 Other aryl-
substituted substrates having an electron-donating group as well
as an electron-withdrawing group were also subjected to the
high-temperature reaction conditions to afford the correspond-
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Organic Letters
Letter
a
Table 2. Scope of Alkynyl α-Ketoanilide 1 and Phosphite 2
b
b
entry
R1
R2
R3
1
R4
2
yield of 3 (%)
yield of 4 (%)
c
d
1
2
Bn
Bn
Me
H
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
1a
1a
1b
1c
1d
1e
1f
iPr
Ph
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
2b
2c
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3ab
88
0
4ab
5
0
3ac
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
4ac
4ba
4ca
4da
4ea
4fa
4ga
4ha
4ia
3
83
0
3
c
4
88
7
d
d
5
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
4-MeO-C6H4
4-Cl-C6H4
4-F-C6H4
3-MeO-C6H4
2-Me-C6H4
n-C5H11
85
78
72
85
28
31
59
68
82
84
6
10
14
5
7
8
1g
1h
1i
9
15
59
35
24
15
0
10
e
11
n-C5H11
1i
3ia
4ia
12
c-C6H11
1j
3ja
4ja
e
13
c-C6H11
1j
3ja
4ja
c
14
Ph
1k
3ka
4ka
a
b
Reaction conditions: 1 (0.25 mmol), 2 (0.25 mmol), P2-t-Bu (0.025 mmol), DMSO (1.0 mL), rt, 4 h. Determined by 1H NMR measurement after
c
d
column chromatography unless otherwise noted. See the Supporting Information for details. Isolated yields. Determined by 1H NMR analysis of
crude mixture. Bn2O was used as the internal standard. The reaction was conducted in DMSO (5.0 mL).
e
Scheme 2. Reactions under High-Temperature Conditions
ing 2-quinolone derivatives in moderate to good yields. In
contrast, the rearrangement of alkyl-substituted 3ja did not
proceed at 90 °C, and further elevation of the reaction
temperature in DMSO resulted in the decomposition of the
product. Thus, a two-step operation was conducted: After
treatment of 1j with 2a in DMSO at room temperature for 4 h,
the crude product was then heated in o-xylene at 140 °C for 10 h
to afford 6ja in 68% yield (Scheme 2b).19
The product of this reaction possesses an allylic phosphate
moiety, which makes further manipulation possible (Scheme 3).
For example, treatment of 3aa with sodium ethoxide in ethanol
provided corresponding alcohol 7 quantitatively. Compound 6aa
was also converted into the corresponding hydroxy-2-quinolone
in excellent yield under the same reaction conditions. On the
other hand, treatment of 3aa with a heteroatom nucleophile,
such as dodecanethiol, as well as a carbon nucleophile, such as
lithium diphenylcuprate, resulted in an SN2′ type substitution
reaction to provide 2-quinolone derivatives 9 and 10,
respectively, where a diethoxyphosphoryloxy group served as
the leaving group.
In conclusion, a novel catalytic cyclization reaction of alkynyl
α-ketoanilide was developed by utilizing the [1,2]-phospha-
Brook rearrangement. This reaction involves the generation of an
amide enolate via the umpolung process followed by the
intramolecular addition of the enolate to an alkyne to construct a
3,4-dihydro-2-quinolone skeleton bearing a handle for further
manipulation. In addition, the reaction system in combination
with the thermal rearrangement of the allylic phosphate moiety
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Organic Letters
Letter
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Scheme 3. Transformation of 3 and 6
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Ed. 2012, 51, 4685.
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Knochel, P. Synlett 2000, 1452.
was also established, which provided 2-quinolone derivatives.
Further application of this concept to other substrates as well as
exploration of novel carbon−carbon bond forming reactions
utilizing the [1,2]-phospha-Brook rearrangement are in progress.
(8) For selected recent examples of cyclization reactions of alkynyl silyl
enol ethers, see: (a) Staben, S. T.; Kennedy-Smith, J. J.; Huang, D.;
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
2010, 12, 4380. (d) Barabe,
Org. Lett. 2011, 13, 5580. (e) Brazeau, J.-F.; Zhang, S.; Colomer, I.;
Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2012, 134, 2742. (f) Schafer,
́
F.; Levesque, P.; Korobkov, I.; Barriault, L.
̈
C.; Miesch, M.; Miesch, L. Chem.−Eur. J. 2012, 18, 8028. (g) Iwai, T.;
Okochi, H.; Ito, H.; Sawamura, M. Angew. Chem., Int. Ed. 2013, 52, 4239
and references cited therein.
(9) (a) Kanazawa, C.; Goto, K.; Terada, M. Chem. Commun. 2009,
5248. (b) Kondoh, A.; Ando, K.; Terada, M. Chem. Commun. 2013,
10254.
(10) Kondoh, A.; Terada, M. Org. Lett. 2013, 15, 4568.
(11) Kondo, Y.; Ueno, M.; Tanaka, Y. J. Synth. Org. Chem., Jpn. 2005,
63, 453.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mterada@m.tohoku.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” from MEXT (Japan) and a
Grant-in-Aid for Scientific Research from the JSPS.
(12) The basicity of TBD seems to lie between those of DBU and P1-t-
+
Bu in DMSO. The pKBH values of those bases in CH3CN are 24.34
(DBU), 26.03 (TBD), and 26.98 (P1-t-Bu), respectively. See ref 11.
(13) The structure of 3 was confirmed by single-crystal X-ray
diffraction analysis of 3ka (CCDC no. 989787). See the Supporting
Information.
(14) Li, J.-N.; Lin, L.; Fu, Y.; Guo, Q.-X. Tetrahedron 2006, 62, 4453.
(15) A small amount of an indole derivative was detected along with
4ca, which was formed by the intramolecular addition to an alkyne at the
nitrogen center.
(16) 3da was unstable, and the attempted purification by silica gel
column chromatography resulted in complete decomposition.
(17) The structure of 5 was determined by NMR analysis, HRMS, and
single-crystal X-ray diffraction analysis of one of the diastereomers of the
analogue of 5 obtained by the reaction of 1l with 2b (CCDC no.
989788). See the Supporting Information.
(18) For an example of thermal rearrangement of allylic phosphates,
see: Mita, T.; Fukuda, N.; Roca, F. X.; Kanai, M.; Shibasaki, M. Org. Lett.
2007, 9, 259 and references cited therein.
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