Efficient one-pot synthesis of dihydroquinolinones in water at room temperature

Article abstract of DOI:10.1016/j.tet.2015.07.016

A mild and robust one-pot protocol for the Rh-catalyzed 1,4-addition of 2-aminoboronic acid to α,β-unsaturated esters for the efficient synthesis of dihydroquinolinones has been developed. Furthermore the addition of a variety of substituted boronic acids to diverse α,β-unsaturated esters has been investigated. The reactions proceed in water containing catalytic amounts of the commercially available designer surfactant TPGS-750-M (via the formation of nanomicelles). This mild and easy to perform process proceeds at room temperature and tolerates a wide range of functionalities.

Full text of DOI:10.1016/j.tet.2015.07.016

Accepted Manuscript
Efficient One-Pot Synthesis of Dihydroquinolinones in Water at Room Temperature
Anna M. Linsenmeier, Wilfried M. Braje
PII:
S0040-4020(15)01053-4
10.1016/j.tet.2015.07.016
TET 26961
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 April 2015
Revised Date: 2 July 2015
Accepted Date: 5 July 2015
Please cite this article as: Linsenmeier AM, Braje WM, Efficient One-Pot Synthesis of
Dihydroquinolinones in Water at Room Temperature, Tetrahedron (2015), doi: 10.1016/
j.tet.2015.07.016.
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ACCEPTED MANUSCRIPT
Efficient One-Pot Synthesis of Dihydroquinolinones in Water at Room
Temperature
Anna M. Linsenmeier and Wilfried M. Braje
AbbVie Deutschland GmbH & Co. KG, Knollstraße, 67061 Ludwigshafen, Germany
Author information: Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for
this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the
publication.
Corresponding Author: E-mail: wilfried.braje@abbvie.com.
Abstract:
A mild and robust one-pot protocol for the Rh-catalyzed 1,4-addition of 2-aminoboronic acid to α,β-unsaturated
esters for the efficient synthesis of dihydroquinolinones has been developed. Furthermore the addition of a
variety of substituted boronic acids to diverse α,β-unsaturated esters has been investigated. The reactions proceed
in water containing catalytic amounts of the commercially available designer surfactant TPGS-750-M (via the
formation of nanomicelles). This mild and easy to perform process proceeds at room temperature and tolerates a
wide range of functionalities.
Keywords: Rh-catalyzed 1,4-addition; Dihyroquinolinone; Micelles; Green Chemistry
1. Introduction
The dihydroquinolinone (dihydroquinolin-2-one) core structure can not only be found in a large number of natural products
but also in important drug candidates. Examples shown in Figure 1 include drugs like cilostazol (1) (a PDE3
phosphodiesterase inhibitor for the treatment of peripheral vascular disease) and aripiprazole (2) (an anti-psychotic used for
the treatment of schizophrenia). Natural products like the insecticidal antibiotic Yaequinolone A1 (3), isolated from the
fungal strain Penicillium sp. FKI-2140,1 and the alkaloid Trigolutesin A (4), isolated from Trigonostemon lutescens,2 also
contain the dihydroquinolinone core.
Figure 1. Drugs and natural products containing the dihydroquinolinone core.
Methods which allow efficient access to substituted dihydroquinolinones are therefore of significant interest, in particular if
such a process allows high functional group tolerance. In addition to the classical Friedel-Crafts cyclization approaches,3
several other methods for the synthesis of dihydroquinolinones have been published over the last few years, e.g. triflic acid-
mediated cyclization of N-benzylcinnamanilides4 or hypervalent iodine oxidative cyclization of aryl-methoxyamides5 and
various metal catalyzed reactions.6-8Alternatively, free radical cyclization of allylsulfonyl substituted N-aryl amide
derivatives9 and radical cyclization of butenyl arylhydroxamate10 were recently disclosed. However, most of the reported
reactions are either multi-step or require reaction conditions which are not suited for the synthesis of dihydroquinolinones
containing sensitive functional groups. Similar limitations are described for a one-pot rhodium catalyzed 1,4-addition of

ACCEPTED MANUSCRIPT
2-aminoarylboronates to α,β-unsaturated esters. The reactions were carried out at reflux in aqueous dioxane using KOH as
base to give the corresponding dihydroquinolinones, albeit in moderate yields.11 Since sensitive substrates may not be stable
under such harsh reaction conditions the goal of the present study was to explore a methodology which proceeds under
milder reaction conditions. In 2012 Lipshutz et al. reported an asymmetric rhodium catalyzed 1,4-addition of aryl boronic
acids to acyclic and cyclic enones in water at room temperature using the nanomicellar system PQS.12 In this particular
publication chiral BINAP was covalently attached to the PQS surfactant and the rhodium catalyst was subsequently inserted
to form the first described chiral transition metal catalyst-tethered surfactant. This alternative to classical organic chemistry is
called micellar catalysis: Instead of using organic solvents the reaction is conducted in water containing nanomicelles derived
from adding catalytic amounts of commercially available and environmentally benign designer surfactants to the water (e.g.
PTS or TPGS-750-M).13 In this case water serves as the macroscopic medium that drives nanoparticle organization due to
entropic factors. Depending on size, shape, concentration and nature of the surfactant two plausible reaction mechanisms
have been proposed: a.) reactions take place in the inner core of a micelle, b.) a phase-transfer-like mechanism where
reactions take place at the interface between nanoparticle and water. With limited levels of surfactant, usually 2 to 5 weight
percent, concentrations of reactants are typically high in the inner core or at the interface of the micelle. As a consequence
reaction rates at room temperature are comparable to those commonly seen at elevated temperatures in organic solvents.
Herein, we applied this methodology of micellar catalysis to the Rh-catalyzed 1,4-addition of 2-aminoboronic acid (5a) to
different α,β-unsaturated esters. Compared to conventional reaction conditions in organic solvents we noted several
additional benefits: The risk of protodeboronation was minimized due to the absence of heating leading to higher yields; the
impurity profile improved significantly which in turn simplified purification; and finally cost savings due to easier product
isolation and the reduced use of organic solvents.
2. Results and discussion
The goal of the present study was to identify a flexible, efficient and green one-pot synthesis of dihydroquinolones (8). We
were particularly interested in fluorinated substituents or sensitive functional groups because a fundamental strategy for
medicinal chemistry is the fluorination of new drug molecules in order to alter activity, selectivity or metabolic stability.
Therefore the synthesis of fluorinated dihydroquinolinones is of significant interest to the pharmaceutical industry. To date,
only a single publication has disclosed the synthesis of 4-perfluoroalkylquinolinones by reacting 2-alkylperfluororinated
anilines with the lithium enolate of acetaldehyde. Unfortunately, the reported yields were poor (less than 15%).14
Our initial work focused on the synthesis of fluorinated alkyl substituents at the 4-position of dihydroquinolinones using
commercially available 2-aminophenylboronic acid (5a) and the trifluoromethyl crotonester 6a (see Table 1). At first, the 1,4-
addition was carried out under conventional reaction conditions using 5 mol% [RhOH(COD)]2 and 2 equivalents of K2CO3
in dioxane at reflux for 1 hour (Table 1, entry 1). The moderate yield can be rationalized by the competing protodeboronation
which occurs at elevated temperatures. Using more than the typically used 2 equivalents of the 2-aminophenylboronic acid
(5a) did not further improve the yield. In order to minimize the risk of protodeboronation the reaction was carried out at room
temperature. Unfortunately, when using the standard reaction conditions at room temperature the desired product could only
be isolated in 20% yield. Performing the reaction in water without any surfactant at room temperature (Table 1, entry 2) also
afforded the desired product, albeit in poor yields. The same reaction was then investigated under micellar catalysis
conditions using 2 mol% of different surfactants in water (Table 1, entries 2-7). The best results were obtained using the
commercially available designer surfactant TPGS-750-M (Table 1, entry 7) yielding the desired 4-trifluoromethyl-
dihydroquinolinone 8a in 78% yield. Other non-ionic surfactants (Table 1, entries 3,4,6,7) and the anionic surfactant SDS
(Table 1, entry 5) gave inferior results. Interestingly, the intermediate 7a could be detected in LC-MS during the course of the
reaction. However upon completion after 24 hours, 8a was the only observed and isolated product.
Table 1. Impact of different solvents.
Entry
Method
Surfactant
Yield [%]
33 (20)*
15
1
2
A
B
-
-

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3
4
5
6
7
8
B
B
B
B
B
B
Triton-X-100
PTS
20
23
39
40
46
78
SDS
TPGS-1000-M
Solutol/Kolliphor
TPGS-750-M
Method A: 1 eq 6a, 2 eq 5a, 5 mol% [RhOH(COD)]2, 2 eq K2CO3, dioxane, reflux, 1h; Method B: 1 eq 6a, 2.00 eq 5a,
5 mol% [RhOH(COD)]2, 2 eq K2CO3, 2 wt% surfactant, H2O, rt, 24 h; * reaction at room temperature.
Since some degree of protodeboronation of the 2-aminophenylboronic acid (5a) was always observed via LC-MS, the use of
the more stable pinacol ester 5b and the potassium trifluoroborate salt 5c (see Table 2) were investigated. While the related
pinacol ester 5b gave the desired product in good yield (but still lower compared to the boronic acid 5a; Table 2, entry 2), the
potassium trifluoroborate salt 5c gave no conversion of starting materials (Table 2, entry 3).
Table 2. Impact of the boron species.
Entry
X
Boron derivative 5
Yield [%]
1
2
3
-B(OH)2
pinacol ester
-BF3K
78
61
0
5a
5b
5c
Subsequently the role of the base was investigated. As described in previous publications, the use of more lipophilic bases
like TIPSOH/KOH and TMSOK may be beneficial for micellar catalysis due to better penetration of such based into the
inner core of a micelle.15 However for this particular reaction, the influence of the base was minimal and comparable yields
using four different bases were observed (Table 3), which would be in agreement with an (at least partly) interfacial
mechanism.
Table 3. Impact of different bases.
Entry
Base
K2CO3
Yield [%]
1
2
3
4
78
73
73
70
TMSOK
TIPSOH/KOH
Et3N
Using the now optimized conditions, a series of functionalized 4-dihydroquinolinones were isolated in good to excellent
yields using differently substituted α,β-unsaturated esters (see Table 4). Fluorinated compounds such as 8a-c (Table 4, entries
1-3) were isolated in good yields. The methyl-derivative 8d and the phenyl-derivative 8e (Table 4, entries 4 and 5) were
obtained with improved yields of 78% and 95% yield compared to the previously published yields of 47% and 58%
respectively.11 Furthermore, products containing quaternary centers could also be formed and the two tricyclic compounds
spiro-cyclobutane 8h and oxetane 8i were isolated in 29% and 30% yield.

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Table 4. Synthesis of highly functionalized dihydroquinolinones 8a-e.
Entry
R1
R2
Product 8
a
Yield [%]
1
CF3
H
78
2
3
4
5
6
7
8
9
CH2CF3
CHF2
Me
H
H
H
H
H
H
75
61
b
c
d
e
f
95
Ph
78 %
83
44
g
h
i
29
30
Method: 1 eq 6, 2 eq 5a, 5 mol% [RhOH(COD)]2, 2 eq K2CO3, 2 wt% TPGS-750-M, H2O, rt, 24 h.
After investigating the reaction of 2-aminophenylboronic acid (5a) with different Michael acceptors 6 we turned our attention
to the synthesis of “open chain” analogues in order to explore the influence of different substituents on the boronic acid. The
rhodium catalyzed 1,4-addition of bronic acids to α,β-unsaturated esters is generally a powerful methodology in organic
chemistry, documented by the large number of publications since the first disclosure by Hayashi and Miyaura in 1997.16
However, most described reactions require high temperatures and organic solvents. Interestingly literature examples are
usually restricted to para- and meta-substituted aryl boronic acids.17 In the case of sterically more hindered ortho substituted
boronic acids, the corresponding products were only isolated in poor to moderate yields.18 One reason for the lower yields
might be the aforementioned protodeboronation of the boronic acid which occurs faster at elevated temperatures. Again,
performing chemistry in micelles would be an attractive alternative since reactions can be performed at room temperature.
Para- and meta-substituted phenylboronic acids 9 added very smoothly and in high yields to crotonester 6d using our
standard reaction conditions. For example ethyl 3-(4-nitrophenyl)butanoate (10a) (Table 5, entry 1) could be isolated after 60
min reaction time in 83% yield and ethyl 3-(4-methoxyphenyl)butanoate (10b) (Table 5, entry 2) after an even shorter time
period of 30 min in 95% yield. The para- and meta- substituted bromo phenylboronic acids 10c and 10d were also isolated in
high yields (Table 5, entries 3 and 4). We then investigated the more challenging reaction of ortho substituted phenylboronic
acids 9f-k (Table 5, entries 5-10). Boronic acids with functionalities such as ortho-methoxy and ortho-methyl reacted
smoothly with crotonester 6d and the desired products 10f and 10g could be isolated in very high yields. However ortho-
nitro- and ortho-hydroxyl-groups slowed down the reaction and corresponding products 10h and 10i were only detected only
in traces (Table 5, entries 7 and 8). The sterically even more hindered ortho-bismethoxy boronic acid 9j gave the desired
product 10j in 80% yield, whereas the ortho-methoxy fluoride substituted compound 10k was isolated only in 34% yield
(Table 5, entries 9 and 10).
Table 5. Impact of substitution on arylboronic acids 9.

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Yield
Time [h]
Entry
R =
10
a
[%]
1
1
83
95
80
95
2
3
4
0.5
0.5
1
b
c
d
5
6
7
8
1
1
87
95
e
f
24
24
traces
traces
g
h
9
1
80
34
i
10
24
j
Method: 1 eq 6d, 2 eq 9, 5 mol% [RhOH(COD)]2, 2 eq K2CO3, 2 wt% TPGS-750-M, H2O, rt, time.
Finally we investigated the influence of substitution on the α,β-unsaturated ester moiety 6. Even sensitive functionalities on
the α,β-unsaturated esters such as oxetanes were well tolerated and compounds 11a and 11b19 (Table 6, entries 1, 2) were
isolated in 70% and 47% yield respectively. The lower yield of 47% of oxetane 11b might be rationalized by the more
difficult formation of a quaternary center. Similarly the spiro-cyclobutyl compound 11c was isolated in 43% yield (Table 6,
entry 3). A longer reaction time did not improve the yield further. Surprisingly spiro-azetidine compound20 11d was obtained
in an excellent 88% yield (Table 6, entry 4).
Table 6. Impact of substitution on α,β-unsaturated esters 6.
Entry
R1 =
R2 =
11
a
Time [h]
Yield [%]
1
H
1
70

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2
3
2
47
b
c
2
43
4
2
88
d
Method: 1 eq 6, 2 eq 9d, 5 mol% [RhOH(COD)]2, 2 eq K2CO3, 2 wt% TPGS-750-M, H2O, rt, time.
3. Conclusion
In conclusion we were able to develop an efficient and mild green chemistry procedure for the rhodium catalyzed 1,4-
addition of 2-aminophenylboronic acid (5a) to a series of different α,β-unsaturated esters to yield highly functionalized
dihydroquinolinones. The use of catalytic amounts of the surfactant TPGS-750-M allows the use of water as solvent and the
performance of the reactions at ambient temperature. In addition, the described method herein was successfully applied to the
rhodium catalyzed 1,4-addition of substituted phenylboronic acids to various α,β-unsaturated esters to give products in
good to excellent yields. These highly functionalized intermediates are of interest to the medicinal chemist.
4. Experimental section
4.1 General information
Reactions were performed in a 5 mL vial containing a Teflon coated stirring bar. All commercially available reagents were
used without further purification. TPGS (2 wt. %) solution in water was purchased from Aldrich. Column chromatography
was performed with an Isco CombiFlash® Companion™ using Grace Reveleris® cartridge (Silica 40 µm). 1H and 13C
NMR spectra were measured on a Bruker DRX 500 spectrometer (500 and 125, 470 MHz, respectively) or on a Bruker
Avance 600 spectrometer (600 and 151 MHz, respectively). Proton NMR data were recorded as follows: chemical shift in
ppm referenced from residual solvent peak (CDCl3, 7.26 ppm), multiplicity (s = singlet; d = doublet; t = triplet; q = quartet; p
= pentet; sx = sextet; m = multiplet), coupling constant (Hz), and integration. 13C Chemical shifts were recorded in ppm
from the solvent resonance employed as the internal standard (CDCl3, 77.00 ppm). Mass spectral data were acquired on a
QExactive (Thermo Scientific).
4.2 General procedure
In a 5 mL microwave vial containing α,β-unsaturated ethyl ester (100 mg, 1.00 eq), boronic ester (2.00 eq), potassium
carbonate (2.00 eq) and [RhOH(COD)]2 (0.05 eq) was added 2% wt. TPGS-750-M solution in water (3 mL). The mixture
was stirred vigorously at ambient temperature for the indicated time. The reaction mixture was then extracted with ethyl
acetate. The organic phase was subsequently dried over MgSO4, filtrated and reduced under vacuum. The crude product was
purified by column chromatography on silica (eluent: 0-10% methanol in dichloromethane) to yield the desired product.
4.3 4-(trifluoromethyl)-3,4-dihydroquinolin-2(1H)-one (8a)
Prepared from ethyl 4,4,4-trifluorobut-2-enoate (100 mg, 0.595 mmol, 1.00 eq) and 2-aminoboronic acid (163 mg, 1.19
mmol, 2.00 eq) according to the general procedure. The reaction mixture was stirred for 24 h. Purification by column
1
chromatography on silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (100 mg, 78%) as white solid. H NMR
(500 MHz, CDCl3): δ 9.05 (s, 1H), 7.32 (td, J = 7.7, 1.5 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.08 (td, J = 7.6, 1.2 Hz, 1H), 6.90
(dd, J = 8.0, 1.2 Hz, 1H), 3.64 (qdd, J = 9.6, 7.1, 2.9 Hz, 1H), 3.00 – 2.89 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ
168.39, 137.83, 130.38, 130.08, 126.12, 123.43, 116.30, 115.57, 41.15, 30.07 ppm. 19F NMR (470 MHz, CDCl3): δ -72.51
ppm. HRMS (ESI) m/z [M + H]+ calcd for [C10H9F3NO]+ 216.0631, found 216.0630.
4.4 4-(2,2,2-trifluoroethyl)-3,4-dihydroquinolin-2(1H)-one (8b)

ACCEPTED MANUSCRIPT
Prepared from ethyl 5,5,5-trifluoropent-2-enoate (100 mg, 0.549 mmol, 1.00 eq) and 2-aminoboronic acid (150 mg, 1.10
mmol, 2.00 eq) according to the general procedure. The reaction mixture was stirred for 24 h. Purification by column
1
chromatography on silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (95 mg, 75%) as white solid. H NMR
(500 MHz, CDCl3): δ 9.28 (s, 1H), 7.28 – 7.17 (m, 2H), 7.05 (td, J = 7.5, 1.2 Hz, 1H), 6.92 – 6.86 (m, 1H), 3.40 (dq, J = 9.1,
5.0 Hz, 1H), 2.84 (dd, J = 16.4, 5.9 Hz, 1H), 2.71 (dd, J = 16.4, 3.6 Hz, 1H), 2.47 – 2.32 (m, 2H) ppm. 13C NMR (125 MHz,
CDCl3): δ 170.43, 136.39, 128.62, 127.67, 126.20, 124.94, 123.67, 116.23, 37.82, 35.80, 30.96 ppm. 19F NMR (470 MHz,
CDCl3): δ -63.33 ppm. HRMS (ESI) m/z [M + H]+ calcd for C11H11F3NO 230.0787, found 230.0783.
4.5 4-(Difluoromethyl)-3,4-dihydroquinolin-2(1H)-one (8c)
Prepared from ethyl 4,4-difluorobut-2-enoate (100 mg, 0.666 mmol, 1.00 eq) and 2-aminoboronic acid (182 mg, 1.33 mmol,
2.00 eq) according to the general procedure. The reaction mixture was stirred for 24 h. Purification by column
1
chromatography on silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (80 mg, 61%) as white solid. H NMR
(500 MHz, CDCl3): δ 9.05 (s, 1H), 7.29 (dt, J = 7.5, 1.4 Hz, 1H), 7.27 – 7.22 (m, 1H), 7.06 (td, J = 7.5, 1.1 Hz, 1H), 6.88 (dd,
J = 7.9, 1.2 Hz, 1H), 5.85 (td, J = 56.0, 4.3 Hz, 1H), 3.44 – 3.33 (m, 1H), 2.94 – 2.82 (m, 2H) ppm. 13C NMR (125 MHz,
CDCl3): δ 169.41, 137.65, 129.55, 129.46, 123.48, 117.92, 116.26, 116.12, 40.95, 29.64 ppm. 19F NMR (470 MHz, CDCl3):
δ -120.87, -123.60 ppm. HRMS (ESI) m/z [M + H]+ calcd for [C10H10F2NO]+ 198.0725, found 198.0730.
4.6 4-Methyl-3,4-dihydroquinolin-2(1H)-one (8d)
Prepared from ethyl but-2-enoate (100 mg, 0.876 mmol, 1.00 eq) and 2-aminoboronic acid (240 mg, 1.75 mmol, 2.00 eq)
according to the general procedure. The reaction mixture was stirred for 24 h. Purification by column chromatography on
silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (134 mg, 95%) as white solid. 1H NMR (500 MHz, CDCl3): δ
9.10 (s, 1H), 7.22 – 7.14 (m, 2H), 7.02 (td, J = 7.5, 1.1 Hz, 1H), 6.88 – 6.81 (m, 1H), 3.14 (h, J = 6.7 Hz, 1H), 2.74 (dd, J =
16.1, 5.8 Hz, 1H), 2.43 (dd, J = 16.1, 7.2 Hz, 1H), 1.32 (d, J = 7.0 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 136.44,
128.72, 127.53, 126.52, 123.35, 115.72, 115.69, 38.38, 30.76, 19.80 ppm. HRMS (ESI) m/z [M + H]+ calcd for [C10H12NO]+
162.0913, found 162.0908.
4.7 4-Phenyl-3,4-dihydroquinolin-2(1H)-one (8e)
Prepared from ethyl cinnamate (100 mg, 0.568 mmol, 1.00 eq) and 2-aminoboronic acid (156 mg, 1.14 mmol, 2.00 eq)
according to the general procedure. The reaction mixture was stirred for 24 h. Purification by column chromatography on
silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (99 mg, 78%) as white solid. 1H NMR (500 MHz, CDCl3): δ
8.92 (s, 1H), 7.33 (dd, J = 8.2, 6.7 Hz, 2H), 7.32 – 7.23 (m, 1H), 7.24 – 7.15 (m, 3H), 6.96 (td, J = 7.5, 1.1 Hz, 1H), 6.94 –
6.85 (m, 2H), 4.30 (t, J = 7.5 Hz, 1H), 3.00 – 2.87 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ 170.87, 141.43, 136.99,
128.89 (2), 128.35, 127.99, 127.79 (2), 127.21, 126.64, 123.35, 115.68, 41.99, 38.40 ppm. HRMS (ESI) m/z [M + H]+ calcd
for [C15H14NO]+ 224.1070, found 224.1063.
4.8 4-(3-Methyloxetan-3-yl)-3,4-dihydroquinolin-2(1H)-one (8f)
Prepared from ethyl 3-(3-methyloxetan-3-yl)acrylate (100 mg, 0.588 mmol, 1.00 eq) and 2-aminoboronic acid (161 mg, 1.18
mmol, 2.00 eq) according to the general procedure. The reaction mixture was stirred for 24 h. Purification by column
1
chromatography on silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (106 mg, 83%) as white solid. H NMR
(500 MHz, CDCl3): δ 9.15 (s, 1H), 7.22 (ddd, J = 8.0, 6.5, 2.3 Hz, 1H), 7.06 – 6.97 (m, 2H), 6.89 – 6.83 (m, 1H), 4.83 (d, J =
5.9 Hz, 1H), 4.63 (d, J = 5.8 Hz, 1H), 4.41 (d, J = 5.7 Hz, 1H), 4.29 (d, J = 6.0 Hz, 1H), 3.57 (dd, J = 7.3, 4.7 Hz, 1H), 2.70
(dd, J = 16.6, 7.3 Hz, 1H), 2.40 (dd, J = 16.7, 4.7 Hz, 1H), 1.32 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 171.45, 137.42,
128.34, 128.06, 123.40, 122.79, 116.16, 82.07, 81.95, 43.56, 42.78, 31.98, 19.10 ppm. HRMS (ESI) m/z [M + H]+ calcd for
[C13H16NO2]+ 218.1176, found 218.1173.
4.9 4-Cyclobutyl-3,4-dihydroquinolin-2(1H)-one (8g)

ACCEPTED MANUSCRIPT
Prepared from ethyl 3-cyclobutylacrylate (100 mg, 0.648 mmol, 1.00 eq) and 2-aminoboronic acid (178 mg, 1.30 mmol, 2.00
eq) according to the general procedure. The reaction mixture was stirred for 24 h. Purification by column chromatography on
silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (58 mg, 44%) as white solid. 1H NMR (500 MHz, CDCl3): δ
8.97 (s, 1H), 7.21 – 7.10 (m, 2H), 6.98 (td, J = 7.5, 1.1 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 2.84 – 2.80 (m, 1H), 2.68 (dd, J =
16.2, 6.2 Hz, 1H), 2.53 – 2.40 (m, 2H), 2.18 – 2.07 (m, 1H), 1.92 – 1.68 (m, 5H) ppm. 13C NMR (125 MHz, CDCl3): δ
171.56, 136.37, 127.98, 127.54, 125.99, 122.86, 115.74, 42.71, 38.76, 33.68, 27.24, 26.70, 17.56 ppm. HRMS (ESI) m/z [M
+ H]+ calcd for [C13H16NO]+ 202.1226, found 202.1224.
4.10 1'H-Spiro[cyclobutane-1,4'-quinolin]-2'(3'H)-one (8h)
Prepared from ethyl 2-cyclobutylideneacetate (100 mg, 0.713 mmol, 1.00 eq) and 2-aminoboronic acid (196 mg, 1.43 mmol,
2.00 eq) according to the general procedure. The reaction mixture was stirred for 24 h. Purification by column
1
chromatography on silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (39 mg, 29%) as white solid. H NMR
(500 MHz, CDCl3): δ 8.66 (d, J = 68.4 Hz, 1H), 7.47 (dd, J = 7.6, 1.4 Hz, 1H), 7.19 (td, J = 7.6, 1.5 Hz, 1H), 7.14 – 7.07 (m,
1H), 6.82 (dd, J = 8.1, 3.7 Hz, 1H), 2.77 (s, 2H), 2.40 – 2.28 (m, 2H), 2.16 – 2.06 (m, 3H), 2.09 – 1.94 (m, 1H) ppm. 13C
NMR (125 MHz, CDCl3): δ 170.36, 135.68, 131.03, 127.48, 124.21, 123.55, 115.75, 31.82, 27.39 (2), 14.91 (2) ppm. HRMS
(ESI) m/z [M + H]+ calcd for [C12H14NO]+ 188.1070, found 188.1065.
4.11 1'H-Spiro[oxetane-3,4'-quinolin]-2'(3'H)-one (8i)
Prepared from ethyl 2-(oxetan-3-ylidene)acetate (100 mg, 0.703 mmol, 1.00 eq) and 2-aminoboronic acid (193 mg, 1.40
mmol, 2.00 eq) according to the general procedure. The reaction mixture was stirred for 24 h. Purification by column
1
chromatography on silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (40 mg, 30%) as white solid. H NMR
(500 MHz, CDCl3): δ 8.93 (s, 1H), 7.70 (dd, J = 7.6, 1.4 Hz, 1H), 7.31 – 7.24 (m, 1H), 7.18 (dd, J = 7.9, 6.8 Hz, 1H), 6.87
(dd, J = 7.7, 1.2 Hz, 1H), 4.88 (d, J = 6.3 Hz, 2H), 4.70 (d, J = 6.2 Hz, 2H), 3.06 (s, 2H) ppm. 13C NMR (125 MHz, CDCl3):
δ 169.61, 135.98, 128.74 (2), 125.66, 124.95, 124.08, 116.10, 81.17, 41.24, 40.93 ppm. HRMS (ESI) m/z [M + H]+ calcd for
[C11H12NO]+ 190.0863, found 190.0862
4.12 Ethyl 3-(4-nitrophenyl)butanoate (10a)
Prepared from ethyl but-2-enoate (100 mg, 0.876 mmol, 1.00 eq) and (4-nitrophenyl)boronic acid (292 mg, 1.75 mmol, 2.00
eq) according to the general procedure. The reaction mixture was stirred for 1 h. Purification by column chromatography on
silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (173 mg, 83%) as yellow oil. 1H NMR (500 MHz, CDCl3): δ
8.19 – 8.11 (m, 2H), 7.41 – 7.36 (m, 2H), 4.06 (qd, J = 7.1, 2.8 Hz, 2H), 3.40 (h, J = 7.2 Hz, 1H), 2.61 (dd, J = 7.6, 1.9 Hz,
2H), 1.33 (d, J = 7.0 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 171.53, 153.32, 146.62, 127.71
(2), 123.78 (2), 60.52, 42.25, 36.39, 21.64, 14.12 ppm. HRMS (ESI) m/z [M + H]+ calcd for [C12H16NO4]+ 238.1074, found
238.1072.
4.13 Ethyl 3-(4-methoxyphenyl)butanoate (10b)
Prepared from ethyl but-2-enoate (100 mg, 0.876 mmol, 1.00 eq) and (4-methoxyphenyl)boronic acid (266 mg, 1.75 mmol,
2.00 eq) according to the general procedure. The reaction mixture was stirred for 30 min. Purification by column
1
chromatography on silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (178 mg, 91%) as yellow oil. H NMR
(500 MHz, CDCl3): δ 7.17 – 7.10 (m, 2H), 6.87 – 6.80 (m, 2H), 4.07 (qd, J = 7.2, 1.1 Hz, 2H), 3.78 (s, 3H), 3.23 (h, J = 7.2
Hz, 1H), 2.53 (qd, J = 14.9, 7.6 Hz, 2H), 1.27 (d, J = 7.0 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (125 MHz,
CDCl3): δ 172.45, 158.06, 137.87, 127.66 (2), 113.81 (2), 60.22, 55.24, 43.27, 35.74, 21.98, 14.20. HRMS (ESI) m/z [M +
H]+ calcd for [C13H19O3]+ 223.1329, found 223.1326.
4.14 Ethyl 3-(4-bromophenyl)butanoate (10c)
Prepared from ethyl but-2-enoate (100 mg, 0.876 mmol, 1.00 eq) and (4-bromophenyl)boronic acid (352 mg, 1.75 mmol,
2.00 eq) according to the general procedure. The reaction mixture was stirred for 2 h. Purification by column chromatography

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on silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (189 mg, 80%) as yellow oil. 1H NMR (500 MHz, CDCl3):
δ 7.43 – 7.38 (m, 2H), 7.11 – 7.08 (m, 2H), 4.07 (qd, J = 7.1, 1.3 Hz, 2H), 3.24 (h, J = 7.2 Hz, 1H), 2.59 – 2.49 (m, 2H), 1.27
(d, J = 7.0 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 172.01, 144.66, 131.49 (2), 128.54 (2),
120.01, 60.33, 42.72, 35.98, 21.75, 14.14 ppm. HRMS (ESI) m/z [M + H]+ calcd for [C12H16BrO2]+ 271.0328, found
271.0092.
4.15 Ethyl 3-(3-bromophenyl)butanoate (10d)
Prepared from ethyl but-2-enoate (100 mg, 0.876 mmol, 1.00 eq) and (3-bromophenyl)boronic acid (352 mg, 1.75 mmol,
2.00 eq) according to the general procedure. The reaction mixture was stirred for 1 h. Purification by column chromatography
on silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (228 mg, 96%) as yellow oil. 1H NMR (500 MHz, CDCl3):
δ 7.36 (q, J = 1.3 Hz, 1H), 7.35 – 7.30 (m, 1H), 7.19 – 7.13 (m, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.25 (sx, J = 7.2 Hz, 1H), 2.61
– 2.49 (m, 2H), 1.29 (d, J = 7.0 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 171.98, 148.08,
130.07, 129.97, 129.52, 125.54, 122.52, 60.40, 42.72, 36.28, 21.71, 14.18 ppm. HRMS (ESI) m/z [M + H]+ calcd for
[C12H16BrO2]+ 273.0328, found 273.0324.
4.16 Ethyl 3-(2-methoxyphenyl)butanoate (10e)
Prepared from ethyl but-2-enoate (100 mg, 0.876 mmol, 1.00 eq) and (2-methoxyphenyl)boronic acid (266 mg, 1.75 mmol,
2.00 eq) according to the general procedure. The reaction mixture was stirred for 1 h. Purification by column chromatography
on silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (169 mg, 87%) as yellow oil. 1H NMR (500 MHz, CDCl3):
δ 7.21 – 7.15 (m, 2H), 6.91 (dt, J = 7.5, 1.1 Hz, 1H), 6.85 (dd, J = 8.1, 1.1 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H),
3.69 – 3.60 (m, 1H), 2.68 (dd, J = 15.0, 6.0 Hz, 1H), 2.50 (dd, J = 15.0, 8.9 Hz, 1H), 1.27 (d, J = 7.0 Hz, 3H), 1.20 (t, J = 7.1
Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 172.85, 156.91, 133.81, 127.21, 126.95, 120.51, 110.53, 60.12, 55.30, 41.28,
30.20, 20.07, 14.22 ppm. HRMS (ESI) m/z [M + H]+ calcd for [C13H19O3]+ 223.1329, found 223.1324.
4.17 Ethyl 3-(o-tolyl)butanoate (10f)
Prepared from ethyl but-2-enoate (100 mg, 0.876 mmol, 1.00 eq) and o-tolylboronic acid (238 mg, 1.75 mmol, 2.00 eq)
according to the general procedure. The reaction mixture was stirred for 1 h. Purification by column chromatography on
silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (175 mg, 97%) as yellow oil. 1H NMR (500 MHz, CDCl3): δ
7.22 – 7.06 (m, 4H), 4.09 (q, J = 7.2 Hz, 2H), 3.58 – 3.51 (m, 1H), 2.63 (dd, J = 15.2, 6.6 Hz, 1H), 2.53 (dd, J = 15.2, 8.5 Hz,
1H), 2.38 (s, 3H), 1.26 (d, J = 6.9 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 172.52, 143.92,
135.27, 130.40, 126.25, 126.03, 125.05, 60.26, 42.19, 31.49, 21.28, 19.43, 14.17 ppm. HRMS (ESI) m/z [M + H]+ calcd for
[C13H19O2]+ 207.1380, found 207.1377.
4.18 Ethyl 3-(2,6-dimethoxyphenyl)butanoate (10i)
Prepared from ethyl but-2-enoate (100 mg, 0.876 mmol, 1.00 eq) and (2,6-dimethoxyphenyl)boronic acid (319 mg, 1.75
mmol, 2.00 eq) according to the general procedure. The reaction mixture was stirred for 1 h. Purification by column
1
chromatography on silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (176 mg, 80%) as yellow oil. H NMR
(500 MHz, CDCl3): δ 7.11 (t, J = 8.3 Hz, 1H), 6.52 (d, J = 8.3 Hz, 2H), 4.06 (q, J = 7.1 Hz, 2H), 4.02 – 3.93 (m, 1H), 3.80 (s,
6H), 2.82 (dd, J = 15.1, 8.6 Hz, 1H), 2.72 (dd, J = 15.1, 6.6 Hz, 1H), 1.29 (d, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H) ppm.
13C NMR (125 MHz, CDCl3): δ 173.60, 158.56 (2), 127.16, 121.51, 104.29 (2), 59.87, 55.69 (2), 39.59, 26.30, 18.66, 14.20
ppm. HRMS (ESI) m/z [M + H]+ calcd for [C14H21O4]+ 253.1434, found 253.1428.
4.19 Ethyl 3-(2-fluoro-6-methoxyphenyl)butanoate (10j)
Prepared from ethyl but-2-enoate (100 mg, 0.876 mmol, 1.00 eq) and (2-fluoro-6-methoxyphenyl)boronic acid (298 mg, 1.75
mmol, 2.00 eq) according to the general procedure. The reaction mixture was stirred for 24 h. Purification by column
1
chromatography on silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (71 mg, 37%) as yellow oil. H NMR
(500 MHz, CDCl3): δ 7.10 (td, J = 8.3, 6.4 Hz, 1H), 6.64 (td, J = 8.7, 8.2, 1.2 Hz, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.87 – 3.81

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(m, 1H), 3.82 (s, 3H), 2.76 – 2.72 (m, 2H), 1.32 (d, J = 6.9 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H) ppm. 19F NMR (470 MHz,
CDCl3): δ -115.04 ppm. 13C NMR (125 MHz, CDCl3): δ 172.86, 161.85, 158.67, 127.47, 120.73, 108.36, 106.54, 60.08,
55.85, 39.75, 26.34, 19.09, 14.13 ppm. HRMS (ESI) m/z [M + H]+ calcd for [C13H18FO3]+ 241.1234, found 241.1233.
4.20 Ethyl 3-(3-bromophenyl)-3-(3-methyloxetan-3-yl)propanoate (11a)
Prepared from ethyl 3-(3-methyloxetan-3-yl)acrylate (100 mg, 0.588 mmol, 1.00 eq) and (3-bromophenyl)boronic acid (236
mg, 1.18 mmol, 2.00 eq) according to the general procedure. The reaction mixture was stirred for 2 h. Purification by column
1
chromatography on silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (135 mg, 70%) as yellow oil. H NMR
(600 MHz, CDCl3): δ 7.36 (ddd, J = 7.9, 2.0, 1.1 Hz, 1H), 7.32 (t, J = 1.9 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 7.11 (dt, J = 7.7,
1.4 Hz, 1H), 4.62 (dd, J = 10.2, 5.9 Hz, 2H), 4.32 (d, J = 5.8 Hz, 1H), 4.08 (d, J = 6.1 Hz, 1H), 4.00 (qq, J = 7.3, 3.7 Hz, 2H),
3.58 (dd, J = 10.9, 4.5 Hz, 1H), 2.73 (dd, J = 15.6, 10.9 Hz, 1H), 2.58 (dd, J = 15.6, 4.5 Hz, 1H), 1.29 (s, 3H), 1.10 (t, J = 7.1
Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ 171.62, 141.96, 131.26, 130.18, 129.89, 127.03, 122.44, 81.56, 81.15, 60.63,
47.97, 42.50, 35.01, 20.64, 14.00 ppm. HRMS (ESI) m/z [M + H]+ calcd for [C15H20BrO3]+ 327.0590, found 327.0583.
4.21 Ethyl 2-(3-(3-bromophenyl)oxetan-3-yl)acetate (11b)
Prepared from ethyl 2-(oxetan-3-ylidene)acetate (100 mg, 0.703 mmol, 1.00 eq) and (3-bromophenyl)boronic acid (283 mg,
1.41 mmol, 2.00 eq) according to the general procedure. The reaction mixture was stirred for 2 h. Purification by column
1
chromatography on silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (99 mg, 47%) as yellow oil. H NMR
(500 MHz, CDCl3): δ 7.38 (dt, J = 8.0, 1.5 Hz, 1H), 7.31 (t, J = 1.9 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.13 – 7.08 (m, 1H),
4.97 (d, J = 6.1 Hz, 2H), 4.84 (d, J = 6.5 Hz, 2H), 4.07 – 3.98 (m, 2H), 3.10 (s, 2H), 1.13 (t, J = 7.1 Hz, 3H) ppm. 13C NMR
(125 MHz, CDCl3): δ 170.32, 145.94, 130.05, 129.94, 129.12, 124.54, 122.61, 81.51 (2), 60.57, 45.23, 44.61, 14.05 ppm.
HRMS (ESI) m/z [M + H]+ calcd for [C13H16BrO3]+ 299.0277, found 299.0272.
4.22 Ethyl 2-(1-(3-bromophenyl)cyclobutyl)acetate (11c)
Prepared from ethyl 2-cyclobutylideneacetate (100 mg, 0.713 mmol, 1.00 eq) and (3-bromophenyl)boronic acid (287 mg,
1.43 mmol, 2.00 eq) according to the general procedure. The reaction mixture was stirred for 2 h. Purification by column
1
chromatography on silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product (90 mg, 43%) as yellow oil. H NMR
(500 MHz, CDCl3): δ 7.31 – 7.29 (m, 2H), 7.18 – 7.13 (m, 1H), 7.10 (dt, J = 7.7, 1.5 Hz, 1H), 3.95 (q, J = 7.1 Hz, 2H), 2.76
(s, 2H), 2.46 – 2.34 (m, 4H), 2.09 (dp, J = 11.5, 8.7 Hz, 1H), 1.91 – 1.82 (m, 1H), 1.08 (t, J = 7.2 Hz, 3H) ppm. 13C NMR
(125 MHz, CDCl3): δ 171.20, 151.12, 129.57, 129.05, 128.82, 124.45, 122.15, 60.04, 46.50, 44.81, 32.91 (2), 15.81, 14.06
ppm. HRMS (ESI) m/z [M + H]+ calcd for [C14H18BrO2]+ 297.0485, found 297.1539.
4.23 tert-Butyl 3-(3-bromophenyl)-3-(2-ethoxy-2-oxoethyl)azetidine-1-carboxylate (11d)
Prepared from tert-butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate (100 mg, 0.414 mmol, 1.00 eq) and (3-
bromophenyl)boronic acid (166 mg, 0.829 mmol, 2.00 eq) according to the general procedure. The reaction mixture was
stirred for 2 h. Purification by column chromatography on silica gel (MeOH in CH2Cl2; 0-10%) afforded the pure product
(146 mg, 88%) as yellow oil. 1H NMR (500 MHz, CDCl3): δ 7.40 – 7.36 (m, 1H), 7.34 (t, J = 1.9 Hz, 1H), 7.21 (t, J = 7.8 Hz,
1H), 7.14 (dt, J = 7.8, 1.4 Hz, 1H), 4.23 (d, J = 8.6 Hz, 2H), 4.18 (d, J = 8.8 Hz, 2H), 4.02 (q, J = 7.1 Hz, 2H), 2.95 (s, 2H),
1.44 (s, 9H), 1.14 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 170.09, 156.28, 146.21, 130.03, 129.97, 129.38,
124.79, 122.56, 79.83, 60.59 (2), 45.51 (2), 39.46, 28.33 (3), 14.04 ppm. HRMS (ESI) m/z [M + H]+ calcd for
[C18H25BrNO4]+ 398.0961, found 398.0951.
Acknowledgements
We thank Monika Franck, Johanna Klee and Tanja Lindner for supporting chemical synthesis, Gisela Backfisch for support
in measuring HRMS, Claudia Krack, Sarah Zauchner, Manuela Diehl, Renate Kostiza and Christian Müller for analytical
support.

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Supplementary data
Copies of 1H 19F and 13C NMR spectra for compound 8a-i, 10a-f, 10i, 10j and 11a-d. Supplementary data related to this
article can be found at (insert link).
References and notes
1 Uchida, R.; Imasato, R.; Yamaguchi, Y.; Masuma, R.; Shiomi, K.; Tomoda, H.; Omura, S. J. Antibiot. 2006, 59, 646-651.
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1495.
3
a) Dhar, A.; Liu, S.; Klucik, J.; Berlin, K. D.; Madler, M. M.; Lu, S.; Ivey, R. T.; Zacheis, D.; Brown, C. W.; Nelson, E. C.;
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Boutin, J. A.; Viaud-Massuard, M.-C. Eur. J. Med. Chem. 2008, 43, 1730-1736.
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14 Strekowski, L.; Lin, S.Y.; Lee, H.; Zhang, Z.-Q.; Mason, J. C. Tetrahedron 1998, 54, 7947-7954.
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19
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Efficient One-Pot Synthesis of Dihydroquinolinones in Water at Room
Temperature
Anna M. Linsenmeiera and Wilfried M. Brajea
a AbbVie Deutschland GmbH & Co. KG, Knollstraße, 67061 Ludwigshafen, Germany
Supplementary Data
1

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4‐(trifluoromethyl)‐3,4‐dihydroquinolin‐2(1H)‐one (8a)
2

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4‐(2,2,2‐trifluoroethyl)‐3,4‐dihydroquinolin‐2(1H)‐one (8b)
3

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4

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4‐(difluoromethyl)‐3,4‐dihydroquinolin‐2(1H)‐one (8c)
5

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4‐methyl‐3,4‐dihydroquinolin‐2(1H)‐one (8d)
6

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4‐phenyl‐3,4‐dihydroquinolin‐2(1H)‐one (8e)
7

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4‐(3‐methyloxetan‐3‐yl)‐3,4‐dihydroquinolin‐2(1H)‐one (8f)
8

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4‐cyclobutyl‐3,4‐dihydroquinolin‐2(1H)‐one (8g)
9

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1'H‐spiro[cyclobutane‐1,4'‐quinolin]‐2'(3'H)‐one (8h)
10

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1'H‐spiro[oxetane‐3,4'‐quinolin]‐2'(3'H)‐one (8i)
11

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ethyl 3‐(4‐nitrophenyl)butanoate (10a)
12

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ethyl 3‐(4‐methoxyphenyl)butanoate (10b)
13

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ethyl 3‐(4‐bromophenyl)butanoate (10c)
14

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ethyl 3‐(3‐bromophenyl)butanoate (10d)
15

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ethyl 3‐(2‐methoxyphenyl)butanoate (10e)
16

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ethyl 3‐(o‐tolyl)butanoate (10f)
17

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ethyl 3‐(2,6‐dimethoxyphenyl)butanoate (10i)
18