Synthesis of 3-amino-3,4-dihydro-1H-quinolin-2-ones through regioselective palladium-catalyzed intramolecular cyclization

Article abstract of DOI:10.1016/j.tetlet.2016.02.094

In this Letter we explored the regioselective cyclization of 2-bromophenylalanine derivatives to access enantiopure dihydroquinolinones via an intramolecular regioselective Buchwald–Hartwig cyclization using Pd₂(dba)₃/XPhos as a catalytic system in the presence of BTPP as organic base. This procedure represents a promising strategy for the direct synthesis of bridged Phe-Xaa dipeptides.

Full text of DOI:10.1016/j.tetlet.2016.02.094

Tetrahedron Letters xxx (2016) xxx–xxx
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Tetrahedron Letters
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Synthesis of 3-amino-3,4-dihydro-1H-quinolin-2-ones through
regioselective palladium-catalyzed intramolecular cyclization
François Hallé a, Olivier Van der Poorten b,c, Christelle Doebelin a, Marie Niederst a, Séverine Schneider a,
Martine Schmitt a, Steven Ballet b,c, Frédéric Bihel a,
⇑
a UMR CNRS/UdS 7200, Faculté de Pharmacie, Université de Strasbourg, 74 route du Rhin, 67401 Illkirch, France
b Department of Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium
c Department of Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter we explored the regioselective cyclization of 2-bromophenylalanine derivatives to access
enantiopure dihydroquinolinones via an intramolecular regioselective Buchwald–Hartwig cyclization
using Pd2(dba)3/XPhos as a catalytic system in the presence of BTPP as organic base. This procedure rep-
resents a promising strategy for the direct synthesis of bridged Phe-Xaa dipeptides.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 18 January 2016
Revised 23 February 2016
Accepted 25 February 2016
Available online xxxx
Keywords:
Bridged peptide
BTPP
Buchwald–Hartwig
Dihydroquinolinone
Indoline
Introduction
O
The 3-amino-3,4-dihydro-1H-quinolin-2-one scaffold has been
used in multiple biologically active compounds, such as converting
enzyme inhibitors (1),1 glycogen phosphorylase inhibitors (2),2–4
cholecystokinin antagonists (3),5 DPP-IV inhibitors (4), or anticoag-
ulants (5),6 all in either (R) or (S) configurations (Fig. 1).
N
CO2Me
H2N
N
H
N
CO2H
Cl
N
CO2tBu
NH2
HO2C
N
H
NH
O
O
O
2
1
3
NH2
O
O
O O
S
The enantiopure core structure can be accessed via asymmetric
NH
N
N
phase-transfer catalyzed alkylation of glycine analog
nitrobenzyl bromide, followed by the reduction of the nitro group
in and subsequent cyclization of the in situ formed 2-
6
by
N
N
N
H
H
H
F
O
O
OH NH
4
5
7
Figure 1. Selected examples of lactam-constrained peptidomimetics containing the
3-amino-3,4-dihydro-1H-quinolin-2-one core.
aminophenylalanine into 3-amino-3,4-dihydroquinolin-2-one 8
(Fig. 2).7,8 This efficient two-step synthesis allows the access to
unsubstituted dihydroquinolinone 8, readily available for further
N-alkylation with various alkylhalides and alkyl
a-haloacetates.
O2N
However, this method does not permit the insertion of an amino
acid-like substituent exhibiting a chiral center at the alpha position
of the nitrogen thus limiting the scope of the accessible structures.
As shown in Figure 1, compounds 1, 2, 3, and 5 show indeed a gly-
cine residue at the N-position of the dihydroquinolinone scaffold.
In this Letter, an alternative strategy was envisaged based on
an intramolecular palladium-catalyzed Buchwald–Hartwig
Ph
a
b
Ph
+
NH
Ph
N
CO2tBu
OtBu
H2N
Ph
N
Br NO2
6
7
O
8
O
N
R2
*
H N
2
O
R1
⇑
Corresponding author.
E-mail address: fbihel@unistra.fr (F. Bihel).
Figure 2. Method developed by Hulin et al. (a) Cinchonidine-derived catalyst,
CsOHÁH2O, CH2Cl2, À30 °C, 92%; (b) H2, Pd/C, MeOH, 2 M HCl, 65%.
http://dx.doi.org/10.1016/j.tetlet.2016.02.094
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Hallé, F.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.02.094

2
F. Hallé et al. / Tetrahedron Letters xxx (2016) xxx–xxx
Table 1
Br
Pd(0)
Ligand
Base
Optimization of the reaction conditions for the intramolecular Buchwald–Hartwig
cyclization of dipeptide 9
+
H
N
R1
N
Solvent
T
Boc
N
R2
Boc
R2
Boc
N
H
N
H
R2
N
O
R1
O
R1
O
H
9
10
11
Figure 3. Synthesis of dihydroquinolinone 10 and/or indoline 11 via an intramolec-
ular Pd(0)-catalyzed Buchwald–Hartwig aryl amidation or carbamation reaction.
#
Ligand
Base
Equiv Solvent
T
Time
%
%
(°C) (h)
10aa 11aa
cyclization (Fig. 3).9–13 Starting from Boc-protected dipeptide tert-
butyl ester 9, cyclization can occur in two different ways to afford
either the six-membered dihydroquinolinone 10 or the five-mem-
bered indoline 11. While establishing the reaction scope, our objec-
tive was to find a convenient, mild, and racemization-free protocol,
favorable for the synthesis substituted 3-amino-3,4-dihydro-1H-
quinolin-2-ones of type 10.
1
2
3
4
5
6
7
8
9
XantPhos
BINAP
DPEPhos
JohnPhos
CyJohnPhos Cs2CO3
XPhos
tBuXPhos
SPhos
RuPhos
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Toluene 100 24
Toluene 100 24
Toluene 100 24
Toluene 100 24
Toluene 100 24
Toluene 100 24
Toluene 100 24
Toluene 100 24
Toluene 100 24
Toluene 100 24
Toluene 100 24
Toluene 100 24
Dioxane 100 24
50
22
9
2
5
50
50
68
6
14
34
4
73
67
63
64
39
12
6
4
17
0
0
0
35
34
39
51
3
12
39
20
35
33
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
63
1
15
23
36
8
13
71
68
66
66
34
0
47
65
66
61
49
3
10 MeO-SPhos Cs2CO3
11 BrettPhos
12 DavePhos
13 XPhos
14 XPhos
15 XPhos
16 XPhos
17 XPhos
18 XPhos
19 XPhos
20 XPhos
21 XPhos
22 XPhos
23 XPhos
24 XPhos
25 XPhos
26 XPhos
27 XPhos
28 XPhos
29 XPhos
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Results and discussion
Dipeptide substrate Boc-2-Br-L-Phe-Gly-OtBu 9a was synthe-
THF
EtOAc
DME
DMF
DMSO
MeCN
100 24
100 24
100 24
100 24
100 24
100 24
sized by standard coupling of commercially available Boc-2-Br-
L
-
Phe-OH and H-Gly-OtBu using HATU-activation. This model sub-
strate was engaged in a Buchwald–Hartwig amidation reaction
under anhydrous and oxygen-free conditions. To determine the
optimal reaction conditions that could selectively lead to dihydro-
quinoline 10a or indoline 11a, different reaction parameters were
screened for the envisaged intramolecular Pd(0)-catalyzed
Buchwald–Hartwig aryl amidation reaction. This optimization pro-
cess is summarized in Table 1.14
Dioxane 100
Dioxane 80
Dioxane 65
Dioxane 50
Dioxane 80
Dioxane 80
Dioxane 80
Dioxane 80
Dioxane 80
Dioxane 65
6
6
6
15
4
4
4
4
4
4
Na2CO3 1.1
K2CO3
Cs2CO3
K3PO4
BTPP
1.1
1.1
1.1
1.1
1.1
14
41
30
65
63
Although complete conversion of the starting material was
obtained under standard coupling conditions with Pd2(dba)3 and
the bidentate ligands XantPhos or BINAP, no or poor selectivity
was observed between both cyclization directions 10a and 11a
(entries 1 and 2). Next, monodentate ligands were screened under
the same reaction conditions. Use of simple dialkylbiaryl phosphi-
nes such as JohnPhos or CyJohnPhos did not provide the targeted
compounds in satisfying amounts (entries 4 and 5), whereas the
addition of bulky isopropyl substituents on the inferior phenyl of
dialkylbiaryl ligands (i.e., in case of XPhos) favored the formation
of dihydroquinolinone 10a (entry 6). In contrast, the presence of
electron-donating groups on the applied biaryl phosphines sys-
tematically favored the formation of indoline 11a (entries 7–12).
A similar observation was made for BrettPhos, which is an analog
of XPhos that exhibits two additional methoxy groups on the
biphenyl moiety (entry 11). Ultimately, XPhos was the only ligand
capable of promoting the formation of the six-membered ring 10a
over indoline 11a. It was found that bulky tert-butyl substituted
phosphines (tBuXPhos) showed no reaction (entry 7), neither did
the use of second generation palladacycles of SPhos and XPhos.15,16
The replacement of toluene by 1,4-dioxane increased the yield
of 10a, while more polar solvents as THF, EtOAc, or DME did not
affect selectivity (entries 14–16). Conversion was diminished in
polar solvents as DMF, DMSO, or acetonitrile (entries 17–19). Ini-
tially performed at 100 °C, the reaction could be completed at
50 °C, but at this temperature, the reaction rate was lowered to
15 h and selectivity for a specific reaction product was lost (entry
23). As regioselectivity started to appear at 65 °C (entry 22),
80 °C was chosen as the optimal temperature (entry 21), allowing
the completion of the reaction and maximal retention of regiose-
lectivity within 6 h (66% of 10a vs 34% of 11a).
BTPP
a
Determined by HPLC quantification. Experimental procedure in footnote 14.
superbase,17,18 afforded dihydroquinolinone 10a in 65% yield after
4 h. Although the use of BTPP in Buchwald–Hartwig cross-coupling
reactions is not yet described in literature, it allowed the expected
intramolecular cyclization to proceed in mild conditions and short
reaction times.
Since BTPP acts as a strong base, the potential racemization of
dihydroquinolinone 10a was evaluated. The Boc group was depro-
tected by acidolysis, and the resulting amine was subsequently
coupled with (1R)-(+)-camphanic acid (Fig. 5).
diastereoisomer was observed. A comparison with the racemic
A
single
mixture obtained from Boc-2-Br-L/D-Phe-Gly-OtBu was made by
HPLC.19 As expected, no racemization was observed when Cs2CO3
was used as base.
Having identified mild and racemization-free conditions favor-
ing the formation of the six-membered ring 10a, the insertion of
other amino acids bearing a side chain in the second position
was explored. L-Alanine and L-phenylalanine were selected and
the corresponding dipeptides 9b and 9c were synthesized using
HATU-activation (Table 2).
Unfortunately, the presence of an alkyl group in
a-position of
the C-terminal amino acid led to a complete inversion of regiose-
lectivity, affording only the five-membered indolines 11b and
11c (Table 2, entries 1–3). Based on this result, the influence of var-
ious alkyl amides (entries 4–17) on regioselectivity was examined.
Passing from glycine to a methyl moiety (9d) allowed the conser-
vation of the previously established selectivity for the dihydro-
quinoline, whereas ethyl or propyl homologs 9e and 9f
remarkably inverted this tendency toward indoline formation
In the next step, a base screening was performed in 1,4-dioxane
at 80 °C (entries 24–28), whereas inorganic bases such as Na2CO3,
K2CO3, or K3PO4 did not result in reaction completion, BTPP
(P1-t-Bu-tris(tetramethylene), Fig. 4), a strong and soluble organic
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F. Hallé et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
Electron rich nitrile 9i or alkyne 9h are probably too reactive and
a loss of yield or no reaction was observed (entries 8 and 9).
Similarly, a lack in selectivity was observed for 2-, 3-, and 4-pyr-
idinyl analogs 9l–n. In addition, these also showed a lack of reac-
tivity, since the conversion of starting material was rather
limited after 4 h of reaction (entries 12–14). Finally, ethyldimethy-
lamine substrate 9o did not favor the formation of dihydroquinoli-
none 10o (entry 15), as in the case of linear ethers 9p and 9q
(entries 16 and 17).
The dissimilarity observed when passing from methyl to ethyl
or propyl functionalities is rather difficult to explain, because these
three alkyl chains are showing a comparable flexibility to glycine.
It was assumed that a particular plier-shaped conformation existed
N
P
N
N
N
Figure 4. Structure of phosphazene base BTPP.
O
O *
*
O
O *
O
OH
*
TFA/CH Cl
2
HATU, DIEA
rt, 30 min
2
Boc
N
O
rt, 1 h
100%
N
O
N
O
N
H
*
H2N *
O
N
H
*
of the 2-Br-L-Phe derivative 9a that is able to chelate the catalytic
O
O
O
OtBu
OH
LnPd(Ar)Br species prior to amide binding. In this way, insertion of
the C-terminal nitrogen would be favored in order to form dihy-
droquinolinone 10a. This hypothesis was not confirmed using sub-
stituents potentially chelating palladium as allyl, pyridines,
ethyldimethylamine, nor linear ethers.
OH
Figure 5. Racemization study of dihydroquinolinone 10a by coupling of (1R)-(+)-
camphanic acid.
Most of the substituted Boc-2-Br-L-Phe derivatives 9 favored
Table 2
the formation of indolines 11 instead of dihydroquinolinones 10,
even in the absence of steric hindrance on substrate level. This
could be explained by the trans conformation of the amide nitro-
gen lone pair, limiting its availability for nucleophilic addition onto
the Pd-based oxidative addition complex.
Reaction scope for the intramolecular Pd-catalyzed cyclization of 9a–9q
Br
Pd2(dba)3(5 mol%)
XPhos (10 mol%)
BTPP (1.1 equiv)
+
H
N
H
N
1,4-dioxane
65°C, 4h
Boc
Boc
N
N
Boc
N
H
R
N
H
R
R
O
O
O
9
10
11
Conclusion
#
1
9
R
% yielda
65
% yielda
35
A new synthetic method has been developed to access chiral
dihydroquinolinones and indolines via an intramolecular
Buchwald–Hartwig cyclization using a Pd2(dba)3/XPhos/BTPP/1,4-
dioxane catalytic system. Since in many cases indoline formation
was favored above dihydroquinolinones, the extension of the reac-
tion substrates remained limited for the latter. Nevertheless, the
prepared indolines could also serve as Pro-like constrained amino
acids. Currently, to avoid cyclic regioisomers, N-terminal double
protection and the use of other transition metals and catalytic sys-
tems are explored for this type of metal-catalyzed intramolecular
amidation reactions toward substituted chiral d-lactams. These
results will be reported in due time.
O
O
9a
10a
10b
11a
OtBu
OtBu
2
3
9b
9c
0
0
11bb
100
91
O
OtBu
10c
11cb
4
5
6
7
9d
9e
9f
10d
10e
10f
10g
82
26
16
23
11d
11e
11f
11g
18
47
45
49
9g
Acknowledgments
8
9
9h
9i
10h
10i
0
11h
11i
0
We thank the MENRT (France) and the Agency for Innovation by
Science and Technology (IWT, Belgium) for financial support.
N
26
12
10
11
12
13
9j
10j
23
24
15
20
11j
43
45
14
28
References and notes
9k
9l
10k
10l
11k
11l
1. Parsons, W. H.; Davidson, J. L.; Taub, D.; Aster, S. D.; Thorsett, E. D.; Patchett, A.
A.; Ulm, E. H.; Lamont, B. I. Biochem. Biophys. Res. Commun. 1983, 117, 108–113.
2. Birch, A.; Kemmitt, P.; Martin, N.; Ward, R. WO2005123685 A1, 2005.
3. Birch, A.; Morley, A.; Stocker, A.; Whittamore, P. WO03074532 A1, 2003.
4. Birch, A.; Morley, A. WO03074513 A2, 2003.
5. Parsons, W. H.; Patchett, A. A. United States Patent: 4692522—Benzofused
Lactams Useful as Cholecystokinin Antagonists 4692522, 1987.
6. Tamura, S. Y.; Goldman, E. A.; Bergum, P. W.; Semple, J. E. Bioorg. Med. Chem.
Lett. 1999, 9, 2573–2578.
7. Birch, A. M.; Kenny, P. W.; Oikonomakos, N. G.; Otterbein, L.; Schofield, P.;
Whittamore, P. R. O.; Whalley, D. P. Bioorg. Med. Chem. Lett. 2007, 17, 394–399.
8. Hulin, B.; Lopaze, M. G. Tetrahedron: Asymmetry 2004, 15, 1957–1958.
9. He, F.; Foxman, B. M.; Snider, B. B. J. Am. Chem. Soc. 1998, 120, 6417–6418.
10. Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52, 7525–7546.
11. Cuny, G.; Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc. 2004, 126, 14475–14484.
12. Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101–1104.
N
N
N
N
9m
10m
11m
14
15
9n
9o
10n
10o
21
17
11n
11o
35
65
16
17
9p
9q
10p
10q
22
15
11p
11q
61
26
O
O
a
Isolated yield.
dr > 95% as determined by 1H NMR.
13. Takahashi, M.; Tanabe, H.; Nakamura, T.; Kuribara, D.; Yamazaki, T.; Kitagawa,
O. Tetrahedron 2010, 66, 288–296.
b
14. Experimental procedures: (A) Amide bond formation with HATU: DIEA (3 equiv)
was added to a solution of carboxylic acid (1 equiv) and HATU (1 equiv) in a
mixture of DCM/DMF (2/1) and then stirred at rt. After 10 min, the amine
derivative (1.2 equiv) was added to the reaction mixture. After 30 min,
volatiles were evaporated and the residue was solubilized in 10 ml of EtOAc.
(entries 5 and 6). An allyl group in 9g also promoted indoline for-
mation (entry 7), as in the case of bulky aromatic moieties such as
benzyl 9j or phenethyl 9k functionalities (entries 10 and 11).
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4
F. Hallé et al. / Tetrahedron Letters xxx (2016) xxx–xxx
Organic phase was washed with 2 Â 10 ml HCl 1 N, 2 Â 10 mL NaHCO3sat,
16. Beletskaya, I. P.; Cheprakov, A. V. J. Organomet. Chem. 2004, 689, 4055–4082.
17. Kaljurand, I.; Kütt, A.; Sooväli, L.; Rodima, T.; Mäemets, V.; Leito, I.; Koppel, I. A.
J. Org. Chem. 2005, 70, 1019–1028.
18. O’Donnell, M. J.; Delgado, F.; Hostettler, C.; Schwesinger, R. Tetrahedron Lett.
1998, 39, 8775–8778.
1 Â 20 mL of brine, dried on Na2SO4, filtered and concentrated under reduce
pressure. The residue was purified if necessary. (B) Buchwald–Hartwig
cyclization: 2-bromophenylalanine derivative (1 equiv), Pd, ligand and base
were degassed 3 times with argon. Previously degassed solvent was added to
the vessel and the mixture was heated for x hours. Reaction mixture is directly
purified on flash chromatography to afford desired cyclized products.
19. Nun, P.; Pérez, V.; Calmès, M.; Martinez, J.; Lamaty, F. Chem.-Eur. J. 2012, 18,
3773–3779.
15. Jin, Z.; Guo, S.-X.; Gu, X.-P.; Qiu, L.-L.; Song, H.-B.; Fang, J.-X. Adv. Synth. Catal.
2009, 351, 1575–1585.
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