Practical synthesis of 3,3-substituted dihydroquinoxalin-2-ones from aryl 1,2-diamines using the Bargellini reaction

Article abstract of DOI:10.1016/j.tetlet.2016.08.057

The reaction of aromatic 1,2-diamines with trichloromethylcarbinols under mild, basic phase-transfer conditions provided expedient access to 3,3-disubsituted quinoxalin-2(1H)-ones in good to moderate yields. The use of unsymmetrical aryl diamines gave a r

Full text of DOI:10.1016/j.tetlet.2016.08.057

Tetrahedron Letters xxx (2016) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Practical synthesis of 3,3-substituted dihydroquinoxalin-2-ones from
aryl 1,2-diamines using the Bargellini reaction
⇑
Thomas A. Alanine, Stephen Stokes , James S. Scott
AstraZeneca, Building 310, Milton Science Park, Cambridge CB4 0FZ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of aromatic 1,2-diamines with trichloromethylcarbinols under mild, basic phase-transfer
conditions provided expedient access to 3,3-disubsituted quinoxalin-2(1H)-ones in good to moderate
yields. The use of unsymmetrical aryl diamines gave a regioisomeric mixture of products with the ratio
shown to be dependent on the electronic nature of the aromatic substituents. 2,3-Diaminopyridines
could also be used, showing excellent selectivity for the dihydro[3,2-b]pyridopyrazin-2-one isomer.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 22 July 2016
Revised 16 August 2016
Accepted 17 August 2016
Available online xxxx
Keywords:
Dihydroquinoxalin-2-one
Bargellini reaction
Trichloromethylcarbinol
Synthetic methodology
Heterocyclic synthesis
Introduction
to heterocyclic examples. In particular, the regioselectivity of the
Bargellini reaction has never been assessed for unsymmetrical aro-
Heterocyclic scaffolds are a ubiquitous feature of small mole-
cule drug discovery programs. In particular, the ability to effi-
ciently generate heterocyclic systems with higher degrees of
three-dimensional shape would be of value to help overcome typ-
ical drawbacks of their flat, extensively aromatic congeners, such
as poor aqueous solubility1 and the propensity to aggregate. Bicyc-
lic aromatics such as quinolones, quinazolines and quinoxalines
are well-represented in medicinal chemistry programs. Partially
saturated analogues are less common, however may offer other
advantages in terms of physicochemical properties. Indeed, the
dihydroquinoxalinone core is a privileged scaffold in drug discov-
ery, commonly employed to engage interactions with biological
targets.2a–e These motifs can be found within a wide variety of
existing bioactive motifs (Fig. 1).
matic 1,2-diamines.7 Furthermore, the ability to utilise heteroaro-
matic diamines, such as pyridines, would provide expedient access
to aza-analogues, valuable heterocyclic motifs for drug, or agro-
chemical discovery.
O
H
N
O
N
S
N
N
O
O
H
N
O
O
N
O
O
S
O
N
H
N
H
O
BET protein inhibitor
Incyte Corporation 3a
Anti-inflammatory agent
A variety of literature protocols exist for the preparation of 3,3-
dihydroquinoxaline cores, however these typically employ either
Santen Pharmaceuticals 3b
H
N
harsh reaction conditions (a-bromoesters, strong base and high
O
temperatures)4a,b or metal catalysis5a–c from the corresponding
haloaniline or nitroaniline derivative. The Bargellini reaction pro-
vides a mild, metal-free alternative to the construction of quinox-
alinones; indeed, a select few examples have been prepared using
this methodology.6 To the best of our knowledge, this approach has
not been extended to analogues where the 3-position is varied or
O
N
HIV-1 reverse transcriptase inhibitor,
DuPont Pharmaceuticals Company3c
Figure 1. Selected examples of biologically active dihydroquinoxalin-2(1H)-one
⇑
derivatives.3a–c
Corresponding author.
E-mail address: steve.stokes@astrazeneca.com (S. Stokes).
http://dx.doi.org/10.1016/j.tetlet.2016.08.057
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Alanine, T. A.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.08.057

2
T. A. Alanine et al. / Tetrahedron Letters xxx (2016) xxx–xxx
Table 1
investigated the reaction of 2a with a range of substituted aromatic
diamine substrates (Table 2).
Scope of 3,3-substituted dihydroquinoxalinone formation
Good to moderate yields were obtained for most substrates,
independent of the nature of the aryl substituents. In cases where
the starting material was insoluble or poorly soluble in dichloro-
methane, the addition of a few drops of methanol or the use of
2-MeTHF was found to facilitate the reaction. For unsymmetrical
substrates 3k–3t we obtained, as anticipated, mixtures of regioiso-
mers which proved in most cases to be inseparable.11 Notably, the
reaction could successfully be applied to pyridine substrates
(entries 11 and 12), despite the weakly nucleophilic 2-amino
group, and showed excellent selectivity for the dihydro[3,2-b]pyri-
dopyrazin-2-one isomer, albeit with a decrease in yield. We spec-
ulated that the product ratio was controlled by the relative
nucleophilicity of the two amine centres, and mediated by the nat-
ure of the substituents on the aromatic ring. In order to investigate
this hypothesis, we sought to establish a relationship between the
isomeric ratio and the electronic influence of the substituent
(Fig. 2). The isomeric ratio was represented numerically as a value
ranging from ꢀ1 to 1, where ꢀ1 represents 100% of isomer 3 and 1
R1
R2
Cl
Cl
Cl
HO
2 eq.
H
N
NH2
NH2
O
2a-h
R1
R2
N
H
3a-h
0.1 eq. BTEAC,
5 eq. 50% aq. NaOH,
CH2Cl2 (0.1 M),
0 °C to r.t.
1a
Entry
R1
R2
Yield
1
2
3
4
5
6
7
8
Me
Et
Me
Me
Me
Me
3a 89%
3b 44%a
3c 66%a
3d 12%a
3e 71%
3f 46%a
3g 62%a
3h 77%
CH2–CH2–Ph
cPr
–CH2–CH2–CH2–CH2–
CH2–OMe
–CH2–CH2–N(Boc)–CH2–
–CH2–CH2–O–CH2–CH2–
Me
a
Racemic mixtures. BTEAC: N-benzyl-N,N-diethylethanaminium chloride.
Results and discussions
Seeking to prepare a range of substituted dihydroquinoxali-
nones, we utilised the method described by Lai and co-workers6
to examine the reaction of o-phenylene diamine 1a (CAUTION:
toxic) with a selection of substituted trichloromethylcarbinol
electrophiles (Table 1), which were readily prepared from the
corresponding ketones and chloroform.8,9
Good to moderate yields of 3-substituted dihydroquinoxali-
nones 3a–h were obtained under these mild phase-transfer
conditions.10 In the cases of differentially substituted
trichloromethylcarbinols, racemic products were obtained.
Heteroatom-containing substrates were tolerated, as well as spiro-
cyclic examples (Table 1, entries 5, 7 and 8), which are challenging
substrates to prepare using alternative methods. However,
branched alkyl substituents performed poorly (entry 4). Next, we
Figure 2. Plot of the 3:30 ratio versus Hammett constants.
Table 2
Scope of aryl substitution
1
1
2a
2 eq.
8
Z
H
H
8
R1
R2
N
O
R2
R1
N
O
0.1 eq. BTEAC
R1
R2
Z
NH2
NH2
7
6
7
6
5 eq. 50% aq. NaOH
2
2
3
3
4
4
CH2Cl2
0 °C to r.t.
N
Z
N
5
H
H
5
3
3'
Entry
R1
R2
Z
3:30 ratioa
Yieldb
1
2
3
4
5
6
7
8
H
Me
Cl
OMe
Me
tBu
CF3
Br
H
Me
Cl
H
H
H
H
H
H
H
H
H
H
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
—
—
—
3a 89%
3i 65%
3j 72%
3k 60%
3l 70%
3m 93%
3n 80%
3o 70%
3p 58%
3q 33%
3r 63%
3s 37%
3t 45%
2.0:1
1.5:1
1.1:1
1:1.3
1:1.5
1:1.5
1:2.2
1:4.7c
19:1
49:1
9
Cl
10
11
12
13
CN
NO2
H
6-Br
N
a
b
c
Determined by 1H NMR analysis of the crude reaction mixture.
Isolated yield of both isomers.
Reaction run in 2-MeTHF.
Please cite this article in press as: Alanine, T. A.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.08.057

T. A. Alanine et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
X
Z
NH2
NH
NH2
NH
NH2
NH2
Cl
O
X
Z
Cl
Cl
Cl
Cl
OH-
X
Z
Cl
Cl
OH
-HCl
O
O
Favoured when
Favoured when
X = EDG or Z = N X = EWG and Z = CH
3
3'
Scheme 1. Proposed mechanism for the Bargellini reaction with unsymmetrical aromatic 1,2-diamines.
represents 100% of isomer 30. These values were then plotted
against the Hammett constants12 rp for the aryl substituents.
A good correlation of the isomeric ratio with the Hammett con-
stants was observed (R2 = 0.84), showing an influence of the elec-
tronics of the ring substituents on the product ratio.13 In
particular, electron-donating substituents favoured the formation
of an excess of the 7-substituted isomer (3) and electron-with-
drawing groups favoured an excess of the 6-substituted isomer
(30). The distribution can be rationalised mechanistically
(Scheme 1), as the initial bond formed involves nucleophilic attack
of the amine group on the carbon atom distal to the chlorine atoms
of the epoxide.14 The resultant intermediate collapses to an acid
chloride moiety which can be intercepted by the less nucleophilic
aromatic amine group to give the observed products.
In summary, the synthesis of 3,3-substituted dihydroquinoxali-
nones from aromatic 1,2-diamines using the Bargellini reaction has
been revisited and the scope expanded. The reaction proceeds
under mild conditions and tolerates a variety of trichloromethyl-
carbinol electrophiles to give useful quaternary 3,3-disubstituted
dihydroquinoxalinones. The mild conditions and generally good
yields of the process highlights the Bargellini process as an efficient
means to access this important class of heterocyclic substrates. In
the case of unsymmetrically substituted arenes, a mixture of
regioisomers was obtained. The isomer ratio can be rationalised
in terms of the electronic effects of the aryl substituents. Pyridine
substrates are also tolerated, and these showed excellent intrinsic
selectivity for the dihydro[3,2-b]pyridopyrazin-2-one isomer.
Efforts to prepare stereodefined trichloromethylcarbinols are cur-
rently underway in order to access enantiomerically pure
dihydroquinoxalinones.
2. For selected examples see: (a) Carta, A.; Piras, S.; Loriga, G.; Paglietti, G. Mini-
Rev. Med. Chem. 2006, 6, 1179–1200; (b) Li, X.; Yang, K. H.; Li, W. L.; Xu, W. F.
Drugs Future 2006, 31, 979–989; (c) Matsumoto, Y.; Tsuzuki, R.; Matsuhisa, A.;
Yoden, T.; Yamagiwa, Y.; Yanagisawa, I.; Shibanuma, T.; Nohira, H. Bioorg. Med.
Chem. 2000, 8, 393–404; (d) Kato, M.; Takai M.; Matsuyama, T.; Kurose, T.;
Hagiwara, Y.; Oki, K.; Matsuda, M.; Mori, T. EP2327699, 2011; (e) Billhardt, U.-
M.; Roesner, M.; Riess, G.; Winkler, I.; Bender, R. US6369057, 2002
3. (a) Combs, A. P.; Maduskuie, Jr., T. P.; Falahatpisheh, N. WO2015/164480, 2015;
(b) Matsuda, M.; Mori, T.; Nagatsuka, M.; Kobayashi, S.; Takaoka, S.; Kato, M.;
Takai, M.; Matsuyama, T.; Kurose, T.; Hagiwara, Y. WO2009035068A1, 2009; (c)
Patel, M.; McHugh, R. J., Jr; Cordova, B. C.; Klabe, R. M.; Erickson-Viitanen, S.;
Trainor, G. L.; Rodgers, J. D. Bioorg. Med. Chem. Lett. 2000, 10, 1729–1731.
4. (a) Kamila, S.; Biehl, E. R. Heterocycles 2006, 68, 1931–1939; (b) TenBrink, R. E.;
Im, W. B.; Sethy, V. H.; Tang, A. H.; Carter, D. B. J. Med. Chem. 1994, 37, 758–768.
5. (a) Tanimori, S.; Inaba, U.; Kato, Y.; Ura, H.; Kashiwagi, H.; Nishimura, T.;
Kirihata, M. Res. Chem. Intermediat. 2014, 40, 2157–2164; (b) Mamedov, V. A.;
Zhukova, N. A.; Syakaev, V. V.; Gubaidullin, A. T.; Beschastnova, T. Y. N.;
Adgamova, D. B. I.; Samigullina, A. I.; Latypov, S. K. Tetrahedron 2013, 69, 1403–
1416; (c) Söderberg, B. C. G.; Wallace, J. M.; Tamariz, J. Org. Lett. 2002, 4, 1339–
1342.
6. Lai, J. T. Synthesis 1982, 71–74.
7. In Ref. 6, a note is made that regioisomeric mixtures are obtained, but no
details are given on the relative amounts.
8. Henegar, K. E.; Lira, R. J. Org. Chem. 2012, 77, 2999–3004.
9. In our hands, efforts to perform the Bargellini reaction directly from chloroform
and ketones were much less successful, leading to complex reaction mixtures,
incomplete conversion and low yields.
10. General procedure for the synthesis of 3a–3t: Representative procedure for 3h:
50% aqueous sodium hydroxide (0.42 mL, 5 equiv) was added dropwise to a
stirred mixture of o-phenylene diamine 1a (CAUTION: toxic) (200 mg, 1 equiv),
4-(trichloromethyl)tetrahydro-2H-pyran-4-ol (812 mg, 2 equiv) and N-benzyl-
N,N-diethylethanaminium chloride (42 mg, 0.1 equiv) in CH2Cl2 (0.1 M) cooled
to 0 °C over a period of 10–20 s under nitrogen. The resulting mixture was
stirred at 0 °C and left to warm to room temperature with stirring over 18 h.
The reaction was monitored by analytical HPLC–MS. When complete, the
reaction mixture was diluted with water (10 mL) until any solid had dissolved
and the layers were separated. The aqueous layer was extracted with CH2Cl2
(3 ꢁ 20 mL). The combined organic layers were dried (MgSO4), filtered and
evaporated to afford the crude product which was purified by flash silica
chromatography, elution gradient 0–50% EtOAc in heptane. The resulting solid
was filtered through a Buchner funnel, rinsed with MTBE (2 ꢁ 10 mL), and
collected to afford 10,2,3,40,5,6-hexahydro-30H-spiro[pyran-4,20-quinoxalin]-30-
one (310 mg, 77%) as a pale yellow powder. Rf = 0.33 (1:1 EtOAc/heptane). 1H
NMR (500 MHz, d6-DMSO): dH 10.21 (1H, s), 6.93–6.33 (1H, m), 6.78 (1H, td,
J = 1.4, 7.6 Hz), 6.73 (1H, dd, J = 1.3, 7.7 Hz), 6.62 (1H, td, J = 1.3, 7.6 Hz), 6.19
(1H, s), 3.72 (4H, dddd, J = 5.0, 10.6, 16.6, 21.6 Hz), 1.90 (2H, ddd, J = 4.5, 9.1,
13.6 Hz), 1.43 (2H, dt, J = 3.5, 13.5 Hz). 13C NMR (126 MHz, d6-DMSO): dc 168.9,
133.0, 126.0, 122.7, 118.1, 114.4, 114.3, 62.2 (2 ꢁ C), 53.3, 32.2 (2 ꢁ C). IR
(cmꢀ1, CH2Cl2): 3340, 2933, 1671, 1503, 1421, 1370, 1311, 1242, 1160, 1101.
HRMS (TOF ES+) Calcd for C12H15N2O2 [M+H]+: 219.1134, found 219.1139. For
substrates 3r and 3s, the aqueous layer was adjusted to pH 7 with saturated
aqueous ammonium chloride (10 mL) and the extraction performed with
EtOAc (3 ꢁ 20 mL).
Acknowledgments
The authors would like to acknowledge Dr. Eva Lenz and Dr.
Paul Davey for NMR and MS support, as well as AstraZeneca IMED
for funding.
Supplementary data
Supplementary data (NMR resonances and accurate masses)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2016.08.057.
11. In the case of 3p, both isomers were successfully separated by column
chromatography.
12. Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165–195.
13. Similar correlations were obtained with Hammett constants r+p and rpꢀ
(R2 = 0.83 and 0.84, respectively).
References and notes
14. Snowden, T. S. Arkivoc 2012, 2, 24–40.
1. Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752–6756.
Please cite this article in press as: Alanine, T. A.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.08.057