Phase-transfer-catalysed asymmetric synthesis of 2,2-disubstituted 1,4-benzoxazin-3-ones

Article abstract of DOI:10.1039/c8cc03635g

1,4-Benzoxazin-3-one is a scaffold which is found in a variety of biologically active molecules. Because of its unique structure and drug-like activities, 1,4-benzoxazin-3-ones have been widely used in drug discovery. However, just a few methods have been developed to access these molecules by catalytic asymmetric synthesis. We report herein the phase-transfer-catalysed asymmetric alkylation of 2-aryl-1,4-benzoxazin-3-ones as a new way for the highly enantioselective synthesis of 2,2-disubstituted 1,4-benzoxazin-3-ones.

Full text of DOI:10.1039/c8cc03635g

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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Phase-transfer-catalysed Asymmetric Synthesis of 2,2-
Disubstituted 1,4-Benzoxazin-3-ones
Martin Pawliczeka, Yuto Shimazakia, Hidenori Kimuraa, Kevin M. Oberga, Saman Zakpura, Takuya
Hashimotoa†, and Keiji Maruoka*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
1,4-Benzoxazin-3-one is a scaffold which is found in a variety of only a few catalytic methods to forge this stereogenic center in
biologically active molecules. Because of its unique structure and an enantiomerically enriched way have been developed to
drug-like activities, 1,4-benzoxazin-3-ones have been widely used date.6-9 Building on the acidity of the hydrogen atom at the 2-
in drug discovery. However, just a few methods have been position of 2-mono-substituted benzoxazinones, we surmised
developed to access these molecules by catalytic asymmetric that the ability of a phase-transfer catalyst which enables an
synthesis. We report herein the phase-transfer-catalysed enantioselective alkylation under basic conditions is suitable
asymmetric alkylation of 2-aryl-1,4-benzoxazin-3-ones as a new for the realisation of such a transformation (Fig. 2).10
H
way for the highly enantioselective synthesis of 2,2-disubstituted
1,4-benzoxazin-3-ones.
R1
R2
O
O
R1
O
O
R2
X
+
chiral
phase-transfer
catalysis
N
N
1,4-Benzoxazin-3-ones are a class of compounds which appear
in a variety of biologically active molecules as represented by a
renin inhibitor developed by Pfizer (Fig. 1).1,2 The structure is
wide-spread not only within synthetic compounds but also
within natural products such as rifamorpholine A, which was
recently isolated and exhibited activity as potential antibiotic.3
Pg
Pg
2,2-disubstituted
1,4-benzoxazin-3-ones
Fig. 2 Synthesis of 2,2-disubstituted 1,4-benzoxazin-3-ones by phase-transfer
catalysis.
OMe OAc OH
OH
We report herein the chiral phase-transfer-catalysed
alkylation of a range of 1,4-benzoxazin-3-ones to give enantio-
enriched 2,2-disubstituted 1,4-benzoxazin-3-ones. The
alkylation worked efficiently with 2-aryl substituted
benzoxazinones by the use of a binaphthyl-based phase-
transfer catalyst bearing N,N-diisopentyl groups as a distinctive
feature.
F
F
Me
OH
Me
O
Me Me
Me
N
O
N
Me
O
O
O
Me
O
Me
O
OMe
H2N
N
NH2
renin inhibitor
Fig. 1 Biologically active 2,2-disubstituted 1,4-benzoxazin-3-ones.
HO
N
H
The initial optimisation was commenced with the
identification of a proper N-protecting group for 2-phenyl
benzoxazinone, which would affect the reactivity and
rifamorpholine A
selectivity of the reaction, using phase-transfer catalyst 1a
,
benzyl bromide and powdered KOH as base in toluene (Table
1). Attachment of a Boc protecting group (4a) was found to be
promising and the benzylated product 5aa could be isolated in
89% yield with 83% ee at 0 °C (entry 1). Benzoxazinone with a
N-Cbz group was converted to the corresponding product with
lower enantioselectivity (entry 2). The stability of the substrate
under strongly basic conditions must be taken into
consideration, as evidenced by the N-benzoyl substrate, with
which facile hydrolysis of the C-N bond was observed (entry 3).
On the other hand, N-benzyl 1,4-benzoxazin-3-one gave only
trace amount of the product (entry 4), underlying the necessity
of an electron-withdrawing N-protecting group. In addition,
Because of these interesting properties, synthetic methods
to construct 1,4-benzoxazin-3-ones have been well studied.4,5
However, despite the existence of a stable stereocenter at the
2-position in form of a 2,2-disubstituted 1,4-benzoxazin-3-one,
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use of solvents more polar than toluene resulted in rapid compound 5af was obtained in 95% ee. In addition to benzylic
decomposition of the substrate and lower enantioselectivity bromides, allyl bromide and 2-methylallyl bromide were
even with the N-Boc substrate (data not shown).
applied as representative allylic bromides and in both cases
We then turned our attention to the optimisation of the the products 5ag and 5ah were obtained with high
catalyst structure. Varying the 3,3’-aryl moieties of catalyst 1a enantioselectivities. The reaction with propargyl bromide
revealed that most of the screened aryl groups had no positive resulted in a slightly lower yield and enantioselectivity (5ai).
effect on the selectivity (data not shown) except for 1b with
Table 2. Alkyl bromide substrate scopea-c
which a slight increase in selectivity was observed (entry 5).
Attempts to achieve a higher enantioselectivity by use of more
complex chiral phase-transfer catalysts bearing two binaphthyl
units such as
2 also failed (entry 6). Further catalyst
optimisations at a lower temperature led us to the adjustment
of the N-alkyl chain, in which the N,N-diisopentyl quaternary
ammonium salt
3 was found to be the most effective catalyst
yielding the product in 96% ee at –25 °C (entries 7-9). The
increased yield at lower temperature is presumably due to the
suppression of the substrate decomposition.
Table 1. Optimisation of the reaction conditionsa
a
Performed with 4a (0.10 mmol), alkyl bromide (0.25 mmol), 3 (2 mol%)
and KOH (0.20 mmol) in toluene (1 mL). b Isolated yield. c Ee determined by
chiral HPLC.
We then shifted the focus to the substrate scope with
respect to the benzoxazinone template (Table 3). Expectedly,
the 2-aryl moiety of benzoxazinone affected the reactivity
substantially. For instance, 4-methoxyphenyl substituted
benzoxazinone showed lower reactivity likely due to the
attenuated acidity of the substrate while the high
entry
1
Pg
Boc (4a)
Cbz
PTC
1a
1a
1a
1a
1b
2
temp. (°C)
% yieldb
% eec
83
53
-
0
0
87 (5aa)
2
<50
-
3
Bz
0
4
Bn
0
8
25
84
69
86
89
96
5
Boc
Boc
Boc
Boc
Boc
0
83
57
68
58
79
6
0
enantioselectivity was sustained
substrates with halogenated aromatic ring were well
tolerated, giving the products 5ca 5fa in good yields and
(5ba). On the contrary,
7d
8d
9d,e
1b
3
–20
–20
–25
a
-
3
enantioselectivities. Attachment of an ortho-substituent to the
aromatic ring completely shut down the alkylation because of
steric hindrance around the reaction site (data not shown).
The absolute configuration of alkylation product was
a
Performed with 2-phenyl benzoxazinone (0.10 mmol), benzyl bromide
b
(0.50 mmol), PTC (2 mol%) and KOH (0.15 mmol) in toluene (1 mL). Isolated
c
d
e
yield. Ee determined by chiral HPLC. Performed with KOH (0.20 mmol).
Performed with benzyl bromide (0.25 mmol).
established to be (R) by X-ray analysis of compound 5ha 11
.
Afterwards, in consideration that the 6-substituent of
benzoxazinones is important for biological activities in many
cases,1,2 we examined substrates bearing a substituent at the
6-position of the heterocycle core. Methyl, methoxy, bromo
and fluoro substituted benzoxazinones all reacted smoothly
With the optimised reaction conditions in hand, we
examined the scope of this transformation using a variety of
benzylic and allylic bromides (Table 2). As for benzylic
bromides,
enantioselectivities regardless of the substitution pattern and
electronic properties 5aa 5ad). In the case of 2,6-
the
reaction
proceeded
with
high
and the corresponding 2,2-disubstituted benzoxazinones 5ia
5la were obtained in good yields and high enantioselectivities.
It should be noted that, in the case of 5ia 5ka and 5la, the
-
(
-
dichlorobenzyl bromide, the reaction became sluggish while
the enantioselectivity remained very high (5ae). In addition, 2-
naphthylmethyl bromide was also a viable reactant with which
,
instability of the substrates under strong basic conditions led
2 | J. Name., 2012, 00, 1-3
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us to implement the reactions using K3PO4 as a weaker base chiral phase-transfer catalysis. The reaction was applicable to a
and mesitylene as a less polar solvent. variety of 2-aryl substituted 1,4-benzoxazin-3-ones with
The asymmetric alkylation was also applicable to a sulphur benzylic, allylic and propargylic bromides serving as
analogue, benzothiazinone, with which compound 5ma was electrophiles. While further optimisation is needed,
obtained in a comparable yield and enantioselectivity using a methylation could also be achieved in one example.
slightly higher catalyst loading and mesitylene as solvent.
With respect to the renin inhibitor developed by Pfizer (Fig.
This work was partially supported by a Grant-in-Aid for
1), we attempted to incorporate a methyl group by use of Scientific Research from MEXT (Japan). M.P. thanks Deutsche
dimethyl sulfate as electrophile. The reaction with 6-methoxy Forschungsgemeinschaft (DFG) for postdoctoral fellowship.
benzoxazinone resulted in a modest result of 49% yield and
49% ee (5jj). The major issue of this methylation, other than
Conflicts of interest
the enantioselectivity, is the O-alkylation of the substrate
which deterred the yield of the desired product.12 It should be
There are no conflicts to declare.
noted that the use of less reactive alkyl halides resulted in
traces of product under our reaction conditions.
Notes and references
Table 3. Benzoxazinone substrate scopea-c
1
(a) R. W. Sarver, J. Peevers, W. L. Cody, F. L. Ciske, J. Dyer, S.
D. Emerson, J. C. Hagadorn, D. D. Holsworth, M. Jalaie, M.
Kaufman, M. Mastronardi, P. McConnell, N. A. Powell, J.
Quin, C. A. Van Huis, E. Zhang and I. Mochalkin, Anal.
Biochem., 2007, 360, 30-40; (b) N. A. Powell, F. L. Ciske, C.
Cai, D. D. Holsworth, K. Mennen, C. A. Van Huis, M. Jalaie, J.
Day, M. Mastronardi, P. McConnell, I. Mochalkin, E. Zhang,
M. J. Ryan, J. Bryant, W. Collard, S. Ferreira, C. Gu, R. Collins
and J. J. Edmunds, Bioorg. Med. Chem., 2007, 15, 5912-5949;
(c) H.Nakahira, Y. Ikuma, N. Fukuda, K. Yoshida, H. Kimura, K.
Suetsugu, A. Fusano, K. Sawamura, J. Ikeda, Y. Nakai, JP
2011026301 A 20110210, 2011.
2
For selected examples, see: (a) M. S. Deshmukh and N.
Jain, ACS Med. Chem. Lett., 2017, 8, 1153-1158; (b) J. Aretz,
H. Baukmann, E. Shanina, J. Hanske, R. Wawrzinek, V. A.
Zapol'skii, P. H. Seeberger, D. E. Kaufmann and C.
Rademacher, Angew. Chem. Int. Ed., 2017, 56, 7292-7296; (c)
A. R. Gangloff, J. Brown, R. de Jong, D. R. Dougan, C. E.
Grimshaw, M. Hixon, A. Jennings, R. Kamran, A. Kiryanov, S.
O’Connell, E. Taylor and P. Vu, Bioorg. Med. Chem. Lett.,
2013, 23, 4501-4505.
3
(a) E. Williams, D. S. Dalisay, J. Chen, E. A. Polishchuck, B. O.
Patrick, G. Narula, M. Ko, Y. Av-Gay, H. Li, N. Magarvey and
R. J. Andersen, Org. Lett., 2017, 19, 766-769; (b) Y. S. Xiao, B.
Zhang, M. Zhang, Z. K. Guo, X. Z. Deng, J. Shi, W. Li, R. H. Jiao,
R. X. Tan and H. M. Ge, Org. Biomol. Chem., 2017, 15, 3909-
3916.
a
Performed with 4 (0.10 mmol), benzyl bromide (0.25 mmol), 3 (2 mol%)
and KOH (0.20 mmol) in toluene (1 mL). b Isolated yield. c Ee determined by
4
5
For a review, see; J. Ilaš, P. Š. Anderluh, M. S. Dolenc and D.
Kikelj, Tetrahedron, 2005, 61, 7325-7348.
d
e
chiral HPLC. –35 °C Benzyl bromide (0.40 mmol),
3
(2 mol%) and K3PO4
(5 mol%) in mesitylene (1 mL) at –
(5 mol%) and Me2SO4 (3.00 mmol).
f
(1.00 mmol) in mesitylene (1 mL).
10 °C. g
3
(a) O. Bodero and A. C. Spivey, Synlett, 2017, 13, 471-474; (b)
E. Martinand-Lurin, L. El Kaïm and L. Grimaud, Tetrahedron
Lett., 2014, 55, 5144-5146; (c) K. E. O. Ylijoki and E. P.
Kündig, Chem. Commun., 2011, 47, 10608-10610; (d) C.
Ramesh, B. R. Raju, V. Kavala, C.-W. Kuo and C.-F.
Yao, Tetrahedron, 2011, 67, 1187-1192.
(a) M. Breznik, V. Hrast, A. Mrcina and D. Kikelj, Tetrahedron:
Asymmetry, 1999, 10, 153-167; (b) M. Breznik, A. Mrcina and
D. Kikelj, Tetrahedron: Asymmetry, 1998, 9, 1115-1116.
3
Deprotection of the Boc group was achieved by treating
the product with trifluoroacetic acid in dichloromethane in
quantitative yield and without loss of the enantioselectivity
(Scheme 1).
6
7
8
9
D. Holsworth and W. Park, U.S. Pat. Appl. Publ. (2009), US
20090311318 A1.
Y. Numajiri, G. Jiménez-Osés, B. Wang, K. N. Houk and B. M.
Stoltz, Org. Lett., 2015, 17, 1082-1085.
D. Kim, M. W. Ha, S. Hong, C. Park, B. Kim, J. Yang and H.-g.
Park, J. Org. Chem., 2017, 82, 4936-4943.
Scheme 1. Deprotection of the N-Boc group.
10 (a) T. Hashimoto and K. Maruoka, Chem. Rev., 2007, 107
,
5656-5682; (b) S. Shirakawa and K. Maruoka, Angew. Chem.,
Int. Ed., 2013, 52, 4312-4348.
In conclusion, we developed the catalytic asymmetric
synthesis of 2,2-disubstituted 1,4-benzoxazin-3-ones by use of
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11 CCDC 1840492 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/structures.
12 Our investigations around the alkylation of the benzoxazine
core revealed the undesired O-alkylation instead of C-
alkylation as a persistent obstacle and reason for diminished
yields. Catalyst structure as well as steric and electronic
modifications of heterocyclic core influenced this selectivity.
Our optimized catalyst
3 not just gave the best
enantioselectivities but also minimised the amount of O-
alkylation product to less than 5% in most cases.
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R1
Br R2
R2
O
X
R1
O
X
PTC (2 mol%)
R4
N
R4
N
Boc
base
solvent
Boc
up to 98% ee
The phase-transfer-catalysed alkylation of 2-aryl-1,4-benzoxazin-3-ones was developed
as a way for the synthesis of enantioenriched 2,2-disubstituted 1,4-benzoxazin-3-ones.