An Expedient Synthesis of 2-Aryl-1,4-benzoxazin-3-ones via Tandem Anionic Cyclisation/Alkylation Reactions of N -Boc- O -benzyl-2-aminophenols

Article abstract of DOI:10.1055/s-0036-1588348

A one-pot, tandem anionic cyclization/alkylation reaction of N-Boc-O-benzylated-2-aminophenols to give 2-aryl-1,4-benzoxazin-3-ones is described. The Boc protecting group plays a crucial role in the process, as the tert-butoxide liberated in the cyclisati

Full text of DOI:10.1055/s-0036-1588348

SYNLETT
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6
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2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
O. Bodero, A. C. Spivey
Letter
Synlett
An Expedient Synthesis of 2-Aryl-1,4-benzoxazin-3-ones via Tan-
dem Anionic Cyclisation/Alkylation Reactions of N-Boc-O-benzyl-
2-aminophenols
O
OLi
O
Olga Bodero
E
Li
Ar
t-BuLi (2.2 equiv)
THF, –78 to –20 °C
Alan C. Spivey*
E-X
–20 °C or r.t.
HN
Ot-Bu
N
HN
Ar
O
O
O
Department of Chemistry, South Kensington Campus,
Imperial College London, SW7 2AZ, UK
a.c.spivey@imperial.ac.uk
15 examples
37–95% yield
Ar
Li–X
R
R
R
E = H, Me, i-Bu, allyl, methallyl, CH2CH2CCH, CH2Ph,
CH23-Py,CH2c-Pr, CH2CN, CH2CO2Et
Ar = Ph, 3-ClC6H4, 4-ClC6H4, 4-MeC6H4
R = H, Me
Received: 17.09.2016
NH
Accepted after revision: 18.10.2016
Published online: 24.11.2016
DOI: 10.1055/s-0036-1588348; Art ID: st-2016-d0617-l
O
O
NH2
HO
OH
N 4
N
2
N
4
O1
O
Abstract A one-pot, tandem anionic cyclization/alkylation reaction of
N-Boc-O-benzylated-2-aminophenols to give 2-aryl-1,4-benzoxazin-3-
ones is described. The Boc protecting group plays a crucial role in the
process, as the tert-butoxide liberated in the cyclisation step facilitates
the benzylic deprotonation necessary for the subsequent alkylation.
The reaction gives expedient access to a range of substitution patterns
in 1,4-benzoxazin-3-ones of potential biological relevance.
Factor Xa inhibitor
F
DIBOA
O
MeO
N
O
NH2
Key words 1,4-benzoxazin-3-one, cyclization, alkylation, reagent re-
cycling, DIBOA
N
F
H2N
N
Renin inhibitor
Many natural and synthetic 1,4-benzoxazin-3-ones per-
form useful ecological roles and exhibit interesting bioac-
tivities.1 For example, 2,4-dihydroxy-1,4-benzoxazin-3-one
(DIBOA) and several related compounds which were first
isolated from Zea mays L.,2 exhibit phytotoxic and antifun-
gal activity.3 As a result of agrochemical and pharmaceuti-
cal research based on these natural products, the 1,4-benz-
oxazin-3-one core has served as a template for the develop-
ment of an array of interesting crop-protection and
therapeutic agents displaying useful antifungal,4 antibacte-
rial,5 antithrombotic (Factor Xa inhibitory6) and antihyper-
tensive (Renin inhibitory7) activity (Figure 1).
Various approaches to the synthesis of the 1,4-benzox-
azin-3-one core have been developed.8 The most widely
used methods involve the ring-annulation of 2-aminophe-
nols (or 2-nitrophenols, incorporating reduction) with 2-
haloacetate derivatives,6,8,9 various multicomponent vari-
ants of these reactions,10 the ring-closure of N-acetyl-2-
haloaniline derivatives via intramolecular Buchwald–
Hartwig O-arylation,11 and the ring-annulation of 2-halo-
Figure 1 Examples of bioactive compounds based on the 1,4-benzox-
azin-3-one scaffold
phenols with 2-haloacetamides via intramolecular Ullmann
N-arylation.12 Although the yields are often good, limited
access to appropriately functionalized substrates and/or
limited compatibility of required functional groups with
the reaction conditions means there is a demand for new
approaches to the synthesis of this important ring system.
In the course of some research directed towards the
synthesis of 2,6-disubstituted aniline derivatives as compo-
nents of α-helix mimetics,13 we had occasion to attempt the
directed ortho lithiaiton14 of N-Boc-O-benzyl-2-aminophe-
nol (1a). The plan was to form the dianion, by deprotona-
tion of the NHBoc function and the ortho ring position us-
ing t-BuLi (2.2. equiv), and then react this with 3-bromo-2-
methylpropene to obtain the C-allylated product. In the
event we were surprised to discover that the exclusive
product of this reaction was 1,4-benzoxazin-3-one 2a in
80% yield (Scheme 1).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
O. Bodero, A. C. Spivey
Letter
Synlett
Table 1 Scope of 1,4-Benzoxazin-3-one Formation with Respect to Al-
kylating Agent RX
O
1) t-BuLi (2.2 equiv)
THF, –78 to –20 °C, 2 h
NHBoc
OBn
HN
Ph
O
O
NC
O
2)
R
1) t-BuLi (2.2 equiv)
THF, –78 to –20 °C, 2 h
NHBoc
OBn
Br
HN
(2 equiv)
N
CN
Ph
Ph
O
2a
O
1a
–20 °C, 2 h
2) R-X (2 equiv)
–20 °C, 2 h
NOT:
NHBoc
OBn
1a
2b–k
3
Entrya
Electrophile (R-X)
Product
Yield (%)
1
2
3
4
5
CH2=CHCH2-Br
i-Bu-Brb
2b
2c
2d
2e
2f
68
77
95
72
63
Scheme 1 Serendipitous tandem 1,4-benoxazin-3-one formation/al-
kylation reaction
H-OMe
HC≡CCH2CH2-Brb
Bn-Brb
The use of just 2.2 equivalents of t-BuLi in this tandem
cyclization/alkylation process implicates the tert-butoxide
generated upon cyclisation as mediating the subsequent
benzylic alkylation (vide infra, Scheme 2). The ‘waste’ tert-
butoxide generated in the first step is thereby internally re-
cycled to facilitate the next step in an environmentally be-
nign fashion,15 a concept pioneered by Shibasaki for recy-
cling triphenylphosphine oxide in sequential Wittig alke-
nylation/asymmetric epoxidation reactions.16 This 1,4-
benzoxazin-3-one synthesis is notable for directly generat-
ing a quaternary benzylic stereocentre at C2, as found in
several bioactive derivatives11,17 (e.g. the renin inhibitor7b
in Figure 1).
To explore the scope of this transformation we first in-
vestigated the use of different electrophiles (Table 1).
Pleasingly, both activated and non-activated electro-
philes participated in the reaction. Thus, allyl bromide, ben-
zyl bromide and 3-(bromomethyl)pyridine afforded the ex-
pected 1,4-benzoxazinones in good yields under the origi-
nal conditions (Table 1, entries 1, 5 and 7). Protonation
could also be achieved using MeOH (Table 1, entry 3).
Isobutyl bromide, 4-butynyl bromide and cyclopropyl-
methyl bromide afforded excellent yields, provided longer
reaction times and higher temperatures were employed
(Table 1, entries 2, 4 and 6). By contrast, bromoacetonitrile,
ethyl bromoacetate and methyl iodide reacted so rapidly
that e.g. when two equivalents of bromoacetonitrile were
added the C,O-dialkylated derivative 3 was the only isolated
product (Table 1, entry 8). Use of just one equivalent how-
ever allowed the formation of the expected product 2h ex-
clusively (Table 1, entry 9). The same applied when using
ethyl bromoacetate (Table 1, entry 10). Methyl iodide was
even more reactive and use of 0.9 equivalent was required
to obtain exclusively 2j in excellent yield (Table 1, entry 11).
Next we briefly examined the possibility of introducing
substituents in the aromatic rings, using 3-bromo-2-meth-
ylpropene as the default alkylating agent (Table 2).
Br
6
7
2g
2h
89
85
b
N
Br
8
9
N≡CCH2-Br
N≡CCH2-Brc
3
53
70
53
93
2i
2j
2k
10
11
EtO2CCH2-Brc
Me-Id
a For general procedure see ref. 18.
b Reaction mixture was stirred for 16 h at r.t. after the addition of the elec-
trophile.
c Amount of electrophile added was 1 equiv.
d Amount of MeI added was 0.9 equiv.
Table 2 Scope of 1,4-Benzoxazin-3-one Formation with Respect to
Aryl Substituents
O
NHBoc
R2
O
1) t-BuLi (2.2 equiv)
HN
THF, –78 to –20 °C
O
R1
2)
R2
Br (2 equiv)
R1
2l–o
1b–i
–20 °C to r.t.
Entry
Substrate
R1
R2
Product
Yield (%)
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
H
4-Me
2l
2m
2n
–
85
75
37
0
H
H
H
H
H
4-Cl
3-Cl
2-Me
4-NO2
3,5-(CF3)2
–
0
1g
1h
1i
–
0
4-Me
4-Cl
H
H
2o
–
76
0
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
O. Bodero, A. C. Spivey
Letter
Synlett
The substrates 1b–i were readily synthesized from the
appropriate 2-aminophenols and benzylic bromides in two
steps (see Supporting Information). For the benzylic ring, 4-
Me, 4-Cl and 3-Cl groups were tolerated (Table 2, entries 1–
3), but 2-Me, 4-NO2 and 3,5-(CF3)2 groups were not, even
when deploying LDA, NaH or LiHMDS in place of t-BuLi; all
conditions led to decomposition of the staring material (Ta-
ble 2, entries 4–6). For the aminophenol ring, just two de-
rivatives were explored: a 4-Me group was tolerated (Table
2, entry 7) but a 4-Cl group led to complex mixtures, appar-
ently due to competing halogen-lithium exchange upon
treatment with t-BuLi (Table 2, entry 8).
1) t-BuOLi (1 equiv)
THF, –20 °C, 2 h
2)
O
Ph
N
Br
O
O
r.t., 16 h
Ph
HN
O
2p
O
1) t-BuOLi (2 equiv)
THF, –20 °C, 2 h
2)
2d
HN
Ph
O
Br
–20 °C, 2 h
A proposed reaction mechanism for this 1,4-benzoxaz-
in-3-one formation-alkylation reaction is shown below
(Scheme 2).
2a
Scheme 3 Confirmation that t-BuOLi can effect mono- and didepro-
tonation of 2d
Li
O
O
O
C
Li
Ph
Li
Ph
16 hours at room temperature complete conversion to O-al-
kylated product 2p was achieved. When two equivalents of
t-BuOLi were added, an orange suspension was formed; af-
ter addition of the electrophile total conversion into C-al-
kylated product 2a was achieved after two hours at –20 °C.
Clearly, t-BuOLi is strong enough as a base to deprotonate
intermediate C in our proposed mechanism (Scheme 2).
In conclusion, we have reported an expedient method
for the synthesis of 2-aryl-1,4-benzoxazin-3-ones via an
unusual tandem anionic cyclisation/alkylation reaction of
N-Boc-O-benzyl-2-aminophenols. The substrates for this
one-pot transformation are readily prepared in two
straightforward steps from commercially available 2-amino-
phenols and benzylic bromides. The convenience of the
procedure allied with the known biological significance of
the product class will hopefully make this a useful addition
to existing methods for the synthesis of 1,4-benzoxazin-3-
ones.
t-BuLi
(2.2 equiv)
N
t-BuO
N
HN
Ot-Bu
O
O
O
Ph
t-BuOLi
B
1a
A
OLi
OLi
OLi
Li
Ph
R
Ph
N
N
N
t-BuOLi
Ph
O
O
O
R–Br
E
D
C
H
O
HN
Ph
O
2a
Scheme 2 Proposed reaction mechanism
Acknowledgment
We gratefully acknowledge financial support for this research by the EC
(IEF to O.B. project: 327114-NHelMimACanL). We thank a referee for a
suggestion regarding the proposed mechanism shown in Scheme 2.
Compound 1a reacts with t-BuLi to give dilithiated in-
termediate A. Loss of t-BuOLi then gives isocyanate B which
undergoes 6-endo-trig ring closure to give intermediate C.
Benzylic deprotonation by the t-BuOLi then generates
dilithiated intermediate D which undergoes alkylation (→
E) and protonation to give the product 2a.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588348.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
To confirm the feasibility of our proposed mechanism,
compound 2d was dissolved in THF at –20 °C and either one
equivalent or two equivalents of t-BuOLi was added fol-
lowed after two hours by 3-bromo-2-methylpropene
(Scheme 3).
When one equivalent of t-BuOLi was added, a white sus-
pension was formed; after addition of the electrophile no
reaction was observed after two hours at –20 °C, but after
References and Notes
(1) (a) Macias, F. A.; Marin, D.; Oliveros-Bastidas, A.; Molinillo, J. M.
G. Nat. Prod. Rep. 2009, 26, 478. (b) Hashimoto, Y.; Shudo, K.
Phytochemistry 1996, 43, 551.
(2) Hamilton, R. H.; Bandurski, R. S.; Reusch, W. H. Cereal Chem.
1962, 39, 107.
(3) Bravo, H. R.; Lazo, W. J. Agric. Food Chem. 1996, 44, 1569.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
O. Bodero, A. C. Spivey
Letter
Synlett
(4) (a) Friebe, A.; Vilich, V.; Hennig, L.; Kluge, M.; Sicker, D. Appl.
Environ. Microbiol. 1998, 64, 2386. (b) Macchiarulo, A.;
Costantino, G.; Fringuelli, D.; Vecchiarelli, A.; Schiaffella, F.;
Fringuelli, R. Bioorg. Med. Chem. 2002, 10, 3415.
cooled at –78 °C, a solution of t-BuLi was added dropwise (1.7 M
in pentane, 0.39 mL, 0.66 mmol). The solution immediately
turned orange. It was stirred at –78 °C for 10 min, then 2 h at
–20 °C. Then the corresponding electrophile was added (0.6
mmol) and the resulting mixture was stirred for an additional 2
h at 20 °C before being quenched with H2O (5 mL). The resulting
mixture was extracted with EtOAc (3 × 10 mL) and the com-
bined organic extracts washed with H2O (20 mL) and brine (20
mL), dried over MgSO4 and filtered. The product was purified by
flash chromatography eluting with hexane–EtOAc (9:1 → 8:2).
Data for selected products (for all data, see Supporting Informa-
tion) follows.
(5) Frechette, R.; Beach, M. PCT Int Appl WO9728167 A1, 1997.
(6) (a) Dudley, D. A.; Bunker, A. M.; Chi, L.; Cody, W. L.; Holland, D.
R.; Ignasiak, D. P.; Janiczek-Dolphin, N.; McClanahan, T. B.;
Mertz, T. E.; Narasimhan, L. S.; Rapundalo, S. T.; Trautschold, J.
A.; Van Huis, C. A.; Edmunds, J. J. J. Med. Chem. 2000, 43, 4063.
(b) Huang, W.; Zhang, P.; Zuckett, J. F.; Wang, L.; Woolfrey, J.;
Song, Y.; Jia, Z. J.; Clizbe, L. A.; Su, T.; Tran, K.; Huang, B.; Wong,
P.; Sinha, U.; Park, G.; Reed, A.; Malinowski, J.; Hollenbach, S. J.;
Scarborough, R. M.; Zhu, B.-Y. Bioorg. Med. Chem. Lett. 2003, 13,
561.
(7) (a) Meguro, K.; Nishikawa, K. Eur. Patent EP0233728 A1, 1987.
(b) Powell, N. A.; Ciske, F. L.; Cai, C.; Holsworth, D. D.; Mennen,
K.; Van Huis, C. A.; Jalaie, M.; Day, J.; Mastronardi, M.;
McConnell, P.; Mochalkin, I.; Zhang, E.; Ryan, M. J.; Bryant, J.;
Collard, W.; Ferreira, S.; Gu, C.; Collins, R.; Edmunds, J. J. Bioorg.
Med. Chem. 2007, 15, 5912.
2a: mp 110–111 °C. 1H NMR (400 MHz, CDCl3): δ = 8.88 (br s, 1
H), 7.54 (d, J = 8.3 Hz, 2 H), 7.20–7.35 (m, 3 H), 7.09–7.18 (m, 1
H), 7.00 (td, J = 7.8, 1.5 Hz, 1 H), 6.90 (td, J = 7.7, 1.3 Hz, 1 H),
6.73 (dq, J = 7.9, 1.4 Hz, 1 H), 4.65–5.13 (m, 2 H), 3.21 (d, J = 14.7
Hz, 1 H), 2.84 (d, J = 14.7 Hz, 1 H), 1.81 (s, 3 H). 13C NMR (101
MHz, CDCl3): δ = 167.3, 142.9, 140.5, 139.0, 128.3, 128.0, 126.1,
125.6, 124.1, 122.4, 120.7, 117.5, 115.5, 115.4, 84.7, 46.8, 28.7,
28.3, 24.5. HRMS (ES): m/z [M + H+] calcd for C18H18NO2:
280.13318; found: 280.1335. IR: 1680, 1502, 1448, 1370, 1155,
(8) Ilaš, J.; Anderluh, P. Š.; Dolenc, M. S.; Kikelj, D. Tetrahedron 2005,
61, 7325.
1057 cm–1
.
(9) Özden, S.; Murat Öztürk, A.; Göker, H.; Altanlar, N. Farmaco
2000, 55, 715.
(10) (a) Xing, X.; Wu, J.; Feng, G.; Dai, W.-M. Tetrahedron 2006, 62,
6774. (b) Martinand-Lurin, E.; El Kaïm, L.; Grimaud, L. Tetrahe-
dron Lett. 2014, 55, 5144.
(11) Ylijoki, K. E. O.; Kundig, E. P. Chem. Commun. 2011, 47, 10608.
(12) Chen, D.; Shen, G.; Bao, W. Org. Biomol. Chem. 2009, 7, 4067.
(13) Bayly, A. R.; White, A. J. P.; Spivey, A. C. Eur. J. Org. Chem. 2013,
2013, 5566.
(14) Maggi, R.; Schlosser, M. J. Org. Chem. 1996, 61, 5430.
(15) (a) Zhou, J.; Zeng, X.-P. In Multicatalyst System in Asymmetric
Catalysis; John Wiley & Sons: New York, 2014, 633–670. (b) Zhu,
F.; Xu, P.-W.; Zhou, F.; Wang, C.-H.; Zhou, J. Org. Lett. 2015, 17,
972.
2g: mp 150–155 °C. 1H NMR (400 MHz, CDCl3): δ = 9.56 (s, 1 H),
7.56 (d, J = 6.8 Hz, 2 H), 7.22–7.36 (m, 3 H), 7.17 (d, J = 7.9 Hz, 1
H), 7.02 (td, J = 7.8, 1.4 Hz, 1 H), 6.91 (td, J = 7.8, 1.4 Hz, 1 H),
6.81 (dd, J = 7.8, 1.4 Hz, 1 H), 2.38 (dd, J = 14.5, 6.8 Hz, 1 H), 2.12
(dd, J = 14.5, 6.8 Hz, 1 H), 0.98–1.08 (m, 1 H), 0.35–0.57 (m, 2 H),
0.19–0.33 (m, 1 H), 0.00–0.08 (m, 1 H). 13C NMR (101 MHz,
CDCl3): δ = 168.2, 143.3, 139.3, 128.3, 127.9, 126.3, 125.7, 124.4,
122.2, 117.3, 115.6, 84.9, 44.6, 6.0, 4.6, 4.4. HRMS (ES): m/z
[M + H+] calcd for C18H18NO2: 280.1338; found: 280.1345, IR:
1688, 1502, 1428, 1368, 1124, 1045 cm–1
.
2h: mp 123–126 °C. 1H NMR (400 MHz, CDCl3): δ = 9.35 (s, 1 H),
8.54 (s, 1 H), 8.40–8.50 (m, 1 H), 7.58 (d, J = 12 Hz, 1 H), 7.46 (dd,
J = 6.1, 1.8 Hz, 2 H), 7.22–7.35 (m, 3 H), 7.06–7.18 (m, 2 H), 6.97
(ddd, J = 7.9, 6.1, 1.8 Hz, 1 H), 6.88 (ddd, J = 7.9, 6.1, 1.8 Hz, 1 H),
6.72 (dt, J = 7.9, 1.8 Hz, 1 H), 3.72 (dd, J = 14.1, 1.6 Hz, 1 H), 3.40
(dd, J = 14.1, 1.6 Hz, 1 H). 13C NMR (101 MHz, CDCl3): δ = 166.6,
152.1, 147.9, 142.7, 138.7, 138.0, 131.3, 128.5, 128.4, 126.1,
125.7, 124.1, 122.8, 122.6, 117.5, 115.5, 84.1, 43.0, 28.2. HRMS
(ES): m/z [M + H+] calcd for C20H17N2O2: 317.1290; found:
(16) Kinoshita, T.; Okada, S.; Park, S.-R.; Matsunaga, S.; Shibasaki, M.
Angew. Chem. Int. Ed. 2003, 42, 4680.
(17) Brindisi, M.; Gemma, S.; Alfano, G.; Kshirsagar, G.; Novellino, E.;
Campiani, G.; Butini, S. Tetrahedron Lett. 2013, 54, 5387.
(18) General Procedure; Anionic Cyclisation/Alkylation Reaction:
To a solution of the appropriate N-Boc-O-benzyl-2-aminophe-
nol (0.3 mmol) in anhyd THF (1 mL) under nitrogen atmosphere
317.1302. IR: 1682, 1502, 1448, 1372, 1128, 1031 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D