Tetrahedron Letters
Facile Construction of an Amino-1,3-Oxazine Scaffold using Burgess
Reagent Under Mild Conditions
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Kouki Fuchino , Moriyasu Masui, Shuhei Yoshida, Ken-ichi Kusakabe
Laboratory for Medicinal Chemistry Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The development of a cyclization reaction to access amino-1,3-oxazines under mild conditions is
described. The synthesis was achieved using dehydrating reagents, such as phosphorus pentoxide and
Burgess reagent. In particular, the cyclization with Burgess reagent proceeded under mild conditions
and tolerated potentially labile functional groups, such as the acetoxy group, and therefore can be used
to synthesize b-secretase (BACE1) inhibitors with a variety of amino-1,3-oxazine warheads.
Ó 2020 Elsevier Ltd. All rights reserved.
Received 5 September 2020
Revised 9 November 2020
Accepted 19 November 2020
Available online 5 December 2020
Keywords:
Amino-1,3-oxazine
Cyclization
Burgess reagent
BACE1 inhibitor
Accumulation of Ab peptides is a hallmark and causal factor of
Alzheimer’s disease (AD) [1]. b-Secretase (BACE1) is a key enzyme
responsible for producing Ab peptides. Inhibition of BACE1 has
therefore emerged as a potential disease-modifying treatment of
AD [2]. Although amidine-based compounds were identified as
potent BACE1 inhibitors, their high basicity caused high P-gp efflux
and hERG inhibitory activity [3a,b]. Our research program identi-
fied amino-1,3-oxazine derivatives, such as compounds 2–5, as
potent BACE1 inhibitors with reduced P-gp efflux and hERG activ-
ity [4]. During the course of this research, the incorporation of a
double bond in dihydro-1,3-oxaine 1 led to 1,3-oxazine 2 with a
pKa value lowered by 2.1 units, which translated into an improved
profile (Fig. 1) [4]. Herein, we disclose the detailed investigations
that led to the efficient synthesis of the amino-1,3-oxazine scaffold
using Burgess reagent.
Our effort began with the synthesis of 6-methyl-1,3-oxazine 3,
according to literature procedures (Scheme 1) [6]. Although the
yield was quite low, the method afforded key intermediate 7 via
the cyclization of thiourea 6. Compound 7 was then successfully
converted into compound 3 in 19% yield over 2 steps [5]. To access
the non-substituted oxazine 2, we next sought to prepare the cor-
responding aldehyde analogue of 6. Unfortunately, the synthesis
failed, as it prompted cyclization to the thiazine ring and not the
oxazine ring. We therefore avoided use of the thiourea intermedi-
ate; instead, urea intermediates were employed. To obtain the
amino-1,3-oxazine scaffold via the urea intermediate, we explored
reaction conditions using urea 8. Various acidic conditions were
investigated, and selected examples are shown in Table 1. Treat-
ment with acetic acid under reflux conditions did not afford the
product (Entry 1). Addition of a dehydrating agent, phosphorus
pentoxide (P2O5), successfully led to cyclization providing 1,3-oxa-
zine 9 in 26% yield along with the formation of side product 12
(Entry 2) [7]. Interestingly, increasing the amount of P2O5
improved the yield to 54%. Further exploration of dehydrating
reagents identified Burgess reagent, a mild and selective dehydrat-
ing agent for secondary and tertiary alcohols, as the optimal one,
which afforded oxazine 9 in 83% yield (Entry 5) [8a,b]. Finally,
the cyclization reaction proceeded with high yield at room temper-
ature (Entry 6).
Having identified the optimal reaction conditions, we returned
our attention to the synthesis of non-substituted 1,3-oxazine 2.
The urea containing an aldehyde moiety (10a) was subjected to
the cyclization reaction to give non-substituted oxazine 11a in
13% yield. Addition of pyridinium p-toluene sulfonate (PPTS)
slightly improved the yield to 27%. To further reduce the basicity
of 2 and 3, oxazines with a fluorine, such as 4 and 5, were designed,
and the corresponding urea intermediates 10b and 10c [4] were
subjected to the reaction using Burgess reagent and PPTS to afford
the cyclization products 11b and 11c in 41% and 62% yield, respec-
tively (Scheme 2).
The proposed reaction mechanism of the 1,3-oxazine cycliza-
tion using Burgess reagent is depicted in Scheme 3. The first step
is acid-catalyzed cyclization of the ketone group with urea A to
form intermediate C. Both Burgess reagent and phosphorus pen-
toxide could generate a small amount of acid via decomposition
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Corresponding author.
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Fuchino, Kouki
