Synthesis of nitrogen heterocycle-fused 1,2,4-benzothiadiazine-1,1-dioxide, quinazolinone, and pyrrolidinone derivatives with a guanidine joint via sequential aza-Wittig reaction/intramolecular NH-addition cyclization/nucleophilic substitution ring closur

Article abstract of DOI:10.1016/j.tet.2009.11.064

We achieved efficient synthesis of imidazo- and pyrimido[1,2-b]benzo-1,2,4-thiadiazine-1,1-dioxides by the tandem aza-Wittig reaction/intramolecular NH-nucleophilic addition/NH-nucleophilic substitution cyclization methodology, involving sulfonamide ester

Full text of DOI:10.1016/j.tet.2009.11.064

Tetrahedron 66 (2010) 653–662
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of nitrogen heterocycle-fused 1,2,4-benzothiadiazine-1,1-dioxide,
quinazolinone, and pyrrolidinone derivatives with a guanidine joint via sequential
aza-Wittig reaction/intramolecular NH-addition cyclization/nucleophilic
substitution ring closure methodology, using functionalized carbodiimides
as key intermediates
Shinsuke Hirota a, Terumi Sakai a, Nobuhide Kitamura a, Keisuke Kubokawa a, Noriki Kutsumura a,
,
Takashi Otani b, Takao Saito a
*
a Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
b Functional Elemento-Organic Chemistry Unit, Advanced Science Institute, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We achieved efficient synthesis of imidazo- and pyrimido[1,2-b]benzo-1,2,4-thiadiazine-1,1-dioxides by
the tandem aza-Wittig reaction/intramolecular NH-nucleophilic addition/NH-nucleophilic substitution
cyclization methodology, involving sulfonamide ester-containing carbodiimides as the key intermediates.
Similarly, imidazo[2,1-b]quinazolinones, imidazo[1,2-a]pyrimidinediones, and imidazo[1,2-a]imidazoli-
dinediones were also synthesized through the aza-Wittig reaction–tandem cyclization strategy. When
Received 28 October 2009
Accepted 12 November 2009
Available online 17 November 2009
homochiral (L)-alanine methyl ester was incorporated as a building block into the corresponding imi-
nophosphorane starting materials, we obtained optically active imidazo[1,2-b]benzo-1,2,4-thiadiazine
and imidazo[2,1-b]quinazolinone derivatives without any racemization through the one-pot tandem
methodology.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
exhibit antagonism activities to the chemokine CXCR2 receptor.11 In
spite of the well studied quinazolinone system, known compounds
Cyclic guanidine moieties often occur in a variety of biologically
active natural compounds such as marine alkaloids.1 Amongst the
most important cyclic guanidine representatives having a wide
range of biological activities are compounds with 2-amino-4-qui-
nazolinone cores.2 Some of these polycyclic guanidine compounds
show biological activities such as anti-tumor,3 broncholytic,4 anti-
hypertensive,5 and immunosuppressive activities.6 Interestingly,
despite the fact that all of these compounds have an identical
2-amino-4-quinazolinone structural core, they exhibit diverse bi-
ological activities. This diversity is mainly due to the attendant
contribution of the ring-fused-heterocyclic moieties in addition to
a variety of different substituents in the molecules.
In contrast, 3-amino-1,2,4-benzothiadiazine-1,1-dioxides, which
are isosteric analogs7 of 2-amino-4-quinazolinones, are also known
to possess biological activities, including potassium8 and calcium9
channel modulations and adrenergic antagonistic effects.2b,10 Fur-
thermore, this class of compounds have recently been found to
of cyclic 3-amino-1,2,4-benzothiadiazine-1,1-dioxide isosters are
still rare; hence, the development of facile and efficient methods for
preparing such attractive heterocycles is very important and
intriguing.2b,10,12
A survey of the literature shows that there are only very
limited synthetic methods to access 2-amino-4-quinazolinones/
3-amino-1,2,4-benzothiadiazine-1,1-dioxides with cyclic guanidine
joints.2b,3–6,10,12 One of the most convenient synthetic methods for
cyclic guanidines would be nucleophilic addition of a nitrogen spe-
cies to the functionalized carbodiimide carbon center. Desired
monocyclic and bicyclic guanidines can be synthesized by arbitrarily
selected cyclization reactions, as illustrated in Chart 1. These vari-
ously functionalized carbodiimides, which could be prepared pref-
erably by the aza-Wittig reaction,13 dehydration from urea, or
elimination of hydrogen sulfide from thiourea,14 undergo an initial
reaction involving the cumulene functionality viz. (1) intermolecular
nucleophilic addition of an amine (or imine) and subsequent various
types of ring-forming reactions between the acyclic guanidine ni-
trogen (N) and the available inner functional group (FG) (Eq.1),15 or
(2) intramolecular addition between a nitrogen functional group (N)
and the cumulene carbon (Eq. 2),16 to give monocyclic guanidines
* Corresponding author.
E-mail address: tsaito@rs.kagu.tus.ac.jp (T. Saito).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.064

654
S. Hirota et al. / Tetrahedron 66 (2010) 653–662
chloride 126–28 with a variety of amino acid methyl ester-hydrogen
FG
N
R'
N
chloride salts 229 in the presence of triethylamine, followed by
a Staudinger reaction30 of the resultant sulfonamide-azides 3 with
triphenylphosphine (Scheme 1, Table 1).
FG
N
1st
R'
N
cyclization
C
N
N
R
N
[1]
R
+
N
R
R"
"Monocyclic
Guanidine"
M G
N
N
R'
2nd
cyclization
: Nitrogen function (amine, imine, etc)
R1
R1
O
O
CO2Me
2
O
O
Cl
FG
FG
( )n
HClH2N
S
CO2Me
( )n
S
1st
cyclization
2nd
cyclization
N
N
N
H
N
N
N
R
N
N
N
R
[2]
[3]
Et3N / CH2Cl2
0 °C r.t.
N3
N3
C
N
"Bicyclic
Guanidine"
"Monocyclic
Guanidine" M G
R
B G
3
1
2a-4a: R1= H n = 0
2b-4b: R1= Me n = 0
2c-4c: R1= Bn n = 0
R1
O
O
S
N
CO2Me
( )n
PPh3
+
X
N
H
X
R'
NR
N
N
N
R'
X
2d-4d: R1= CH2CO2Me n = 0
2e-4e: R1= CO2Et n = 1
2f-4f: R1= H n = 1
CH2Cl2
r.t.
+
PPh3
N
H
N
H
R"
NR
N
H
C
N
4
Batzelladine A(+), D(-)
2g-4g: R1= H n = 2
Chart 1. Various tandem cyclization pathways leading to cyclic guanidines.
Scheme 1. Preparation of iminophosphoranes 4.
(MGs).13 The second cyclization of the MGs, in which the FG or R0
group is a suitable functional group reacting with the internal ni-
trogen (amino) functionality (N), leads to the formation of bicyclic
guanidines (BGs).13 Indeed, researchers have successfully applied
various types of second cyclization reactions such as nucleophilic
substitution,16g,h,j nucleophilic addition, 15i,j,t,16i,17 Michael addition,18
iodoamination,15u–w,16h and aromatic C–N coupling reaction.19
Intramolecular ring-closing metathesis of MGs via Eq. 1 was also
reported when R and R0 were alkenyl (allyl) groups.20 Pericyclic
reactions such as electrocyclization21 and [4þ2] cycloaddition22 were
also employed in an initial reaction. For example, Gin et al. demon-
strated a total synthesis of the marine alkaloid, (þ)-batzelladine A
and (ꢀ)-batzelladine D, using [4þ2] cycloaddition as a key step for
construction of the bicyclic guanidine core (Eq. 3).23 Thus, synthetic
methods for a variety of BGs have been developed by the tandem24
double cyclization methodology using a wide range of bond-forming
transformations.25
Table 1
Preparation of sulfonamidic iminophosphoranes 4
Entry
2 (DL
)
n
R1
Iminophosphorane 4
Yield a(%)
1
2
3
4
5
6
7
8
2a
2b
0
0
0
0
0
1
1
2
H
Me
Me
Bn
CH2CO2Me
CO2Et
H
H
4a
4b
88
85
87
90
92
81
86
98
b
2b
2c
2d
2e
2f
*
4b
4c
4d
4e
4f
*
2g
4g
a
Isolated overall yield of 4 from 1.
b
(
L)-Alanine methyl ester was used. Symbol denotes ‘enantiomerically pure’.
*
When the reaction of iminophosphorane 4b thus derived from
sulfonyl chloride 1þ alanine ester 2b (R1¼Me) with phenyl iso-
cyanate 5a (R2¼Ph) was performed at room temperature in
dichloromethane, the reaction proceeded slowly and required 32 h
to produce imidazo[1,2-b]-benzo-1,2,4-thiadiazine-1,1-dioxide
9a2b,10,12a,b,e in 92% yield (Scheme 2, Table 2, entry 7). When the same
reaction was performed at 80 ꢁC in benzene, the reaction time was
shortened by 2 h yet maintaining a high yield (93%) of 9a (entry 8).
Similarly, aromatic isocyanates 5b–d reacted with 4b at 80 ꢁC for
2.5–3.5 h to give 9b–d in 92–96% yields (entries 9–11). With aliphatic
isocyanates 5e–g (R1¼n-Pr, benzyl, and allyl), the reaction required
a higher temperature (110 ꢁC) in toluene to be completed within 6 h
affording 91–99% yields of 9e–g (entries 12–14). Similarly, the imi-
nophosphoranes 4a and 4c derived from glycine ester (R1¼H) and
phenylalanine ester (R1¼Bn) also reacted with various aromatic and
aliphatic isocyanates to give imidazobenzothiadiazines 8 and 10 in
good to high yields (entries 1–6 and 15–20). We did not observe any
marked substituent effects of the aromatic isocyanates (5a–d) on the
overall reaction rates except for the case of 5d with a MeO group,
In our previous report,26 we demonstrated the tandem cycli-
zation methodology using 2-(N-alkenylsulfamoyl)phenylcarbodii-
mides as the key intermediates for the synthesis of a variety of
diazaheterocyclic ring-fused 1,2,4-benzothiadiazine-1,1-dioxides,
where we employed iodocyclization and hydroamination with
Hg(II)–NaBH4 (aminomercuration–demercuration) as the second
ring-forming reaction between alkenyl and amine groups after the
initial cyclization by internal nucleophilic sulfonamide–NH-addi-
tion onto the heterocumulene carbon.
In this paper, we report the novel and facile synthesis of cyclic
guanidines, five- to six-membered diazaheterocyclic ring-fused
1,2,4-benzothiadiazine-1,1-dioxides I, quinazolinones II, and imid-
azolidinones and pyrimidinones III (Fig. 1) via the tandem24 aza-
Wittig reaction/double cyclizations methodology.27
R1
R1
O
O
N
R1
O
N
II
O
S
N
N
N
n
n
O
R1
N
R1
O
O
N
O
N
N
O
O
N
H
N
O
R2NCO
5
S
N
R2
R2
R2
S
N
CO2Me
O
N
5a: R2= Ph
5b: R2= p-Tol
5c: R2= p-ClPh
5d: R2= p-MeOPh
5e: n-Pr
PPh3
n = 0,1
III n = 0,1
I
R2
4a: R1=H
4b: R1=Me
4c: R1=Bn
8: R1=H
9: R1=Me
10: R1=Bn
Figure 1. Targeted cyclic guanidines.
2. Results and discussion
5f: Bn
5g: Allyl
Forthesynthesisofthefirsttargetheterocycles, benzothiadiazine-
1,1-dioxide derivatives I, we prepared the pre-requisite iminophos-
phoranes 4 in high yields by the reaction of o-azidobenzenesulfonyl
Scheme 2. Tandem aza-Wittig/double cyclizations of 4 producing imidazobenzothia-
diazine-1,1-oxides 8–10.

S. Hirota et al. / Tetrahedron 66 (2010) 653–662
655
Table 2
Table 3
Synthesis of imidazo[1,2-b]benzo-1,2,4-thiadiazine-1,1-dioxides 8–10 via sequential
Synthesis of imidazo[1,2-b]benzo-1,2,4-thiadiazine-1,1-dioxides 13 via the tandem
aza-Wittig/tandem cyclization methodology
cyclization with high regioselectivity
R2
Product
Yield a(%)
Entry
4
R1
R2
Tempa (ꢁC)
Time (h)
8–10
Yieldb (%)
Entry
Isocyanate
1
2
3
4
5
6
7
4a
4a
4a
4a
4a
4a
4b
H
H
H
H
H
H
Me
Ph
80
80
80
80
110
110
rt
4
4.5
5
6
3
8a
8b
8c
8d
8e
8f
88
87
83
86
85
92
92
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
Ph
13a
13b
13c
13d
13e
13f
98
88
85
85
80
88
p-Tol
p-ClPh
p-MeOPh
n-Pr
Bn
Ph
p-Tol
p-ClPh
p-MeOPh
n-Pr
1
32
Bn
9a
a
Isolated yield of 13 from 4dþ5 in a one-pot reaction.
8
9
4b
4b
4b
4b
4b
4b
4b
Me
Me
Me
Me
Me
Me
Me
Ph
80
80
80
80
110
110
110
2
9a
9b
9c
9d
9e
9f
93
92
94
96
95
99
91
p-Tol
p-ClPh
p-MeOPh
n-Pr
Bn
Allyl
2.5
2.5
3.5
5.5
5
10
11
12
13
14
1–5 h gave single cyclization products in good yields (Table 3),
which were assigned as imidazobenzothiadiazine-1,1-dioxides 13
formed via the cyclization of 12 in a 5-exo-trig mode instead of
pyrimidine-fused 14 via 6-exo-trig mode cyclization.31 In order to
confirm the structures of 13 and the cyclization mode, the reaction
of 5b with iminophosphorane 4e derived from aspartic methyl ethyl
ester was examined (Scheme 5). As a result, the single cyclization
4
9g
15
16
17
18
19
20
4c
4c
4c
4c
4c
4c
Bn
Bn
Bn
Bn
Bn
Bn
Ph
80
80
80
80
110
110
1
1
1
4
5.5
6
10a
10b
10c
10d
10e
10f
97
96
92
92
95
99
p-Tol
p-ClPh
p-MeOPh
n-Pr
product 13b was exclusively obtained in 98% yield and its 1H and 13
C
NMR and IR spectra clearly showed the existence of a methyl ester
group. We did not detect the pyrimidine-fused compound 14b (Et)
by 6-exo-trig mode cyclization. Thus, 5-exo-trig mode cyclization of
12 was preferred over 6-exo-trig mode, although the both modes are
‘allowed’ according to the Baldwin rule.31
Bn
a
rt in CH2Cl2; 80 ꢁC in (CH2Cl)2 or benzene; 110 ꢁC in toluene.
Isolated yield.
b
which required longer reaction times (entries 4, 11, and 18). The
functionalized carbodiimide 6 was the most probable intermediate
formed by the initial aza-Wittig reaction of the iminophosphorane 4
with the isocyanate 5 (Scheme 3).13,16f Subsequent intramolecular
nucleophilic addition of NH to the cumulene carbon of 6 to form the
monocyclic guanidines 7,26–28 followed by intramolecular nucleo-
philic substitution ring closure, provided the pre-meditated bicyclic
guanidine compounds 8–10 as the final products.16g,h,j,26,27
Next, we examined the reaction of isocyanates 5 with imino-
phosphorane 4f, which had a b-alanine methyl ester group in which
6-exo-trig mode cyclization (16/17) should be involved to yield py-
rimidine-fused compounds 17 (Scheme 6). When we reacted 4f with
isocyanates 5a–f in toluene under gentle refluxing (110 ꢁC) for 2–15 h
(Method A), we obtainedthe initial cyclizationproducts16a–f ingood
yields (Table 4). Thereactionseveninthepresenceofadditivessuchas
Et3N, DBU, silica gel, and p-toluenesulfonic acid as well as at higher
R1
O
R1
O
R1
O
R1
O
R2NCO
5
O
O
O
O
S
-MeOH
S
N
S
N
S
N
N
CO2Me
N
N
CO2Me
NH
R2
N
CO2Me
O
H
H
N C N R2
N
PPh3
R2
8-10
4
7
6
Scheme 3. Tandem aza-Wittig reaction/nucleophilic NH-addition cyclization/nucleophilic NH-substitution cyclization methodology via functionalized carbodiimides 6 producing
imidazobenzothiadiazine-1,1-oxides 8–10.
Next, we examined the tandem reaction using aspartic dimethyl
ester-derived iminophosphorane 4d (Scheme 4). The reaction of 4d
with aromatic and aliphatic isocyanate 5 in toluene at 110 ꢁC for
temperatures (e.g., 143 ꢁC in xylene) afforded compounds 16a–f in
variable amounts, but the double cyclization products 17a–f were not
detected. These observations are consistent with the facts that the 6-
exo-trig mode of the cyclization 12/14 does not easily proceed
compared to the 5-exo-trig mode cyclization of 7/8–10 and 12/13.
CO2Me
R2NCO
5
CO2Me
CO2Me
O
O
CO2Me
O
O
N
H
p-TolNCO
CO2Me
CO2Et
S
N
S
O
O
N
CO2Me
O
O
5b
H
S
N
S
N
Toluene
110 °C
PPh3
N
CO2Et
N C N R2
N
H
Toluene
110 °C, 3h
4d
11
NH
p-Tol
12b (Et)
PPh3
CO2Me
O
O
O
O
N
4e
5-Exo-Trig
S
N
6-Exo-Trig
5-Exo-Trig
N
CO2Me
R2
CO2Me
O
O
N
13
S
N
CO2Et
CO2Me
O
CO2Me
NH
R2
O
O
O
O
O
S
N
S
S
N
N
N
N
N
O
N
N
N
O
12
R2
6-Exo-Trig
p-Tol
13b (98% yield)
Scheme 5. Regioselectivity of 5-exo-trig vs 6-exo-trig mode cyclizations giving 13b or 14b.
p-Tol
14
14b (Et)
Scheme 4. Tandem aza-Wittig/double cyclizations reaction with high regioselectivity
to give imidazobenzothiadiazine-1,1-oxides 13.

656
S. Hirota et al. / Tetrahedron 66 (2010) 653–662
R2NCO
5
The diazaheterocyclic ring-fused benzo-1,2,4-thiadiazine-
O
O
O
O
1,1-dioxides of type I thus obtained had a substituent (R2) that
originated from its starting isocyanate. In order to synthesize such
benzo-1,2,4-thiadiazine-1,1-dioxide derivatives of the unsub-
stituted NH group (R2¼H) in this position,36 amino deprotection
cleavage of an allyl group or a benzyl group in the corresponding
compounds was performed. Although the cleavage of the allyl group
in compound 9g using Pd-[Ph3P]4/dimethylbarbituric acid37 was
unsuccessful, catalytic hydrogenolysis37 of N-benzyl-substituted
compounds (8f–10f, 13f, and 17f) gave the corresponding depro-
tected compounds 20a–e quantitatively (Scheme 8).
S
N
CO2Me
S
CO2Me
N
N
H
H
C N R2
N PPh3
Method A or
Method B
4f
15
O
O
O
O
N
S
N
S
N
CO2Me
N
N
O
NH
R2
R2
16
R1
17
R1
O
O
O
O
N
H2 / Pd-C
S
N
Scheme 6. Tandem aza-Wittig/cyclization of 4f. Method A: 110 ꢁC in toluene, 2–15 h;
Method B: 80 ꢁC in (CH2Cl)2, followed by addition of TiCl4 (5.0 equiv) in one pot.
S
N
( )n
N
( )n
MeOH-THF
r.t., 1-4 h
> 99% yield
N
H
O
N
Bn
O
a: R1= H, n = 0
20
Table 4
8f, 9f, 10f,
b: R1= Me, n = 0
c: R1= Bn, n = 0
Synthesis of benzo-1,2,4-thiadiazine-1,1-dioxides 16 via the tandem aza-Wittig/cy-
13f, and 17f
clization reaction (Method A)
d: R1= CH2CO2Me, n = 0
e: R1= H, n = 1
Entry
Isocyanate
R2
Time (h)
Product
Yield a(%)
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
Ph
3.5
2
2.5
2.5
15
4.5
16a
16b
16c
16d
16e
16f
81
82
80
87
83
93
Scheme 8. Preparation of N-unsubstituted compounds 20.
p-Tol
p-ClPh
p-MeOPh
n-Pr
The advantages of introducing amino acids as building blocks
into target molecules in organic synthesis include the availability of
amino acids possessing diverse substituents, their versatile re-
activities, and their utility as a chiral pool in asymmetric synthe-
sis.38 We therefore examined whether this one-pot tandem
methodology can be applicable to the non-racemic, asymmetric
heterocycle synthesis. When the optically pure iminophosphorane
)-alanine methyl ester HCl salt (2b ),
was allowed to react with p-tolyl isocyanate (5b) in toluene at room
temperature for 27 h or even at 110 ꢁC for 3 h, we obtained enan-
Bn
a
Isolated yield of 16 from 4fþ5 in a one-pot reaction.
However, during our search for an effective additive to the 6-exo-trig
mode cyclization 16/17,32–34 we fortunately found that in the
presence of TiCl4 (5.0 equiv),35 compound 16a was converted to the
cyclization product 17a (99% yield) after refluxing in CH2Cl2 for 5 h.
Therefore, we performed the one-pot tandem reaction starting from
the aza-Wittig reaction of iminophosphorane 4f with isocyanates 5a–
f and the initial cyclization at 80 ꢁC in (CH2Cl)2 followed by the ami-
dation cyclization caused by subsequent addition of TiCl4 (5.0 equiv)
in one pot under the same conditions (see Table 5). As expected,
4b
*
(>99% ee) derived from (
L
*
tiomerically pure product 9b
in 88% and 72% yields, respectively (Scheme 9).
*
(>99% ee) without any racemization
O
O
O
O
p-Tol-NCO
5b
S
S
N
CO2Me
pyrimido[1,2-b]benzo-1,2,4-thiadiazine-1,1-dioxides
17
were
N
CO2Me
H
H
obtained in good yields.
N C N p-Tol
6b*
N PPh3
4b* (>99%ee)
Table 5
Synthesis of pyrimido[1,2-b]benzo-1,2,4-thiadiazine-1,1-dioxides 17 via the tandem
aza-Wittig/double cyclization one-pot reaction (Method B)
O
O
N
O
O
N
S
N
S
N
R2
Time (h)
Product
Yield a(%)
CO2Me
NH
p-Tol
Entry
Isocyanate
O
4/16b
16/17
N
p-Tol
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
Ph
3
4.5
5
5
10
9.5
5
4.5
3
1
3
17a
17b
17c
17d
17e
17f
72
82
72
72
81
72
9b*
7b*
p-Tol
p-ClPh
p-MeOPh
n-Pr
Scheme 9. Preparation of optically active 9b
*
via the one-pot tandem methodology.
Bn
3
We next applied this tandem methodology tothe synthesis of the
guanidine-jointing ring-fused heterocycles of types II and III (Fig.1).
The iminophosphoranes 22 were prepared in good yields via the
amidation of amino acid methyl esters 2 with o-azidobenzoyl
chloride,39 followed by the Staudinger reaction of the azide 21 with
triphenylphosphine according to the literature (Scheme 10).40
The reaction of iminophosphoranes 22a–c with p-tolyl iso-
cyanate (5b) in toluene at 110 ꢁC for 1–6 h produced imidazoqui-
nazolines 25a, c, e in good yields (Scheme 11, Table 6, entries 1, 3,
and 5).41 In contrast, when we performed the reaction with benzyl
isocyanate 5f under similar reaction conditions, the reaction step
22/24 smoothly proceeded but the reaction step 24/25 was
reluctant to yield 25b, d, f (entries 2, 4, and 6). After we ascertained
the consumption of 22 and formation of 24 by TLC and then added
powdered K2CO3 to the reaction upon heating for another 0.5–1.5 h
under the same reaction conditions, we obtained compounds 25b,
a
Isolated yield of 17 from 4fþ5 in a one-pot reaction.
b
Addition of TiCl4 after consumption of 4f checked by TLC.
However, similar treatment of 18, which had one more longer
methylene chainthan16 withTiCl4 (5.0 equiv), didnotgivediazepane
ring-fused benzo-1,2,4-thiadiazine-1,1-dioxide 19 (Scheme 7).
O
O
N
O
O
N
5.0 equiv.
TiCl4
S
N
S
N
CO2Me
NH
p-Tolyl
N
(CH2Cl)2
80 °C
O
p-Tolyl
10 h
18
19
Scheme 7.

S. Hirota et al. / Tetrahedron 66 (2010) 653–662
657
R1
O
O
O
R1
CO2Me
p-Tol-NCO
5b
O
C
CO2Me
HClH2N
N
H
CO2Me
N
CO2Me
N
H
2
Cl
H
N C N p-Tol
N PPh3
22b* (>99%ee)
Et3N / CH2Cl2
N3
N3
0 °C
r.t.
23c*
21
O
R1
CO2Me
PPh3
O
O
2a, 21a, 22a: R1= H
PPh3
N
H
N
O
N
CO2Me
NH
p-Tol
2b, 21b, 22b: R1= Me
2d, 21c, 22c: R1= CH2CO2Me
CH2Cl2
r.t.
N
N
N
N
p-Tol
22
25c*
24c*
Scheme 10. Preparation of iminophosphoranes 22.
(>99% ee, 98%)
Scheme 12. Preparation of optically active 25c via the one-pot tandem methodology.
*
d, f in good yields (entries 2, 4, and 6). In the reaction of 22c derived
from aspartic dimethyl ester involving cyclization of 24e, f, the 5-
exo-trig cyclization mode also dominated the 6-exo-trig mode,
similar to the reaction of 4d (Scheme 4 and Table 3). The greater
reluctance for the cyclization 24/25 of 24b, d, f (R2¼Bn) than that
of 24a, c, e (R2¼p-tolyl) could be ascribed mainly to the steric
hindrance between the NHR2 group and the CO2Me group rather
than to the factor of nucleophilicity of the NHR2 group because the
nucleophilicity of the NHBn group would be stronger than that of
the NHTol-p group.42 Thus, obtained 25b, d, f bearing a benzyl
group each were debenzylated by hydrogenolysis to give the N1-
unsubstituted 26a–c in excellent yields (Table 6).
Fortunately, however, the formation of 33b (R1¼Me) was realized,
albeit in low yield, by heating 32b in the presence of silica gel at
140 ꢁC in Ph2O. Furthermore, we found that removing the formed
EtOH under a reduced pressure (19 mmHg) raised the yield of 33b to
46% (entry 2). Similarly, imidazoimidazolidinediones 33c and 33d
(R1¼Me) were obtained in 58 and 56% yields (entries 3 and 4), re-
spectively. In the case of 32e, which possessed two ester groups in
a molecule, compounds 34 and 35 of both cyclization modes, 5-exo-
trig and 6-exo-trig, formed with the latter predominating (entry 5). As
the bulkiness of the substituent R1 increases (H<Me<CO2Et), the
reactivity of compounds 32 for the cyclization and the yield increase.
H2 / Pd-C
R1
CO2Me
R1
CO2Me
R1
O
R1
O
O
R1
CO2Me
O
O
R2NCO
5
MeOH-THF
r.t., overnight
N
N
N
H
N
H
N
O
O
N
H
N
N
N C N R2
N
for R2 = Bn
Toluene
110 °C
N
N
NH
R2
PPh3
R2
22a: R1=H
23
24
25
26
5b: R2=p-Tol
5f: R2=Bn
22b: R1=Me
22c: R1=CH2CO2Me
Scheme 11. Tandem aza-Wittig/double cyclizations of 22 producing imidazoquinazolinones 25 and their hydrogenolysis to afford 26.
Table 6
Synthesis of imidazo[2,1-b]quinazolin-4-ones 25/26 via the tandem aza-Wittig/double cyclization one-pot reaction and hydrogenolysis
Entry
Iminophosphorane
R1
R2
Time (h)
Product
Yield (%)
Product
Yield (%)
1
2
3
4
5
6
22a
22a
22b
22b
22c
22c
H
H
Me
Me
CH2CO2Me
CH2CO2Me
p-Tol
Bn
p-Tol
Bn
p-Tol
Bn
5
25a
25b
25c
25d
25e
25f
80
80
97
80
81
70
d
d
92
d
91
d
96
1.5þ1.5a
1
26a
d
6.5þ1.5a
6
26b
d
1.5þ0.5a
26c
a
In the presence of K2CO3 (powder, 1 equiv).
The optically pure iminophosphorane 22b
from ( )-alanine methyl ester HCl salt (2b
*
(>99% ee) derived
This is consistent with the known ‘substituent effect (facilitated
transition or reactive rotamer).’44
L
*
) reacted with 5b at
in 98% yield
110 ꢁC for 1 h to furnish the imidazoquinazoline 25c
*
with >99% ee even at the higher temperature of 110 ꢁC without any
racemization (Scheme 12).
R1
R1
CO2Et
O
O
HClH2N CO2Et
27
The aliphatic azides 29 were prepared via the amidation of amino
acid ethyl ester HCl salts 27 with a-chloro-acetyl chloride followed by
N
H
Cl
Cl
Cl
K2CO3 / CH2Cl2
the azidation of the formed amides 28 (Scheme 13). Thus, obtained
azides 29 underwent the Staudinger reaction with triphenylphos-
phine to yield the aliphatic iminophosphoranes 30 (Scheme 14). As
the iminophosphoranes 30 were too labile to allow isolation (as they
were apt to hydrolyze), we performed the aza-Wittig reaction with
isocyanates 5 in one pot by slow dropwise addition of 5 to produce
the initial cyclization products, imidazolinones 32 in 80–91% yields
(Table 7). Upon heating in one pot at 80 ꢁC or at a higher temperature
(210 ꢁC), or even in the presence of silica gel, p-TsOH, TiCl4, Et3N, or
DBU, compound 32a (R1¼H) did not undergo the second cyclization
to give the expected imidazoimidazolidinedione 33a (entry 1).43
28
-20 °C
0 °C, 6 h
R1
O
NaN3 / NaI
N
H
CO2Et
DMF, r.t.
1 week
N3
29a: R1= H, 81%
29b: R1= Me, 73%
29c: R1= CH2CO2Et, 71%
Scheme 13. Preparation of azides 29.

658
S. Hirota et al. / Tetrahedron 66 (2010) 653–662
spectroscopy, and CDCl3 (
d
¼77.0) or DMSO-d6 (
d
¼39.7) for 13C NMR
R1
CO2Et
R1
CO2Et
O
O
R2NCO
r.t.,3 h
5
PPh3
spectroscopy. Mass spectra were measured on a Bruker Daltonics
microTOF, a Hitachi double-focusing M-80B, or a JEOL JMS-SX 102
spectrometer. Elemental analyses were performed with a YANACO
CHN-CODER MT-6 model analyzer. Column chromatography was
conducted on silica gel (Kanto Chemical Co. or Merck Co. Ltd).
Enantiomeric excess values were determined by chiral HPLC
measurement using a Dicel Chiralpak AD column on a Millipore-
WatersTM 996. Optical rotations were recorded on a Nippon Bunko
Model DIP-370 digital polarimeter and are reported in units of
10ꢀ1 deg cm2 gꢀ1. All reactions were performed under an argon
atmosphere except for hydrogenolysis.
N
H
N
H
MS4A
N3
PPh3
Benzene
N
0
r.t.
°C
29
30
For
R1
CO2Et
R1
O
O
Me
O
R1= Me
N
H
N
N
CO2Et
O
Silica gel
N C N R2
N
N
N
NH
R2
140 °C, Ph2O
19 mmHg
R2
31
32
33
Silica gel
140 °C, Ph2O
19 mmHg
For
R1=CH2CO2Et
4.2. Typical procedurefor preparation of sulfonamidic azides 3
CO2Et
CO2Et
O
O
N
A solution of o-azidobenzenesulfonyl chloride 126–28 (500 mg,
2.30 mmol) in CH2Cl2 (3 mL) was dropwise added to a mixture of
alanine methyl ester hydrochloride salt (320 mg, 2.30 mmol) and
Et3N (0.95 mL, 6.90 mmol) in CH2Cl2 (3 mL) at 0 ꢁC. The reaction
mixture was warmed to room temperature with stirring for 4 h and
then quenched with saturated aqueous NH4Cl. The organic layer
was separated, and the aqueous layer was extracted with CH2Cl2
(20 mLꢂ2). The combined organic extracts were washed with wa-
ter and brine, dried over MgSO4, and then concentrated under re-
duced pressure. The residue was purified by silica gel column
chromatography with EtOAc/hexane (1:2) as the eluent to yield 3b
(600 mg, 91%) as brown oil.
N
O
6-Exo-Trig
5-Exo-Trig
N
N
N
O
N
R2
R2
35
Scheme 14. Synthesis of bicyclic guanidines 33–35.
34
Table 7
Synthesis of imidazo[1,2-a]imidazolidinediones 33/34 and imidazo[1,2-a]pyr-
imidinediones 35 via the tandem aza-Wittig/double cyclization reaction
Entry R1
R2
Product Yield (%) Product Time (h) Yield (%)
1
2
3
4
5
H
Ph
Ph
32a
32b
80
90
83
91
91
33a
33b
33c
33d
34, 35
d
4
6
6
4
da
4.2.1. Methyl
2-{[(2-azidophenyl)sulfonyl]amino}propanoate
Me
Me
Me
46
58
56
(3b). Brown oil; 1H NMR (500 MHz, CDCl3)
d
1.40 (d, J¼7.2 Hz, 3H),
p-Tol 32c
p-ClPh 32d
3.51 (s, 3H), 4.04 (dq, J¼7.2, 8.0 Hz, 1H), 6.03 (d, J¼8.0 Hz, 1H), 7.24
(ddd, J¼0.8, 7.7, 7.7 Hz, 1H), 7.31 (dd, J¼0.5, 8.0 Hz, 1H), 7.61 (ddd,
J¼1.5, 7.8, 7.9 Hz, 1H), 7.93 (dd, J¼1.3, 7.9 Hz, 1H); 13C NMR
CH2CO2Et Ph
32e
28, 44 (72)b
a
No cyclization product was obtained.
In parentheses, total yield of 34þ35.
b
(125 MHz, CDCl3)
d 19.08 (CH3), 51.44 (CH3), 52.06 (CH), 119.26
(CH), 124.18 (CH), 129.46 (C), 129.56 (CH), 133.79 (CH), 137.68 (C),
171.82 (C). IR (KBr): 3293, 2136, 1743, 1465, 1342, 1126, 1064,
763 cmꢀ1. Anal. Calcd for C10H12N4O4S: C, 42.25; H, 4.25; N, 19.71.
Found: C, 42.63; H, 4.44; N, 19.77.
3. Conclusion
In conclusion, we have developed a new, facile, and practical
one-pot synthetic method for diazaheterocyclic ring-fused 1,2,4-
4.3. Typical procedure for preparation of sulfonamidic
iminophosphoranes 4 (Table 1, entry 2)
benzothiadiazine-1,1-dioxides
I
via the tandem aza-Wittig
reaction/intramolecular NH-nucleophilic addition/NH-nucleophilic
substitution cyclization, mediated by the sulfonamide ester–
carbodiimide bifunctions. The advantages of this methodology are
that it is simple, and it produces high yields of the target com-
pounds, owing to easiness and efficiency of the procedure based on
the one-pot reaction and tandem sequences and to the diversity,
versatility, and utility/chirality of the targeted molecules based on
the characteristics of the amino acid and isocyanate reactants. We
have extended this methodology to the synthesis of diaza-ring-
fused derivatives of quinazolinones II and imidazolidinones and
pyrimidinones III.
Triphenylphosphine (450 mg, 1.70 mmol) was added to a solu-
tion of 3b (440 mg, 1.55 mmol) in CH2Cl2 (7 mL). The reaction
mixture was stirred at room temperature for 7 h and then con-
centrated under reduced pressure. The residue was purified by
silica gel column chromatography with CH2Cl2 as the eluent fol-
lowed by recrystallization from CH2Cl2/hexane to yield 4b (740 mg,
93%) as colorless crystals.
4.3.1. Methyl
sulfonyl)amino]propanoate (4b). Colorless crystals; mp 155.7–
156.8 ꢁC; 1H NMR (500 MHz, CDCl3)
2-[({2-[(triphenylphosphoranylidene)amino]phenyl}
d
1.24 (d, J¼7.0 Hz, 3H), 3.32
4. Experimental
4.1. General
(s, 3H), 3.97 (dq, J¼6.7, 7.0 Hz, 1H), 6.46 (d, J¼8.0 Hz, 1H), 6.62
(dd, J¼7.3, 7.6 Hz, 1H), 6.94–7.02 (m, 1H), 7.41–7.49 (m, 6H), 7.50–
7.57 (m, 4H), 7.76–7.89 (m, 7H); 13C NMR (125 MHz, CDCl3)
d
19.00 (CH3), 51.61 (CH3), 51.89 (CH), 115.84 (CH), 121.85 (d,
All melting points were determined on a Yanaco melting point
apparatus and are uncorrected. Infrared spectra were recorded on
3JP,C¼12.4 Hz, CH), 128.43 (d, 4JP,C¼1.5 Hz, CH), 128.72
3
1
(d, JP,C¼12.7 Hz,6CH), 128.97 (d, JP,C¼100.3 Hz, 3C), 130.71 (d,
a Hitachi 270-30 or a Horiba FT-710 spectrophotometer. 1H and 13
C
2JP,C¼24.0 Hz, C), 132.06 (d, 4J
¼2.0 Hz, 3CH), 132.28 (d,
P,C
NMR spectral data were obtained with a Bruker AV 600, a JEOL JNM-
EX 500, a JEOL JNM-LA 400, a Bruker DPX 300, a JEOL JNM-EX 300, or
2JP,C¼10.3 Hz, 6CH), 132.46 (CH), 149.09 (C), 172.07 (C). IR (KBr):
1743, 1581, 1465, 1342, 1157, 1110, 1049, 755, 717, 524 cmꢀ1
.
a JEOL JNM-EX 270 instrument. Chemical shifts (
d
) are quoted in
HRMS-ESI (m/z): [MþNa]þ calcd for C28H27N2NaO4PS, 541.1321;
parts per million using tetramethylsilane (
d
¼0) for 1H NMR
found 541.1309.

S. Hirota et al. / Tetrahedron 66 (2010) 653–662
659
4.4. Typical procedure for tandem aza-Wittig reaction/double
cyclization reaction from sulfonamidic iminophosphoranes
4a–e to produce imidazo[1,2-b][1,2,4]benzothiadiazine-5,5-
dioxides 8–10 and 13 (Table 2, entry 11)
which was then heated at 80 ꢁC for 4.5 h. After being cooled to
room temperature, the reaction mixture was quenched with satu-
rated aqueous NaHCO3 and extracted with CH2Cl2 (30 mLꢂ2). The
combined organic extracts were washed with water and brine,
dried over MgSO4, and then concentrated under reduced pressure.
The residue was purified by silica gel column chromatography with
EtOAc/hexane (1:2) as the eluent followed by recrystallization from
CH2Cl2/hexane to yield 17b (54 mg, 82%) as colorless needles.
p-Methoxyphenyl isocyanate (5d, 0.051 mL, 0.386 mmol) was
added to a solution of 4b (200 mg, 0.386 mmol) in benzene (13 mL)
with stirring and then the reaction mixture was heated at 80 ꢁC for
3.5 h. After being cooled to room temperature, the reaction mixture
was concentrated under reduced pressure. The residue was purified
by silica gel column chromatography with EtOAc/hexane (1:2) as
the eluent followed by recrystallization from CH2Cl2/hexane to
yield 9d (132 mg, 96%) as colorless needles. The enantiomeric ex-
4.6.1. 1-(4-Methylphenyl)-3,4-dihydropyrimido[1,2-b][1,2,4]benzo-
thiadiazin-2(1H)-one 6,6-dioxide (17b). Colorless needles; mp 267–
268 ꢁC; 1H NMR (500 MHz, CDCl3)
d 2.43 (s, 3H), 3.06–3.16 (m, 2H),
4.17–4.30 (m, 2H), 7.11 (d, J¼8.3 Hz, 2H), 7.15–7.22 (m, 1H), 7.26–
cess of 9b was determined by HPLC using a chiral column (column:
*
7.38 (m, 3H), 7.48–7.57 (m, 1H), 7.83 (dd, J¼1.5, 7.9 Hz, 1H); 13C
Dicel Chiralpak AD, mobile phase: hexane/2-propanol 90/10, flow
rate:0.9 mL/min).
NMR (75 MHz, CDCl3) d 21.38 (CH3), 33.22 (CH2), 35.63 (CH2),
121.37 (CH), 124.79 (C), 125.62 (CH), 127.82 (CH), 128.55 (2CH),
129.00 (2CH), 132.84 (C), 133.84 (CH), 138.57 (C), 142.02 (C), 145.34
4.4.1. 1-(4-Methoxyphenyl)-3-methyl-1H-imidazo[1,2-b][1,2,4]ben-
(C), 167.33 (C). IR (KBr): 1720, 1565, 1511, 1465, 1334, 1180 cmꢀ1
.
zothiadiazin-2(3H)-one 5,5-dioxide (9d). Colorless needles; mp
Anal. Calcd for C17H15N3O3S: C, 59.81; H, 4.43; N, 12.31. Found: C,
60.11; H, 4.51; N, 12.26.
184–185 ꢁC; 1H NMR (500 MHz, CDCl3)
d
1.86 (d, J¼7.0 Hz, 3H),
3.86 (s, 3H), 5.03 (q, J¼7.0 Hz, 1H), 7.04 (d, J¼8.9 Hz, 2H), 7.34–
7.39 (m, 4H), 7.61 (ddd, J¼1.4, 7.8, 8.1 Hz, 1H), 7.92 (dd, J¼1.4,
4.7. Typical procedure for hydrogenolysis of N-
benzylimidazo/pyrimido[1,2-b][1,2,4]benzothiadiazine-5,5/
6,6-dioxides 8f, 9f, 10f, 13f and 17f to produce N1-
unsubstituted compounds 20
8.3 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 17.59 (CH3), 53.62 (CH),
55.50 (CH3), 114.59 (2CH), 122.05 (CH), 123.31 (C), 125.63 (CH),
125.87 (C), 127.48 (CH), 128.36 (2CH), 134.35 (CH), 142.38 (C),
148.74 (C), 159.93 (C), 169.92 (C). IR (KBr): 1766, 1635, 1581, 1511,
1457, 1334, 1303, 1257, 1180, 1133, 1025, 779, 586 cmꢀ1. Anal.
Calcd for C17H15N3O4S: C, 57.13; H, 4.23; N, 11.76. Found: C, 57.00;
H, 4.27; N, 11.73.
A
solution of imidazobenzothiadiazine dioxide 8f (50 mg,
0.15 mmol) in THF/MeOH (3 mL, v/v¼1/2) in the presence of palla-
dium on carbon (10%, 50 mg) was stirred vigorously under a hydro-
gen atmosphere at room temperature for 1 h. The reaction mixture
was filtered through Celite and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography with EtOAc as the eluent to yield 20a (37 mg,
quant.) as colorless solid.
4.5. Typical procedure for tandem aza-Wittig reaction/
cyclization reaction from sulfonamidic iminophosphorane 4f
to produce benzo-1,2,4-thiadiazine-1,1-dioxides 16 (Method A)
(Table 4, entry 3)
p-Chlorophenyl isocyanate (5c, 0.081 mL, 0.64 mmol) was
added to a solution of 4f (300 mg, 0.58 mmol) in toluene (10 mL)
with stirring and then the mixture was heated at 110 ꢁC for 2.5 h.
After being cooled to room temperature, the reaction mixture was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography with EtOAc/hexane (1:2) as the
eluent followed by recrystallization from CH2Cl2/hexane to yield
16c (182 mg, 80%) as colorless crystals.
4.7.1. 1H-Imidazo[1,2-b][1,2,4]benzothiadiazin-2(3H)-one 5,5-dioxide
(20a). Colorless solid; mp (sublim.) 247–249 ꢁC; 1H NMR
(500 MHz, DMSO-d6)
J¼7.9, 7.3 Hz, 1H), 7.96 (d, J¼7.9 Hz, 1H), one signal (NH) missing;
13C NMR (125 MHz, DMSO-d6)
45.48 (CH2), 122.10 (CH), 124.49
d 4.59 (s, 2H), 7.33–7.50 (m, 2H), 7.74 (dd,
d
(C), 125.21 (CH), 125.90 (CH), 134.80 (CH), 142.21 (C), 169.75 (C), one
signal (C) missing. IR (KBr): 2761, 2699, 1766, 1681, 1581, 1473, 1334,
1211, 1203, 1187, 763, 586 cmꢀ1. HRMS-ESI (m/z): [MþNa]þ calcd for
C9H7N3NaO3S, 260.0100; found 260.0101.
4.5.1. Methyl 3-{3-[(4-chlorophenyl)amino]-1,1-dioxido-2H-1,2,4-ben-
zothiadiazin-2-yl}propanoate
(16c). Colorless
crystals;
mp
4.8. Typical procedure for preparation of iminophosphoranes 22
136–137 ꢁC; 1H NMR (500 MHz, CDCl3)
d
3.07–3.12 (m, 2H), 3.86 (s,
3H), 3.95–4.00 (m, 2H), 7.24–7.29 (m, 1H), 7.33 (d, J¼8.8 Hz, 2H),
7.43 (br d, J¼8.0 Hz, 1H), 7.56–7.61 (m, 1H), 7.74–7.79 (m, 3H), 9.59
Thionyl chloride (1.2 ml, 18 mmol) and catalytic amount of DMF
were added to
a solution of o-azidobenzoic acid (980 mg,
(br s, 1H); 13C NMR (125 MHz, CDCl3)
d
35.40 (CH2), 44.06 (CH2),
6.0 mmol) in benzene (20 mL). The reaction mixture was stirred at
room temperature for 2 h and then concentrated under reduced
pressure. The residue was dissolved in CH2Cl2 (20 mL), and glycine
methyl ester hydrochloride salt (1.5 g, 12 mmol) and Et3N (2.5 mL,
18 mmol) were added successively to the solution. The reaction
mixture was stirred overnight at room temperature and then
quenched with water. The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (30 mLꢂ2). The combined
organic extracts were washed with saturated aqueous NH4Cl and
brine, dried over MgSO4, and then concentrated under reduced
pressure. The residue was dissolved in CH2Cl2 (30 mL), and tri-
phenylphosphane (1.6 g, 6.0 mmol) was added to the solution. The
mixture was stirred at room temperature for overnight and then
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography with EtOAc/hexane (1:1) as the
eluent followed by recrystallization from EtOAc/hexane to yield 22a
(2.07 g, 75%) as colorless powder.
52.93 (CH3), 121.12 (2CH), 121.40 (CH), 123.97 (CH), 126.32 (C),
126.44 (CH), 128.33 (C), 128.89 (2CH), 133.64 (CH), 137.65 (C),
143.74 (C), 146.70 (C), 175.13 (C). IR (KBr): 3270, 1720, 1612, 1581,
1334, 1180 cmꢀ1
C17H16ClN3NaO4S, 416.0442; found 416.0437.
.
HRMS-ESI (m/z): [MþNa]þ calcd for
4.6. Typical procedure for tandem aza-Wittig reaction/
cyclization reaction from sulfonamidic iminophosphorane 4f
to produce pyrimido[1,2-b][1,2,4]benzothiadiazine-6,6-
dioxides 17 in one pot (Method B) (Table 5, entry 2)
p-Tolyl isocyanate (5b, 0.026 mL, 0.21 mmol) was added to
a solution of 4f (100 mg, 0.19 mmol) in (CH2Cl)2 (2 mL). The re-
action mixture was heated at 80 ꢁC for 4.5 h with stirring and
cooled to room temperature. Titanium tetrachloride (0.95 mL,1.0 M
solution in CH2Cl2, 0.95 mmol) was added to the reaction mixture,

660
S. Hirota et al. / Tetrahedron 66 (2010) 653–662
4.8.1. Methyl ({2-[(triphenylphosphoranylidene)amino]benzoyl}amino)-
ꢀ60 ꢁC with stirring. The reaction mixture was warmed to 0 ꢁC
with stirring for 6 h and then quenched with water. The organic
layer was separated, and the aqueous layer was extracted with
CH2Cl2 (100 mLꢂ2). The combined organic extracts were washed
with water and brine, dried over MgSO4, and then concentrated
under reduced pressure. NaN3 (1.29 g, 19.9 mmol) and catalytic
amount of NaI (149 mg, 0.99 mmol) were added to a solution of the
residue in DMF (100 mL). The mixture was stirred at room tem-
perature for a week and then quenched with water. The solution
was extracted with Et2O (300 mLꢂ2). The combined organic ex-
tracts were washed with water and brine, dried over MgSO4, and
then concentrated under reduced pressure. The residue was puri-
fied by silica gel column chromatography with EtOAc/hexane (1:1)
as the eluent to yield 29a (3.0 g, 81%) as yellow solid.
acetate (22a). Colorless powder; mp 136.6–138.4 ꢁC; 1H NMR
(300 MHz, CDCl3)
d
3.64 (s, 3H), 4.20 (br d, J¼5.5 Hz, 2H), 6.45 (dd,
J¼0.8, 8.0 Hz, 1H), 6.68–6.79 (m, 1H), 6.87–6.96 (m, 1H), 7.40–7.65
(m, 9H), 7.67–7.81 (m, 6H), 8.21–8.30 (m, 1H), 11.60–11.90 (br t,
J¼5.5 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 41.30 (CH2), 51.82
3
(CH3), 117.47 (CH), 122.45 (d, JP,C¼12.0 Hz, CH), 124.44 (d,
2JP,C¼20.0 Hz, C), 128.90 (d, JP,C¼12.0 Hz, 6CH), 129.45 (d,
3
1JP,C¼100.0 Hz, 3C), 131.08 (CH), 131.54 (d, JP,C¼2.0 Hz, CH),
4
4
2
132.27 (d, JP,C¼2.7 Hz, 3CH), 132.56 (d, JP,C¼10.0 Hz, 6CH),
150.07 (C), 168.23 (C), 170.23 (C). IR (KBr): 3463, 3347, 3023, 2954,
2931, 1751, 1643, 1542, 1465, 1442, 1342, 1195, 1164, 1110, 1010,
755, 516 cmꢀ1. HRMS-ESI (m/z): [MþH]þ calcd for C28H26N2O3P,
469.1676; found 469.1664.
4.11.1. Ethyl [(azidoacetyl)amino]acetate (29a). Yellow solid; mp
4.9. Typical procedure for tandem aza-Wittig reaction/double
cyclization reaction from iminophosphoranes 22 to produce
imidazo[2,1-b]quinazolin-4-ones 25 (Table 6, entry 3)
29.3–29.4 ꢁC; 1H NMR (400 MHz, CDCl3)
d
1.29 (t, J¼7.1 Hz, 3H),
4.04 (s, 2H), 4.07 (d, J¼5.6 Hz, 2H), 4.24 (q, J¼7.1, 2H), 6.91 (br s,1H);
13C NMR (100 MHz, CDCl3)
14.13 (CH3), 41.17 (CH2), 52.47 (CH2),
61.75 (CH2), 166.99 (C), 169.38 (C). IR (KBr): 3336, 2992, 2116, 1748,
1674, 1540, 1206 cmꢀ1
d
p-Tolyl isocyanate (5b, 0.061 mL, 0.48 mmol) was added to
a solution of 22b (200 mg, 0.40 mmol) in toluene (15 mL) with
stirring and then the reaction mixture was heated at 110 ꢁC for 1 h.
After being cooled to room temperature, the reaction mixture was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography with EtOAc/hexane (1:2) as the
eluent followed by recrystallization from EtOAc/hexane to yield 25c
(119 mg, 97%) as colorless powder.
.
4.12. Typical procedure for tandem Staudinger reaction/aza-
Wittig reaction/cyclization reaction from azides 29 to produce
imidazolinoes 32 (Table 7, entry 1)
Triphenylphosphine (52.4 mg, 0.20 mmol) was added to
a mixture of 29a (37.3 mg, 0.20 mmol) and molecular sieve 4 Å
(100 mg) in benzene (5 mL). The reaction mixture was stirred for
0.5 h, and heated at 80 ꢁC for 3 h. After being cooled to room
temperature, a solution of phenyl isocyanate (5a, 0.0196 ml,
0.18 mmol) in benzene (5 mL) was added dropwise to the reaction
mixture at a rate of 2.5 mL/h by syringe pump with stirring. The
reaction mixture was stirred for 1 h at same temperature, and
then filtered. The filtrate was concentrated under reduced pres-
sure and the residue was purified by silica gel column chroma-
tography with EtOAc/hexane (1:1) as the eluent to yield 32a
(41.8 mg, 80%) as colorless solid.
4.9.1. 3-Methyl-1-(4-methylphenyl)imidazo[2,1-b]quinazoline-
2,5(1H,3H)-dione (25c). Colorless powder; mp 223.4–225.1 ꢁC; 1H
NMR (300 MHz, CDCl3)
d
1.90 (d, J¼7.0 Hz, 3H), 2.44 (s, 3H), 4.91
(q, J¼7.0 Hz, 1H), 7.30–7.47 (m, 5H), 7.50–7.56 (m, 1H), 7.67 (ddd,
J¼1.5, 7.2, 8.1 Hz, 1H), 8.24 (dd, J¼1.6, 7.9 Hz, 1H); 13C NMR
(75 MHz, CDCl3)
d 15.33 (CH3), 21.33 (CH3), 54.89 (CH), 120.10 (C),
125.51 (CH), 126.63 (CH), 126.66 (2CH), 126.80 (CH), 128.21 (C),
130.03 (2CH), 134.74 (CH), 139.25 (C), 148.08 (C), 148.74 (C),
159.41 (C), 170.97 (C). IR (KBr): 1758, 1689, 1627 cmꢀ1. HRMS-ESI
(m/z): [MþNa]þ calcd for C18H15N3NaO2, 328.1056; found
328.1056.
4.12.1. Ethyl (2-anilino-5-oxo-4,5-dihydro-1H-imidazol-1-yl)acetate
(32a). Colorless solid; mp 111.3–113.0 ꢁC; 1H NMR (270 MHz,
4.10. Typical procedure for hydrogenolysis of
CDCl3)
4.40 (s, 2H), 4.80 (s, 1H), 6.93–7.32 (m, 5H); 13C NMR (67.8 MHz,
CDCl3) 14.05 (CH3), 39.96 (CH2), 46.92 (CH2), 61.63 (CH2), 122.22
(2CH), 123.27 (CH), 129.34 (2CH), 146.54 (C), 149.43 (C), 167.18 (C),
170.90 (C). IR (KBr): 3304, 1760, 1732, 1674, 1206 cmꢀ1
d
1.29 (t, J¼7.3 Hz, 3H), 3.96 (s, 2H), 4.23 (q, J¼7.3 Hz, 2H),
N-benzylimidazo[2,1-b]quinazolin-4-ones 25b, d, f to produce
N-unsubstituted compounds 26 (Table 6, entry 2)
d
A solution of 25b (53.2 mg, 0.18 mmol) in THF/MeOH (10 mL,
v/v¼1/1) in the presence of palladium on carbon (10%, 50 mg)
was stirred vigorously under a hydrogen atmosphere at room
temperature for 6.5 h. The reaction mixture was filtered through
Celite and the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
with EtOAc as the eluent to yield 26a (36.2 mg, 92%) as colorless
solid.
.
4.13. Typical procedure for cyclization reaction of
imidazolinoes 32 to produce imidazo[1,2-
a]imidazolidindiones 33/34 and imidazo[1,2-a]pyrimidinones
35 (Table 7, entry 2)
A mixture of 32b (48.3 mg, 0.175 mmol) and silica gel (4.8 mg) in
Ph2O (3 mL) was stirred at 140 ꢁC for 9 h under reduce pressure
(19 mmHg). After being cooled to room temperature, the reaction
mixture was filtered and the filtrate was concentrated under re-
duced pressure. The residue was purified by silicagel column
chromatography with EtOAc/hexane (1:1) as the eluent to yield 33b
(18.5 mg, 46%) as yellow oil.
4.10.1. Imidazo[2,1-b]quinazoline-2,5(1H,3H)-dione (26a)45
(500 MHz, DMSO-d6) 4.54 (s, 2H), 7.41–7.47 (m, 1H), 7.56 (d,
J¼8.1 Hz, 1H), 7.78–7.85 (m, 1H), 8.13 (d, J¼8.0 Hz, 1H), one signal
(NH) missing; 13C NMR (125 MHz, DMSO-d6)
47.90 (CH2), 118.91
(C), 124.49 (CH), 125.59 (CH), 126.06 (CH), 134.58 (CH), 148.51(C),
151.89 (C), 158.35 (C), 170.83 (C).
.
1H NMR
d
d
4.11. Typical procedure for preparation of azides 29
4.13.1. 3-Methyl-1-phenyl-1H-imidazo[1,2-a]imidazole-2,5(3H,6H)-
dione (33b). Yellow oil; 1H NMR (400 MHz, CDCl3)
d
1.74 (t,
J¼7.1 Hz, 3H), 4.35 (s, 2H), 4.54 (q, J¼7.1 Hz, 1H), 7.27–7.65 (m, 5H);
13C NMR (100 MHz, CDCl3)
15.30 (CH3), 52.90 (CH), 61.20 (CH2),
124.40 (2CH), 128.48 (CH), 129.42 (2CH), 131.24 (C), 156.37 (C),
Chloroacetyl chloride (2.24 g, 19.9 mmol) was added dropwise
to a mixture of glycine ethyl ester hydrochloride salt (2.79 g,
19.9 mmol) and K2CO3 (5.51 g, 39.9 mmol) in CH2Cl2 (100 mL) at
d

S. Hirota et al. / Tetrahedron 66 (2010) 653–662
661
D. V.; Veira, C. P.; Quintela Lopez, J. M. Tetrahedron 2004, 60, 275; (r) Blanco, G.;
Segui, N.; Quintela, J. M.; Peinador, C.; Chas, M.; Toba, R. Tetrahedron 2006, 62,
11124; (s) Blanco, G.; Segui, N.; Quintela, J. M.; Peinador, C. Tetrahedron 2007, 63,
2034; (t) Blanco, G.; Segui, N.; Quintela, J. M.; Peinador, C. Tetrahedron 2008, 64,
1333; (u) Okawa, T.; Eguichi, S.; Kakehi, A. J. Chem. Soc., Perkin Trans. 11996, 247;
(v) Watanabe, M.; Okada, H.; Teshima, T.; Noguchi, M.; Kakehi, A. Tetrahedron
1996, 52, 2827; (w) Noguchi, M.; Okada, H.; Watanabe, M.; Okuda, K.; Naka-
mura, O. Tetrahedron 1996, 52, 6581.
172.95 (C), 174.74 (C). IR (neat): 1744, 1678, 1598, 1504, 1444,
1342 cmꢀ1. LRMS-EI (m/z): 229 (Mþ, 100%), 201 (Mþꢀ28, 45%), 173
(Mþꢀ58, 36%), 145 (Mþꢀ84, 96%). HRMS-EI (m/z): [M]þ calcd for
C12H11N3O2, 229.0851; found 229.0845.
Supplementary data
16. (a) Molina, P.; Alajarin, M.; Saez, J. R. Synthesis 1984, 983; (b) Molina, P.; Alajarin,
M.; Saez, J. R.; Foces-Foces, M. d. l. C.; Cano, F. H.; Claramunt, R. M.; Elguero, J. J.
Chem. Soc., Perkin Trans. 11986, 2037; (c) Molina, P.; Fresneda, P. M.; Delgado, S.;
Bleda, J. A. Tetrahedron Lett. 2002, 43, 1005; (d) Molina, P.; Alajarin, M.; Vidal, A. J.
Org. Chem.1992, 57, 6703; (e) Molina, P.; Arques, A.; Alias, A. J. Org. Chem.1993, 58,
5264; (f) Molina, P.; Lorenzo, A.; Aller, E. Synthesis 1992, 297; (g) Molina, P.;
Alajarin, M.; Vidal, A. Tetrahedron 1989, 45, 4263; (h) Okawa, T.; Kawase, M.;
Eguchi, S.; Kakehi, A.; Shiro, M. J. Chem. Soc., Perkin Trans. 1 1998, 2277; (i) Na-
gamatsu, K.; Akiyoshi, E.; Ito, H.; Fujii, H.; Kakehi, A.; Abe, N. Heterocycles 2006, 69,
167; (j) Xie, C.; Huang, N.-Y.; Ding, M.-W. ARKIVOC 2009, x, 220.
17. (a) Hu, Y.-G.; Yang, S.-J.; Ding, M.-W. ARKIVOC 2008, xv, 297; (b) Zhao, J.-F.; Xie,
C.; Xu, S.-Z.; Ding, M.-W.; Xiao, W.-J. Org. Biomol. Chem. 2006, 4, 130.
18. Saito, T.; Tsuda, K. Tetrahedron Lett. 1996, 37, 9071.
19. Bleda, J. A.; Fresneda, P. M.; Orenes, R.; Molina, P. Eur. J. Org. Chem. 2009, 2490.
20. Turos, G.; Csampai, A.; Lovasz, T.; Gyorfi, A.; Wamhoff, H.; Sohar, P. Eur. J. Org.
Chem. 2002, 3801.
21. (a) Huang, N.-Y.; Nie, Y.-B.; Ding, M.-W. Synlett 2009, 611; (b) Peinador, C.;
Moreira, M. J.; Quintela, J. M. Tetrahedron 1994, 50, 6705; (c) Blanco, G.;
Fernandez-Mato, A.; Quintela, J. M.; Peinador, C. Synthesis 2009, 438; (d)
Nagamatsu, K.; Fujii, H.; Abe, N.; Kakehi, A. Heterocycles 2004, 64, 291; (e)
Isomura, Y.; Yamasaki, S.; Okada, H.; Noguchi, M. Heterocycl. Commun. 1995, 1,
421.
22. (a) Saito, T.; Ohkubo, T.; Kuboki, H.; Maeda, M.; Tsuda, K.; Karakasa, T.; Satsu-
mabayashi, S. J. Chem. Soc., Perkin Trans. 1 1998, 3065; (b) Oton, F.; Tarraga, A.;
Espinosa, A.; Velasco, M. D.; Bautista, D.; Molina, P. J. Org. Chem. 2005, 70, 6603;
(c) Okawa, T.; Osakada, N.; Eguichi, S.; Kakehi, A. Tetrahedron 1997, 53, 16061;
(d) Nitta, M.; Morito, T.; Mitsumoto, Y.; Naya, S. Heterocycles 2005, 65, 1629; (e)
Nitta, M.; Ohtsuki, D.; Mitsumoto, Y.; Naya, S. Tetrahedron 2005, 61, 6073; (f)
Nagamatsu, K.; Serita, A.; Zeng, J.-H.; Fujii, H.; Abe, N.; Kakehi, A. Heterocycles
2006, 67, 337; (g) Wamhoff, H.; Schmidt, A.; Nieger, M. Tetrahedron Lett. 1991,
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23. (a) Arnold, M. A.; Duron, S. G.; Gin, D. Y. J. Am. Chem. Soc. 2005, 127, 6924; (b)
Arnold, M. A.; Day, K. A.; Duron, S. G.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128,
13255.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.11.064.
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tassium channels (or pancreatic KATP channels). Furthermore, derivatization by
introducing another possible substituent is feasible.8b
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