Suzuki reaction of cyclopenta[d][1,2]oxazine in aqueous solvent with water-soluble phosphine ligand

Article abstract of DOI:10.1016/j.tetlet.2006.05.147

A convenient and facile modification of cyclopenta[d][1,2]oxazines through Suzuki cross-coupling reaction by use of water-soluble phosphine ligand was accomplished. In aqueous solvent, 7-iodocyclopenta[d][1,2]oxazines readily afford the corresponding 7-ar

Full text of DOI:10.1016/j.tetlet.2006.05.147

Tetrahedron Letters 47 (2006) 5237–5240
Suzuki reaction of cyclopenta[d][1,2]oxazine in aqueous solvent
with water-soluble phosphine ligand
Sung Yun Cho,* Seung Kyu Kang, Jin Hee Ahn, Jae Du Ha and Joong-Kwon Choi
Bio-Organic Science Division, Korea Research Institute of Chemical Technology, 100 Jang-dong, Yuseong-gu,
Daejeon 305-600, Republic of Korea
Received 17 May 2006; accepted 24 May 2006
Available online 12 June 2006
Abstract—A convenient and facile modification of cyclopenta[d][1,2]oxazines through Suzuki cross-coupling reaction by use of
water-soluble phosphine ligand was accomplished. In aqueous solvent, 7-iodocyclopenta[d][1,2]oxazines readily afford the corre-
sponding 7-arylcyclopenta[d][1,2]oxazines in moderate to excellent yields.
Ó 2006 Elsevier Ltd. All rights reserved.
Cyclopenta[d][1,2]oxazine framework is seldom found in
natural products or pharmaceuticals. There have been
only a handful of reports on the synthesis of cyclo-
penta[d][1,2]oxazine and its derivatives, presumably due
to limited stability of cyclopenta[d][1,2]oxazine skeletons.
penta[d][1,2]oxazines and palladium-catalyzed cross-cou-
pling reaction of 7-iodocyclopenta[d][1,2]oxazines by use
of water soluble phosphine.
Me
X
Me
O
B(OH)
2
O
N
N
+
Pd(0)
Lloyd and Preston1 first reported the synthesis of cyclo-
penta[d][1,2]oxazine by the reaction of diaroylcyclo-
pentadiene with hydroxylamine. They also reported that
treatment of cyclopenta[d][1,2]oxazine with N-bromosuc-
cinimide afforded 7-bromocyclopenta[d][1,2]oxazine.
In an effort to pursue inhibitors of the protein tyrosine
phosphatase 1B (PTP1B),2 it was required to synthesize
the targeting compounds via Suzuki cross-coupling of
7-iodocyclopenta[d][1,2]oxazines. Palladium catalyzed
cross-coupling reaction of aryl halides with boronic acid
is a powerful synthetic method for arylation in carbon–
carbon bond formation.3 Aqueous-phase palladium cata-
lyzed cross-coupling reactions are of interest with respect
to environmental friendly synthetic process, the simplifi-
cation of product separation and the economy of using
water as a solvent in large-scale industrial syntheses.4 In
particular, aqueous palladium catalyzed cross-coupling
reactions were considered to be highly versatile and useful
method for heat or base labile compounds for decompo-
sition, such as cyclopenta[d][1,2]oxazines. Herein, we
report a synthetic method for halogenated cyclo-
OMe
MeO
OMe
OMe
1 (X = Br, I)
3
2
ð1Þ
For initial studies, we examined the coupling of 1 and 2
in the presence of palladium acetate. All experiments
were run at 50 °C and at room temperature with 1 and
2.0 equiv of lithium acetate, Cs2CO3, K2CO3 in
CH3CN–H2O (1:1) or 1,4-dioxane. We failed to produce
any biaryl adduct of cyclopenta[d][1,2]oxazine 3 without
remaining substrate 1, even under a condition where
triethylamine acted as a base in DMF at room temper-
ature. From this result, we found that cyclopenta[d]
[1,2]oxazines were not tolerable under heated condition.
Indeed, we turned our attention to aqueous Suzuki aryl
coupling of cyclopenta[d][1,2]oxazines with water solu-
ble phosphine ligand mediated by palladium acetate.
Initially, all of the 7-iodo and 7-bromocyclopenta[d]
[1,2]oxazines were synthesized through several steps
(Table 1).
For iodination reaction, treatment of cyclopenta[d]-
[1,2]oxazine by N-iodosuccinimide in MeCN in the pres-
ence of trifluoroacetic acid gave 1b in excellent yield.
Water soluble phosphine ligand was prepared by a
known procedure as cited in the literature.5
Keywords: Suzuki reaction; Cyclopenta[d][1,2]oxazine; Water-soluble
phosphine ligand.
*
Corresponding author. Tel.: +82 42 860 7077; fax: +82 42 860
7160; e-mail: sycho@krict.re.kr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.147

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S. Y. Cho et al. / Tetrahedron Letters 47 (2006) 5237–5240
Table 1.
soluble phosphine ligand, [2-(di-tert-butyl phosphanyl)
ethyl] trimethyl ammonium iodide I, as cited in the liter-
ature.6 The result given in Table 2 reveals that toluene
was the solvent of choice to afford the desired 7-aryl-
cyclopenta[d][1,2]oxazine along with CS2CO3 as a base
without decomposition of the substrate at room temper-
ature in moderate yield.
O
O
N
N
I
OR
OR
1b (R = CH CO Et)
2
2
Iodination reagent
Solvent
Yield (%)
ICI
ICI
NIS
AcOH
TFA/CH2Cl2
TFA/MeCN
11
80
91
Suzuki reactions were not preceded under typical cou-
pling condition with Pd(OAc)2, tri(o-tolyl) phosphine
in dioxane at 50 °C, and no substrate was recovered.
(Table 2 entry 1 and 2) The reactions that were executed
in water alone occurred more slowly than in water-mis-
cible co-solvents (entry 5 in Table 2). With solvents,
MeCN and water, the Suzuki reactions did not give rise
to the desired product with satisfactory yields (entries 4–
7). It was observed that the substrate was decomposed in
either toluene or MeOH as a sole solvent without the
addition of water. It was improved in yield with the
addition of toluene in the reaction mixture, presumably
because of better forming homogeneous reaction mix-
ture (entry 8).
Table 2.
O
B(OH)2
O
N
N
MeO
R′
+
Pd(OAc)2
OR
OR
OMe
3p (R = CH CO Et)
2
2
Entry R0 Condition
Yield (%)
1
2
3
4
5
6
7
8
Br CS2CO3, P(o-tolyl)3, 1,4-dioxane, 50 °C
CS2CO3, P(o-tolyl)3, 1,4-dioxane, 50 °C
Br NaOAC, I, MeCN–H2O (1:1)
0a
0a
0
8
7
I
To evaluate the scope and limitation for this procedure
to cyclopenta[d][1,2]oxazine acting as a substrate, we
performed a number of coupling reaction with several
aryl boronic acids and 7-iodocyclopenta[d][1,2]oxazines.
All reactions were run at room temperature and cesium
carbonate was used as a base of choice in toluene–
MeOH–water (1:1:1) which was used as a solvent as
given in Table 3. [2-(di-tert-butyl phosphanyl) ethyl]
Trimethyl ammonium iodide I has allowed the first gen-
eral coupling of aryl iodide to cyclopenta[d][1,2]oxazine
at room temperature under nitrogen atmosphere. To
I
I
I
I
I
NaOAC, I, MeCN–H2O (1:1)
NaOAC, I, H2O
CS2CO3, I, MeCN–H2O (1:1)
NEt3, I, MeCN–H2O (1:1)
8
6
Toluene–MeOH–H2O (1:1:1), I, CS2CO3 66
a No substrate was recovered.
For initial assessment of coupling reaction, Suzuki
cross-coupling reactions were performed with a water
Table 3. Suzuki-coupling of 6-iodocyclopenta[d][1,2]oxazines
1
1
O
O
R
R
N
N
ArB(OH)
+
2
2
2
Ar
I
R
R
1
3a - 3s
Compound no.
R1
R2
Ar
Yield (%)
65
3a
Me
–CO2Me (a)
OMe
Cl
3b
Me
a
75
3c
3d
Me
Me
a
a
65
67
Cl
S
3e
3f
Me
Me
a
a
75
78
F
Br

S. Y. Cho et al. / Tetrahedron Letters 47 (2006) 5237–5240
5239
Table 3 (continued)
Compound no.
R1
R2
Ar
Yield (%)
72
3g
Me
a
O
O
3h
3i
Me
Me
a
a
77
59
OAc
OMe
3j
Me
Me
a
a
93
51
S
3k
S
3l
Me
Me
a
a
65
68
3m
O
3n
3o
H
H
72
65
OCH2CO2Et (b)
O
b
b
Cl
3p
3q
H
H
66
80
OMe
OMe (c)
s
3r
3s
H
H
c
c
19a
67
s
s
a 7-Bromocyclopenta[d][1,2]oxazine was used in place of 7-iodocyclopenta[d][1,2]oxazine.
date, there have been no examples of cross-coupling of
cyclopenta[d][1,2]oxazines possessing limited stability
in ordinary cross-coupling condition to construct car-
bon–carbon bond formation. 7-Iodo cyclopenta[d][1,2]
oxazines 1b provided coupled products in moderate to
excellent yields at room temperature in aqueous solvent.
It was unsatisfactory in yield when we used 7-bromocy-
clopenta[d][1,2]oxazine in place of its iodide (3r). Then,
we applied this type of cross-coupling reaction in
aqueous solvent with satisfaction. In summary, we ob-
served that palladium catalyzed aryl boronic acid cou-
pling reaction in water afforded a wide variety of 7-
arylcyclopenta[d][1,2]oxazines, including base-sensitive
or acid-sensitive ones which have tolerability in such
conditions.
(1.9 g, 6.39 mmol) in CH3CN (40 mL) were added N-
iodosuccinimide (1.58 g, 7.02 mmol) and trifluoroacetic
acid (0.15 mL, 1.92 mmol). The reaction mixture was
stirred for 2 h at room temperature. The resulting mix-
ture was poured into water and extracted with ethyl ace-
tate. The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The residue was
purified by column chromatography to afford 1b as a
yellow solid (2.45 g, 91%): 1H NMR (300 MHz, CDCl3)
d 8.83 (d, J = 1.4 Hz, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.45
(d, J = 2.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.86 (dd,
J = 2.8, 1.4 Hz, 1H), 4.70 (s, 2H), 4.30 (q, J = 7.2 Hz,
2H), 1.32 (t, J = 7.2 Hz, 3H); MS m/e (relative intensity)
423 (M+, 0.8), 353 (0.9), 297 (46), 224 (7), 210
(100). Compound (3a): To a sealed tube were added 7-
iodo-1-methylcyclopenta[d][1,2]oxazine-4-carboxylic acid
methyl ester (0.1 g, 0.32 mol), 4-methoxyphenyl boronic
acid (0.07 g, 0.47 mol), Pd(OAc)2 (0.01 g, 0.05 mmol),
Typical procedure: To a stirred solution of 4-cyclo-
penta[d][1,2]oxazin-4-yl-phenoxy acetic acid ethyl ester

5240
S. Y. Cho et al. / Tetrahedron Letters 47 (2006) 5237–5240
[2-(di-tert-butyl phosphanyl) ethyl] trimethyl ammo-
nium iodide (0.015 g, 0.05 mmol), Cs2CO3 (0.205 g,
0.63 mmol) and toluene–MeOH–H2O (1:1:1, 4.5 mL)
under nitrogen atmosphere. The reaction mixture was
stirred for 15 h at room temperature. The resulting mix-
ture was poured into water and extracted with ethyl ace-
tate. The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The residue was
purified by column chromatography to afford 3a
References and notes
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2004, 485, 333; (c) Ahn, J. H.; Cho, S. Y.; Ha, J. D.; Kang,
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1
(62 mg, 65%) as a yellow solid: H NMR (300 MHz,
CDCl3) d 7.39 (d, J = 3.1 Hz, 1H), 7.32 (dd, J = 6.7,
2.1 Hz, 2H), 7.24 (d, J = 3.1 Hz), 6.98 (dd, J = 6.7,
2.1 Hz, 2H), 4.06 (s, 3H), 3.86 (s, 3H), 2.59 (s, 3H);
MS m/e (relative intensity) 297 (M+, 40), 223 (12), 207
(12), 70 (12), 59 (55), 43 (100).
Acknowledgements
The authors appreciate the financial support of the Min-
istry of Commerce, Industry and Energy of Korea and
Bioneer Corporation.
6. Shaughnessy, K. H.; Booth, R. S. Org. Lett. 2001, 3, 2757.