Efficient synthesis of heterocyclic compounds using ethenetricarboxylic acid diesters

Article abstract of DOI:10.1039/b818878e

Ethenetricarboxylic acid diester 1a is a useful compound bearing two reactive sites, a CO₂H group and a Michael acceptor. Reactions of 1a and reagents with oxygen and nitrogen nucleophilic moieties have been examined. The reaction of 1a with 2-

Full text of DOI:10.1039/b818878e

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Efficient synthesis of heterocyclic compounds using ethenetricarboxylic
acid diesters†
Shoko Yamazaki,* Yuko Iwata and Yugo Fukushima
Received 24th October 2008, Accepted 24th November 2008
First published as an Advance Article on the web 8th January 2009
DOI: 10.1039/b818878e
Ethenetricarboxylic acid diester 1a is a useful compound bearing two reactive sites, a CO2H group and
a Michael acceptor. Reactions of 1a and reagents with oxygen and nitrogen nucleophilic moieties have
been examined. The reaction of 1a with 2-aminoalcohols in the presence of EDCI and HOBt in one pot
gave N,O-containing heterocyclic compounds, regioselectively. The stepwise method has also been
carried out. Deprotection of N-Boc protected aminoesters, followed by basic aqueous workup, gave
various 1,4-oxazine derivatives. Deprotection of the O-TBS protected amides also leads to spontaneous
cyclization and affords 1,4-oxazine derivatives. They have the opposite regiochemistry to those from the
one-pot reaction. Thus, both ester or amide regioisomers can be prepared. These synthetic methods
represent a new general strategy for the construction of diverse heterocyclic systems such as
morpholine-derived heterocycles.
may be accessible by one-pot or simple stepwise reactions of
1a and reagents with oxygen and nitrogen nucleophilic moieties.
Control of the regioselectivity for formation of oxazines I or
II is also of interest. The products I or II can be valuable
building blocks for the synthesis of more complex derivatives.
The common condensation reaction of 1a with reagents such
Introduction
Six-membered heterocyclic compounds containing nitrogen and
oxygen, such as oxazine, dioxane and diazine skeletons are
of considerable interest, due to their biological activity.1,2 Sev-
eral methods have been reported for the preparation of these
compounds.3 Various new synthetic strategies to construct them by
as 2-aminoalcohols, 2-aminophenol, 1,2-diols, 1,2-diamines and
the reactions of 2-aminoalcohols, 1,2-diamines, or 1,2-diols have
their 1,3-analogues were examined in this study. The scope and
been studied recently.4 Reagents bearing two nucleophilic sites
and C–C components with two electrophilic sites react effectively
and lead to heterocycle formation. It is desirable to find new
limitations of the reaction are described.
Results and discussion
highly functionalized acceptors with regioselective reactivity for
the construction of diversely substituted heterocyclic systems.
Previously, we have shown the utility of ethenetricarboxy-
A. Cyclization of 1 in one pot
lates for various synthetic reactions, as highly reactive Michael
acceptors.5 Ethenetricarboxylic acid diester 1a is considered to be
a useful compound bearing two reactive sites: a CO2H group and
a Michael acceptor (Scheme 1).5d,f We envisioned that heterocycles
The reaction of 1a with various 2-aminoalcohols 2 in the pres-
ence of EDCI (3-(3-dimethylaminopropyl)-1-ethylcarbodiimide
hydrochloride) and HOBt (1-hydroxybenzotriazole) in THF was
examined. The reaction with secondary 2-aminoethanols 2a–d
gave N,O-containing heterocyclic compounds 3a–d regioselec-
tively with preference for 1,4-addition of amines (eqn 1). For the
reaction of 2a, a minor regioisomer (23a, vide post), an amide
oxazine was obtained in 13% yield. For the other derivatives, only
isomers 3 were observed, even though the yields were modest.6
(1)
Scheme 1
The one-pot reaction of 1a with 2-piperidinemethanol 4 in
the presence of EDCI and HOBt in THF gave a bicyclic N,O-
containing heterocyclic compound 5a as a single diastereomer in
51% yield, exclusively (eqn 2). Dibenzyl ester derivative 1b also
Department of Chemistry, Nara University of Education, Takabatake-cho,
Nara 630-8528, Japan. E-mail: yamazaks@nara-edu.ac.jp
† Electronic supplementary information (ESI) available: Additional exper-
imental procedures and spectral data. See DOI: 10.1039/b818878e
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reacted with 4 to give the heterocycle 5b in 63% yield. On the
other hand, the reaction of 1a with (S)-2-pyrrolidinemethanol 6
gave a mixture of N,O-regioisomers 7 (45%, dr = 3:1)7 and 8 (33%,
dr = 2.8:1) (eqn 3). In this example, the major product 7 is still a
N-Michael adduct, however, the selectivity is low. The effect of the
stereochemical factor on N/O selectivity is under investigation.
The regiochemistry of the major N-Michael adducts was deter-
mined by the absence of IR amide absorption (~1660 cm-1), which
appears in the regioisomers, and NOE and HMBC correlations.
(5)
(2)
The reaction of 1a with 2-hydroxymethylaniline 13 gave a
benzo[e][1,4]oxazepine derivative 14 in 44% yield as the major
isolable product (eqn 6).
(6)
(3)
The reaction of 1a with aliphatic 1,2-diols such as ethylene
glycol, trans-cyclohexane-1,2-diol and cis-cyclohexane-1,2-diol
gave complex mixtures. The reaction of 1a with aromatic 1,2-diol,
pyrocatechol 15, gave a cyclized product 16 in 46% yield (eqn 7).
(7)
The reaction of 1a with symmetric secondary 1,2-diamine 9a
and 1,3-diamine 9b was examined next. The reaction in the
presence of EDCI and HOBt in THF gave 1,4-pyrazine 10a and
the seven-membered 1,4-diazaheptane 10b in good yields (eqn 4).
In the N/O one-pot reactions, determination of whether amine
addition or ester formation occurs first may be complicated. The
amine may react faster because of its stronger nucleophilicity. Also,
the amine conjugate addition may be reversible.
B. Stepwise cyclization via N-Boc aminoesters
(4)
Next, the stepwise method was carried out. N-Boc protected
aminoesters 18 were prepared from 1a and N-Boc protected amino
alcohols 17 under Mitsunobu conditions or by EDCI/DMAP or
EDCI/HOBt condensation (eqn 8 and Table 1).9 Deprotection
of the N-Boc group by trifluoroacetic acid (TFA) to give a TFA
salt 19, followed by basic aqueous workup (aq. NaHCO3), gave
various 1,4-oxazine derivatives 20. Intramolecular 1,4-addition
of amines occurs spontaneously.10 The products have the same
regiochemistry as the one-pot reaction. The N-Boc protected
aminoesters lead to primary aliphatic amine adducts, which could
not be obtained by one-pot reactions.
The reaction of 1a with primary aliphatic amines, 2-
aminoalcohols, gave a complex mixture. On the other hand, the
reaction of 1a with primary aromatic amines, 2-aminophenols
11, gave cyclized products, 1,4-benzoxazines 12 efficiently in up to
74% yield (eqn 5).8 The products 12 arise from N-Michael adducts,
selectively. Dibenzyl ester 1b also gave 12g as a major product.
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Table 1 Preparation of esters 18 and their cyclization reactions
Aminoalcohol 17
Condensation method
DEAD, PPh3 Et2O
N-Boc aminoester 18
Yield
71%
Product 20
Yield
86% dr = 1.7:1~1:0a (1,3-cis:trans)b
17b
18b
20b
20c
7
17c
EDCI, HOBt THF
DEAD, PPh3 Et2O
18c
18d
50%
45%
53%
17d
79% dr = 3:5 (1,3-cis:trans)b
17e
EDCI, DMAP CH2Cl2
18e
30%
5a
78%
a The diastereomer ratio changed on standing.7 b Cis:trans refers to substitution in the oxazine ring.
(9)
(8)
In summary, the reaction of ethenetricarboxylic acid diester 1
with secondary 2-aminoalcohols in the presence of EDCI and
HOBt in one pot gave N,O-containing heterocyclic compounds
regioselectively, with a preference for 1,4-addition of amines.
The stepwise methods involving N-Boc protected aminoesters or
O-TBS protected amides afforded the regioisomeric 1,4-oxazine
derivatives, respectively. These metal-free synthetic methods rep-
resent a new general strategy for the construction of diverse hetero-
cyclic systems such as morpholine-derived heterocycles. Also, the
present reaction has potential with regard to other bifunctional
nucleophiles i.e. thiophenol or other SH-containing substrates.
Transformation of the products, including monodecarboxylation
of the diester groups,13 to potentially useful compounds is under
investigation.
The use of chiral amino acid-derived aminoalcohols 17b,d gave
chiral cyclized products 20b and 7, although the products were
obtained as diastereomer mixtures.7 Selective formation of 5a from
18e as well as the one-pot formation described above may arise
from the stability of the diequatorial 1,3-cis substituents adopting
a chair-like conformation for the six-membered 1,4-oxazine ring.11
In the ring closed products, the amine addition and elimination
may be reversible, leading to the stable isomer 5a.
C. Stepwise cyclization via O-TBS amides
t
The stepwise method via O-TBS (OSiMe2 Bu) protected amides
22 was also examined (eqn 9 and Table 2). The amides 22 were
prepared from 1a and O-TBS protected amines 21. Deprotection
of the O-TBS group of 22a,b,c by trifluoroacetic acid or tetra-
butylammonium fluoride (for 22b) gave 1,4-oxazine derivatives
23a,b,c. The substituted derivatives 23b,c were also obtained as
diastereomer mixtures. The products 23a,b have the opposite
regiochemistry to that of the one-pot reaction. Thus, both ester or
amide regioisomers can be prepared. Attempts to obtain seven-
membered rings by this deprotonation method failed. The reaction
of 22d with TFA gave deprotonated alcohol derivative 24d in
quantitative yield.12
Experimental section
Typical experimental procedure (eqn 1)
To a solution of 1,1-diethyl 2-hydrogen ethenetricarboxylate
1a (216 mg, 1 mmol) (prepared from 1,1-diethyl 2-tert-butyl
ethenetricarboxylate upon treatment with CF3CO2H)5d in THF
(4 mL) were added HOBt (1-hydroxybenzotriazole) (135 mg,
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Table 2 Preparation of amides 22 and the deprotection reaction
O-TBS amine 21 O-TBS amide 22 Yield Deprotection method Product 23
21b
Yield
91% dr = 1.3:1 (1,4-trans:cis) 89% dr = 1:1
22b
55%
TFA TBAF
23b
21c
22c
63%
TFA
23c 89% dr = 3:1 (1,3-trans:cis)
21d
22d 45%
TFA
24d 100%
1 mmol), EDCI (1-[3-dimethylaminopropyl]-3-ethylcarbodiimide
hydrochloride) (199 mg, 1.04 mmol) and 2-(methylamino)ethanol
2a (75 mg, 1 mmol) at 0 ◦C. The reaction mixture was allowed
to warm to rt and stirred for 13 h. The mixture was concentrated
in vacuo and the residue was diluted with CH2Cl2. The organic
phase was washed with saturated aqueous NaHCO3 solution, 2M
aqueous citric acid, saturated aqueous NaHCO3 and water, dried
(Na2SO4), and evaporated in vacuo. The residue was purified by
column chromatography over silica gel eluting with ether to give
3a (186 mg, 68%) and 23a (36 mg, 13%).
39), 228 (53), 154 (96), 86 (100%); HRMS M+ 273.1213 (calcd for
C12H19NO6 273.1212).
5a. Rf = 0.5 (hexane : ether = 1 : 4); Pale yellow oil; 1H NMR
(400 MHz, CDCl3) d (ppm) 1.11 (dddd, J = 12.8, 12.8, 11.2,
4.0 Hz, 1H, H9), 1.25–1.39 (m, 1H, H8), 1.29 (t, J = 7.1 Hz, 3H,
CH2CH3), 1.31 (t, J = 7.1 Hz, 3H, CH2CH3), 1.47 (dddd, J =
13.2, 13.2, 3.8, 3.8 Hz, 1H, H7), 1.57–1.62 (m, 1H, H9), 1.67–1.72
(m, 1H, H7), 1.78–1.82 (m, 1H, H8), 2.09 (ddd, J = 11.7, 11.7,
2.5 Hz, 1H, H6), 2.51 (dddd, J = 10.4, 10.4, 2.8, 2.8 Hz, 1H, H9a),
3.04 (ddd, J = 11.2, 2.7, 2.7 Hz, 1H, H6), 3.66 (d, J = 3.8 Hz, 1H,
H4), 3.87 (d, J = 3.8 Hz, 1H, CH(CO2Et)2), 4.07 (dd, J = 10.8,
3.1 Hz, 1H, H1), 4.12 (dd, J = 10.3, 10.3 Hz, 1H, H1), 4.20–4.35
(m, 4H, CH2CH3). Selected NOEs are between d 2.51 and d 3.66;
13C NMR (100.6 MHz, CDCl3) d (ppm) 13.95 (q), 14.03 (q), 23.20
(t), 25.00 (t), 26.94 (t), 52.51 (t), 53.72 (d), 56.23 (d), 61.67 (t), 61.88
(t), 64.67 (d), 71.47 (t), 167.15 (s), 167.63 (s), 168.52 (s). Selected
HMBC correlations are between d 2.09 and d 64.67 (C4), between
d 3.66 and d 52.51 (C6), and between d 2.09, 3.04 and d 56.23 (C9a);
IR (neat) 2982, 2940, 1739, 1460, 1373, 1282, 1215, 1093 cm-1; MS
(EI) m/z 313 (M+, 30), 221 (93), 193 (83), 154 (100%); HRMS M+
313.1526 (calcd for C15H23NO6 313.1525).
1
3a. Rf = 0.3 (ether); Pale yellow oil; H NMR (400 MHz,
CDCl3) d (ppm) 1.30 (t, J = 7.1 Hz, 3H, CH2CH3), 1.31 (t, J =
7.1 Hz, 3H, CH2CH3), 2.43 (s, 3H, NCH3), 2.72 (ddd, J = 12.8,
11.2, 2.9 Hz, 1H, NCHH), 2.90 (ddd, J = 12.8, 2.4, 2.4 Hz, 1H,
NCHH), 3.64 (d, J = 3.8 Hz, 1H, NCH), 3.89 (d, J = 3.8 Hz, 1H,
CH(CO2Et)2), 4.18–4.37 (m, 5H, CH2CH3, OCHH), 4.50 (ddd,
J = 10.9, 10.9, 2.5 Hz, 1H, OCHH). Selected NOEs are between
d 2.43 and d 2.72, 2.90, 3.64, 3.89; 13C NMR (100.6 MHz, CDCl3)
d (ppm) 13.84 (q), 13.89 (q), 43.38 (q), 50.94 (t), 53.34 (d), 61.65
(t), 61.81 (t), 65.75 (d), 67.00 (t), 166.93 (s), 167.33 (s), 167.98
(s). Selected HMBC correlations are between d 2.43 and d 50.94
(NCH2), 65.75 (NCH), and between d 3.64 and d 43.38 (NCH3);
IR (neat) 2983, 1738, 1463, 1373, 1300, 1201, 1150 cm-1; MS (EI)
m/z 273 (M+, 9), 181 (17), 114 (100%); exact mass M+ 273.1211
(calcd for C12H19NO6 273.1212).
1
23a. Rf = 0.1 (ether); Pale yellow oil; H NMR (400 MHz,
CDCl3) d (ppm) 1.28 (t, J = 7.1 Hz, 3H, CH2CH3), 1.29 (t, J =
7.0 Hz, 3H, CH2CH3), 3.01 (s, 3H, NCH3), 3.14 (bd, J = 11.9 Hz,
1H, NCHH), 3.71 (td, J = 11.7, 4.3 Hz, 1H, NCHH), 3.87 (td,
J = 11.7, 3.0 Hz, 1H, OCHH), 4.06 (ddd, J = 11.9, 4.2, 1.5 Hz,
1H, OCHH), 4.11 (d, J = 4.3 Hz, 1H, CH(CO2Et)2), 4.19–4.29
(m, 4H, CH2CH3), 4.67 (d, J = 4.3 Hz, 1H, OCH). Selected NOEs
are between d 3.01 and d 3.14, 3.71 and between d 3.87 and d 4.67;
13C NMR (100.6 MHz, CDCl3) d (ppm) 14.00 (q), 14.02 (q), 34.44
(q), 48.41 (t), 54.20 (d), 61.58 (t), 61.67 (t), 63.37 (t), 75.52 (d),
166.69 (s), 167.01 (s), 167.21 (s). Selected HMBC correlations are
12a. Rf = 0.7 (hexane : ether = 1 : 4); Pale yellow crystals;
mp 67–70 ◦C; 1H NMR (400 MHz, CDCl3) d (ppm) 1.18 (t, J =
7.1 Hz, 3H, CH2CH3), 1.33 (t, J = 7.1 Hz, 3H, CH2CH3), 4.06–
4.17 (m, 2H, CH2CH3), 4.23 (d, J = 4.4 Hz, 1H, CH(CO2Et)2),
4.25–4.37 (m, 2H, CH2CH3), 4.64 (d, J = 4.4 Hz, 1H, H3), 4.94
(bs, 1H, H4), 6.74–6.76 (m, 1H, H5), 6.81 (td, J = 7.8, 1.5 Hz,
1H, H7), 6.96–7.01 (m, 2H, H6,8); 13C NMR (100.6 MHz, CDCl3)
d (ppm) 13.81 (q), 13.98 (q), 53.44 (d), 54.25 (d), 62.34 (t), 62.44
(t), 115.18 (d), 116.80 (d), 120.15 (d), 125.33 (d), 131.15 (s), 140.19
=
between d 3.01 and d 167.21 (NC O); IR (neat) 2982, 1747, 1736,
1661, 1505, 1372, 1343, 1267, 1150 cm-1; MS (EI) m/z 273 (M+,
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(s), 164.51 (s), 166.72 (s), 167.92 (s). Selected HMBC correlations
are between d 4.64 and d 131.15 (C4a); IR (KBr) 3366, 2989, 1735,
1732, 1358, 1282, 1234, 1180 cm-1; MS (EI) m/z 307 (M+, 43),
187 (46), 147 (61), 120 (100%); HRMS M+ 307.1060 (calcd for
C15H17NO6 307.1056).
J. Chen, W. Fitzpatrick, Q. Gao, V. K. Gribkoff, D. G. Harden, H.
He, R. J. Knox, J. Natale, R. L. Pieschl, J. E. Starrett, Jr, L.-Q.
Sun, M. Thompson, D. Weaver, D. Wu and S. I. Sworetzky, Bioorg.
Med. Chem. Lett., 2004, 14, 1991; (c) K. Torisu, K. Kobayashi, M.
Iwahashi, Y. Nakai, T. Onoda, T. Nagase, I. Sugimoto, Y. Okada, R.
Matsumoto, F. Nanbu, S. Ohuchida, H. Nakai and M. Toda, Bioorg.
Med. Chem., 2004, 12, 5361; (d) X. Chen, D. J. Kempf, L. Li, H. L.
Sham, S. Vasavanonda, N. E. Wideburg, A. Saldivar, K. C. Marsh, E.
MacDonald and D. W. Norbeck, Bioorg. Med. Chem. Lett., 2003, 13,
3657.
Preparation of 20a (eqn 8)
To a solution of 18a (74 mg, 0.2 mmol) in dichloromethane
(0.7 mL) was added trifluoroacetic acid (0.7 mL) at 0 ◦C. The
reaction mixture was allowed to warm to rt and stirred for 1 h. The
mixture was concentrated in vacuo and the residue was diluted with
CH2Cl2. The organic phase was washed with saturated aqueous
NaHCO3 solution and water, dried (Na2SO4), and evaporated
in vacuo. The residue was purified by column chromatography over
silica gel eluting with CH2Cl2–MeOH (4 : 1) to give 20a (42 mg,
79%).
3 (a) Six-membered hetarenes with two unlike or more than two
heteroatoms and fully unsaturated larger-ring heterocycles, Science of
Synthesis, Houben-Weyl Method of Molecular Transformation, Vol. 17,
ˇ
S. M. Weinreb, ed. George Tieme, Sttutgart, 2004; (b) J. Ilasˇ, P. S.
Anderluh, M. S. Dolenc and D. Kikelj, Tetrahedron, 2005, 61, 7325;
(c) For recent examples of the synthesis of 1,4-oxazines, see: M. Vasylyev
and H. Alper, Org. Lett., 2008, 10, 1357; (d) B. Gabriele, G. Salerno, L.
Veltri, R. Mancuso, Z. Li, A. Crispini and A. Bellusci, J. Org. Chem.,
2006, 71, 7895; (e) E. Claveau, I. Gillaizeau, J. Blu, A. Bruel and G.
Coudert, J. Org. Chem., 2007, 72, 4832; (f) S.-C. Yang, H.-C. Lai and
Y.-C. Tsai, Tetrahedron Lett., 2004, 45, 2693; (g) P. Stefanic, K. Turnsek
and D. Kikelj, Tetrahedron, 2003, 59, 7123.
20a. Rf = 0.7 (CH2Cl2 : MeOH = 4 : 1); Colorless oil; 1H NMR
(400 MHz, CDCl3) d (ppm) 1.30 (t, J = 7.1 Hz, 3H, CH2CH3),
1.31 (t, J = 7.1 Hz, 3H, CH2CH3), 2.71 (bs, 1H, NH), 3.08–3.18
(m, 2H, NCH2), 4.11 (d, J = 3.5 Hz, 1H, NCH), 4.21–4.31 (m,
5H, CH2CH3, CH(CO2Et)2), 4.39–4.51 (m, 2H, OCH2). Selected
NOEs are between d 3.08–3.18 and d 4.11; 13C NMR (100.6 MHz,
CDCl3) d (ppm) 14.03 (q), 14.08 (q), 42.31 (t), 53.89 (d), 57.81 (d),
62.09 (2 ¥ t), 70.32 (t), 167.83 (s), 168.23 (s), 168.55 (s). Selected
HMBC correlations are between d 3.08–3.18 and d 57.81 (NCH);
IR (neat) 3346, 2983, 1739, 1466, 1373, 1294, 1203, 1034 cm-1;
MS (FAB) m/z 260 (M + H)+; HRMS (FAB) (M + H)+ 260.1150
(calcd for C11H18NO6 (M + H) 260.1134).
4 For examples: (a) Y. Fukudome, H. Naito, T. Hata and H. Urabe, J. Am.
Chem. Soc., 2008, 130, 1820; (b) T. P. Zabawa and S. R. Chemler, Org.
Lett., 2007, 9, 2035; (c) D. Xu, A. Chiaroni, M.-B. Fleury and M.
Largeron, J. Org. Chem., 2006, 71, 6374; (d) C. S. Cho and S. G. Oh,
Tetrahedron Lett, 2006, 47, 5633; (e) C. O. Okafor and M. U. Akpuaka,
J. Chem. Soc. Perkin Trans. 1, 1993, 159.
5 (a) S. Yamazaki, H. Kumagai, T. Takada and S. Yamabe, J. Org.
Chem., 1997, 62, 2968; (b) S. Yamazaki, K. Yamada, S. Yamabe and
K. Yamamoto, J. Org. Chem., 2002, 67, 2889; (c) S. Yamazaki, S.
Morikawa, Y. Iwata, M. Yamamoto and K. Kuramoto, Org. Biomol.
Chem., 2004, 2, 3134; (d) S. Yamazaki, K. Ohmitsu, K. Ohi, T. Otsubo
and K. Moriyama, Org. Lett., 2005, 7, 759; (e) S. Yamazaki and Y.
Iwata, J. Org. Chem, 2006, 71, 739; (f) S. Yamazaki, M. Yamamoto and
A. Sumi, Tetrahedron, 2007, 63, 2320.
6 The aqueous workup described in the Experimental section gave only
the major products usually.
7 The products 7 and 20b are somewhat unstable and the diastereomer
ratios sometimes change on standing, possibly due to the reversibility of
the amine elimination and addition. The product 5a is always obtained
as a single diastereomer. (a) G. Bartoli, M. Bartolacci, A. Giuliani, E.
Marcantoni, M. Massaccesi and E. Torregiani, J. Org. Chem., 2005, 70,
169; (b) G. Bartoli, M. Bosco, E. Marcantoni, M. Petrini, L. Sambri and
E. Torregiani, J. Org. Chem., 2001, 66, 9052; (c) F. Toda, H. Takumi,
M. Nagami and K. Tanaka, Heterocycles, 1998, 47, 467.
8 In the reaction in eqn 5, byproducts 12¢ were observed in small amounts.
12¢a (R = Et/R¢ = H, trace) and 12¢g (R = CH2Ph/R¢ = H, 23%)
were isolated and characterized. Formation of 12¢ may arise from
decarboxylation.
Preparation of 23a (eqn 9)
To 22a (105 mg, 0.27 mmol) was added trifluoroacetic acid
◦
(1.1 mL) at 0 C. The reaction mixture was allowed to warm to
rt and stirred for 1 h. The mixture was concentrated in vacuo and
the residue was purified by column chromatography over silica gel
eluting with CH2Cl2–AcOEt (1 : 4) to give 23a (61 mg, 82%).
Acknowledgements
This work was supported by the Ministry of Education, Culture,
Sports, Science, and Technology of the Japanese Government. We
thank Ms. A. Sumi, Ms. A. Matsubara and Mr. M. Matsubara
(Nara University of Education) for experimental help. We thank
Nara Institute of Science and Technology (NAIST) and Prof.
K. Kakiuchi (NAIST) for mass spectra. We also thank Prof.
S. Umetani (Kyoto University) for mass spectra and elemental
analyses.
9 The yields of condensation of 1a and 17 vary sometimes, therefore the
optimized conditions were used.
10 Similar amine deprotection and subsequent cyclization was also
reported: B. J. Turunen and G. I. Georg, J. Am. Chem. Soc., 2006,
128, 8702.
11 There is 7.5 kcal/mol free energy difference between 1,3-cis and
1,3-trans stereoisomers of 5a by B3LYP/6–31G* calculations. In
comparison, the difference between 1,3-cis and trans isomers of 7 is
3.1 kcal/mol and that of 20b is 4.5 kcal/mol.
12 The cyclization of 24d was attempted by treatment of 24d with ZnCl2
in CH2Cl2. However, the reaction gave a complex mixture along with
the recovered 24d.
13 (a) A. P. Krapcho, Synthesis, 1982, 805 and 893; (b) V. Wascholowski,
K. R. Knudsen, C. E. T. Mitchell and S. V. Ley, Chem. Eur. J., 2008,
14, 6155.
References
1 (a) A. E. A. Porter, Comprehensive Heterocyclic Chemistry, A. R.
Katritzky, and C. W. Rees, eds.; Pergamon Press, Oxford, 1984; Vol. 3,
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A. R. Katritzky, and C. W. Rees, eds.; Pergamon Press, Oxford, 1984;
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2 For some recent examples of biologically active 1,4-oxazine derivatives:
(a) W. Yang, Y. Wang, Z. Ma, R. Golla, T. Stouch, R. Seethala, S.
Johnson, R. Zhou, T. Gu¨ngo¨r, J. H. M. Feyen and J. K. Dickson,
Bioorg. Med. Chem. Lett., 2004, 14, 2327; (b) Y.-J. Wu, C. G. Boissard,
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The Royal Society of Chemistry 2009
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