A concise α-amino acid-based synthetic approach to [1,4]oxazepin-2-ones from Baylis-Hillman adducts

Article abstract of DOI:10.1016/j.tetlet.2009.01.048

An original two-step process for the synthesis of [1,4]oxazepin-2-ones starting from Baylis-Hillman (BH) adducts is reported. The protocol involves a nucleophilic substitution of the acetates of BH adducts with renewable natural α-amino esters followed by

Full text of DOI:10.1016/j.tetlet.2009.01.048

Tetrahedron Letters 50 (2009) 1423–1426
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A concise
a-amino acid-based synthetic approach to [1,4]oxazepin-2-ones
from Baylis–Hillman adducts
*
Lal Dhar S. Yadav , Vishnu P. Srivastava, Rajesh Patel
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An original two-step process for the synthesis of [1,4]oxazepin-2-ones starting from Baylis–Hillman (BH)
adducts is reported. The protocol involves a nucleophilic substitution of the acetates of BH adducts with
Received 4 November 2008
Revised 30 December 2008
Accepted 9 January 2009
Available online 14 January 2009
renewable natural
a-amino esters followed by base-catalyzed intramolecular Michael addition. These
sequential reactions are operationally simple, performed under ambient conditions, and give 81–93%
yields of the target [1,4]oxazepin-2-ones. Thus, the present invention opens up a new aspect for the syn-
thetic utility of BH adducts.
Keywords:
Baylis–Hillman adducts
[1,4]Oxazepines
Ó 2009 Elsevier Ltd. All rights reserved.
Amino acids
Nucleophilic substitution
Michael-addition
Cyclization reactions
In general, the chemistry of seven-membered heterocycles has
been far less extensively studied than that of five- and six-mem-
bered ones as well as the inherently strained small ring
heterocycles. The abundance of oxygen and nitrogen-containing
seven-membered and medium rings in natural products, pharma-
ceuticals, and agrochemicals continues to ensure that they are
important synthetic targets for organic chemists.1 Over the past
decades, the design and synthesis of heterocycles having a ring size
in the range of 7–11 have received a lot of attention in synthetic
organic chemistry as a consequence of their wide variety of appli-
cations such as biologically active natural products,2 drug candi-
dates,3 materials,4 and catalysts.5 Heterocyclic seven-membered
rings constitute the core or a key fragment of a number of bioactive
compounds including that isolated from natural sources.6,7 Among
them, seven-membered heterocycles with two heteroatoms in 1,4-
distance are known to possess manifold biological activities. In
particular, aryl-annelated [1,4]oxazepine8 units are crucial moie-
ties in several psychoactive pharmaceuticals, for example, oxaze-
pam (a tranquilizer).9 Moreover, Mukaiyama10 and Tietze11 have
shown that 6-benzylidene-oxazepane-5,7-dione is a valuable chi-
ral template for stereoselective synthesis.
mations.12 BH adducts incorporate a minimum of three chemo-
specific groups, that is, hydroxyl (or amino), alkene, and electron-
withdrawing groups. These groups could be appropriately tailored
to generate an array of cyclic scaffolds directly from the BH
adducts. Very recently, an excellent review has covered applica-
tions of BH adducts in the synthesis of cyclic frameworks.13 At
present, the adoption of renewable natural sources as starting
materials by the chemical industry is necessary and topical, as
our mineral resources continue to be consumed at a prodigious
pace. Natural a-amino acids and their derivatives provide the most
abundant renewable natural chiral pool, and can form efficient,
practical, facile precursors for various organic syntheses.14
The synthesis of 7- to 11-membered heterocycles is difficult
because of enthalpic and entropic reasons, which make direct
cyclization methods ineffective unless certain conformational
restraints are present in the acyclic precursor.2a,15 Hence, the
development of general and effective protocols to construct 7- to
11-membered heterocyclic systems is an interesting target of
investigation. Here, BH chemistry has been applied for this pur-
pose. BH adducts are useful substrates for a variety of nucleophilic
reactions such as SN2, SN20, and Michael addition, and amino acids/
alcohols provide two nucleophilic groups, which pose severe che-
moselectivity problems in their combinations. This fact should be
the main reason why only a few reports are available in the litera-
ture on the reaction of BH adducts with amino acids/alcohols.16
In view of the above valid points and our ongoing efforts to
develop new convenient cyclization processes,17 we were intrigued
by the question of whether allylic acetates 4 could be reacted with
The Baylis–Hillman (BH) reaction is a synthetically useful and
atom-economical carbon–carbon bond-forming reaction yielding
functionalized allylic alcohols, thereby providing handles for
further manipulation in a multitude of synthetic organic transfor-
* Corresponding author. Tel.: +91 5322500652; fax: +91 5322460533.
E-mail address: ldsyadav@hotmail.com (L.D.S. Yadav).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.048

1424
L.D.S. Yadav et al. / Tetrahedron Letters 50 (2009) 1423–1426
Table 1
R
R
Optimization of the catalyst for the cyclization of 2a to afford 1aa
R'
R'
N
R'
R
OAc
N
CO2Me
CN
N
CO2Me
H
Ar
OH
H
3
CN
N
HN
CO2Me
CN
HN
CO2M
CN
O
Ar
Ph
Ar
MeOH
NC
O
O
2
4
Ph
Ph
1
catalyst
rt
NC
O
1a
Scheme 1. Disconnection approch to [1,4]oxazepin-2-ones 1.
2a
5a
Entry
Catalyst
LiOH
NaOH
KOH
Ca(OH)2
Ba(OH)2
NH4OH
0.1M TFA/H2O
0.1M H2SO4/H2O
Timeb (h)
Yieldc (%)
OAc
HN
CO2Me
CN
1
2
3
4
5
6
7
8
12
6
3
12
10
12
48
21
51
70
84
42
48
33
30
38
i) KOH
ii) I2
3a
DABCO
THF/H2O
CN
Ph
Ph
4a
HN
Ph
2a
H
N
CO2K
Ph
NC
O
CN
O
a
b
c
For the experimental procedure, see Ref. 18.
Time for completion of the reaction at rt as indicated by TLC.
Yield of isolated and purified products.
5a
1a
H
N
O
O
O
I
HN
NC
Ph
NC
NC
Ph
O
O
Ph
adduct 4a was reacted with glycine ester 3a in THF/H2O (1:1) in
the presence of DABCO to afford 2a, which on treatment with
KOH and molecular iodine in methanol did not undergo iodolact-
onization, and [1,4]oxazepin-2-one 1a was obtained in 84% yield
instead of 7a or 7b. Interestingly, the same yield (84%) of 1a was
obtained, when the reaction was performed without using molec-
ular iodine. This demonstrates that 5a is a very good substrate for a
facile 7-endo-trigonal ring closure rather than an iodolactonization
reaction. The formation of iodonium ion 6a is probably hampered
by the electron-deficient olefinic bond of 5a; hence, the ensuing
iodolactonization to furnish 7a or 7b is not feasible (Scheme 2).
O
N
H
or
I
I
7a
6a
7b
Scheme 2. Formation of [1,4]oxazepin-2-one 1a from BH adduct 4a.
esters of
a
-amino acids 3 and subsequently cyclized under basic
conditions to afford [1,4]oxazepin-2-ones 1, a family of compounds
not explored to date (Scheme 1).
Initially, we investigated the possibility of the formation of 7a
or 7b via iodolactonization as depicted in Scheme 2. Thus, BH
Table 2
Base-catalyzed synthesis of [1,4]oxazepin-2-ones 1 at rt (Scheme 3)
Entry
Ester 2
Final product 1
Reaction timea (h)
Yieldb,c (%)
O
HN
CO2Me
CN
HN
O
1
3
84
2a
2b
2c
2d
NC
HN
1a
1b
1c
O
HN
CO2Me
CN
O
2
3
4
2.5
90
87
93
Cl
CN
Cl
O
HN
HN
CO2Me
HN
O2N
O
CN
3
O2N
CN
O
CO2Me
CN
HN
O
2
O2N
CN
O2N
1d
CH3
H3C
HN
O
HN
CO2Me
CN
O
5
6
3.5
2.5
85
89
CN
1e
1f
2e
2f
CH3
CO2Me
CN
H3C
HN
O
HN
O
CN
Cl
Cl

L.D.S. Yadav et al. / Tetrahedron Letters 50 (2009) 1423–1426
1425
Table 2 (continued)
Entry
Ester 2
Final product 1
Reaction timea (h)
Yieldb,c (%)
H3C
O
CH3
CO2Me
CN
HN
HN
HN
7
8
O
3
86
O2N
O2N
CN
1g
1h
2g
2h
CH3
H3C
HN
O
CO2Me
CN
O
2
90
CN
O2N
O2N
O
N
CO2Me
CN
N
O
9
4
81
85
CN
N
1i
1j
2i
2j
O
N
CO2Me
CN
O
10
3.5
CN
Cl
Cl
O
N
N
N
CO2Me
CN
O
11
4
3
83
89
O2N
O2N
CN
1k
1l
2k
2l
O
N
CO2Me
CN
O
12
CN
O2N
O2N
a
Time for completion of the reaction at rt as indicated by TLC.
Yield of isolated and purified products.
b
c
All compounds gave C, H and N analyses within 0.38% and satisfactory spectral (IR, 1H NMR, 13C NMR and EIMS) data.
Next, optimization of the catalyst for the cyclization of 2a to
very suitable stereochemical configuration for cyclization through
intramolecular Michael addition via a seven-membered transition
state. The seven-membered transition state probably exists in chair
form and ring closed via 7-endo-trigonal ring closure (Scheme 3).
afford 1a was investigated and it was found that among the cata-
lysts tested, KOH gave the best result (Table 1, entry 3). It is worth
noting that the catalyst used exhibited distinguishing effects as
manifested by reaction times and yields (Table 1). In general, bases
(Table 1, entries 1–6) were found to be more effective than acid
catalysts (Table 1, entries 7 and 8). This is presumably because,
in the former case, the nucleophilic carboxylate anion is available
for causing the cyclization, whereas in the latter case, a relatively
weaker nucleophile –COOH (5a, K+ = H) is available (Scheme 2).
The divergence in the observed catalytic behaviour of bases (Table
1, entries 1–6) can be explained in terms of their strength, which
increases the rate of hydrolysis of the adduct 2a as well as the abil-
ity of their countercations to form an ion-pair with the carboxylate
anion, thereby affecting its nucleophilicity. Thus, the highest cata-
lytic efficacy of KOH is attributed to its highest basicity and to the
formation of a weak ion-pair between K+ and –COOꢀ, which leaves
the nucleophile –COOꢀ much more open than in the case of other
bases (Table 1, entries 1–6).
In summary, we have demonstrated a concise
a-amino acid-
based synthetic approach to disubstituted [1-4]oxazepin-2-ones
via sequential intermolecular nucleophilic substitution and intra-
molecular Michael addition reactions. The present simple protocol
involves the combination of renewable natural a-amino acids and
BH chemistry for the synthesis of chemically and pharmacologi-
R
R'
OAc
Ar
N
CO2Me
CN
O
3 a-c
KOH, MeOH
CN
N
R'
Ar
R
CN
Ar
rt
rt
O
2
5
4
NC
N
NC
δ
δ
O
O
Ar
O
R'
Ar
O
O
The present optimized synthesis of [1,4]oxazepin-2-ones 1
N
N
involves stirring of BH adduct-derived
a-amino esters 2 with
Ar
R
R
R
CN
R'
KOH in methanol at rt for 2–4 h to afford 1.18 In order to investigate
the substrate scope, a wide range of esters 2 incorporating various
R'
O
1
aryl and a-amino acid moieties were reacted under optimized con-
ditions. As listed in Table 2, all the reactions went well and gave
the desired products 1 in consistently good yields (81–93%). The
CH3
CH
3b
COOMe
3c
CH2
3a
H N
COOMe
HCl.
H N
HCl.
COOMe
2
2
N
H
requisite BH adduct-derived a-amino esters 2 and their precursor
.HCl
BH adducts 4 were prepared employing known methods.16a,19 Car-
boxylate anions 5 generated by basic hydrolysis of esters 2 have
Scheme 3. A plausible mechanism for the formation of [1,4]oxazepin-2-ones 1.

1426
L.D.S. Yadav et al. / Tetrahedron Letters 50 (2009) 1423–1426
8. Ninomiya, I.; Naito, T.; Miyata, O. Compr. Heterocycl. Chem. II 1996, 217–231.
9. Julien, R. M. Drogen und Psychopharmaka; Spektrum Akad.: Heidelberg,
1997.
10. Mukaiyama, T.; Takeda, T.; Osaki, M. Chem. Lett. 1977, 1165–1168.
11. Tietze, L. F.; Brand, S.; Pfeiffer, T.; Antel, J.; Harms, K.; Sheldrick, G. M. J. Am.
Chem. Soc. 1987, 109, 921–923.
cally interesting 1,4-oxazepines, and is capable of being extended
to amino acid-derived chiral heterocycles of this family. Thus, the
present invention opens up a new aspect for the synthetic utility
of BH adducts.
12. (a) Basavaiah, D.; Jaganmohan, A.; Satyanarayana, T. Chem. Rev. 2003, 103, 811–
891; (b) Basavaiah, D.; Aravindu, K. Org. Lett. 2007, 9, 2453–2456; (c)
Basavaiah, D.; Reddy, K. R. Org. Lett. 2007, 9, 57–60; (d) Basavaiah, D.; Roy, S.
Org. Lett. 2008, 10, 1819–1822.
Acknowledgement
We sincerely thank SAIF, Punjab University, Chandigarh, for
providing microanalyses and spectral data.
13. Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511–4574.
14. Sardina, F. J.; Rapport, H. Chem. Rev. 1996, 96, 1825–1872.
15. Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; John Wiley &
Sons: New York, 1994.
16. (a) Pathak, R.; Batra, S. Tetrahedron 2007, 63, 9448–9455; (b) Reinhard, R.;
Doring, K.; Reiser, O. J. Org. Chem. 2000, 65, 6932–6939; (c) Niloy, D.; Räcker, R.;
Reiser, O. Synthesis 2002, 2232–2242.
17. (a) Yadav, L. D. S.; Patel, R.; Srivastava, V. P. Synlett 2008, 583–585; (b) Yadav, L.
D. S.; Srivastava, V. P.; Patel, R. Tetrahedron Lett. 2008, 49, 5652–5654; (c)
Yadav, L. D. S.; Awasthi, C.; Rai, V. K.; Rai, A. Tetrahedron Lett. 2007, 48, 4899–
4902; (d) Yadav, L. D. S.; Yadav, S.; Rai, V. K. Green Chem. 2006, 8, 455–458; (e)
Yadav, L. D. S.; Yadav, S.; Rai, V. K. Tetrahedron 2005, 61, 10013–10017; (f)
Yadav, L. D. S.; Kapoor, R. J. Org. Chem. 2004, 69, 8118–8120.
References and notes
1. Crimmince, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653–5660.
2. (a) Nubbemeyer, U. Top. Curr. Chem. 2001, 216, 125–196; (b) Maier, M. E.
Angew. Chem., Int. Ed. 2000, 39, 2073–2077; (c) Evans, P. A.; Holmes, B.
Tetrahedron 1991, 47, 9131–9166; (d) Lindström, U. M.; Somfai, P. Chem. A-Eur.
J. 2001, 7, 94–98; (e) Bieraügel, H.; Jansen, T. P.; Schoemaker, H. E.; Hiemstra,
H.; van Maarseveen, J. H. Org. Lett. 2002, 4, 2673–2674; (f) Derrer, S.; Davies, J.
E.; Holmes, A. B. J. Chem. Soc., Perkin Trans. 1 2000, 2957–2967; (g) Nicolaou, K.
C.; Vourloumis, D.; Winssinger, N.; Baran, P. Angew. Chem., Int. Ed. 2000, 39, 44–
122.
3. (a) Taunton, J.; Collins, J. L.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 10412–
10422; (b) Murray, P. J.; Kranz, M.; Ladlow, M.; Taylor, S.; Berst, F.; Holmes, A.
B.; Keavey, K. N.; Jaxa-Chamiec, A.; Seale, P. W.; Stead, P.; Upton, R. J.; Croft, S.
L.; Clegg, W.; Elsegood, M. R. Bioorg. Med. Chem. Lett. 2001, 11, 773–776.
4. (a) Sanchez-Quesada, J.; Ghadiri, M. R.; Bayley, H.; Braha, O. J. Am. Chem. Soc.
2000, 122, 11757–11766; (b) Bong, D. T.; Clark, T. D.; Granja, J. R.; Ghadiri, M. R.
Angew. Chem., Int. Ed. 2001, 40, 988–1011.
18. General procedure for the synthesis of [1,4]oxazepin-2-ones 1: A solution of
a-
amino ester 2 (1 mmol) and KOH (1.5 mmol) in methanol (3 mL) was stirred at
rt for 2–4 h (Table 2). After completion of the reaction (monitored by TLC),
water (10 mL) was added and the reaction mixture was extracted with ethyl
acetate (2 ꢁ 10 mL). The combined organic phase was dried over MgSO4,
filtered, and evaporated under reduced pressure. The resulting crude product
was purified by silica gel column chromatography using a mixture of hexane/
ethyl acetate (9:1) to afford an analytically pure sample of 1. Physical data of
representative compounds. Compound 1a: Colorless liquid, yield 84%. IR: mmax
(neat) 3300, 2989, 2243, 1740, 1604, 1495, 1451, 752, 705, cmꢀ1 1H NMR (400
.
5. Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481–2495.
MHz; CDCl3/TMS): d 2.13 (s, 1H, NH), 3.20 (d, 1H, J = 11.2 Hz, COCHa), 3.31 (d,
1H, J = 11.2 Hz, COCHb), 3.48–3.56 (m, 2H, CHCN and PhCH), 4.36–4.42 (m, 2H,
OCH2), 7.25–7.71 (m, 5Harom). 13C NMR (100 MHz; CDCl3/TMS): d 34.0, 55.5,
60.2, 72.1, 119.2, 124.3, 128.0, 128.8, 139.0, 172.0. EIMS (m/z): 216 (M+). Anal.
Calcd for C12H12N2O2, C, 66.65; H, 5.59; N, 12.96. Found: C, 66.95; H, 5.36; N,
12.65. Compound 1e: Colorless liquid, yield 85%. IR: mmax (neat) 3302, 2980,
6. (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell: Oxford, 2000;
(b) Cutignano, A.; Tramice, A.; De Caro, S.; Villani, G.; Cimino, G.; Fontana, A.
Angew. Chem., Int. Ed. 2003, 42, 2633–2636; (c) Renneberg, D.; Dervan, P. B.
J. Am. Chem. Soc. 2003, 125, 5707–5716; (d) Occhiato, E. G.; Prandi, C.; Ferrali,
A.; Guarna, A.; Venturello, P. J. Org. Chem. 2003, 68, 9728–9741; (e) Hepworth, J.
D.; Heron, B. M. Prog. Heterocycl. Chem. 2001, 13, 317–339; (f) Zimmer, R.
Synthesis 1993, 165–178; (g) Deng, J.; Zhao, S.; Miao, Z. Nat. Prod. Lett. 1993, 2,
283–286; (h) Evans, P. A.; Holmes, A. B. Tetrahedron 1991, 47, 9131–9166.
7. (a) Geronikaki, A. A.; Dearden, J. C.; Filimonov, D.; Galaeva, I.; Garibova, T. L.;
Gloriozova, T.; Krajneva, V.; Lagunin, A.; Macaev, F. Z.; Molodavkin, G.;
Poroikov, V. V.; Pogrebnoi, S. I.; Shepeli, F.; Voronina, T. A.; Tsitlakidou, M.;
Vlad, L. J. Med. Chem. 2004, 47, 2870–2876; (b) Dutton, F. E.; Lee, B. H.; Johnson,
S. S.; Coscarell, E. M.; Lee, P. H. J. Med. Chem. 2003, 46, 2057–2073; (c)
Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003,
59, 2953–2989; (d) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew.
Chem., Int. Ed. 2002, 41, 3247–3249; (e) Zhan, Z.-Y.; Dervan, P. B. Bioorg. Med.
Chem. 2000, 8, 2467–2474; (f) Bujard, M.; Gouverneur, V.; Mioskowski, C. J. Org.
Chem. 1999, 64, 2119–2123; (g) Hodge, C. N.; Pierce, J. Bioorg. Med. Chem. Lett.
1993, 3, 1605–1608; (h) Cooper, C. S.; Klock, P. L.; Chu, D. T. W.; Fernandes, P. B.
J. Med. Chem. 1990, 33, 1246–1252; (i) Boegesoe, K. P.; Arnt, J.; Boeck, V.;
Christensen, A. V.; Hyttel, J.; Jensen, K. G. J. Med. Chem. 1988, 31, 2247–2256.
2850, 2240, 1740, 1603, 1490, 1450, 754, 708 cmꢀ1 1H NMR (400 MHz; CDCl3/
.
TMS): d 2.04 (s, 1H, NH), 1.91 (d, 3H, J = 7.5 Hz, –CH3), 3.33 (q, 1H, J = 7.5 Hz,
COCH), 3.43–3.54 (m, 2H, CHCN and PhCH), 4.27–4.32 (m, 2H, OCH2), 7.05–
7.71 (m, 5Harom). 13C NMR (100 MHz; CDCl3/TMS): d 20.2, 34.2, 57.2, 60.5, 72.1,
119.1, 128.6, 129.1, 132.1, 141.0, 172.6. EIMS (m/z): 230 (M+). Anal. Calcd for
C13H14N2O2, C, 67.81; H, 6.13; N, 12.17. Found: C, 67.46; H, 6.49; N, 12.54.
Compound 1i: Colorless liquid, yield 81%. IR: mmax (neat) 2950, 2254, 1745,
1600, 1491, 1438, 750, 698 cmꢀ1 1H NMR (400 MHz; CDCl3/TMS): d 1.46–1.96
.
(m, 4H, C–CH2CH2–C), 2.20–2.28 (m, 2H, NCH2), 3.35 (t, 1H, J = 6.80 Hz, COCH),
3.41–3.53 (m, 2H, CHCN and PhCH), 4.30–4.37 (m, 2H, CH2O), 7.05–7.71 (m,
5Harom). 13C NMR (100 MHz; CDCl3/TMS): d 23.2, 28.3, 34.2, 55.1, 60.5, 69.2,
72.1, 119.1, 128.6, 129.8, 132.1, 141.0, 172.6. EIMS (m/z): 256 (M+). Anal. Calcd
for C15H16N2O2, C, 70.29; H, 6.29; N, 10.93. Found: C, 70.67; H, 6.50; N, 11.21.
19. Basavaiah, D.; Krishnamacharyaulu, M.; Suguna Hyma, R.; Sarma, P. K. S.;
Kumarrangurubaran, N. J. Org. Chem. 1999, 64, 1197–1200.