Photochemical synthesis of 3,4-dihydro-2H-1,3-oxazin-4-ones

Article abstract of DOI:10.1055/s-2001-15061

The first example of a C - O bond formation in the course of the Norrish - Yang reaction is described. Starting with readily accessible α-mesyloxy-β-keto amides 4, a δ-hydrogen transfer to the excited carbonyl group occurs and the diradicals thus formed undergo a very rapid elimination of methane sulfonic acid providing enolate diradicals. These ambidental enolate diradicals undergo a regioselective cyclization to 3,4-dihydro-2H-1,3-oxazin-4-ones 5. In two cases a cleavage reaction is observed, giving cyclic imines. The mechanism is investigated by means of DFT- and ab initio methods.

Full text of DOI:10.1055/s-2001-15061

1258
PAPER
Photochemical Synthesis of 3,4-Dihydro-2H-1,3-oxazin-4-ones
Photochemica
a
l
Synthesis
b
of 3,4-Dihyd
l
ro-2
H
-
o
1,3-oxazin-4-onesWessig,* Jutta Schwarz, Ute Lindemann, Max C. Holthausen
Institut für Organische und Bioorganische Chemie, Humboldt-Universität zu Berlin, Hessische Straße 1–2, 10115 Berlin
Fax +49(30)20936940; E-mail: pablo=wessig@chemie.hu-berlin.de
Received 5 February 2001
coupling of -ketocarboxylic acids with amines, provided
Abstract: The first example of a C–O bond formation in the course
of the Norrish–Yang reaction is described. Starting with readily ac-
cessible -mesyloxy- -keto amides 4, a -hydrogen transfer to the
excited carbonyl group occurs and the diradicals thus formed under-
-lactams 2 and was investigated previously.5 Upon treat-
3
ment with 1-hydroxy-1-phenyl- -iodanyl mesylate 3, the
amides 1 were converted into the corresponding -mesy-
go a very rapid elimination of methane sulfonic acid providing eno- loxy- -keto amides 4 with good yields6 (Scheme 1,
late diradicals. These ambidental enolate diradicals undergo a
regioselective cyclization to 3,4-dihydro-2H-1,3-oxazin-4-ones 5.
Table 1). Only in the case of the iminodiacetic acid deriv-
ative, the morpholinedione 6 was obtained instead of the
In two cases a cleavage reaction is observed, giving cyclic imines.
desired mesylate.
The mechanism is investigated by means of DFT- and ab initio
methods.
R1
R1
Key words: Norrish–Yang reaction, diradicals, oxazinones, photo-
R2
O
R2
O
cyclization, heterocycles
hν
O
N
HO
R4
N
ref. 5
R4
R3
R3
The Norrish–Yang reaction is one of the best investigated
and widely used photochemical reactions.1 Over the last
years many interesting synthetic applications have been
published and have impressively proven its preparative
value. Besides the synthesis of cyclobutanes, which was
developed more than 40 years ago by Yang and Yang,2 the
reaction was successfully applied on the preparation of
highly functionalized heterocycles, in particular.3 The
field of application extends from azetidines up to macro-
cyclic compounds. Possibly, the most important advan-
tage of the reaction is the ability to attack non- or less
activated C–H bonds highly regioselectively. But this fact
implies at the same time a limitation because the size of
ring formed in the course of a Norrish–Yang reaction of a
given reactant may barely be influenced. Consequently, a
process that would change the number of atoms between
the radical centers of intermediate diradical and thus alter
the ring size of the product should widen the scope of the
Norrish–Yang reaction considerably.
1
2
R1
R2
R4=Ph
O
N
i
Ph
O
OH
R3 OMs
Ph
I
3
OMs
4
Scheme 1 Reagents and conditions: i) 3, CH2Cl2, for react. time and
temp. see Table 1
The irradiation of -sulfonyloxy- -keto amides 4 was per-
formed according to the conditions optimized for the syn-
thesis of cyclopropanes (CH2Cl2, 2 equivalents N-
methylimidazole,
300 nm).4 In the initial photo-
IRR
chemical step, a hydrogen abstraction from the -position
by the n- * excited carbonyl group occurs, giving the 1,5-
diradicals A followed by a rapid elimination of methane-
sulfonic acid. We could not detect any product of a direct
cyclization of diradicals A in analogy to the formation of
2 (see Scheme 1). Obviously, the acid elimination pro-
ceeds very fast. The newly formed diradicals B are char-
acterized by three features. Firstly, the spin density of one
of the radical centers in A is shifted to the neighboring at-
om. Secondly, the diradicals B are ambidental in that both
a 1,6-diradical B1 and a 1,4-diradical B2 must be consid-
ered. Nevertheless, diradicals B are conjugated (provided
that none of the dihedral angles between the radical cen-
ters amounts exactly 90°, which is not very likely). Bear-
ing in mind that the spin density of enolate radicals is
markedly higher at the carbon atom and based on our pre-
vious experience,4 we expected that diradicals B react as
1,4-C-C-diradicals B2. Surprisingly, we obtained solely
the 3,4-dihydro-2H-1,3-oxazin-4-ones 5 which originate
from the 1,6-O-C diradicals B1 (Scheme 2, Table 2).
Very recently we published a novel route to cyclopro-
panes starting with alkyl aryl ketones bearing a leaving
group in the -position with respect to the carbonyl
group.4 The basic idea of our method was an adaptation of
the well-known behavior of -hydroxy radicals, i.e., to
eliminate acids very rapidly if a leaving group is bonded
to the carbon atom adjacent to the radical center. Herein,
we wish to report on the second application of this ap-
proach, the photochemical behavior of -sulfonyloxy- -
keto amides.
The photochemical cyclization of -keto amides 1, which
are easily accessible by aminolysis of -keto esters or by
Synthesis 2001, No. 8, 18 06 2001. Article Identifier:
1437-210X,E;2001,0,08,1258,1262,ftx,en;C01201SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Photochemical Synthesis of 3,4-Dihydro-2H-1,3-oxazin-4-ones
1259
R1
3
Table 1 Reaction of -Keto Amides 1 with 1-Hydroxy-1-phenyl-
3-iodanyl Mesylate 3
R1
R2
O
R2
O
HO
N
O
N
hν, CH2Cl2, λIRR > 300 nm
2 equiv N-methylimidazole
Product
R3
React. Temp
Yield
(%)
Ph
Ph
Time (h) (°C)
R3 OMs
R3 OMs
A
4
4a
4b
4c
-NMe2
H
H
H
1
40
20
40
97
91
90
-MsOH
R1
3
R1
R1
24
R2
R2
R2
O
N
O
N
O
N
ISC
1.5
Ph
O
Ph
O
Ph
O
R3
R3
R3
B1
4d
4e
H
H
4 d
4 d
20
20
88
75
B2
5
Scheme 2
ence as very likely based on quantum chemical
calculations. Thus, we found a very low activation barrier
for the reaction A B (approx. 1 kcal/mol).
4f
H
H
16
20
40
90
75
The structure of products 5 could be proven unambigu-
ously by X-ray structure analysis of 5c.15 3,4-Dihydro-
2H-1,3-oxazin-4-ones 5, which may be considered as cy-
clic derivatives of -keto acids, are versatile synthetic
building blocks,7 and have also been found in natural
products.8 Up to now only few methods are known to ob-
tain these compounds and most of them are characterized
either by low yields8b,9 or by low flexibility with respect
to the substituents (e.g., using diketene as reactant7).
4g
1
4h
4i
-N(i-Pr)2
H
24
1
20
40
95
61
Me
In case the radical center formed in the heterocycle is
more stabilized, the reaction goes another way. Thus,
upon irradiation of the N-acylated oxazolidines 4j, k, the
intermediate diradicals C undergo a cleavage giving ox-
azolines 7.10 Due to the UV spectroscopic properties of
the oxazinones 5, we can rule out that a subsequent pho-
tochemical cleavage of these compounds is responsible
for the reaction outcome of oxazolidines 4j, k. Obviously,
the thermodynamical driving force of the cleavage of the
diradicals C prevents cyclization. Benzoylketene is as-
sumed to be the second cleavage product but could not be
isolated, presumably due to its high reactivity. Although
this course of reaction should be limited to such reactants
bearing radical stabilizing groups at the carbon atom adja-
cent to the nitrogen atom, it should be an interesting syn-
thetic route to cyclic imines, which are barely accessible
by any other methods. Interestingly, 7a shows a remark-
able tendency to react with oxygen. An attempt to grow
crystals of 7a provided the stable hydroperoxide 8
(Scheme 3).
4j
4k
6
H
H
H
1
16
24
20
20
20
50
55
46a
a Compound 6 was obtained (Figure 1).
Although the main emphasis of this issue is synthetic ap-
plications, we wish to discuss the mechanism of photo-
chemical oxazinone synthesis briefly. The aim was to
determine why the cyclization of diradicals B (Scheme 2)
is characterized by an opposite regioselectivity compared
with our previously investigated systems.4 In order to en-
able quantum chemical investigations at a high level of
theory, we simplified the structure of the intermediate of
Figure 1
It should be noted that despite there is not yet an experi-
mental proof for the diradicals B, we consider their exist-
Synthesis 2001, No. 8, 1258–1262 ISSN 0039-7881 © Thieme Stuttgart · New York

1260
P. Wessig et al.
PAPER
Table 2 3,4-Dihydro-2H-1,3-oxazin-4-ones 5
Product
Yield
(%)
Mp
(°C)
IR (KBr) (cm–1)
1H NMR (300 MHz, CDCl3/TMS) , MS m/z (%)
J (Hz)
5a
44
117
1657, 1486, 1449, 1380, 1082,
1022, 886, 823, 781, 771, 693
7.70–7.66 (m, 2H), 7.47–7.41 (m,
3H), 5.94 (s, 1H, CH), 5.22 (s, 2H,
CH2-N), 3.04 (s, 3H, CH3-N)
189 (M+, 42)
201 ( M+, 10)
5b
5c
5d
58
–
1657, 1449, 1417, 1377, 1238,
1176, 1096, 771
7.66–7.62 (m, 2H), 7.44–7.39 (m,
3H), 5.95 (dd, 1H, J = 3.6, 5.5, CH-
N), 5.88 (s, 1H, CH), 4.34 (dt, 1H,
J = 5.7, 9.0), 4.08 (dt, 1H, J = 6.0,
8.1), 2.89–2.68 (m, 2H)
42
57
106
74
3072, 1657, 1447, 1379, 1349,
773, 695
7.69–7.66 (m, 2H), 7.48–7.28 (m,
3H), 5.93 (s, 1H, CH=), 5.51 (dd, 1H,
CH-N), 3.80–3.75 (m, 1H), 3.53–3.47
(m, 1H), 2.45–2.32 (m, 2H), 2.08–
1.93 (m, 2H)
215 (M+, 52)
229 (M+, 41)
3395, 2950, 2872, 1675, 1664,
1661, 1449, 1414, 1377, 774,
693
7.71–7.65 (m, 2H), 7.45–7.38 (m,
3H), 5.87 (s, 1H, CH), 5.17 (dd, 1H,
J = 4.3, 9.2, CH-N), 4.31–4.24 (m,
1H), 2.78–2.68 (m, 1H), 2.32–2.25
(m, 1H), 1.97–1.80 (m, 3H), 1.63–
1.44 (m, 2H)
5e
64
82
2923, 1647, 1461, 1453, 1424,
1371, 1309, 772, 693
7.69–7.65 (m, 2H), 7.44–7.34 (m,
3H), 5.94 (s, 1H, CH), 5.41 (dd, 1H,
J = 2.8, 5.1, CH-N), 4.19 (dd, 1H,
J = 5.7, 14.7), 3.21 (dd, 1H, J = 9.4,
14.7), 2.47–2.38 (m, 1H), 2.16–1.94
(m, 2H), 1.78–1.47 (m, 5H)
243 (M+, 13)
5f
42
73
61
68
1662, 1449, 1421, 1394, 1370,
1279, 1123, 989, 773, 691
7.71–7.39 (m, 5H), 5.90 (s, 1H, CH), 231 (M+, 11)
5.25 (dd, 1H, J = 4.5, 9.0, CH-N),
4.28 (dd, 1H, J = 4.5, 11.3), 4.13–3.99
(m, 2H), 3.72–3.59 (m, 2H), 3.10–
3.00 (m, 1H)
5ga
1667, 1452, 1436, 1392, 1363,
770, 691
7.70–7.41 (m, 5H), 5.91 (s, 1H, CH), 243 (M+, 15)
5.10 (d, 1H, J = 7.2, CH-N), 3.86 (dd,
1H, J = 7.9, 11.3, N-CHAHB), 3.16
(dd, 1H, J = 10.0, 11.3, N-CHAHB),
2.15–2.07 (m, 1H, CH-CH-N), 1.98–
1.90 (m, 1H, CH-CH2), 1.27 (d, 3H,
J = 6.4, CH3), 1.15 (d, 3H, J = 6.4,
CH3)
5h
5i
43
44
47
68
2929, 1656, 1450, 1422, 1379,
1359, 769, 692
7.67–7.62 (m, 2H), 7.42–7.36 (m,
3H), 5.79 (s, 1H, CH), 3.70 (br s, 1H,
CH), 1.75 (s, 6H, 2 CH3), 1.51/1.49
(s/s, 6H, 2 CH3
245 (M+, 8)
1641, 1629, 1450, 1376, 1076,
1064, 758, 703
7.50–7.49 (m, 2H), 7.43–7.39 (m,
3H), 5.47 (dd, 1H, J = 4.1, 5.7, CH-
N), 3.86–3.78 (m, 1H), 3.53–3.45 (m,
1H), 2.42–2.33 (m, 1H), 2.29–2.18
(m, 1H), 2.10–1.83 (m, 2H), 1.98 (s,
3H, CH3-C)
229 (M+, 28)
a Mixture of diastereomers.
interest. Thus, we chose the diradical D, derived from N- (amide radical moiety). Bearing in mind the well-known
formylacetyl methylamine, as a model system. It is easy to high rotation barrier of amide bonds, we only considered
recognize that the diradical D consists of two nearly pla- the s-cis- and s-trans-conformers with respect to the eno-
nar subunits defined, at the one hand, by atoms 1–3 (eno- late radical moiety. After a conformational analysis of
late radical moiety) and, on the other hand, by atoms 4–7 both types (B3PW91/6–31G*11), we determined accurate
Synthesis 2001, No. 8, 1258–1262 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Photochemical Synthesis of 3,4-Dihydro-2H-1,3-oxazin-4-ones
1261
trans-conformers D3 and D4 and therefore the question
arose whether a rotation around the bond 1–2-3–4 in the
enolate radical moiety is actually possible within the life-
time of the triplet diradicals (approx. 100 ns13). We found
that the activation barrier for such a rotation amounts to
approx. 13 kcal/mol and thus only conformers D1 and D2
can be considered. In fact, the regioselectivity could be
understood by the lower energy of the diradical conformer
D1 compared with D2 (Figure 2).
O
O
O
O
R
R
hν
Ph
N
Ph
N
Ph
Ph
MsO
O
O
C
4j R = Ph
4k R = Me
Ph
Ph
R
Ph
O2
(R = Ph)
O
Nevertheless, we should not withhold another possible ex-
planation. As mentioned above, the diradicals B–D must
be considered as coupled diradicals, which means that a
conjugation exists between the two radical-bearing moi-
eties. The consequence of this fact is exactly that what
was called “increased ionic character” of the singlet state
in the legendary rules by Salem and Rowland.14 These
rules allow a qualitative estimation of the spin orbit cou-
pling (SOC), which is the most important mechanism for
the intersystem crossing. From this point of view, we can-
not rule out that the lifetimes of the diradicals B and C are
extremely short and that the observed regioselectivity
simply reflects the reactant conformation (memory ef-
fect). We will investigate this aspect thoroughly in future.
OH
N
O
N
O
8
7a 69%
7b 26%
Scheme 3
energies of the appropriate minimum geometries at a very
high level of theory (CBS-QB312). Amongst the four ob-
tained diradical conformers D1–D4, the conformer D3 was
identified as the global minimum, followed by D4. The
formation of oxazinones 5 cannot be realized from s-
Figure 2 CBS-Q(B3)-Energies (0 K), dihedral angles 2–3-4–6 and relative energies of the diradical conformers D1–D4
Synthesis 2001, No. 8, 1258–1262 ISSN 0039-7881 © Thieme Stuttgart · New York

1262
P. Wessig et al.
PAPER
Tokyo, 1995, 449.
In summary, we have developed a novel efficient method
for the preparation of 3,4-dihydro-2H-1,3-oxazin-4-ones
and cyclic imines. The method is especially remarkable in
that it allows the regioselective oxidation of less activated
C-H bonds. It should be noted, that the ring-closure de-
scribed herein is the first example of a C–O bond forma-
tion in the course of the Norrish–Yang reaction.
(2) Yang, N. C.; Yang, D.-H. J. Am. Chem. Soc. 1958, 80, 2913.
(3) (a) Wessig, P. Synlett 1999, 1465. (b) Wessig, P.
Tetrahedron Lett. 1999, 40, 5987. (c) Lindemann, U.;
Wulff-Molder, D.; Wessig, P. Tetrahedron: Asymmetry
1998, 9, 4459. (d) Wessig, P.; Schwarz, J. Helv. Chim. Acta
1998, 81, 1803. (e) Lindemann, U.; Reck, G.; Wulff-
Molder, D.; Wessig, P. Tetrahedron 1998, 54, 2529.
(f) Wessig, P.; Schwarz, J.; Wulff-Molder, D.; Reck, G.
Monatsh. Chem. 1997, 128, 849. (g) Steiner, A.; Wessig, P.;
Polborn, K. Helv. Chim. Acta 1996, 79, 1843. (h) Wessig,
P.; Wettstein, P.; Giese, B.; Neuburger, M.; Zehnder, M.
Helv. Chim. Acta 1994, 77, 829. (i) Wessig, P.; Legart, F.;
Hoffmann, B.; Henning, H.-G. Liebigs Ann. Chem. 1991,
979.
TLC was performed on alumina sheets with silica gel 60 F254 (Mer-
ck), detected by UV light. Silica gel 40–63 m (Merck) and mobile
phase of CH2Cl2–MeOH mixtures were used for flash chromatogra-
phy. The uncorrected mps were determined on a Boetius micro
melting point apparatus (Wagema). IR spectra were taken with a
Perkin–Elmer-881 (solids as KBr pellets, oils on NaCl plates).
NMR spectra were recorded with a Bruker DPX300 (1H 300 MHz,
13C 75.5 MHz), using TMS as internal standard. EI-mass spectra
were taken with a Hewlett Packard 5995 A, 70 eV at 293–593 K.
(4) Wessig, P.; Mühling, O. Angew. Chem., Int. Ed. 2001, 40,
1064.
(5) (a) Hasegawa, T.; Aoyama, H. J. Chem. Soc., Chem.
Commun. 1974, 743. (b) Hasegawa, T.; Aoyama, H.;
Omote, Y. J. Chem. Soc., Perkin Trans. 1 1976, 2055.
(c) Gramain, J.-C.; Remuson, R.; Vallée, D. J. Org. Chem.
1985, 50, 710.
(6) Lazbin, I. M.; Koser, G. F. J. Org. Chem. 1986, 51, 2669.
(7) Meyers, A. I.; Leonard, W. R.; Romine, J. L. Tetrahedron
Lett. 1991, 32, 597.
(8) (a) Moya, P.; Castillo, M.; Primo-Yúfera, E.; Couillaud, F.;
Martínez-Máñez, R.; Garcerá, M.; Miranda, M. A.; Primo,
J.; Martínez-Pardo, R. J. Org. Chem. 1997, 62, 8544.
(b) Cantín, Á.; Moya, P.; Castillo, M.-A.; Primo, J.;
Miranda, M. A.; Primo-Yúfera, E. Eur. J. Org. Chem. 1999,
221.
-Sulfonyloxy- -keto Amides 4; General Procedure
Amide 1 (1.00 mmol) dissolved in anhyd CH2Cl2 (30 mL) was treat-
ed with 1-hydroxy-1-phenyl- 3-iodanyl mesylate 3 (1.00 mmol, for
reaction time and temperature see Table 1). Reaction completion
was detected by TLC (CH2Cl2–MeOH, 100:1 to 100:2). Products 4
were isolated by crystallization or flash chromatography.
Photocyclization of -Sulfonyloxy- -keto Amides 4 to 3,4-
Dihydro-2H-1,3-oxazin-4-ones 5; General Procedure
Irradiations of amides 4 were performed in CH2Cl2 (300 mL) at con-
centrations of 3 mg/mL in the presence of N-methylimidazole (2
equiv), using a high-pressure mercury arc lamp (150 W). Light of
wavelength below 300 nm was absorbed using a Pyrex™ glass jack-
et between the lamp and the reaction vessel. The reaction was moni-
tored by TLC and aborted when the reactant had completely disap-
peared. The solution was washed with H2O, dried and evaporated in
vacuo. The products 4 were isolated by flash chromatography.
(9) Bertolini, G.; Aquino, M.; Ferrario, F.; Favich, G.; Zaliani,
A.; Sala, A. J. Org. Chem. 1996, 61, 3358.
(10) Compound 7a was previously prepared by another
photochemical method: (a) Giezendanner, H.; Märky, M.;
Jackson, B.; Hansen, H.-J.; Schmid, H. Helv. Chim. Acta
1972, 55, 745. (b) Giezendanner, H.; Heimgartner, H.;
Jackson, B.; Winkler, T.; Hansen, H.-J.; Schmid, H. Helv.
Chim. Acta 1973, 56, 2611.
(11) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(b) Perdew, J. P.; Burke, K.; Wang, Y. Phys. Rev. B 1996,
54, 16533.
Acknowledgement
We are grateful for financial support from the Deutsche For-
schungsgemeinschaft (We-1850/3–1).
(12) Montgomery, J. A.; Frisch, M. J.; Ochterski, J. W. J. Chem.
Phys. 2000, 112, 6532.
(13) Johnston, L. J.; Scaiano, J. C. Chem. Rev. 1989, 89, 521.
(14) Salem, L.; Rowland, C. Angew. Chem., Int. Ed. Engl. 1972,
11, 92.
(15) We thank Dr. D. Wulff-Molder for performing the X-ray
structure analysis of 5c. Details of the structure investigation
are available on request from the Cambridge
Crystallographic Data Centre, on quoting the depository
number CCDC 157275.
References
(1) (a) Wagner, P. J. Acc. Chem. Res. 1971, 4, 168.
(b) Wagner, P. J. Top. Curr. Chem. 1976, 66, 1.
(c) Wagner, P. J. Acc. Chem. Res. 1989, 22, 83.
(d) Wagner, P. J.; Park, B. In Organic Photochemistry;
Padwa, A., Ed.; Marcel Dekker: New York, Basel, 1991,
227. (e) Wagner, P. J. In CRC Handbook of Organic
Photochemistry and Photobiology; Horspool, W. M.; Song,
P.-S., Eds.; CRC Press: Boca Raton, New York, London,
Synthesis 2001, No. 8, 1258–1262 ISSN 0039-7881 © Thieme Stuttgart · New York