The photochemistry of acyl azides; X: Aroylnitrenes for heterocycle synthesis

Article abstract of DOI:10.1055/s-2001-15054

Stereoselective cycloaddition of aroylnitrenes, generated by photolysis of the corresponding azides 2a,b with the racemic mixtures of cyclic enol ethers 5b and 5c was achieved with the formation of oxazolines 8. Both the chiral auxiliary attached to the a

Full text of DOI:10.1055/s-2001-15054

PAPER
1125
The Photochemistry of Acyl Azides; X: Aroylnitrenes for Heterocycle
Synthesis
P
hotochemistry of
.
A
cyl
AzidesRoeske, W. Abraham*
Humboldt-University, Institute of Chemistry, Hessische Str. 1–2, 10115 Berlin, Germany
Fax +49 30 2093 7343; E-mail: abraham@chemie.hu-berlin.de
Received 22 January 2001; revised 29 March 2001
Dedicated to Prof. Howard E. Zimmerman on the occasion of his 75th birthday
es as to the possibility of a stereoselective cycloaddition
reaction of aroyl nitrenes. Aroyl nitrenes carrying chiral
auxiliaries at the phenyl group may be an alternative in-
ducing group of stereoselective addition reactions of acyl
Abstract: Stereoselective cycloaddition of aroylnitrenes, generated
by photolysis of the corresponding azides 2a,b with the racemic
mixtures of cyclic enol ethers 5b and 5c was achieved with the for-
mation of oxazolines 8. Both the chiral auxiliary attached to the
aroylnitrene and the substituent in the substrate is necessary in order nitrenes.
to selectively allow the formation of the trans-adducts 8. The cy-
Here we present results obtained with the photolysis of
cloaddition of aroylnitrenes bearing chiral auxiliaries with ketones
did not occur stereoselectively. Benzoyl azides bearing a neigh-
bouring amide group were found to react unexpectedly by intramo-
lecular insertion into the N–H bond.
newly designed aroyl azides (Scheme 1) in the absence
and in the presence of cyclic enol ethers and ketones, re-
spectively, which are known to react with acyl nitrenes by
the formation of five-membered heterocycles.4
Key words: acyl nitrenes, photolysis, enolether, ketone, chiral aux-
iliaries, heterocycles
In order to generate aroylnitrenes bearing chiral auxilia-
ries, menthyl and phenylcyclohexyl substituents were ap-
pended to the corresponding azides 2 (Table 1). The o-
position of the auxiliary was chosen in order to ensure its
vicinity to the reaction centre. Ester groups were used as
they allow the easy removal of the auxiliary. The amide
group is harder to remove but may induce better stereose-
lectivity due to the hindered rotation around the amide
bond compared to the ester bond.
Aroylnitrenes, as a type of acylnitrene, are highly reactive
and short living intermediates which can only be generat-
ed via the excited state of the corresponding precursors.1
The photolysis of aromatic acyl azides matches, at best,
the requirements for the effective generation of aroylni-
trenes.2 Despite their high reactivity, aroylnitrenes gener-
ated via the excited state of the corresponding azides have
been shown to react selectively with -bonds.2 Depending
on the character of the -bond, three- or five-membered
heterocycles are formed. One drawback of the photoge-
neration of aroylnitrenes is in the concomitant formation
of aryl isocyanates via the excited singlet state.1 Recently
we have shown that the formation of isocyanates can be
avoided due to the special excitation conditions of the
aroyl azides, these being the sensitisation of the azide de-
composition by electron transfer from excited electron do-
nors in the triplet state, such as Michler’s ketone.3
The esters 2a and 2b were synthesized by the sequence (1)
shown in Scheme 1; the amide 4c was prepared in an anal-
ogous manner [sequence (2) in Scheme 1]. Achiral amido
substituted benzoyl azides 4a,b,d (Table 1) were also pre-
pared via the anhydride method.
The activation energy of the thermal Curtius rearrange-
ment is diminished by a substituent in the o-position to the
azidocarbonyl group;6 therefore, photoreactions of the
azides have to be carried out at or below 0°C.
The most important question to be answered is whether
nitrenes will be formed by photolysis of the corresponding
azides. It turns out that the corresponding isocyanate iden-
tified as the urethane by the addition of methanol, was the
only product that could be isolated after the photolysis of
2 in acetonitrile solution. The proportion of this undesired
photo-Curtius rearrangement amounts to some 40%.
Products of the nitrene reaction with the solvent acetoni-
trile, such as oxadiazole,1 were not obtained. In addition,
amides, which are expected to be formed from aroyl ni-
trenes in the triplet state, were not found.
Further problems that exist are the competitive reaction of
the aroylnitrene with the solvent such as cycloaddition to
acetonitrile, bond insertion with alcohols or alkanes and
insertion into the C–Cl bond of dichloromethane.4 How-
ever, suitable conditions can be found in order to achieve
the desired reaction on a preparative scale.
Recently it has been shown that the diastereoselectivity of
the addition of benzoylnitrene towards cyclic enol ethers
is controlled by the substrate.5 The introduction of a chiral
substituent into an alkoxyacyl nitrene resulted in a negli-
gible diastereomeric excess.5 Therefore the question aris-
In the case of the azide 2a, it was proven that no isocyan-
ate was formed by sensitisation of the azide decomposi-
tion using Michler's ketone in acetonitrile solution,
however, 95% of the corresponding amide was obtained.3
Synthesis 2001, No. 8, 18 06 2001. Article Identifier:
1437-210X,E;2001,0,08,1125,1132,ftx,en;C00501SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
In view of the lack of a reaction of a potential chiral aroyl
nitrene with the solvent acetonitrile, the question arises as

1126
Y. Roeske, W. Abraham
PAPER
Table 1 Aroyl Azides 2 and 4
Producta Yield
(%)
Mp
(°C)
1H NMR (CDCl3)
, J (Hz)
13C NMR (CDCl3)
MS
m/z (%)
IR (KBr)
(CON3)
(cm–1)
2a
53
62–64
0.81 (t, J = 7.0, 3 H, CH3),
0.89 (t, J = 7.0, 3 H, CH3),
0.93 (t, J = 6.6, 3 H, CH3),
1.0–1.6 (m, 5 H, CH2), 1.7
16.1 (CH3), 20.8 (CH3), 22.0
(CH3), 23.3 (CH2), 26.2 (CH), 31.4 (97), 95 (80), 90
(CH), 34.2 (CH2), 40.4 (CH2), 47.1 (84), 81 (88), 55
146 (100), 138
2185, 2140
(CH), 76.0 (CH), 128.8 (CH),
(78), 43 (52)
(m, 2 H, CH2), 1.95 (m, 1 H, 128.9 (CH), 130.7 (CH), 131.7 (C),
CH2), 2.2 (m, 1 H, CH2), 4.9 132.2 (CH), 133.3 (C), 167.0 (C),
(m, 1 H, CH), 7.6 (m, 2
173.5 (C)
Harom), 7.8 (m, 1 Harom), 7.9
(m, 1 Harom
)
2b
45
30
64–67
1.3–2.1 (m, 7 H, CH2), 2.4
(m, 1 H, CH2), 2.75 (m, 1 H, (CH2), 33.9 (CH2), 49.9 (CH), 77.7 (100), 146 (50), 91
CH), 5.25 (m, 1 H, CH), 6.9 (CH), 126.5 (CH), 127.6 (CH),
(m, 1 Harom), 7.25 (m, 5
24.7 (CH2), 25.8 (CH2), 31.9
159 (17), 158
2188, 2143
2150, 2134
(83), 86 (77), 59
(56), 58 (38), 28
128.3 (CH), 129.0 (CH), 130.2
(CH), 130.5 (C), 132.4 (CH), 133.9 (99)
(C), 142.9 (C), 167.0 (C), 172.7 (C)
Harom), 7.4 (m, 2 Harom), 7.7
(m, 1 Harom
)
4ab
104
0.8–1.0 (m, 9 H, CH3), 1.1– 20.7 (CH3), 21.1 (CH3), 22.3
300 (2), 163 (34),
2.2 (m, 9 H, CH2, CH), 4.5
(m, 1 H, CH), 5.8 (d,
(CH3), 25.5 (CH2), 27.0 (CH), 29.7 146 (100), 138 (4),
(CH), 34.7 (CH2), 39.5 (CH2), 46.2 95 (12), 81 (10),
J = 10.0, 1 H, NH), 7.35 (m, (CH), 46.8 (CH), 127.8 (CH),
55 (16), 43 (19)
1 Harom), 7.43 (m, 1 Harom),
7.5 (m, 1 Harom), 7.85 (m, 1
129.5 (CH), 130.1 (CH), 133.0
(CH), 139.1 (C), 168.1 (C), 172.3
(C)
Harom
)
4bb
33
89–91
0.9–1.9 (m, 16 H, CH3,
19.8/20.1 (CH3), 20.4 (CH3), 25.1/ 286 (1), 243 (6),
2171, 2137
CH2), 2.7 (m, 1 H, CH), 3.05 25.3 (CH2), 25.6 (CH2), 26.6
203 (3), 146 (100),
130 (62), 102 (24),
90 (45), 76 (10),
(m, 1 H, CH), 7.2 (m, 1
Harom), 7.4 (m, 1 Harom), 7.6
(m, 1 Harom), 8.0 (m, 1 Harom
(CH2), 9.2/29.8 (CH2), 30.4/30.7
(CH2), 46.9/51.2 (CH), 4.7/60.0
)
(CH), 6.2/126.3 (CH), 127.0/127.1 70 (10), 55 (22),
(C), 128.09/128.14 (CH), 30.6
(CH), 133.76/133.85 CH), 140.8/
140.9 (C), 169.3/169.4 (C), 71.48/
171.53 (C)
43 (25), 41
(34)
4cb
45
93–96
0.8–2.0 (m, 26 H, CH3,
CH2), 3.0–3.2 (m, 3 H, CH2, (CH2), 25.9 (CH2), 30.4 (CH2),
14.2/16.0 (CH3), 25.1 (CH2), 25.6
286 (2), 243 (7),
174 (13), 146
2168, 2131
CH), 3.5 (m, 2 H, CH2), 4.4 31.3 (CH2), 36.4/39.7 (CH2), 54.2/ (100), 90 (41), 55
(m, 1H, CH), 7.2 (m, 1
59.1 (CH), 126.7/127.5 (CH), 27.1/ (17), 43 (16), 41
Harom), 7.3 (m, 1 Harom), 7.4
127.4 (C), 28.36/128.40 (CH),
(20)
(m, 2 Harom), 7.6 (m, 2 Harom), 130.5/130.6 (CH), 133.7 (CH),
8.0 (m, 2 Harom
)
139.9/140.1 (C), 169.3 (C), 170.2/
171.5 (C)
c
4d
39
oil
1.8–2.0 (m, 4 H, CH2), 3.1 (t, 24.2 (CH2), 25.5 (CH2), 45.3
J = 6.7, 2 H, CH2), 3.7 (t, (CH2), 48.0 (CH2), 126.7 (C),
J = 6.7, 2 H, CH2), 7.3 (m, 1 126.9 (CH), 128.6 (CH), 130.1
-
2170, 2136
Harom), 7.4 (m, 1 Harom), 7.6
(m, 1 Harom), 8.0 (m, 1 Harom
(CH), 134.0 (CH), 139.5 (C), 168.5
(C), 171.4 (C)
)
a Satisfactory microanalyses obtained.
b Two rotamers.
c HRMS: m/z Calcd 216.0898, found 216.0899.
to whether trapping the nitrene by electron rich alkenes in the product 7 provided by the chiral auxiliary amounts
such as dihydropyrans 5 will be possible. Indeed, it is only to only 2%, according to 13C NMR spectra.
by using a large excess of the enol ether (5 M) that the re-
action of the nitrene generated by the photolysis of 2a
with the achiral enol ether 5a (see Scheme 2) yields the
The trans-axial position of the substituents of 7 is con-
cluded by the coupling constant of J = 2.4 Hz between the
protons at C-2 and C-3 which are typical for the equatorial
oxazoline that was characterised by the ring-opened prod-
position of both hydrogen atoms.7
uct 7 at a low yield (Scheme 2). The asymmetric induction
Synthesis 2001, No. 8, 1125–1132 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Photochemistry of Acyl Azides
1127
The combination of the effects of substituents in both the
nitrene and the substrate leads to complete diastereoselec-
tivity because only one set of these distinct carbon reso-
nances is observed; i.e. the trans-oxazolines 8 are
exclusively formed. The enol ethers 5b and 5c were used
as racemic mixtures leading to two enantiomers of the
“trans“-diastereomer. A slight selectivity was observed in
the reaction with the two enantiomers of the enol ether and
some carbon resonances (but not those of C-5 and C-3a)
were doubled. According to the 13C NMR spectra, a rela-
tive excess of one of the trans-diastereomers (13%) was
detected.
i: ClCO2Et, NEt3
ii: NaN3
COOR
COOH
COOR
CON3
(1)
1
2
Me
Ph
a: R =
b: R =
i: ClCO2Et,
NEt3
ii: NaN3
CONR1R2
COOH
CONR1R2
CON3
(2)
3
4
2a, b
+
Me
O
OR'
5b: R = Me
5c: R = i-Bu
b: R1 = i-Propyl
R2 = Cyclohexyl
a: R1 = H, R2
=
hν
– N2
d: R1, R2 = (CH2)4
c: R1 = Et
R2 = Cyclohexyl
COOR
COOR
Scheme 1
+
O
O
N
O
N
The addition of aroylnitrenes to cyclic enol ethers 5b,c re-
sults in two diastereomers; in the cis-diastereomer the
newly formed bonds and the substituent are situated at the
same site; in the trans-diastereomer they are on opposite
sites of the ring plane (Scheme 3). These two diastere-
omers can be differentiated by their 13C NMR spectra. C-
5 and C-3a, of the trans-3a,6,7,7a-tetrahydro-5H-pyra-
no[3,2-d]oxazoles resonate at about 98 ppm whilst those
of the cis-diastereomer resonate at about 100 ppm.5
O
R'O
R'O
trans-8
Me
Ph
8 a: R =
R' = Me
8 b: R =
R' = i-Bu
Scheme 3
COOR
COOR
hν
N
+
The cycloadduct 8a was also obtained by the sensitised
decomposition of 2a by Michler’s ketone using the exci-
tation wavelength of 365 nm. In this case, the formation
of the isocyanate can be avoided, but the yield of the cy-
cloadduct amounts to only 8% because the main product
is the corresponding amide.
– N2
O
O
CON3
2a
hν
5 a
O
– N2
MeOH
COOR
COOR
CO
COOR
The addition of the aroylnitrenes generated from 2 to-
wards the carbonyl group of 9 and 11, is not hampered by
the presence of the bulky auxiliary (Scheme 4). However,
neither the chiral auxiliary of the azide 2a nor that of 2b
induced a degree of selectivity regarding the addition of
the corresponding nitrenes towards the diastereotopic fac-
es of the ketones 9 and 11 (see Scheme 4 and Table 2).
NCO
CO
HN
HN
+
MeOH
MeO
O
MeO
O
COOR
7
NHCOOMe
6a
The aroylnitrene generated from 4a was designed to pro-
vide better stereoselectivity due to the more rigid amide
function, however, it turned out that only the intramolec-
ular insertion into the neighboured N–H bond is able to
occur, as displayed in Scheme 5.
R =
Me
Scheme 2
Synthesis 2001, No. 8, 1125–1132 ISSN 0039-7881 © Thieme Stuttgart · New York

1128
Y. Roeske, W. Abraham
PAPER
Table 2 Aroyl Nitrene Aducts
Azide
Nitrene Conc./
Adducta Yield
(%)/
Other
Products/
Yield (%)
1H NMR (CDCl3),
, J (Hz)
13C NMR (CDCl3)
HRMS (M+) or
MS m/z (%)
Trap
Irrad.
Time
de (%)
2a
5a
5 M/27 7b
12/2
6a/7
0.7 (d, J = 6.9, 3 H, 16.2 (CH3), 20.7 (CH2),
Calcd for
C24H35NO5 + H
418.2593
Found
CH3), 0.8 (m, 6 H,
CH3), 1.0–2.2 (m,
13 H, CH2), 3.3 (s,
20.8 (CH3), 22.0 (CH3),
22.8/22.9 (CH2), 23.3
(CH2), 26.14/26.19 (CH),
3 H, CH3), 3.5 (m, 1 31.4 (CH), 34.2 (CH2), 40.6 418.2591
H, CH2), 3.8 (dt,
J = 2.4, 11.4, 1 H,
CH), 4.1 (m, 1 H,
CH2), 4.5 (m, 1 H,
CH), 4.8 (dt,
(CH2), 46.94/46.98 (CH),
47.1 (CH), 54.8 (CH3), 59.6
(CH2), 75.4/75.5 (CH),
99.5 (CH), 127.8 (CH),
129.4 (CH), 129.6/129.7
(C), 129.9 (CH), 131.7
(CH), 138.3/138.4 (C),
J = 3.9, 10.6, 1 H,
CH), 6.3 (m, 1 H,
NH), 7.3–7.5 (m, 3 165.8/165.9 (C), 168.6/
Harom), 7.8 (m, 1
Harom
168.7 (C)
)
2a
5b
1 M/25 8ab
10/11
6a/54
0.71 (d, J = 6.9, 3
H, CH3), 0.72 (d,
J = 6.9, 3 H, CH3),
16.17/16.22 (CH3), 20.9
(CH3), 22.0 (CH3), 22.3/
22.4 (CH2), 23.3 (CH2),
Calcd for
C24H33NO5
415.2359
Found
0.9 (m, 12 H, CH3), 26.1/26.2 (CH), 27.6
1.0–2.4 (m, 26 H,
CH2, CH), 3.44 (s,
3 H, CH3), 3.46 (s,
(CH2), 31.4 (CH), 34.2
(CH2), 40.6 (CH2), 47.1
(CH), 49.3/49.4 (CH), 55.9/
415.2347
3 H, CH3), 3.9 (m, 2 56.2 (CH3), 75.5/75.6
H, CH), 4.5 (m, 2
H, CH), 4.8 (dt,
J = 4.3, 10.9, 2 H,
CH), 6.07 (d,
J = 7.2, 1 H, CH),
6.14 (d, J = 7.2, 1
(CH), 100.2 (CH), 101.0
(CH), 127.9/128.0 (CH),
129.5 (CH), 129.66/129.75
(C), 129.82/129.88 (CH),
131.7 (CH), 138.1/138.2
(C), 166.0/166.1 (C),
H, CH), 7.3–7.5 (m, 168.98/168.05 (C)
6 Harom), 7.8 (m, 2
Harom
)
2a
9
1 M/34 10a
41/-
6a/49
0.8 (d, J = 7.0, 3 H, 16.2 (CH3), 20.8 (CH3),
Calcd for
CH3), 0.9 (m, 6 H, 22.0 (CH3), 23.4 (CH2),
C24H33NO4
CH3), 1.0–2.2 (m, 9 24.6 (CH), 26.2 (CH), 31.4 399.2410
H, CH2, CH), 4.9 8 (CH), 34.2 (CH2), 34.3
Found
(dt, J = 4.4, 10.9, 1
H, CH), 7.5 (m, 2
Harom), 7.7 (m, 2
(CH2), 34.4 (CH2), 40.7
(CH2), 47.1 (CH), 75.6
(CH), 117.0 (C), 123.2 (C),
129.2 (CH), 130.1 (CH),
130.8 (CH), 131.0 (CH),
132.7 (C), 158.1 (C), 166.0
(C)
399.2410
Harom
)
2a
11
neat/41 12ab
21/2
6a/43
0.79 (d, J = 6.9 Hz, 7.46/7.53 (CH3), 16.22/
3 H, CH3), 0.80 (d, 16.25 (CH3), 20.8 (CH3),
Calcd for
C22H31NO4
373.2253
Found
J = 6.9 Hz, 3 H,
CH3), 0.8–2.2 (m,
46 H, CH3, CH2,
CH), 4.9 (m, 2 H,
CH), 7.5 (m, 4
22.0 (CH3), 23.0 (CH3),
23.4 (CH2), 26.2 (CH),
31.11/31.15 (CH2), 31.4
(CH), 34.2 (CH2), 40.57/
40.63 (CH2), 47.0 (CH),
75.55/75.63 (CH), 118.3
(C), 122.8 (C), 128.9/129.0
(CH), 129.80/129.85 (CH),
130.8 (CH), 132.9 (C),
157.9 (C), 166.3 (C)
373.2254
Harom), 7.7 (m, 4
Harom
)
Synthesis 2001, No. 8, 1125–1132 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Photochemistry of Acyl Azides
1129
Table 2 Aroyl Nitrene Aducts (continued)
Azide
Nitrene Conc./
Adducta Yield
(%)/
Other
Products/
Yield (%)
1H NMR (CDCl3),
, J (Hz)
13C NMR (CDCl3)
HRMS (M+) or
MS m/z (%)
Trap
Irrad.
Time
de (%)
2b
5c
1 M/23 8b
16/13
Isocya-
nate/43
0.9 (d, J = 7.2, 12
H, CH3), 1.4–2.5
(m, 26 H, CH2,
CH), 2.8 (m, 2 H,
CH), 3.2 (m, 2 H,
CH2), 3.7 (m, 2 H,
CH2), 3.9 (m, 2 H,
CH), 4.65 (t,
19.31/19.38 (CH3), 23.0/
23.4 (CH2), 24.7 (CH2),
25.8 (CH2), 28.2/28.3
(CH2), 28.4 (CH), 32.03/
32.09 (CH2), 33.9 (CH2),
49.7/49.9 (CH), 55.8 (CH), 130 (22), 117
75.74/75.78 (CH2), 77.5
(CH), 99.5/99.7 (CH),
477 (1), 349 (2),
307 (7), 228 (6),
176 (8), 173 (9),
160 (18), 159
(92), 149 (11),
(20), 104 (27), 91
(100)
J = 3.5, 2 H, CH),
5.2 (m, 2 H, CH),
100.8/101.1 (CH), 126.4/
126.5 (CH), 127.53/127.58
5.9 (d, J = 6.0, 1 H, (CH), 127.7 (CH), 128.0
CH), 6.1 (d, J = 6.0, (CH), 129.4 (CH), 128.28/
1 H, CH), 7.1 (m, 2 128.32 (CH), 129.8/129.9
Harom), 7.3 (m, 12
Harom), 7.4 (m, 4
(C), 131.3 (CH), 137.5/
137.7 (C), 143.2/143.0 (C),
166.0/166.1 (C), 168.8 (C)
Harom
)
2b
11
neat/49 12b
30/0
isocya-
nate/39
1.02 (t, J = 7.5, 3 H, 7.4 (CH3), 22.8/22.9 (CH3), 237 (2), 236 (16),
CH3), 1.03 (t,
24.7 (CH2), 25.8 (CH2),
31.00/31.06 (CH2), 31.89/
31.94 (CH2), 33.9 (CH2),
159 (22), 158
(16), 148 (10),
146 (16), 130
(24), 117 (11), 92
J = 7.5, 3 H, CH3),
1.4–2.4 (m, 22 H,
CH3, CH2), 2.8 (m, 49.8 (CH), 77.3 (CH),
2 H, CH), 5.2 (m, 2 118.04/118.12 (C), 122.20/ (11), 91 (100), 90
H, CH), 6.84 (m, 1
H arom), 6.89 (m, 1
Harom), 7.1–7.2 (m,
122.23 (C), 126.46/126.50
(CH), 127.5 (CH), 128.29/
128.32 (CH), 128.50/
(23), 81 (15), 73
(10), 43 (80)
12 Harom), 7.4 (m, 2 128.55 (CH), 129.18/
Harom), 7.6 (m, 2
Harom
129.26 (CH), 130.4 (CH),
130.57/130.61 (CH),
132.66/132.75 (C), 143.0
(C), 157.63/157.64 (C),
166.1 (C)
)
a Satisfactory microanalyses obtained. All products are oils, except 8b; mp 148°C.
b Mixture of diastereomers.
Even in solvents such as methanol or in neat ketones, no trene into the N–H bond of an amide has never been ob-
intermolecular reaction could be observed. This finding is served.8 The isocyanate formed in parallel with the nitrene
surprising in so far as the intermolecular insertion of a ni- reacts with the tautomeric isomer of 13.
In order to block the insertion position, the tertiary amides
4b and 4c were synthesised and studied with respect to
their photoproducts. However, despite the lack of N–H
bonds, these nitrenes also react by intramolecular reaction
at the amide group, by either substituting the alkyl group,
O
COOR
hν
2a +
N
– N2,
– isocyanate
O
O
or by rearrangement (see Scheme 5).
9
As usual, about 50% isocyanate was obtained by direct
azide excitation (254 nm).
10
The single crystal structure of compound 13 (Figure, see
Experimental Section) reveals the loss of the isopropyl
group and the dipolar structure shown in Scheme 5 is like-
ly to be the intermediate in the reaction sequence. De-
pending on the stability of the carbenium ion to be
formed, elimination or rearrangement dominates, yielding
either 13 or 14. To test this assumption, the azide 4d
(Scheme 1) was irradiated. Indeed, the intramolecular ni-
trene reaction yields the hydrazide 15 (Scheme 5).
COOR
O
hν
2a or 2b +
N
– N2,
– isocyanate
11
Me
O
O
12
Ph
12 b:
R =
12 a:
R =
Scheme 4
Synthesis 2001, No. 8, 1125–1132 ISSN 0039-7881 © Thieme Stuttgart · New York

1130
Y. Roeske, W. Abraham
PAPER
CONR1R2
hν
4a,b
– N2
CON
O
O
NR2
N
NR2
NH
13
OH
O
Me
Figure X-ray crystal analysis of the compound 20
13a: R2 =
13b: R2
=
2-{[Cyclohexyl(isopropyl)amino]carbonyl}benzoic Acid (3b,
two rotamers)
O
hν
Monomethyl phthalate (5 g, 27.8 mmol) was refluxed together with
SOCl2 (22.6 g, 189.9 mmol) for 1 h. After evaporating under re-
duced pressure, the residue was treated with toluene (3 25 mL)
and evaporated in order to remove all SOCl2. The remaining oil (5.5
g) was used without further purification to react with N-cyclohexyl-
N-isopropylamine (3.9 g, 27.7 mmol) in the presence of Et3N (2.8
g, 27.7 mmol) in toluene (15 mL) at 0°C. After stirring at r.t. for 24
h, H2O (20 mL) was added. The organic layer was then separated
and washed with 0.5 M HCl (2 15 mL), 2 M aq NaOH (2 10 mL,
2 M) and H2O (15 mL). The organic phase was then dried (MgSO4)
and concentrated yielding methyl 2-{[cyclohexyl(isopropyl)ami-
no]carbonyl}benzoate (7.7 g, 90%) as an oil.
N
N
4c
– N2
O
14
O
hν
N
O
N
4d
– N2
15
O
R1
R1
O
1H NMR: = 0.9–1.9 (m, 32 H, CH3, CH2), 2.7 (m, 2 H, CH), 3.05
(m, 2 H, CH), 3.7 (s, 6 H, CH3), 7.1 (m, 1 Harom), 7.2 (m, 1 Harom),
7.35 (m, 2 Harom), 7.5 (m, 2 Harom), 8.0 (m, 2 Harom ).
N
N
N
N
O
13C NMR: = 19.1/19.2 (CH3), 19.6/19.8 (CH3), 24.3/24.6 (CH2),
24.8 (CH2), 25.8 (CH2), 28.6/29.0 (CH2), 29.5/30.0 (CH2), 45.9/
50.3 (CH), 51.1 (CH3), 53.6/59.0 (CH,), 125.07/125.17 (CH),
127.18/127.23 (CH), 129.87 (CH), 131.75/131.87 (CH), 125.86/
125.98 (C), 139.74/139.90 (C), 165.35/165.42 (C), 168.97/169.03
(C).
O
Scheme 5
Commercially available chemicals were used as received, unless
otherwise stated. Solvents were dried according to standard proce-
dures. Column chromatography (CC) was carried out on 200 mesh
silica gel (Merck). Analytical high-pressure liquid chromatography
and preparative HPLC were carried out with the help of equipment
provided by Fa. Knauer, Berlin; both UV- and Chiralizer-detectors
were used. Columns containing Eurospher Si 100 (NP), Eurospher
100 (RP 18), Chiralcel OD, Chiralcel ODH and Chiral AGP served
as stationary phases. All NMR spectra were recorded in CDCl3 so-
lution, unless otherwise indicated, using a Bruker DPX 300 spec-
trometer (1H NMR, 300 MHz; 13C NMR, 75 MHz). Mass spectra
were obtained using a Concept 1H spectrometer (MSI) and a
GCMS-5995-A (Hewlett-Packard).
The ester was hydrolized with KOH (1.4 g in EtOH–H2O) by reflux-
ing for 2 h. After evaporation of the solvent the residue was treated
with HCl to separate 3b, which was dissolved in Et2O and dried
(MgSO4). After removing the solvent under reduced pressure the
oily residue (6.5 g) was dissolved in acetone (40 mL) and consecu-
tively treated with Et3N (2.7 g, 22.5 mmol) in acetone (10 mL), eth-
yl chlorocarbonate (3.2 g, 29 mmol) in acetone (10 mL) and NaN3
(2.3 g, 35 mmol) in NaOH (8 mL, 0.5 M) according to the general
procedure.
2-{[Cyclohexyl(ethyl)amino]carbonyl}benzoic Acid (3c, two
rotamers)
A mixture of phthalic anhydride (7.2 g, 56.7 mmol) and N-cyclo-
hexyl-N-ethylamine (10 g, 67.6 mmol) was heated to 130–145°C
for 3 h. After cooling to r.t., the mixture was dissolved in acetone
(10 mL). The substituted benoic acid crystallised from the solution;
yield: 4.6 g (30%); mp 149–152°C.
1H NMR: = 0.8–2.0 (m, 26 H, CH3, CH2), 3.0–3.2 (m, 3 H, CH2,
CH), 3.3–4.1 (m, 2 H, CH2), 4.4 (m, 1 H, CH), 7.2 (m, 1 Harom), 7.3
(m, 1 Harom), 7.4 (m, 2 Harom), 7.6 (m, 2 Harom), 8.0 (m, 2 Harom), 10.7
(s, 2 H, OH).
13C NMR: = 14.0/15.9 (CH3), 25.1 (CH2), 25.6 (CH2), 25.7/25.9
(CH2), 30.3 (CH2), 30.9/31.4 (CH2), 36.5/39.8 (CH2), 54.3/59.1
(CH), 126.2/127.2 (CH), 127.1/127.3 (C), 128.3/128.4 (CH), 131.0/
131.2 (CH), 132.6/132.7 (CH), 139.3/139.6 (C), 169.5/169.6 (C),
170.6/171.4 (C).
Photolyses were carried out using homemade merry-go-round
equipment fitted with low-pressure mercury lamps HNU 6 (6 W)
(NARVA, Berlin) and a rayonet reactor fitted with RPR-3500
lamps (Southern N. E. Ultraviolet Co). The solutions were cooled
by the use of a thermostat (Haake K20) and a cryostat (Colora
Messtechnik GmbH).
Unless otherwise mentioned, chemicals were purchased from Ald-
rich. Mono[(1R,2S)-trans-2-phenylcyclohexyl]phthalate (1b),9 2-
[N-(+)-neomenthylphthalamido]benzoic acid (3a),10 2-(pyrrolidi-
nylcarbonyl)benzoic acid (3d),11 2-isobutoxy-3,4-dihydro-2H-pyr-
an (5c)12 were prepared using established procedures.
Synthesis 2001, No. 8, 1125–1132 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Photochemistry of Acyl Azides
1131
MS: m/z (%) = 275 (9), 274 (22), 176 (17), 149 (100), 126 (22), 98
(28), 93 (23), 84 (83), 76 (11), 65 (33), 56 (22), 44(36), 41 (27).
13C NMR: = 21.2 (CH3), 21.3 (CH3), 22.6 (CH3), 25.7 (CH), 29.1
(CH), 25.8 (CH2), 35.3 (CH2), 40.2 (CH2), 46.4 (CH), 51.6 (CH),
123.8 (CH), 127.6 (CH), 129.3 (C), 131.9 (C), 132.6 (C), 158.8 (C).
2-Substituted Benzoyl Azides 2a,b and 4a–d; General
Procedure
MS: m/z (%) = 300 (2), 283 (5), 217 (7), 176 (6), 163 (100), 148
(21), 130 (31), 105 (17), 104 (17), 102 (11), 95 (17), 83 (10), 81
(14), 77 (20), 76 (15), 69 (13), 67 (15), 55 (31).
A suspension of the corresponding phthalate 1 or 3 (16.4 mmol) in
acetone (20 mL) was cooled to –5°C. A clear solution was formed
by the addition of Et3N (2 g, 19.8 mmol) in acetone (8 mL). Ethyl
chlorocarbonate (2.6 g, 24.1 mmol) in acetone (8 mL) was added
slowly to form the insoluble mixed acid anhydride. After stirring for
30 min at –5 °C, NaN3 (1.7 g, 26.2 mmol) in NaOH (20 mL, 0.5 M)
was added dropwise and the suspension stirred for 1 h at –5 °C
yielding a clear solution. The mixture was then poured onto ice and
the water phase extracted with Et2O (5 50 mL). The combined or-
ganic layers were then dried (MgSO4) and the solvent evaporated
under vacuum at 0 °C. The remaining residue was treated with cold
hexane resulting in a solid (Table 1).
HRMS: m/z Calcd for C18H24N2O2: 300.1838; found: 300.1824.
2-Cyclohexyl-4-hydroxy-1,2-dihydro-1-phthalazinone/2-
Cyclohexyl-1,2,3,4-tetrahydro-1,4-phthalazindione (13b)
A solution of 4b (267 mg, 0.85 mmol) in MeCN (50 mL) was irra-
diated (254 nm) at –10°C for 47 h. The solution was treated with
MeOH and concentrated. Product 13b (95 mg, 46%) was isolated
by CC [cyclohexane–propan-2-ol (8%)]; white solid; mp 153–
156°C.
1H NMR: = 1.0–1.8 (m, 10 H, CH2), 4.9 (m, 1 H, CH), 7.8 (m, 2
H
arom), 8.1 (m, 1 Harom), 8.5 (m, 1 Harom), 9.1 (br s, 1 H, OH).
Photolysis of 2a and 2b in Acetonitrile; General Procedure
A solution of 2a and 2b, respectively, in MeCN (50 mL, 50 mmol)
was irradiated at 0°C and –10°C, respectively, at 254 nm for 9 h un-
til almost 100% of the azides were consumed. The reaction was fol-
lowed by HPLC after adding MeOH to a sample (RP 18- and NP-
column, respectively, MeCN–H2O, 9:1 and cyclohexane–propan-2-
ol (0.2%), respectively). Urethanes, such as 6a, were quantitatively
analysed by calibrating with an authentic sample.
13C NMR: =25.3 (CH2), 25.6 (CH2), 30.4 (CH2), 55.3 (CH), 124.6
(CH), 127.6 (CH), 124.9 (C), 129.7 (C), 132.5 (C), 132.8 (C), 151.8
(C), 157.4 (C).
1H NMR (solid state): = 0–3, 7–9, 10 (OH), (Bruker spectrometer,
400 MHz, spektra range: 250000 Hz, number of scans: 320, rotation
1
rate: 15000 Hz, 90°-pulse, H-channel: 2.4 s). According to the
solid-state 1H NMR spectrum, compound 13b exists mainly as the
OH tautomer.
(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl-2-[(methoxycarbon-
yl)amino]benzoate (6a)
Compound 2a (150 mg, 0.456 mmol) in MeOH (15 mL) were
stirred for 48 h at r.t. After evaporating the solution pure 6a result-
ed; oil (150 mg, ~100%).
1H NMR: = 0.76 (d, J = 6.9 Hz, 3 H, CH3), 0.89 (d, J = 6.9 Hz, 3 H,
CH3), 0.91 (d, J = 6.5 Hz, 3 H, CH3), 1.0–2.1 (m, 9 H, CH2, CH), 3.8
(s, 3 H, CH3), 4.9 (dt, J = 4.4, 10.9 Hz, 1 H, CH), 7.0 (m, 1 Harom),
7.5 (m, 1 Harom), 8.0 (m, 1 Harom), 8.4 (m, 1 Harom), 10.6 (s, 1 H, NH).
MS: m/z (%) = 244 (6), 163 (100), 148 (21), 132 (11), 130 (37), 105
(20), 104 (32), 101 (14), 77 (25), 76 (27), 55 (23), 41 (47).
X-Ray Crystal Structure Analysis of 13b
Crystal Data: C14 H16 N2 O2 1/3 C3 H6 O, Mr: 226.32, monoclinic,
C2/c no. 15, a = 28.030(3) Å, b = 16.743(3) Å, c = 18.026(4) Å,
= 90°, = 92.17(3)°, = 90°. T = 298(2) K, (Mo K ) = 0.71073 Å,
V = 8454(3) Å3, Z: 24, Dx (calculated): 1.235 Mg/m3, = 0.085
mm–1, F(000): 3376.
13C NMR: = 16.4 (CH3), 20.7 (CH3), 22.0 (CH3), 23.5 (CH2), 26.5
(CH), 31.5 (CH), 34.2 (CH2), 40.8 (CH2), 47.1 (CH), 52.2 (CH3),
75.4 (CH), 115.0 (C), 118.7 (CH), 121.4 (CH), 130.8 (CH), 134.4
(CH), 141.9 (C), 154.1 (C), 167.6 (C).
Data Collection and Reduction: Crystal Size: 0.19 0.77 0.77
mm, 2.7–25.0°, Index ranges: –33
h
33, –19
k
19, –21
l
21, Reflections collected: 41042, Independent reflections: 7105
[R(int) = 0.056], Absorption correction: None, Refinement method:
Full-matrix least-squares on F2, Data/restraints/parameters: 7105/ 0/
705, Goodness-of-fit on F2: 0.924, Final R indices [I>2 (I)]:
R1 = 0.0523, wR2 = 0.1373, R indices (all data): R1 = 0.0828,
wR2 = 0.1540. Largest diff. Peak and hole: 0.32 and –0.25 eÅ3.
IPDS-2.75 (Stoe, 1997), Computing cell refinement: IPDS-2.75
(Stoe, 1997), Computing data reduction: IPDS-2.75 (Stoe, 1997),
Computing structure solution: SHELX-86 (Sheldrick, 1990), Com-
puting structure refinement: SHELX-97 (Sheldrick, 1997), Com-
puting molecular Graphics: Diamond-2.1c (Brandenburg, 1999),
Computing publication material: Platon-99 (Farrugia, 1999), Full
details have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication no. CCDC 155600. Cop-
ies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK.
HRMS: m/z Calcd for C19H27NO4: 333.1940; found 333.1942.
Photolysis of Azides 2a and 2b in the Presence of Nitrene
Quenchers; General Procedure
A solution of nitrene 2 (1.9 mmol), the appropriate cyclic enol ether
5 (250 mmol) or ketone 9, 11 (250 mmol) in MeCN (50 mL) were
irradiated (254 nm) at 0°C; in the case of 2a at –10°C and in the
case of 2b until at least 95% of the azide was consumed (see
Table 2). The solution was concentrated, treated with MeOH and
worked up by preparative HPLC (RP18-column, CH3CN–H2O,
10%). Beside the urethane formed from the rearrangement product
isocyanate, the adducts were separated (Table 2).
4-Hydroxy-2-[(1S,2S,5R)-2-isopropyl-5-methylcyclohexyl]-1,2-
dihydro-1-phthalazinone/ -[(1S,2S,5R)-2-Isopropyl-5-methyl-
cyclohexyl]-1,2,3,4-tetrahydro-1,4-phthalazindione (13a)
A solution of 4a (165 mg, 0.53 mmol) in MeCN (25 ml) was irradi-
ated (254 nm) at –10°C for 94 h. The precipitate consisting of the
isocyanate adduct was filtered. The filtrate was treated with MeOH
and concentrated. By CC (ligroin–EtOAc, 4:1) 13a (50 mg, 31%)
was obtained as white solid; mp 244°C.
MS: m/z (%) = 244 (6), 163 (100), 148 (21), 132 (11), 130 (37), 105
(20), 104 (32), 101 (14), 77 (25), 76 (27), 55 (23), 41 (47).
2-[Cyclohexyl(ethyl)amino]isoindolin-1,3-dione (14)
A solution of 4c (361 mg, 1.2 mmol) in MeOH (25 mL) was irradi-
ated (254 nm) at –10°C for 84 h. The reaction solution was concen-
trated and 14 (oil, 108 mg, 33%) was separated from the urethane
formed from the corresponding isocyanate with the help of CC (li-
groin–propan-2-ol.
1H NMR: =1.0 (t, J = 7.2 Hz, 3 H, CH3), 1.1–1.3 (m, 5 H, CH2),
1.6 (d, J = 10.9 Hz, 1 H, CH2), 1.8 (m, 2 H, CH2), 1.9 (m, 2 H, CH2),
3.4 (m, 3 H, CH2, CH), 7.8 (m, 2 Harom), 7.85 (m, 2 Harom).
1H NMR: = 0.8–2.2 (m, 18 H, CH3, CH2, CH), 5.4 (m, 1 H, CH),
7.1–7.4 (br s, 1 H, OH), 7.8 (m, 2 Harom), 8.0 (m, 1 Harom), 8.5 (m, 1
Harom).
Synthesis 2001, No. 8, 1125–1132 ISSN 0039-7881 © Thieme Stuttgart · New York

1132
Y. Roeske, W. Abraham
PAPER
13C NMR: =12.5 (CH3), 24.7 (CH2), 25.6 (CH2), 30.9 (CH2), 44.8
(CH2), 61.7 (CH), 123.2 (CH), 129.7 (C), 134.1 (CH), 168.3 (C).
References
(1) Lwowski, W. In Azides and Nitrenes; Scriven, E. F. V., Ed.;
Academic Press: New York, 1984, 205–246.
(2) Abraham, W. Trends in Photochemistry & Photobiology,
Research Trends, Vol. 4; Trivantrum: India, 1997, 13.
(3) (a) Abraham, W.; Siegert, S.; Buck, K.; Csongar, C. J. Prakt.
Chem. 1991, 333, 73. (b) Abraham, W.; Buchallik, M.; Zhu,
Q. Q.; Schnabel, W. J. Photochem. Photobiol. A: Chem.
1993, 71, 119.
(4) Clauss, K.-U.; Buck, K.; Abraham, W. Tetrahedron 1995,
51, 7181.
(5) Buck, K.; Jacobi, J.; Plögert, Y.; Abraham, W. J. Prakt.
Chem. 1994, 336, 678.
(6) Yukawa, Y.; Tsuno, Y. J. Am. Chem. Soc. 1958, 80, 6346.
(7) Driguez, H.; Vermes, J.-P.; Lessarf, J. Can. J. Chem. 1978,
56, 119.
(8) Experiments carried out with benzoylnitrene and N-cyclo-
hexyl, N-i-propylbenzamide in MeCN revealed that the
amide was not attacked by the nitrene.
(9) (a) Hückel, W.; Wagner, H. Ber. Dtsch. Chem. Ges. 1941,
74, 657. (b) Marvel, C. S.; Frank, R. L.; Prill, E. J. Am.
Chem. Soc. 1943, 65, 1647.
MS: m/z (%) = 272 (1), 229 (19), 175 (8), 148 (9), 130 (22), 125
(43), 110 (17), 86 (65), 84 (100), 76 (11), 55 (16), 43 (38).
Photolysis of 4d
A solution of 4d (187 mg, 0.865 mmol) in MeOH (50 mL) was ir-
radiated (254 nm) at –10°C for 70 h. The reaction mixture contain-
ing unreacted 4d (16%) and 15 besides uncharacterised byproducts
was concentrated and separated by CC (ligroin–propan-2-ol, 20%).
2-Tetrahydro-1H-1-pyrrolylisoindolin-1,3-dione (15)
White solid (28 mg, 18%); mp 140–145°C.
1H NMR: = 2.0 (m, 4 H, CH2), 3.4 (m, 4 H, CH2), 7.7 (m, 2 Harom),
7.8 (m, 2 Harom).
13C NMR: = 24.0 (CH2), 52.1 (CH2), 123.2 (CH), 130.3 (C), 134.2
(CH), 167.3 (C).
MS: m/z (%) = 216 (11), 148 (19), 147 (11), 130 (49), 105 (40), 104
(36), 77 (14), 76 (49), 70 (100).
HRMS: m/z Calcd. for C12H12N2O2: 216.0898; found: 216.0896.
(10) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Clark, J.; Read, J.
J. Chem. Soc. (London) 1934, 1775.
(11) Eilers, J.; Wilken, J.; Martens, J. Tetrahedron: Asymmetry
1996, 7, 2343.
(12) Longley, R. I. Jr.; Emerson, W. S. J. Am. Chem. Soc. 1950,
72, 3079.
Acknowledgement
We acknowledge the financial support by Fonds der Chemischen
Industrie, Deutsche Forschungsgemeinschaft and Fazit-Stiftung
and thank Dr. Burkhard Ziemer, Humboldt-Universität, Institut für
Chemie for the X-ray crystal analysis.
Synthesis 2001, No. 8, 1125–1132 ISSN 0039-7881 © Thieme Stuttgart · New York