Control of the mode selectivity (ene reaction versus [2 + 2] cycloaddition) in the photooxygenation of ene carbamates: Directing effect of an alkenylic nitrogen functionality

Article abstract of DOI:10.1021/ja028407m

The geometry of the double bond in oxazolidinone-substituted ene carbamates controls the mode selectivity (ene reaction versus [2+2] cycloaddition) of singlet oxygen through stereoelectronic effects, whereas the chiral auxiliary provides high diastereoselectivity through steric shielding. Copyright

Full text of DOI:10.1021/ja028407m

Published on Web 11/05/2002
Control of the Mode Selectivity (Ene Reaction versus [2 + 2] Cycloaddition) in
the Photooxygenation of Ene Carbamates: Directing Effect of an Alkenylic
Nitrogen Functionality
Waldemar Adam,*,† Sara G. Bosio,† and Nicholas J. Turro‡
Institut fu¨r Organische Chemie, UniVersita¨t Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany, and Department
of Chemistry, Columbia UniVersity, New York, New York 10027
Received September 4, 2002
Table 1. Diastereomeric Ratios of the Ene Carbamates E,Z-1 in
The control of the mode selectivity (ene reaction, [2 + 2] and
the Condensation of Oxazolidinones and 2-Phenylpropanal
[4 + 2] cycloaddition) in the reaction of singlet oxygen with olefins
persist to be a formidable challenge to this day.1 For example, in
the photooxygenation of electron-rich olefins with allylic hydrogen
atoms, ene reaction and [2 + 2] cycloaddition may occur concur-
rently, and usually ene reactivity dominates.2 Nevertheless, the
1
substrate
R
E-1
Z-1
[2 + 2] cycloaddition becomes the preferred reaction mode when
the allylic C-H bond is conformationally not properly aligned
(coplanar with the π bond)3 or when the incoming singlet oxygen
is steered to the side of the double bond without an abstractable
allylic hydrogen atom.3,4 Such a steering effect is exercized by
allylic nitrogen4 or oxygen5 functionalities, which promote
[2 + 2] cycloaddition.
1a
1b
1c
1d
1e
H
53
73
71
50
83
47
27
29
50
17
Me
iPr
Ph
tBu
a Determined from the area under the characteristic signals in the 1H
NMR spectrum directly on the crude product (error (5% of the stated value).
No examples appear to have been reported in which an alkenyl
nitrogen functionality controls the mode selectivity in the competi-
tion between ene reaction and [2 + 2] cycloaddition of singlet oxy-
gen. For this purpose, we have chosen the E and Z diastereomers
of the ene carbamates 1 (Table 1), equipped with an oxazolidinone
chiral auxiliary to assess also the π-facial selectivity for the com-
peting reaction modes, a novel concept that merits mechanistic
examination. The ene carbamates 1 are well suited substrates to
test the mode selectivity because all three reaction modes may take
place, namely the ene reaction (allylic proton), [2 + 2] cycloaddition
(activated double bond), and [4 + 2] cycloaddition (styrene
functionality).
The ene carbamates 1 were obtained by condensing Evans’ chiral
oxazolidinones6 with the 2-phenylpropanal (Table 1). The E/Z ratio
depended on the size of the substituent in the oxazolidinone ring.
While the unsubstituted ene carbamate 1a and the phenyl derivative
1d were formed nondiastereoselectively (ca. 50:50 mixture of the
two double-bond isomers), the methyl and the isopropyl substituent
gave appreciable amounts of E diastereomers. As expected, the tert-
butyl substituent displayed the highest E selectivity since the steric
repulsion with the phenyl group on the double bond is the most
effective.
After chromatographic separation of the double-bond isomers,
the individual E and Z diastereomers of the optically active ene
carbamates 1 were photooxygenated at -32 °C with 5,10,15,20-
tetrakis(pentafluorophenyl)porphine (TPFPP) as sensitizer and an
800-W sodium lamp as light source (Table 2).
As a general trend, a substantial difference in the mode selectivity
is displayed by the product data in Table 2: Whereas the photooxy-
genation of the ene carbamates E-1 leads preferably to the hydro-
peroxides 3 (entries 1 and 3-6), the reaction of the Z-1 diastereomer
yields mainly the [2 + 2]-cycloadducts 2 (entries 2 and 7-10).
Table 2. Photooxygenation of the Enecarbamates 1a-e
selectivitya
mode
diastereo
ene [2 + 2]
1
2
3
entryb substrate
R
R
R
[2 + 2]:ene 2:3
1
2
E-1a
Z-1a
E-1b
E-1c
E-1d
E-1e
Z-1b
Z-1c
Z-1d
Z-1e
H
H
Me Ph
Ph Me
15:85
80:20
16:84
36:64
8:92
23:77
80:20
75:25
87:13
60:19c
-
-
-
-
3
(R)-Me Me Ph
88:12
83:17
71:29
91:9
n.d.
n.d.
n.d.
n.d.
4
(R)-iPr
(S)-Ph
(S)-tBu
Me Ph
Me Ph
Me Ph
5
6
7
(R)-Me Ph
Me
Me
Me
Me
53:47 >95:5
56:44 >95:5
85:15 >95:5
8
(R)-iPr
(S)-Ph
(S)-tBu
Ph
Ph
Ph
9
10
>95:5
>95:5
a Determined from the area under the characteristic signals in the 1H
NMR spectrum directly on the photooxygenate (error (5% of the stated
value) at the very beginning (5-10% conversion) of the photooxygenation,
at which point the decomposition products are still absent. b Run in CDCl3
at -32 °C with TPFPP as sensitizer; 100% conversion of the enecarbamate.
c Also 21% of the endoperoxide 4e was obtained (see Supporting Informa-
tion).
This diastereomer-dependent dichotomy in the mode selectivity
may be understood in terms of an orbital-directing effect of the
enamine-type functionality. The orbital interaction between the
HOMO (Figure 1, for Z-1d) of the ene carbamate and the LUMO
of the incoming singlet oxygen directs the attack onto the side that
bears the nitrogen atom. Since for the ene carbamates Z-1 no allylic
hydrogen atom is present on this side of the double bond, [2 + 2]
cycloaddition takes place preferably (entries 2 and 7-10). The
[4 + 2] and the [2 + 2] cycloadditions may compete, when the
double-bond and the phenyl substituent are essentially coplanar,
as is presumably the case for substrate Z-1e (Table 2, entry 10).
In contrast, in the case of enecarbamates E-1, the nitrogen atom
and the methyl group are located on the same side of the double
* To whom correspondence should be addressed. E-mail: adam@
chemie.uni-wuerzburg.de.
† Universita¨t Wu¨rzburg.
‡ Columbia University.
9
14004
J. AM. CHEM. SOC. 2002, 124, 14004-14005
10.1021/ja028407m CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Steric Shielding in the [2 + 2] Cycloaddition of Singlet
Oxygen to the Z-1 Substrates
sively from above for all R1 substituents (Table 2, entries 7-10),
except R1 ) H (Table 2, entry 2). The absolute configuration of
the dioxetanes was determined by their conversion to the corre-
sponding diols9 and HPLC analysis, with the enantiomerically pure
diol as reference (see Supporting Information). In the case of the
ene carbamates E-1, the diastereoselectivity could not be determined
because the dioxetanes were too labile and only the decomposition
products were detected. The high diastereoselectivity in the dioxe-
tane formation from the Z-1 ene carbamates may be explained in
Figure 1. HOMO of the Z-1d ene carbamate (calculated by the B3LYP
method) and its orbital-directing effect of the singlet oxygen attack.
1
terms of complete steric hindrance10 (Scheme 1) of the O2 attack
Figure 2. X-ray crystal structure of the hydroperoxide 3c.
on the lower side of the double bond by the R1 oxazolidinone
substituent.
The present study demonstrates that the choice of the diastere-
omeric ene carbamates E-1 and Z-1 has been most fortunate in
assessing the control of the mode selectivity of singlet oxygen,
namely the ene reaction versus [2 + 2] cycloaddition. For the first
time, the usually preferred ene reactivity may be supressed in favor
of [2 + 2] cycloaddition by manipulating the double-bond geometry
in the ene carbamate. Additionally, the oxazolidinone chiral auxi-
liary provides high π-facial selectivity through purely steric shield-
ing by its R1 substituent for both the ene reaction and the [2 + 2]
cycloaddition. Thus, through the judicious combination of the
double-bond geometry and the chiral auxiliary in olefinic substrates,
mode-selective photooxygenations with high diastereoselectivity
may be developed, an unprecedented concept in singlet-oxygen
chemistry.
Acknowledgment. The work at the University of Wu¨rzburg was
generously supported by the Deutsche Forschungsgemeinschaft
(Schwerpunktprogramm “Peroxidchemie”) and the Fonds der
Chemischen Industrie; the work at Columbia University was
financed by the National Science Foundation through Grant CHE-
01-10655. We thank Dr. M. Schwarm (Degussa Hu¨ls AG, Hanau)
for a generous gift of the optically active oxazolidinones and
alaninol.
Figure 3. Steric shielding for the ene reaction of singlet oxygen with Z-1
and E-1 substrates.
bond. Thus, the incoming singlet oxygen abstracts an allylic
hydrogen atom from the methyl group and a high mode selectivity
in favor of the ene reaction is expressed (entries 1 and 3-6). A
similar effect (cis-methoxy effect7) was found for the addition of
singlet oxygen to methoxy styrenes,8 but in that case the competition
occurs between the ene reaction and [4 + 2] cycloaddition.
The diastereoselectivity of the ene reaction for the ene carbamates
E-1 ranges from 71:29 to 91:9 (Table 2), except for the encarbam-
ates E-1a and Z-1a without a substituent at the oxazolidinone ring,
for which no diastereomers are possible (entries 1 and 2, Table 2).
The absolute configuration for the major diastereomer of the
hydroperoxide 3c (entry 5) was determined to be 1S,4′R by means
of X-ray analysis (Figure 2). The ene reaction of the Z-1 isomer
gave diastereomeric ratios that ranged from 53:47 to >95:5. For
both sets of E/Z ene products, the increasing trend in the dr values
(Table 2) follows the steric demand of the R1 substituent in the
oxazolidinone ring, but for the Z isomers (entries 7-10) the differ-
entiation is more pronounced than for the E isomers (entries 3-6).
To obtain ene products, the attack of singlet oxygen must occur
on the side of the methyl group (Figure 3). As expected, for the
smaller methyl and isopropyl substituents (Table 2, entries 7 and
8), the steric shielding is not as effective as for the larger phenyl
and tert-butyl groups (entries 9 and 10). The latter R1 substituents
are sufficiently spacious to cover up the double bond from below
and block sterically hydrogen abstraction from the methyl group
Supporting Information Available: Experimental details (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
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1
in the Z-1 substrates. Not only does the O2 attack occur pref-
erentially from above (Figure 3), but also the ene reactivity is
suppressed in favor of [2 + 2] cycloaddition compared to that in
the E-1 isomers. In the case of the E-1 substrates, the oxazolidinone
ring is on the same side of the double bond as the methyl group.
Such proximity of the latter to the nitrogen functionality favors
ene reactivity (orbital steering in Figure 1). The more severe steric
interactions of the substituents of the E-1 substrates with singlet
oxygen are responsible for the increased but less differentiated attack
from above compared to that in the Z-1 diastereomers.
In regard to the diastereoselectivity of the [2 + 2] cycloaddition,
the photooxygenation of the ene carbamates Z-1 proceeds exclu-
JA028407M
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J. AM. CHEM. SOC. VOL. 124, NO. 47, 2002 14005