Photochemical type II reaction of atropchiral benzoylformamides to point chiral oxazolidin-4-ones. Axial chiral memory leading to enantiomeric resolution of photoproducts

Article abstract of DOI:10.1039/c0cc00470g

Atropisomeric benzoylformamides 1 undergo Type II reaction leading to cis-2 and trans-2 oxazolidin-4-one photoproducts. The N-C(Aryl) chiral axis is maintained during the course of the phototransformation in spite the reaction proceeding through a near pl

Full text of DOI:10.1039/c0cc00470g

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Photochemical type II reaction of atropchiral benzoylformamides to
point chiral oxazolidin-4-ones. Axial chiral memory leading to
enantiomeric resolution of photoproductsw
Josepha L. Jesuraj and J. Sivaguru*
Received 18th March 2010, Accepted 20th April 2010
First published as an Advance Article on the web 25th May 2010
DOI: 10.1039/c0cc00470g
Atropisomeric benzoylformamides 1 undergo Type II reaction
leading to cis-2 and trans-2 oxazolidin-4-one photoproducts. The
N–C(Aryl) chiral axis is maintained during the course of the
phototransformation in spite the reaction proceeding through a
near planar intermediate(s). As the rotational barrier of the
N–C(Aryl) chiral axis in the cis-2 and trans-2 photoproducts
is lowered when compared with the reactant 1, the isolated
optically pure trans-2 isomer is converted to the ent-cis-2
isomer without affecting the C-5 stereogenic center, resulting
in resolution of the cis-2 enantiomers.
b-lactam as the photoproduct with very high enantiomeric
excess in CHCl3.
This provided us with an opportunity to investigate the
Type II reaction involving atropisomeric benzoylformamides
1a–d leading to point chiral oxazolidin-4-one 2a–d. Previous
investigations17–21 involving achiral benzoylformamides have
established the formation of oxazolidin-4-ones as photo-
products via a planar zwitterionic intermediate (Z2) or via a
diradical intermediate (D) depending on the substituents on
the amide nitrogen and the reaction conditions.17–21
We synthesized atropchiral benzoylformamide derivatives
1a–b with N-(2-propyl), 1c with N-(cyclopentyl) and 1d with
N-(cyclohexyl) substituents. The individual P and M isomers
were easily isolable on a chiral stationary phase and were
characterized by NMR spectroscopy, CD spectroscopy,
Asymmetric induction during photochemical transformations
in solution has presented formidable challenges to chemists.1–7
Due to the short lifetime of the excited state(s)/intermediate(s)
involved during phototransformations, constraining molecular
motions using confined environments have shown promise for
achieving high stereoselectivity.8,9 However, achieving high
stereoselectivity in solution leading to enantiomerically enriched
photoproducts by a generalized methodology is yet to be
established.6,10 In this regard we have been exploring the use
of axially chiral compounds to achieve high stereoselectivity in
the photoproducts during light induced transformations in
solution.11,12 In this communication, we report the Type II
reaction of axially chiral benzoylformamides 1 leading to point
chiral oxazolidin-4-ones 2 in which the N–C(Aryl) chiral axis
is maintained during the course of the photochemical trans-
formation. The low rotational barrier of the N–C(Aryl) chiral
axis in the photoproducts 2 was utilized to resolve photo-
product enantiomers with high optical purity (>95% ee) and
in good yields (80% isolated yield), in spite of the reaction
proceeding with very low diastereoselectivity (cis/trans
selectivity).
22
optical rotation, HRMS and single crystal XRD.z These
axially chiraloptically pure 1a–d were stable at room tempera-
ture and can be stored for months without enantiomerization.
Even at 50 1C, the rate of enantiomerization was slow, and
hence the DGz of enantiomerization (DGzenant) of optically
pure 1 was performed at 75 1C. For example, in the case of 1b,
DGz
was found to be B30.8 kcal. molꢀ1 (kenant: 3.3 ꢁ
10ꢀ7enant
s
ꢀ1; t1/2: B12 days at 75 1C).22
Photoirradiation of optically pure atropisomers (P or M
isomers) of 1a–d (Scheme 1) was performed using a 450 W
medium pressure Hg lamp with Pyrex cutoff and a cooling
jacket under constant flow of nitrogen at various temperatures
1
(5, 25 and 50 1C). The reaction progress was followed by H
NMR spectroscopy and was found to be clean and efficient
with >90% conversion and an B80% isolated yield 2a–d.
The photoproduct 2 was purified by chromatography and
characterized by NMR spectroscopy, CD spectroscopy,
optical rotation and single crystal XRD.22 The oxazolidin-4-
one 2 photoproduct was found to be a mixture of cis-2 and
trans-2 isomers based on the orientation of the o-tert-butyl
group with respect to the phenyl substituent at the C-5 chiral
center. 1H NMR spectroscopy analysis of photoproducts
showed a cis-2:trans-2 ratio (diastereomeric ratio, d.r.) of
B66 : 34 irrespective of the reaction temperature (Table 1;
entries 1–6). HPLC analysis of the individual cis-2 and trans-2
photoproducts gave the ee values (enantiomeric excess) as
listed in Table 1. The optical antipode of 1 gave ent-cis-2
and ent-trans-2 photoproduct (enantiomeric photoproducts),
indicating that the system was well behaved. The absolute
configuration at the C-5 stereogenic center was opposite in
cis-2 and trans-2 photoproducts from a given optically pure
axially chiral benzoylformamides 1. The cis-2 and trans-2
We recently reported11,12 that a-oxoamides with o-tert-
butyl-substituent on the N-phenyl ring are axially chiral due
to the restricted N–C(Aryl) bond rotation,13–16 and success-
fully employed them for Norrish/Yang cyclization leading to
Department of Chemistry and Molecular Biology, North Dakota State
University, Fargo, ND 58105, USA.
E-mail: sivaguru.jayaraman@ndsu.edu
w Electronic supplementary information (ESI) available: Experimental
procedures for photoreactions, synthesis and characterization of
reactants/photoproducts by 1H NMR, 13C NMR, DEPT, HRMS,
optical rotation, circular dichroism and single crystal XRD and HPLC
analysis condition on
a
chiral stationary phase. CCDC
759989–759993. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0cc00470g
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Scheme 1 Photochemical type II reaction axially chiral 1 in which the N–C(Aryl) chiral axis is maintained in the photoproduct 2.
Table 1 Enantiomeric excess in the oxazolidin-4-one photoproduct 2a
Entry
Compd
Time/h
T 1C
% Conv
cis-2:trans-2 (d.r.)
% ee (trans-2)
% ee (cis-2)
1
2
3
4
5
6
7
8
(+)1a
18
15
12
18
15
12
15
15
15
15
15
15
5
25
50
5
25
50
25
25
25
25
25
25
40
95
98
40
95
98
80
82
81
80
83
81
69 : 31
65 : 35
64 : 36
69 : 31
65 : 35
63 : 37
64 : 36
64 : 36
65 : 35
64 : 36
67 : 33
66 : 34
99 (B)
97 (B)
88 (B)
99 (A)
97 (A)
89 (A)
93 (A)
93 (B)
98 (B)
97 (A)
98 (B)
98 (A)
99 (A)
97 (A)
86 (A)
99 (B)
97 (B)
87 (B)
94 (A)
93 (B)
97 (A)
98 (B)
99 (A)
98 (B)
(ꢀ)1a
(+)1b
(ꢀ)1b
(+)1c
(ꢀ)1c
(+)1d
(ꢀ)1d
9
10
11
12
a
Values are an average of 3 runs (ꢃ3% error). (+)-1 and (ꢀ)-1 represents the sign of optical rotation. cis-2:trans-2 ratio and % conversion based
1
on relative integration by H NMR spectroscopy using succinimide as internal standard. Mass balance >95% (isolated yield B80%). A and B
refers to the first and second peak that elutes in the HPLC on a chiral stationary phase for a given pair of enantiomers.
isomers were separated by column chromatography or by
preparative TLC. The presence of gem-alkyl substituents at
the C-2 position in oxazolidin-4-one 2 hindered the N–C(Aryl)
bond rotation at ambient conditions, but at elevated
temperatures (75–120 1C depending on the gem-alkyl substituent)
the N–C(Aryl) bond was found to rotate freely. It has been
previously shown that the N–C(Aryl) bond rotates freely due
to the reduced C–N–C bond angle in b-lactams.11,12,23 This
provided an opportunity to convert the enantiopure trans-2
isomer to the corresponding cis-2 isomer. For example, photo-
irradiation of 1d resulted in an ee value of >97% at 25 1C in
both the cis-2d and trans-2d diastereomers. The optically pure
cis-2d and trans-2d photoproducts were isolated by column
chromatography or by preparative TLC. The isolated trans-2d
photoproduct was heated in n-octane/isopropanol (4 : 1 v/v)
that resulted in an equilibrium ratio of 66 : 34 favoring the
ent-cis-2d photoproduct. Thus we were able to resolve the
cis-enantiomers without affecting the chirality at the C-5
stereogenic center (Fig. 1).
the electron transfer pathway,17–21 which is in contrast to
aromatic ketones that undergo hydrogen abstraction efficiently
from np* triplet state.18,19,24 As shown in Scheme 1, the
resultant intermediate could be a diradical D or a zwitterion
Z1 depending on the reaction conditions19 (substituent on the
amide nitrogen, reaction medium etc.) that subsequently leads
to the planar zwitterionic intermediate Z2 (via ketene-imine
geminate pair if D is involved), which cyclizes to 2.17–21
In the present case, based on the stereochemistry of cis-2
and trans-2 photoproducts,22 the configuration of the chiral
axis [(N–C(Aryl) bond] remains unchanged during the photo-
reaction. Photoirradiation of optically pure (P or M isomers)
The mechanism17–21 concerning Type II photoreaction of
achiral benzoylformamides as described by Whitten and
co-workers19 occurred via a planar zwitterionic intermediate
(Z2; Ar = Phenyl) and involved a net hydrogen transfer to the
photoexcited carbonyl group either by direct hydrogen
abstraction or in a sequential two-step process viz. single
electron transfer (SET) followed by proton transfer
(Scheme 1). Benzoylformamides undergo Type II photo-
reaction even from the unreactive pp* triplet excited state by
Fig. 1 Resolution of cis-2d enantiomers. The configuration represented
is based on the relative orientation by single crystal XRD.
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Crystal data for cis-2a (colorless chunk): C21H25NO2, M = 323.42,
ꢀ
Triclinic, space group P1, a = 9.354(4) A, b = 9.792(5) A, c =
atropisomers of 1a–d likely undergoes Type II reaction in a
pathway as suggested by Whitten and co-workers19 for
achiral benzoylformamides. The presence of ortho-tert-butyl
substituent is not expected to affect the type of intermediates
proposed by Whitten and co-workers,19 but is expected to
affect the relative population of the reactive intermediates
(ketene-imine pair could be converted to the zwitterionic
intermediate Z2 by heterolytic N–CQO bond cleavage).
Stereochemical analysis of the photoproducts (Fig. 1) indicates
that the configuration of the chiral axis is maintained in the
intermediate(s) during the course of the phototransformation.
We believe that the relative rate of reaction from the
excited-state/intermediates(s) leading to 2 is favored over the
N–C(Aryl) bond rotation. Due to the reduced C–N–C bond
angle in 2, the rotational barrier of the N–C(Aryl) chiral axis
in the photoproduct 2 is lowered when compared to the
reactant 1. This enables the conversion of the isolated optically
pure trans-2 isomer to the ent-cis-2 isomer without affecting
the C-5 stereogenic center resulting in enantiomeric resolution
of cis-2 oxazolidin-4-one photoproduct with high optical
purity (ee values >98%).22
10.162(5) A, a = 79.581 (9)1, b = 85.526 (10)1 g = 87.199 (10), V =
912.1(8) A3, z = 2, 273 K, crystal size 0.66 ꢁ 0.22 ꢁ 0.14 mm,
m(Mo-Ka) = 0.075 mmꢀ1, 7296 reflections measured, 3296 inde-
pendent reflections (Rint = 0.0597). The final R(I > 2s(I))/R(all data)
were: R1 [%] = 5.58/12.01 and wR2 [%] = 14.01/17.63. The goodness
of fit on F2 was 0.938. Crystal data for trans-2d (colorless chunk):
C24H29NO2, M = 363.48, Monoclinic, space group P21/n, a =
12.223(8) A, b = 10.426(6) A, c = 16.072(10) A, b = 93.259 (9)1,
V = 2045(2) A3, z = 4293 K, crystal size 0.4 ꢁ 0.4 ꢁ 0.36 mm,
m(Mo-Ka) = 0.074 mmꢀ1, 13 837 reflections measured, 3657 inde-
pendent reflections (Rint = 0.0555). The final R(I > 2s(I))/R(all data)
were: R1 [%] = 4.64/6.22 and wR2 [%] = 12.63/13.94. The goodness
of fit on F2 was 1.059.
Crystal data for cis-2d (colorless plate): C24H29NO2, M = 363.48,
Monoclinic, space group P21/n, a = 8.784(2) A, b = 10.399(2) A, c =
22.804(5) A, b = 99.457 (3)1, V = 2054.6(7) A3, z = 4293 K, crystal
size 0.56 ꢁ 0.50 ꢁ 0.15 mm, m(Mo-Ka) = 0.074 mmꢀ1, 18 137
reflections measured, 4488 independent reflections (Rint = 0.0489).
The final R(I > 2s(I))/R(all data) were: R1 [%] = 5.05/7.84 and
wR2 [%] = 13.86/16.20. The goodness of fit on F2 was 1.069.
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Our investigation on employing axially chiral benzoyl-
formamides to chiral oxazolidin-4-one has opened up the
opportunity to resolve enantiomers with high optical purity
in good yields. The mechanistic analysis indicates that the
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Notes and references
z X-ray structures of the reactants and the photoproducts are
available from Cambridge Crystallographic Data Center. (CCDC
deposition #759989 to 759993).
XRD Structure determination: Single crystal X-ray diffraction data
sets were collected on a SIEMENS diffractometer with a 1 K CCD
area detector (graphite-monochromated Mo-Ka radiation, crystals
protected with Parathone-N oil). All structures, except cis-2a, were
solved by direct methods and refined on F2 using the SHELXL, after
integration and absorption corrections with SAINT 6.45 A.
Compound cis-2a was solved by direct method, but the integrations
and absorption corrections were performed with SAINT 7.34 A and
SADABS version 2007/4.
Crystal data for 1a (colorless plate): C21H25NO2, M = 323.42,
Monoclinic, space group P21/n, a = 8.698(4) A, b = 16.685(8) A, c =
13.029(6) A, b = 99.478 (9)1, V = 1864.9(15) A3, z = 4273 K, crystal
size 0.78 ꢁ 0.72 ꢁ 0.10 mm, m(Mo-Ka) = 0.073 mmꢀ1, 13 357
reflections measured, 3261 independent reflections (Rint = 0.0349).
The final R(I > 2s(I))/R(all data) were: R1 [%] = 4.51/7.48 and
wR2 [%] = 13.77/15.68. The goodness of fit on F2 was 1.030.
Crystal data for 1d (colorless prism): C24H29NO2, M = 363.48,
Monoclinic, space group P21/c, a = 12.312(3) A, b = 8.543(2) A, c =
19.637(5) A, b = 94.405 (4)1, V = 2059.4(8) A3, z = 4293 K, crystal
size 0.66 ꢁ 0.40 ꢁ 0.20 mm, m(Mo-Ka) = 0.074 mmꢀ1, 16 527
reflections measured, 4062 independent reflections (Rint = 0.0610).
The final R(I > 2s(I))/R(all data) were: R1 [%] = 4.69/6.93 and
wR2 [%] = 12.51/14.29. The goodness of fit on F2 was 1.034.
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Chem. Commun., 2010, 46, 4791–4793 | 4793