Light-induced stereospecific intramolecular [2+2]-cycloaddition of atropisomeric 3,4-dihydro-2-pyridones

Article abstract of DOI:10.1039/c2cc37123e

Atropisomeric 3,4-dihydro-2-pyridones undergo stereospecific [2+2]-photocycloaddition in solution with high stereoselectivity (ee > 98% and de > 96%) in the product. The chiral transfer during phototransformation was rationalized based on the stability/reactivity of the biradical.

Full text of DOI:10.1039/c2cc37123e

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Light-induced stereospecific intramolecular
[2+2]-cycloaddition of atropisomeric
3,4-dihydro-2-pyridones†‡§
Cite this: Chem. Commun., 2013,
49, 4346
Received 1st October 2012,
Accepted 1st November 2012
Elango Kumarasamy and J. Sivaguru*
DOI: 10.1039/c2cc37123e
www.rsc.org/chemcomm
Atropisomeric 3,4-dihydro-2-pyridones undergo stereospecific
[2+2]-photocycloaddition in solution with high stereoselectivity
(ee > 98% and de > 96%) in the product. The chiral transfer during
phototransformation was rationalized based on the stability/reac-
tivity of the biradical.
The field of asymmetric organic photochemistry has been witnessing
rapid development in recent years due to the prospect of synthesizing
complex structural motifs with control of stereochemistry.1 This
progress is in part due to the understanding of the nature of the
excited states and manipulation of their reactivity by channeling the
excited state energy through molecular confinement by employing
different organized supramolecular assemblies.2 Organized supra-
molecular assemblies like crystals,2c–e zeolites,2f cyclodextrins2g and
molecular recognition motifs2h have been employed with varying
degrees of success to achieve high enantioselectivity during
photochemical transformations. Developing a general strategy for
achieving high stereoselectivity in solution during photoreactions to
complement established asymmetric thermal transformations how-
ever still remains an elusive task.1a To address this problem, we have
been working on a general methodology that employs nonbiaryl
atropisomeric compounds that undergo stereospecific photoreaction
in solution leading to high enantioselectivity in the photoproducts.3
Using this strategy we have successfully achieved high enantio-
selectivity in the photoproduct during 6p-photocyclization of acryl-
anilides,3a Norrish–Yang reactions of a-oxoamides3b,c and photo-
chemical 4p-ring closure of 2-pyridones.3d In our continuing efforts
to extend this methodology, we now wish to report a new class of
atropisomeric4 3,4-dihydro-2-pyridones 1a–c that undergo efficient
Scheme 1 Intramolecular [2+2]-photocycloaddition of 1a–c.
intramolecular [2+2]-photocycloaddition5 under triplet sensitized
irradiation conditions to access photoproduct(s) in good yields with
excellent stereoretention (diastereomeric ratio > 98 : 2 and enantio-
selectivity > 98%).
The [2+2]-photocycloaddition reactions have remained a valuable
tool in organic synthesis to obtain various chiral building blocks,5
due to the ease of accessing various natural products.5e This
prompted us to investigate stereospecific intramolecular [2+2]-photo-
cycloaddition of 1a–c (Scheme 1), which we felt would expand the
existing arsenal for organic synthesis to build chiral building blocks
with quaternary chiral centers. Axially chiral 1a–c were synthesized
and characterized by NMR spectroscopy and mass spectrometry.6
The axial chirality arising due to the restricted rotation of N–C (aryl)
substituents led to P and M isomers that were easily separated by
HPLC on a chiral stationary phase. The purity of the individual P and
M isomers of 1 was established by optical rotation.6
In order to utilize atropisomeric compounds for stereospecific
photochemical transformation, it is essential to ascertain the barrier
for racemization i.e., N–C (aryl) rotation barrier in 1a–c.7 Our kinetic
study established that 1a–c racemize slowly at room temperature
indicating a high energy barrier for N–C (aryl) bond rotation. Due to
slow racemization of optically pure 1a–c at room temperature (no
racemization observed after 2 months) racemization kinetics were
performed at elevated temperatures in various solvents (Table 1). For
example, in the case of 1b at 75 1C, the activation barrier for
racemization DG‡rac in 2-propanol was found to be B30.46 kcal molÀ1
with a racemization rate constant (krac) of 5.4 Â 10À7 s that
corresponds to a half-life of racemization (t1/2) of 15 days (Table 1,
entry 4). These results indicate that newly synthesized atropisomeric
1a–c have fairly high energy for racemization even at 75 1C.3d
Department of Chemistry and Biochemistry, North Dakota State University, Fargo,
North Dakota 58108, USA. E-mail: sivaguru.jayaraman@ndsu.edu;
Fax: +1 701-231-8831; Tel: +1 701-205-8338
† This manuscript is dedicated to Prof. Mukund P. Sibi, an esteemed colleague
and a friend, on the occasion of his 60th birthday.
‡ This article is part of the ChemComm ‘Emerging Investigators 2013’ themed issue.
§ Electronic supplementary information (ESI) available: Experimental procedures
for single crystal XRD, characterization data and analysis conditions. CCDC
903368–903372. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2cc37123e
c
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Table 1 Racemizationa rate constant (krac), half-life (t1/2) and activation free
energy (DG‡rac) for optically pure 1a–c
indicating the lack of diastereomers in the photoproduct.6 HPLC
analyses after irradiation of 1 on a chiral stationary phase gave the
ee values for the photoproduct (Table 2).
T
krac
t1/2
(days) (kcal molÀ1
DG‡rac
Entry Compound Solvent (1C) (sÀ1
)
)
Inspection of Table 2 reveals a very high enantiomeric excess in
the photoproduct (ee values of 98% or higher). In the case of 1a and
1c, photoproduct 2 was observed exclusively (dr > 98 : 2; Table 2,
entries 1–6 and 13–18). On the other hand, in the case of 1b both
photoproducts 2 and 3 were observed with a dr of 2.8 : 1 for acetone
sensitization (Table 2, entries 7 and 8) and a dr of 4.3 : 1 for
acetophenone and xanthone sensitization (Table 2, entries 9–12).
For example, triplet sensitized irradiation of (À)-1a gave (+)-(S,S,S)-2a
as the photoproduct. Similarly, triplet sensitized irradiation of (+)-1a
gave the optical antipode of the photoproduct (À)-(R,R,R)-2a sug-
1
2
3
4
5
6
1a
1b
1c
Acetone 50
IPA 75
Acetone 50
IPA 75
Acetone 50
IPA 75
9.3 Â 10À8 86.6
8.2 Â 10À7 9.82
4.5 Â 10À8 177
5.4 Â 10À7 15
4.6 Â 10À8 176
7.8 Â 10À7 10.2
29.35
30.17
29.81
30.46
29.81
30.20
a
Racemization values carry an error of Æ5%. In MeOH at 50 1C, t1/2
=
355 days for 1a and no racemization was observed even after 60 days for
1b and 1c. Refer to ESI for experimental details.
Photoirradiation6 of optically pure atropisomers (P and M iso- gesting that the system was well behaved.6 To ascertain the reaction
mers with ee values above 98%) was carried out at a given pathway and to gain insight into the reaction multiplicity, we
temperature (À30 1C for 1a–b and 25 1C for 1c) in dry acetone performed steady state emission and lifetime measurements6 for
(acetone serving as both the solvent and a triplet sensitizer) and in compounds 1a–c in both polar (ethanol) and non-polar (methyl-
methanol (with acetophenone or xanthone as a triplet sensitizer) cyclohexane) solvents. All the three compounds showed similar
using a 450 W medium pressure Hg lamp placed inside a water- emission and lifetime profiles. For example, in ethanol at room
cooled jacket with a Pyrex cutoff filter under constant flow of temperature, a structureless fluorescence emission with a lmax
nitrogen.6 The reaction progress was monitored by thin layer centered around 383 nm was observed. Phosphorescence emission
chromatography. After the consumption of reactant 1, the solvent in ethanol glass at 77 K for 1 revealed a slightly structured emission
was evaporated and the residue was purified by chromatography to with a lifetime of B0.49 s. The triplet energy (ET) of 1a–c was
get pure photoproducts. The photoproducts were analyzed by NMR established to be around B73 kcal molÀ1 above the ground state.
spectroscopy, HRMS, CD spectroscopy, optical rotation and single The ET of 1 provided insight into the photochemical reactivity where
crystal XRD.6,8 The relative orientation of the hydrogen atoms in the the conversion to the photoproduct for a given irradiation time was
cyclobutane fused to the lactam ring was cis in photoproduct 2, dependent on the type of sensitizer that was employed (Table 2). For
while it was trans in the case of photoproduct 3. The diastereomeric example, in the case of 1a for 3 h irradiation, the conversion with
1
ratio (dr) between photoproducts 2 and 3 was ascertained by H- acetone and xanthone as triplet sensitizers was 70% and 76%,
NMR spectroscopy of the crude photoreaction mixture. The enan- respectively. On the other hand, the conversion with acetophenone
tiomeric relation in the photoproduct was established by CD as a triplet sensitizer was 29%.
spectroscopy and by its optical rotation values. Variable temperature
Based on the photophysical data and photochemical reaction
1H-NMR studies on optically pure 2a did not show any diastereo- we believe that the [2+2]-photocycloaddition of 1 proceeds
meric protons upon varying the temperature (À50 to 50 1C) through the excited triplet state of 1 ([1]*3) upon sensitization.
Table 2 Stereospecific [2+2]-photocycloaddition of 3,4-dihydro-2-pyridones 1a–ca
Entry
Solvent
Acetone
t (h)
Triplet sensitizer
Acetone
Substrates
Tb (1C)
% eec (2)
drd (2 : 3)
% Convne
70
% MBe
96
1
2
3
4
5
6
7
8
3
(À)-1a
(+)-1a
(À)-1a
(+)-1a
(À)-1a
(+)-1a
(À)-1b
(+)-1b
(À)-1b
(+)-1b
(À)-1b
(+)-1b
(À)-1c
(+)-1c
(À)-1c
(+)-1c
(À)-1c
(+)-1c
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
25
>98% (S,S,S)
>98% (R,R,R)
>98% (S,S,S)
>98% (R,R,R)
>98% (S,S,S)
>98% (R,R,R)
>98% (A)g
>98 : 2
>98 : 2
>98 : 2
>98 : 2
>98 : 2
>98 : 2
2.8 : 1
2.8 : 1
4.3 : 1
4.3 : 1
4.3 : 1
4.3 : 1
>98 : 2
>98 : 2
>98 : 2
>98 : 2
>98 : 2
>98 : 2
MeOH
MeOH
Acetone
MeOH
MeOH
Acetone
MeOH
MeOH
3
3
Xanthonef
76
29
39
21
20
90
92
33
89
92
79
82
87
77
84
86
Acetophenonef
Acetone
24
3
>98% (B)g
9
Xanthonef
>98% (A)g
10
11
12
13
14
15
16
17
18
>98% (B)g
12
2.5
2.5
12
Acetophenonef
Acetone
>98% (A)g
>98% (B)g
>98% (S,S,S)
>98% (R,R,R)
>98% (S,S,S)
>98% (R,R,R)
>98% (S,S,S)
>98% (R,R,R)
25
25
25
25
Xanthonef
Acetophenonef
25
a
b
(+) and (À) represent the sign of optical rotation (MeOH at 25 1C). Reported values are an average of 3 runs with Æ3% error. Reaction
temperature was chosen to prevent unwanted side products. For 1a and 1c an uncharacterized product was observed with 8–10% yield. No side
products were observed with 1b. A and B refer to the elution order for a given pair of enantiomers in the HPLC. The ee values were determined by
HPLC on a chiral stationary phase. Absolute configuration was determined by single crystal XRD using Flack parameters. The diastereomeric
ratio (dr) was determined by H-NMR spectroscopy. Conversion (% Convn) and mass balance (% MB) were calculated by H-NMR spectroscopy
c
d
1
e
1
f
g
with Ph3CH as an internal standard. 30 mol% of the sensitizer was used. Identical ee values were observed for both photoproducts 2b and 3b.
c
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photoproducts 2 and 3 respectively. The relative stability of the
triplet and singlet biradicals and the ease of intersystem crossing
will dictate the diastereomeric ratio for the photoproduct. As we
observed high enantioselectivity for the photoproduct, the axial
chiral transfer likely occurred in the cyclization step that produced
the triplet diradical (e.g. t-BR1 for 1a) with defined stereochemistry
at the a-carbon (to the amide nitrogen) and the carbon that bears
the R2 substituent. This also provided us an opportunity to build
quaternary chiral centers (e.g. substrate 1c with R2 alkyl substituent)
with high optical purity.
Thus our study has uncovered axial to point chirality transfer in
[2+2]-photocycloaddition involving atropisomeric 3,4-dihydro-2-
pyridones. The individual atropisomers are highly stable at room
temperature with no noticeable racemization even after 2 months.
The photoreaction occurs likely via triplet sensitization with
excellent ee values in the photoproducts. The diastereocontrol in
the reaction is dictated by the allyl substituent(s) on the phenyl
ring due to the stability of the type of biradical produced in
the reaction pathway. The highly stereospecific chiral transfer
opens up avenues to synthesize complex structural motifs with
quaternary chiral centers with excellent stereocontrol.
The authors thank the National Science Foundation for
generous support for their research (CHE-1213880). EK
thanks the NSF ND-EPSCoR for a doctoral dissertation fellowship
Scheme 2 Mechanistic rationale for stereospecific [2+2]-photocycloaddition of 1a–c. (EPS-0814442). The authors also thank the generous funding from
NSF-CRIF (CHE-0946990) for the purchase of departmental X-ray
diffractometer. The authors thank Dr Angel Ugrinov for solving the
single crystal XRD structures.
This conjecture is quite reasonable as the triplet energy transfer to 1
from acetone (ET B 79 kcal molÀ1; serving as both a solvent and
a sensitizer), xanthone (ET B 74 kcal molÀ1) and acetophenone
Notes and references
(ET B 73 kcal molÀ1) is energetically feasible. We also ruled out the
1 (a) Y. Inoue, in Chiral Photochemistry, ed. Y. Inoue and
V. Ramamurthy, Marcel Dekker, New York, 2004, p. 129;
reaction proceeding via the singlet manifold as direct irradiation (in
the absence of the sensitizer) in methanol, acetonitrile, chloroform
or toluene did not produce the photoproduct 2 or 3 with complete
recovery of 1. Based on the ee values observed for the photoproduct,
there is complete transfer of axial chirality from the reactant to point
chirality in the photoproduct. A tentative mechanism for transfer of
chirality from 1 to the photoproducts is given in Scheme 2. We
believe that upon energy transfer from the triplet sensitizer to the
substrate 1, triplet excited 1 ([1]*3) is produced which cyclizes to
form the triplet 1,4-biradical t-BR1. This triplet 1,4-biradical t-BR1
can be a primary radical at the carbon bearing the R1 substituent as
in the case of 1a and 1c or a tertiary radical as in the case of 1b.
Based on the observed selectivity in which there is complete
diastereo- and enantio-control, we believe that t-BR1 produced in
the case of 1a and 1c with a primary radical center at the carbon
bearing the R1 substituent rapidly intersystem crosses to the
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leakage in diastereocontrol with high enantioselectivity in the
photoproduct (2b and 3b; Table 2, entries 7–12). We believe that
t-BR1 produced in the case of 1b lives much longer (due to a tertiary
radical center at the carbon bearing the R1 substituent), which
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allows for pyramidal inversion at the b-carbon of the lactam 6 Refer to ESI§.
7 C. Wolf, Dynamic Stereochemistry of Chiral Compounds. Principles and
ring leading to t-BR2. The two biradicals, viz., t-BR1 and t-BR2,
intersystem cross to the corresponding singlet biradicals s-BR1
and s-BR2 that subsequently cyclize to form diastereomeric
Applications, RSC publishing, Cambridge, UK, 2008.
8 CCDC 903368–903372. Refer to ESI§ for details on XRD structure
determination.
c
4348 Chem. Commun., 2013, 49, 4346--4348
This journal is The Royal Society of Chemistry 2013