Intramolecular Paterno-Buechi reaction of atropisomeric α-oxoamides in solution and in the solid-state

Article abstract of DOI:10.1039/c3cc44281k

Atropisomeric α-oxoamides were synthesized and employed for intramolecular Paterno-Buechi reaction leading to very high enantio- and diastereoselectivity in the bicyclic oxetane photoproduct. A reversal of product selectivity was observed in solution and in the solid-state.

Full text of DOI:10.1039/c3cc44281k

ChemComm
View Article Online
View Journal
COMMUNICATION
`
Intramolecular Paterno–Buchi reaction of atropisomeric
¨
a-oxoamides in solution and in the solid-state†
Cite this: DOI: 10.1039/c3cc44281k
Ramya Raghunathan, Elango Kumarasamy, Akila Iyer, Angel Ugrinov and
J. Sivaguru*
Received 6th June 2013,
Accepted 26th July 2013
DOI: 10.1039/c3cc44281k
www.rsc.org/chemcomm
Atropisomeric a-oxoamides were synthesized and employed for
Based on the structural parameters derived from crystals and
`
intramolecular Paterno–Buchi reaction leading to very high enantio- the photoreactivity of benzoylformamides in the solid-state,
¨
and diastereoselectivity in the bicyclic oxetane photoproduct. Sakamoto and co-workers7 detailed the importance of several
A reversal of product selectivity was observed in solution and in structural features necessary to access the oxetane product. Their
the solid-state.
pioneering work revealed the key requirements concerning the role
of N–CO bond orientation where the s-trans, s-trans conformer
Light induced transformations are an important class of reactions geometry was required for an efficient photochemical reaction (due
in the field of organic synthesis that are often utilized to synthesize to the optimal orientation of the excited ketone chromophore with
structurally important molecules.1 While phototransformations are the alkene) with the conformer geometry being dictated by steric
elegant, quite frequently it becomes challenging to control the and electronic factors on the N-aryl substituent.7 They cleverly
excited state processes that often result in poor selectivity. In an exploited the confinement offered by the crystalline matrix to
attempt to address this bottleneck, photoreactions were done in freeze the molecular conformation to dictate the photochemical
confined media with capricious success.2 This presents a distinct reactivity.7,8 We were interested in biasing the photochemical
challenge to control photoreactions in solutions and achieve high reactivity in solution leading to an enhanced reaction specificity
stereoselectivity.1a In that regard, we have been successful in and product selectivity. One of the bottlenecks that had to be
utilizing atropisomeric non-biaryl3 photochromophores to navigated for reactions done in solution was the presence of
perform various asymmetric photoreactions with good control multiple conformations that caused differential reactivity leading
over stereochemistry.4 These include 6p-photocyclization,4a 4p- to loss of specificity/selectivity.9 This provided us the opportunity to
photocyclization,4d [2+2]-photocycloaddition4e and Norrish– examine the extent of axial chiral transfer from atropisomeric o-tert-
Yang reactions.4b,c Now we wish to report the stereospecific butyl substituted a-oxoamides 1 to the oxetane in solution and
`
Paterno–Bu¨chi reaction of a-oxoamides in solution that results in a compare their reactivities in the solid-state.
bicyclic oxetane photoproduct with very high stereoselectivity.
Atropisomeric o-tert-butyl substituted a-oxoamides (Scheme 1)
The [2+2]-photocycloaddition between a carbonyl group and were synthesized by a sequential acylation reaction from the
`
an alkene termed as Paterno–Bu¨chi reaction generates an corresponding aniline and were characterized by NMR spectro-
oxetane ring that has interesting chemical properties and scopy, mass spectrometry and single crystal X-ray analysis.† The
structural features.5 The mechanism of cycloaddition is quite axial chirality arising due to the restricted rotation of N–C(aryl)
distinct depending on the interacting orbitals that initiate the substituents led to P and M isomers that were easily separated by
reaction as well as the nature of alkenes (electron rich or HPLC on a chiral stationary phase. The purity of the individual P
electron poor alkenes).6 In this report we present the stereo- and M isomers of atropisomeric a-oxoamides was established
`
specific Paterno–Bu¨chi reaction of atropisomeric a-oxoamides by optical rotation and by analysis on a chiral stationary phase.†
with a built-in photo-excitable ketone functionality and an
electron deficient alkene unit.
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: +1 701-231-8923
† Electronic supplementary information (ESI) available: Experimental proce-
dures, single crystal XRD (CIF format), characterization data and analysis condi-
tions. CCDC 942921–942927. For ESI and crystallographic data in CIF or other
Scheme 1 Intramolecular Paterno`–Buchi reaction of 1a–d.
electronic format see DOI: 10.1039/c3cc44281k
¨
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.

View Article Online
Communication
ChemComm
Table 1 Racemization parameters for optically pure 1a-b at 50 1Ca
Table 2 Intramolecular Paterno`–Buchi reaction of a-oxoamides 1a–da
¨
Entry Cpd Solvent
krac (sÀ1
)
t
1/2(days) DG‡ (kcal molÀ1
)
Entry
Cpdb
Solvent
dr (2 : 3)c
% eed,e
Yieldf
78
rac
1
2
3
4
1a
1b
MeCN
1.26 Â 10À6 6.4
2.27 Â 10À6 3.5
27.7
27.4
27.3
27.0
1
2
3
4
5
6
7
8
(À)-1a
(+)-1a
(À)-1a
(+)-1a
(M)-1b
(P)-1b
(M)-1b
(P)-1b
(M)-1b
(P)-1b
1c
MeCN
MeCN
Benzene
Benzene
MeCN
71 : 29
98 (R,R,M)-2a
98 (S,S,P)-2a
97 (R,R,M)-2a
97 (S,S,P)-2a
99 (R,R,M)-2b
98 (S,S,P)-2b
99 (R,R,M)-2b
98 (S,S,P)-2b
98 (A)-3b
98 (B)-3b
—
Benzene 2.11 Â 10À6 3.8
MeCN
55 : 45
82 : 18
78 : 22
90
81
78
Benzene 3.81 Â 10À6 2.1
a
Values carry an error of Æ5%. Kinetics followed by HPLC analysis,
MeCN
refer to ESI.
Benzene
Benzene
Crystal
Crystal
MeCN
Benzene
MeCN
9
15 : 85
15 : 85
95 : 05
89 : 11
—
—
—
91
90
30
10
11
12
13
`
To employ atropisomeric a-oxoamides for stereospecific Paterno–
Bu¨chi reaction, it became critical to ascertain the barrier for
racemization i.e., N–C(aryl) rotation barrier in 1a-b. Our kinetic
studies established that 1a-b racemize slowly at room temperature
indicating a high barrier for N–C(aryl) bond rotation. Due to the
slow racemization of optically pure 1a-b at room temperature,
1c
1d
—
—
a
Reported values are an average of 3 runs with Æ3% error. 2.5 h
b
irradiation for 1a–c, 12 h irradiation for 1d. (+) and (À) represent the
c
sign of optical rotation, refer to ESI. The diastereomeric ratio (dr) was
determined using 1H-NMR spectroscopy. From HPLC analysis. A and
d
racemization kinetics were performed at elevated temperatures in B refer to the elution order for a given pair of enantiomers. Absolute
e
configuration from single crystal XRD using Flack parameter. Identical
ee values for both 2 and 3. Isolated yield.
polar acetonitrile (MeCN) and non-polar benzene (Table 1). For
f
example, in the case of 1a at 50 1C, the activation barrier for
racemization (DG‡rac) in MeCN was found to be B27.7 kcal molÀ1
with a racemization rate constant (krac) of 1.26 Â 10À6 sÀ1 that diminished reactivity.7 The slow reactivity of 1d likely reflected the
corresponded to a half-life of racemization (t1/2) of 6.4 days (Table 1; conformational distribution where the s-trans, s-trans conformer
entry 1). Upon changing the solvent to benzene, the activa- was not preferred in solution. The diastereomeric ratio (dr)
tion barrier for racemization (DG‡rac) at 50 1C was found to be determined by NMR. The dr value in acetonitrile was higher than
B27.4 kcal molÀ1 with a racemization rate constant (krac) of in benzene. For example, in the case of 1a, the dr values were
2.11 Â 10À6 sÀ1 that corresponded to a half-life of racemization 71 : 29 in MeCN and 55 : 45 in benzene (Table 2; compare entries 1
(t1/2) of 3.8 days (Table 1; entry 2). We have already established and 3). Considerably higher dr values (82 : 18 in MeCN and 78 : 22
that non-bonding interactions and solvent polarity affected the in benzene; Table 2; entries 5 and 7) were observed in the case of
rates and half-life of racemization.4d,e The current results with 1b. To further improve the diastereoselectivity, we carried out the
the newly synthesized atropisomeric a-oxoamides 1a-b indi- photoreaction in the solid-state as we were successful in crystal-
cated that they have a fairly high energy barrier for racemiza- lizing the individual atropisomers of 1b. Irradiation of optically
tion even at higher temperatures (50 1C) and could be employed pure crystals of 1b gave a dr value of 15 : 85. While the dr values in
for desired photochemical transformations at room tempera- solution and in the solid-state were comparable, the enhanced
ture without loss of their absolute configuration.
diastereomer was different (Table 2; compare entries 5–8 with 9
Irradiation of optically pure atropisomers of 1 was carried out at and 10). Despite the reversal in dr values, analysis of the reaction
room temperature in benzene or acetonitrile using either a 450 W mixture upon irradiation in solution and in the solid-state on a
medium pressure Hg lamp placed inside a water-cooled jacket with chiral stationary phase showed very high enantiomeric excess
a Pyrex cut off filter or a Rayonet reactor equipped with B350 nm (ee values B98%) in both 2 and 3 photoproducts (Table 2). A clear
bulbs (24 Watts  16 bulbs) under a constant flow of nitrogen.† mechanistic rationale for the observed high selectivity is needed.
`
To understand the reactivity and selectivity during the Paterno–
After the consumption of reactants, the crude photoproduct was
purified by chromatography and analysed by NMR spectroscopy, Bu¨chi reaction of atropisomeric a-oxoamides, it is critical to
HRMS, optical rotation and single crystal XRD.10† The relative appreciate not only the structural features (observed in single crystal
orientation of the oxygen atom in the oxetane ring was syn to the X-ray analysis) but also the conformational influence arising from
N-aryl ortho-tert-butyl substituent in photoproduct 2, while it was atropisomerism as well as the excited state reactivity of ketones with
anti in the case of photoproduct 3. The dr between photoproducts 2 electron deficient alkenes. To understand the photochemical reac-
1
and 3 was ascertained using H-NMR spectroscopy.‡ The enantio- tivity, we need to have a closer look at the excited state of the
meric relation in the individual photoproduct was established by its a-oxoamide chromophore. Based on the photochemical paradigm6
optical rotation values. HPLC analysis on a chiral stationary phase of reactivity of excited ketones with electron deficient alkenes, it is
gave the ee values for the individual photoproduct 2 or 3.
likely that the half filled p* orbital triggered the reaction by charge
`
Table 2 reveals that Paterno–Bu¨chi reaction of atropisomeric transfer with the LUMO p* of the electron deficient alkene leading
a-oxoamides are facile with 78–91% isolated yields of the oxetane to oxetane formation.11 The p*CQO - p*CQC charge transfer
photoproduct with excellent mass balance (even for large-scale interaction has important consequences in the stereochemical
irradiation). We believe that the presence of a bulky ortho-tert-butyl features of the photoproduct as they will be dictated by the orbital
substituent on the N-phenyl ring influences the formation of the overlap.11 A good overlap between the p*CQO and p*CQC orbitals
s-trans, s-trans conformer in solution, leading to enhanced reactivity is necessary to initiate oxetane formation rather than the conven-
in the atropisomeric substrates.7 Control studies with 1d that lacked tional radical stability that determines the reaction outcome of the
the bulky ortho-tert-butyl substituent on the N-phenyl ring showed photochemical transformations involving a-oxoamides.11 Due to
c
Chem. Commun.
This journal is The Royal Society of Chemistry 2013

View Article Online
ChemComm
Communication
‘‘conf-A’’. In the crystalline state, single crystal XRD analysis10
ascertained that ‘‘conf-A’’ is preferred that leads to photoproduct 3
as the major isomer. A closer inspection of the crystal structure10 of
1b revealed that the distance between the keto carbonyl function-
ality and the alkene double bond is at an optimal distance viz.,
OCÁÁÁCH2QC is B3.083 Å and COÁÁÁCQCH2 is 2.986 Å (Scheme 2)
for undergoing photochemical transformation. As both ‘‘conf-A’’ and
‘‘conf-D’’ are atropisomeric, the axial chirality influences the forma-
tion of point chirality in the bicyclic oxetane with high stereospeci-
ficity that is reflected in the high ee value.
Our study has shown that atropisomeric chromophores can be
`
employed for stereospecific Paterno–Bu¨chi reaction both in solution
and in the solid-state. The reactivity and selectivity are likely dictated
by the degree of orbital overlap between the excited ketone and the
electron deficient alkene. The stereospecificity is dependent on
conformational aspects of the atropisomeric a-oxoamides. Our
strategy opens up avenues for developing asymmetric phototrans-
formations with a high degree of specificity to access molecules with
unique stereochemical features.
The authors thank NSF for generous support of their research
(CHE-1213880). EK and JS thank the NSF ND-EPSCoR for a doctoral
dissertation fellowship (EPS-0814442). The authors also thank NSF-
CRIF (CHE-0946990) for the purchase of the departmental X-ray
diffractometer. The authors thank Ms Sabine Volla (nee’ Rabe) and
Dr Saravanakumar Rajendran for their contributions towards pre-
Scheme 2 Mechanistic rationale for a stereospecific Paterno`–Buchi reaction
¨
involving atropisomeric a-oxoamides.
the required p*CQO - p*CQC charge transfer interaction, the first paring this manuscript.
bond that is likely formed during photochemical excitation of
Notes and references
a-oxoamides will be the bond between the alkene CH2 (unsub-
stituted b-alkene carbon) and the carbonyl carbon, as they will
have the largest orbital coefficients.11 This initial bond forma-
tion leading to a 1,4-diradical will dictate the stereochemical
features of the oxetane product. The bulky ortho-tert-butyl sub-
stituent on the N-phenyl ring likely dictates the conformation
responsible for the observed selectivity in solution and in the
solid-state. Based on the stereochemistry of the photoproducts, it
is clear that in addition to the s-trans, s-trans geometry at the
CO–N bond, the conformation of the CO–CC bond is also critical.
It is likely that the reactivity of the four s-trans, s-trans conformers
viz., conf-A, conf-B, conf-C and conf-D that arise due to the CO–CC
and CO–CO bond rotations dictates the product ratio and selec-
tivity (Scheme 2, top right inset). As observed in the case of
oxetane 2 and 3, the cycloaddition likely occurred from ‘‘conf-D’’
and ‘‘conf-A’’, respectively. Based on the orbital overlap between
p*CQO and p*CQC orbitals, upon photoexcitation of a-oxoamide,
formation of diradical DR1 is likely. Photoexcitation of ‘‘conf-A’’
and ‘‘conf-D’’ will lead to DR1-(A) and DR1-(D) respectively, that
subsequently cyclize to the corresponding diastereomeric photo-
products 3 and 2. The other diradicals (DR2, DR3 and DR4;
Scheme 2, bottom inset) from individual conformers (‘‘conf-A’’
and ‘‘conf-D’’) are feasible depending on the orbital coefficient in
the excited chromophore, steric, electronic features present in the
system as well as the substitution on the alkene double bond.
The ratios of the conformers depend on the solvent polarity, the
reaction media (solution vs. solid-state) as well as the steric and
electronic features of the a-oxoamide. As 2 is observed as the major
photoproduct in solution, it is likely that conformation ‘‘conf-D’’ is
preferred in solution/reacts much faster upon photo-excitation than
‡ We were not able to interconvert the 2 and 3 diastereomers at elevated
temperatures (100 1C for 14 h), indicating a high-energy barrier for
N–C(aryl) bond rotation in the photoproduct.
1 (a) Y. Inoue, in Chiral Photochemistry, ed. Y. Inoue and
V. Ramamurthy, Marcel Dekker, New York, 2004, p. 129;
(b) Y. Inoue, Chem. Rev., 1992, 92, 741.
2 (a) V. Ramamurthy, Photochemistry in Organized and Constrained Media,
Wiley-VCH, New York, 1991, pp. 429–493; (b) T. Mori, R. G. Weiss and
Y. Inoue, J. Am. Chem. Soc., 2004, 126, 8961; (c) J. N. Gamlin, R. Jones,
M. Leibovitch, B. Patrick, J. R. Scheffer and J. Trotter, Acc. Chem. Res.,
1996, 29, 203; (d) J. Sivaguru, A. Natarajan, L. S. Kaanumalle, J. Shailaja,
S. Uppili, A. Joy and V. Ramamurthy, Acc. Chem. Res., 2003, 36, 509;
(e) C. Yang, T. Mori, Y. Origane, Y. H. Ko, N. Selvapalam, K. Kim and
Y. Inoue, J. Am. Chem. Soc., 2008, 130, 8574.
3 (a) A. Ates and D. P. Curran, J. Am. Chem. Soc., 2001, 123, 5130;
(b) A. Honda, K. M. Waltz, P. J. Carroll and P. J. Walsh, Chirality,
2003, 15, 615; (c) J. Clayden, Chem. Commun., 2004, 127.
4 (a) A. J.-L. Ayitou and J. Sivaguru, J. Am. Chem. Soc., 2009, 131, 5036; (b)
A. J.-L. Ayitou, J. L. Jesuraj, N. Barooah, A. Ugrinov and J. Sivaguru, J. Am.
Chem. Soc., 2009, 131, 11314; (c) J. L. Jesuraj and J. Sivaguru, Chem.
Commun., 2010, 46, 4791; (d) E. Kumarasamy, J. L. Jesuraj, J. N. Omlid,
A. Ugrinov and J. Sivaguru, J. Am. Chem. Soc., 2011, 133, 17106;
(e) E. Kumarasamy and J. Sivaguru, Chem. Commun., 2013, 49, 4346.
5 G. Bu¨chi, C. G. Inman and E. S. Lipinsky, J. Am. Chem. Soc., 1954, 76, 4327.
6 N. J. Turro, V. Ramamurthy and J. C. Scaiano, Modern Molecular
Photochemistry of Organic Molecules, University Science Books,
Sausalito, CA, 2010, pp. 629–704.
7 M. Sakamoto, M. Takahashi, T. Fujita, S. Watanabe, T. Nishio, I. Iida
and H. Aoyama, J. Org. Chem., 1997, 62, 6298.
8 I. Azumaya, K. Yamaguchi, I. Okamoto, H. Kagechika and K. Shudo,
J. Am. Chem. Soc., 1995, 117, 9083.
9 C. F. Degenhardt, J. M. Lavin, M. D. Smith and K. D. Shimizu, Org.
Lett., 2005, 7, 4079.
10 CCDC 942921–942927. Refer to ESI† for XRD details.
11 (a) J. C. Dalton, P. A. Wriede and N. J. Turro, J. Am. Chem. Soc., 1970,
92, 1318; (b) J. A. Barltrop and H. A. J. Carless, J. Am. Chem. Soc., 1972,
94, 1951.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.