Diastereomer-differentiating photochemistry of β-arylbutyrophenones: Yang cyclization versus type II elimination

Article abstract of DOI:10.1021/ja0523643

The diastereomers of ketones 2 and 3 are shown to exhibit distinct photochemical reactivities due to conformational preferences; while the anti isomers of 2 and 3 undergo efficient Yang cyclization in 75-90% yields with a remarkable diastereoselectivity (> 90%), the syn isomers predominantly undergo Norrish Type II elimination. The differences in the product profiles of the diastereomers are consistent with a mechanistic picture involving the formation of precursor diastereomeric triplet 1,4-biradicals in which the substituents at α and β-positions stabilize the cisoid (cyclization) or transoid (elimination) geometry. The fact that such a diastereomeric relationship does indeed ensue at the triplet-excited-state itself is demonstrated via the nanosecond laser-flash photolysis of model ketones 1. The diastereomeric discrimination in the product profiles observed for ketones 2 and 3 as well as in the triplet lifetimes observed for ketones 1 can both be mechanistically traced back to different conformational preferences of the ground-state diastereomeric ketones and the intermediary 1,4-biradicals. Additionally, it emerges from the present study that the syn and anti diastereomers of ketones 2 and 3 represent two extremes of a broad range of widely examined butyrophenones, which lead to varying degrees of Yang photocyclization depending on the alkyl substitution pattern.

Full text of DOI:10.1021/ja0523643

Published on Web 09/27/2005
Diastereomer-Differentiating Photochemistry of
â-Arylbutyrophenones: Yang Cyclization versus Type II
Elimination
†
§
†
‡
Nidhi Singhal, Apurba L. Koner, Prasenjit Mal, Paloth Venugopalan,
§,
†,
Werner M. Nau, * and Jarugu Narasimha Moorthy *
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India, and
Department of Chemistry, Panjab UniVersity, Chandigarh 160 014, India, and
School of Engineering and Sciences, Campus Ring 1, International UniVersity Bremen,
28725 Bremen, Germany
Received April 12, 2005; E-mail: moorthy@iitk.ac.in; w.nau@iu-bremen.de
Abstract: The diastereomers of ketones 2 and 3 are shown to exhibit distinct photochemical reactivities
due to conformational preferences; while the anti isomers of 2 and 3 undergo efficient Yang cyclization in
75-90% yields with a remarkable diastereoselectivity (> 90%), the syn isomers predominantly undergo
Norrish Type II elimination. The differences in the product profiles of the diastereomers are consistent with
a mechanistic picture involving the formation of precursor diastereomeric triplet 1,4-biradicals in which the
substituents at R and â-positions stabilize the cisoid (cyclization) or transoid (elimination) geometry. The
fact that such a diastereomeric relationship does indeed ensue at the triplet-excited-state itself is
demonstrated via the nanosecond laser-flash photolysis of model ketones 1. The diastereomeric
discrimination in the product profiles observed for ketones 2 and 3 as well as in the triplet lifetimes observed
for ketones 1 can both be mechanistically traced back to different conformational preferences of the ground-
state diastereomeric ketones and the intermediary 1,4-biradicals. Additionally, it emerges from the present
study that the syn and anti diastereomers of ketones 2 and 3 represent two extremes of a broad range of
widely examined butyrophenones, which lead to varying degrees of Yang photocyclization depending on
the alkyl substitution pattern.
3
Introduction
phenyl alkyl ketones. It was of our interest to translate such
discrimination in the triplet lifetimes into differences in the
1
In contrast to reactions in the solid state and microhetero-
reactivity of the diastereomers of appropriately substituted
photoreactive carbonyl compounds. Indeed, reactions in which
SS/RR and RS/SR diastereomers exhibit differing reactivity are
2
geneous media, control of the photoreactivity of a substrate
that can potentially exploit two or more reaction pathways in a
homogeneous solution state is governed by conformational
preferences. Conceivably, the bond rotations between two
contiguous stereogenic centers of a substrate should be suf-
ficiently restricted to permit substantial differences in confor-
mational populations of the two diastereomers. It is precisely
this strategy that has been exploited to demonstrate unprec-
edented diastereomeric discrimination in the triplet lifetimes of
4
termed “diastereomer-differentiating”. The first example of a
photochemical reaction wherein the two diastereomers of a
substrate with two contiguous stereogenic centers, a hexa-1,5-
diene, yielded two different types of products was reported by
5,6
Margaretha and co-workers. Apart from this, we are aware
of only one other case of such a reaction, which involves
7,8
γ-hydrogen abstraction (vide infra).
†
(3) (a) Moorthy, J. N.; Patterson, W. S.; Bohne, C. J. Am. Chem. Soc. 1997,
Department of Chemistry, Indian Institute of Technology, Kanpur 208
1
19, 11094. (b) Moorthy, J. N.; Monahan, S. L.; Sunoj, R. B.; Chan-
0
16, India.
‡
drasekhar, J.; Bohne, C. J. Am. Chem. Soc. 1999, 121, 3093.
4) Izumi, Y.; Tai, A. In Stereo-Differentiating Reactions; Academic Press:
New York, 1977.
Department of Chemistry, Panjab University, Chandigarh 160 014,
India.
(
(
§
School of Engineering and Science, Campus Ring 1, International
University Bremen, 28725 Bremen, Germany.
5) Wrobel, M. N.; Margaretha, P. Chem. Commun. 1998, 541.
(6) Conformationally locked cyclic axial and equatorial isomers are funda-
mentally different from the diastereomers of a substrate with two contiguous
stereogenic centres. For diastereomer-dependent (axial versus equatorial)
photochemistry of cyclohexyl phenyl ketones, see: Lewis, F. D.; Johnson,
R. W.; Johnson, D. E. J. Am. Chem. Soc. 1974, 96, 6090.
(7) (a) Griesbeck, A. G.; Heckroth, H.; Lex, J. Chem. Commun. 1999, 1109.
(b) Griesbeck, A. G.; Heckroth, H. J. Am. Chem. Soc. 2002, 124, 396.
(8) For diastereodiscrimination in long-range hydrogen abstractions, see: (a)
Bosca, F.; Andreu, I.; Morera, I. M.; Samadi, A.; Miranda, M. A. Chem.
Commun. 2003, 1592. (b) Pischel, U.; Abad, S.; Domingo, L. R.; Bosca,
F.; Miranda, M. A. Angew. Chem., Int. Ed. 2003, 42, 2531. (c) Perez-
Prieto, J.; Lahoz, A.; Bosca, F.; Martinez-Manez, R.; Miranda, M. A. J.
Org. Chem. 2004, 69, 374.
(
1) (a) Ramamurthy, V.; Venkatesan, K. Chem. ReV. 1987, 87, 433. (b) Toda,
F. Acc. Chem. Res. 1995, 28, 480. (c) Gamlin, J. N.; Jones, R.; Leibovitch,
M.; Patrick, B.; Scheffer, J. R.; Trotter, J. Acc. Chem. Res. 1996, 29, 203.
(
d) Ito, Y. Synthesis 1998, 1. (e) Garcia-Garibay, M. A. Acc. Chem. Res.
2
003, 36, 491. (f) For a recent study on enantioselective Yang cyclization
in the crystalline medium, see: Natarajan, A.; Mague, J. T.; Ramamurthy,
V. J. Am. Chem. Soc. 2005, 127, 3568, and references therein.
2) (a) For control of photoreactions by various microheterogeneous media,
see: Photochemistry in Organized and Constrained Media; Ramamurthy,
V., Ed.; VCH Publishers: New York, 1991. (b) Sivaguru, J.; Natarajan,
A.; Kaanumalle, L. S.; Shailaja, J.; Uppilli, S.; Joy, A.; Ramamurthy, V.
Acc. Chem. Res. 2003, 36, 509.
(
10.1021/ja0523643 CCC: $30.25 © 2005 American Chemical Society
J. AM. CHEM. SOC. 2005, 127, 14375-14382
9
14375

A R T I C L E S
Chart 1
Singhal et al.
The photochemistry of butyrophenone/valerophenone is well
propiophenone.15 The reaction has been suggested to proceed
via the intermediacy of an intramolecular exciplex involving
the â-anisyl ring and triplet-excited carbonyl group.
9
established; indeed, it is a frequently employed chemical ac-
tinometer in quantum yield measurements.1 The early inves-
tigations by Lewis and co-workers have thoroughly established
the effect of R- and â-substitution on Yang cyclization versus
0
11
Norrish Type II elimination (eq 1). Accordingly, R-substitution
of butyrophenone increases the percentage of cyclization, while
â-substitution causes only a marginal effect.
â-Phenylpropiophenone has served as a prototypal example
to understand the long-recognized influence of aromatic solvents
such as benzene, toluene, etc. in shortening the triplet
We designed ketones 2 and 3 in such a way that their two
diastereomers incorporate, in their lowest energy conformations,
the structural attributes necessary for the two different reaction
mechanisms (cf. â- and γ-hydrogen abstraction in eq 1 and 2),
and three reaction products (cyclopropanol, cyclobutanol, and
cleavage products) with potentially different syn/anti stereo-
chemistry; the spectrum of potential photoproducts should
greatly facilitate the experimental detection of diastereodiffer-
entiating photochemical effects of the racemic anti and syn
diastereomers of ketones 2 and 3. The photobehavior of ketones
1
2
lifetimes of ketones. By nanosecond transient absorption
spectroscopy, Scaiano and co-workers13 showed that the orienta-
tion in which the â-phenyl ring is gauche to the carbonyl group
1
4
leads to intramolecular charge-transfer-induced quenching.
This remarkable phenomenon causes the triplet lifetime, for
example, of the representative â-phenylpropiophenone to be
shortened by more than 2-3 orders of magnitude to ca. 1 ns.
Later, Wagner and co-workers reported that photocyclization
via charge transfer-promoted â-hydrogen transfer to cyclopro-
panol (eq 2) occurs when the â-phenyl ring is substituted with
an electron-rich group such as methoxy as in â-(p-anisyl)-
1
and 4-7 (Chart 1) was investigated to gain a comprehensive
understanding of the photochemical reaction pathways in this
type of chromophores.
Results
(
9) Wagner, P. J.; Kemppainen, A. E. J. Am. Chem. Soc. 1972, 94, 7495.
10) Wagner, P. J.; Kochevar, I. E.; Kemppainen, A. E. J. Am. Chem. Soc. 1972,
4, 7489.
Synthesis and Characterization of Ketones. The synthetic
protocol followed for the preparation of ketones 1-5 is shown
in Scheme 1. Accordingly, the trimethylsilyl enol ether of pro-
piophenone, prepared from propiophenone using trimethyl-
(
(
(
(
(
9
11) (a) Lewis, F. D.; Hilliard, T. A. J. Am. Chem. Soc. 1970, 92, 6672. (b)
Lewis, F. D.; Hilliard, T. A. J. Am. Chem. Soc. 1972, 94, 3852.
12) Scaiano, J. C.; Perkins, M. J.; Sheppard, J. W.; Platz, M. S.; Barcus, R. L.
J. Photochem. 1983, 21, 137.
16
silyl chloride and triethylamine in DMF, was subjected to
13) Netto-Ferreira, J. C.; Leigh, W. J.; Scaiano, J. C. J. Am. Chem. Soc. 1985,
1
7
1
07, 2617.
Mukaiyama aldol condensation with propanaldehyde/phenyl-
14) For laser-flash photolysis studies of â-phenyl quenching, see: (a) Wis-
montski-Knittel, T.; Kilp, T. J. Phys. Chem. 1984, 88, 110. (b) Leigh, W.
J. J. Am. Chem Soc. 1985, 107, 6114. (c) Boch, R.; Bohne, C.; Netto-
Ferreira, J. C.; Scaiano, J. C. Can. J. Chem. 1991, 69, 2053. (d) Leigh, W.
J.; Banisch, J.-A. H.; Workentin, M. S. J. Chem. Soc., Chem. Commun.
(15) Weigel, W.; Wagner P. J. J. Am. Chem. Soc. 1996, 118, 12858.
(16) House, H. O.; Czuba, L. J.; Gall, M.; Olmstead, H. D. J. Org. Chem. 1969,
34, 2324.
1
1
993, 988. (e) Boch, R.; Bohne, C.; Scaiano, J. C. J. Org. Chem. 1996, 61,
(17) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 6,
423.
7503.
14376 J. AM. CHEM. SOC.
9
VOL. 127, NO. 41, 2005

Yang Cyclization versus Type II Elimination
A R T I C L E S
Scheme 1
Table 1. Product Composition and Disappearance Quantum
acetaldehyde in the presence of TiCl4 in DCM at -78 °C. The
resulting aldols were dehydrated using PTS in benzene to the
corresponding R,â-unsaturated ketones.18 The 1,4-addition reac-
tion of the latter with ArMgBr (Ar ) phenyl or p-anisyl) yielded
ketones 2-5 as mixtures of two diastereomers.19 Ketones 1 were
prepared in a similar manner starting from p-methoxypropiophe-
none. The ketones 6 and 720 were prepared by 1,4-addition of
MeMgI and EtMgI to p-methoxychalcone, respectively.
The diastereomers of ketones 1-5 were separated by silica
Yields for Photolysis of Ketones 2 and 3a
product distribution (%)b
mass
propiophenone
conv. balance
+
(%)b
(%)b
c
entry
ketone
solvent
cyclobutanol
styrene/stilbene
φ
r
1
2
3
4
5
6
7
8
2-anti C6D6
CD3CN
2-syn C D6
CD3CN
3-anti C6D6
CD3CN
3-syn C6D6
CD3CN
95
60
100
78
57
74
>90
>90
82
90
90
>90
82
90
75
25
20
100
100
15
<10
92
92
0.18
0.18
0.10
0.10
80 (71)d
6
e
e
85 (79)d
1
gel column chromatography and characterized by IR, H, and
>90d
1
3
C NMR analyses. The configurational assignment of the
62
90
8
8
d
diastereomers was accomplished as follows. First of all, the
stereochemistry for one of the diastereomers of ketone 3 was
established based on a single-crystal X-ray structure determi-
nation of the crystalline isomer. The X-ray analysis revealed
its stereochemistry to be ‘syn’ (Figure 1). The second diaste-
a
All the photolyses were conducted using Pyrex-filtered radiation from
a 200 W high-pressure Hg-lamp at ca. 25 °C for 2-4 h. The sample (ca.
8-10 mg) contained in a deuterated solvent (ca. 0.5-0.6 mL) was purged
with dry nitrogen gas for 15 min. b Based on H NMR (400 MHz) analysis
1
c
using methyl benzoate as an internal standard; error ( 10%. Error ( 0.02.
d
Isolated yield from a preparative photolysis of ca. 0.15 g of the ketone.
No cyclobutanol could be isolated.
e
Solution-State Photolysis and Characterization of Photo-
products. The direct photolysis (high-pressure Hg lamp, λ g
3
00 nm) of the anti diastereomers of both 2 and 3 in benzene
and acetonitrile led to the formation of the corresponding
cyclobutanols in high yields (ca. 75-90%) with the associated
Type II elimination products, namely propiophenone and
p-methoxy-â-methylstyrene/p-methoxystilbene, in low yields (eq
3
; entries 1, 2, 5, and 6, Table 1). The photochemistry proceeded
Figure 1. Molecular structure of ketone 3-syn. Notice that the benzoyl
and p-anisyl rings are gauche to each other, while the R-methyl and p-anisyl
rings are anti.
therefore in accordance with eq 1, and not eq 2, i.e., the
formation of cyclopropanols was not observed. The H NMR
monitoring of the reaction conducted in deuterated C6D6 and
2
1
1
reomer was assigned the ‘anti’ stereochemistry by default. It
was recognized that the doublets in H NMR due to R-methyl
CD CN solvents for both 2-anti and 3-anti revealed the
formation of some other minor product in less than 5%, which
3
1
protons of anti and syn diastereomers of ketone 3 resonate very
distinctly and occur at δ 0.98 and 1.37, respectively. The upfield
shift in the case of anti diastereomer is due presumably to
anisotropic shielding of the R-methyl protons by the â-aryl ring,
which is gauche in the lowest energy conformation (vide infra).
A similar difference (ca. 0.3) in the chemical shifts of the
R-methyl protons was observed for the diastereomers of all other
ketones, i.e., 1, 2, 4, and 5. Thus, the anti stereochemistry was
assigned to that isomer for which the doublet of the R-methyl
protons was found to be upfield shifted.
could not be isolated from a preparative-scale photolysis for
characterization. Remarkably, only one out of eight possible
diastereomers was obtained from the photolysis of the anti
diastereomers of ketones 2 and 3, suggesting thereby a high
diastereoselectivity in the cyclization. The identical stereochem-
istry of the cyclobutanols from ketones 2-anti and 3-anti was
established based on NOE experiments (cf. Supporting Informa-
tion) and ultimately by a single-crystal X-ray crystallographic
elucidation of the structure of one of the cyclobutanols, i.e.,
the cyclobutanol isolated from 3-anti (Figure 2). Thus, in both
of the cyclobutanols derived from the anti diastereomers of 2
(
18) Fleming, I.; Iqbal, J.Tetrahedron Lett. 1983, 24, 2913.
(
19) Wagner, P. J.; Kelso, P. A.; Zepp, R. G. J. Am. Chem. Soc. 1972, 94,
7
480.
(21) The lack of formation of cyclopropanol (<3% detection limit) was
1
(20) Moorthy, J. N.; Mal, P. Tetrahedron Lett. 2003, 44, 2493.
established based on H NMR analysis of the photolysates.
J. AM. CHEM. SOC.
9
VOL. 127, NO. 41, 2005 14377

A R T I C L E S
Singhal et al.
to decompose ca. 2-fold faster than that of the syn isomer (φr
)
0.10 ( 0.02). No marked solvent dependence on the
decomposition quantum yield was found for both syn and anti
diastereomers in the polar (acetonitrile) and nonpolar (benzene)
solvents.
Laser Flash Photolysis Studies. â-Phenyl quenching of
9
-1 12-14
phenyl ketones is an efficient process (>10 s ),
such that
transients attributable to the triplet ketones 1-7 were not a priori
expected to be observable in ns-time-resolved flash photolysis
experiments. It has been shown, however, that the deactivation
via charge-transfer-induced â-Ph quenching gets subdued when
the benzoyl ring is substituted with an electron-rich group such
Figure 2. Molecular structure of the cyclobutanol derived from the ketone
3
-anti. Observe that the phenyl and p-anisyl rings at the 1,3 positions are
syn as are the phenyl and methyl group at the 2,4 positions of the
cyclobutane.
13
as para-methoxy in ketone 1. In this case, the lowest-excited-
state character of the triplet switches from n,π* to π,π*.
Quenching does not prevail from the latter, however, but occurs
instead less efficiently from the energetically proximate n,π*
state via thermal equilibration. Therefore, the triplets of meth-
oxy-substituted â-arylpropiophenones as 1 become amenable
to lifetime measurements in the nanosecond time domain. In
fact, the methoxy-substituted diastereomers (2 mM) of 1 yielded
strong and readily recognizable transient absorptions with a
maximum at 400 nm (Figure 3). By comparison of the spectral
characteristics with those of p-methoxy-substituted acetophe-
and 3, the hydroxy group is syn to the R-methyl as well as the
γ-methyl/phenyl groups and anti to the â-anisyl rings.
13,22
nones reported in the literature
oxygen, the transients were readily assigned to the ketone T-T
triplet-triplet) absorption. The lifetimes for the two diastere-
and based on quenching with
(
omers were found to be different in both methanol (460 ns for
anti and 290 ns for syn) as well as in acetonitrile (100 ns for
anti and 75 ns for syn), establishing a diastereomeric discrimina-
tion of this photophysical property.
In striking contrast, photolysis of the syn diastereomers of 2
and 3 led predominantly to elimination products, Viz., pro-
piophenone and the olefin (p-methoxy-â-methylstyrene and
p-methoxystilbene in 2-syn and 3-syn, respectively). The olefinic
photoproducts were characterized by comparison of their spectral
data with those of the authentic samples (entries 3, 4, 7, and 8,
The transient spectroscopy of the remaining ketones did not
produce signals unequivocally attributable to the ketones triplets,
presumably due to shorter triplet lifetimes as expected from â-Ph
1
12,13
Table 1). A careful H NMR (400 MHz) analysis provided again
quenching of n,π*-excited states.
No significant transient
21
no indication for the formation of cyclopropanols. In the case
absorption was observed in ketones 4, 5, and 6. In the case of
of 3-syn, cyclobutanol was isolated in 8% yield (entries 7 and
the diastereomers of ketone 3, immediate stilbene photoproduct
2
3
8
), and its stereochemistry, which is different from that derived
formation (λmax ) 317 nm) was observed by flash photolysis,
which precluded the assignment of residual intermediary
transients. The transients produced from the diastereomers of
the anisyl ketones 2 and 7 could not be unequivocally assigned.
from 3-anti, was established from NOE experiments (eq 4). No
perceptible change in the products was observed when the
photolyses were conducted in the two different solvents, Viz.,
benzene and acetonitrile. The photochemistry of ketones 4 and
AM1 Calculations. To examine the preferred conformations
of ketones 1-5, we calculated the energies for the gauche
conformations about the C2-C3 bond for the two diastereomers
of ketone 2 as representative cases; AM1 computations were
5
was found to be similar to those of 2 and 3, as revealed from
1
H NMR analyses of the irradiated samples.
24
performed within HyperChem. The low-energy conformations
were further refined by computing the energies for rotation about
the C1-C2 as well as C3-C4 bonds until lowest energy was
achieved in each case. The relative energies of the conformers
‘a-c’ for 2-anti and those of ‘d-f’ for 2-syn are given in
Scheme 2. The conformers ‘a’ and ‘d’ were found to be the
lowest energy ones for the 2-anti and 2-syn diastereomers,
respectively; the conformers ‘b’ and ‘e’ are higher in energy
-
1
than those of ‘a’ and ‘d’, respectively, by ca. 1.0 kcal mol . It
is noteworthy that the lowest-AM1-energy conformer ‘d’
corresponds to the structure actually revealed by the X-ray
analysis for the case of 3-syn (Figure 2).
The ketone disappearance quantum yields were representa-
tively determined for the two diastereomers of ketone 2 for
irradiation at 313 nm using valerophenone as an actinometer,
1
0
(22) Lutz, H.; Breheret, E.; Lindqvist, L. J. Phys. Chem. 1973, 77, 1758.
Φ313nm ) 0.33 for the formation of acetophenone in benzene
Table 1). The anti diastereomer (φr ) 0.18 ( 0.02) was found
(
23) Roberts, J. C.; Pincock, J. A. J. Org. Chem. 2004, 69, 4279.
(
(24) Hyperchem 7.01; Hypercube, Inc.: Gainsville, FL.
14378 J. AM. CHEM. SOC.
9
VOL. 127, NO. 41, 2005

Yang Cyclization versus Type II Elimination
A R T I C L E S
Figure 3. The T-T absorption spectrum of 1-syn diastereomer in MeOH recorded with a 200-ns delay (left) and the triplet decay traces of 1-anti (upper
trace) and 1-syn (lower trace) in MeOH (right). The T-T absorption spectrum for 1-anti was similar.
Scheme 2
Thus, the origin for diastereodifferentiation of triplet lifetimes
observed for ketones 1 should be sought from the differences
in the reactivities of the triplet states. The triplet lifetimes of
â-aryl substituted alkyl aryl ketones with n,π* lowest excited
states are known to be short (<1 ns) as a consequence of â-Ph
1
2-14
quenching.
This was confirmed by the absence of the
characteristic triplet ketone absorption in all cases but ketone
1
, which has a less reactive π,π*-excited state.
The diastereomeric triplet-excited ketones 2-5 undergo two
distinct reaction pathways, namely â-Ph quenching and γ-H
abstraction. The rate of â-Ph quenching can become as fast as
9
-1 13
8
-1
1
0 s
,
while γ-hydrogen abstraction (kγ-H > 10 s ) is
2
5
certainly competitive. The conformational distributions are
essential to understand the relative contribution of each pathway
for the different diastereomers. We concentrate here on the
situation for ketones 2, but assume implicitly a similar scenario
for ketones 3-5.
Discussion
As mentioned at the outset, our objective in investigating the
photochemistry of ketones 2 and 3 was to expand the well-
established diastereodifferentiation in a photophysical property
For ketone 2-anti, the most stable conformation ‘a’ is destined
for γ-hydrogen abstraction, while â-phenyl quenching can only
occur from the higher energy conformers ‘b’ and ‘c’. Indeed,
this accounts readily for the substantial quantum yield (ca. 20%)
for photoproduct formation from 2-anti. In contrast, 2-syn is
destined, in its lowest energy conformation ‘d’, to undergo
deactivation via â-phenyl quenching, while the γ-hydrogen
abstraction can occur only from the proximate higher energy
conformer ‘e’. This accounts immediately for the much lower
quantum yield for photoproduct formation measured for 2-syn
(ca. 10%). Further, since the rate of â-Ph quenching is presumed
to be intrinsically faster than γ-H abstraction (see above), one
expects a shorter lifetime for the triplet state in which the
preferred conformation is set up for â-Ph quenching, i.e., for
the syn diastereomer. This expectation could not be verified
for ketones 2 or 3 as a consequence of very short triplet lifetimes,
but is nicely met for the less reactive model compounds 1 (see
Results), for which the triplet state of syn (290 ns in MeOH) is
indeed significantly shorter lived than that for anti (460 ns in
MeOH).
(variation in triplet lifetimes) of ketones with two contiguous
stereogenic centers to actual photoreactiVity (different products).
The lifetimes observed for the diastereomers of ketone 1 and
the photochemical results recorded in Table 1 for the diaster-
eomers of ketones 2 and 3 clearly attest to disparate pathways
of triplet deactivation and reactivity of the syn and anti
diastereomers. Insofar as the reactivity is concerned, the anti
isomers undergo efficient photocyclization with a remarkable
stereoselectivity as established from NMR and X-ray crystal-
lographic analyses, while the syn counterparts undergo elimina-
tion predominantly. To rationalize the observed stereodifferen-
tiation in triplet lifetimes as well as reactivity, we shall assume,
as a starting point, that the conformations ‘a’ and ‘d’ in Scheme
2
are the most stable ones for 2-anti and 2-syn, which indeed is
borne out by both AM1 calculations as well as X-ray structural
investigations (only for 3-syn). Of course, the same conforma-
tional preferences are assumed to prevail for ketones 1 and 3-5
as well. As will be seen later, these conformational preferences
are entirely consistent with the observed diastereodifferentiation
of the photophysical property (for ketone 1 as a model) as well
as the photoreactivity.
Diastereomer-Differentiating Photoreactivity. The triplet-
excited ketones have to pass through a chairlike transition state
2
6
to achieve efficient γ-hydrogen abstraction, which leads to
triplet 1,4-biradicals; the geometrical criteria for this process
have been extensively investigated by Scheffer and co-workers
Mechanistic Background and Diastereodifferentiation in
the Triplet Lifetimes. Our mechanistic interpretations in terms
of conformational preferences are independent, in a first
approximation, of the spin multiplicity of the reactive intermedi-
ates. The photochemistry of alkyl phenyl ketones is well
2
7
for solid-state photolysis. There are three possible ways by
which the triplet 1,4-biradicals might decay (cf. Schemes 3 and
2
5
(25) (a) Wagner, P. J. Acc. Chem. Res. 1971, 4, 168. (b) Wagner, P. J.; Park,
B.-S. In Organic Photochemistry; Pawda. A., Ed.; Marcel Dekker: New
York, 1991; Vol 11, Chapter 4.
understood. Due to rapid intersystem crossing, the triplet-
excited n,π* state is normally responsible for product formation.
J. AM. CHEM. SOC.
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A R T I C L E S
Scheme 3
Singhal et al.
4
): (i) reverse hydrogen transfer may occur to regenerate the
has shown that the geometry of the 1,4-biradical does influence
its partitioning, but that the full understanding of its behavior
requires also consideration of the magnitude of strain associated
ground-state ketone, (ii) cleavage of the central C2-C3 bond
may lead to an alkene and an enol, and (iii) the radicals may
combine at C1 and C4 positions to afford Yang cyclization
products, namely cyclobutanols. All of these three processes
are necessarily accompanied by a triplet-singlet intersystem
crossing (isc), concerning which two schools of thought exist.
The first due to Wagner and co-workers considers the triplet
3
0
with cyclization.
In the context of the presently observed diastereomer-
dependent product distributions (cyclization being preferred for
anti, and elimination for syn, cf. Table 1), it is important to
realize that the 1,4-biradicals derived from ketones 2 and 3 are
also diastereomeric in nature, such that the outcome of a
diastereodifferentiating photoreaction can also be determined
at this stage. In fact, Griesbeck and co-workers have re-
cently examined the diastereodifferentiating photochemistry of
R-amido- and R-methoxycarbonyl-â-methylvalerophonones,6
and have rationalized their results also on the basis of the
stability and spin-orbit coupling efficiencies in the intermediary
1,4-biradical partitioning as being controlled by kinetic barriers
25b
such that isc accompanies the product formation. The second
due originally to Scaiano views intersystem crossing as control-
ling the behavior of the 1,4-biradical.28 Accordingly, the singlet
biradical is assumed to react immediately in the conformation
in which it is born, and the geometry of this conformation, which
may be vastly different from the ones thought to favor reverse
hydrogen transfer, cyclization and cleavage, is considered to
be the favorable one for isc. This mechanism has been expanded
1,4-biradicals. The specific reasons are not directly transferable
to the 1,4-biradicals derived from ketones 2 and 3 studied herein,
since, e.g., no intramolecular hydrogen bonding applies, but
â-aryl quenching needs to be mechanistically considered. In
other words, consideration of conformational preferences should
be pivotal to understanding the diastereodifferentiating behavior
of the 1,4-biradicals. Our premise to rationalize the results
constitutes the following: cyclization would be observed only
if the 1,4-biradical assumes the cisoid geometry, while C2-C3
cleavage may occur predominantly from the transoid geometry;
of course, competitive cleavage, which is driven by the
stereoelectronic requirement of the overlap of the orbitals of
29
by Griesbeck and co-workers in a variety of photocyclizations.
Although certain structural features for biradical reactivity are
well established, such as the requirement of good overlap during
the cleavage between the C2-C3 bond and the singly occupied
orbitals at C1 and C4, there is still no clear-cut understanding
as to how the biradical structure affects partitioning among the
three processes discussed above. Indeed, recent work by Scheffer
and co-workers on bi- and tricyclic ketones in the solid state
(26) Dorigo, A. E.; McCarrick, M. A.; Loncharich, R. J.; Houk, K. N. J. Am.
Chem. Soc. 1990, 112, 7508.
(
(
(
27) Ihmels, H.; Scheffer, J. R. Tetrahedron 1999, 55, 885.
28) Scaiano, J. C. Tetrahedron 1982, 38, 819.
29) Griesbeck, A. G.; Fiege, M. In Molecular and Supramolecular Photo-
chemistry, Vol 6; Ramamurthy, V.; Schanze, K. S. Eds; Marcel Dekker.
New York; 1999; p 33.
(30) Braga, D.; Chen, S.; Filson, H.; Maini, L.; Netherton, M. R.; Patrick, B.
O.; Scheffer, J. R.; Scott, C.; Xia, W. J. Am. Chem. Soc. 2004, 126,
3511.
14380 J. AM. CHEM. SOC.
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VOL. 127, NO. 41, 2005

Yang Cyclization versus Type II Elimination
A R T I C L E S
Scheme 4
the breaking bond with singly occupied p-orbitals, cannot be
ruled out in the cisoid geometry.
steric repulsions are minimum. This accounts directly for the
observed predominant elimination. Importantly, the isolation in
small yield (8%) of the cyclobutanol with a syn stereochemistry
between C2-methyl and C3-anisyl substituents from 3-syn
(entries 9 and 10, Table 1) is suggestive of a minor reactivity
from the cis-BR1 biradical as well, which is also fully consistent
with this mechanistic picture.
Clearly, the origin of the diastereomer-differentiating pho-
toreactivity of ketones 2-5 is traceable to the geometries of
the triplet 1,4-biradicals. In the anti diastereomers, the stabiliza-
tion of the triplet 1,4-biradical in the cisoid conformation leads
predominantly to cyclization (Scheme 3), while the destabiliza-
tion of the triplet 1,4-biradical derived from the syn diastere-
omers due to steric repulsions between the C2 and C3
substituents in the cisoid conformation promotes elimination
via the more stable transoid conformation, i.e., trans-BR
(Scheme 4). The diastereomeric discrimination observed in the
deactivation of the triplets of the diastereomers of 1 need not
necessarily be related to the photochemical outcome of ketones
2 and 3. However, it is the unique design of ketones with a
rational selection of substituents at R and â positions that renders
the diastereodifferentiation observable in triplet lifetimes as well
as product profiles.
Let us consider ketone 2 as a representative case. The lowest-
energy conformations that undergo γ-hydrogen abstraction as
a primary photochemical event to yield the diastereodifferen-
tiating photochemical outcome are ‘a’ and ‘e’ for the anti and
syn diastereomers, respectively. Scheme 3 shows the conse-
quences of triplet-excited conformer ‘a’ derived from the anti
isomer. In this instance, the triplet 1,4-biradical, generated after
γ-hydrogen abstraction via six-membered cyclic transition state,
is likely to exist in the most stable cisoid conformation, i.e.,
cis-BR1, due to the anti relationship between C2-methyl and
C3-aryl substituents. This biradical may undergo cyclization
predominantly after intersystem crossing such that the stereo-
chemistry about C1 and C4 carbons of the cyclobutanols is
controlled by nonbonded interactions as the two ends of the
biradical begin to bond. While the formation of elimination
products is, in principle, possible from trans-BR, it is unlikely
that the latter is populated due to steric repulsions between the
cis-related C2-methyl and C3-aryl substituents in this conforma-
tion (Scheme 3). Thus, this mechanistic picture accounts for
the formation of cyclobutanol in a highly diastereoselective
manner as well as its stereochemistry.
Scheme 4 shows the consequences of the reactivity of the
triplet-excited syn diastereomer in the conformation ‘e’. In
contrast to the previous case, the 1,4-biradical generated after
γ-hydrogen abstraction would be destabilized in the cisoid-
conformation due to steric repulsion between C2-methyl and
C3-aryl groups. It may, therefore, undergo reaction from the
most stable transoid-conformation, i.e., trans-BR, in which the
Dependence of Photocyclization Propensity on the Sub-
stitution Pattern and Stereochemistry. In addition to the clear
manifestation of diastereodifferentiation, the present study has
afforded valuable data on photoproduct distributions (cyclization
versus elimination) for additional alkyl aryl ketones, which can
now be compared with literature data in an effort to reach more
general conclusions. Incidentally, it is the influence of both
J. AM. CHEM. SOC.
9
VOL. 127, NO. 41, 2005 14381

A R T I C L E S
Scheme 5
Singhal et al.
substituents at R and â-positions (as in ketones 2 and 3) that
has been least examined in the otherwise exhaustively inves-
tigated butyropheonones, which are prototype substrates for
exhibit distinct photochemical reactivities due to conformational
preferences; while the anti isomers of 2 and 3 undergo efficient
Yang cyclization in 75-90% yields with a remarkable diaste-
reoselectivity (>90%), the syn isomers undergo Norrish Type
II elimination predominantly. The differences in the product
profiles of the diastereomers are consistent with a mechanistic
picture involving the formation of precursor diastereomeric
triplet 1,4-biradicals in which the substituents at the R- and
â-positions stabilize the cisoid (cyclization) or transoid (elimina-
tion) geometry. The fact that such a diastereomeric relationship
does also ensue at the triplet-excited-state itself is demonstrated
via the nanosecond laser-flash photolysis of the diastereomers
of model ketone 1. Thus, the diastereomeric discrimination in
the product profiles of ketones 2 and 3 and in the triplet lifetimes
of ketone 1 can both be linked to conformational differences
as imposed by the different relative stereochemistry. Addition-
ally, it emerges from the present study that the syn and anti
diastereomers of ketones 2 and 3 represent two extremes of a
broad range of widely examined butyrophenones, which lead
to varying degrees of Norrish Type II photocyclization depend-
ing on the extent as well as the pattern of alkyl substitution.
11,25
Norrish Type II reaction.
For example, Lewis and co-
1
1
workers showed long ago that the behavior of 1,4-biradical
intermediates is highly sensitive to the position and number of
substituents. The cyclization yields for butyrophenones and
valerophenones with varying substitutions in a solvent such as
benzene are known.1
1,31
Including the present results for the
diastereomers 2 and 3, the general dependence of the propensity
for photocyclization (% yields) on the alkyl substitution pattern
follows, therefore, the general order in Scheme 5.
It follows from Scheme 5 that the degree of alkylation is
very important in promoting cyclization over elimination.
However, and this also constitutes an additional important
conclusion from the present results, the diastereochemistry of
the ketones is even more important! Solely switching the
diastereochemistry from anti to syn allows principally a variation
over the entire range of alkylation degree from one extreme
reactivity pattern to the other. Since the fate of the reaction, as
demonstrated herein, depends ultimately on the diastereomeric
1
,4-biradicals, conformational preferences at the biradical stage
Acknowledgment. J.N.M. is thankful to AvH foundation for
supporting the collaborative effort at the International University
Bremen, Germany, and to DST, India for generous financial
support. P.M. and N.S. are grateful to CSIR, New Delhi for
research fellowships. We thank the reviewers for invaluable
suggestions and comments.
appear to be very critical for determining cyclization versus
elimination. It transpires from the present study that the cisoid
geometry crucial for cyclization is best achieved via R,â-
disubstitution with anti stereochemistry.
Conclusions
We have examined the possibility of diastereomer-dif-
ferentiating photoreactivity in a rationally designed set of â-aryl
ketones. The diastereomers of ketones 2 and 3 are shown to
Supporting Information Available: Experimental details of
synthesis and photolysis of ketones, characterization details of
photoproducts (figures showing the NOE interactions), descrip-
tion of laser-flash photolysis studies, and X-ray crystal structure
determination details for 3-syn and 3-anti-CB. This material is
available free of charge via the Internet at http://pubs.acs.org.
(
31) In general, R-substitution has been found to promote cyclization, while
â-substitution has only a marginal effect, see ref 11. We have recently
shown that the photolysis of â-anisyl ketone 7, which lacks an R-methyl
group, yields, in contrast to the presently studied ketones 2-5, a highly
solVent-dependent mixture of two diastereomeric cyclobutanols in 30-
4
0% yields, see ref 20.
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