Single-crystal-to-single-crystal photocyclization of 4-(2,4,6-triisopropylbenzoyl)benzoic acid in the salt crystal with (S)-phenylethylamine

Article abstract of DOI:10.1016/j.tetlet.2008.05.041

Ultraviolet irradiation of a salt crystal of 4-(2,4,6-triisopropylbenzoyl)benzoic acid with (S)-phenylethylamine promoted single-crystal-to-single-crystal photocyclization to give an enantiopure (R,R)-cyclopentenol and almost racemic cyclobutenol. The reaction paths were elucidated by X-ray crystallographic analysis of the crystal before and after irradiation.

Full text of DOI:10.1016/j.tetlet.2008.05.041

Tetrahedron Letters 49 (2008) 4346–4348
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Single-crystal-to-single-crystal photocyclization of
4-(2,4,6-triisopropylbenzoyl)benzoic acid in the salt
crystal with (S)-phenylethylamine
a
a
b
b
Hideko Koshima a, , Yuya Ide , Michitaro Fukano , Kotaro Fujii , Hidehiro Uekusa
*
a Department of Materials Science and Biotechnology, Graduate School of Science and Engineering, Ehime University, Matsuyama 790-8577, Japan
b Department of Chemistry and Materials Science, Tokyo Institute of Technology, O-Okayama, Meguro-ku, Tokyo 152-8551, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Ultraviolet irradiation of a salt crystal of 4-(2,4,6-triisopropylbenzoyl)benzoic acid with (S)-phenylethyl-
amine promoted single-crystal-to-single-crystal photocyclization to give an enantiopure (R,R)-cyclopen-
tenol and almost racemic cyclobutenol. The reaction paths were elucidated by X-ray crystallographic
analysis of the crystal before and after irradiation.
Received 2 April 2008
Revised 2 May 2008
Accepted 8 May 2008
Available online 11 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Solid-state photoreactions of chiral crystals lead to high enan-
tio- and diastereodifferentiation due to the restricted motion of
molecules in the crystal lattice.1,2 Chiral salt crystals are relatively
easily prepared by combining carboxylic acids and amines, one of
which is a chiral compound with an ionic chiral handle.3 Therefore,
reactions based on chiral salt crystals provide promising methodo-
logies for asymmetric synthesis. Isopropylbenzophenone deriva-
tives are known to undergo Norrish type II photocyclization in
the crystalline state.4 We have previously reported that the enan-
tioselective photocyclization of carboxylic acid derivatives was
achieved in salt crystals with chiral amines and that the reactions
proceeded via single-crystal-to-single-crystal transformation.5,6
Absolute asymmetric induction has been also achieved by utilizing
chiral salt crystals spontaneously formed from achiral carboxylic
acid derivatives and achiral amines.7 Here, we report diastereo-
and enantiospecific photocyclization in the salt crystal of
4-(2,4,6-triisopropylbenzoyl)benzoic acid 1 with (S)-phenylethyl-
amine (S)-2 via single-crystal-to-single-crystal transformation.
The salt crystals of 1Á(S)-2 were prepared by crystallization from
the ethanol solution of both components.8 The pulverized crystals
1Á(S)-2 (200 mg) were placed between two Pyrex glass plates and
irradiated with a 400 W high-pressure mercury lamp under argon
at 288 K for 48 h. The irradiated mixture was methylated with
CH2N2 and the products were separated by preparative HPLC to
give a diastereomeric cyclopentenol 3 and a cyclobutenol 4 in
26% and 21% yield at 89% conversion, respectively (Scheme 1).
The low yields are due to the loss in the separation process. The
enantiomeric excess was determined by HPLC using a chiral col-
umn (Daicel, Chiralpak AD) to be (R,R)-39 in 100% ee and (S)-4 in
6% ee; the ratio of (R,R)-3, (S)-4, and (R)-4 was 55:24:21.
Scheme 1.
Photoirradiation of the single crystals of 1Á(S)-2 maintained the
initial transparency, confirming the single-crystal-to-single-crystal
reaction. Finally, a piece of single crystal (0.38 Â 0.31 Â 0.31 mm)
of 1Á(S)-2 was submitted to X-ray crystallographic analysis at
293 K, and the absolute structure was determined on the basis of
the S configuration of the phenylethylamine molecule 2.10,11 The
ORTEP drawing of a salt bond pair arranged in the reactant 1Á(S)-
2 is given (Fig. 1).
Next, the single crystal was irradiated successively at >290 nm
with a high-pressure mercury lamp through Pyrex under argon
at 288 K, and the cell constant was measured periodically at
293 K. The reaction proceeded slowly and was completed after
irradiation for 240 h. The sizes of the unit cells changed, increasing
* Corresponding author. Tel./fax: +81 89 927 8523.
E-mail address: koshima@eng.ehime-u.ac.jp (H. Koshima).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.041

H. Koshima et al. / Tetrahedron Letters 49 (2008) 4346–4348
4347
Scheme 2 shows the possible reaction mechanism. The reaction
paths should be discussed on the bases of the crystal structure (Fig.
1). Irradiation of the crystal at >290 nm with a high-pressure
mercury lamp through Pyrex glass causes n–p* excitation of the
carbonyl group of the molecule 1. The O1 atom of the excited
carbonyl group should abstract the methyl H1 d-hydrogen atom
of the o-isopropyl group A in the highest priority due to the short-
est O1–H1 distance (2.64 Å) and the favorable C1@O1–H1 angle
Å
Å
(99.3°) to give the ketyl radical C1 and the methyl radical C2.12
This corresponds to the biradical 5 in Scheme 2. Other methyl
hydrogen atoms cannot be abstracted by the O1 atom due to the
long distances (3.9–5.4 Å). As the C4–C5 bond of the o-isopropyl
group A rotates in the clockwise direction, the ÅC1 and ÅC2 radicals
gradually approach each other and finally couple to form the new
C1–C2 bond, giving cyclopentenol (R,R)-3.
Furthermore, both the O1–H2 (2.94 Å) and O1–H3 (3.00 Å) dis-
tances are short; the angles of C1@O1–H2 (52.0°) and C1@O1–H3
(56.9°) are similar. The angles are defined as the degree to which
the abstracted H2 and H3 c-hydrogen atoms lie outside the mean
plane of the carbonyl group. The angles themselves are also similar
and are 51.3° and 55.1°, respectively. Therefore, the O1 atom of the
excited carbonyl group has the other possibility of abstraction from
both the methine H2 and H3 c-hydrogen atoms of two o-isopropyl
groups B and A to produce the ketyl radical and the corresponding
methine radicals (6 and 7 in Scheme 2). The radicals then approach
each other and finally couple to confer the enantiomeric cyclobute-
nols (S)-4 and (R)-4, respectively. The enantiomeric excess was
only 6% ee in slight excess of (S)-4, reflecting the slightly shorter
O1–H2 distance (2.94 Å) compared with the O1–H3 (3.00 Å).
Finally, we would like to discuss briefly why the compound 3
was not produced nearly exclusively despite that the O1–H1 dis-
tance (2.64 Å) to make 3 is considerably shorter than the corre-
sponding distances (2.94 and 3.00 Å) required for the production
of 4. One of the reasons is that the major product 3 can be formed
via a seven-membered transition state of the Norrish type II reac-
tion, which is unusual in ketone photochemistry, in contrast to the
normal six-membered transition state to give the minor product
4.12 Very few examples of the seven-membered transition state
have been reported in the photolysis of the phenyl ketones.13 Sec-
ond, the methyl radical (5 in Scheme 2) formed from the methyl
group is energetically less favorable than the methine radicals (6
and 7) from the methine groups. These two factors most probably
lead to the formation of not only 3 but also 4. We have previously
obtained the cyclopentenol as a major product and the cyclobute-
nol as a minor product by the absolute asymmetric photocycliza-
tion of 4-(2,5-diisopropylbenzoyl)benzoic acid in the salt crystal
with 2,4-dichlorobenzylamine via single-crystal-to-single-crystal
transformation.7
Figure 1. ORTEP drawing of the reactant crystal of 1Á(S)-2 at the 15% probability
level. Please note that the methyl H1, methine H2, and H3 atoms are projected
toward carbonyl O1 oxygen atom for abstraction to yield the corresponding cyclo-
pentenol and cyclobutenol products 3 and racemic 4, respectively.
(+3.02%) along the a-axis, decreasing (À3.29%) along the b-axis,
and increasing (+0.37%) along the c-axis, resulting overall in no
change (0.0%) in total cell volume.
However, the structure analysis of the product crystal after irra-
diation was not successful, probably due to the deterioration of the
crystal during prolonged irradiation. The crystal structure could be
solved by the data collected at 93 K as the disordered structure of
the cyclopentenol (R,R)-3 and the enantiomeric (S)-4 and (R)-4 in
57:29:14 occupancy (Fig. 2a).10,11 The ORTEP drawings of (R,R)-3
and (S)-4 are shown separately (Fig. 2b and c, respectively).
After the X-ray structure analysis was completed, the irradiated
single crystal was treated with CH2N2 and analyzed by HPLC using
a chiral column (Daicel, Chiralpak AD) to give (R,R)-3, (S)-4, and
(R)-4 in 55:24:21; (R,R)-3 in 100% ee; and (S)-4 in 6% ee, which
were consistent with results obtained by the preparative scale
photoreaction of the powdered crystals mentioned above, and
fairly consistent with the 57:29:14 occupancy obtained by X-ray
crystallographic analysis.
Such a photocyclization, however, did not greatly change the
molecular conformation. The ionic bridge between the carboxylate
anion of 1 and the ammonium cation of (S)-2 forms a twofold
helical chain in the reactant crystal. The helical salt bridges remain
after the reaction. The strong salt bonding is believed to fix the
molecules and promote the complete reaction without destroying
the crystal; that is, it leads to single-crystal-to-single-crystal
transformation.
In the case of the single-crystal-to-single-crystal photocycliza-
tion in the salt crystal of 1 with L-prolinol, the low optical purity
of (R)-4 (30% ee) was due to the pseudo mirror image-related
arrangement of the bonzophenone moiety in the asymmetric unit.5
The enantiospecific single-crystal-to-single-crystal photocycliza-
tion in the salt crystal of 4-(2,5-diisopropylbenzoyl)benzoic acid
with (S)-2 was due to enantiomeric c-hydrogen abstraction from
the o-isopropyl group by the carbonyl oxygen atom of the excited
benzophenone unit.6 Thus, the enantioselectivity of the crystalline
state reaction is controlled by the crystal structure.
Figure 2. (a) Coexistence of the products (red) (R,R)-3, (green) (S)-4, and (blue)
(R)-4; hydrogen atoms are omitted for clarity. ORTEP drawings of (b) (R,R)-3, and (c)
(S)-4, at the 25% probability level.

4348
H. Koshima et al. / Tetrahedron Letters 49 (2008) 4346–4348
Scheme 2. Possible reaction mechanisms in the crystal 1Á(S)-2.
1418; (b) Hirotsu, K.; Okada, K.; Mizutani, H.; Koshima, H.; Matsuura, T. Mol.
Cryst. Liq. Cryst. 1996, 277, 99–106.
6. Koshima, H.; Matsushige, D.; Miyauchi, M. CrystEngComm 2001, 33, 1–3.
7. Koshima, H.; Kawanishi, H.; Nagano, M.; Yu, H.; Shiro, M.; Hosoya, T.; Uekusa,
H.; Ohashi, Y. J. Org. Chem. 2005, 70, 4490–4497.
In conclusion, we achieved single-crystal-to-single-crystal
photocyclization of the salt crystal of the triisopropylbenzophe-
none derivative.
8. Salt crystal of 1Á(S)-2; colorless needles; mp 183–185 °C; IR (KBr): m 3314,
1668 cmÀ1
.
Acknowledgments
9. Methyl ester of (R,R)-3: white powder; mp 56.7–57.0 °C; 1H NMR (300 MHz,
CDCl3): d 7.94 (d, J = 4.8 Hz, 2H), 7.31 (d, J = 4.8 Hz, 2H), 7.05 (s, 1H), 6.98 (s,
1H), 3.90 (s, 3H), 3.01–3.12 (m, 1H), 2.92–3.00 (m, 2H), 2.68 (dd, J = 14.6,
8.5 Hz, 1H), 2.04 (dd, J = 14.6, 9.5 Hz, 1H), 1.38 (d, J = 7.7 Hz, 3H), 1.30 (d,
J = 7.7 Hz, 3H), 1.29 (d, J = 7.7 Hz, 3H), 1.17 (d, J = 7.7 Hz, 3H), 0.75 (d, J = 7.5 Hz,
3H); IR (KBr): m 3552, 1715 cmÀ1; HRMS calcd for C24H30O3 (M)+ 366.2195,
found 366.2197.
This study was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology of Japan, the Asahi Glass Foundation, and Ehime
University COE incubation program.
10. CrystalStructure, Ver. 3.7, Rigaku Corporation, Tokyo, 2005.
11. X-ray diffractions were collected on a Rigaku RAXIS-RAPID imaging plate two-
dimensional area detector using graphite-monochromatized Mo-Ka radiation.
All crystallographic calculations were performed using CrystalStructure
crystallographic software of the Rigaku/MSC and Rigaku Corporation.10 The
structure was solved by direct methods and expanded using Fourier
techniques. The non-hydrogen atoms were refined anisotropically and the
hydrogen atoms were not refined. Hydrogen atoms attached to carbon atoms
were located in the calculated positions. The absolute structures for 1Á(S)-2
before and after irradiation were determined by reference to the known
configuration of the chiral amine molecule (S)-2. Crystal data for 1Á(S)-2:
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.05.041.
References and notes
C
23H27O3ÁC8H12N; fw = 473.65, orthorhombic, P212121, colorless block
measuring 0.38 Â 0.31 Â 0.31 mm, T = 293 K, a = 6.2434(14), b = 13.787(3),
c = 32.470(8) Å, V = 2795.0(12) Å3, Z = 4, Dc = 1.123 mg mmÀ3, l = 0.071 mmÀ1
Tmax = 0.978, Tmin = 0.798, GOF = 1.063, R = 0.0653, wR2 = 0.1891. CCDC-
683361. Crystal data for 1Á(S)-2 after irradiation: 23H27O3ÁC8H12N;
fw = 473.65, orthorhombic, P212121, colorless block measuring
0.38 Â 0.31 Â 0.31 mm, T = 93 K, a = 6.3355(17), b = 13.129(4), c = 32.62(1) Å,
V = 2713.3(14) Å3, Z = 4, Dc = 1.159 mg mmÀ3 l = 0.073 mmÀ1
Tmax = 0.978,
Tmin = 0.983, GOF = 1.048, R = 0.0753, wR2 = 0.2117. CCDC-683363.
1. Organic Solid-State Reactions; Toda, F., Ed.; Kluwer Academic Publishers:
Dordrecht, 2002.
2. Chiral Photochemistry; Inoue, Y., Ramamurthy, V., Eds.; Mercel Dekker: New
York, 2004.
3. (a) Gudmundsdottir, D.; Scheffer, J. R. Tetrahedron Lett. 1991, 31, 6807–6810;
(b) Gamlin, J. N.; Jones, R.; Leibovitch, M.; Patrick, B.; Scheffer, J. R.; Trotter, J.
Acc. Chem. Res. 1996, 29, 203–209.
4. (a) Ito, Y.; Nishimura, H.; Umehara, Y.; Yamada, Y.; Tone, M.; Matsuura, T. J. Am.
Chem. Soc. 1983, 105, 1590–1597; (b) Ito, Y.; Matsuura, T. Tetrahedron Lett.
1988, 29, 3087–3090.
,
C
,
,
12. Scheffer, J. F. In Organic Solid State Chemistry; Desiraju, G. R., Ed.; Elsevier: New
York, 1987; pp 1–45.
5. (a) Koshima, H.; Maeda, A.; Matsuura, T.; Hirotsu, K.; Okada, K.; Mizutani, H.;
Ito, Y.; Fu, T. Y.; Scheffer, J. R.; Trotter, J. Tetrahedron: Asymmetry 1994, 5, 1415–
13. Wagner, P. J.; Kelso, P. A.; Kemppainen, A. E.; Zepp, R. G. J. Am. Chem. Soc. 1972,
94, 7500–7506.