Unusual stereo- and chemo-selective photocyclization of chiral α-aminoacid-incorporated 2-acyl benzamides by control of chiral memory

Article abstract of DOI:10.1016/j.tetlet.2012.11.077

An unusual decarboxylative photocyclization of 2-acyl benzamides with intramolecular chiral α-aminoacids was studied. The reaction exclusively yields bi- and tri-cyclic benzo-oxazepines via distinct chemoselective C-O bond formation. High enantio- and dia

Full text of DOI:10.1016/j.tetlet.2012.11.077

Tetrahedron Letters 54 (2013) 541–544
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Unusual stereo- and chemo-selective photocyclization of chiral
a-aminoacid-incorporated 2-acyl benzamides by control of chiral memory
⇑
Cai-E Liu, Qiang Han, Nan Ma, Zheng-Song Geng, Rong-Hua Zhang , Zhi-Qin Jiang
Department of Chemistry, Tongji University, Shanghai 200092, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An unusual decarboxylative photocyclization of 2-acyl benzamides with intramolecular chiral
Received 22 August 2012
Revised 14 November 2012
Accepted 20 November 2012
Available online 29 November 2012
a
-aminoacids was studied. The reaction exclusively yields bi- and tri-cyclic benzo-oxazepines via distinct
chemoselective C–O bond formation. High enantio- and diastereo-selectivities (ee = 87–99% and dr = 85/
15–95/5) for the products were achieved. Evidence indicates that the formation of the two chiral carbon
centers is controlled by chiral memory.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
2-Acyl benzamide
Photocyclization
Stereoselectivity
Chemoselectivity
a-Aminoacids
In recent years, photoinduced asymmetric syntheses have
a-Aminoacids are important chiral sources that are widely em-
attracted increasing attention because of their uniqueness,
simplicity, and benefit in green chemistry.1–4 However, enantio-
and diastereo-selectivities in many photochemical reactions are
usually lower than in conventional thermal chiral reactions. Conse-
quently, the application of asymmetric photochemical synthesis is
considerably restricted. This drawback may be attributed to the
highly energetic excited states and short-lived reactive intermedi-
ates, so that the stereoselectivity is difficultly controlled. Therefore,
achieving high chiral selectivity for photochemical reactions is a
challenging task. Efforts to achieve this goal have been focused
on supramolecular systems containing confined space,5 which
can enhance the stereoselectivity. Furthermore, recent studies
indicated memory of chirality (MOC) proposed by Fuji6 have pro-
vided a novel approach to asymmetric synthesis although its pro-
gress is still in the early stage.7
ployed in asymmetric synthesis. Natural -aminoacids are used as
a
external chiral auxiliary molecules to construct chiral compounds
for a number of synthetic reactions such, as Aldol,11 Ullmann,12
and Michael13 reactions. However, application of the chiral
a-ami-
noacid blocks in asymmetric synthesis is much less explored.
In this work, we try to explore a novel and facile ET decarboxy-
lative photocyclization of
a-aminoacids-incorporated 2-aroyl
benzamides. A series of cyclic and acyclic chiral
a
-aminoacid-
incorporated 2-acyl benzamides 1–15 as starting materials are
designed and prepared. To investigate further the stereoselectivity,
chiral (S) and racemic (S, R) a-aminoacids were also utilized as chi-
ral source.
Photochemical reactions of the title compounds 1–15 in meth-
anol/water (9:1–8:1) under UV light were conducted in the pres-
ence of potassium carbonate. 2-Acyl benzamides containing the
Electronically excited carbonyl chromophores in ketones, alde-
hydes, imides, or amides are strong electron acceptors that can effi-
ciently oxidize alkenes, amines, thioethers, or carboxylates.8 The
combined use of the oxidative removal of internal electron-donat-
ing groups, such as carboxyl, benzyl, and trialkylsilyl, provides a
useful tool in photoinduced electron transfer (PET) reactions. Mari-
ano, Yoon,9 and Griesbeck et al.10 reported a series of electron
transfer (ET) photocyclizations of phthalimides via C–C bond
formation.
chiral a-aminoacids readily underwent one-pot decarboxylative
photocyclization (Scheme 1 and 2) to furnish the corresponding
bicyclic and tricyclic benzo-oxazepine products14 (1a–15a) in
moderate yields (40–80%). It was found that the reactions pro-
ceeded via distinct chemoselective C–O bond formation15 to yield
exclusively seven-member ring of oxazepine derivatives rather
than the usual C–C bond formation to form six member ring of aze-
pines or diazepines in the reported decarboxylative ET photocycli-
zation of
a-benzamidophthalimides. The oxazepine formation of
seven-member ring was also verified by structure determination
from X-ray analysis (see Fig. 1).
A brief elucidation of the above reaction pathways is depicted in
Scheme 3. Upon irradiation with UV light, the excitation of
⇑
Corresponding author. Tel.: +86 2165982653 8542; fax: +86 2165981097.
E-mail address: rhzhang@tongji.edu.cn (R.-H. Zhang).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.077

542
C.-E. Liu et al. / Tetrahedron Letters 54 (2013) 541–544
R1
R1
O
O
hν , Κ2CO3
O
3
N
5
1
MeOH / H2O
N
COOH
O
1a - 7a
1 - 7
Yield / %a
R1
Substrate
Tricyclic azepine
1
2
3
4
5
(S)
4-CH3C6H4
4-CH3C6H4
4-ClC6H4
4-ClC6H4
CH3
1a (3R, 5R)
2a (3S, 5S) (3R, 5R)
3a (3R, 5R)
a
39
40
41
41
35
30
48
(S, R)
(S)
(S, R)
(S)
4
5
6
7
(3S, 5S) (3R, 5R)
(3R, 5R)
a
a
a
6 (S, R)
7 (S)
CH3
C6H5
(3R, 5R) (3R, 5R)
(3R, 5R)
a Yields are given forisolated products.
Scheme 1. Formation of tricyclic benzo-oxoazepines 1a–7a by photocyclization of
substrates 1–7 with chiral a-proline.
Figure 1. Single crystal structure and HPLC chromatogram of the product 1a.
R1
R1
hν , Κ CO
O
3
N
2
3
5
O
O
R2
1
Table 1
Enantio- and diastereo-selectivities of the title photocyclization
MeOH / H O
2
N
R2
O
Entry
Substrates
Products
eea (%)
dra
COOH
1
2
3
4
5
6
7
8
1 (S)
1a (3R, 5R)
1a (3R, 5R)
2a (3S, 5S)(3R, 5R)
3a (3R, 5R)
4a (3S, 5S)(3R, 5R)
5a (3R, 5R)
96
>99
95:5
95:5
91:9
85:15
97:3
94:6
94:6
99:1
8a 15a
-
8 - 15
1 (S) in b-CD
2 (S, R)
3 (S)
4 (S, R)
5 (S)
R1
R2
Bicyclic azepine
Yield / %a
Substrate
96
CH3
CH3
4-CH3C6H4
4-CH3C6H4
C6H5
C6H5
4-ClC6H4
4-ClC6H4
H
CH3
H
CH3
H
CH3
H
8a (5R, 5S)
9a (3R, 5R)
10a (5R, 5S)
11a (3R, 5R)
12a (5R, 5S)
13a (3R, 5R)
14a (5R, 5S)
15a (3R, 5R)
8
42
38
76
57
78
60
82
64
9 (S)
87
89
—
10
5 (S) in b-CD
6 (S, R)
5a (3R, 5R)
6a (3S, 5S)(3R, 5R)
11 (S)
12
13 (S)
a
ee and dr of chiral compounds were measured by HPLC chromatograms on
varian HPLC instrument using AD-H chiral column, respectively.
14
CH3
15 (S)
carboxylate anion16 at internal
a-aminoacid block in the presence
a
Yields are given for isolated products.
of base (K2CO3) readily induces the intramolecular ET from the car-
boxylate anion to the carbonyl at the 2-acyl group, producing the
reactive diradical intermediate B, ketyl anion radical and carboxyl-
ate radical. Decarboxylation of the carboxylate radical produces
the carbon-centered diradical C. The electron-deficient nitrogen
of pyrrolidine favors the transformation from C to the iminium
Scheme 2. Formation of bicyclic benzo-oxoazepines 8a–15a by photocyclization of
substrates 8–15 with chiral acyclic -aminoacids.
a
carbonyl at the 2-acyl group of the substrate A predominantly
leads to the triplet state. Strong electron-donating ability of the
R1
R1
N
R1
R1
.
_
.
_
.
_
O
O
1. hv 2. ET
O
O
decarboxylation
O
O
O
O
.
_
N
.
N
+
N
COO
.
COO
C
D
B
A
nucleophilic
attack of OH
R1 OH
R1
O
N
O
F
O
E
Scheme 3. ET photocyclization mechanism of a-aminoacid-incorporated 2-acyl benzamides.

C.-E. Liu et al. / Tetrahedron Letters 54 (2013) 541–544
543
tained when the reaction was carried out with substrate 1 loaded
in b-CD (entry 2). In addition, high diastereoselectivities (dr = 85/
15–95/5) were found in all cases (entry 1–8). This is verified by
HPLC chromatograms in Figs. 1 and 2, which show that the enati-
omers with (3R, 5R) or stereoisomer with opposite (3S, 5S) and (3R,
5R) are main components, respectively, whereas the stereoisomers
with (R, S)- and (S, R)-configurations are always minor.
Conclusions
In this work, a novel and facile ET decarboxylative photocycliza-
tion of
a-aminoacid-incorporated 2-aroyl benzamides was
explored. The reaction gives rise exclusively to unusual bi- and
tri-cyclic benzo-oxazepine compounds via a distinct C–O other
than C–C bond formation. Both high enantio- and diastereo-selec-
tivities of two chiral carbon centers produced during the reaction
were successfully achieved. Evidences indicate that the product
chirality is controlled by intramolecular chiral
a-aminoacid with
reservation of configuration. The present work may be helpful for
providing an effective asymmetric synthesis method to establish
high chirality and insight into to chiral origin mechanism.
Experimental section
Substrates of chiral
a-aminoacid-incorporated 2-acyl-1-benz-
amides 1–15 were conveniently prepared by two-step reactions
according to literature.17 The total yields were 60–80%.
Photolysis was performed on a photochemical quartz-glass
reactor with a water-cooled jacket equipped with an automatic
controller. The light source was a 500 W medium-pressure mer-
cury lamp.
Figure 2. Twin crystal structure and HPLC chromatogram of the racemic product 6a
with opposite configuration.
Typical procedure of photocyclization
radicalcation D, which is in accord with the early proposal of Mari-
ano.15 D follows a subsequent nucleophilic attack by –OH or –OÀ of
the ketyl anion to furnish the target benzo-oxazepines of seven
member ring E via chemoselective C–O bond formation. However,
usual C–C bond formation to produce six-member ring of benzo-d-
valerolactam F, as expected through the intramolecular combina-
tion of the carbon radical and ketyl radical of C, is not observed
in our case.
Three hundred milligram (0.9 mmol) of 1, 700 mg (5 mmol) of
potassium carbonate and 8 mL of water were mixed in a quartz-glass
tube with stirring for a few min, and then 72 mL of methanol was
added. The solution was irradiated for 8 h by a 500 W medium-pres-
sure mercury lamp in a water-jacket photochemical reactor. The
reaction was monitored by TLC. After reaction completion, the solu-
tion was evaporated. The residue was finally isolated on a silica-gel
column with elution of ethyl acetate/petrol ether. Hundred and fif-
teen milligram of pure 1a was obtained. The yield was 39%.
In order to study the reaction stereochemistry, we chose the
substrates with internal chiral proline 1–6 to carry out the photo-
cyclization. The results indicate that high stereoselectivity is an-
other intriguing feature of the reaction. The data in Table 1
clearly show that the substrates (1, 3, and 5) with chiral (S)-proline
exclusively yield the corresponding (S, S)-enantiomers, that is, tri-
cyclic (3S, 5S)-benzooxoazepines (1a, 3a, and 5a), which possess
two chiral carbon centers at 3, 5 positions (entries 1, 2, 4, 6, and
7). This chiral structure is confirmed by X-ray analysis for the sin-
gle crystal of enantiomer 1a (Fig. 1), and HPLC exhibits that (3R, 5R)
configuration at oxazepine ring is predominant. Whereas, racemic
(S, R)-proline-incorporated substrates (2, 4, and 6) merely lead to
racemic products (2a, 4a, and 6a) with the opposite (3S, 5S) and
(3R, 5R) configurations (see entries 3, 5, and 8), respectively. These
opposite configurations in the racemic products are demonstrated
again by X-ray analysis and HPLC measurement for the twin crystal
of racemic product 6a (Fig. 2). The above finding indicates that the
initial chirality in substrate can be reserved to the product with
same configuration which is consistent with the MOC theory7.
On the other hand, high enantioselectivities (ee = 87–99%) for
all chiral (3R, 5R) oxazepine products (1a, 3a, and 5a) listed in
Table 1 are successfully achieved (see entry 1, 2, 4, 6 and 7). The
HPLC chromatogram in Figure 1 has proved that only trace
amounts of products with (S, S)-, (R, S)- and (S, R)-configurations
were detected. Even ee value of 99.8% for product 1a was also ob-
Enantiomer 1a, (3R,5R)-5-p-tolyl-1,2,3,3a-tetrahydrobenzo[e]
pyrrolo[2,1-b][1,3]oxoazepin-10(5H)-one, 1H NMR (400 MHz,
CDCl3):
d 7.83 (d, J = 8.4 Hz, 1H,), 7.42–7.22 (m, 6H), 6.64
(d, J = 6.0 Hz, 1H), 5.83 (s, 1H), 5.04 (s, 1H), 3.98–3.93 (t,
J = 9.2 Hz, 1H), 3.59 (m, 1H), 2.40 (s, 3H), 2.22–2.02 (m, 4H); 13C
NMR (100 MHz, DMSO-d6): d 162.2, 146.8, 138.4, 136.2, 132.3,
129.3, 128.4, 127.5, 126.5, 125.1, 74.9, 65.3, 45.3, 27.0, 22.1, 20.5;
HRMS (ESI): m/z, calcd for [C19H19NO2+Na]: 316.1314; found:
316.1310.
The experimental procedures of photocyclization for other sub-
strates (2–15) are similar to the above one.
Acknowledgment
This work was supported by the National Science Foundation of
China (20972113/B020502).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
11.077.

544
C.-E. Liu et al. / Tetrahedron Letters 54 (2013) 541–544
10. (a) Griesbeck, A. G.; Kramer, W.; Lex, J. Angew. Chem. Int. Ed. 2001, 40, 577; (b)
References and notes
Griesbeck, A. G.; Heinrich, T.; Oelgemoeller, M.; Lex, J.; Molis, A. J. Am. Chem. Soc.
2002, 124, 10972; (c) Griesbeck, A. G.; Heinrich, T.; Oelgemoeller, M.; Molis, A.;
Heidtmann, A. Hel. Chim. Acta 2002, 85, 4561; (d) Kim, A. R.; Lee, K. S.; Lee, C. W.;
Yoo, D. J.; Hatoumc, F.; Oelgemoeller, M. Tetrahedron Lett. 2005, 46, 3395.
11. (a) Rodriguez, B.; Bruckmann, A.; Bolm, C. Chem. Eur. J. 2007, 13, 4710; (b)
Yoshitomi, Y.; Makino, K.; Hamada, Y. Org. Lett. 2007, 9, 2457; (c) Wang, W.; Li,
H.; Wang, J.; Zu, L. J. Am. Chem. Soc. 2006, 128, 10354; (d) Samanta, S.; Zhao, C. J.
Am. Chem. Soc. 2006, 128, 7442; (e) Casas, J.; Sunden, H.; Cordova, A.
Tetrahedron Lett. 2004, 45, 6117.
12. (a) Pei, L.; Qian, W. Synlett 2006, 1719; (b) Wang, Z.; Bao, W.; Jiang, Y. Chem.
Commun. 2005, 41, 2849; (c) Schulz, K.; Ratjen, L.; Martens, J. Tetrahedron 2011,
67, 546; (d) Feng, L.; Sun, Y.; Tang, W.; Xu, L.; Lam, K.; Zhou, Z.; Chan, A. S. C.
Green Chem. 2010, 12, 949; (e) Chandler, C.; Galzerano, P.; Michrowska, A.; List,
B. Angew. Chem., Int. Ed. 2009, 48, 1978.
13. (a) Freund, M. H.; Tsogoeva, S. B. Synlett 2011, 503; (b) Ma, A.; Ma, D. Org. Lett.
2010, 12, 3634; (c) Enders, D.; Wang, C.; Mukanova, M.; Greb, A. Chem.
Commun. 2010, 46, 2447.
14. (a) Ilyin, A. P.; Parchinski, V. Z.; Peregudova, J. N.; Trifilenkov, A. S.; Poutsykina,
E. B.; Tkachenko, S. E.; Kravchenko, D. V.; Ivachtchenko, A. V. Tetrahedron Lett.
2006, 47, 2649; (b) Ghandi, M.; Olyaei, A.; Raoufmoghaddam, S. J. Heterocycl.
Chem., 2009, 46, 914.
1. (a) Inoue, Y.; Ramavurthy, V. Chiral Photochemistry; Marcel Dekker Press: New
York, 2004; (b) Inoue, Y. Chem. Rev. 1992, 92, 741; (c) Feringa, B. L.; Van Delden,
R. A. Angew. Chem., Int. Ed. 1999, 38, 3419.
2. (a) Renaud, P.; Leong, P. Science 2008, 322, 55; (b) Wessig, P. Angew. Chem., Int.
Ed. 2006, 45, 2168; (c) Oelgemöller, M.; Griesbeck, A. G. J. Photochem. Photobiol.,
C 2002, 3, 109.
3. (a) Scheffer, J. R. Can. J. Chem. 2001, 79, 349; (b) Sakamoto, M.; Sekine, N.;
Miyoshi, H.; Mino, T.; Fujita, T. J. Am. Chem. Soc. 2000, 122, 10210.
4. (a) Santamaria, J. Pure Appl. Chem. 1995, 67, 141; (b) Griesbeck, A. G.; Hoffmann,
N.; Warzecha, K. Acc. Chem. Res. 2007, 40, 128.
5. (a) Natarajan, A.; Joy, A.; Kaanumalle, L. S.; Scheffer, J. R.; Ramamurthy, V. J. Org.
Chem. 2002, 67, 8339; (b) Natarajan, A.; Ramamurthy, V. Org. Biomol. Chem.
2006, 4, 4533; (c) Joy, A.; Uppili, S.; Netherton, M. R.; Scheffer, J. R.;
Ramamurthy, V. J. Am. Chem. Soc. 2000, 122, 728; (d) Nakamura, A.; Inoue, Y.
J. Am. Chem. Soc. 2003, 125, 966; (e) Ikeda, H.; Nihei, T.; Ueno, A. J. Org. Chem.
2005, 70, 1237; (f) Sivaguru, J.; Nataraian, A.; Kaanumalle, L. S.; Shaila, J.; Uppili,
S.; Joy, A.; Ramamurthy, V. Acc. Chem. Res. 2003, 36, 509.
6. Fuji, K.; Kawabata, T. Chem. Eur. J. 1998, 4, 373.
7. (a) Zhao, H.; Hsu, D. C.; Carlier, P. R. Synthesis 2005, 1; (b) Sinicropi, A.; Barbosa,
F.; Basosi, R.; Giese, B.; Olivucci, M. Angew. Chem., Int. Ed. 2005, 44, 2390; (c)
Jesuraj, J. L.; Sivaguru, J. Chem. Commun. 2010, 46, 4791; (d) Sakamoto, M.;
Kawanishi, H.; Mino, T.; Fujita, T. Chem. Commun. 2008, 44, 2132.
8. (a) Cho, D. W.; Choi, J. H.; Oh, S. W.; Quan, C.; Yoon, U. C.; Wang, R.; Yang, S.;
Mariano, P. S. J. Am. Chem. Soc. 2008, 130, 2276; (b) Sung, N. K.; Cho, D. W.; Choi,
J. H.; Choi, K. W.; Yoon, U. C. J. Org. Chem. 2007, 72, 8831.
9. (a) Yoon, U. C.; Jin, Y. X.; Oh, S. W.; Park, C. H.; Park, J. H.; Campana, C. F.; Cai, X.;
Duesler, E. N.; Mariano, P. S. J. Am. Chem. Soc. 2003, 125, 10664; (b) Yoon, U. C.
Acc. Chem. Res. 2001, 34, 523; (c) Yoon, U. C.; Kwon, H. C.; Hyung, T. G.; Choi, K.
H.; Oh, S. W.; Yang, S.; Zhao, Z.; Mariano, P. S. J. Am. Chem. Soc. 2004, 126, 1110.
15. (a) Wang, R.; Chen, C.; Duesler, E.; Mariano, P. S. J. Org. Chem. 2004, 69, 1215;
(b) Aoyama, H.; Hasegawa, T.; Watabe, M.; Shirashi, H.; Omote, Y. J. Org. Chem.
1978, 43, 419.
16. (a) Yoo, D. J.; Kim, E. Y.; Oelgemoeller, M.; Shim, S. C. Photochem. Photobiol. Sci.
2004, 3, 311; (b) Yokoi, H.; Nakano, T.; Fujita, W.; Ishiguro, K.; Sawaki, Y. J. Am.
Chem. Soc. 1998, 120, 12453; (c) Griesbeck, A. G.; Kramer, W.; Bartoschek, A.;
Schmickler, H. Org. Lett. 2001, 3, 537.
17. More, S. S.; Shanmughapriya, D.; Lingam, Y.; Patel, N. B. Synth. Commun. 2009,
39, 2058.