Retention of chirality of 5-membered alicyclic α-amino acids bearing N-(2-phenyl)benzoyl group in photoinduced decarboxylative intermolecular radical addition to acrylonitrile

Article abstract of DOI:10.1016/j.tet.2019.130493

Photoinduced decarboxylative radical additions of 5-membered alicyclic α-amino acids bearing a (2-phenyl)benzoyl protective group to acrylonitrile under mild organic photoredox catalysis conditions furnished γ-amino acid derivatives with high retention of chirality via the memory of chirality (MOC) strategy. The retention of chirality in the photoinduced decarboxylation was strongly dependent on the structure of the alicyclic α-amino acids and alkenes. To the best of our knowledge, this is the first example of the decarboxylative intermolecular radical addition to alkenes with retention of chirality at the position of radical generation using the MOC strategy.

Full text of DOI:10.1016/j.tet.2019.130493

Tetrahedron 75 (2019) 130493
Contents lists available at ScienceDirect
Tetrahedron
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Retention of chirality of 5-membered alicyclic -amino acids bearing
a
N-(2-phenyl)benzoyl group in photoinduced decarboxylative
intermolecular radical addition to acrylonitrile
Yui Ozaki a, Tomoaki Yamada a, Taisei Mizuno a, Kazuyuki Osaka a, Mugen Yamawaki a,
,
*
Hajime Maeda b, Toshio Morita a, Yasuharu Yoshimi a
a Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, University of Fukui, 3-9-1 Bunkyo, Fukui 910-8507, Japan
b Division of Material Chemistry, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192,
Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Photoinduced decarboxylative radical additions of 5-membered alicyclic
a-amino acids bearing a (2-
Received 16 May 2019
Received in revised form
27 July 2019
Accepted 30 July 2019
Available online 1 August 2019
phenyl)benzoyl protective group to acrylonitrile under mild organic photoredox catalysis conditions
furnished -amino acid derivatives with high retention of chirality via the memory of chirality (MOC)
strategy. The retention of chirality in the photoinduced decarboxylation was strongly dependent on the
structure of the alicyclic -amino acids and alkenes. To the best of our knowledge, this is the first
example of the decarboxylative intermolecular radical addition to alkenes with retention of chirality at
the position of radical generation using the MOC strategy.
g
a
Keywords:
Retention of chirality
© 2019 Elsevier Ltd. All rights reserved.
5-Membered alicyclic a-amino acid
Photoinduced decarboxylation
Photoinduced decarboxylative
intermolecular radical addition
Memory of chirality
1. Introduction
Decarboxylative radical reactions of carboxylic acids in the
presence of a photoredox catalyst have recently been identified as a
powerful and environment-friendly tool in polymer chemistry [1]
and synthetic organic chemistry [2,3]. This is because carboxylic
acids exist widely in nature and are easy to handle, and decar-
boxylation releases the nonflammable and nontoxic product CO2
under mild conditions (e.g., room temperature). The process is
initiated by oxidation of the carboxylate ions via photoinduced
electron transfer (PET) to form carboxy radicals. As per our previous
report [3], the radical cation of phenanthrene (Phen) generated by
PET between Phen and 1,4-dicyanobenzene (DCB) can oxidize the
carboxylate ions to form carboxy radicals (Scheme 1a). The carboxy
radicals undergo decarboxylation smoothly to generate the corre-
sponding alkyl radicals, which can react with a variety of reagents
to provide the corresponding products in high yields. However, the
* Corresponding author.
Scheme 1. Loss and retention of chirality of N-Boc amino acids in photoinduced
E-mail address: yyoshimi@u-fukui.ac.jp (Y. Yoshimi).
decarboxylative radical addition.
https://doi.org/10.1016/j.tet.2019.130493
0040-4020/© 2019 Elsevier Ltd. All rights reserved.

2
Y. Ozaki et al. / Tetrahedron 75 (2019) 130493
Table 1
radical generated from chiral carboxylic acids such as N-Boc
a-
Effect of protective group in photoinduced decarboxylative radical addition of 1e2A
for retention of chirality.
amino acids via a photoinduced decarboxylation lost the chirality at
the radical-generated position to yield products as a racemic
mixture due to the generation of the planar radical by a hyper-
conjugation (p-radical). In fact, photoinduced decarboxylative
radical addition of N-Boc-L-a-amino acids to electron-deficient al-
kenes yielded racemic adducts [4]. There are only four reported
examples in which the loss of chirality at the radical formed via
decarboxylation is prevented [5]. MacMillan reported the enan-
tioselective decarboxylative arylation of N-Boc a-amino acids using
both Ir photoredox and chiral Ni catalysts [5c]. The other three
examples5a,b,d pertain to intramolecular radical cyclization via
decarboxylation using the memory of chirality [6] (MOC) strategy.
The latter (MOC strategy) is not required to add another chiral
source such as the chiral metal catalyst, and is employed by only
substrate chirality. Thus, we attempted the intermolecular radical
addition of
a-amino acids bearing a highly hindered protective
group such as N-(2-phenyl)benzoyl to alkenes via photoinduced
decarboxylation using the MOC strategy for retention of chirality,
because the resulting products are useful g-amino acid derivatives
[7] (Scheme 1b). Interestingly, photoinduced decarboxylative
intermolecular radical reactions with MOC have not been reported
till date.
2. Results and discussion
First, we chose N-(2-phenyl)benzoyl- -proline 1a as the sub-
L
strate and acrylonitrile 2A as an electron-deficient alkene for the
photoinduced decarboxylative radical addition because alicyclic
amino acids bearing the N-(2-phenyl)benzoyl group showed high
retention of chirality via the generation of a carbenium ion by
electrochemical oxidation [8]. Irradiation of an aqueous acetonitrile
solution (CH3CN/H2O ¼ 9:1) containing 1a (10 mM), 2A (10 mM),
NaOH (10 mM), Phen (3 mM), and DCB (3 mM) by a 100 W high-
pressure mercury lamp through a Pyrex filter (>280 nm) under
argon atmosphere for 3 h at room temperature afforded adduct
3 aA in high yield (85%) and with moderate enantiomeric excess
(48% ee) (Table 1). Unfortunately, decreasing the temperature (0 ꢀC)
did not affect the retention of chirality under these conditions. The
photoreaction of N-(2-phenyl)benzoyl- -proline 1b yielded adduct
D
3bA in a similar yield (80%) but with a slight decrease of retention
of chirality (ꢁ42%ee). In order to investigate effect of the N-benzoyl
group on the retention of chirality, prolines 1cei with various N-
benzoyl groups were subjected to the abovementioned photore-
action conditions. Photoinduced decarboxylative addition of N-
Scheme 2. Effect of alkenes 2BeD in photoinduced decarboxylative radical addition of
1a.
benzoyl-
racemic product 3 cA in a similar yield (80%). The photoreactions of
N-(3-phenyl)benzoyl- -proline 1d and N-(4-phenyl)benzoyl- -pro-
L-proline 1c to 2A under the same conditions provided
L
L
retention of chirality, and promoted radical cyclization at the ipso-
position. Thus, for the retention of chirality of proline 1 via the
photoinduced decarboxylative radical addition, an N-(2-phenyl)
benzoyl protective group and acrylonitrile 2A as an alkene are
required.
Next, the substrate scope of alicyclic amino acids for the
retention of chirality was explored, and five-membered alicyclic
amino acids 5 and 7 derived from serine and threonine bearing N-
benzoyl group were subjected to the above reaction conditions
(Table 2 and Scheme 3). The more hindered cyclic amino acids 5a,
line 1e did not lead to retention of chirality, and gave decreased
yield of 3 dA (57%) along with the formation of side-reaction
products in the case of 1d. These results indicated that the reten-
tion of chirality of proline 1 in the photoinduced decarboxylation
requires a substituent at the 2-position of the benzoyl group. The
photoreactions of 2-substituted benzoyl prolines 1fei having
methyl, bromo, iso-propyl, and 20-methylphenyl groups resulted in
a significantly low ee% and similar yields of 3 fAeiA. In addition, the
use of relatively bulky electron-deficient alkenes such as methyl
acrylate 2B, t-butyl acrylate 2C, and N-t-butyl acrylamide 2D
instead of 2A provided almost racemic adducts 3 aBeaD in low
yields, along with polymeric materials and spirodihy-
droisoquinolinone 4 via our previously reported ipso-radical cycli-
zation [9] (Scheme 2). These results indicated that the poor electron
accepting ability and high steric hindrance of the alkenes decreased
the rate of intermolecular radical addition of 1a to 2 without
which is prepared from N-(2-phenyl)benzoyl-L-serine methyl ester
in two steps [9], was excited under the same conditions to lead the
similar yield of 6 aA (75%) and the improved retention of chirality
(79% ee). The photoreaction of 5b having cyclohexyl part in the
place of dimethyl part provided the similar yield of 6bA (70%) and
the moderate retention (61% ee). Interestingly, N-benzoyl alicyclic

Y. Ozaki et al. / Tetrahedron 75 (2019) 130493
3
Table 2
Retention of chirality in photoinduced decarboxylative radical addition of 5 to 2A.
Scheme 4. Loss of chirality in photoinduced decarboxylative radical addition of 10 to
2A.
photoreaction of 5a with 2C did not lead to the formation of adduct
6 aC and yielded only the cyclized product 12 (Scheme 5). Thus, the
high retention of chirality of
a-amino acid via the photoinduced
decarboxylation requires both the suitable hindrance of alicyclic
a
-
amino acid bearing N-(2-phenyl)benzoyl group as a substrate and
the low hindrance of alkene.
To gain further information about the retention of chirality us-
ing the MOC strategy in the photoreaction of alicyclic amino acids,
molecular orbital calculations were carried out by using the HF/3-
21G basis set (Fig. 1). For this purpose, two conformers (open and
closed) arising from rotation about the CO (carbonyl)eC (phenyl)
Scheme 5. Photoreaction of 5a to 2C.
Scheme 3. Retention of chirality in photoinduced decarboxylative radical addition of 7
to 2A.
amino acid 5c in the absence of 2-phenyl group led to the low
retention of chirality (13% ee) in 6 cA even though the corre-
sponding proline 1c yielded racemic mixture of 3 cA (Table 1). Thus,
the more bulky alicyclic amino acid 5a than 1a is proven to improve
the retention of chirality, but 5b bearing cyclohexyl part than 5a
decreased ee%. The photoreaction of 7a, which is also prepared
from N-(2-phenyl)benzoyl-L-threonine methyl ester [9], under the
same conditions yielded the single diastereomer of adduct 8a (44%)
and cyclized product 9a (27%) (Scheme 3). Increase of the con-
centration of 2A (20 and 30 mM) caused an increase of the yield of
the single diastereomer 8a (70 and 78%) and a decrease of the yield
of 9a (16 and 13%), indicating that the additional methyl part
disturbed intermolecular radical addition to 2A to require the high
concentration of the alkene for the formation of 8a. In addition, this
situation also promoted the radical cyclization at ipso-position and
restricted the formation of another diastereomer to lead to the high
retention of chirality. To exclude the possibility that the diaster-
eoselectivity arises from the methyl group adjacent to the radical
center, the photoreaction of threonine derivative bearing benzoyl
group 7b was examined. Unfortunately, the similar photoreaction
of 7b provided complex mixture. As reported previously [7], the
photoreaction of the corresponding N-Boc threonine derivative
with methyl acrylate using Ir photocatalyst gave the diastereomer
mixture (65:35) of adduct, indicating that N-(2-phenyl)benzoyl
group in 7a promoted the retention of chirality by MOC. On the
other hand, the photoreaction of open serine derivative 10 provided
Fig. 1. Proposed mechanism and molecular orbital calculations for retention of
chirality of 1a, 5a, and 1b.
the racemic adduct 11 in
a 53% yield (Scheme 4). Similar

4
Y. Ozaki et al. / Tetrahedron 75 (2019) 130493
bond (green bond in Fig. 1) were subjected to geometry optimiza-
tion. Other rotamers including s-cis conformer of the amide bond
were not observed for minimization of energy by this calculation.
The photochemical process is much faster than rotation in the
ground state, and the ratio of the retention of chirality in adducts is
directly determined by the ratio of the conformers in the ground
state [10]. Thus, the axial chirality of CO (carbonyl)eC (phenyl)
bond in the ground state could lead to the enantio- and diaster-
eoselectivity of radical adducts. Molecular orbital calculations
1.98g, 3-phenylbenzoic acid: 1.98g, 4-phenylbenzoic acid: 1.98g, 2-
methylbenzoic acid: 1.36 g, 2-bromobenzoic acid: 2.00 g, 2-iso-
propylbenzoic acid: 1.64 g, 2-(20-methyl)phenylbenzoic acid:
2.12g), and stirred for 4 h. The organic solvent was concentrated in
vacuo to give the corresponding benzoyl chlorides. To ice-cooled
solution of NaOH (20 mmol, 0.800 g) in H2O (20 mL) was added
proline (10 mmol, 1.15 g) at 0 ꢀC, and then THF (10 mL) solution of
the corresponding benzoyl chloride (10 mmol) was slowly added.
The mixture was stirred overnight at rt and then THF was evapo-
rated. The aqueous layer was acidified (1 M HCl) to a pH 1e2 and
then extracted with EtOAc and washed with brine. The combined
organic layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by silica-
gel column chromatography using hexane/EtOAc ¼ 3:1 as the
eluent, and the obtained product was recrystallized by hexane/
EtOAc ¼ 1:2 to yield the corresponding prolines 1aei. Similar pro-
showed that the relative energy difference (DE) between the two
conformers of open and closed-1a is 5.0 kcal/mol (Eq. (1)), because
of which the ratio of closed-1a was smaller. The similar trend in the
carboxylate ion of 1a is observed by this calculation. Addition of a
dimethyl unit to an alicyclic amino acid such as 5a caused an
inversion of the energy difference (ꢁ0.6 kcal/mol) between open
and closed-5a by restricting the bond rotation due to the steric
hindrance in the dimethyl region (Eq. (2)). This in turn led to a high
ratio of closed-5a and high retention of chirality in 6 aA. Further-
more, the additional methyl unit in the alicyclic amino acid, for
example, threonine derivative 7a, prevented the one direction of
radical addition of 2A through the closed-7a radical (not shown,
similar closed-5a radical) to yield only a single diastereomer 8a.
cedure from
L-serine provided N-(2-phenyl)benzoyl-L-serine 10.
Compounds 1aeg and 10 have been previously reported.
4.2.1. N-(2-Phenyl)benzoyl-
1.91 g, 65%, white solid; 1H NMR (300 MHz, CDCl3)
(m, 9H), 4.47 (m, 1H), 2.88 (m, 2H), 2.30e2.23 (m, 1H), 1.71e1.62 (m,
2H), 1.36 (m, 1H); 13C NMR (125 MHz, CDCl3)
173.05, 172.07,
L
-proline (1a)[8b,9]
d
7.57e7.38
The slightly larger energy difference (7.4 kcal/mol) in
D-proline 1b
d
than in -proline 1a decreased the retention of chirality (Eq. (3)).
L
139.40, 135.71, 134.50, 130.47, 129.71, 128.83, 128.62, 128.50, 128.20,
127.97, 127.55, 60.12, 48.80, 45.83, 30.22, 27.53, 24.30, 22.42.
The high steric hindrance in alkenes such as 2BeD rendered the
addition to closed-1a and 5a radical (Eqs. (1) and (2)) difficult.
Consequently, cyclized products 4 and 12 were formed via closed-
1a and 5a radical and poor retention of chirality was observed.
4.2.2. N-(2-Phenyl)benzoyl-
0.89 g, 30%, white solid; 1H NMR (300 MHz, CDCl3)
(m, 9H), 4.46 (m,1H), 2.87 (m, 2H), 2.29e2.22 (m,1H),1.72e1.62 (m,
2H), 1.36 (m, 1H); 13C NMR (125 MHz, CDCl3)
173.38, 172.68,
D-proline (1b)[9]
d
7.57e7.38
3. Conclusion
d
139.43, 134.28, 130.36, 129.70, 128.81, 128.63, 128.55, 128.14, 127.93,
127.58, 59.84, 48.70, 46.92, 30.61, 27.90, 24.33, 22.24.
High retention of chirality in the photoinduced decarboxylative
radical addition of 5-membered alicyclic amino acids bearing an N-
(2-phenyl)benzoyl group to alkenes was achieved using the suit-
able steric hindrance of both substrate and alkene with the MOC
4.2.3. N-Benzoyl-
L
-proline (1c)[9,11]
strategy, despite the formation of a planar radical from the
a
-amino
0.75 g, 34%, white solid; 1H NMR (300 MHz, CDCl3)
d 7.57e7.44
acid. In particular, threonine derivative 7a exclusively provided a
single diastereomer. Further investigation is being carried out on
(m, 5H), 4.80 (dd, J ¼ 8.2, 5.0 Hz, 1H), 3.64e3.54 (m, 2H), 2.51 (m,
1H), 2.22e2.18 (m, 1H), 2.06e1.89 (m, 2H); 13C NMR (125 MHz,
the retention of chirality of non-alicyclic
a
-amino acids (simple
a
-
CDCl3)
d 173.41, 171.65,141.65, 140.15,135.82, 129.46, 129.02, 127.92,
amino acids such as valine and phenylalanine) using new protective
groups in this photoinduced decarboxylative radical addition.
127.25, 126.06, 60.14, 50.71, 28.38, 25.29.
4.2.4. N-(3-Phenyl)benzoyl-
L
-proline (1d)[9]
4. Experimental section
2.18 g, 74%, white solid; 1H NMR (500 MHz, CDCl3)
d
7.76e7.67
(m, 2H), 7.61e7.35 (m, 7H), 5.76 (br, 1H), 4.76 (m, 1H), 3.61 (m, 2H),
4.1. General information
2.37e2.21 (m, 2H), 2.06e1.87 (m, 2H); 13C NMR (125 MHz, CDCl3)
d
173.50, 171.68, 141.70, 141.66, 141.61, 140.21, 140.14, 139.99, 135.85,
All reagents and solvents were used as received from commer-
cial suppliers. IR spectra were recorded on an FT-IR spectrometer.
1H NMR spectra were recorded in CDCl3 and DMSO‑d6 containing
tetramethylsilane as an internal standard, and were acquired on
either a 300 or 500 MHz spectrometers. 13C{1H} NMR spectra were
acquired on a 125 MHz spectrometer. High-resolution mass spectra
were obtained using double-focusing magnetic sector mass spec-
trometer coupled with FAB. The light source was a high-pressure
(100 W) mercury arc. Column chromatography was performed on
135.81, 135.45, 129.58, 129.47, 129.33, 129.02, 127.98, 127.92, 127.58,
127.25, 126.06, 60.14, 50.83, 50.71, 50.64, 28.37, 25.29.
4.2.5. N-(4-Phenyl)benzoyl-
L
-proline (1e)[8b,9,12]
2.18 g, 74%, white solid; 1H NMR (300 MHz, CDCl3)
d
7.69e7.59
(m, 6H), 7.50e7.37 (m, 3H), 4.82 (dd, J ¼ 8.1, 4.9 Hz, 1H), 3.72e3.62
(m, 2H), 2.53 (m, 1H), 2.24e2.11 (m, 1H), 2.11e1.91 (m, 2H); 13C
NMR (125 MHz, CDCl3)
129.47, 129.02, 127.92, 127.25, 126.06, 60.14, 50.71, 28.37, 25.29.
d 173.66, 171.68, 141.66, 140.14, 135.81,
Wakogel C-300, particle size 45e75 mm. Theoretical calculations
using the HF/3-21G basis set were performed by with the Gaussian
09 software package.
4.2.6. N-(2-Methyl)benzoyl-
L
-proline (1f)[8b]
0.77 g, 33%, white solid; 1H NMR (500 MHz, CDCl3)
d
7.30e7.21
4.2. Procedure for the synthesis of N-benzoyl prolines 1aei and N-
(m, 4H), 4.78 (m, 0.9H), 4.11 (m, 0.1H), 3.79 (m, 0.1H), 3.27 (m,
(2-phenyl)benzoyl serine 10
2.9H), 2.45 (m, 1H), 2.30 (m, 3H), 2.18 (m, 1H), 2.02e1.97 (m, 1H),
1.90e1.87 (m, 1H); 13C NMR (125 MHz, CDCl3)
d 175.31, 174.68,
Oxaly chloride (12 mmol, 0.87 mL) was added to the mixture of
toluene (10 mL), THF (10 mL), and DMF (0.2 mL) solution containing
benzoic acids (10 mmol, benzoic acid: 1.22g, 2-phenylbenzoic acid:
171.52, 170.89, 136.23, 136.07, 134.47, 130.65, 129.44, 129.27, 125.93,
125.67, 60.89, 58.90, 49.26, 46.02, 31.28, 29.14, 24.76, 22.74, 19.03,
18.91.

Y. Ozaki et al. / Tetrahedron 75 (2019) 130493
5
4.2.7. N-(2-Bromo)benzoyl-
L
-proline (1g)[13]
dialkyl-4-oxazolidine methyl esters ((4R)-N-benzoyl-2,2-dimethyl-
4-oxazolidine methyl ester: 1.84 g, 70%; (4R)-N-(2-phenyl)benzoyl-
2,2-dimethyl-4-oxazolidine methyl ester: 2.54 g, 75%; (4R)-N-(2-
phenyl)benzoyl-2-cyclohexyl-4-oxazolidine methyl ester: 2.80 g,
74%; (4R, 5R)-N-(2-phenyl)benzoyl-2,2,5-trimethyl-4-oxazolidine
methyl ester: 2.26 g, 64%).
2.20 g, 75%, white solid; 1H NMR (300 MHz, CDCl3)
d
7.63 (m,
1H), 7.45e7.29 (m, 3H), 4.82 (dd, J ¼ 8.3, 3.6 Hz, 0.9H), 4.20 (m,
0.1H), 3.83 (m, 0.2H), 3.35e3.31 (m, 1.8H), 2.57 (m, 1H), 2.22e1.94
(m, 3H); 13C NMR (125 MHz, CDCl3)
d
174.08, 171.45, 135.38, 130.73,
128.49, 127.34, 59.97, 50.55, 28.57, 25.29.
The obtained methyl esters (3 mmol, (4R)-N-benzoyl-2,2-
dimethyl-4-oxazolidine methyl ester: 0.78 g, (4R)-N-(2-phenyl)
benzoyl-2,2-dimethyl-4-oxazolidine methyl ester: 1.02 g, (4R)-N-
4.2.8. N-(2-iso-Propyl)benzoyl-
1.04 g, 40%, white solid; m.p. 132e131 ꢀC; IR (KBr, cmꢁ1) 3432,
3051, 1732, 1625; 1H NMR (300 MHz, CDCl3)
7.40e7.37 (m, 2H),
L
-proline (1h)
d
(2-phenyl)benzoyl-2-cyclohexyl-4-oxazolidine
methyl
ester:
7.24e7.16 (m, 2H), 4.80 (dd, J ¼ 8.2, 4.0 Hz, 1H), 3.29e3.25 (m, 2H),
1.09 g, (4R, 5R)-N-(2-phenyl)benzoyl-2,2,5-trimethyl-4-oxazolidine
methyl ester: 1.06 g) were hydrolyzed by using NaOH (6 mmol,
0.24 g) in the mixture of THF (12 mL) and H2O (4 mL) solution at
room temperature until starting materials were consumed
completely (by TLC monitoring, about 3 h). After each reaction is
complete, the solution was washed by Et2O, and then 1 M H2SO4
was added until pH ¼ 3 and the solution was extracted with EtOAc.
The organic layer was washed with H2O and brine, and dried over
with Na2SO4, and concentrated in vacuo giving a residue that was
subjected to silica gel column chromatography using hexane/
EtOAc ¼ 1:1 as the eluent to yield the desired 4-oxazolidine car-
boxylic acids 5 and 7. Compounds 5a, 5c, and 7a, 7b have been
previously reported.
3.03e2.94 (m, 1H), 2.57e2.47 (m, 1H), 2.23e1.84 (m, 3H), 1.27e1.22
(m, 6H); 13C NMR (125 MHz, CDCl3)
d 172.83, 171.38, 144.42, 134.05,
129.03, 125.27, 58.43, 48.98, 30.15, 29.79, 29.68, 27.70, 23.91, 23.34,
23.10; HRMS (FAB) calcd for (M þ H)þ C15H19NO3: 262.1438, found
262.1451.
4.2.9. N-[2-(20-Methyl)phenyl]benzoyl-
1.05 g, 34%, white solid; m.p. 62e61 ꢀC; IR (KBr, cmꢁ1) 3439,
3060, 1735, 1621; 1H NMR (300 MHz, CDCl3)
10.38 (br, 1H),
L
-proline (1i)
d
7.50e7.18 (m, 8H), 4.36 (m, 0.9H), 3.95 (m, 0.1H), 3.57 (m, 0.1H),
3.23e3.00 (m, 1.9H), 2.45e2.24 (m, 3H), 2.14e1.97 (m, 2H),
1.82e1.26 (m, 2H); 13C NMR (125 MHz, CDCl3)
d 175.86, 173.95,
171.44,169.85,138.62,136.48,135.72,130.58,130.44,129.88,129.25,
128.00, 127.83, 127.61, 127.47, 126.76, 125.53, 59.25, 48.70, 45.52,
30.37, 28.14, 24.51, 22.41, 20.21, 20.04; HRMS (FAB) calcd for
(M þ H)þ C19H19NO3:310.01438, found 310.1444.
4.3.1. (4R)-N-(2-Phenyl)benzoyl-2,2-dimethyl-4-oxazolidine
carboxylic acid (5a)[5c,9]
0.76 g, 78%, white solid; 1H NMR (300 MHz, CDCl3)
d
9.67 (s, 1H),
7.46e7.23 (m, 9H), 3.85 (m, 1H), 3.72 (m, 1H), 3.24 (m, 1H), 1.72 (s,
3H),1.23 (s, 3H); 13C NMR (125 MHz, CDCl3)
174.35,168.33,139.42,
4.2.10. N-(2-Phenyl)benzoyl-
White solid; 1H NMR (500 MHz, DMSO‑d6)
1H), 7.50e7.26 (m, 8H), 4.28e4.25 (m, 1H), 3.64e3.56 (m, 2H), 3.31
(s, 1H); 13C NMR (125 MHz, DMSO‑d6)
172.36, 169.60, 140.55,
L
-serine (10)[4a,9]
d
d
8.35 (d, J ¼ 8.0 Hz,
137.69, 136.08, 129.79, 129.43, 128.96, 128.84, 128.18, 127.74, 96.80,
66.64, 60.02, 25.48, 22.39.
d
139.91, 136.90, 130.47, 130.23, 129.00, 128.67, 128.59, 127.63, 127.50,
61.76, 55.61.
4.3.2. (4R)-N-(2-Phenyl)benzoyl-2-cyclohexyl-4-oxazolidine
carboxylic acid (5b)
0.73 g, 67%, white solid; m.p. 228e227 ꢀC; IR (KBr, cmꢁ1) 3431,
4.3. Procedure for the synthesis of N-benzoyl-2,2-dialkyl-4-
oxazolidine carboxylic acids 5aec and 7a,b from serine and
threonine methyl esters
3060, 1746, 1625; 1H NMR (300 MHz, CDCl3)
d 7.49e7.25 (m, 9H),
7.14e6.70 (m, 1H), 3.84 (dd, J ¼ 8.3, 4.5 Hz, 1H), 3.73 (d, J ¼ 5.9 Hz,
1H), 3.24e3.19 (m, 1H), 2.75e2.65 (m, 1H), 2.29e2.25 (m, 1H),
1.75e1.24 (m, 7H), 0.99e0.89 (m, 1H); 13C NMR (125 MHz, CDCl3)
THF solution (20 mL) of the corresponding benzoyl chloride
d 174.74, 168.80, 139.36, 137.56, 136.22, 129.69, 129.39, 128.97,
(20 mmol) was added dropwise to
L
-serine or threonine methyl
128.81, 128.17, 128.08, 127.66, 98.43, 66.51, 60.16, 33.53, 29.29,
24.52, 23.17, 23.11; HRMS (FAB) calcd for (M þ H)þ C22H23NO4:
366.1700, found 366.1700.
esters (3.12 or 3.40 g, 20 mmol) in an aq. NaHCO3 (3.36 g, 40 mmol)
solution (40 mL) at 0 ꢀC. The mixture was stirred overnight at room
temperature, and then extracted with EtOAc, and washed with
brine. The combined organic layers were dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude
product was purified by silica-gel column chromatography using
hexane/EtOAc ¼ 4:1 as the eluent to yield the corresponding N-
4.3.3. (4R)-N-Benzoyl-2,2-dimethyl-4-oxazolidine carboxylic acid
(5c)[5b]
0.43 g, 58%, white solid; 1H NMR (300 MHz, CDCl3)
d
7.38 (m,
5H), 5.63 (br, 1H), 4.43 (m, 1H), 4.26e4.18 (m, 2H), 1.72 (s, 3H), 1.23
(s, 3H); 13C NMR (125 MHz, CDCl3)
174.85, 168.99, 137.19, 129.91,
benzoyl-
L
-serine or threonine methyl esters (N-benzoyl-
-serine methyl
-threonine methyl ester:
L-serine
d
methyl ester: 1.90 g, 65%; N-(2-phenyl)benzoyl-
ester: 3.88 g, 34%; N-(2-phenyl)benzoyl-
L
128.64, 126.13, 97.14, 67.11, 61.06, 24.91, 24.06.
L
2.13 g, 34%).
4.3.4. (4R, 5R)-N-(2-Phenyl)benzoyl-2,2,5-trimethyl-4-oxazolidine
The mixture of benzene (24 mL) and chloroform (14 mL) solu-
tion containing N-benzoyl- -serine or threonine methyl esters
(10 mmol, N-benzoyl- -serine methyl ester: 2.24 g, N-(2-phenyl)
benzoyl- -serine methyl ester: 3.00 g, N-(2-phenyl)benzoyl-
threonine methyl ester: 3.13 g), p-TsOH (20 mg, 0.1 mmol), and 2,2-
dimethoxypropane or 1,1-dimethoxycyclohexane (2.45 or 3.04 mL,
20 mmol) was reflux for 4 h at 80 ꢀC. The organic solvent was
removed by distillation, and quenched by saturated aq. NaHCO3
solution, and then extracted with EtOAc, and washed with brine.
The combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was pu-
rified by silica-gel column chromatography using hexane/
EtOAc ¼ 7:1 as the eluent to yield the corresponding N-benzoyl-2,2-
carboxylic acid (7a)[5c]
L
0.86 g, 84%, white solid; 1H NMR (300 MHz, CDCl3)
d 10.10 (br,
L
1H), 7.53e7.19 (m, 9H), 4.03 (m, 1H), 3.24 (d, J ¼ 5.3 Hz, 1H), 1.63 (s,
L
L-
3H),1.53 (s, 3H), 0.84 (d, J ¼ 13.6 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 174.07, 174.02, 168.90, 139.46, 138.08, 135.30, 130.04, 129.55,
129.37, 129.06, 128.82, 128.41, 127.41, 97.39, 74.93, 65.97, 25.44,
24.42, 19.61; HRMS (FAB) calcd for (M þ H)þ C20H20N2O2: 305.1649,
found 305.1674.
4.3.5. (4R, 5R)-N-Benzoyl-2,2,5-trimethyl-4-oxazolidine carboxylic
acid (7b)[8a]
0.81 g, 80%, white solid; 1H NMR (500 MHz, DMSO‑d6)
d
7.46e7.38 (m, 5H), 4.24 (d, J ¼ 6.0 Hz, 1H), 4.15e4.12 (m, 1H), 1.67

6
Y. Ozaki et al. / Tetrahedron 75 (2019) 130493
(s, 3H), 1.61 (s, 3H), 1.36 (d, J ¼ 5.0 Hz, 3H); 13C NMR (125 MHz,
C20H20N2O: 305.1649 found 305.1656.
DMSO‑d6)
d 171.08, 167.98, 137.40, 129.94, 128.24, 127.20, 95.78,
74.70, 67.45, 26.07, 23.20, 18.95.
4.4.6. N-(2-Methyl)benzoyl-2-pyrrolidinepropanenitrile (3fA)
0.084 g, 77%, colorless oil; IR (neat, cmꢁ1) 2952, 2245, 1629; 1H
4.4. General procedure for the photoreaction of 1 with 2
NMR (500 MHz, CDCl3) d 7.28e7.19 (m, 4H), 4.35e4.33 (m, 0.9H),
3.81 (m, 0.1H), 3.62 (m, 0.2H), 3.20e3.13 (m, 1.8H), 2.55e2.50 (m,
2H), 2.30 (s, 3H), 2.16e2.12 (m, 1H), 2.01e1.75 (m, 4H), 1.61 (m, 1H);
An aqueous CH3CN solution (CH3CN 36 mL, H2O 4 mL) of 1
(10 mM), 2 (10 mM), NaOH (10 mM, 0.016g), Phen (3 mM, 0.0213g),
and DCB (3 mM, 0.0153g) in Pyrex vessels (18 mm ꢂ 180 mm) was
purged with Ar for 10 min. The mixture was irradiated with a
100 W high-pressure mercury lamp for 3 h, and then the solvent
was removed under reduced pressure. The crude product was pu-
rified by silica-gel column chromatography using hexane/
EtOAc ¼ 4:1 as the eluent to yield adduct 3 and cyclized product 4.
Similar photoreactions of 5, 7, and 10 with 2 were carried out under
the same conditions to yield 6, 8, 9,11, and 12. Compounds 4,11, and
12 have been previously reported.
13C NMR (125 MHz, CDCl3)
d 170.89, 137.45, 133.78, 130.59, 129.09,
126.06, 125.76,119.86, 56.05, 48.82, 30.50, 30.21, 24.49, 19.12, 14.78;
HRMS (FAB) calcd for (M þ H)þ C15H18N2O: 243.1492 found
243.1485.
4.4.7. N-(2-Bromo)benzoyl-2-pyrrolidinepropanenitrile (3gA)
0.104 g, 85%, colorless oil; IR (neat, cmꢁ1) 2973, 2245, 1633; 1H
NMR (500 MHz, CDCl3)
d 7.58e7.54 (m, 1H), 7.36e7.21 (m, 3H),
4.36e4.34 (m, 0.9H), 3.93e3.69 (m, 0.1H), 3.63e3.39 (m, 0.1H),
3.25e3.15 (m, 1.9H), 2.62e2.51 (m, 2H), 2.25e2.03 (m, 2H),
1.97e1.73 (m, 4H); 13C NMR (125 MHz, CDCl3)
d 168.08, 139.20,
4.4.1. N-(2-Phenyl)benzoyl-2-pyrrolidinepropanenitrile
(3aA) þ48ee%
132.90, 130.48, 127.98, 127.57, 119.96, 118.54, 57.79, 56.33, 48.34,
45.44, 30.40, 30.03, 24.22, 22.41, 14.82, 14.01; HRMS (FAB) calcd for
(M þ H)þ C14H15BrN2O: 307.0441 found 307.0468.
0.103 g, 85%, colorless oil; IR (neat, cmꢁ1) 2940, 2245, 1625; 1H
NMR (300 MHz, CDCl3)
(m, 0.5H), 2.96e2.88 (m, 1H), 2.71 (m, 0.5H), 2.32e1.25 (m, 8H); 13
NMR (125 MHz, CDCl3) 170.49, 140.03, 139.82, 138.39, 136.83,
d 7.52e7.40 (m, 9H), 4.16 (m, 1H), 3.46e3.25
C
4.4.8. N-(2-iso-Propyl)benzoyl-2-pyrrolidinepropanenitrile (3hA)
d
0.079 g, 73%, colorless oil; IR (neat, cmꢁ1) 3007, 2248, 1628; 1H
130.01, 129.73, 129.50, 128.82, 128.71, 128.55, 127.99, 127.85, 126.93,
119.86, 55.95, 48.04, 45.49, 30.06, 29.48, 29.39, 24.07, 21.99, 14.37,
14.25; HRMS (FAB) calcd for (M þ H)þ C20H20N2O: 305.1649 found
305.1661.
NMR (500 MHz, CDCl3) d 7.35e7.30 (m, 2H), 7.21e7.13 (m, 2H), 4.33
(m, 0.9H), 3.80 (m, 0.1H), 3.57 (m, 0.1H), 3.15 (m, 1.9H), 3.00e2.94
(m, 1H), 2.56e2.46 (m, 2H), 2.28 (m, 1H), 2.14e2.09 (m, 1H),
2.02e1.76 (m, 4H), 1.27e1.19 (m, 6H); 13C NMR (125 MHz, CDCl3)
d
170.94, 144.79, 136.49, 129.69, 129.40, 126.05, 126.00, 125.77,
4.4.2. N-(2-Phenyl)benzoyl-2-pyrrolidinepropanenitrile
119.89, 57.76, 56.04, 49.25, 30.64, 30.52, 30.17, 30.04, 24.42, 24.00,
14.72; HRMS (FAB) calcd for (M þ H)þ C17H22N2O: 271.1805 found
271.1809.
(3bA) ꢁ42ee%
0.098 g, 80%, colorless oil; IR (neat, cmꢁ1) 3060, 2246, 1621; 1
H
NMR (300 MHz, CDCl3)
(m, 0.5H), 2.96e2.88 (m, 1H), 2.70 (m, 0.5H), 2.28e1.25 (m, 8H); 13
NMR (125 MHz, CDCl3) 170.38, 170.07, 139.94, 139.72, 136.73,
129.91, 129.63, 129.50, 129.41, 128.72, 128.61, 128.45, 127.90, 127.76,
126.84, 119.77, 118.29, 55.86, 47.94, 45.39, 29.96, 29.68, 29.29, 28.31,
23.96, 21.89, 15.25, 15.08, 14.27, 14.15; HRMS (FAB) calcd for
(M þ H)þ C20H20N2O: 305.1649 found 305.1674.
d 7.47e7.38 (m, 9H), 4.17 (m, 1H), 3.46e3.25
C
4.4.9. N-[2’-(200-Methyl)phenyl]benzoyl-2-
pyrrolidinepropanenitrile (3iA)
d
0.120 g, 91%, colorless oil; IR (neat, cmꢁ1) 3060, 2245, 1630; 1H
NMR (500 MHz, CDCl3)
1H), 3.00e2.79 (m, 1H), 2.32e2.17 (m, 3H), 2.05e1.98 (m, 2H),
1.73e1.49 (m, 6H); 13C NMR (125 MHz, CDCl3)
170.21, 137.60,
d 7.41e7.21 (m, 8H), 4.14 (m, 1H), 3.13 (m,
d
130.58, 130.28, 129.04, 128.31, 128.18, 127.70, 120.00, 55.48, 48.41,
30.12, 29.86, 24.49, 24.24, 20.32, 13.88; HRMS (FAB) calcd for
(M þ H)þ C21H22N2O: 319.1805, found 319.1826.
4.4.3. N-Benzoyl-2-pyrrolidinepropanenitrile (3cA)
0.073 g, 80%, colorless oil; IR (neat, cmꢁ1) 2992, 2247, 1621; 1H
NMR (500 MHz, CDCl3)
d 7.52e7.36 (m, 5H), 4.37e4.34 (m, 0.9H),
4.02 (m, 0.1H), 3.77 (m, 0.1H), 3.52e3.40 (m, 1.9H), 2.50e2.47 (m,
4.4.10. N-(2-Phenyl)benzoyl-2-pyrrolidine methyl propionate (3aB)
0.092 g, 68% (using hexane/EtOAc ¼ 2:1 as the eluent), colorless
oil; IR (neat, cmꢁ1) 2980, 1737, 1634; 1H NMR (300 MHz, CDCl3)
2H), 2.23e2.13 (m, 2H), 1.97e1.69 (m, 4H); 13C NMR (125 MHz,
CDCl3)
d 171.00, 136.78, 130.32, 128.39, 127.44, 119.95, 56.44, 50.37,
30.58, 30.15, 25.14, 14.44; HRMS (FAB) calcd for (M þ H)þ
d 7.50e7.32 (m, 9H), 4.14 (m, 1H), 3.70 (s, 3H), 3.55 (m, 1H),
C14H16N2O: 229.1336 found 229.1351.
3.44e3.39 (m, 0.5H), 3.20 (m, 0.5H), 2.91e2.84 (m, 1H), 2.40e2.05
(m, 1H), 1.93 (m, 1H), 1.72e1.26 (m, 5H); 13C NMR (125 MHz, CHCl3)
4.4.4. N-(3-Phenyl)benzoyl-2-pyrrolidinepropanenitrile (3dA)
d 173.82, 172.88, 169.91, 139.92, 137.11, 136.26, 132.24, 129.54,
1
0.059 g, 48%, colorless oil; IR (neat, cmꢁ1) 2949, 2246, 1623; H
129.44, 129.23, 128.75, 128.61, 128.49, 128.42, 127.77, 127.64, 127.07,
57.33, 56.20, 51.60, 47.71, 45.06, 42.06, 30.99, 30.56, 29.76, 29.33,
29.25, 23.89, 21.81; HRMS (FAB) calcd for (M þ H)þ C21H23NO3:
338.1751, found 338.1760.
NMR (300 MHz, CDCl3)
3.57e3.51 (m, 2H), 2.56e2.51 (m, 2H), 2.30e2.17 (m, 2H), 2.01e1.74
(m, 4H); 13C NMR (125 MHz, CDCl3)
170.88, 141.68, 140.18, 137.13,
d 7.76e7.35 (m, 9H), 4.44e4.39 (m, 1H),
d
128.98, 128.88, 127.79, 127.24, 126.18, 119.78, 56.52, 50.42, 30.62,
30.21, 25.14, 14.51; HRMS (FAB) calcd for (M þ H)þ C20H20N2O:
305.1649 found 305.1661.
4.4.11. N-(2-Phenyl)benzoyl-2-pyrrolidine t-butyl propionate (3aC)
0.091 g, 60% (using hexane/EtOAc ¼ 5:1 as the eluent), colorless
oil; IR (neat, cmꢁ1) 2926, 1725, 1622; 1H NMR (300 MHz, CDCl3)
4.4.5. N-(4-Phenyl)benzoyl-2-pyrrolidinepropanenitrile (3eA)
0.098 g, 80%, white solid; m.p. 119e118 ꢀC; IR (KBr, cmꢁ1) 2952,
d
7.51e7.34 (m, 9H), 4.11 (m, 1H), 3.27 (m, 0.5H), 2.87 (m, 1H), 2.63
(m, 0.5H), 2.22e1.63 (m, 4H), 1.52e1.30 (m, 13H); 13C NMR
(125 MHz, CDCl3) 172.68, 171.91, 169.77, 139.90, 137.17, 136.33,
2336, 1621; 1H NMR (300 MHz, CDCl3)
d
7.63e7.37 (m, 9H), 4.42 (m,
1H), 3.60e3.54 (m, 2H), 2.53 (m, 2H), 2.29e2.16 (m, 2H), 2.04e1.72
(m, 4H); 13C NMR (125 MHz, CDCl3)
170.73, 143.12, 140.18, 135.35,
d
129.51, 129.20, 128.75, 128.59, 128.44, 128.40, 127.76, 127.61, 127.09,
80.36, 80.13, 57.62, 56.31, 47.68, 45.11, 32.52, 32.10, 29.64, 29.44,
29.24, 28.11, 28.00, 23.86, 21.84; HRMS (FAB) calcd for (M þ H)þ
C24H29NO3: 380.2220, found 380.2210.
d
128.90, 128.00, 127.85, 127.37, 127.16, 126.98, 119.88, 56.45, 50.38,
30.51, 30.08, 25.13, 14.36; HRMS (FAB) calcd for (M þ H)þ

Y. Ozaki et al. / Tetrahedron 75 (2019) 130493
7
4.4.12. N-(2-Phenyl)benzoyl-2-pyrrolidine N0-t-butyl propionamide
(3aD)
27.59, 26.50, 20.55, 14.17; HRMS (FAB) calcd for (M þ H)þ
C22H24N2O2: 349.1911, found 349.1898.
0.077 g, 50% (using hexane/EtOAc ¼ 1:1 as the eluent), colorless
oil; IR (neat, cmꢁ1
)
2967, 1612; 1H NMR (300 MHz, CDCl3)
4.4.18. 2,2,4-Trimethyl-3-oxo-spirodihydroisoquinolinone (9)
0.032 g, 27% in the case of 10 mM of 2A or 0.019 g,16% in the case
of 20 mM of 2A or 0.015 g, 13% in the case of 30 mM of 2A (using
hexane/EtOAc ¼ 7:1 as the eluent), white solid; m.p. 174e173 ꢀC; IR
d
7.49e7.37 (m, 9H), 6.67 (br, 1H), 4.11 (m, 1H), 2.85 (m, 2H), 2.05
(m, 1H), 1.91 (m, 1H), 1.52e1.29 (m, 13H), 1.24 (m, 2H); 13C NMR
(125 MHz, CDCl3) 172.12, 170.41, 139.93, 136.87, 129.66, 129.34,
d
128.75, 128.59, 128.50, 128.36, 127.74, 126.90, 56.10, 51.04, 47.72,
34.90, 31.59, 30.42, 30.16, 28.83, 28.74, 25.36, 23.69, 22.66, 14.15;
HRMS (FAB) calcd for (M þ H)þ C24H30N2O2: 379.2380, found
379.2378.
(KBr, cmꢁ1) 3053, 1654; 1H NMR (300 MHz, CDCl3)
d 8.08e8.06 (m,
1H), 7.50e7.44 (m, 1H), 7.38e7.33 (m, 1H), 7.29e7.23 (m, 1H),
6.30e6.26 (m, 1H), 5.85e5.82 (m, 1H), 5.72e5.62 (m, 2H), 4.19e4.10
(m, 1H), 3.51 (d, J ¼ 9.0 Hz, 1H), 2.78 (m, 2H), 1.80 (s, 3H), 1.69 (s,
3H), 1.37e1.34 (m, 3H); 13C NMR (125 MHz, CDCl3)
d 160.78, 144.30,
4.4.13. Spirodihydroisoquinolinone (4)[9]
132.89, 132.40, 129.19, 128.90, 127.99, 127.38, 127.18, 126.47, 126.35,
125.28, 117.11, 116.79, 93.42, 73.36, 67.85, 42.08, 26.71, 26.43, 24.12,
19.12; HRMS (FAB) calcd for (M þ H)þ C19H21NO2:296.164500,
found 296.1649.
0.007 g, 7% in the case of 2B or 0.019 g, 19% in the case of 2C or
0.013 g, 13% in the case of 2D (using hexane/EtOAc ¼ 7:1 as the
eluent), white solid; 1H NMR (300 MHz, CDCl3)
d 8.11e8.08 (m, 1H),
7.48e7.42 (m, 1H), 7.37e7.31 (m, 1H), 7.27e7.23 (m, 1H), 6.24e6.18
(m, 1H), 5.84e5.80 (m, 1H), 5.63e5.54 (m, 2H), 3.89e3.76 (m, 2H),
3.64e3.56 (m, 1H), 2.78e2.75 (m, 2H), 2.02e1.77 (m, 4H); 13C NMR
4.4.19. 4-Hydroxymethyl-4-[N-(20-phenyl)benzoyl]
(125 MHz, CDCl3)
d 162.92, 144.90, 131.98, 128.79, 128.37, 127.95,
aminobutyronitrile (11)[4a]
0.067 g, 53%, colorless oil; 1H NMR (300 MHz, CDCl3)
d 7.86 (d,
127.50, 127.04, 126.61, 126.51, 125.40, 63.95, 45.77, 44.03, 28.66,
26.74, 22.85.
J ¼ 7.7 Hz, 1H), 7.58e7.39 (m, 3H), 7.30e7.08 (m, 5H), 4.70 (d,
J ¼ 9.2 Hz, 1H), 3.96e3.83 (m, 2H), 3.64 (m, 1H), 1.91e1.63 (m, 2H),
1.25e1.14 (m, 1H), 0.95e0.83 (m, 1H); 13C NMR (125 MHz, CDCl3)
4.4.14. N-(2-Phenyl)benzoyl-2,2-dimethyl-4-
oxazolidinepropanenitrile (6aA)
d
169.77,168.34,142.23,142.16,140.09,139.41,135.57,131.87,131.04,
0.104 g, 75%, white solid; m.p. 115e114 ꢀC; IR (KBr, cmꢁ1) 3060,
130.70,130.46, 130.15, 129.82, 128.79, 128.61, 128.52, 128.33,128.29,
128.20, 127.77, 127.57, 127.48, 119.05, 66.33, 47.05, 27.17, 13.88;
HRMS (FAB) calcd for (M þ H)þ C18H18N2O2: 295.1441, found
295.1439.
2246, 1635; 1H NMR (300 MHz, CDCl3)
d 7.56e7.39 (m, 9H), 3.42 (d,
J ¼ 9.3 Hz, 1H), 3.32 (m, 1H), 2.98 (m, 1H), 2.17e1.93 (m, 2H), 1.68 (s,
3H), 1.58 (s, 3H), 1.30e1.25 (m, 2H); 13C NMR (125 MHz, CDCl3)
d
167.91, 139.55, 137.81, 136.35, 130.06, 129.99, 129.15, 128.84,
128.10, 127.90, 127.79, 117.98, 95.56, 65.91, 56.67, 29.16, 27.11, 21.77,
14.18; HRMS (FAB) calcd for (M þ H)þ C21H22N2O2: 335.1754, found
335.1768.
4.4.20. 2,2-Dimethyl-3-oxo-spirodihydroisoquinolinone (12)[9]
0.039 g, 35% (using hexane/EtOAc ¼ 7:1 as the eluent), white
solid; 1H NMR (300 MHz, CDCl3)
d 8.10e8.07 (m, 1H), 7.51e7.45 (m,
1H), 7.40e7.35 (m, 1H), 7.27e7.21 (m, 1H), 6.26e6.22 (m, 1H),
5.89e5.86 (m, 1H), 5.69e5.61 (m, 2H), 4.09e4.02 (m, 2H),
3.95e3.91 (m, 1H), 2.78 (m, 2H), 1.78 (s, 3H), 1.70 (s, 3H); 13C NMR
4.4.15. N-(2-Phenyl)benzoyl-2-cyclohexyl-4-
oxazolidinepropanenitrile (6bA)
0.106 g, 70%, white solid; m.p. 76e75 ꢀC; IR (KBr, cmꢁ1) 2932,
2336, 1633; 1H NMR (500 MHz, CDCl3)
d 7.54e7.39 (m, 9H), 3.40 (d,
(125 MHz, CDCl3)
d 160.75, 144.35, 132.33, 129.32, 129.12, 128.07,
127.34, 126.48, 126.42, 125.78, 95.24, 66.15, 62.10, 42.08, 26.66,
25.57, 23.89.
J ¼ 9.2 Hz, 1H), 3.28 (m, 1H), 2.92 (m, 1H), 2.77 (m, 1H), 2.30 (m, 1H),
2.02e1.92 (m, 2H), 1.65e1.26 (m, 9H), 0.98 (m, 1H); 13C NMR
(125 MHz, CDCl3)
d 168.11, 139.50, 137.69, 136.68, 130.04, 129.88,
129.16, 128.80, 128.08, 127.86, 127.77, 118.00, 97.10, 65.62, 56.64,
35.46, 29.26, 28.42, 24.48, 23.27, 23.05, 14.21; HRMS (FAB) calcd for
(M þ H)þ C24H26N2O2: 375.2067, found 375.2086.
4.5. Chiral-HPLC analysis of the retention of
photoinduced decarboxylative radical addition
a-chirality in the
In order to measure the retention of a-chirality of adducts in the
4.4.16. N-Benzoyl-2,2-dimethyl-4-oxazolidinepropanenitrile (6cA)
0.082 g, 76% (using hexane/EtOAc ¼ 6:1 as the eluent), color-
less.s oil; IR (neat, cmꢁ1) 2983, 2245, 1635; 1H NMR (300 MHz,
photoinduced decarboxylative radical addition, chiral HPLC anal-
ysis of adducts were carried out under these conditions. (1) For
3 aAeiA, 3 aB, 6 aAeiA, 8, and 11, Column: Daicel CHIRALPAK OD-H,
eluent: hexane/2-propanol ¼ 15/1, flow rate: 0.2 mLminꢁ1, room
temperature, UV detector: l ¼ 254 nm. (2) For 3 aC, Column: Daicel
CHIRALPAK OD-H, eluent: hexane/2-propanol ¼ 50/1, flow rate:
0.2 mLminꢁ1, room temperature, UV detector: l ¼ 254 nm. (3) For
3aD, Column: Daicel CHIRALPAK OD-H, eluent: hexane/2-prop-
anol ¼ 30/1, flow rate: 0.2 mLminꢁ1, room temperature, UV detec-
tor: l ¼ 254 nm. Microanalyses should be included whenever
possible. Under appropriate circumstances, high-resolution mass
spectra may serve in lieu of microanalysis, if accompanied by
suitable NMR criteria for sample homogeneity.
CDCl3)
d
7.46e7.40 (m, 5H), 4.13e4.09 (m, 2H), 3.82 (d, J ¼ 5.3 Hz,
1H), 2.20e2.10 (m, 2H), 1.73e1.60 (m, 8H); 13C NMR (125 MHz,
CDCl3)
d 167.80, 137.29, 129.88, 128.78, 126.04, 95.62, 66.56, 57.35,
29.44, 26.82, 23.41, 14.04; HRMS (FAB) calcd for (M þ H)þ
C15H18N2O2: 259.1441, found 259.1426.
4.4.17. N-(2-Phenyl)benzoyl-2,2,5-triimethyl-4-
oxazolidinepropanenitrile (8)
0.060 g, 44% in the case of 10 mM of 2A or 0.098 g, 70% in the
case of 20 mM of 2A or 0.110 g, 78% in the case of 30 mM of 2A
(using hexane/EtOAc ¼ 10:1 as the eluent), white solid; m.p.
94e93 ꢀC; IR (KBr, cmꢁ1) 3059, 2247, 1633; 1H NMR (500 MHz,
CDCl3)
d
7.60e7.36 (m, 9H), 3.79e3.75 (m, 1H), 2.98e2.96 (m, 1H),
Acknowledgments
1.97e1.95 (m, 1H), 1.89e1.87 (m, 1H), 1.74e1.63 (m, 1H), 1.60e1.54
(m, 6H), 1.48e1.44 (m, 1H), 0.41 (d, J ¼ 6.3 Hz, 3H); 13C NMR
This work was partially supported by the Japan Society for the
Promotion of Science (JSPS), Grant-in-Aid no. 17K05779, for scien-
tific research.
(125 MHz, CDCl3)
d 168.26, 139.61, 137.60, 136.26, 130.33, 130.13,
129.29, 128.96, 128.35, 128.27, 127.85, 117.77, 96.03, 62.14, 29.82,

8
Y. Ozaki et al. / Tetrahedron 75 (2019) 130493
(c) Y. Yoshimi, S. Washida, Y. Okita, K. Nishikawa, K. Maeda, S. Hayashi,
Appendix A. Supplementary data
T. Morita, Tetrahedron Lett. 54 (2013) 4324e4326;
(d) L. Chu, C. Ohta, Z. Zuo, D.W.C. MacMillan, J. Am. Chem. Soc. 136 (2014)
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Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2019.130493.
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