Asymmetric synthesis of 4-aryl dihydroisoquinolin-3-ones and 2-aryl morpholin-3-ones using AgOTf-activated α-bromo arylacetate

Article abstract of DOI:10.1016/j.tet.2019.130841

A novel asymmetric synthetic strategy to prepare 4-aryl-dihydroisoquinolinones has been developed through a highly regioselective Friedel-Crafts alkylation of benzylamine derivatives with (αR)-α-bromo arylacetates and subsequent facile lactamization. In a

Full text of DOI:10.1016/j.tet.2019.130841

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Asymmetric synthesis of 4-aryl dihydroisoquinolin-3-ones and 2-aryl morpholin-3-ones
using AgOTf-activated α-bromo arylacetate
Su Kyung Hong, Wongi Park, Yong Sun Park
PII:
S0040-4020(19)31249-9
https://doi.org/10.1016/j.tet.2019.130841
TET 130841
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 November 2019
Revised Date: 26 November 2019
Accepted Date: 28 November 2019
Please cite this article as: Hong SK, Park W, Park YS, Asymmetric synthesis of 4-aryl
dihydroisoquinolin-3-ones and 2-aryl morpholin-3-ones using AgOTf-activated α-bromo arylacetate,
Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.130841.
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Table of Contents Graphic
Asymmetric Synthesis of 4-Aryl Dihydroisoquinolin-3-ones and 2-Aryl Morpholin-3-ones using AgOTf-
activated α-Bromo Arylacetate
Su Kyung Hong, Wongi Park and Yong Sun Park*

Asymmetric Synthesis of 4-Aryl Dihydroisoquinolin-3-ones and 2-Aryl
Morpholin-3-ones using AgOTf-activated α-Bromo Arylacetate
Su Kyung Hong, Wongi Park and Yong Sun Park*
Department of Chemistry, Konkuk University, Seoul, Korea
E-mail: parkyong@konkuk.ac.kr
Abstract:
A
novel asymmetric synthetic strategy to prepare 4-aryl-
dihydroisoquinolinones has been developed through a highly regioselective Friedel-
Crafts alkylation of benzylamine derivatives with (αR)-α-bromo arylacetates and
subsequent facile lactamization. In addition, an efficient asymmetric synthesis of 2-
aryl morpholinones is demonstrated with 2-aminoethanol derivatives using the
same convenient substitution-lactamization protocol.
1

1. Introduction
Tetrahydroisoquinolines constitute a broad class of frameworks in biologically active materials.1 In
particular, 4-aryl substituted tetrahydroisoquinolines attract substantial attention due to their potent
neuropharmacological activities.1c,1d Some notable examples of this class of compounds include
nomifensine, dichlofensine, latifine and cherylline.2 Despite their enantioselective pharmacological
activities, the studies on the asymmetric synthesis of 4-aryl tetrahydroisoquinolines have been
sparsely reported in the literature.3 The asymmetric synthetic methods used include the
stereoselective protonation of lactam enolates,3a,3b Friedel–Crafts alkylation3c,3d and Suzuki coupling
of aryl boronic acid.3e Although these methods are generally reliable, the efficient stereocontrol of
the gem-diarylmethine C(4)-stereogenic center remains challenging in asymmetric synthesis. In this
paper, we present the highly regioselective arene C-H bond functionalization of benzylamine
derivatives with configurationally labile α-bromo arylacetates for the asymmetric synthesis of 4-aryl-
1,4-dihydroisoquinolin-3(2H)-ones, which could be easily reduced to provide the corresponding 4-
aryl-tetrahydroisoquinoline. In addition, we have investigated the reactions of arene nucleophiles
bearing a competing alcohol nucleophile and the related reactions of α-bromo phenylacetate with 2-
aminoethanol-derived nucleophiles were presented for the asymmetric synthesis of 2-aryl-
morpholin-3-one derivatives.
Figure 1. Retrosynthetic analysis for asymmetric preparation of 4-aryl-dihydroisoquinolinones.
Our new strategy to construct the enantioenriched 4-aryl substituted dihydroisoquinolinone
is based on the regioselective Friedel-Crafts alkylation at the ortho-position of benzylamine
derivatives with α-bromo arylacetates, followed by lactamization after deprotection as shown in
Figure 1. We previously reported that highly diastereoenriched (αR)-α-bromo arylacetates (>99:1 dr)
were obtained as a solid through crystallization induced dynamic resolution (CIDR) using N-
benzoyl-L-threonine isopropyl ester and then developed as generally useful optically pure
2

electrophiles in various substitution reactions.4a-d For the substitution to be of asymmetric synthetic
value, the substitution should occur fast with respect to the epimerization of (αR)-α-bromo
arylacetate under the reaction conditions. Therefore, the use of highly reactive benzylamine
derivatives bearing electron donating substituents on the arene group is necessary for the efficient
preparation of highly enantioenriched dihydroisoquinolinones.4c In addition, due to the existence of a
potentially unstable diaryl substituted stereocenter of products, the use of mild reaction conditions is
needed for both the alkylation and the lactamization reactions.4e
A major challenge involved in the Friedel-Crafts alkylation of the benzylamine derivative is
the control of the regioselectivity for the reaction at one of multiple arene C–H bonds. When two
electron-donating substituents are already present, they may have cooperating or conflicting directing
effects on the third substitution. For the desired lactamization depicted in Figure 1, highly
regioselective C-H functionalization at the ortho-position to the aminomethyl substituent is required
to minimize waste production and enhance synthetic efficiency. Installing a carbonyl protecting
group on the aminomethyl substituent could be one solution for directing the alkylation at ortho-
position. Based on our previous studies investigating the reactions of α-bromo arylacetates, we
envisaged that the efficient asymmetric synthesis of 4-aryl-dihydroisoquinolinone would be possible
through the regioselective Friedel-Crafts alkylation of meta-electron donating group substituted N-
Boc-benzylamines in the presence of AgOTf and with subsequent N-Boc deprotection and
lactamization under mild conditions.
2. Results and Discussion
In our initial model studies with 3-methylanisole, which has two activating substituents, the Friedel-
Crafts alkylation with (R)-α-bromo phenylacetate (1a) in the presence of AgOTf (1.0 equiv) in
CHCl3 successfully afforded the desired product 2 in 95% yield with 90:10 dr (diastereomeric ratio)
after 3 h. However, as shown in Scheme 1, the reaction produced two regioisomers in a
regioisomeric ratio (rr) of 74:26.5 The structure of major regioisomer 2 was confirmed after the
conversion to N-benzyl-2-(4-methoxy-2-methylphenyl)-2-phenylacetamide by the comparison of H-
NMR with the authentic compound.3e A strongly activating methoxy substituent is the major director
over a weakly activating methyl substituent. Under the same conditions, the reaction of 4-
methylanisole does not afford the substitution product. The results indicate that the presence of a
strong electron-donating group at the meta-position of benzylamine is necessary for our strategy to
build a dihydroisoquinolinone scaffold and the inherent low regioselectivity can be a potent problem
hindering the development of practical synthetic methods.
3

Ph
AgOTf
Ph
+
Br
CO2R*
MeO
CH2X
1a
Ph
CO2R*
NHBoc
CO2R*
CH3
MeO
MeO
3
2
91%, 99:1 rr, 96:4 dr
95%, 74:26 rr, 90:10 dr
Ph
Ph
CO2R*
OAc
CO2R*
O
CH3
MeO
MeO
4
5
80%, 99:1 rr, 99:1 dr
87%, 80:20 rr, 92:8 dr
Scheme 1. Regioselective Friedel-Crafts alkylation with (αR)-α-bromo phenylacetate
Encouraged by recent reports of the highly ortho-selective C-H functionalization of
benzylamine derivatives by employing a directing group,6 we next examined whether incorporating
the N-Boc aminomethyl group into the arene nucleophile can affect the regioselectivity. When N-Boc
3-methoxybenzylamine was treated with (αR)-1a and AgOTf for 3 h, we observed that the ortho-
alkylated regioisomer 3 was exclusively isolated in 91% yield with a higher dr of 96:4, as was
desired. Further, we investigated whether installing the O-Ac hydroxyl group helped in directing
reactions toward an ortho-substituted product. Interesting high regioselectivity was also observed in
the reaction of O-acetyl 3-methoxybenzylalcohol under the same conditions to afford 4 exclusively
with 99:1 dr. In order to understand the possible role of the carbonyl groups in N-Boc and O-Ac
protection, we conducted the reaction of 3-methoxybenzyl ethyl ether with no carbonyl group under
the same conditions and obtained the substitution product 5 with a regioisomeric ratio (rr) of 80:20
with 92:8 dr. Although the origin of the high regioselectivity in the syntheses of 3 and 4 currently
remains unclear, the coordination of the N-Boc or O-Ac directing group to the silver ion may be
crucial in bringing the Lewis acid catalyst in proximity to the ortho C-H bond to activate, therefore,
ensuring high levels of regioselectivity and stereoselectivity.6
4

Ar
1. AgOTf
X
+
NHBoc
Br
CO2R*
2. TFA
3. Et3N
1a (Ar = Ph)
1b (Ar = p-BrC6H4)
1c (Ar = p-ClC6H4)
Ph
Ph
MeO
MeO
O
O
NH
85%, 97:3 er
NH
MeO
7
6
79%, 96:4 er
C6H4-p-Br
OMe Ph
MeO
MeO
O
O
NH
NH
MeO
9
8
72%, 95:5 er
69%, 97:3 er
C6H4-p-Cl
MeO
MeO
O
NH
10
89%, 94:6 er
Scheme 2. Substitution-lactamization protocol for asymmetric synthesis of 4-aryl-
dihydroisoquinolinones
Following simple N-Boc deprotection with trifluoroacetic acid (TFA), intramolecular
lactamization to remove the chiral auxiliary was successfully completed within 1 h in the presence of
Et3N to ultimately afford (R)-dihydroisoquinolinone 6 in 89% yield with 96:4 er.7 We next examined
a simple procedure that does not involve purification of the substitution product 3 and instead uses
the crude material in the following lactamization step. After the reaction mixture was rapidly filtered
through silica gel, subjecting the crude mixture to the deprotection and cyclization afforded
dihydroisoquinolinone 6 in a comparable overall yield of 79% as shown in Scheme 2. Using the
optimized substitution-lactamization protocol, the reactions of two 3-methoxybenzylamine
derivatives with two different α-bromo arylacetates 1b and 1c were carried out to examine the effect
of changing the substituents on the two aromatic rings of reactants. The reactions of (αR)-1a with N-
Boc-3,4-dimethoxybenzylamine
and
N-Boc-3,5-dimethoxybenzylamine
produced
dihydroisoquinolinones 7 and 8, respectively, with a slightly higher er of 97:3. In addition,
dihydroisoquinolinones 9 and 10 were obtained with 95:5 er and 94:6 er from the reactions of N-
5

Boc-3,4-dimethoxybenzylamine with 4-bromoaryl substituted α-bromoacetate 1b and 4-chloroaryl
substituted α-bromoacetate 1c, respectively. The results indicate that the variations of the substituents
of the two aryl groups of reactants did not significantly influence the er of 4-aryl-
dihydroisoquinolinones.
Boc
N
Ph
1. AgOTf
X
+
R
Br
CO2R*
2. TFA
3. Et3N
1a
Ph
Ph
O
O
N
Ph
N
MeO
MeO
11
12
51%, 91:9 er
61%, 90:10 er
Ph
O
Ph
MeO
MeO
O
N
N
MeO
CH3
14
13
61%, 96:4 er
54%, 90:10 er
Ph
Ph
MeO
O
MeO
MeO
O
N
N
Ph
MeO
MeO
CH3
16
15
63%, 96:4 er
58%, 94:6 er
OMe Ph
Ph
O
MeO
MeO
O
N
N
CH3
18
42%, 96:4 er
17
48%, 92:8 er
Scheme 3. Asymmetric Synthesis of N-alkyl substituted 4-aryl-dihydroisoquinolinones.
The scope of the substitution-lactamization protocol was further extended to the synthesis of
various N-substituted dihydroisoquinolinones as shown in Scheme 3. The reactions of (αR)-1a with
N-allyl,
N-benzyl
or
N-methyl
substituted
N-Boc
3-methoxybenzylamine
gave
dihydroisoquinolinones 11, 12 and 13, respectively, in 61-51% yields with ers of 91:9 and 90:10. The
reactions were somewhat slower most likely due to the steric effect of the N-alkyl groups than the
reactions of nucleophiles bearing no N-substituent shown in Scheme 2 and consequently showed
6

lower yields and ers of 11-13 under the same conditions. The diminished ers indicate that the
substitution was not sufficiently fast in terms of the epimerization, and the competitive epimerization
of (αR)-1a led to a slight reduction of enantioselectivities. When N-substituted nucleophiles are
activated with two methoxy groups, the same protocol provided improved ers of products. The
reactions of (αR)-1a with N-allyl, N-benzyl, N-methyl or N-n-propyl substituted N-Boc-3,4-
dimethoxybenzylamine gave dihydroisoquinolinones 14, 15, 16 and 17 with 96:4 er, 94:6 er, 96:4 er
and 92:8 er, respectively. The protocol was readily extended to N-allyl substituted N-Boc-3,5-
dimethoxybenzylamine to give dihydroisoquinolinone 18 in 48% yield with 96:4 er. This synthetic
strategy enables the convenient preparation of highly enantioenriched N-alkyl substituted 4-phenyl-
dihydroisoquinolinones.
In a recent study, we reported that alcohols can be used as a nucleophile for the substitution
of α-bromo arylacetates in the presence of Lewis acid.4d With the substitution-lactamization protocol
investigated for 3-methoxybenzylamine derivatives, we were curious to know the competing
reactivity of alcohol nucleophiles towards C–O bond forming reactions. As shown in in Scheme 4,
compounds bearing two competing nucleophiles i.e. arene and alcohol were examined. The
substitution-lactamization with N-Boc-N-(3-methoxybenzyl)-2-aminoethanol (19a) gave two
products 20a and 20b in a ratio of 75:25. Morpholinone 20a was produced in 45% yield with 94:6 er,
while dihydroisoquinolinone 20b was produced in 17% yield with 91:9 er. The electrophile, α-bromo
phenylacetate, was preferentially attacked by the alcohol nucleophile and underwent subsequent
lactamization after removing Boc protection to give 2-phenyl-morpholin-3-one 20a as a major
product. The observed chemoselectivity between two different reactive functional groups in a
nucleophile is based on the innate reactivities of two competing nucleophiles. In this case, the
presence of the additional electron-donating methoxy group on the arene was sufficient to ensure the
differentiation of two nucleophiles, and therefore switch chemoselectivity. The reaction of N-Boc-N-
(3,4-dimethoxybenzyl)-2-aminoethanol (19b) gave dihydroisoquinolinone 21 exclusively in 71%
yield with 92:8 er. In addition, the reaction of 3-methoxybenzylalcohol was carried out to examine
the competing reactivities between the arene and benzylic alcohol. Under the same conditions, the
reaction produced racemic 4-phenyl-isochromanone 22 in 83% yield through the Friedel-Crafts
reaction and spontaneous cyclization to give the lactone.8 Due to the poor nucleophility of benzylic
alcohol,9 the substitution occurred preferentially with the arene nucleophile. By sharp contrast, the
reaction of (αR)-1a with N-Boc-N-benzyl-2-aminoethanol (19c) exclusively produced morpholin-3-
one 23 in 76% yield with 96:4 er as shown in Scheme 5. The substitution with the aliphatic alcohol is
substantially faster than that with arene nucleophile bearing no strongly activating substituents. The
7

results shown in Scheme 4 and 5 indicate that the substitution of α-bromo arylacetate with the
nucleophile bearing two competing nucleophilic functional groups offers strategies for the
asymmetric synthesis of two different chiral lactams, dihydroisoquinolinone and morpholinone,
switching chemoselectivity within the similar precursors.
Scheme 4. Chemoselective reactions of two competing nucleophiles
The related asymmetric synthesis of 2-phenyl morpholin-3-one was achieved using the
substitution-lactamization of (αR)-1a with N-Boc-2-aminoethanol (19d) to give 24 in 70% yield with
96:4 er as shown in Scheme 5. Given the prevalence and importance of highly substituted
morpholinones,10 we applied the synthetic protocol to the asymmetric preparation of 2,5-
disubstituted morpholinones using 2-alkyl-2-aminoethanols 19e-i as nucleophiles. The substitutions
of (αR)-1a with L-phenylalanine, L-leucine, L-valine or L-alanine-derived N-Boc-2-aminoethanol
(19e, 19f, 19g or 19h) and subsequent lactamization respectively afforded cis-2,5-disubstituted
morpholinones 25, 26, 27 and 28 in good yields with 99:1 dr. Compared to the substitution for the
preparation of 24, a much higher stereoselectivity of 99:1 dr was observed in the substitution with N-
8

Boc-2-(S)-alkyl-2-aminoethanols 19e-h under the same reaction conditions. No stereo-differentiation
was observed in the reaction with D-alanine-derived N-Boc-2-(R)-methyl-2-aminoethanol (19i).
Using the same protocol, trans-5-methyl-2-phenyl-morpholin-3-one 29 was obtained in 88% yield
with 99:1 dr. The relative configurations of 28 and 29 were confirmed by the comparison of H-NMR
with the authentic compound after the reduction to the corresponding morpholines.11
Scheme 5. Substitution-lactamization for the synthesis of 2-aryl-morpholinones
3. Conclusions
We report
a
novel asymmetric synthetic method for two chiral lactams, 4-aryl-
dihydroisoquinolinones and 2-aryl-morpholinones, which has been rarely reported in the literature.
The synthetic strategy for 4-aryl-dihydroisoquinolinones has been developed through the Friedel-
Crafts alkylation of N-Boc-benzylamine derivatives with α-bromo arylacetates and subsequent facile
lactamization. The highly regioselective and fast alkylation at the ortho-C-H bond of 3-
methoxybenzylamine derivatives and the convenient lactamization under mild reaction conditions
9

are crucial factors to achieve the observed excellent product yields and stereoselectivities. In addition,
the convenient substitution-lactamization protocol was also useful for the preparation of highly
enantioenriched 2-aryl-morpholinones with N-Boc-2-aminoethanol derivatives. Notably, to our
knowledge, we have presented the first general asymmetric synthetic method for 2-aryl-morpholin-3-
ones. Furthermore, we simply demonstrate that the substitution of α-bromo arylacetate with the
nucleophile bearing two competing nucleophilic functional groups, i.e. arene and alcohol, can offer
strategies for the asymmetric synthesis of the two different lactams, switching chemoselectivity
within the similar precursors. Considering the importance of the dihydroisoquinolinones and
morpholinones in various ranges of biologically active substances, this operationally simple
methodology should be useful for a number of applications in a variety of fields.
4. Experimental
General Methods: All reactions were performed in oven-dried glassware under nitrogen atmosphere.
All chemicals were obtained from commercial sources and were used as received. Analytical thin
layer chromatography (TLC) was performed on silica gel plates with QF-254 indicator and TLC
visualization was carried out with UV-light. Flash column chromatography was performed with 230–
1
13
1
400 mesh silica gel. H and C NMR spectra were acquired on Bruker (400 MHz H, 100.6 MHz
13C) spectrometer using chloroform-d (CDCl3) as the internal standard. Chemical shifts (δ) are
1
13
reported in ppm relative to chloroform-d (7.26 ppm H, 77.07 ppm C). Multiplicities are indicated
by: s (singlet), d (doublet), t (triplet), q (quartet) and br (broad). Coupling constants (J) are reported
in Hz.
I. General Procedure for the asymmetric preparation of dihydroisoquinolinones 6-21: To a
solution of L-threonine-derived α-bromo ester 1a-c (1.0 equiv, >99:1 dr) at room temperature were
added AgOTf (1.2 equiv) and benzylamine nucleophile (10 equiv). After the mixture was stirred at rt
for 3 h in the least possible amount of solvent, CHCl3, the resulting mixture was filtered through
silica gel, and concentrated under reduced pressure. The crude material was stirred in 50%
trifluoroacetic acid/CH2Cl2 at room temperature for 1 h, washed with saturated NaHCO3 solution,
dried with anhydrous MgSO4, and concentrated under reduced pressure. After the mixture was
treated with Et3N (2 equiv) in CH2Cl2 for 1 h and concentrated under reduced pressure, the
chromatographic separation of the mixture on silica gel afforded a highly enantioenriched
dihydroisoquinolinone (6-21). The ers of products were determined by CSP-HPLC.
1
7-Methoxy-4-phenyl-1,4-dihydroisoquinolin-3-one (6): 79% yield; H NMR (CDCl3, 400 MHz)
7.29-7.22 (m, 4H), 7.17-7.15 (m, 2H), 7.03-7.01 (m, 1H), 6.84-6.82 (m, 1H), 6.74-6.73 (m, 1H), 4.75
10

(s, 1H), 4.51 (d, J = 16.0 Hz, 1H), 4.31 (dd, J = 16.0 and 4.0 Hz, 1H), 3.81 (s, 3H); 13C NMR (CDCl3,
100 MHz) 173.2, 158.7, 139.0, 132.8, 129.9, 128.7, 128.0, 127.3, 127.2, 113.8, 110.6, 55.4, 51.7,
45.2. The spectral data were identical to those of the authentic material reported previously.12a HPLC:
96:4 er, tR (R)-major enantiomer, 18.4 min; tR (S)-minor enantiomer, 23.8 min (Chiralcel OJ-H
column; 40% 2-propanol in hexane; 0.5 mL/min).
6,7-Dimethoxy-4-phenyl-1,4-dihydroisoquinolin-3-one (7) 85% yield; 1H NMR (CDCl3, 400 MHz)
7.91 (br, 1H), 7.29-7.16 (m, 5H), 6.78 (s, 1H), 6.55 (s, 1H), 4.69 (s, 1H), 4.50 (d, J = 16.0 Hz, 1H),
13
4.31 (dd, J = 16.0 and 4.0 Hz, 1H), 3.89 (s, 3H), 3.78 (s, 3H); C NMR (CDCl3, 100 MHz) 173.0,
148.7, 148.2, 139.3, 128.7, 128.0, 127.2, 127.0, 123.5, 111.1, 108.2, 56.0, 55.0, 51.8, 44.8; HRMS:
calcd. for C17H18NO3 [M++1] 284.1287; found 284.1285; Chiral HPLC: 97:3 er, tR (R)-major
enantiomer, 21.7 min; tR (S)-minor enantiomer, 16.5 min (Chiralcel OJ-H column; 40% 2-propanol in
hexane; 0.5 mL/min).
5,7-Dimethoxy-4-phenyl-1,4-dihydroisoquinolin-3-one (8) 69% yield; 1H NMR (CDCl3, 400 MHz)
7.66 (br, 1H), 7.25-7.15 (m, 5H), 6.38 (d, J = 2.4 Hz, 1H), 6.32 (d, J = 2.4 Hz, 1H), 5.02 (s, 1H), 4.51
(d, J = 16.0 Hz, 1H), 4.24 (dd, J = 16.0 and 4.4 Hz, 1H), 3.81 (s, 3H), 3.69 (s, 3H); 13C NMR (CDCl3,
100 MHz) 173.6, 160.0, 157.7, 138.8, 133.8, 128.5, 127.6, 126.9, 116.4, 101.3, 97.6, 55.6, 55.5, 46.1,
45.3; HRMS: calcd. for C17H18NO3 [M++1] 284.1287; found 284.1289; Chiral HPLC: 97:3 er, tR (R)-
major enantiomer, 76.0 min; tR (S)-minor enantiomer, 57.8 min (Chiralcel OD column; 40% 2-
propanol in hexane; 0.5 mL/min).
6,7-Dimethoxy-4-(4-bromophenyl)-1,4-dihydroisoquinolin-3-one (9) 72% yield; 1H NMR (CDCl3,
400 MHz) 7.40 (d, J = 8.8 Hz, 1H), 7.21 (br, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.70 (s, 1H), 6.51 (s, 1H),
4.66 (s, 1H), 4.51 (d, J = 16.0 Hz, 1H), 4.35 (dd, J = 16.0 and 3.6 Hz, 1H), 3.90 (s, 3H), 3.79 (s, 3H);
13C NMR (CDCl3, 100 MHz) 172.1, 148.9, 148.4, 138.2, 131.8, 129.8, 126.3, 123.2, 121.4, 111.1,
108.2, 56.1, 56.0, 51.1, 44.9; HRMS: calcd. for C17H17BrNO3 [M++1] 362.0392; found 362.0389;
Chiral HPLC: 95:5 er, tR (R)-major enantiomer, 19.4 min; tR (S)-minor enantiomer, 17.1 min
(Chiralcel OJ-H column; 40% 2-propanol in hexane; 0.5 mL/min).
6,7-Dimethoxy-4-(4-chlorophenyl)-1,4-dihydroisoquinolin-3-one (10) 89% yield; 1H NMR
(CDCl3, 400 MHz) 7.59 (br, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.69 (s, 1H),
6.51 (s, 1H), 4.67 (s, 1H), 4.50 (d, J = 15.6 Hz, 1H), 4.34 (dd, J = 15.6 and 3.6 Hz, 1H), 3.90 (s, 3H),
3.79 (s, 3H); 13C NMR (CDCl3, 100 MHz) 172.5, 148.9, 148.4, 137.7, 133.2, 129.5, 128.8, 126.3,
123.3, 111.1, 108.3, 56.1, 56.0, 51.0, 44.8; HRMS: calcd. for C17H17ClNO3 [M++1] 318.0897; found
318.0899; Chiral HPLC: 94:6 er, tR (R)-major enantiomer, 17.5 min; tR (S)-minor enantiomer, 15.0
min (Chiralcel OJ-H column; 40% 2-propanol in hexane; 0.5 mL/min).
11

1
2-Allyl-7-methoxy-4-phenyl-1,4-dihydroisoquinolin-3-one (11) 51% yield; H NMR (CDCl3, 400
MHz) 7.26-7.05 (m, 6H), 6.87-6.84 (m, 1H), 6.76-6.75 (m, 1H), 5.78-5.68 (m, 1H), 5.16-5.06 (m,
2H), 4.85 (s, 1H), 4.48 (d, J = 16.0 Hz, 1H), 4.23-4.17 (m, 2H), 4.03 (dd, J = 15.6 and 6.0 Hz, 1H),
3.82 (s, 3H); 13C NMR (CDCl3, 100 MHz) 170.1, 158.7, 138.9, 133.1, 132.4, 129.6, 128.6, 127.8,
127.7, 127.1, 117.7, 113.8, 110.6, 55.4, 52.3, 49.8, 49.4; HRMS: calcd. for C19H20NO2 [M++1]
294.1494; found 294.1494; Chiral HPLC: 91:9 er, tR (R)-major enantiomer, 17.8 min; tR (S)-minor
enantiomer, 23.6 min (Chiralcel OJ-H column; 40% 2-propanol in hexane; 0.5 mL/min).
1
2-Benzyl-7-methoxy-4-phenyl-1,4-dihydroisoquinolin-3-one (12): 61% yield; H NMR (CDCl3,
400 MHz) 7.19-7.08 (m, 10H), 7.03-7.00 (m, 1H), 6.88-6.80 (m, 1H), 6.62 (s, 1H), 4.94 (s, 1H), 4.76
13
(d, J = 2.8 Hz, 1H), 4.45 (d, J = 16.0 Hz, 1H), 4.17 (d, J = 16.0 Hz, 1H), 3.83 (s, 3H); C NMR
(CDCl3, 100 MHz) 170.4, 158.7, 139.1, 136.7, 132.9, 129.6, 128.7, 128.6, 127.9, 127.8, 127.5, 127.4,
127.2, 113.9, 110.5, 55.4, 52.3, 50.2, 50.0. The spectral data were identical to those of the authentic
material reported previously.3d Chiral HPLC: 90:10 er, tR (R)-major enantiomer, 25.1 min; tR (S)-
minor enantiomer, 36.4 min (Chiralcel OJ-H column; 40% 2-propanol in hexane; 0.5 mL/min).
1
7-Methoxy-2-methyl-4-phenyl-1,4-dihydroisoquinolin-3-one (13) 54% yield; H NMR (CDCl3,
400 MHz) 7.27-7.11 (m, 5H), 7.04-7.02 (m, 1H), 6.86-6.76 (m, 1H), 6.75 (s, 1H), 4.81 (s, 1H), 4.61
13
(d, J = 16.0 Hz, 1H), 4.26 (d, J = 16.0 Hz, 1H), 3.82 (s, 3H), 3.07 (s, 3H); C NMR (CDCl3, 100
MHz) 170.2, 158.6, 139.4, 132.6, 129.6, 128.6, 127.9, 127.7, 127.1, 113.9, 110.4, 55.4, 52.6, 51.9,
34.9; HRMS: calcd. for C17H18NO2 [M++1] 268.1338; found 268.1339; Chiral HPLC: 90:10 er, tR
(R)-major enantiomer, 22.1 min; tR (S)-minor enantiomer, 25.3 min (Chiralcel OJ-H column; 40% 2-
propanol in hexane; 0.5 mL/min).
1
2-Allyl-6,7-dimethoxy-4-phenyl-1,4-dihydroisoquinolin-3-one (14) 61% yield; H NMR (CDCl3,
400 MHz) 7.29-7.14 (m, 5H), 6.72 (s, 1H), 6.60 (s, 1H), 5.78-5.69 (m, 1H), 5.16-5.07 (m, 2H), 4.81
(s, 1H), 4.49 (d, J = 15.6 Hz, 1H), 4.24-4.17 (m, 2H), 4.01 (dd, J = 15.6 and 6.0 Hz, 1H), 3.90 (s,
3H), 3.81 (s, 3H); 13C NMR (CDCl3, 100 MHz) 169.7, 148.9, 148.2, 139.1, 132.5, 128.6, 127.8,
127.4, 127.2, 123.7, 117.6, 111.0, 108.2, 56.1, 56.0, 52.5, 49.5, 49.4; HRMS: calcd. for C20H22NO3
[M++1] 324.1600; found 324.1604; Chiral HPLC: 96:4 er, tR (R)-major enantiomer, 21.0 min; tR (S)-
minor enantiomer, 18.4 min (Chiralcel OJ-H column; 40% 2-propanol in hexane; 0.5 mL/min).
2-Benzyl-6,7-dimethoxy-4-phenyl-1,4-dihydroisoquinolin-3-one (15) 58% yield; 1H NMR (CDCl3,
400 MHz) 7.30-7.12 (m, 10H), 6.62 (s, 1H), 6.60 (s, 1H), 4.89 (s, 1H), 4.75 (d, J = 15.2 Hz, 1H),
4.65 (d, J = 15.2 Hz, 1H), 4.43 (d, J = 15.6 Hz, 1H), 4.16 (d, J = 15.6 Hz, 1H), 3.85 (s, 3H), 3.80 (s,
3H); 13C NMR (CDCl3, 100 MHz) 170.0, 148.9, 148.2, 139.2, 136.7, 128.7, 127.9, 127.8, 127.5,
127.2, 123.5, 110.9, 108.1, 56.0, 52.5, 50.2, 49.6; HRMS: calcd. for C24H24NO3 [M++1] 374.1756;
12

found 374.1755; Chiral HPLC: 94:6 er, tR (R)-major enantiomer, 36.1 min; tR (S)-minor enantiomer,
28.1 min (Chiralcel OJ-H column; 40% 2-propanol in hexane; 0.5 mL/min).
6,7-Dimethoxy-2-methyl-4-phenyl-1,4-dihydroisoquinolin-3-one (16): 63% yield; 1H NMR
(CDCl3, 400 MHz) 7.29-7.14 (m, 5H), 6.72 (s, 1H), 6.57 (s, 1H), 4.77 (s, 1H), 4.62 (d, J = 15.6 Hz,
1H), 4.26 (d, J = 15.6 Hz, 1H), 3.90 (s, 3H), 3.79 (s, 3H), 3.07 (s, 3H); 13C NMR (CDCl3, 100 MHz)
169.8, 148.9, 148.2, 139.5, 128.6, 127.9, 127.4, 127.1, 123.3, 110.9, 108.0, 56.1, 56,0, 52.3, 52.1,
34.9. The spectral data were identical to those of the authentic material reported previously.12c Chiral
HPLC: 96:4 er, tR (R)-major enantiomer, 21.4 min; tR (S)-minor enantiomer, 19.7 min (Chiralcel OJ-
H column; 40% 2-propanol in hexane; 0.5 mL/min).
6,7-Dimethoxy-4-phenyl-2-propyl-1,4-dihydroisoquinolin-3-one (17) 48% yield; 1H NMR (CDCl3,
400 MHz) 7.28-7.13 (m, 5H), 6.74 (s, 1H), 6.61 (s, 1H), 4.79 (s, 1H), 4.53 (d, J = 15.6 Hz, 1H), 4.20
(d, J = 15.6 Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 3.55-3.48 (m, 1H), 3.40-3.33 (m, 1H), 1.62-1.52 (m,
2H), 0.83 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) 169.8, 148.9, 148.2, 139.0, 128.6, 127.7,
127.6, 127.1, 124.0, 111.0, 108.2, 56.1, 56.0, 52.7, 50.2, 48.9, 20.5, 11.1; HRMS: calcd. for
C20H24NO3 [M++1] 326.1756; found 326.1756; Chiral HPLC: 92:8 er, tR (R)-major enantiomer, 16.0
min; tR (S)-minor enantiomer, 13.8 min (Chiralcel OJ-H column; 40% 2-propanol in hexane; 0.5
mL/min).
1
2-Allyl-5,7-dimethoxy-4-phenyl-1,4-dihydroisoquinolin-3-one (18) 42% yield; H NMR (CDCl3,
400 MHz) 7.30-7.14 (m, 5H), 6.72 (s, 1H), 6.60 (s, 1H), 5.79-5.69 (m, 1H), 5.17-5.07 (m, 2H), 4.82
(s, 1H), 4.49 (d, J = 15.6 Hz, 1H), 4.24-4.19 (m, 2H), 4.01 (dd, J = 15.6 and 6.0 Hz, 1H), 3.90 (s,
3H), 3.81 (s, 3H); 13C NMR (CDCl3, 100 MHz) 169.7, 148.9, 148.2, 139.1, 132.5, 128.6, 127.8,
127.4, 127.2, 123.7, 117.6, 111.0, 108.2, 56.1, 56.0, 52.5, 49.5, 49.4; HRMS: calcd. for C20H22NO3
[M++1] 324.1600; found 324.1603; Chiral HPLC: 96:4 er, tR (R)-major enantiomer, 18.7 min; tR (S)-
minor enantiomer, 16.8 min (Chiralcel OJ-H column; 40% 2-propanol in hexane; 0.5 mL/min).
2-(2-Hydroxyethyl)-7-methoxy-4-phenyl-1,4-dihydroisoquinolin-3-one (20b) 17% yield; 1H
NMR (CDCl3, 400 MHz) 7.29-7.13 (m, 5H), 7.06 (d, J = 8.4 Hz, 1H), 6.87-8.85 (m, 1H), 6.77 (d, J =
2.4 Hz, 1H), 4.85 (s, 1H), 4.67 (d, J = 16.0 Hz, 1H), 4.39 (d, J = 16.0 Hz, 1H), 3.84 (s, 3H), 3.83-
13
3.59 (m, 4H); C NMR (CDCl3, 100 MHz) 172.1, 158.7, 138.8, 132.8, 129.6, 128.7, 127.8, 127.4,
127.2, 113.9, 110.5, 61.8, 55.4, 52.4, 52.2, 51.2; HRMS: calcd. for C18H20NO3 [M++1] 298.1443;
found 298.1441; Chiral HPLC: 91:9 er, tR (R)-major enantiomer, 18.1 min; tR (S)-minor enantiomer,
23.9 min (Chiralpak AD-H column; 40% 2-propanol in hexane; 0.5 mL/min).
1
6,7-Dimethoxy-2-(2-Hydroxyethyl)-4-phenyl-1,4-dihydroisoquinolin-3-one (21) 71% yield; H
NMR (CDCl3, 400 MHz) 7.30-7.14 (m, 5H), 6.72 (s, 1H), 6.58 (s, 1H), 4.80 (s, 1H), 4.68 (d, J = 15.6
13

Hz, 1H), 4.38 (dd, J = 15.6 Hz, 1H), 3.90 (s, 3H), 3.82-3.55 (m, 4H), 3.80 (s, 3H); 13C NMR (CDCl3,
100 MHz) 171.7, 149.0, 148.3, 139.0, 128.7, 127.8, 127.3, 127.2, 123.4, 110.9, 108.1, 61.6, 56.1,
56.0, 52.4, 52.0, 51.1; HRMS: calcd. for C19H22NO4 [M++1] 328.1549; found 328.1549; Chiral
HPLC: 92:8 er, tR (R)-major enantiomer, 21.0 min; tR (S)-minor enantiomer, 19.2 min (Chiralpak AD-
H column; 40% 2-propanol in hexane; 0.5 mL/min).
II. General Procedure for the asymmetric preparation of morpholinones 20a and 23-29: To a
solution of L-threonine-derived α-bromo ester 1a-c (1.0 equiv, >99:1 dr) at room temperature were
added AgOTf (1.2 equiv) and 2-aminoethanol nucleophile (10 equiv). After the mixture was stirred at
rt for 10 h in the least possible amount of solvent, CHCl3, the resulting mixture was filtered through
silica gel, and concentrated under reduced pressure. The crude material was stirred in 50%
trifluoroacetic acid/CH2Cl2 at room temperature for 1 h, washed with saturated NaHCO3 solution,
dried with anhydrous MgSO4, and concentrated under reduced pressure. After the mixture was
treated with Et3N (2 equiv) in CH2Cl2 (or ethanol) for 1 h and concentrated under reduced pressure,
the chromatographic separation of the mixture on silica gel afforded a highly enantioenriched
morpholinone (20a and 23-29). The ers of 20a, 23, and 24 were determined by CSP-HPLC. The drs
of 25-29 were determined by the 1H NMR integration of the hydrogens of the two diastereomers.
1
4-(3-Methoxybenzyl)-2-phenyl-morpholin-3-one (20a) 45% yield; H NMR (CDCl3, 400 MHz)
7.49-7.24 (m, 6H), 6.89-6.84 (m, 3H), 5.26 (s, 1H), 4.70 (d, J = 14.4 Hz, 1H), 4.59 (d, J = 14.4 Hz,
13
1H), 4.01-3.97 (m, 1H), 3.89-3.86 (m, 1H), 3.79 (s, 3H), 3.50-3.47 (m, 1H), 3.34-3.29 (m, 1H); C
NMR (CDCl3, 100 MHz) 167.6, 160.0, 137.9, 137.5, 129.8, 128.5, 128.4, 127.9, 120.6, 113.6, 113.4,
79.6, 61.8, 55.3, 49.9, 46.1; HRMS: calcd. for C18H20NO3 [M++1] 298.1443; found 298.1440; Chiral
HPLC: 94:6 er, tR (R)-major enantiomer, 53.1 min; tR (S)-minor enantiomer, 65.6 min (Chiralcel OJ-
H column; 40% 2-propanol in hexane; 0.5 mL/min).
4-Benzyl-2-phenyl-morpholin-3-one (23) 76% yield; 1H NMR (CDCl3, 400 MHz) 7.49-7.29 (m,
10H), 5.26 (s, 1H), 4.67 (s, 3H), 4.00-3.97 (m, 1H), 3.88-3.82 (m, 1H), 3.52-3.46 (m, 1H), 3.33-3.28
(m, 1H); 13C NMR (CDCl3, 100 MHz) 167.6, 137.4, 136.3, 128.8, 128.6, 128.5, 128.4, 128.3, 127.9,
127.8, 127.6, 79.7, 61.8, 50.0, 46.1. The spectral data were identical to those of the authentic material
reported previously.10b Chiral HPLC: 96:4 er, tR (R)-major enantiomer, 40.0 min; tR (S)-minor
enantiomer, 63.1 min (Chiralcel OJ-H column; 40% 2-propanol in hexane; 0.5 mL/min).
2-phenyl-morpholin-3-one (24) 70% yield; 1H NMR (CDCl3, 400 MHz) 7.47-7.34 (m, 5H), 7.06 (br,
1H), 5.26 (s, 1H), 5.17 (s, 1H), 4.04-4.00 (m, 1H), 3.90-3.84 (m, 1H), 3.64-3.59 (m, 1H), 3.46-3.42
(m, 1H); 13C NMR (CDCl3, 100 MHz) 170.1, 136.9, 128.5, 128.0, 79.7, 61.7, 42.1. The spectral data
were identical to those of the authentic material reported previously.4b Chiral HPLC: 96:4 er, tR (R)-
14

major enantiomer, 11.0 min; tR (S)-minor enantiomer, 10.3 min (Chiralpak AD-H column; 10% 2-
propanol in hexane; 0.5 mL/min).
cis-5-Benzyl-2-phenyl-3-morpholinone (25) 73% yield; 1H NMR (CDCl3, 400 MHz) 7.48-7.18 (m,
10H), 6.45 (br, 1H), 5.18 (s, 1H), 3.89-3.85 (m, 1H), 3.78-3.75 (m, 2H), 2.99-2.94 (m, 1H), 2.89-2.83
13
(m, 1H); C NMR (CDCl3, 100 MHz) 169.4, 136.5, 136.3, 129.3, 129.0, 128.6, 128.0, 127.2, 79.4,
64.6, 53.5, 40.2; HRMS: calcd. for C17H18NO2 [M++1] 268.1338; found 268.1336.
cis-5-(2-Methylpropyl)-2-phenyl-3-morpholinone (26) 72% yield; 1H NMR (CDCl3, 400 MHz)
7.48-7.33 (m, 5H), 6.50 (br, 1H), 5.20 (s, 1H), 3.88-3.84 (m, 1H), 3.68-3.65 (m, 2H), 1.71-1.64 (m,
13
1H), 1.59-1.52 (m, 1H), 1.46-1.39 (m, 1H), 0.96-0.93 (m, 6H); C NMR (CDCl3, 100 MHz) 169.5,
136.6, 128.5, 128.4, 127.9, 79.1, 65.2, 50.4, 42.7, 24.3, 22.9, 22.2; HRMS: calcd. for C14H20NO2
[M++1] 234.1494; found 234.1495.
cis-5-Isopropyl-2-phenyl-3-morpholinone (27) 73% yield; 1H NMR (CDCl3, 400 MHz) 7.47-7.31
(m, 5H), 6.54 (br, 1H), 5.18 (s, 1H), 3.84-3.82 (m, 2H), 3.30-3.27 (m, 1H), 1.92-1.87 (m, 1H), 1.00
(d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) 169.8, 136.5, 128.5, 128.4,
128.0, 79.0, 63.0, 57.9, 31.2, 18.7, 18.5; HRMS: calcd. for C13H18NO2 [M++1] 220.1338; found
220.1335.
cis-5-Methyl-2-phenyl-3-morpholinone (28) 74% yield; 1H NMR (CDCl3, 400 MHz) 7.49-7.34 (m,
5H), 6.83 (br, 1H), 5.19 (s, 1H), 3.87-3.82 (m, 1H), 3.76-3.75 (m, 1H), 3.60-3.56 (m, 1H), 1.27 (d, J
= 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) 169.6, 136.6, 128.5, 128.4, 128.0, 78.7, 66.1, 48.0, 19.4;
HRMS: calcd. for C11H14NO2 [M++1] 192.1025; found 192.1025.
trans-5-Methyl-2-phenyl-3-morpholinone (29) 88% yield; 1H NMR (CDCl3, 400 MHz) 7.46-7.33
(m, 5H), 6.83 (br, 1H), 5.08 (s, 1H), 4.05-4.02 (m, 1H), 3.90-3.85 (m, 1H), 3.51-3.45 (m, 1H), 1.19
(d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) 169.8, 137.0, 128.6, 128.5, 128.0, 79.5, 68.9, 48.2,
18.1; HRMS: calcd. for C11H14NO2 [M++1] 192.1025; found 192.1029.
III. General Procedure for the asymmetric preparation of 2,2-diarylacetates 2, 4, and 5: To a
solution of L-threonine-derived α-bromo ester 1a (1.0 equiv, >99:1 dr) at room temperature were
added a nucleophile (10 equiv) and AgOTf (1.2 equiv). After the mixture was stirred at rt for 3 h in
the least possible amount of solvent, CHCl3, the resulting mixture was washed with saturated
NaHCO3 solution, dried with anhydrous MgSO4, concentrated and purified by column
1
chromatography to afford a diarylacetate (2, 4 and 5). The drs were determined by the H NMR
integration of the hydrogens of the two diastereomers.
N-Benzoyl-O-[α-(4-methoxy-2-methylphenyl)phenylacetyl]-L-threonine Isopropyl Ester (2)
Obtained as an inseparable mixture (74:26) with two regioisomers in 95% yield; 1H NMR (CDCl3,
15

400 MHz) 7.60-7.12 (m, 10H), 6.90-6.41 (m, 4H), 5.60-5.32 (m, 1H), 5.26 (s, minor), 5.14 (s, 1H,
major), 5.01-4.81 (m, 2H), 3.74 (s, minor), 3.73 (s, 3H, major), 2.32 (s, minor), 2.24 (s, 3H, major),
1.35-1.17 (m, 9H); 13C NMR (CDCl3, 100 MHz) 171.6, 169.3, 167.5, 158.7, 138.2, 137.8, 133.5,
131.9, 129.4, 129.1, 129.0, 128.8, 128.6, 127.2, 127.1, 116.4, 111.2, 71.6, 70.0, 56.0, 55.1, 53.2, 21.8,
21.6, 20.1, 17.5; HRMS: calcd. for C30H34NO6 [M++1] 504.2386; found 504.2388. To a solution of
diarylacetate 2 in THF (0.5 M) was added a solution of LiAlH4 (1.0 M in THF, 3 equiv) at 0˚C. After
the reaction mixture was stirred at room temperature for 2 h, the reaction was quenched with
saturated NH4Cl solution and the aqueous layer was extracted with EtOAc. The combined organic
extracts were dried with anhydrous MgSO4, filtered and concentrated under reduced pressure.
Chromatographic separation on silica gel afforded 2-(4-methoxy-2-methylphenyl)-2-phenylethanol
1
in 65% yield. H-NMR (CDCl3, 400MHz) δ 7.29-7.02 (m, 6H), 6.77-6.68 (m, 2H), 4.60 (t, J = 7.2
Hz, minor), 4.30 (t, J = 7.2 Hz, 1H, major), 4.11-4.07 (m, 2H), 3.76 (s, 3H, major), 3.75 (s, minor),
2.31 (s, minor), 2.21 (s, 1H, major). The er of major regioisomer were determined by chiral
stationary phase-HPLC analysis. Chiral HPLC: 90:10 er, tR (R)-major enantiomer, 23.8 min; tR (S)-
minor enantiomer, 37.4 min (Chiralcel OJ-H column; 40% 2-propanol in hexane; 0.5 mL/min).
N-Benzoyl-O-[α-(2-acetoxymethyl-4-methoxyphenyl)phenylacetyl]-L-threonine Isopropyl Ester
(4) 80% yield; 1H NMR (CDCl3, 400 MHz) 7.65-7.19 (m, 11H), 6.94-6.83 (m, 2H), 6.63 (d, J = 9.2
Hz, 1H), 5.60-5.58 (m, 1H), 5.29 (s, 1H), 5.11-5.05 (m, 2H), 4.94-4.88 (m, 2H), 3.76 (s, 3H), 1.92 (s,
3H), 1.35 (d, J = 6.4 Hz, 1H), 1.20 (d, J = 6.0 Hz, 1H), 1.13 (d, J = 6.4 Hz, 1H); 13C NMR (CDCl3,
100 MHz) 171.3, 170.7, 169.2, 167.6, 158.8, 138.4, 135.4, 133.5, 131.9, 130.4, 129.2, 128.62,
128.59, 129.55, 127.3, 127.2, 116.1, 114.0, 71.7, 70.0, 64.1, 55.9, 55.3, 52.0, 21.7, 21.5, 20.7, 17.5;
HRMS: calcd. for C32H36NO8 [M++1] 562.2441; found 562.2438.
N-Benzoyl-O-[α-(2-ethoxymethyl-4-methoxyphenyl)phenylacetyl]-L-threonine Isopropyl Ester
(5) Obtained as an inseparable mixture (80:20) with two regioisomers in 87% yield; 1H NMR (CDCl3,
400 MHz) 7.61-7.22 (m, 11H), 6.97-6.54 (m, 3H), 5.59-5.55 (m, 1H), 5.41 (s, 1H, major), 5.30 (s,
minor), 5.05-4.88 (m, 2H), 5.45 (s, 2H), 3.77 (s, minor), 3.73 (s, 3H, major), 3.55-3.44 (m, 2H),
13
1.34-1.16 (m, 12H); C NMR (CDCl3, 100 MHz) 171.5, 169.3, 167.5, 158.7, 138.6, 137.8, 133.5,
131.9, 130.4, 129.4, 129.1, 128.7, 128.6, 128.5, 127.2, 115.4, 113.1, 71.5, 71.1, 70.0, 65.7, 56.2, 55.2,
52.0, 21.8, 21.6, 17.5, 15.1; HRMS: calcd. for C32H38NO7 [M++1] 548.2648; found 548.2649.
References and Notes
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The absolute configurations of dihydroisoquinolinones were assigned to be (R) by the chiral
17

stationary phase HPLC analysis of previously reported dihydroisoquinolinones 6 and 12.12a,3d
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Acknowledgements
This work was supported by Konkuk University in 2018.
Supporting Information. The copies of NMR spectra and HPLC chromatograms are provided in
supporting information.
18

ꢀ Novel asymmetric synthetic method for two chiral lactams
ꢀ Friedel-Crafts alkylation of -Boc-benzylamine derivatives
N
ꢀ Highly ortho-selective C-H functionalization of benzylamine derivatives
ꢀ Competing reactivities between the arene and benzylic alcohol

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: