Stereoselective photoinduced electrocyclic ring closure of aromatic enehydrazides. Asymmetric synthesis of 3-aryl dihydroisoquinolones and tetrahydroisoquinolines

Article abstract of DOI:10.1016/j.tet.2012.06.037

A flexible route for the stereoselective synthesis of a variety of 3-aryl dihydroisoquinolones and tetrahydroisoquinolines has been developed. The key step is a diastereoselective photoinduced 6π-electrocyclic ring closure of enantiopure aromatic enehydrazides via a 1,4-remote asymmetric induction. N-N bond cleavage to release the chiral appendage from the preliminary annulated compounds and/or concomitant reduction of the lactam carbonyl group completed the synthesis of the title compounds.

Full text of DOI:10.1016/j.tet.2012.06.037

Tetrahedron 68 (2012) 7140e7147
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective photoinduced electrocyclic ring closure of aromatic
enehydrazides. Asymmetric synthesis of 3-aryl dihydroisoquinolones
and tetrahydroisoquinolines
a
,
,
,
c
,
a,b
Melanie Dubois b, Eric Deniau a b, Axel Couture a , Pierre Grandclaudon
*
ꢀ
a Univ Lille Nord de France, F-59000 Lille, France
ˇ
b USTL, Laboratoire de Chimie Organique Physique, EA CMF 4478, Batiment C3(2), F-59655 Villeneuve d’Ascq Cedex, France
ˇ
c CNRS, UMR 8181 ‘UCCS’, Batiment C3(2), F-59655 Villeneuve d’Ascq Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A flexible route for the stereoselective synthesis of a variety of 3-aryl dihydroisoquinolones and tetra-
hydroisoquinolines has been developed. The key step is a diastereoselective photoinduced 6 -electro-
cyclic ring closure of enantiopure aromatic enehydrazides via a 1,4-remote asymmetric induction. NeN
bond cleavage to release the chiral appendage from the preliminary annulated compounds and/or
concomitant reduction of the lactam carbonyl group completed the synthesis of the title compounds.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 23 March 2012
Received in revised form 6 June 2012
Accepted 8 June 2012
p
Available online 15 June 2012
Keywords:
Asymmetric synthesis
Enol phosphates
Cross-coupling
Chiral enehydrazides
Photocyclization
3-Arylisoquinolones
1. Introduction
The 3-arylated models fall into this category and are of partic-
ular interest since they are known as a relevant class of compounds
The isoquinoline core is one of Nature’s most popular structural
motif and this ring system lies at the heart of a large number of
natural and synthetic bioactive compounds.1 In particular those in
which the azaheterocycle unit is partially hydrogenated occupy
a noticeable place in this class of interesting alkaloids because of
their manifold pharmacological properties, e.g., fibrinolytic, anti-
viral, tranquilizing, muscle relaxant, hypotensive and positive ino-
tropic effects.1,2 Isoquinolinones are somewhat less prominent but
very often they serve a key role as advanced intermediates prior to
their conversion to isoquinolines. Consequently the development of
general methodologies leading to molecular diversity in a highly
efficient stereo and enantioselective manner is a permanent chal-
lenging task for organic chemists and interest in this field continues
unabated.3e5 While much effort has been devoted to the asym-
metric synthesis of 1-substituted models,5m,6 the stereoselective
elaboration of 3-substituted dihydroisoquinolones and tetrahy-
droisoquinolines has much less precedent in the literature.
among the isoquinoline alkaloids.1 They can be regarded as im-
portant synthetic intermediates for the construction of structurally
related alkaloids like protoberberines, e.g., xylopinine, pavines, e.g.,
(ꢀ)-argemonine, and benzo[c]phenanthridines, e.g., chelerythrine
(Fig. 1).1,7 They are also enjoying considerable attention as potential
therapeutic agents8 as evinced by bombesin-2 (BB2) receptor an-
tagonist9 and MDM2-p53 interaction inhibitors10 (Fig. 1).
The asymmetric synthetic methods for the elaboration of
3-arylated dihydroisoquinolones can be cursorily classified into
three main categories whose fundamental tenets come within the
scope of the lateral metalation methodology pioneered by Clark
et al.11 (Scheme 1). The first one hinges upon a tandem addition/
cyclization of lithiated 2-methylbenzamides to imine appended
chiral auxiliary, such as sulfinyl imines developed by Davies5b,e,l,12
and Chrzanowska4a,b (path 1a) or SAMP hydrazones exploited by
Enders13 (path 1b). For the second one (path 2) enantioinduction is
secured by making use of achiral imines and laterally lithiated (S) or
(R)-o-toluamides equipped with a chiral auxiliary derived from (S)
or (R)-phenylalaninol. At last the same synthetic approach was
skillfully developed by Snieckus5a and Liu4c starting from achiral
substrates and enantioinductionwas achieved this time via addition
of the chiral ligand (ꢀ)-sparteine (path 3). It is also worth noting that
* Corresponding author. Tel.: þ33 (0) 3 20 43 44 32; fax: þ33 (0) 3 20 33 63 09;
e-mail address: axel.couture@univ-lille1.fr (A. Couture).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.037

M. Dubois et al. / Tetrahedron 68 (2012) 7140e7147
7141
aromatic enehydrazides 3 as substrates for photoinduced ring
closure to secure the formation of the lactam unit, that is ring B in
the title compounds (Scheme 2). Ensuing deprotection by NeN
cleavage of the hydrazide bond of the preliminary annulated
compounds4 possibly associated with reduction of the carbonyl
function then should provide an entry to the targeted optically
active compounds 1,2.
H
MeO
MeO
OMe
OMe
N
H
MeO
MeO
NMe
H
OMe
OMe
(-)-Xylopinine
(-)-Argemonine
N
O
OMe
OMe
MeO
NMe
N
X
Cl
O
O
O
N
NH
N
A
B
A
B
2
3
2
3
R
R
1
R
R
1
HN
Ph
O
R
Cl
R
Chelerythrine
4
4
R
R
O
N
1
X = O
X = H
4
Bombesin-2 (BB2)
receptor antagonist
2
F
2
OMe
N
HO C
OMe
2
O
Inhibitor of the MDM2-p53 interaction
N
2
3
R
R
1
Fig. 1. Natural and synthetic bioactive compounds incorporating the 3-
arylisoquinoline or isoquinolone skeleton.
R
4
3
R
a stereocontrolled synthesis of 3-aryltetrahydroisoquinoline by
a PicteteSpengler heterocyclization reaction of optically active 1,2-
diarylethylamines has been developed but the resulting com-
pounds were invariably alkylated at the C1 position.5 The same
unsubstituted models could also be obtained by deoxygenation of
isoquinolinols prepared from chiral arylglycines under ionic hy-
drogenation conditions.4d All these methods are generally efficient
and of procedural simplicity but they have also been claimed to
proceed with varying degrees of success with regard to their enan-
tioselectivities. Consequently the development of alternative and
efficient methodologies, which may find generality for constructing
polyhydroisoquinolones and isoquinolines with aryl appendage at
C3 in a stereoselective manner is currently the object of synthetic
endeavor.4,13
Scheme 2. Retrosynthetic analysis.
The photocyclization of enamides has been developed as an
efficient synthetic route toward six-membered azaheterocycles and
a wide range of alkaloids has been synthesized in this way.14 Under
oxidative, non oxidative and reductive conditions enamides A un-
dergo smooth photochemical cyclization via
a common in-
termediate B (Scheme 3) and the formation of the lactam unit at
different oxidation levels can be rationalized by loss of hydrogen,
[1,5]-hydrogen shift or hydride fixation, respectively.
O
O
O
R
R
R
N
N
N
hν
1
5
H
O
H H
B
X
CH2
A
Ar
NH
oxidative
-H
+
N
*
H
Y
2
Ar
O
R
non oxidative
[1,5]-H shift
chiral
N
p-tolyl or t-butyl
metal
S
path 1a Y =
path 1b Y =
hydride
reductive
O
H
Path 1
X = CONEt2
Ph
H
O
O
N
(SMP)
R
R
N
N
O
H
H
H
R
*
H
OMe
H
N
H H
H H
H
H
O
N
Path 2
Path 3
X =
Y = R
H H
Scheme 3. Photochemical behavior of enamides upon irradiation under various
conditions.
O
X = CONEt2
Y = R , (-)-sparteine added
Although a number of possibilities exist for inducing stereo-
selectivities in photochemical reactions15 little attention has been
paid to the development of photocyclization processes that could
Scheme 1. Synthetic strategies for the stereoselective synthesis of 3-arylated
dihydroisoquinolones.
ensure the control of the stereogenic center
a challenging task in alkaloid total synthesis. In a few early reports
reductive photocyclization of enamides was carried out in the
a to the nitrogen atom,
In this paper we wish to delineate a novel route to a variety of
diversely substituted 3-aryl polyhydroisoquinolones and quino-
lines, 1 and 2, respectively, that is based upon the use of chiral

7142
M. Dubois et al. / Tetrahedron 68 (2012) 7140e7147
presence of chiral metal hydride complex (Scheme 3) but both the
chemical yields and enantioselectivities were rather modest.16
Methodologies based upon the photoinduced cyclization of chiral
aromatic enamides are rather scarce. These photochemical studies
have been indeed confined to aliphatic dienamides17 and to
structurally sophisticated models that require additional tedious
chemical transformation to access the targeted compounds,18 both
with moderate selectivities.
mandatory styrene unit through a palladium-mediated cross-cou-
pling reaction. Since the pioneering work of Oshima et al.20 several
group have successfully and elegantly used constitutionally diverse
enol phosphates in a variety of Pd(PPh3)4 catalyzed cross-coupling
reaction.21 It has been notably demonstrated that enol phosphates
deriving from N-alkylamides are effective substrates for such cou-
pling reaction provided that the model compounds are further
equipped with electron withdrawing groups on nitrogen atom. De-
spite the fact that to the best of our knowledge such studies have not
been performed with N-substituted hydrazides we were reasonably
optimistic about the chances of success for this approach since the
diacylated hydrazines 8 fulfill these stringent structural criterions.
Initially the benzoyl chlorides 7a,bwere efficientlyconverted into the
corresponding hydrazides (S)-9a,b under standard conditions.
Deprotonation of (S)-9a,b with NaH inTHFand subsequent capture of
the transient sodium salt with acetyl chloride delivered quite satis-
factory yields of the chiral N-acetylated hydrazides (S)-8a,b. With
rapid access to these diacylated models the focus of the research
shifted to the use of these compounds as advanced intermediates for
the concise and efficient conversion of the acetyl moiety into a sty-
rene unit.
We were then pleased to observe that exposure of compounds
(S)-8a,b to KHMDS in THF at ꢀ78 ꢁC provided a potassium enolate,
which was intercepted with diphenyl chlorophosphate to afford
the sensitive vinyl phosphate 10. Subsequent Pd-catalyzed Suzu-
kieMiyaura coupling reaction was then applied under well defined
conditions. The vinyl phosphate thus obtained 10, a suitably aro-
matic boronic acid 11aee, Pd(PPh3)4 as the catalyst, aqueous
Na2CO3 (2 M), a few drops of EtOH were refluxed in THF. Under
these conditions the expected enantiopure styrene hydrazides (S)-
3aef, candidates for the planned photoinduced ring closure, were
isolated in very satisfactory yields (Scheme 4, Table 1). As far as we
2. Results and discussion
Our new synthetic approach hinges upon the photoinduced cy-
clization of aromatic enehydrazides 3 equipped with a temporary
activating auxiliary issued from the chiral pool, that is (S)-O-meth-
ylprolinol (Scheme 2). We speculated that upon photoinduced ring
closure under anaerobic conditions, the presence of this rather bulky
appendage could have a marked impact on the [1,5]-H shift from
intermediate structurally related to B and then force and favor the
privileged formation of diastereomerically enriched annulated
models 4. The first facet of the synthesis, which is depicted in Scheme
4 was then the elaboration of the enehydrazides 3. The construction
of these unsaturated compounds revealed to be more problematic
that we had anticipated. All attempts to access the desired precursors
following the classical method usually employed for the synthesis of
styrenic enamides,19 that is base-induced treatment of hydrazones 5
issued from the condensation of suitable benzophenones 6 and (S)-
aminomethoxymethylpyrrolidine (SAMP), with an appropriate acid
chloride 7 met with no success, probably due to competing acylation
sites. We then set out to achieve an alternative strategy to secure the
creation of the styrene unit tailed to the aromatic hydrazide moiety.
We surmised that the acetylated hydrazides 8 would possess the
appropriate functionalities required for the installation of the
OMe
OMe
OMe
H N N
O
2
O
O
1. NaH , THF
N
N
2. MeCOCl
(SAMP)
Cl
N
N
H
1
1
1
93-95%
R
Me
R
O
R
1
7a,b
(S)-9a,b
(S)-8a R = H
(74%)
1
(S)-8b R = OMe (71%)
1. Pd(PPh ) 5% mol
3 4
Na CO , H O
2
3
2
2.
2
R
OMe
O
OMe
N
3
1. KHMDS
(HO) B
R
2
O
2.
O
N
N
4
Cl
P
11a-e
R
N
OPh
2
O
THF , H O
OPh
R
R
2
1
1
R
O P
R
OPh
3
(55-70%)
OPh
4
R
10a,b
(S)-3a-f
O
OMe
N
OMe
Cl
1
R
H N N
O
2
7
N
2
3
R
R
2
3
(SAMP)
Me
R
R
Et N
3
Me
4
R
4
R
6
5
Scheme 4. Synthesis of the parent aromatic enehydrazides 3aef.

M. Dubois et al. / Tetrahedron 68 (2012) 7140e7147
7143
Table 1
then occurs exclusively on the less hindered diastereotopic face and
this highly diastereoselective electrocyclization is actually achieved
via an unusual 1,4-remote asymmetric induction. These results are
Compounds 3aef, 4aef, 1aef and 2a,d,e prepared
R1
R2
R3
R4
in good agreement with the stereoselective 6p-electron cyclic ring
8a
8a
8a
8a
8a
H
H
H
H
H
11a
H
H
H
H
8aþ11a/3a 65% 4a 68% 1a 75% 2a 63%
closure of structurally related amidotrienes.23 Ultimate treatment
of (S,S)-4aef with magnesium monoperoxyphthalate (MMPP)24
triggered off the exclusive cleavage of the chiral appendage and
this operation delivered very satisfactory yields of the virtually
enantiopure 3-aryl-1(2H)-dihydroisoquinolones (S)-1aef (Scheme
5, Table 1).
11b OMe OMe
8aþ11b/3b 70% 4b 63% 1b 70%
d
d
d
d
11c OMe OMe OMe 8aþ11c/3c 58% 4c 67% 1c 74%
11d
11e OCH2O
H
OMe
H
H
H
8aþ11d/3d 62% 4d 62% 1d 72% 2d 68%
8aþ11e/3e 68% 4e 65% 1e 73% 2e 58%
8b OMe 11b OMe OMe
8bþ11b/3f 55% 4f 61% 1f 67%
d d
Finally treatment with the borane/THF complex of (S,S)-4aef
followed by aqueous alkaline work up effected reductive NeN
bond cleavage with the concomitant reduction of the lactam car-
bonyl group to afford the targeted 3-aryltetrahydroisoquinolines
(S)-2a,d,e. The absolute configuration of the newly created stereo-
genic center in 1 and 2 that was confirmed to be (S) as well as the
enantiopurity of our synthetic compounds were clearly established
from the sign and value of the optical rotation that matched those
reported from authentic sample assembled by conceptually dif-
are aware such reactions performed in the hydrazide series are
unprecedented and should be of interest for alternative synthetic
planning. For the crucial photocyclization process a carefully
degassed methanolic solution of chiral enehydrazides (S)-3aef
(4 10ꢀ3 M; lmax¼205, 260, 300 nm) was placed in a quartz vessel
and irradiated under Ar in a Rayonet RPR photoreactor equipped
with eight 254 nm lamps for 4 h. Subsequent removal of the solvent
and flash column chromatography delivered very satisfactory
yields of the requisite annulated (S,S)-4aef (Scheme 5, Table 1). To
our delight these lactamic compounds were obtained essentially as
single diastereomers detectable by NMR (de ꢂ98% after chro-
matographic treatment)22 making evident the high selectivity of
the initial diastereofacial [1,5]-hydrogen shift process allowing
introduction of the absolute stereochemistry at the newly created
benzylic carbon center. From a mechanistic point of view one can
tentatively assume that the chiral auxiliary is blocking the lower
face of the plane of the hexatriene mesomeric form of (S)-3aef.
ferent synthetic approaches, e.g., {(S)-1a: mp 130e131 ꢁC, ½a D20
ꢃ
ꢀ198.3 (c 0.97, CHCl3); lit.:5e mp 130e131 ꢁC, ½a 2D0
ꢀ203.4 (c 1.03,
ꢃ
a 20
CHCl3)} and {(S)-2a: ½ ꢃD ꢀ125.5 (c 0.48, CH2Cl2); lit.:25 (R)-enan-
tiomer ½ ꢃD þ125.0 (c 0.55, CH2Cl2)}.
a 20
3. Conclusion
In conclusion we have devised a new, convenient and flexible
method for the enantioselective synthesis of 3-arylisoquinolones
and isoquinolines. The key step is the highly diastereoselective
photoinduced electrocyclization of enantiopure aromatic enehy-
drazides to generate the six-membered azaheterocyclic ring sys-
tem via a 1,4-remote asymmetric induction. The main advantages
of this synthetic approach lie in the small number of synthetic
Upon the 6p-electrocyclization process the two terminal vinyl and
aromatic strands rotate in a conrotatory manner away from the
pendant methoxymethyl group of the pyrrolidine auxiliary, which
may sterically interacts with the styrene unit (Scheme 5). The
suprafacial [1,5]-H shift from the transient hydrazinium species
6π-electron
electrocyclic
suprafacial
[1,5]-H shift
O
O
O
R1
R1
R1
ring-closure
H
H
N
N
O
Me
N
N
O
Me
N
N
O
Me
conrotatory
process
H
Ar
Ar
Ar
OMe
N
OMe
N
hν , 254 nm
O
O
MeOH , Ar , 4 h
N
N
R2
R3
R2
R3
(61-68%)
R1
R1
R4
R4
BH3
THF , reflux
(58-68%)
.
THF
(S,S)-4a-f
MMPP,
(S)-3a-f
MeOH , r.t. (67-75%)
O
NH
R2
R3
NH
R2
R1
R1
R3
R4
(S)-2a,d,e
R4
(S)-1a-f
Scheme 5. Synthesis and mechanistic rationalization for the enantioselective construction of 3-arylated isoquinolones and isoquinolines).

7144
M. Dubois et al. / Tetrahedron 68 (2012) 7140e7147
steps and the ready accessibility to the chiral SAMP hydrazides,
which are easily assembled through a newly developed Suzu-
kieMiyaura cross-coupling reaction involving tailor-made enol
phosphates. Owing to the availability of the RAMP chiral auxiliary
we believe that this synthetic strategy should also allow for the
construction of both antipodes of these 3-arylated isoquinolones
and isoquinolines.
Ar. Then a solution of acetyl chloride (942 mg, 12 mmol) in THF
(5 mL) was added dropwise. The mixture was refluxed for 3 h.
After cooling to rt water (10 mL) was added and the organic
layer was separated. The aqueous layer was extracted with
CH2Cl2 (3ꢄ30 mL) and the combined organic layers were dried
(MgSO4). Evaporation of the solvent furnished the crude acety-
lated hydrazide 8a,b as an oily product, which was purified by
flash column chromatography using EtOAc/hexanes (10:90) as
eluent.
4. Experimental section
4.1. General
4.3.1. N-Acetyl-N-((S)-2-methoxymethylpyrrolidin-1-yl)benzamide
[(S)-8a]. Colorless oil, ½a D20
ꢃ
ꢀ38.2 (c 1.73, CHCl3). IR (neat)
n
¼3191,
Melting points were determined on a Reichert-Thermopan
apparatus and are uncorrected. NMR spectra were recorded on
Bruker AM 300 spectrometer and were referenced against internal
TMS. IR spectra were recorded on a Nicolet 380 FT-IR spectrometer
and UV spectra on a Shimadzu UV-2450 spectrometer. Optical
rotations were measured with a Perkin Elmer 343 digital polar-
imeter at 589 nm. Enantiomeric excesses (ee >96%) were de-
termined by HPLC analysis with a Chiracel OD column (hexane/2-
propanol, as eluent), UV detector 254 nm. Elemental analyses
were obtained using a Carlo-Erba CHNS-11110 equipment. Flash
1686, 1644, 1533 cmꢀ1 1H NMR (300 MHz, C6D6, mixture of
.
rotamers)
d
(major rotamer)¼0.91e1.15 (m, 1H), 1.22e1.58 (m, 2H),
1.78e2.09 (m, 2H), 2.51 (s, 3H), 2.73e2.89 (m, 1H), 2.95e3.18 (m,
4H), 3.52e3.67 (m, 1H), 3.73e4.10 (m, 1H), 7.13e7.28 (m, 3H),
7.57e7.82 (m, 2H) ppm. 13C NMR (75 MHz, C6D6, mixture of
rotamers):
d
(major rotamer)¼20.2 (CH3), 23.6 (CH2), 28.2 (CH2),
52.5 (CH2), 58.2 (CH3), 61.6 (CH), 76.6 (CH2), 127.6 (2ꢄ CH), 128.1
(2ꢄ CH), 130.6 (CH), 137.6 (C), 172.6 (CO), 175.9 (CO) ppm. Anal.
Calcd for C15H20N2O3: C, 65.20; H, 7.30; N, 10.14%. Found: C, 65.03;
H, 7.10; N, 10.05%.
chromatography was performed on Sorbent Technologies
ꢁ
32e63
m
m 60 A silica gel. Reactions were monitored by thin layer
4.3.2. N-Acetyl-4-methoxy-N-((S)-2-methoxymethylpyrrolidin-1-yl)-
chromatography with Sorbent Technologies 0.20 mm silica gel
60 A plates. Dry glassware was obtained by oven-drying and as-
benzamide [(S)-8b]. Colorless oil, ½a D20
ꢃ
ꢀ44.4 (c 1.63, CHCl3). IR
(neat)
mixture of rotamers)
n
¼3188, 1688, 1662, 1540 cmꢀ1
.
1H NMR (300 MHz, C6D6,
ꢁ
sembly under Ar and dry Ar was used as the inert atmosphere. The
glassware was equipped with rubber septa and reagent transfer
was performed by syringe techniques. Tetrahydrofuran (THF) was
distilled from sodium benzophenone ketyl immediately before
use. Methanol was distilled over magnesium turning and CH2Cl2
over CaH2.
d
(major rotamer)¼1.11e1.69 (m, 3H),
1.73e2.18 (m, 2H), 2.50 (s, 3H), 2.70e3.42 (m, 3H), 3.11 (s, 3H), 3.33
(s, 3H), 3.79e4.15 (m, 1H), 6.79 (d, J¼8.2 Hz, 2H), 7.83 (d, J¼8.2 Hz,
2H) ppm. 13C NMR (75 MHz, C6D6, mixture of rotamers):
d (major
rotamer)¼21.1 (CH2), 23.3 (CH3), 26.0 (CH2), 52.7 (CH2), 56.8 (CH3),
59.3 (CH3), 62.6 (CH), 74.0 (CH2), 114.3 (2ꢄ CH), 126.0 (C), 128.3
(2ꢄ CH), 158.4 (C), 165.0 (CO), 165.1 (CO) ppm. Anal. Calcd for
C16H22N2O4: C, 62.73; H, 7.24; N, 9.14%. Found: C, 62.96; H, 6.96; N,
8.97%.
4.2. Hydrazides (S)-9a,b
Hydrazides (S)-9a,b were synthesized by following a previously
reported procedure.26
4.4. Synthesis of enehydrazides (S)-3aef. General procedure
4.2.1. N-((S)-2-Methoxymethylpyrrolidin-1-yl)benzamide [(S)-9a].
Recrystallization from hexane/toluene: colorless crystals, mp
A solution of KHMDS (0.5 M in toluene, 3 mL, 1.5 mmol) was
added dropwise to a stirred solution of benzamide 8a,b (1 mmol)
and diphenyl chlorophosphate (0.31 mL, 1.5 mmol) in anhydrous
THF (15 mL) at ꢀ78 ꢁC under Ar. After stirring for 30 min at ꢀ78 ꢁC,
water (10 mL) was added and the mixture was extracted with Et2O
(2ꢄ30 mL). The combined organic layers were dried (MgSO4) and
concentrated under vacuum to afford the intermediate vinyl
phosphate 10a,b as an oily product, which was then used in the
coupling step without further purification.
Aqueous Na2CO3 solution (2 M, 1 mL, 2 mmol), Pd(PPh3)4
(58 mg, 5 mol %) and aromatic boronic acid 11aee (1.5 mmol) were
added under Ar to a stirred solution of crude 10a,b (1 mmol) in THF
(10 mL). The mixture was refluxed for 2 h, then diluted with water
(10 mL) and extracted with Et2O (3ꢄ15 mL). The combined organic
layers were dried (MgSO4) and concentrated under vacuum to give
orange oil. Purification by flash column chromatography using
EtOAc/hexanes (40:60) as eluent afforded enehydrazide (S)-3aef as
pale yellow oil.
156e157 ꢁC, ½a 2D0
ꢃ
ꢀ27.3 (c 0.77, CHCl3). IR (neat) ¼3193, 1644,
n
1531 cmꢀ1
.
1H NMR (300 MHz, CDCl3)
d
¼1.61e1.77 (m, 1H),
1.80e1.94 (m, 2H), 1.96e2.12 (m, 1H), 3.00 (q, J¼8.5 Hz, 1H),
3.20e3.57 (m, 7H), 7.34e7.48 (m, 3H), 7.58 (br s, 1H), 7.72e7.85 (m,
2H) ppm. 13C NMR (75 MHz, CDCl3):
d
¼21.3 (CH2), 26.4 (CH2), 55.4
(CH2), 59.2 (CH3), 64.5 (CH), 74.9 (CH2), 127.1 (2ꢄ CH), 128.6
(2ꢄ CH), 131.5 (CH), 133.8 (C), 166.5 (CO) ppm. Anal. Calcd for
C13H18N2O2: C, 66.64; H, 7.74; N, 11.96%. Found: C, 66.79; H, 7.70; N,
11.67%.
4.2.2. 4-Methoxy-N-((S)-2-methoxymethylpyrrolidin-1-yl)benza-
mide [(S)-9b]. Recrystallization from hexane/toluene: colorless
crystals, mp 157e158 ꢁC, ½a D20
ꢃ
ꢀ3.7 (c 1.39, CHCl3). IR (neat)
n
¼3190,
1636, 1537 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d
¼1.60e1.78 (m, 2H),
1.84e1.96 (m, 2H), 1.98e2.15 (m, 1H), 2.95 (q, J¼8.3 Hz, 1H),
3.17e3.30 (m, 1H), 3.34 (s, 3H), 3.39e3.58 (m, 2H), 3.84 (s, 3H), 6.91
(d, J¼8.3 Hz, 2H), 7.12 (br s, 1H), 7.71 (d, J¼8.3 Hz, 2H) ppm. 13C NMR
(75 MHz, CDCl3):
d
¼21.4 (CH2), 26.4 (CH2), 53.8 (CH2), 54.4 (CH3),
4.4.1. N-((S)-2-Methoxymethylpyrrolidin-1-yl)-N-(1-phenylvinyl)-
59.2 (CH3), 64.3 (CH), 75.3 (CH2), 114.3 (2ꢄ CH), 125.7 (C), 128.7
(2ꢄ CH), 159.9 (C), 162.4 (CO) ppm. Anal. Calcd for C14H20N2O3: C,
63.62; H, 7.63; N, 10.60%. Found: C, 63.47; H, 7.87; N, 10.49%.
benzamide [(S)-3a]. Pale yellow oil, ½a D20
ꢀ115.7 (c 1.54, CHCl3). IR
ꢃ
(neat)
d
n
¼2922, 1640, 1513 cmꢀ1
.
1H NMR (300 MHz, C6D6)
¼1.25e2.12 (m, 3H), 2.17e2.72 (m, 1H), 2.78e2.92 (m, 1H), 3.27 (s,
3H), 4.88 (br s, 1H), 5.12 (br s, 1H), 6.78e6.85 (m, 3H), 7.11e7.28 (m,
4.3. Acetylation of hydrazides (S)-9a,b. General procedure
4H), 7.35e7.64 (m, 3H) ppm. 13C NMR (75 MHz, C6D6):
d¼23.0
(CH2), 26.6 (CH2), 51.0 (CH2), 59.0 (CH3), 61.5 (CH), 75.4 (CH2), 115.4
(CH2), 127.5 (2ꢄ CH), 127.7 (2ꢄ CH), 128.0 (2ꢄ CH), 128.1 (2ꢄ CH),
127.8 (C), 127.9 (CH), 129.5 (C), 131.5 (CH), 147.3 (C), 171.8 (CO) ppm.
A suspension of hydrazide (S)-9a,b (10 mmol) and NaH 60%
(460 mg, 12 mmol) in THF (25 mL) was stirred at rt for 3 h under

M. Dubois et al. / Tetrahedron 68 (2012) 7140e7147
7145
Anal. Calcd for C21H24N2O2: C, 74.97; H, 7.19; N, 8.33%. Found: C,
74.79; H, 7.34; N, 8.12%.
2H) ppm. 13C NMR (75 MHz, CHCl3):
d
¼23.3 (CH2), 30.1 (CH2),
51.7 (CH2), 54.9 (CH3), 55.6 (CH3), 55.7 (CH3), 58.7 (CH3), 61.5
(CH), 76.3 (CH2), 109.5 (CH2), 111.1 (CH), 111.9 (CH), 113.3
(2ꢄ CH), 119.8 (CH), 128.1 (C), 129.7 (2ꢄ CH), 130.4 (C), 131.2 (C),
149.9 (C), 150.5 (C), 161.6 (C), 169.7 (CO) ppm. Anal. Calcd for
C24H30N2O5: C, 67.59; H, 7.09; N, 6.57%. Found: C, 67.76; H, 7.28;
N, 6.75%.
4.4.2. N-[1-(3,4-Dimethoxyphenyl)vinyl]-N-((S)-2-methoxymethylp-
yrrolidin-1-yl)benzamide [(S)-3b]. Pale yellow oil,
½
a 2D0
ꢃ
ꢀ110.0
(c 1.03, CHCl3). UV (MeOH, 10ꢀ4 M) lmax¼205.8 (ε¼26ꢄ103), 263.6
(ε¼9750), 297.6 (ε¼5200) nm. IR (neat)
n
¼2928, 1651, 1514 cmꢀ1
.
1H NMR (300 MHz, C6D6)
d
¼1.22e2.12 (m, 3H), 2.19e2.68 (m, 1H),
3.24e3.65 (m, 5H), 3.22 (s, 3H), 3.47 (s, 3H), 3.55 (s, 3H), 4.96 (br
s, 1H), 5.13 (br s, 1H), 6.65 (d, J¼8.3 Hz, 1H), 7.11e7.33 (m, 5H),
4.5. Photocyclization of enehydrazides (S)-3aef. Synthesis of
isoquinolinones (S,S)-4aef. General procedure
7.87e7.95 (m, 2H) ppm. 13C NMR (75 MHz, C6D6):
d
¼23.1 (CH2),
28.3 (CH2), 51.8 (CH2), 55.6 (CH3), 55.7 (CH3), 58.7 (CH3), 61.7
(CH), 76.3 (CH2), 109.2 (CH2), 111.1 (CH), 111.9 (CH), 119.8 (CH),
128.0 (2ꢄ CH), 128.1 (C), 128.3 (CH), 130.2 (2ꢄ CH), 131.1 (C), 137.9
(C), 149.9 (C), 150.5 (C), 170.2 (CO) ppm. Anal. Calcd for
C23H28N2O4: C, 69.68; H, 7.12; N, 7.07%. Found: C, 69.72; H, 6.91;
N, 7.20%.
Irradiations were performed in quartz vessel in a Rayonet RPR-
208 photoreactor fitted with eight Rul 253.7 nm lamps. A solution
of the enehydrazide (S)-3aef (0.4 mmol) in MeOH (100 mL) was
deareated by flushing it with Ar for 30 min. Deaeration and stirring
of the solution were maintained during irradiation (4 h). Ar was
freed of O2 by passing it through a BTS catalyst and dried (P2O5).
After irradiation the solvent was evaporated under vacuum and
the residual photoproduct was purified by flash column chroma-
tography using EtOAc/hexanes (20:80) as eluent. The solid iso-
quinolinones (S,S)-4aef were finally recrystallized from hexane/
toluene.
4.4.3. N-((S)-2-Methoxymethylpyrrolidin-1-yl)-N-[1-(3,4,5-trimeth-
oxyphenyl)vinyl]benzamide [(S)-3c]. Pale yellow oil, ½a D20
ꢀ83.4 (c
ꢃ
1.27, CHCl3). IR (neat)
n
¼2930, 1651, 1518 cmꢀ1. 1H NMR (300 MHz,
C6D6)
d
¼1.20e2.07 (m, 3H), 2.15e2.68 (m, 1H), 2.74e2.91 (m, 1H),
3.12e3.60 (m, 4H), 3.21 (s, 3H), 3.47 (s, 3H), 3.55 (s, 3H), 5.05 (br s,
1H), 5.22 (br s, 1H), 6.68 (s, 2H), 7.10e7.40 (m, 3H), 7.47e7.71 (m,
4.5.1. (S)-2-((S)-2-Methoxymethylpyrrolidin-1-yl)-3-phenyl-3,4-
2H) ppm. 13C NMR (75 MHz, C6D6):
d
¼21.3 (CH2), 26.0 (CH2), 51.3
dihydro-2H-isoquinolin-1-one [(S,S)-4a]. Colorless crystals, mp
(CH2), 55.3 (CH3), 55.8 (2ꢄ CH3), 58.9 (CH3), 61.4 (CH), 75.7 (CH2),
105.4 (2ꢄ CH), 109.4 (CH2), 127.7 (C), 128.2 (2ꢄ CH), 130.1 (2ꢄ CH),
130.8 (C), 132.8 (CH), 135.7 (C), 143.5 (C), 154.1 (2ꢄ C), 169.8 (CO)
ppm. Anal. Calcd for C24H30N2O5: C, 67.59; H, 7.09; N, 6.57%. Found:
C, 67.37; H, 7.25; N, 6.62%.
140e141 ꢁC, ½a 2D0
ꢃ
ꢀ8.0 (c 0.71, CHCl3). IR (neat)
n
¼2934, 1652,
1494 cmꢀ1 1H NMR (300 MHz, C6D6)
. d
¼1.64e2.07 (m, 3H), 2.62
(dd, J¼2.2, 15.7 Hz, 2H), 2.67 (br s, 1H), 2.87 (t, J¼8.8 Hz, 1H),
2.96 (s, 3H), 3.27e3.39 (m, 2H), 3.80 (br s, 1H), 4.31 (br s, 1H),
4.79 (dd, J¼2.2, 7.0 Hz, 1H), 6.64 (d, J¼7.5 Hz, 1H), 6.97e7.14
(m, 6H), 7.16 (t, J¼7.5 Hz, 1H), 8.59 (dd, J¼1.3, 7.7 Hz, 1H) ppm.
4.4.4. N-((S)-2-Methoxymethylpyrrolidin-1-yl)-N-[1-(4-methoxyph-
13C NMR (75 MHz, C6D6):
d
¼24.0 (CH2), 28.5 (CH2), 37.1 (CH2),
enyl)vinyl]benzamide [(S)-3d]. Pale yellow oil, ½a D20
ꢃ
ꢀ113.8 (c 1.67,
52.4 (CH2), 58.4 (CH3), 61.3 (CH), 64.9 (CH), 76.1 (CH2), 127.0
(3ꢄ CH), 127.3 (CH), 127.6 (CH), 128.1 (CH), 128.5 (2ꢄ CH), 131.6
(C), 131.8 (CH), 135.4 (C), 142.5 (C), 162.9 (CO) ppm. Anal. Calcd
for C21H24N2O2: C, 74.97; H, 7.19; N, 8.33%. Found: C, 75.24; H,
7.33; N, 8.52%.
CHCl3). IR (neat)
n
¼2926,1654,1508 cmꢀ1. 1H NMR (300 MHz, C6D6)
d
¼1.22e2.12 (m, 3H), 2.18e2.56 (m, 1H), 3.00e3.38 (m, 2H), 3.19 (s,
3H), 3.37 (s, 3H), 3.42e3.64 (m, 1H), 3.66e3.92 (m, 1H), 4.31e4.60
(m, 1H), 4.89 (br s, 1H), 5.05 (br s, 1H), 6.84 (d, J¼8.7 Hz, 2H),
6.98e7.21 (m, 3H), 7.54 (d, J¼8.7 Hz, 2H), 7.81e7.97 (m, 2H) ppm.
13C NMR (75 MHz, C6D6):
d¼23.2 (CH2), 28.3 (CH2), 51.6 (CH2), 55.1
4.5.2. (S)-3-(3,4-Dimethoxyphenyl)-2-((S)-2-methoxymethylpyrroli-
(CH3), 58.7 (CH3), 61.5 (CH), 76.2 (CH2), 109.5 (CH2), 114.2 (2ꢄ CH),
127.8 (C), 128.0 (2ꢄ CH), 128.2 (2ꢄ CH), 128.3 (2ꢄ CH), 130.2 (CH),
130.7 (C), 137.8 (C), 160.4 (C), 170.1 (CO) ppm. Anal. Calcd for
C22H26N2O3: C, 72.11; H, 7.15; N, 7.64%. Found: C, 72.28; H, 7.04; N,
7.55%.
din-1-yl)-3,4-dihydro-2H-isoquinolin-1-one
[(S,S)-4b]. Colorless
ꢀ8.6 (c 0.98, CHCl3). IR (neat) ¼2935,
¼1.74e2.09 (m, 3H),
crystals, mp 85e86 ꢁC, ½a D20
ꢃ
n
1650, 1515 cmꢀ1 1H NMR (300 MHz, C6D6)
. d
2.69 (dd, J¼2.0, 15.6 Hz, 2H), 2.85 (br s, 1H), 2.98 (t, J¼8.7 Hz, 1H),
3.01 (s, 3H), 3.29e3.48 (m, 2H), 3.38 (s, 3H), 3.43 (s, 3H), 3.87 (br s,
1H), 4.38 (br s, 1H), 4.80 (dd, J¼1.8, 6.8 Hz, 1H), 6.42 (d, J¼8.2 Hz,
1H), 6.64e6.75 (m, 3H), 7.10 (dt, J¼1.6, 7.4 Hz, 1H), 7.18 (t, J¼7.4 Hz,
4.4.5. N-(1,1,3-Benzodioxol-5-ylvinyl)-N-((S)-2-methoxymethylpyrr-
olidin-1-yl)benzamide [(S)-3e]. Pale yellow oil, ½a D20
ꢃ
ꢀ72.2 (c 1.64,
1H), 8.63 (d, J¼7.5 Hz, 1H) ppm. 13C NMR (75 MHz, C6D6):
¼24.0
d
CHCl3). IR (neat)
n
¼2930, 1650, 1515 cmꢀ1
.
1H NMR (300 MHz,
(CH2), 28.6 (CH2), 37.4 (CH2), 52.5 (CH2), 55.4 (CH3), 55.5 (CH3), 58.5
(CH3), 61.4 (CH), 64.8 (CH), 76.3 (CH2), 110.9 (CH), 112.0 (CH), 119.2
(CH), 127.2 (CH), 127.5 (CH), 127.8 (CH), 131.7 (C), 131.8 (CH), 134.8
(C), 135.7 (C), 149.5 (C), 149.9 (C), 163.0 (CO) ppm. Anal. Calcd for
C23H28N2O4: C, 69.68; H, 7.12; N, 7.07%. Found: C, 69.55; H, 6.85; N,
7.29%.
C6D6)
d
¼1.51e2.04 (m, 3H), 2.21e2.59 (m, 1H), 3.04e3.34 (m, 2H),
3.19 (s, 3H), 3.39e3.94 (m, 2H), 4.15e4.58 (m, 1H), 4.81 (br s, 1H),
4.94 (br s, 1H), 5.33e5.37 (m, 2H), 6.70 (d, J¼8.1 Hz, 1H), 7.01e7.14
(m, 3H), 7.22 (d, J¼1.6 Hz, 1H), 7.27 (s, 1H), 7.82e7.93 (m, 2H) ppm.
13C NMR (75 MHz, C6D6):
d
¼23.2 (CH2), 28.3 (CH2), 51.6 (CH2), 58.7
(CH3), 61.3 (CH), 76.3 (CH2), 107.7 (CH), 108.3 (CH), 109.8 (CH2),
121.1 (CH), 127.9 (C), 128.0 (2ꢄ CH), 128.3 (CH), 130.2 (2ꢄ CH),
132.7 (C), 137.8 (C), 148.3 (C), 148.4 (C), 170.0 (CO) ppm. Anal. Calcd
for C22H24N2O4: C, 69.46; H, 6.36; N, 7.36%. Found: C, 69.29; H,
6.18; N, 7.17%.
4.5.3. (S)-2-((S)-2-Methoxymethylpyrrolidin-1-yl)-3-(3,4,5-trimeth
oxyphenyl)-3,4-dihydro-2H-isoquinolin-1-one [(S,S)-4c]. Colorless
crystals, mp 98e99 ꢁC, ½a D20
ꢃ
ꢀ7.6 (c 1.52, CHCl3). IR (neat)
n
¼2944,
1645, 1594 cmꢀ1. 1H NMR (300 MHz, C6D6)
d
¼1.72e2.07 (m, 3H),
2.71 (d, J¼15.3 Hz, 2H), 2.84 (br s, 1H), 2.98 (t, J¼9.1 Hz, 1H), 3.00
(s, 3H), 3.32e3.43 (m, 2H), 3.42 (s, 6H), 3.83 (s, 3H), 3.87 (br s, 1H),
4.33 (br s, 1H), 4.77 (d, J¼6.7 Hz, 1H), 6.39 (s, 2H), 6.73 (d, J¼7.1 Hz,
1H), 7.09 (t, J¼7.0 Hz, 1H), 7.17 (t, J¼7.7 Hz, 1H), 8.58 (d, J¼7.5 Hz,
4.4.6. N-[1-(3,4-Dimethoxyphenyl)vinyl]-4-methoxy-N-((S)-2-
methoxymethylpyrrolidin-1-yl)benzamide [(S)-3f]. Pale yellow oil,
½
a 2D0
ꢃ
ꢀ104.1 (c 1.22, CHCl3). IR (neat)
n
¼2951, 1651, 1512 cmꢀ1. 1H
NMR (300 MHz, CHCl3)
d
¼1.17e1.98 (m, 3H), 2.18e2.56 (m, 1H),
1H) ppm. 13C NMR (75 MHz, C6D6):
(CH2), 52.5 (CH2), 55.6 (2ꢄ CH3), 56.3 (CH3), 58.5 (CH3), 60.4 (CH),
64.7 (CH), 76.5 (CH2), 104.5 (2ꢄ CH), 127.3 (CH), 127.8 (CH), 127.9
(CH), 131.5 (C), 131.8 (CH), 135.6 (C), 137.7 (C), 145.5 (C), 154.0
d
¼24.0 (CH2), 28.7 (CH2), 37.3
3.10e3.22 (m, 1H), 3.20 (s, 3H), 3.24e3.43 (m, 1H), 3.39 (s, 3H),
3.48e3.91 (m, 3H), 3.55 (s, 3H), 3.62 (s, 3H), 4.94 (br s, 1H), 5.20
(br s, 1H), 6.63e6.74 (m, 3H), 7.14e7.27 (m, 2H), 7.89 (d, J¼8.3 Hz,

7146
M. Dubois et al. / Tetrahedron 68 (2012) 7140e7147
(2ꢄ C), 170.1 (CO) ppm. Anal. Calcd for C24H30N2O5: C, 67.59; H,
4.6.1. (S)-3-Phenyl-3,4-dihydro-2H-isoquinolin-1-one [(S)-1a]. Co
7.09; N, 6.57%. Found: C, 67.80; H, 6.81; N, 6.77%.
lorless crystals, mp 130e131; lit.:5e mp 130e131 ꢁC, ½a 2D0
ꢀ198.3
ꢃ
(c 0.97, CHCl3); lit.:5e
½
a 2D0
ꢃ
ꢀ203.4 (c 1.03, CHCl3). Spectral data were
4.5.4. (S)-2-((S)-2-Methoxymethylpyrrolidin-1-yl)-3-(4-methoxyph-
identical to those already published.5e
enyl)-3,4-dihydro-2H-isoquinolin-1-one [(S,S)-4d]. Colorless crys-
tals, mp 114e115 ꢁC, ½a D20
ꢃ
ꢀ6.3 (c 1.52, CHCl3). IR (neat)
n
¼2942,
4.6.2. (S)-3-(3,4-Dimethoxyphenyl)-3,4-dihydro-2H-isoquinolin-1-
1647, 1509 cmꢀ1
.
1H NMR (300 MHz, C6D6)
d
¼1.70e2.06 (m, 3H),
one [(S)-1b]. Colorless crystals, mp 149e150; lit.:4a mp 149e150 ꢁC,
2.65 (dd, J¼2.2, 15.7 Hz, 2H), 2.77 (br s, 1H), 2.93 (t, J¼9.2 Hz, 1H),
3.00 (s, 3H), 3.23e3.42 (m, 2H), 3.29 (s, 3H), 3.81 (br s, 1H), 4.32 (br
s, 1H), 4.78 (dd, J¼2.1, 6.8 Hz, 1H), 6.63 (d, J¼8.7 Hz, 2H), 6.71 (d,
J¼7.4 Hz, 1H), 7.01 (d, J¼8.7 Hz, 2H), 7.11 (dt, J¼1.5, 7.4 Hz, 1H), 7.19
(t, J¼7.4 Hz, 1H), 8.62 (dd, J¼1.3, 7.6 Hz, 1H) ppm. 13C NMR (75 MHz,
½
a 2D0
ꢃ
ꢀ102.8 (c 1.04, CHCl3); lit.:4a ee 72% ½a D20
ꢀ76.2 (c 0.28, MeOH).
ꢃ
Spectral data were identical to those already published.4a
4.6.3. (S)-3-(3,4,5-Trimethoxyphenyl)-3,4-dihydro-2H-isoquinolin-
1-one [(S)-1c]. Colorless crystals, mp 97e98 ꢁC, ½a D20
ꢀ123.0 (c 0.96,
ꢃ
C6D6):
d
¼23.9 (CH2), 28.5 (CH2), 37.4 (CH2), 52.4 (CH2), 54.7 (CH3),
CHCl3). IR (neat)
d
n
¼3171, 1655 cmꢀ1
.
1H NMR (300 MHz, CDCl3)
58.4 (CH3), 61.3 (CH), 64.4 (CH), 76.2 (CH2), 114.0 (2ꢄ CH), 127.2
(2ꢄ CH), 128.1 (CH), 128.2 (2ꢄ CH), 131.7 (C), 131.8 (CH), 134.4 (C),
135.7 (C), 159.5 (C), 163.0 (CO) ppm. Anal. Calcd for C22H26N2O3: C,
72.11; H, 7.15; N, 7.64%. Found: C, 72.33; H, 7.31; N, 7.88%.
¼3.05e3.26 (m, 2H), 3.86 (s, 9H), 4.79 (dd, J¼5.0, 10.5 Hz, 1H), 6.29
(br s, 1H), 6.62 (s, 2H), 7.20 (d, J¼7.4 Hz, 1H), 7.39 (t, J¼7.3 Hz, 1H),
7.48 (d, J¼1.4 Hz, 1H), 8.11 (d, J¼7.6 Hz, 1H) ppm. 13C NMR (75 MHz,
CDCl3):
d
¼37.7 (CH2), 56.2 (2ꢄ CH3), 56.5 (CH3), 60.9 (CH), 103.3
(2ꢄ CH), 127.3 (2ꢄ CH), 128.0 (CH), 128.2 (C), 132.6 (CH), 136.7 (C),
137.6 (C), 137.7 (C), 153.6 (C), 166.5 (CO) ppm. Anal. Calcd for
C18H19NO4: C, 69.00; H, 6.11; N, 4.47%. Found: C, 69.18; H, 6.26; N,
4.29%.
4.5.5. (S)-3,1,3-Benzodioxol-5-yl-2-((S)-2-methoxymethylpyrrolidin-
1-yl)-3,4-dihydro-2H-isoquinolin-1-one [(S,S)-4e]. Colorless crys-
tals, mp 101e102 ꢁC, ½a D20
ꢃ
ꢀ10.0 (c 1.32, CHCl3). IR (neat)
n
¼2940,
1643, 1484 cmꢀ1 1H NMR (300 MHz, C6D6)
. d
¼1.70e2.05 (m, 3H),
2.60 (dd, J¼2.5, 15.7 Hz, 2H), 2.91 (br s, 1H), 3.00 (t, J¼8.5 Hz, 2H),
3.06 (s, 3H), 3.18e3.36 (m, 2H), 3.77 (br s, 1H), 4.32 (br s, 1H), 4.68
(dd, J¼2.5, 6.8 Hz, 1H), 5.25 (d, J¼1.2 Hz, 1H), 5.29 (d, J¼1.2 Hz, 1H),
6.46e6.60 (m, 2H), 6.63e6.74 (m, 2H), 7.07 (dt, J¼1.6, 7.4 Hz, 1H),
7.14 (t, J¼7.3 Hz, 1H), 8.54 (dd, J¼1.6, 7.3 Hz, 1H) ppm. 13C NMR
4.6.4. (S)-3-(4-Methoxyphenyl)-3,4-dihydro-2H-isoquinolin-1-one
[(S)-1d]. Colorless crystals, mp 91e92 ꢁC, ½a D20
ꢀ163.6 (c 1.04,
ꢃ
CHCl3). Spectral data were identical to those already published for
a racemic sample.27
(75 MHz, C6D6):
d
¼23.9 (CH2), 28.5 (CH2), 37.3 (CH2), 52.3 (CH2),
4.6.5. (S)-3,1,3-Benzodioxol-5-yl-3,4-dihydro-2H-isoquinolin-1-one
58.5 (CH3), 61.3 (CH), 64.4 (CH), 76.3 (CH2), 101.0 (CH2), 107.6 (CH),
108.2 (CH), 120.4 (CH), 127.3 (CH), 128.2 (CH), 131.4 (C), 131.8 (CH),
135.5 (C), 136.4 (C), 147.4 (C), 148.1 (C), 163.0 (CO) ppm. Anal. Calcd
for C22H24N2O4: C, 69.46; H, 6.36; N, 7.36%. Found: C, 69.22; H, 6.31;
N, 7.44%.
[(S)-1e]. Colorless crystals, mp 103e104 ꢁC, ½a D20
ꢀ142.2 (c 1.10,
ꢃ
CHCl3). IR (neat)
d
n
¼3169, 1656 cmꢀ1
.
1H NMR (300 MHz, CDCl3)
¼3.00e3.22 (m, 2H), 4.77 (dd, J¼5.1, 10.5 Hz, 1H), 5.97 (s, 2H), 6.17
(br s, 1H), 6.76e6.90 (m, 3H), 7.18 (d, J¼7.4 Hz, 1H), 7.37 (t, J¼7.2 Hz,
1H), 7.46 (dt, J¼1.3, 7.4 Hz, 1H), 8.10 (d, J¼7.6 Hz, 1H) ppm. 13C NMR
(75 MHz, CDCl3):
d
¼37.6 (CH2), 55.9 (CH), 101.3 (CH2), 106.8 (CH),
4.5.6. (S)-3-(3,4-Dimethoxyphenyl)-6-methoxy-2-((S)-2-methoxy
108.5 (CH), 120.1 (CH), 127.3 (CH), 127.4 (CH), 128.1 (CH), 128.3 (C),
132.5 (CH), 134.8 (C), 137.6 (C), 147.6 (C), 148.1 (C), 166.3 (CO) ppm.
Anal. Calcd for C16H13NO3: C, 71.90; H, 4.90; N, 5.24%. Found: C,
71.87; H, 5.11; N, 5.00%.
methylpyrrolidin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one [(S,S)-4f].
Colorless crystals, mp 118e119 ꢁC, ½a D20
þ26.8 (c 0.81, CHCl3). IR
ꢃ
(neat)
n
¼2951, 1651, 1512 cmꢀ1
.
1H NMR (300 MHz, CDCl3)
d
¼1.62e2.06 (m, 3H), 2.23 (br s, 1H), 2.72 (br s, 1H), 2.89 (dd, J¼1.8,
15.7 Hz, 2H), 2.98 (s, 3H), 3.15e3.30 (m, 2H), 3.67e3.89 (m, 2H),
3.69 (s, 3H), 3.78 (s, 3H), 3.81 (s, 3H), 4.90 (d, J¼6.2 Hz, 1H), 6.50 (d,
J¼2.3 Hz,1H), 6.58 (d, J¼1.8 Hz,1H), 6.65 (dd, J¼2.0, 8.3 Hz,1H), 6.72
(d, J¼8.3 Hz, 1H), 6.84 (dd, J¼2.3, 8.5 Hz, 1H), 8.04 (d, J¼8.5 Hz, 1H)
4.6.6. (S)-3-(3,4-Dimethoxyphenyl)-6-methoxy-3,4-dihydro-2H-iso-
quinolin-1-one [(S)-1f]. Colorless crystals, mp 118e119 ꢁC, ½a D20
ꢃ
ꢀ96.1 (c 1.12, CHCl3). IR (neat)
n
¼3191, 1655 cmꢀ1
.
1H NMR
(300 MHz, CDCl3)
d
¼2.98e3.23 (m, 2H), 3.84 (s, 3H), 3.89 (s, 6H),
ppm. 13C NMR (75 MHz, CDCl3):
d
¼27.6 (CH2), 29.7 (CH2), 37.5
4.78 (dd, J¼4.7, 11.3 Hz, 1H), 6.05 (br s, 1H), 6.67 (s, 1H), 6.81e6.98
(CH2), 52.1 (CH2), 55.3 (CH3), 55.7 (CH3), 55.8 (CH3), 58.7 (CH3), 60.9
(CH), 64.9 (CH), 75.6 (CH2), 109.7 (CH), 110.8 (CH), 112.5 (CH), 112.8
(CH), 118.8 (CH), 123.4 (C), 129.5 (CH), 134.4 (C), 137.2 (C), 148.3 (C),
148.7 (C), 162.5 (C), 164.0 (CO) ppm. Anal. Calcd for C24H30N2O5: C,
67.59; H, 7.09; N, 6.57%. Found: C, 67.35; H, 6.88; N, 6.79%.
(m, 4H), 8.05 (d, J¼8.5 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3):
d
¼38.0 (CH2), 55.4 (CH3), 56.0 (2ꢄ CH3),109.2 (CH),111.2 (CH),112.5
(CH), 112.6 (CH), 118.8 (CH), 125.3 (C), 130.2 (CH), 133.6 (C), 139.9
(C), 148.9 (C), 149.3 (C), 162.9 (CþCO) ppm. Anal. Calcd for
C18H19NO4: C, 69.00; H, 6.11; N, 4.47%. Found: C, 68.88; H, 5.94; N,
4.29%.
4.6. Synthesis of (S)-3-aryl-3,4-dihydro-2H-isoquinolin-1-
ones (S)-1aef
4.7. Synthesis of (S)-3-aryl-1,2,3,4-tetrahydroisoquinolines
(S)-2a,d,e
Magnesium monoperoxyphthalate hexahydrate (MMPP)
(247 mg, 0.5 mmol) was added to a solution of the isoquinolinone
4aef (0.2 mmol) in MeOH (5 mL), and the resulting mixture was
then stirred at rt under argon for 2 h. The mixture was then poured
in CH2Cl2 (20 mL) and treated with a saturated NaHCO3 solution
(20 mL). The aqueous layer was extracted with CH2Cl2 (3ꢄ15 mL)
and the combined extracts were washed successively with water
(10 mL), brine (10 mL) and finally dried (MgSO4). After evaporation
of the solvent the residue was purified by flash column chroma-
tography using acetone/hexanes (30:70) as eluent to afford iso-
quinolinone (S)-1aef as a solid, which was recrystallized from
hexane/toluene.
Boran/tetrahydrofuran complex (BH3$THF, 3.0 mL, 3.0 mmol,
1 M solution in THF) was added to an ice-cooled stirred solution of
isoquinolinone 4a,d,e (0.2 mmol) in dry THF (4 mL) under argon.
The mixture was stirred at 0 ꢁC for 1 h and then refluxed for 24 h.
Aqueous 6 N HCl (2 mL) was added to the cooled reaction mixture
and the resulting mixture was stirred at rt for 1 h and then
refluxed for 1 h. The mixture was concentrated under vacuum, the
residue was made basic with aqueous 2 N NaOH and extracted
with CH2Cl2 (3ꢄ10 mL). The combined organic layers were dried
(MgSO4) and the solvent evaporated under vacuum. Purification by
flash column chromatography using EtOAc/hexanes (90:10) as
eluent.

M. Dubois et al. / Tetrahedron 68 (2012) 7140e7147
7147
Corey, E. J.; Gin, D. Y. Tetrahedron Lett. 1996, 37, 7163e7166; (e) Cox, E. D.; Cook,
J. M. Chem. Rev. 1995, 95, 1797e1842; (f) Larsen, R. D.; Reamer, R. A.; Corley, E.
G.; Davis, P.; Grabowski, E. J. J.; Reider, P. J.; Shinkai, I. J. Org. Chem. 1991, 56,
6034e6038.
4.7.1. (S)-3-Phenyl-1,2,3,4-tetrahydroisoquinoline [(S)-2a]. Pale yel-
low oil, ½a 2D0
ꢃ
ꢀ125.5 (c 0.48, CH2Cl2); lit.:24 (R)-enantiomer ½a 2D0
ꢃ
þ125.0 (c 0.55, CH2Cl2). Spectral data were identical to those
already published.24
7. (a) Vicario, J. L.; Badia, D.; Dominguez, E.; Carrillo, L. Tetrahedron: Asymmetry
2000, 11, 1227e1237; (b) Vicario, J. L.; Badia, D.; Dominguez, E.; Crespo, A.;
Carrillo, L. Tetrahedron: Asymmetry 1999, 10, 1947e1959; (c) Ishikawa, T.; Ishii,
H. Heterocycles 1999, 50, 627e639; (d) Carrillo, L.; Badia, D.; Dominguez, E.;
Vicario, J. L.; Tellitu, I. J. Org. Chem. 1997, 62, 6716e6721; (e) Meyers, A. I. Tet-
4.7.2. (S)-3-(4-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline [(S)-
2d]. Pale yellow oil, ½a D20
ꢃ
ꢀ118.8 (c 1.05, CHCl3); lit.:13 (R)-enan-
tiomer ½a 2D0
þ119.1 (c 1.39, CHCl3). Spectral data were identical to
ꢃ
€
rahedron 1992, 48, 2589e2612; (f) Gozler, B. In; Brossi, A., Ed.; The Alkaloids;
Academic: San Diego, 1987; Vol. 31, pp 317e388; (g) Bhakuni, D. S.; Jain, S. In;
Brossi, A., Ed.; The Alkaloids; Academic: Orlando, 1986; Vol. 28, pp 95e181; (h)
Santavy, F. In; Manske, R. H. F., Rodrigo, R. G. A., Eds.; The Alkaloids; Academic:
New York, NY, 1979; Vol. 17, pp 385e544.
8. (a) Valenta, V.; Holubek, J.; Svatek, E.; Dlabac, A.; Bartosova, M.; Protiva, M.
Collect. Czech. Chem. Commun. 1983, 48, 1447e1464; (b) Cushman, M.; Choong,
T. C.; Valko, J. T.; Koleck, M. P. J. Org. Chem. 1980, 45, 5067e5073; (c) Shamma,
M.; Tomlinson, H. H. J. Org. Chem. 1978, 43, 2852e2855; (d) Ito, K.; Furukawa,
H.; Iida, T.; Lee, K.-H.; Soine, T. O. J. Chem. Soc., Chem. Commun. 1974,
1037e1038; (e) Kametani, T.; Hirata, S.; Ogasawara, K. J. Chem. Soc., Perkin Trans.
1 1973, 1466e1470.
9. Hisamichi, H.; Shimada, I.; Ishihara, T.; Takuwa, T.; Shimizu, T.; Ishikawa, N.;
Maeno, K.; Seki, N. PCT Int. Appl., WO 2008146774, 2008; Chem. Abstr. 2008,
150, 20012.
10. Rothweiler, U.; Czarna, A.; Krajewski, M.; Ciombor, J.; Kalinski, C.; Khazak, V.;
Ross, G.; Skobeleva, N.; Weber, L.; Holak, T. A. ChemMedChem 2008, 3,
1118e1128.
11. (a) Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 1e314; (b) Snieckus, V. Chem.
Rev. 1990, 90, 879e933; (c) Clark, R. D.; Jahangir, A. J. Org. Chem. 1989, 54,
1174e1178; (d) Jahangir, A.; Fisher, L. E.; Clark, R. D.; Muchowski, J. M. J. Org.
Chem. 1989, 54, 2992e2996; (e) Clark, R. D.; Jahangir, A. J. Org. Chem. 1988, 53,
2378e2381; (f) Clark, R. D.; Jahangir, A. J. Org. Chem. 1987, 52, 5378e5382.
12. (a) Davis, F. A.; Chao, B.; Andemichael, Y. W.; Mohanty, P. K.; Fang, T.; Burns, D.
M.; Rao, A.; Szewczyk, J. M. Heteroat. Chem. 2002, 13, 486e492; (b) Davis, F. A.;
Mohanty, P. K. J. Org. Chem. 2002, 67, 1290e1296.
those already published for the enantioenriched (ee 92%) (R)-2d.24
4.7.3. (S)-3,1,3-Benzodioxol-5-yl-1,2,3,4-tetrahydroisoquinoline [(S)-
2e]. Pale yellow oil, ½a D20
ꢃ
ꢀ115.5 (c 0.97, CHCl3). IR (neat)
n
¼2897,
1485, 1434, 1230 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d
¼1.88 (br s, 1H),
2.90 (d, J¼7.2 Hz, 2H), 3.90 (t, J¼7.2 Hz, 1H), 4.12 (d, J¼15.5 Hz, 1H),
4.22 (d, J¼15.5 Hz, 1H), 5.91 (s, 2H), 6.78 (d, J¼8.0 Hz, 1H), 6.87 (dd,
J¼1.5, 8.0 Hz, 1H), 6.94 (d, J¼1.5 Hz, 1H), 7.01e7.18 (m, 4H) ppm. 13C
NMR (75 MHz, CDCl3):
d
¼37.9 (CH2), 49.3 (CH2), 58.4 (CH), 101.0
(CH2), 107.1 (CH), 108.2 (CH), 119.7 (CH), 125.9 (CH), 126.2 (CH),
126.3 (CH), 129.1 (CH), 134.9 (C), 135.0 (C), 138.5 (C), 146.7 (C), 147.8
(C) ppm. Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N, 5.53%.
Found: C, 76.04; H, 6.12; N, 5.77%.
Acknowledgements
This research was supported by the CNRS and by MENESR.
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