C-H activation guided by aromatic N-H ketimines: Synthesis of functionalized isoquinolines using benzyl azides and alkynes

Article abstract of DOI:10.1021/jo501465q

Aromatic N-H ketimines were in situ generated from various benzylic azides by ruthenium catalysis for the subsequent Rh-catalyzed annulation reaction with alkynes to give the corresponding isoquinolines. In contrast to conventional synthetic methods for aromatic N-H ketimines, our protocol works under mild and neutral conditions, which enabled the synthesis of isoquinolines having various functionalities such as carbonyl, ester, alkenyl, and ether groups. In addition, the imidates generated from α-azido ethers were successfully used for the synthesis of 1-alkoxyisoquinolines.

Full text of DOI:10.1021/jo501465q

Article
pubs.acs.org/joc
C−H Activation Guided by Aromatic N−H Ketimines: Synthesis
of Functionalized Isoquinolines Using Benzyl Azides and Alkynes
Sreya Gupta,† Junghoon Han,† Yongjin Kim,† Soon W. Lee,‡ Young Ho Rhee,*,† and Jaiwook Park*,†
†Department of Chemistry, POSTECH (Pohang University of Science and Technology), Pohang, 790-784, Republic of Korea
‡Department of Chemistry, Sungkyunkwan University Natural Science Campus, Suwon, 440-746, Republic of Korea
S
* Supporting Information
ABSTRACT: Aromatic N−H ketimines were in situ generated
from various benzylic azides by ruthenium catalysis for the subsequent
Rh-catalyzed annulation reaction with alkynes to give the
corresponding isoquinolines. In contrast to conventional synthetic
methods for aromatic N−H ketimines, our protocol works under mild
and neutral conditions, which enabled the synthesis of isoquinolines
having various functionalities such as carbonyl, ester, alkenyl, and ether
groups. In addition, the imidates generated from α-azido ethers were
successfully used for the synthesis of 1-alkoxyisoquinolines.
Isoquinolines and their derivatives have been recognized as an
important class of compounds that are frequently found in
numerous bioactive natural products.8 Even though numerous
processes for the synthesis of isoquinolines by imine directed
C−H bond activation reactions exist,7,9 it is hard to find practical
ones to construct isoquinolines having important func-
tional groups such as carbonyl,8d,e α-chiral8f or C-1 alkoxy-
functionalities,8g despite of the vast prevalence of these
functionalities in natural products (Figure 1). In most of the
previous processes, N-protected imines were prepared from the
corresponding carbonyl compounds; it is difficult to construct
isoquinolines having carbonyl groups (Scheme 2a).3,7 Diphenyl
N−H ketimine was the sole example tested in the Rh-catalyzed
reaction, while diaryl N−H ketimines and aryl n-butyl ketimines
were tested in the Mn-catalyzed reaction for the synthesis of
isoquinolines (Scheme 2b).4a,c The recent process using vinyl
azides as the precursors of N−H imines showed a broad reaction
scope; however, it is difficult to synthesize isoquinolines having a
chiral or sp2 carbon center at the C-1 position (Scheme 2c).10
Herein, we wish to report a new cascade synthesis of func-
tionalized isoquinolines from various benzylic azides through
Ru-catalyzed transformation into imines and Rh-catalyzed
N-annulation with alkynes (Scheme 2d). The essential merit of
our protocol is a broad scope of applicable benzylic azides,
including those having carbonyl groups and α-chiral center.
Furthermore, N−H imidates are available with our protocol
from the corresponding α-azido ethers and applicable for
the Rh-catalyzed annulation reaction with alkynes to give
1-alkoxyisoquinolines.
INTRODUCTION
■
Metal catalyzed C−H bond activation guided by a directing
group is one of the most attractive tools in organic synthesis.1
Recently, chelation-assisted electrophilic metalation of an ortho
C(sp2)−H bond directed by the lone pair of a nitrogen atom
offers an advanced route for the construction of azacyclic
compounds.2 Among the numerous nitrogen-containing direct-
ing groups, N-substituted aromatic imines have been widely
employed for the synthesis of various heteroaromatic com-
pounds.1b,d,2 However, the substituents of the imines are usually
removed in the final step to give neutral products.3 In the viewpoint of
atom economy, N-unsubstituted imines (N−H imines) would be
more desirable over N-substituted ones. Recently, several reports by
Miura,4a Glorius,4b Wang,4c Zhao,4d,e and Cramer4f have shown the
unique utility and promising importance of N−H imines by using
Rh-, Mn-, and Ru-catalysts for C−H bond activation and consequent
annulation with alkynes, carbenes and allenes (Scheme 1). However,
the significance of their work is limited by the demonstrated scope of
N−H imines, which are simple and relatively stable N−H aromatic
ketimines prepared by methods using strongly nucleophilic Grignard
reagents or alkyllithiums.5 Thus, alternative synthetic methods for
N−H imines having various functional groups are important to
extend the utilities of known reactions and to develop new ones.
Recently, we have reported a novel method for the synthesis of
N−H imines from alkyl azides by using a diruthenium catalyst
(1), which were utilized in various reactions under mild con-
ditions.6 Then we wondered if the seemingly unstable N−H
imines can be utilized for the reactions requiring more harsh
conditions. To show the versatility of our synthetic protocol
for N−H imines, we selected the Rh-catalyzed synthesis of
isoquinolines requiring heating and stoichiometric amount of
cupric acetate as an oxidant.7
Received: July 2, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo501465q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 1. N−H Imines in C−H Bond Activation Reactions
Figure 1. Natural products containing isoquinoline moieties having various functional groups.
Scheme 2. Metal-Catalyzed Synthesis of Isoquinolines by C−H Bond Activation
the presence of the diruthenium catalyst 1, was added to another
solution of diphenylacetylene, copper acetate (Cu(OAc)2), and
the rhodium catalyst 2 in dimethylformamide (DMF). Copper
acetate was essential, and the use of less than 1 equiv (amount of
copper acetate was used with respect to diphenylacetylene)
RESULTS AND DISCUSSION
■
First, we tested the Rh-catalyzed annulation reaction of
1-phenylethanimine (4a) with diphenylacetylene to give
1-methyl-3,4-diphenylisoquinoline (5a) (Table 1). A solution
of the imine 4a generated from (1-azidoethyl)benzene (3a) in
B
dx.doi.org/10.1021/jo501465q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Table 1. Optimization of the Ru/Rh Tandem Catalysis
a
entry
CuOAc2 (equiv)
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
7
−
THF:DMF = 1:4
THF:DMF = 1:4
THF:DMF = 1:4
THF:DMF = 1:4
THF:DMF = 1:4
THF:DMF = 1:4
THF
90
90
90
90
75
50
75
75
75
75
trace
43
0.2
0.5
1.0
1.0
1.0
1.0
1.0
1.0
74
98
95
21
95
35
b
8
THF
c
9
THF
90
d
10
1.0
THF
no reaction
a
b
c
d
1
Determined by H NMR analysis. One-pot one-step reaction. One-pot two-step reaction. Without using catalyst 2.
lowered the yield of 5a (entries 1−4). Heating (>75 °C) was
needed for a satisfactory yield (entries 5 and 6). For the
annulation step, tetrahydrofuran (THF) was also effective, so the
use of polar solvent such as DMF was not necessary (entry 7).11
Fortunately, the activity of 2 in the presence of 1 eliminates the
extra step of unstable imine separation, although mixing all the
reagents at the beginning of the reaction (one-pot one-step) gave
a mixture of unreacted azide and isoquinoline product, strongly
suggesting the inhibition of the activity of 1 (entry 8).12 Notably,
5a was obtained in about 90% when diphenylacetylene, catalyst 2
and Cu(OAc)2 were added into the same reaction pot containing
4a (one-pot two-step reaction sequence, entry 9). However,
we do believe that two-pot procedure would be more reliable
and reproducible as various imines were often susceptible to
hydrolysis. No isoquinoline (5a) was formed from 4a by using
only catalyst 1 (entry 10).
Under the optimized conditions for the synthesis of
isoquinoline 5a, we explored the scope of this tandem catalytic
process (Table 2). The substituent effect of the aromatic ring was
not significant on the reaction efficiency; comparable results
were obtained from the reactions of an electron-rich (3b) and an
electron-poor (3c) substrates.10 The C−Br bond in 3c remained
intact during the tandem catalytic process. The reaction with a
dialkyl substituted alkyne was proceeded smoothly to give 5d in
91% yield. The annulation of unsymmetrical alkynes such as
1-phenyl-1-butyne, methyl 3-phenylpropiolate, and 3-phenylprop-
2-yn-1-ol were occurred regioselectively to give isoquinolines
(5e−f,h) in good yields. Notably, (6-chlorohex-1-ynyl)benzene
and silyloxy-protected 3-phenylprop-2-yn-1-ol gave 5g and 5i as
regioisomeric mixtures (regioisomeric ratio of 5g and 5i was 92:8
and 95:5, respectively). 1-(1-Azidoethyl)naphthalene (3j) was
also a successful substrate for the annulation. An azafluoranthene
derivative (5k), the core structure of which is abundant in many
natural products such as triclisine, imelutenine, and rufescine13
was obtained in 75% yield from 9-azido-9H-fluorene. Various
substituents such as phenyl, vinyl, alkoxymethyl, and methoxy-
carbonyl groups could be introduced at the C-1 position of
isoquinolines (5m−p) in good yields, although the simple
isoquinoline 5l was formed in a poor yield probably due to the
low thermal stability of the benzaldimine precursor.
Our catalyst system has turned out to be effective for the
synthesis of isoquinolines containing a chiral substituent at the
C-1 position, which are essential components in many natural
products such as annocherine and artabonatine B.8f Previously,
isoquinolines having α-hydroxy chiral centers were synthesized
by either chiral catalysts14a or kinetic resolution;14b however, the
protocols were limited to specific substrates and gave low yields.
In our process, an optically active N−H imine (7) was syn-
thesized without any deterioration of optical purity by the ring-
opening reaction of (2S,3S)-2-methyl-3-phenyloxirane (6),15
methoxymethyl ether (MOM) protection of the resulting
alcohol, and Ru-catalyzed imine formation (Scheme 3). The
subsequent Rh-catalyzed annulation of 7 with diphenylacetylene
produced the isoquinoline 8 containing a chiral carbon
substituent at the C-1 position.
Another interesting application of our protocol is the syn-
thesis of isoquinolines having carbonyl groups such as 10a and
10b (Scheme 4). The corresponding imines were successfully
generated from the keto azides 9a and 9b by the Ru-catalysis in
high yields, and the Rh-catalyzed annulation proceeded with the
direction of the resulting imine functionality. Notably, the
unsymmetrical keto azide 9b selectively led to the less sterically
hindered regioisomer 10b.16
Recently, amidines and imidoyl halides have been employed
for the synthesis of 1-aminoisoquinolines17a and 1-haloisoqui-
nolines,17b respectively. We envisioned that α-azido ethers,
which can be prepared from benzyl ethers by the selective
azidation at the benzylic position,18 are precursors suitable for
C
dx.doi.org/10.1021/jo501465q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 2. Tandem Catalysis for the Synthesis of Isoquinolines
a
A solution containing azide (3, 0.3 mmol), and 1 (2.0 mol %) in THF (0.5 mL) was irradiated by fluorescent light (30 W). After 2−4 h with
monitoring the conversion of benzyl azide by TLC, the reaction mixture was transferred to the solution of alkynes (0.25 mmol), 2 (5.0 mol %), and
b
c
Cu(OAc)2 (1.0 equiv) in THF and then heated for 12 h. Isolated yields were based on the amount of alkynes. Only single regioisomer was
d
e
f
obtained. Two regioisomers were obtained (regioisomeric ratio of 5g and 5i was 92:8 and 95:5, respectively). 2 equiv of 3l were used. 10 mol % of
2 was used.
a
Scheme 3. Synthesis of an Isoquinoline Containing a Chiral Substituent at the C-1 Position
a
DIEA = N,N-diisopropylethylamine.
Scheme 4. Synthesis of Isoquinolines Containing Carbonyl Groups
the synthesis of a wide range of 1-alkoxyisoquinolines. The
transformation of azidobenzyl ethers into the corresponding
imidates was tested with (azido(ethoxy)methyl)benzene (11a);
the azidoether in THF-d8 was illuminated with fluorescent light
in the presence of 1 (8.0 mol %) at room temperature for 3 h to
give the imidate 12a in 70% yield along with benzonitrile (27%)
and EtOH.19,20 Having established the chemoselective access to
various N−H imidates, we then explored the Rh-catalyzed
isoquinoline synthesis (Table 3).21,22 A solution of an imidate
(2.0 equiv) in THF was transferred with a cannula into the flask
containing a solution of an alkyne, the rhodium catalyst 2
(5.0 mol %), and Cu(OAc)2 (1.2 equiv of copper acetate was
used with respect to alkynes) in THF. 1-Alkoxyisoquinolines
were obtained in 50−92% isolated yields with respect to alkynes,
D
dx.doi.org/10.1021/jo501465q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 3. Tandem Catalysis for the Synthesis of the 1-Alkoxy Isoquinolines
a
A solution containing α-azido ether (11, 0.5 mmol), and 1 (8.0 mol %) in THF (1.5 mL) was irradiated by fluorescent light (30 W). After 3 h, the
reaction mixture was transferred to the solution of alkyne (0.25 mmol), 2 (5.0 mol %), and Cu(OAc)2 (1.2 equiv) in THF and then heated for 12 h.
b
Isolated yield.
Scheme 5. Rhodium Intermediates for the Isoquinoline Formation
in which the alkoxy substituents contain methyl, ethyl, benzyl,
and olefinic groups. However, the attempt to synthesize a siloxy
derivative (13e) was not successful, although the imidate 12e was
formed in 61% yield. The annulation with unsymmetrical
1-phenyl-1-butyne proceeded regioselectively to give 13f in
70% isolation yield. The high yield of isoquinoline 13g was a
noticeable result showing the compatibility of aryl bromide
moiety with our catalytic system. Another noticeable result is the
successful synthesis of 13h using the corresponding imidate 12h
containing nitrile group, which cannot be afforded by the
conventional acid-catalyzed synthesis of imidates using aromatic
nitriles and alcohols.23,24
Scheme 6. Reaction Pathway for the Formation of
Isoquinolines from Benzylic Azides and Alkynes by Tandem
Ru/Rh Catalysis
Fortunately, for the first time, we succeeded to isolate the
N−H imine rhodium complex 14 from the stoichiometric
reaction of the ketimine 4a with the dirhodium complex 2 at
room temperature, and the five-membered rhodacycle 15 having
N−H moiety by the treatment of 14 with sodium acetate at 80 °C
(Scheme 5).25 Their molecular structures were elucidated by
X-ray crystallography.26 Interestingly, the structure of 14
shows an anti-geometry of the rhodium moiety and the phenyl
group, which should be rearranged to a syn-geometry for the
next C−H activation step. The intermediacy of 14 and 15 were
confirmed by the formation of isoquinoline 5a in high yield in
the reaction with diphenylacetylene in the presence of cupric
acetate.25
The reaction pathway for the formation of isoquinolines can
be suggested by combining our observations and the previous
reports describing the Rh-catalyzed reactions of N-substituted
imines with alkynes (Scheme 6).7,27 As we have reported,6 N−H
imines are formed from benzylic azides by the ruthenium
catalysis involving the liberation of N2 and [1,2]-H shift. Then
the Rh-catalyzed reaction is initiated by forming the N−H imine
rhodium complex A,26 which is transformed to the rhodacycle B
while liberating acetic acid. An alkyne is inserted in the Rh−C
bond of B to give the seven-membered rhodacycle inter-
mediate C.27 The reductive elimination reaction of C gave a
3,4-disubstituted isoquinoline along with a Rh(I) species.
The catalytic cycle is completed by the regeneration of the
Rh(III) species by the oxidation of the Rh(I) species with Cu(II)
species.
E
dx.doi.org/10.1021/jo501465q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(1R,2S)-1-azido-1-phenylpropane-2-ol (0.27 mg, 1.5 mmol) and DIEA
(0.79 mL, 4.5 mmol) in dry CH2Cl2 (5.0 mL), MOMCl (0.34 mL,
4.5 mmol) was added dropwise at 0 °C. After being stirred for 12h at
room temperature, the reaction was quenched by addition of saturated
aqueous NH4Cl solution at 0 °C. Then the crude products were
extracted with CH2Cl2 (25 mL × 3) and the combined organic layer was
dried over anhydrous Na2SO4 and filtered through a glass filter. The
filtrate was concentrated at reduced pressure, and the resulting residue
was purified by column chromatography over silica-gel (n-hexane/
Et2O) to give pale yellow oil (Yield: 0.32 g, 95%): DIEA = N,N-
CONCLUSION
■
In summary, we demonstrated the utility of N−H imines and
N−H imidates under conditions requiring heating and stoi-
chiometric amounts of oxidant for the synthesis of various
isoquinolines, including those containing carbonyl groups on
the aromatic ring and chiral substituents and alkoxy groups at the
C-1 position. The N−H imines were generated under mild
and neutral conditions from benzyl azides by a Ru-catalysis and
utilized in the tandem Rh-catalyzed annulation with internal alkynes.
Our demonstration will stimulate the use of N−H imines and the
development of new reactions employing functional N−H imines.
20
diisopropylethylamine, MOMCl = chloromethyl methyl ether; [α]D
−116.5 (c 0.01, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.16 (d, J = 6.3
Hz, 3H), 3.24 (s, 3H), 3.88−3.96 (m, 1H), 4.55 (d, J = 6.8 Hz, 1H), 4.60
(d, J = 5.2, 1H), 4.64 (d, J = 6.8, 1H), 7.30−7.39 (m, 5H); 13C NMR
(CDCl3, 75 MHz) δ 16.0, 55.6, 69.9, 76.3, 95.4, 127.8, 128.3, 128.7,
137.1; IR (NaCl) ν cm−1 919, 1033, 1104, 1154, 1216, 1254, 1289, 1349,
1381, 1401, 1453, 1586, 1604, 1953, 2104, 2779, 2824, 2844, 2891,
2935, 3032, 3065; HRMS (FAB) m/z calcd for C11H16N3O2 [M + H]+
222.1243, found 222.1241.
EXPERIMENTAL SECTION
■
General Information. All solvents were purified according to the
standard methods before use. Synthesis of isoquinolines was performed
in a flame-dried Schlenk flask under argon atmosphere. Syntheses of
N-unsubstituted ketimines and imidates were performed using NMR
tubes equipped with J-Young valves (5 mm, 400 MHz). Flash column
chromatography was carried out on silica gel (230−400 mesh). 1H and
13C NMR spectra were recorded on 300 or 600 MHz spectrometers. 1H
Synthesis of 1-(4-(1-Azidopropyl)phenyl)ethanone (9a). A solution
of 1-(4-propylphenyl)ethanone (1.6 g, 10 mmol), NBS (2.3 g, 13 mmol),
and benzoyl peroxide (0.24 g, 0.10 mmol) in carbon tetrachloride
(30 mL) was stirred at 60 °C for 12 h. After being cooled down to room
temperature, the reaction mixture was filtered through a silica-pad, and
concentrated at reduced pressure. The resulting residue and NaN3
(1.3 g, 20 mmol) were dissolved in DMF (30 mL), and the solution was
stirred at 60 °C for 12 h. The reaction mixture was diluted with water
(25 mL), and crude products were extracted with EtOAc (30 mL × 3).
The combined organic layer was washed with H2O (25 mL) and brine
(25 mL), dried over anhydrous MgSO4, and filtered through a glass
filter. The filtrate was concentrated, and the resulting residue was
purified by column chromatography over silica-gel (n-hexane/CH2Cl2)
to give 9a as a pale yellow liquid (Yield: 1.24 g, 61%): NBS = N-
NMR spectra were referenced to residual peaks of CDCl3 (7.26 ppm),
THF-d8 (3.58 ppm), CD2Cl2 (5.32 ppm) and reported as follows;
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, quint = quintet, m = multiplet). Chemical shifts of the 13C NMR
spectra were measured relative to CDCl3 (77.23 ppm), THF-d8 (67.57
ppm) and CD2Cl2 (54.00 ppm). 2D NMR spectra (COESY and
NOESY) were recorded on a 600 MHz spectrometer. Mass spectral data
were obtained by high resolution mass spectrometer. Infrared spectra
were recorded neat as thin films. All X-ray data were collected using a
diffractometer equipped with a Mo X-ray tube. Collected data were
corrected for absorption with SADABS based upon the Laue symmetry by
using equivalent reflections. All calculations were carried out with SHELXTL
programs. Ruthenium catalyst 1 was synthesized according to the literature
procedure.12 [RhCp*Cl2]2 (2), anhydrous Cu(OAc)2, (1S,2S)-(−)-1-
phenylpropylene oxide, (R)-(−)-α-methoxyphenyl acetic acid, alcohols,
halides, epoxides and ketones were purchased from commercial sources.
Synthesis and Characterization of Internal Alkynes. Dipheny-
lacetylene, oct-4-yne, but-1-ynylbenzene and 3-phenylprop-2-yn-1-ol
were purchased from commercial sources. tert-Butyldimethyl(3-phenyl-
prop-2-ynyloxy)silane,28a methyl 3-phenylpropiolate28b and (6-chlor-
ohex-1-ynyl)benzene28c were prepared according to the literature procedures.
Synthesis and Characterization of Benzylic Azides. 3a−c, 3j−n,
and 3p were prepared according to the literature procedures.29 New
azides 3o, ((1R,2S)-1-azido-2-(methoxymethoxy)propyl)benzene, 9a
and 9b were prepared by following procedures.
Synthesis of (1-Azido-2-(benzyloxy)ethyl)benzene (3o). 2-Azido-2-
phenylethanol was synthesized according to the literature procedure.29g
To a solution of 2-azido-2-phenylethanol (0.32 g, 2.0 mmol) and benzyl
bromide (0.48 mL, 4.0 mmol) in dry THF (10 mL), NaH (0.10 g,
2.6 mmol) was added portion wise at 0 °C. After being stirred for 12 h at
room temperature, the reaction was quenched by addition of saturated
aqueous NH4Cl solution at 0 °C. Then the crude products were
extracted with EtOAc (25 mL × 3), and the combined organic layer was
dried over anhydrous Na2SO4 and filtered through the glass filter. The
filtrate was concentrated at reduced pressure, and the resulting residue
was purified by column chromatography over silica-gel (n-hexane/
EtOAc) to give 3o as a colorless oil (Yield: 0.39 g, 78%): 1H NMR (300
MHz, CDCl3) δ 3.73 (d, J = 6.3 Hz, 2H), 4.65 (dd, J = 19.2, 12.1 Hz,
2H), 4.80 (t, J = 6.4 Hz, 1H), 7.34−7.44 (m, 10H); 13C NMR (75 MHz,
CDCl3) δ 65.4, 73.5, 74.2, 127.1, 127.7, 127.9, 128.5, 128.6, 128.8,
136.8, 137.8; IR (NaCl) ν cm−1 1605, 1617, 1646, 1953, 2099, 2502,
2861, 2906, 3032, 3065, 3089; HRMS (FAB) m/z calcd for C15H16N3O
[M + H]+ 254.1293, found 254.1290.
1
bromosuccinimide, DMF = N,N-dimethylformamide; H NMR (300
MHz, CDCl3) δ 0.93 (t, J = 7.4 Hz, 3H), 1.72−1.92 (m, 2H), 2.61 (s,
3H), 4.43 (t, J = 7.0 Hz, 1H), 7.38−7.41 (m, 2H), 7.95−7.99 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 10.7, 26.8, 29.5, 67.4, 127.2, 129.0, 137.0,
145.1, 197.7; IR (NaCl) ν cm−1 1268, 1306, 1360, 1414, 1463, 1507,
1574, 1609, 1651, 1681, 2098, 2480, 2879, 2937, 2972, 3058, 3353;
HRMS (EI) m/z calcd for C11H13N3O [M] 203.1059, found 203.1057.
Synthesis of 1-(3-(1-Azidoethyl)phenyl)ethanone (9b). To a
solution of 3-acetyl-α-methylbenzyl alcohol29i (0.82 mL, 5.0 mmol) in
dry toluene (15 mL), DPPA (1.3 mL, 6.0 mmol) was added slowly
at 0 °C under argon atmosphere. After being stirred for 10 min, DBU
(0.90 mL, 6.0 mmol) was added dropwise at 0 °C over 15 min. After
being stirred at room temperature for 12 h, the reaction mixture was
diluted with H2O (25 mL), and crude products were extracted with
CH2Cl2 (30 mL × 3). The combined organic layer was washed with
H2O (25 mL) and brine (25 mL), dried over anhydrous MgSO4, and
filtered through a glass filter. The filtrate was concentrated, and the
resulting residue was purified by column chromatography over silica-gel
(n-hexane/CH2Cl2) to give 9b as colorless oil (Yield: 0.57 g, 62%):
DPPA = diphenylphosphoryl azide, DBU = 1,8-Diazabicycloundec-7-
ene; 1H NMR (300 MHz, CDCl3) δ 1.55 (d, J = 6.8 Hz, 3H), 2.62 (s,
3H), 4.70 (q, J = 4.8 Hz, 1H), 7.46−7.56 (m, 2H), 7.88−7.92 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 21.6, 26.6, 60.6, 126.0, 128.1, 129.1,
130.9, 137.5, 141.6, 197.7; IR (NaCl) ν cm−1 1259, 1359, 1378, 1436,
1488, 1587, 1603, 1686, 2103, 2480, 2932, 2981, 3067, 3441; HRMS
(EI) m/z calcd for C10H11N3O [M] 189.0902, found 189.0901.
General Procedure for the Synthesis of Isoquinolines Using
Benzylic Azides and Alkynes. In a Schlenk flask, 3 (0.30 mmol), 1
(6.3 mg, 2.0 mol %), and dry THF (0.50 mL) were charged under argon
atmosphere. The reaction mixture was stirred for 2−4 h at room
temperature under 30 W fluorescent light. The complete conversion was
monitored by TLC. Then the reaction mixture in flask 1 was transferred
to another flask containing alkyne (0.25 mmol), 2 (7.7 mg, 5.0 mol %),
and Cu(OAc)2 (46 mg, 0.25 mmol) through a cannula and THF
(2.0 mL) was added. The reaction mixture was stirred at 75 °C for 12 h,
and filtered through a silica gel pad. The filtrate was concentrated under
reduced pressure, and the resulting residue was purified by column
Synthesis of ((1R,2S)-1-Azido-2-(methoxymethoxy)propyl)-
benzene. (1R,2S)-1-Azido-1-phenylpropane-2-ol was prepared accord-
ing to literature procedure.15 ((1R,2S)-1-Azido-2-(methoxymethoxy)-
propyl)benzene was synthesized from (1R,2S)-1-azido-1-phenylpro-
pane-2-ol according to modified literature procedure.29h To a solution of
F
dx.doi.org/10.1021/jo501465q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
chromatography over silica-gel (n-hexane/EtOAc or CH2Cl2) to give
corresponding isoquinolines.
7.17−7.26 (m, 5H), 7.32−7.44 (m, 5H), 7.54 (d, J = 9.1 Hz, 1H), 7.61−
7.66 (m, 1H), 7.69−7.73 (m, 1H), 7.90 (dd, J = 1.4, 7.7 Hz, 1H), 8.89 (d,
J = 8.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 30.7, 124.1, 124.4, 126.8,
127.0, 127.3, 127.4, 127.5, 127.8, 128.4, 128.9, 129.8, 130.4 (over-
lapped), 131.3, 131.8, 133.1, 137.4, 138.2, 140.8, 151.1, 155.6.
2,3-Diphenylindeno[1,2,3-ij]isoquinoline (5k). Pale yellow solid
(Yield: 67 mg, 75%): mp 174−176 °C; 1H NMR (300 MHz, CDCl3) δ
7.21−7.28 (m, 5H), 7.31−7.35 (m, 3H), 7.41−7.47 (m, 4H), 7.55 (dd,
J = 8.4, 0.4 Hz, 1H), 7.64 (dd, J =8.4, 6.4Hz, 1H), 7.79−7.85 (m, 2H), 8.16−
8.19 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 120.6, 122.1, 122.7, 125.6,
125.7, 127.3, 127.4, 127.9, 128.2, 128.8, 130.0, 130.1, 130.8, 131.6, 132.7,
133.1, 137.2, 137.5, 139.3, 140.8, 141.5, 154.3, 160.2; IR (NaCl) ν cm−1 3057,
3027, 1950, 1882, 1811, 1619, 1583, 1568, 1497, 1476, 1427, 1367; HRMS
(EI) m/z calcd for C27H17N [M] 355.1361, found 355.1362.
1-Methyl-3,4-diphenylisoquinoline (5a).10 White solid (Yield:
1
66 mg, 89%): H NMR (300 MHz, CDCl3) δ 3.07 (s, 3H), 7.13−
7.25 (m, 5H), 7.29−7.39 (m, 5H), 7.57−7.61 (m, 2H), 7.63−7.68 (m,
1H), 8.16−8.19 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 22.9, 125.7,
126.3, 126.4, 126.6, 127.1, 127.2, 127.7, 128.3, 129.3, 130.0, 130.4, 131.5,
136.1, 137.7, 141.2, 149.6, 157.9.
6-Methoxy-1-methyl-3,4-diphenylisoquinoline (5b).10 White solid
(Yield: 63 mg, 77%): 1H NMR (300 MHz, CDCl3) δ 3.01 (s, 3H), 3.72
(s, 3H), 6.91 (d, J = 2.4 Hz, 1H), 7.14−7.25 (m, 6H), 7.29−7.36 (m,
5H), 8.10 (d, J = 9.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 22.8, 55.4,
104.6, 118.8, 122.0, 127.0, 127.2, 127.6, 127.7, 128.4, 128.7, 130.4, 131.5,
138.0, 138.2, 141.4, 150.3, 157.2, 160.7.
3,4-Diphenylisoquinoline (5l).30 White solid (Yield: 30 mg, 42%):
1H NMR (300 MHz, CDCl3) δ 7.17−7.25 (m, 5H), 7.33−7.39 (m, 5H),
7.60−7.69 (m, 3H), 8.03−8.06 (m, 1H), 9.37 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 125.8, 127.0, 127.2, 127.54, 127.59, 127.7, 127.8, 128.5,
130.4, 130.7, 130.8, 131.4, 136.1, 137.4, 140.9, 150.8, 151.9.
6-Bromo-1-methyl-3,4-diphenylisoquinoline (5c).10 White solid
(Yield: 83 mg, 89%): 1H NMR (300 MHz, CDCl3) δ 3.04 (s, 3H), 7.17−
7.21 (m, 5H), 7.31−7.38 (m, 5H), 7.66 (dd, J = 1.8, 8.9 Hz, 1H), 7.80 (d,
J = 1.8 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
22.9, 124.8, 125.2, 127.3, 127.5, 127.6, 127.8, 128.5, 128.6, 130.2, 130.4,
131.5, 137.0, 137.6, 140.8, 150.8, 157.9.
1,3,4-Triphenylisoquinoline (5m).3c White solid (Yield: 87 mg,
97%): 1H NMR (300 MHz, CDCl3) δ 7.15−7.21 (m, 3H), 7.28−7.31
(m, 2H), 7.34−7.44 (m, 5H), 7.47−7.60 (m, 5H), 7.71 (d, J = 8.2 Hz,
1H), 7.82 (dd, J = 8.3, 1.6 Hz, 2H), 8.18 (d, J = 8.0 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 125.6, 126.2, 126.7, 127.1, 127.4, 127.7 (over-
lapped), 128.5 (overlapped), 128.7, 129.9, 130.1, 130.4, 130.6, 131.5,
137.1, 137.7, 140.0, 141.1, 149.8, 160.0.
1-Methyl-3,4-dipropylisoquinoline (5d).10 White solid (Yield: 52
mg, 91%): 1H NMR (300 MHz, CDCl3) δ 1.06 (t, J = 7.3 Hz, 3H), 1.11
(t, J = 7.3 Hz, 3H), 1.63−1.74 (m, 2H), 1.75−1.87 (m, 2H), 2.90−3.02
(m, 7H), 7.51 (ddd, J = 8.8, 6.7, 1.1 Hz, 1H), 7.66 (ddd, J = 8.7, 6.8, 1.2
Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 8.09 (dd, J = 8.4, 0.6 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 14.5, 14.8, 22.5, 24.0, 30.0, 37.6, 123.7, 125.4,
126.20, 126.29, 126.3, 129.5, 135.6, 151.8, 155.8.
(E)-3,4-Diphenyl-1-styrylisoquinoline (5n).9b White solid (Yield:
73 mg, 76%): 1H NMR (300 MHz, CDCl3) δ 7.19−7.27 (m, 5H), 7.32−
7.48 (m, 8H), 7.56−7.62 (m, 2H), 7.67−7.73 (m, 3H), 8.08 (d, J = 15.5
Hz, 1H), 8.15 (d, J = 15.6 Hz, 1H), 8.42−8.45 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 123.1, 124.5, 125.6, 125.5, 126.8, 127.2, 127.4, 127.71,
127.74, 128.5, 128.7, 128.9, 130.01, 130.07, 130.7, 131.6, 136.3, 137.0,
137.3, 137.9, 141.3, 150.0, 153.6.
4-Ethyl-1-methyl-3-phenylisoquinoline (5e).3c White solid (Yield:
57 mg, 92%): 1H NMR (300 MHz, CDCl3) δ 1.26 (t, J = 7.4 Hz, 3H),
2.97 (s, 3H), 2.99 (q, J = 7.5 Hz, 2H), 7.38−7.54 (m, 5H), 7.58 (ddd, J =
8.1, 6.8, 1.2 Hz, 1H), 7.72 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H), 8.07 (d, J = 8.5
Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 15.9,
21.8, 22.7, 124.3, 126.3, 126.5, 126.9, 127.6, 128.3, 128.7, 129.4, 130.0,
135.3, 142.1, 150.9, 156.0.
1-(Benzyloxymethyl)-3,4-diphenylisoquinoline (5o). White solid
Methyl 1-methyl-3-phenylisoquinoline-4-carboxylate (5f).10
1
(Yield: 72 mg, 72%): mp 91−93 °C; H NMR (300 MHz, CDCl3) δ
1
White solid (Yield: 48 mg, 70%): H NMR (300 MHz, CDCl3) δ
4.72 (s, 2H), 5.26 (s, 2H), 7.17−7.23 (m, 5H), 7.29−7.40 (m, 10H),
7.56−7.61 (m, 2H), 7.63−7.67 (m, 1H), 8.42−8.47 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 73.1, 73.8, 126.0, 126.2, 126.3, 127.0, 127.2, 127.4,
127.8, 127.9, 128.2, 128.4, 128.5, 130.2, 130.5, 131.2, 131.4, 136.8, 137.5,
138.2, 140.9, 149.3, 156.3; IR (NaCl) ν cm−1 1029, 1073, 1099, 1156,
1179, 1265, 1347, 1373, 1448, 1504, 1554, 1571, 1614, 1735, 1952,
2856, 2924, 3030, 3060; HRMS (FAB) m/z calcd for C29H24NO
[M + H]+ 402.1858, found 402.1859.
3.04(s, 3H), 3.73 (s, 3H), 7.37−7.49 (m, 3H), 7.60−7.65 (m, 1H),
7.70−7.77 (m, 3H), 8.00 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 23.1, 52.6, 121.9, 124.9, 125.8, 126.0,
127.5, 128.6, 128.8, 131.3, 133.5, 140.5, 149.9, 160.4, 169.7.
4-(4-Chlorobutyl)-1-methyl-3-phenylisoquinoline (5g).3c Yellow
1
liquid (Yield: 58 mg, 72%): H NMR (300 MHz, CDCl3) δ (Major
isomer) 1.69−1.81 (m, 4H), 2.96−3.01 (m, 5H), 3.41 (t, J = 6.2 Hz, 2H),
7.39−7.51 (m, 5H), 7.55−7.61 (m, 1H), 7.70−7.75 (m, 1H), 8.04 (d, J =
8.4 Hz, 1H), 8.15 (dd, J = 8.4, 0.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
(Major isomer) 22.6, 27.6, 28.2, 32.4, 44.5, 124.1, 126.43, 126.46, 126.5,
126.7, 127.6, 128.3, 129.3, 130.1, 135.3, 141.8, 151.2, 156.2; 1H NMR (300
MHz, CDCl3) δ (Minor isomer) 1.69−1.81 (m, 4H), 2.96−3.01 (m, 5H),
3.39 (t, J = 6.2 Hz, 2H), 7.39−7.51 (m, 5H), 7.55−7.61 (m, 1H), 7.70−7.75
(m, 1H), 8.08−8.12 (m, 2H); 13C NMR (75 MHz, CDCl3) δ (Minor
isomer) 22.6, 27.5, 29.8, 34.7, 44.9, 125.4, 125.6, 126.0, 126.5, 126.7, 127.6,
128.6, 129.8, 130.4, 136.1, 137.7, 150.7, 157.6. [Note: major and minor
isomers were obtained as inseparable mixture in 92:8 ratio.]
Methyl-3,4-diphenylisoquinoline-1-carboxylate (5p).9b White
1
solid (Yield: 72 mg, 85%): H NMR (300 MHz, CDCl3) δ 4.11 (s,
3H), 7.17−7.25 (m, 5H), 7.36−7.39 (m, 5H), 7.62−7.73 (m, 3H),
8.71−8.74 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 52.2, 125.3, 126.2,
126.3, 127.6, 127.90, 127.93, 128.1, 128.5, 130.6, 130.7, 131.2, 134.0,
137.0, 137.2, 140.1, 148.6, 149.8, 166.9.
(S)-1-(1-(Methoxymethoxy)ethyl)-3,4-diphenylisoquinoline (8).
20
White solid (Yield: 77 mg, 83%, >95% ee): mp 84−86 °C; [α]D
−83.7 (c 0.01, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.84 (d, J = 6.9
Hz, 3H), 3.40 (s, 3H), 4.80 (d, J = 6.7 Hz, 1H), 4.76 (d, J = 6.7 Hz, 1H),
6.15−7.23 (m, 5H), 7.33−7.39 (m, 5H), 7.54−7.59 (m, 2H), 7.65−7.69
(m, 1H), 8.66−8.69 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 21.4, 76.3,
95.4, 124.9, 125.6, 126.5, 126.6, 127.1, 127.4, 127.7, 128.42, 128.49, 129.9,
130.4, 130.6, 131.4, 131.5, 137.2, 137.7, 140.9, 149.1, 159.8; IR (NaCl)
ν cm−1 979, 993, 1033, 1099, 1119, 1155, 1213, 1265, 1343, 1375, 1445,
1505, 1553, 1602, 1614, 1951, 2776, 2822, 2887, 2931, 2980, 3027, 3057;
HRMS (EI) m/z calcd for C25H23NO2 [M] 369.1729, found 369.1730.
Determination of the Optical Purity of 8. The optical purity of 8
was determined by 1H NMR spectroscopy after converting to the
corresponding (R)-methoxyphenylacetic acid (MPA) ester derivative of
1-(3,4-diphenylisoquinoline-1yl)ethanol. Deprotection of methoxy-
methyl ether (MOM) moiety from 8 gave (S)-1-(3,4-diphenylisoquino-
line-1yl)ethanol. The deprotection was carried out by the following
procedure:31 BF3·Et2O (0.14 mL, 0.55 mmol) was added dropwise to a
solution of 8 (67 mg, 0.18 mmol) in dimethyl sulfide (3.5 mL) at 0 °C
and the mixture was stirred for 6 h at room temperature. The reaction
mixture was quenched by the saturated aqueous solution of NaHCO3.
(1-Methyl-3-phenylisoquinoline-4-yl)methanol (5h).9b Yellow
1
solid (Yield: 39 mg, 63%): H NMR (300 MHz, CDCl3) δ 2.10 (t,
J = 4.8 Hz, 1H), 2.99 (s, 3H), 4.99 (d, J = 4.7 Hz, 2H), 7.40−7.49 (m,
3H), 7.60−7.66 (m, 3H), 7.75−7.80 (m, 1H), 8.18 (d, J = 8.4 Hz, 1H),
8.27 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 22.8, 59.6, 124.3,
124.6, 126.3, 126.9, 128.1, 128.4, 129.8 (overlapped), 130.7, 135.9,
140.6, 151.9, 158.8.
4-((tert-Butyldimethylsilyloxy)methyl)-1-methyl-3-phenylisoqui-
noline (5i).9b Pale yellow solid (Yield: 69 mg, 76%): H NMR (300
1
MHz, CDCl3) δ (Major isomer) 0.09 (s, 6H), 0.92 (s, 9H), 3.01 (s, 3H),
5.00 (s, 2H), 7.42−7.50 (m, 3H), 7.58−7.63 (m, 1H), 7.70−7.78 (m, 3H),
8.17 (d, J = 8.5 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ (Major isomer) −5.11, 18.5, 22.9, 26.0, 60.3, 124.6, 125.1, 126.0,
126.6, 126.8, 128.0, 128.2, 130.1, 136.4, 140.8, 151.6, 158.4. [Note: major
and minor isomers were obtained as inseparable mixture in 95:5 ratio.]
1-Methyl-3,4-diphenylbenzo[h]isoquinoline (5j).10 White solid
1
(Yield: 50 mg, 81%): H NMR (300 MHz, CDCl3) δ 3.43 (s, 3H),
G
dx.doi.org/10.1021/jo501465q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
The resulting mixture was washed with water and brine, and the organic
layer was dried over anhydrous Na2SO4. After filtration and
concentration, the residue was purified by column chromatography
(silica gel column; n-hexane/Et2O) to give 1-(3,4-diphenylisoquinoline-
1yl)ethanol (Yield: 53 mg, 89%):10 1H NMR (300 MHz, CDCl3) δ 1.69
(d, J = 6.4 Hz, 3H), 5.55 (d, J = 6.4 Hz, 1H), 5.64−5.73 (m, 1H), 7.20−
7.30 (m, 5H), 7.35−7.41 (m, 5H), 7.59−7.65 (m, 2H), 7.69−7.74 (m,
1H), 8.09−8.14 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 25.7, 66.1,
123.5, 124.2, 126.9, 127.0, 127.5, 127.6, 127.8, 128.5, 128.6, 130.5,
131.51, 131.57, 137.0, 137.4, 140.5, 147.9, 161.1. Then, in a dry round-
bottom flask (10 mL), 1-(3,4-diphenylisoquinoline-1yl)ethanol (17 mg,
0.05 mmol), (R)-2-methoxy-2-phenylacetic acid (11 mg, 0.07 mmol),
DCC (14 mg, 0.07 mmol), and DMPA (3.0 mg, 0.03 mmol) were added
under argon atmosphere, and dissolved in dry dichloromethane
(1.0 mL). The reaction mixture was stirred at room temperature for
12 h. The resulting mixture was washed with water and brine, and the
organic layer was dried over anhydrous Na2SO4. Then the crude prod-
uct was purified by column chromatography (n-hexane/Et2O) to the
MPA ester as white gum (Yield: 21 mg, 89%, >95 ee): DCC = N,N′-
Dicyclohexylcarbodiimide; DMAP = N,N′-Dimethylaminopyridine;
1494, 1643, 1739, 2105, 2877, 2938; HRMS (EI) m/z calcd for
C12H15N3O [M] 217.1215, found 217.1218.
(Azido(phenyl)methoxy)(tert-butyl)dimethylsilane (11e). Color-
1
less oil (Yield: 0.57 g, 43%): H NMR (300 MHz, CDCl3) δ 0.14 (s,
3H), 0.23 (s, 3H), 0.96 (s, 9H), 5.70 (s, 1H), 7.35−7.47 (m, 5H); 13C
NMR (75 MHz, CDCl3) δ −5.1, −4.4, 18.4, 25.8, 86.5, 125.8, 128.7,
129.0, 139.7; IR (NaCl) ν cm−1 1363, 1390, 1408, 1455, 1472, 1494,
1588, 1728, 1951, 2106, 2713, 2742, 2859, 2887, 2931, 2957, 3034,
3067, 3090; HRMS (EI) m/z calcd for C13H21N3OSi [M] 263.1454,
found 263.1453.
1-(Azido(methoxy)methyl)-4-bromobenzene (11g). Colorless oil
(Yield: 0.48 g, 40%): 1H NMR (300 MHz, CDCl3) δ 3.56 (s, 3H), 5.32
(s, 1H), 7.30−7.34 (m, 2H), 7.51−7.56 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 56.4, 93.2, 123.4, 128.0, 131.9, 136.0; IR (NaCl) ν cm−1 1335,
1404, 1486, 1593, 2106, 2833, 2935, 2956, 3001; HRMS (EI) m/z calcd
for C8H7BrN3O [M − H]+ 239.9772, found 239.9771.
1-(Azido(methoxy)methyl)-4-benzonitrile (11h). Colorless oil
1
(Yield: 0.81 g, 86%): H NMR (300 MHz, CDCl3) δ 3.60 (s, 3H),
5.39 (s, 1H), 7.56−7.58 (m, 2H), 7.69−7.76 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 56.6, 92.6, 113.2, 118.5, 127.1, 132.6, 141.8; IR (NaCl)
ν cm−1 1282, 1305, 1333, 1409, 1446, 1504, 1574, 1611, 1729, 1933,
2108, 2231, 2837, 2939, 3004, 3064; HRMS (FAB) m/z calcd for
C9H9N4O [M + H]+ 189.0776, found 189.0779.
20
[α]D −60.8 (c 0.01, CHCl3); 1H NMR (300 MHz, CDCl3) δ
(Major isomer) 1.76 (d, J = 6.5 Hz, 3H), 3.37 (s, 3H), 4.86 (s, 1H), 6.79
(q, J = 6.5 Hz, 1H), 7.16−7.25 (m, 8H), 7.31−7.39 (m, 8H), 7.45−7.50
1
(m, 2H), 8.14 (d, J = 7.8 Hz, 1H); H NMR (300 MHz, CDCl3) δ
General Procedure for the Synthesis of Isoquinolines Using
Azidoethers and Alkynes. In a Schlenk flask, 11 (0.50 mmol), 1
(43 mg, 8.0 mol %), and dry THF (1.0 mL) were charged under argon
atmosphere. The reaction mixture was stirred for 3 h at room
temperature under 30 W fluorescent light. The complete conversion
was monitored by TLC. Then the reaction mixture in flask 1 was
transferred to another flask containing alkyne (0.25 mmol), 2 (7.7 mg,
5.0 mol %), and Cu(OAc)2 (55 mg, 0.30 mmol) through a cannula and
THF (2 mL) was added. The reaction mixture was stirred at 80 °C for
12 h, and then filtered through a silica gel pad. The filtrate was
concentrated at reduced pressure, and the resulting residue was purified
by column chromatography over silica-gel (n-hexane/diethyl ether) to
give the corresponding isoquinolines 13a−h.
(Minor isomer) 1.90 (d, J = 6.5 Hz, 3H), 3.42 (s, 3H), 4.84 (s, 1H), 6.77
(q, J = 6.5 Hz, 1H), 7.16−7.25 (m, 8H), 7.31−7.39 (m, 8H), 7.45−7.50
(m, 2H), 7.87 (d, J = 7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
(Major + Minor) 19.1. 57.5, 72.0, 82.8, 124.4, 124.7, 126.7, 127.0,
127.2.127.5, 127.6, 127.7, 128.5, 128.6, 128.7, 128.8, 130.0, 130.5, 130.6,
130.9, 131.3, 131.5, 136.3, 137.0, 137.6, 140.8, 148.9, 156.5, 170.5; IR
(NaCl) ν cm−1 1005, 1031, 1076, 1116, 1286, 1338, 1364, 1376, 1413,
1445, 1504, 1556, 1613, 2851, 2924, 2991, 3060, 3369; HRMS (EI) m/z
calcd for C32H27NO3 [M] 473.1991, found 473.1993.
1-(1-Ethyl-3,4-diphenylisoquinolin-6-yl)ethanone (10a). White
1
solid (Yield: 68 mg, 77%): mp 116−118 °C; H NMR (300 MHz,
CDCl3) δ 1.53 (t, J = 7.5 Hz, 3H), 2.52 (s, 3H), 3.45 (q, J = 7.5 Hz, 2H),
7.18−7.26 (m, 5H), 7.35−7.41 (m, 5H), 8.10 (dd, J = 8.7, 1.7 Hz, 1H),
8.26 (d, J = 1.2 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 13.9, 26.8, 29.0, 124.6, 125.9, 126.9, 127.4, 127.7, 127.8, 128.4,
128.7, 130.0, 130.5, 131.5, 136.2, 137.1, 137.6, 140.8, 150.5, 162.4,
198.1; IR (NaCl) ν cm−1 1370, 1384, 1413, 1446, 1496, 1549, 1572,
1601, 1688, 1729, 2854, 2874, 2932, 2971, 3029, 3058, 3084; HRMS
(EI) m/z calcd for C25H21NO [M] 351.1623, found 351.1624.
1-Ethoxy-3,4-diphenylisoquinoline (13a). White solid (Yield:
1
72 mg, 89%): mp 131−133 °C; H NMR (300 MHz, CDCl3) δ 1.53
(t, J = 7.1 Hz, 3H), 4.68 (q, J = 7.1 Hz, 2H), 7.14−7.23 (m, 5H), 7.29−
7.34 (m, 3H), 7.38−7.42 (m, 2H), 7.46−7.48 (m, 1H), 7.51−7.53 (m,
2H), 8.32−8.36 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 14.9, 62.1,
118.6, 124.1, 124.8, 125.5, 126.2, 127.10, 127.14, 127.5, 128.5, 130.4,
130.5, 131.9, 138.2, 138.5, 141.1, 147.0, 159.4. IR (NaCl) ν cm−1 1379,
1414, 1443, 1464, 1478, 1506, 1563, 1578, 1617, 1738, 1883, 1948,
2851, 2902, 2927, 2951, 2978, 3025, 3058. HRMS (EI) m/z calcd for
C23H19NO [M] calcd 325.1467, found 325.1464.
1-(1-Methyl-3,4-diphenylisoquinolin-7-yl)ethanone (10b). White
1
solid (Yield: 53 mg, 63%): mp 200−202 °C; H NMR (300 MHz,
CDCl3) δ 2.76 (s, 3H), 3.15 (s, 3H), 7.19−7.23 (m, 5H), 7.35−7.39 (m,
5H), 7.86 (d, J = 8.8 Hz, 1H), 8.10 (dd, J = 8.8, 1.7 Hz, 1H), 8.81 (d, J =
1.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 23.0, 26.9, 125.6, 127.0,
127.4, 127.5, 127.6, 127.9, 128.2, 128.6, 129.3, 130.4, 131.4, 134.9, 137.2,
138.6, 140.6, 151.9, 159.5, 197.5; IR (NaCl) ν cm−1 1389, 1421, 1485,
1506, 1556, 1582, 1611, 1681, 1734, 1811, 1819, 1881, 1891, 1947,
1959, 2921, 2957, 3027, 3056, 3084; HRMS (EI) m/z calcd for
C24H19NO [M] 337.1467, found 337.1465.
1-Methoxy-3,4-diphenylisoquinoline (13b). White solid (Yield:
64 mg, 82%): mp 173−175 °C; 1H NMR (300 MHz, CDCl3) δ 4.21 (s,
3H), 7.16−7.24 (m, 5H), 7.31−7.45 (m, 5H), 7.48−7.56 (m, 3H),
8.30−8.33 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 54.3, 114.2, 118.9,
119.7, 124.6, 125.6, 127.2, 127.8, 127.9, 128.9, 130.4, 131.5, 131.6, 136.6,
138.0, 140.1, 149.1, 159.4; IR (NaCl) ν cm−1 1379, 1414, 1443, 1464,
1478, 1506, 1563, 1578, 1617, 1738, 1883, 1948, 2851, 2902, 2927,
2951, 2978, 3025, 3058; HRMS (EI) m/z calcd for C22H17NO [M]
311.1310, found 311.1311.
1-(Benzyloxy)-3,4-diphenylisoquinoline (13c). White solid (Yield:
48 mg, 50%): mp 136−138 °C; 1H NMR (300 MHz, CDCl3) δ 5.70 (s,
2H), 7.14−7.24 (m, 6H), 7.32−7.44 (m, 8H), 7.50−7.60 (m, 4H),
8.38−8.41 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 67.9, 118.6, 124.2,
125.2, 125.6, 126.4, 127.1, 127.2, 127.6, 127.9, 128.09, 128.2, 128.5,
128.6, 128.8, 130.6, 131.8, 137.9, 138.7, 140.9, 146.9, 159.1; IR (NaCl)
ν cm−1 1274, 1335, 1354, 1411, 1444, 1505, 1577, 1600, 1617, 1738,
1807, 1883, 1949, 2886, 2945, 3031, 3061; HRMS (EI) m/z calcd for
C28H21NO [M] 387.1623, found 387.1620.
Synthesis and Characterization of Azidoethers. Azidoethers
11a−c were prepared according to the literature procedures.18
Unknown azidoethers including 11d, 11e, 11g, and 11h were prepared
by following procedure.18a To solution of benzyl ether (5.0 mmol) and
PhI(OAc)2 (4.2 g, 13 mmol) in dry acetonitrile (38 mL), TMSN3
(1.7 mL, 13 mmol) was added dropwise over 20 min at 0 °C under argon
atmosphere. The reaction mixture was stirred at room temperature for
6 h. Volatiles were removed at reduced pressure, and the resulting
residue was purified by column chromatography over silica-gel
(n-hexane/EtOAc or CH2Cl2) to give corresponding azidoethers.
PhI(OAc)2 = (diacetoxyiodo)benzene, TMSN3 = trimethylsilyl azide.
(Azido(pent-4-enyloxy)methyl)benzene (11d). Colorless oil (Yield:
0.24 g, 22%): 1H NMR (300 MHz, CDCl3) δ 1.79 (dt, J = 14.3, 6.4 Hz,
2H), 2.20 (q, J = 7.2 Hz, 2H), 3.74 (ddt, J = 84.9, 9.23, 6.3 Hz, 2H),
4.97−5.08 (m, 2H), 5.41 (s, 1H), 5.76−5.90 (m, 1H), 7.36−7.47 (m,
5H); 13C NMR (75 MHz, CDCl3) δ 29.0, 30.5, 68.6, 92.9, 115.4, 126.4,
128.9, 129.4, 137.5, 138.2; IR (NaCl) ν cm−1 1235, 1288, 1372, 1453,
1-(Pent-4-enyloxy)-3,4-diphenylisoquinoline (13d). White solid
1
(Yield: 60 mg, 66%): mp 72−74 °C; H NMR (300 MHz, CDCl3)
δ 1.99−2.08 (m, 2H), 2.31−2.38 (m, 2H), 4.65 (t, J = 6.4 Hz, 2H),
5.00−5.14 (m, 2H), 5.87−6.00 (m, 1H), 7.15−7.24 (m, 5H); 13C NMR
(75 MHz, CDCl3) δ 28.6, 30.7, 65.6, 115.2, 118.6, 124.1, 124.8, 125.6,
126.2, 127.13, 127.17, 127.6, 128.5, 130.51, 130.54, 131.9, 138.2, 138.4,
H
dx.doi.org/10.1021/jo501465q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
138.6, 141.0, 147.0, 159.5; IR (NaCl) ν cm−1 1363, 1414, 1444, 1506,
1578, 1617, 1641, 1738, 2104, 2361, 2951, 2976, 3028, 3063; HRMS
(EI) m/z calcd for C26H23NO [M] 365.1780, found 365.1780.
4-Ethyl-1-methoxy-3-phenylisoquinoline (13f). White solid (Yield:
59 mg, 89%): mp 112−114 °C; 1H NMR (300 MHz, CDCl3) δ 1.27 (t,
J = 7.3 Hz, 3H), 2.95 (q, J = 7.4 Hz, 2H), 4.09 (s, 3H), 7.36−7.59 (m,
6H), 7.70 (dt, J = 7.6, 1.3 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 8.30 (d, J =
8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 16.0, 21.5, 53.6, 119.2,
123.7, 123.9, 124.7, 126.0, 127.5, 128.1, 129.5, 130.4, 137.6, 141.9, 148.1,
158.5; IR (NaCl) ν cm−1 1319, 1339, 1367, 1443, 1454, 1506, 1574,
1740, 2875, 2935, 2973, 3033, 3060; HRMS (EI) m/z calcd for
C18H17NO [M] 263.1310, found 263.1312.
6-Bromo-1-methoxy-3,4-diphenylisoquinoline (13g). White solid
(Yield: 90 mg, 92%): mp 242−244 °C; 1H NMR (300 MHz, CDCl3) δ
4.20 (s, 3H), 7.17−7.21 (m, 5H), 7.34−7.40 (m, 5H), 7.60 (dd, J = 8.7,
1.9 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 54.0, 117.0, 124.1, 125.8, 126.0, 127.4, 127.5, 127.6,
127.9, 128.7, 129.8, 130.4, 131.7, 137.3, 140.0, 140.6, 148.4, 159.7; IR
(NaCl) ν cm−1 1276, 1335, 1372, 1408, 1442, 1486, 1569, 1607, 2865,
2891, 2956, 3024, 3055, 3066, 3081; HRMS (EI) m/z calcd for
C22H16BrNO [M] 389.0415, found 389.0412.
concentrated under reduced pressure, and 1,3,5-trimethoxybenzene was
added as an internal standard to the crude reaction mixture to analyze it
by 1H NMR spectroscopy (NMR yield of 5a was >99%).
Synthesis of 5a from 15. In a flame-dried Schlenk flask, 15 (20 mg,
0.05 mmol), diphenylacetylene (10 mg, 0.05 mmol) and Cu(OAc)2
(9.1 mg, 0.05 mmol) were charged under argon atmosphere. Dry THF
(1.0 mL) was added, and the reaction mixture was stirred at 75 °C for
12 h. After 12 h, the reaction mixture was cooled down to room tem-
perature, and filtered through a silica gel pad. The filtrate was con-
centrated under reduced pressure, and 1,3,5-trimethoxybenzene was
added as an internal standard to the crude reaction mixture to analyze it
by 1H NMR spectroscopy (NMR yield of 5a was 86%).
Catalytic Activity of 14 and 15 for the Formation of 5a. To
a solution of 1 (2.8 mg, 2.0 mol %) in dry THF (0.50 mL), 3a (18 mg,
0.12 mmol) was added under argon atmosphere. The reaction mixture
was illuminated with 30 W fluorescent light for 2 h. The conversion of 3a
was monitored by TLC. After complete conversion of 3a, the reaction
mixture was transferred through a cannula to another Schlenk flask
containing diphenylacetylene (18 mg, 0.10 mmol), 14 or 15 (10 mol %),
and Cu(OAc)2 (18 mg, 0.10 mmol) under argon atmosphere. The
reaction mixture was stirred at 75 °C for 12 h. After 12 h, the reaction
mixture was cooled down to room temperature, and filtered through a
silica gel pad. The filtrate was concentrated under a reduced pressure,
and 1,3,5-trimethoxybenzene was added as an internal standard to
1-Methoxy-3,4-diphenylisoquinoline-6-carbonitrile (13h). White
1
solid (Yield: 60 mg, 71%): mp 142−144 °C; H NMR (300 MHz,
CDCl3) δ 4.23 (s, 3H), 7.18−7.22 (m, 5H), 7.38−7.42 (m, 5H), 7.67
(dd, J = 8.6, 1.4 Hz, 1H), 7.91 (d, J = 0.8 Hz, 1H), 8.41 (dd, J = 8.5, 0.5
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 53.8, 118.6, 124.1, 125.0, 125.6,
126.3, 127.1, 127.2, 127.6, 128.0, 128.5, 130.5, 131.8, 138.1, 138.5, 141.0,
146.9, 159.7; IR (NaCl) ν cm−1 1321, 1340, 1378, 1427, 1460, 1479,
1602, 2839, 2905, 2942, 3003, 3075; HRMS (EI) m/z calcd for
C23H16N2O [M] 336.1263, found 336.1260.
1
analyze the crude reaction mixture by H NMR spectroscopy (NMR
yields of 5a catalyzed by 14 and 15 were 99% and 86% respectively).
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR data for all isoquinolines, unknown azides, and
azidoethers, and the X-ray crystallographic data (CIF) for Rh-
complexes 14 and 15. This material is available free of charge via
the Internet at http://pubs.acs.org.
Synthesis of Rh-Imine Complex 14. A solution of 3a (18 mg,
0.12 mmol) and 1 (3.0 mg, 2.0 mol %) in dry dichloroethane (0.50 mL)
was stirred and illuminated under 30 W fluorescent light for 2 h at room
temperature. To the reaction mixture a solution of [Cp*RhCl2]2 (37 mg,
0.060 mmol) in dry dichloroethane (2.0 mL) was added, and the
resulting mixture was stirred for 2 h at room temperature. Volatiles were
removed at reduced pressure and the resulting solid was crystallized
from dichloromethane/n-hexane (1:1) at room temperature to give
AUTHOR INFORMATION
Corresponding Authors
*E-mail: yhrhee@postech.ac.kr.
*E-mail: pjw@postech.ac.kr.
■
1
microcrystalline 14 (Yield: 46 mg, 90%): mp 160 °C dec.; H NMR
(300 MHz, CD2Cl2) δ 1.67 (s, 15H, 5Me-Cp*), 2.77 (s, 3H, Me), 7.43−
7.57 (m, 5H, Ph), 9.48 (bs, 1H, N−H); 13C NMR (75 MHz, CD2Cl2) δ
9.6 (Me-Cp*), 24.4, 94.6 (d, J = 8.3 Hz, Rh-Cp*), 126.6, 129.4, 132.3,
138.1, 182.7 (CN); IR (NaCl) ν cm−1 875, 1025, 1081, 1160, 1228,
1270, 1354, 1375, 1396, 1449, 1491, 1598, 1625 (NH), 1681, 2916,
2966, 3297, 3495; HRMS (FAB) m/z calcd for C18H25NCl2Rh [M + H]+
428.0419, found 428.0422, calcd for C18H24NClRh [M − HCl]+
392.0652, found 392.0642.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Research Foundation
of Korea Grant funded by the Korea government (No. 2012-
007235 and No. 2008-0061892).
Synthesis of Rh-Imine Complex 15. In a Schlenk flask, 14 (52 mg,
0.12 mmol), NaOAc (44 mg, 0.26 mmol: NaOAc was dried at 120 °C for
24 h under a high vacuum prior to use), 4 Å molecular sieves (25 mg)
and dry dichloroethane (3.0 mL) were charged under argon
atmosphere. The reaction mixture was stirred for 5 h at 80 °C, and
filtered through a Celite pad. The filtrate was concentrated at reduced
pressure, and resulting residue was crystallized from dichloromethane/
n-hexane (1:2) mixture at room temperature to give microcrystalline 15
(Yield: 36 mg, 76%): mp 190 °C dec 1H NMR (300 MHz, CD2Cl2) δ 1.66
(s, 15H, 5Me-Cp*), 2.51 (d, J = 0.6 Hz, 3H, Me), 7.03 (dt, J = 7.4, 1.0 Hz,
1H), 7.23 (ddd, J = 7.6, 7.4, 1.5 Hz, 1H), 7.40 (dd, J = 7.6, 1.2 Hz, 1H), 7.78
(d, J = 7.6 Hz, 1H), 8.94 (bs, 1H, N−H); 13C NMR (75 MHz, CD2Cl2) δ
9.6 (Me-Cp*), 22.7 (d, J = 2.1 Hz, Rh-Me), 99.0 (d, J = 6.5 Hz, Rh-Cp*),
122.6, 128.0, 131.9, 137.2, 146.7, 185.02 (d, J = 31.8 Hz, Rh−C(Ph)),
185.09 (NC); IR (NaCl) ν cm−1 856, 877, 1377, 1395, 1427, 1455, 1548,
1576, 1603, 1737, 2912, 2977, 3051, 3097, 3168; HRMS (EI) m/z calcd for
C18H24ClNRh [M − H]+ 391.0574, found 391.0570.
REFERENCES
■
(1) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529−531. (b) Fukuyama, T.;
Chatani, N.; Kakiuchi, F.; Murai, S. J. Org. Chem. 1997, 62, 5647−5650.
(c) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue, Y. Org.
Lett. 2001, 3, 2579−2581. (d) Thalji, R. K.; Ahrendt, K. A.; Bergman, R.
G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 9692−9693. (e) Yoshikai,
N.; Matsumoto, A.; Norinder, J.; Nakamura, E. Angew. Chem., Int. Ed.
2009, 48, 2925−2928. (f) Shang, M.; Sun, S.-Z.; Dai, H.-X.; Yu, J.-Q. J.
Am. Chem. Soc. 2014, 136, 3354−3357. (g) Park, S. H.; Kwak, J.; Shin,
K.; Ryu, J.; Park, Y.; Chang, S. J. Am. Chem. Soc. 2014, 136, 2492−2502.
(2) (a) Chan, W.-W.; Lo, S.-F.; Zhou, Z.; Yu, W.-Y. J. Am. Chem. Soc.
2012, 134, 13565−13568. (b) Lian, Y.; Hummel, J. R.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2013, 135, 12548−12551. (c) Brasse, M.;
́
Campora, J.; Ellman, J. A.; Bergman, R. G. J. Am. Chem. Soc. 2013, 135,
Synthesis of 5a from 14. In a flame-dried Schlenk flask, 14 (52 mg,
0.12 mmol), diphenylacetylene (22 mg, 0.12 mmol) and Cu(OAc)2
(22 mg, 0.12 mmol) were charged under argon atmosphere. Dry THF
(1.0 mL) was added, and the reaction mixture was stirred at 75 °C for
12 h. After 12 h, the reaction mixture was cooled down to room
temperature, and filtered through a silica gel pad. The filtrate was
6427−6430. (d) Kim, H. J.; Ajitha, M. J.; Lee, Y.; Ryu, J.; Kim, J.; Lee, Y.;
Jung, Y.; Chang, S. J. Am. Chem. Soc. 2014, 136, 1132−1140.
(e) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012,
112, 5879−5918. (f) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem.
Rev. 2010, 110, 624−655.
I
dx.doi.org/10.1021/jo501465q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(3) For the synthesis of isoquinolines by Rh-catalysis: (a) Guimond,
N.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2011, 133, 6449−6457.
(b) Wang, H.; Grohmann, C.; Nimphius, C.; Glorius, F. J. Am. Chem.
Soc. 2012, 134, 19592−19595. For the synthesis of isoquinolines by Ru-
catalysis: (c) Kornhaaß, C.; Li, J.; Ackermann, L. J. Org. Chem. 2012, 77,
9190−9198. (d) Villuendas, P.; Urriolabeitia, E. P. J. Org. Chem. 2013,
78, 5254−5263. (e) Chinnagola, R. K.; Pimparkar, S.; Jeganmohan, M.
Org. Lett. 2012, 14, 3032−3035. (f) Li, J.; Ackermann, L. Tetrahedron
2014, 70, 3342−3348. For the synthesis of isoquinolines by Pd-
catalysis: (g) Gerfaud, T.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed.
2009, 48, 572−577.
(4) (a) Fukutani, T.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M.
Chem. Commun. 2009, 5141−5143. (b) Shi, Z.; Koester, D. C.;
Boultadakis-Arapinis, M.; Glorius, F. J. Am. Chem. Soc. 2013, 135,
12204−12207. (c) He, R.; Huang, Z.-T.; Zheng, Q.-Y.; Wang, C. Angew.
Chem., Int. Ed. 2014, 53, 4950−4953. (d) Zhang, J.; Ugrinov, A.; Zhao,
P. Angew. Chem., Int. Ed. 2013, 52, 6681−6684. (e) Sun, Z.-M.; Chen, S.-
P.; Zhao, P. Chem.Eur. J. 2010, 16, 2619−2627. (f) Tran, D. N.;
Cramer, N. Angew. Chem., Int. Ed. 2013, 52, 10630−10634.
(5) (a) A conventional method for the synthesis of N−H ketimines is
the reaction of organic nitriles with alkyl lithium or Gregnard reagents,
followed by protonation with methanol; see: Chen, G.-M.; Brown, H. C.
J. Am. Chem. Soc. 2000, 122, 4217−4218. (b) N−H imines often exist as
mixtures of E/Z isomers; see: Gosselin, F.; O’Shea, P. D.; Roy, S.;
Reamer, R. A.; Chen, C.-Y.; Volante, R. P. Org. Lett. 2005, 7, 355−358.
(c) The hydrochloride salts of N−H ketimines can be isolated and used
for the enantioselective hydrogenation to give the corresponding chiral
amines: Hou, G.; Gosselin, F.; Li, W.; McWilliams, J. C.; Sun, Y.; Weisel,
M.; O’Shea, P. D.; Chen, C.-Y.; Davies, I. W.; Zhang, X. J. Am. Chem. Soc.
2009, 131, 9882−9883.
(6) (a) Lee, J. H.; Gupta, S.; Jeong, W.; Rhee, Y. H.; Park, J. Angew.
Chem., Int. Ed. 2012, 51, 10851−10855. (b) Jeong, W.; Lee, J. H.; Kim,
J.; Lee, W. J.; Seong, J.-H.; Park, J.; Rhee, Y. H. RSC Adv. 2014, 4,
20632−20635. (c) Han, J.; Jeon, M.; Pak, H. K.; Rhee, H. Y.; Park, J. Adv.
Synth. Catal. 2014, DOI: 10.1002/adsc.201400584.
Lett. 2005, 46, 4385−4386. (c) Cava, M. P.; Buck, K. T.; daRocha, A. I. J.
Am. Chem. Soc. 1972, 94, 5931−5931.
(14) (a) Chen, C.; Reamer, R. A.; Chilenski, J. R.; McWilliams, C. J.
Org. Lett. 2003, 5, 5039−5042. (b) Uenishi, J.; Hiraoka, T.; Hata, S.;
Nishiwaki, K.; Yonemitsu, O. J. Org. Chem. 1998, 63, 2481−2487.
(15) (a) Saito, K.; Okawara, M.; Harada, K. React. Polym. 1991, 15, 79−
83. (b) Besse, P.; Veschambre, H.; Chenevert, R.; Dickman, M.
Tetrahedron: Asymmetry 1994, 5, 1727−1744.
(16) For the steric effect in the regioselective C−H activation by Rh-
catalyst, see: Li, L.; Brennessel, W. W.; Jones, W. D. Organometallics
2009, 28, 3492−3500.
(17) (a) Wei, X.; Zhao, M.; Du, Z.; Li, X. Org. Lett. 2011, 13, 4636−
4639. (b) Chinnagolla, R. K.; Pimparkar, S.; Jeganmohan, M. Chem.
Commun. 2013, 49, 3703−3705.
(18) (a) Viuf, C.; Bols, M. Angew. Chem., Int. Ed. 2001, 40, 623−625.
(b) Pedersen, C. M.; Marinescu, L. G.; Bols, M. Org. Biomol. Chem.
2005, 3, 816−822.
(19) The N−H imidate decomposed slowly to benzonitrile and
MeOH under the reaction conditions; after 24 h, a 6:4 mixture of 12a
and benzonitrile was observed by 1H NMR spectroscopy.
(20) The formation of the imidate was further confirmed by the
subsequent reaction with HCl to give its imidate salt. See: Yadav, V. K.;
Babu, K. G. Eur. J. Org. Chem. 2005, 452−456.
(21) N-substituted benzimidates have been used in the Rh(III)-
catalyzed synthesis of phthalides by cascade addition and cyclization
with aldehydes; see: Lian, Y.; Bergman, R. G.; Ellman, J. A. Chem. Sci.
2012, 3, 3088−3092.
(22) Very recently, Glorius and co-workers have reported the synthesis
of 1H-indazoles, where simple imidates such as methyl- and ethyl
benzimidate were employed in the RhIII/CuII-cocatalyzed reaction with
tosyl azide; see: Yu, D.-G.; Suri, M.; Glorius, F. J. Am. Chem. Soc. 2013,
135, 8802−8805.
(23) The imidate 12h was formed in 54% yield in the ruthenium
catalyzed reaction of the corresponding azide.
(24) Recently, Jeganmohan and co-workers have reported the
ruthenium-catalyzed aerobic oxidative cyclization of aromatic and
heteroaromatic nitriles with alkynes to give isoquinolones; see: Reddy,
M. C.; Manikandan, R.; Jeganmohan, M. Chem. Commun. 2013, 49,
6060−6062.
(7) Guimond, N.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 12050−
12051.
(8) (a) Pike, V. W.; Halldin, C.; Crouzel, C.; Barre, L.; Nutt, D. J.;
́
Osman, S.; Shah, F.; Turton, D. R.; Waters, S. L. Nucl. Med. Biol. 1993,
20, 503−525. (b) Weissman, B. A.; Raveh, L. J. Neurochem. 2003, 84,
432−437. (c) Rinehart, K. L. Med. Res. Rev. 2000, 20, 1−27. (d) Lee, J.
C.; Cha, J. K. J. Am. Chem. Soc. 2001, 123, 3243−3246. (e) Castillo, V.
C.; Fuentes, M. R.; Theoduloz, C.; Cassels, B. K. J. Nat. Prod. 2010, 73,
1951−1953. (f) Chen, C.-Y.; Chang, F.-R.; Pan, W.-B.; Wu, Y.-C.
Phytochemistry 2001, 56, 753−757. (g) Ullyot, G. E. US Patent
2612503−19520930, 1952. (h) Migliarese, J. F.; De Salva, J. S. US
Patent 3172805−19650309, 1965. (i) Gamage, S. A.; Spicer, J. A.;
Rewcastle, G. W.; Milton, J.; Sohal, S.; Dangerfield, W.; Mistry, P.;
Vicker, N.; Charlton, P. A.; Denny, W. A. J. Med. Chem. 2002, 45, 740−
743. (j) C.-Castillo, V.; S.-Rozas, C.; Pabon, A.; Perez, E. G.; Cassels, B.
́ ́
K.; Blair, S. Bioorg. Med. Chem. Lett. 2013, 23, 327−329. (k) Bentley, K.
W. Nat. Prod. Rep. 2006, 23, 444−463.
(9) (a) Parthasarathy, K.; Cheng, C.-H. J. Org. Chem. 2009, 74, 9359−
9364. (b) Too, P. C.; Wang, Y.-F.; Chiba, S. Org. Lett. 2010, 12, 5688−
5691. (c) Lim, S.-G.; Lee, J. H.; Moon, C. W.; Hong, J.-B.; Jun, C.-H.
Org. Lett. 2003, 5, 2759−2761. (d) Colby, D. A.; Tsai, A. S.; Bergman, R.
G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814−825.
(25) See Experimental Section.
(26) CCDC 965136 (14) and 965137 (15) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
(27) Analogous N-methylimine rhodium complex has been reported;
see: Li, L.; Brennessel, W. W.; Jones, W. D. J. Am. Chem. Soc. 2008, 130,
12414−12419.
(28) (a) Wang, C.; Rakshit, S.; Glorius, F. J. Am. Chem. Soc. 2010, 132,
14006−14008. (b) Rooke, D. A.; Ferreira, E. M. Angew. Chem., Int. Ed.
2012, 51, 3225−3230. (c) Semba, K.; Fujihara, T.; Xu, T.; Terao, J.;
Tsuji, Y. Adv. Synth. Catal. 2012, 354, 1542−1550.
(29) (a) Pardin, C.; Roy, I.; Lubell, W. D.; Keillor, J. W. Chem. Biol.
Drug Des. 2008, 72, 189−196. (b) Muruli, A.; Puppala, M.; Varghese, B.;
Baskaran, S. Eur. J. Org. Chem. 2011, 5297−5302. (c) Myers, E. L.;
Raines, R. T. Angew. Chem., Int. Ed. 2009, 48, 2359−2363. (d) Trillo, P.;
́
Baeza, A.; Najera, C. J. Org. Chem. 2012, 77, 7344−7354.
(e) Matyjaszewski, K.; Tsarevsky, N. US Patent 6624262 B2, 2003.
(f) Freitas, L. B. O.; Eisenberger, P.; Crudden, C. M. Organometallics
2013, 32, 6635−6638. (g) Yadav, J. S.; Reddy, B. V. S.; Jypthirmai, B.;
Murty, M. S. R. Tetrahedron Lett. 2005, 46, 6559−6562. (h) Naito, H.;
Kawahara, E.; Maruta, K.; Maeda, M.; Sasaki, S. J. Org. Chem. 1995, 60,
4419−4427. (i) Onishi, Y.; Nishimoto, Y.; Yasuda, M.; Baba, A. Org.
Lett. 2011, 13, 2762−2765.
(10) Wang, Y.-F.; Toh, K. K.; Lee, J.-Y.; Chiba, S. Angew. Chem., Int. Ed.
2011, 50, 5927−5931.
(11) Conventionally polar solvents such as DMF and MeOH were
used for the Rh-catalyzed annulation.
(12) A ruthenium acetate or a ruthenium chloride species would be
formed, which is not active for the transformation of alkyl azides into the
corresponding imines. For the formation of ruthenium triflate in the
reaction using AgOTf, see: Casey, C. P.; Vos, T. E.; Singer, S. W.; Guzei,
I. A. Organometallics 2002, 21, 5038−5046.
(30) Korivi, R. P.; Cheng, C.-H. Org. Lett. 2005, 7, 5179−5182.
(31) Naito, H.; Kawahara, E.; Maruta, K.; Maeda, M.; Sasaki, S. J. Org.
Chem. 1995, 60, 4419−4427.
(13) (a) Menachery, M. D.; Muthler, C. D. J. Nat. Prod. 1987, 50, 726−
729. (b) Ramana, M. M. V.; Sharma, R. H.; Parihar, J. A. Tetrahedron
J
dx.doi.org/10.1021/jo501465q | J. Org. Chem. XXXX, XXX, XXX−XXX