Direct functionalization of (Un)protected tetrahydroisoquinoline and isochroman under iron and copper catalysis: Two metals, two mechanisms

Article abstract of DOI:10.1021/jo201511d

A highly facile, straightforward synthesis of 1-(3-indolyl)- tetrahydroisoquinolines was developed using either simple copper or iron catalysts. N-protected and unprotected tetrahydroisoquinolines (THIQ) could be used as starting materials. Extension of t

Full text of DOI:10.1021/jo201511d

ARTICLE
pubs.acs.org/joc
Direct Functionalization of (Un)protected Tetrahydroisoquinoline
and Isochroman under Iron and Copper Catalysis: Two Metals,
Two Mechanisms
Michael Ghobrial, Michael Schn€urch,* and Marko D. Mihovilovic
Institute of Applied Synthetic Chemistry, Vienna University of Technology, 1060 Vienna, Austria
S Supporting Information
b
ABSTRACT: A highly facile, straightforward synthesis of 1-(3-indolyl)-tetrahydroiso-
quinolines was developed using either simple copper or iron catalysts. N-protected and
unprotected tetrahydroisoquinolines (THIQ) could be used as starting materials.
Extension of the substrate scope of the pronucleophile from indoles to pyrroles and
electron-rich arenes was realized. Additionally, methoxyphenylation is not limited to
THIQ but can be carried out on isochroman as well, again employing iron and copper
catalysis.
’ INTRODUCTION
adducts. Such reactions have been reported by Murahashi et al.,15
Li et al.,16 and others.17
Functionalized, nitrogen-containing heterocycles constitute a
widespread structural motif in biologically active compounds1
and an invaluable template for chiral auxiliaries2 in asymmetric
synthesis.3 In particular, tetrahydroisoquinolines (THIQs) and
indoles are common structural motifs in important compounds
such as natural products4 as well as pharmaceuticals5 and display
significant antitumor activities.6 1-Arylated THIQs have been
demonstrated to have interesting pharmacological properties,7
including anti-HIV8 and neuroprotective activity.9 Due to the
broad application possibilities of these compounds, methods for
their ever more efficient preparation are continuously sought
after. In this respect, transition-metal-catalyzed cross-coupling
reactions of various reactive functional groups have been devel-
oped as powerful methods for constructing CÀC bonds.10
However, it would be even more desirable to use CÀH bonds
directly for CÀC bond formation. Such transformations are
usually termed CÀH activation reactions.11 In the case of sp3
CÀH bonds, it was found that CÀH bonds adjacent to a
nitrogen could be efficiently activated, and several protocols
were reported.12 Such reactions display much better atom
efficiency in comparison to traditional cross-coupling reactions,
since prefunctionalization of building blocks for later CÀC bond
formation can be avoided.3b,13 This also helps to make synthetic
schemes shorter and more efficient. However, it would be even
more efficient to use the CÀH bonds of two substrates to be
coupled directly with each other for CÀC bond formation. This
was realized in cross dehydrogenative coupling (CDC) reactions,
which are defined as the cross-coupling of two different CÀH
bonds of pronucleophiles and proelectrophiles.14 Using THIQ as
substrate it was reported that N-arylated THIQs can be coupled
to a series of nucleophiles, such as NaCN, nitroalkanes, terminal
alkynes, malonates, malononitriles, pyrroles, 2-naphthol, and
phenylboronic acids, as well as MoritaÀBaylisÀHillman (MBH)
One inspiration for the research published within this con-
tribution was a recent report by the group of Li on the CDC
between functionalized indoles and position 1 of N-arylated
THIQs. The presence of tert-butyl hydroperoxide (tBHP as a
solution in decane) as oxidant proved to be necessary, but no
additional solvent was needed using copper(I) bromide as
catalyst.18 However, there is one significant limitation of this
protocol, the removal of the N-phenyl group, which would allow
further functionalization of the THIQ on its amine group.
Although the removal of phenyl from amines was reported, it
required conditions which are only tolerated by a small set
of organic compounds (100 equiv of Li/NH3/THF/À40 °C,
3 h).19 Alternatively, the authors used the p-methoxyphenyl group
(PMP), which should be removable in principle; however, using
standard deprotection conditions20 we were unable to deprotect
the indolated THIQs. Using a generally removable protecting
group (PG) instead would open the possibility to perform
further transformations after the initial CÀC bond forming step.
This would be highly desirable if a cheap and readily available
catalyst could be used for the CDC reaction. Copper catalysts are
highly attractive, since they are significantly cheaper and environ-
mentally more benign compared to noble metal catalysts such as
Pd, Ru, and Rh. An early example of a CÀC bond forming
process using Cu catalysts was the Ullmann coupling reaction.21
In recent years copper catalysis has regained much attention and
several interesting contributions have been reported.22 An even
more attractive metal for catalytic systems would be iron, since it
is environmentally and economically superior to copper and
there are already many literature reports where iron catalysts
Received: July 20, 2011
Published: September 09, 2011
r
2011 American Chemical Society
8781
dx.doi.org/10.1021/jo201511d J. Org. Chem. 2011, 76, 8781–8793
|

The Journal of Organic Chemistry
ARTICLE
Table 1. Optimization of the Catalyst System and Choice
of PG
Scheme 1. Copper-Catalyzed Indolation and Benzylic Oxi-
dation of Boc-NTHIQ
entry
R
cat.
oxidant
tBHP
yield (%)
c
c
c
c
c
c
c
c
1
Ac (1a)
Cu(NO3)2
CuBr
54
’ RESULTS AND DISCUSSION
2
Ac (1a)
tBHP
tBHP
tBHP
tBHP
tBHP
tBHP
tBHP
tBHP
tBHP
tBHP
tBHP
tBHP
tBHP
tBHP
tBHP
tBHP
tBHP
tBHP
tBHP
tBHP
tBHP
47
3
Piv (1b)
Piv (1b)
Bn (1c)
Cu(NO3)2
CuBr
26
Initially, various protected THIQs were synthesized according
to literature protocols5b,25 to identify protected THIQs suitable
for the proposed transformations. They were then submitted to
standard indolation conditions18 using copper(I) bromide as
catalyst and tBHP as oxidizing agent at 50 °C. Copper(I)
bromide was chosen, since indolation of N-phenyl-THIQ was
reported in the presence of this catalyst (Table 1).
4
21
5
Cu(NO3)2
CuBr
60
6
Bn (1c)
36
7
Bz (1d)
Cu(NO3)2
CuBr
40
8
Bz (1d)
10
9
CBz (1e)
CBz (1e)
Tos (1f)
Tos (1f)
2-Py (1g)
2-Py (1g)
Boc (1h)
Boc (1h)
Boc (1h)
Boc (1h)
Boc (1h)
Boc (1h)
Boc (1h)
Boc (1h)
Boc (1h)
Boc (1h)
Boc (1h)
Boc (1h)
Boc (1h)
Boc (1h)
Cu(NO3)2
CuBr
60
The starting material carrying the Boc protecting group (1h)
afforded the best product yield (79%, entry 15), followed by Ac-
protected 1a (47%, entry 2), CBz-protected 1e (41%, entry 10),
and benzyl-protected 1c (Bn, 36%, entry 6). The benzoyl-
protected substrate 1d (Bz, 10%, entry 8) was less efficient. In
the case of Piv-protected 1b (21%, entry 2) the significantly
lower yield can be attributed to steric hindrance. Heterocyclic
substituents such as 2-pyridinyl (1g) gave the indolated product
in 44% yield (entry 14); however, this group requires a two-step
protocol for cleavage.12a,26 Only the tosyl PG (substrate 1f)
seemed to be ineffective in this transformation (entry 16). In
summary, the copper-catalyzed indolation is not limited to pro-
tective groups carrying a carbonyl function as was the case for our
previously disclosed iron-catalyzed protocol.24 Since the Boc
group (substrate 1h) turned out to be the most suitable PG using
copper(I) bromide as catalyst, this substrate was selected for a
subsequent round of parameter optimizations, starting with the
catalyst species. Interestingly, copper(II) nitrate (entry 11)
showed the best conversion (82%), closely followed by copper-
(II) acetate (entry 18) and copper halide salts (entries 19À22).
In the case of copper(I) iodide (entry 19) significant byproduct
formation (oxidized THIQ 4h and other unidentified byproduct,
Scheme 1) could be monitored by HPLC, resulting in a decrease
in conversion to the desired product, whereas cleaner conver-
sions were achieved when employing copper(I) chloride (74%,
entry 21) or copper(II) fluoride (76%, entry 22). Such a benzylic
oxidation was already reported in the literature under related
conditions (82 °C, excess tBHP, iron(III) chloride hexahydra-
te).27 Double substitution at the C3 and N1 positions of the
indole with 1h was not observed, as was reported in a similar
CDC reaction of N,N-dimethylanilines with indoles.28
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
41
Cu(NO3)2
CuBr
traces
traces
61
Cu(NO3)2
CuBr
44
Cu(NO3)2
CuBr
79
72
CuCN
(65)
(74)
(61)
(73)
(74)
(76)
nca
Cu(OAc)2
CuI
CuBr
CuCl
CuF2
CuCl
CuCl2
nca
tracesb
tracesb
tracesb
nc
c
c
c
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
H2O2 (30%)
mCPBA
DBPO
tBHP
nc = no conversion. 1 equiv of catalyst was employed. b Monitoring
a
according to GC/MS, conversion in parentheses according to HPLC.
c Cu(NO3)2 3H2O employed.
3
show promising properties in many synthetically valuable trans-
formations.16e,23 Also, our group contributed to this field
by disclosing an improved protocol for the direct indola-
tion and methoxyarylation of protected THIQs and isochroman
by employing cheap iron salts as catalysts.24 Even more impor-
tantly, removable protecting groups such as the Boc group
could be used instead of phenyl or PMP, and these were easily
cleaved under very mild reaction conditions in most cases in
quantitative yield.
Within this contribution, we report a method for the indola-
tion, pyrrolation, and methoxyphenylation of THIQs and isochroman
under copper catalysis in the absence of any protecting group on
THIQ. Additionally, iron- and copper-catalyzed protocols for the
transformations of protected THIQs and isochroman were investi-
gated. Advantages and limitations of the catalytic systems will be dis-
cussed in detail.
To confirm that copper(II) nitrate is the catalyst of choice in
combination with Boc as the best PG, the other protected THIQs
were also submitted to the indolation process using copper(II)
nitrate as catalyst. Generally, all yields obtained with copper(II)
nitrate were slightly higher in comparison to the corresponding
transformation catalyzed by copper(I) bromide, and again the
best yield of the desired product (79%, entry 15) was obtained
using 1h as starting material. CBz (1e, 60%, entry 10), Bn (1c,
60%, entry 5), and 2-pyridinyl (1g, 61%, entry 13) also per-
formed well. With Bz as the PG (1d), the yield could be
significantly increased from 10% (entry 8) to 40% (entry 7).
8782
dx.doi.org/10.1021/jo201511d |J. Org. Chem. 2011, 76, 8781–8793

The Journal of Organic Chemistry
ARTICLE
Scheme 2. A Comparison: Tentative Mechanisms of the Iron/Copper-Catalyzed Indolation of (N-PG)THIQ
Again, Tos-protected starting material 1f was not accepted in this
transformation (entry 11). Finally, the role of the oxidant was
examined: tBHP without catalyst (entry 28) or stoichiometric
amounts of copper in absence of an oxidant failed to perform the
reaction, independent of the oxidation state of the copper salt
(entries 23 and 24). Hence, it seems that the oxidizing agent is
not only required to reoxidize the copper salt from copper(I) to
copper(II) in the catalytic cycle. However, this additional role of
the oxidizing agent has not yet been elucidated. This result
supports the proposed mechanism of Li et al., which suggests that
a peroxide is required as oxidant to convert copper to the oxy-
copper species B2, which then coordinates to the nitrogen of
THIQ and forms the iminium-type intermediate C2 by elimina-
tion of water, which is then attacked by a nucleophile to form the
desired product (Scheme 2).29 In contrast to the iron-catalyzed
transformation, a carbonyl group adjacent to the nitrogen of the
THIQ is not mandatory for the copper-catalyzed reaction,
indicating a complexation of the copper with the nitrogen to
form species A2 rather than with the oxygen of the carbonyl
group. In the copper(II) nitrate catalyzed transformation addi-
tion of TEMPO, a radical scavenger, did not result in a decrease
in product formation, in contrast to our results when employing
iron salts as catalysts.24 This indicates that the product is formed
by an ionic mechanism rather than through a radical pathway.
Other oxidants such as hydrogen peroxide (entry 25) and mCPBA
(entry 26) only showed traces of the desired product. Thus,
tBHP seems to be mandatory as the oxidant in this reaction. In
Scheme 2 the proposed mechanism for the iron- and copper
catalyzed transformations are displayed.
good yields in both the copper- and iron-catalyzed processes (3h,
79% and 54% respectively). N-Methylindole (Table 2, entry 2)
was also well tolerated by both catalysts; however, copper
performed slightly better than the iron catalyst (3i, 70% vs
65% yield). A significant difference in substrate conversion was
observed when employing 2-methylindole: in the copper-cata-
lyzed reaction the desired product 3j was obtained in 67% yield
(Table 2, entry 3). This good yield is especially remarkable, since
it shows that sterically hindered indoles can also be applied in this
transformation; this was not the case for the iron catalyst, where
only 23% of 3j could be obtained. This result is in line with our
proposed mechanism for the iron-catalyzed indolation process,
where the iron species coordinates to the carbonyl group of the
Boc PG as well as to the nitrogen of the indole.24 Thus,
complexation might be hindered due to the methyl group at
position C-2 of indole, resulting in a decreased yield. On the
other hand, a free amine functionality (Table 2, entry 4) was not
tolerated at all in copper catalysis and only 16% of 3k could be
isolated when using iron(III) nitrate as catalyst. In copper
catalysis both electron-withdrawing (3mÀo) and electron-do-
nating (3l) substituents are well tolerated at position C-5 of
indole. Substituents at positions 6 (Table 2, entry 9) and 7
(Table 2, entry 10) were also tolerated (3p,q). The picture
completely changes when looking at the iron-catalyzed yields:
with 5-nitro (Table 2, entry 6), 5-chloro (Table 2, entry 8), and
7-nitro substituents (Table 2, entry 10) even better yields were
obtained in comparison to the case for the copper-catalyzed
reactions (3m, 66% vs 59%; 3o, 72% vs 66%; 3q, 70% vs 46%). In
these cases, the oxidized N-Boc THIQ byproduct 4h that always
formed was formed to a lesser extent compared to the case for the
copper-catalyzed protocol. Since iron has a high affinity toward
oxygen,30 it was not surprising that the 5-methoxy-substituted
product 3l was obtained in a notably lower yield (Table 2, entry 5),
and the ester substituent (Table 2, entry 7) was even less
tolerated as a functional group (3n). In addition to indole, also
other ring systems could be applied as coupling partners, such as
7-azaindole (3r, 42% and 44%) and 6-chlorodeazapurine
After we established optimized reaction conditions, a set of
various functionalized indoles was reacted with N-Boc THIQ.
The results of the copper-catalyzed variant are compared with the
results of our previously disclosed iron-catalyzed protocol in
Table 2.
It was found that, depending on the indole derivative applied,
either iron or copper gave better results, whereas the latter metal
was favored in most cases. Simple indole (Table 2, entry 1) gave
8783
dx.doi.org/10.1021/jo201511d |J. Org. Chem. 2011, 76, 8781–8793

The Journal of Organic Chemistry
ARTICLE
Table 2. Indolation of Boc-THIQ 1h
decomposition of the starting materials was observed and the protocol
was hence not generally applicable.
Overall, a three-step procedure for the synthesis of 1-indolated
THIQs was developed which delivers high yields due to the high-
yielding introduction and cleavage of a versatile protecting group.
However, CDC of unprotected THIQ and substituted indoles
would represent an even more atom efficient transformation. In
such a process, two reaction steps (installation and cleavage of
the protecting group) could be circumvented, which also saves
time and material resources otherwise needed for purification of
the intermediate products. To our delight, indolation of THIQ 6
toward products 5 could be achieved in good yields (Table 3)
even without N-protection using copper(II) nitrate as catalyst.
When standard conditions were applied for indolation from the
above series of experiments on Boc-protected precursors, THIQ
(1.0 equiv of indole, 0.8 equiv of THIQ) could be indolated in
approximately 50% yield, independent of the functional group
of the indole (Table 3, entries 4, 7, 9, 11, 14, 16, and 17). 3,4-
Dihydroisoquinoline (DHIQ) was also formed as a byproduct via
oxidative dehydrogenation to approximately the same extent as the
desired products.34 Changing the ratio of substrates to 2 equiv of
THIQ and 1.0 equiv of indole resulted in an increased yield of the
desired product 5h of 74% (Table 3, entry 3). A further improved
yield of 5h of 85% (Table 3, entry 2) was achieved when 4 equiv of 6
was employed. These results indicate that DHIQ byproduct forma-
tion occurs at approximately the same reaction rate as the desired
product formation. An even higher excess of THIQ (8 equiv) did
not improve the yield further (Table 3, entry 1). Also in other cases
an excess of 2 equiv of THIQ (Table 3, entries 10, 12, and 18) gave
better yields. It has to be pointed out, that 1-methyl- (Table 3, entry 6),
3-methyl- (Table 3, entry 8), and 7-nitroindoles (Table 3, entry 15)
are ineffective substrates in this particular transformation. The
failure of 1-methylindole might indicate that a free indole NH
group is mandatory for complexation with the copper catalyst
and that this step is important for initiating the reaction. In the
case of 3-methylindole, the C2 position of the indole is probably
not sufficiently electron rich to undergo this type of transforma-
tion (Table 3, entry 8). On the other hand, 7-nitroindole
competes with the free NH group for complexation with the
copper-species, and therefore no desired product is formed.35
Also, iron catalysis was investigated for this transformation but
did not give any indolated product. Thus, protection of nitrogen
with a carbonyl PG is mandatory for this metal, since only THIQs
with a PG containing a carbonyl group showed successful
indolation, due to coordination of the iron species with the
oxygen of the carbonyl group.24
yield of
indolation (%)
deprotection
yield
Cub entry product (%)e
entry
1
R
X/Y product Fea
H
CH/CH 3h
CH/CH 3i
CH/CH 3j
54
65
79
70
13
14
5h
5i
100c
89d
100c
97d
100c
np
2
1-CH3
3
4
5
6
7
8
9
2-CH3
5-NH2
5-OCH3
5-NO2
23
16
43
66
5
67
nc
52
59
50
66
75
46
44
40
15
16
17
18
19
20
21
22
23
24
5j
CH/C
CH/C
CH/C
3k
3l
5l
99c
100c
3m
3n
3o
5m
5-COOMe CH/C
np
5-Cl
6-Cl
CH/C
72
56
70
42
nc
5o
5p
5q
5r
100c
86c
99c
CH/CH 3p
10 7-NO2
11 H
C/CH
N/CH
N/N
3q
3r
3s
100c
12 6-Cl
np
a Fe(NO3)3 9H2O. b Cu(NO3)2 3H2O. c Conditions: TMSCl, MeOH,
3
3
room temperature. d Conditions: ethylene glycol, 250 °C, microwave, 30 s.
e yYield after deprotection of the Boc PG; np = not performed.
(Table 2, entry 12). In the case of 7-azaindole (Table 2, entry 11)
comparably mediocre yields were achieved with copper as well as
with iron catalysis. Using copper(II) nitrate as catalyst 40% of the
desired product derived from 6-chlorodeazapurine 3s was isolated.
On the other hand, the desired product was only observed in traces
on TLC when using iron(III) nitrate. Benzo[b]furan, benzo-
[b]thiophene, and benzimidazole gave no conversion.
Having established two protocols for the indolation of N-Boc-
THIQ, we finally attempted to cleave the Boc protecting group in
order to obtain the free NH 1-indolated NH-THIQs. Initially,
standard acidic deprotection conditions31 were used however
decomposition of the starting material 3h was observed. Only in
refluxing AcOH was a mediocre yield of 40% of 5h obtained, in
addition to decomposition products. In the search for milder
conditions we found that using TMSCl in MeOH at room
temperature gave excellent results (Table 2).32 In most cases
quantitative yields of the deprotected products were obtained,
independent of the nature of the substituents on the indole core.
The deprotection in the presence of 6-Cl-indole toward com-
pound 5p gave the lowest but still satisfactory yield of 86%
(Table 2, entry 21). A second alternative thermal deprotection
of the Boc group under microwave irradiation33 would be an
operationally simple alternative strategy to classical deprotection. It
was found that starting materials 3h,i could be deprotected in excellent
yield to afford 5h (89%, Table 2, entry 13) and 5i (97%, Table 2,
entry 14) on heating to 250 °C under microwave irradiation. This
method proved to be very time efficient, since 30 s of hold time was
sufficient for complete deprotection. Unfortunately, in other cases
On comparison of the two outlined methods, reaction of the
unprotected THIQ is superior with regard to atom efficiency,
even though an excess of THIQ is required in order to obtain
high yields (Scheme 3). The same is true regarding time
efficiency, since two reaction steps can be avoided. Still, the iron-
and copper-catalyzed protocols can be useful alternatives in cases
where the free NH of THIQ is not tolerated. Two such examples
were encountered: i.e., 1-methyl- (Table 2, entry 2) and 7-ni-
troindole (Table 2, entry 10). In these cases the protocol
employing Fe(NO3)3 as catalyst gave 57% and 63% yields over
three steps and the Cu(NO3)2-catalyzed method gave 63% and
41% yields, respectively, again over three steps. Generally, when
the overall yield over three steps is compared to the yield of the
direct protocol, higher yields are obtained in the direct method
when 2 equiv of THIQ is applied. When only 1 equiv of this
substrate is used, the three-step protocol including protection
8784
dx.doi.org/10.1021/jo201511d |J. Org. Chem. 2011, 76, 8781–8793

The Journal of Organic Chemistry
ARTICLE
Table 3. Copper-Catalyzed Indolation of THIQ
Scheme 3. Indolation of Unprotected THIQ vs Protec-
tionÀDeprotection Pathway
entry
R
X
amt of THIQ (equiv)
yield (%)
1 (5h)
2 (5h)
3 (5h)
4 (5h)
5 (5h)
6 (5i)
H
H
H
H
H
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
8.0
4.0
2.0
0.8
0.4
0.8
0.8
0.8
0.8
2.0
0.8
2.0
2.0
0.8
0.8
0.8
0.8
2.0
84
85
74
48
53
1
1-Me
7 (5j)
2-Me
43
ncb
48
71
53a
62a
58
46
2
8
3-Me
9 (5l)
5-OMe
5-OMe
5-NO2
5-NO2
5-COOMe
6-Cl
Scheme 4. Copper-Catalyzed Pyrrolation of THIQa
10 (5l)
11 (5m)
12 (5m)
13 (5n)
14 (5p)
15 (5q)
16 (5r)
17 (5t)
18 (5t)
7-NO2
43
48
68
7-Me
7-Me
CH
CH
a Reaction time: 2 days. b nc = no conversion.
and deprotection compares favorably. Hence, it can be con-
cluded that all three protocols (copper-catalyzed indolation of
unprotected THIQ, copper-catalyzed indolation of N-protected
THIQ, and iron-catalyzed indolation of N-protected THIQ) can
be of value, depending on the synthetic problem. The protec-
tionÀdeprotection pathway might be of special value when more
elaborate and, hence, more expensive THIQ derivatives are used
as substrates.
a Conditions: Cu(NO3)2 3H2O (5 mol %), tBHP (1.3 equiv), 50 °C,
3
15 h.
After we established the principal reactivity on indole, it was
further investigated whether pyrroles can also undergo a CDC
with THIQ. Thus, pyrrole 7a was reacted with 2 equiv of THIQ
6, which afforded the desired product 8a in 44% yield
(Scheme 4). The new carbonÀcarbon bond was formed in this
case between C1 of THIQ and C2 of pyrrole, so again the more
electron rich position of the pronucleophile reacts.
The yield dropped dramatically when the pyrrolation was
performed on Boc-protected 1h: only traces of the desired
product 8d were observed employing copper catalysis and only
11% of the desired product could be isolated in the iron-catalyzed
reaction (see the Supporting Information).
Thus, the scope of the pyrrolation was investigated on 6: also
4,5,6,7-tetrahydroindole gave the desired product in 41% yield.
Electron-poor pyrroles such as 2-acetylpyrrole did not show any
conversion according to GC/MS. Notably, also 1-methylpyrrole
was ineffective, which is in line with results obtained for
1-methylindole (Table 3, entry 6); we understand this as further
evidence of the importance of a free NH group in the pronu-
cleophile. Interestingly, the reaction was also successful when
using 2,5-dimethylpyrrole 7b as substrate, this time leading to
CÀC bond formation at C3 of pyrrole, affording product 8b.
However, the yield dropped to 27% (Scheme 4).
On the basis of the above results, we became interested in extending
the substrate scope of the transformation to other coupling partners in
addition to (aza)indoles and pyrroles. Since the pronucleophile needs
to be electron rich, high electron density arenes were submitted to the
reaction conditions with THIQs. Gratifyingly, Boc-protected 1h
(Table 4, entry 1), Bz-protected 1d (Table 4, entry 2), and CBz-
protected 1e (Table 4, entry 3) were found to be suitable substrates for
methoxyarylation with 1,3,5-trimethoxybenzene. In marked contrast
to the indolation reactions, unprotected THIQ 6, Bn-protected 1c
(Table 4, entry 4) and PMP-protected THIQ (Table 4, entry 5) were
inefficient under both copper and iron catalysis.
The best yield in this methoxyarylation reaction was obtained
using 1,3,5-trimethoxybenzene as the most electron rich aryl
coupling partner and Boc-protected 1h as substrate, where a
good yield of 81% in iron catalysis and 76% (Table 4, entry 1) in
copper catalysis was obtained. Decreasing the electron density on
the aryl coupling partner as in 1,3-dimethoxybenzene also
8785
dx.doi.org/10.1021/jo201511d |J. Org. Chem. 2011, 76, 8781–8793

The Journal of Organic Chemistry
ARTICLE
Table 4. Scope of Methoxyphenylation on N-PG THIQ and
Isochroman
broadening the substrate scope considerably. Comparable less
electron rich 1,3-dimethoxybenzene also showed product forma-
tion, but again with lower yields of 12% (11c, entry 12, Fe) and
23% (11c, entry 12, Cu). With regard to 1,2,4-trimethoxybenzene
(11d, entry 13) and 1,2,3,5-tetramethoxybenzene (11b, entry 11)
the same trends in yield were observed as for the corresponding
reactions on THIQ 1h. For both starting materials 1h and 9
anisole is no longer sufficiently activated and no arylated product
was formed.
’ CONCLUSION
In summary, an alternative copper- and iron-catalyzed method
for the indolation, pyrrolation, and methoxyphenylation of
THIQs and for the methoxyphenylation of isochroman was
developed. Most importantly, cleavable N-protecting groups
can be applied using the outlined protocols, which represents a
significant extension of this methodology in comparison to
previous reports. The Boc group can be removed under mild
conditions with TMSCl or within seconds in excellent yield using
high-temperature microwave conditions. It could be demon-
strated that unprotected THIQ could be directly functionalized
with indoles and pyrroles in a copper-catalyzed reaction. This
emphasizes that copper and iron catalyses often complement
each other.
yield (%)
entry
R1
R2
R3
R4
X
Fe
Cu
1 (10a)
2 (10b)
3 (10c)
4
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
H
OMe NBoc
OMe NBz
OMe NCBz
OMe NBn
OMe NPMP
OMe NH
81
76
46a
51a
nc
nc
nc
23
46
41
51
39
23
32
H
H
H
H
H
H
H
54a
58a
ncb
nc
H
H
5
H
6
H
nc
7 (10d)
8 (10e)
9 (10f)
10 (11a)
OMe
H
H
NBoc
47
OMe OMe
OMe NBoc
OMe NBoc
52
’ EXPERIMENTAL SECTION
H
H
H
H
34a
General notes and instrumentation are provided in the Supporting
Information. Protected THIQs and 4,5,6,7-tetrahydro-1H-indole were
synthesized according to literature procedures.25
OMe
H
OMe
OMe
OMe
H
O
O
O
O
55
11 (11b) OMe OMe
H
17
12 (11c)
H
H
H
H
12a
General Procedure for Indolation of N-Protected THIQ. A
mixture of protected THIQ (0.857 mmol, 1.0 equiv), catalyst
(Cu(NO3)2 3H2O, 10.4 mg; Fe(NO3)3 9H2O, 17.3 mg; 42.9 μmol,
13 (11d) OMe
OMe
15
a 36 h of reaction time. b nc = no conversion according to GC/MS.
3
3
0.05 equiv), and indole (1.03 mmol, 1.2 equiv) was placed into a 5 mL
glass vial in air. tBHP (203 μL, 5.5 M in decane, 1.3 equiv) was added
dropwise at 0 °C in air, and the dark greenish slurry was stirred for
10 min at 0 °C. The neat mixture was then slowly heated to 50 °C,
whereupon the color changed to dark brown, and stirring was continued
for 15 h in a heating block. The reaction was monitored by TLC and/or
GC-MS. The dark brown slurry was diluted with DCM (3 mL) and
directly subjected to flash column chromatography (100 g of SiO2),
applying the solvent mixture used for TLC.
showed product formation of 10f but, as could be expected, with
a lower yield of 34% (copper) and 41% (iron) (Table 4, entry 9).
Also, a less favorable arrangement of three methoxy groups led to
decreased product yield: 1,2,4-trimethoxybenzene led to 47%
(Table 4, entry 7, Fe) and 23% (Table 4, entry 7, Cu) 10d,
respectively. It has to be noted that only arylation product
deriving from a reaction at position 5 of 1,2,4-trimethoxybenzene
was observed. Principally, position 3 would be activated to a
similar extent but is sterically less favored. The presence of four
methoxy groups in the aryl coupling partner gave, especially in
the Cu-catalyzed protocol, again a higher yield (10e, Table 4,
entry 8). Generally, the Fe-catalyzed variant performed better in
most cases.
1-[1-(1H-Indol-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanone
(3a): yield for Cu 134 mg (54%) and for Fe traces; pale yellow solid; mp
208À211 °C; TLC Rf (PE/EtOAc 1/1) = 0.18; GC/MS (EI+) m/z (rel
intensity) 290 (M+, 50), 273 (14), 248 (18), 247 (100), 232 (29), 230
(14), 218 (28), 217 (28), 132 (16), 131 (24), 130 (50), 117 (25), 115
1
(27), 103 (21), 89 (12), 77 (12); H NMR (200 MHz, DMSO- d6)
Next, we investigated possible extensions to other proelec-
trophiles; therefore, isochroman 9 was tested as the starting
material as well (Table 4, entries 10À13). Attempts to use 9 as
starting material for indolations unfortunately failed, leading
rather to bis-indolation via CÀH bond oxidation and CÀO
cleavage, which is in line with recent reports by Li et al.36 However,
1,3,5-trimethoxybenzene also reacted with9 as coupling partner to
afford the desired product 11a in 55% and 51% yields, respectively
(Table 4, entry 10). This confirms that thisarylation reactionisnot
limited to THIQ but also isochroman can be used as substrate;
however, lower yields were obtained for both metal catalysts in
comparison to the case for THIQ substrates. Still, this is an
interesting extension to existing protocols, since it demonstrates
that the transformation is limited neither to THIQ starting
materials nor to indole or pyrrole coupling partners, consequently
mixture of rotamers 1:0.17, δ 2.10 (s, 3H), 2.25 (s, 0.51H), 2.74À2.90
2
3
3
(m, 1.30H), 3.02 (ddd, J = 17.2 Hz, J = 11.6 Hz, J = 5.8 Hz, 1H),
3.24À3.45 (m, 1.30H), 3.77 (dd, 2J = 13.7 Hz, 3 J = 5.4 Hz, 1H), 4.26 (bs,
0.16H), 6.40 (bs, 0.17H), 6.58 (d, 3J = 2.0 Hz, 1H), 6.89À7.27 (m, 8H),
7.34 (d, 3J = 7.9 Hz, 1.35H), 7.57 (d, 3J = 7.8 Hz, 1H), 10.93 (s, 1H),
11.10 (s, 0.17H); 13C NMR (50 MHz, DMSO-d6): mixture of rotamers
1:0.17, δ 21.4 (q), 28.4 (t), 39.1 (t, overlap with DMSO signal), 47.9 (d),
111.4 (d), 117.1 (s), 118.7 (d), 119.2 (d), 121.3 (d), 125.4 (d), 125.7 (d),
126.1 (s), 126.5 (d), 128.2 (d), 128.8 (d), 134.4 (s), 136.2 (s), 136.3 (s),
167.7 (s).
2,2-Dimethyl-1-(1-(1H-indol-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-
propan-1-one (3b): yield for Cu 73 mg (26%) and for Fe traces; off
white powder; mp 184À186 °C; TLC Rf (PE/EtOAc 2/1) = 0.27; GC/
MS (EI+) m/z (rel intensity) 332 (M+, 27), 248 (19), 247 (100), 232
(35), 231 (14), 218 (25), 217 (23), 144 (11), 132 (26), 130 (28), 117
8786
dx.doi.org/10.1021/jo201511d |J. Org. Chem. 2011, 76, 8781–8793

The Journal of Organic Chemistry
ARTICLE
(10), 115 (17), 57 (24); 1H NMR (200 MHz, CDCl3) δ 1.24 (s, 9H),
2.73 (ddd, 2J = 16.4 Hz, 3J = 4.1 Hz, 3J = 0.9 Hz, 1H), 3.04 (ddd, 2J = 17.0
Hz, 3J = 12.4 Hz, 3J = 6.1 Hz, 1H), 3.44 (ddd, 2J = 13.9 Hz, 3J = 12.6 Hz,
3J = 4.2 Hz, 1H), 4.05 (ddd, 2J = 13.6 Hz, 3J = 6.2 Hz, 3J = 1.4 Hz, 1H),
6.56 (d, 4J = 2.3 Hz, 1H), 6.97 (ddd, 3J = 8.0 Hz, 3J = 7.1 Hz, 4J = 1.1 Hz,
calculated for C22H19N3 326.1652, found 326.1652 [M + H]+; 1H NMR
(200 MHz, CDCl3) δ 2.80 (dt, 2J = 16.1 Hz, 3J = 3.9 Hz, 1H), 3.12 (ddd,
2J = 16.3 Hz, 3J = 10.7 Hz, 3J = 5.6 Hz, 1H), 3.63 (ddd, 2J = 13.6 Hz, 3J =
10.7 Hz, 3J = 4.4 Hz, 1H), 3.98 (td, 2J = 13.6 Hz, 3J = 4.3 Hz, 1H), 6.58
(dd, 3J = 7.0 Hz, 3J = 5.0 Hz, 1H), 6.65 (d, 4J = 2.2 Hz, 1H), 6.76 (d, 3J =
8.6 Hz, 1H), 7.04 (t, 3J = 7.1 Hz, 1H), 7.10À7.23 (m, 5H), 7.27À7.35
(m, 2H), 7.47 (ddd, 3J = 8.8 Hz, 3J = 7.2 Hz, 4J = 2.0 Hz, 1H), 7.70 (d, 3J =
3
1H), 7.04À7.16 (m, 5H), 7.16À7.21 (m, 1H), 7.25 (d, J = 8.0 Hz,
3
1H), 7.50 (d, J = 7.9 Hz, 1H), 8.06 (s, 1H); 13C NMR (50 MHz,
7.8 Hz, 1H), 8.06 (s, 1H), 8.28 (dd, 3J = 4.9 Hz, 3J = 1.9 Hz, 1H); 13
C
CDCl3) δ 28.4 (3C, q), 29.2 (t), 39.1 (s), 39.6 (t), 50.4 (d), 110.9 (d),
119.1 (s), 119.8 (d), 120.4 (d), 122.2 (d), 125.6 (d), 125.9 (d), 126.4
(s), 126.6 (d), 128.6 (d), 128.7 (d), 133.7 (s), 136.4 (s), 136.5 (s),
175.7 (s).
NMR (50 MHz, APT, CDCl3) δ 26.9 (t), 38.9 (t), 52.2 (d), 106.5 (d),
111.0 (d), 112.0 (d), 119.2 (s), 119.5 (d), 120.1 (d), 122.0 (d), 124.4
(d), 125.6 (d), 126.5 (d), 126.6 (s), 128.3 (d), 128.8 (d), 135.4 (s), 136.5
(s), 137.4 (s), 137.5 (d), 148.1 (d), 157.9 (s).
2-Phenylmethyl-1-(1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline
(3c): yield for Cu 181 mg (60%) and for Fe 20 mg (7%); pale yellow
solid; mp 55À60 °C; TLC Rf (PE/Et2O 1/1) = 0.45; GC/MS (EI+) m/z
(rel intensity) 338 (M+, 75), 337 (56), 247 (32), 245 (16), 231 (22),
219 (50), 218 (100), 217(35), 130 (11), 106 (15), 91 (31);HRMS(ESI+):
exact mass calculated for C24H22N2 339.1856, found: 339.1852 [M + H]+;
1H NMR (200 MHz, DMSO-d6) δ 2.32À2.47 (m, 1H), 2.70À2.88
(m, 1H), 2.92À3.12 (m, 2H), 3.26 (d, 2J = 13.7 Hz, 1H), 3.81 (d, 2J =
13.7 Hz, 1H), 4.88 (s, 1H), 6.75À7.39 (m, 13H), 7.45 (d, 3J = 7.8 Hz,
1H), 10.97 (s, 1H); 13C NMR (50 MHz, APT, DMSO-d6) δ 28.8 (t),
47.1 (t), 58.2 (t), 61.2 (d), 111.4 (d), 116.4 (s), 118.2 (d), 120.2 (d),
120.9 (d), 125.3 (d), 125.49 (d), 125.53 (d), 125.9 (s), 126.5 (d), 127.9
(d), 128.0 (d, 2C), 128.1 (d), 128.4 (d, 2C), 134.3 (s), 136.9 (s), 138.7
(s), 139.6 (s).
1,1-Dimethylethyl-1-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-
carboxylate (3h): yield for Cu 235 mg (79%) and for Fe 160 mg (54%);
off white powder; mp 137À139 °C; TLC Rf (PE/Et2O 2/1) = 0.18;
GC/MS (EI+) m/z (rel intensity) 248 (46), 247 (91), 245 (100), 230
(18), 218 (53), 130 (52), 121 (46), 117 (38), 108 (50), 103 (21);
HRMS (ESI+) exact mass calculated for C22H24N2O2 371.1735. found
371.1730 [M + Na]+; 1H NMR (400 MHz, DMSO-d6) δ 1.46 (s, 9H),
2.77 (d, 2J = 15.8 Hz, 1H), 2.84À2.96 (m, 1H), 3.07 (dt, 2J = 12.8 Hz,
3J = 4.3 Hz, 1H), 3.94 (bs, 1H), 6.37À6.85 (m, 2H), 6.96 (t, 3J = 7.4 Hz,
1H), 7.08 (t, 3J = 7.6 Hz, 1H), 7.15 (bs, 2H), 7.22 (d, 3J = 3.1 Hz, 2H),
7.36 (d, 3J = 8.1 Hz, 1H), 7.58 (bs, 1H), 10.95 (s, 1H); 1H NMR (200
MHz, CDCl3) δ 1.55 (s, 9H), 2.63À2.85 (m, 1H), 2.92À3.27 (m, 1H),
4.05 (bs, 1H), 6.60 (bs, 1H), 6.75 (bs, 1H), 7.06À7.25 (m, 6H), 7.35 (d,
3J = 7.7 Hz, 1H), 7.80 (bs, 1H), 8.14 (bs, 1H); 13C NMR (50 MHz, APT,
CDCl3) δ 28.4 (3C, q), 28.5 (t), 37.6 (t), 50.5 (d), 79.7 (s), 111.1 (d),
118.6 (s), 119.5 (d), 119.9 (d), 122.0 (d), 125.0 (d), 125.6 (d), 126.4 (s),
126.5 (d), 128.3 (s), 128.3 (d), 129.0 (d), 134.8 (s), 136.3 (s), 136.4 (s),
154.3 (s).
(1-(1H-Indol-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(phenyl)-meth-
anone (3d): yield for Cu 120 mg (40%) and for Fe 67 mg (22%); brown
solid; mp 226À228 °C; TLC Rf (PE/EtOAc 2/1) = 0.29; GC/MS (EI+)
m/z (rel intensity) 352 (M+, 40), 248 (20), 247 (100), 232 (32), 218
(21), 217 (21), 130 (18), 115 (12), 105 (56), 77 (44); HRMS (ESI+)
exact mass calculated for C24H20N2O 353.1648, found 353.1639 [M +
1,1-Dimethylethyl-1-(1-methyl-1H-indol-3-yl)-3,4-dihydroisoqui-
noline-2(1H)-carboxylate (3i): yield for Cu 218 mg (70%) and for Fe
203 mg (65%); white powder; mp 70À72 °C; TLC Rf (PE/EtOAc 3/1)
= 0.78; GC/MS (EI+) m/z (rel intensity) 262 (48), 261 (100), 259
(33), 245 (12), 232 (22), 217 (20), 157 (6), 130 (22), 103 (7), 77 (5);
HRMS (ESI+) exact mass calculated for C23H26N2O2 363.2067, found
1
2
H]+; H NMR (400 MHz, CDCl3) δ 2.75 (d, J = 14.6 Hz, 1H),
2
3
2.97À3.11 (m, 1H), 3.47 (dt, J = 13.4 Hz, J = 3.3 Hz, 1H), 3.66
(dd, 2J = 13.2 Hz, 3J = 5.7 Hz, 1H), 6.68 (s, 1H), 7.13 (t, 3J = 7.3 Hz, 1H),
7.18À7.54 (m, 12H), 7.85 (d, 3J = 7.6 Hz, 1H), 8.34 (bs, 1H); 1H NMR
(200 MHz, DMSO-d6) δ 2.75 (d, 2J = 16.0 Hz, 1H), 2.86À3.10 (m, 1H),
3.20À3.60 (m, 2H), 6.64 (bs, 1H), 6.89À7.51 (m, 13H), 7.65 (d, 3J = 7.9
Hz, 1H), 11.03 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 29.5 (t), 40.6 (t),
49.0 (d), 111.1 (d), 118.6 (s), 120.0 (d), 120.3 (d), 122.3 (d), 125.7
(d), 126.1 (d), 126.4 (2d), 126.9 (d), 127.3 (s), 128.5 (4C, d), 128.8 (d),
128.9 (d), 129.4 (d), 133.8 (s), 135.7 (s), 136.4 (s), 136.6 (s), 169.9 (s);
13C NMR (50 MHz, APT, DMSO-d6) δ 28.6 (t), (CH2 group at 40.6
ppm in CDCl3 overlaps with DMSO signal), 48.4 (d), 111.6 (d), 116.8 (s),
118.9 (d), 119.0 (d), 121.4 (d), 125.8 (d), 125.9 (s), 126.1 (d), 126.8 (d),
128.2 (d), 128.5 (4C, d), 128.9 (d), 129.3 (d), 134.0 (s), 135.6 (s), 136.4
(2C overlapping, s), 168.6 (s).
1
363.2072 [M + H]+; H NMR (200 MHz, CDCl3) δ 1.58 (s, 9H),
2.68À2.88 (m, 1H), 2.96À3.30 (m, 2H), 3.70 (s, 3H), 3.88À4.32 (m,
1H), 6.49 (s, 1H), 6.74 (bs, 1H), 7.08À7.36 (m, 7H), 7.82 (bs, 1H); 13C
NMR (50 MHz, APT, CDCl3) δ 28.4 (t), 28.6 (3C, q), 32.6 (q), 37.5
(t), 50.4 (d), 79.5 (s), 109.1 (d), 117.4 (s), 119.2 (d), 120.4 (d), 121.8
(d), 125.6 (d), 126.5 (d), 127.0 (s), 128.4 (d), 129.0 (d), 129.4 (d),
135.0 (s), 136.5 (s), 137.1 (s), 154.2 (s).
1,1-Dimethylethyl-1-(2-methyl-1H-indol-3-yl)-3,4-dihydroisoqui-
noline-2(1H)-carboxylate (3j): yield for Cu 209 mg (67%) and for Fe 72
mg (23%); pale yellow powder; mp 81À84 °C; TLC Rf (PE/EtOAc
2/1) = 0.69; GC/MS (EI+) m/z (rel intensity) 262 (62), 261 (100), 245
(61), 244 (37), 219 (21), 218 (44), 131 (34), 130 (85), 103 (18), 77 (20);
HRMS (ESI+) exact mass calculated for C23H26N2O2 385.1886, found
385.1896 [M + Na]+; 1H NMR (200 MHz, CDCl3) δ 1.49 (s, 9H), 2.24
(s, 3H), 2.78 (dd, 2J = 16.7 Hz, 3J = 3.0 Hz, 1H), 3.00À3.80 (m, 2H), 4.14
Phenylmethyl-1-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-
carboxylate (3e): yield for Cu 171 mg (60%) and for Fe 135 mg (41%);
white powder; mp 62À64 °C; TLC Rf (PE/EtOAc 5/1) = 0.55; GC/MS
(EI+) m/z (rel intensity) 382 (M+, 3), 292 (7), 291 (40), 248 (20), 247
(100), 218 (8), 217 (7), 130 (12), 103 (5), 91 (6); HRMS (ESI+) exact
mass calculated for C25H22N2O2 383.1754, found 383.1722 [M + H]+;
1H NMR (200 MHz, CDCl3) δ 2.73 (dd, 1H, 2J = 16.7 Hz, 3J = 2.7 Hz,
1H), 2.90À3.36 (m, 2H), 3.80À4.30 (m, 1H), 5.10À5.46 (m, 2H),
6.48À6.84 (m, 2H), 6.88À7.82 (m, 13H), 8.19 (bs, 1H); 13C NMR (50
MHz, APT, CDCl3) δ 28.6 (t), 37.4 (t), 51.5 (d), 67.1 (t), 111.0 (d),
118.5 (s), 119.8 (d), 120.2 (d), 122.2 (d), 125.0 (d), 125.8 (d, 2C), 126.4 (s),
126.7 (d), 127.7 (d), 128.0 (d), 128.4 (d), 128.5 (d, 2C), 129.0 (d),
134.6 (s), 136.0 (s), 136.3 (s), 136.7 (s), 154.9 (s).
2
3
(dd, J = 11.8 Hz, J = 3.5 Hz, 1H), 6.66 (s, 1H), 6.83À6.94 (m, 1H),
6.98À7.13 (m, 4H), 7.17À7.26 (m, 3H), 7.91 (bs, 1H); 1H NMR (200
MHz, DMSO-d6) δ 1.44 (s, 9H), 2.19 (s, 3H), 2.74À3.28 (m, 3H), 4.01
2
3
(dd, J = 13.3 Hz, J = 3.3 Hz, 1H), 6.50 (s, 1H), 6.67À6.78 (m, 1H),
6.81À7.02 (m, 3H), 7.05À7.15 (m, 1H), 7.15À7.28 (m, 3H), 10.95 (s,
1H); 13C NMR (50 MHz, APT, CDCl3) δ 12.6 (q), 28.5 (3C, q), 28.6 (t),
38.3 (t), 51.0 (d), 79.7 (s), 110.1 (d), 113.3 (s), 119.3 (d), 119.5 (d),
120.9 (d), 126.3 (d), 126.5 (d), 128.3 (d), 128.5 (s), 129.0 (d), 133.9 (s),
134.9 (s), 134.9 (s), 137.0 (s), 154.2 (s); 13C NMR (50 MHz, APT,
DMSO-d6) δ 11.9 (q), 27.9 (t), 28.0 (3C, q), 37.8 (t), 50.3 (d), 78.9 (s),
110.4 (d), 111.6 (s), 118.1 (d), 118.4 (d), 119.9 (d), 126.0 (d), 126.4 (d),
127.7 (s), 127.8 (d), 128.8 (d), 134.2 (s), 134.4 (s), 134.8 (s), 136.7 (s),
153.3 (s).
1-(1H-Indol-3-yl)-2-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline
(3g): yield for Cu 171 mg (61%); pale yellow powder; mp 177À178 °C;
TLC Rf (PE/EtOAc 2/1) = 0.51; GC/MS (EI+) m/z (rel intensity) 325
(M+ 40), 248 (19), 247 (100), 232 (24), 230 (15), 218 (24), 217 (27),
195 (12), 130 (17), 117 (14), 115 (15); HRMS (ESI+) exact mass
8787
dx.doi.org/10.1021/jo201511d |J. Org. Chem. 2011, 76, 8781–8793

The Journal of Organic Chemistry
ARTICLE
1,1-Dimethylethyl-1-(5-amino-1H-indol-3-yl)-3,4-dihydroisoquino-
line-2(1H)-carboxylate (3k): yield for Cu no conversion and for Fe 50
mg (16%); dark brown solid; mp 96À98 °C; TLC Rf (PE/Et2O 1/1) =
0.31; GC/MS (EI+) m/z (rel intensity) 263 (48), 262 (30), 258 (40),
246 (75), 245 (100), 233 (13), 218 (17), 132 (23), 130 (20); HRMS
(ESI+) exact mass calculated for C22H25N3O2 386.1839, found 386.
1854 [M + Na]+; 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 9H), 2.82 (dd,
2J = 16.4 Hz, 3J = 2.9 Hz, 1H), 3.09À3.22 (m, 1H), 3.41 (dt, 2J = 13.3 Hz,
3J = 3.6 Hz, 1H), 4.07 (dd, 2J = 13.6 Hz, 3J = 5.7 Hz, 1H), 6.66 (s, 1H),
5.13 (s, 1H), 6.68 (d, 3J = 8.6 Hz, 1H), 6.78 (t, 4J = 2.7 Hz, 1H), 7.03 (d,
3J = 7.7 Hz, 1H), 7.10 (t, 3J = 7.3 Hz, 1H), 7.14 (d, 3J = 8.6 Hz, 1H),
7.19À7.24 (m, 2H), 7.86 (s, 1H), NH2 group gives a broad signal
between 2 and 5 ppm; 13C NMR (101 MHz, APT, CDCl3) δ 28.4 (q,
3C), 28.5 (t), 39.2 (t), 53.8 (d), 80.2 (s), 101.3 (d), 111.7 (d), 113.8 (d),
116.0 (s), 123.7 (d), 126.3 (d), 126.5 (d), 128.4 (s), 128.9 (d), 128.9 (d),
130.8 (s), 134.8 (s), 137.4 (s), 139.9 (s), 155.5 (s).
(d), 128.2 (d), 129.1 (d), 134.9 (s), 135.8 (s), 139.2 (s), 154.2 (s),
168.2 (s).
1,1-Dimethylethyl-1-(5-chloro-1H-indol-3-yl)-3,4-dihydroisoquino-
line-2(1H)-carboxylate (3o): yield for Cu 215 mg (66%) and for Fe 236
mg (72%); pale pink powder; mp 202À204 °C; TLC Rf (PE/EtOAc
3/1) = 0.56; GC/MS (EI+) m/z (rel intensity) 284 (13), 283 (38), 282
(42), 281 (100), 279 (14), 265 (9), 253 (21), 252 (22), 217 (30), 216
(11), 164 (8), 130 (26), 103 (9); HRMS (ESI+): exact mass calculated
1
for C22H23N2O2Cl 405.1340; found 405.1350 [M + Na]+; H NMR
(200 MHz, DMSO-d6) δ 1.49 (s, 9H), 2.65À3.09 (m, 3H), 3.91 (bs,
1H), 6.50 (s, 1H), 6.63 (bs, 1H), 7.09 (dd,3 J = 8.6 Hz, 4 J = 1.9 Hz, 1H),
7.13À7.26 (m, 4H), 7.38 (d, 3J = 8.6 Hz, 1H), 7.66 (d, 4J = 1.8 Hz, 1H),
11.15 (s, 1H); 13C NMR (50 MHz, APT, DMSO-d6) δ 27.7 (t), 28.0 (q,
3C), (CH2-group at 37.7 ppm in CDCl3 overlaps with DMSO signal),
50.1 (d), 79.3 (s), 113.1 (d), 117.0 (s), 118.3 (d), 121.2 (d), 123.4 (s),
125.6 (d), 126.7 (d), 126.8 (d), 127.0 (s), 127.9 (d), 129.0 (d), 134.4 (s),
134.8 (s), 135.6 (s), 163.4 (s); 13C NMR (50 MHz, APT, CDCl3) δ
28.3 (t), 28.6 (3C, q), 37.7 (t), 51.0 (d), 79.3 (s), 112.0 (d), 118.9 (s),
119.7 (d), 122.6 (d), 125.5 (s), 125.7 (d), 126.1 (d), 126.8 (d), 127.5 (s),
128.3 (d), 129.1 (d), 134.7 (s), 135.0 (s), 135.8 (s), 154.2 (s)
1,1-Dimethylethyl-1-(5-methoxy-1H-indol-3-yl)-3,4-dihydroisoqui-
noline-2(1H)-carboxylate (3l): yield for Cu 174 mg (52%) and for Fe
140 mg (43%); off-white powder; mp 69À72 °C; TLC Rf (PE/EtOAc
5/1) = 0.27; GC/MS (EI+) m/z (rel intensity) 278 (59), 277 (100), 261
(53), 249 (22), 248 (24), 233 (12), 218 (10), 204 (10), 132 (10), 130
(14); HRMS (ESI+) exact mass calculated for C23H26N2O3 401.1836,
found 401.1822 [M + Na]+; 1H NMR (200 MHz, DMSO-d6) δ 1.46 (s,
9H), 2.63À3.19 (m, 3H), 3.69 (s, 3H), 3.88 (bs, 1H), 6.52 (bs, 2H), 6.73
1,1-Dimethylethyl-1-(6-chloro-1H-indol-3-yl)-3,4-dihydroisoquino-
line-2(1H)-carboxylate (3p): yield for Cu 245 mg (75%) and for Fe 184
mg (56%); white powder; mp 83À85 °C; TLC Rf (PE:EtOAc=3:1) =
0.63; GC/MS (EI+) m/z (rel intensity) 284 (14), 283 (33), 282 (40),
281 (100), 279 (22), 265 (22), 253 (35), 252 (25), 217 (30), 216
(16), 130 (27), 103 (12); HRMS (ESI+): exact mass calculated for
C22H23N2O2Cl 405.1340; found 405.1339 [M + Na]+; 1H NMR (200
MHz, CDCl3) δ 1.52 (s, 9H), 2.63À2.81 (m, 1H), 2.90À3.20 (m, 2H),
4.07 (bs, 1H), 6.52À6.75 (m, 2H), 7.05 (dd, 3J = 8.6 Hz, 4J = 1.8 Hz,
1H), 7.10À7.23 (m, 4H), 7.31 (d, 4J = 1.7 Hz, 1H), 7.68 (bs, 1H), 8.19
(bs, 1H); 1H NMR (200 MHz, DMSO-d6) δ 1.45 (s, 9H), 2.66À3.12
(m, 3H), 3.90 (bs, 1H), 6.50 (s, 1H), 6.68 (bs, 1H), 7.00 (dd, 3J = 8.5 Hz,
4J = 1.9 Hz, 1H), 7.06À7.27 (m, 4H), 7.41 (d, 4J = 1.8 Hz, 1H), 7.54 (d,
3J = 7.5 Hz, 1H), 11.09 (s, 1H); 13C NMR (50 MHz, APT, DMSO-d6) δ
27.8 (t), 28.0 (3C, q), CH2 group at 37.5 ppm in CDCl3 overlaps with
DMSO signal, 50.2 (d), 79.1 (s), 111.2 (d), 117.3 (s), 119.0 (d), 120.3
(d), 124.8 (s), 125.7 (d), 126.0 (s), 126.2 (d), 126.6 (d), 127.9 (d), 128.9
(d), 134.4 (s), 135.8 (s), 136.7 (s), 153.4 (s); 13C NMR (50 MHz, APT,
CDCl3) δ 28.4 (t), 28.5 (3C, q), 37.5 (t), 50.5 (d), 79.8 (s), 110.9 (d),
119.2 (s), 120.5 (d), 121.2 (d), 125.1 (s), 125.4 (d), 125.7 (d), 126.7 (d),
128.2 (s), 128.3 (d), 129.1 (d), 134.9 (s), 135.9 (s), 136.8 (s), 154.4 (s).
1,1-Dimethylethyl-1-(7-nitro-1H-indol-3-yl)-3,4-dihydroisoquino-
line-2(1H)-carboxylate (3q): yield for Cu 155 mg (46%) and for Fe 235
mg (70%); bright yellow powder; mp 88À91 °C; TLC Rf (PE/EtOAc
5/1) = 0.45; GC/MS (EI+) m/z (rel intensity) 293 (56), 292 (100), 291
(17), 290 (38), 264 (15), 263 (24), 246 (20), 244 (16), 217 (32), 216
(20), 189 (13), 188 (10), 132 (21), 130 (27), 121 (16), 108 (26), 103
(13); 1H NMR (200 MHz, DMSO-d6) δ 1.46 (s, 9H), 2.66À3.13 (m,
3H), 3.92 (d, 2J = 12.1 Hz, 1H), 6.60 (s, 1H), 6.73 (bs, 1H), 7.06À7.29
(m, 5H), 8.01À8.13 (m, 2H), 11.80 (s, 1H); 13C NMR (50 MHz, APT,
DMSO-d6) δ 27.7 (t), 28.0 (q, 3C), 37.0 (t), 49.8 (d), 79.3 (s), 118.7
(d), 118.9 (d), 119.2 (s), 125.8 (d), 126.9 (d), 127.6 (d), 127.9 (d),
128.2 (d), 128.5 (s), 129.1 (d), 130.3 (s), 132.6 (s), 134.5 (s), 135.2 (s),
153.5 (s).
(dd, 3J = 8.8 Hz, 4J = 2.1 Hz, 1H), 7.01À7.32 (m, 6H), 10.78 (s, 1H); 13
C
NMR (50 MHz, APT, DMSO-d6) δ 27.8 (t), 28.0 (3C, q), 37.0 (t),
50.1 (d), 55.0 (q), 78.8 (s), 100.7 (d), 111.5 (d), 112.2 (d), 116.8 (s),
125.6 (d), 126.4 (s), 126.5 (d), 127.9 (d), 128.9 (d), 131.4 (s), 134.4 (s),
136.0 (s), 153.1 (s), 153.4 (s).
1,1-Dimethylethyl-1-(5-nitro-1H-indol-3-yl)-3,4-dihydroisoquino-
line-2(1H)-carboxylate (3m): yield for Cu 200 mg (59%) and for Fe 222
mg (66%); bright yellow solid; mp 219À221 °C; TLC Rf (PE/EtOAc
3/1) = 0.22; GC/MS (EI+) m/z (rel intensity) 393 (43), 292 (100), 276
(10), 263 (24), 246 (34), 217 (30), 189 (8), 146 (6), 132 (6), 130 (12);
HRMS (ESI+) exact mass calculated for C22H23N3O4 416.1581, found
416.1589 [M + Na]+; 1H NMR (200 MHz, DMSO-d6) δ 1.50 (s, 9H),
2.63À3.07 (m, 3H), 3.76À4.09 (m, 1H), 6.62 (s, 1H), 6.80 (s, 1H),
7.09À7.29 (m, 4H), 7.55 (d, 3J = 9.0 Hz, 1H), 8.02 (dd, 3J = 9.0 Hz, 4J =
2.2 Hz, 1H), 8.73 (s, 1H), 11.50À11.86 (m, 1H); 13C NMR (50 MHz,
APT, DMSO-d6) δ 27.7 (t), 27.9 (q, 3C), 37.0 (t), 49.9 (d), 79.5 (s),
112.1 (d), 116.4 (d), 116.8 (d), 119.9 (s), 125.3 (s), 125.7 (d), 126.8 (d),
128.0 (d), 128.9 (d), 129.0 (d), 134.5 (s), 135.1 (s), 139.6 (s), 140.6 (s),
153.3 (s).
1,1-Dimethylethyl-1-(5-(methoxycarbonyl)-1H-indol-3-yl)-3,4-di-
hydroisoquinoline-2(1H)-carboxylate (3n): yield for Cu 175 mg (50%)
and for Fe 17 mg (5%); pale yellow powder; mp 221À224 °C; TLC Rf
(PE/Et2O 1/1) = 0.18; GC/MS (EI+) m/z (rel intensity) 306 (45), 305
(100), 289 (12), 276 (18), 247 (8), 244 (8), 217 (15), 189 (6), 144 (8),
130 (16); HRMS (ESI+) exact mass calculated for C24H26N2O4
1
429.1785, found 429.1771 [M + Na]+; H NMR (200 MHz, CDCl3)
δ 1.62 (s, 9H), 2.60À2.83 (m, 1H), 2.90À3.18 (m, 2H), 3.90 (s, 3H),
4
3.93À4.27 (m, 1H), 6.58 (d, J = 1.9 Hz, 1H), 6.61À6.89 (m, 1H),
7.08À7.24 (m, 4H), 7.34 (d, 3J = 8.6 Hz, 1H), 7.91 (dd, 3J = 8.6 Hz, 4J =
1.2 Hz, 1H), 8.58 (bs, 1H); 8.63 (s, 1H), 1H NMR (200 MHz, DMSO-
d6) δ 1.52 (s, 9H), 2.64À3.10 (m, 3H), 3.82 (s, 3H), 3.90 (bs, 1H), 6.58
(bs, 1H), 6.63 (bs, 1H), 7.07À7.30 (m, 4H), 7.45 (d, 3J = 8.6 Hz, 1H),
1,1-Dimethylethyl-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,4-dihydroi-
soquinoline-2(1H)-carboxylate (3r): yield for Cu 133 mg (44%) and for
Fe 126 mg (42%); white powder; mp 84À86 °C; TLC Rf (PE/Et2O
1/1) = 0.11; GC/MS (EI+) m/z (rel intensity) 249 (56), 248 (100),
245 (36), 244 (57), 219 (50), 190 (10), 144 (14), 132 (24), 130 (28),
119 (34), 109 (27), 103 (18), 95 (16); HRMS (ESI+) exact mass cal-
culated for C21H23N3O2 350.1863; found 350.1871 [M + H]+; 1H NMR
(200 MHz, DMSO-d6) δ 1.45 (s, 9H), 2.68À3.15 (m, 3H), 3.92 (d, 2J =
11.2 Hz, 1H), 6.50 (s, 1H), 6.77 (bs, 1H), 7.03 (dd, 3J = 7.9 Hz, 3J = 4.7 Hz,
1H), 7.09À7.28 (m, 4H), 7.82 (bs, 1H), 8.20 (dd, 3J = 4.6 Hz,
3
7.75 (d, J = 8.6 Hz, 1H), 8.49 (s, 1H), 11.34 (s, 1H); 13C NMR
(50 MHz, APT, DMSO-d6) δ 27.6 (t), 27.9 (3C, q), (CH2 group at 36.2
ppm in CDCl3 overlaps with DMSO signal), 50.4 (d), 51.4 (q), 79.5 (s),
111.5 (d), 118.6 (s), 120.3 (s), 121.9 (d), 122.4 (d), 125.57 (s), 125.61
(d), 126.7 (d), 127.0 (d), 127.9 (d), 129.1 (d), 134.5 (s), 135.6 (s), 139.0
(s), 153.4 (s), 167.1 (s); 13C NMR (50 MHz, APT, CDCl3) δ 28.1 (t),
28.4 (q, 3C), 36.2 (t), 51.2 (d), 51.6 (q), 80.7 (s), 111.0 (d), 120.1 (s),
121.5 (s), 122.7 (d), 123.7 (d), 125.6 (d), 126.0 (s), 126.4 (d), 126.8
8788
dx.doi.org/10.1021/jo201511d |J. Org. Chem. 2011, 76, 8781–8793

The Journal of Organic Chemistry
ARTICLE
4J = 1.4 Hz, 1H), 11.54 (s, 1H); 13C NMR (50 MHz, APT, DMSO-d6) δ
27.8 (t), 28.0 (q, 3C), 37.1 (t), 50.4 (d), 79.1 (s), 115.3 (d), 115.9 (s),
118.2 (s), 125.1 (d), 125.7 (d), 126.7 (d), 127.1 (d), 127.9 (d), 128.9
(d), 134.5 (s), 135.4 (s), 142.7 (d), 148.4 (s), 153.4 (s).
10/1/1) = 0.57; GC/MS (EI+) m/z (rel intensity) 262 (M+, 60), 261
(100), 245 (6), 233 (14), 232 (24), 217 (12), 131 (22), 130 (29), 115
(11), 108 (14); 1H NMR (200 MHz, CDCl3) δ 2.52 (s, 1H), 2.83À3.17
(m, 3H), 3.19À3.35 (m, 1H), 3.73 (s, 3H), 5.52 (s, 1H), 6.79 (s, 1H),
6.97À7.36 (m, 7H), 7.51 (d, 3J = 7.9 Hz, 1H); 13C NMR (50 MHz, APT,
CDCl3) δ 29.7 (t), 32.7 (q), 41.5 (t), 53.6 (d), 109.3 (d), 118.1 (s),
119.1 (d), 119.4 (d), 121.7 (d), 125.6 (d), 126.1 (d), 126.9 (s), 127.9
(d), 128.5 (d), 128.9 (d), 135.2 (s), 137.2 (s), 138.3 (s).
1,1-Dimethylethyl-1-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-
3,4-dihydroisoquinoline-2(1H)-carboxylate (3s). yield for Cu 145 mg
(44%) and for Fe no conversion; white powder; mp 87À91 °C; TLC Rf
(PE/Et2O 1/5) = 0.28; GC/MS (EI+) m/z (rel intensity) 286 (14), 285
(35), 284 (41), 283 (100), 254 (26), 219 (11), 191 (11), 166 (6), 130
(14), 103 (8); HRMS (ESI+) exact mass calculated for C20H21N4O2Cl
385.1426; found 385.1423 [M + H]+; 1H NMR (200 MHz, CDCl3) δ
1.42 (s, 9H), 2.75 (d, 2J = 16.2 Hz, 1H), 2.94À3.38 (m, 2H), 4.10 (bs,
1H), 6.81 (bs, 1H), 6.86 (bs, 1H), 7.12À7.28 (m, 4H), 8.64 (s, 1H),
11.02 (s, 1H); 13C NMR (50 MHz, APT, CDCl3) δ 28.0 (t), 28.4 (3C,
q), 38.2 (t), 50.6 (d), 80.2 (s), 115.6 (s), 119.0 (s), 126.0 (d), 127.0 (d),
128.1 (d), 129.3 (d), 134.6 (s), 135.8 (s), 150.3 (d), 152.4(s), 152.6 (s),
155.0 (s).
Deprotection of the Boc PG. Method A: Microwave-As-
sisted Deprotection. 3h (150 mg, 0.450 mmol) or 3i (50 mg, 0.138
mmol) was suspended in ethylene glycol (3h, 20 mL; 3i, 10 mL) and
microwaved at 250 °C for 30 s (hold time). The reaction mixture was
diluted with water and extracted three times with diethyl ether. The
combined organic layers were washed twice with brine, dried over
sodium sulfate, filtered, and evaporated. The crude product was purified
by flash column chromatography (100 g of SiO2, PE/EtOAc 100/0 f
0/100 (30 min), EtOAc/EtOH 95/5 f 60/40 (30 min)). In the case of
3i the reaction mixture was diluted with water, chilled with liquid nitro-
gen, and lyophilized to afford the desired product as a pale brown solid.
Deprotection of the Boc PG. Method B: General Procedure
for TMSCl-Promoted Boc Deprotection. TMSCl (272 mg, 2.50
mmol, 5.0 equiv) was added dropwise to an argon-degassed solution of
the corresponding Boc-protected amine (0.5 mmol, 1.0 equiv) in dry
MeOH (4 mL) at room temperature, and the reaction mixture was
stirred for 4 to 24 h under argon. After the reaction mixture was cooled to
0 °C, it was poured into ice cold 2 N aqueous NaOH. The suspension
was extracted three times with EtOAc, and the combined organic layers
were washed once with 2 N NaOH. The combined organic layers were
then dried over sodium sulfate, filtered, and evaporated to afford the
desired product in quantitative yields.
Method C: General Procedure for Indolation of THIQ. THIQ
(200 mg, 1.50 mmol, 1.0 equiv), catalyst(18.1mg,75μmol, 0.05 equiv), and
the corresponding indole (1.80 mmol, 1.2 equiv) were placed into a 5 mL glass
vial in air and stirred for 10 min at 0 °C. tBHP (390 μL, 5.5 M in decane, 1.3
equiv) was added dropwise at 0 °C in air and the dark greenish slurry was
stirred for 1 h at 0 °C. The neat mixture was then slowly heated to 50 °C
(within 1 h), whereupon the color changed to black and stirring was continued
for 15 h in a heating block. The reaction was monitored by GC-MS. The
mixture was diluted with DCM (3 mL) and directly subjected to flash column
chromatography, using PE/EtOAc as eluent to afford the desired product.
1-(1H-Indol-3-yl)-1,2,3,4-tetrahydroisoquinoline (5h): method A 95
mg (89%), method B 124 mg (100%), method C 179 mg (48%); brown
solid; mp 44À46 °C; TLC Rf (EtOAc/EtOH 5/1) = 0.20; GC/MS (EI
+) m/z (rel intensity) 248 (M+, 38), 247 (100), 231 (15), 219 (22), 218
(32), 217 (19), 130 (20); HRMS (ESI+) exact mass calculated for
C17H16N2 249.1398, found 249.1386 [M + H]+; 1H NMR (200 MHz,
CDCl3) δ 2.02 (bs, 1H), 2.80À3.37 (m, 4H), 5.51 (s, 1H), 6.88 (d, 3J =
1.9 Hz, 1H), 6.95À7.23 (m, 6H), 7.33 (d, 3J = 8.0 Hz, 1H), 7.49 (d, 3J =
7.8 Hz, 1H), 8.34 (bs, 1H); 13C NMR (50 MHz, APT, CDCl3) δ 29.4 (t),
41.5 (t), 53.6 (d), 111.3 (d), 118.6 (s), 119.1 (d), 119.3 (d), 121.8 (d),
124.1 (d), 125.6 (d), 126.1 (d), 126.2 (s), 127.8 (d), 128.8 (d), 134.9 (s),
136.5 (s), 138.1 (s).
1-(2-Methyl-1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline (5j):
method B 131 mg (100%), method C 170 mg (43%); pale yellow solid;
mp 68À70 °C; TLC Rf (EtOAc/EtOH 10/1) = 0.14; GC/MS (EI+)
m/z (rel intensity) 262 (M+, 86), 261 (100), 247 (24), 245 (60), 244 (37),
233 (22), 230 (21), 218 (38), 217 (41), 130 (46); HRMS (ESI+) exact
1
mass calculated for C18H18N2 263.1543, found 263.1548 [M + H]+; H
NMR (200 MHz, CDCl3) δ 1.94 (bs, 1H), 2.35 (s, 3H), 2.79À3.00 (m,
1H), 3.03À3.46 (m, 3H), 5.43 (s, 1H), 6.79À7.28 (m, 8H), 7.99 (bs, 1H);
13C NMR (50 MHz, APT, CDCl3) δ 11.9 (q), 29.8 (t), 43.3 (t), 53.6 (d),
110.2 (d), 113.6 (s), 118.8 (d), 119.2 (d), 120.8 (d), 125.9 (d), 126.0 (d),
127.3 (s), 127.4 (d), 128.8 (d), 133.3 (s), 134.9 (s), 135.4 (s), 138.5 (s).
1-(5-Methoxy-1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline (5l):
method B 137 mg (99%), method C 202 mg (48%); light brown solid;
mp 74À76 °C; TLC Rf (EtOAc/EtOH 5/1) = 0.11; GC/MS (EI+) m/z
(rel intensity) 278 (M+, 62), 277 (100), 261 (49), 249 (26), 248 (26),
234 (10), 233 (8), 217 (7), 132 (9), 130 (12); HRMS (ESI+) exact mass
1
calculated for C18H18N2O 279.1492; found 279.1499 [M + H]+; H
NMR (200 MHz, CDCl3) δ 1.98 (bs, 1H), 2.79À3.36 (m, 4H), 3.76 (s,
3
3H), 5.47 (s, 1H), 6.79À6.88 (m, 2H), 6.91 (d, J = 2.3 Hz, 1H),
6.95À7.18 (m, 4H), 7.22 (d, 3J = 8.7 Hz, 1H), 8.18 (bs, 1H); 13C NMR
(50 MHz, APT, CDCl3) δ 27.8 (t), 40.5 (t), 52.9 (d), 55.6 (q), 100.8
(d), 112.1 (d), 112.2 (d), 115.0 (s), 126.1 (d), 126.2 (d), 126.6 (s), 126.8
(d), 128.1 (d), 128.7 (d), 131.5 (s), 133.6 (s), 135.8 (s), 153.8 (s).
1-(5-Nitro-1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline (5m):
method B 146 mg (100%), method C 233 mg (53%); shining dark
yellow solid; mp 83À85 °C; TLC Rf (EtOAc/EtOH 5/1) = 0.21; GC/
MS (EI+) m/z (rel intensity) 293 (M+, 43), 292 (100), 276 (12), 263
(22), 246 (31), 218 (14), 217 (27), 130 (12); HRMS (ESI+) exact mass
1
calculated for C17H15N3O2 294.1237; found 294.1239 [M + H]+; H
NMR (200 MHz, CDCl3) δ 1.93 (bs, 1H), 2.80À3.34 (m, 4H), 5.51 (s,
1H), 6.92 (d, 3J = 7.6 Hz, 1H), 6.97À7.23 (m, 4H), 7.32 (d, 3J = 9.0 Hz,
1H), 8.06 (dd, 3J = 9.0 Hz, 4J = 2.1 Hz, 1H), 8.51 (d, 4J = 2.0 Hz, 1H),
8.91 (bs, 1H); 13C NMR (50 MHz, CDCl3) δ 29.4 (t), 41.6 (t), 53.5
(d), 111.2 (d), 117.1 (d), 117.7 (d), 121.9 (s), 125.8 (d), 125.9 (s), 126.6
(d), 127.0 (d), 127.5 (d), 129.3 (d), 135.1 (s), 137.2 (s), 139.6 (s),
141.5 (s).
1-(5-Methoxycarbonyl-1H-indol-3-yl)-1,2,3,4-tetrahydroisoquino-
line (5n): method C 321 mg (58%); pale yellow solid; mp 195À197 °C;
TLC Rf (EtOAc/EtOH 5/1) = 0.17; GC/MS (EI+) m/z (rel intensity)
306 (M+, 41), 305 (100), 289 (8), 276 (16), 253 (20), 244 (8), 217 (14),
191 (16), 144 (8), 130 (12); HRMS (ESI+) exact mass calculated for
1
C19H18N2O2 307.1441, found 307.1446 [M + H]+; H NMR (200
MHz, CDCl3) δ 1.77 (bs, 1H), 2.79À3.33 (m, 4H), 3.90 (s, 3H), 5.55 (s,
1H), 6.98À7.20 (m, 5H), 7.36 (d, 3J = 8.6 Hz, 1H), 7.90 (dd, 3J = 8.6 Hz,
1
4J = 1.5 Hz, 1H), 8.37 (bs, 2H); H NMR (200 MHz, DMSO-d6) δ
2.57À3.21 (m, 5H), 3.78 (s, 3H), 5.31 (s, 1H), 6.79 (d, 3J = 7.6 Hz, 1H),
6.97 (dt, 3J = 7.3 Hz, 4J = 1.9 Hz, 1H), 7.03À7.17 (m, 2H), 7.19 (d, 3J =
1.9 Hz, 1H), 7.42 (d, 3J = 8.6 Hz, 1H), 7.69 (dd, 3 J = 8.6, 4J = 1.4 Hz,
1H), 8.19 (d, 4J = 1.1 Hz, 1H), 11.30 (s, 1H); 13C NMR (50 MHz, APT,
CDCl3) δ 25.8 (t), 40.0 (t), 51.8 (q), 51.9 (d), 111.5 (d), 113.0 (s),
121.6 (d), 121.6 (s), 123.2 (d), 125.8 (s), 126.8 (d), 127.8 (d), 128.0 (d),
128.1 (d), 128.7 (d), 132.1 (s), 132.9 (s), 138.9 (s), 168.1 (s).
1-(5-Chloro-1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline (5o):
method B 141 mg (100%, reaction time 7 h); pale yellow solid; mp
148À151 °C; TLC Rf (EtOAc/Et3N 11/1) = 0.29; GC/MS (EI+) m/z
(rel intensity) 284 (19), 283 (38), 282 (M+, 57), 281 (100), 254 (12), 253
1-(1-Methyl-1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline (5i):
method A 35 mg (97%), method B 131 mg (100%), method C 4 mg
(1%); pale yellow solid; mp 55À58 °C; TLC Rf (EtOAc/EtOH/TEA
8789
dx.doi.org/10.1021/jo201511d |J. Org. Chem. 2011, 76, 8781–8793

The Journal of Organic Chemistry
ARTICLE
(19), 252 (27), 217 (30), 131 (14), 130 (26), 109 (17); HRMS (ESI+):
exact mass calculated for C17H15N2Cl 283.0997, found 283.0998 [M +
H]+; 1H NMR (200 MHz, CDCl3) δ 1.93 (bs, 1H), 2.79À3.34 (m, 4H),
5.43 (s, 1H), 6.91 (s, 1H), 6.94 (d, 3J = 8.0 Hz, 1H), 6.99À7.19 (m, 4H),
7.23(d, 3J = 8.7 Hz, 1H), 7.46 (d, 4J =1.8 Hz, 1H), 8.36(s, 1H); 13C NMR
(50MHz, APT, CDCl3) δ 29.4 (t), 41.7(t), 53.6(d), 112.3(d), 118.7 (s),
118.8 (d), 122.3 (d), 125.1 (s), 125.4 (d), 125.7 (d), 126.4 (d), 127.3 (s),
127.6 (d), 129.0 (d), 134.9 (s), 134.9 (s), 137.7 (s).
1-(6-Chloro-1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline (5p):
method B 122 mg (86%, reaction time 4 h), method C 197 mg (46%);
off white powder; mp 146À148 °C; TLC Rf (EtOAc/EtOH 5/1) = 0.15;
GC/MS (EI+) m/z (rel intensity) 284 (18), 283 (38), 282 (M+, 56), 281
(100), 265 (10), 253 (22), 252 (28), 217 (29), 132 (19), 131 (19), 130
(35), 123 (13), 109 (29); HRMS (ESI+) exact mass calculated for
C17H15N2Cl 283.0997, found 283.1000 [M + H]+; 1H NMR (200 MHz,
CDCl3) δ 2.23 (s, 1H), 2.79À3.37 (m, 4H), 5.44 (s, 1H), 6.87 (s, 1H),
6.93 (d, 3J = 7.6 Hz, 1H), 6.96À7.09 (m, 2H), 7.13À7.21 (m, 2H), 7.25
(d, 4J = 1.7 Hz, 1H), 7.32 (d, 3J = 8.5 Hz, 1H), 8.61 (s, 1H); 13C NMR
(50 MHz, APT, DMSO-d6) δ 20.3 (t), 32.8 (t), 45.1 (d), 102.6 (d),
109.7 (s), 110.8 (d), 111.7 (d), 116.6 (s), 117.1 (d), 117.2 (d), 117.9 (d),
118.8 (s), 119.4 (d), 120.3 (d), 126.4 (s), 129.1 (s), 129.5 (s).
1-(7-Nitro-1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline (5q): meth-
odB 145mg(99%, reactiontime6 h), methodC:7 mg(2%); shining dark
yellow solid; mp 58À61 °C; TLC Rf (EtOAc/MeOH 11/1) = 0.35; GC/
MS (EI+) m/z (rel intensity) 293 (M+, 57), 292 (100), 264 (15), 263
(23), 246(18), 217(26), 189 (10), 132(10), 131 (8), 130(14), 109 (11);
1H NMR (200 MHz, CDCl3) δ 1.87 (bs, 1H), 2.79À3.36 (m, 4H), 5.48
(s, 1H), 6.90 (d, 3J = 7.5Hz, 1H), 6.96À7.22 (m, 5H), 7.84 (d, 3J = 7.7 Hz,
1H), 8.13 (d, 3J = 8.1 Hz, 1H), 9.86 (bs, 1H); 13C NMR (50 MHz, APT,
CDCl3) δ 29.6 (t), 42.0 (t), 53.8 (d), 119.0 (d), 119.3 (d), 121.1 (s),
125.7 (d), 126.1 (d), 126.5 (d), 127.5 (d), 128.4 (d), 129.1 (d), 130.0 (s),
130.2 (s), 132.9 (s), 135.1 (s), 137.6 (s).
to polar unidentified impurities, the desired product was further purified
by preparative HPLC.
1-(1H-Pyrrol-2-yl)-1,2,3,4-tetrahydroisoquinoline (8a): 327 mg (44%);
white solid; mp 117À118 °C; TLC Rf (EtOAc/EtOH 5/1) = 0.11; GC/
MS (EI+) m/z (rel intensity) 198 (M+, 50), 197 (100), 182 (99), 169 (36),
168 (95), 167 (40), 132 (46), 131 (28), 130 (60), 115 (21), 103 (21), 77
(22); HRMS (ESI+) exact mass calculated for C13H14N2 199.1230, found
199.1223 [M + H]+; 1H NMR (200 MHz, CDCl3) δ 2.07 (s, 1H), 2.76 (dt,
2J = 16.4 Hz, 3J = 5.3 Hz, 1H), 2.84À3.26 (m, 3H), 5.14 (s, 1H), 6.06 (dd,
3J=3.3 Hz, 3J=2.5 Hz, 1H), 6.14 (dd, 3 J=5.7 Hz, 3J=2.8 Hz, 1H), 6.68 (dd,
3J = 4.1 Hz, 3J = 2.5 Hz, 1H), 6.95À7.04 (m, 1H), 7.05À7.23 (m, 3H), 9.11
(s, 1H); 13C NMR (50 MHz, APT, CDCl3) δ 29.2 (t), 41.9 (t), 55.1 (d),
107.4 (d), 107.9 (d), 117.6 (d), 125.6 (d), 126.5 (d), 127.6 (d), 129.1 (d),
133.7 (s), 134.8 (s), 137.0 (s).
1-(2,5-Dimethyl-1H-pyrrol-3-yl)-1,2,3,4-tetrahydroisoquinoline (8b):
230 mg (27%); off-white crystals; mp 127À129 °C; TLC Rf (EtOAc/
EtOH/TEA 10/1/1) = 0.53; GC/MS (EI+) m/z (rel intensity) 226 (M+,
100), 225 (96), 209 (79), 208 (56), 196 (38), 194 (32), 182 (39), 167
(28), 132 (24), 130 (36), 94 (78), 91 (28); HRMS (ESI+) exact mass
calculated for C15H18N2 227.1543; found 227.1544 [M + H]+; 1H NMR
(200 MHz, CDCl3) δ 1.84 (s, 1H), 2.13 (s, 3H), 2.15 (s, 3H), 2.71À3.15
(m, 3H), 3.32 (dt, 2J = 15.9 Hz, 3 J = 7.0 Hz, 1H), 5.01 (s, 1H), 5.51 (d,
3
4J = 2.3 Hz, 1H), 6.90 (d, J = 6.9 Hz, 1H), 6.98À7.13 (m, 3H), 7.74
(s, 1H); 13C NMR (50 MHz, CDCl3) δ 11.1 (q), 12.9 (q), 29.9 (t), 42.6
(t), 54.1 (d), 105.9 (d), 122.5 (s), 123.2 (s), 125.1 (s), 125.5 (d), 125.6
(d), 127.7 (d), 128.7 (d), 135.0 (s), 139.8 (s).
1-(4,5,6,7-tetrahydro-1H-indol-2-yl)-1,2,3,4-tetrahydroisoquinoline
(8c): 387 mg (41%); pale yellow solid; mp 115À117 °C; TLC Rf
(EtOAc/EtOH 5/1) = 0.14; GC/MS (EI+) m/z (rel intensity) 252
(M+, 46), 251 (52), 236 (56), 223 (44), 222 (39), 194 (31), 180 (39),
132 (43), 131 (65), 130 (100), 105 (32), 103 (31), 93 (72), 77 (31);
HRMS (ESI+) exact mass calculated for C17H20N2 253.1699, found
1
253.1692 [M + H]+; H NMR (200 MHz, CDCl3) δ 1.68À1.88 (m,
1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline (5r):
method B 124 mg (100%), method C 160 mg (43%); light brown solid;
mp 172À174 °C; TLC Rf (EtOAc/EtOH 5/1) = 0.11; GC/MS (EI+)
m/z(rel intensity) 249 (M+, 36), 248 (100), 232 (7), 220 (18), 219 (30), 218
(11), 131 (8), 130 (10), 119 (12); HRMS (ESI+) exact mass calculated for
4H), 2.21 (s, 1H), 2.44À2.55 (m, 4H), 2.68À3.30 (m, 4H), 5.10 (s, 1H),
5.76 (d, 4J = 2.3 Hz, 1H), 7.03À7.21 (m, 4H), 8.27 (s, 1H); 13C NMR
(50 MHz, APT, CDCl3) δ 22.7 (t), 22.8 (t), 23.4 (t), 23.8 (t), 29.3 (t),
41.6 (t), 55.1 (d), 107.1 (d), 116.1 (s), 125.5 (d), 126.4 (d), 126.8 (s),
127.8 (d), 129.0 (d), 131.8 (s), 134.9 (s), 137.1 (s).
1
C16H15N3 250.1339; found 250.1352 [M + H]+; H NMR (200 MHz
DMSO-d6) δ 2.63À3.24 (m, 4H), 3.70 (s, 1H), 5.30 (s, 1H), 6.80 (d, J =
7.6 Hz, 1H), 6.85À7.02 (m, 2H), 7.03À7.18 (m, 2H), 7.27 (d, 4J = 1.3 Hz,
1H), 7.66 (dd, 3J = 7.8 Hz, 4J =1.3 Hz, 1H), 8.15 (d, 3J = 3.6 Hz, 1H), 11.48
(s, 1H); 13C NMR (50 MHz, APT, DMSO-d6) δ 29.0 (t), 41.7 (t), 53.9
(d), 114.8 (d), 116.8 (s), 118.4 (s), 124.8 (d), 125.2 (d), 125.8 (d), 127.0
(d), 128.0 (d), 128.7 (d), 135.0 (s), 138.5 (s), 142.3 (d), 148.9 (s).
1-(7-Methyl-1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline (5t): meth-
od C 189 mg (48%); pale brown solid; mp 141À144 °C; TLC Rf (EtOAc/
EtOH 5/1) = 0.12; GC/MS (EI+) m/z (rel intensity) 262 (M+, 56), 261
(100), 245 (11), 233 (14), 232 (21), 217 (12), 132 (9), 131 (12), 130 (20),
1,1-Dimethylethyl-1-(1H-pyrrol-2-yl)-3,4-dihydroisoquinoline-
2(1H)-carboxylate (8d): 55 mg (11%); yellow oil; TLC Rf (PE/EtOAc 5/1)
= 0.53; GC/MS (EI+) m/z (rel intensity) 298 (M+, 8), 242 (49), 198 (30),
197 (100), 182 (42), 168 (26), 167 (15), 132 (10), 130 (18), 57 (20); 1H
NMR (200 MHz, CDCl3) δ1.51(s, 9H), 2.70À3.03(m, 2H), 3.26(bs, 1H),
3.98 (bs, 1H), 5.58 (bs, 1H), 6.02 (dd, 3 J = 5.0 Hz, 3J = 2.5 Hz, 1H), 6.30 (bs,
1H), 6.73 (dd, 3J=4.1 Hz, 3J=2.5 Hz, 1H), 7.14À7.23 (m, 4H), 9.14 (s, 1H);
13C NMR (101 MHz, CDCl3) δ 28.6 (q, 3C), 28.7 (t), 39.1 (t), 51.6 (d),
80.2 (s), 107.1 (d), 107.7 (d), 117.7 (d), 125.9 (d), 127.0 (d), 128.5 (d),
128.6 (d), 134.1 (s), 134.3 (s), 135.2 (s), 156.2 (s).
1
115 (10); H NMR (200 MHz, CDCl3) δ 2.08 (bs, 1H), 2.48 (s, 3H),
General Procedure for Methoxyarlyation of N-Protected
THIQ. 2-Protected 1,2,3,4-tetrahydroisoquinoline (PG = Boc, 200 mg;
PG = Bz, 203 mg; PG = Cbz; 229 mg; 0.857 mmol, 1.0 equiv), catalyst
(Cu(NO3)2 3H2O, 10.4 mg; Fe(NO3)3 9H2O, 17.3 mg; 42.9 μmol,
2.81À3.37 (m, 4H), 5.51 (s, 1H), 6.87 (d, 3J = 2.3 Hz, 1H), 6.94À7.22 (m,
6H), 7.30À7.41 (m, 1H), 8.26 (bs, 1H); 13C NMR (50 MHz, APT,
CDCl3) δ 16.6 (q), 29.6 (t), 41.7 (t), 53.9 (d), 117.0 (d), 119.8 (d), 120.5
(s), 122.6 (d), 123.7 (d), 125.6 (d), 125.9 (s), 126.1 (d), 127.9 (d), 128.9
(d), 135.0 (s), 136.1 (s), 138.2 (s).
3
3
0.05 equiv), and the methoxybenzene derivative (1.03 mmol, 1.2 equiv)
were placed into a 5 mL glass vial. tBHP (203 μL, 5.5 M in decane, 1.3
equiv) was added dropwise at 0 °C in air and the reaction mixture stirred
for 10 min at 0 °C. The neat mixture was then slowly heated to 50 °C and
stirred for 15 h in a heating block. The reaction was monitored by TLC
and/or GC-MS. The reaction mixture was diluted with DCM (3 mL)
and directly subjected to flash column chromatography. The desired
product was obtained after MPLC, where the solvent mixture used for
TLC was also used for column chromatography (100 g of SiO2). If
necessary, the product was finally purified by preparative HPLC.
1,1-Dimethylethyl-1-(2,4,6-trimethoxyphenyl)-3,4-dihydroisoqui-
noline-2(1H)-carboxylate (10a): yield for Cu 260 mg (76%) and for Fe
General Procedure for Pyrrolation of THIQ. THIQ (999 mg,
7.50 mmol, 2.0 equiv), catalyst (45.3 mg, 0.188 mmol, 0.05 equiv), and
the corresponding pyrrole (3.75 mmol, 1.0 equiv) were placed in a 5 mL
glass vial in air and cooled to 0 °C and stirred for 10 min. tBHP (975 μL,
5.5 M in decane, 1.3 equiv) was added dropwise at 0 °C in air and the
dark greenish slurry stirred for 1 h at 0 °C. The neat mixture was then
slowly heated to 50 °C (within 1 h), upon which the mixture turned
black, and stirred for 15 h in a heating block. The reaction was monitored
by GC-MS. The mixture was diluted with DCM (3 mL) and directly
subjected to flash chromatography, using EtOAc/EtOH as eluent. Due
8790
dx.doi.org/10.1021/jo201511d |J. Org. Chem. 2011, 76, 8781–8793

The Journal of Organic Chemistry
ARTICLE
278 mg (81%); white solid; mp 109À111 °C; TLC Rf (PE/Et2O 1/1) =
0.10; GC/MS (EI+) m/z (rel intensity) 348 (24), 299 (60), 298 (100),
282 (26), 268 (90), 239 (14), 180 (18), 179 (20), 151 (16), 132 (9);
HRMS (ESI+): exact mass calculated for C23H29NO5 400.2118, found
(q), 79.2 (s), 91.7 (d), 118.9 (s), 125.6 (d), 125.7 (d), 126.5 (d), 128.1 (d),
135.1 (s), 136.5 (s), 137.3 (s), 152.6 (s), 152.7 (s), 153.6 (s), 155.1 (s).
1,1-Dimethylethyl-1-(2,4-dimethoxyphenyl)-3,4-dihydroisoquino-
line-2(1H)-carboxylate (10f): yield for Cu 131 mg (41%) and for Fe 108
mg (34%); white solid; mp 36À37 °C; TLC Rf (PE/Et2O 1/1) = 0.33;
HRMS (ESI+) exact mass calculated for C22H27NO4 370.2013, found
370.2010 [M + H]+; GC/MS (EI+) m/z (rel intensity) 269 (46), 268
(100), 252 (22), 239 (12), 238 (32), 132 (15), 130 (10); 1H NMR (200
MHz, CDCl3) δ 1.42 (s, 9H), 2.81 (dt, 2J = 16.0 Hz, 3J = 3.9 Hz, 1H),
2.99 (ddd, J = 15.9 Hz, J = 10.3 Hz, J = 5.6 Hz, 1H), 3.29À3.48
(m, 1H), 3.78 (s, 3H), 3.82 (s, 3H), 3.99À4.22 (m, 1H), 6.34 (dd, 3J =
8.4 Hz, 4J = 2.4 Hz, 1H), 6.47 (s, 1H), 6.48 (s, 1H), 6.83 (d, 3J = 8.3 Hz,
1H), 7.00À7.18 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 28.3 (q, 3C),
28.8 (t), 38.6 (t), 52.6 (d), 55.15 (q), 55.19 (q), 79.3 (s), 98.4 (d), 103.4
(d), 125.1 (s), 125.9 (d), 126.2 (d), 127.9 (d), 128.5 (d), 130.0 (d),
135.0 (s), 136.8 (s), 154.7 (s), 158.0 (s), 159.9 (s).
1
400.2122 [M + H]+; H NMR (200 MHz, CDCl3) δ 1.28 (s, 9H),
2.73À3.01 (m, 2H), 3.49 (ddd, 2J = 12.6 Hz, 3J = 10.6 Hz, 3J = 4.5 Hz,
1H), 3.69 (s, 6H), 3.81 (s, 3H), 4.30À4.45 (m, 1H), 6.12 (s, 2H),
6.45 (s, 1H), 6.80 (d, 3J = 7.2 Hz, 1H), 6.95À7.16 (m, 3H); 13C NMR
(50 MHz, APT, CDCl3) δ 28.3 (3C, q), 30.5 (t), 39.4 (t), 49.4 (d),
55.2 (q), 55.5 (2C, q), 79.1 (s), 90.5 (2C, d), 114.0 (s), 125.4 (d), 125.8
(d), 126.3 (d), 127.9 (d), 135.2 (s), 137.2 (s), 155.4 (s), 158.8 (2C, s),
160.1 (s).
2
3
3
Phenyl-(1-(2,4,6-trimethoxyphenyl)-3,4-dihydroisoquinolin-2(1H)-
yl)methanone (10b): yield for Cu 159 mg (46%) and for Fe 187 mg
(54%); white solid; mp 67À69 °C; TLC Rf (PE/Et2O 1/1) = 0.09; GC/
MS (EI+) m/z (rel intensity) 403 (M+, 7), 373 (26), 372 (100), 299 (4),
298 (13), 282 (6), 105 (10), 77 (9); HRMS (ESI+) exact mass calculated
for C25H25NO4 404.1856, found 404.1852 [M + H]+; 1H NMR (400
MHz, DMSO-d6, 80 °C) δ 2.86 (bs, 1H), 3.61 (s, 6H), 3.63À3.74 (m,
1H), 3.78 (s, 3H), 4.07 (bs, 1H), 6.21 (s, 2H), 6.64 (bs, 1H), 6.72 (d, 3J =
General Procedure for Methoxyarylation of Isochroman.
Isochroman 9 (200 mg, 1.49 mmol, 1.0 equiv), catalyst (Cu(NO3)2
3
3H2O, 18.0 mg; Fe(NO3)3 9H2O, 30.1 mg; 74.5 μmol, 0.05 equiv), and
3
the corresponding methoxybenzene (1.79 mmol, 1.2 equiv) were placed
into a 5 mL glass vial. tBHP (352 μL, 5.5 M in decane, 1.3 equiv) was
added dropwise at 0 °C in air and the reaction mixture stirred for 10 min
at 0 °C. The neat mixture was then slowly heated to 50 °C and stirred for
15 h in a heating block. Finally, the reaction temperature was raised to
80 °C, and the reaction mixture was stirred for another 24 h. The
reaction was monitored by TLC and/or GC-MS. The reaction mixture
was diluted with DCM (3 mL) and directly subjected to flash column
chromatography. The desired product was obtained after MPLC, where
the solvent mixture used for TLC was also used for column chroma-
tography (100 g of SiO2). If necessary, the product was finally purified by
preparative HPLC.
3
3
7.5 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H),
7.13À7.26 (m, 3H), 7.31À7.44 (m, 3H); 13C NMR (101 MHz, DMSO-
d6, 80 °C) δ 29.5 (t), 49.2 (s), 54.8 (q), 55.4 (q, 2C), 91.4 (d, 2C), 112.4
(s), 125.1 (d), 125.4 (d, 2C), 126.0 (d, 2C), 127.4 (d), 127.5 (d, 2C
overlapping), 128.3 (d), 134.3 (s), 136.5 (s), 137.3 (s), 158.4 (s), 159.9
(s, 2C), 169.2 (s).
Phenylmethyl-1-(2,4,6-trimethoxyphenyl)-3,4-dihydroisoquino-
line-2(1H)-carboxylate (10c): yield for Cu 190 mg (51%) and for Fe 215
mg (58%); pale yellow solid; mp 115À116 °C; TLC Rf (PE/Et2O 1/1) =
0.32; GC/MS (EI+) m/z (rel intensity) 433 (M+, 1), 342 (3), 299 (20),
298 (100), 283 (5), 282 (17), 90 (6); HRMS (ESI+) exact mass
1
calculated for C26H27NO5 434.1962, found 434.1966 [M + H]+; H
1-(2,4,6-Trimethoxyphenyl)isochroman (11a): yield for Cu 230 mg
(51%) and for Fe 246 mg (55%); white solid; mp 118À120 °C; TLC Rf
(PE/Et2O 1/1) = 0.32; GC/MS (EI+) m/z (rel intensity) 300 (M+, 50),
282 (22), 272 (50), 269 (100), 251 (26), 241 (98), 239 (48), 208 (23),
195 (27), 181 (35), 168 (22), 139 (28); HRMS (ESI+) exact mass
calculated for C18H20O4 301.1434; found 301.1442 [M + H]+; 1H NMR
(200 MHz, CDCl3) δ 2.66 (d, 2J = 15.9 Hz, 1H), 3.09À3.35 (m, 1H),
3.61 (s, 6H), 3.80 (s, 3H), 3.93 (dt, 2J = 11.2 Hz, 3J = 3.1 Hz, 1H), 4.30
(ddd, 2J = 11.1 Hz, 3J = 5.6 Hz, 3J = 1.9 Hz, 1H), 6.12 (s, 2H), 6.30 (s,
1H), 6.67 (d, 3J = 7.6 Hz, 1H), 6.92À7.12 (m, 3H); 13C NMR (50 MHz,
APT, CDCl3) δ 29.0 (t), 55.2 (q), 55.9 (2C, q), 65.3 (t), 70.2 (d), 91.4
(2C, d), 111.7 (s), 124.2 (d), 125.1 (d), 125.5 (d), 127.8 (d), 133.8 (s),
139.7 (s), 159.9 (2C, s), 161.2 (s).
NMR (200 MHz, CDCl3) δ 2.75À3.06 (m, 2H), 3.29À3.79 (m, 7H),
3.83 (s, 3H), 4.46 (d, 2J = 11.0 Hz, 1H), 5.03 (d, 2J = 16.7 Hz, 1H), 5.09
(d, 2J = 17.4 Hz, 1H), 6.08 (s, 2H), 6.56 (s, 1H), 6.79 (d, 3J = 7.3 Hz,
1H), 6.96À7.41 (m, 8H); 13C NMR (50 MHz, APT, CDCl3) δ 30.4 (t),
39.9 (t), 49.3 (d), 55.2 (q), 55.4 (q, 2C), 66.8 (t), 90.8 (d, 2C), 113.3 (s),
125.5 (d), 125.9 (d), 126.2 (d), 127.5 (d), 127.8 (d), 127.9 (d, 2C),
128.2 (d, 2C), 134.7 (s), 136.0 (s), 137.0 (s), 155.6 (s), 158.9 (s), 160.2
(s, 2C).
1,1-Dimethylethyl-1-(2,4,5-trimethoxyphenyl)-3,4-dihydroisoqui-
noline-2(1H)-carboxylate (10d): yield for Cu 80 mg (23%) and for Fe
160 mg (47%); white solid; mp 84À86 °C; TLC Rf (PE/Et2O 3/1) =
0.13; HRMS (ESI+) exact mass calculated for C23H29NO5 400.2118,
found 400.2123 [M + H]+; GC/MS (EI+) m/z (rel intensity) 399 (M+, 4),
343 (5), 299 (58), 298 (100), 284 (24), 268 (73), 253 (12), 239 (12),
168 (8), 132 (15); 1H NMR (200 MHz, CDCl3) δ 1.40 (s, 9H),
2.75À3.07 (m, 2H), 3.35À3.55 (m, 1H), 3.69 (s, 3H), 3.77 (s, 3H), 3.87
(s, 3H), 4.03À4.24 (m, 1H), 6.53 (s, 1H), 6.42 (s, 1H), 6.56 (s, 1H),
7.01À7.17 (m, 4H); 13C NMR (50 MHz, APT, CDCl3) δ 28.3 (3C, q),
29.0 (t), 39.1 (t), 53.0 (q), 56.0 (q), 56.1 (d), 56.7 (q), 79.4 (s), 97.5 (d),
113.8 (d), 124.2 (s), 125.9 (d), 126.2 (d), 127.8 (d), 128.4 (d), 134.8 (s),
136.7 (s), 142.4 (s), 148.8 (s), 151.5. (s), 154.7 (s).
1,1-Dimethylethyl-1-(2,3,4,6-tetramethoxyphenyl)-3,4-dihydroiso-
quinoline-2(1H)-carboxylate (10e): yield for Cu 170 mg (46%) and for
Fe 190 mg (52%); pale yellow solid; mp 116À118 °C; TLC Rf (PE/
Et2O 2/1) = 0.17; GC/MS (EI+) m/z (rel intensity) 429 (M+, 8), 329
(27), 328 (100), 299 (10), 298 (49), 183 (10), 132 (20), 130 (10), 57
(12); HRMS (ESI+): exact mass calculated for C24H31NO6 430.2224,
found 430.2230 [M + H]+; 1H NMR (200 MHz, CDCl3) δ 1.33 (s, 9H),
2.74À3.03 (m, 2H), 3.40À3.61 (m, 4H), 3.75 (s, 3H), 3.75 (s, 3H), 3.88
(s, 3H), 4.36 (d, 3J = 12.3 Hz, 1H), 6.29 (s, 1H), 6.48 (s, 1H), 6.80 (d,
3J=6.9 Hz, 1H), 6.96À7.16 (m, 3H); 13CNMR(50MHz, APT, CDCl3) δ
28.3 (q, 3C), 30.2 (t), 39.4 (t), 49.8 (d), 55.7 (q), 55.9 (q), 59.8 (q), 60.7
1-(2,3,4,6-Tetramethoxyphenyl)isochroman (11b): yield for Cu 190
mg (39%) and for Fe 85 mg (17%); white solid; mp 55À58 °C; TLC Rf
(PE/EtOAc 5/1) = 0.19; GC/MS (EI+) m/z (rel intensity) 330 (M+,
100), 315 (23), 312 (14), 299 (99), 284 (10), 271 (18), 238 (16), 198
(24), 195 (16), 183 (23); HRMS (ESI+) exact mass calculated for
C19H22O5 331.1540, found 331.1544 [M + H]+; 1H NMR (200 MHz,
CDCl3) δ 2.69 (d, 2J = 16.0 Hz, 1H), 3.46 (s, 3H), 3.14À3.35 (m, 1H),
3.69 (s, 3H), 3.78 (s, 3H), 3.88 (s, 3H), 3.91À4.02 (m, 1H), 4.32 (ddd,
2J = 11.1 Hz, 3J = 5.6 Hz, 3J = 1.7 Hz, 1H), 6.25 (s, 1H), 6.30 (s, 1H), 6.69
3
(d, J = 7.3 Hz, 1H), 6.96À7.17 (m, 3H); 13C NMR (50 MHz, APT,
CDCl3) δ 28.9 (t), 55.9 (q), 56.3 (q), 60.5 (q), 60.8 (q), 65.3 (t), 70.8
(d), 92.7 (d), 116.8 (s), 124.5 (d), 125.4 (d), 125.6 (d), 128.1 (d), 133.8
(s), 136.7 (s), 139.6 (s), 153.5 (s), 153.8 (s), 154.5 (s).
1-(2,4-Dimethoxyphenyl)isochroman (11c): yield for Cu 92 mg (23%)
andforFe48mg(12%);colorlessoil;TLCRf (PE/Et2O1/1) =0.28;GC/MS
(EI+) m/z (rel intensity) 270 (M+, 65), 255 (100), 239 (43), 225 (16),
209 (16), 194 (13), 178 (8), 165 (24), 104 (10), 77 (8); HRMS (ESI+)
exact mass calculated for C17H18O3 271.1329; found 271.1324 [M +
H]+; 1H NMR (200 MHz, CDCl3) δ 2.84 (dt, 2J = 16.3 Hz, 3J = 4.4 Hz,
1H), 3.01À3.22 (m, 1H), 3.81 (s, 3H), 3.88 (s, 3H), 3.90À4.03 (m, 1H),
8791
dx.doi.org/10.1021/jo201511d |J. Org. Chem. 2011, 76, 8781–8793

The Journal of Organic Chemistry
ARTICLE
4.18 (dt, 2J = 11.0 Hz, 3J = 5.0 Hz, 1H), 6.22 (s, 1H), 6.43 (dd, 3J = 8.4
Hz, 4J = 2.4 Hz, 1H), 6.55 (d, 4J = 2.4 Hz, 1H), 6.80 (d, 3J = 7.4 Hz, 1H),
6.96 (d, 3J = 8.4 Hz, 1H), 7.03À7.21 (m, 3H); 13C NMR (50 MHz, APT,
CDCl3) δ 28.8 (t), 55.3 (q), 55.6 (q), 63.3 (t), 72.2 (d), 98.4 (d), 104.2
(d), 123.3 (s), 125.8 (d), 126.2 (d), 126.6 (d), 128.5 (d), 130.7 (d),
134.2 (s), 137.9 (s), 158.6 (s), 160.5 (s)
1-(2,4,5-Trimethoxyphenyl)isochroman (11d): yield for Cu 145 mg
(32%) and for Fe 67 mg (15%); white solid; mp 46À48 °C; TLC Rf
(PE/EtOAc 5/1) = 0.39; GC/MS (EI+) m/z (rel intensity) 300 (M+,
100), 285 (35), 269 (39), 257 (9), 239 (26), 225 (9), 208 (12), 195 (14),
168 (25), 153 (13); HRMS (ESI+) exact mass calculated for C18H20O4
301.1434, found 301.1436 [M + H]+; 1H NMR (400 MHz, CDCl3) δ
2.80 (dt, 2J = 16.2 Hz, 3J = 3.2 Hz, 1H), 3.21 (ddd, 2J = 16.0 Hz, 3J = 10.0
Hz, 3J = 5.8 Hz, 1H), 3.73 (s, 3H), 3.89 (s, 3H), 3.93 (s, 3H), 3.99 (dt,
2J = 11.1 Hz, 3J = 3.8 Hz, 1H), 4.27 (ddd, 2J = 11.2 Hz, 3J = 5.6 Hz, 3J = 3.1
Hz, 1H), 6.20 (s, 1H), 6.61 (s, 1H), 6.66 (s, 1H), 6.78 (d, 3J = 7.6 Hz,
1H), 7.05À7.12 (m, 1H), 7.14À7.21 (m, 2H); 13C NMR (101 MHz,
APT, CDCl3) δ 28.8 (t), 56.0 (q), 56.4 (q), 56.8 (q), 64.4 (t), 72.6 (d),
97.4 (d), 113.0 (d), 122.2 (s), 125.8 (d), 126.2 (d), 126.5 (d), 128.5 (d),
133.9 (s), 138.0 (s), 143.2 (s), 149.4 (s), 151.9 (s).
2006, 102, 50. (d) Liu, C.; Jin, L.; Lei, A. Synlett 2010, 2527.(e) Negishi,
E.; de Meijere, A. Handbook of Organopalladium Chemistry for Organic
Synthesis; Wiley: Hoboken, NJ, 2002; Vols. 1 and 2. (f) de Meijere, A.;
Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; Wiley-
VCH: Weinheim, Germany, 2004; Vols. 1 and 2.
(11) (a) Shilov, A. E.; Shul’pin, G. B. Chem. Rev. 1997, 97, 2879. (b)
Murai, S., Ed. Activation of unreactive bonds and organic synthesis.
Topics in Organometallic Chemistry; Springer: New York, 1999; Vol. 3,
p 272. (c) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211. (d)
Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507. (e) Godula, K.;
Sames, D. Science 2006, 312, 67. (f) Kakiuchi, F.; Chatani, N. Adv.
Synth. Catal. 2003, 345, 1077.(g) Dyker, G., Ed. Handbook of
C-H Transformations: Applications in Organic Synthesis; Wiley-VCH:
Weinheim, Germany, 2005; Vols. 1 and 2.
(12) (a) Prokopcova, H.; Bergman, S. D.; Aelvoet, K.; Smout, V.;
Herrebout, W.; Van der Veken, B.; Meerpoel, L.; Maes, B. U. W. Chem.
Eur. J. 2010, 16, 13063. (b) Pastine, S. J.; Gribkov, D. V.; Sames, D. J. Am.
Chem. Soc. 2006, 128, 14220.
(13) (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2009, 48, 5094. (b) Fuchibe, K.; Kaneko, T.; Mori, K.;
Akiyama, T. Angew. Chem., Int. Ed. 2009, 48, 8070. (c) Davies, H. M. L.;
Nikolai, J. Org Biomol Chem 2005, 3, 4176. (d) Bellina, F.; Rossi, R.
Chem. Rev. 2010, 110, 1082.
’ ASSOCIATED CONTENT
(14) For recent reviews see: (a) Zeng, T.; Song, G.; Moores, A.; Li,
C.-J. Synlett 2010, 2002. (b) Li, C.-J. Acc. Chem. Res. 2009, 42, 335.
(c) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (d) Li, C.-J.;
Yoo, W.-J. Top. Curr. Chem. 2010, 292, 281. (e) Scheuermann, C. J.
Chem. Asian J. 2010, 5, 436. (f) Guo, X.; Li, Z.; Li, C. Huaxue Jinzhan
2010, 22, 1434. (g) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew.
Chem., Int. Ed. 2009, 48, 9792. For recent contributions to the field see:
(h) Bugaut, X.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 7479. (i)
Xiong, T.; Li, Y.; Bi, X.; Lv, Y.; Zhang, Q. Angew. Chem., Int. Ed. 2011,
50, 7140. (j) Murarka, S.; Studer, A. Org. Lett. 2011, 13, 2746. (k) Chen,
L.; Shi, E.; Liu, Z.; Chen, S.; Wei, W.; Li, H.; Xu, K.; Wan, X. Chem. Eur. J.
2011, 17, 4085. (l) Han, W.; Mayer, P.; Ofial, A. R. Angew. Chem., Int. Ed.
2011, 50, 2178. (m) Xie, J.; Huang, Z.-Z. Angew. Chem., Int. Ed. 2010,
49, 10181.
S
Supporting Information. Text giving experimental pro-
b
cedures and analytical data and figures giving NMR spectra of
compounds unknown in the literature. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: mschnuerch@ioc.tuwien.ac.at.
’ ACKNOWLEDGMENT
(15) Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya, N. J. Am. Chem.
Soc. 2008, 130, 11005.
We acknowledge the Austrian Science Foundation (FWF,
project P21202-N17) for financial support of this work.
(16) (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810. (b) Li, Z.;
Li, C.-J. Eur. J. Org. Chem. 2005, 3173. (c) Li, Z.; Li, C.-J. J. Am. Chem.
Soc. 2005, 127, 3672. (d) Li, Z.; MacLeod, P. D.; Li, C.-J. Tetrahedron:
Asymmetry 2006, 17, 590. (e) Li, Z.; Yu, R.; Li, H. Angew. Chem., Int. Ed.
2008, 47, 7497.
(17) (a) Liu, P.; Zhou, C.-Y.; Xiang, S.; Che, C.-M. Chem. Commun.
2010, 46, 2739. (b) Sureshkumar, D.; Sud, A.; Klussmann, M. Synlett
2009, 1558. (c) Yang, F.; Li, J.; Xie, J.; Huang, Z.-Z. Org. Lett. 2010,
12, 5214. (d) Hari, D.-P.; K€onig, B. Org. Lett. 2011, 13, 3852. (e) Boess,
E.; Sureshkumar, D.; Sud, A.; Wirtz, C.; Fares, C.; Klussmann, M. J. Am.
Chem. Soc. 2011, 133, 8106.
’ REFERENCES
(1) Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005, 5127.
(2) (a) Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. J. Chem.
Rev. 2006, 106, 2734. (b) Blaser, H. U. Chem. Rev. 1992, 92, 935.
(3) (a) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004,
104, 3341. (b) Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069.
(4) (a) Higuchi, K.; Kawasaki, T. Nat. Prod. Rep. 2007, 24, 843. (b)
Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010,
110, 4489. (c) Cang, S.; Ohta, S.; Chiba, H.; Johdo, O.; Nomura, H.;
Nagamatsu, Y.; Yoshimoto, A. J. Antibiot. 2001, 54, 304. (d) DeCuypere,
M.; Kalabokis, V. N.; Hao, R.; Schroeder, D.; Miller, D. D.; LeDoux,
M. S. J. Neurosci. Res. 2008, 86, 2543.
(5) (a) Dalence-Guzman, M. F.; Toftered, J.; Oltner, V. T.; Wensbo,
D.; Johansson, M. H. Bioorg. Med. Chem. Lett. 2010, 20, 4999. (b)
Ludwig, M.; Hoesl, C. E.; Hoefner, G.; Wanner, K. T. Eur. J. Med. Chem.
2006, 41, 1003. (c) Zhang, Y. Tetrahedron Lett. 2005, 46, 6483. (d) Yi
Chae, S.; Yun Sang, Y. J. Am. Chem. Soc. 2005, 127, 17000.
(6) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669.
(7) Wang, S.; Onaran, M. B.; Seto, C. T. Org. Lett. 2010, 12, 2690.
(8) Cheng, P.; Huang, N.; Jiang, Z.-Y.; Zhang, Q.; Zheng, Y.-T.;
Chen, J.-J.; Zhang, X.-M.; Ma, Y.-B. Bioorg. Med. Chem. Lett. 2008,
18, 2475.
(18) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968.
(19) (a) Girard, N.; Hurvois, J.-P.; Toupet, L.; Moinet, C. Synth.
Commun. 2005, 35, 711. (b) Girard, N.; Gautier, C.; Malassene, R.;
Hurvois, J.-P.; Moinet, C.; Toupet, L. Synlett 2004, 2005. (c) Girard, N.;
Hurvois, J.-P. Tetrahedron Lett. 2007, 48, 4097.
(20) (a) Chincholkar, P. M.; Kale, A. S.; Gumaste, V. K.; Deshmukh,
A. R. A. S. Tetrahedron 2009, 65, 2605. (b) Abraham, C. J.; Paull, D. H.;
Dogo-Isonagie, C.; Lectka, T. Synlett 2009, 1651. (c) Giera, D. S.;
Sickert, M.; Schneider, C. Synthesis 2009, 3797. (d) Taniyama, D.;
Hasegawa, M.; Tomioka, K. Tetrahedron: Asymmetry 1999, 10, 221.
(21) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382. (b)
Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337.
(c) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
Rev. 2002, 102, 1359.
(9) Gao, M.; Kong, D.; Clearfield, A.; Zheng, Q.-H. Bioorg. Med.
Chem. Lett. 2006, 16, 2229.
(22) (a) Dollimore, D. Handbook of Copper Compounds and Applica-
tions Marcel Dekker: New York, 1997; p 231. (b) Nandivada, H.;
Lahann, J. Click Chemistry for Biotechnology and Materials Science; Wiley:
New York, 2009; p 291. (c) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc.
(10) (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4442. (b) Geissler, H. Transition Met. Org. Synth. 1998,
1, 158. (c) Fairlamb, I. J. S. Annu. Rep. Prog. Chem., Sect. B: Org. Chem.
8792
dx.doi.org/10.1021/jo201511d |J. Org. Chem. 2011, 76, 8781–8793

The Journal of Organic Chemistry
ARTICLE
Chem. Res. 2009, 42, 1074. (d) Zhang, M. Appl. Organomet. Chem. 2010,
24, 269.
(23) (a) Volla, C. M. R.; Vogel, P. Org. Lett. 2009, 11, 1701.
(b) Zhang, S.-Y.; Tu, Y.-Q.; Fan, C.-A.; Zhang, F.-M.; Shi, L. Angew.
Chem., Int. Ed. 2009, 48, 8761. (c) Li, P.; Zhang, Y.; Wang, L. Chem. Eur.
J. 2009, 15, 2045. (d) Han, W.; Ofial, A. R. Chem. Commun. 2009, 6023.
(e) Czaplik, W. M.; Mayer, M.; Cvengros, J.; Jacobi von Wangelin, A.
ChemSusChem 2009, 2, 396. (f) Sherry, B. D.; Fuerstner, A. Acc. Chem.
Res. 2008, 41, 1500. (g) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem.
Rev. 2004, 104, 6217. (h) Correa, A.; Garcia Mancheno, O.; Bolm, C.
Chem. Soc. Rev. 2008, 37, 1108. (i) Maiti, S.; Biswas, S.; Jana, U. J. Org.
Chem. 2010, 75, 1674. (j) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011,
111, 1293.
(24) Ghobrial, M.; Harhammer, K.; Mihovilovic, M. D.; Schn€urch,
M. Chem. Commun. 2010, 46, 8836.
(25) (a) Shu, X.-Z.; Xia, X.-F.; Yang, Y.-F.; Ji, K.-G.; Liu, X.-Y.; Liang,
Y.-M. J. Org. Chem. 2009, 74, 7464. (b) Morphy, J. R.; Rankovic, Z.;
York, M. Tetrahedron Lett. 2001, 42, 7509. (c) Al-Hiari, Y. M.; Bennett,
S. J.; Cox, B.; Davies, R. J.; Khalaf, A. I.; Waigh, R. D.; Worsley, A. J.
J. Heterocycl. Chem. 2005, 42, 647. (d) Alonso, E.; Ramon, D. J.; Yus, M.
Tetrahedron 1997, 53, 14355. (e) Berglund, M.; Dalence-Guzman, M. F.;
Skogvall, S.; Sterner, O. Bioorg. Med. Chem. 2008, 16, 2513. (f) Siu, J.;
Baxendale, I. R.; Lewthwaite, R. A.; Ley, S. V. Org. Biomol. Chem. 2005,
3, 3140. (g) Aubert, C.; Huard-Perrio, C.; Lasne, M.-C. J. Chem. Soc.,
Perkin Trans. 1 1997, 2837. (h) Ludwig, M.; Hoesl, C. E.; Hoefner, G.;
Wanner, K. T. Eur. J. Med. Chem. 2006, 41, 1003. (i) Proctor, G. R.;
Thomson, R. H. J. Chem. Soc. 1957, 2312. (m) Toma, G.; Fujita, K.-i.;
Yamaguchi, R. Eur. J. Org. Chem. 2009, 4586. (j) Dubs, C.; Hamashima,
Y.; Sasamoto, N.; Seidel, T. M.; Suzuki, S.; Hashizume, D.; Sodeoka, M.
J. Org. Chem. 2008, 73, 5859. (k) De Kimpe, N.; Keppens, M.
Tetrahedron 1996, 52, 3705.
(26) (a) Jana, C. K.; Studer, A. Angew. Chem., Int. Ed. 2007, 46, 6542.
(b) Glorius, F.; Spielkamp, N.; Holle, S.; Goddard, R.; Lehmann, C. W.
Angew. Chem., Int. Ed. 2004, 43, 2850. (c) Jana, C. K.; Grimme, S.;
Studer, A. Chem. Eur. J. 2009, 15, 9078.
(27) Nakanishi, M.; Bolm, C. Adv. Synth. Catal. 2007, 349, 861.
(28) Huang, L.; Niu, T.; Wu, J.; Zhang, Y. J. Org. Chem. 2011, 76,
1759.
(29) Li, Z.; Bohle, S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103,
8928.
(30) (a) Shih, K.-C.; Angelici, R. J. J. Org. Chem. 1996, 61, 7784.
(b) Gast, R.; Glokler, J.; Hoxter, M.; Kiesz, M.; Frank, R.; Tegge, W.
Anal. Biochem. 1999, 276, 227. (c) Goswami, S.; Chakrabarty, R. Chem.
Lett. 2010, 39, 100.
(31) Dharanipragada, R.; Ferguson, S. B.; Diederich, F. J. Am. Chem.
Soc. 1988, 110, 1679.
(32) Chen, B.-C.; Skoumbourdis, A. P.; Guo, P.; Bednarz, M. S.;
Kocy, O. R.; Sundeen, J. E.; Vite, G. D. J. Org. Chem. 1999, 64, 9294.
(33) (a) Thaqi, A.; McCluskey, A.; Scott, J. L. Tetrahedron Lett.
2008, 49, 6962. (b) Choy, J.; Jaime-Figueroa, S.; Jiang, L.; Wagner, P.
Synth. Commun. 2008, 38, 3840. (c) Siro, J. G.; Martin, J.; Garcia-Navio,
J. L.; Remuinan, M. J.; Vaquero, J. J. Synlett 1998, 147.
(34) (a) Choi, H.; Doyle, M. P. Chem. Commun. 2007, 745.
(b) Murahashi, S.; Naota, T.; Taki, H. J. Chem. Soc., Chem. Commun.
1985, 613.
(35) (a) Barba-Behrens, N.; Mutio-Rico, A. M.; Joseph-Nathan, P.;
Contreras, R. Polyhedron 1991, 10, 1333. (b) Collamati, I.; Ercolani, C.;
Rossi, G. Gazz. Chim. Ital. 1977, 107, 473. (c) Ge, C. H.; Zhang, X. D.;
Guan, W.; Liu, Q. T. Chin. Chem. Lett. 2005, 16, 1255.
(36) Guo, X.; Pan, S.; Liu, J.; Li, Z. J. Org. Chem. 2009, 74, 8848.
8793
dx.doi.org/10.1021/jo201511d |J. Org. Chem. 2011, 76, 8781–8793