A simple efficient sequential one-pot intermolecular aza-Michael addition and intramolecular Buchwald-Hartwig α-arylation of amines: Synthesis of functionalized tetrahydroisoquinolines

Article abstract of DOI:10.1016/j.tet.2012.06.106

An efficient one-pot sequential intermolecular aza-Michael addition and Pd-catalyzed intramolecular Buchwald-Hartwig α-arylation of secondary amines have been investigated, for the synthesis of tetrahydroisoquinolines. This method is simple and furnished

Full text of DOI:10.1016/j.tet.2012.06.106

Tetrahedron 68 (2012) 8003e8010
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Tetrahedron
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A simple efficient sequential one-pot intermolecular aza-Michael
addition and intramolecular BuchwaldeHartwig a-arylation
of amines: synthesis of functionalized tetrahydroisoquinolines
*
Alavala Gopi Krishna Reddy, Gedu Satyanarayana
Department of Chemistry, Indian Institute of Technology (IIT) Hyderabad, Ordnance Factory Estate Campus, Yeddumailaram, Medak District, Andhra Pradesh 502 205, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 May 2012
Received in revised form 16 June 2012
Accepted 26 June 2012
Available online 10 July 2012
An efficient one-pot sequential intermolecular aza-Michael addition and Pd-catalyzed intramolecular
BuchwaldeHartwig a-arylation of secondary amines have been investigated, for the synthesis of tetra-
hydroisoquinolines. This method is simple and furnished products in very good yield and also suc-
cessfully applied for the synthesis of novel aza-spirotricylcic ethers.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Pd-catalysis
Aza-Michael
Sequential one-pot
a
-Arylation
Tetrahydroisoquinolines
1. Introduction
one-pot processes involving both base promoted and Pd-catalyzed
transformations would also be an ideal choice. In continuation of
One-pot synthetic processes are considered as convenient
methods to synthesize organic molecules with high degree of
complexity, without isolating intermediates.1 Such one-pot pro-
cesses could be made possible using one metal complex to catalyze
multiple reaction sequence,2 or various metal catalysts could be
added in a sequential manner to achieve multiple reaction se-
quence.3 These types of reactions have been called as multi catalytic
cascades, pseudo domino strategies, and tandem catalysis. These
processes proved to have several advantages over step-wise oper-
ations, as it avoids the isolation of intermediate species, thereby
considerably reducing the waste generation, increasing efficiency,
minimizing the use of solvents, reagents, time, and energy.4
Moreover, it was also found that in most cases the overall yields
in one-pot processes are usually higher than those obtained from
the corresponding step-wise operations. Those one-pot process
that form multiple CeC bonds and cyclic structures are of great
interest, as complex cyclic structures are part of the core structure
in many biologically active natural products.
our interest in the development of palladium-catalysis,7 we re-
cently reported an efficient step-wise strategy for the synthesis of
tetrahydroisoquinolines using Pd-catalyzed intramolecular Buch-
waldeHartwig
a
-arylation.7a As an extension of our step-wise
method, herein we report an efficient one-pot sequential strategy
for the synthesis of tetrahydroisoquinolines. Unlike our previous
report, the present work is based on an efficient one-pot sequential
intermolecular aza-Michael additionePd-catalyzed intramolecular
a-arylation starting from secondary amines. Moreover, the present
strategy has been extensively studied on various secondary amines
bearing simple to electron rich aromatic rings and also on different
Michael acceptors (Scheme 1).
Recently, transition metal catalyzed one-pot processes are
gaining much importance due to several procedural advantages.5,6
Since, most Pd-catalyzed transformations are promoted by base,
* Corresponding author. Tel.: þ91 (40) 2301 6054; fax: þ91 (40) 2301 6032;
Scheme 1. Comparison of present one-pot versus previous step-wise processes of our
access to tetrahydroisoquinolines.
e-mail address: gvsatya@iith.ac.in (G. Satyanarayana).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.106

8004
A.G.K. Reddy, G. Satyanarayana / Tetrahedron 68 (2012) 8003e8010
1,2,3,4-Tetrahydroisoquinoline moiety is a ubiquitous structural
core present in a number of isoquinoline alkaloid natural products,8
which exhibit very good biological activities, such as antitumor,9
anti-microbial,9,10 anti-inflamatory,11 anti-HIV,12 and anti-analge-
sic13 activities. Representative examples of such structures are
cherylline, latifine,14,15 nor-armepavine, nor-roefractine,16,17 6,6a-
dihydrodemethoxygaudiscine,18 dinapsoline,19 and canadine,20
(Fig. 1).
Scheme 2. Retrosynthetic analysis for 1,2,3,4-tetrahydroisoquinolines.
Scheme 3. Synthesis of secondary amines 2aeh using bromobenzaldehydes 1aef.
Table 1
Synthesis of secondary amine 2aeha
Aldehyde 1
R1
R2
R3
R4
Yield of 2b (%)
1a
1b
1c
1d
1e
1f
H
H
OMe
H
H
H
H
H
H
H
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
2a 94
2b 91
2c 91
2d 93
2e 93
2f 74
2g 83
2h 74
OMe
OMe
H
OCH2e
H
OMe
OMe
OMe
OCH2e
OBn
H
1a
1e
H
OCH2e
OCH2e
a
In case of methylamine, reaction was performed at ice to room temperature and
without acetic acid.
Fig. 1. Representative examples of naturally occurring tetrahydroisoquinoline alkaloid
natural products.
b
Isolated yields of chromatographically pure products.
With the secondary amines 2aeh in hand, initially the key one-
pot aza-MichaelePd-mediated a-arylation of secondary amine 2a
was performed by concomitant addition of both reagent Michael
acceptor ethyl acrylate and the palladium catalyst, using similar
conditions to that used for Pd-mediated BuchwaldeHartwig
Highlighting the importance of transition metal catalysis, as an
alternative to PicteteSpengler reaction for the synthesis of tetra-
hydroisoquinoline,21 Hartwig et al., reported the synthesis of
a
d
-lactam using Pd-mediated intramolecular
poor yield.22a Later the research group of Honda improved the
strategy, by incorporating an -aryl group to the amide, thereby
increasing the acidity of
-hydrogen atom.22b Buchwald and
Gaertzen, disclosed Pd-catalyzed -arylation on esters, wherein
-carbon to the nitrogen atom.22c
a-arylation, albeit in
a
-arylation reaction reported in our previous report. To our dis-
a
appointment, the outcome was not satisfactory and produced the
product 4c, in very poor yield 15% (Scheme 4). Inferior yield of
product may be attributed to a competitive palladium insertion to
CeBr bond of the aryl halide prior to aza-Michael addition.
a
a
ester functionality resides on
a
ꢀ
Very recently, Daniel Sole et al., reported amino-tethered 2- and
3-iodoindoles.22d Our approach was based on one-pot sequential
intermolecular aza-Michael addition and intramolecular Buch-
waldeHartwig
in which the ester functionality is connected to a
nitrogen atom.
a
-arylation of (N-2-bromobenzyl)-
b-amino-esters,
-carbon to the
b
Scheme 4. Attempted one-pot aza-MichaelePd-mediated
a-arylation of secondary
amine 2a by concomitant addition of Michael acceptor ethyl acrylate and Pd-catalyst.
2. Results and discussion
Our approach for the synthesis of substituted 1,2,3,4-
Since one-pot aza-MichaelePd-mediated a-arylation was found
tetrahydroisoquinolines 4 is based on a key one-pot aza-MichaelePd-
mediated a-arylation of secondary amine 2. The required precursors 2
to be inferior by concomitant addition of both reagent Michael
acceptor ethyl acrylate and the palladium catalyst, we thought that
it may be better, in the first stage to optimize aza-Michael addition
reaction and then in situ treatment of the ester intermediate 3c for
could be obtained from the readily available ortho-bromobenzalde-
hydes 1 by a reductive amination (Scheme 2).
Accordingly, treatment of 2-bromobenzaldehydes 1aef23 with
benzylamine in refluxing methanol in the presence of a catalytic
amount of acetic acid followed by addition of sodium borohydride,
led to the secondary amines 2aeh in very good (74e94%) yields
(Scheme 3, Table 1).7a
subsequent Pd-catalyzed a-arylation. At this stage, it is important
to identify suitable conditions for aza-Michael that should also be
amenable to subsequent Pd-catalyzed CeH activation, preferably
using established conditions for subsequent Pd-catalyzed CeH ac-
tivation (toluene and Cs2CO3 as solvent and base, respectively).7a

A.G.K. Reddy, G. Satyanarayana / Tetrahedron 68 (2012) 8003e8010
8005
Thus, aza-Michael addition was explored with Cs2CO3 as the base
and toluene as aprotic, nonpolar solvent under varying tempera-
ture (50e100 ꢀC) conditions. Discouragingly, all these trials fur-
nished the product 3c, in poor to moderate yields (10e45%) (entries
1e4, Table 2). A similar outcome was observed by omitting base and
just heating the reaction mixture at 100 ꢀC in toluene (entries 5 and
6, Table 2). Interestingly, an increment in yield was observed by
replacing the solvent toluene with xylene at high temperature
130 ꢀC (entry 7, Table 2). On the other hand, treatment of neat
compound under microwave irradiation was also found to be in-
ferior (entry 9, Table 2). Heating the secondary amine 2a with
Michael acceptor (1.5 equiv) without the solvent as well as the base,
furnished the product in poor yield (entry 8, Table 2). Low con-
version to intermediate 3c may be attributed to lower boiling point
of Michael acceptor ethyl acrylate (100 ꢀC). Therefore, we thought
that excess amount of ethyl acrylate might help us to improve yield
of 3c. To our delight, reaction with 5 equiv of ethyl acrylate at 110 ꢀC
for 48 h, showed 100% conversion to the addition product 3c, which
the yield (77%) of 4c appears less than that obtained from the step-
wise Pd-catalyzed -arylation of previous report (88% and 82% for
a
reductive amination and Pd-catalyzed
a-arylation, respectively,
overall yield 72%),7a still proved to be better with regards to its
overall yield.
After optimizing the reaction conditions, the generality of the
reaction was established by a one-pot sequential aza-MichaelePd-
catalyzed
a-arylation on various secondary amines 2 using dif-
ferent alkyl acrylates to give the tetrahydroisoquinolines 4. In
general, these results were fairly comparable to that obtained for
the secondary amine 2a, and furnished the tetrahydroisoquino-
lines 4 possessing simple as well as electron rich aromatic func-
tionality on aromatic rings, in very good yields (Table 3). It was
observed that aza-Michael reaction was completed in 24 h in case
of ethyl and methyl acrylates, whereas tert-butyl acrylate took up
to 48 h and subsequent Pd-catalyzed a-arylation was completed in
24e48 h.
Finally, to check the scope and applicability of the method for
further extensions, we explored the synthesis of novel 2-benzyl-
2,3,40,70-tetrahydro-1H-spiro[isoquinoline-4,30-oxepine] system.
Spiro-cyclic systems are recognized as useful fragments for drug
discovery and exhibit good biological properties. Moreover, spiro-
cyclic systems are described as privileged scaffolds because they
have been successfully employed as ligands for a variety of tar-
gets.24 We envisioned that target spiro-system can be achieved via
C-alkylation of the cyclic ester 4c, reduction of the ester moiety,
O-allylation, and finally ring closing metathesis protocol. Thus,
allylation of the ester enolate prepared by lithium diisopropyl
amide (LDA), gave the alkylated product 5, in very good yield. Re-
duction of the ester with lithium aluminum hydride (LiAlH4), fur-
nished the primary alcohol 6 in excellent yield. Base induced
O-allylation transformed the hydroxyl group to the corresponding
allyl ether 7. Finally, ring closing metathesis reaction of the diene 7
with 5 mol % of Grubb’s first generation catalyst in methylene
chloride at room temperature, smoothly furnished the target spiro-
tricyclic system 8, in very good yield (Scheme 5).
on in situ Pd-catalyzed
a-arylation, gave us the final cyclized
product 4c, albeit in moderate yield 43% (entry 10, Table 2). Mod-
erate yield of the product 4c, may be justified due to the in-
termolecular interference of excess ethyl acrylate with the
intermediate aryl-Pd-species. Therefore, in order to minimize the
intermolecular interaction with the excess ethyl acrylate, we
thought that increasing dilution might help us to improve the yield
of product 4c. Thus the reaction with high dilution slightly im-
proved the yield (entry 11, Table 2), but still the presence of in-
terference due to excess ethyl acrylate remained. Finally, we
decided to remove excess ethyl acrylate in order to avoid its in-
terference with aryl-Pd-species. Gratifyingly, simple removal of
excess ethyl acrylate under vacuum (10ꢁ2 mbar) and then sub-
jecting reaction mixture to subsequent Pd-catalyzed
a-arylation,
furnished the product 4c in very good yield 77%. It is noteworthy to
mention that when aza-Michael reaction was conducted on amine
2a, reaction time reduced from 48 to 24 h, with 5 equiv of ethyl
acrylate (entry 12, Table 2). Though, in the present one-pot process,
Table 2
Attempted optimization one-pot reaction conditions for the synthesis of 1,2,3,4-tetrahydroisoquinolines
Entry
Reaction conditions for aza-Michael addition
Reaction conditions for Pd-catalyzed a-arylation
Ethyl acrylate (equiv)
Base (equiv)
Solvent
Temp (ꢀC)
Time (h)
Yield of 3 (%)
Toluene (mL)
Time (h)
Yield of 4h (%)
1a
1.5
5
5
5
1.5
5
5
1.5
5
5
5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
dc
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Xylene
d
80
50
50
48
24
48
48
48
48
48
48
1
10
18
30
45
10
40
60
30
d
d
d
d
d
d
d
d
d
4
d
d
d
d
d
d
d
d
d
24
48
24
d
d
d
d
d
d
d
d
d
43
48
77
2a
3a
4a
100
100
100
130
110
80 (
110
110
110
5a
6a
dc
7a
dc
8a
dd
9a
dd
d
mw)
25
10b
11b
12b
dd
d
48
48
24
100e
100e
100f,g
dd
d
8
3
5
dd
d
a
Isolated yields of chromatographically pure product 3c and not subjected to the subsequent Pd-catalyzed
The product 3c was not isolated and the complete conversion of secondary amine 2a to product 3c was confirmed by TLC.
Base omitted in these attempts.
Both base and solvent omitted in these entries, only neat reaction conditions were employed.
Reaction was performed on 100 mg scale of secondary amine 2a.
Reaction performed on 1 mmol scale of secondary amine 2a.
a
-arylation.
b
c
d
e
f
g
h
Excess ethyl acrylate was removed under vacuum (0.02 mbar) just before the addition of Pd-catalyst, base and solvent, for subsequent Pd-catalyzed a-arylation.
Isolated yields of chromatographically pure product 4c.

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A.G.K. Reddy, G. Satyanarayana / Tetrahedron 68 (2012) 8003e8010
Table 3
One-pot sequential aza-MichaelePd-catalyzed a
-arylation for the synthesis of 1,2,3,4-tetrahydroisoquinolines 4 starting from amines 2a,b
a
For details see Supplementary data.
Isolated yields of chromatographically pure products.
b
intermolecular aza-Michael addition to generate
which were not isolated and subjected to subsequent Pd-catalyzed
intramolecular -arylation. The strategy is very efficient and ame-
b-aminoesters,
a
nable for the synthesis of a number of analogues, a structural core
present in many tetrahydroisoquinoline based alkaloid natural
products, which exhibit very good biological activities. Moreover,
the present method has been successfully applied for the synthesis
of novel 2-benzyl-2,3,40,70-tetrahydro-1H-spiro[isoquinoline-4,30-
oxepine] system.
4. Experimental section
4.1. General
IR spectra were recorded on Bruker Tensor 37 (FTIR) and Bru-
kerALPHA (FTIR) spectrophotometers. 1H NMR spectra were
recorded on Bruker Avance 400 (400 MHz) spectrometer at 295 K
in CDCl3; chemical shifts (
reported in standard fashion with reference to either internal
d ppm) and coupling constants (Hz) are
Scheme 5. Synthesis of spiro-tricyclic system 8 from 4.
standard tetramethylsilane (TMS)
(
400 (100 MHz) spectrometer at room temperature in CDCl3;
(
dH¼0.00 ppm) or CHCl3
3. Conclusion
dH¼7.25 ppm). 13C NMR spectra were recorded on Bruker Avance
In summary, we have developed an efficient route to the syn-
thesis of functionalized 1,2,3,4-tetrahydroisoquinolines based on
one-pot sequential intermolecular aza-Michael addition and
chemical shifts
[
(
d
ppm) are reported relative to CDCl3
dC¼77.00 ppm (central line of triplet)]. In the 13C NMR, the nature
of carbons (C, CH, CH2, and CH3) was determined by recording the
DEPT-135 spectra, and is given in parentheses and noted as
s¼singlet (for C), d¼doublet (for CH), t¼triplet (for CH2), and
Pd-catalyzed intramolecular BuchwaldeHartwig
a-arylation of
secondary amines. An optimized method was developed for an

A.G.K. Reddy, G. Satyanarayana / Tetrahedron 68 (2012) 8003e8010
8007
q¼quartet (for CH3). In the 1H NMR, the following abbreviations
were used throughout: s¼singlet, d¼doublet, t¼triplet, q¼quartet,
qui¼quintet, m¼multiplet, and br s¼broad singlet. The assignment
of signals was confirmed by 1H, 13C CPD, and DEPT spectra. High-
resolution mass spectra (HRMS) were recorded using Agilent
6538 UHD Q-TOF using multimode [electron spray ionization (ESIþ)
and atmospheric pressure chemical ionization (APCIþ)] source. All
small scale dry reactions were carried out using Schlenk tube and
standard syringe-septum technique. Reactions were monitored by
TLC on silica gel using a combination of petroleum ether and ethyl
acetate as eluents. Reactions were generally run under inert (argon
or a nitrogen) atmosphere. Solvents: toluene, tetrahydrofuran
(THF), and diethyl ether were dried over sodium metal wire,
whereas dimethylformamide (DMF) and dichloromethane (DCM)
were dried over calcium hydride prior to use. Solvents: petroleum
ether, ethyl acetate, dichloromethane, methanol were distilled
prior to use; petroleum ether with a boiling range of 60e80 ꢀC was
used. Methylamine was used as 25% CH3NH2 in methanol. Ethyl
acrylate (with purity 99.5%) was purchased from SigmaeAldrich,
whereas methyl acrylate (with purity 99%) and tert-butyl acrylate
(with purity 98%) were purchased from other commercial
sources and used as received. All benzaldehydes (with purity 98%)
in order to make corresponding 2-bromobenzaldehydes [except
2-bromobenzaldehyde, which was commercially available (with
purity 98%)] were purchased from commercial sources and used as
received. Acme’s silica gel (60e120 mesh) was used for column
chromatography (approximately 20 g per 1 g of crude material).
acetate (3ꢂ20 mL). The organic layer was washed with saturated
NaCl solution, dried (Na2SO4), and filtered. Evaporation of the filtrate
under reduced pressure and purification of the crude material by
silica gel column chromatography (petroleum ether/ethyl acetate
10:90 to 90:10) furnished the amine 2h (1.18 g, 74%) as viscous liquid
[TLC control (ethyl acetate/methanol 90:10), Rf (1e)¼0.90, Rf (2h)¼
0.35, UV detection]. IR (MIR-ATR, 4000e600 cmꢁ1): nmax¼3291,
2893, 1501, 1473, 1408, 1389, 1369, 1230, 1114, 1033, 929, 859, 830,
786, 719, 673, 650 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d
¼6.96 (s, 1H,
AreH), 6.86 (s, 1H, AreH), 5.93 (s, 2H, OCH2O), 3.71 [s, 2H,
AreCH2N(H)Me], 2.50 (br s,1H, NH), 2.40 (s, 3H, NCH3) ppm.13C NMR
(CDCl3, 100 MHz):
d
¼147.3 (s, AreC), 147.3 (s, AreC), 131.7 (s, AreC),
114.2 (s, AreC), 112.6 (d, AreCH), 110.1 (d, AreCH), 101.6 (t, OCH2O),
55.2 [t, ArCH2N(H)Me], 35.4 (q, NCH3) ppm. HRMS (APCIþ) m/z cal-
culated for [C9H9BrNO2]þ¼[MꢁH]þ: 241.9811; found 241.9802.
4.4. tert-Butyl 2-methyl-1,2,3,4-tetrahydroisoquinoline-4-
carboxylate (4m)
GP-1 was followed for the amine 2a (200 mg, 1 mmol) with tert-
butyl acrylate (640 mg, 5 mmol) at 110 ꢀC for 36 h. Then treated
with Pd(OAc)2 (22.4 mg, 10 mol %), PPh3 (52.4 mg, 20 mol %), and
Cs2CO3 (651.6 mg, 2 mmol) in toluene (3 mL) at 80 ꢀC, for 36 h.
Purification of the crude material by silica gel column chromatog-
raphy (petroleum ether/ethyl acetate, 80:20 to 60:40) furnished the
tetrahydroisoquinoline 4m (175 mg, 71%) as colorless viscous liquid
[TLC control (petroleum ether/ethyl acetate 20:80), Rf (2g)¼0.15, Rf
(4m)¼0.45,
iodine
chamber
detection].
IR
(MIR-ATR,
4.2. General procedure-1 [for sequential one-pot reaction, for
the synthesis of tetrahydroisoquinoline (4)]
4000e600 cmꢁ1): nmax¼2974, 2934, 2773, 1724, 1453, 1367, 1274,
1246, 1138, 1101, 1033, 969, 850, 745 cmꢁ1 1H NMR (CDCl3,
.
400 MHz):
d
¼7.19 (dd, 1H, J¼4.9 and 3.4 Hz, AreH), 7.10 (d, 1H,
To an oven dried Schlenk tube, were added amine 2 (1 mmol)
and alkyl (ethyl or methyl or tert-butyl) acrylate (5 mmol) at room
temperature under nitrogen atmosphere. The reaction mixture was
stirred at 110 ꢀC in an oil bath, for 24 h (in case of methyl as well as
ethyl acrylates) and for 48 h (in case of tert-butyl acrylate). Progress
of the Michael addition was monitored by TLC. The reaction mixture
was allowed to attain room temperature, and excess of alkyl acry-
late was removed under vacuum (10ꢁ2 mbar). To the resultant re-
action intermediate (i.e., Michael addition product 3) at room
temperature, were added Pd(OAc)2 (10 mol %), PPh3 (20 mol %), and
Cs2CO3 (2 mmol) followed by toluene (3 mL) under nitrogen at-
mosphere. The reaction mixture was then allowed to stir at 80 ꢀC for
24 h (in case of 4aec and 4f), 36 h (in case of 4d, 4e, 4g, 4i, 4j and
4len), and 48 h (in case of 4h and 4k) in an oil bath and the progress
was monitored by TLC. The mixture was cooled to room tempera-
ture, treated with aqueous NH4Cl solution and then extracted with
ethyl acetate (3ꢂ15 mL). The organic layer was washed with satu-
rated NaCl solution, dried (Na2SO4), and filtered. Evaporation of the
solvent under reduced pressure and purification of the crude ma-
terial by silica gel column chromatography (petroleum ether/ethyl
acetate) furnished the tetrahydroisoquinoline 4 (70e85%).
J¼3.4 Hz, AreH), 7.08 (d, 1H, J¼3.4 Hz, AreH), 6.96 (dd, 1H, J¼4.9
and 3.4 Hz, AreH), 3.74 (dd, 1H, J¼6.5 and 5.9 Hz, CHCOOtBu), 3.58
[d, 1H, J¼14.9 Hz, NeCH2(a,b)], 3.44 [d, 1H, J¼14.9 Hz, NeCH2(a,b)],
2.91 (dd, 1H, J¼11.5 and 6.5 Hz, NeCH2aCHCOOtBu), 2.76 (dd, 1H,
J¼11.5 and 5.3 Hz, NeCH2bCHCOOtBu), 2.37 (s, 3H, NCH3), 1.40 [s,
9H, C(CH3)3] ppm. 13C NMR (CDCl3, 100 MHz):
d
¼172.3 (s, O]CeO),
134.9 (s, AreC), 131.3 (s, AreC), 128.9 (d, AreCH), 126.6 (d, AreCH),
126.5 (d, AreCH), 126.2 (d, AreCH), 80.9 [s, COOC(CH3)3], 57.9 (t,
NeCH2), 55.4 (t, NeCH2), 45.9 (q, NCH3), 45.8 (d, CHCOOtBu), 28.0
[q, 3C, C(CH3)3] ppm. HRMS (APCIþ) m/z calculated for
[C15H22NO2]þ¼[MþH]þ: 248.1645; found 248.1646.
4.5. tert-Butyl 6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]
isoquinoline-8-carboxylate (4n)
GP-1 was followed for the amine 2h (244 mg, 1 mmol) with tert-
butyl acrylate (640 mg, 5 mmol) at 110 ꢀC for 48 h. Then treated
with Pd(OAc)2 (22.4 mg, 10 mol %), PPh3 (52.4 mg, 20 mol %), and
Cs2CO3 (651.6 mg, 2 mmol) in toluene (3 mL) at 80 ꢀC, for 36 h.
Purification of the crude material by silica gel column chromatog-
raphy (petroleum ether/ethyl acetate, 80:20 to 55:45) furnished the
tetrahydroisoquinoline 4n (204 mg, 70%) as pale yellow viscous
liquid [TLC control (petroleum ether/ethyl acetate 20:80), Rf (2h)¼
0.12, Rf (4n)¼0.43, UV detection]. IR (MIR-ATR, 4000e600 cmꢁ1):
nmax¼2974, 2935, 2789, 1725, 1504, 1483, 1390, 1367, 1250, 1238,
Secondary amines 2aef,7a 2g,25 and tetrahydroisoquinolines
4cef7a were already known in the literature.
4.3. N-[(6-Bromo-1,3-benzodioxol-5-yl)methyl]-N-methyl-
amine (2h)
1145, 1125, 1035, 938, 850 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d
¼6.71
(s, 1H, AreH), 6.48 (s, 1H, AreH), 5.89 (d, 1H, J¼1.4 Hz, OCH2aO),
5.87 (d, 1H, J¼1.4 Hz, OCH2bO), 3.68 (dd, 1H, J¼6.4 and 5.0 Hz,
CHCOOtBu), 3.55 [d, 1H, J¼14.7 Hz, NeCH2(a,b)], 3.38 [d, 1H,
J¼14.7 Hz, NeCH2(a,b)], 2.91 (dd, 1H, J¼11.4 and 6.4 Hz,
NeCH2aCHCOOtBu), 2.76 (dd, 1H, J¼11.4 and 5.0 Hz,
NeCH2bCHCOOtBu), 2.41 (s, 3H, NCH3), 1.46 [s, 9H, C(CH3)3] ppm.
To an ice cold round bottomed flask containing 2-bromo pipera-
nal 1e (1.5 g, 6.55 mmol), were added methanol (25 mL) followed by
methylamine (609 mg, 19.65 mmol). The reaction mixture was
allowed to stir at the same temperature for 1 h. To this ice cold
reaction mixture, was added sodium borohydride (374 mg,
9.82 mmol), slowly allowed to attain room temperature, and stirred
for an additional 3 h. Solvent was removed under reduced pressure,
treated with aqueous NH4Cl solution, and extracted with ethyl
13C NMR (CDCl3, 100 MHz):
146.1 (s, AreC), 128.4 (s, AreC), 124.2 (s, AreC), 108.7 (d, AreCH),
106.2 (d, AreCH), 100.8 (t, OCH2O), 81.0 [s, COOC(CH3)3], 57.9 (t,
d
¼172.4 (s, O]CeO), 146.4 (s, AreC),

8008
A.G.K. Reddy, G. Satyanarayana / Tetrahedron 68 (2012) 8003e8010
NeCH2), 55.4 (t, NeCH2), 45.8 (q, NCH3), 45.7 (d, CHCOOtBu), 28.1
[q, 3C, C(CH3)3] ppm. HRMS (APCIþ) m/z calculated for
[C16H22NO4]þ¼[MþH]þ: 292.1543; found 292.1538.
127.4 (d, 2C, AreCH), 127.1 (d, AreCH), 118.0 (t, CH2CH]CH2), 113.3
(d, AreCH), 111.9 (d, AreCH), 80.8 [s, C(CH3)3], 69.9 (t, OCH2Ph),
62.9 (t, NeCH2), 57.5 (t, NeCH2), 56.8 (t, NeCH2), 50.8 [s, C(COOtBu)
CH2CH]CH2], 42.8 (t, CH2CH]CH2), 28.0 [q, 3C, C(CH3)3] ppm.
HRMS (APCIþ) m/z calculated for [C31H36NO3]þ¼[MþH]þ:
470.2690; found 470.2698.
4.6. Ethyl 4-allyl-2-benzyl-1,2,3,4-tetrahydroisoquinoline-4-
carboxylate (5c)
To a cold (ꢁ15 ꢀC), magnetically stirred solution of diisopro-
pylamine (0.10 mL, 1.35 mmol) in dry THF (1 mL) was slowly added
a solution of nBuLi (2.5 M in hexane, 0.43 mL, 1.08 mmol) and the
reaction mixture was stirred for 5 min, at the same temperature. To
the LDA thus formed, was added drop-wise, a solution of ester 4c
(160 mg, 0.54 mmol) in dry THF (2 mL), and the reaction mixture
was stirred for 30 min, at the same temperature. The enolate was
treated with allyl bromide (0.09 mL, 1.08 mmol), and stirred at
room temperature for 4 h. The progress was monitored by TLC. The
reaction mixture was treated with aqueous NH4Cl solution, and
extracted with ethyl acetate (3ꢂ15 mL). The organic layer was
washed with saturated NaCl solution, dried (Na2SO4), and filtered.
Evaporation of the solvent under reduced pressure and purification
of the crude material by silica gel column chromatography (pe-
troleum ether/ethyl acetate 98:2 to 95:5) furnished the allylated
ester 5c (140.3 mg, 77%) as a pale yellow viscous liquid [TLC control
(petroleum ether/ethyl acetate 90:10), Rf (4c)¼0.50, Rf (5c)¼0.60,
UV detection]. IR (MIR-ATR, 4000e600 cmꢁ1): nmax¼3027, 2978,
2805, 1722, 1638, 1493, 1452, 1367, 1205, 1145, 1093, 1027, 918, 736,
4.8. (4-Allyl-2-benzyl-1,2,3,4-tetrahydroisoquinolin-4-yl)
methanol (6c)
To a cold (0 ꢀC), magnetically stirred solution of an ester 5c
(100 mg, 0.30 mmol) in dry ether (10 mL), was added LiAlH4
(34 mg, 0.89 mmol). Then the reaction mixture stirred for 1 h. The
reaction mixture was quenched with drop wise addition of ethyl
acetate, treated with aqueous NH4Cl solution, and extracted with
ethyl acetate (3ꢂ15 mL). The organic layer was washed with satu-
rated NaCl solution, dried (Na2SO4), and filtered. Evaporation of the
filtrate under reduced pressure, and purification of the crude ma-
terial by silica gel column chromatography (petroleum ether/ethyl
acetate 80:20 to 70:30) furnished the alcohol 6c (73.3 mg, 84%) as
colorless viscous liquid [TLC control (petroleum ether/ethyl acetate
90:10), Rf (5c)¼0.60, Rf (6c)¼0.30, UV detection]. IR (MIR-ATR,
4000e600 cmꢁ1): nmax¼3396, 3065, 3028, 2915, 2813, 1638, 1493,
1451, 1368, 1094, 1072, 1034, 916, 755, 734, 700 cmꢁ1
.
1H NMR
(CDCl3, 400 MHz):
d
¼7.30e7.10 (m, 7H, AreH), 7.05 (dd, 1H, J¼7.5
and 7.5 Hz, AreH), 6.89 (d, 1H, J¼7.5 Hz, AreH), 5.50e5.35 (m, 1H,
CH2CH]CH2), 5.33 (br s, 1H, OH), 4.92 (d, 1H, J¼17.1 Hz, CH2CH]
CH2trans), 4.88 (d, 1H, J¼10.2 Hz, CH2CH]CH2cis), 3.78e3.65 (m, 2H,
CH2OH), 3.66e3.55 (m, 2H, NCH2Ar), 3.51 (d, 1H, J¼12.8 Hz,
NCH2aPh), 3.23 (d,1H, J¼12.8 Hz, NCH2bPh), 2.87 [dd,1H, J¼11.5 and
1.6 Hz, NCH2aC(CH2OH)CH2CH]CH2], 2.53 [dd, 1H, J¼11.5 and
2.5 Hz, NeCH2bC(CH2OH)CH2CH]CH2], 2.42 (dd, 1H, J¼14.4 and
6.0 Hz, CH2aCH]CH2), 2.11 (dd, 1H, J¼14.4 and 8.4 Hz, CH2bCH]
699 cmꢁ1
.
1H NMR (CDCl3, 400 MHz):
d
¼7.35 (d, 1H, J¼7.3 Hz,
AreH), 7.29 (d, 2H, J¼7.0 Hz, AreH), 7.24 (dd, 2H, J¼7.0 and 7.0 Hz,
AreH), 7.18 (dd, 1H, J¼7.3 and 7.3 Hz, AreH), 7.15e7.01 (m, 2H,
AreH), 6.91 (d, 1H, J¼7.0 Hz, AreH), 5.70e5.31 (m, 1H, CH2CH]
CH2), 4.99e4.85 (m, 2H, CH2CH]CH2), 4.18e3.95 (m, 2H,
OCH2CH3), 3.58 (s, 2H, NCH2), 3.54 (s, 2H, NCH2), 3.06 (d, 1H,
J¼11.5 Hz, NeCH2aCHCOOEt), 2.75e2.60 (m, 3H, CH2CH]CH2 and
NeCH2bCHCOOEt), 1.12 (t, 3H, J¼7.1 Hz, OCH2CH3) ppm. 13C NMR
CH2) ppm. 13C NMR (CDCl3, 100 MHz):
d¼137.6 (s, AreC), 136.9 (s,
(CDCl3, 100 MHz):
d¼174.3 (s, O]CeO), 138.3 (s, AreC), 135.9 (s,
AreC), 135.6 (s, AreC), 133.7 (d, CH2CH]CH2), 129.1 (d, 2C, AreCH),
128.6 (d, 2C, AreCH), 127.6 (d, AreCH), 127.0 (d, AreCH), 126.3 (d,
AreCH), 126.2 (d, AreCH), 125.8 (d, AreCH), 118.0 (t, CH2CH]CH2),
75.3 (t, CH2OH), 63.0 (t, NeCH2), 60.7 (t, NeCH2), 56.6 (t, NeCH2),
41.7 [s, C(CH2OH)CH2CH]CH2], 40.0 (t, CH2CH]CH2) ppm. HRMS
(APCIþ) m/z calculated for [C20H24NO]þ¼[MþH]þ: 294.1852; found
294.1845.
AreC), 135.1 (s, AreC), 134.2 (d, CH2CH]CH2), 129.1 (d, AreCH),
128.2 (d, 2C, AreCH), 127.9 (d, 2C, AreCH), 127.1 (d, AreCH), 126.6
(d, AreCH), 126.5 (d, AreCH), 126.2 (d, AreCH), 118.3 (t, CH2CH]
CH2), 62.8 (t, NeCH2), 60.9 (t, OCH2CH3), 57.0 (t, NeCH2), 56.7 (t,
NeCH2), 51.0 [s, C(COOEt)CH2CH]CH2], 42.7 (t, CH2CH]CH2), 14.1
(q, OCH2CH3) ppm. HRMS (APCIþ) m/z calculated for
[C22H26NO2]þ¼[MþH]þ: 336.1958; found 336.1942.
4.9. [4-Allyl-2-benzyl-7-(benzyloxy)-1,2,3,4-tetrahydro-
isoquinolin-4-yl]methanol (6h)
4.7. tert-Butyl 4-allyl-2-benzyl-7-(benzyloxy)-1,2,3,4-
tetrahydroisoquinoline-4-carboxylate (5h)
The reaction is performed with the ester 5h (191 mg, 0.41 mmol),
ether (10 mL), and LiAlH4 (46.4 mg, 1.22 mmol) as described above
(cf. 6c). Purification of the crude material by silica gel column chro-
matography (petroleum ether/ethyl acetate 80:20 to 60:40) fur-
nished the alcohol 6h (158.5 mg, 97%) as colorless viscous liquid [TLC
control (petroleum ether/ethyl acetate 75:25), Rf (5h)¼0.65, Rf (6h)¼
0.30, UV detection]. IR (MIR-ATR, 4000e600 cmꢁ1): nmax¼3295,
3029, 2912, 2824,1637,1609,1500,1453,1382,1319,1278,1241,1091,
The reaction is performed with the ester 4h (260 mg,
0.61 mmol), diisopropylamine (0.16 mL, 1.51 mmol), nBuLi (2.5 M in
hexane, 0.50 mL, 1.21 mmol), allyl bromide (0.10 mL, 1.21 mmol),
and dry THF (3 mL) as described above (cf. 5c). Purification of the
residue by silica gel column chromatography (petroleum ether/
ethyl acetate 97:3 to 90:10) furnished the allylated ester 5h
(221.6 mg, 78%) as a colorless viscous liquid [TLC control (petro-
leum ether/ethyl acetate 90:10), Rf (4h)¼0.45, Rf (5h)¼0.55, UV
detection]. IR (MIR-ATR, 4000e600 cmꢁ1): nmax¼3064, 2976, 1718,
1638, 1609, 1499, 1454, 1366, 1240, 1161, 1135, 1094, 1027, 915, 847,
1073, 1026, 909, 731, 697 cmꢁ1
.
1H NMR (CDCl3, 400 MHz):
d¼7.45e7.20 (m, 11H, AreH), 6.88 (dd, 1H, J¼8.8 and 2.9 Hz, AreH),
6.59 (d, 1H, J¼2.9 Hz, AreH), 5.65e5.40 (m, 1H, CH2CH]CH2), 5.38
(br s, 1H, OH), 5.10e4.91 (m, 4H, OCH2Ph and CH2CH]CH2),
3.85e3.55 (m, 5H, CH2OH, NCH2Ar and NCH2aPh), 3.29 (d, 1H,
J¼14.7 Hz, NCH2bPh), 2.94 [dd, 1H, J¼11.7 and 2.0 Hz,
NeCH2aC(CH2OH)CH2CH]CH2], 2.53 [dd, 1H, J¼11.7 and 2.5 Hz,
NeCH2bC(CH2OH)CH2CH]CH2], 2.42 (dd, 1H, J¼14.7 and 6.3 Hz,
CH2aCH]CH2), 2.11 (dd, 1H, J¼14.7 and 8.8 Hz, CH2bCH]CH2) ppm.
734, 697 cmꢁ1
.
1H NMR (CDCl3, 400 MHz):
d
¼7.45e7.20 (m, 11H,
AreH), 6.82 (dd, 1H, J¼8.8 and 2.9 Hz, AreH), 6.57 (d, 1H, J¼2.9 Hz,
AreH), 5.75e5.55 (m, 1H, CH2CH]CH2), 5.10e4.90 (m, 4H,
CH2CH]CH2 and OCH2Ph), 3.70e3.55 (m, 2H, NCH2), 3.53 (s, 2H,
NCH2), 3.09 (d, 1H, J¼11.2 Hz, NeCH2aCHCOOtBu), 2.77e2.66 (m,
3H, CH2CH]CH2 and NeCH2bCHCOOtBu), 1.41 [s, 9H, OC(CH3)3]
ppm. 13C NMR (CDCl3, 100 MHz):
d
¼173.5 (s, O]CeO), 157.2 (s,
13C NMR (CDCl3,100 MHz):
AreC), 136.8 (s, AreC), 133.8 (d, CH2CH]CH2), 129.9 (s, AreC), 129.1
(d, 2C, AreCH), 128.6 (d, 2C, AreCH), 128.5 (d, 2C, AreCH), 127.9 (d,
AreCH), 127.6 (d, AreCH), 127.4 (d, 2C, AreCH), 126.9 (d, AreCH),
d
¼157.1 (s, AreC),137.0 (s, AreC),136.9(s,
AreC), 138.4 (s, AreC), 137.1 (s, AreC), 136.4 (s, AreC), 134.5 (d,
CH2CH]CH2), 129.2 (d, AreCH), 129.1 (d, 2C, AreCH), 128.8 (s,
AreC), 128.5 (d, 2C, AreCH), 128.2 (d, 2C, AreCH), 127.9 (d, AreCH),

A.G.K. Reddy, G. Satyanarayana / Tetrahedron 68 (2012) 8003e8010
8009
117.9 (t, CH2CH]CH2), 114.3 (d, AreCH), 111.7 (d, AreCH), 75.2 (t,
OCH2Ph), 69.9 (t, CH2OH), 63.0 (t, NeCH2), 60.9 (t, NeCH2), 56.8 (t,
NeCH2), 41.2 [s, C(CH2OH)CH2CH]CH2], 40.0 (t, CH2CH]CH2) ppm.
HRMS (APCIþ) m/z calculated for [C27H28NO2]þ¼[MꢁH]þ: 398.2115;
found 398.2104.
J¼14.2 and 7.8 Hz, NeCH2aC(CH2OCH2CH]CH2)CH2CH]CH2], 2.46
(d, 1H, J¼11.2 Hz, CH2bCH]CH2) ppm. 13C NMR (CDCl3, 100 MHz):
d¼156.9(s, AreC),138.8(s, AreC),137.2(s, AreC),137.1 (s, AreC),135.4
(d, CH2CH]CH2),135.2 (d, CH2CH]CH2),130.9 (s, AreC),128.9 (d, 2C,
AreCH), 128.5 (d, 2C, AreCH), 128.3 (d, AreCH),128.2 (d, 2C, AreCH),
127.9 (d, AreCH), 127.4 (d, 2C, AreCH), 127.0 (d, AreCH), 117.1 (t,
CH2CH]CH2), 116.3 (t, CH2CH]CH2), 113.2 (d, AreCH), 111.9 (d,
AreCH), 76.6 (t, OCH2CH]CH2), 72.2 (t, CH2OCH2CH]CH2), 69.9 (t,
OCH2Ph), 62.8 (t, NeCH2), 57.4 (t, NeCH2), 56.8 (t, NeCH2), 42.3 [s,
C(CH2OCH2CH]CH2)CH2CH]CH2], 40.8 (t, CH2CH]CH2) ppm.
HRMS (APCIþ) m/z calculated for [C30H34NO2]þ¼[MþH]þ: 440.2584;
found 440.2581.
4.10. 4-Allyl-4-[(allyloxy)methyl]-2-benzyl-1,2,3,4-
tetrahydroisoquinoline (7c)
To an oven dried round bottomed flask, were added alcohol 6c
(47 mg, 0.16 mmol), sodium hydride (19 mg, 0.48 mmol) in dry DMF
(3 mL) followed by addition of allyl bromide (58.2 mg, 0.48 mmol)
under nitrogen atmosphere at room temperature and the reaction
mixture was allowed to stir at room temperature for 1 h. The re-
action mixture was treated with aqueous NH4Cl solution, and
extracted with ethyl acetate (3ꢂ10 mL). The organic layer was
washed with saturated NaCl solution, dried (Na2SO4), and filtered.
Evaporation of the filtrate under reduced pressure and purification
of the crude material by silica gel column chromatography (petro-
leum ether/ethyl acetate 99:1 to 95:5) furnished the allyl ether 7c
(44.2 mg, 83%) as colorless liquid [TLC control (petroleum ether/
ethyl acetate 85:15), Rf (6c)¼0.35, Rf (7c)¼0.75, UV detection]. IR
(MIR-ATR, 4000e600 cmꢁ1): nmax¼3064, 3027, 2924, 2853, 1639,
4.12. 2-Benzyl-2,3,40,70-tetrahydro-1H-spiro[isoquinoline-
4,30-oxepine] (8c)
To an oven dried round bottomed flask containing allyl ether 7c
(29 mg, 0.09 mmol)indryDCM (7 mL)undernitrogenatmosphereat
room temperature, was added Grubb’s first generation catalyst
(3.6 mg, 5 mol %) (Note: usually room temperature is in the range of
35e40 ꢀC in this hot summer, in India), and stirred at the same
temperature for 10 h and progress was monitored by TLC. Solvent
was removed under reduced pressure and purification of the crude
material by silica gel column chromatography (petroleum ether/
ethyl acetate 98:2 to 93:7) furnished the oxepine 8c (22 mg, 82%) as
colorless liquid [TLC control (petroleum ether/ethyl acetate 95:5), Rf
(7c)¼0.50, Rf (8c)¼0.45, iodine chamber detection]. IR (MIR-ATR,
4000e600 cmꢁ1): nmax¼3061, 3023, 2926, 2753, 1603, 1492, 1452,
1368, 1264, 1247, 1138, 1099, 1074, 1026, 922, 755, 732, 699 cmꢁ1. 1H
1493,1452,1368,1345,1145,1090,1027, 996, 916, 757, 730, 698 cmꢁ1
1H NMR (CDCl3, 400 MHz):
¼7.45e7.20 (m, 6H, AreH), 7.15 (dd,1H,
.
d
J¼7.2 and7.2 Hz, AreH), 7.10 (dd,1H, J¼7.4and7.4 Hz, AreH), 6.96(d,
1H, J¼7.4 Hz, AreH), 5.95e5.75 (m,1H, CH2CH]CH2), 5.65e5.50 (m,
1H, CH2CH]CH2), 5.19 (d, 1H, J¼17.2 Hz, CH2CH]CH2trans), 5.10 (d,
1H, J¼10.4 Hz, CH2CH]CH2cis), 4.96 (d, 1H, J¼17.4 Hz, CH2CH]
CH2trans), 4.91 (d, 1H, J¼10.4 Hz, CH2CH]CH2cis), 3.95e3.84 (m, 2H,
CH2OCH2CH]CH2), 3.72e3.56 (m, 4H, CH2OCH2CH]CH2 and
NCH2Ar), 3.45 (dd, 2H, J¼16.6 and 9.4 Hz, NCH2Ph), 2.82 (d, 1H,
J¼11.4 Hz, CH2aCH]CH2), 2.62 [dd, 1H, J¼14.3 and 6.4 Hz,
NeCH2aC(CH2OCH2CH]CH2)CH2CH]CH2], 2.53 [dd,1H, J¼14.3 and
7.9 Hz, NeCH2aC(CH2OCH2CH]CH2)CH2CH]CH2], 2.46 (d, 1H,
NMR (CDCl3, 400 MHz):
d¼7.47 (dd,1H, J¼7.8 and 1.0 Hz, AreH), 7.38
(d, 2H, J¼7.3 Hz, AreH), 7.31 (dd, 2H, J¼7.3 and 7.3 Hz, AreH), 7.25 (t,
1H, J¼7.3 Hz, AreH), 7.18 (dd, 1H, J¼7.8 and 7.8 Hz, AreH), 7.10 (ddd,
1H, J¼7.8, 7.8 and 1.0 Hz, AreH), 6.95 (d, 1H, J¼7.8 Hz, AreH),
5.77e5.64 (m, 1H, CHa]CHb), 5.63e5.50 (m, 1H, CHa]CHb),
4.38e4.20 (m, 2H, CH2OCH2CH]CH), 4.00 (d, 1H, J¼12.2 Hz,
CH2aOCH2CH]CH), 3.77 (d, 1H, J¼12.2 Hz, CH2bOCH2CH]CH), 3.76
(d,1H, J¼13.2 Hz, NCH2aAr), 3.56 (d,1H, J¼14.7 Hz, NCH2aPh), 3.55 (d,
1H, J¼13.2 Hz, NCH2bAr), 3.50 (d, 1H, J¼14.7 Hz, NCH2bPh), 2.69 [d,
1H, J¼11.7 Hz, NeCH2aC(CH2OCH2)CH2CH]CH], 2.63e2.44 [m, 3H,
NeCH2bC(CH2OCH2)CH2CH]CH and CH2CH]CH] ppm. 13C NMR
J¼11.5 Hz, CH2bCH]CH2) ppm. 13C NMR (CDCl3, 100 MHz):
¼138.8
d
(s, AreC), 138.5 (s, AreC), 135.8 (s, AreC), 135.3 (d, CH2CH]CH2),
135.2 (d, CH2CH]CH2), 128.9 (d, 2C, AreCH), 128.2 (d, 2C, AreCH),
127.2 (d, AreCH), 127.0 (d, AreCH), 126.5 (d, AreCH), 126.0 (d,
AreCH), 125.9 (d, AreCH), 117.1 (t, CH2CH]CH2), 116.3 (t, CH2CH]
CH2), 76.6 (t, OCH2CH]CH2), 72.3 (t, CH2OCH2CH]CH2), 62.9 (t,
NeCH2), 57.2 (t, NeCH2), 56.7 (t, NeCH2), 42.9 [s, C(CH2OCH2CH]
CH2)CH2CH]CH2], 40.8 (t, CH2CH]CH2) ppm. HRMS (APCIþ) m/z
calculated for [C23H28NO]þ¼[MþH]þ: 334.2165; found 334.2150.
(CDCl3, 100 MHz):
d¼141.4 (s, AreC), 138.6 (s, AreC), 134.7 (s, AreC),
129.4 (d, CHa]CHb),128.9 (d, 2C, AreCH),128.2 (d, 2C, AreCH),128.0
(d, AreCH), 127.0 (d, AreCH), 126.7 (d, AreCH), 126.6 (d, AreCH),
126.3 (d, AreCH), 126.0 (d, CHa]CHb), 78.9 (t, OCH2CH]CH), 71.7 (t,
CH2OCH2CH]CH), 62.8 (t, NeCH2), 58.7 (t, NeCH2), 56.7 (t, NeCH2),
44.9 [s, C(CH2OCH2)CH2CH]CH], 37.1 (t, CH2CH]CH) ppm. HRMS
(ESIþ) m/z calculated for [C21H23NNaO]þ¼[MþNa]þ: 328.1672; found
328.1686.
4.11. 4-Allyl-4-[(allyloxy)methyl]-2-benzyl-7-(benzyloxy)-
1,2,3,4-tetrahydroisoquinoline (7h)
The reaction is performed with the alcohol 6h (132.0 mg,
0.33 mmol), sodium hydride (23.8 mg, 0.99 mmol), dry DMF (3 mL),
and allyl bromide (120.1 mg, 0.99 mmol) as described above (cf. 7c).
Purification of the crude material by silica gel column chromatogra-
phy (petroleum ether/ethyl acetate 97:3 to 90:10) furnished the allyl
ether 7h (130.8 mg, 90%) as colorless liquid [TLC control (petroleum
ether/ethyl acetate 75:25), Rf (6h)¼0.30, Rf (7h)¼0.75, iodine cham-
ber detection]. IR (MIR-ATR, 4000e600 cmꢁ1): nmax¼3064, 3029,
2851, 1637, 1609, 1578, 1499, 1453, 1342, 1278, 1240, 1139, 1091, 1019,
4.13. 2-Benzyl-7-(benzyloxy)-2,3,40,70-tetrahydro-1H-spiro
[isoquinoline-4,30-oxepine] (8h)
The reaction is performed with the allyl ether 7h (37 mg,
0.08 mmol), Grubb’s first generation catalyst (3.5 mg, 5 mol %), and
dry DCM (6 mL) as described above (cf. 8c). Purification of the crude
material by silica gel column chromatography (petroleum ether/
ethyl acetate 97:3 to 94:6) furnished the oxepine 8h (29.0 mg, 83%) as
colorless viscous liquid [TLC control (petroleum ether/ethyl acetate
90:10), Rf (7h)¼0.55, Rf (8h)¼0.45, iodine chamber detection]. IR
(MIR-ATR, 4000e600 cmꢁ1): nmax¼3062, 3026, 2926, 1609, 1580,
1499, 1454, 1318, 1239, 1134, 1097, 1021, 908, 732, 697 cmꢁ1. 1H NMR
915, 843, 735, 697 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d¼7.50e7.20 (m,
11H, AreH), 6.80 (dd, 1H, J¼8.8 and 2.4 Hz, AreH), 6.59 (d, 1H,
J¼2.4 Hz, AreH), 5.90e5.75 (m, 1H, CH2CH]CH2), 5.70e5.50 (m, 1H,
CH2CH]CH2), 5.20 (d, 1H, J¼17.2 Hz, CH2CH]CH2trans), 5.11 (d, 1H,
J¼10.4 Hz, CH2CH]CH2cis), 4.98 (s, 2H, OCH2Ph), 5.00e4.90 (m, 2H,
CH2CH]CH2), 3.95e3.84 (m, 2H, CH2OCH2CH]CH2), 3.70e3.55 (m,
4H, CH2OCH2CH]CH2 and NCH2Ar), 3.41 (dd, 2H, J¼16.6 and 9.3 Hz,
NCH2Ph), 2.79 (d, 1H, J¼11.7 Hz, CH2aCH]CH2), 2.59 [dd, 1H, J¼14.2
and 6.4 Hz, NeCH2aC(CH2OCH2CH]CH2)CH2CH]CH2], 2.50 [dd, 1H,
(CDCl3, 400 MHz):
d
¼7.40e7.10 (m, 11H, AreH), 6.74 (dd, 1H, J¼8.8
and 2.9 Hz, AreH), 6.49 (d, 1H, J¼2.9 Hz, AreH), 5.70e5.57 (m, 1H,
CHa]CHb), 5.55e5.45 (m, 1H, CHa]CHb), 4.90 (s, 2H, OCH2Ph),
4.25e4.18 (m, 2H, CH2OCH2CH]CH), 3.93 (d, 1H, J¼12.2 Hz,
CH2aOCH2CH]CH), 3.68 (d, 1H, J¼13.2 Hz, NCH2aAr), 3.65 (d, 1H,

8010
A.G.K. Reddy, G. Satyanarayana / Tetrahedron 68 (2012) 8003e8010
2011, 9, 5856; (b) Lubkoll, J.; Millemaggi, A.; Perry, A.; Taylor, R. J. K. Tet-
rahedron 2010, 66, 6606; (c) Rao, M. L. N.; Dasgupta, P. Tetrahedron Lett.
2012, 53, 162; (d) Laleu, B.; Lautens, M. J. Org. Chem. 2008, 73, 9164; (e)
J¼12.2 Hz, CH2bOCH2CH]CH), 3.47 (d,1H, J¼13.2 Hz, NCH2bAr), 3.42
(d,1H, J¼14.7 Hz, NCH2aPh), 3.38 (d,1H, J¼14.7 Hz, NCH2bPh), 2.62 [d,
1H, J¼11.2 Hz, NeCH2aC(CH2OCH2)CH2CH]CH], 2.52e2.35 [m, 3H,
NeCH2bC(CH2OCH2)CH2CH]CH and CH2CH]CH] ppm. 13C NMR
ꢀ
Selander, N.; Szabo, K. J. J. Org. Chem. 2009, 74, 5695; (f) Cheng, Y.; Duan, Z.;
Yu, L.; Li, Z.; Zhu, Y.; Wu, Y. Org. Lett. 2008, 10, 901; (g) Satyanarayana, G.;
Maier, M. E. Org. Lett. 2008, 10, 2361; (h) Kim, I.; Kim, K. Org. Lett. 2010, 12,
2500; (i) Satyanarayana, G.; Maier, M. E. Eur. J. Org. Chem. 2008, 5543; (j)
Leogane, O.; Lebel, H. Angew. Chem. 2008, 120, 356; Angew. Chem., Int. Ed.
(CDCl3, 100 MHz):
d¼156.9 (s, AreC), 138.6 (s, AreC), 137.1 (s, AreC),
136.1 (s, AreC), 133.8 (s, AreC), 129.4 (d, CHa]CHb), 128.8 (d, 2C,
AreCH),128.5 (d, 2C, AreCH),128.2 (d, 2C, AreCH),128.0 (d, AreCH),
127.9 (d, AreCH), 127.8 (d, CHa]CHb), 127.4 (d, 2C, AreCH), 127.0 (d,
AreCH), 113.8 (d, AreCH), 111.6 (d, AreCH), 78.9 (t, OCH2CH]CH),
71.6 (t, CH2OCH2CH]CH), 69.9 (t, OCH2Ph), 62.8 (t, NeCH2), 58.8
(t, NeCH2), 56.8 (t, NeCH2), 44.2 [s, C(CH2OCH2)CH2CH]CH], 37.2
(t, CH2CH]CH) ppm. HRMS (ESIþ) m/z calculated for
[C28H30NO2]þ¼[MþH]þ: 412.2271; found 412.2279.
~
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Financial support by the Council of Scientific and Industrial Re-
search [(CSIR), 02(0018)/11/EMR-II] and Department of Science and
Technology [(DST), CHE/2010-11/006/DST/GSN] and, New Delhi is
gratefully acknowledged. We thank Dr. P.C. Ravi Kumar and Dr.
Santosh J. Gharpure for valuable suggestions. A.G.K. thanks CSIR,
New Delhi, for the award of research fellowship.
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Copies of 1H and 13C NMR spectra. Supplementary data related
to this article can be found online at http://dx.doi.org/10.1016/
j.tet.2012.06.106.
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