Weinreb amide based synthetic equivalents for convenient access to 4-aryl-1,2,3,4-tetrahydroisoquinolines

Article abstract of DOI:10.1016/j.tet.2010.03.074

New synthetic equivalents, N-methoxy-N-methyl-N′-phenylsulfonyl glycinamide and N-methoxy-N-methyl-N′-benzyl-N′-tert-butyloxy carbonyl glycinamide based on WA functionality were developed for the convenient synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinoline framework. Two simple reactions, N-benzylation and addition of arylmagnesium halide on the WA functionality of the former afforded the key intermediate for convenient synthesis of N-phenylsulfonyl protected 4-aryl-1,2,3,4-tetrahydroisoquinoline, through reduction and acid promoted cyclization. With the latter, the addition of arylmagnesium halide on the WA functionality followed by the same protocol afforded the direct synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinolines in good yields. The acid promoted cyclization step enabled concomitant removal of N-Boc protection.

Full text of DOI:10.1016/j.tet.2010.03.074

Tetrahedron 66 (2010) 3723–3729
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Weinreb amide based synthetic equivalents for convenient access to
4-aryl-1,2,3,4-tetrahydroisoquinolines
*
Harikrishna Kommidi, Sivaraman Balasubramaniam, Indrapal Singh Aidhen
Department of Chemistry, Indian Institute of Technology Madras, Sardar Patel Road, Chennai 600036, TN, India
a r t i c l e i n f o
a b s t r a c t
New synthetic equivalents, N-methoxy-N-methyl-N0-phenylsulfonyl glycinamide and N-methoxy-N-
methyl-N0-benzyl-N0-tert-butyloxy carbonyl glycinamide based on WA functionality were developed for
the convenient synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinoline framework. Two simple reactions,
N-benzylation and addition of arylmagnesium halide on the WA functionality of the former afforded the
key intermediate for convenient synthesis of N-phenylsulfonyl protected 4-aryl-1,2,3,4-tetrahy-
droisoquinoline, through reduction and acid promoted cyclization. With the latter, the addition of ar-
ylmagnesium halide on the WA functionality followed by the same protocol afforded the direct synthesis
of 4-aryl-1,2,3,4-tetrahydroisoquinolines in good yields. The acid promoted cyclization step enabled
concomitant removal of N-Boc protection.
Article history:
Received 18 January 2010
Received in revised form 18 March 2010
Accepted 18 March 2010
Available online 24 March 2010
Keywords:
Weinreb amide
Grignard addition
4-Aryl-tetrahydroisoquinoline
Acid promoted cyclization
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
as a key intermediate for regioselective cyclization towards the
targeted 4-aryl-1,2,3,4-tetrahydroisoquinoline skeleton has been
The synthesis of isoquinoline alkaloids has been a field of
increasing interest in synthetic organic chemistry both of natural
and synthetic origin1 because of their biological significance.
Compared to 1-substituted tetrahydroisoquinolines, 4-substituted
tetrahydroisoquinoline derivatives are less. The 4-aryl-tetrahydro-
isoquinolines 1, in particular, have evoked considerable interest
because of their biological activity and potential application for the
treatment of depression,2 oestrogen-related disorders,3 Alzheim-
er’s disease and Parkinson’s disease.4 Cherylline is a unique alkaloid
that has produced long-standing interest, possesses basic 4-aryl-
1,2,3,4-tetrahydroisoquinoline skeleton.5 Recently, during molecu-
lar modelling studies, Prat et al.6 observed close chemical analogies
between 5-hydroxytryptamine (5-HT) and 4-(pyrid-4-yl)-1,2,3,4-
tetrahydroisoquinoline. This initiated their efforts to synthesize
tetrahydroisoquinolines bearing a pyridyl group at the 4-position.
The 4-aryl-1,2,3,4-tetrahydroisoquinoline framework has been
conveniently synthesized by three prominent approaches. The first
approach7,8 relies on acid promoted cyclization on to an aromatic
ring in 2-benzylamino-1-arylethanol framework mimicking
nature’s approach and the second is based on Pictet–Spengler re-
action.9 The regioselectivity problem associated with the former
approach is completely circumvented by an elegant use of an
intramolecular Barbier reaction.10 The use of p-quinone methides
particularly useful when the aryl group has a free hydroxy at the
para position.11a Ring closure involving formation of either of the
two C–N bonds present in tetrahydroisoquinoline, as a final step,
has been rare.11b A recent report using an intramolecular Friedel–
Crafts alkylation strategy for the construction of 4-aryl-1,2,3,4-tet-
rahydroisoquinolines moiety, summarizes all the distinct strategies
most commonly employed in the literature towards this
objective.12
2. Results and discussion
The importance of the target, our continued interest in
developing synthetic equivalents based on the Weinreb amide
(WA) functionality,13,14 prompted these studies. Use of this func-
tionality in the industry on kilogram scale further reflects the po-
tentials associated with this functionality.15 The absence of
a strategy based on the proposed disconnection was the additional
factor to undertake this study. The N-protected glycine derived
Weinreb amides 2 and 3 were the envisaged WA-based building
block towards the synthesis of target 1 (Fig. 1).The potency of these
building blocks to quickly and conveniently assemble the benzyl
and aryl residues on to it through N-benzylation and nucleophilic
addition of ArMgX onto WA functionality renders themselves as
valuable template for the synthesis of key intermediate 4 towards
the synthesis of 1. Since N-phenylsulfonyl group offers a robust
protection and should also facilitate the desired N-benzylation, the
synthesis of 2 and its use for the stated objective was undertaken
* Corresponding author. Fax: þ91 44 22574202; e-mail address: isingh@iitm.ac.in
(I.S. Aidhen).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.074

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H. Kommidi et al. / Tetrahedron 66 (2010) 3723–3729
Table 1
Preparation of various 4-aryl-N-phenylsulfonyl-1,2,3,4-tetrahydroisoquinolines
ArMgBr
Arylketones
(Yield%)a
4-Aryl-N-phenylsulfonyl-
1,2,3,4-tetrahydroisoquinoline
(Yield%)a
8a (74%)
8b (78%)
8c (72%)
10a (85%)
10b (94%)
10c (95%)
Figure 1.
first. The synthetic equivalent 2 was readily prepared in gram scale
from commercially available glycine 5 (Scheme 1). Glycine 5 was
converted to N-phenylsulfonyl glycine 6 by the literature16 pro-
cedure using benzenesulfonylchloride and NaOH at 0 ꢀC. The acid
functionality in 6 was converted to corresponding WA 2 after
several trials by in situ activation of the carboxyl group using
oxalylchloride. The apparent difficulty in the formation of acid
chloride was partly due to low solubility of 6 in dichloromethane.
After exploring several solvents it was found that a combination of
DMF and dichloromethane (1:5) was an appropriate medium for
the facile formation of the acid chloride. The reaction of in situ
generated acid chloride with N,O-dimethyl hydroxylamine (DMHA)
released from the N,O-dimethyl hydroxylamine hydrochloride
(DMHA$HCl) in presence of pyridine at 0 ꢀC afforded the WA based
synthetic equivalent 2 in 75% yield (Scheme 1), as stable crystalline
solid with unlimited shelf life.
8d (75%)
8e (83%)
8f (80%)
10d (92%)
10e (90%)
10f (86%)
8g (62%)
10g (65%)
a
Isolated yields after column chromatography. New compounds 8a–g, 10a–g
exhibited satisfactory analytical and spectral data.
Although, N-phenylsulfonyl group offers a rugged protection, its
removal has been difficult and requires strongly reductive condi-
tions.17 Replacing the sulfonyl group by an easily removable pro-
tecting group on nitrogen should, therefore, further enhance the
significance and the potential of this glycine derived WA building
block 2. In order to have an easily removable during the last step in
the synthetic scheme, we turned our attention to N-Boc protected
building block 3.
Scheme 1. Reagents and conditions: (a) PhSO2Cl (1.1 equiv), NaOH, Et2O, 0 ꢀC, 1.5 h,
93%; (b) COCl2 (1.1 equiv), DMF: DCM (1:5), 0 ꢀC to rt, 2 h; (c) DMHA$HCl (1.1 equiv),
Pyridine (2.1 equiv), DCM, 0 ꢀC, 1 h, 75% (two steps).
Although 318 could be easily prepared by N-Boc protection on
glycine 5 followed by conversion of the carboxyl group in 11 to its
WA using the mixed anhydride approach,19 its failure to undergo N-
benzylation to afford the key intermediate 12 was a surprise and
disappointment. In sharp contrast to the N-sulfonyl protected gly-
cinamide 2, which had undergone clean N-benzylation with the use
of K2CO3 in DMF at 60 ꢀC as a base, compound 3 was recovered
under these conditions. Replacing K2CO3 with DBU also made no
difference, whereas with the use of NaH as base, the starting ma-
terial 3 underwent decomposition.
The key intermediate 12 was prepared alternatively using ben-
zyl amine as the source of nitrogen and not glycine. Alkylating
benzyl amine 13 with ethyl-2-bromo acetate 14 in the presence of
triethylamine led to the formation of 2-aminoester 15.20 The Boc-
protection on the amine 15 furnished 16. Saponification of 16 fol-
lowed by WA preparation using the mixed anhydride approach gave
the required N-Boc protected WA building block 12 (Scheme 3).
A similar reaction sequence was performed on 12 as discussed
earlier for N-sulfonyl protected 8, which included addition of
ArMgBr onto 12 (Table 2), followed by sodium borohydride re-
duction of ketones 17a–e and acid promoted cyclization to arrive at
the 4-aryl-tetrahydroisoquinolines 18a–e. The concomitant re-
moval of the Boc-protection occurred with the use of excess
equivalents of trifluoroacetic acid during the cyclization step. The
aqueous basic work-up allowed isolation of the free amines 18a–e
for their quick structural characterization and confirmation. They
were converted to corresponding hydrochloride salts 19a–e using
solution of dry HCl gas in dry ether for convenient storage (Table 3).
Facile N-benzylation on the WA 2 using benzyl bromide K2CO3
in DMF at 60 ꢀC for 5 h yielded the N-benzylated compound 7 with
80% yield (Scheme 2). The addition of various aryl Grignard re-
agents on to the 7 at 0 ꢀC in THF gave exclusively the corresponding
aryl ketones 8a–g in 70–80% yields (Table 1). No nucleophilic ad-
dition of the Grignard reagent on to the electrophilic sulfur atom
was observed even at room temperature. The ketones 8a–g were
reduced using NaBH4 in methanol to furnish the 2-(N-benzyl-N-
phenylsulfonyl)-1-hydroxy-(1-aryl)-ethyl amino derivatives 9a–g
in quantitative yields. Using the literature precedence,7b the ami-
noalcohols 9a–g were cyclized to tetrahydroisoquinoline derivative
using a mixture of trifluoroacetic acid and concd sulfuric acid
(Scheme 2). The resultant crude products were purified by silica-gel
column chromatography to afford pure compounds 10a–g in 65–
95% isolated yields. This two-step protocol on aryl ketones 8a–g led
to the generalization and confirmation of the usefulness of the WA-
based template
2 for the 4-aryl-N-phenylsulfonyl tetrahy-
droisoquinoline framework (Table 1).
3. Conclusion
Scheme 2. Reagents and conditions: (a) K2CO3 (3.0 equiv), BnBr (1.2 equiv), DMF,
60 ꢀC, 5 h, 80%; (b) ArMgBr (4.0 equiv), THF, 0 ꢀ
C to rt, 2 h, 70–80%; (c) NaBH4
(1.0 equiv), MeOH, 0 ꢀC to rt, 2 h, 95–100%; (d) TFA (1.1 equiv), H2SO4 (1.1 equiv), DCM,
rt, 0.5 h, 65–95%.
In summary, N-methoxy-N-methyl-N0-phenylsulfonyl glycina-
mide 2,
a crystalline solid with unlimited shelf life and

H. Kommidi et al. / Tetrahedron 66 (2010) 3723–3729
3725
4. Experimental section
4.1. General
All reactions were carried out in an oven dried glasswares. Dry
DMF was prepared by stirring with Calcium hydride, downward
distilled and stored on 4 Å molecular sieves. Dry THF was distilled
as needed from Na/benzophenone ketyl. Solvents used for column
chromatography were LR grade. Magnesium metal was cleaned
using 20% HCl (thrice) followed by washing with distilled water and
acetone, which was dried by keeping it in hot air oven for 12 h at
100 ꢀC. Grignard reagent prepared was estimated using menthol
(dry) and 1, 10-phenanthroline as indicator in dry THF.21 Thin-layer
chromatography was performed on aluminium plates coated with
silica gel 60. Visualization was observed by UV light or by dipping
into a solution of cerium (IV) sulfate (2.5 g) and ammonium mo-
lybdate (6.25 g) in 10% sulfuric acid (250 mL) followed by charring
on a hot plate. Melting points were determined in capillaries and
are uncorrected. 1H NMR (400 MHz) and 13C NMR (100 MHz)
spectra were recorded in chloroform-d (CDCl3) and D2O as the
solvents and tetramethylsilane (TMS) as reference. HRMS were
recorded on a MICRO-Q TOF mass spectrometer by using the ESI
technique at 10 eV.
Scheme 3. Reagents and conditions: (a) (Boc)2O (1.1 equiv), 1 N NaOH, Dioxane/water
(2:1), pH (9–10), 0 ꢀC to rt, 12 h, 93%; (b) (CH3)3CCOCl (1.1 equiv), TEA (1.5 equiv), DCM,
0
ꢀC, 2.5 h; (c) DMHA$HCl (1.1 equiv), TEA (1.5 equiv), DCM, 0 ꢀC to rt, 1.5 h, 75% (two
steps); (d) TEA (1.1 equiv), THF, rt, 4 h, 90%; (e) (Boc)2O (1.2 equiv), TEA (2.2 equiv),
DCM, 0 ꢀC to rt, 7 h, 90%; (f) 2 N NaOH, MeOH, rt, 3 h; (g) (CH3)3CCOCl (1.1 equiv), TEA
(1.5 equiv), THF, 0 ꢀC, 2.5 h; (h) DMHA$HCl (1.1 equiv), TEA (1.5 equiv), THF, 0 ꢀC to rt,
1.5 h, 76% (three steps).
Table 2
Preparation of various N-benzyl-N-tert-butyloxy carbonyl (2-aryl)-aminoketones
4.1.1. N-Methoxy-N-methyl-2-(phenylsulfonamido)-acetamide
(2). To the solution of glycine (3 g, 40 mmol) in 2 N NaOH (20 mL),
benzenesulfonylchloride (5.1 mL, 40 mmol) in ether (50 mL) was
added at 0 ꢀC and stirred for 1.5 h. The reaction mixture was
washed with 2 N HCl (2ꢁ50 mL), followed by brine (50 mL), dried
over Na2SO4 and the solvent was removed under vacuum to afford
compound 7 as a colourless solid (8 g, 93%). Compound 7 (2 g,
9.3 mmol) was dissolved in the mixture of anhydrous DMF (3 mL)
and anhydrous DCM (15 mL). The solution was cooled to 0 ꢀC and
oxalylchloride (1 mL, 9.6 mmol) was added drop-wise to it. The
reaction mixture was stirred for 2 h at room temperature and
cooled to 0 ꢀC. N,O-Dimethyl hydroxylamine hydrochloride (1 g,
11 mmol) and solution of anhydrous pyridine (1.65 mL, 20 mmol) in
anhydrous DCM (10 mL) were added to it, stirred for 1 h and
allowed to attain room temperature. The reaction mixture was
washed with 2 N HCl (2ꢁ25 mL), followed by saturated aqueous
NaHCO3 solution (25 mL) and brine (25 mL). The organic layer
was dried over Na2SO4 and concentrated to afford crude prod-
uct that was subjected to column chromatography to obtain
ArMgBr
Arylketones
(Yield%)a
17a (76%)
17b (80%)
17c (76%)
17d (74%)
17e (78%)
a
Isolated yields after column chromatography. New compound 17a–e exhibited
satisfactory analytical and spectral data.
Table 3
pure
N-methoxy-N-methyl-N0-phenylsulfonyl
glycinamide
Preparation of various 4-aryl-1,2,3,4-tetrahydroisoquinolines and their amine
hydrochlorides
(1.75 g, 75%) as a colourless solid. Mp: 66–68 ꢀC; Rf (90% CH2Cl2/
MeOH) 0.24; nmax(liquid film) 3239, 1659, 1446, 1383, 1327,
Ar
Ar
Ar
1155, 1091, 988, 688 cmꢂ1
; dH (400 MHz, CDCl3) 7.86–7.90 (2H,
1.NaBH4/MeOH
Et2O-HCl
NH
O
NH2
Cl
2.TFA/H2SO4
in DCM
m, SO2Ph, ArH-2,6), 7.45–7.62 (3H, m, SO2Ph, ArH-3,4,5), 5.6
(1H, br, NH), 3.9 (2H, s, NCH2), 3.6 (3H, s, OCH3), 3.1 (3H, s,
NCH3); dC (100 MHz, CDCl3) 168.2, 139.2, 132.7, 129.0, 127.1, 61.5,
43.1, 32.4; HRMS (ESI): MHþ, found 259.0746. C10H15N2O4S
requires 259.0753.
NBoc
Et2O
18
19
Arylketones
4-Aryl-tetrahydrol-
soquinoline (Yield%)a
4-Aryl-1,2,3,4-tetrahydroi-
soquinoline amine
hydrochlorides (Yield%)
17a
17b
17c
17d
17e
18a (92%)
18b (91%)
18c (90%)
18d (90%)
18e (92%)
19a (99%)
19b (97%)
19c (97%)
19d (97%)
19e (98%)
4.1.2. 2-(N0-Benzylphenylsulfonamido)-N-methoxy-N-methyl-acet-
amide (7). To a solution of compound 2 (2 g, 7.7 mmol) in anhy-
drous DMF (12 mL), benzyl bromide (1.1 mL, 9.3 mmol) and
anhydrous potassium carbonate (3.2 g, 23.2 mmol) were added and
heated at 60 ꢀC for 5 h. The reaction mixture was cooled to room
temperature and extracted into ethylacetate (2ꢁ50 mL). The com-
bined ethylacetate extracts were washed with water (5ꢁ50 mL)
and later with brine (50 mL). The organic layer was dried over
Na2SO4 and concentrated to afford crude product that was purified
by column chromatography to give compound 7 (2.16 g, 80%) as
a colourless solid. Mp: 110–112 ꢀC; Rf (80% hexanes/EtOAc) 0.22;
a
Isolated yields after column chromatography.
N-methoxy-N-methyl-N0-benzyl-N0-tert-butyloxy carbonyl glyci-
namide 12, based on the WA functionality serve as useful
templates for the general synthesis of 4-aryl-1,2,3,4-tetrahydroiso-
quinoline derivatives. The templates provide an efficient route for
the preparation of various 4-aryl-1,2,3,4-tetrahydroisoquinolines.
nmax(liquid film) 1678, 1334, 1156, 1094, 743 cmꢂ1
CDCl3) 7.82–7.84 (2H, m, SO2Ph, ArH-2,6), 7.37–7.49 (3H, m, SO2Ph,
; dH (400 MHz,

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H. Kommidi et al. / Tetrahedron 66 (2010) 3723–3729
ArH-3,4,5), 7.12–7.22 (5H, m, Ph, ArH), 4.45 (2H, s, NCH2CO), 4.02
(2H, s, CH2Ph), 3.55 (3H, s, OCH3), 2.93 (3H, s, NCH3); dC (CDCl3,
100 MHz) 160.1, 141.2, 136.2, 133.4, 129.9, 129.6, 129.5, 128.8, 125.4,
127.2, 62.0, 51.9, 46.4, 33.1; HRMS (ESI): MHþ, found 349.1218.
C17H21N2O4S requires 349.1222.
51.6, 51.5; HRMS (ESI): MNaþ, found 406.0885. C21H18NO3FS
requires 406.0889.
4.2.3. N-Benzyl-N-(2-(4-methoxyphenyl)-2-oxoethyl)-
benzenesulfonamide (8c). Mp: 104–106 ꢀC; Rf (80% hexanes/EtOAc)
0.38; nmax(liquid film) 1688, 1600, 1331, 1262, 1160, 1093 cmꢂ1
; dH
4.1.3. N-Methoxy-N-methyl-N0-benzyl-N0-tert-butyloxy carbonyl gly-
cinamide (12). To a solution of N-benzyl-N-tert-butyloxy glycine
(2 g, 7.5 mmol) in anhydrous THF (25 mL), triethylamine (1.5 mL,
11.3 mmol) was added, followed by drop wise addition of pivaloyl
chloride (1.0 mL, 8.3 mmol) at 0 ꢀC and stirred for 2.5 h at room
temperature. To the reaction mixture, N,O-dimethyl hydroxylamine
hydrochloride (0.817 g, 8.3 mmol), triethylamine (1.49 mL,
11.3 mmol) and anhydrous THF (10 mL) were added at 0 ꢀC and
stirred at room temperature for 1 h. TLC revealed the complete
consumption of starting material. The solvent was evaporated un-
der reduced pressure, water (50 mL) was added to the residue and
the mixture was extracted with ethylacetate (2ꢁ50 mL). The com-
bined organic extracts were washed with saturated aqueous
NaHCO3 solution (40 mL) and later with brine (40 mL). The organic
layer was dried over Na2SO4 and concentrated under reduced
pressure to afford the crude product, which was purified by column
chromatography to obtain compound 12 (1.75 g, 76%) as a liquid. Rf
(70% hexanes/EtOAc) 0.39; nmax(liquid film) 2937, 1681, 1452, 1392,
(400 MHz, CDCl3) 7.77–7.81 (2H, m, SO2Ph, ArH-2,6), 7.59–7.64 (2H,
m, SO2Ph, ArH-3,5), 7.44–7.49 (1H, m, ArH-4), 7.36–7.41 (2H, m,
ArH), 7.08–7.16 (5H, m, CH2Ph, ArH), 6.71–6.74 (2H, m, ArH), 4.48
(2H, s, NCH2CO), 4.45 (2H, s, CH2Ph), 3.68 (3H, s, OCH3); dC
(100 MHz, CDCl3) 192.2, 171.1, 140.2, 135.2, 132.6, 130.2, 130.1, 129.0,
128.9, 128.75, 128.71, 128.6, 128.0, 127.9, 127.7, 127.5, 127.4, 113.9,
113.8, 55.5, 51.3, 51.1; HRMS (ESI): MNaþ, found 418.1092.
C22H21NO4S requires 418.1089.
4.2.4. N-Benzyl-N-(2-oxo-2-p-tolylethyl)benzenesulfonamide
(8d). Mp: 90–92 ꢀC; Rf (80% hexanes/EtOAc) 0.42; nmax(liquid film)
1694, 1446, 1413, 1332, 1238, 1160 cmꢂ1
; dH (400 MHz, CDCl3) 7.77–
7.81 (2H, m, SO2Ph, ArH-2,6), 7.53 (2H, d, J¼8.4 Hz, SO2Ph, ArH-3,5),
7.44–7.49 (1H, m, SO2Ph, ArH-4), 7.38 (2H, t, J¼8.2 Hz, ArH),
7.08–7.16 (5H, m, Ph. ArH), 7.06 (2H, d, J¼8.0 Hz, ArH), 4.51 (2H, s,
NCH2CO), 4.45 (2H, s, CH2Ph), 2.24 (3H, s, CH3); dC (100 MHz, CDCl3)
193.4, 144.7, 140.2, 135.2, 132.7, 132.3, 129.4, 128.93, 128.92, 128.76,
128.73, 128.6, 128.1, 127.97, 127.93, 127.9, 127.5, 127.4, 51.3, 21.7;
HRMS (ESI): MNaþ, found 402.1144. C22H21NO3S requires 402.1140.
1241, 1161, 765 cmꢂ1
; dH (CDCl3, 400 MHz). Mixture of two rotamers
(60:40) 7.14–7.27 (5H, m, Ph, ArH), 4.46, 4.49 (2H, s, NCH2CO), 3.88,
4.02 (2H, s, CH2Ph), 3.50, 3.55 (3H, s, OCH3), 3.0 (3H, s, NCH3), 1.39
(9H, s, C(CH3)3); dC (CDCl3, 100 MHz) 170.3, 170.1, 156.1, 156.0, 138.0,
137.8, 128.6, 128.4, 128.2, 127.4, 127.2, 80.3, 80.1, 61.1, 51.5, 50.8, 46.8,
46.7, 29.6; HRMS (ESI): MNaþ, found 331.1635. C16H24N2O4 requires
331.1634.
4.2.5. N-Benzyl-N-(2-oxo-2-(thiophen-2-yl)ethyl)benzenesulfona-
mide (8e). Mp: 60–62 ꢀC; Rf (80% hexanes/EtOAc) 0.47; nmax(liquid
film) 1674, 1446, 1413, 1332, 1160, 1093 cmꢂ1
; dH (400 MHz, CDCl3)
7.78 (2H, d, J¼7.6 Hz, SO2Ph, ArH-2,6), 7.43–7.50 (3H, m, ArH-3,4,5),
7.38 (2H, t, J¼3.6 Hz, ArH), 7.05–7.15 (5H, m, CH2Ph, ArH), 6.92 (1H,
t, J¼4.0 Hz, ArH), 4.42 (4H, s, NCH2CO, CH2Ph); dC (100 MHz, CDCl3)
186.6, 140.6, 139.5, 134.5, 134.0, 132.4, 132.0, 128.6, 128.5, 128.3,
128.2, 127.9, 127.7, 127.0, 51.2, 51.0; HRMS (ESI): MNaþ, found
394.0551. C19H17NO3S2 requires 394.0548.
4.2. General procedure for the addition of Grignard reagents
on to the Weinreb amide 7 and 12
To
a
solution of aryl or hetero arylmagnesium bromide
4.2.6. N-Benzyl-N-(2-(4-chlorophenyl)-2-oxoethyl)benzene-
(2.8 mmol) in dry THF (3 mL), a solution of alkane WA (0.7 mmol) in
3 mL of dry THF, was added under inert atmosphere at ꢂ10 ꢀC and
the mixture was stirred for 3 h between ꢂ10 and 10 ꢀC. TLC
revealed the complete consumption of starting material. Sub-
sequent hydrolysis was achieved by the cautious addition of satu-
rated ammonium chloride solution. Aqueous layer was extracted
with ethylacetate, washed with water, dried over Na2SO4 and
concentrated to get crude product. This was purified by column
chromatography using hexanes/ethylacetate mixture, to get the
desired ketones 8a–g and 17a–e.
sulfonamide (8f). Mp: 60–62 ꢀC; Rf (80% hexanes/EtOAc) 0.43;
nmax(liquid film) 1697, 1596, 1446, 1330, 1092 cmꢂ1
; dH (400 MHz,
CDCl3) 7.80–7.83 (2H, m, SO2Ph, ArH-2,6), 7.66–7.72 (2H, m, SO2Ph,
ArH-3,5), 7.51–7.56 (1H, m, SO2Ph, ArH-4), 7.42–7.48 (2H, m, ArH),
7.10–7.19 (5H, m, CH2Ph, ArH), 6.95–7.01 (2H, m, C6H4Cl, ArH), 4.49
(2H, s, NCH2CO), 4.45 (2H, s, CH2Ph); dC (100 MHz, CDCl3) 193.0,
140.1, 139.8, 134.8, 132.7, 129.2, 129.0, 128.99, 128.96, 128.84, 128.80,
128.76, 128.71, 128.2, 127.44, 127.41, 51.7, 51.5; HRMS (ESI): MNaþ,
found 422.0595. C21H18NO3ClS requires 422.0594.
4.2.7. N-Benzyl-N-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)benzene-
4.2.1. N-Benzyl-N-(2-oxo-2-phenylethyl) benzenesulfonamide (8a). Mp:
66–68 ꢀC; Rf (80% hexanes/EtOAc) 0.50; nmax(liquid film) 1697, 1446,
sulfonamide (8g). Mp: 96–98 ꢀC; Rf (80% hexanes/EtOAc) 0.28;
nmax(liquid film) 2922, 1446, 1340, 1090, 753 cmꢂ1
; dH (400 MHz,
1330, 1225, 1155 cmꢂ1
;
dH (400 MHz, CDCl3) 7.77–7.81 (2H, m, SO2Ph,
CDCl3) 7.81 (2H, d, J¼7.6 Hz, SO2Ph, ArH-2,6), 7.49 (1H, t, J¼7.2 Hz,
SO2Ph, ArH-4), 7.41 (2H, t, J¼7.2 Hz, SO2Ph, ArH-3,5), 7.27 (1H, d,
J¼8.4 Hz, ArH), 7.21–7.24 (1H, s, ArH), 7.08–7.17 (5H, m, CH2Ph,
ArH), 6.69 (1H, d, J¼8.4 Hz, ArH), 4.50 (2H, s, NCH2CO), 4.44 (2H, s,
CH2Ph), 3.80 (3H, s, OCH3C6H3), 3.75 (3H, s, OCH3C6H3); dC
(100 MHz, CDCl3) 192.4, 153.7,149.0,140.0, 135.1,132.6,128.6, 128.5,
127.9, 127.4, 122.5, 110.0, 60.3, 56.1, 56.0, 51.4; HRMS (ESI): MNaþ,
found 448.1196. C23H23NO5S requires 448.1195.
ArH-2,6), 7.59–7.64 (2H, m, SO2Ph, ArH-3,5), 7.44–7.50 (1H, m, SO2Ph,
ArH-4), 7.36–7.43 (3H, m, ArH), 7.25 (2H, t, J¼7.6 Hz, ArH), 7.07–7.15
(5H, m, CH2Ph, ArH), 4.52 (2H, s, NCH2CO), 4.45 (2H, s, CH2Ph); dC
(100 MHz, CDCl3) 193.9, 140.1, 135.1, 134.8, 133.7, 132.7, 129.0, 128.7,
128.2, 128.1, 127.8, 127.1, 51.5, 51.3; HRMS (ESI): MNaþ, found 388.0983.
C21H19NO3S requires 388.0983.
4.2.2. N-Benzyl-N-(2-(4-fluorophenyl)-2-oxoethyl) benzenesulfona-
mide (8b). Rf (80% hexanes/EtOAc) 0.45; nmax(liquid film) 1697,
4.2.8. tert-Butyl benzyl(2-oxo-2-phenylethyl)carbamate (17a). Rf
(70% hexanes/EtOAc) 0.54; nmax(liquid film) 2973, 1692, 1598, 1226,
1446, 1330,1326, 1152 cmꢂ1
; dH (400 MHz, CDCl3) 7.80–7.83 (2H, m,
SO2Ph, ArH-2,6), 7.66–7.72 (2H, m, SO2Ph, ArH-3,5), 7.51–7.56 (1H,
m, ArH-4), 7.42–7.48 (2H, m, ArH), 7.10–7.19 (5H, m, CH2Ph, ArH),
6.95–7.01 (2H, m, ArH), 4.50 (2H, s, NCH2CO), 4.45 (2H, s, CH2Ph); dC
(100 MHz, CDCl3) 192.4, 167.2, 164.7, 139.8, 134.9, 132.7, 131.2, 130.6,
130.5, 128.9, 128.8, 128.77, 128.70, 128.6, 128.1, 127.4, 116.0, 115.7,
1156 cmꢂ1
; dH (400 MHz, CDCl3). Mixture of two rotamers (53:47)
7.77–7.83 (4H, dd, J¼7.6, 16 Hz, ArH), 7.47–7.50 (2H, m, ArH),
7.32–7.35 (4H, m, ArH), 7.13–7.28 (10H, m, ArH), 4.53, 4.55 (2H, s,
NCH2CO), 4.38, 4.47 (2H, s, CH2Ph), 1.33, 1.42 (9H, s, C(CH3)3); dC
(100 MHz, CDCl3) 195.1, 194.8, 156.0, 155.9, 137.8, 137.6, 135.3, 135.2,

H. Kommidi et al. / Tetrahedron 66 (2010) 3723–3729
3727
133.4, 129.5, 128.7, 128.67, 128.61, 128.5, 128.1, 127.9, 127.7, 127.5,
127.4, 120.1, 115.3, 80.6, 80.4, 52.4, 52.1, 51.4, 51.0, 28.3, 28.2; HRMS
(ESI): MNaþ, found 348.1569. C20H23NO3 requires 348.1576.
benzylic alcohol. The alcohol was subjected to cyclization without
further purification.
For N-sulfonyl protected substrates: To a solution of alcohol
(0.2 mmol) in DCM (4 mL), a mixture of H2SO4 (0.02 mL, 0.3 mmol)
and CF3CO2H (0.02 mL, 0.26 mmol) acids were added and stirred at
room temperature for 0.5 h. TLC revealed the complete consump-
tion of starting material. The solvent was evaporated under reduced
pressure, ethylacetate was added to the residue, washed with 10%
aqueous K2CO3 (10 mL), water (10 mL) and later with brine (10 mL).
The organic layer was dried over Na2SO4 and concentrated to afford
crude product, which was purified by silica-gel flash column
chromatography using ethylacetate/hexanes mixture, to get the
cyclised products 10a–g in good yields.
4.2.9. tert-Butylbenzyl(2-(4-fluorophenyl)-2-oxoethyl)carbamate
(17b). Rf (70% hexanes/EtOAc) 0.61; nmax(liquid film) 2796, 1700,
1589, 1366, 1162 cmꢂ1
; dH (400 MHz, CDCl3). Mixture of two
rotamers (52:48) 7.87–7.98 (4H, m, ArH), 7.22–7.41 (10H, m, ArH),
7.05–7.18 (4H, m, ArH), 6.81–6.89 (4H, m, ArH), 6.72–6.81 (2H, m,
ArH), 4.57–4.66 (4H, m, NCH2CO), 4.48 (4H, s, CH2Ph), 1.44,1.53 (9H,
s, C(CH3)3); dC (100 MHz, CDCl3) 193.6, 193.3, 167.2, 164.7, 157.9,
156.2,156.1,155.5,152.5,137.5,137.3,131.5,130.6,130.5,130.4,130.3,
128.6,128.0, 127.5,116.2,116.1, 115.9,115.7, 81.1, 80.8, 52.3, 52.1, 51.6,
51.1, 28.3, 28.2; HRMS (ESI): MNaþ, found 366.1489. C20H22NO3F
requires 366.1481.
For N-Boc-protected substrates: To
a solution of alcohol
(0.2 mmol) in DCM (4 mL), a mixture of H2SO4 (0.02 mL, 0.3 mmol)
and CF3CO2H (0.20 mL, 2.6 mmol) acids were added, excess TFA was
used to remove the Boc-protection during cyclization. The mixture
was stirred at room temperature for 6–7 h. TLC revealed the com-
plete consumption of starting material. A similar work up pro-
cedure as mentioned for N-sulfonyl protected substrate was
followed to get crude product. This was purified by silica-gel flash
column chromatography using dichloro-methane/methanol mix-
ture, to get the cyclised products 18a–e in good yields. The obtained
free amine was converted in to its hydrochloride salt by stirring the
amine (0.18 mmol) with ether/HCl solution (3 ml) for 5–10 min.
The precipitated salt was filtered, washed with ether and dried
under high vacuum to get the pure amine hydrochlorides 19a–e in
very high yields.
4.2.10. tert-Butyl benzyl(2-(4-methoxyphenyl)-2-oxoethyl)carbamate
(17c). Rf (70% hexanes/EtOAc) 0.25; nmax(liquid film) 2974, 1690,
1452, 1365, 1228 cmꢂ1
; dH (400 MHz, CDCl3). Mixture of two
rotamers (54:46) 7.76–7.82 (4H, m, ArH), 7.76–7.82 (4H, m, ArH),
7.10–7.30(11H, m, ArH), 6.75–6.85 (5H, m, ArH), 6.66–6.74 (2H, m,
ArH), 4.50–4.65 (5H, m), 4.34, 4.47 (2H, s, CH2Ph), 3.65, 3.73 (3H, s,
OCH3), 1.32, 1.40 (9H, s, C(CH3)3); dC (100 MHz, CDCl3) 193.4, 193.2,
171.1, 163.7, 156.0, 153.0, 150.7, 137.9, 137.7, 130.1, 129.0, 128.6, 128.4,
128.3, 128.2, 128.0, 127.5, 127.3, 116.0, 114.6, 113.9, 113.8, 80.5, 80.2,
55.6, 55.3, 52.0, 51.8, 51.4, 51.0, 28.3, 28.1; HRMS (ESI): MNaþ, found
378.1685. C21H25NO4 requires 378.1681.
4.2.11. tert-Butyl benzyl(2-oxo-2-p-tolylethyl)carbamate (17d). Rf (70%
hexanes/EtOAc) 0.46; nmax (liquid film) 2976, 1700, 1589, 1366,
4.3.1. 4-Phenyl-2-(phenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline
1162 cmꢂ1
;
dH (400 MHz, CDCl3). Mixture of two rotamers (52:48)
(10a). Mp: 66–68 ꢀC; Rf (80% hexanes/EtOAc) 0.45; nmax(liquid
7.77–7.87 (4H, m, ArH), 7.21–7.39 (14H, m, ArH), 6.96–7.10 (1H, m,
ArH), 6.75–6.80 (1H, m, ArH), 4.62–4.68 (4H, m, NCH2CO), 4.49, 4.59
(4H, s, CH2Ph), 2.26, 2.41 (3H, s, CH3Ph), 1.45, 1.54 (9H, s, C(CH3)3); dC
(100 MHz, CDCl3) 194.6, 194.4, 156.1, 156.0, 144.4, 144.3, 137.8, 137.6,
132.7, 129.8, 129.4, 129.3, 128.8, 128.6, 128.5, 128.1, 128.0, 127.8, 127.5,
127.4, 127.3, 115.2, 80.6, 80.4, 52.3, 52.1, 51.4, 51.0, 28.3, 28.2, 20.7,
20.5; HRMS (ESI): MNaþ, found 362. 1730. C21H25NO3 requires
362.1732.
film) 2924, 1508, 1343, 1168, 1168, 1091 cmꢂ1
; dH (400 MHz,
CDCl3) 7.67–7.71 (2H, m, SO2Ph, ArH-2,6), 7.46–7.51 (1H, m,
SO2Ph, ArH-4), 7.38–7.44 (2H, m, SO2Ph, ArH-3,5), 7.15–7.23 (4H,
m, ArH), 6.96–7.03 (4H, m, ArH), 6.76 (1H, d, J¼8.0 Hz, ArH), 4.44
(1H, d, J¼15.2 Hz, CHaHbC6H4), 4.20 (1H, dd, J¼5.6, 8.0 Hz,
NCH2CH), 4.12 (1H, d, J¼14.8 Hz, CHaHbC6H4), 3.72 (1H, dd, J¼5.6,
12.0 Hz, NCHaHbCH), 3.01 (1H, dd, J¼8.0, 12.0 Hz, NCHaHbCH); dC
(100 MHz, CDCl3) 142.3, 136.3, 136.2, 132.9, 131.8, 129.5, 129.1,
128.9, 128.8, 128.6, 127.7, 127.1, 127.0, 126.7, 126.2, 51.0, 48.0, 45.2;
HRMS (ESI): MNaþ, found 350.1217. C21H20NO2S requires
350.1215.
4.2.12. tert-Butyl benzyl(2-(4-chlorophenyl)-2-oxoethyl)carbamate (17e). Rf
(70% hexanes/EtOAc) 0.47; nmax (liquid film) 2943, 2686, 1570, 1451,
1184 cmꢂ1
; dH (400 MHz, CDCl3). Mixture of two rotamers (54:46)
7.70–7.60 (4H, m, ArH), 7.25–7.36 (5H, m, ArH), 7.12–7.25 (13H, m,
ArH), 7.04 (1H, d, J¼8.4 Hz, ArH), 6.66 (1H, J¼8.4 Hz, d, ArH), 4.40–
4.52 (m, 7H), 4.34 (s, 2H, CH2Ph), 1.32, 1.41 (9H, s, C(CH3)3); dC
(100 MHz, CDCl3) 194.0, 193.7, 156.3, 156.1, 155.2, 140.08, 140.03,
137.4, 137.2, 133.4, 133.3, 129.3, 129.2, 129.1, 128.8, 128.7, 128.6,
128.0,127.5,124.4,116.7,124.4, 116.7, 81.2, 80.9, 52.4, 52.2, 51.6, 51.2,
28.4, 28.2; HRMS (ESI): MNaþ, found 382.1192. C20H22NO3Cl re-
quires 382.1186.
4.3.2. 4-(4-Fluorophenyl)-2-(phenylsulfonyl)-1,2,3,4-tetrahy-
droisoquinoline (10b). Rf (80% hexanes/EtOAc) 0.42; nmax(liquid
film) 1508, 1446, 1354, 1168, 1091 cmꢂ1
; dH (400 MHz, CDCl3) 7.69
(2H, d, J¼7.6 Hz, SO2Ph, ArH-2,6), 7.47–7.52 (1H, m, SO2Ph, ArH-4),
7.41 (2H, t, J¼7.2 Hz, SO2Ph, ArH-3,5), 7.09 (1H, t, J¼7.2 Hz ArH),
6.95–7.04 (4H, m, ArH), 6.84–6.90 (2H, m, ArH), 6.77 (1H, d,
J¼7.6 Hz, ArH), 4.35 (1H, d, J¼14.8 Hz, CH2C6H4), 4.16–4.22 (2H, m),
3.60 (1H, dd, J¼4.8, 12.0 Hz, NCHaHbCH), 3.08 (1H, dd, J¼8.0, 12 Hz,
NCHaHbCH); dC (100 MHz, CDCl3) 162.0, 159.6, 137.2, 135.1, 134.9,
131.8, 130.7, 129.3, 129.2, 128.4, 128.0, 126.6, 126.0, 125.8, 125.2,
114.4, 114.2, 49.9, 46.7, 43.3; HRMS (ESI): MNaþ, found 390.0934.
C21H18NO2SF requires 390.0940.
4.3. General procedure for the reduction of aryl ketones 8a–g
and 17a–e and subsequent cyclization to 4-aryl-
tetrahydroisoquinolines 10a–g and 18a–e, respectively
To the solution of aryl ketone (0.5 mmol) in MeOH (2 mL), so-
dium borohydride (1.0 mmol) was added at 0 ꢀC. The mixture was
stirred at room temperature for 1.5 h, the complete consumption of
starting material as revealed by TLC. Excess sodium borohydride
was quenched by cautious addition of acetic acid. Methanol was
evaporated under reduced pressure and water was added to the
residue. The aqueous suspension was extracted with ethylacetate
(2ꢁ15 mL), the combined ethylacetate extracts were washed with
water (2ꢁ15 mL) and later with brine (15 mL). The organic layer
was dried over Na2SO4 and concentrated to afford corresponding
4.3.3. 4-(4-Methoxyphenyl)-2-(phenylsulfonyl)-1,2,3,4-tetrahy-
droisoquinoline (10c). Mp: 105–107 ꢀC; Rf (80% hexanes/EtOAc)
0.32; nmax(liquid film) 1508, 1446, 1348, 1160, 1089 cmꢂ1
; dH
(400 MHz, CDCl3) 7.70 (2H, d, J¼7.2 Hz, SO2Ph, ArH-2,6), 7.45–7.52
(1H, m, SO2Ph, ArH-4), 7.41 (2H, t, J¼7.6 Hz, SO2Ph, ArH-3,5), 7.05–
7.11 (2H, m, ArH), 6.97–7.03 (2H, m, ArH), 6.91–6.96 (2H, m, ArH),
6.77–6.81 (1H, m, ArH), 6.72–6.76 (2H, m, C6H4OMe, ArH-3,5), 4.43
(1H, d, J¼14.8 Hz, CHaHbC6H4), 4.16 (1H, dd, J¼5.6, 7.6 Hz, NCH2CH),
4.14 (1H, d, J¼14.8 Hz, CHaHbC6H4), 3.70 (3H, s, OCH3), 3.66–3.72
(1H, m, NCHaHbCH), 2.97 (1H, dd, J¼7.6, 12.0 Hz NCHaHbCH); dC

3728
H. Kommidi et al. / Tetrahedron 66 (2010) 3723–3729
(100 MHz, CDCl3) 158.6,136.7,136.2,134.3,132.8, 131.8,129.9,129.5,
129.1, 129.0, 128.8, 127.7, 127.6, 126.9, 126.6, 126.1, 114.0, 113.9, 55.2,
51.1, 47.9, 44.4; HRMS (ESI): MNaþ, found 402.1145. C22H21NO3S
requires 402.1140.
137.3, 136.1, 130.2, 128.8, 128.4, 126.4, 126.3, 125.8, 52.2, 48.4, 44.8;
HRMS (ESI): MHþ, found 210.1283. C15H16N requires 210.1283.
4.3.9. 4-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (18b). Rf (90%
CH2Cl2/MeOH) 0.21; nmax(liquid film) 2633, 1589, 1197, 1080 cmꢂ1
; dH
4.3.4. 2-(Phenylsulfonyl)-4-p-tolyl-1,2,3,4-tetrahydroisoquinoline
(400 MHz, CDCl3) 7.18–7.22 (1H, m, ArH), 7.06–7.15 (3H, m, ArH), 6.96–
7.04 (2H, m, ArH), 6.91 (1H, d, J¼6.0 Hz ArH), 4.07–4.20 (3H, m),
3.40 (1H, dd, J¼4.4, 10.4 Hz, NCHaHbCH), 3.08 (1H, dd, J¼5.2,
10.4 Hz, NCHaHbCH), 2.2 (1H, br s,); dC (100 MHz, CDCl3) 162.7,
160.3, 140.5, 137.0, 136.0, 130.1, 126.4, 126.0, 115.3, 115.1, 52.2, 48.3,
44.0; HRMS (ESI): MHþ, found 228.1185. C15H15NF requires
228.1189.
(10d). Mp: 66–68 ꢀC; Rf (80% hexanes/EtOAc) 0.37; nmax(liquid
film) 2922, 1446, 1340, 1182, 1090 cmꢂ1
; dH (400 MHz, CDCl3)
7.66–7.70 (2H, m, SO2Ph, ArH-2,6), 7.45–7.51 (1H, m, SO2Ph, ArH-4),
7.37–7.43 (2H, m, SO2Ph, ArH-3,5), 7.02–7.07 (1H, m, ArH), 6.95–
7.01 (4H, m, ArH), 6.87–6.91 (2H, m, ArH), 6.76 (1H, d, J¼7.6 Hz,
ArH), 4.43 (1H, d, J¼15.6 Hz, CHaHbC6H4), 4.17 (1H, dd, J¼5.6, 8.0 Hz,
NCH2CH), 4.09 (1H, d, J¼15.6 Hz, CHaHbC6H4), 3.71 (1H, dd, J¼5.6,
11.6 Hz, NCHaHbCH), 2.95 (1H, dd, J¼8.4, 11.6 Hz, NCHaHbCH), 2.23
(3H, s, C6H4CH3); dC (100 MHz, CDCl3) 139.2, 136.7, 136.6, 136.2,
132.8, 131.8, 129.3, 129.2, 128.8, 127.7, 127.0, 126.6, 126.1, 51.1, 48.8,
44.8, 21.1; HRMS (ESI): MNaþ, found 386.1191. C22H21NO2S requires
386.1191.
4.3.10. 4-(4-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (18c). Rf
(90% CH2Cl2/MeOH) 0.18; nmax(liquid film) 2895, 2734, 1439, 1200,
1120, 1026 cmꢂ1
;
dH (400 MHz, CDCl3) 7.15 (1H, d, J¼6.0 Hz, ArH),
7.02–7.11 (3H, m, ArH), 7.00 (1H, d, J¼6.8 Hz, ArH), 6.82 (1H, d,
J¼6.8 Hz, ArH), 6.75 (1H, s, ArH), 4.02–4.06 (3H, m), 3.76 (3H, s,
OCH3), 3.36 (1H, dd, J¼4.0, 6.0 Hz, NCHaHbCH), 3.02–3.09 (1H, m,
NCHaHbCH); dC (100 MHz, CDCl3) 157.1, 138.1, 137.7, 135.9, 127.2,
126.8, 126.2, 125.7, 111.2, 55.0, 52.0, 48.2, 44.1; HRMS (ESI): MHþ,
found 240.1385. C16H18NO requires 240.1388.
4.3.5. 2-(Phenylsulfonyl)-4-(thiophen-2-yl)-1,2,3,4-tetrahy-
droisoquinoline (10e). Mp: 110–112 ꢀC; Rf (80% hexanes/EtOAc)
0.40; nmax(liquid film) 2921, 1446, 1340, 1166, 1090 cmꢂ1
; dH
(400 MHz, CDCl3) 7.71–7.75 (2H, m, SO2Ph, ArH-2,6), 7.49–7.51 (1H,
m, SO2Ph, ArH-4), 7.42–7.7.47 (2H, m, SO2Ph, ArH-3,5), 7.02–7.14
(3H, m, ArH), 6.99 (2H, t, J¼7.2 Hz, ArH), 6.86 (1H, m, ArH), 6.81 (1H,
d, J¼3.2 Hz, ArH), 4.50 (1H, t, J¼5.6 Hz, NCH2CH), 4.32 (1H, d,
J¼14.8 Hz, CHaHbC6H4), 4.22 (1H, d, J¼14.8 Hz, CHaHbC6H4), 3.62
(1H, dd, J¼4.8, 12.0 Hz, NCHaHbCH), 3.31 (1H, dd, J¼7.2, 12.0 Hz,
NCHaHbCH); dC (100 MHz, CDCl3) 145.2, 136.3, 135.9, 132.9, 131.2,
129.1, 127.7, 127.1, 127.0, 126.6, 126.2, 126.0, 124.7, 60.4, 50.8, 47.7,
40.3; HRMS (ESI): MHþ, found 356.0776. C19H18NO2S2 requires
356.0779.
4.3.11. 4-p-Tolyl-1,2,3,4-tetrahydroisoquinoline (18d). Rf (90% CH2Cl2/
MeOH) 0.20; nmax(liquid film) 2918, 1491, 1103, 812, 737 cmꢂ1
; dH
(400 MHz, CDCl3) 7.12–7.18 (1H, m, ArH), 7.04–7.12 (4H, m, ArH),
6.95–7.01 (2H, m, ArH), 6.90 (1H, d, J¼7.2 Hz, ArH), 4.03–4.17 (3H, m),
3.38 (1H, dd, J¼4.8, 12.8 Hz, NCHaHbCH), 3.07 (1H, dd, J¼6.4, 13.2 Hz,
NCHaHbCH), 2.31 (3H, s, C6H4CH3), 2.18 (1H, NH); dC (100 MHz, CDCl3)
141.8, 137.5, 136.0, 135.9, 130.2, 129.1, 128.2, 126.2, 125.7, 52.2, 48.4,
44.4, 20.9; HRMS (ESI): MHþ, found 224.1443. C16H18N requires
224.1439.
4.3.6. 4-(4-Chlorophenyl)-2-(phenylsulfonyl)-1,2,3,4-tetrahy-
4.3.12. 4-(4-Chlorophenyl)-1,2,3,4-tetrahydroisoquinoline (18e). Rf
(90% CH2Cl2/MeOH) 0.20; nmax(liquid film) 2924, 1488, 1449, 1089,
droisoquinoline (10f). Mp: 80–82 ꢀC; Rf (80% hexanes/EtOAc) 0.37;
nmax(liquid film) 2921, 1514, 1446, 1166, 1090 cmꢂ1
;
dH (400 MHz,
1013, 826 cmꢂ1
;
dH (400 MHz, CDCl3) 7.23 (2H, d, J¼8.0 Hz, C6H4Cl,
CDCl3) 7.67–7.71 (m, 2H, SO2Ph, ArH-2,6), 7.48–7.54 (m, 1H, SO2Ph,
ArH-4), 7.40–7.46 (m, 2H, SO2Ph, ArH-3,5), 7.09–7.19 (m, 3H, ArH),
7.01–7.06 (m, 2H, C6H4Cl, ArH-2,6), 6.93–6.97 (m, 2H C6H4Cl, ArH-
3,5), 6.78 (d, 1H, J¼8.0 Hz, ArH), 4.37 (d, 1H, J¼14.4 Hz, CH2C6H4),
4.16–4.24 (m, 2H), 3.61 (dd, 1H, J¼4.8, 12 Hz, NCHaHbCH), 3.10 (dd,
1H, J¼7.2, 12 Hz, NCHaHbCH); dC (100 MHz, CDCl3) 140.0, 136.3,
135.6, 132.9, 131.8, 130.2, 129.5, 129.1, 128.7, 127.6, 127.1, 127.0, 126.3,
50.8, 47.8, 44.5; HRMS (ESI): MNaþ, found 406.0645. C21H18NO2ClS
requires 406.0644.
H-2,6), 7.16 (1H, t, J¼7.6 Hz, ArH), 7.07 (2H, t, J¼8.0 Hz, ArH), 7.02
(2H, d, J¼8.4 Hz, ArH), 6.86 (1H, d, J¼7.2 Hz, C6H4Cl, H-3,5), 4.02–
4.17 (3H, m), 3.37 (1H, dd, J¼5.2, 12.8 Hz, NCHaHbCH), 3.04 (1H, dd,
J¼6.4, 13.2 Hz, NCHaHbCH), 2.63 (1H, br s, NH); dC (100 MHz, CDCl3)
143.3, 136.8, 136.1, 132.1, 130.1, 130.0, 128.5, 126.4, 125.9, 60.3, 52.1,
48.3, 44.2; HRMS (ESI): MHþ, found 244.0896. C15H15NCl requires
244.0893.
4.3.13. 4-Phenyl-1,2,3,4-tetrahydroisoquinoline
hydrochloride
dH
(19a). nmax(liquid film) 2943, 2686, 1570, 1451, 1184 cmꢂ1
;
4.3.7. 4-(3,4-Dimethoxyphenyl)-2-(phenylsulfonyl)-1,2,3,4-tetrahy-
(400 MHz, D2O) 7.26–7.35 (3H, m, ArH), 7.19–7.26 (2H, m, ArH),
7.11–7.18 (3H, m, ArH), 6.86 (1H, d, J¼8.0 Hz, ArH), 4.44–4.52
(2H, m), 4.38 (1H, d, J¼15.2 Hz, CH2C6H4), 3.71 (1H, dd, J¼6.0,
12.0 Hz, NCHaHbCH), 3.39 (1H, dd, J¼10.0, 12.0 Hz, NCHaHbCH);
dC (100 MHz, D2O) 143.4, 137.2, 131.9, 131.5, 130.7, 130.3, 130.0,
129.1, 50.0, 47.0, 43.7.
droisoquinoline (10g). Rf (80% hexanes/EtOAc) 0.23; nmax(liquid
film) 2975, 1688, 1449, 1365, 1159 cmꢂ1
; dH (400 MHz, CDCl3)
7.70–7.74 (2H, m, SO2Ph, ArH-2,6), 7.49–7.54 (1H, m, SO2Ph,
ArH-4), 7.41–7.46 (2H, m, SO2Ph, ArH-3,5), 7.08–7.13 (1H, m,
ArH), 7.00–7.06 (2H, m, ArH), 6.84 (1H, d,) ArH, 6.71 (1H, d, ArH),
6.55–6.60 (2H, m, ArH), 4.43 (1H, d, J¼14.8 Hz, CH2C6H4), 4.12–
4.20 (2H, m), 3.79 (3H, s, OCH3), 3.71 (3H, s, OCH3), 3.68–3.74
(1H, m, NCHaHbCH), 3.03 (1H, dd, J¼8.0, 12 Hz, NCHaHbCH); dC
(100 MHz, CDCl3) 148.0, 147.1, 136.5, 134.8, 132.8, 131.7, 129.5,
129.1, 127.6, 127.0, 126.7, 126.1, 121.1, 112.0, 111.1, 55.8, 51.0, 47.9,
44.8; HRMS (ESI): MHþ, found 410.1423. C23H24NO4S requires
410.1426.
4.3.14. 4-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline hydrochlo-
ride (19b). nmax(liquid film) 2755, 2650, 1589, 1508, 1222 cmꢂ1
; dH
(400 MHz, D2O) 7.19–7.30 (3H, m, ArH), 7.13–7.18 (2H, m, ArH),
7.02–7.08 (2H, m, ArH), 6.90 (1H, d, J¼8.0 Hz, ArH), 4.46–4.55 (2H,
m), 4.39 (1H, d, J¼16.0 Hz, CH2C6H4), 3.74 (1H, dd, J¼5.6, 12.4 Hz,
NCHaHbCH), 3.40 (1H, dd, J¼10.0,12.4 Hz, NCHaHbCH); dC (100 MHz,
D2O) 162.2, 134.7, 130.9, 130.8, 129.4, 128.3, 128.2, 127.6, 126.7, 115.8,
115.6, 47.9, 44.9, 40.5.
4.3.8. 4-Phenyl-1,2,3,4-tetrahydroisoquinoline (18a). Rf (90% CH2Cl2/
MeOH) 0.21; nmax(liquid film) 2755, 2650,1589,1508,1222 cmꢂ1
; dH
(400 MHz, CDCl3) 7.25–7.7.31 (2H, m, ArH), 7.13–7.24 (3H, m, ArH),
7.05–7.11 (4H, m, ArH), 6.90 (1H, d, J¼8.0 Hz, ArH), 4.04–4.18 (3H,
m), 3.39 (1H, dd, J¼5.2, 12.8 Hz, NCHaHbCH), 3.09 (1H, dd, J¼6.0,
12.8 Hz, NCHaHbCH), 2.49 (1H, br s, NH); dC (100 MHz, CDCl3) 144.8,
4.3.15. 4-(4-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline hydrochlo-
ride (19c). nmax(liquid film) 2633, 1589, 1197, 1080, 856 cmꢂ1
; dH
(400 MHz, D2O) 7.33 (2H, d, J¼8.0 Hz, ArH), 7.23 (3H, m, ArH), 7.12
(2H, d, J¼8.0 Hz, ArH), 6.89 (1H, d, J¼7.6 Hz, ArH), 4.46–4.55 (2H,

H. Kommidi et al. / Tetrahedron 66 (2010) 3723–3729
3729
3. Chesworth, R.; Zawistoski, M. P.; Lefker, B. A.; Cameron, K. O.; Day, R. F.; Man-
gano, F. M.; Rosati, R. L.; Colella, S.; Petersen, D. N.; Brault, A.; Lu, B.; Pan, L. C.;
Perry, P.; Ng, O.; Castle-berry, T. A.; Owen, T. A.; Brown, T. A.; Thompson, D. D.;
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5. Brossi, A.; Grethe, G.; Teitel, S.; Wildman, W. C.; Bailey, D. T. J. Org. Chem. 1970,
35, 1100.
m), 4.38 (1H, d, J¼16.0 Hz, CH2C6H4), 3.74 (1H, dd, J¼5.6,12.0 Hz,
NCHaHbCH), 3.38 (1H, dd, J¼10.0,12.0 Hz, NCHaHbCH); dC (100 MHz,
D2O) 158.2,135.0,133.4,130.2,129.3,128.2,128.0,127.4,127.4,126.6,
114.4, 55.4, 47.9, 44.8, 40.4.
4.3.16. 4-p-Tolyl-1,2,3,4-tetrahydroisoquinoline hydrochloride
6. Prat, L.; Bureau, R.; Daveu, C.; Levacher, V.; Dupas, G.; Que-guiner, G.; Bour-
guignon, J. J. Heterocycl. Chem. 2000, 37, 767.
(19d). nmax(liquid film) 2895, 2734, 1439, 1200, 1120, 1026 cmꢂ1
; dH
7. (a) Schwartz, M. A.; Scott, S. W. A. J. Org. Chem. 1971, 36, 1827; (b) Pridgen, L. N.;
Kilmer, L. B.; Webb, R. L. J. Org. Chem. 1982, 47, 1985; (c) Coote, S. J.; Davies, S. G.;
Middlemiss, D.; Naylor, A. J. Chem. Soc., Perkin Trans. 1 1989, 2233.
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Zara-Kaczian, E.; Deak, G.; Szollosy, A.; Brlik, J. Acta Chim. Hung. 1990, 127, 743;
(c) Toda, J.; Sonobe, A.; Ichikawa, T.; Saitoh, T.; Horiguchi, Y.; Sano, T. ARKIVOC
2000, 1, 165.
9. (a) Bates, H. A. J. Org. Chem. 1981, 46, 4931; (b) Bates, H. A. J. Org. Chem. 1983, 48,
1932; (c) Bates, H. A.; Bagheri, K.; Vertino, P. M. J. Org. Chem. 1986, 51, 3061; (d)
Katakawa, J.; Yoshimatsu, H.; Yoshida, M.; Zhang, Y.; Irie, H.; Yajima, H. Chem.
Pharm. Bull. 1988, 36, 3928; (e) Ruchirawat, S.; Tontoolarug, S.; Sahakitpichan, P.
Heterocycles 2001, 55, 635.
(400 MHz, D2O)7.18–7.28 (3H, m, ArH), 7.16 (2H, d, J¼8.0 Hz, C6H4CH3,
H-2,6), 7.05 (2H, d, J¼8.0 Hz, C6H4CH3, H-3,5), 6.87 (1H, d, J¼7.6 Hz,
ArH), 4.43–4.51(2H, m), 4.37 (1H, d, J¼16.0 Hz, CH2C6H4), 3.70(1H, dd,
J¼6.0,12.4 Hz, NCHaHbCH), 3.38 (1H, dd, J¼10.0,12.4 Hz, NCHaHbCH),
2.23 (3H, s, CH3); dC (100 MHz, D2O) 139.3, 136.6, 132.8, 129.5, 129.3,
129.1, 128.8, 127.7, 126.9, 126.1, 51.1, 48.0, 44.8, 21.0.
4.3.17. 4-(4-Chlorophenyl)-1,2,3,4-tetrahydroisoquinoline hydrochlo-
ride (19e). nmax(liquid film) 2761, 2644, 1513, 1440, 1421 cmꢂ1
; dH
10. Kihara, M.; Kashimoto, M.; Kobayashi, Y. Tetrahedron 1992, 48, 67.
11. (a) China Raju, B.; Neelakantan, P.; Bhalerao, U. T. Tetrahedron Lett. 2004, 45,
7487; (b) Seijas, J. A.; Vazquez-Tato, M. P.; Martinez, M. M.; Pizzolatti, M. G.
Tetrahedron Lett. 2005, 46, 5827 and references cited therein.
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Sivaraman, B.; Aidhen, I. S. Synlett 2007, 959; (c) Manjunath, B. N.; Sane, N. P.;
Aidhen, I. S. Eur. J. Org. Chem. 2006, 2851.
(400 MHz, D2O) 7.34 (2H, d, J¼8.4 Hz, C6H4Cl, H-2,6), 7.19–7.26 (3H,
m, ArH), 7.13 (2H, d, J¼8.4 Hz, C6H4Cl, H-3,5), 6.88 (1H, d, J¼8.0 Hz,
ArH), 4.46–4.55 (2H, m), 4.39 (1H, J¼16.0 Hz, CH2C6H4), 3.74 (1H,
dd, J¼6.0, 12.4 Hz, NCHaHbCH), 3.40 (1H, dd, J¼10.0, 12.4 Hz,
NCHaHbCH); dC (100 MHz, D2O) 142.0, 133.1, 131.9, 131.4, 130.8,
130.1, 129.5, 129.2, 50.2, 47.4, 43.1.
14. N-Methoxy- N-methyl amides are popularly called as Weinreb amides. For
a review on Weinreb amide chemistry see: (a) Sivaraman, B.; Aidhen, I. S.
Synthesis 2008, 3723; (b) Singh, J.; Satyamurthi, N.; Aidhen, I. S. J. Prakt. Chem.
2000, 342, 340; (c) Mentzel, M.; Hoffmann, H. M. R. J. Prakt. Chem. 1997, 339,
517; (d) Sibi, M. P. Org. Prep. Proceed. Int. 1993, 25, 15.
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Schaer, K.; Gamboni, R.; Chen, W.; Loeser, E.; Kinder, F. R., Jr.; Konigsberger, K.;
Prasad, K.; Ramsey, T. M.; Repic, O.; Wang, R. M.; Florence, G.; Lyothier, I.; Pa-
terson, I. Org. Process Res. Dev. 2004, 8, 122.
Acknowledgements
We thank DST-New Delhi for the funding towards 400 MHz
NMR machine to the Department of Chemistry, IIT-Madras under
the IRHPA scheme and ESIMS facility under the FIST program. KHK
and BSR are thankful to CSIR for Fellowship
16. El-Sharief, A. M.; Ammar, Y. A.; Zahran, M. A.; Ali, A. H.; El-Gaby, M. S. Molecules
2001, 6, 267.
Supplementary data
17. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; John
Wiley & Sons,: New York, NY, 1991; p 379.
18. Coffin, A. R.; Rousell, M. A.; Tserlin, E.; Pelkey, E. T. J. Org. Chem. 2006, 71, 6678
Observing difficulties with the use of DCC mentioned in this report for the
carboxyl activation, we resorted to activation by simpler, mixed anhydride
method.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.03.074.
References and notes
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