Palladium-catalyzed intramolecular hydroarylation of 2-bromobenzyl propargyl ethers: A new access to exocyclic isochromans

Article abstract of DOI:10.1055/s-0031-1289545

An efficient, stereo- and regioselective palladium-catalyzed 6-exo-dig intramolecular hydroarylation of propargyl ethers which provides a concise access to functionalized isochromans in high yields has been developed. A wide range of substrates possessing aromatic, aliphatic and heteroaromatic alkynes can be efficiently transformed into the targeted isochromans. Irrespective of the nature of the substrates, the cyclization follows highly selective -stereo- and regiochemistry.

Full text of DOI:10.1055/s-0031-1289545

LETTER
2733
Palladium-Catalyzed Intramolecular Hydroarylation of 2-Bromobenzyl
Propargyl Ethers: A New Access to Exocyclic Isochromans
New
A
ccess to E
x
v
ocyclic Isoch
a
romans nashiappan Nandakumar, Krishnamoorthy Balakrishnan, Paramasivan Thirumalai Perumal*
Organic Chemistry Division, Central Leather Research Institute (CSIR), Adyar, Chennai 600020, India
Fax +91(44)24911589; E-mail: ptperumal@gmail.com
Received 2 August 2011
As a result, a variety of methods for isochroman synthesis
has emerged. However, there still remains a significant
need for more direct methods to afford functionalized iso-
chroman derivatives. In our ongoing program aimed at de-
Abstract: An efficient, stereo- and regioselective palladium-cata-
lyzed 6-exo-dig intramolecular hydroarylation of propargyl ethers
which provides a concise access to functionalized isochromans in
high yields has been developed. A wide range of substrates possess-
ing aromatic, aliphatic and heteroaromatic alkynes can be efficient- veloping new approaches to generate small molecules,12
ly transformed into the targeted isochromans. Irrespective of the
we wish to report a new and efficient protocol for the syn-
nature of the substrates, the cyclization follows highly selective
stereo- and regiochemistry.
thesis of substituted isochromans applying a microwave-
assisted Pd-catalyzed regio- and stereoselective intramo-
lecular acetylene hydroarylation process.
Key words: palladium, isochroman, carbocyclization, 6-exo-dig
regiochemistry, acetylene
OH
OH
HO
HO
The development of efficient and versatile strategies for
the synthesis of heterocycles continues to be of major sig-
O
O
nificance in synthetic organic chemistry.1 In this regard,
transformations that employ readily available substrates
NH2
NH2
to provide access to multiply functionalized heterocycles
are highly desirable. Transition-metal-catalyzed reactions
A-68930
A-77,636
have emerged as a useful tool for the synthesis of hetero-
MeO
MeO
F
cyclic compounds because of the intriguing selectivity,
atom economy,2 and exceptional ability to activate p-sys-
tems, especially alkynes, towards intermolecular and in-
tramolecular nucleophilic attack.3 Among the transition-
metal-catalyzed reactions, palladium is extensively used
because of its tolerance of many functional groups and ap-
plicability to complex molecules, and have therefore
achieved an important place in the arsenal of the practic-
ing organic chemist.4–6 Herein we report that palladium-
catalyzed regio- and stereoselective intramolecular hy-
droarylation of 2-bromobenzyl propargyl ethers offers an
efficient, direct route to substituted isochromans.
O
N
N
U-54537
Figure 1 Representative structure of biologically active isochro-
mans
In initial studies we used 1-[3-(2-bromo-4,5-dimethoxy-
benzyloxy)prop-1-ynyl]-4-methylbenzene (6b) as a mod-
el substrate for optimization of reaction conditions. The
requisite propargyl ethers were synthesized by two differ-
ent paths shown in Scheme 1. Path A consists of three
The isochromans and related heterocycles occur in nature,
such as stephaoxocanine,7a glucoside B, an aphid insect
pigment derivative7b and the topoisomerase II inhibitor
CJ-12,373,7c among bioactive compounds of interest, in-
cluding medicines, agrochemicals and drug candidates.8,9
D1 dopaminergic agonists with 1,3-disubstituted isochro-
man skeletons are among the few D1 agonists known to
date (Figure 1). The synthesis of isochromans typically
requires oxa-Pictet–Spengler cyclizations,10 oxa-Pictet–
Spengler rearrangement of 5-aryl-1,3-dioxolanes9 or cy-
clization of ortho-hydroxyalkylated aziridines.11
Table 1 Unsubstituted Propargyl Ethers 6a–f
Entry
Ar
Precursor 6
Yield (%)a,b
1
2
3
4
5
6
Ph
6a
6b
6c
6d
6e
6f
85
83
82
86
80
75
4-MeC6H4
3-MeC6H4
4-MeOC6H4
2-thienyl
3-(1-tosyl)indolyl
SYNLETT 2011, No. 18, pp 2733–2739
Advanced online publication: 19.10.2011
DOI: 10.1055/s-0031-1289545; Art ID: D24511ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1
a Isolated yields.
b All reactions were carried out with Pd(PPh3)2Cl2 (3 mol%), CuI (3
mol%), propargyl ether (1.1 equiv) and ArI (1 equiv) in Et3N for 6 h.

2734
A. Nandakumar et al.
LETTER
path A
MeO
Pd(PPh3)2Cl2, CuI,
ArI, Et3N
1. NaH (1.5 equiv), 0 °C
anhyd THF
MeO
CHO
MeO
MeO
MeO
MeO
NaBH4 (1 equiv)
6 h
O
OH
O
2. Propargylbromide
(1.5 equiv)
MeOH
Br
MeO
Br
MeO
path B
R
Br
Br
1
2
3
Ar
6a–f
OH
OH
MeO
Pd(PPh3)2Cl2
CuI, ArI, Et3N
2
O
method A or B
R
R
MeO
Br
Ar
method A : R = Ph, anhyd FeCl3 (5 mol%), MeCN
method B : R = c-Hex, CuBr2 (5 mol%), MeNO2
Ar
6g–n
4a: R = Ph
4b: R = c-Hex
5a: R = Ph, Ar = Ph
5b: R = Ph, Ar = 3-MeC6H4
5c: R = Ph, Ar = 4-MeOC6H4
5d: R = Ph, Ar = 2-thienyl
5e: R = c-Hex, Ar = C6H4
5f: R = c-Hex, Ar = 4-MeC6H4
5g: R = c-Hex, Ar = 4-MeOC6H4
5h: R = 4-MeC6H4, Ar = n-Bu
Scheme 1 Synthesis of propargyl ethers
steps. 2-Bromo-4,5-dimethoxybenzaldehyde was reduced 86% yield.13 Propargyl ethers 6a–f were obtained by
with sodium borohydride using methanol as a solvent to Sonagashira coupling reaction of 3 with different aryl io-
afford the corresponding (2-bromo-4,5-dimethoxyphe- dides using Pd(PPh3)2Cl2, CuI and triethylamine as a base
nyl)methanol (2) in 90% yield. The compound 2 was then (Table 1, entries 1–6).14 The substituted propargyl ethers
subjected to O-alkylation using propargyl bromide, NaH 6g–m were synthesized by a two-step protocol (path B).
in THF and DMF mixture to afford 1-bromo-4,5- Propargyl alcohols 5a–g were obtained by coupling termi-
dimethoxy-2-[(prop-2-ynyloxy)methyl]benzene (3) in nal propargyl alcohols 4a,b with different aryl iodides un-
der standard Sonagashira conditions.15 Propargyl alcohol
5h was synthesized from p-tolualdehyde and 1-hexyne us-
Table 2 Substituted Propargyl Ethers 6g–n
ing a literature procedure.16 Nucleophilic substitution re-
Entry Ar
R
Precursor 6 Yield (%)a
action of 2 with 5a–h (Method A or Method B shown in
Scheme 1) resulted in the substituted propargyl ethers 6g–
n in good to moderate yields (Table 2).17 Having synthe-
sized the starting materials in satisfactory yields, we then
investigated the cyclization of the propargyl ethers apply-
ing our previously reported Pd-catalyzed intramolecular
propargylamine hydroarylation protocol using 3 mol% of
Pd(PPh3)4 as catalyst and sodium formate as a reducing
agent under conventional heating in DMF–H2O (3:1;
Scheme 2).12a The optimized conditions resulted in 36%
yield after three hours (Table 3, entry 1) and by allowing
the reaction for a further period of five hours (monitoring
by TLC), 78% of yield was obtained (Table 3, entry 4).
Further time extensions did not improve the yield
(Table 3, entry 5). Other palladium catalysts did not have
any significant influence on the reaction rate and the prod-
uct yield (Table 3, entries 2 and 3).18 Thus, having found
appropriate conditions under conventional heating for the
1
2
3
4
5
6
7
8
Ph
Ph
6g
6h
6i
85b
84b
82b
82b
72c
70c
71c
78b
3-MeC6H4
4-MeOC6H4
2-thienyl
Ph
Ph
Ph
Ph
6j
c-Hex
c-Hex
c-Hex
4-MeC6H4
6k
6l
4-MeC6H4
4-MeOC6H4
n-Bu
6m
6n
a Isolated yields.
b The reactions of 5 (1 mmol) with 2 (3 mmol) were carried out in the
presence of FeCl3 (0.05 mmol) in MeCN (2 mL) at r.t. overnight.
c The reactions of 5 (1 mmol) with 2 (3 mmol) were carried out in the
presence of CuBr2 (0.05 mmol) in MeCN (2 mL) at r.t. overnight.
MeO
MeO
O
O
MeO
O
Pd0
MeO
Br
and/or
MeO
MeO
HCOONa
DMF–H2O (3:1)
Δ or MW
CH3
H3C
H3C
6b
7b
7b'
Scheme 2 Optimization of palladium-catalyzed cyclization reaction
Synlett 2011, No. 18, 2733–2739 © Thieme Stuttgart · New York

LETTER
New Access to Exocyclic Isochromans
2735
tion showed that the vinylic proton is not adjacent to the
OCH2 protons which ruled out the possibility of formation
of a seven-membered ring 7b¢ (Scheme 2). The disappear-
ance of two acetylenic carbons at d = 84.3 and 86.9 ppm
in the 13C NMR spectrum confirmed the conversion of
starting material. From HETCOR and HMBC NMR data
of compound 7b, the peaks at d = 106.1 and 124.8 ppm in
the 13C NMR spectrum could be assigned to olefinic car-
bons, characteristic of the exocyclic alkylidene moiety. In
the IR spectrum, absorptions at 1602 and 2930 cm–1 re-
vealed the presence of an olefinic linkage and olefinic
proton respectively. All these findings confirmed the for-
mation of an isochroman.
Table 3 Optimization of Palladium-Catalyzed Cyclization Reaction
Entry Solvent
Catalyst
Time
(min)
Yield
(%)
1
2
DMF–H2O (3:1)
Pd(PPh3)4
180
180
180
480
600
10
36a
DMF–H2O (3:1)
DMF–H2O (3:1)
DMF–H2O (3:1)
DMF–H2O (3:1)
DMF–H2O (3:1)
DMF–H2O (3:1)
DMF–H2O (3:1)
DMF–H2O (3:1)
DMF–H2O (3:1)
Pd(OAc)2 + 2PPh3
PdCl2 + 2PPh3
Pd(PPh3)4
27a
3
25a
4
78a
5
Pd(PPh3)4
77a
6
Pd(PPh3)4
75b,c
80b,c
78b,c
78c,d
60c,e
7
Pd(PPh3)4
15
Having established the optimal reaction conditions for the
conversion of 6b,19 the substrate scope of the cyclization
reaction was examined (Scheme 3). The reaction appears
to be general and works well regardless of the nature of
the substituents on the triple bond terminus (Table 4, en-
tries 1–14). The presence of a substituent at the propagylic
position did not have deleterious effects on the cycliza-
tion. When the substrates 6g–j containing a phenyl group
on the alkynyl moiety was subjected to the reaction, the
isochromans 7g–j were obtained in good yields (Table 4,
entries 7–10). The reactions of the substrates 6k–m,
which have a cyclohexyl group, also afforded the isochro-
mans 6k–m in good yields (Table 4, entries 11–13). When
the reaction of the substrate 6n containing an n-butyl
group at triple bond terminus was carried out, the corre-
sponding product 7n was similarly obtained in a good
yield (Table 4, entry 14). It is noteworthy that substrates
possessing a heteroaromatic motif such as thiophene or in-
dole at the triple bond terminus were tolerated well under
the reaction conditions (Table 4, entries 5, 6 and 10).
8
Pd(PPh3)4
20
9
Pd(PPh3)4
15
10
Pd(PPh3)4
15
a The reactions were carried out with propargyl ether 6b (0.4 mmol)
in the presence of HCOONa (0.6 mmol) as a reductant in DMF–H2O
(3:1; 6 mL) at 100 °C (oil bath temperature) in 70 mM concentration.
b The reactions were carried out in a domestic Samsung MW73BD
model microwave oven in a pressure tube applying a power of 300 W.
c Caution: see general procedure in reference 19 for more detailed pro-
cedure to avoid explosion of pressure tube.
d The reaction was carried out at 400 W.
e The reaction was carried out at 180 W.
synthesis of isochromans, we investigated application of
microwave irradiation. Experiments were carried out in a
domestic Samsung MW73BD model microwave oven in
a pressure tube applying a maximum power of 300 W.
Under these conditions, the reaction rate was dramatically
increased, while the yield remained satisfactorily high
(80%; Table 3, entries 6–8). It was found that changing
MW power did not improve the reaction rate or the yield
(Table 3, entries 9 and 10).
The olefin stereochemistry of compound 7b has been as-
signed using a 1D NOE experiment. Selective irradiation
of the vinylic proton effected enhancement of the signal of
H-5 (18%) and there was no enhancement of the H-3 pro-
tons. Irradiation of H-5 only effected enhancement of the
vinylic proton (22%; Figure 2). These observations con-
firmed that the vinylic proton is cis to H-5 and thus com-
The high regio- and stereoselectivity of the cyclization
step leading to one isomer exclusively was confirmed
1
with the aid of 1D and 2D NMR techniques. In the H
NMR spectrum of compound 7b, a singlet at d = 7.21 ppm
1
8
confirmed the presence of a vinylic proton. This observa-
MeO
MeO
9
7
2H
H
O
6
4
Pd(PPh3)4 (3 mol%)
3
MeO
MeO
MeO
MeO
10
R1
R2
O
5
HCOONa (1.5 equiv)
O
R1
R2
H
H
DMF–H2O (3:1)
MW (300 W)
Br
R3
R3
6a–n
7a–n
X
Scheme 3 Synthesis of isochroman derivatives 7a–n
Figure 2 1D NOE enhancement of compound 7b
O
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
'Pd0'
O
O
O
Br
Pd
Br
Ph
Pd
Ph
Ph
Ph
6a
7a
Scheme 4 A plausible mechanism for the formation of compound 7a
Synlett 2011, No. 18, 2733–2739 © Thieme Stuttgart · New York

2736
A. Nandakumar et al.
LETTER
pound 7b has Z-configuration. The exclusive formation of lyzed intramolecular carbocylization is shown in
the Z-isomer can be attributed to syn-addition of the Pd Scheme 4.
onto the triple bond. A possible pathway of the Pd-cata-
Table 4 Synthesis of Isochroman Derivatives 7a–n
Entry
Substrate
Product
MeO
Yield (%)a–c
MeO
O
O
MeO
Br
MeO
1
78
7a
6a
MeO
O
MeO
MeO
O
MeO
Br
2
80
7b
6b
MeO
MeO
O
O
MeO
MeO
Br
3
76
6c
7c
MeO
O
MeO
O
MeO
Br
MeO
4
5
6
82
77
60
OMe
MeO
7d
6d
MeO
MeO
MeO
O
O
MeO
Br
S
S
7e
6e
MeO
O
MeO
MeO
O
MeO
Br
TsN
NTs
7f
6f
Synlett 2011, No. 18, 2733–2739 © Thieme Stuttgart · New York

LETTER
New Access to Exocyclic Isochromans
2737
Table 4 Synthesis of Isochroman Derivatives 7a–n (continued)
Entry
Substrate
Product
Yield (%)a–c
MeO
MeO
MeO
O
O
Ph
MeO
Br
Ph
7
77
7g
6g
MeO
MeO
O
O
Ph
MeO
Br
MeO
Ph
8
78
7h
6h
MeO
O
MeO
O
Ph
MeO
Br
MeO
Ph
9
78
OMe
MeO
7i
6i
MeO
MeO
MeO
O
O
Ph
MeO
Br
S
Ph
10
70
S
7j
6j
MeO
MeO
O
O
MeO
Br
MeO
11
75
7k
6k
MeO
O
MeO
MeO
O
MeO
Br
12
76
7l
6l
Synlett 2011, No. 18, 2733–2739 © Thieme Stuttgart · New York

2738
A. Nandakumar et al.
LETTER
Table 4 Synthesis of Isochroman Derivatives 7a–n (continued)
Entry
13
Substrate
Product
Yield (%)a–c
MeO
O
MeO
MeO
O
MeO
Br
78
OMe
MeO
7m
6m
MeO
MeO
O
O
MeO
MeO
Br
14
74
6n
7n
a Isolated yields.
b All the compounds were characterized by IR, 1H NMR and 13C NMR spectroscopy and mass spectrometry.
c All the reactions were carried out with propargyl ether (0.4 mmol) in the presence of HCOONa (0.6 mmol) as a reductant in DMF–H2O (3:1;
6 mL) using an unmodified microwave oven operating at its 300 W power for 15 min (Caution: see general procedure in reference 19 for more
detailed procedure to avoid explosion of pressure tube).
Satoh, T.; Miura, M. Angew. Chem. Int. Ed. 2008, 47, 4019;
Angew. Chem. 2008, 120, 4083. (e) Bhunia, S.; Wang, K.
C.; Liu, R. S. Angew. Chem. Int. Ed. 2008, 47, 5063; Angew.
Chem. 2008, 120, 5141. (f) Kelin, A. V.; Sromek, A. W.;
Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074.
In conclusion, we have developed a palladium-catalyzed
hydroarylation of propargyl ethers. The process produces
substituted isochromans in a highly regio- and stereose-
lective manner. Since various natural products possessing
an isochroman structure have been reported,7–9 our meth-
odology provides a new protocol for the synthesis of these
compounds with high efficiency.
(4) (a) Pfeffer, M. Recl. Trav. Chim. Pays-Bas 1990, 109, 567.
(b) Spencer, J.; Pfeffer, M.; DeCian, A.; Fisher, J. J. Org.
Chem. 1995, 60, 1005. (c) Tsuji, J. Palladium Reagents and
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Organopalladium Chemistry for the XXI Century; Tsuji, J.,
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(c) Tsuji, J. Palladium Reagents and Catalysts Innovation in
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Acknowledgment
One of the authors (A.N.) thanks the Council of Scientific and Indu-
strial Research (CSIR), New Delhi, India for a Research Fel-
lowship.
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LETTER
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New Access to Exocyclic Isochromans
2739
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1 H, ArH), 7.10 (d, J = 8.4 Hz, 2 H, ArH), 7.34 (d, J = 7.65
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(19) General Procedure for the Synthesis of Isochromans 7a–
n: Pd(PPh3)4 (3 mol%) and HCOONa (1.5 equiv) were added
to a pressure tube and the tube was flushed with nitrogen.
The requisite propargyl ether (0.4 mmol) dissolved in DMF
(4.5 mL) was added, followed by distilled H2O (1.5 mL).
The pressure tube was exposed to microwave irradiation for
1 min using an unmodified microwave oven operating at 300
W. The reaction mixture was cooled and was irradiated
again for the same time. After fifteen of such successive
irradiations and cooling sequences, the reaction mixture was
diluted with EtOAc. The organic phase was washed with
brine, dried (anhyd Na2SO4) and concentrated under reduced
pressure. The crude product was purified by chromatogra-
phy (petroleum ether–EtOAc as eluent) and the yields are
shown in Table 4.
(14) General Procedure for Sonogashira Coupling of O-
Propargylated Benzyl Alcohol with Aryl Iodide 6a–f: To
a solution of aryl iodide (1.0 mmol), Pd(PPh3)2Cl2 (3 mol%),
and CuI (3 mol%) in freshly distilled Et3N was slowly added
a solution of alkyne 3 (1.1 mmol) in Et3N and the resulting
suspension was magnetically stirred for 6 h. H2O (50 mL)
was added to the reaction mixture, the residue was extracted
into EtOAc (4 × 15 mL), and the extract was dried over
anhyd Na2SO4. Removal of the solvent under reduced
pressure gave the crude product, which was further purified
by column chromatography on silica gel using EtOAc–
petroleum ether as eluent to afford pure product.
Analytical Data for 6,7-Dimethoxy-4-(4-methylbenzylidene)-
isochroman (7b): pale yellow solid; mp 186–188 °C. IR
(KBr): 1088, 1109, 1234, 1353, 1457, 1513, 1602, 2844,
2930 cm–1. 1H NMR (500 MHz, CDCl3): d = 2.36 (s, 3 H,
Me), 3.88 (s, 3 H, OMe), 3.94 (s, 3 H, OMe), 4.73 (s, 2 H,
OCH2), 4.74 (s, 2 H, OCH2), 6.52 (s, 1 H, ArH), 6.99 (s, 1 H,
ArH), 7.12 (d, J = 7.65 Hz, 2 H, ArH), 7.17 (d, J = 8.4 Hz, 2
H, ArH), 7.21 (s, 1 H, =CH). 13C NMR (125 MHz, CDCl3):
d = 21.3, 56.0, 56.1, 66.8, 68.4, 106.1, 107.2, 121.3, 124.8,
127.8, 129.1, 129.2, 131.4, 134.0, 136.8, 148.4, 148.2. MS
(EI): m/z 297.50 [M+H]+. Anal. Calcd for C19H20O3: C,
77.00; H, 6.80. Found: C, 76.96; H, 6.82.
Analytical Data for 1-[3-(2-Bromo-4,5-dimethoxybenzyl-
Synlett 2011, No. 18, 2733–2739 © Thieme Stuttgart · New York

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