Palladium catalyzed Suzuki Miyaura cross coupling of 3-chloroisochromen-1-one: Synthesis of glomellin and reticulol analogues

Article abstract of DOI:10.1016/j.tetlet.2014.12.114

A facile protocol has been developed for a series of 3-substituted isochromen-1-ones utilizing Suzuki coupling strategy. The reaction of 3-chloroisochromen-1one, 1 with different boronic acids utilizing PdCl₂(PPh₃)₂-Ruphos catalytic system gave diversified 3-substituted isochromen-1-ones in excellent yields. The methodology has been utilized in the synthesis of glomellin and reticulol analogues.

Full text of DOI:10.1016/j.tetlet.2014.12.114

Accepted Manuscript
Palladium catalyzed Suzuki Miyaura cross coupling of 3-chlroisochromen-1-
one: synthesis of glomellin and reticulol analogues
Yadavalli Suneel Kumar, Changalaraya Dasaradhan, Kamalakannan
Prabakaran, Pitchai Manivel, Fazlur-Rahman Nawaz Khan, Euh Duck Jeong,
Eun Hyuk Chung
PII:
S0040-4039(14)02192-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.12.114
TETL 45639
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 October 2014
19 December 2014
21 December 2014
Please cite this article as: Kumar, Y.S., Dasaradhan, C., Prabakaran, K., Manivel, P., Nawaz Khan, F-R., Jeong,
E.D., Chung, E.H., Palladium catalyzed Suzuki Miyaura cross coupling of 3-chlroisochromen-1-one: synthesis of
glomellin and reticulol analogues, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.12.114
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Palladium catalyzed Suzuki Miyaura cross coupling of 3-chlroisochromen-
1-one: synthesis of glomellin and reticulol analogues
Yadavalli Suneel Kumara#, Changalaraya Dasaradhana#, Kamalakannan Prabakarana, Pitchai Manivela, Fazlur-
Rahman Nawaz Khana*,b* Euh Duck Jeongb*, Eun Hyuk Chungb
#Equally contributed
a Organic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division,School of Advanced Sciences, VIT-
University, Vellore 632 014, Tamil Nadu, India..
*Correspondence: E-mail; Prof. F. Nawaz Khan: nawaz_f@yahoo.co.in; fnkn@kbsi.re.kr
bKorea Basic Science Institute, Busan Center, Busan 618 230, South Korea. Dr ED Jeong, edjeong@kbsi.re.kr
Abstract A facile protocol has been developed for a series of 3-substituted isochromen-1-ones utilizing Suzuki coupling strategy. The reaction of
3-chloroisochromen-1one, 1 with different boronic acids utilizing PdCl2(PPh3)2-Ruphos catalytic system gave diversified 3-substituted isochromen-
1-ones in excellent yields. The methodology has been utilized in the synthesis of glomellin and reticulol analogues.
There are few illustrations of terminal and internal alkynes as
Control experiments revealed that the reaction did not proceed
reagents in palladium catalyzed Sonagashira coupling and C-C bond
forming reaction where the alkyne functionality is lost in the
formation of 3- or 3,4- disubstituted isochromen-1-one ring moiety1,
2. The Suzuki cross coupling methodology is extremely versatile for
the generation of C-C bonds.3 Nevertheless; no reports on Suzuki
coupling are avalilable in the formation of highly functionalized 3-
substituted isochromen-1-ones. Our continuing efforts and interests
in metal-catalyzed C-C bond formations4-10 and cyclization reactions
incited us to investigate the reaction of aryl/heteroaryl/ alkyboronic
acids and 3-chloroisochromen-1-one as important motifs for rapid
access to known and obscure highly functionalized 3-
arylisochromen-1-ones. The application of this strategy in the
synthesis of natural isochromen-1-one analogues is examined as well.
Notwithstanding this, few exertions have been regulated to
investigate a productive catalytic combination in the synthesis of
diversified 3-substituted isochromen-1-one.
without palladium (Table 1, entry 10). In cross-coupling reactions of
organoboron compounds, the presence of a base is essential; as no
reaction occurs without a base. Further, many organic compounds
are sensitive to bases. Consequently, a careful use of bases is
required in such cases, for instance, K2CO3. Na2CO3, K3PO4, Cs2CO3,
KOBut , Et3N The results showed that K2CO3 was the best base for
the present study with a moderate conversion and 37% yield (Table
1, entry 9). In K3PO4 gave 45% yield, likewise in other bases, though
conversion is 100 % gave poor yields (Table 1, entries 11-15).
These preliminary reaction conditions inspired us to develop a
suitable catalytic combination utilizing ligand mediated Suzuki
coupling methods. Interestingly, the exploration of phosphine,
bisphosphine ligands (Table 1, entry 16-19) demonstrated that
Ruphos was the best ligand with respect to the yield and conversion
time utilizing 5mol% Pd(OAC)2. In the optimization of the reaction
condition, we were satisfied to find that the yield was greatly
enhanced to 82% (Table 1, entry 19) when DMF-water mixture was
utilized as the solvent in just 30min., Sphos, Xphos are comparable,
whereas PPh3, despite a complete conversion gave a lower isolated
yield 76% (Table 1, entry 16). The utilization of 10 mol% of Ruphos
ligand and K2CO3 as the base in DMF solvent condition
demonstrated a decent conversion rate in 1h but the isolated yield
was moderate 56% (Table 1, entry 20). With this optimized
condition in hand, we have tested variations in the amount of
palladium loading, reaction time. Increasing the reaction time, Pd
loading did not show any increment in the yield and it was moderate
in all cases (Table 1, entries 21,22). In the literature, it is reported
that utilizing aryl chlorides as a part of Suzuki couplings obliged a
strong electron withdrawing substituent on the aryl chloride.
Nevertheless, in the present methodology, no such special substitute
for the reactivity is involved.
Results and Discussion
The 3-chloroisochromen-1-one, 1a and phenylboronic acid, 2a
was picked as a model substrate for the palladium-catalyzed Suzuki
coupling reaction, (Scheme 1, Table 1). At first, the reaction was
done in the presence of 5 mol% of Pd(OAc)2, DMF or water as
solvent, K2CO3 or Na2CO3 as a base, but the reaction did not proceed
well (Table 1, entries 1- 4). The conversion and yield was very less
in the absence of ligands. The assessment of the solvents revealed
that the transformation was highly sensitive to the reaction medium.
The protic polar solvents, for instance, MeOH, EtOH, Dioxane, THF
displayed lower reactivity (Table 1, entries 5-8). Gratifyingly, the
mixed solvent combination of DMF/H2O (1:1) gave the best result in
conversion and yield 37% (Table 1, entry 9).
B(OH)2
2a
O
O
O
Pd catalyst
OH
POCl3
90 o
O
Base, Solvent
O
Cl
1a (95%)
heated at 80 °C
C
HO
O
3a
Homophthalic acid
Scheme 1. Design of synthesis of 3-substituted isochromen-1-one by
a Suzuki coupling reaction
|
1

Table 1. Palladium acetate catalyzed Suzuki coupling of 3-chloro-1H-isochromen-1-one with phenyl boronic acid: Optimization of the reaction
conditionsa
Catalyst
Ligand/
mol %
Conversion
%
Time
h
Pd(OAc)2
Entry
Solvent
Yield (%)
mol %
1
2
5
5
5
5
5
5
5
5
5
0
5
5
5
5
5
-
-
DMF,
Traces
Traces
20
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
-
-
DMFb
3
4
-
-
H2O,
15
26
-
H2Ob
30
5
-
MeOH
EtOH
Dioxane
THF
10
15
25
20
6
7
8
-
-
-
-
18
16
37
-
9
No
No
No
No
No
No
No
DMF/H2O
DMF/H2O
DMF/H2Ob
DMF/H2Oc
DMF/H2Od
DMF/H2Oe
DMF/H2Of
45
10
11
12
13
14
15
NR
100
100
100
100
50
32
45
32
21
35
16
17
18
19
20
21
22
5
PPh3/10
DMF/H2O
DMF/H2O
DMF/H2O
DMF/ H2O
DMF/
100
100
100
100
80
0.5
0.5
0.5
0.5
1
76
81
79
82
56
71
75
5
5
5
X-phos/10
S-phos/10
Ruphos/10
Ruphos/10
Ruphos/10
Ruphos/10
5
10
5
DMF/H2O
DMF/H2O
100
100
0.5
1
The reactions were performed in a round bottomed flask with 3-chloro-1H-isochromen-1-one, 1a (1 mmol), phenylboronic acid, 2a (1 mmol), catalyst,
f
ligand, base K2CO3 unless otherwise stated and solvent heated for 0.5-2 h. bNa2CO3, cK3PO4, dCs2CO3, eKOBut Et3N
Table 2. PdCl2(PPh3)2 catalyzed Suzuki coupling of 3-chloro-1H-isochromen-1-one, 1a with phenylboronic acid, 2a: Optimization of the reaction
conditionsa
Conversio
n %
Entry
Catalyst/ mol %
Ligand/ mol %
Solvent
time
Yield (%)
1
2
3
4
PdCl2(PPh3)2/10
PdCl2(PPh3)2/10
PdCl2(PPh3)2/10
PdCl2(PPh3)2/10
No
No
No
PPh3/10
DMF
DMFb
DMF/H2O
DMF/H2O
25
40
60
100
2 h
2 h
2 h
0.5
0.5
18
34
56
82
5
6
7
8
PdCl2(PPh3)2/5
PdCl2(PPh3)2/5
PdCl2(PPh3)2/5
PdCl2(PPh3)2/5
PPh3/10
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
100
100
100
100
84
95
93
94
0.5
0.5
0.5
Ruphos/10
Ruphos/5
Ruphos/15
The reactions were performed in a round bottomed flask with 3-chloro-1H-isochromen-1-one, 1a (1 mmol), phenylboronic acid, 2a (1 mmol), catalyst, ligand,
base (K2CO3) unless otherwise stated, and solvent heated for ½ _ 2 h b Na2CO3
In continuation, with this excellent result in hand, we have further
Encouraged by these initial perceptions, we focused on the
improvisation of the yield by utilizing different palladium sources.
Correspondingly, as in palladium acetate, we have tested utilizing
bis-triphenylphosphine palladium dichloride catalyst and were
pleased to find that, the reaction behaves in a comparative way when
utilizing 10 mol% of PdCl2(PPh3)2, either K2CO3 or Na2CO3 as the
base and DMF with or without aqueous conditions heated at 80°C
(Table 2, entries 1-3). Nonetheless, the reaction worked well in the
presence of phosphine ligand and the yield was also good
comparable to palladium acetate source. Further, there was no
impact on the variation of the amount of palladium load (Table 2,
entries 4, 5). To enhance the yield, we have done reactions utilizing
10 or 5 mol% of Ruphos ligand, 5 mol% of PdCl2(PPh3)2 catalysts,
K2CO3 as the base and DMF: water mxture as a solvent which
produced an excellent yield (93-95%) and was also consistent (Table
2, entry 6-8).
extended the optimization study utilizing Palladium tetrakis.
Nonetheless, in the Pd(PPh3)4, the conversion was complete and the
desired product was obtained with a good yield. We noticed that the
Suzuki coupling of 3-chloro-1H-isochromen-1-one, 1a with phenyl
boronic acid, 2a using 10 mol % of Palladium tetrakis catalyst,
K2CO3 as the base and DMF: water mixture as a solvent afforded a
75% yield (Table 3, entry 3). Further, when reduced the amount of
palladium load to 5 mol%, observed a 67% yield (Table 3, entry 4).
Based on our earlier observations, this reaction required additional
ligand to drive the reaction for better conversion and invariably for
getting an excellent yield and purity. An extended the optimization
study using Palladium tetrakis and Ruphos ligand with variations in
the amount of load was carried out. We are pleased to inform that,
the result was an excellent as that of Palladium dikis (Table 3,
entries 7-10). The complete screening results are summarized in
Table 3.
2

Table 3. Pd(PPh3)4 catalyzed Suzuki coupling of 3-chloro-1H-isochromen-1-one, 1a with phenylboronic acid, 2a:
Optimization of the reaction conditionsa
Solvent
Time
h,
Entry
Catalyst/ mol %
Ligand/ mol %
Conv %
Yield (%)
H2O
1
2
3
4
5
6
7
Pd(PPh3)4/10
Pd(PPh3)4/10
Pd(PPh3)4/10
Pd(PPh3)4/5
Pd(PPh3)4/10
Pd(PPh3)4/5
Pd(PPh3)4/10
No
50
1
45
57
75
67
76
80
86
DMF
No
65
1
DMF/H2O
No
100
85
1
DMF/H2O
DMF/H2O
No
1
PPh3/10
PPh3/10
Ruphos/10
100
100
100
0.5
0.5
0.5
0.5
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
8
Pd(PPh3)4/5
Pd(PPh3)4/5
Pd(PPh3)4/5
Ruphos/10
Ruphos/5
Ruphos/15
100
100
100
92
92
91
0.5
0.5
9
10
aThe reactions were performed in a round bottomed flask with 3-chloro-1H-isochromen-1-one, 1a (1 mmol), phenylboronic acid, 2a (1 mmol),
catalyst, ligand, base and solvent heated for ½ h-2h
Table 4 Synthesis of 3-Substituted isocoumarins from 3-chloro-1H-isochromen-1-onea
O
O
O
O
O
O
O
O
OMe
N
S
3c (90%)
3a (95%)
3d (89%)
3b (91%)
O
O
O
O
O
O
O
O
F
3f (91 %)
3e (93 %)
3h (88 %)
3g (82 %)
H3CO
C(CH3)3
CF3
OMe
O
O
O
O
O
O
O
O
O
O
O
S
3i (86 %)
3l (88 %)
3k (86 %)
3j (89 %)
N
O
O
O
O
O
O
O
O
O
O
F
3m (84 %)
3o (87 %)
3n (90 %)
O
3p (91 %)
O
O
F
O
O
F
O
O
Cl
O
O
O
3r (91%)
3q (88 %)
NO2
3t (92 %)
3s (90%)
Cl
O
O
O
O
O
O
O
O
OCH3
CH3
N
3v (90 %)
3w (82 %)
3u (88 %)
3x
(87%)
O
CH3
H3CO
O
O
O
O
O
O
O
O
3za(77%)
3z(74%)
3y(72%)
3zb(71%)
O
S
aThe reactions were performed in a round bottomed flask with 3-chloro-1H-isochromen-1-one, 1a (1 mmol), aliphatic/aryl/hetero/alicyclic boronic acid, 2 (1
mmol), PdCl2(PPh3)2 catalyst (5 mol %), Ruphos ligand (5 mol %), K2CO3 (2.0 eq.) base and DMF: water mixture (9:1, 15 v) solvent, heated at 80 °C for 30
min.
The optimization studies envisaged that the use of PdCl2(PPh3)2- mixture conditions offered a greater efficiency in the synthesis of
Ruphos catalytic system, K2CO3 as the base and DMF-water solvent diversified 3-substituted isochromen-1-one with amazing yields. The
3

transformation proceeded with an excellent conversion and yield boronic acid 2e and the desired products 3e and 4a, yields were
regardless of the electronic properties of the substituent (Table 4). determined by isolating yield.
With this optimized condition in hand, the Suzuki coupling of 3-
chloro-1H-isochromen-1-one was done with various boronic acids The results are presented in supporting documents. Interestingly, the
using 5 mol% of PdCl2(PPh3)2 catalyst, 5 mol% of Ruphos ligand, desired products are obtained with one-pot as excellent yields with
2.0 eq. of base and DMF : water mixture (10:1 ratio) with heating at the above optimised reaction conditions in both the intermolecular
80 °C for 30 min. We are pleased to inform that the Suzuki coupling experiments which suggests that the intermolecular reactions
reaction worked efficiently well in all the cases and the yield was approach may effectively be used in the preparation of several
consistent and excellent. This novel and efficient method was isochromen-1-ones simultaneously without any practical difficulty
employed with various substituted phenylboronic acids 2a-z with 3- through one-pot multi-product formation, reduced catalyst loading,
chloroisochromen-1-one (1a) under the optimized reaction lesser reaction time period, and a reduction in the number of column
conditions. Gratifyingly, excellent yields were observed for these purifications and so on. The proposed mechanism of the reaction is
substrates with electron-donating or electron-withdrawing groups depicted in scheme 5 (see SI). .
and the results are summarized in Table 4. Current protocol is highly
efficient, economical, environmentally benign and practical for the
arylboronic acids with electron-donating or electron-withdrawing
Conclusions
groups as well with other ortho-substitutions. The transformation
proceeded with an excellent conversion and yield regardless of the
To conclude, we have successfully developed a novel and
efficient, experimentally simple, high yielding, PdCl2(PPh3)2-
electronic properties of the substituent.
Ruphos catalyzed Suzuki coupling of 3-chloroisochromen-1-
one with aryl boronic acids under mild conditions in the
synthesis of diversified 3-disubstituted isocoumarins, in the
presence K2CO3 base and DMF: water mixture. The catalytic
reaction proceeds smoothly and provides various 3-substituted
isochromen-1-ones through C-C bond formation with good
yields. The highlights of this catalytic combination are high
catalytic activity, ready availability of the catalyst and aqueous
mediated reaction conditions. The methodology is entirely new
for the synthesis of diversified 3-disubstituted isocoumarins.
More applications of this methodology, in natural product
synthesis, are in progress.
Encouraged by the resulting outcomes, we were interested in
extending the scope of the reaction towards accomplishing the
natural isochromen-1-one analogues. Finally, we have demonstrated
the utility of the current benign protocol in the synthesis of natural
isochromen-1-ones, namely glomellin and reticulol analogues as
depicted in scheme 2. The dimethoxyhomopthalic acid required for
the natural isochromen-one was obtained as reported elsewhere.11, 12
Initially, the bromination of the dimethoxybenzoic acid using
Conc.HCl and bromine resulted in a 2-bromodimethoxybenzoic acid,
which, when reacted with diethylmalonate in the presence of
Cu(I)/base combination offered a corresponding intermediate that in
turn hydrolyzed to the homophthalic acid analogue.The as obtained
dimethoxyhomopthalic acid when reacted with POCl3 resulted in the
active starting material chloro derivatives, 1b for the functionalized
isochromen-ones, namely the glomellin and reticulol analogues as
depicted in scheme 2. Accordingly, Thungberginol A, B, Cytogenion,
etc. may also be obtained following the above protocol, 12, which are
under progress in our laboratory.
Acknowledgements
The authors wish to express their gratitude to the VIT
University Vellore for the support and facilities and SIF-VIT
for their support of NMR (DST-FIST Fund), GCMS and IR
facilities. This work was supported by the grant No. R0001026
from the Ministry of Trade, Industry & Energy and Busan
Metropolitan City, Korea.
O
O
O
O
O
Diethyl malonate
O
O
Con HCl
Br2
OH
O
O
OH
O
OH
References and notes
CuBr
NaH
Br
Dimethoxy benzoic acid
O
O
O
1. a) Pal, S.; Chatare, V.; Pal, M. Current Organic Chemistry
782-800; b) Fei, X.-D.; Ge, Z.-Y.; Tang, T.; Zhu, Y.-M.; Ji, S.-J. J.
Org. Chem. 2012 77, 10321-10328; c) Ge, Z.-Y.; Fei, X.-D.; Tang,
T.; Zhu, Y.-M.; Shen, J.-K. J. Org. Chem., 2012 77, 5736-5743; d)
Subramanian, V.; Batchu, V. R.; Barange, D.; Pal, M. J. Org. Chem.,
2005 70 , 4778–4783.
2. a) Guo, X.-X. J. Org. Chem., 2013
Org. Chem., 2013 78, 1660–1664.
3. a) Suzuki, A. Pure Appl. Chem 1994
95, 2457–2483; c) Suzuki, A. J.
576, 147-1 68.
, 2011, 15,
NaOH
THF
,
,
O
O
O
O
O
Glomellin Analogs
OH
OH
POCl3
,
O
or
O
Cl
2c
Reticulol Analogs
1b (after 4 steps 69%)
O
,
O
O
O
O
,
78, 1660-1664; b) Guo, X-X J.
O
O
O
O
O
O
O
O
O
,
4a (91%)
4b (84%)
.
, 44, 213-222; b) Miyaura, N.;
4c (87%)
O
Suzuki, A. Chem. Rev
Organomet. Chem. 1999
.
,
1995,
Scheme 2. Design of natural 3-substituted isochromen-1-one- Glomellin and
Reticulol analogues by a Suzuki coupling reaction
4. Prabakaran, K.; Nawaz Khan, F.; Jin, J. S.Res Chem Intermed 2012
38
Tetrahedron Lett.
,
,
337–346; b) Prabakaran, K.; Nawaz Khan, F.; Jin, J. S.
Further, we were interested in
a sustainable and
,
2011, 52, 2566–2570.
environmentally friendly approach for the synthesis of the desired
target materials. With this intention in mind, the intermolecular
competition experiments were carried out initially using mono
equivalents of each chloro derivatives 1a and 1b and biequivalent of
5. Manivel, P.; Roopan, S. M.; Khan, F. N. J. Chil. Chem. Soc., 2008, 53
,
1609-1610 .
4

6. a) Tajudeen, S. S.; Khan, F. N. Synth. Commun
b) Prabakaran, K.; Khan, F. N.; Jin, J. S. Res. Chem. Intermed.,
2012 38, 337-346.
7. a) Patil, N. T.; Nawaz Khan, F.; Yamamoto, Y. Tetrahedron Lett.
2004 45, 8497–8499, b) Prabakaran, K.; Nawaz Khan, F.; Jin, J. S.
Tetrahedron Lett. 2011 52, 2566–2570; c) Isogai, Y.; Nawaz Khan,
F.; Asao, N. Tetrahedron 2009, 65, 9575-9582.
8. a) Subashini, R.; Khan, F. R. N. Monatsh. Chem., 2012
. 2007, 37, 3649-3656;
,
,
,
,
,
,
,
143, 485-489;
b) Roopan, S. M.; Khan, F. R. N. Med. Chem. Res., 2011, 20, 732-
737.
9. a) Krishnakumar, V.; Nawaz Khan, F.; Mandal, B. K.; Jeong, E. D.
Tetrahedron Lett., 2014,55, 3717-3720 b) Manivel, P.; Prabakaran,
K.; Krishnakumar, V.; Nawaz Khan, F.; Maiyalagan, T
. Ind. Eng.
Chem. Res., 2014, 53, 7866–7870; c) Gund, M.; Khan, F. R.N.;
Khanna, A.; Krishnakumar, V. Eur. J. Pharm. Sci., 2013, 49, 227–
232.
10. a) Ethiraj, K. R.; Jesil Mathew, A.; Khan, F. N. Chem. Biol. Drug
Des., 2013
N. Med. Chem. Res., 2013
F. R. N.; Jin, J. S.; Jeong E. D.; Manivel, P. Chem. Pap., 2011
883–889; d) Roopan, S. M.; Khan F. R. N.; Mandal, B. K.
Tetrahedron Lett., 2010 51(17), 2309–2311; e) Roopan, S. M.;
,
82,732–742; b) Ethiraj, K. R.; Aranjani J. M.; Khan
22, 5408–5417; c) Prabakaran, K.; Khan,
65(6),
, F.
,
,
,
Maiyalagan, T.; Khan, F. N. Can. J. Chem., 2008, 86(11), 1019–
1025.
11. Nakao, R. PCT Int. Appl. 2012, , WO 2012077673 A1; b) Bardiot,
D.; Blanche, E.; Chaltin, P.; Koukni, M.; Leyssen, P.; Neyts,
J. ;Marchand, A.; Vliegen, I. PCT Int. Appl. 2010, WO 2010055164
A2.
12. Experimental Section-Procedure for the synthesis of 3-chloro
isochromen-1-one, 1a
-See supporting document .
Preparation of 4,5-dimethoxyhomophthalic acid, 3-chloro
isochromen-1-one, 1b and intermolecular competition
experiments:
-See supporting document.
Typical procedure for the palladium-catalyzed synthesis of 3-
phenyl isochromen-1-one, 3a
A sealed tube containing PdCl2(PPh3)2 (38.96 mg, 0.055 mmol, 5
mol %), Ruphos (5 mol%) 3-Chloroisochromen-1-one 1a
(200.45mg, 1.11 mmol), arylboronic acid 2a (1.22 mmol) and
K2CO3 (306.82 mg, 2.22 mmol) were purged with nitrogen gas
three times. Then, DMF (3.00 mL) was added with a syringe. The
reaction mixture was stirred at 80 °C for 30 min and was diluted
with ethyl acetate (30 mL). The mixture was filtered through a
celite bed and washed with ethyl acetate. The filtrate was
concentrated under reduced pressure and the residue was purified
on a silica gel column using hexane/ethyl acetate as eluent to
afford the desired product, 3a.
-See supporting document for spectral data of compounds 3a-zb
and 4a-c.
5

Palladium catalyzed Suzuki
Miyaura cross coupling of 3-
chlroisochromen-1-one: synthesis of
glomellin and reticulol analogues
Yadavalli Suneel Kumara#, Changalaraya
Dasaradhana#, Kamalakannan Prabakarana, Pitchai
Manivela, Fazlur-Rahman Nawaz Khana*,b* Euh Duck
Jeongb*, Eun Hyuk Chungb
#Equally contributed
O
O
O
O
Dimethoxy benzoic acid
Pd-catalysis/ Glomellin Analogues
Suzuki Miyaura
And
OH
O
O
4- steps
O
Cl
Reticulol Analogues
1b
69 %
6