Synthesis of heterocycle-annulated medium-sized oxacycles and lactone derivative by intramoleculer heck reaction

Article abstract of DOI:10.1055/s-0029-1217702

An efficient and convergent methodology for the highly strained medium-sized oxacyclic compounds and lactone derivatives has been developed via palladium-catalyzed intramoleculer Heck reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217702

LETTER
2083
Synthesis of Heterocycle-Annulated Medium-Sized Oxacycles and Lactone
Derivative by Intramoleculer Heck Reaction
Synthesis of
H
eter
.
ocycle-Annu
C
lated
M
edium-Si
.
zedOxacycl
M
es ajumdar,* Rajendra Narayan De, Buddhadeb Chattopadhyay, B. Roy
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
E-mail: kcm_ku@yahoo.co.in
Received 20 April 2009
ring closure are often slow11 and inhibited by an unfavor-
able entropy and enthalpy (the strain exerted in so many
medium rings) and also transannular interaction.12 Today,
palladium chemistry occupies a special place amongst the
so far reported intramoleculer cyclization strategy of both
applied and academic interests.13 The aforesaid finding
inspired us to undertake a study of the formation of
medium-sized oxa-heterocycles by the application of
palladium-mediated intramoleculer Heck reaction, and
herein we report the results.
Abstract: An efficient and convergent methodology for the highly
strained medium-sized oxacyclic compounds and lactone deriva-
tives has been developed via palladium-catalyzed intramoleculer
Heck reaction.
Key words: intramoleculer Heck reaction, palladium acetate, 8-exo-
trig, eight-membered oxacycle, lactone
In recent years, tremendous interest1 has been shown in
the application of transition-metal-mediated protocols for
the construction of heterocyclic systems. Besides its syn-
thetic utility, transition-metal chemistry involving het-
eroatom-containing compounds is of interest from the
mechanistic point of view,2 and this is attributed to the
unique characteristics derived from the heteroatom
present in the substrates.3
Intramoleculer Heck reaction may undergo cyclization
via two modes14 such as exo-trig and/or endo-trig. Entro-
py and enthalpy factors15 as well as transannular interac-
tion play an important role in the cyclization. The exo-trig
mode is favorable for small to common ring-forming
reactions, and the endo-trig mode is favorable only for
large ring-forming reactions. In the case of a medium
ring-forming reaction, both exo- and endo-trig mode may
occur, depending on the nature of the alkene present in the
Heck precursor. The Heck reaction usually proceed
through endo-trig mode of cyclization with an alkene hav-
ing a Michael type of olefinic fragment.16
As a part of our ongoing research project on the synthesis
of heterocyclic compounds, we recently reported the first
example4 of the palladium-catalyzed unusual [1,3]-aryl-
oxy shift followed by a cycloisomerization, leading to po-
tentially bioactive heterocyclic systems. We also reported
the first example5 of eight-membered sulfur heterocycles
from a sulfone ester tether precursor by the palladium-
mediated Heck reaction. Moreover, most recently we
have also reported the synthesis6 of eight-membered azo-
cine derivatives by catalyzed aza-Claisen rearrangement7
and intramoleculer Heck reaction sequences. In continua-
tion to our work on the palladium chemistry,8 we intended
to extend the intramoleculer Heck cyclization leading to
ultimate synthesis of the medium-sized heterocyclic com-
pounds by varying the heterocyclic core moiety as the
smallest unit.
The precursors 3, 5, and 7 for our present investigation
were prepared in 60–80% yields by classical allylation of
1, 4, and 6 with either 2-bromobenzyl bromide 2a or
2-bromo-5-methoxybenzyl bromide 2b in dry acetone in
the presence of anhydrous K2CO3 and a small amount of
sodium iodide17 (Scheme 1).
We next attempted palladium-catalyzed intramolecular
Heck reaction with these substrates. To this end, the first
experiment was carried out with 3a as a model substrate.
Initially, the substrate 3a was allowed to react in dry DMF
in the presence of Pd(OAc)2 (10 mol%) as the catalyst, an-
hydrous potassium acetate as the base and in conjunction
with TBAB at 95 °C for three hours under nitrogen atmo-
sphere to give the corresponding cyclized product 8a18 in
46% yield (Scheme 2, entry 1, Table 1).
Usually, medium-sized heterocycles are regarded as an
exceedingly important group of compounds, the structural
basic units of which are regularly found in the framework
of a variety of natural products.9 Principally, eight- and
nine-membered heterocycles are constituents of a number
of compounds with increased pharmacological proper-
ties.10 Large number of medium rings containing oxygen
or nitrogen atom(s) in medicinally interesting compounds
continue to insure that they are important synthetic targets
for organic chemists. The synthetic routes for the con-
struction of medium-sized heterocycles involving direct
However, when the same reaction was performed for a
longer period (6 h), pleasingly the yield of the cyclized
product was increased considerably (57%, entry 2,
Table 1).
When the same reaction was conducted by changing the
catalytic composition from entry 1 to entry 3 in Table 1,
the yield of the product was maximum (71%), that is, the
catalyst Pd(PPh3)4 has exhibited better catalytic activity
over the commonly used Pd(OAc)2 catalyst as evident
SYNLETT 2009, No. 13, pp 2083–2088
x
x
.x
x
.2
0
0
9
Advanced online publication: 16.07.2009
DOI: 10.1055/s-0029-1217702; Art ID: G10109ST
© Georg Thieme Verlag Stuttgart · New York

2084
K. C. Majumdar et al.
LETTER
new result. However, the formation of 8a in only 35%
yield was observed (Table 1, entry 7 and 8). We have also
conducted the Heck reaction using the IL-mediated20 sys-
tems under different conditions, but no reaction occurred
(Table 1, entry 11 and 12). Interestingly, when the reac-
tion was carried out in DMF–H2O21 (7:2), the product 8a
was obtained in 46% yield. However, the reaction did not
proceed at all when carried out in water alone (Table 1,
entry 10). Compound 8a was characterized from its ele-
mental analysis and spectral data.18
Br
Br
R
OH
Br
O
O
i
+
N
O
R
N
R
1
Me
2
Me
R = H, OMe
3a, R = H
3b, R = OMe
Br
OH
O
Br
Br
+
i
We next turned our attention to other heterocyclic sub-
strates for Heck cyclization. Substrate 3b was treated un-
der the optimized conditions: Pd(PPh3)4, TBAB, KOAc,
DMF, 95 °C to give the Heck product 8b in 49% yield.
However, by changing the reaction conditions (entry 14,
Table 1) we have successfully obtained an excellent yield
(84%) of 8b. Longer reaction time slightly improved the
yield of 8b to 87% (entry 15).
Me
N
O
Me
N
O
R
Me
4
Me
R
2
5a, R = H
5b, R = OMe
R = H, OMe
OH
Br
O
Br
Br
+
i
We have also extended this protocol to other heterocyclic
systems such as 4-hydroxypyridone (4), 4-hydroxyaza-
naphthyridine (7), 4-hydroxypyrone (14a), and 4-hydroxy-
coumarin (14b) systems. When Heck reactions were
carried out with these systems each precursor smoothly
underwent cyclization leading to the formation of the cor-
responding exo-Heck (kinetically controlled) product in
good to excellent yields except for 7b and 14a,b
(Scheme 3).
N
N
O
R
N
N
O
6
Ph
2
Ph
7a, R = H
7b, R = OMe
R = H, OMe
Scheme 1 Reagents and conditions: (i) dry acetone, K2CO3, NaI,
reflux.
from the shorter reaction time and better yield of the prod-
uct. We have also examined other reaction conditions (en-
try 4–6, Table 1) and DMF is found to be the solvent of
choice; KOAc is the most resourceful base, though it is
the nucleophilic in nature yet it plays a vital role in this
reaction. Pd(PPh3)4 is the suitable catalyst.
It is well known19 that the additions of silver carbonate or
thallium salts cleanly suppressed the double bond isomer-
ization and accelerate the cyclization, possibly by remov-
ing halide ions strongly attached to Pd from a
coordination sphere to generate a cationic Pd catalyst,
making the insertion easier and faster. Therefore, we per-
formed the Heck reaction in the presence of Ag2CO3 in
place of KOAc. Unfortunately, we could not achieve any
In the case of substrate 7b, the Heck reaction performed
under the conditions shown in Table 1, entry 1, afforded
exclusively the endo-Heck cyclization product 10b22
Br
Br
Heck
conditions
Heck
conditions
no reaction
O
O
Me
O
O
O
O
14a
14b
Scheme 3
Br
9
8
conditions
O
O
conditions
O
N
O
N
O
N
O
3a
8a
Me
Me
Me
kinetically controlled
product favored
Me
8
O
N
O
Me
thermodynamically controlled
product unfavored
Scheme 2
Synlett 2009, No. 13, 2083–2088 © Thieme Stuttgart · New York

LETTER
Synthesis of Heterocycle-Annulated Medium-Sized Oxacycles
2085
Table 1 Screening and Optimization of the Heck Reactions
membered oxa-heterocyclic product was obtained exclu-
sively in 51% yield. However, we are unable to provide
any rationalization for this cyclization.
Entry Conditions
Prod. Yield
(%)
Heck reactions of the substrates 14a,b were carried out
under several (different) reaction conditions. The entire
starting materials disappeared giving a complex mixture
from which no product could be isolated as the substrate
lactones 14a,b are base sensitive.
1
2
3
4
5
6
7
8
9
Pd(OAc)2, TBAB, KOAc, DMF, 95 °C, 3 h
8a 46
Pd(OAc)2, TBAB, KOAc, DMF, 95 °C, 6 h
Pd(PPh3)4, TBAB, KOAc, DMF, 95 °C, 2 h
Pd(PPh3)2Cl2, TBAB, KOAc, DMF, 95 °C, 6 h
Pd(OAc)2, TBAB, KOAc, THF, 70 °C, 12 h
Pd(OAc)2, TBAB, KOAc, MeCN, 70 °C, 12 h
Pd(OAc)2, TBAB, Ag2CO3, DMF, 120 °C, 4 h
Pd(PPh3)4, TBAB, Ag2CO3, DMF, 120 °C, 4 h
8a 57
8a 71
8a <5
Recently, Guy et al.23 attempted the synthesis of medium-
sized lactone derivatives from the highly activated Heck
precursors. However, their attempts to synthesize medi-
um-sized lactone derivatives by palladium-catalyzed
Heck reaction failed. In fact, it is very difficult to con-
struct this type of lactone derivatives perhaps due to the
lack of a satisfactory synthetic procedure. In general,
Heck reactions are carried out in the presence of a strong
base, and therefore, the reaction medium becomes basic in
nature making the synthesis of the lactones by the appli-
cation of the Heck reaction a great challenge. Keeping this
in mind, we have attempted to synthesize medium-sized
lactone derivatives. For this purpose, the starting material
11 was prepared as depicted in Scheme 4. The reaction of
the acid chloride 13 (prepared from 2-iodobenzoic acid
and thionyl chloride in CH2Cl2) with 4-allyl-3-hydroxy-
N-methylquinolone in CH2Cl2–Et3N at 0 °C to room tem-
perature for four hours afforded the Heck precursor 11.
8a
8a
0
0
8a 35
8a 22
Pd(OAc)2, TBAB, KOAc, DMF–H2O, 120 °C, 6 h 8a 46
10 Pd(OAc)2, TBAB, KOAc, H2O, 120 °C, 12 h
11 Pd(OAc)2, TBAB, KOAc, IL,a 120 °C, 6 h
12 Pd(OAc)2, KOAc, IL,a 120 °C, 6 h
8a n.r.b
8a n.r.b
8a n.r.b
8b 49
13 Pd(PPh3)4, TBAB, KOAc, DMF, 95 °C, 2 h
14 Pd(OAc)2, TBAB, KOAc, DMF, 110 °C, 3.5 h
15 Pd(OAc)2, TBAB, KOAc, DMF, 120 °C, 6 h
16 Pd(OAc)2, TBAB, KOAc, DMF, 95 °C, 5 h
17 Pd(OAc)2, TBAB, KOAc, DMF, 120 °C, 5 h
18 Pd(OAc)2, TBAB, KOAc, DMF, 85 °C, 5 h
19 Pd(OAc)2, TBAB, KOAc, DMF, 120 °C, 5 h
20 Pd(OAc)2, TBAB, KOAc, DMF, 95 °C, 3.5 h
21 Pd(OAc)2, TBAB, KOAc, DMF, 120 °C, 5 h
8b 84
8b 87
Attempted synthesis of the lactone from its precursor 11
using the reaction conditions shown in Table 1, entries
22–25 miserably failed, and the starting material remained
unchanged. Consequently, we altered the reaction condi-
tions, and when we performed the same reaction under the
conditions described in Scheme 5, Table 1, entry 26, we
were delighted to obtain the corresponding lactone deriv-
ative 12 in 43% yield. The cyclized product was formed
via 8-exo-trig mode of cyclization followed by a double-
bond isomerization.
9a 54
9a 69
9b 34
9b 59
10a 73
10b 51
22 Pd(OAc)2, TBAB, KOAc, DMF, 100 °C, 3–12 h 12
23 Pd(PPh3)4, TBAB, KOAc, DMF, 110 °C, 2–12 h 12
24 Pd(PPh3)2Cl2, TBAB, KOAc, DMF, 130 °C, 2–12 h12
25 Pd(PPh3)2Cl2, TBAB, KOAc, DMF, 130 °C, 2–12 h12
0
0
0
0
Here it is noteworthy that the final product 12 is a thermo-
dynamically controlled one because the kinetically con-
trolled exocyclic product 14 isomerizes to 12 under these
reaction conditions. The results of the Heck reactions are
presented in Table 2.
26 Pd(PPh3)2Cl2, TBAB, NaOAc, DMA, 130 °C, 2 h 12 43
In short, we have developed important synthetic protocols
for the synthesis of heterocycle-annulated medium-sized
ring compounds including the lactone derivative which is
quite difficult to synthesize via this type of Heck protocol.
The developed method is simple, straightforward, and
a IL = ionic liquid [N-alkylated imidazolium ion, alkyl group =
(CH2)11Me].
b n.r. = no reaction.
through a 9-endo-trig mode of cyclization. Formation of high-yielding. The cyclization mode and related chemis-
nine-membered products is quite difficult compared to the try is also attractive. We are continuing this work, and a
eight-membered products. Yet in this system the nine- full account will be communicated later.
COCl
I
I
OH
O
anhyd CH2Cl2–Et3N
4 h, 0 °C to r.t.
O
O
+
N
O
N
Me
1
13
11
Me
Scheme 4
Synlett 2009, No. 13, 2083–2088 © Thieme Stuttgart · New York

2086
K. C. Majumdar et al.
LETTER
Me
I
O
O
O
O
O
O
O
O
conditions
O
N
N
N
Me
11
14
12
Me
Me
kinetically controlled
product
thermodynamically
controlled product
stable
unstable
Scheme 5
Table 2 Results of Heck Reactions
Entry Substrate
Optimized conditions
Products
Yield (%)
Br
O
O
1
Pd(PPh3)4, TBAB, KOAc, DMF, 95 °C, 2 h
Pd(OAc)2, TBAB, KOAc, DMF, 120 °C, 6 h
Pd(OAc)2, TBAB, KOAc, DMF, 120 °C, 5 h
71
O
N
N
O
Me
Me
3a
8a
OMe
Br
OMe
O
O
2
87
O
O
N
N
Me
Me
3b
8b
O
O
Br
3
69
Me
Me
N
O
N
O
Me
Me
5a
9a
OMe
Br
OMe
O
O
4
Pd(OAc)2, TBAB, KOAc, DMF, 95 °C, 3.5 h
59
Me
Me
N
O
N
O
Me
Me
5b
9b
O
O
Br
5
Pd(OAc)2, TBAB, KOAc, DMF, 95 °C, 3.5 h
73
N
N
O
N
N
O
Ph
Ph
7a
10a
Synlett 2009, No. 13, 2083–2088 © Thieme Stuttgart · New York

LETTER
Synthesis of Heterocycle-Annulated Medium-Sized Oxacycles
2087
Table 2 Results of Heck Reactions (continued)
Entry
Substrate
Optimized conditions
Products
Yield (%)
MeO
OMe
Br
O
O
6
Pd(OAc)2, TBAB, KOAc, DMF, 120 °C, 5 h
51
N
N
O
N
N
O
Ph
Ph
7b
10b
Me
I
O
O
7
Pd(PPh3)2Cl2, TBAB, NaOAc, DMA, 130 °C, 2 h
43
O
O
O
O
N
N
Me
Me
11
12
Lett. Org. Chem. 2008, 5, 276. (f) Majumdar, K. C.;
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674.
Acknowledgment
We thank the CSIR (New Delhi) and the DST (New Delhi) for fi-
nancial assistance. Two of us (B.C and R.N.D) are grateful to the
CSIR and the UGC, respectively, for fellowships.
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LETTER
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(18) General Procedure for the Synthesis of the Compound
by Heck Reaction
A mixture of 3a (70 mg, 0.182 mmol), TBAB (147 mg,
0.455 mmol), and dry KOAc (26 mg, 0.265 mmol) was taken
in dry DMF (10 mL). Pd(OAc)2 (10 mol%, 4.1 mg) was
added, and the mixture was stirred on an oil bath at 110 °C
for ca. 2 h. The reaction mixture was cooled, DMF was
removed under reduced pressure, H2O (3 mL) was added and
extracted with EtOAc (3 × 20 mL) and washed with H2O
(2 × 20 mL), followed by brine (20 mL). The organic layer
was dried (Na2SO4), and the solvent was distilled off to
furnish a viscous mass which was purified by column
chromatography over silica gel. Elution of the column with
20% EtOAc–hexane afforded the product 8a. Similarly,
other compounds were synthesized.
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(22) The spectral data, especially NMR studies, showed that the
OCH2 protons appears as two separate singlets which is
further supported by the DEPT experiment. DEPT contains
two extra methylene groups due to the rapid interconversion
of the existing possible conformers.
Compound 10b: yellow solid, mp 250 °C. IR (KBr): 2941,
Compound 8a: white solid, mp 174 °C. IR (KBr): 2918,
2838, 1647, 1625 cm–1 1H NMR (300 MHz, CDCl3):
.
2899, 1643, 1600 cm–1 1H NMR (400 MHz, CDCl3):
d = 3.45–3.61 (m, 2 H, =CHCH2), 3.80 (s, 3 H, OCH3), 4.89
(s, 1 H, OCHa), 5.44 (s, 1 H, OCHb), 6.74 (d, 1 H, J = 11.4
Hz, =CHa), 7.11–7.15 (m, 1 H, =CHb), 7.19–7.22 (m, 5 H,
ArH), 7.43–7.54 (m, 4 H, ArH), 8.23 (d, 1 H, J = 7.5 Hz,
ArH), 8.46 (d, 1 H, J = 3.2 Hz, ArH). 13C NMR (75 MHz,
CDCl3): d = 31.6, 59.4, 109.2, 112.6, 112.7, 115.1, 119.2,
125.3, 125.8, 128.5, 128.9, 129.5, 136.0, 136.7, 138.8,
138.3, 154.1, 154.7, 159.8, 172.5, 194.6. (TOF MS ES+):
m/z = 419.08 [M + Na]. Anal. Calcd (%) for C25H20N2O3: C,
75.74; H, 5.08; N, 7.07. Found: C, 75.81; H, 5.03; N, 7.21.
(23) Leggy, A. A.; Wenchen, L.; Guy, R. K. Org. Lett. 2004, 6,
3005.
.
d = 3.66 (s, 3 H, NCH3), 4.02 (s, 2 H,=CCH2), 5.17 (s, 1 H,
=CHa), 5.42 (s, 1 H, =CHb), 5.48 (s, 2 H, OCH2), 7.12–7.19
(m, 4 H, ArH), 7.20 (t, 1 H, J = 7.88 Hz, ArH), 7.25 (d, 1 H,
J = 5.2 Hz, ArH), 7.43 (t, 1 H, J = 7.80 Hz, ArH), 7.65 (d, 1
H, J = 7.96 Hz, ArH). 13C NMR (75 MHz, CDCl3):
d = 29.67, 36.98, 73.86, 114.17, 114.26, 120.53, 122.31,
123.83, 127.86, 128.37, 128.45, 128.65, 128.69, 133.47,
133.93, 137.01, 141.33, 143.94, 148.03, 159.00. MS (TOF
MS ES+): m/z = 326.13 [M + Na+]. Anal. Calcd (%) for
C20H17NO2: C, 79.19; H, 5.65; N, 4.62. Found: C, 79.29; H,
5.77; N, 4.57.
Synlett 2009, No. 13, 2083–2088 © Thieme Stuttgart · New York

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