Novel synthesis of nine-membered oxa-heterocycles by Pd(0)-catalyzed intramolecular Heck reaction via unusual 9-endo-trig-mode cyclization

Article abstract of DOI:10.1055/s-2008-1072510

Syntheses of nine-membered oxa-heterocyclic compounds by the application of the intramolecular Heck reaction have been difficult to develop. Herein, we describe the synthesis of this class of compounds through the 9-endo-trig cyclization and S-endo-trig cyclization, respectively - a rare mode of cyclization in the literature. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072510

LETTER
979
Novel Synthesis of Nine-Membered Oxa-Heterocycles by Pd(0)-Catalyzed In-
tramolecular Heck Reaction via Unusual 9-endo-trig-Mode Cyclization
Synthesis of
N
ine-
.
M
emberedO
C
xa-Heterocycles. Majumdar,* B. Chattopadhyay
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
E-mail: kcm_ku@yahoo.co.in
Received 23 October 2007
O
O
Abstract: Syntheses of nine-membered oxa-heterocyclic com-
pounds by the application of the intramolecular Heck reaction have
been difficult to develop. Herein, we describe the synthesis of this
9
X
I
class of compounds through the 9-endo-trig cyclization and 8-endo-
trig cyclization, respectively – a rare mode of cyclization in the lit-
erature.
COOEt
COOEt
O
O
Key words: Claisen rearrangement, intramolecular Heck reaction,
9-endo-trig, Pd(OAc)2 catalyst, oxa-heterocycles, medium-sized
ring compounds
O
O
X
9
I
COOEt
COOEt
During the final quarter of the twentieth century, palladi-
um catalysts emerged as extremely powerful tools for the
construction of carbon–carbon, as well as carbon–het-
eroatom bonds.1 Numerous monographs and review arti-
cles have documented1,2 the increasing frequency with
which palladium-catalyzed coupling processes are ap-
plied to a wide array of endeavors, which range from syn-
thetic organic chemistry to material science. Their
popularity stems in part from their tolerance of different
functional groups, which allows them to be employed in
the synthesis of highly complex molecules.2 Generally,
many natural products, as for examples rhazinilam3 and
its congener rhazinal4 that contain medium-sized hetero-
cyclic rings fused to aryl rings, have attracted consider-
able attention in both the biological and synthetic
communities.5 The formation of medium-sized rings via
intramolecular Heck reaction has been rare. Furthermore
Negishi et al. supported6 the lack of formation of a nine-
membered ring by the cyclic Heck reaction and reported
only a 2% yield. Recently, Majumdar et al. have reported7
the synthesis of medium-sized ring compounds, mainly
seven- and eight-membered, based on the ring-closing
metathesis reactions and Guy et al. reported the synthesis
of seven- and eight-membered heterocyclic ring8 fused
with aryl rings by the application of intramolecular Heck
reaction. Guy et al. also tried to synthesize nine-mem-
bered ring by the same reaction. But, unfortunately their
attempts to apply the intramolecular Heck reaction proto-
col to the synthesis of nine-membered ring failed
(Scheme 1).
Scheme 1 Attempted scheme for the synthesis of nine-membered
ring
exo
Pd
Pd
endo
Pd
Pd
Scheme2 Mode of exo-trig and endo-trig cyclization
In the intramolecular Heck reaction, entropic factors dom-
inate and control the mode of cyclization. In the majority
of studied cases, this reaction proceeded in the exo-trig
mode, as this way is by far less sterically9 demanding. The
endo-trig mode requires the olefinic bond to move inside
the loop in the intermediate p-complex, which requires a
much more flexible tether between it and the aromatic
ring to be able to bend freely into the proper conformation
(Scheme 2) and is highly improbable due to geometric
reasons.9
This has prompted us to undertake a study on the phos-
phine-free10 Pd(0)-catalyzed intramolecular Heck11 reac-
tion
of
different
6-allyl-1,3-dimethyl-5-(2¢-
bromoaryloxymethyl)uracil derivatives with a view to
synthesize nine-membered oxa-heterocycles fused with a
benzene and uracil moieties synthetically, which is a chal-
lenge due to the presence of strain within such com-
pounds. Additional interest is derived from our continued
efforts on the synthesis of heterocycles annulated with
bioactive moieties7a and pyrimidine system is well known
for its bioactivity.12
SYNLETT 2008, No. 7, pp 0979–0982
Advanced online publication: 17.03.2008
DOI: 10.1055/s-2008-1072510; Art ID: D34107ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8
The required Heck precursors 4a–f for our present study
were synthesized in 85–96% yields by refluxing 1,3-di-
methyl-6-allyl-5-hydroxyuracil 3a–c13 with different allyl

980
K. C. Majumdar, B. Chattopadhyay
LETTER
O
Table 1 Yields of the Starting Materials 4a–f
O
R1
Me
O
OH
Me
O
O
(i)
R1
R2
R3
Yield (%)
N
N
Entry
Starting
materials
N
N
Me
R2
Me
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
H
Me
Me
H
H
93
89
96
87
91
85
1
2a,b
H
OMe
H
H
(iii)
R3
Br
H
H
OMe
H
O
O
Me
Me
Ph
Ph
Me
O
OH
R2
Me
O
O
N
(iv)
N
R1
OMe
N
N
Me
R2
R1
Me
etone at refluxing conditions. The results are summarized
in Table 1.
4a–d
3a,b
The intramolecular Heck reactions were performed16 in
dry N,N-dimethylformamide (DMF) using potassium ace-
tate as a base, tetrabutylammoniumbromide (TBAB) as a
promoter,17 and Pd(OAc)2 as catalyst under nitrogen at-
mosphere at 100 °C for about 2–3.5 hours. All reactions
gave the endo-Heck heterocyclic ring compounds 5a–f
fused with aryl ring and uracil moiety by the unusual 9-
endo and 8-endo cyclization mode exclusively in 88–96%
yield except for compound 4c. Compound 4c gave the 9-
endo product 5c (74%) along with the formation of the
eight-membered ring compound 6a (12%) by the 8-exo-
cyclization mode (Scheme 4). The results are summarized
in Table 2.
R3
Br
O
O
N
Me
O
O
Me
O
OH
(iv)
N
(ii)
N
1
R1
R1
N
R2
R2
Me
Me
3c
4e,f
Scheme 3 Reagents and conditions: (i) allylbromide, K2CO3, aceto-
ne, NaI; (ii) cinnamyl bromide, K2CO3, acetone, NaI; (iii) chloroben-
zene, reflux; (iv) benzylbromide, acetone, K2CO3, NaI.
bromides in dry acetone for about 2–3 hours in the pres-
ence of anhydrous potassium carbonate and a small
amount of sodium iodide (Finkelstein conditions14). The
compounds 3a–c in turn were prepared in good yields by
the reaction of 5-hydroxyuracil with allyl bromide fol-
lowed by [3,3]-sigmatropic rearrangement in refluxing
chlorobenzene15 for 1–1.5 hours (Scheme 3). In the case
of compound 3c, O-alkylation with cinnamyl bromide,
[3,3]-sigmatropic rearrangement and double-bond
isomerization occur simultaneously in a single step in ac-
The intramolecular Heck reaction has two modes of ring
closure, i.e. exo and endo cyclization. A large-size ring
(ca. 20) formation with a flexible tether generally
favours18 endo cyclization and small to medium-size ring
formation usually exo cyclization since the corresponding
endo cyclization is very demanding. In our present cases,
the mechanistic interpretation for the formation of the 8-
exo-trig cyclization mode19 is quite reasonable because of
the less steric demand. But the formation of the products
5a–f, i.e. the nine-membered rings and eight-membered
R3
R3
O
O
O
Me
N
Me
O
O
(i)
N
O
N
Br
R1
N
5a–d
2
Me
R
Me
R2
R1
unexpected but observed
4a–d
O
N
R3
O
Me
O
N
R2
Me
R1
expected but not observed, as a minor
product (20%) only in case of 4c
Scheme 4 Synthesis of nine-membered ring compounds by the intramolecular Heck reaction. Reagents and conditions: (i) dry DMF, 10 mol%
Pd(OAc)2, KOAc (2.75 equiv), TBAB (1.2 equiv), N2 atmosphere.
Synlett 2008, No. 7, 979–982 © Thieme Stuttgart · New York

LETTER
Synthesis of Nine-Membered Oxa-Heterocycles
981
to explain why the yield of the endo cyclization product
steadily grows with longer chain length – a behavior not
common in the cyclization chemistry.20 Interestingly, in
our present cases the nine-membered rings are obtained in
excellent yields (which Guy et al. failed to synthesize) by
the 9-endo-trig cyclization mode. To our knowledge this
mode of cyclization is rare in the literature.20
Table 2 Summarized Results of the Heck Reactions
Entry Substrate
Product
O
O
1
O
Me
O
Me
O
N
N
Br
N
O
N
Me
Me
Me
Me
In conclusion, we have developed a general strategy for
the synthesis of nine-membered ring using transition-met-
al catalysis by the unusual 9-endo trig cyclization mode.
This method has a lot of advantage because this strategy
is straightforward and offers a convergent synthesis of tri-
cyclic compounds containing nine-membered rings. The
tolerance of various functional groups on the substrates is
another advantage of this protocol. Implementation of this
strategy to the synthesis of a heterocyclic library is under
way and will be reported in due course.
4a21
5a22 (90%)
2
OMe
OMe
O
O
Me
N
O
Me
O
O
N
O
N
Br
Me
N
Me
Me
Me
5b (94%)
4b
3
O
O
O
Me
N
Me
O
O
N
Acknowledgment
Br
O
N
N
We thank the DST (New Delhi) and the CSIR (New Delhi) for fi-
nancial assistance. B. Chattopadhyay is grateful to the CSIR (New
Delhi) for a Junior Research Fellowship. We thank Prof. A. T. Khan
of the Indian Institute of Technology (Gauhati) for some spectral
data.
Me
Me
5c (74%)
4c
O
O
Me
N
References and Notes
O
N
Me
Me
(1) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F.; Stang, P. J., Eds.; Wiley-VCH: New York, 1998.
(b) Tsuji, J. Palladium Reagents and Catalysts: Innovations
in Organic Synthesis; Wiley: New York, 1995.
(2) Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis;
VCH: New York, 1996, Chap. 13.
(3) (a) Linde, H. H. A. Helv. Chim. Acta 1965, 48, 1822.
(b) Abraham, D. J.; Rosenstein, R. D.; Lyon, R. L.; Fong, H.
H. S. Tetrahedron Lett. 1972, 13, 909.
6a23 (12%)
4
OMe
Br
OMe
O
O
O
Me
N
Me
O
O
N
O
N
N
Me
Me
5d (96%)
(4) Kam, T.-S.; Tee, Y.-M.; Subramaniam, G. Nat. Prod. Lett.
4d
1998, 12, 307.
5
6
O
O
(5) Baudoin, O.; Guenard, D.; Gueritte, F. Mini-Rev. Org.
Chem. 2004, 1, 333.
O
Me
N
Me
O
O
N
(6) Ma, S.; Negishi, E.-i. J. Am. Chem. Soc. 1995, 117, 6345.
(7) (a) Majumdar, K. C.; Rahaman, H.; Islam, R.; Roy, B.
Tetrahedron Lett. 2006, 47, 2111. (b) Majumdar, K. C.;
Islam, R.; Rahaman, H.; Roy, B. Org. Biomol. Chem. 2006,
4, 2393. (c) Majumdar, K. C.; Rahaman, H.; Muhuri, S.;
Roy, B. Synlett 2006, 466. (d) Majumdar, K. C.; Rahaman,
H.; Roy, B. Lett. Org. Chem. 2006, 3, 526.
Br
O
N
Me
N
Me Ph
Me
Ph
Me
5e (88%)
4e
OMe
O
O
Me
N
OMe
O
Me
O
(8) Leggy, A. A.; Wenchen, L.; Guy, R. K. Org. Lett. 2004, 6,
O
N
3005.
O
N
Br
(9) (a) Rawal, V. H.; Michovd, C. J. Org. Chem. 1993, 58,
5583. (b) Owczarczyk, Z.; Lamaty, F.; Vawter, E. J.;
Negishi, E.-I. J. Am. Chem. Soc. 1992, 114, 10091.
(c) Albeniz, A. C.; Espinet, P.; Lin, Y.-S. J. Am. Chem. Soc.
1996, 118, 7145.
Me
Me
N
Ph
Me
Ph
Me
5f (92%)
4f
(10) (a) Christoph, G.; Buchwald, S. L. Chem. Eur. J. 1999, 5,
3107. (b) Bumagin, N. A.; Bykov, V. V.; Sukhomlinova, L.
I.; Tolstaya, T. P.; Beletskaya, I. P. Organomet. Chem. 1995,
486, 259. (c) Bumagin, N. A.; More, P. G.; Beletskaya, I. P.
J. Organomet. Chem. 1989, 371, 397. (d) Reetz, M. T.;
Westermann, E.; Lohmer, R.; Lohmer, G. Tetrahedron Lett.
1998, 39, 8449. (e) Moreno-Mañas, M.; Pleixats, R.;
Roglans, A. Synlett 1997, 1157.
rings by the 9-endo-trig and 8-endo-trig cyclization mode
is quite interesting.
Generally in those cases when the endo mode is favored
for electronic reasons (e.g., if the substrate going into the
cyclization contains a Michael-type olefinic fragment in
the intramolecular Heck reaction) the reaction can lead to
larger cycles. The need for a more flexible chain is likely
Synlett 2008, No. 7, 979–982 © Thieme Stuttgart · New York

982
K. C. Majumdar, B. Chattopadhyay
LETTER
(11) (a) Ashimori, A.; Bachand, B.; Calter, M. A.; Govek, S. P.;
Overman, L. E.; Poon, D. J. Am. Chem. Soc. 1998, 120,
6488. (b) Shibasaki, M.; Boden, C. D. J.; Kojima, A.
Tetrahedron Lett. 1997, 53, 7371. (c) Kundig, E. P.; Ratni,
H.; Crousse, B.; Bernardinelli, G. J. Org. Chem. 2001, 66,
1852. (d) Yoshikawa, E.; Radhakrishna, K. V.; Yamamoto,
Y. J. Am. Chem. Soc. 2000, 122, 7280. (e) Coperet, C.;
Negishi, E.-I. Org. Lett. 1999, 1, 165. (f) Ma, S.; Ni, B. J.
Org. Chem. 2002, 67, 8280. (g) Miyabe, H.; Torieda, M.;
Inoue, K.; Tajiri, K.; Kiguchi, T.; Naito, T. J. Org. Chem.
1998, 63, 4397.
acetone (75 mL) in the presence of NaI was refluxed for a
period of 2–3 h. After cooling the reaction mixture was
filtered and the solvent was removed. The residual mass was
extracted with CHCl3, washed with H2O, followed by brine–
H2O, and dried (Na2SO4). Removal of CHCl3 gave a crude
product, which was chromatographed over silica gel (60–
120 mesh). Elution of the column with PE–EtOAc (2:1) gave
compounds 4a–f.
Compound 4a: yield 93%, white solid, mp 101–102 °C. IR
(KBr): nmax = 1649, 1701 cm–1. 1H NMR (400 MHz, CDCl3):
d = 1.24 (d, 3 H, =CHCH3, J = 7.2 Hz), 3.32 (s, 3 H, NCH3),
3.39 (s, 3 H, NCH3), 4.28–4.31 (m, 1 H, =CHCH3), 5.02 (dd,
1 H, =CHCHaHb, J = 2.1, 17.4 Hz), 5.11 (dd, 1 H,
=CHCHaHb, J = 2.1, 12.2 Hz), 5.12 (s, 2 H, OCH2), 5.72–
5.80 (m, 1 H, CH2=CH), 7.18 (dt, 1 H, ArH, J = 1.6, 7.7 Hz),
7.31 (dt, 1 H, ArH, J = 1.0, 7.4 Hz), 7.51–7.56 (m, 2 H,
ArH). 13C NMR (125 MHz, CDCl3): d = 16.1, 28.1, 33.2,
34.0, 73.0, 115.6, 123.5, 127.4, 129.6, 130.0, 130.8, 132.5,
135.9, 137.7, 147.7, 151.3, 157.6. MS: m/z = 378 [M+], 380
[M+ + 2]. Anal. Calcd (%) for C17H19BrN2O3: C, 53.84; H,
5.05; N, 7.39. Found: C, 53.88; H, 5.09; N, 7.23.
(12) (a) Heidelberger, C. Pyrimidine and Pyrimidine
Antimetabolites in Cancer Medicine; Holland, J. F.; Frei, E.,
Eds.; Lea and Febiger: Philadelphia, 1984, 801.
(b) Heidelberger, C.; King, D. H. Antiviral Agents in
Pharmacology and Therapeutics, Vol. 6; Shugar, D., Ed.;
Pergamon: Oxford, 1979, 427. (c) Fischl, M. A.; Richman,
D. D.; Grieco, M. H.; Gottlieb, M. S.; Volberding, P. A.;
Laskin, O. L.; Leedon, J. M.; Groopman, J. E.; Mildvan, D.;
Schooley, R. T.; Jacson, G. G.; Durack, D. T.; King, D. N.
Engl. J. Med. 1987, 317, 185. (d) Griengl, H.; Bodenteich,
M.; Hayden, W.; Wanek, E.; Streicher, W.; Stutz, P.;
Bachmayer, H.; Ghazzouli, I.; Rosenwirth, B. J. Med. Chem.
1985, 28, 1679. (e) Macilwain, C. Nature (London) 1993,
365, 378. (f) Chu, C. K.; Schimagi, R. F.; Ahn, M. K.; Ulas,
G. V.; Gu, G. P. J. Med. Chem. 1989, 32, 612.
(22) Synthesis of Compounds 5a–f and 6a; General
Procedure
A mixture of the compound 4a (100 mg, 0.265 mmol),
TBAB (1.2 equiv), dry KOAc (2.75 equiv) was taken in dry
DMF (10 mL) under nitrogen atmosphere. Then, the catalyst
Pd(OAc)2 (10 mmol%, 5.92 mg) was added and the mixture
was stirred in an oil bath at 100 °C for about 2–3.5 h. The
reaction mixture was cooled, and H2O (3 mL) was added. It
was extracted with EtOAc (3 × 10 mL), washed with H2O (2
× 10 ml), and followed by brine (15 mL). The organic layer
was dried (Na2SO4), evaporation of EtOAc furnished the
crude mass, which was purified by column chromatography
over silica gel. Elution of the column with 10% EtOAc–PE
afforded the product 5a. Similarly, the other substrates 4b–f
were subjected to the reaction under the same conditions to
give products 5b–f and 6a.
Compound 5a: yield 90%, white solid, mp 193–194 °C. IR
(KBr): nmax = 1648, 1700 cm–1. 1H NMR (400 MHz, CDCl3):
d = 1.84 (s, 3 H, =CCH3), 3.27 (d, 2 H, =CHCH2, J = 8.6
Hz), 3.35 (s, 3 H, NCH3), 3.43 (s, 3 H, NCH3), 4.65 (d, 1 H,
OCHaHb, J = 12.6 Hz), 5.40 (d, 1 H, OCHaHb, J = 12.6 Hz),
5.87 (t, 1 H, J = 8.6 Hz, CH2CH), 7.24–7.27 (m, 2 H, ArH),
7.32–7.36 (m, 2 H, ArH). 13C NMR (135 mode, CDCl3):
d = 21.9, 28.6, 34.4, 36.7, 77.2, 123.3, 127.3, 129.5, 130.3,
130.6, 132.0, 133.9, 137.1, 138.5, 143.5, 151.9, 161.1.
DEPT (135 mode, CDCl3): d = 21.9, 28.6, 34.4, 36.7 (CH2),
77.2 (OCH2), 127.3, 129.5, 130.3, 130.6, 133.9. HRMS: m/z
calcd: 299.1406 [M + H], 321.1250 [Na + H]. Found:
299.1448 [M + H], 321.1224 [Na + H]. Anal. Calcd (%) for
C17H18N2O3: C, 68.44; H, 6.08; N, 9.39. Found: C, 68.59; H,
6.07; N, 9.55.
(13) Otter, B. A.; Taube, A.; Fox, J. J. J. Org. Chem. 1971, 36,
1251.
(14) (a) Gazith, M.; Noys, R. M. J. Am. Chem. Soc. 1955, 77,
6091. (b) Gardner, I. J.; Noys, R. M. J. Am. Chem. Soc.
1961, 83, 2409.
(15) Majumdar, K. C.; Khan, A. T. Synth. Commun. 1987, 1589.
(16) General Procedure for the Synthesis of Compounds 5a–f
and 6a
A mixture of the compound 4a (100 mg, 0.265 mmol),
TBAB (1.2 equiv), dry KOAc (2.75 equiv) was taken in dry
DMF (10 mL) under nitrogen atmosphere. Then, the catalyst
Pd(OAc)2 (10 mmol%, 5.92 mg) was added and the mixture
was stirred in an oil bath at 100 °C for about 2–3.5 h. The
reaction mixture was cooled, and H2O (3 mL) was added. It
was extracted with EtOAc (3 × 10 mL) and washed with H2O
(2 ×10 mL), followed by brine (15 mL). The organic layer
was dried (Na2SO4) and evaporation of EtOAc furnished the
crude mass, which was purified by column chromatography
over silica gel. Elution of the column with 10% EtOAc–PE
afforded the product 5a. Similarly, the other substrates 4b–f
were subjected to the reaction under the same conditions to
give products 5b–f and 6a.
(17) Jeffery, T. Tetrahedron 1996, 52, 10113.
(18) (a) Geng, X.; Miller, L. M.; Lin, S.; Ojima, I. Org. Lett.
2003, 5, 3733. (b) De M, A.; Meyer, F. E. Angew. Chem.
1994, 106, 2473. (c) Shibasaki, M.; Boden, C. D. J.; Kojima,
A. Tetrahedron 1997, 53, 7371.
(19) (a) Denieul, M.-P.; Skrydstrup, T. Tetrahedron Lett. 1999,
40, 4901. (b) Dygos, J. H.; Yonan, E. E.; Scaros, M. G.;
Goodmonson, O. J.; Getman, D. P.; Periana, R. A.; Beck, G.
R. Synthesis 1992, 741. (c) Finkelstein, J.; Holden, K. G.;
Perchonock, C. D. Tetrahedron Lett. 1978, 1629.
(d) Alcaide, B.; Polanco, C.; Sierra, M. A. Eur. J. Org.
Chem. 1998, 2913.
The benzylic CH2 protons appear at d = 4.65 and 5.40 ppm
perhaps due to the slow exchange of the two nine-membered
ring conformers in NMR time scale. However, DEPT (135
mode) experiment showed that the CH2 carbon is present in
benzylic CH2O moiety. This was again confirmed by HMBC
and COSY experiments.
(23) Compound 6a: yield 12%, viscous liquid. IR (neat):
n
max = 1648, 1701 cm–1. 1H NMR (400 MHz, CDCl3):
(20) Gibson, S. E.; Guillo, N.; Middleton, R. J.; Thuilliez, A.;
Tozer, M. J. J Chem. Soc., Perkin Trans. 1 1997, 447.
(21) Synthesis of the Precursors 4a–f; Typcial Procedure
A mixture of compound 3 and different 2-
d = 2.34 (s, 3 H, =CHCH3), 3.21 (s, 3 H, NCH3), 3.27 (s, 3
H, NCH3), 5.24 (s, 2 H, OCH2), 6.02 (s, 1 H, =CH), 7.19–
7.25 (m, 2H, ArH), 7.26–7.33 (m, 2 H, ArH). MS: m/z = 284
[M+]. Anal. Calcd (%) for C16H16N2O3: C, 67.59; H, 5.67; N,
9.85. Found: C, 67.71; H, 5.66; N, 9.88.
bromobenzylbromides and dry K2CO3 (2.0 mg) in dry
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