Ruthenium-Mediated Isomerization and Ring-Closing Metathesis: Versatile Syntheses of 6-, 7- and 8-Membered Benzo-Fused Heterocycles

Article abstract of DOI:10.1055/s-2003-42032

Ruthenium-mediated isomerization and ring-closing metathesis (RCM) were the key steps used to convert a simple substrate, 2-allyl-3-isopropoxy-4-methoxybenzaldehyde, into a variety of 6-, 7- and 8-membered nitrogen- and oxygen-containing benzofused hetero

Full text of DOI:10.1055/s-2003-42032

LETTER
1859
Ruthenium-Mediated Isomerization and Ring-Closing Metathesis: Versatile
Syntheses of 6-, 7- and 8-Membered Benzo-Fused Heterocycles
R
uthenium-Mediated Is
i
omeriz
l
a
tion an
l
d
R
ing
e
-Closing M
m
etathesis A. L. van Otterlo,* Rakhi Pathak, Charles B. de Koning*
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits, 2050, Johannesburg, South Africa
E-mail: willem@aurum.chem.wits.ac.zu; E-mail: dekoning@aurum.chem.wits.ac.za
Received 27 June 2003
subsequent RCM reaction is described. The advantage of
Abstract: Ruthenium-mediated isomerization and ring-closing
our approach is that the strategic use of isomerization fol-
lowed by RCM allows one access to 6-, 7- and 8-mem-
bered benzo-fused ring systems from a common
precursor.
metathesis (RCM) were the key steps used to convert a simple sub-
strate, 2-allyl-3-isopropoxy-4-methoxybenzaldehyde, into a variety
of 6-, 7- and 8-membered nitrogen- and oxygen-containing benzo-
fused heterocycles.
Key words: ruthenium catalysts, metathesis, ring closure, isomer-
izations
Benzo-Fused Nitrogen-Containing Compounds
Initially we chose to synthesize the 8-membered nitrogen-
containing benzannelated ring system 5, starting from the
readily available substituted benzaldehyde 3.22 Two-step
reductive amination of 3 with allylamine and NaBH4 gave
the amine 4a which was converted to the N-tosylamide 4b
(Scheme 1).23 Subsequent RCM of 4b with catalyst 1
afforded the substituted 1,2,3,6-tetrahydro-2-benzazocine
(5) in excellent yield.
Benzo-fused cyclic molecules are often referred to as
‘privileged structures’ owing to their ubiquitous appear-
ance in natural products as well as in modern pharma-
ceuticals.1 This has prompted the use of many different
methods for their synthesis including the well-known
ruthenium-mediated ring closing metathesis reaction
(RCM).2–6 Ring-closing metathesis has been shown to be
a versatile method for the construction of small and medi-
um ring systems, including benzannelated examples.7–17
Very often the catalyst of choice used in these reactions is
the Grubbs’ second generation catalyst, compound 1, be-
cause of its tolerance to a variety of functional groups,
solvent impurities and molecular oxygen and it has been
shown to exhibit high metathesis reactivity (Figure 1).
Ts
N
MeO
OiPr
d
5
R
N
CHO
a,b
MeO
MeO
OiPr
OiPr
4a R = H
4b R = Ts
3
c
Figure 1
e
Ruthenium-mediated catalysis has also gained popularity
for the isomerization of terminal alkenes to internal alk-
enes. A particularly robust ruthenium isomerization
catalyst, compound 2, has been extensively studied and
used by Krompiec and co-workers.18,19
Ts
Ts
N
N
f
MeO
MeO
OiPr
OiPr
6
7
Examples of ruthenium-catalyzed isomerization reactions
coupled with RCM have recently been published.20,21 In
this paper we describe an extension in which the synthesis
of a series of N- and O-benzo-fused heterocycles using a
ruthenium-mediated isomerization reaction followed by a
Scheme 1 Reagents and conditions: (a) Allylamine, toluene, p-
TsOH (cat.), Dean–Stark apparatus, 110 °C; (b) NaBH4, MeOH, 0 °C,
93% over two steps; (c) TsCl, Et3N, CH2Cl2, r.t., 4 h, quantitative; (d)
5% catalyst 1, toluene, 60 ºC, 1 h, quantitative; (e) catalyst 2 (0.5%),
toluene, 110 ºC, 2 h; (f) 5% catalyst 1, toluene, 110 ºC, 3 h, 76% over
two steps.
SYNLETT 2003, No. 12, pp 1859–1861
Advanced online publication: 19.09.2003
DOI: 10.1055/s-2003-42032; Art ID: D15903st.pdf
© Georg Thieme Verlag Stuttgart · New York
2
9
.0
9
.2
0
0
3
Secondly in this series, bis-allyl compound 4b was sub-
jected to an in situ isomerization reaction using ruthenium

1860
W. A. L. van Otterlo et al.
LETTER
catalyst 2 (Scheme 1).18,19 When TLC analysis confirmed
consumption of the starting material, presumably to afford
intermediate 6, Grubbs’ catalyst 1 was added to the reac-
tion mixture. After 3 hours the reaction was stopped and
subsequent silica gel column chromatography afforded
the substituted 6-membered 1,2-dihydroisoquinoline ring
system 7 in excellent yield.24 Other research groups have
described in situ isomerizations of alkenes before25,26 or
after27,28 metathesis by the ruthenium metathesis catalysts
or their by-products.29
O
O
O
MeO
OiPr
c
12
CHO
MeO
MeO
OiPr
OiPr
Finally, the synthesis of the 7-membered benzannelated
system was approached in a slightly different manner.
Allylbenzaldehyde 3 was first converted into the N-tosyl-
imine in an unoptimized yield and then isomerized to the
thermodynamically favoured substituted styrene 8 using
ruthenium complex 2, according to established proce-
dures (Scheme 2).18 The N-tosylimine, 8, was then re-
duced (NaBH4) and the resultant amine alkylated with
allyl bromide under standard conditions to give 9. This
compound was then readily converted into the desired
2,3-dihydro-1H-2-benzazepine (10) by treatment with
Grubbs’ catalyst 1.
11
3
d
O
e
MeO
MeO
OiPr
OiPr
13
14
Scheme 3 Reagents and conditions: (a) LiAlH4, THF, 40 ºC, 12 h,
86%; (b) allyl bromide, NaH, THF, reflux, 20 h, 77%; (c) 5% catalyst
1, toluene, 60°C, 52%; (d) catalyst 2 (1%), toluene, 80 ºC; (e) 5% ca-
talyst 1, toluene, 60°C, 83% over two steps.
CHO
Ts
a,b
c,d
N
consumed (TLC). This was followed by treatment with
Grubbs’ catalyst 1, which gratifyingly afforded the 6-
membered 1H-isochromene system, 14, presumably by
way of intermediate 13 (Scheme 3).
MeO
MeO
MeO
OiPr
OiPr
3
8
Ts
Ts
Finally, we used another allyl isomerization method to ob-
tain a 7-membered oxygen-containing heterocycle, com-
pound 16. The C-allyl group of compound 11 was
isomerized selectively by using t-BuOK as base.31,32 In
this way compound 15 was obtained in high yield. Subse-
quent exposure of this compound to catalyst 1 gave the
cyclized product 16 in a satisfactory yield (Scheme 4).
This result then extends the versatility of our methodology
to include the synthesis of substituted 1,3-dihydro-2-
benzoxepines.
N
N
e
MeO
OiPr
OiPr
9
10
Scheme 2 Reagents and conditions: (a) TsNH2, toluene, 110 ºC, 4
d, 8 20% and recovered 3 78%; (b) catalyst 2 (1%), toluene, 80 ºC,
quantitative; (c) NaBH4, MeOH, 0 ºC, 30 min, 98%; (d) allyl bromide,
NaH, THF, 6 h, r.t., 64%; (e) 5% catalyst 1, toluene, 60 ºC, 2 h, quan-
titative.
a
O
O
Benzo-Fused Oxygen-Containing Compounds
MeO
MeO
OiPr
OiPr
O
Having been successful in applying the isomerization/
RCM strategy to nitrogen-containing benzannelated
heterocycles we decided to see if we could extend our
methodology to include oxygen-containing benzo-fused
compounds.
15
11
b
MeO
OiPr
The conversion of substituted benzaldehyde 3 into com-
pound 11 was easily accomplished by reduction (LiAlH4)
followed by O-alkylation using allyl bromide (Scheme 3).
Ring-closing metathesis on 11 was successful using 1 in
hot toluene to afford the substituted 3,6-dihydro-1H-2-
benzoxocine skeleton (12) in a yield of 52%.30
16
Scheme 4 Reagents and conditions: (a) t-BuOK, DMF, r.t., 18 h,
quantitative; (b) 5% catalyst 1, toluene, 2 h at 60 ºC, then 2 h at 80 ºC,
Compound 16 64% yield and compound 15 28% yield.
We have thus shown that ruthenium-mediated allyl
isomerization to the corresponding styrene and/or enol
ether, complemented by ruthenium-mediated RCM, can
lead to a variety of ring systems starting from the same
precursor. Using this approach we have been successful in
Furthermore, we also managed to extend our two-step/one
pot procedure to the synthesis of product 14 from bis-allyl
compound 11. Reaction of 11 with isomerization catalyst
2 was allowed to proceed until all starting material was
Synlett 2003, No. 12, 1859–1861 © Thieme Stuttgart · New York

LETTER
Ruthenium-Mediated Isomerization and Ring-Closing Metathesis
1861
(20) Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A. Angew.
Chem. Int. Ed. 2002, 41, 4732.
(21) van Otterlo, W. A. L.; Ngidi, E. L.; de Koning, C. B.
Tetrahedron Lett. 2003, 44, 6483.
(22) de Koning, C. B.; Michael, J. P.; Rousseau, A. L. J. Chem.
Soc., Perkin Trans. 1 2000, 787.
obtaining 6-, 7- and 8-membered benzo-fused hetero-
cyclic ring systems containing nitrogen and oxygen
atoms. We believe that this methodology will extend the
applicability of RCM in the synthesis of a wider selection
of compounds and we are presently extending this work to
include the synthesis of benzo-fused natural products.
(23) Taken from the ongoing PhD of Rakhi Pathak.
(24) To a degassed solution of N-allyl-N-(2-allyl-3-isopropoxy-
4-methoxybenzyl)-4-methylbenzenesulfonamide (4b) (120
mg) in toluene (10 cm3) was added [RuClH(CO)(PPh3)3]
(0.5 mol%). The reaction mixture was heated at 110 °C for 2
h under a N2 atmosphere. Grubbs’ catalyst 1 (5 mol%) was
added and the reaction mixture was stirred for another 3 h at
110 °C under N2. After cooling the mixture, the toluene was
evaporated under reduced pressure and the organic residue
was then subjected to silica gel column chromatography (5–
20% EtOAc–hexane) to afford the desired product, 5-
isopropoxy-2-[(4-methylphenyl)sulfonyl]-1,2-dihydro-6-
isoquinolinylmethyl ether (7) as a brown oil (0.079 g, 76%).
Found: M+, 373.1348. C20H23NSO4 requires M+, 373.1348.
IR (CHCl3): nmax = 1625 and 1597 (ArC=C) and 1167
(NSO2) cm–1. 1H NMR (300 MHz, CDCl3, Me4Si): d = 1.21
[6 H, d, J = 6.2 Hz, CH(CH3)2], 2.37 (3 H, s, ArCH3), 3.77
(3 H, s, OCH3), 4.35 {1 H, sept, J = 6.2 Hz, [CH(CH3)2]},
4.48 (2 H, s, NCH2), 6.22 (1 H, d, J = 7.9 Hz, ArCH=CH),
6.64 (2 H, s, 7-ArH and 8-ArH), 6.74 (1 H, d, J = 7.9 Hz,
NCH=CHAr), 7.25 (2 H, d, J = 8.1 Hz, 2 × ArH), 7.67 (2 H,
d, J = 8.1 Hz, 2 × ArH). 13C NMR (75 MHz, CDCl3): d =
21.4 (ArCH3), 22.4 [CH(CH3)2], 46.8 (NCH2), 55.7 (OCH3),
75.2 [CH(CH3)2], 106.3 (CH), 110.7 (CH), 120.4 (CH),
120.7 (C), 125.3 (C), 126.1 (CH), 126.9 (C), 127.1 (2 × CH),
129.2 (C), 129.7 (2 × CH), 143.9 (C), 152.4 (C). MS:
m/z (%) = 374 (24), 373 (90) [M+], 218 (18), 176 (100),
175 (89), 161 (35), 144 (45), 132 (30) and 91 (43).
(25) Fürstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.;
Nolan, S. P. J. Org. Chem. 2000, 65, 2204.
(26) For an in situ tandem palladium(0)-phosphine-allylic acetate
isomerization, ruthenium-mediated RCM investigation see:
Braddock, D. C.; Matsuno, A. Tetrahedron Lett. 2002, 43,
3305.
(27) Schmidt, B. Eur. J. Org. Chem. 2003, 816.
(28) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L.
J. Am. Chem. Soc. 2002, 124, 13390.
(29) For a concept paper highlighting the catalytic non-
metathetic behavior of Grubbs’ carbene see: Alcaide, B.;
Almendros, P. Chem.–Eur. J. 2003, 9, 1258.
(30) For a similar approach to these compounds see: Wang, E.-
C.; Wang, C.-C.; Hsu, M.-K.; Huang, K.-S. Heterocycles
2002, 57, 2021.
Acknowledgment
This work was supported by the National Research Foundation
(NRF, GUN 2053652), Pretoria, and the University of the Witwa-
tersrand (University Research Council). Prof. J. P. Michael is
thanked for many helpful discussions and Mr L. K. Li is also
thanked for conducting some of the preliminary work on this pro-
ject.
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Synlett 2003, No. 12, 1859–1861 © Thieme Stuttgart · New York