A new one-pot synthetic approach to the highly functionalized (Z)-2-(buta-1,3-dienyl)phenols and 2-methyl-2H-chromenes: Use of amine, ruthenium and base-catalysis

Article abstract of DOI:10.1002/ejoc.200800472

A practical and simple one-pot multi-catalysis process for the synthesis of highly substituted benzo[b]oxepines 5, (Z)-2-(buta-1,3-dienyl)phenols 6 and 2-methyl-2H-chromenes 7 from simple starting materials was achieved for the first time through ring-closing metathesis/base-induced ring opening/[1,7]-sigmatropic hydrogen shift reactions. The synthesis of privileged (Z)-2-(buta-1,3-dienyl)phenols 6 via base-induced ring opening of highly functionalized benzo[b]oxepines 5 is described. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800472

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800472
A New One-Pot Synthetic Approach to the Highly Functionalized (Z)-2-(Buta-
1,3-dienyl)phenols and 2-Methyl-2H-chromenes: Use of Amine, Ruthenium and
Base-Catalysis
Dhevalapally B. Ramachary,*[a] Vidadala V. Narayana,[a] and Kinthada Ramakumar[a]
Keywords: Heterocycles / Phenols / Multi-catalysis reactions / Ring closing metathesis
A practical and simple one-pot multi-catalysis process for the
synthesis of highly substituted benzo[b]oxepines 5, (Z)-2-
(buta-1,3-dienyl)phenols 6 and 2-methyl-2H-chromenes 7
from simple starting materials was achieved for the first time
through ring-closing metathesis/base-induced ring opening/
[1,7]-sigmatropic hydrogen shift reactions. The synthesis of
privileged (Z)-2-(buta-1,3-dienyl)phenols 6 via base-induced
ring opening of highly functionalized benzo[b]oxepines 5 is
described
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
ring opening of highly substituted 2,5-dihydrobenzo[b]-
oxepines has not been reported before in the literature up
to now.
Introduction
Functionalized 2-(buta-1,3-dienyl)phenols and 2-methyl-
2H-chromenes are of considerable importance in a variety
of industries. They are, for instance, versatile building
blocks for the synthesis of natural products.[1] As such, the
development of new and more general catalytic methods for
their preparation is of significant interest.[1] Recently Sher-
burn et al.[2a] discovered the phosphane-mediated reaction
of 2-hydroxybenzaldehyde with allyltriphenylphosphonium
bromide in the presence of strong base providing a 2-(buta-
1,3-dienyl)phenol in moderate yield.
Herein we describe a novel one-pot and multi-catalysis
technology for the synthesis of highly substituted (Z)-2-
(buta-1,3-dienyl)phenols and 2-methyl-2H-chromenes start-
ing from highly substituted dienes [Equation (1)]. A ruthe-
nium/base/silica-catalyzed one-pot ring-closing metathesis
(RCM) and ring-opening/[1,7]-sigmatropic hydrogen shift
reactions are crucial steps in the reaction sequence. Func-
tionalized 2-(buta-1,3-dienyl)phenols are useful materials as
additives for rubbers and plastics, antioxidants, antibacte-
rial agents, antibiotics and hair dyeing.[1] The base-induced
Results and Discussion
Based on our recent discovery of piperdine/K2CO3-cata-
lyzed cascade enamine amination/iso-aromatization/alky-
lation (EA/IA/A) reaction of Hagemann’s esters 1 with ni-
trosobenzene and allyl bromide leading to functionalized
olefins 2,[3] we reasoned that these olefins 2 might be a suit-
able starting material for the synthesis of highly function-
alized dienes 4 as precursors for RCM reaction [Equation
(2)]. Then we initiated our synthesis by the combination
of cascade EA/IA reaction, O- and C-allylations and diene
metathesis as key steps for the synthesis of highly substi-
tuted benzo[b]oxepines 5 starting from Hagemann’s ester 1a
and nitrosobenzene as shown in Equation (2). The piperi-
dine/K2CO3-catalyzed cascade EA/IA/A reaction of 1a, ni-
trosobenzene and allyl bromide furnished the monoene
amine 2a in 95% yield. Claisen rearrangement of 2a in
DMF at 190 °C for 18 h yielded the expected phenol 3a in
75% yield, which on O-allylation with allyl bromide and
K2CO3 gave the diene amine 4a in 80% yield. Six more
functionalized dienes 4 were synthesized in very good yields
using different Hagemann’s esters 1b–g. Interestingly,
Claisen rearrangement of tert-butyl 4-allyloxy-2-methyl-3-
(phenylamino)benzoate (2c) in DMF at 190 °C for 18 h fur-
nished the decarboxylated phenol 3c, which on O-allylation
with allyl bromide and K2CO3 furnished the diene amine
4c in 85% yield [see Equation (2) and also the Supporting
Information for more details]. Interestingly, RCM reaction
of free diene amine 4a using Grubbs’ first-generation cata-
(1)
[a] School of Chemistry, University of Hyderabad,
Hyderabad 500046, India
Fax: +91-40-23012460
E-mail: ramsc@uohyd.ernet.in
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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D. B. Ramachary, V. V. Narayana, K. Ramakumar
SHORT COMMUNICATION
lyst [Cl2Ru=CHPh(PCy3)2] in CH2Cl2 at 25 °C for 2 h fur- cis-6a with good yields (entries 6–8). Reaction in THF gave
nished the benzo[b]oxepine 5a in 99% yield (Table 1). The the ring-opened product cis-6a with poor yield (entry 10).
technical advantage of this RCM reaction is the ruthenium The ruthenium-catalyzed RCM reaction of diene 4a and
catalysis applied to the free diene amine 4a without the need tBuOK-induced ring opening of the resulting benzo[b]oxep-
of in situ salt formation.[4] Maybe the secondary amine ine 5a was conducted according to the one-pot technique
group (HNAr2) in 4a does not interact with the ruthenium and furnished the expected product cis-6a in 97% yield with
catalyst, because the nucleophilicity of the amine is de- Ͼ99% Z-selectivity (Table 1, entry 9). We envisioned the
creased as a result of its direct interaction with two elec- optimized condition to be addition of 2 equiv. of tBuOK to
tron-deficient phenyl groups.
the mixture of in situ generated 5a in DMSO at 25 °C to
furnish the substituted (Z)-2-(buta-1,3-dienyl)phenol 6a in
97% yield with Ͼ99% Z-selectivity (Table 1, entry 9).
With the optimized reaction conditions in hand, the
scope of the ruthenium- and base-induced RCM/BIRO one-
pot reactions was investigated with variety of functionalized
dienes 4 as shown in Table 2. A series of 6-substituted Hag-
emann’s esters 1b–g were converted into diene amines 4b–g
in good yields as shown in Equation (2). RCM reaction of
free diene amines 4b–g using Grubbs’ first-generation cata-
lyst (2 mol-%) in CH2Cl2 at 25 °C for 2 h furnished the
benzo[b]oxepines 5b–g in 95–97% yield, which on treatment
with 2 equiv. of tBuOK at 25 °C for 0.5 h furnished the ex-
pected highly functionalized selective (Z)-2-(buta-1,3-di-
enyl)phenols 6b–g with good yields under both two-step
and one-pot conditions (Table 2, entries 1–5). Interestingly,
enyne metathesis followed by base-induced ring opening of
enyne 4h furnished the expected product cis-6h in 55% yield
(Table 2, entry 6). To demonstrate the scope of the rutheni-
um- and base-induced RCM/BIRO one-pot reactions, we
synthesized simple dienes 4i–n from corresponding phenols
1i–n through O-allylation/Claisen rearrangement/O-al-
lylation sequence (see Supporting Information for details)
and transformed them into the expected single isomeric
products cis-6i–n in very good yields via RCM/BIRO reac-
tions (Table 2, entries 7–11). Structure and regio-chemistry
of (Z)-2-(buta-1,3-dienyl)phenols 6 was confirmed by X-ray
structure analysis on cis-6a as shown in Figure 1.[5]
(2)
(a) Ph–N=O, piperidine (5 mol-%), DMF (0.6 ), 25 °C, 1 h;
K2CO3 (5 equiv.), H2C=CHCH2Br (3 equiv.), 25 °C, 24 h, 50–98%;
(b) DMF (1.0 ), 190 °C, 18 h, 73–80%; (c) K2CO3 (1.5 equiv.),
H2C=CHCH2Br (1.2 equiv.), EtOH (0.1 ) or DMF (0.5 ), 25 °C,
24 h, 80–95%.
Table 1. Reaction optimization.
[a] Yield refers to the column purified product. [b] Reaction per-
formed in both two steps and one-pot conditions.
Once the benzo[b]oxepine 5a was formed the base-
induced ring opening (BIRO) was initiated as shown in
Table 1. InterestinglyϪas we expectedϪtreatment of
2 equiv. of NaH with 5a in N-methylpyrrolidin-2-one
(NMP) at 25 °C for 1 h furnished the ring-opened product
cis-6a as major single isomeric product with 96% yield and
Ͼ99% Z-selectivity (Table 1, entry 1). The ring-opening re-
Figure 1. Crystal structure of ethyl (Z)-5-(buta-1,3-dienyl)-4-hy-
droxy-2-methyl-3-(phenylamino)benzoate (6a).
Some of the (Z)-2-(buta-1,3-dienyl)phenols 6 are un-
action of benzo[b]oxepine 5a was further studied by using stable at 25 °C and slowly rearrange to the 2-methyl-2H-
other bases like NaOMe, tBuOK and Bu3P; among these chromenes 7 by [1,7]-sigmatropic hydrogen shift ([1,7]-SHS)
tBuOK gave the best results as shown in Table 1, entries 2– followed by rapid cyclization.[6] Compounds cis-6f and cis-
5. The BIRO reaction in protic polar/aprotic polar solvents 6h–k are unstable at 25 °C and are rapidly converted into
like tBuOH, DMF and DMSO also furnished the product the functionalized 2-methyl-2H-chromenes 7f and 7h–k af-
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One-Pot Multi-Catalysis Process
Table 2. Synthesis of the substituted (Z)-2-(buta-1,3-dienyl)phenols 6.[a]
[a] Yield refers to the column-purified product.
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D. B. Ramachary, V. V. Narayana, K. Ramakumar
SHORT COMMUNICATION
ter aqueous workup. This reaction can be accelerated by methyl-2H-chromenes 7 were generated in good yields with
heat or addition of silica and CHCl3 to the crude phenols high selectivity as shown in Table 3. This method will show
6 (see Table 3). With synthetic and pharmaceutical applica- much impact on synthesis of highly substituted 2-methyl-
tions in mind,[1] we extended the transformation of other 2H-chromenes 7 for medicinal applications.[1] As shown in
phenols 6 into functionalized 2-methyl-2H-chromenes 7 by Table 3, Condition A (thermal activation) is the best
a novel thermal or silica-induced [1,7]-SHS reaction fol- method for the conversion of different (Z)-2-(buta-1,3-di-
lowed by rapid cyclization. Reaction of cis-6a in DMF at enyl)phenols 6 into 2-methyl-2H-chromenes 7.
120–140 °C for 20 h furnished the expected 2-methyl-2H-
In order to check the general applicability of the RCM/
chromene 7a in 90% yield, but the same reaction (catalyzed BIRO/[1,7]-SHS reaction sequence, we tried to synthesize
by SiO2/CHCl3 at 25 °C for 7 days) furnished 7a with only the C2-symmetric 2,8-dimethyl-2,8-dihydro-1,7-dioxachry-
50% conversion (Table 3, entry 1). Functionalized 2- sene 7oЈЈ [Equation (3)]. RCM reaction of 1,5-diallyl-2,6-
bis(allyloxy)naphthalene (4o) at 50 °C for 6 h in CH2Cl2
furnished the C2-symmetric benzo[b]oxepine 5o in 85%
yield, which on treatment with 1.5 equiv. of tBuOK fol-
lowed by treatment with SiO2/CHCl3 at 25 °C for 6–8 h fur-
nished the non-symmetric 2-methyl-2H-chromene 7oЈ in
70% yield [Equation (3)]. The same RCM reaction when
applied to 4o at 50 °C for 6 h in CH2Cl2 followed by reac-
tion with 5 equiv. of tBuOK at 25 °C for 3 h and then treat-
ment with SiO2/CHCl3 at 25 °C for 6–8 h furnished the C2-
symmetric chrysene 7oЈЈ in 65% yield [Equation (3)].
A possible reaction mechanism for the BIRO/[1,7]-SHS
reaction sequence is given in Scheme 1. The first step could
be the base-catalyzed formation of a carbanion (the allylic/
benzylic hydrogen of 5 is acidic) that will rearrange accord-
ing to a concerted reaction pathway to give the ring-opened
product cis-6. A [1,7]-sigmatropic shift of the phenolic hy-
drogen in cis-6 would give rise to the ortho-quinone methide
8, which rapidly cyclizes to yield 7 with recovery of the
thermodynamic stability through oxa-6π electrocyclization
or [3,3]-rearrangement. Interestingly, we did not find the
formation of [1,2]-Wittig-rearrangement-type products via
alternative deprotonation in α-position to oxygen in the
benzo[b]oxepines 5.[7]
Table 3. Chemically diverse libraries of 2-methyl-2H-chromenes
7.[a]
[a] Yield refers to the column purified product.
(3)
Scheme 1. Proposed reaction mechanism.
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One-Pot Multi-Catalysis Process
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Conclusions
In summary, we have found a selective, diversity-oriented
synthesis of highly functionalized benzo[b]oxepines 5, (Z)-
2-(buta-1,3-dienyl)phenols 6, and 2-methyl-2H-chromenes 7
from simple starting materials via EA/IA/A, RCM, BIRO
and [1,7]-SHS reactions under amine, ruthenium and base
catalysis. This chemistry (RCM/BIRO/[1,7]-SHS) per-
formed in one-pot with good yields and selectivity. Further
work is in progress to utilize novel combination of RCM,
BIRO and [1,7]-SHS reactions in synthetic chemistry.
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Experimental procedures, characterization data for new products,
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article).
Acknowledgments
This study was supported by the Department of Science and Tech-
nology (DST), New Delhi. V. V. N. and K. R. K. thank the Council
of Scientific and Industrial Research (CSIR), New Delhi for their
research fellowships. We thank Dr. P. Raghavaiah for X-ray struc-
tural analysis.
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Received: May 14, 2008
Published Online: July 4, 2008
Eur. J. Org. Chem. 2008, 3907–3911
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