The Baylis-Hillman acetates in organic synthesis: Development of a facile strategy for synthesis of functionalized unsaturated benzo-fused macrocyclic ethers and [n] metacyclophanes

Article abstract of DOI:10.1039/c3ra40926k

A general synthetic protocol for obtaining functionalized unsaturated benzo-fused macrocyclic ethers and [n] metacyclophanes containing 13-, 14-, 15-, 16- and 20-membered rings has been developed using Baylis-Hillman (BH) acetates as starting materials and ring closing metathesis as a key step.

Full text of DOI:10.1039/c3ra40926k

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The Baylis–Hillman acetates in organic synthesis:
development of a facile strategy for synthesis of
functionalized unsaturated benzo-fused macrocyclic
ethers and [n] metacyclophanes3
Cite this: DOI: 10.1039/c3ra40926k
Received 22nd February 2013,
Accepted 23rd April 2013
DOI: 10.1039/c3ra40926k
Deevi Basavaiah,* Katta Santosh Kumar, Kunche Aravindu and Balthu Lingaiah
www.rsc.org/advances
A general synthetic protocol for obtaining functionalized unsatu-
rated benzo-fused macrocyclic ethers and [n] metacyclophanes
containing 13-, 14-, 15-, 16- and 20-membered rings has been
developed using Baylis–Hillman (BH) acetates as starting materials
and ring closing metathesis as a key step.
Accordingly we focussed our attention for preparation of desired
diene 5a (Table 1, Entry 1). We have thus performed alkylation of
2a (dimedone) with methyl 3-acetoxy-3-(2-allyloxyphenyl)-2-methy-
lenepropanoate (1a; acetatate of BH alcohol obtained from
2-allyloxybenzaldehyde and methyl acrylate) and then
O-alkylation of the in situ resulting product 3a with allyl bromide
4a to obtain 5a. Best results in this direction were obtained when
we treated BH-acetate 1a (2 mmol) with 2a (2 mmol) in the
presence of K2CO3 (2 mmol) in DMF (3 mL) at room temperature
for 6 h. The in situ resulting product 3a, on treatment with allyl
bromide 4a (10 mmol) in the presence of K2CO3 (2 mmol) at room
temperature for 4 h provided the required diene 5a (E-selectivity
95%) in 68% (for two steps) yield (Table 1, Entry 1).
Attempted ring closing olefin metathesis (RCM)7 reactions of
5a with Grubbs’ first generation catalyst as well as with Grubbs’
second generation catalyst were not successful. However, we have
obtained encouraging results using Ti(OiPr)4 (20 mol%) as co-
catalyst.8 Thus treatment of 5a (0.5 mmol) with Grubbs’ first
generation catalyst (3 mol%) in the presence of Ti(OiPr)4 (20
mol%) in dichloromethane (DCM) under high dilution at reflux
temperature for 4 h provided 6a [(4E,15E)-10,10-dimethyl-2,7-
dioxa-15-methoxycarbonyltricyclo[15.4.0.08,13]henicosane-1(17),
4,8(13),15,18,20-hexaen-12-one] after usual workup followed by
column chromatography and crystallization of the resulting solid
Development of simple and facile strategies for synthesis of large
ring (.12-membered) compounds continues to attract the
attention of synthetic chemists.1 This is because of two main
reasons 1) some important marketed drugs have such structural
features, 2) challenges and opportunities involved in developing simple
and facile strategies for their synthesis.1 Cyclophanes belong to a
unique class of macrocycles containing bridged aromatic groups
and exhibit important properties such as molecular recognition
and catalysis.2 Therefore there has been, in recent years,
increasing interest in the development of convenient synthetic
methodologies for obtaining these structural frame-works.1c–e,2,3 In
continuation of our interest in the synthesis of heterocyclic and
carbocyclic molecules4 using the Baylis–Hillman (BH) adducts/
derivatives we herein report a general protocol for obtaining
functionalized unsaturated benzo-fused macrocyclic ethers and [n]
metacyclophanes.
The Baylis–Hillman reaction5,6 has indeed become a reaction
of choice for obtaining diverse classes of densely functionalized
molecules which have been utilized in many organic transforma-
tions and also in the synthesis of various biologically active
molecules. Based on our vast experience in the area of Baylis–
Hillman reaction and its applications we planned the retro-
synthetic strategy for obtaining unsaturated benzo-fused macro-
cyclic ethers and [n] metacyclophanes as shown in Scheme 1.
School of Chemistry, University of Hyderabad, Hyderabad, 500 046, India.
E-mail: dbsc@uohyd.ernet.in; Fax: +91 40-23012460
Electronic supplementary information (ESI) available: Representative experimental
3
procedure, with all spectral data of 5a–x, 6a–o, 7a–i, crystal data and ORTEP diagram
of 6a, 6c (E & Z), 6k, 6m, 6n, 6o, 7a (E & Z) and 7g. CCDC 6a (CCDC # 914817), 6c–E
(CCDC # 914818), 6c–Z (CCDC # 914819), 6k (CCDC # 917199), 6m (CCDC # 915410),
6n (CCDC # 917200), 6o (CCDC # 915411), 7a–E (CCDC # 915412), 7a–Z (CCDC #
917201) and 7g (CCDC # 915413). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c3ra40926k
Scheme 1 Retro-synthetic strategy for synthesis of unsaturated benzo-fused
macrocyclic ethers and [n] metacyclophanes.
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Table 1 Synthesis of dienes 5a–o via the reaction of 1a–d with 2a–c followed by
treatment of the resulting mono-alkylated cyclic-1,3-diones with alkenyl
bromides, 4a–ea
Table 2 Synthesis of unsaturated benzo-fused macrocyclic ethers 6a–o via ring
closing olefin metathesis of 5a–oa10,12
Entry Diene R2
R4
R
n
m
Productb Yield (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
H
H
H
H
H
H
H
OMe
OMe
OMe
H
H
H
H
H
H
Me
H
H
1
1
0
1
1
1
1
1
1
0
1
1
0
0
0
1
1
1
1
1
1
1
1
1
1
2
2
3
4
8
6ac
6b
6cc
6d
6e
6f
6g
6h
6i
70d
63d
Entry
Acetate
Dione
Bromide
Productb
Yield (%)
53(E) + 35(Z)e
61d
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1b
1c
1c
1d
1d
1d
1a
1a
1a
1a
1a
2a
2b
2c
2a
2b
2a
2b
2a
2b
2c
2a
2b
2c
2c
2c
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4c
4d
4e
5ac
5bc
5c
68
67
58
56
62
66
62
57
62
65
56
60
64
65
67
Br Me
Br
Cl Me
H
58d
68d
Cl
H
H
H
H
H
H
H
H
H
Me
H
H
Me
H
H
H
H
61d
5d
56d
5ed
5fc
5g
9
59d
10
11
12
13
14
15
6j
48(E) + 30(Z)e
6kc
6l
70d
78d
82f
91f
85d
5hc
5id
5jc
9
6mc
6nc
6oc
10
11
12
13
14
15
5ke
5le
H
H
5mc
5n
a
All reactions were carried out on 0.5 mmol scale of diene (5a–o)
with Grubbs’ first generation catalyst (3 mol%) and Ti(OiPr)4 (20 mol
%) in dichloromethane under high dilution at reflux temperature.
5od
b
c
a
All compounds were fully characterized (see ESI). Structures of
All reactions were carried out on 2 mmol scale of BH-acetate (1a–d)
with 2 mmol of dione (2a–c) in the presence of K2CO3 (2 mmol) in
DMF at room temperature followed by treatment of the resulting
products with alkenyl bromide 4a–e (4 or 10 mmol) in the presence
these compounds were further confirmed by single crystal X-ray data
analysis.9 d Only (E)-isomer is isolated.10,11 e (E)- & (Z)- isomers were
isolated by column chromatography.11 f Only (Z)- isomer is
isolated.11
b
of K2CO3 (2 mmol) at room temperature or 80 uC. All compounds
were fully characterized (see ESI). These compounds contain minor
c
d
Z-isomer (3–5%). These compounds contain minor Z-isomer (6–
e
7%). 5k contains 20% while 5l has 15% corresponding minor
Z-isomer (see ESI).
isomers of 6c. We obtained the compounds 6k, 6l (n = 1, m = 2)
and 6o (n = 0, m = 8) as (E)-isomers while molecules 6m (n = 0, m =
3) and 6n (n = 0, m = 4) were isolated as (Z)-isomers after column
chromatography followed by re-crystallization (see ESI ). Structures
3
[containing minor (4Z)-isomer (#10%)] (from 40% ethyl acetate in
hexanes) in 70% yield (Table 2, entry 1). Structure of the molecule
6a was further confirmed by single-crystal X-ray data analysis9 (see
and stereochemistry of compounds 6k, 6m–o were further
confirmed by single-crystal X- ray data analysis.9,10 After successful
synthesis of tricyclic compounds with middle ring as a macrocycle,
we directed our attention towards synthesis of [n] metacyclo-
phanes. Accordingly we prepared the required dienes 5p–x from
1e–f (BH acetates), cyclic-1,3-diones 2a–c, and alkenyl bromides
4a–c following the similar procedure used for 5a (Table 3, entries
1–9). RCM reactions of 5p–x were performed as in the case of 5a to
afford the corresponding [n] metacyclophanes 7a–i containing 14-,
15-, and 16-membered rings (Table 4, entries 1–9) in 70–90%
yields. It is interesting to note that metacyclophanes 7a–e (n = 0, 1,
m = 1) were obtained as mixture of (E)- and (Z)-isomers (separated
by column chromatography). However metacyclophanes 7f–i (n =
ESI ). Encouraged by this result we have prepared various dienes
3
5b–o from the BH-acetates 1a–d, cyclic-1,3-diones 2a–c, and
alkenyl bromides 4a–e following the similar reaction sequence
used for 5a in 56–68% isolated yields (Table 1).
To examine the generality of this strategy we subjected the
dienes 5b–o to RCM reaction under similar conditions as in the
case of 5a (Table 2, entry 1) to provide unsaturated benzo-fused
macrocyclic ethers 6b–o containing 13-, 14-, 15-, 16-, and 20-
membered rings in 56–91% isolated yields (Table 2, entries 2–15).
Macrocyclic compounds (n = 1 and m = 1) (6a, 6b, 6d, 6e, 6f, 6g, 6h,
and 6i)10 were obtained as (E)-isomers11 after column chromato-
graphy followed by re-crystallization (from ethyl acetate and
hexanes mixture). In the case of compounds 6c and 6j (n = 0
and m = 1) we could isolate both (E)- & (Z)-isomers11 (separated by
column chromatography). Structures of both (E)- & (Z)-isomers11 of
6c were also confirmed by single-crystal X-ray data analysis.9
Stereochemistry of (E)- & (Z)-isomers11 of 6j is assigned in
comparison of their NMR spectral data with that of (E)- & (Z)-
0,1;
m = 2,3) were isolated as (E)-isomers after column
chromatography followed by re-crystalization (see ESI ).
3
Structures of 7g and both (E)- & (Z)-isomers of 7a were further
confirmed by single-crystal X-ray data analysis.9,11 In the 1H NMR
spectrum of (E)-7a one of the aromatic protons (probably Ha)
appeared at d 6.67 while the same proton in (Z)-isomer appeared
at d 7.39. In the 13C NMR spectrum of (E)-7a allyloxy carbons (C3 &
C6) appeared at d 66.97 & 69.03 where as these carbons in the (Z)-
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In summary, we have developed a convenient protocol for
synthesis of benzo-fused macrocyclic ethers and metacyclophanes
thus further demonstrating the importance of Baylis–Hillman
acetates as useful synthons in organic synthesis.
Table 3 Synthesis of dienes 5p–x via the reaction of 1e–f with 2a–c followed by
treatment of the resulting mono-alkylated cyclic-1,3-diones with alkenyl
bromides 4a–ca
We thank the DST (New Delhi) for funding this project. K.A.
and B.L. thank the CSIR (New Delhi) for their research fellowships.
K.S.K. thanks the CSIR and DST for research fellowship. We thank
the UGC (New Delhi) for support and providing some instru-
mental facilities. We thank the National Single Crystal X-ray facility
funded by DST. We also thank Professors T.P. Radha Krishnan, K.
C. Kumara Swamy, and S. Pal, School of Chemistry, University of
Hyderabad, for helpful discussions regarding X-ray data analysis.
Entry
Acetate
Dione
Bromide
Productb
Yield (%)
1
2
3
4
5
6
7
8
9
1e
1e
1e
1f
2a
2b
2c
2b
2c
2a
2b
2b
2c
4a
4a
4a
4a
4a
4b
4b
4c
4c
5pc
5qc
5rc
5sc
5tc
5u
63
69
52
63
67
58
62
61
69
Notes and references
1f
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1e
1e
1e
1e
5v
5wc
5xc
a
All reactions were carried out on a 2 mmol scale of BH acetates
b
(1e–f) following similar procedure as in 5a–o. All compounds were
fully characterized (see ESI). These contain minor Z-isomer (3–5%)
(see ESI).
c
isomer appeared at d 61.83 & 65.14. Similarly in 1HNMR spectra of
(E)-7b–e one of the aromatic protons (probably Ha) appeared
between d 6.57–6.72 while the same proton in (Z)-7b–e appeared
between d 7.32–7.63. In the 13C NMR spectra of allyloxy carbons
(C3 & C6) of (E)-7b–e appeared between d 66.86–68.28 & 68.75–
70.15 where as these carbons appeared between d 61.97–63.47 &
64.74–65.82 in the case of (Z)-7b–e.
Table 4 Synthesis of unsaturated [n] metacyclophanes 7a–i via ring closing
metathesis of 5p–xa10,11
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Entry
Diene
R3
R
n
m
Productb
Yield (%)
1
2
3
4
5
6
7
8
9
5p
5q
5r
5s
5t
5u
5v
5w
5x
H
H
H
OMe
OMe
H
H
H
Me
H
H
H
H
Me
H
H
1
1
0
1
0
1
1
1
0
1
1
1
1
1
2
2
3
3
7ac
7b
7c
7d
7e
7f
56(E) + 27(Z)d
58(E) + 32(Z)d
48(E) + 31(Z)d
53(E) + 33(Z)d
48(E) + 28(Z)d
70e
7gc
7h
7i
79e
81e
H
H
85e
a
All reactions were carried out on a 0.5 mmol scale of diene (5p–x)
with Grubbs’ catalyst following a similar procedure as in the case of
b
c
6a–o. All compounds were fully characterized (see ESI). Structures
were further confirmed by single crystal X-ray data analysis.9 d Both
(E)- and (Z)-isomers were isolated.11 e Only (E)-isomer is isolated.10,11
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9 Detailed X-ray crystallographic data is available from the CCDC,
Cambridge (UK) for compounds 6a (CCDC # 914817), 6c–E
(CCDC # 914818), 6c–Z (CCDC # 914819), 6k (CCDC # 917199),
6m (CCDC # 915410), 6n (CCDC # 917200), 6o (CCDC #
915411), 7a–E (CCDC # 915412), 7a–Z (CCDC # 917201) and 7g
(CCDC # 915413).
10 (E)-Stereochemistry of double bond in 6b, 6d–i and 6l (after
RCM reaction) was assigned in comparison of chemical shift
values of allyloxy carbons (13CNMR) with that of 6a and 6k. (E)-
Stereochemistry in 7f, h, i was assigned in comparison of
chemical shift values of allyloxy carbons with that of 7g.
11 (E)- and (Z)-Stereochemistry refers to the newly formed double
bond after RCM reaction.
12 Sinceall the dienes 5a–x (except 5k and 5l) contain very less
quantities of minor (Z)-isomer we did not look for the
corresponding macrocyclic compounds in RCM reactions. In
the case of 5k and 5l we could not isolate any macrocyclic
compounds corresponding to minor (Z)-isomer, probably
minor (Z)-isomers did not participate in RCM reaction.
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