An easy access to halogenated and non-halogenated spiro-hexadienones

Article abstract of DOI:10.1016/j.tetlet.2014.07.114

We describe an improved protocol for the synthesis of spiro-hexadienones from Morita-Baylis-Hillman adducts. Solvent modification and temperature resulted in a significant increase in the yield. This protocol was used to synthesize mono- and dibrominated spiro-hexadienones in good overall yields. This report is the first to describe the synthesis of halogenated spiro-hexadienones from Morita-Baylis-Hillman adducts.

Full text of DOI:10.1016/j.tetlet.2014.07.114

Tetrahedron Letters 55 (2014) 5264–5267
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Tetrahedron Letters
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An easy access to halogenated and non-halogenated
spiro-hexadienones
Lucimara J. Martins a, Bruno R. V. Ferreira a, Wanda P. Almeida a, Marcelo Lancellotti b, Fernando Coelho a,
⇑
a University of Campinas, Institute of Chemistry, PO Box 6154, 13083-970 Campinas, SP, Brazil
b University of Campinas, Institute of Biology, Rua Monteiro Lobato 255, 13083-862 Campinas, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe an improved protocol for the synthesis of spiro-hexadienones from Morita–Baylis–Hillman
adducts. Solvent modification and temperature resulted in a significant increase in the yield. This proto-
col was used to synthesize mono- and dibrominated spiro-hexadienones in good overall yields. This
report is the first to describe the synthesis of halogenated spiro-hexadienones from Morita–Baylis–
Hillman adducts.
Received 9 July 2014
Revised 26 July 2014
Accepted 26 July 2014
Available online 5 August 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Morita–Baylis–Hillman
Spiro-hexadienones
Heck reaction
Hypervalent iodine
Brominated compounds
Compounds that contain the spiro-hexadienone moiety as part
of their structures typically exhibit remarkable biological activities.
This structural architecture with varied substitution patterns can
be observed in certain natural products.1 Most often, the biological
effects exhibited by these natural products are closely related to
the presence of the spiro-hexadienone motif. In Figure 1, some
examples of this class of biologically active natural compounds
are shown.
The chemical and biological relevance of spiro-hexadienones
has attracted the attention of the chemical community. Therefore,
several approaches for the synthesis of this class of compounds
have been developed. For example, radical chemistry,2 electro-
philic cyclization,3 carbene chemistry,4 multi-component reac-
tions5 or palladium mediated reactions6 have been employed to
synthesize spiro-hexadienones. Most recently, a sustainable phe-
nol oxidation mediated by NaNO2 was also used for the synthesis
of spiro-hexadienones.7
(36%) to moderate levels (70%). To circumvent this problem, in this
Letter, we describe the optimization of our methodology based on
varying key reaction parameters, such as solvent and temperature.
Basically, our methodology takes advantage of phenol oxidation
mediated by hypervalent iodine reagents. The suitably substituted
b-keto esters, which were used as substrates for the key oxidation
step, were directly and efficiently prepared from Morita–Baylis–
Hillman adducts using the phosphine-free Mizoroki–Heck
reaction.11
In this communication, we report an improved and efficient
protocol for the synthesis of halogenated and non-halogenated
spiro-hexadienones from Morita–Baylis–Hillman adducts.
First, a set of Morita–Baylis–Hillman adducts, which were syn-
thesized according to a method developed by our group several
years ago, were prepared.12 In all cases, we observed yields ranging
from good to excellent. The adducts were obtained in a straightfor-
However, despite these methodologies, the most commonly
employed methods are those based on phenol oxidation mediated
by hypervalent iodine.8
Due to our interest in the use of Morita–Baylis–Hillman adducts
as building blocks for organic synthesis,9 we have recently devel-
oped a new synthetic strategy to prepare spiro-hexadienones.10
Although it is operationally simple, the yields varied from low
O
O
MeO
Br
O
Br
NCH3
MeO
O
O
OH
H
OH
O
12
N
H
O
Pronuciferine (2)
Gimnastatin I (1)
(-)-Aculeatin A (3)
⇑
Corresponding author. Tel.: +55 19 3521 3085; fax: +55 19 3521 3023.
E-mail address: coelho@iqm.unicamp.br (F. Coelho).
Figure 1. Examples of biologically active natural products that contain the spiro-
hexadienone moiety in their structures.
http://dx.doi.org/10.1016/j.tetlet.2014.07.114
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

L. J. Martins et al. / Tetrahedron Letters 55 (2014) 5264–5267
5265
Table 1
Table 2
Preparation of Morita–Baylis–Hillman adducts
Preparation of a-arylated b-keto esters
DABCO
Phosphine-free Mizoroki-Heck reaction
OH
O
ultrasound
R2
Cl
Cl
R1
R1
H
Iodophenol,
O
OH
R2
Nájera's catalyst
DMF, 110 0C, 2h
R2
R2
MBH adducts
R1
R1
N
Pd Cl
4-14
HO
Nájera's catalyst
Entry
MBH adducts
Yielda,b,c (%)
MBH adducts
OH
4-14
-Arylated-β-keto esters
α
1
2
3
4
5
6
7
8
9
4, R1 = C6H5; R2 = CO2CH3
85
96
90
70
71
80
99
77
85
85
90
5, R1 = 4-NO2–C6H4; R2 = CO2CH3
6, R1 = 2-C4H4S; R2 = CO2CH3
15-25
Entry
MBH adducts
Yielda (%)
7, R1 = 3,4-(OCH2O)–C6H3; R2 = CO2CH3
8, R1 = 3,4,5-CH3O–C6H2; R2 = CO2CH3
9, R1 = 3,4,5-CH3O–C6H2; R2 = CO2C2H5
10, R1 = 4-CH3O–C6H4; R2 = CO2CH3
11, R1 = 3-CH3O–C6H4; R2 = CN
1
2
3
4
5
6
7
8
9
4, R1 = C6H5; R2 = CO2CH3
15, 91
16, 71
17, 90
18, 68
19, 82
20, 65
21, 73
22, 80
23, 85
24, 75
5, R1 = 4-O2N–C6H4; R2 = CO2CH3
6, R1 = 2-C4H4S; R2 = CO2CH3
7, R1 = 3,4-(OCH2O)–C6H3; R2 = CO2CH3
8, R1 = 3,4,5-(CH3O)3–C6H2; R2 = CO2CH3
9, R1 = 3,4,5-(CH3O)3–C6H2; R2 = CO2C2H5
10, R1 = 4-CH3O–C6H4; R2 = CO2CH3
11, R1 = 3-CH3O–C6H4; R2 = CN
12, R1 = CH3CH2; R2 = CO2C2H5
10
11
13, R1 = CH3(CH2)7CH2; R2 = CO2CH3
14, R1 = 4-F3C–C6H4; R2 = CO2CH3
a
Yields refer to isolated and purified products.
Spectral data (1H, 13C NMR, IR, HRMS) are all compatible with the proposed
12, R1 = C2H5; R2 = CO2C2H5
b
10
13, R1 = C9H19; R2 = CO2CH3
structures.
c
Reaction times varied from 15 min to 96 h.
a
Yields refer to isolated and purified products.
ward manner, and after isolation, only filtration on silica gel was
required to achieve a high level of purity (P98%). The results are
summarized in Table 1.
With the purified adducts in hand, the b-keto esters can be pre-
pared. a-Substituted b-keto esters are classically prepared by Cla-
The change in the solvent results in a net increase in the yield
and rate of the reaction. The yield increased from 55% to 70%,
and the reaction medium was cleaner than when acetonitrile
was used. We also observed a net effect on the rate of reaction.
After only 3 min, the substrate was completely transformed to
the reaction product based on TLC analysis. Therefore, we decided
to test this experimental protocol with the entire set of b-keto
esters. The results are summarized in Table 3.
For some cases, we observed a net increase in the yield of the
reaction (Table 3, entries 6, 8 and 9). For other cases, no changes
were observed (Table 3, entries 2–6). In all of the cases, no decrease
in the yield was observed. Apparently, the increase in the yields is
substantial for those b-keto esters substituted by alkyl groups
(entries 8 and 9, Table 3). However, for all of the cases, the reaction
times substantially decreased from 10 to 3 min. These results are
due to the high polarity of HFIP. This solvent stabilizes the cationic
intermediate formed in this oxidative process, which contributes
to an increase in the yield and rate of the reaction.14
isen condensation following by alkylation or via a Knoevenagel
reaction between b-keto esters and aldehydes followed by hydro-
genation of a double bond. Although these approaches are very
simple, they present some drawbacks. Di-alkylation can occur,
requiring additional purification. Otherwise, depending on the sub-
stituents present in the alkylating agent or in the aldehyde, a step
involving a protecting group could also be required with both reac-
tions (alkylation or Knoevenagel). In both cases, substituted b-keto
esters can be obtained in 2 or 3 steps, if no protecting step is
involved.
Several years ago, Alonso et al.13 described a Mizoroki–Heck
reaction using new oxime-derived palladacycle catalysts. Based
on this catalyst, which provides an in situ source of palladium(0)
nanoparticles, we have developed a phosphine-free method to pre-
To increase the structural pattern diversity of our spiro-hexa-
dienones, we decided to evaluate the feasibility of this methodol-
ogy for the preparation of brominated spirohexadienones due to
the biological potential exhibited by this particular class of spiro-
hexadienones.1 Bromine atoms can be incorporated into our
sequence using two different approaches. First, the bromination
pare mono-a-arylated b-keto esters in good yields and high selec-
tivity using the Mizoroki–Heck reaction and the MBH adducts as
substrates.11 This approach provides the required b-keto esters in
one step from a MBH without the need of any protecting group.
Therefore, a solution of the MBH adduct in DMF was treated with
iodophenol in the presence of a catalytic amount (0.5 mol %) of
the oxime-derived palladacycle (Nájera’s catalyst) to afford the
required
a-arylated-b-keto esters in good yields, low reaction
O
times and good selectivity. The results are summarized in Table 2.
In our previous communication,11 the key phenolic oxidation
step, which is mediated by a hypervalent iodine reagent, exhibited
only moderate yields, which decreased the overall yields of our
synthetic sequence. Initially, we decided to optimize this experi-
mental condition by changing the solvent used in the oxidative
step. Dohi et al.14 reported the use of hexa-fluoroisopropanol
(HFIP) in phenolic oxidation mediated by hypervalent iodine
reagents. Due to its particular physical and chemical characteristics
(i.e., low nucleophilicity, high polarity and high hydrogen-bond
donor ability), this solvent increases the yield of this oxidative step.
We decided to carry out a phenolic oxidation with HIFP and PIFA
[phenyliodine bis(trifluoroacetate)] and compare this reaction to
the one carried out in acetonitrile. The b-keto ester 15 was used
as a model for both reactions. The results are shown in Scheme 1.
PIFA, CH3CN
O
- 10 0C, 10 min.
55%
O
O
CO2CH3
OCH3
26
O
OH
PIFA, HFIP
15
O
- 10 0C, 3 min.
70%
CO2CH3
26
Scheme 1. Testing a fluorinated solvent for the phenolic oxidation of substituted b-
keto esters.

5266
L. J. Martins et al. / Tetrahedron Letters 55 (2014) 5264–5267
Table 3
The bromination reaction worked nicely, but it led to a mixture
of mono- and dibrominated compounds where the major com-
pounds are always dibrominated. A careful analysis of the NMR
spectra of the separated isomers indicated that the halogenation
reaction was highly regioselective and occurred only on the phenol
aromatic ring. To improve the ratio between the brominated prod-
ucts in favour of the monobrominated, we have performed several
experiments where we decreased the amount of sodium bromide
to 1 equiv. This strategy was only partially successful because the
di-brominated compounds remain in the mixture (Table 4, entries
2, 5 and 9).
Improved synthesis of spiro-hexadienones from b-keto esters
O
O
O
R1
OR2
PIFA, HFIP
0 0C, 3 min.
O
OH
R1
R2
Spiro-hexadienones
α-Arylated-β-keto esters (16-24)
(27-35)
Entry
b-Keto esters
Yielda (%)
1
2
3
4
5
6
7
8
9
16, R1 = 4-O2N–C6H5; R2 = CO2CH3
17, R1 = 2-C4H4S; R2 = CO2CH3
27, 40 (36)b
28, 40 (40)b
29, 70 (70)b
30, 70 (69)b
31, 65 (65)b
32, 58 (36)b
33, 40 (35)b
34, 75 (40)b
35, 81 (19)b
To complete our study, a solution of the mono- and dibrominat-
ed compounds was treated separately with PIFA in HFIP to afford
the corresponding brominated spiro-hexadienones in moderate
to excellent yields.
18, R1 = 3,4-(OCH2O)C6H3; R2 = CO2CH3
19, R1 = 3,4,5-(CH3O)3–C6H2; R2 = CO2CH3
20, R1 = 3,4,5-(CH3O)3–C6H2; R2 = CO2C2H5
21, R1 = 4-CH3O–C6H4; R2 = CO2CH3
22, R1 = 3-CH3O–C6H4; R2 = CN
Interestingly, an increase in the rate of these reactions was
observed, and the reactions were complete after only 1 min.
The results are summarized in Table 5.
23, R1 C2H5; R2 = CO2CH3
24, R1 = C9H19; R2 = CO2CH3
In contrast to our first communication,11 the improved protocol
described herein has allowed for the synthesis of several new
a
Yields refer to isolated and purified products.
Yields obtained using acetonitrile as solvent.
b
spiro-hexadienones in
3 steps from Morita–Baylis–Hillman
adducts with overall yields ranging from 23% to 54%. 1,1,1,3,3,3-
Hexafluoropropanol (HFIP) has resulted in a remarkable modifica-
tion in the reaction profile, as noted by Dohi.14 A huge increase in
the reaction yield was observed for some cases, and no decrease in
the yields was observed for the other cases. In all of the cases, the
rates of the reaction increased.
The b-keto esters were brominated with good selectivity using
an easy and simple bromination reaction. By dosing the concentra-
tion of the brominating agent in the reaction medium, it was pos-
sible to drive the reaction towards mono- or dibrominated b-keto
esters. These halogenated compounds were easily transformed into
halogenated spiro-hexadienones in four steps from the Morita–
Baylis–Hillman adducts. The overall yields for these transforma-
tions were moderate to good and varied from 6% to 35% for the
monobrominated spirohexadienones and from 19% to 37% for the
dibrominated spirohexadienones.
could be performed after the formation of the spiro compounds.15
Alternatively, regioselective bromination of the b-keto esters was
carried out before the phenolic oxidation step.
Hara et al.15 reported the direct and easy halogenation of spiro-
hexadienones by quenching the crude reaction medium with an
aqueous solution of NaBr. Unfortunately, this bromination protocol
did not work in our hands.
Recently, Barontini et al.16 described a bromination reaction
based on a combination of NaBr with oxone and a mixture of dim-
ethylcarbonate and water. Therefore, a subset of the b-keto was
submitted to this experimental protocol to yield the corresponding
brominated compounds as a mixture of mono- and dibrominated
derivatives in good overall yields. The results are summarized in
Table 4.
Table 4
Selective halogenation of b-keto esters obtained from Morita–Baylis–Hillman adducts
O
O
O
O
O
O
R1
OR2
Br
R1
OR2
R1
OR2
NaBr (2.1), Oxone
+
Br
Br
DMC:H2O (1:1)
90 min., r.t.
OH
OH
OH
α-Arylated-β-ketoesters
(15, 16, 18, 19, 21, 23, 24, 25
Mono-brominated
β-ketoesters
(36a-43a)
Di-brominated
β-ketoesters
(36b-43b)
)
Entry
b-Keto esters
Brominated b-keto esters%a,b
Mono-
Di-
1
2
3
4
5
6
7
8
9
15, R1 = C6H5; R2 = CO2CH3
15, R1 = C6H5; R2 = CO2CH3
36a, 32
36ac, 64
37a, —d
38a, 12
38ac, 65
39a, 20
40a, 24
41a, 11
41ac, 67
42a, 22
43a, 15
36b, 62
36bc, 17
37b, 52
38b, 76
38bc, 23
39b, 79
40b, 71
41b, 75
41bc, 21
42b, 68
43b, 61
16, R1 = 4-O2N–C6H4; R2 = CO2CH3
18, R1 = 3,4-(OCH2O)–C6H3; R2 = CO2CH3
18, R1 = 3,4-(OCH2O)–C6H3; R2 = CO2CH3
19, R1 = 3,4,5 (CH3O)3–C6H2; R2 = CO2CH3
21, R1 = 4-(CH3O)–C6H4; R2 = CO2CH3
23, R1 = C2H5; R2 = CO2C2H5
23, R1 = C2H5; R2 = CO2C2H5
10
11
24, R1 = C9H19; R2 = CO2CH3
25, R1 = 4-F3C-C6H4; R2 = CO2CH3
a
b
c
Mono- and dibrominated b-keto esters are easily separable by silica gel chromatography.
Yields refer to isolated and purified products.
1 equiv of NaBr.
d
The monobrominated product was not obtained.

L. J. Martins et al. / Tetrahedron Letters 55 (2014) 5264–5267
5267
Table 5
Synthesis of mono- and di-brominated spiro-hexadienones from Morita–Baylis–Hillman adducts
O
O
O
O
Br
Br
Br
PIFA
HFIP
PIFA
HFIP
R1
OR2
R4
O
O
0
0C, 1 min
0 0C, 1 min
OH
R1
CO2R2
R1
CO2R2
R3
Di-brominated
Mono-brominated
Mono-brominated β-keto ester (36a-43a)
Di-brominated β-keto ester (36b-43b)
spiro-hexadienones
spiro-hexadienones
(51-58
44-50
)
)
(
Entry
Brominated b-keto esters
Brominated spiro-hexadienones (%)a,b
Mono-brominated
Di-brominated
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
36a, R1 = C6H5; R2 = CH3; R3 = Br; R4 = H
36b, R1 = C6H5; R2 = CH3; R3, R4 = Br
44, 81
—
—
45, 45
—
46, 51
—
47, 38
—
48, 71
—
49, 80
—
50, 74
—
—
51, 91
52, 53
—
37b, R1 = 4-O2N–C6H4; R2 = CH3; R3, R4 = Br
38a, R1 = 3,4-(OCH2O)–C6H3; R2 = CH3; R3 = Br; R4 = H
38b, R1 = 3,4-(OCH2O)–C6H3; R2 = CH3; R3, R4 = Br
39a, R1 = 3,4,5-(CH3O)3–C6H2; R2 = CH3; R3 = Br; R4 = H
39b, R1 = 3,4,5-(CH3O)3–C6H2; R2 = CH3; R3, R4 = Br
40a, R1 = 4-CH3O–C6H4; R2 = CH3; R3 = Br; R4 = H
40b, R1 = 4-CH3O- C6H4; R2 = CH3; R3, R4 = Br
41a, R1 = R2 = C2H5; R3 = Br; R4 = H
53, 66
54, 66
—
55, 47
—
56, 54
—
57, 87
—
41b, R1 = R2 = C2H5; R3, R4 = Br
42a, R1 = C9H19; R2 = CH3; R3= Br; R4 = H
42b, R1 = C9H19; R2 = CH3; R3, R4 = Br
43a, R1 = 4-F3C–C6H4; R2 = CH3; R3 = Br; R4 = H
43b, R1 = 4-F3C–C6H4; R2 = CH3; R3, R4 = Br
58, 65
a
Yields refer to isolated and purified products.
b
Spectral data (1H, 13C NMR, IR, HRMS) are all compatible with the proposed structures.
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halogenated and halogenated spiro-hexadienones from Morita–
Baylis–Hillman adducts. The method is simple and allows for great
structural substitution diversity by only controlling the substitu-
tion pattern of the MBH adducts. The structure of the MBH adducts
is totally incorporated into the spiro-hexadienones, which contrib-
utes to the great atom economy exhibited by this approach. As the
cyclization occurs mediated by a hypervalent iodine reagent, the
whole sequence presents a reasonable level of sustainability. Due
to that, this method could be considered as one of the most
efficient to access these types of compounds. To the best of our
knowledge, this report is the first to describe the synthesis of
halogenated spiro-hexadienones from Morita–Baylis–Hillman
adducts.
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Acknowledgments
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W. P. A., M. L. and F. C. are grateful to the National Council for
Scientific and Technological Development (CNPq – Brazil) for
financial support and research fellowships. F. C. and L. J. M. are
grateful to São Paulo Research Foundation (FAPESP – Brazil)
for Grants (2011/20033-5; 2009/51602-5) and fellowship
(2009/18390-4), respectively.
10. Pirovani, R. V.; Ferreira, B. R. V.; Coelho, F. Synlett 2009, 2333–2337.
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Supplementary data
12. (a) Coelho, F.; Almeida, W. P.; Veronese, D.; Mateus, C. R.; Lopes, E. C. S.; Rossi,
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Supplementary data (all spectra (1H and 13C NMR) of com-
pounds synthesized in this work) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2014.07.114.
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References and notes
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