Michael addition/pericyclization/rearrangement - A multicomponent strategy for the synthesis of substituted resorcinols

Article abstract of DOI:10.1039/c2ob25776a

The combination of methyl 3,7-dioxo-2-diazo-4-octenoate from the zinc triflate catalyzed Mukaiyama-Michael reaction of methyl 3-tert-butylsilyloxy-2- diazobutenoate and 4-methoxy-3-buten-2-one with Michael acceptors (methyl vinyl ketone, N-phenylmaleimide, β-nitrovinylarenes) in the presence of a catalytic amount of base provides convenient access to highly substituted resorcinol derivatives. This transformation is achieved in an efficient one-pot multi-component transformation by the sequential addition of the reagents. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob25776a

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PAPER
Michael addition/pericyclization/rearrangement – a multicomponent strategy
for the synthesis of substituted resorcinols†
Yu Liu and Michael P. Doyle*
Received 23rd April 2012, Accepted 30th May 2012
DOI: 10.1039/c2ob25776a
The combination of methyl 3,7-dioxo-2-diazo-4-octenoate from the zinc triflate catalyzed Mukaiyama–
Michael reaction of methyl 3-tert-butylsilyloxy-2-diazobutenoate and 4-methoxy-3-buten-2-one with
Michael acceptors (methyl vinyl ketone, N-phenylmaleimide, β-nitrovinylarenes) in the presence of a
catalytic amount of base provides convenient access to highly substituted resorcinol derivatives. This
transformation is achieved in an efficient one-pot multi-component transformation by the sequential
addition of the reagents.
Introduction
Resorcinol and its derivatives are building blocks in organic
synthesis that can be recognized in many natural products,1,2
some of which exhibit biological activity.3–6 Efficient methods
for the synthesis of functionalized resorcinols are important, but
the primary route available to them is from resorcinol, especially
by electrophilic substitution, whose limitations include the direc-
tional selectivity of its hydroxyl groups.1 A limited number of
other methods that include ketene and diketene reactions
are available, but their general applicability is lacking.7,8
Using 3-tert-butylsilyloxy-substituted vinyl diazoacetates in
Mukaiyama type addition reactions to assemble complex
molecules,9,10 we have recently reported a new methodology that
provides access to 6-methyl-2-carboalkoxyresorcinols by a novel
base-catalyzed pericyclization/rearrangement reaction of an ene-
dione-diazoester, prepared from methyl 3-tert-butylsilyloxy-
2-diazobut-3-enoate (1) with 4-methoxy-3-buten-2-one (2).11
Scheme 1 Synthesis of 4-substituted-6-methyl-2-carboalkoxyresorci-
The product of the Mukaiyama–Michael reaction undergoes
elimination of tert-butyldimethylsilyl methyl ether to form 3 that
nols from methyl vinyl ketone.11
in the presence of a catalytic amount of base forms resorcinol
derivative 5 through pericyclic ring closure that occurs with the
loss of dinitrogen (Scheme 1). In that communication we pro-
vided evidence that the enedione-diazoester 3 underwent, in
competition with formation of 6-methyl-2-carboalkoxyresorcinol
transformation by evaluating the suitability of other nucleophiles
for the production of multi-substituted resorcinol derivatives.
We now report examples that suggest the scope and limitations
of the double Michael addition/pericyclization/rearrangement
process that produces 4-substituted-6-methyl-2-carboalkoxy-
resorcinol derivatives, and we demonstrate that this complex
process can be performed conveniently as a one-pot synthesis.
(5), base catalyzed Michael addition with methyl vinyl ketone
and subsequent conversion to the corresponding resorcinol com-
pounds (7).11 Encouraged by these results, we have explored this
Department of Chemistry and Biochemistry, University of Maryland,
Results and discussion
College Park, Maryland 20742, USA. E-mail: mdoyle3@umd.edu;
Tel: +301-405-1788
†Electronic supplementary information (ESI) available: NMR spectra,
HMBC experiment for structural elucidation of 13c, attempted reactions
with 20. See DOI: 10.1039/c2ob25776a
In our previous report, methyl vinyl ketone was shown to be
able to intercept enolate intermediate 4 to form the correspond-
ing Michael addition product (6) and subsequently converted to
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Table 1 One-pot reactions of 3, formed from 1 + 2 catalyzed by zinc
triflate, with N-phenylmaleimide under various conditionsa
Table 2 One-pot reactions of 3, formed from 1 + 2 catalyzed by zinc
triflate, with β-nitrostyrene under various conditionsa
Equiv.
NS
Yield
Entry
Base
Temp. 5 + 9 (%) 5 : 9
Equiv.
PMI
Yield of
5 + 8 (%)
Entry Base
Temp.
5 : 8
1
2
3
4
5
6
7
0.1 eq NaOH (aq)
0.1 eq NaOH (aq)
0.1 eq NaOH (aq)
0.1 eq NaOH (aq)
0.1 eq NaOH (aq)
0.2 eq NaOH (aq)
5 mol% Et3N
2
4
8
4
4
4
2
rt
rt
rt
0 °C
40 °C
rt
80
81
47
73
70
50
61
67 : 33
54 : 46
55 : 45
52 : 48
55 : 45
24 : 76
<4 : >96
1
2
3
4
5
6
7
0.1 eq NaOH (aq)
1
2
4
2
2
2
2
rt
rt
rt
0 °C
40 °C
rt
83
82
53
78
54
27
26b
75 : 25
52 : 48
49 : 51
50 : 50
57 : 43
32 : 68
—
0.1 eq NaOH (aq)
0.1 eq NaOH (aq)
0.1 eq NaOH (aq)
0.1 eq NaOH (aq)
0.2 eq NaOH (aq)
5 mol% Et3N
rt
rt
a Yields and product ratios are determined based on internal standard in
the reaction mixture.
a Yields and product ratios were determined by proton NMR
spectroscopy based on internal standard. b Yield of product 8, product 5
was not observed.
completely overcome the competing intramolecular pericycliz-
ation of 4 to 5.
resorcinol 7. By lowering the reaction temperature from ambient
to 0 °C and using six equivalents of methyl vinyl ketone, the
competing intramolecular reaction that forms resorcinol 5 could
be prevented, and Michael adduct 6 became the sole product of
this transformation (67% isolated yield). In our efforts to extend
this chemistry with other Michael acceptors, N-phenylmaleimide
(PMI) was employed in reactions with enedione-diazoacetate 3
based on its reactivity as an electrophile in conjugate addition
reactions.12,13 The intended reaction occurs but, unlike reactions
with methyl vinyl ketone in which the Michael addition product
(6) is stable under the reaction conditions, the Michael addition
product is not observed and, instead, resorcinol 8 is directly pro-
duced under the reaction conditions. The major competing reac-
tion is pericyclization/rearrangement of 3 that forms 5. Yields
and product ratios (8 : 5) as a function of different reaction con-
ditions with PMI are reported in Table 1. The yield of 8 and the
relative ratio of 8 : 5 increase significantly when two equivalents
of N-phenylmaleimide are employed (entries 1 and 2). However,
a further increase in the relative amount of N-phenylmaleimide
did not improve the product ratio and led to a decrease in
product yield (entry 3), possibly because of anionic polymeriz-
ation of PMI.14 Unlike reactions in which methyl vinyl ketone
was employed, where a lower temperature increased the ratio of
the Michael addition/pericyclization/rearrangement product (7)
relative to 5, with N-phenylmaleimide a lower reaction tempera-
ture did not increase the 8 : 5 ratio (entry 4). Also, heating the
reaction mixture at 40 °C in an oil bath did not alter the product
ratio, and the yields of both 5 and 8 decreased with increasing
temperature (entry 5). Increasing the amount and concentration
of aqueous sodium hydroxide had a detrimental effect on the
reaction by decreasing the yield of 8 although providing an
increase in the 8 : 5 ratio (entry 6). The use of a catalytic amount
of triethylamine instead of aqueous sodium hydroxide was also
evaluated, but only a small amount of the intended product (8)
was observed under these conditions (entry 7). These results
suggest that, although N-phenylmaleimide is sufficiently reactive
to capture enolate intermediate 4, it is not reactive enough to
β-Nitrostyrenes (NS) are widely applied as electrophiles in
Michael addition reactions.15 Due to the strong electron-with-
drawing nature of the nitro group, β-nitrostyrene has shown
higher reactivity compared to α,β-unsaturated carbonyl com-
pounds.16 With β-nitrostyrene as the electrophile in reactions
with α-diazo-β-ketoester 3, Michael adduct 9 is observed with
resorcinol 5 formed as by-product. To overcome the competition,
use of four equivalents of β-nitrostyrene was shown to be
optimum (Table 2, entry 2), but in this case temperature had
little influence on the product ratio (entries 4 and 5). An increase
in the amount and concentration of sodium hydroxide solution
does not provide a higher yield of the intended product, albeit
the ratio of 9 : 5 does improve (entry 6). However, in contrast to
the reactions with N-phenylmaleimide, switching from the
heterogeneous reaction conditions that employ aqueous sodium
hydroxide to homogeneous conditions that use triethylamine
improves the result significantly: the resorcinol by-product is no
longer observed in the reaction mixture, and the desired product
is obtained in 61% isolated yield. Furthermore, the amount of
β-nitrostyrene required could be reduced to two equivalents with
triethylamine as the catalyst (entry 7).
Efforts were made to convert compound 9 to the correspon-
dent resorcinol by treating compound 9 with a catalytic amount
of triethylamine. The reaction was sluggish at room temperature
with 10 mol% of triethylamine and could not reach full conver-
sion. Performing the reaction at 40 °C, however, allowed the
production of resorcinol 10 in good isolated yield (eqn (1)).
ð1Þ
To evaluate substrate scope with nitrostyrenes, we varied the
aryl group (Table 3). These reactions were performed in one pot
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Table 3 Synthesis of 4-(1′-aryl-2′-nitroethyl)resorcinols
Compound
Ar
Yield of 12 + 13a (%)
12 : 13
a
b
c
d
e
4-MeOC6H4
C6H5
4-FC6H4
4-CF3C6H4
1-Furyl
64
61b
72
74
89
88 : 12
82 : 18
78 : 22
77 : 23
71 : 29c
a Isolated yield after purification. b Yield of compound 10 (= 12b); for
13b see ESI. c Structure 13 was obtained as a complicated mixture of
several isomers.
Scheme 2 Proposed pathway from 9 to resorcinols 12 and the bis-
Michael addition products 13.
ð2Þ
by combining vinyl ether and enone overnight followed by
addition of the β-nitrostyrene and a catalytic amount of triethyl-
amine. Interestingly, in all cases the initial Michael adducts 9
were partially converted to the corresponding resorcinols 12 in
2 h, and with an extended reaction time of 24 h, the intermediate
Michael addition products (9) were fully consumed and re-
sorcinols 12 became the major products of these reactions. A by-
product resulting from a second addition of the nitrostyrene was
also identified in these cases, and its structure was determined to
be that of 13 by 1D and 2D NMR experiments.17 At this point,
we reexamined the reaction with β-nitrostyrene, and we found
that compound 9 could also be completely converted to resorci-
nol 10 at room temperature given a longer reaction time. The one
pot reaction provides better yield than the stepwise approach
(50% yield compared to 41% combined yield in two steps). The
nitrostyrene with an electron-withdrawing para-trifluoromethyl
substituent seems to favor by-product 13 more than those with
electron-donating groups, and a trend can be noticed when
switching from 4-methoxylphenyl (11a) to 4-trifluoromethyl
group (11d). However the difference in the 12 : 13 product ratio
is rather small. A nitrovinyl compound with a heterocyclic ring
(11e) also worked under these conditions.
From a mechanistic perspective, once the first addition
product (9) is formed, deprotonation gives enolate 14 that can
undergo pericyclization and rearrangement to resorcinol 12, but
it is also able to react with a second nitrostyrene at the position
α to the carbonyl group, which is sterically favored compared to
the γ position. Tautomerization of the double bond would lead to
13 (Scheme 2). The formation of 13 is an indication of the high
reactivity of nitrostyrenes in comparison with other electrophiles
since this second addition is not observed in reactions with other
electrophiles in this system.
ð3Þ
Replacing the CH2 group in 1 with an NH group could
potentially lead to formation of poly-substituted pyridines if the
pericyclization/rearrangement transformation is possible with
this compound. In order to explore this transformation, ethyl
carbamoyl diazoacetate (19) was synthesized (eqn (4)).18
ð4Þ
We subjected 19 and 4-methoxy-3-buten-2-one (2) to the con-
ditions developed for the Mukaiyama–Michael addition reaction.
The enone substrate 2 was fully consumed; however, the desired
adduct 20 was obtained only in 35% yield (eqn (5)). Using
an alternative procedure in which trialkylsilyl triflate was used
to promote an aza-Michael addition of a primary amide and
α,β-unsaturated ketones,19 we were able to synthesize diazoester
20 in 66% yield (eqn (5)). In contrast to enedione-diazoester 3,
ethyl 2-(3-oxobut-1-enylcarbamoyl) diazoacetate (20) is suffi-
ciently stable to undergo silica gel purification. In addition, the
1H NMR spectrum of compound 20 shows a coupling constant
of 8 Hz between the two vinyl protons indicating a cis geometry
of the alkene double bond. By contrast, a 16 Hz coupling con-
1
Commonly used enones such as cyclohexenone and chalcone
failed to provide the corresponding adducts, and resorcinol
5 was the only product observed (e.g., eqn (2) and (3)).
Apparently these enones were not sufficiently reactive, due to
electronic or steric factors, to capture the transient enolate inter-
mediate (5) and thus could not compete with the pericyclization
reaction.
stant between the vinyl protons was observed in the H NMR
spectrum of compound 3 which indicates the trans geometry of
the alkene. One possible explanation for this difference is that
compound 20 takes a cis geometry so it can benefit from an
intramolecular hydrogen bond while formation of a hydrogen
bond is not an option in the structure of 3. However, ethyl
2-(3-oxobut-1-enylcarbamoyl)diazoacetate (20) was unable to
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undergo the desired cyclization/rearrangement reaction under a
wide variety of reaction conditions.†
then added 2.0 mmol N-phenylmaleimide and 2 mL DCM, fol-
lowed by 1.0 mL of 0.1 mol L−1 aqueous NaOH (0.1 mmol).
After rapid stirring for 2 h, the stirrer was discontinued where-
upon a deep red aqueous phase separated from a yellow organic
phase. The organic phase was then removed by pipet and run
through a short silica plug to remove the small amount of water.
The resulting solution was concentrated under reduced pressure.
The crude reaction mixture was purified by silica gel chromato-
graphy, eluting with 1 : 2 EtOAc–hexane to give 129 mg
(0.363 mmol) yellow solid (39%). 8: 1H NMR (400 MHz,
CDCl3) δ 9.88 (br, 2H), 7.49 (t, J = 8.0 Hz, 2H), 7.40 (t, J = 8.0
Hz, 1H), 7.36 (d, J = 4.0 Hz, 2H), 7.20 (s, 1H), 4.09 (s, 3H),
3.98 (dd, J = 4.0, 12.0 Hz, 1H), 3.23 (dd, J = 8.0, 12.0 Hz, 1H),
2.97 (dd, J = 4.0, 16.0 Hz, 1H), 2.17 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 177.6, 175.7, 170.0, 139.3, 132.4, 137.4,
129.1, 128.5, 126.6, 117.0, 115.1, 100.0, 77.2, 53.1, 43.6, 36.1,
15.1; IR (neat): 3369, 3068 (br), 2926, 2854, 1706, 1667, 1625
1600 cm−1; HRMS (ESI) for C19H18NO6 [M + H]+ calcd
356.1135; found 356.1111.
ð5Þ
Conclusions
We report a straightforward synthesis of complex resorcinol
derivatives through a novel multi-component strategy that begins
with an efficient Lewis acid catalyzed Michael addition of enone
2 to enol diazoacetate 1 and continues with a base catalyzed
Michael addition of a vinyl ketone, a maleimide, or a β-nitro-
styrene and pericyclization/rearrangement. The second Michael
addition and pericyclization/rearrangement are highly sensitive
to base strength. The overall process can be achieved with the
three components added in sequence in a one-pot manner, which
is highly efficient and raises interest for further elaboration.
Synthesis of methyl 3,7-dioxo-4-(1-phenyl-2-nitroethyl)-2-
diazo-(E)-oct-5-enoate (9). The mixture of zinc triflate and 2
identical to that used for the synthesis of 8 was stirred at room
temperature, then methyl 3-tert-butyldimethylsilanyloxy-2-dia-
zobut-3-enoate (1) (281 mg, 1.10 mmol) was added all at once.
After 16 h 2 equiv. of solid β-nitrostyrene (298 mg, 2.00 mmol)
was added to the reaction solution. When the yellow solid
(β-nitrostyrene) was fully dissolved 5.0 mol% of triethylamine
(5 mg, 0.05 mmol) was added causing the color of the solution
to turn from yellow to deep red. The reaction was stirred at room
temperature for 2 h during which the color of the solution
became darker. Product isolation was performed as previously
described, and the product was isolated as a yellow syrup in
204 mg (0.567 mmol, 61%) as a mixture of two diastereomers
that could not be separated by chromatography. NMR analysis
Experimental section
Materials and methods
Reactions were performed in oven-dried (140 °C) or flame-dried
glassware. Dichloromethane (DCM) was passed through a
solvent column prior to use and was not distilled. Thin layer
chromatography (TLC) was carried out using EM Science silica
gel 60 F254 plates. The developed chromatogram was visualized
by UV lamp (254 nm) or ethanolate phosphomolybdic acid
(PMA). Liquid chromatography was performed using a forced
flow (flash chromatography) of the indicated system on silica gel
(230–400 mesh). NMR spectra were measured on a 400 MHz
spectrometer (1H at 400 MHz, 13C at 100 MHz); chemical shifts
are reported in ppm with the solvent signals as reference, and
coupling constants (J) are given in hertz. Peak information is
described as: br = broad, s = singlet, d = doublet, t = triplet,
q = quartet, hept = heptet, m = multiplet, comp = composite.
High Resolution Mass Spectra (HRMS) were recorded by a
ESI-TOF instrument in positive mode. 3-tert-Butyldimethylsila-
nyloxy-2-diazobut-3-enoate (1) was prepared by the method
described by Ueda and Davies.20 Zinc triflate, 4-methoxy-3-
buten-2-one (2) and β-nitrostyrenes were purchased from Aldrich
and used as received. The characterization of compound 19 has
been reported.19
1
showed a 2 : 1 diastereomeric ratio. 9, major isomer: H NMR
(400 MHz, CDCl3) δ 7.33–7.18 (comp, 5H), 6.69 (dd, J = 8.0,
16.0 Hz, 1H), 6.35 (d, J = 16.0 Hz, 1H), 5.14 (t, J = 8.0 Hz,
1H), 4.68–4.57 (comp, 2H), 4.20–4.05 (m, 1H), 3.79 (s, 3H);
2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.4, 188.7,
160.8, 140.2, 136.6, 135.8, 128.9, 128.3, 128.0, 78.3, 52.8,
1
52.4, 45.0, 27.3; 9, minor isomer: H NMR (400 MHz, CDCl3)
δ 6.40 (dd, J = 8.0 Hz, 16.0 Hz, 1H), 5.98 (d, J = 16.0 Hz, 1H),
4.94 (t, J = 8.0 Hz, 1H), 4.76 (dd, J = 8.0 Hz, 12.0 Hz, 1H),
4.68–4.57 (m, 1H), 4.20–4.05 (m, 1H), 3.85 (s, 3H); 2.04
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.5, 189.6, 161.0,
141.1, 136.0, 134.5, 129.0, 128.8, 128.1, 77.8, 52.6, 52.2, 45.6,
26.8; IR (neat): 2955, 2924, 2856, 2361, 2336, 2143, 1717,
1677, 1651 cm−1; HRMS (ESI) for C17H18N3O6 [M + H]+ calcd
360.1195; found: 360.1197.
Synthesis of methyl 2,6-dihydroxy-3-methyl-5-(2,5-dioxo-1-
phenylpyrrolidin-3-yl)benzoate (8). To a 4 dram vial was added
zinc triflate (4 mg, 0.01 mmol), followed by trans-4-methoxy-3-
buten-2-one (2) (103 mg, 0.930 mmol) and 4.0 mL of dry DCM.
The mixture was stirred at room temperature. Methyl 3-tert-
butyldimethylsilanyloxy-2-diazobut-3-enoate (1) (307 mg,
1.20 mmol) was added via syringe all at once. After 16 h the
reaction mixture was concentrated under reduced pressure. To
the resulting concentrated reaction mixture in a 4 dram vial was
Synthesis of methyl 2,6-dihydroxy-3-methyl-5-(1-phenyl-2-
nitroethyl)benzoate (10). To a 4 dram vial was added 33 mg
of methyl-3,7-dioxo-4-(1-phenyl-2-nitroethyl)-2-diazo-(E)-oct-5-
enoate 9a (0.10 mmol) and 0.5 mL DCM, then 1 mg of triethyl-
amine (0.01 mmol). The reaction mixture was heated with
stirring at 40 °C in an oil bath for 1 h. The resulting solution was
concentrated under reduced pressure. The crude reaction mixture
was purified with a short silica plug, eluting with DCM to give
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20 mg (0.067 mmol, 67%) of a yellow oil. 10: 1H NMR
(400 MHz, CDCl3) δ 9.92 (br, 2H), 7.34–7.22 (comp, 5H), 7.03
(s, 1H), 5.16 (t, J = 8.0 Hz, 1H), 5.06 (dd, J = 8.0, 12.0 Hz, 1H),
4.96 (dd, J = 8.0, 12.0 Hz, 1H), 4.05 (s, 3H), 2.10 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 170.1, 158.0, 155.9, 138.9, 136.9,
128.8, 127.8, 127.3, 116.8, 116.7, 99.7, 77.7, 53.0, 43.1, 15.4;
IR (neat): 3427, 3121, 3026, 2959, 2921, 2849, 2358, 2329,
1673, 1624, 1549 cm−1; HRMS (ESI) for C17H18NO6 [M + H]+
calcd 332.1134; found 332.1128.
Methyl 2,6-dihydroxy-3-methyl-5-[1-(4-methoxyphenyl)-2-
nitroethyl]benzoate (12a). 1H NMR (400 MHz, CDCl3) δ 9.86
(br, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.01 (s, 1H), 6.84 (d, J = 8.0
Hz, 2H), 5.10 (t, J = 8.0 Hz, 1H), 5.02 (dd, J = 8.0 Hz, 12.0 Hz,
1H), 4.90 (dd, J = 8.0 Hz, 12.0 Hz, 1H), 4.04 (s, 3H), 3.76
(s, 3H), 2.10 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.2,
158.8, 157.9, 155.8, 136.8, 130.8, 128.9, 117.1, 117.0, 116.7,
114.2, 77.9, 55.2, 53.0, 42.4, 15.4; IR (neat): 3381, 3167, 2957,
2838, 1676, 1613, 1549, 1436 cm−1; HRMS (ESI) for
C18H20NO7 [M + H]+ calcd 362.1240; found 362.1224.
Synthesis of methyl 2,6-dihydroxy-3-methyl-5-(1-phenyl-2-
nitroethyl)benzoate (10) (one-pot method). To a 4 dram vial was
added zinc triflate (2 mg, 0.005 mmol), followed by enone 2
(50 mg, 0.45 mmol) and 2 mL of dry DCM. The mixture was
stirred at room temperature. Enol diazoacetate 1 (180 mg,
0.70 mmol) was added all at once. The yellow solution was
allowed to react overnight. After 16 h, 2 equiv. of β-nitrostyrene
(150 mg, 1.00 mmol) was added to the solution, followed by tri-
ethylamine (3 mg, 0.03 mmol, 5 mol%) after β-nitrostyrene was
fully dissolved. The color of the solution turned from yellow to
deep red upon addition of the base. The reaction was stirred at
room temperature for 24 h during which time the solution
became cloudy, and the red color became darker. The resulting
solution was concentrated under reduced pressure, and the
residue was purified by silica gel chromatography, eluting with
1 : 6 EtOAc–hexane, to give 76 mg (0.23 mmol, 50%) of a pale
yellow syrup as methyl 2,6-dihydroxy-3-methyl-5-(1-phenyl-2-
nitroethyl)benzoate (10 or 12b). Switching the eluent to 1 : 2
EtOAc–hexane allowed the isolation of 25 mg (0.049 mmol,
11%) of the double addition by-product (13b) as a mixture
of multiple isomers that could not be separated by
chromatography.†
Methyl 3,7-dioxo-4,6-[1-(4-methoxyphenyl)-2-nitroethyl]-2-
diazooct-5-enoate (13a). Major isomer: 1H NMR (400 MHz,
CDCl3) δ 7.44 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H),
6.94 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 8.0 Hz, 2H), 6.62 (d, J =
8.0 Hz, 1H), 5.51 (t, J = 12.0 Hz, 1H), 5.26 (dd, J = 8.0 Hz,
12.0 Hz, 1H), 4.87 (dd, J = 4.0 Hz, 8.0 Hz, 1H), 4.74 (dd, J =
4.0 Hz, 12.0 Hz, 1H), 3.95 (comp, 1H), 3.85 (s, 3H), 3.81
(s, 3H), 3.76 (s, 3H), 3.74 (comp, 1H), 3.52 (dd, J = 8.0 Hz,
12.0 Hz, 1H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 200.5, 189.0, 161.2, 159.6, 159.3, 144.4, 140.6, 130.8, 129.7,
129.1, 127.9, 114.8, 114.4, 77.6, 77.5, 55.4, 55.2, 52.6, 48.9,
45.6, 43.0, 27.6; IR (neat): 2957, 2923, 2145, 1711, 1673, 1649,
1610, 1549, 1512, 1437 cm−1; HRMS (ESI) for C27H29N4O10
[M + H]+ calcd 569.1874; found 569.1874.
Synthesis of methyl 2,6-dihydroxy-3-methyl-5-[1-(4-fluoro-
phenyl)-2-nitroethyl]benzoate (12c) and methyl 3,7-dioxo-4,6-
(1-(4-fluorophenyl)-2-nitroethyl)-2-diazooct-5-enoate (13c). To a
4 dram vial was added zinc triflate (2 mg, 0.005 mmol), fol-
lowed by enone 2 (50 mg, 0.45 mmol) and 2 mL of dry DCM.
The resulting mixture was stirred at room temperature. Enol dia-
zoacetate 1 (180 mg, 0.70 mmol) was added all at once. The
yellow solution was allowed to react overnight. After 16 h, 2.0
equiv. of solid 4-fluoro-β-nitrostyrene (167 mg, 1.00 mmol) was
added to the solution followed by triethylamine (3 mg,
0.03 mmol, 5 mol%) when 4-fluoro-β-nitrostyrene was fully dis-
solved. Reaction was performed as for the synthesis of 12a and
13a. The resulting solution was concentrated under reduced
pressure, and the residue was purified by silica gel chromato-
graphy, eluting with 1 : 6 EtOAc–hexane, to give 88 mg
(0.25 mmol, 56%) of 12c as pale yellow liquid then 40 mg
(0.072 mmol, 16%) of 13c as a yellow syrup which is a
2 : 1 mixture of two diastereomers that could not be separated by
chromatography.
Synthesis of methyl 2,6-dihydroxy-3-methyl-5-[1-(4-methoxy-
phenyl)-2-nitroethyl]benzoate (12a) and methyl 3,7-dioxo-4,6-
[1-(4-methoxyphenyl)-2-nitroethyl]-2-diazooct-5-enoate
(13a).
To a 4 dram vial was added zinc triflate (2 mg, 0.005 mmol), fol-
lowed by enone 2 (50 mg, 0.45 mmol) and 2 mL of dry DCM.
The mixture was stirred at room temperature. Enol diazoacetate 1
(180 mg, 0.70 mmol) was added all at once. The resulting
yellow solution was allowed to react overnight. After 16 h, 2.0
equiv. of 4-methoxy-β-nitrostyrene (179 mg, 1.0 mmol) was
added to the solution, followed by triethylamine (3 mg,
0.03 mmol, 5 mol%) when 4-methoxy-β-nitrostyrene was fully
dissolved. The color of the solution turned from yellow to deep
red upon addition of the base. The reaction mixture was stirred at
room temperature for 24 h during which time the solution
became cloudy and the color became darker. The resulting sol-
ution was concentrated under reduced pressure, and the residue
was purified by silica gel chromatography, eluting with 1 : 4
EtOAc–hexane, to give 90 mg (0.25 mmol, 56%) of a pale
yellow solid identified as methyl 2,6-dihydroxy-3-methyl-5-
[1-(4-methoxyphenyl)-2-nitroethyl]benzoate (12a). Switching
the eluent to 1 : 2 EtOAc–hexane allowed the isolation of 21 mg
(0.036 mmol, 8%) of a yellow syrup of methyl 3,7-dioxo-4,6-
[1-(4-methoxyphenyl)-2-nitroethyl]-2-diazooct-5-enoate (13a) as
a 6 : 1 mixture of two diastereomers that could not be separated
by chromatography.
Methyl 2,6-dihydroxy-3-methyl-5-[1-(4-fluorophenyl)-2-nitro-
ethyl]benzoate (12c). 1H NMR (400 MHz, CDCl3) δ 9.99 (br,
1H), 9.86 (br, 1H), 7.26 (t, J = 8.0 Hz, 2H), 7.00 (t, J = 8.0 Hz,
2H), 7.00 (s, 1H), 5.12 (t, J = 8.0 Hz, 1H) 5.05 (dd, J = 8.0 Hz,
16.0 Hz, 1H), 4.92 (dd, J = 8.0 Hz, 16.0 Hz, 1H), 4.06 (s, 3H),
2.10 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.1, 161.9
(d, JCF = 240 Hz), 158.0, 158.9, 136.7, 134.6, 129.4 (d, JCF
=
10 Hz), 116.9, 116.5, 115.8 (d, JCF = 20 Hz), 99.8, 77.7, 53.0,
42.6, 15.4; IR (neat): 3432, 3117, 2962, 1673, 1625, 1551,
1510, 1437 cm−1; HRMS (ESI) for C17H16FNO6 [M + H]+
calcd 350.1040; found 350.1019.
Methyl 3,7-dioxo-4,6-[1-(4-fluorophenyl)-2-nitroethyl]-2-dia-
zooct-5-enoate (13c). Major isomer: 1H NMR (400 MHz,
6392 | Org. Biomol. Chem., 2012, 10, 6388–6394
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CDCl3) δ 7.45 (dd, J = 4.0 Hz, 8.0 Hz, 2H), 7.14–7.10 (comp,
2H), 7.02–6.94 (comp, 4H), 6.65 (d, J = 8.0 Hz, 1H), 5.53
(t, J = 8.0 Hz, 1H), 5.22 (dd, J = 8.0 Hz, 12.0 Hz, 1H), 4.91(dd,
J = 4.0 Hz, 12.0 Hz, 1H), 4.76 (dd, J = 4.0 Hz, 8.0 Hz, 1H),
4.04 (ddd, J = 4.0 Hz, 8.0 Hz, 12.0 Hz, 1H), 3.86 (s, 3 H), 3.83
(dd, J = 4.0 Hz, 12.0 Hz, 1H) 3.66 (dd, J = 8.0 Hz, 12.0 Hz,
1H); 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.0, 188.9,
162.4 (d, JCF = 200 Hz), 162.4 (d, JCF = 190 Hz), 161.3, 144.0,
140.8, 134.4 (d, JCF = 0.3 Hz), 131.8 (d, JCF = 0.3 Hz), 130.2
(d, JCF = 10 Hz), 129.8 (d, JCF = 10 Hz), 116.4 (d, JCF = 20
Hz), 116.0 (d, JCF = 20 Hz), 77.5, 77.2, 52.7, 48.9, 45.5, 42.9,
8.0 Hz, 1H), 5.60 (t, J = 8.0 Hz, 1H), 5.23 (dd, J = 8.0 Hz, 12.0
Hz, 1H), 5.07 (dd, J = 4.0 Hz, 12.0 Hz, 1H), 5.06 (comp, 1H),
4.65 (dd, J = 8.0 Hz, 12.0 Hz, 1H), 4.56 (dd, J = 4.0 Hz, 12.0
Hz, 1H), 4.27 (ddd, J = 4.0 Hz, 8.0 Hz, 12.0 Hz, 1H), 3.56
(s, 3H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) 198.7,
188.4, 160.6, 143.0, 142.3, 141.6, 139.9, 137.4, 137.1, 128.7,
127.5, 126.3, 126.0 (d, JCF = 3 Hz), 125.6 (d, JCF = 3 Hz),
123.7 (q, JCF = 270 Hz), 77.1, 77.1, 52.5, 49.0, 46.4, 42.07,
1
27.1; visible signals of the minor isomer: H NMR (400 MHz,
CDCl3) δ 7.13 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H),
5.76 (t, J = 8.0 Hz, 1H), 4.12 (s, 3H), 2.19 (s, 3H); 13C NMR
(100 MHz, CDCl3) 129.9, 127.3, 125.2 (d, JCF = 3 Hz), 125.1(d,
1
27.5; visible signals of the minor isomer: H NMR (400 MHz,
CDCl3) δ 7.24 (dd, J = 4.0 Hz, 8.0 Hz, 2H), 7.12–7.10 (comp,
4H), 7.07 (dd, J = 4.0 Hz, 8.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 1H),
5.52 (comp, 1H), 4.99 (dd, J = 4.0 Hz, 12.0 Hz, 1H), 4.56 (dd,
J = 8.0 Hz, 12.0 Hz, 1H), 4.48 (dd, J = 4.0 Hz, 8.0 Hz, 1H),
4.15–4.09 (comp, 1H), 3.86–3.81 (1H), 3.63–3.68 (1H), 2.37
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 199.1, 188.9, 161.5,
JCF = 3 Hz), 53.1, 48.7, 44.1, 40.8; IR (neat): 2960, 2923, 2853,
2154, 1714, 1679, 1651, 1621, 1554, 1439 cm−1; HRMS (ESI)
for C27H22F6N4O8 [M + H]+ calcd 645.1419; found 645.1425.
Synthesis of methyl 2,6-dihydroxy-3-methyl-5-[1-(1-furyl)-2-
nitroethyl]benzoate (12e). To a 4 dram vial was added zinc
triflate (2 mg, 0.005 mmol), followed by enone 2 (50 mg,
0.45 mmol) and 2 mL of dry DCM. With stirring at room temp-
erature enol diazoacetate 1 (180 mg, 0.70 mmol) was added all
at once, and the yellow solution was allowed to react overnight.
After 16 h, 2.0 equiv. of 2-(2-nitrovinyl)furan (150 mg,
1.00 mmol) was added, followed by 5 mol% triethylamine
(3 mg, 0.03 mmol) when 2-(2-nitrovinyl)furan was fully dis-
solved. The color of the solution turned from yellow to deep red
upon addition of the base. The reaction solution was stirred at
room temperature for 24 h during which time the color of the
solution became darker. The resulting solution was concentrated
under reduced pressure, and the crude residue was purified by
silica gel chromatography, eluting with 1 : 6 EtOAc–hexane,
to give 90 mg (0.28 mmol, 63%) of a yellow solid as major
product 12e. In addition, 58 mg (0.12 mmol, 26%) double
addition by-product was obtained as a mixture of multiple
isomers which could not be separated by chromatography. 12e:
1H NMR (400 MHz, CDCl3) δ 9.94 (br, 2H), 7.37 (s, 1H), 7.02
(s, 1H), 6.32 (d, J = 4.0 Hz), 6.18 (J = 4.0 Hz), 5.25 (t, J = 8.0
Hz), 4.91 (hept, J = 8.0 Hz), 4.07 (s, 3H), 2.10 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 170.1, 158.4, 155.7, 142.4, 137.1,
117.0, 114.4, 110.5, 107.3, 99.6, 76.3, 53.0, 37.2, 15.3; IR
160.6, 143.4, 141.0, 131.8 (d, JCF = 0.3 Hz), 130.0 (d, JCF
=
7 Hz), 129.0 (d, JCF = 7 Hz), 115.8 (d, JCF = 17 Hz), 115.5 (d,
JCF = 17 Hz), 77.5, 77.3, 52.4, 49.0, 46.3, 41.6, 27.1; IR (neat):
2148, 1711, 1675, 1649, 1550, 1510, 1437 cm−1; HRMS (ESI)
for C25H23F2N4O8 [M + H]+ calcd 545.1484; found 545.1492.
Synthesis of methyl 2,6-dihydroxy-3-methyl-5-[1-(4-trifluoro-
methylphenyl]-2-nitroethyl)benzoate (12d) and methyl 3,7-
dioxo-4,6-[1-(4-trifluoromethylphenyl)-2-nitroethyl]-2-diazooct-
5-enoate (13d). To a 4 dram vial was added zinc triflate (2 mg,
0.005 mmol), followed by enone 2 (50 mg, 0.45 mmol) and
2 mL of dry DCM. The mixture was stirred at room temperature.
Enol diazoacetate 1 (180 mg, 0.70 mmol) was added all at once.
The yellow solution was allowed to react overnight. After 16 h,
2.0 equiv. of solid 4-trifluoromethyl-β-nitrostyrene (216 mg,
1.00 mmol) was added to the solution followed by triethylamine
(3 mg, 0.03 mmol, 5 mol%) when the 4-trifluoromethyl-β-nitros-
tyrene was fully dissolved. Reaction was performed as for the
synthesis of 12a and 13a. The resulting solution was concen-
trated under reduced pressure, and the residue was purified by
silica gel chromatography, eluting with 1 : 6 EtOAc–hexane, to
give 87 mg (0.26 mmol, 57%) of 12d as pale yellow oil then
48 mg (0.075 mmol, 17%) and 13d as a yellow syrup which is a
3 : 1 mixture of two diastereomers that could not be separated by
chromatography.
(neat): 3392, 3125, 2967, 2923, 1669, 1626, 1545, 1437 cm−1
;
HRMS (ESI) for C15H16NO7 [M + H]+ calcd 322.0927; found
322.0906.
Methyl 2,6-dihydroxy-3-methyl-5-[1-(4-trifluoromethyl-
phenyl)-2-nitroethyl]benzoate (12d). 1H NMR (400 MHz,
CDCl3) δ 10.02 (br, 1H), 9.87 (br, 1H), 7.57 (d, J = 8.0 Hz),
7.42 (d, J = 8.0 Hz), 7.02 (s, 1H), 5.19 (t, J = 8.0 Hz) 5.09 (dd,
J = 8.0 Hz, 12.0 Hz), 5.02 (dd, J = 8.0 Hz, 12.0 Hz), 4.07
(s, 3H), 2.11 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.1,
158.3, 155.9, 143.1, 136.7, 134.6, 129.6 (d, JCF = 30 Hz),
129.4, 128.2, 125.7(d, JCF = 3 Hz), 124.0 (q, JCF = 270 Hz),
99.8, 77.2, 53.1, 43.2, 15.3; IR (neat): 3435, 3110, 2965, 2924,
1674, 1621, 1553, 1439 cm−1; HRMS (ESI) for C18H17F3NO6
[M + H]+ calcd 400.1008; found. 400.1014.
Acknowledgements
The support of the National Institutes of Health (GM 46503) for
this research is gratefully acknowledged.
Notes and references
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This journal is © The Royal Society of Chemistry 2012
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This journal is © The Royal Society of Chemistry 2012