Ortho-amidoalkylation of phenols via tandem one-pot approach involving oxazine intermediate

Article abstract of DOI:10.1021/jo3017132

A new and efficient method for ortho-amidoalkylation of phenols via Mannich-type condensation with formaldehyde and lactams using recyclable solid acid catalyst is described. This is the first report for ortho-amidoalkylation of phenols by lactams via Mannich-type condensation. LC-ESI-MS/MS based mechanistic study revealed that reaction proceeds through o-quinone methide (o-QM) and an oxazine intermediate via tandem Knoevenagel condensation, formal [4 + 2]-Diels-Alder cycloaddition and acid catalyzed oxazine ring-opening.

Full text of DOI:10.1021/jo3017132

Note
pubs.acs.org/joc
ortho-Amidoalkylation of Phenols via Tandem One-Pot Approach
Involving Oxazine Intermediate
Ramesh Mudududdla,† Shreyans K. Jain,‡ Jaideep B. Bharate,† Ajai P. Gupta,§ Baldev Singh,‡
Ram A. Vishwakarma,*,†,‡ and Sandip B. Bharate*,†
†Medicinal Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu-180001, India
‡Natural Products Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu-180001, India
§Quality Assurance and Quality Control Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu-180001, India
S
* Supporting Information
ABSTRACT: A new and efficient method for ortho-
amidoalkylation of phenols via Mannich-type condensation
with formaldehyde and lactams using recyclable solid acid
catalyst is described. This is the first report for ortho-
amidoalkylation of phenols by lactams via Mannich-type
condensation. LC-ESI-MS/MS based mechanistic study
revealed that reaction proceeds through o-quinone methide
(o-QM) and an oxazine intermediate via tandem Knoevenagel
condensation, formal [4 + 2]-Diels−Alder cycloaddition and
acid catalyzed oxazine ring-opening.
annich reaction is one-pot multicomponent approach
for aminoalkylation of enolizable CH-acidic substrates.
reaction conditions of available amidoalkylation protocols
necessitates development of an efficient, widely applicable,
diversity oriented protocol.
M
It is one of the most widely used reactions in synthetic and
medicinal chemistry,1−4 and its utility in asymmetric synthesis
of α- and β-amino acids2 and complex natural products5 has
been reported. Further, Mannich bases and derivatives are
versatile synthetic intermediates and are employed in diverse
types of organic transformations.6 The reaction tolerates
diversity of reactants such as ammonia, primary or secondary
aliphatic as well as aromatic amines and active hydrogen
components such as ketones, esters, α-alkyl pyridines as well as
electron-rich aromatics.4 Although several variations of this
reaction are published,3,7 its utility for cyclic ortho-amidoalky-
lation of phenols has never been reported. In the present paper,
we discovered new simple and efficient protocol for ortho-
amidoalkylation of phenols using modified Mannich reaction.
Amidoalkylation is a useful variation of classical Mannich
reaction, wherein amine precursor is replaced with amide.8,9
The reaction has great utility for synthesis of versatile synthons
in total synthesis of alkaloids,9 for example, pyrrolidinone/
piperidinone class of alkaloids, that widely occur in nature.10
Primarily two types of amidoalkylation protocols are known viz.
acid-catalyzed and metal catalyzed electrophilic substitution
reactions. Acid catalyzed protocols involve the use of various
amidomethyl electrophiles11 in the presence of acidic catalysts
such as H2SO4, HCl, TFA, methanesulfonic acid or Lewis acid.
Metal-catalyzed protocols include dinuclear Zn-catalyzed
sulfonamidoalkylation,12 Ru(bpy)3Cl2 catalyzed amidoalkyla-
tion of electron-rich aromatics,13 bismuth(III) triflate catalyzed
amidoalkylation of α-acetoxy lactams using allyltrimethylsilane
nucleophile14 and SmI3 catalyzed amidoalkylation of 1,3-
dicarbonyl compounds.8 Poor substrate scope and harsh
In continuation to our recent methodology15 for one-pot
multicomponent synthesis of flavans directly from phenolic
precursors, we observed formation of Mannich-type product
1a2 when 2,4-diformyl phloroglucinol (2a) was treated with N-
vinyl caprolactam (3a) and formaldehyde (4) in presence of
silica−HClO4 (50 mol %) in acetonitrile as depicted in Figure
1. On the basis of our flavan protocol, we expected formation of
2-caprolactam linked benzopyran product 1a1; however,
Mannich-type product 1a2 was obtained.
Figure 1. Reaction of 2,4-diformyl phloroglucinol (2a) with
formaldehyde (4) and N-vinyl caprolactam (3a).
Formation of Mannich-type of product 1a2 indicated that the
reaction sequence must be involving devinylation of N-vinyl-
caprolactam (3a) followed by Mannich-type of condensation.
Thus, first we sought to investigate reaction conditions essential
for devinylation for which control experiments shown in Table
1 were performed. It was interesting to observe that no thermal
degradation occurred in presence of only acetonitrile (entry 1)
Received: August 12, 2012
© XXXX American Chemical Society
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Note
Further, we investigated whether the reaction proceeds
simply with the use of caprolactam (5a) instead of N-vinyl
caprolactam (3a). Reaction of ortho-cresol (2g) with
caprolactam (5a) and formaldehyde (4) in presence of
silica−HClO4 in acetonitrile produced Mannich-type product
1h in 85% yield (Table 2, entry 1). This result further
Table 1. Investigation of Reaction Conditions for
Devinylation
Table 2. Optimization of Reaction Conditions for Mannich-
Type Reaction
a
entry
reaction conditions
ACN, 80 °C
ACN, HCHO, 80 °C
time (h)
% yield of 9a
b
1
2
3
4
4
4
2
6
0
b
0
ACN, Silica−HClO4, 80 °C
70
b
ACN, Silica−HClO4, rt
0
a
b
GC−MS yield. Unreacted starting material 3a was recovered.
temp
time
(h)
yield
a
or with formaldehyde and acetonitrile (entry 2). However,
when N-vinyl caprolactam (3a) was heated in presence of
silica−HClO4 in acetonitrile at 80 °C, caprolactam (5a) was
formed in 70% yield. These results indicated that devinylation
occurs only under acidic conditions. Further optimization
revealed that presence of silica−HClO4 catalyst as well as
heating condition is required for devinylation.
entry
solvent
MeCN
catalyst
(°C)
(%)
1
2
3
4
Silica−HClO4
none
80
100
80
6
6
6
6
85
0
DMSO
MeOH
none
0
MeOH:H2O
(1:1)
none
80
0
5
6
MeCN
none
80
90
6
6
0
0
After investigating devinylation of N-vinyl lactam, we then
looked at the substrate scope of tandem three-component
devinylation followed by Mannich-type condensation reaction
by varying vinyl caprolactam as well as phenolic precursors
(Figure 2). Like N-vinyl caprolactam (3a), N-vinyl pyrrolidi-
none (3b) also participated well in this reaction (products 1f
and 1i). Diacyl phloroglucinols 2b−2e produced corresponding
Mannich-type products 1b−1f in good yields. Next, we studied
this reaction for phenol and ortho-substituted phenols, which
produced the corresponding Mannich products 1g1, 1h and 1i
in good yields. o-Cresol showed better reactivity compared to
MeOH:H2O
(1:1)
Silica−HClO4
7
8
MeCN:H2O
(1:1)
Silica−HClO4
90
80
6
<5
Acetic acid
Acetic acid/
CH3COONa
10
<10
a
Isolated yields after silica gel (#100−200) column chromatography.
supported our assumption that devinylation occurs before
Mannich-type condensation. Solvents commonly employed in
classical Mannich reaction were not found suitable for
amidoalkylation (entries 2−5). When the reaction was
performed in the presence of acetic acid/sodium acetate
(entry 8), the desired Mannich-type product was formed,
phenol. Earlier, Bieraugel et al.16 prepared compound 1g1 in 7-
̈
steps starting from salicylaldehyde, as key precursor to
synthesize corresponding lactam.
Figure 2. Scope of the reaction for tandem devinylation followed by Mannich-type condensation. Reaction time and isolated yields are shown in the
parentheses. For entry 1g1, a dicaprolactam linked product 1g2 was also formed (∼35% yield); however, it was difficult to isolate.
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Note
Figure 3. Mannich-type condensation of phenols with lactams. Reaction time and isolated yields are shown in the parentheses. For entry 1g1, a
dicaprolactam linked product 1g2 was also formed (∼32%); however, it was difficult to isolate.
however only in <10% yield. Thus, silica−HClO4 (50 mol %)
in acetonitrile at 80 °C for 6 h was found be optimal condition
for preparation of Mannich-type products. These optimization
results clearly indicate that presence of acidic catalyst is
necessary for the reaction to occur. Furthermore, the reaction
works well with acetonitrile but not with protic solvents such as
methanol or water. This is probably due to leveling of acidity of
the catalyst (“buffer effect”) through partial protonation/
exchange with the protic solvent. The catalyst needs to be
acidic enough for the reaction to proceed. Next, we studied
reactivity difference between N-vinyl lactam and parent NH-
lactam, for which a model reaction between o-cresol (2g), 4 and
N-vinyl lactam 3a or NH-lactam 5a was chosen. During initial 1
h, the rate of reaction for formation of Mannich product 1h was
higher in the case of NH-lactam 5a as compared to N-vinyl
lactam 3a; however, both reactions required similar time for
completion (6 h) with similar yields of Mannich product 1h
(>85%). To check formation of side products (dimers) in
absence of one of the coupling partners, a series of experiments
were carried out. When the model reaction between 2g, 4 and
5a was performed under optimized reaction conditions in the
absence of either 2g or 5a, we could not see formation of
expected dimers viz. o-cresol-CH2-o-cresol or caprolactam-CH2-
caprolactam. However, when 2,4-diacetyl phloroglucinol (2b)
was treated with formaldehyde under similar conditions, dimer
6 (dimer of 2b linked with methylene unit; structure shown in
the Experimental Section) was formed in 55% yield.
in acetonitrile in presence of silica−HClO4 (50 mol %) led to
formation of Mannich type products 1a2 and 1j in 80 and 78%
yield, respectively. Similarly 2,4-diacyl phloroglucinols pro-
duced Mannich products 1b−1e in good yields. Phenol also
participated well in this reaction, which on reaction with
caprolactam (5a) produced mono- and disubstituted Mannich
products 1g1 and 1g2. Cresols showed better reactivity in this
reaction producing excellent yields of Mannich products 1h, 1k
and 1l1‑1l2.
The method applicability was also investigated for
amidoalkylation of natural product butin (7).17 Reaction of
0.152 mmol of 7 with formaldehyde (4) and caprolactam (5a)
under optimized reaction conditions produced corresponding
Mannich-type products 8a and 8b in 42 and 34% yield,
respectively, as depicted in Figure 4. It is noteworthy to
mention that apart from high yields of the reaction, silica−
HClO4 catalyst showed recyclability, thus making the process
eco-friendly and economical.
For synthesis of Mannich products 1 (or 8a,b), three
mechanisms are considered: first via classical Mannich reaction
involving a Schiff base intermediate, second via formation of o-
quinone methide (o-QM) followed by formal [4 + 2]-Diels−
Alder cycloaddition to form oxazine intermediate, and last via
formation of o-QM followed by Michael addition.18 In the case
of lactams, the nitrogen electrons get delocalized into the
carbonyl and exist as a resonance mixture of 5a1 and 5a2. Thus
unlike amines, amides are less reactive toward nucleophilic
addition to carbonyl group of aldehyde to generate electrophilic
Schiff base, which is a key reactive intermediate in classical
Mannich reaction. To unravel the mechanism for formation of
Mannich-type product 1, model reaction between o-cresol (2g),
Under optimized reaction conditions, the scope was explored
for different lactams and phenolic precursors (Figure 3).
Reaction of 2,4-diformyl phloroglucinol (2a) with form-
aldehyde (4) and caprolactam (5a) or piperidin-2-one (5b)
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To confirm our proposed mechanism, we performed a
stepwise experiment in which o-cresol (2g), formaldehyde (4)
and silica−HClO4 in acetonitrile were refluxed for 2 h. The
reaction was monitored for formation of o-QM by TLC
(indication for disappearance of 2g in TLC) and MS studies.
MS analysis indicated formation of o-quinone methide species
II at m/z 121 [M + 1]+ (see Section S-1 of the Supporting
Information). Further addition of 5a to the reaction led to
formation of desired product 1h, indicative of the reaction
proceeding via o-quinone methide II intermediate. Next, in
order to prove the formation of oxazine intermediate III,
reaction of 2g, HCHO (4) and 5a in presence of Silica−HClO4
in acetonitrile after 2 h reflux was analyzed by LC-ESI-MS/MS.
LC spectrum showed two peaks with same mass m/z 234 [M +
1]+ at tR 3.8 and 8.2 min (Figure 6a,c,d). Mannich product 1h
and oxazine intermediate III, both having same molecular
weight (mol. wt. 233.14) appeared as separate peaks in LC−
MS, which evidenced formation of III during the course of
reaction. Next, we assigned these peaks as tR 3.8 min for III and
tR 8.2 min for 1h by analyzing pure isolated product 1h (Figure
6b). As observed in optimization studies (Table 2), catalyst
needs to be acidic enough for the reaction to proceed, probably
because the high acidity of perchloric acid causes the O-
protonation of the amide 5a1 allowing a fast lactam 5a1−lactim
5a2 equilibrium to occur. Because the lactim form 5a2 is a key
intermediate for the [4 + 2]-Diels−Alder cycloaddition,
formation of the final product heavily depends on this step.
Thus, our proposed mechanism involves formation of o-
quinone methide II from 2g and 4. The transient o-quinone
methide II further undergoes formal [4 + 2]-Diels−Alder
cycloaddition with enol form of caprolactam to produce
oxazine intermediate III. This intermediate, on protonation,
undergoes ring-opening to produce product 1h.
Figure 4. Mannich-type condensation of butin (7) with caprolactam
(5a).
formaldehyde (4) and caprolactam (5a) was chosen. Since we
always observed solely ortho-selectivity, we presumed that the
product 1h gets formed via second mechanism involving
formation of o-QM II and oxazine intermediate III (Figure 5).
In conclusion, we have reported new method for ortho-
amidoalkylation of phenols and a proposed mechanism via
Mannich-type condensation involving oxazine intermediate.
Figure 5. Proposed mechanism for formation of Mannich product 1h.
Figure 6. LC-ESI-MS/MS analysis to investigate mechanism for formation of 1h. (a) LC spectra for product scan of reaction mixture after 2 h; (b)
LC spectra of pure product 1h; (c) MS spectra for peak at tR 3.8 min; (d) MS spectra for peak at tR 8.2 min.
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Note
1-(2,4,6-Trihydroxy-3,5-diformyl-benzyl)azepan-2-one (1a1).
Light yellow solid: mp 167−169 °C; H NMR (CDCl3, 500 MHz)
Method is regioselective for ortho-substitution. The developed
protocol can be utilized for short and efficient synthesis of a
diverse range of natural and synthetic alkaloids.
1
δ 13.62 (s, 1H, OH), 13.56 (s, 1H, OH), 12.88 (s, 1H, OH), 10.14 (s,
2H, 2 x CHO), 4.40−4.01 (brs, 2H), 3.82−3.54 (brs, 2H), 2.59 (t, J =
5.6 Hz, 2H), 1.75−1.67 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ
193.4, 191.6, 179.4, 169.6, 169.5, 169.0, 104.8, 103.4, 103.1, 51.3, 41.5,
36.1, 29.7, 27.7, 22.7; IR (CHCl3) νmax 3368, 2854, 2925, 1503, 1445,
1304, 1176, 1194, 1019 cm−1; ESI-MS m/z 308.0 [M + 1]+; HRMS
m/z 306.0985 calcd for C15H17NO6 − H+ (306.0978).
EXPERIMENTAL SECTION
■
General Information. All chemicals were obtained from Sigma-
Aldrich Company and used as received. H, 13C and DEPT NMR
1
spectra were recorded on Bruker-Avance DPX FT-NMR 500 and 400
MHz instruments. Chemical data for protons are reported in parts per
million (ppm) downfield from tetramethylsilane and are referenced to
the residual proton in the NMR solvent (CDCl3, 7.26 ppm). Carbon
nuclear magnetic resonance spectra (13C NMR) were recorded at 125
or 100 MHz; chemical data for carbons are reported in parts per
million (ppm, δ scale) downfield from tetramethylsilane and are
referenced to the carbon resonance of the solvent (CDCl3, 77 ppm).
ESI-MS and HRMS spectra were recorded on Agilent 1100 LC-Q-
TOF and HRMS-6540-UHD machines. IR spectra were recorded on
Perkin-Elmer IR spectrophotometer. Melting points were recorded on
digital melting point apparatus. LC-ESI-MS/MS analysis was carried
out on Agilent Triple-Quad LC−MS/MS system (model 6410).
Procedure for Preparation of 2,4-Diformyl Phloroglucinol
(2a). Phosphoryl chloride (1.6 mL, 16.7 mmol) was added dropwise to
DMF (1.3 mL, 16.7 mmol) with strong stirring, at room temperature
under a nitrogen atmosphere. Stirring was continued for 30 min. This
Vilsmeier reagent was then slowly added to a stirred solution of
anhydrous phloroglucinol (1 g, 7.9 mmol) in dioxane (5 mL) at room
temperature, under a nitrogen atmosphere. This solution was then
stirred at room temperature for 12 h, whereupon it turned into a
yellow amorphous solid. This solid mixture was cooled to 0 °C before
being added to ice−water slurry (∼40 mL). The solution was allowed
to slowly warm to room temperature, and stirring was continued for a
further 4 h, during which time a salmon colored precipitate formed.
This precipitate was then filtered off and washed with more water, to
get 2,4-diformyl phloroglucinol 2a (1.22 g): Yield 85%; cream colored
solid; mp 218−220 °C; 1H NMR (CDCl3, 400 MHz) δ 10.09 (s, 2H),
5.83 (s, 1H); ESI-MS m/z 183 [M + 1]+.15
1-(2,4,6-Trihydroxy-3,5-diacetyl-benzyl)azepan-2-one (1b). Light
1
yellow solid: mp 149−151 °C; H NMR (CDCl3, 400 MHz) δ 16.36
(s, 1H, OH), 15.48 (s,1H, OH), 12.85 (s, 1H, OH), 4.49−4.28 (brs,
2H), 3.71−3.49 (brs, 2H), 2.77 (s, 6H), 2.63 (t, J = 7.6 Hz, 2H),
1.73−1.59 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 205.0, 204.5,
179.2, 171.8, 170.0, 167.3, 104.6, 103.8, 103.3, 51.3, 42.4, 36.2, 33.1,
33.0, 29.8, 27.7, 23.0; IR (CHCl3) νmax 3400, 2925, 2853, 1620, 1503,
1425, 1366, 1277, 1152, 1116, 1021 cm−1; ESI-MS m/z 336 [M + 1]+;
HRMS m/z 336.1419 calcd for C17H21O6 + H+(336.1442).
1-(2,4,6-Trihydroxy-3,5-dipropanoyl-benzyl)azepan-2-one (1c).
White solid: mp 114−116 °C; 1H NMR (CDCl3, 400 MHz) δ
̀
16.45 (s, 1H), 15.55 (s, 1H), 12.77 (s, 1H), 4.60−4.2 (m, 2H), 3.71
(brs, 2H), 3.21 (m, 4H), 2.58 (d, J = 10.4 Hz, 2H), 1.71−1.66 (m,
6H), 1.18 (d, J = 2.4 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ 208.3,
207.8, 179.2, 171.6, 169.8, 166.9, 104.2, 103.6, 103.4, 51.3, 42.5, 37.6,
36.2, 29.9, 27.8, 23.0, 8.7, 8.6; IR (CHCl3) νmax 2934, 2853, 1620,
1592, 1503, 1422, 1365, 1202, 1034 cm−1; ESI-MS m/z 362.1 [M-1]+;
HRMS m/z 362.1619 calcd for C19H25NO6 − H+ (362.1604).
1-(2,4,6-Trihydroxy-3,5-diisovaleryl-benzyl)azepan-2-one (1d).
1
Light yellow solid: mp 87−88 °C; H NMR (CDCl3, 400 MHz) δ
12.7 (s, 1H), 4.42−4.23 (m, 2H), 3.65−3.52 (brs, 2H), 2.94 (d, J = 6.8
Hz, 4H), 2.51 (d, J = 9.6 Hz, 2H), 2.23−2.12 (m, 2H), 1.66−1.60 (m,
6H), 0.99 (d, J = 6.4 Hz, 12H); 13C NMR (CDCl3,100 MHz) δ 207.3,
206.9, 179.1, 171.8, 170.1, 166.9, 104.5, 103.9, 103.4, 52.9, 51.3, 42.5,
36.2, 29.8, 27.8, 25.2, 25.1, 23.0, 22.8; IR(CHCl3) νmax 2956, 2869,
2503, 1620, 1503, 1463, 1421, 1367, 1300, 1262, 1201, 1124, 1072,
1049 cm−1; ESI-MS m/z 420.2 [M + 1]+; HRMS m/z 418.2248 calcd
for C23H33NO6 − H+ (418.2230).
1-(2,4,6-Trihydroxy-3,5-dibutanoyl-benzyl)azepan-2-one (1e).
Yellow solid: mp 122−123 °C; 1H NMR (CDCl3, 400 MHz) δ
16.50 (s, 1H), 15.59 (s, 1H), 12.75 (s, 1H), 4.43−4.13 (brs, 2H), 3.73
(brs, 2H), 3.13 (m, 4H), 2.58 (d, J = 10.4 Hz, 2H), 1.74−1.62 (m,
10H), 0.99 (d, J = 3.2 Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ 207.6,
207.2, 179.2, 171.7, 170.0, 166.9, 104.3, 103.7, 103.4, 51.3, 46.2, 42.5,
36.2, 29.9, 27.8, 23.0, 18.1, 18.0, 14.0, 13.9; IR (CHCl3) νmax 3745,
3400, 2957, 2929, 2875, 1619, 1503, 1460, 1421, 1376, 1199, 1043
cm−1; ESI-MS m/z 392.0 [M + 1]+; HRMS m/z 390.1927 calcd for
C21H29NO6 − H+(390.1917).
General Procedure for Preparation of Diacylphloroglucinols
2b−2e. A solution of phloroglucinol (10 g, 79.36 mmol) and acetic
acid or propionic acid/isovaleric acid/butyric acid (3 equiv) in BF3−
etherate (100 mL) was refluxed at 100 °C for 2.5 h. Reaction mixture
was cooled to room temperature, poured into crushed ice and
extracted with ethyl acetate (100 mL × 3). Combined organic layers
were evaporated on rotary evaporator. Crude product was purified by
silica gel (#100−200) column chromatography to get diacyl
phloroglucinols. 1,3-Diacetyl-2,4,6-trihydroxy benzene (2b): Yield
70%; cream colored solid; mp 172−174 °C; 1H NMR (CD3OD,
400 MHz) δ 5.84 (s, 1H), 2.65 (s, 6H); ESI-MS m/z 211 [M + 1]+.
1,3-Dipropanoyl-2,4,6-trihydroxy benzene (2c): Cream colored solid;
1-(2,4,6-Trihydroxy-3,5-dibutanoyl-benzyl) pyrrolidin-2-one (1f).
1
White solid: mp 128−130 °C; H NMR (CDCl3, 400 MHz) δ 16.48
1
(s, 1H), 16.47 (s, 1H), 15.42 (s, 1H), 12.07 (s, 1H), 4.34 (s, 2H), 3.69
(t, J = 7.2 Hz, 2H), 3.14 (m, 4H), 2.48 (t, J = 8.0 Hz, 2H), 2.07 (m,
2H), 1.72 (m, 4H), 1.01 (t, J = 7.2 Hz, 6H); 13C NMR (CDCl3, 125
MHz) δ 207.6, 207.2, 178.1, 171.6, 169.8, 166.3, 104.5, 103.9, 103.1,
49.3, 46.2, 35.9, 30.3, 18.1, 18.0, 13.9; IR (CHCl3) νmax 3369, 2930,
2873, 1621, 1588, 1507, 1475, 1421, 1377, 1201, 1179, 1021 cm−1;
ESI-MS m/z 364.1 [M + 1]+; HRMS m/z 364.1763 calcd for
C19H25NO6+H+ (364.1755).
mp 158−160 °C; H NMR (CDCl3, 500 MHz) δ 16.21 (s, 1H), 5.81
(s, 1H), 3.15 (q, J = 6.8, 13.8 Hz, 4H), 1.27 (d, J = 7.0 Hz, 6H); ESI-
MS m/z 239.0 [M + 1]+. 1,3-Di-(3-methyl-butanoyl)-2,4,6-trihydroxy
1
benzene (2d): Yield 75%; yellow solid; mp 114−116 °C; H NMR
(CDCl3, 200 MHz) δ 5.85 (s, 1H), 2.99 (d, J = 6.7 Hz, 4H), 2.26 (m,
2H), 0.99 (d, J = 6.7 Hz, 12H); ESI-MS m/z 295 [M + 1]+. 1,3-
Dibutanoyl-2,4,6-trihydroxy benzene (2e): Cream colored solid; mp
1
130−132 °C; H NMR (CDCl3, 500 MHz) δ 16.27 (s, 1H), 5.81 (s,
1-(2-Hydroxybenzyl)azepan-2-one (1g1). White solid: mp 110−
1H), 3.10 (t, J = 7.2 Hz, 4H), 1.75 (m, 4H), 1.01 (t, J = 7.3 Hz, 6H);
1
ESI-MS m/z 267.0 [M + 1]+.15
112 °C; H NMR (CDCl3, 400 MHz) δ 9.58 (s, 1H), 7.21 (t, J = 7.6
Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.80 (t, J =
7.6 Hz, 1H), 4.41 (s, 2H), 3.46 (t, J = 5.6 Hz, 2H), 2.56 (t, J = 6.0 Hz,
2H), 1.73−1.62 (m, 4H), 1.59−1.52 (m, 2H); 13C NMR (CDCl3, 125
MHz) δ 178.01, 156.1, 130.7, 130.1, 122.3, 119.1, 117.4, 49.8, 49.4,
36.3, 29.6, 27.4, 22.9; IR (CHCl3) νmax 3744, 2928, 2854, 1731, 1607,
1494, 1445, 1353, 1245, 1185, 1141, 1104, 1083, 1032 cm−1; ESI-MS
m/z 220.1 [M + 1]+; HRMS m/z 220.1332 calcd for C13H17NO2+H+
(220.1332).
General Procedure for ortho-Amidoalkylation: Synthesis of
Mannich-Type Products 1a−1l and 8a,b. To a solution of
phenolic precursor (2 or 7, 300 mg, 1 equiv) in acetonitrile was added
formaldehyde (4, 3 equiv), N-vinyl lactam (3, 1.5 equiv) or NH-lactam
(5, 1.5 equiv) and silica−HClO4 (50% w/w). Reaction mixture was
then refluxed at 80 °C for 6−10 h. Completion of the reaction was
monitored by TLC. Reaction mixture was cooled to room temperature
and filtered through Whatman filter paper. Filtrate was concentrated
on vacuo rotavapor to get crude product. Crude products were
purified by silica gel (#100−200) column chromatography to get
Mannich-type products 1a−1l and 8a,b in 75−85% yield.
1-(2-Hydroxy-3-methyl benzyl)azepan-2-one (1h). White solid:
1
mp 141−143 °C; H NMR (CDCl3, 400 MHz) δ 9.63 (s, 1H), 7.10
(d, J = 7.6 Hz, 1H), 6.96 (d, J = 6.4 Hz, 1H), 6.71 (t, J = 7.6 Hz, 1H),
E
dx.doi.org/10.1021/jo3017132 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
4.42 (s, 2H), 3.44 (t, J = 4.8 Hz, 2H), 2.57 (d, J = 6.0 Hz, 2H), 2.28 (s,
3H), 1.74−1.71 (m, 4H), 1.69−1.63 (m, 2H); 13C NMR (CDCl3, 100
MHz) δ 178.1, 154.5, 131.4, 128.6, 126.5, 121.9, 118.8, 50.0, 49.7,
36.6, 29.9, 27.6, 23.2, 16.6; IR (CHCl3) νmax 3089, 2929, 2855, 1609,
1590, 1496, 1445, 1354, 1261, 1229, 1197, 1174, 1085, 1019 cm−1;
ESI-MS m/z 234.1 [M + 1]+; HRMS m/z 234.1495 calcd for
C14H19NO2+H+ (234.1489).
1-((3,4-Dihydro-7-hydroxy-2-(3,4-dihydroxyphenyl)-6-(2-oxoaze-
pan-1-yl-methyl)-4-oxo-2H-chromen-8-yl)methyl)azepan-2-one
1
(8b). Light yellow solid: mp 240−242 °C; H NMR (CD3OD, 500
MHz) δ 7.72 (s, 1H), 6.97 (s, 1H), 6.85 (m, 2H), 5.42 (d, J = 12.6 Hz,
1H), 4.53 (m, 4H), 3.62 (brs, 2H), 3.49 (brs, 2H), 3.06 (m, 1H), 2.76
(m, 1H), 2.72−2.56 (m, 4H), 1.75−1.50 (m, 12H); 13C NMR
(CD3OD, 100 MHz) δ 193.2, 180.5 (2 x CO-N), 175.2, 163.5, 162.7,
147.2, 146.7, 131.6, 129.1, 120.9, 119.4, 116.4, 114.8, 114.7, 113.1,
81.9, 51.8, 50.9, 47.9, 44.8, 43.1, 37.5, 36.8, 30.8, 30.6, 30.1, 24.3, 24.1,
24.0; IR (CHCl3) νmax 3401, 2923, 2852, 1610, 1402, 1384, 1155, 1021
cm−1; ESI-MS m/z 521 [M-1]+; HRMS m/z 521.2318 calcd for
C29H34N2O7 − H+ (521.2293).
Dimerization of 2,4-Diacetyl Phloroglucinol. To check
formation of any side product(s) in the absence of one of coupling
partner, this experiment was carried out. To a solution of 2,4-diacetyl
phloroglucinol (2b, 1 equiv) in acetonitrile was added formaldehyde
(4, 3 equiv) and silica−HClO4 (50% w/w). Reaction mixture was then
refluxed at 80 °C for 6 h. Reaction mixture was cooled to room
temperature and filtered through Whatman filter paper. Filtrate was
concentrated on vacuo rotavapor to get crude product. Crude product
was purified by silica gel (#100−200) column chromatography to get
methylene-bis-(3,5-diacetyl-2,4,6-trihydroxybenzene) (6) in 55% yield.
1-(2-Hydroxy-3-methyl benzyl)pyrrolidin-2-one (1i). White solid:
1
mp 105−107 °C; H NMR (CDCl3, 400 MHz) δ 9.26 (s, 1H), 7.30
(d, J = 7.2 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H) 6.78 (t, J = 7.6 Hz, 1H),
4.36 (s, 1H), 3.56 (t, J = 4.0 Hz, 2H), 2.49 (t, J = 4.0 Hz, 2H), 2.30 (s,
3H), 2.11 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 176.7, 153.8,
131.1, 128.3, 126.7, 121.2, 118.9, 47.6, 43.8, 30.2, 17.4, 16.3; IR
(CHCl3):νmax 3233, 2926, 2728, 1651, 1594, 1498, 1470, 1438, 1380,
1350, 1314, 1257, 1228, 1161, 1117, 1090, 1020 cm−1; ESI-MS m/z
206.1 [M + 1]+; HRMS m/z 204.1027 calcd for C12H15NO −
H+(204.1025).
1-(2,4,6-Trihydroxy-3,5-diformyl-benzyl)piperidin-2-one (1j).
1
Light yellow solid: mp 150−152 °C; H NMR (CDCl3, 400 MHz)
δ 13.60 (s, 1H), 13.59 (s, 1H), 13.12 (s, 1H), 10.14 (s, 1H), 10.10 (s,
1H), 4.66−4.24 (brs, 2H), 3.57−3.40 (brs, 2H), 2.45 (brs, 2H), 1.83
(brs, 4H); 13C NMR (CDCl3, 100 MHz) δ 193.4, 191.6, 173.3, 169.7,
169.2, 104.8, 103.4, 102.6, 49.5, 40.1, 31.4, 22.7, 20.4; IR (CDCl3) νmax
2951, 2635, 1742, 1633, 1510, 1469, 1429, 1383, 1353, 1334, 1196,
1176, 1142, 1015 cm−1; ESI-MS m/z 292.1 [M-1]+; HRMS m/z
294.0976 calcd for C14H15NO6+H+ (294.0972).
1-(2-Hydroxy-3-methyl benzyl)piperidin-2-one (1k). Light yellow
1
solid: mp 68−70 °C; H NMR (CDCl3, 400 MHz) δ 9.92 (s, 1H),
7.11 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.70 (t, J = 7.2 Hz,
1H), 4.42 (s, 2H), 3.41 (t, J = 4.0 Hz, 2H), 2.43 (t, J = 6.4 Hz, 2H)
2.25 (s, 3H), 1.81 (m, 4H); 13C NMR (CDCl3,125 MHz) δ 171.9,
154.4, 131.3, 128.9, 126.6, 121.2, 118.5, 48.7, 47.7, 31.6, 22.6, 20.6,
16.5; IR (CDCl3) νmax 3368, 2945, 2872, 1607, 1588, 1504, 1470,
1444, 1417, 1354, 1258, 1231, 1151, 1078, 1020 cm−1; ESI-MS m/z
220.1 [M + 1]+; HRMS m/z 218.1184 calcd for C13H17NO2 − H+
(218.1186).
Cream colored solid: mp 279−281 °C; 1H NMR (CDCl3, 400
MHz) δ 17.37 (s, 2H), 16.20 (s, 2H), 10.22 (s, 2H), 3.74 (s, 2H), 2.76
(s, 6H), 2.73 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ 205.7, 171.4,
169.1, 166.5, 106.6, 105.8, 104.9, 34.1, 33.1, 15.6; ESI-MS m/z 433.1
[M + 1]+; IR (KBr) νmax 3204, 1617, 1586, 1470, 1366, 1268, 1180,
1010 cm−1.19
Silica−HClO4 Catalyst: Preparation, Recyclability Studies
and Determination of Acidity. Perchloric acid (1.25 g, as a 70%
aqueous solution) was added to the suspension of silica gel (23.75 g,
#230−400) in Et2O. The mixture was concentrated and the residue
heated at 100 °C for 72 h under a vacuum to afford HClO4−SiO2 as a
free-flowing powder.20
Recyclability of the catalyst was checked to prove the heterogeneous
nature and its repeated use. To a solution of ortho-cresol (2g, 300 mg,
1 equiv) in acetonitrile (10 mL) were added formaldehyde (4, 3
equiv), caprolactam (5a, 3.57 mmol) and silica−HClO4 (250 mg, 50%
w/w). Mixture was then refluxed at 80 °C for 6 h. After completion of
reaction, catalyst was recovered by filtration followed by washing with
acetonitrile. Recovered catalyst was dried in oven and reused in next
cycle. Product 1h was obtained in 80, 62, 54% yield over three cycles,
respectively. In order to understand the reason for decreased catalytic
activity of Silica−HClO4 catalyst after its use, total acidity of fresh and
used catalyst (after first use) was determined by ammonia-TPD
experiment using CHEMBET-3000 TPD/TPR/TPO instrument,
containing a quartz reactor and TCD detector. Prior to TPD studies,
samples were pretreated at 250 °C for 2 h with continuous flow of
pure nitrogen (99.9%) and then cooled to room temperature. After
pretreatment, samples were saturated with NH3 gas until saturated
adsorption. Temperature was increased to 80 °C and kept there for 2
h, while a helium flow of 20 cm3/min removed the physisorbed
ammonia. Finally the system was heated from 80 to 1000 °C at the
rate of 10 °C/min and desorbed gas monitored with TCD detector.
All the flow rates were maintained at normal temperature and pressure.
Total acidity of the fresh catalyst was found to be 10.95 mmol NH3/
g; however it was decreased to 7.8 mmol NH3/g after first use. This
decreased acidity is a clear indication of the catalyst leaching after its
use, which justifies the reason for a decrease in the product yield from
80% (fresh catalyst) to 62% (first recycle). However, the catalyst could
be recycled up to three times, producing >50% yield of desired
Mannich product.
1-(2-Hydroxy-4-methyl benzyl)azepan-2-one (1l1). Light yellow
1
solid: mp 75−76 °C; H NMR (CDCl3, 400 MHz) δ 9.47 (s, 1H),
6.99 (d, J = 7.6 Hz, 1H), 6.74 (s, 1H), 6.61 (d, J = 7.6 Hz, 1H), 4.39
(s, 2H), 3.47 (t, J = 5.2 Hz, 2H), 2.56 (t, J = 4.8 Hz, 2H), 2.31 (s, 3H),
1.70−1.60 (m, 4H), 1.58−1.52 (m, 2H); 13C NMR (CDCl3, 100
MHz) δ 178.0, 156.0, 140.3, 130.6, 120.0, 119.6, 118.1, 49.9, 49.3,
36.4, 29.7, 27.6, 23.0, 21.1; IR (CHCl3) νmax 3203, 2928, 2856, 1609,
1508, 1493, 1445, 1367, 1287, 1262, 1190, 1142, 1113, 1020 cm−1;
ESI-MS m/z 234.1 [M + 1]+; HRMS m/z 234.1494 calcd for
C14H19NO2+H+ (234.1489).
1-(2-Hydroxy-6-methyl benzyl)azepan-2-one (1l2). Light yellow
1
solid: mp 155−157 °C; H NMR (CDCl3, 400 MHz) δ 9.57 (s, 1H),
7.11 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 7.6 Hz,
1H), 4.60 (s, 2H), 3.50 (t, J = 8.0 Hz, 2H), 2.60 (t, J = 6.4 Hz, 2H),
2.44 (s, 3H), 1.72−1.58 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ
178.5, 157.0, 137.1, 129.1, 121.6, 121.1, 115.3, 50.0, 44.5, 36.3, 29.6,
27.5, 23.0, 20.6; IR (CHCl3):νmax 3369, 2927, 2855, 1726, 1606, 1579,
1465, 1364, 1285, 1196, 1020 cm−1; ESI-MS m/z 234.1 [M + 1]+,
256.1 [M + Na]+; HRMS m/z 232.1341 calcd for C14H19NO2 − H+
(232.1338).
1-((3,4-Dihydro-7-hydroxy-2-(3,4-dihydroxyphenyl)-4-oxo-2H-
chromen-8-yl)methyl) azepan-2-one (8a). Light yellow solid: mp
1
250−252 °C; H NMR (CD3OD, 500 MHz) δ 7.79 (d, J = 8.8 Hz,
1H), 6.98 (d, J = 2.0 Hz, 1H), 6.68 (m, 2H), 6.60 (d, J = 8.8 Hz, 1H),
5.42 (d, J = 10.2 Hz, 1H), 4.58 (d, J = 14.5 Hz, 1H), 4.53 (d, J = 14.5
Hz, 1H), 3.59 (m, 2H), 3.10 (dd, J = 13.7, 16.9 Hz, 1H), 2.76 (dd, J =
3.0, 16.9 Hz, 1H), 2.55 (m, 2H), 1.72 (m, 2H), 1.69 (m, 2H), 1.62 (m,
2H); 13C NMR (DMSO-d6, 100 MHz) δ 190.2, 177.3, 163.3, 161.3,
145.6, 145.2, 129.8, 127.7, 117.6, 115.3; 114.0, 113.4, 111.4, 111.1,
79.4, 49.1, 43.0, 40.8, 35.5, 29.8, 27.2, 22.6; IR (CHCl3) νmax 3369,
2923, 2852, 1742, 1609, 1446, 1266, 1080, 1020 cm−1; ESI-MS m/z
396 [M-1]+; HRMS m/z 396.1471 calcd for C22H23NO6 − H+
(396.1452).
F
dx.doi.org/10.1021/jo3017132 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Chem. 1970, 7, 1289−1293. (b) Buc, S. R. J. Am. Chem. Soc. 1947, 69,
254−256. (c) Dirlam, N. L.; Moore, B. S.; Urban, F. J. J. Org. Chem.
1987, 52, 3587−3591. (d) Eberson, L.; Malmberg, M.; Nyberg, K.
Acta Chem. Scand. 1984, 38, 345−350. (e) Malmberg, M.; Nyberg, K.
Acta Chem. Scand. 1979, 33, 69−72. (f) Malmberg, M.; Nyberg, K.
Acta Chem. Scand. 1981, 35, 411−417. (g) Ross, S. D.; Finkelstein, M.;
Petersen, R. C. J. Org. Chem. 1966, 31, 133−137. (h) Rozentsveig, I.
B.; Levkovskaya, G. G.; Mirskova, A. N. Russ. J. Org. Chem. 1999, 35,
895−898.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data, NMR spectra
scans. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: ram@iiim.ac.in; sbharate@iiim.ac.in.
Notes
The authors declare no competing financial interest.
IIIM Publication Number. IIIM/1494/2012.
■
(12) Wang, B.-L.; Li, N.-K.; Zhang, J.-X.; Liu, G.-G.; Liu, T.; Shen,
Q.; Wang, X.-W. Org. Biomol. Chem. 2011, 9, 2614−2617.
(13) Dai, C.; Meschini, F.; Narayanam, J. M. R.; Stephenson, C. R. J.
J. Org. Chem. 2012, 77, 4425−4431.
(14) Pin, F.; Comesse, S.; Garrigues, B.; Marchalin, S.; Daich, A. J.
Org. Chem. 2007, 72, 1181−1191.
(15) Bharate, S. B.; Mudududdla, R.; Bharate, J. B.; Battini, N.;
Battula, S.; Yadav, R. R.; Singh, B.; Vishwakarma, R. A. Org. Biomol.
Chem. 2012, 10, 5143−5150.
ACKNOWLEDGMENTS
■
R.M. and S.K.J. are thankful to CSIR for award for research
fellowship. Authors thank the Analytical Department, IIIM, for
analytical support.
(16) Bieraugel, H.; Jansen, T. P.; Schoemaker, H. E.; Hiemstra, H.;
̈
van Maarseveen, J. H. Org. Lett. 2002, 4, 2673−2674.
(17) Zhang, R.; Lee, I. K.; Piao, M. J.; Kim, K. C.; Kim, A. D.; Kim,
H. S.; Chae, S.; Kim, H. S.; Hyun, J. W. Int. J. Mol. Sci. 2011, 12,
3871−3887.
REFERENCES
■
(1) For reviews on Mannich reaction, see: (a) Verkade, J. M. M.; van
Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc.
(18) Wang, M.; Song, Z.-G.; Liang, Y. Org. Prep. Proced. Int. 2011, 43,
484−488.
Rev. 2008, 37, 29−41. (b) Arrayas
Rev. 2009, 38, 1940−1948.
(2) Weiner, B.; Szymanski, W.; Janssen, D. B.; Minnaard, A. J.;
́
, R. G.; Carretero, J. C. Chem. Soc.
(19) (a) Chauthe, S. K.; Bharate, S. B.; Sabde, S.; Mitra, D.; Bhutani,
K. K.; Singh, I. P. Bioorg. Med. Chem. 2010, 18, 2029−2036.
(b) Chauthe, S. K.; Bharate, S. B.; Periyasamy, G.; Khanna, A.;
Bhutani, K. K.; Mishra, P. D.; Singh, I. P. Bioorg. Med. Chem. Lett.
2012, 22, 2251−2256.
́
Feringa, B. L. Chem. Soc. Rev. 2010, 39, 1656−1691.
(3) Marques, M. M. B. Angew. Chem., Int. Ed. 2006, 45, 348−352.
Cordova, A. Acc. Chem. Res. 2004, 37, 102−112.
(20) Chakraborti, A. K.; Gulhane, R. Chem. Commun. 2003, 1896−
1897.
(4) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed.
1998, 37, 1044−1070.
(5) For application in natural products synthesis, see: (a) Toure, B.
B.; Hall, D. G. Chem. Rev. 2009, 109, 4439−4486. (b) Martin, S. F.
́
Acc. Chem. Res. 2002, 35, 895−904. (c) Norsikian, S.; Soule, J.-F.;
Cannillo, A.; Guillot, R.; Dau, M.-E. T. H.; Beau, J.-M. Org. Lett. 2012,
14, 544−547. (d) Corey, E. J.; Balanson, R. D. J. Am. Chem. Soc. 1974,
96, 6516−6517. (e) Martin, S. F.; Liras, S. J. Am. Chem. Soc. 1993, 115,
10450−10451. (f) Martin, S. F.; Barr, K. J. J. Am. Chem. Soc. 1996, 118,
3299−3300. (g) Benson, W.; Winterfeldt, E. Chem. Ber. 1979, 112,
1913−1915.
(6) Balasubramanian, K. K.; Selvaraj, S. J. Org. Chem. 1980, 45,
3726−3727.
(7) (a) Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.; Gois, P. M.
P. Chem. Rev. 2010, 110, 6169−6193. (b) Hwang, D.-R.; Uang, B.-J.
Org. Lett. 2002, 4, 463−466. (c) Kano, T.; Song, S.; Kubota, Y.;
Maruoka, K. Angew. Chem., Int. Ed. 2012, 51, 1191−1194. (d) Li, Y.;
Xu, M.-H. Org. Lett. 2012, 14, 2062−2065. (e) Notz, W.; Tanaka, F.;
Watanabe, S.; Chowdari, N. S.; Turner, J. M.; Thayumanavan, R.;
Barbas, C. F. J. Org. Chem. 2003, 68, 9624−9634. (f) Taylor, M. S.;
Tokunaga, N.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 6700−
6704. (g) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
12964−12965. (h) Yang, J. W.; Chandler, C.; Stadler, M.; Kampen, D.;
List, B. Nature 2008, 452, 453−455. (i) Zhao, D.; Wang, L.; Yang, D.;
Zhang, Y.; Wang, R. Angew. Chem., Int. Ed. 2012, 51, 7523−7527.
(j) Chavan, S. P.; Chittiboyina, A. G.; Ravindranathan, T.; Kamat, S.
K.; Kalkote, U. R. J. Org. Chem. 2005, 70, 1901−1903.
(8) Wang, X.; Mao, H.; Yu, Y.; Zhu, X.; Zhu, C. Synth. Commun.
2007, 37, 3751−3758.
(9) Kraus, G. A.; Neuenschwander, K. Tetrahedron Lett. 1980, 21,
3841−3844.
(10) For naturally occurring pyrrolidinone/piperidinone alkaloids,
see: (a) Duan, X.-J.; Li, X.-M.; Wang, B.-G. J. Nat. Prod. 2007, 70,
1210−1213. (b) Jang, D. S.; Lee, G. Y.; Lee, Y. M.; Kim, Y. S.; Sun, H.;
Kim, D. H.; Kim, J. S. Chem. Pharm. Bull. 2009, 57, 397−400.
(c) Zhao, J.; Ma, M.; Wang, S.; Li, S.; Cao, P.; Yang, Y.; Lu, Y.; Shi, J.;
Xu, N.; Fan, X.; He, L. J. Nat. Prod. 2005, 68, 691−694.
(11) (a) Barry, J. E.; Mayeda, E. A.; Ross, S. D. Tetrahedron 1977, 33,
369−372. (i) Ben-Ishai, D.; Ben-Et, G.; Warshawsky, A. J. Heterocycl.
G
dx.doi.org/10.1021/jo3017132 | J. Org. Chem. XXXX, XXX, XXX−XXX