Weinreb amide based building blocks for convenient access to analogues of phenstatin

Article abstract of DOI:10.1002/ejoc.201000532

Bifunctional synthetic equivalents containing a Weinreb amide as one of the functionalities have been synthesized from commercially available o-, m-, and p-toluic acid. These bifunctional building blocks enabled efficient C-C bond formation through Wittig reaction with simple and functionalized aldehydes on one hand and a clean nucleophilic addition of 3,4,5-trimethoxy phenylmagnesium bromide onto the Weinreb amide functionality on the other hand, therebypaving way for an efficient and convenient synthesis of novel analogues of phenstatin with highly functionalized appendages. Further addition of various aryl or heteroarylmagnesium bromides onto theWeinreb amide functionality provided a general strategy for synthesizing unsymmetrical diaryl ketones conjugated to a monosaccharide moiety for the first time.

Full text of DOI:10.1002/ejoc.201000532

FULL PAPER
DOI: 10.1002/ejoc.201000532
Weinreb Amide Based Building Blocks for Convenient Access to Analogues of
Phenstatin
Balasubramaniam Sivaraman[a] and Indrapal Singh Aidhen*[a]
Dedicated to Professor Richard R. Schmidt on the occasion of his 75th birthday
Keywords: Weinreb amides / Diaryl ketones / Wittig reactions / Natural products / Carbohydrates
Bifunctional synthetic equivalents containing a Weinreb
amide as one of the functionalities have been synthesized
from commercially available o-, m-, and p-toluic acid. These
bifunctional building blocks enabled efficient C–C bond for-
mation through Wittig reaction with simple and function-
alized aldehydes on one hand and a clean nucleophilic ad-
dition of 3,4,5-trimethoxy phenylmagnesium bromide onto
the Weinreb amide functionality on the other hand, thereby
paving way for an efficient and convenient synthesis of novel
analogues of phenstatin with highly functionalized append-
ages. Further addition of various aryl or heteroarylmagnes-
ium bromides onto the Weinreb amide functionality provided
a general strategy for synthesizing unsymmetrical diaryl
ketones conjugated to a monosaccharide moiety for the first
time.
is detrimental to its biological activity, any change in the B
ring was welcome,[6] and the bridge size, distance between
the two rings proved to be critical.[7]
Introduction
Combretastatins 1 are a class of natural stilbenoids iso-
lated by Pettit et al. in the late 1980s from the bark of Com-
bretum caffrum, commonly known as South African bush
willow, and are known to be potential anticancer agents.[1]
A number of combretastatin analogues have been synthe-
sized and evaluated for their structure–activity relation-
ships;[2] currently, the phosphate prodrug combretastatin A-
4 (1b) is in phase-III clinical trials.[3] Phenstatin (2a), a
benzophenone-type compound, was obtained by accidental
oxidation of the well-known anticancer drug combretasta-
tin (1a, Figure 1) and displays potent anticancer and anti-
mitotic activities.[4] In terms of both potency and cytotoxi-
city, phenstatin (2a) and its phosphate prodrug 2b are quite
similar to combretastatin A-4 phosphate prodrug 1b.[4] Mo-
lecules that fall into the broader family of combretastatin
and phenstatin generally share three common structural
features, which include (1) a trimethoxy “A” ring, (2) a “B”
ring containing substituents mainly at the C3 and C4 posi-
tions, and (3) a bridge in the form of Z stilbenes for com-
bretastatin[5a] and more recently a ketone bridge for phen-
statin to provide the rigidity between the two rings.[5b,5c]
Over the years it has been found that changing the A ring
Polar substituents in the form of hydroxy or amino
groups have been introduced onto the B ring to increase the
solubility of the compounds in water, thereby increasing the
structure–activity relationship.[8] On basis of these critical
observations, we aimed at synthesizing novel analogues of
phenstatin 3 by keeping the A ring intact and by appending
a monosaccharide moiety to the B ring for the first time
(Figure 1). This would possibly increase the hydrophilic na-
ture of the compound, and the sugar moiety could also
bring some specificity towards certain cell lines. Also, in
light of the fact that the bioconjugation concept, wherein
two or more molecular entities with distinct properties are
coupled to form novel conjugates,[9] have lately surfaced as
a promising technique towards significant medicinal appli-
cations, the envisioned targets hold significant promise.
Although Phenstatin (2) and targeted novel compounds 3
falls under the broader class of diaryl ketones,[10] an impor-
tant structural motif in organic chemistry, to the best of our
knowledge, diaryl ketones appended to hydrophilic sugar
residues have never been synthesized in any context.
Three major strategies have been used in the literature
for the synthesis of diaryl ketones. (1) The classical Lewis
acid promoted FC acylation of arenes[11] and acylation of
the organolithium, -magnesium, and -aluminum reagents
with acid derivatives.[12] (2) Palladium-catalyzed coupling of
ArM (M = SnR3, BR2, ZnX) with acid derivatives.[13]
(c) Transition-metal-catalyzed three-component cross-cou-
pling of aryl–X (X = Br, I, OTf, N2+) derivatives, carbon
View this journal online at
[a] Department of Chemistry, Indian Institute of Technology
Madras,
Chennai 600036, India
Fax: +91-44-22574202
E-mail: isingh@iitm.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000532.
wileyonlinelibrary.com
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B. Sivaraman, I. S. Aidhen
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Figure 1. Structure of combretastatin A-4, phenstatin, and phenstatin analogues.
monoxide, and arylmetal reagents.[14] Besides these three
Results and Discussion
main strategies, the transition-metal-catalyzed coupling of
organic halides or triflates with aldehydes as starting sub-
strate has surfaced as a promising alternative due to the
high commercial availability of aldehydes. In Hartwig’s pro-
cedure, rhodium-catalyzed intermolecular Heck-type reac-
tions occurs between aryl iodides and N-pyrazylaldimines
derived from aldehydes[15] to give ketimines, which upon hy-
drolysis afford diaryl ketones, whereas Cheng’s method con-
stitutes Ni0-catalyzed direct coupling of aryl iodides with
aryl aldehydes by using a bidentate phosphane complex.[16]
The successful Heck-type coupling of aryl aldehydes with
potassium trifluoro(organo)borates[17] under rhodium ca-
talysis and with organoboronic[18] acids in recent times un-
der palladium catalysis reflects the promise that this new
strategy holds for the obtainment of diaryl ketones. Despite
these advances towards the synthesis of diaryl ketones in
general, we envisaged a new methodology for the specific
objective set before us. The growing importance of the
Weinreb amide (WA) functionality,[19] our continued inter-
est in developing and using synthetic equivalents based on
the WA functionality,[20] and the increasing confidence in
the use of this functionality on kilogram scale[21] in industry
led to the proposal of bifunctional building block 4a
towards the synthesis of unsymmetrical diaryl ketones 6
with highly functionalized appendages at the para position.
Building block 4a would allow efficient C–C bond forma-
tion through well-established Wittig reaction and the WA
functionality therein would facilitate clean acylation with
aryl- or heteroarylmagnesium reagents for the obtainment
of desired diaryl ketones 6 (Scheme 1).
Analytically pure compound 4a was conveniently pre-
pared in three steps by using commercially available p-toluic
acid. It involved facile benzylic bromination of the amide,
followed by nucleophilic substitution with triphenylphos-
phane of benzylic amide 7 under acetone reflux conditions
to give the corresponding Wittig salt 4a in good yields
(Scheme 2).
Scheme 2. Preparation of building block 4a.
To implement the proposed strategy for diaryl ketones 6,
phosphonium salt 4a was subjected to Wittig reaction with
pentafluorobenzaldehyde (Table 1, Entry 1) as a representa-
tive aldehyde by using NaH (1.1 equiv.) as the base in DMF
at room temperature. Clean reaction ensued, furnishing the
expected olefinated product as an E/Z (1:3) mixture after
column purification. The olefinated product was then sub-
jected to hydrogenation by using 10% Pd/C in EtOAc,
which afforded alkane WA 5a in 85% yield. Alkane WA 5a
was treated with naphthalen-2-ylmagnesium bromide as a
representative Grignard reagent to afford para-substituted
diaryl ketone 8 in good yield (82%; Table 1). To our satis-
faction, various electron-rich/electron-poor aromatic,
heterocyclic, and aliphatic aldehydes reacted cleanly with
Wittig salt 4a, thereby bringing in the different substitutions
at the para positions. Further addition of variety of aryl or
heteroarylmagnesium reagents onto the WA functionality
provided the generality and versatility of the developed
strategy for diaryl ketones through bifunctional synthetic
equivalent 4a (Table 1). All isolated new compounds exhib-
ited satisfactory spectral and analytical details.
To further generalize the developed strategy, regioisom-
eric phosphonium salts 4b and 4c (Figure 2) were also pre-
pared from the corresponding toluic acid WA by following
the procedure as described for 4a in Scheme 2.
Scheme 1. General scheme for the preparation of diaryl ketones.
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Weinreb Amide Based Building Blocks for Analogues of Phenstatin
Table 1. Synthesis of diaryl ketones with building block 4a.
Table 2. Synthesis of diaryl ketones with building blocks 4b and 4c.
[a] Yield of isolated product after flash chromatography.
[a] Yield of isolated product after flash chromatography.
Scheme 3. Ultimate precursor for the anti-inflammatory drug Sup-
rofen.
These functionalized aldehydes also reacted smoothly
with building blocks 4a and 4b to furnish the corresponding
alkane WAs 29–38, having the monosaccharide residue at
Figure 2. Regioisomeric building blocks.
Much to our delight, phosphonium salts 4b and 4c the meta and para positions, after hydrogenation of the ole-
underwent clean Wittig reaction with the representative al- finated product (Table 3). Addition of a Grignard reagent
dehydes, and subsequent hydrogenation of the olefinated to functionalized alkane WAs 29, 31, and 33 enabled us to
products furnished alkane WAs (13–15, Table 2). Grignard arrive at a new class of diaryl ketones, hitherto unreported
addition onto the alkane WA yielded the corresponding in the literature (Table 4). Synthesis of these diaryl ketones
meta- and ortho-substituted diaryl ketones 16–20 in good having highly functionalized appendages at the para posi-
yields (Table 2), thus firmly establishing the generality asso- tion illustrates our successful bioconjugation efforts.
ciated with the developed new strategy for functionalized
Having successfully established the methodology of ob-
unsymmetrical diaryl ketones. Diaryl ketone 21, the final taining the diaryl ketone scaffold conjugated to a carbo-
precursor of the commercially important nonsteroidal anti- hydrate moiety, we then aimed at synthesizing analogues of
inflammatory drug Suprofen,[14a] was obtained in two sim- phenstatin, especially bringing in changes at the C3Ј and
ple high-yielding reactions, involving classical Wittig ole- C4Ј positions. A recent report confirming the 2-naphthyl
fination of paraformaldehyde with 4a and facile Grignard ring being a bioisostere for the isovanillin moiety of phen-
addition of thiophen-2-ylmagnesium bromide to vinyl statin makes the presence of the OMe group on the B ring
benzamide 22. This illustrates the importance of the devel- insignificant.[24]
oped strategy (Scheme 3).
Towards the latter objective, addition of the Grignard
Having succeeded with the commercially available alde- reagent generated from 3,4,5-trimethoxybromobenzene to
hydes we now extended this methodology towards coupling the WA functionality of the alkane WA would bring in the
with more functionalized aldehydes from the domain of essential A ring much required for biological activity. 3,4,5-
carbohydrates as part of our major objective towards phen- Trimethoxybromobenzene was prepared easily in two steps
statin analogues. Aldehydes 23–28 were prepared through from 2,6-dimethoxyphenol by a literature procedure[25] in-
known, multistep reactions starting from readily available volving simple ring bromination followed by O-methylation
monosaccharides.[23]
of the phenolic compound. Initial studies led to the unsuc-
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B. Sivaraman, I. S. Aidhen
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Table 3. Coupling of Wittig salts 4a and 4b with highly function-
alized aldehydes.
Table 4. Highly functionalized para-substituted diaryl ketones.
[a] Yield of isolated product after flash chromatography.
peared that the formation was convenient only on a larger
scale.[26b] No consistency was seen with regard to reaction
conditions. After exploring several reaction conditions it
was found that a catalytic amount of MeI was required for
initiation and complete consumption of the magnesium
metal. We were then successful in generating Grignard rea-
gent on a 4.0-mmol scale from 3,4,5-trimethoxybromoben-
zene at 50–55 °C (before initiation) by using MeI (0.02 mL)
as the initiator. After checking the reproducibility of the
formation thrice on the aforementioned scale, we then
scaled down carefully to 1.6 mmol of 3,4,5-trimethoxybro-
mobenzene. Successful formation and addition of the Grig-
nard reagent to WA functionality in 5a was confirmed by
the obtainment of ketone 46 in 72% yield. For phenstatin
analogues, various alkane WAs (Table 3) having highly
functionalized appendages were subjected to nucleophilic
addition with 3,4,5-trimethoxyphenylmagnesium bromide
(4 equiv.) for 2–3 h at 0 °C. Clean reactions were observed
[a] Yield of isolated product after flash chromatography.
cessful generation of the Grignard reagent from 3,4,5-tri- in all cases, thus paving the way for the targeted novel ana-
methoxybromobenzene. Even with utmost care, both at logues of phenstatin (Table 5). Compound 47 having a lat-
room temperature as well as under reflux conditions, no ent amino functionality and compounds 48–56 having
initiation of the reaction was observed in our hands as re- carbohydrate residues as their appendage will become inter-
ported in the literature.[26a] The change of solvent from esting and promising analogues for biological studies from
THF to diethyl ether was also unfruitful. On a closer look a solubility perspective. We then planned to investigate the
at the literature, pertaining to the formation of the Grig- biological activities of two compounds. For this, the isopro-
nard reagent from 3,4,5-trimethoxybromobenzene, it ap- pylidene protections in compounds 50 and 51 were removed
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Weinreb Amide Based Building Blocks for Analogues of Phenstatin
to afford regioisomeric tetrols 57 and 58, for which the bio- further converted into tetraacetate derivatives 59 and 60,
logical activity was tested,[27] and these compounds were respectively, for complete characterization of the obtained
tetrols (Scheme 4).
Table 5. Novel analogues of phenstatins.
Scheme 4. Preparation of tetrols and tetraacetates.
Biological Studies
Serial dilutions of tetrols 57 and 58 were incubated with
the mouse fibroblast cell line L929 and the HeLa clone KB-
3-1 in 96-well plates. After 5 d, growth was measured with
an MTT assay. Whereas para-appended tetrol had no
growth inhibiting activity up to 40 µg/mL, meta-appended
tetrol 58 was fairly active, showing IC50 values of 11 and
1.8 µg/mL for the two cell lines, respectively. Interestingly
the KB-3-1 cancer cells are more sensitive than L929, which
is also a transformed cell line but not derived from cancer.
Influence on the microtubules of PtK2 cells with Long-
nosed potoroo was also checked. There was a clear inter-
ference with mitotic spindle formation and a slight impair-
ment of microtubule cytoskeleton of normal interphase
cells was seen with meta compound 58 (5 and 10 µg/mL;
Figure 3). Study of the biological activity of other meta-
substituted compounds is currently underway.
Figure 3. Ptk2 cells from potoroo were incubated with 58 (b) or
with methanol (a) and stained for microtubules (green) and nuclei
(blue). In Figure (b), a disturbed mitotic spindle and a reduced
microtubular network in interphase cells can be seen.
Conclusions
To conclude, three new isomeric bifunctional building
[a] Yield of isolated product after flash chromatography.
blocks capable of performing C–C bond formation through
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B. Sivaraman, I. S. Aidhen
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10% Pd/C (20 wt.-%), and EtOAc (3 mL/mmol) for 8–12 h. The
reaction mixture was filtered through a Celite bed, and the bed was
thoroughly washed with ethyl acetate. The ethyl acetate layer was
concentrated to give the pure alkane WA in quantitative yield.
Wittig reaction and undergoing nucleophilic addition have
been synthesized. The benzylic phosphonium salt and
Weinreb amide functionality, the two reaction centers in
these building blocks, have enabled a new, general, and ef-
ficient strategy for synthesizing para-, meta-, and ortho-sub-
stituted diaryl ketones with highly functionalized append-
ages. Novel analogues of phenstatin were synthesized,
wherein the diaryl ketone motif was conjugated to the
monosaccharide moiety for the first time. The biological
activity of regioisomeric phenstatin analogues 57 and 58
revealed that meta-appended compound 58 is more potent
than para-57. In the context of this observation, other meta
analogues have become interesting cases for biological stud-
ies, which is currently underway. These bifunctional build-
ing blocks show great potential for other applications in
chemistry, and their applicability is left to the imagination
of synthetic organic chemists.
General Procedure for the Addition of Grignard Reagent to the
Alkane Weinreb Amides: To a stirred solution of alkane WA
(0.7 mmol) in dry THF (3 mL) was added the appropriate solution
of aryl- or heteroarylmagnesium bromide (2.1 mmol) in dry THF
(5 mL) under an inert atmosphere at 0 °C, and the mixture was
stirred between 0 and 20 °C for 3 h. TLC revealed the complete
consumption of the starting material. Subsequent hydrolysis was
achieved by cautious addition of a saturated ammonium chloride
solution. The aqueous layer was extracted with ethyl acetate
(3ϫ15 mL) and the ethyl acetate layer was washed with water,
dried with Na2SO4, and concentrated to give a crude product,
which was purified by silica-gel flash chromatography (ethyl acet-
ate/hexanes) to give the desired diaryl ketones in good yields.
General Procedure for the Addition of 3,4,5-Trimethoxyphenylmag-
nesium Bromide to the Alkane Weinreb Amides: To precleaned mag-
nesium turnings (3.08 mmol) was added iodine (one crystal), and
the mixture was roasted at 55 °C under vacuum for 5 min and then
allowed to cool to room temperature under a nitrogen atmosphere.
To this mixture was added dry THF (3 mL), and the resulting sus-
pension was warmed to 55 °C followed by the addition of MeI
(0.02 mL). At this temperature, freshly prepared 3,4,5-trimethoxy-
bromobenzene (3.08 mmol), azeotroped with dry benzene (3ϫ5 mL)
and dried under high vacuum for 5 min, dissolved in dry THF
(2 mL) was added drop by drop under vigorous stirring. Once the
addition was complete, initiation of the Grignard reaction could be
seen within 2–3 min, at which point the hot bath was removed, and
the reaction mixture was stirred for 1 h. Slight exothermicity was
observed till the complete consumption of magnesium metal; the
generated Grignard reagent is an off-white suspension. To this
Grignard reagent was added the alkane WA (0.77 mmol) dissolved
in dry THF (2 mL) at 0 °C, and the mixture was stirred between 0
and 20 °C. A clean reaction ensued as revealed by TLC after 2–
3 h. Subsequent hydrolysis was achieved by cautious addition of
a saturated ammonium chloride solution. The aqueous layer was
extracted with ethyl acetate (3ϫ15 mL), washed with brine, dried
with Na2SO4, and concentrated under vacuum to give the crude
product, which was purified by silica-gel flash chromatography
(ethyl acetate/hexanes or dichloromethane/hexanes) to give the de-
sired phenstatin analogues in good yields.
Experimental Section
General Information: All reactions were carried out in dry glass-
ware. Dry DMF was prepared by stirring with calcium hydride and
was stored over 4 Å molecular sieves after downward distillation.
Dry THF was distilled as and when needed from Na/benzophenone
ketyl. Magnesium metal was cleaned by using 20% HCl (3ϫ) fol-
lowed by washes with distilled water and acetone and was dried by
keeping it in an oven for 12 h at 100 °C. The Grignard reagent
prepared was estimated by using menthol (dry) and 1,10-phenan-
throline as indicator in dry THF. Solvents used for chromatography
were LR grade. Thin-layer chromatography was performed on alu-
minum plates coated with silica gel 60. Visualization was observed
by UV light irradiation or by dipping into a solution of cerium(IV)
sulfate (2.5 g) and ammonium molybdate (6.25 g) in 10% sulfuric
acid (250 mL) followed by charring on a hot plate. Melting points
were determined in capillaries. 1H (400 MHz) and 13C NMR
(100 MHz) spectra were recorded with CDCl3 or CD3OD as sol-
vent and tetramethylsilane (TMS) as reference. Mass spectra were
recorded with a MICRO-Q TOF mass spectrometer by using the
ESI technique at 10 eV. Optical rotations were measured with an
Autopol IV polarimeter at room temperature.
General Procedure for the Preparation of the Wittig Salts: To the
benzylic bromide compound (4.0 mmol, 1.0 equiv.) dissolved in the
suitable solvent (10 mL, acetone for 7a and 7b and p-xylene for 7c)
was added triphenylphosphane (1.2 equiv.), and the mixture was
heated at reflux for 8–12 h and cooled to room temperature. The
precipitated solid was filtered, washed with the corresponding sol-
vent, and dried under vacuum to give the pure Wittig salts as white
solids.
{4-[Methoxy(methyl)carbamoyl]benzyl}triphenylphosphonium Bro-
mide (4a): Yield: 80%. White solid. M.p. 238–246 °C. 1H NMR
(400 MHz, CD3OD): δ = 3.32 (s, 3 H, -NCH3), 3.57 (s, 3 H,
-OCH3), 5.06 (d, J = 15.2 Hz, 2 H, -CH2), 7.12 (d, J = 8.0 Hz, 2
H, Ar-H3, H5), 7.49 (d, J = 8.0 Hz, 2 H, Ar-H2, H6), 7.69–7.76 (m,
12 H, ArH), 7.90–7.94 (m, 3 H, ArH) ppm. 13C NMR (100 MHz,
CD3OD): δ = 30.3, 30.8, 61.7, 118.5, 119.4, 129.6, 131.5, 131.8,
131.9, 132.0, 135.3, 135.5, 135.7, 136.6, 136.6, 170.7 ppm. IR
General Procedure for the Preparation of the Alkane Weinreb Amide:
To a stirred suspension of NaH (0.2922 mmol) in dry DMF (4 mL/
mmol) was added the Wittig salt (0.2656 mmol) directly under a
nitrogen atmosphere, followed by the addition of aldehyde
(0.2922 mmol) dissolved in dry DMF (1 mL). The mixture was
stirred at room temperature, and a clean reaction ensued as re-
vealed by TLC analysis after 6–8 h. The reaction mixture was
quenched with aqueous ammonium chloride solution and extracted
with ethyl acetate (3ϫ15 mL). The ethyl acetate layer was washed
with water, dried with Na2SO4, concentrated, and purified by silica-
gel flash chromatography (ethyl acetate/hexanes) to give the ole-
finated product, which was subjected to hydrogenation with H2,
(CHCl3):
ν =
˜
2926, 1645, 1368, 1165 cm–1. C28H27BrNO2P
(520.40): calcd. C 64.62, H 5.23, N 2.69; found C 63.66, H 4.54, N
2.66.
{3-[Methoxy(methyl)carbamoyl]benzyl}triphenylphosphonium Bro-
mide (4b): Yield: 75%. White solid. M.p. 225–228 °C. 1H NMR
(400 MHz, CD3OD): δ = 3.23 (s, 3 H, -NCH3), 3.40 (s, 3 H,
-OCH3), 5.07 (d, J = 14.8 Hz, 2 H, -CH2), 7.14–7.16 (m, 1 H, ArH),
7.30–7.34 (m, 1 H, ArH), 7.55–7.57 (m, 1 H, ArH), 7.69–7.76 (m,
12 H, ArH), 7.90–7.94 (m, 4 H, ArH) ppm. 13C NMR (100 MHz,
CD3OD): δ = 30.5, 34.1, 61.7, 118.5, 119.4, 129.6, 131.5, 131.8,
131.9, 132.0, 135.3, 135.5, 135.7, 136.6, 136.6, 170.3 ppm. IR
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Weinreb Amide Based Building Blocks for Analogues of Phenstatin
(CHCl3):
2926, 1645, 1368, 1165 cm–1. C28H27BrNO2P
(520.40): calcd. C 64.62, H 5.23, N 2.69; found C 63.73, H 4.29, N
2.61.
ν
˜
=
= 8.0 Hz, 2 H, Ar-H3, H5), 7.53 (d, J = 8.0 Hz, 2 H, Ar-H2,
H6) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.1, 22.6, 29.1, 31.2,
31.8, 33.9, 35.9, 61.0, 128.1, 128.3, 131.2, 146.0, 170.1 ppm. IR
(CHCl ): ν = 2925, 2854, 1644, 1462, 1376 cm–1. HRMS (ESI):
˜
3
{2-[Methoxy(methyl)carbamoyl]benzyl}triphenylphosphonium Bro-
mide (4c): Yield: 60%. White solid. M.p. 195–198 °C. 1H NMR
(400 MHz, CD3OD): δ = 3.16 (s, 3 H, -NCH3), 3.44 (s, 3 H,
calcd. for C16H25NO2Na [M + Na]+ 286.1783; found 286.1777.
N-Methoxy-N-methyl-3-(pentafluorophenylethyl)benzamide
(13):
-OCH3), 5.25 (d, J = 14.8 Hz, 2 H, -CH2), 7.25–7.35 (m, 3 H, ArH), Yield: 75%. Rf = 0.45 (hexane/ethyl acetate, 8:2), colorless solid.
1
7.69–7.76 (m, 12 H, ArH), 7.90–7.94 (m, 4 H, ArH) ppm. 13C
NMR (100 MHz, CD3OD): δ = 29.6, 33.8, 61.4, 117.5, 118.3,
129.6, 131.5, 131.8, 131.9, 132.0, 135.3, 135.5, 135.7, 136.6, 136.6,
M.p. 76–78 °C. H NMR (400 MHz, CDCl3): δ = 2.90–2.96 (m, 2
H, -CH2CH2), 2.99–3.04 (m, 2 H, -CH2), 3.35 (s, 3 H, -NCH3),
3.54 (s, 3 H, -OCH3), 7.24 (d, J = 7.2 Hz, 1 H, Ar-H4), 7.31 (t, J
= 7.6 Hz, 1 H, Ar-H5), 7.47 (s, 1 H, Ar-H2), 7.52 (d, J = 7.2 Hz, 1
H, Ar-H6) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.3, 33.7, 35.1,
167.8 ppm. IR (CHCl3):
ν =
˜
2926, 1645, 1368, 1165 cm–1.
C28H27BrNO2P (520.40): calcd. C 64.62, H 5.23, N 2.69; found C
63.68, H 4.36, N 2.64.
60.9, 126.3, 128.1, 130.5, 134.4, 139.8, 169.8 ppm. IR (CHCl ): ν =
˜
3
2924, 1651, 1519, 1504, 948 cm–1. HRMS (ESI): calcd. for
C17H15NO2F5 [M + H]+ 360.1023; found 360.1022.
N-Methoxy-N-methyl-4-(pentafluorophenylethyl)benzamide
(5a):
Yield: 85%. Rf = 0.38 (hexane/ethyl acetate, 8:2), colorless solid.
1
M.p. 110–112 °C. H NMR (400 MHz, CDCl3): δ = 2.81–2.85 (m, N-Methoxy-N-methyl-3-(4-methylphenethyl)benzamide (14): Yield:
2 H, -CH2), 2.91–2.94 (m, 2 H, -CH2), 3.26 (s, 3 H, -NCH3), 3.44
70%. Rf = 0.55 (hexane/ethyl acetate, 8:2), colorless liquid. 1H
(s, 3 H, -OCH3), 7.08 (d, J = 8.0 Hz, 2 H, Ar-H3, H5), 7.52 (d, J NMR (400 MHz, CDCl3): δ = 2.21 (s, 3 H, ArCH3), 2.77–2.81 (m,
= 8.0 Hz, 2 H, Ar-H2, H6) ppm. 13C NMR (100 MHz, CDCl3): δ
23.2, 32.7, 34.1, 59.9, 127.0, 127.6, 129.3, 131.4, 142.8,
2 H, -CH2CH2), 2.82–2.85 (m, 2 H, ArCH2), 3.22 (s, 3 H, -NCH3),
3.45 (s, 3 H, -OCH3), 6.94–6.99 (m, 4 H, ArH), 7.14–7.22 (m, 2 H,
ArH), 7.38–7.39 (m, 2 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.4, 33.9, 37.3, 37.8, 60.9, 125.6, 128.3, 128.7, 129.0,
=
168.7 ppm. IR (CHCl ): ν = 2921, 2851, 1712, 1637, 1456,
˜
3
1166 cm–1. HRMS (ESI): calcd. for C17H14NO2NaF5 [M + Na]+
382.0842; found 382.0837.
130.8, 134.1, 138.3, 141.7, 170.2 ppm. IR (CHCl ): ν = 2928, 1650,
˜
3
1529, 1514, 958 cm–1. HRMS (ESI): calcd. for C18H22NO2 [M +
N-Methoxy-N-methyl-4-[2-(pyridin-2-yl)ethyl]benzamide (5b): Yield:
80%. Rf = 0.25 (hexane/ethyl acetate, 7:3), colorless liquid. 1H
NMR (400 MHz, CDCl3): δ = 3.03 (s, 4 H, 2 CH2), 3.25 (s, 3 H,
H]+ 284.1651; found 284.1646.
N-Methoxy-N-methyl-2-(pentafluorophenylethyl)benzamide
(15):
-NCH3), 3.46 (s, 3 H, -OCH3), 6.98 [d, J = 7.6 Hz, 1 H, (py)Ar- Yield: 70%. Rf = 0.50 (hexane/ethyl acetate, 8:2), colorless solid.
1
H3Ј], 7.03–7.06 [m, 2 H, (py)Ar-H4Ј, H5Ј], 7.12 (d, J = 8.0 Hz, 2 H,
Ar-H3, H5), 7.50 (d, J = 8.0 Hz, 2 H, Ar-H2, H6), 8.49 [s, 1 H, (py)
Ar-H6Ј] ppm. 13C NMR (100 MHz, CDCl3): δ = 33.8, 35.7, 39.3,
60.9, 121.4, 123.3, 128.1, 128.4, 131.7, 136.9, 144.2, 148.7, 160.4,
M.p. 64–66 °C. H NMR (400 MHz, CDCl3): δ = 2.78–2.82 (m, 2
H, -CH2CH2), 2.91–2.95 (m, 2 H, ArCH2), 3.26 (s, 3 H, -NCH3),
3.44 (s, 3 H, -OCH3), 7.14–7.30 (m, 4 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 24.2, 33.6, 35.1, 60.9, 127.8, 128.1, 128.6,
171.9 ppm. IR (CHCl ): ν = 2921, 2851, 1712, 1637, 1456,
134.4, 169.8 ppm. IR (CHCl ): ν = 2923, 1651, 1519, 1504,
˜
˜
3
3
1166 cm–1. HRMS (ESI): calcd. for C16H19N2O2 [M + H]+
948 cm–1. HRMS (ESI): calcd. for C17H15NO2F5 [M + H]+
271.1447; found 271.1451.
360.1023; found 360.1022.
N-Methoxy-N-methyl-4-(3,4,5-trimethoxyphenethyl)benzamide (5c):
Yield: 60%. Rf = 0.35 (hexane/ethyl acetate, 8:2), colorless liquid.
1H NMR (400 MHz, CDCl3): δ = 2.81–2.82 (m, 2 H, -CH2CH2),
N-Methoxy-N-methyl-4-vinylbenzamide (22): Yield: 75%. Rf = 0.40
(hexane/ethyl acetate, 8:2), colorless liquid. 1H NMR (400 MHz,
CDCl3): δ = 3.26 (s, 3 H, -NCH3), 3.47 (s, 3 H, -OCH3), 5.25 (d, J
2.87–2.88 (m, 2 H, -COArCH2), 3.27 (s, 3 H, -NCH3), 3.48 (s, 3 = 10.8 Hz, 1 H, -CHCHaHb), 5.74 (d, J = 17.6 Hz, 1 H, -CHCHaHb),
H, -OCH3), 3.73 (s, 6 H, 2 ArOCH3), 3.75 (s, 3 H, ArOCH3), 6.28
6.65 (dd, J = 17.6, 10.8 Hz, 1 H, ArCH), 7.35 (d, J = 8.0 Hz, 2 H,
[s, 2 H, (OCH3)3Ar-H2Ј, H6Ј], 7.12 (d, J = 8.0 Hz, 1 H, Ar-H3, H5), Ar-H3, H5), 7.58 (d, J = 8.0 Hz, 2 H, Ar-H2, H6) ppm. 13C NMR
7.53 (d, J = 8.0 Hz, 1 H, Ar-H2, H6) ppm. 13C NMR (100 MHz,
CDCl3): δ = 33.8, 37.8, 37.9, 56.0, 60.8, 105.3, 128.2, 128.4, 131.6,
(100 MHz, CDCl3) δ = 33.8, 60.9, 115.6, 125.7, 128.6, 133.1, 136.1,
139.7, 169.5 ppm. IR (CHCl ): ν = 2928, 2864, 1710, 1647, 1446,
˜
3
137.1, 144.5, 153.1, 169.9 ppm. IR (CHCl ): ν = 2923, 1651, 1519,
1186 cm–1. HRMS (ESI): calcd. for C11H14NO2 [M
+
H]+
˜
3
1504, 1220, 1130 cm–1. HRMS (ESI): calcd. for C20H26NO5 [M +
H]+ 360.1811; found 360.1809.
192.1025; found 192.1026.
(S)-4-[2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl]-N-methoxy-N-meth-
tert-Butyl 3-{4-[Methoxy(methyl)carbamoyl]phenyl}propylcarbamate ylbenzamide (29): Yield: 55%. Rf = 0.30 (hexane/ethyl acetate, 7:3).
1
(5d): Yield: 60%. Rf = 0.22 (hexane/ethyl acetate, 7:3), colorless
solid. M.p. 82–84 °C. H NMR (400 MHz, CDCl3): δ = 1.44 (s, 9
[α]D = –6.6 (c = 1, CHCl3), colorless liquid. H NMR (400 MHz,
CDCl3): δ = 1.28 (s, 3 H, -CH3), 1.36 (s, 3 H, -CH3), 1.74–1.89 (m,
1
H, -C(CH3)3), 1.79–1.83 (m, 2 H, -CH2), 2.66 (t, J = 8.0 Hz, 2 H, 2 H, -CH2CH2), 2.61–2.74 (m, 2 H, ArCH2), 3.28 (s, 3 H, -NCH3),
ArCH2), 3.13–3.15 (m, 2 H, -NCH2), 3.34 (s, 3 H, -NCH3), 3.55 (s,
3 H, -OCH3), 4.62 (br. s, 1 H, -NH), 7.20 (d, J = 8.0 Hz, 2 H, Ar-
H3, H5), 7.60 (d, J = 8.0 Hz, 2 H, Ar-H2, H6) ppm. 13C NMR
(100 MHz, CDCl3): δ = 28.4, 31.4, 32.9, 33.9, 40.2, 60.9, 79.1,
3.46 (t, J = 8.0 Hz, 1 H, -CHCHaHb), 3.49 (s, 3 H, -OCH3), 3.94
(dd, J = 6.0, 8.0 Hz, 1 H, -CHCHaHb), 4.01–4.05 (m, 1 H,
-CHaHbCH), 7.15 (d, J = 8.0 Hz, 2 H, Ar-H3, H5), 7.54 (d, J =
8.0 Hz, 2 H, Ar-H2, H6) ppm. 13C NMR (100 MHz, CDCl3): δ =
25.6, 26.9, 31.9, 33.8, 35.0, 60.9, 69.2, 75.2, 108.8, 128.0, 128.4,
127.9, 128.4, 131.6, 144.6, 156.0, 169.8 ppm. IR (CHCl ): ν = 2923,
˜
3
1646, 1471, 1264 cm–1. HRMS (ESI): C17H26N2O4Na [M + Na]+
131.8, 144.4, 169.8 ppm. IR (CHCl ): ν = 2935, 1638, 1369, 1213,
˜
3
345.1790; found 345.1790.
1062 cm–1. HRMS (ESI): calcd. for C16H24NO4 [M + H]+
294.1705; found 294.1707.
4-Heptyl-N-methoxy-N-methylbenzamide (5e): Yield: 70%. Rf
=
0.35 (hexane/ethyl acetate, 8:2), colorless liquid. 1H NMR
(400 MHz, CDCl3): δ = 0.81 (t, J = 7.2 Hz, 3 H, -CH3), 1.19–1.26
(m, 8 H, 4 CH2), 1.53–1.57 (m, 2 H, -CH2), 2.56 (t, J = 8.0 Hz, 2
H, ArCH2), 3.29 (s, 3 H, -NCH3), 3.50 (s, 3 H, -OCH3), 7.13 (d, J
(S)-3-[2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl]-N-methoxy-N-meth-
ylbenzamide (30): Yield: 60%. Rf = 0.28 (hexane/ethyl acetate, 7:3).
[α]D = –6.1 (c = 1, CHCl3), colorless liquid. H NMR (400 MHz,
1
CDCl3): δ = 1.28 (s, 3 H, -CH3), 1.36 (s, 3 H, -CH3), 1.64–1.90 (m,
Eur. J. Org. Chem. 2010, 4991–5003
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4997

B. Sivaraman, I. S. Aidhen
FULL PAPER
2 H, -CH2CH2), 2.60–2.76 (m, 2 H, ArCH2), 3.28 (s, 3 H, -NCH3),
3.46 (t, J = 7.6 Hz, 1 H, -CHCHaHb), 3.49 (s, 3 H, -OCH3), 3.94
(dd, J = 6.0, 7.6 Hz, 1 H, -CHCHaHb), 4.01–4.04 (m, 1 H,
13C NMR (100 MHz, CDCl3): δ = 23.8, 24.9, 28.7, 32.8, 33.1, 59.9,
67.8, 76.5, 78.8, 79.2, 84.2, 104.2, 111.2, 126.9, 127.4, 130.5, 136.3,
143.6, 168.8 ppm. IR (CHCl ): ν = 2918, 1648, 14906, 1102,
˜
3
-CHaHbCH), 7.19–7.25 (m, 2 H, ArH), 7.41–7.43 (m, 2 H, 1071 cm–1. HRMS (ESI): calcd. for C25H31NO6 [M + H]+
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.7, 27.0, 31.9,
442.2230; found 442.2231.
33.9, 35.2, 61.1, 69.3, 75.3, 108.9, 125.7, 128.1, 130.7, 134.3, 141.5,
3-{2-[(3aS,4R,6S,6aS)-6-(Benzyloxy)-2,2-dimethyltetrahydrofuro-
[3,4-d][1,3]dioxol-4-yl]ethyl}-N-methoxy-N-methylbenzamide (35):
Yield: 60%. Rf = 0.33 (hexane/ethyl acetate, 7:3). [α]D = –8.6 (c =
1, CHCl3), colorless liquid. 1H NMR (400 MHz, CDCl3): δ = 1.25
(s, 3 H, -CH3), 1.37 (s, 3 H, -CH3), 1.91–2.04 (m, 2 H, -CH2CH2),
2.65–2.76 (m, 2 H, ArCH2), 3.24 (s, 3 H, -NCH3), 3.45 (s, 3 H,
-OCH3), 3.86–3.89 (m, 1 H, 4-H), 4.37 (d, J = 12.0 Hz, 1 H, 3a-
H), 4.54–4.56 (m, 3 H, -CH2Ph, 6a-H), 4.98 (s, 1 H, -OCHOBn),
7.16–7.26 (m, 7 H, ArH), 7.39–7.41 (m, 1 H, ArH), 7.46 (s, 1 H,
Ar-H2) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.9, 26.1, 29.9,
32.2, 33.9, 61.0, 68.8, 79.1, 80.3, 85.2, 105.0, 112.3, 125.7, 128.0,
170.1 ppm. IR (CHCl ): ν = 2935, 1638, 1369, 1213, 1062 cm–1.
˜
3
HRMS (ESI): calcd. for C16H24NO4 [M + H]+ 294.1705; found
294.1703.
N-Methoxy-N-methyl-4-{2-[(4S,4ЈR,5R)-2,2,2Ј,2Ј-tetramethyl-4,4Ј-
bi(1,3-dioxolan)-5-yl]ethyl}benzamide (31): Yield: 80%. Rf = 0.28
(hexane/ethyl acetate, 7:3). [α]D = 13.6 (c = 1, CHCl3), colorless
1
liquid. H NMR (400 MHz, CDCl3): δ = 1.26 (s, 3 H, -CH3), 1.29
(s, 3 H, -CH3), 1.32 (s, 3 H, -CH3), 1.34 (s, 3 H, -CH3), 1.79–2.01
(m, 2 H, -CH2CH2), 2.73–2.82 (m, 2 H, ArCH2), 3.28 (s, 3 H,
-NCH3), 3.49 (s, 3 H, -OCH3), 3.51–3.53 (m, 1 H, -OCHaHb), 3.85–
3.94 (m, 3 H, -OCHaHb, 4,5-H), 4.02–4.06 (m, 1 H, -CHaHbCH),
7.18 (d, J = 8.0 Hz, 2 H, Ar-H3, H5), 7.54 (d, J = 8.0 Hz, 2 H, Ar-
H2, H6) ppm. 13C NMR (100 MHz, CDCl3) δ = 23.1, 24.6, 24.8,
25.2, 29.8, 31.7, 32.8, 58.8, 65.6, 74.5, 77.5, 79.0, 106.7, 107.4,
128.5, 130.8, 134.2, 137.5, 141.7, 170.1 ppm. IR (CHCl ): ν = 2985,
˜
3
1642, 1456, 1371, 1215, 1066 cm–1. HRMS (ESI): calcd. for
C25H31NO6 [M]+ 441.2151; found 441.2159.
4-{2-[(3aS,4R,6aR)-2,2-Dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-
yl]ethyl}-N-methoxy-N-methylbenzamide (36): Yield: 63%. Rf =
0.25 (hexane/ethyl acetate, 7:3). [α]D = –10.6 (c = 1, CHCl3), color-
126.2, 126.4, 129.5, 142.7, 167.8 ppm. IR (CHCl ): ν = 2985, 1642,
˜
3
1456, 1371, 1215, 1066 cm–1. HRMS (ESI): calcd. for C21H32NO6
[M + H]+ 394.2230; found 394.2221.
1
less liquid. H NMR (400 MHz, CDCl3): δ = 1.16 (s, 3 H, CH3),
1.36 (s, 3 H, CH3), 1.87–1.97 (m, 2 H, -CH2CH2), 2.68–2.69 (m, 2
H, ArCH2), 3.20 (s, 3 H, NCH3), 3.24–3.30 (m, 2 H, -OCH2CH),
3.43 (s, 3 H, OCH3), 3.85 (d, J = 10.0 Hz, 1 H, 4-H), 4.37 (d, J =
10.0 Hz, 1 H, 3a-H), 4.60 (d, J = 10.0 Hz, 1 H, 6a-H), 7.15 (d, J =
8 Hz, 2 H, Ar-H3, H5), 7.54 (d, J = 8 Hz, 2 H, Ar-H2, H6) ppm.
13C NMR (100 MHz, CDCl3): δ = 23.9, 26.0, 29.8, 32.1, 33.7, 60.8,
72.4, 80.8, 81.4, 108.8, 127.9, 128.4, 131.7, 144.5, 169.8 ppm. IR
N-Methoxy-N-methyl-3-{2-[(4S,4ЈR,5R)-2,2,2Ј,2Ј-tetramethyl-4,4Ј-
bi(1,3-dioxolan)-5-yl]ethyl}benzamide (32): Yield: 75%. Rf = 0.30
(hexane/ethyl acetate, 7:3). [α]D = 12.8 (c = 1, CHCl3), colorless
1
liquid. H NMR (400 MHz, CDCl3): δ = 1.24 (s, 3 H, -CH3), 1.28
(s, 3 H, -CH3), 1.30 (s, 3 H, -CH3), 1.33 (s, 3 H, -CH3), 1.81–2.03
(m, 2 H, -CH2CH2), 2.65–2.84 (m, 2 H, ArCH2), 3.25 (s, 3 H,
-NCH3), 3.47 (s, 3 H, -OCH3), 3.50–3.52 (m, 1 H, -OCHaHb), 3.83–
3.93 (m, 3 H, -OCHaHb, 4,5-H), 4.00–4.04 (m, 1 H, -CHaHbCH),
7.22–7.25 (m, 2 H, ArH), 7.38–7.39 (m, 1 H, ArH), 7.44 (s, 1 H,
Ar-H2) ppm. 13C NMR (100 MHz, CDCl3) δ = 25.2, 26.7, 27.0,
27.4, 31.9, 33.9, 35.2, 61.0, 67.7, 76.8, 79.7, 81.2, 108.8, 109.5,
(CHCl ): ν = 2989, 1648, 1450, 1401, 1219, 1061 cm–1. HRMS
˜
3
(ESI): calcd. for C18H26NO5 [M + H]+ 336.1811; found 336.1809.
3-{2-[(3aS,4R,6aR)-2,2-Dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-
yl]ethyl}-N-methoxy-N-methylbenzamide (37): Yield: 65%. Rf =
0.30 (hexane/ethyl acetate, 7:3). [α]D = –11.2 (c = 1, CHCl3), color-
125.5, 128.4, 130.7, 134.2, 141.8, 170.2 ppm. IR (CHCl ): ν = 2988,
˜
3
1640, 1449, 1380, 1228, 1076 cm–1. HRMS (ESI): calcd. for
1
less liquid. H NMR (400 MHz, CDCl3): δ = 1.16 (s, 3 H, -CH3),
C21H32NO6 [M + H]+ 394.2230; found 394.2224.
1.36 (s, 3 H, -CH3), 1.87–1.97 (m, 2 H, -CH2CH2), 2.68–2.69 (m,
2 H, ArCH2), 3.20 (s, 3 H, -NCH3), 3.24–3.30 (m, 2 H, -OCH2CH),
3.43 (s, 3 H, -OCH3), 3.85 (d, J = 10.0 Hz, 1 H, 4-H), 4.37 (d, J =
10.0 Hz, 1 H, 3a-H), 4.60 (d, J = 10.0 Hz, 1 H, 6a-H), 7.22–7.27
(m, 2 H, ArH), 7.41–7.43 (m, 2 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 23.9, 26.0, 29.8, 32.1, 33.7, 60.8, 72.4, 80.8,
81.4, 108.8, 125.7, 127.9, 128.4, 131.7, 144.5, 169.8 ppm. IR
N-Methoxy-N-methyl-4-{2-[(2R,3R,4S,5R,6S)-3,4,5-tris(benzyl-
oxy)-6-methoxytetrahydro-2H-pyran-2-yl]ethyl}benzamide (33):
Yield: 70%. Rf = 0.35 (hexane/ethyl acetate, 7:3). [α]D = 33.9 (c =
1, CHCl3), colorless liquid. 1H NMR (400 MHz, CDCl3): δ = 1.54–
1.59 (m, 1 H, -CHCHaHb), 2.04–2.05 (m, 1 H, -CHCHaHb), 2.49–
2.55 (m, 1 H, ArCHaHb), 2.73–2.77 (m, 1 H, ArCHaHb), 3.13 (t, J
= 9.6 Hz, 1 H, 2-H), 3.24 (s, 3 H, -NCH3), 3.26 (s, 3 H, -CHOCH3),
3.42–3.46 (m, 4 H, -OCH3, 3-H), 3.54 (td, J = 8.0, 2.0 Hz, 1 H, 4-
H), 3.83–3.88 (m, 1 H, 5-H), 4.48–4.91 (m, 7 H, 3 CH2Ph, -OCH-
OCH3), 7.07 (d, J = 8.0 Hz, 2 H, Ar-H3, H5), 7.15–7.28 (m, 15 H,
PhH), 7.51 (d, J = 8.0 Hz, 2 H, Ar-H2, H6) ppm. 13C NMR
(100 MHz, CDCl3): δ = 31.7, 33.1, 33.9, 55.1, 61.0, 69.7, 73.3, 75.2,
75.8, 80.2, 82.0, 98.0, 127.6, 127.8, 128.0, 128.5, 131.5, 138.3, 138.7,
(CHCl ): ν = 2985, 1640, 1451, 1361, 1205, 1076 cm–1. HRMS
˜
3
(ESI): calcd. for C18H26NO5 [M + H]+ 336.1811; found 336.1807.
3-{2-[(3aS,4R,6R,6aS)-6-(Methoxy)-2,2-dimethyltetrahydrofuro-
[3,4-d][1,3]dioxol-4-yl]ethyl}-N-methoxy-N-methylbenzamide (38):
Yield: 60%. Rf = 0.38 (hexane/ethyl acetate, 7:3). [α]D = –9.4 (c =
1, CHCl3), colorless liquid. 1H NMR (400 MHz, CDCl3): δ = 1.24
(s, 3 H, -CH3), 1.39 (s, 3 H, -CH3), 1.71–1.88 (m, 2 H, -CH2CH2),
2.65–2.73 (m, 2 H, ArCH2), 3.28 (s, 3 H, -NCH3), 3.32 (s, 3 H,
-CHOCH3), 3.49 (s, 3 H, -OCH3), 4.08 (dd, J = 6.0, 9.6 Hz, 1 H,
4-H), 4.48 (d, J = 6.0 Hz, 1 H, 3a-H), 4.55 (d, J = 6.0 Hz, 1 H, 6a-
H), 4.91 (s, 1 H, 6-H), 7.22–7.27 (m, 2 H, ArH), 7.41–7.42 (m, 1
H, ArH), 7.43 (s, 1 H, Ar-H2) ppm. 13C NMR (100 MHz, CDCl3):
δ = 24.9, 26.4, 32.4, 36.7, 55.16, 61.1, 84.2, 85.6, 86.3, 109.6, 112.3,
144.9, 169.9 ppm. IR (CHCl ): ν = 2923, 1640, 1496, 1092,
˜
3
1070 cm–1. HRMS (ESI): calcd. for C38H43NO7Na [M + Na]+
648.2937; found 648.2927.
4-{2-[(3aS,4R,6S,6aS)-6-(Benzyloxy)-2,2-dimethyltetrahydrofuro-
[3,4-d][1,3]dioxol-4-yl]ethyl}-N-methoxy-N-methylbenzamide (34):
Yield: 62%. Rf = 0.35 (hexane/ethyl acetate, 7:3). [α]D = –8.9 (c =
1, CHCl3), colorless liquid. 1H NMR (400 MHz, CDCl3): δ = 1.24
(s, 3 H, -CH3), 1.89 (s, 3 H, -CH3), 1.83–2.04 (m, 2 H, -CH2CH2),
2.64–2.76 (m, 2 H, ArCH2), 3.24 (s, 3 H, -NCH3), 3.43 (s, 3 H,
125.8, 128.2, 130.7, 134.3, 141.3, 170.1 ppm. IR (CHCl ): ν = 2975,
˜
3
1642, 1456, 1379, 1225, 1070 cm–1. HRMS (ESI): calcd. for
C19H28NO6 [M + H]+ 366.1917; found 366.1919.
-OCH3), 3.84–3.87 (m, 1 H, 4-H), 4.38 (d, J = 12.0 Hz, 1 H, 3a- Naphthalen-2-yl[4-(pentafluorophenylethyl)phenyl]methanone (8):
H), 4.51–4.58 (m, 3 H, -CH2Ph, 6a-H), 4.98 (s, 1 H, -OCHOBn),
Yield: 82%. Rf = 0.40 (hexane/ethyl acetate, 9:1), red solid. M.p.
7.15–7.25 (m, 7 H, ArH), 7.52 (d, J = 8.0 Hz, 2 H, Ar-H2, H6) ppm.
88–92 °C. 1H NMR (400 MHz, CDCl3): δ = 2.78–2.81 (m, 2 H,
4998
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4991–5003

Weinreb Amide Based Building Blocks for Analogues of Phenstatin
-CH2CH2), 2.85–2.88 (m, 2 H, ArCH2), 7.07 (d, J = 8.0 Hz, 2 H, CDCl3): δ = 21.6, 24.3, 35.1, 127.2, 128.3, 128.9, 129.6, 130.2,
Ar-H3, H5), 7.31–7.44 (m, 4 H, ArH), 7.63 (d, J = 8.0 Hz, 2 H, Ar-
H2, H6), 7.75 (d, J = 8.0 Hz, 1 H, Ar-H4Ј), 7.83 (d, J = 8.0 Hz, 2
132.1, 132.9, 134.9, 138.3, 140.2, 143.4, 196.4 ppm. IR (CHCl ): ν
˜
3
= 2926, 1655, 1519, 1503, 945 cm–1. HRMS (ESI): calcd. for
H, Ar-H7Ј, H6Ј), 7.91 (d, J = 8.0 Hz, 2 H, Ar-H5Ј, H8Ј) ppm. 13C C22H16OF5 [M + H]+ 391.1121; found 391.1118.
NMR (100 MHz, CDCl3): δ = 23.9, 35.2, 124.3, 125.7, 126.4, 127.1,
[3-(Pentafluorophenylethyl)phenyl](thiophen-2-yl)methanone
127.8, 128.2, 128.4, 130.7, 130.9, 131.2, 133.7, 136.5, 136.9, 145.8,
(17):
Yield: 70%. Rf = 0.45 (hexane/ethyl acetate, 9:1), colorless solid.
197.5 ppm. IR (CHCl ): ν = 2921, 1656, 1519, 1501 cm–1. HRMS
˜
3
1
M.p. 64–66 °C. H NMR (400 MHz, CDCl3): δ = 2.94–2.98 (m, 2
(ESI): calcd. for C25H15ONaF5 [M + Na]+ 449.0941; found
H, -CH2CH2), 3.02–3.06 (m, 2 H, ArCH2), 7.16–7.18 (m, 1 H,
ArH), 7.37–7.44 (m, 2 H, ArH), 7.58–7.59 (m, 1 H, ArH), 7.63 (s,
1 H, Ar-H2), 7.70–7.74 (m, 2 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 24.2, 35.1, 127.9, 128.6, 128.9, 132.3, 134.3, 134.7,
449.0939.
Phenyl{4-[2-(pyridin-2-yl)ethyl]phenyl}methanone (9): Yield: 78%.
Rf = 0.40 (hexane/ethyl acetate, 8:2), colorless liquid. 1H NMR
(400 MHz, CDCl3): δ = 3.06 (s, 4 H, 2 CH2), 7.00 (d, J = 7.6 Hz,
1 H, ArH), 7.04–7.07 (m, 1 H, ArH), 7.21 (d, J = 8.0 Hz, 2 H, Ar-
H3, H5), 7.37–7.40 (m, 2 H, ArH), 7.47–7.52 (m, 1 H, ArH), 7.64
(d, J = 8.0 Hz, 2 H, Ar-H2, H6), 7.69–7.71 (m, 2 H, ArH), 8.48 [d,
J = 4.8 Hz, 1 H, Ar(Py)-H6Ј] ppm. 13C NMR (100 MHz, CDCl3):
δ = 36.7, 39.6, 121.4, 123.0, 128.2, 128.7, 129.9, 130.4, 132.2, 135.4,
138.5, 140.4, 188.1 ppm. IR (CHCl ): ν = 2921, 1635, 1519, 1503,
˜
3
1415 cm–1. HRMS (ESI): calcd. for C19H11ONaSF5 [M + Na]+
405.0348; found 405.0348.
[3-(4-Methylphenethyl)phenyl](thiophen-2-yl)methanone (18): Yield:
78%. Rf = 0.50 (hexane/ethyl acetate, 9:1), colorless solid. M.p. 60–
62 °C. 1H NMR (400 MHz, CDCl3): δ = 2.25 (s, 3 H, ArCH3),
2.80–2.83 (m, 2 H, -CH2CH2), 2.87–2.89 (m, 2 H, ArCH2), 6.95 [d,
J = 8.0 Hz, 2 H, (CH3)Ar-H2ЈЈ, H6ЈЈ], 7.01 [d, J = 8.0 Hz, 2 H,
(CH3)Ar-H3ЈЈ, H5ЈЈ], 7.02 [dd, J = 5.2, 4.0 Hz, 1 H, Ar(S)-H4Ј], 7.30
[d, J = 4.8 Hz, 1 H, Ar(S)-H3Ј], 7.37 [dd, J = 3.6, 0.8 Hz, 1 H,
136.5, 137.9, 146.7, 149.3, 160.6, 196.5 ppm. IR (CHCl ): ν = 2931,
˜
3
2861, 1702, 1641, 1466, 1156 cm–1. HRMS (ESI): calcd. for
C20H18NO [M + H]+ 288.1388; found 288.1393.
(4-Methoxyphenyl)[4-(3,4,5-trimethoxyphenethyl)phenyl]methanone
(10): Yield: 75%. Rf = 0.55 (hexane/ethyl acetate, 9:1), solid. M.p.
76–78 °C. 1H NMR (400 MHz, CDCl3): δ = 2.82–2.84 (m, 2 H,
-CH2CH2), 2.89–2.91 (m, 2 H, ArCH2), 3.71 (s, 6 H, 2 ArOCH3),
3.77 (s, 3 H, ArOCH3), 3.79 (s, 3 H, ArOCH3), 6.29 [s, 2 H, (OCH3)3-
Ar-H2ЈЈ, H6ЈЈ], 6.87 [dd, J = 6.8, 2.0 Hz, 2 H, (OCH3)Ar-H3Ј, H5Ј],
7.12 (d, J = 8.0 Hz, 2 H, Ar-H3, H5), 7.60 (d, J = 8.0 Hz, 2 H, Ar-
H2, H6), 7.72 [dd, J = 6.8, 2.0 Hz, 2 H, (OCH3)Ar-H2Ј, H6Ј] ppm.
13C NMR (100 MHz, CDCl3): δ = 37.9, 55.5, 56.0, 60.9, 105.5,
113.5, 128.4, 130.4, 132.4, 136.0, 136.9, 146.1, 153.1, 163.1,
Ar(S)-H5Ј], 7.53 (s, 1 H, Ar-H2), 7.58–7.60 (m, 2 H, ArH) ppm. 13
NMR (100 MHz, CDCl3): δ = 21.4, 37.3, 37.8, 127.9, 128.2, 128.4,
C
129.1, 129.3, 132.5, 133.0, 135.4, 138.1, 142.1, 143.8, 188.3 ppm.
IR (CHCl ): ν = 2921, 1635, 1519, 1503, 1215 cm–1. HRMS (ESI):
˜
3
calcd. for C20H19OS [M + H]+ 307.1157; found 307.1153.
[2-(Pentafluorophenylethyl)phenyl](phenyl)methanone (19): Yield:
70%. Rf = 0.55 (hexane/ethyl acetate, 9:1), colorless solid. M.p. 68–
72 °C. 1H NMR (400 MHz, CDCl3): δ = 2.98 (s, 4 H, 2 CH2), 7.25–
7.34 (m, 3 H, ArH), 7.40–7.47 (m, 3 H, ArH), 7.57–7.60 (m, 1 H,
ArH), 7.76–7.78 (m, 2 H, ArH) ppm. 13C NMR (100 MHz, CDCl3)
δ = 24.5, 32.4, 125.9, 128.3, 128.4, 129.1, 130.1, 130.5, 133.2, 138.3,
195.2 ppm. IR (CHCl ): ν = 2923, 1651, 1519, 1504, 1220,
˜
3
1130 cm–1. HRMS (ESI): calcd. for C25H27O5 [M + H]+ 407.1858;
found 407.1855.
139.2, 197.8 ppm. IR (CHCl ): ν = 2927, 1736, 1662, 1502,
˜
3
tert-Butyl 3-(4-Benzoylphenyl)propylcarbamate (11): Yield: 75%. Rf
= 0.60 (hexane/ethyl acetate, 8:2), colorless solid. M.p. 90–96 °C.
1H NMR (400 MHz, CDCl3): δ = 1.37 [s, 9 H, -C(CH3)3], 1.76–
1.79 (m, 2 H, ArCH2CH2), 2.65 (t, J = 8.0 Hz, 2 H, ArCH2), 3.09–
3.11 (m, 2 H, NCH2), 4.62 (br. s, 1 H, -NH), 7.21 (d, J = 8.0 Hz,
2 H, Ar-H3, H5), 7.37–7.41 (m, 2 H, PhH), 7.48–7.50 (m, 1 H,
PhH), 7.65–7.71 (m, 4 H, ArH) ppm. 13C NMR (100 MHz, CDCl3)
δ = 27.9, 28.2, 31.7, 38.7, 77.8, 126.7, 128.5, 128.9, 130.8, 133.9,
965 cm–1. HRMS (ESI): calcd. for C21H14OF5 [M + H]+ 377.0965;
found 377.0963.
[2-(Pentafluorophenylethyl)phenyl](thiophen-2-yl)methanone
(20):
Yield: 80%. Rf = 0.75 (hexane/ethyl acetate, 9:1), colorless solid.
1
M.p. 60–62 °C. H NMR (400 MHz, CDCl3): δ = 2.89–2.92 (m, 2
H, -CH2CH2), 2.96–3.02 (m, 2 H, ArCH2), 7.03 [dd, J = 5.2,
4.0 Hz, 1 H, Ar(S)-H4Ј], 7.17 [m, 1 H, Ar(s)-H3Ј], 7.23 (td, J = 7.2,
0.8 Hz, 1 H, Ar-H5), 7.27 [dd, J = 3.6, 0.7 Hz, 1 H, Ar(s)-H2Ј], 7.35
(td, J = 7.6, 1.2 Hz, 1 H, Ar-H3), 7.40 (dd, J = 7.6, 0.8 Hz, 1 H,
Ar-H4), 7.65 (dd, J = 7.6, 0.8 Hz, 1 H, Ar-H6) ppm. 13C NMR
(100 MHz, CDCl3): δ = 25.4, 33.0, 126.8, 128.9, 129.4, 131.5, 136.0,
136.3, 145.3, 154.5, 195.0 ppm. IR (CHCl ): ν = 2926, 1697, 1655,
˜
3
1277, 924 cm–1. HRMS (ESI): calcd. for C21H25NO3Na [M +
Na]+ 362.1732; found 362.1726.
(4-Heptylphenyl)(thiophen-2-yl)methanone (12): Yield: 80%. Rf
=
136.3, 139.1, 139.8, 145.8, 190.5 ppm. IR (CHCl ): ν = 2921, 1635,
˜
3
0.60 (hexane/ethyl acetate, 9:1), colorless liquid. 1H NMR
(400 MHz, CDCl3): δ = 0.79 (t, J = 8.0 Hz, 3 H, -CH3), 1.11–1.25
(m, 8 H, 3 CH2), 1.54–1.59 (m, 2 H, -CH2), 2.59 (t, J = 8.0 Hz, 3
H, ArCH2), 7.04 [dd, J = 4.8, 4.0 Hz, 1 H, Ar(S)-H4Ј], 7.19 (d, J
= 8.0 Hz, 2 H, Ar-H3, H5), 7.55–7.60 (m, 2 H, ArH), 7.70 (d, J =
8.0 Hz, 2 H, Ar-H2, H6) ppm. 13C NMR (100 MHz, CDCl3): δ =
13.1, 21.6, 28.1, 28.3, 30.1, 30.7, 34.9, 126.8, 127.3, 127.5, 128.3,
132.7, 132.8, 133.5, 134.5, 142.8, 147.0, 186.9 ppm. IR (CHCl3):
1519, 1503, 1415 cm–1. HRMS (ESI): calcd. for C19H11ONaSF5 [M
+ Na]+ 405.0348; found 405.0348.
Thiophen-2-yl(4-vinylphenyl)methanone (21): Yield: 80%. Rf = 0.50
(hexane/ethyl acetate, 9:1), colorless solid. M.p. 46–48 °C. 1H NMR
(400 MHz, CDCl3): δ = 5.26 (d, J = 10.8 Hz, 1 H, -CHCHaHb),
5.75 (d, J = 17.6 Hz, 1 H, -CHCHaHb), 6.64 (dd, J = 17.6, 10.8 Hz,
1 H, ArCH), 7.02 [dd, J = 4.0 Hz, 1 H, Ar(S)-H4Ј], 7.38 (d, J =
8.0 Hz, 2 H, Ar-H3, H5), 7.52 [d, J = 4.0 Hz, 1 H, Ar(S)-H3Ј], 7.57
[d, J = 4.0 Hz, 1 H, Ar(S)-H5Ј], 7.72 (d, J = 8.0 Hz, 2 H, Ar-H2,
H6) ppm. 13C NMR (100 MHz, CDCl3): δ = 116.2, 125.8, 128.8,
129.3, 133.5, 134.3, 135.7, 136.9, 141.2, 143.3, 187.2 ppm. IR
ν = 2925, 2854, 1644, 1462, 1376 cm–1. HRMS (ESI): calcd. for
˜
C18H22ONaS [M + Na]+ 309.1289; found 309.1281.
[3-(Pentafluorophenylethyl)phenyl](p-tolyl)methanone (16): Yield:
75%. Rf = 0.50 (hexane/ethyl acetate, 9:1), colorless solid. M.p.
106–110 °C. 1H NMR (400 MHz, CDCl3): δ = 2.44 (s, 3 H,
ArCH3), 2.93–2.96 (m, 2 H, -CH2CH2), 3.03–3.04 (m, 2 H,
(CHCl ): ν = 2921, 1625, 1602, 1411, 1288 cm–1. HRMS (ESI):
˜
3
calcd. for C13H10ONaS [M + Na]+ 237.0350; found 237.0354.
ArCH2), 7.27 [d, J = 8.0 Hz, 2 H, (CH3)Ar- H3Ј, H5Ј], 7.37–7.41 (S)-{4-[2-(2,2-Dimethyl-1,3-Dioxolan-4-yl)ethyl]phenyl}(phenyl)meth-
(m, 2 H, ArH), 7.57 (s, 1 H, Ar-H2), 7.60–7.62 (m, 1 H, ArH), 7.67
[d, J = 8.0 Hz, 2 H, (CH3)Ar-H2Ј, H6Ј] ppm. 13C NMR (100 MHz,
anone (39): Yield: 75%. Rf = 0.60 (hexane/ethyl acetate, 8:2). [α]D
= –2.1 (c = 1, CHCl3), colorless liquid. 1H NMR (400 MHz,
Eur. J. Org. Chem. 2010, 4991–5003
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4999

B. Sivaraman, I. S. Aidhen
FULL PAPER
CDCl3): δ = 1.28 (s, 3 H, -CH3), 1.34 (s, 3 H, -CH3), 1.77–1.89 (m, 109.6, 115.4, 128.1, 128.4, 130.2, 132.4, 132.6, 134.0, 135.2, 147.2,
2 H, -CH2CH2), 2.64–2.76 (m, 2 H, ArCH2), 3.46 (t, J = 8.0 Hz, 1 165.0, 195.0 ppm. IR (CHCl ): ν = 2924, 1658, 1599, 1371, 1277,
H, -CHCHaHb), 3.93 (dd, J = 8.0, 6.0 Hz, 1 H, -CHCHaHb), 4.09– 1226, 1067 cm–1. HRMS (ESI): calcd. for C25H30O5F [M + H]+
˜
3
4.15 (m, 1 H, -CHaHbCH), 7.20 (d, J = 8.0 Hz, 2 H, Ar-H3, H5),
7.35 (d, J = 8.0 Hz, 2 H, Ar-H2, H6), 7.46 (t, J = 7.2 Hz, 1 H, Ph-
H4Ј), 7.64–7.69 (m, 3 H, ArH) ppm. 13C NMR (100 MHz, CDCl3):
δ = 25.6, 27.0, 32.0, 35.0, 69.2, 75.1, 108.9, 128.2, 128.3, 129.9,
429.2077; found 429.2073.
(2-Methoxyphenyl)(4-{2-[(4S,4ЈR,5R)-2,2,2Ј,2Ј-tetramethyl-4,4Ј-
bi(1,3-dioxolan)-5-yl]ethyl}phenyl)methanone (44): Yield: 70%. Rf =
0.45 (hexane/ethyl acetate, 8:2). [α]D = 9.9 (c = 1, CHCl3), colorless
130.4, 132.1, 135.5, 137.9, 146.7, 196.2 ppm. IR (CHCl ): ν = 2929,
˜
1
3
liquid. H NMR (400 MHz, CDCl3): δ = 1.24 (s, 3 H, -CH3), 1.28
1655, 1605, 1276, 1064 cm–1. HRMS (ESI): calcd. for C20H22O3Na
(s, 3 H, -CH3), 1.30 (s, 3 H, -CH3), 1.33 (s, 3 H, -CH3), 1.79–2.01
(m, 2 H, -CH2CH2), 2.72–2.84 (m, 2 H, ArCH2), 3.50 (t, J =
8.0 Hz, 1 H, -OCHaHb), 3.64 (s, 3 H, ArOCH3), 3.84–3.95 (m, 3
[M + Na]+ 333.1467; found 333.1472.
(S)-{4-[2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl]phenyl}(4-fluoro-
phenyl)methanone (40): Yield: 72%. Rf = 0.55 (hexane/ethyl acetate,
8:2). [α]D = –2.5 (c = 1, CHCl3), colorless liquid. 1H NMR
(400 MHz, CDCl3): δ = 1.26 (s, 3 H, -CH3), 1.34 (s, 3 H, -CH3),
1.78–1.88 (m, 2 H, -CH2CH2), 2.61–2.79 (m, 2 H, ArCH2), 3.45 (t,
J = 7.2 Hz, 1 H, -CHCHaHb), 3.93 (dd, J = 7.2, 6.0 Hz, 1 H,
-CHCHaHb), 4.12–4.19 (m, 1 H, -CHaHbCH), 7.01–7.06 (m, 2 H,
ArH), 7.21 (d, J = 8.0 Hz, 2 H, Ar-H3, H5), 7.60 (d, J = 8.0 Hz, 2
H, Ar-H2, H6), 7.70–7.73 (m, 2 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 25.6, 27.0, 32.0, 35.0, 69.2, 75.1, 108.9,
115.3, 128.2, 130.2, 132.4, 134.1, 135.3, 146.8, 165.1, 194.7 ppm.
H, -OCHaHb 4,5-H), 4.01–4.05 (m, 1 H, -CHaHbCH), 6.89–6.96
,
(m, 2 H, ArH), 7.19 (d, J = 8.0 Hz, 2 H, Ar-H3, H5), 7.23–7.25 (m,
1 H, ArH), 7.34–7.38 (m, 1 H, ArH), 7.66 (d, J = 8.0 Hz, 2 H, Ar-
H2, H6) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.1, 26.6, 26.7,
27.2, 32.1, 35.2, 55.4, 67.6, 76.6, 79.5, 81.0, 108.7, 109.1, 111.3,
120.3, 128.3, 128.9, 129.1, 130.0, 131.4, 135.5, 147.5, 157.0,
195.9 ppm. IR (CHCl ): ν = 2934, 1644, 1609, 1249, 1170,
˜
3
1265 cm–1. HRMS (ESI): calcd. for C26H32O6Na [M + Na]+
463.2097; found 463.2097.
p-Tolyl(4-{2-[(2R,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-methoxy-
tetrahydro-2H-pyran-2-yl]ethyl}phenyl)methanone (45): Yield: 70%.
Rf = 0.20 (hexane/ethyl acetate, 8:2). [α]D = 28.5 (c = 1, CHCl3),
IR (CHCl ): ν = 2931, 1655, 1597, 1276, 1225, 1154 cm–1. HRMS
˜
3
(ESI): calcd. for C20H22O3F [M + H]+ 329.1553; found 329.1555.
1
colorless liquid. H NMR (400 MHz, CDCl3): δ = 1.58–1.61 (m, 1
(S)-{4-[2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl]phenyl}(4-methoxy-
phenyl)methanone (41): Yield: 70%. Rf = 0.48 (hexane/ethyl acetate,
8:2). [α]D = –4.4 (c = 1, CHCl3), colorless liquid. 1H NMR
(400 MHz, CDCl3): δ = 1.37 (s, 3 H, -CH3), 1.44 (s, 3 H, -CH3),
1.86–1.98 (m, 2 H, -CH2CH2), 2.73–2.85 (m, 2 H, ArCH2), 3.55 (t,
J = 7.6 Hz, 1 H, -CHCHaHb), 3.86 (s, 3 H, ArOCH3), 4.03 (dd, J
= 7.6, 6.0 Hz, 1 H, -CHCHaHb), 4.11–4.18 (m, 1 H, -CHaHbCH),
6.94 [d, J = 11.2 Hz, 2 H, (OCH3)Ar-H3Ј, H5Ј], 7.29 (d, J = 8.0 Hz,
2 H, Ar-H3, H5), 7.69 (d, J = 8.0 Hz, 2 H, Ar-H2, H6), 7.81 (d, J
= 11.2 Hz, 2 H, (OCH3)Ar-H2Ј, H6Ј) ppm. 13C NMR (100 MHz,
CDCl3) δ = 25.6, 27.0, 32.0, 35.0, 55.4, 69.2, 75.2, 108.8, 113.5,
H, -CHCHaHb), 2.06–2.08 (m, 1 H, -CHCHaHb), 2.34 (s, 3 H,
ArCH3), 2.56–2.59 (m, 1 H, ArCHaHb), 2.79–2.82 (m, 1 H, ArCH-
aHb), 3.12–3.17 (m, 1 H, 2-H), 3.28 (s, 3 H, -CHOCH3), 3.44–3.47
(m, 1 H, 3-H), 3.55–3.58 (m, 1 H, 4-H), 3.83–3.88 (m, 1 H, 5-H),
4.50–4.92 (m, 7 H, 3 CH2Ph, -OCHOCH3), 7.22–7.30 (m, 19 H,
ArH), 7.60–7.63 (m, 4 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.7, 31.9, 33.2, 55.2, 69.7, 73.4, 75.3, 75.8, 80.2, 82.1,
98.0, 127.7, 127.8, 127.9, 128.0, 128.1, 128.5, 128.9, 130.2, 138.2,
138.7, 143.0, 146.9, 196.3 ppm. IR (CHCl ): ν = 2921, 2852, 1651,
˜
3
1606, 1092, 1051 cm–1. HRMS (ESI): calcd. for C43H44O6Na [M +
Na]+ 679.3036; found 679.3046.
128.2, 130.4, 131.6, 134.3, 146.1, 163.1, 195.1 ppm. IR (CHCl ): ν
˜
3
= 2934, 1649, 1599, 1508, 1249, 1170 cm–1. HRMS (ESI): calcd.
[4-(Pentafluorophenethyl)phenyl](3,4,5-trimethoxyphenyl)methanone
for C21H24O4 Na [M + Na]+ 363.1572; found 363.1573.
(46): Yield: 72%. Rf = 0.40 (hexane/ethyl acetate, 9:1), colorless
1
solid. M.p. 78–82 °C. H NMR (400 MHz, CDCl3): δ = 2.92–2.97
(4-{2-[(4S,4ЈR,5R)-2,2,2Ј,2Ј-Tetramethyl-4,4Ј-bi(1,3-dioxolan)-5-
yl]ethyl}phenyl)(p-tolyl)methanone (42): Yield: 70%. Rf = 0.50 (hex-
ane/ethyl acetate, 8:2). [α]D = 7.6 (c = 1, CHCl3), colorless liquid.
1H NMR (400 MHz, CDCl3): δ = 1.24 (s, 3 H, -CH3), 1.28 (s, 3
H, -CH3), 1.30 (s, 3 H, -CH3), 1.33 (s, 3 H, -CH3), 1.79–2.04 (m, 2
H, -CH2CH2), 2.33 (s, 3 H, ArCH3), 2.71–2.77 (m, 2 H, ArCH2),
(m, 2 H, -CH2CH2), 3.01–3.06 (m, 2 H, ArCH2), 3.88 (s, 6 H, 2
ArOCH3), 3.94 (s, 3 H, ArOCH3), 7.06 [s, 2 H, (OCH3)3Ar-H2,
H6], 7.32–7.42 (m, 2 H, ArH), 7.62–7.63 (m, 2 H, ArH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 24.3, 35.2, 56.3, 61.0, 107.9, 4 128.3,
129.6, 132.2, 132.5, 138.3, 140.4, 142.3, 152.9, 195.7 ppm. IR
(CHCl ): ν = 2929, 1690, 1643, 1364, 1164 cm–1. HRMS (ESI):
3.50 (t, J = 8.0 Hz, 1 H, -OCHaHb), 3.85–3.95 (m, 3 H, -OCHaHb
˜
3
,
C24H20O4F5 [M + H]+ 467.1282; found 467.1283.
4,5-H), 4.01–4.05 (m, 1 H, -CHaHbCH), 7.16 (d, J = 8.0 Hz, 2 H,
Ar-H3, H5), 7.23 (d, J = 8.0 Hz, 2 H, Ar-H2, H6), 7.60–7.685 (m,
4 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.6, 25.3, 26.7,
27.0, 27.4, 34.9, 36.6, 67.8, 77.1, 79.6, 81.1, 108.9, 109.6, 128.2,
128.3, 128.9, 130.3, 135.1, 135.6, 142.9, 146.9, 196.2 ppm. IR
tert-Butyl 3-[4-(3,4,5-Trimethoxybenzoyl)phenyl]propylcarbamate
(47): Yield: 75%. Rf = 0.20 (hexane/ethyl acetate, 9:1), colorless
1
liquid. H NMR (400 MHz, CDCl3): δ = 1.45 [s, 9 H, -C(CH3)3],
1.85–1.89 (m, 2 H, ArCH2CH2), 2.74 (t, J = 8.0 Hz, 2 H, ArCH2),
3.18–3.20 (m, 2 H, -NCH2), 3.88 (s, 6 H, 2 ArOCH3), 3.94 (s, 3 H,
ArOCH3), 4.60 (br. s, 2 H, -NH), 7.06 [s, 2 H, (OCH3)3Ar-H2Ј,
H6Ј], 7.30 (d, J = 8.0 Hz, 2 H, Ar-H3, H5), 7.74 (d, J = 8.0 Hz, 2
H, Ar-H2, H6) ppm. 13C NMR (100 MHz, CDCl3): δ = 28.4, 31.4,
33.1, 40.2, 56.3, 60.9, 79.2, 107.6, 128.2, 130.3, 132.8, 135.5, 141.8,
(CHCl ): ν = 2921, 2851, 1712, 1637, 1456, 1166 cm–1. HRMS
˜
3
(ESI): calcd. for C26H32O5Na [M + Na]+ 447.2147; found 447.2140.
(4-Fluorophenyl)(4-{2-[(4S,4ЈR,5R)-2,2,2Ј,2Ј-tetramethyl-4,4Ј-
bi(1,3-dioxolan)-5-yl]ethyl}phenyl)methanone (43): Yield: 75%. Rf =
0.55 (hexane/ethyl acetate, 8:2). [α]D = 8.1 (c = 1, CHCl3), colorless
146.6, 152.8, 155.9, 195.5 ppm. IR (CHCl ): ν = 2929, 1690, 1643,
˜
1
3
liquid. H NMR (400 MHz, CDCl3): δ = 1.26 (s, 3 H, -CH3), 1.29
1364, 1164 cm–1. HRMS (ESI): C24H32NO6 [M + H]+ 430.2230;
(s, 3 H, -CH3), 1.32 (s, 3 H, -CH3), 1.35 (s, 3 H, -CH3), 1.85–2.05
(m, 2 H, -CH2CH2), 2.73–2.84 (m, 2 H, ArCH2), 3.51 (t, J =
found 430.2228.
8.0 Hz, 1 H, -OCHaHb), 3.86–3.96 (m, 3 H, -OCHaHb 4,5-H), (S)-{4-[2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl]phenyl}(3,4,5-tri-
,
4.02–4.07 (m, 1 H, -CHaHbCH), 7.07–7.09 (m, 2 H, ArH), 7.25 (d, methoxyphenyl)methanone (48): Yield: 65%. Rf = 0.20 (hexane/
J = 8.0 Hz, 2 H, Ar-H3, H5), 7.63 (d, J = 8.0 Hz, 2 H, Ar-H2, H6),
dichloromethane, 1:3). [α]D = –4.8 (c = 1, CHCl3), colorless liquid.
7.73–7.75 (m, 2 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 1H NMR (400 MHz, CDCl3): δ = 1.44 (s, 3 H, -CH3), 1.47 (s, 3
25.2, 26.8, 26.9, 27.4, 32.2, 36.6, 67.8, 76.7, 79.7, 81.1, 108.9, 109.4, H, -CH3), 1.89–2.02 (m, 2 H, -CH2CH2), 2.78–2.90 (m, 2 H,
5000
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4991–5003

Weinreb Amide Based Building Blocks for Analogues of Phenstatin
ArCH2), 3.57–3.61 (m, 1 H, -CHCHaHb), 3.90 (s, 6 H, 2 ArOCH3),
(s, 1 H, -OCHOBn), 7.06 [s, 2 H, (OCH3)3Ar-H2Ј, H6Ј], 7.22–7.29
3.96 (s, 3 H, ArOCH3), 4.05–4.09 (m, 1 H, -CHCHaHb), 4.14–4.18 (m, 7 H, ArH), 7.67 (d, J = 8.0 Hz, 2 H, Ar-H2, H6) ppm. 13C
(m, 1 H, -CHaHbCH), 7.09 [s, 2 H, (OCH3)3Ar-H2Ј, H6Ј], 7.35 (d, NMR (100 MHz, CDCl3): δ = 24.9, 26.1, 29.7, 32.4, 56.3, 61.0,
J = 8.0 Hz, 2 H, Ar-H3, H5), 7.77 (d, J = 8.0 Hz, 2 H, Ar-H2, 69.0, 79.1, 80.3, 85.3, 105.2, 107.7, 112.4, 127.9, 128.5, 130.3, 132.9,
H6) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.7, 27.0, 32.1, 35.0,
56.4, 60.9, 69.2, 75.2, 107.8, 108.9, 128.3, 130.3, 132.9, 135.6, 142.0,
135.5, 137.4, 141.9, 147.0, 152.8, 195.6 ppm. IR (CHCl ): ν = 2929,
˜
3
1655, 1601, 1256 cm–1. HRMS (ESI): calcd. for C32H37O8 [M +
H]+ 549.2488; found 549.2494.
146.6, 152.9, 195.4 ppm. IR (CHCl ): ν = 2924, 1650, 1602, 1255,
˜
3
1171 cm–1. HRMS (ESI): calcd. for C23H29O6 [M + H]+ 401.1964;
(3-{2-[(3aS,4R,6S,6aS)-6-(Benzyloxy)-2,2-dimethyltetrahydrofuro-
[3,4-d][1,3]dioxol-4-yl]ethyl}phenyl)(3,4,5-trimethoxyphenyl)meth-
found 401.1964.
(S)-{3-[2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl]phenyl}(3,4,5-tri- anone (53): Yield: 60%. Rf = 0.42 (hexane/ethyl acetate, 8:2). [α]D
methoxyphenyl)methanone (49): Yield: 68%. Rf = 0.25 (hexane/
= –4.2 (c = 1, CHCl3), colorless liquid. 1H NMR (400 MHz,
dichloromethane, 1:3). [α]D = –4.4 (c = 1, CHCl3), colorless liquid. CDCl3): δ = 1.23 (s, 3 H, -CH3), 1.37 (s, 3 H, -CH3), 1.94–2.11 (m,
1H NMR (400 MHz, CDCl3): δ = 1.39 (s, 3 H, -CH3), 1.47 (s, 3 2 H, -CH2CH2), 2.72–2.94 (m, 2 H, ArCH2), 3.78 (s, 6 H, 2 Ar-
H, -CH3), 1.82–1.96 (m, 2 H, -CH2CH2), 2.78–2.90 (m, 2 H,
OCH3), 3.84 (s, 3 H, ArOCH3), 3.87–3.91 (m, 1 H, 4-H), 4.39 (d,
J = 12.0 Hz, 1 H, 3a-H), 4.55–4.58 (m, 3 H, -CH2Ph, 6a-H), 5.00
ArCH2), 3.57–3.60 (m, 1 H, -CHCHaHb), 3.90 (s, 6 H, 2 ArOCH3),
3.98 (s, 3 H, ArOCH3), 4.07–4.09 (m, 1 H, -CHCHaHb), 4.14–4.18 (s, 1 H, -OCHOBn), 7.06 [s, 2 H, (OCH3)3Ar-H2Ј, H6Ј], 7.19–7.22
(m, 1 H, -CHaHbCH), 7.09 [s, 2 H, (OCH3)3Ar-H2Ј, H6Ј], 7.43–7.46 (m, 5 H, ArH), 7.32–7.41 (m, 2 H, ArH), 7.54 (d, J = 8.0 Hz, 1 H,
(m, 2 H, ArH), 7.63–7.65 (m, 1 H, ArH), 7.65 (s, 1 H, Ar-H2) ppm. ArH), 7.63 (s, 1 H, Ar-H2) ppm. 13C NMR (100 MHz, CDCl3): δ
13C NMR (100 MHz, CDCl3): δ = 25.7, 27.0, 32.1, 35.0, 56.4, 60.9,
69.2, 75.2, 107.8, 108.9, 127.8, 128.3, 129.8, 132.5, 138.0, 142.0,
= 24.9, 25.6, 30.1, 32.3, 56.3, 61.0, 68.9, 79.1, 80.3, 85.3, 105.1,
107.7, 112.4, 127.9, 128.1, 128.5, 129.9, 132.5, 137.4, 137.9, 141.9,
152.9, 195.4 ppm. IR (CHCl ): ν = 2934, 1649, 1612, 1249,
152.8, 195.6 ppm. IR (CHCl ): ν = 2924, 1650, 1602, 1255,
˜
˜
3
3
1179 cm–1. HRMS (ESI): calcd. for C23H29O6 [M + H]+ 401.1964;
1171 cm–1. HRMS (ESI): calcd. for C32H37O8 [M + H]+ 549.2488;
found 401.1959.
found 549.2488.
(4-{2-[(4S,4ЈR,5R)-2,2,2Ј,2Ј-Tetramethyl-4,4Ј-bi(1,3-dioxolan)-5-
yl]ethyl}phenyl)(3,4,5-trimethoxyphenyl)methanone (50): Yield:
70 %. Rf = 0.40 (hexane/ethyl acetate, 8:2). [α]D = 7.6 (c = 1,
CHCl3), colorless liquid. 1H NMR (400 MHz, CDCl3): δ = 1.34 (s,
3 H, -CH3), 1.38 (s, 3 H, -CH3), 1.40 (s, 3 H, -CH3), 1.43 (s, 3 H,
(4-{2-[(3aS,4R,6aR)-2,2-Dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-
yl]ethyl}phenyl)(3,4,5-trimethoxyphenyl)methanone (54): Yield:
80%. Rf = 0.20 (hexane/ethyl acetate, 8:2). [α]D = –5.2. (c = 1,
CHCl3), colorless liquid. 1H NMR (400 MHz, CDCl3): δ = 1.28 (s,
3 H, -CH3), 1.33 (s, 3 H, -CH3), 2.02–2.18 (m, 2 H, -CH2CH2),
-CH3), 1.79–2.01 (m, 2 H, -CH2CH2), 2.72–2.94 (m, 2 H, ArCH2), 2.75–2.94 (m, 2 H, ArCH2), 3.43–3.47 (m, 2 H, -OCH2CH), 3.87
3.60–3.62 (m, 1 H, -OCHaHb), 3.88 (s, 6 H, 2 ArOCH3), 3.94 (s, 3 (s, 6 H, 2 ArOCH3), 3.93 (s, 3 H, ArOCH3), 4.01–4.04 (m, 1 H, 4-
H, ArOCH3), 3.96–4.05 (m, 3 H, -OCHaHb 4,5-H), 4.11–4.13 (m, H), 4.58–4.60 (m, 1 H, 3a-H), 4.75–4.77 (m, 1 H, 6a-H), 7.05 [s, 2
,
1 H, -CHaHbCH), 7.06 [s, 2 H, (OCH3)3Ar-H2Ј, H6Ј], 7.34 (d, J = H, (OCH3)3Ar-H2Ј, H6Ј], 7.34 (d, J = 8.0 Hz, 2 H, Ar-H3, H5), 7.73
8.0 Hz, 2 H, Ar-H3, H5), 7.75 (d, J = 8.0 Hz, 2 H, Ar-H2, H6) ppm.
13C NMR (100 MHz, CDCl3): δ = 25.2, 26.8, 27.0, 27.4, 32.2, 34.9,
56.3, 60.9, 67.8, 76.7, 79.7, 81.2, 107.7, 108.9, 109.6, 128.4, 130.3,
(d, J = 8.0 Hz, 2 H, Ar-H2, H6) ppm. 13C NMR (100 MHz,
CDCl3): δ = 22.7, 24.8, 29.3, 32.5, 56.3, 61.0, 72.6, 81.0, 81.6, 107.8,
112.0, 128.4, 130.1, 132.9, 135.5, 141.9, 147.0, 152.8, 195.6 ppm.
132.9, 135.5, 141.9, 147.1, 152.8, 195.5 ppm. IR (CHCl ): ν = 2923,
IR (CHCl ): ν = 2948, 1645, 1602, 1255, 1179 cm–1. HRMS (ESI):
˜
˜
3
3
1658, 1601, 1260, 1170 cm–1. HRMS (ESI): calcd. for C28H37O8 [M
+ H]+ 501.2488; found 501.2487.
calcd. for C25H31O7 [M + H]+ 443.2070; found 443.2067.
(3-{2-[(3aS,4R,6aR)-2,2-Dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-
yl]ethyl}phenyl)(3,4,5-trimethoxyphenyl)methanone (55): Yield:
78 %. Rf = 0.22 (hexane/ethyl acetate, 8:2). [α]D = –5.6 (c = 1,
CHCl3), colorless liquid. 1H NMR (400 MHz, CDCl3): δ = 1.25 (s,
3 H, -CH3), 1.41 (s, 3 H, -CH3), 2.02–2.18 (m, 2 H, -CH2CH2),
2.75–2.94 (m, 2 H, ArCH2), 3.35–3.39 (m, 2 H, -OCH2CH), 3.80
(3-{2-[(4S,4ЈR,5R)-2,2,2Ј,2Ј-Tetramethyl-4,4Ј-bi(1,3-dioxolan)-5-
yl]ethyl}phenyl)(3,4,5-trimethoxyphenyl)methanone (51): Yield:
68%. Rf = 0.30 (hexane/ethyl acetate, 8.8:1.2). [α]D = 8.4 (c = 1,
CHCl3), colorless liquid. 1H NMR (400 MHz, CDCl3): δ = 1.25 (s,
3 H, -CH3), 1.29 (s, 3 H, -CH3), 1.30 (s, 3 H, -CH3), 1.34 (s, 3 H,
-CH3), 1.79–2.08 (m, 2 H, -CH2CH2), 2.70–2.91 (m, 2 H, ArCH2), (s, 6 H, 2 ArOCH3), 3.87 (s, 3 H, ArOCH3), 3.93–3.96 (m, 1 H, 4-
3.51–3.53 (m, 1 H, -OCHaHb), 3.80 (s, 6 H, 2 ArOCH3), 3.90 (s, 3 H), 4.49–4.52 (m, 1 H, 3a-H), 4.68–4.71 (m, 1 H, 6a-H), 7.05 [s, 2
H, ArOCH3), 3.91–3.95 (m, 3 H, -OCHaHb 4,5-H), 4.01–4.08 (m, H, (OCH3)3Ar-H2Ј, H6Ј], 7.32–7.38 (m, 2 H, ArH), 7.53–7.55 (m,
,
1 H, -CHaHbCH), 6.99 [s, 2 H, (OCH3)3Ar-H2Ј, H6Ј], 7.32–7.40 (m, 1 H, ArH), 7.60 (s, 1 H, Ar-H2) ppm. 13C NMR (100 MHz,
2 H, ArH), 7.53 (d, J = 7.6 Hz, 1 H, Ar-H6), 7.60 (s, 1 H, Ar-
H2) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.6, 25.2, 26.7, 27.4,
32.0, 35.3, 56.1, 60.9, 67.8, 76.7, 79.8, 81.2, 107.8, 109.0, 109.7,
CDCl3): δ = 24.8, 26.1, 30.1, 32.3, 56.3, 61.0, 72.6, 81.0, 81.7, 107.8,
112.0, 127.7, 128.3, 129.9, 132.5, 137.9, 142.2, 152.8, 196.0 ppm.
IR (CHCl ): ν = 2924, 1650, 1602, 1255, 1171 cm–1. HRMS (ESI):
˜
3
127.6, 128.2, 129.8, 132.5, 132.7, 137.9, 142.1, 142.3, 152.8, calcd. for C25H31O7 [M + H]+ 443.2070; found 443.2072.
195.9 ppm. IR (CHCl ): ν = 2964, 1648, 1610, 1258, 1171 cm–1.
˜
3
(3-{2-[(3aS,4R,6R,6aS)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-
HRMS (ESI): calcd. for C28H37O8 [M + H]+ 501.2488; found
d][1,3]dioxol-4-yl]ethyl}phenyl)(3,4,5-trimethoxyphenyl)methanone
501.2489.
(56): Yield: 62%. Rf = 0.32 (hexane/ethyl acetate, 8:2). [α]D = –6.6
1
(4-{2-[(3aS,4R,6S,6aS)-6-(Benzyloxy)-2,2-dimethyltetrahydrofuro-
[3,4-d][1,3]dioxol-4-yl)ethyl]phenyl}(3,4,5-trimethoxyphenyl)meth-
(c = 1, CHCl3), colorless liquid. H NMR (400 MHz, CDCl3): δ =
1.26 (s, 3 H, -CH3), 1.40 (s, 3 H, -CH3), 2.02–2.18 (m, 2 H,
anone (52): Yield: 62%. Rf = 0.40 (hexane/ethyl acetate, 8:2). [α]D -CH2CH2), 2.62–2.85 (m, 2 H, ArCH2), 3.30 (s, 3 H, CHOCH3),
= –3.6 (c = 1, CHCl3), colorless liquid. 1H NMR (400 MHz,
3.80 (s, 6 H, 2 ArOCH3), 3.87 (s, 3 H, ArOCH3), 4.08–4.12 (m, 1
CDCl3): δ = 1.28 (s, 3 H, -CH3), 1.39 (s, 3 H, -CH3), 1.94–2.11 (m, H, 4 H), 4.48–4.56 (m, 2 H, 3a, 6a-H), 4.91 (s, 1 H, 6-H), 7.00 [s,
2 H, -CH2CH2), 2.72–2.94 (m, 2 H, ArCH2), 3.78 (s, 6 H, 2 Ar-
2 H, (OCH3)3Ar-H2Ј, H6Ј], 7.32–7.35 (m, 2 H, ArH), 7.53–7.55 (m,
OCH3), 3.88 (s, 3 H, ArOCH3), 3.92–3.94 (m, 1 H, 4-H), 4.42 (d, 1 H, ArH), 7.58 (s, 1 H, Ar-H2) ppm. 13C NMR (100 MHz,
J = 12.0 Hz, 1 H, 3a-H), 4.58–4.60 (m, 3 H, -CH2Ph, 6a-H), 5.01 CDCl3): δ = 24.9, 26.1, 32.4, 36.7, 55.2, 56.3, 61.0, 72.6, 84.1, 85.6,
Eur. J. Org. Chem. 2010, 4991–5003
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5001

B. Sivaraman, I. S. Aidhen
FULL PAPER
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[6]
a) G. C. Tron, T. Pirali, G. Sorba, F. Pagliai, S. Busacca, A.
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Boyd, E. Hamel, R. K. Pettit, J. Med. Chem. 2000, 43, 2731;
c) G. R. Pettit, J. W. Lippert, D. L. Herald, J. Org. Chem. 2000,
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C. Perez-Melero, C. Mateo, D. Alonso, J. L. Fernandez, C. Gaj-
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C. M. Lin, S. B. Singh, P. S. Chu, R. O. Dempcy, J. M.
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H.-P. Hsieh, J.-P. Liou, Y.-T. Lin, N. Mahindroo, J.-Y. Chang,
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C.-H. Lin, Y.-Y. Chang, C.-C. Wang, Bioorg. Med. Chem. Lett.
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For reviews, see: a) S. Dedola, S. A. Nepogodiev, R. A. Field,
Org. Biomol. Chem. 2007, 5, 1006; b) P. Wu, V. V. Fokin, Ald-
richimica Acta 2007, 40, 7; c) W. H. Binder, R. Sachsenhofer,
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Hiemstra, J. H. van Maarseveen, Eur. J. Org. Chem. 2006, 51;
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2005, 2, 293.
a) S. Budavari, The Merck Index, 11th ed., Merck, Rahway,
USA, 1989; b) N. Krause, Modern Organocopper Chemistry,
Wiley-VCH, Weinheim, 2002; for representative examples con-
taining the diaryl ketone scaffold as an important structural
motif, see: c) Cotoin: O. R. Gottlieb, W. B. Mors, J. Am. Chem.
Soc. 1958, 80, 2263; d) Papaveraldine: H. H. Wasserman, R.
Amici, R. Frechette, J. H. van Duzer, Tetrahedron Lett. 1989,
30, 869; e) Suprofen: http://en.wikipedia.org/wiki/Suprofen; f)
Ketoprofen: http://en.wikipedia.org/wiki/Ketoprofen; g) Fenof-
ibrate: T. Aoki, T. Asaki, T. Hamamoto, Y. Sugiyama, S.
Ohmachi, K. Kuwabara, K. Murakami, M. Todo, Bioorg. Med.
Chem. Lett. 2008, 18, 2128 and references cited therin; h) Suli-
sobenzone: http://en.wikipedia.org/wiki/Sulisobenzone; i) Oxy-
benzone: http://en.wikipedia.org/wiki/oxybenzone.
For a review, see: G. A. Olah, Friedel Crafts and Related Reac-
tions, Wiley, New York, 1964, vol. 1.
For reviews, see: a) B. T. O’Nesill, Comprehensive Organic Syn-
thesis (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991,
vol. 1, p. 397; b) R. K. Dieter, Tetrahedron 1999, 55, 4177.
For a minireview, see: A. Zapf, Angew. Chem. Int. Ed. 2003,
42, 5394.
a) H. Neumann, A. Brennfuhrer, M. Beller, Chem. Eur. J. 2008,
14, 3645 and references cited therein; b) review: J.-J. Brunet, R.
Chauvin, Chem. Soc. Rev. 1995, 24, 89.
T. Ishiyama, J. Hartwig, J. Am. Chem. Soc. 2000, 122, 12043.
Y.-C. Huang, K. Majumdar, H. Cheng, J. Org. Chem. 2002, 67,
1682.
M. Pucheault, S. Darses, J.-P. Genet, J. Am. Chem. Soc. 2004,
126, 15356.
C. Qin, J. Chen, H. Wu, J. Cheng, Q. Zhang, B. Zuo, W. Su, J.
86.1, 107.8, 109.7, 112.3, 127.8, 128.3, 129.9, 132.6, 137.9, 141.7,
152.9, 196.0 ppm. IR (CHCl ): ν = 2934, 1658, 1612, 1249,
˜
3
1181 cm–1. HRMS (ESI): calcd. for C26H33O8 [M + H]+ 473.2175;
found 473.2175.
(2R,3S,4R)-6-[4-(3,4,5-Trimethoxybenzoyl)phenyl]hexane-1,2,3,4-
tetrayltetraacetate (59): Yield: 80%. Rf = 0.30 (hexane/ethyl acetate,
7:3). [α]D = –3.6 (c = 1, CHCl3), colorless crystalline solid. M.p.
68–72 °C. 1H NMR (400 MHz, CDCl3): δ = 1.81–1.93 (m, 2 H,
-CH2CH2), 2.06 (s, 9 H, 3 OCOCH3), 2.15 (s, 3 H, -OCOCH3),
2.71–2.76 (m, 2 H, ArCH2), 3.88 (s, 6 H, 2 ArOCH3), 3.94 (s, 3 H,
ArOCH3), 4.15–4.28 (m, 2 H, -OCHCH2), 5.15–5.16 (m, 1 H, 4-
H), 5.26–5.28 (m, 1 H, 3-H), 5.36–5.38 (m, 1 H, 2-H), 7.06 [s, 2 H,
(OCH3)3Ar-H2Ј, H6Ј], 7.29 (d, J = 8.0 Hz, 2 H, Ar-H3, H5), 7.74 (d,
J = 8.0 Hz, 2 H, Ar-H2, H6) ppm. 13C NMR (100 MHz, CDCl3): δ
= 20.8, 31.6, 32.3, 56.4, 60.9, 61.9, 68.5, 70.3, 107.8, 128.3, 130.3,
132.8, 135.8, 142.1, 145.8, 152.9, 170.0, 170.6, 195.3 ppm. IR
[7]
[8]
(CHCl ): ν = 2924, 1702, 1650, 1602, 1590, 1255, 1171 cm–1
.
[9]
˜
3
HRMS (ESI): calcd. for C30H37O12 [M + H]+ 589.2285; found
589.2287.
(2R,3S,4R)-6-[3-(3,4,5-Trimethoxybenzoyl)phenyl]hexane-1,2,3,4-
tetrayltetraacetate (60): Yield: 76%. Rf = 0.30 (hexane/ethyl acetate,
7:3). [α]D = –3.2 (c = 1, CHCl3), colorless crystalline solid. M.p.
55–58 °C. 1H NMR (400 MHz, CDCl3): δ = 1.79–1.82 (m, 2 H,
-CH2CH2), 1.99 (s, 9 H, 3 -OCOCH3), 2.05 (s, 3 H, -OCOCH3),
2.62–2.66 (m, 2 H, ArCH2), 3.81 (s, 6 H, 2 ArOCH3), 3.87 (s, 3 H,
ArOCH3), 4.06–4.17 (m, 2 H, -OCHCH2), 5.06–5.07 (m, 1 H, 4-
H), 5.19–5.20 (m, 1 H, 3-H), 5.26–5.30 (m, 1 H, 2-H), 6.99 [s, 2 H,
(OCH3)3Ar-H2Ј, H6Ј], 7.31–7.33 (m, 2 H, ArH), 7.52–7.54 (m, 2 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.8, 31.6, 32.8,
56.4, 61.0, 61.9, 68.3, 70.2, 107.7, 128.0, 128.3, 129.6, 132.4, 132.6,
[10]
138.1, 141.2, 142.0, 152.9, 170.0, 170.5, 195.9 ppm. IR (CHCl ): ν
˜
3
= 2931, 1701, 1660, 1612, 1589, 1259, 1176 cm–1. HRMS (ESI):
calcd. for C30H37O12 [M + H]+ 589.2285; found 589.2286.
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra of all new compounds.
[11]
[12]
Acknowledgments
[13]
[14]
The authors thank the Department of Science and Technology
(DST), New Delhi for funding towards a 400 MHz NMR machine
to the Department of Chemistry, IIT-Madras under the Intensifi-
cation of Research in High Priority Areas (IRHPA) Scheme and
ESI-MS facility under the Fund for Improvement of Science &
Technology infrastructure (FIST) program. The Board of Research
in Nuclear Sciences (BRNS) is acknowledged for funding of project
2008/37/21/BRNS. B.S.R. is thankful to CSIR for a fellowship. We
sincerely thank Dr. Florenz Sasse and Miss Yazh Muthukumar for
their efforts in biological studies.
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Received: April 16, 2010
Published Online: July 29, 2010
Eur. J. Org. Chem. 2010, 4991–5003
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5003