Synthesis of functionalized cinnamaldehyde derivatives by an oxidative heck reaction and their use as starting materials for preparation of Mycobacterium tuberculosis 1-deoxy-d-xylulose-5-phosphate reductoisomerase inhibitors

Article abstract of DOI:10.1021/jo201715x

Cinnamaldehyde derivatives were synthesized in good to excellent yields in one step by a mild and selective, base-free palladium(II)-catalyzed oxidative Heck reaction starting from acrolein and various arylboronic acids. Prepared α,β-unsaturated aldehydes were used for synthesis of novel α-aryl substituted fosmidomycin analogues, which were evaluated for their inhibition of Mycobacterium tuberculosis 1-deoxy-d-xylulose 5-phosphate reductoisomerase. IC₅₀ values between 0.8 and 27.3 μM were measured. The best compound showed activity comparable to that of the most potent previously reported α-aryl substituted fosmidomycin-class inhibitor.

Full text of DOI:10.1021/jo201715x

ARTICLE
pubs.acs.org/joc
Synthesis of Functionalized Cinnamaldehyde Derivatives by an
Oxidative Heck Reaction and Their Use as Starting Materials for
Preparation of Mycobacterium tuberculosis 1-Deoxy-D-xylulose-
5-phosphate Reductoisomerase Inhibitors
Anneli Nordqvist,† Christofer Bj€orkelid,‡ Mounir Andaloussi,† Anna M. Jansson,‡ Sherry L. Mowbray,‡
Anders Karlꢀen,† and Mats Larhed*,†
†Division of Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Biomedical Center, Box 574,
SE-751 23 Uppsala, Sweden
‡Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden
S Supporting Information
b
ABSTRACT: Cinnamaldehyde derivatives were synthesized in
good to excellent yields in one step by a mild and selective, base-
free palladium(II)-catalyzed oxidative Heck reaction starting
from acrolein and various arylboronic acids. Prepared α,β-
unsaturated aldehydes were used for synthesis of novel α-aryl
substituted fosmidomycin analogues, which were evaluated for their inhibition of Mycobacterium tuberculosis 1-deoxy-D-xylulose
5-phosphate reductoisomerase. IC50 values between 0.8 and 27.3 μM were measured. The best compound showed activity
comparable to that of the most potent previously reported α-aryl substituted fosmidomycin-class inhibitor.
’ INTRODUCTION
the oxidative Heck reaction employs very mild, base-free condi-
tions at room temperature.8,18 The readily available, low toxicity,
and easily handled starting materials in the form of boronic
acids,19 used together with various olefins, provides an excellent
framework for the synthesis of α,β-unsaturated aromatic deriva-
tives. The use of acrolein as the olefin has been troublesome in
the base-requiring palladium(0)-catalyzed HeckꢀMizoroki reac-
tion at elevated temperatures, providing low yields due to
competing polymerization processes.20,21 Thus only a limited
number of palladium(0)-catalyzed HeckꢀMizoroki reactions
with acrolein22ꢀ30 have been reported. The use of acrolein in
an oxidative Heck is limited,18 but the palladium(II)-catalyzed
Heck coupling of the related methyl vinyl ketone with various
boronic acids has been reported with yields between 50% and
88%.4,8,10,31
Tuberculosis (TB) is still one of the most serious infectious
diseases, with 9.4 million new cases and almost 1.7 million deaths
in the year 2009.32 The lengthy and complicated treatment and
the emergence of multidrug-resistant strains make the need for
new drugs acting on new targets urgent. DXR (EC 1.1.1.267) is
the second enzyme in the nonmevalonate pathway that is present
in most eubacteria, including Mycobacterium tuberculosis (Mt),
many parasites, and the plastids of plants.33 It catalyzes the
conversion of 1-deoxy-D-xylulose 5-phosphate (DOXP) to 2-C-
methyl-D-erythrose 4-phosphate (MEP), which is used for the
biosynthesis of isopentyl diphosphate (IPP) and dimethylallyl
The palladium(II)-mediated oxidative Heck reaction with an
organoborane substrate was first reported by Dieck and Heck in
1975,1 but it was not until the development of a catalytic
protocol2 that this reaction began to receive more attention.3
Initially the Cu(OAc)2 reoxidant4 was used to regenerate Pd(II)
from Pd(0) but could in 2003 be replaced by molecular oxygen,5
avoiding the generation of stoichiometric amounts of heavy
metal salts. In 2004 the ligand-modulated oxidative Heck reac-
tion with arylboronic acids was introduced, in which the 2,9-
dimethyl-1,10-phenanthroline (dmphen) ligand facilitated palla-
dium reoxidation, catalytic stability, and control of the regios-
electivity with electron-rich olefins.6,7 The reaction conditions
became even milder when the base-free reaction using boronic
acids was discovered.8 Some recent developments involve oxy-
gen and base-free reactions without external oxidant9 and the
identification of new nonphenanthroline type ligands.10
α,β-Unsaturated aldehydes are important starting materials in
various synthetic applications.11,12 Cinnamaldehydes are com-
monly synthesized in one or more steps by the Wittig reaction13
or crossed aldol condensation,13 but various additional methods
can be employed, such as HornerꢀWadsworthꢀEmmons
reaction,14,15 Peterson reaction,16 oxidation of primary allylic
alcohols,13 and reduction of carboxylic acid derivatives.13 The use
of a palladium-catalyzed reaction with aryl halides and acetal
protected acrolein, with subsequent acetal deprotection under
acidic conditions, is another convenient possibility to obtain
cinnamaldehyde derivatives.17 A major drawback of many of the
methods mentioned is the harsh reaction conditions. In contrast,
Received: August 18, 2011
Published: September 21, 2011
r
2011 American Chemical Society
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arylboronic acids as arylating agents are reported. Five of the
resulting cinnamaldehyde derivatives were used for the synthesis
of 11 fosmidomycin analogues to further explore α-aryl substitu-
tions, which were evaluated for inhibition of MtDXR.
’ RESULTS AND DISCUSSION
In the preparation of novel α-aryl substituted fosmidomycin
analogues we aimed to explore the effect of introducing biaryl
substituents and other aromatic rings, as compared to the phenyl
and thiophene groups investigated previously.12,52 It has recently
been shown that biaryl and bicyclic aromatic groups in this
position can be accommodated by the E. coli enzyme.56,57 It is
reasonable to assume that MtDXR can also accommodate
such substituents. Recently, the complex structure of MtDXR
with 3 (2YIG, 3RAS)55,57 and its formyl analogue (2Y1D)55 were
published, showing that the 3,4-dichlorophenyl ring binds in a
large solvent-exposed site. To investigate this area further a series
of α-aryl analogues incorporating heteroraomatic and aliphatic
rings that varied in lipophilicity were prepared. Different fused
heterocycles such as naphthalene and 2-benzofuran or biaryl
rings were considered. The Clog P value of the selected
substituents varied between 1.5 and 4.5. The synthesis of α-aryl
substituted fosmidomycin analogues starts from the appropri-
ately substituted cinnamaldehyde.12
An initial optimization study was conducted to identify
suitable reaction conditions for the synthesis of the functional-
ized cinnamaldehydes from acrolein and p-tolylboronic acid
(Table 1). Two different palladium(II) catalysts, with a phenan-
throline (8a) or a phosphine ligand (8b), p-benzoquinone
(p-bzq, 9) versus air as reoxidant, and different solvents were
investigated, as well as a microwave protocol. The response was
measured by GCꢀMS as the peak area of product divided by the
internal standard peak, multiplied by the internal standard
concentration divided by the concentration of the yield-deter-
mining reactant according to eq 1.
Figure 1. Structures of known MtDXR inhibitors.
Table 1. Optimization of the Reaction Conditions with
Acroleina
GCꢀMS
entry catalytic mixb solvent time
temp
responsec ratio 4a:5j
1
2
3
4
5
6
7
8
9
7a/8a/9
7a/8a/9
7a/8a/9
7b/8a/9
7a/8b/9
7a/8a/air
7a/8a/9
7a/8a/9
7a/8a/9
DMF
24 h rt
80
85
<1
77
<1
81
65
66
60
1:2
1:2
1:2
1:2
1:2
1:2
1:2
2:1
5:1
MeCN 24 h rt
ethanol 24 h rt
MeCN 24 h rt
MeCN 24 h rt
MeCN 24 h rt
MeCN 0.5 h 100 °C
MeCN 24 h rt
MeCN 24 h rt
a All reactions were carried out with acrolein (4a) and p-tolylboronic
acid (5j), on a 1 mmol scale with Pd(II) catalyst (0.02 mmol), ligand
(0.024 mmol), reoxidant (p-bzq, 1 mmol or air), and solvent (2 mL) for
the time and temperature indicated. b Combination of Pd(II) catalyst,
ligand, and reoxidant, consisting of either Pd(OAc)2 (7a) or Pd-
(OCOCF3)2 (7b), dmphen (8a) or dppp (8b), and p-bzq (9) or air
as indicated. c Naphthalene was added to each reaction and the GCꢀMS
response was calculated according to (peak area of 6j/naphthalene peak
area) ꢁ (cnaphthalene/c4a or 5j) ꢁ 100. The amount of homocoupled
product was <5%. No double arylated Heck product was detected.
peakarea6j
cnaphthalene
GCꢀMS response ¼
ꢁ
ꢁ 100
c4a or 5j
peakareanaphthalene
ð1Þ
diphosphate (DMAPP), two basic precursors for the essential
isoprenoids. All enzymes in the non-mevalonate pathway are
attractive drug targets, since humans make use of the mevalonate
pathway for the synthesis of isoprenoids instead.34 DXR
has been established as a drug target in the malaria parasite in
clinical trials35ꢀ37 with the DXR inhibitor fosmidomycin
(1, Figure 1).38,39 Together with its acetyl derivative FR-90009840
(2, Figure 1), fosmidomycin acts as a potent inhibitor of
Plasmodium falciparum DXR in vitro and in vivo in P. vinckei
infected mice.41 Despite the good inhibition of DXR, fosmido-
mycin suffers from poor pharmacokinetic properties42,43 and is
inactive on Mt at the whole cell level due to poor uptake.44,45
Many attempts to improve in vitro and in vivo activity of
fosmidomycin have been made,12,46ꢀ55 and some of the most
successful DXR inhibitors have been compounds with an aryl
substituent in the α-position relative to the phosphonate group
(3, Figure 1).12 Recently, three X-ray structures of Escherichia coli
DXR in complex with inhibitors comprising only the phospho-
nate group and the aryl substituent were published.56
Either air or p-bzq could be used as reoxidant, and DMF could
be replaced by acetonitrile; all provided equally successful
reaction conditions (Table 1, entries 1, 2, and 6). Pd(OCOCF3)2
was not superior to Pd(OAc)2, and the microwave protocol
indicated a lower yield in agreement with previous results for the
reaction at room temperature or with microwave heating
(Table 1, entries 4 and 7).18 Use of 1,3-bis(diphenylphos-
phino)propane (dppp, Table 1, entry 5) or ethanol (Table 1,
entry 3) was associated with poor yields. Due to the volatile
nature of the olefin employed and the long reaction time (24 h),
p-bzq was generally used as a reoxidant instead of air, and thus the
reaction vessel could be capped. The use of p-bzq also decreased
phenol formation resulting from the oxidation of the boronic acid
by hydrogen peroxide58 that occurs in the catalytic process under
air.59 Phenol formation was especially prominent in the case of
2-benzofuranyl boronic acid. Further, traces of the expected
homocoupled bitolyl byproduct could be observed in all seven
test reactions.8,60 Acetonitrile was selected over DMF due to its
lower toxicity. Attempts to invert the reaction stoichiometry did
not improve the outcome (Table 1, entries 8 and 9). In summary,
Herein the development and scope of the oxidative Heck
reaction with acrolein or methyl vinyl ketone as olefins and
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Table 2. Oxidative Heck Reactions with Acrolein (4a) or
the best reaction conditions were essentially the same as those
previously used (Table 1, entry 2).18
Methyl Vinyl Ketone (4b) and Different Boronic Acidsa
With the selected standard conditions, an investigation of the
scope and limitations of different boronic acids was performed
(Table 2). As expected, terminal arylation with E-selectivity was
evident for all the cinnamaldehyde derivatives synthesized.5,9 In
the set of boronic acids examined, variations in the electronic
properties of the aromatic system did not have a significant effect
on the yields. Further, the sterically hindered ortho-substituted 5g
gave cinnamaldehyde 6g in high yield (92%, Table 2, entry 7).
Good chemoselectivity was also found, since the halogenated
boronic acids (5d and 5k, Table 2, entries 4 and 11) afforded the
corresponding cinnamaldehydes (6d and 6k) without side-
product formation from a competing Pd(0)-catalyzed Heck
reaction or dehalogenation. Heteroaromaticboronic acids
(5h and 5m) furnished products in 52% and 92% yield, respec-
tively (Table 2, entries 8 and 13), and the sulfur-containing 5m
did not disturb the efficiency of the catalytic system. The acid-
labile Boc group of 5i remained unaffected (Table 2, entry 9). For
the boronic acids with larger aromatic groups (5f, 5h, and 5l,
Table 2, entries 6, 8 and 12), DMF was used as a solvent due
to poor solubility in acetonitrile. Attempts with several six-
membered nitrogen-containing heterocyclicboronic acids were
unsuccessful.61
Heterocyclic 5e did not provide a useful yield under the
standard reaction conditions, and a large amount of homo-
coupled product was detected (Table 2, entry 5). Since we were
interested in a fosmidomycin analogue with 2-benzofuran as an
aryl substituent, the reaction conditions were altered to produce
6e in an acceptable yield of 43%. To achieve this outcome, the
olefin:boronic acid ratio was inverted to provide acrolein in a
14-fold excess, and the reaction was performed with microwave
heating at 100 °C for 30 min.
For the final fosmidomycin analogues (13aꢀk) various aryl
substituents were selected to span a range in lipophilicity,
considering the size of the biaryl and fused ring substituents
employed by Deng et al.56,57 and the solvent exposed area from
the published X-ray structures.55,57 The fosmidomycin analogues
13aꢀk (Table 3) were prepared, essentially as previously
described,12 from the cinnamaldehydes (6aꢀe) synthesized in
the oxidative Heck reaction (Scheme 1). The phosphonate
functionality was introduced by a 1,4-addition of triethylpho-
sphite in the presence of phenol, which gave the acetal inter-
mediate. After acetal deprotection, the aldehyde (10aꢀe) was
isolated in 26ꢀ76% yield. The benzyloxyamine was introduced
by a reductive amination, and the intermediates were further
reacted with acetyl chloride to give 11aꢀe in 39ꢀ99% yield over
three steps.
The linear synthetic scheme could be shortened by using
(E)-3-(4-bromophenyl)acrylaldehyde (6d) as a starting material
since the bromo substituent was unaffected by the Pd(II)-
catalyzed reaction. Diversification could then be smoothly con-
ducted by microwave-assisted Pd(0)-catalyzed Suzuki reac-
tions62,63 of 11d employing m-tolylboronic acid and five- or
six-membered heterocycles to furnish compounds 11fꢀj in
yields between 61% and 92% (Scheme 2). A BuchwaldꢀHartwig
amination64 with morpholine was employed in the synthesis
of 11k. The basic reaction conditions yielded a mixture of
11k and deacetylated product. The product mixture was reace-
tylated using the reaction conditions from Scheme 1. Compound
11k was obtained in 33% yield from 11d, with no detected
debenzylation (Scheme 3). Benzyl deprotection was carried out
a Reaction conditions: closed vessel charged with olefin (1.0 mmol),
arylboronic acid (2.0 mmol), p-bzq (1.0 mmol), Pd(OAc)2 (0.02
mmol), dmphen (0.024 mmol), and acetonitrile (7.5 mL) stirred at
room temperature for 24ꢀ48 h. b Isolated yield with purity g95%
(GCꢀMS). Yields were calculated according to 100% acrolein. c Reac-
tion conditions: sealed microwave vessel charged with olefin (8.58
mmol), arylboronic acid (0.613 mmol), p-bzq (0.333 mmol), Pd(OAc)2
(0.0062 mmol), dmphen (0.0077 mmol), and acetonitrile (2 mL) with
microwave heating at 100 °C for 30 min. d DMF as a solvent instead of
acetonitrile.
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Table 3. Activity of α-Aryl Substituted Fosmidomycin
Analogues as MtDXR Inhibitors
Scheme 1
Scheme 2
For example, the second most potent compound (13a), with a
benzo[d][1,3]dioxolyl substituent, had an IC50 = 1.5 μM and the
lowest calculated Clog P = 1.5, while the least active compound
(13k) had the second lowest Clog P = 2.0.
The relative insensitivity of the inhibitory activity to the nature
of the R1 group probably arises from the limited number of
interactions this group makes with the protein once the
Gly198ꢀMet208 flap is displaced (Figure 2). However, given
both the flexibility of the protein and the different conformation
seen for the backbone of fosmidomycin compared to its
derivatives,55 predictions of the precise mode of binding the
various compounds are difficult to make.
by classical catalytic hydrogenation to afford 12aꢀc, 12eꢀh, and
12jꢀk (61ꢀ96%). Deprotection of 11d and 11i was done with
BCl3,52 and 12d and 12i could be isolated in 76% and 49% yield,
respectively. The phosphonate esters were cleaved with TMSBr
to afford the final compounds 13aꢀk in 54ꢀ98% yield after
purification on preparative HPLC (Schemes 1, 2, and 3).
The inhibitory capacity of 13aꢀk was evaluated in a spectro-
photometric assay, in which the MtDXR-catalyzed NADPH-
dependent rearrangement and reduction of DXP to form MEP is
monitored at 340 nm. All compounds were found to inhibit
MtDXR with IC50 values between 0.8 and 27.3 μM (Table 3).
The best compound in the series was the 4-(pyridin-3-yl)phenyl
functionalized analogue (13f, IC50 = 0.8 μM), which had activity
’ CONCLUSIONS
Acrolein has been employed as the olefin in the oxidative Heck
reaction with arylboronic acids for the smooth synthesis of
cinnamaldehydes to serve as starting materials for α-aryl sub-
stituted fosmidomycin analogues. Despite the volatile nature and
the tendency of the olefin used to polymerize, the mild reaction
comparable to that of the 3,4-dichloro substituted 3, IC50
=
0.7 μM (Figure 2). Overall there was no correlation between the
calculated log P values of the substituents and the IC50 values.
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Scheme 3
of NADPH at 340 nm. Reactions had a final volume of 50 μL and
contained 50 mM HEPES-NaOH pH 7.5, 100 mM NaCl, 1.5 mM
MnCl2, 0.2 mM NADPH, 0.2 mM DXP, and 0.096 μM MtDXR, as well
as inhibitory compound at various concentrations. Initial screening was
performed with an inhibitor concentration of 100 μM. IC50 measure-
ments were performed using six inhibitor concentrations ranging
between 0.01 and 1000 μM. Reactions were initiated by adding DXP
and followed simultaneously in a 96-well plate (UV-Star, Greiner) at
22 °C. Absorbance was measured every 5 s during a 250 s period. The
slope of the linear phase of each reaction was used to calculate the initial
velocity. This was compared to the velocity of the uninhibited reaction to
calculate enzyme activity. Enzyme activities were plotted against the
corresponding inhibitor concentration and data points were fitted to
eq 2, where Hi is the estimated highest enzyme activity at zero inhibitor
concentration, Lo is the estimated lowest enzyme activity at infinite
inhibitor concentration, X is the concentration of inhibitor, and Y is the
measured enzyme activity. IC50 values presented are the average of three
independent experiments.
Hi ꢀ Lo
Y ¼ Lo þ
ð2Þ
X
1 þ
IC50
Molecular Modeling. Docking calculations were done with
Glide66,67 in SP mode. The protein (chain A of 2Y1G) was prepared
using the protein preparation wizard implemented in Maestro68 with
default settings. All waters but 2262 and 2133, which are close to the
phosphonate, were deleted. The gridbox was defined from 3 in the X-ray
structure. Poses resembling the X-ray pose of 3 were selected.
General. Nuclear magnetic resonance (NMR) spectra were re-
corded on two instruments: 1H (at 400 MHz) and 13C (at 101 MHz).
NMR chemical shifts were reported as δ (ppm) and referenced using the
residual solvent signal (1H, CDCl3 at 7.26 ppm, CD3OD at 3.31 ppm;
13C, CDCl3 at 77.16 ppm, CD3OD at 49.00 ppm). Molecular mass (HR-
ESI-MS) was determined on a mass spectrometer equipped with an
electrospray ion source. GCꢀMS analyses were performed with a CP-
SIL 8 CB Low Bleed (30 m ꢁ 0.25 mm) or a Factor Four VF 5 ms (30 m
ꢁ 0.25 mm) capillary column using a 70ꢀ300 °C temperature gradient
and EI ionization at 70 eV.
Analytical HPLCꢀMS was performed using a C18 column (50 ꢁ 4.6
mm) on an HPLC system (detection by UV-DAD) coupled with a
quadrupole mass spectrometer (ESI-MS). Analytical UHPLCꢀMS was
performed with an ion trap mass spectrometer and UV-DAD detection
using a C18 column (50 ꢁ 3 mm). Acetonitrile or methanol in 0.05%
aqueous formic acid was used as mobile phase at a flow rate of 4 mL/min.
The final compounds (13aꢀk) were purified on a preparative HPLC,
using an SB-C8 (21.2 ꢁ 150 mm) or Nucleodur C18 HTec (21.2 ꢁ
150 mm) column with UV detection at 220 nm. The compounds were
eluted with acetonitrile in 0.1% aqueous trifluoroacetic acid at a flow rate
of 5ꢀ15 mL/min and isolated after freeze-drying. Purity analysis of the
final fosmidomycin analogues was done on an HPLC system equipped
with two different columns, biphenyl (4.6 ꢁ 50 mm) and C18 (4.6 ꢁ 50
mm), with UV detection at 220 and 254 nm. Compounds were eluted
with acetonitrile in 0.1% aqueous trifluoroacetic acid at a flow rate of
2 mL/min. Silica gel (Merck 60, 40ꢀ63 μm) was used for flash
chromatography. Analytical thin layer chromatography was done using
aluminum sheets precoated with silica gel (Merck, F254); detection was
by UV (254 nm).
Figure 2. Compound 13f (turquoise carbon atoms) docked in the
X-ray structure of MtDXR in complex with 3 (PDB code 2Y1G,55 orange
carbon atoms). Included in pink ribbon is the Gly198ꢀMet208 flap
from the 2JVC structure65 representing MtDXR bound to 1.
conditions in the oxidative Heck furnished the synthesis of
terminally arylated (E)-α,β-unsaturated aldehydes from acrolein
and various boronic acids in yields between 43% and 92%.
Diversity could thereafter be introduced in the preparation of
biaryl fosmidomycin analogues through Suzuki cross-coupling
reactions. The activity of the fosmidomycin analogues tested
demonstrated that a variety of α-aromatic substituents can be
tolerated by the DXR enzyme. The best new compound (13f, α =
4-(pyridin-3-yl)phenyl) had an IC50 value of 0.8 μM, an activity
comparable to that of the most potent previously reported α-aryl
substituted fosmidomycin derivative (3, α = 3,4-dichlorophenyl,
IC50 = 0.7 μM).
The microwave reactions were performed in a single-mode micro-
wave reactor (Initiator, Biotage AB) producing controlled irradiation at
2450 MHz with a power of 0ꢀ300 W. The reaction temperature was
determined using the built-in online IR-sensor.
All reagents were purchased from commercial suppliers and used
without further purification. Dichloromethane (DCM) was freshly
’ EXPERIMENTAL SECTION
Inhibition Assay. Inhibition of MtDXR activity was measured in a
spectrophotometric assay65 by monitoring the NADPH-dependent
rearrangement and reduction of DXP to form MEP, using the absorption
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distilled from calcium hydride under nitrogen immediately before use.
Compounds 6a,69 6b,17,70 6c,17 6d,76 6e,71 6j,17 6k,17 6m,72 and 6n73 are
known compounds; 6g, 6h, and 6i are new compounds. Compounds
6f74 and 6l75 are known, but there are no NMR data reported in the
literature. All final compounds were g95% pure as determined by
GCꢀMS, NMR or HPLCꢀUV. The fosmidomycin analogues (13aꢀk)
decompose upon storage at ꢀ20 °C showing a loss of m/z 42 indicating
a deacetylation according to ESI+ LCꢀMS.
(1.06 g, 5.29 mmol), acetonitrile (7.5 mL). Time: 24 h. Eluent: pentane/
diethylether, 4/1. 6d (0.378 g, 1.79 mmol) was isolated as a pale yellow
solid in77%yield, mp 81ꢀ82 °C. 1H NMR (400 MHz, CDCl3) δ 9.65 (d,
J =7.6 Hz, 1H), 7.47ꢀ7.52 (m, 2H), 7.33ꢀ7.40 (m, 3H), 6.64 (dd, J = 7.6,
16.0 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 193.3, 151.0, 132.9, 132.3,
129.8, 128.9, 125.6; HRMS (ESI+) calcd for C9H8BrO (M + H+),
210.9759; found, 210.9763.
(E)-3-(Benzofuran-2-yl)acrylaldehyde (6e). Prepared accord-
ing to the oxidative Heck protocol with microwave heating. Reagents:
Pd(OAc)2 (0.0014 g, 0.0062 mmol), dmphen (0.0016 g, 0.0077 mmol),
acrolein (0.481 g, 8.58 mmol), p-bzq (0.0360 g, 0.333 mmol), 2-benzo-
furanylboronic acid (0.0992 g, 0.613 mmol), acetonitrile (2 mL). Eluent:
isohexane/etylacetate, 4/1. 6e (0.045 g, 0.26 mmol) was isolated as a
Oxidative Heck Reaction at Room Temperature. Pd(OAc)2
(0.05 mmol, 0.020 equiv) and dmphen (0.06 mmol, 0.024 equiv) were
dissolved in acetonitrile (2.5 mL), and the mixture was stirred for 30 min
at room temperature. A 10 mL round bottomed flask was charged with
acrolein (1 mmol, 1 equiv), p-bzq (1 mmol, 1 equiv), and arylboronic
acid (2 mmol, 2 equiv). The catalystꢀligand mixture and more
acetonitrile (5 mL) were added, the flask was sealed with a stopper
and the reaction mixture was stirred at room temperature for 24ꢀ48 h.
The reaction was evaporated on silica and purified by column chroma-
tography on silica gel.
Oxidative Heck with Microwave Heating. Pd(OAc)2 (0.0062
mmol, 0.010 equiv) and dmphen (0.062 mmol, 0.010 equiv) were
dissolved in acetonitrile (1 mL), and the mixture was stirred for 30 min at
room temperature. A 2ꢀ5 mL microwave vial was charged with acrolein
(9.3 mmol, 15 equiv), p-bzq (0.31 mmol, 0.5 equiv), and arylboronic
acid (0.62 mmol, 1 equiv). The catalystꢀligand mixture and more
acetonitrile (1 mL) were added, the vial was sealed, and the reaction
mixture was irradiated to 100 °C for 30 min. The reaction was
evaporated on silica and purified by column chromatography on
silica gel.
(E)-3-(Benzo[d][1,3]dioxol-5-yl)acrylaldehyde (6a). Reagents:
Pd(OAc)2 (0.0119 g, 0.053 mmol), dmphen (0.0126 g, 0.061 mmol),
acrolein (0.126 g, 2.25 mmol), p-bzq (0.270 g, 2.50 mmol), benzo[d]-
[1,3]dioxol-5-ylboronic acid (0.997 g, 6.01 mmol), acetonitrile (7.5 mL).
Time: 24 h. Eluent: pentane/diethylether, 5/1. 6a (0.305 g, 1.73 mmol)
was isolated as a white solid in 77% yield. 1H NMR (400 MHz, CDCl3) δ
9.58 (d, J = 7.7 Hz, 1H), 7.32 (d, J = 15.8 Hz, 1H), 6.98ꢀ7.03 (m, 2H),
6.78ꢀ6.82 (m, 1H), 6.49 (dd, J = 7.9, 15.8 Hz, 1H), 5.98ꢀ5.99 (m, 2H);
13C NMR (101 MHz, CDCl3) δ 193.5, 152.6, 150.5, 148.5, 128.5, 126.7,
125.3, 108.7, 106.7, 101.8.
(E)-3-(Naphthalen-2-yl)acrylaldehyde (6b). Reagents: Pd-
(OAc)2 (0.094 g, 0.042 mmol), dmphen (0.0104 g, 0.050 mmol),
acrolein (0.104 g, 1.86 mmol), p-bzq (0.224 g, 2.07 mmol), naphtha-
lene-2-ylboronic acid (0.712 g, 4.14 mmol), acetonitrile (6 mL). Time:
24 h. Eluent: pentane/diethylether, 4/1. 6b (0.290 g, 1.59 mmol) was
isolated as a pale yellow solid in 85% yield, mp 125ꢀ126 °C. 1H NMR
(400 MHz, CDCl3) δ 9.73 (d, J = 7.6 Hz, 1H), 7.93 (s, 1H), 7.80ꢀ7.90
(m, 3H), 7.64 (dd, J = 1.5, 8.6 Hz, 1H), 7.49ꢀ7.60 (m, 3H), 6.80 (dd, J =
7.8, 16.0 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 193.8, 152.8, 134.7,
133.2, 131.6, 130.8, 129.0, 128.8, 128.7, 127.92, 127.87, 127.0, 123.6;
HRMS (ESI+) calcd for C13H11O (M + H+), 183.0810; found,
183.0806.
1
pale yellow solid in 43% yield, mp 64ꢀ65 °C. H NMR (400 MHz,
CDCl3) δ 9.69 (d, J = 7.7 Hz, 1H), 7.60 (ddd, J = 0.7, 1.3, 7.9 Hz, 1H),
7.49 (qd, J = 0.9, 8.4 Hz, 1H), 7.36ꢀ7.42 (m, 1H), 7.31 (d, J = 15.9 Hz,
1H), 7.23ꢀ7.28 (m, 1H), 7.04ꢀ7.07 (m, 1H), 6.79 (ddd, J = 0.5, 7.8,
15.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 192.8, 156.0, 151.9,
137.9, 128.4, 128.3, 127.3, 123.7, 122.1, 113.0, 111.7; HRMS (ESI+)
calcd for C11H9O2 (M + H+), 173.0603; found, 173.0600.
(E)-3-(4-Phenoxyphenyl)acrylaldehyde (6f). Reagents: Pd-
(OAc)2 (0.0114 g, 0.051 mmol), dmphen (0.0128 g, 0.061 mmol),
acrolein (0.144 g, 2.57 mmol), p-bzq (0.272 g, 2.52 mmol), 4-phenox-
yphenylboronic acid (1.07 g, 4.98 mmol), DMF (7.5 mL). Time: 48 h.
Eluent: pentane/diethylether, 4/1. 6f (0.426 g, 1.90 mmol) was isolated
1
as a white solid in 74% yield, mp 72ꢀ73 °C. H NMR (400 MHz,
CDCl3) δ 9.67 (d, J = 7.4 Hz, 1H), 7.50ꢀ7.57 (m, 2H), 7.35ꢀ7.47 (m,
3H), 7.15ꢀ7.22 (m, 1H), 7.04ꢀ7.10 (m, 2H), 6.99ꢀ7.04 (m, 2H), 6.64
(dd, J = 7.6, 15.8 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 193.7, 160.6,
155.8, 152.2, 130.4, 130.1, 128.7, 127.5, 124.5, 120.0, 118.4; HRMS
(ESI+) calcd for C15H13O2 (M + H+), 225.0916; found, 225.0913.
(E)-3-(5-(tert-Butyl)-2-methoxyphenyl)acrylaldehyde
(6g). Reagents: Pd(OAc)2 (0.0117 g, 0.050 mmol), dmphen (0.0127 g,
0.061 mmol), acrolein (0.126 g, 2.25 mmol), p-bzq (0.301 g, 2.78
mmol), (5-(tert-butyl)-2-methoxyphenyl)boronic acid (0.997 g, 4.79
mmol), acetonitrile (7.5 mL). Time: 24 h. Eluent: pentane/diethylether,
4/1. 6g (0.451 g, 2.06 mmol) was isolated as a dark red oil in 92% yield.
1H NMR (400 MHz, CDCl3) δ 9.67 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 16.0
Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 7.43 (dd, J = 2.5, 8.7 Hz, 1H), 6.88 (d,
J = 8.7 Hz, 1H), 6.82 (dd, J = 7.9, 16.0 Hz, 1H), 3.87 (s, 3H), 1.30
(s, 9H); 13C NMR (101 MHz, CDCl3) δ 194.6, 156.3, 148.9, 143.5,
129.9, 128.9, 125.8, 122.2, 111.0, 55.6, 34.13, 31.37; HRMS (ESI+) calcd
for C14H19O2 (M + H+), 219.1385; found, 219.1389.
(E)-3-(Dibenzo[b,d]furan-4-yl)acrylaldehyde (6h). Reagents:
Pd(OAc)2 (0.0127 g, 0.057 mmol), dmphen (0.0140 g, 0.067 mmol),
acrolein (0.127 g, 2.26 mmol), p-bzq (0.266 g, 2.46 mmol), dibenzo-
[b,d]furan-3-ylboronic acid (1.489 g, 7.02 mmol), acetonitrile (2.5 mL),
DMF (5 mL). Time: 48 h. Eluent: pentane/diethylether, 4/1. 6h (0.262 g,
1.18 mmol) was isolatedas a pale yellow solid in 52% yield, mp 87ꢀ88 °C.
1H NMR (400 MHz, CDCl3) δ 9.74 (d, J = 7.8 Hz, 1H), 7.85ꢀ7.92 (m,
2H), 7.64 (d, J = 16.1 Hz, 1H), 7.53ꢀ7.57 (m, 1H), 7.43ꢀ7.49 (m, 2H),
7.32ꢀ7.37 (m, 1H), 7.27ꢀ7.32 (m, 1H), 7.21 (dd, J = 7.8, 16.1 Hz, 1H);
13C NMR (101 MHz, CDCl3) δ 194.3, 156.1, 154.2, 146.9, 131.3, 127.9,
127.8, 125.2, 123.4, 123.4 (as confirmed by HMBC and HSQC), 123.3,
123.1, 120.8, 119.2, 111.9; HRMS (ESI+) calcd for C15H11O2 (M + H+),
223.0759; found, 223.0763.
(E)-3-([1,10-Biphenyl]-4-yl)acrylaldehyde (6c). Reagents: Pd-
(OAc)2 (0.0116 g, 0.052 mmol), dmphen (0.013 g, 0.062 mmol),
acrolein (0.151 g, 2.70 mmol), p-bzq (0.276 g, 2.55 mmol), [1,10-
biphenyl]-4-ylboronic acid (1.059 g, 5.35 mmol), acetonitrile (7.5 mL).
Time: 24 h. Eluent: pentane/diethylether, 4/1. 6c (0.430 g, 2.07 mmol)
1
was isolated as a pale yellow solid in 77% yield, mp 121ꢀ123 °C. H
NMR (400 MHz, CDCl3) δ 9.73 (d, J = 7.8 Hz, 1H), 7.60ꢀ7.72 (m,
6H), 7.45ꢀ7.55 (m, 3H), 7.38ꢀ7.45 (m, 1H), 6.76 (dd, J = 7.5, 16.0 Hz,
1H); 13C NMR (101 MHz, CDCl3) δ 193.8, 152.4, 144.0, 139.8, 132.9,
129.1, 129.0, 128.4, 128.2, 127.7, 127.1; HRMS (ESI+) calcd for
C15H13O (M + H+), 209.0966; found, 209.0971.
(E)-tert-Butyl (4-(3-Oxoprop-1-en-1-yl)phenyl)carbamate
(6i). Reagents: Pd(OAc)2 (0.0041, 0.018 mmol), dmphen (0.0051 g,
0.024 mmol), acrolein (0.049 g, 0.88 mmol), p-bzq (0.093 g, 0.86
mmol), 4-aminophenylboronic acid Boc protected (0.412 g, 1.74
mmol), acetonitrile (3 mL). Time: 25 h. Eluent: pentane/diethylether,
7/3. 6i (0.143 g, 0.576 mmol) was isolated as an orange solid in 66%
yield, mp 180ꢀ181 °C. 1H NMR (400 MHz, CDCl3:CD3OD, 2:1) δ
9.55 (d, J = 7.9 Hz, 1H), 8.36 (br. s., 1H), 7.39ꢀ7.51 (m, 5H), 6.58 (dd,
(E)-3-(4-Bromophenyl)acrylaldehyde (6d). Reagents: Pd(OAc)2
(0.138 g, 0.061 mmol), dmphen (0.0160 g, 0.077 mmol), acrolein (0.130 g,
2.33 mmol), p-bzq (0.299 g, 2.77 mmol), 4-bromophenylboronic acid
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The Journal of Organic Chemistry
ARTICLE
J = 7.9, 15.8 Hz, 1H), 1.48 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
193.8, 152.6, 152.4, 141.5, 129.8, 128.7, 127.2, 118.5, 81.4, 28.4; HRMS
(ESI+) calcd for C14H18NO3 (M + H+), 248.1287; found, 248.1290.
(E)-3-(p-Tolyl)acrylaldehyde (6j). Reagents: Pd(OAc)2 (0.047
g, 0.021 mmol), dmphen (0.0054 g, 0.026 mmol), acrolein (0.052 g,
0.923 mmol), p-bzq (0.107 g, 0.990 mmol), p-tolylboronic acid (0.272 g,
2.00 mmol), acetonitrile (2 mL). Time: 17 h. Eluent: isohexane/ethyl
acetate, 9/1. 6j (0.0786 g, 0.538 mmol) was isolated as a pale yellow solid
in 58% yield, mp 39ꢀ41 °C. 1H NMR (400 MHz, CDCl3) δ 9.66 (d, J =
7.8 Hz, 1H), 7.38ꢀ7.47 (m, 3H), 7.22 (d, J = 8.2 Hz, 2H), 6.66 (dd, J =
7.8, 16.0 Hz, 1H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.9,
153.0, 142.1, 131.4, 130.0, 128.6, 127.8, 21.7; HRMS (ESI+) calcd for
C10H11O (M + H+), 147.0810; found, 147.0806.
Diethyl (1-(Benzo[d][1,3]dioxol-5-yl)-3-oxopropyl)pho-
sphonate (10a). Reagents: 6a (0.30 g, 1.7 mmol), phenol (0.417 g,
4.43 mmol) and triethylphosphite (0.334 g, 2.01 mmol). Time: 4.5 h.
Reagents: H2O (2.4 mL), HCl (2M, 6.3 mL), acetone (14 mL). Time:
24 h. 10a (0.342 g, 1.09 mmol) was isolated as an oil in 64% yield. 1H
NMR (400 MHz, CDCl3) δ 9.57 (s, 1H), 6.58ꢀ6.86 (m, 3H), 5.76ꢀ
5.92 (m, 2H), 3.81ꢀ4.08 (m, 3H), 3.68ꢀ3.81 (m, 1H), 3.49ꢀ3.65
(m, 1H), 2.87ꢀ3.12 (m, 2H), 1.21 (t, J = 7.4 Hz, 3H), 1.08 (t, J = 7.0 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 198.7 (d, JCꢀP = 16.2 Hz), 147.7
(d, JCꢀP = 2.2 Hz), 146.8 (d, JCꢀP = 3.0 Hz), 128.5 (d, JCꢀP = 7.4 Hz),
122.3 (d, JCꢀP = 7.4 Hz), 109.2 (d, JCꢀP = 5.9 Hz), 108.2 (d, JCꢀP = 3.0
Hz), 101.0, 62.8 (d, JCꢀP = 7.4 Hz), 62.0 (d, JCꢀP = 7.4 Hz), 43.9 (d,
JCꢀP = 2.2 Hz), 37.4 (d, JCꢀP = 143.0 Hz), 16.2 (d, JCꢀP = 5.9 Hz), 16.1
(d, JCꢀP = 5.9 Hz); HRMS (ESI+) calcd for C14H20O6P (M + H+),
315.0998; found, 315.0991.
(E)-3-(4-Chlorophenyl)acrylaldehyde (6k). Reagents: Pd-
(OAc)2 (0.0115 g, 0.051 mmol), dmphen (0.0138 g, 0.066 mmol),
acrolein (0.125 g, 2.23 mmol), p-bzq (0.275 g, 2.54 mmol), 4-chlor-
ophenylboronic acid (0.790 g, 5.05 mmol), acetonitrile (7.5 mL). Time:
24 h. Eluent: pentane/diethylether, 4/1. 6k (0.292 g, 1.75 mmol) was
isolated as a pale yellow solid in 78% yield, mp 58ꢀ59 °C. 1H NMR (400
MHz, CDCl3) δ 9.66 (d, J = 7.6 Hz, 1H), 7.43ꢀ7.49 (m, 2H),
7.33ꢀ7.42 (m, 3H), 6.64 (dd, J = 7.6, 16.0 Hz, 1H); 13C NMR (101
MHz, CDCl3) δ 193.3, 151.0, 137.2, 132.5, 129.6, 129.4, 128.9; HRMS
(ESI+) calcd for C9H8ClO (M + H+), 167.0264; found, 167.0266.
(E)-3-(4-Benzoylphenyl)acrylaldehyde (6l). Reagents: Pd-
(OAc)2 (0.0117 g, 0.052 mmol), dmphen (0.0130 g, 0.062 mmol),
acrolein (0.194 g, 3.46 mmol), p-bzq (0.278 g, 2.57 mmol), 4-benzoyl-
phenylboronic acid (1.15 g, 5.08 mmol), DMF (7.5 mL). Time: 48 h.
Eluent: pentane/diethylether, 4/1. 6l (0.610 g, 2.58 mmol) was isolated
Diethyl (1-(nNaphthalen-2-yl)-3-oxopropyl)phosphonate
(10b). Reagents: 6b (0.290 g, 1.60 mmol), phenol (0.391 g, 4.15 mmol)
and triethylphosphite (0.692 g, 4.16 mmol). Time: 3.5 h. Reagents: H2O
(2.2 mL), HCl (2M, 5.9 mL), acetone (13 mL). Time: 24 h. 10b (0.286
g, 892 mmol) was isolated as an oil in 56% yield. 1H NMR (400 MHz,
CDCl3) δ 9.63 (s, 1H), 7.72ꢀ7.81 (m, 4H), 7.36ꢀ7.51 (m, 3H), 3.95ꢀ
4.12 (m, 2H), 3.81ꢀ3.94 (m, 2H), 3.64ꢀ3.78 (m, 1H), 3.12ꢀ3.29 (m,
2H), 1.24 (t, J = 6.9 Hz, 3H), 1.05 (t, J = 6.9 Hz, 2H); 13C NMR (101
MHz, CDCl3) δ 198.7 (d, JCꢀP = 15.5 Hz), 133.2 (d, JCꢀP = 3.0 Hz),
132.7 (d, JCꢀP = 7.4 Hz), 132.6 (d, JCꢀP = 2.2 Hz), 128.3 (d, JCꢀP = 2.2
Hz), 127.9 (d, JCꢀP = 8.1 Hz), 127.7 (d, JCꢀP = 1.5 Hz), 127.5 (d, JCꢀP
=
1.5 Hz), 126.9 (d, JCꢀP = 5.2 Hz), 126.2, 126.0 (d, JCꢀP = 1.5 Hz), 62.9
(d, JCꢀP = 7.4 Hz), 62.2 (d, JCꢀP = 7.4 Hz), 44.0 (d, JCꢀP = 2.2 Hz), 38.0
(d, JCꢀP = 140.8 Hz), 16.3 (d, JCꢀP = 5.9 Hz), 16.2 (d, JCꢀP = 5.9 Hz);
HRMS (ESI+) calcd for C17H22O4P (M + H+), 321.1256; found,
321.1258.
1
as a white solid in 75% yield, mp 175ꢀ176 °C. H NMR (400 MHz,
CDCl3) δ 9.76 (d, J = 7.6 Hz, 1H), 7.82ꢀ7.88 (m, 2H), 7.77ꢀ7.82 (m,
2H), 7.65ꢀ7.70 (m, 2H), 7.58ꢀ7.64 (m, 1H), 7.46ꢀ7.56 (m, 3H), 6.79
(dd, J = 7.6, 16.0 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 195.8, 193.4,
150.9, 139.6, 137.6, 137.2, 132.9, 130.7, 130.4, 130.1, 128.5, 128.3; HRMS
(ESI+) calcd for C16H13O2 (M + H+), 237.0916; found, 237.0923.
(E)-3-(Thiophen-3-yl)acrylaldehyde (6m). Reagents:Pd(OAc)2
(0.124 g, 0.055 mmol), dmphen (0.0147 g, 0.071 mmol), acrolein (0.144
g, 2.57 mmol), p-bzq (0.272 g, 2.52 mmol), thiophen-3-ylboronic acid
(0.648 g, 5.06 mmol), acetonitrile (7.5 mL). Time: 24 h. Eluent: pentane/
diethylether, 4/1. 6m (0.272 g, 1.97 mmol) was isolated as a yellow oil in
92% yield. 1H NMR (400 MHz, CDCl3) δ 9.62 (d, J = 7.8 Hz, 1H), 7.60
(dd, J = 1.3, 2.9 Hz, 1H), 7.44 (d, J = 15.8 Hz, 1H), 7.35 (ddd, J = 0.5, 2.9,
5.0 Hz, 1H), 7.28ꢀ7.31 (m, 1H), 6.50 (dd, J = 7.8, 15.8 Hz, 1H); 13C
NMR (101 MHz, CDCl3) δ 193.8, 145.8, 137.4, 129.6, 128.4, 127.5,
125.4; HRMS (ESI+) calcd for C7H7OS (M + H+), 139.0218; found,
139.0216.
Diethyl (1-([1,10-Biphenyl]-4-yl)-3-oxopropyl)phospho-
nate (10c). Reagents: 6c (0.430 g, 2.07 mmol), phenol (0.510 g,
5.42 mmol) and triethylphosphite (0.860 g, 5.18 mmol). Time: 3 h.
Reagents: H2O (2.9 mL), HCl (2M, 7.7 mL), acetone (16 mL). Time:
24 h. 10c (0.544 g, 1.57 mmol) was isolated as an oil in 76% yield. 1H
NMR (400 MHz, CDCl3) δ 9.58 (s, 1H), 7.43ꢀ7.54 (m, 4H), 7.29ꢀ
7.40 (m, 4H), 7.20ꢀ7.27 (m, 1H), 3.94ꢀ4.07 (m, 2H), 3.82ꢀ3.93 (m,
1H), 3.64ꢀ3.81 (m, 2H), 2.99ꢀ3.18 (m, 2H), 1.21 (t, J = 7.0 Hz, 1H),
1.06 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 198.6 (d,
JCꢀP = 15.5 Hz), 140.2 (d, JCꢀP = 1.5 Hz), 140.0 (d, JCꢀP = 3.0 Hz),
134.1 (d, JCꢀP = 7.4 Hz), 129.3 (d, JCꢀP = 6.6 Hz), 128.6, 127.2, 127.0
(d, JCꢀP = 3.0 Hz), 126.7, 62.7 (d, JCꢀP = 7.4 Hz), 62.0 (d, JCꢀP = 6.6
Hz), 43.7 (d, JCꢀP = 2.2 Hz), 36.6 (d, JCꢀP = 141.5 Hz), 16.2 (d, JCꢀP
= 5.9 Hz), 16.0 (d, JCꢀP = 5.9 Hz); HRMS (ESI+) calcd for
C19H24O4P (M + H+), 347.1412; found, 347.1415.
(E)-4-(Naphthalen-2-yl)but-3-en-2-one (6n). Reagents: Pd-
(OAc)2 (0.0045 g, 0.020 mmol), dmphen (0.0054 g, 0.026 mmol),
methyl vinyl ketone (0.070 g, 1.00 mmol), p-bzq (0.109 g, 1.00 mmol),
naphthalene-2-ylboronic acid (0.344 g, 2.00 mmol), acetonitrile (3 mL).
Time: 24 h. Eluent: pentane/diethylether, 4/1. 6n (0.167 g, 0.85 mmol)
was isolated as a white solid in 85% yield, mp 94ꢀ95 °C. 1H NMR (400
MHz, CDCl3) δ 7.87 (s, 1H), 7.75ꢀ7.83 (m, 3H), 7.58ꢀ7.65 (m, 2H),
7.45ꢀ7.53 (m, 2H), 6.78 (d, J = 16.3 Hz, 1H), 2.38 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 198.3, 143.4, 134.3, 133.2, 131.8, 130.3, 128.7,
128.5, 127.8, 127.4, 127.1, 126.7, 123.4, 27.5; HRMS (ESI+) calcd for
C14H13O (M + H+), 197.0966; found, 197.0964.
Diethyl (1-(4-Bromophenyl)-3-oxopropyl)phosphonate
(10d). Reagents: 6d (1.13 g, 5.37 mmol), phenol (1.34 g, 14.3 mmol)
and triethylphosphite (1.07 g, 6.45 mmol). Time: 3 h. Reagents: H2O
(7.5 mL), HCl (2M, 20 mL), acetone (30 mL). Time: 26 h. 10d (0.915 g,
1
2.62 mmol) was isolated as an oil in 49% yield. H NMR (400 MHz,
CDCl3) δ 9.56 (td, J = 1.09, 2.17 Hz, 1H), 7.32ꢀ7.37 (m, 2H),
7.12ꢀ7.17 (m, 2H), 3.88ꢀ4.03 (m, 2H), 3.78ꢀ3.88 (m, 1H), 3.66ꢀ
3.78 (m, 1H), 3.60 (ddd, J = 4.7, 9.4, 22.7 Hz, 1H), 2.92ꢀ3.13 (m, 2H),
1.18 (t, J = 7.0 Hz, 3H), 1.05 (dt, J = 0.4, 7.0 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 198.2 (d, JCꢀP = 15.3 Hz), 134.4 (d, JCꢀP = 6.9 Hz),
131.61, 131.58, 130.7 (d, JCꢀP = 6.9 Hz), 121.3 (d, JCꢀP = 3.8 Hz), 62.9
(d, JCꢀP = 6.9 Hz), 62.2 (d, JCꢀP = 7.7 Hz), 43.7 (d, JCꢀP = 2.3 Hz), 37.2
(d, JCꢀP = 141.9 Hz), 16.2 (d, JCꢀP = 5.4 Hz), 16.1 (d, JCꢀP = 5.4 Hz);
HRMS (ESI+) calcd for C13H19BrO4P (M + H+), 349.0204; found,
349.0197.
1,4-Addition12. A round-bottom flask equipped with a condenser
was charged with α,β-unsaturated aldehyde 6 (1 equiv), phenol (2.6
equiv), and triethylphosphite (1.2 equiv). The reaction mixture was
stirred at 100 °C for the time indicated below. The reaction mixture was
concentrated. H2O, HCl (2 M), and acetone were added, and the
mixture was refluxed for 24 h. The reaction mixture was extracted with
diethylether and dried over MgSO4. The product was purified by
column chromatography on silica gel with ethyl acetate as eluent.
Diethyl (1-(Benzofuran-2-yl)-3-oxopropyl)phosphonate
(10e). Reagents: 6e (0.300 g, 1.74 mmol), phenol (0.430 g, 4.57 mmol)
and triethylphosphite (0.341 g, 2.05 mmol). Time: 2.5 h. Reagents: H2O
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The Journal of Organic Chemistry
ARTICLE
(2.4 mL), HCl (2M, 6.5 mL), acetone (15 mL). Time: 25 h. 10e
(0.141 g, 0.454 mmol) was isolated as an oil in 26% yield. H NMR
(s, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 171.6, 133.9, 132.9, 132.4 (d, JCꢀP = 7.4 Hz),
132.2, 128.7, 128.4, 128.1, 127.9 (d, JCꢀP = 5.2 Hz), 127.8, 127.3, 127.2,
126.7 (d, JCꢀP = 5.2 Hz), 125.7, 125.5, 75.8, 62.1 (d, JCꢀP = 6.6 Hz), 61.5
1
(400 MHz, CDCl3) δ 9.68 (td, J = 1.1, 2.0 Hz, 1H), 7.42ꢀ7.48 (m, 1H),
7.36ꢀ7.42 (m, 1H), 7.11ꢀ7.22 (m, 2H), 6.62 (td, J = 0.7, 4.0 Hz, 1H),
3.88ꢀ4.11 (m, 5H), 3.06ꢀ3.26 (m, 2H), 1.25 (dt, J = 0.4, 7.0 Hz, 3H),
1.17 (dt, J = 0.5, 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 198.1 (d,
JCꢀP = 13.8 Hz), 154.6 (d, JCꢀP = 1.5 Hz), 151.6 (d, JCꢀP = 9.2 Hz),
128.2 (d, JCꢀP = 3.1 Hz), 124.0 (d, JCꢀP = 1.5 Hz), 122.8, 120.7, 110.9,
105.2 (d, JCꢀP = 8.4 Hz), 63.0 (d, JCꢀP = 7.7 Hz), 62.8 (d, JCꢀP = 6.9
(d, JCꢀP = 6.6 Hz), 42.5 (d, JCꢀP = 137.9 Hz), 26.5, 20.0 (d, JCꢀP
=
3.0 Hz), 16.0 (d, JCꢀP = 5.9 Hz), 15.8 (d, JCꢀP = 5.9 Hz); HRMS (ESI+)
calcd for C26H33NO5P (M + H+), 470.2096; found, 470.2092.
Diethyl (1-([1,10-Biphenyl]-4-yl)-3-(N-(benzyloxy)acetamido)-
propyl)phosphonate (11c). Reagents: 10c (0.54 g, 1.56 mmol) was
dissolved in ethanol (9 mL). O-Benzylhydroxylamine hydrochloride
(0.374 g, 2.34 mmol) and pyridine (6 mL). Time: 3 h. Reagents:
NaBH3CN (0.294 g, 4.68 mmol), methanol (19 mL), HCl (37%,
2.1 mL). Time: 2 h. Reagents: Triethylamine (0.230 g, 2.27 mmol),
acetyl chloride (0.148 g, 1.89 mmol) and DCM (9 mL). Time: 4.5 h. 11c
(0.408 g, 0.823 mmol) was isolated as an oil in 53% yield. 1H NMR (400
MHz, CDCl3) δ 7.51ꢀ7.63 (m, 4H), 7.24ꢀ7.48 (m, 10H), 4.64ꢀ4.77
(m, 2H), 3.97ꢀ4.14 (m, 2H), 3.85ꢀ3.97 (m, 1H), 3.71ꢀ3.82 (m, 1H),
3.56ꢀ3.70 (m, 1H), 3.45ꢀ3.56 (m, 1H), 3.05ꢀ3.20 (m, 1H),
2.42ꢀ2.56 (m, 1H), 2.24ꢀ2.40 (m, 1H), 1.94ꢀ2.09 (s, 3H), 1.28 (t,
J = 7.0 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
170.6, 140.0, 139.5 (d, JCꢀP = 3.7 Hz), 133.9, 133.8, 129.2 (d, JCꢀP = 6.6
Hz), 128.7, 128.4, 128.3, 128.1, 126.8, 126.6 (d, JCꢀP = 2.2 Hz), 126.4,
75.8, 62.1 (d, JCꢀP = 6.6 Hz), 61.4 (d, JCꢀP = 7.4 Hz), 43.4, 41.3 (d,
JCꢀP = 138.6 Hz), 26.4, 19.9, 15.9 (d, JCꢀP = 5.9 Hz), 15.8 (d, JCꢀP = 5.9
Hz); HRMS (ESI+) calcd for C28H35NO5P (M + H+), 496.2253; found,
496.2257.
Diethyl (3-(N-(Benzyloxy)acetamido)-1-(4-bromophenyl)-
propyl)phosphonate (11d). Reagents: 10d (0.915 g, 2.62 mmol)
was dissolved in ethanol (14 mL). O-Benzylhydroxylamine hydrochlor-
ide (0.627 g, 3.93 mmol) and pyridine (10 mL). Time: 5 h. Reagents:
NaBH3CN (0.495 g, 7.88 mmol), methanol (35 mL), HCl (37%,
3.5 mL). Time: 2 h. Reagents: Triethylamine (0.80 g, 7.9 mmol), acetyl
chloride (0.41 g, 5.2 mmol) and DCM (15 mL). Time: 1.5 h. 11d (0.922
g, 1.85 mmol) was isolated as an oil in 71% yield. 1H NMR (400 MHz,
CDCl3) δ 7.35ꢀ7.41 (m, 2H), 7.29ꢀ7.34 (m, 3H), 7.20ꢀ7.26 (m, 2H),
7.10ꢀ7.17 (m, 2H), 4.60ꢀ4.70 (m, 2H), 3.92ꢀ4.06 (m, 2H), 3.79ꢀ
3.92 (m, 1H), 3.65ꢀ3.77 (m, 1H), 3.45ꢀ3.57 (m, 1H), 3.34ꢀ3.45 (m,
1H), 2.98 (ddd, J = 3.7, 11.3, 22.8 Hz, 1H), 2.34ꢀ2.47 (m, 1H),
2.08ꢀ2.22 (m, 1H), 1.97 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.1
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.1, 134.4 (d, JCꢀP = 7.7
Hz), 134.2, 131.6 (d, JCꢀP = 2.3 Hz), 130.9 (d, JCꢀP = 6.1 Hz), 129.1,
128.9, 128.6, 121.2 (d, JCꢀP = 3.8 Hz), 76.4, 62.6 (d, JCꢀP = 6.9 Hz), 62.0
(d, JCꢀP = 7.7 Hz), 43.6, 41.6 (d, JCꢀP = 139.6 Hz), 26.8 (d, JCꢀP = 2.3
Hz), 20.4, 16.3 (d, JCꢀP = 6.1 Hz), 16.2 (d, JCꢀP = 6.1 Hz); HRMS
(ESI+) calcd for C22H30BrNO5P (M + H+), 498.1045; found, 498.1044.
Diethyl (1-(Benzofuran-2-yl)-3-(N-(benzyloxy)acetamido)-
propyl)phosphonate (11e). Reagents: 10e (0.141 g, 0.454 mmol)
was dissolved in ethanol (2.5 mL). O-Benzylhydroxylamine hydrochlor-
ide hydrochloride (0.111 g, 0.695 mmol) and pyridine (1.8 mL). Time:
2.5 h. Reagents: NaBH3CN (0.091 g, 1.45 mmol), methanol (6 mL),
HCl (37%, 0.6 mL). Time: 2 h. Reagents: Triethylamine (0.13 g, 1.3
mmol), acetyl chloride (0.07 g, 0,9 mmol) and DCM (2.5 mL). Time:
3 h. 11e (0.135 g, 0.294 mmol) was isolated as an oil in 65% yield. 1H
NMR (400 MHz, CDCl3) δ 7.46ꢀ7.52 (m, 1H), 7.37ꢀ7.44 (m, 1H),
7.13ꢀ7.34 (m, 7H), 6.63 (d, J = 4.0 Hz, 1H), 4.70 (s, 2H), 3.85ꢀ4.15
(m, 4H), 3.54ꢀ3.74 (m, 2H), 3.40 (ddd, J = 4.4, 10.7, 22.8 Hz, 1H),
2.26ꢀ2.52 (m, 2H), 2.02 (s, 3H), 1.26 (t, J = 7.4 Hz, 3H), 1.17 (t, J = 7.1
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.2, 154.7 (d, JCꢀP = 1.5
Hz), 152.4 (d, JCꢀP = 10.0 Hz), 134.2, 129.1, 128.9, 128.6, 128.4 (d,
JCꢀP = 2.3 Hz), 123.9, 122.8, 120.7 (d, JCꢀP = 1.5 Hz), 111.0, 105.4 (d,
JCꢀP = 8.4 Hz), 76.4, 62.7 (d, JCꢀP = 6.9 Hz), 62.5 (d, JCꢀP = 6.9 Hz),
43.8, 36.6 (d, JCꢀP = 141.1 Hz), 25.7, 20.4, 16.4 (d, JCꢀP = 6.1 Hz), 16.3
(d, JCꢀP = 6.1 Hz); HRMS (ESI+) calcd for C24H31NO6P (M + H+),
460.1889; found, 460.1893.
Hz), 41.7 (d, JCꢀP = 2.3 Hz), 32.3 (d, JCꢀP = 144.2 Hz), 16.2 (d, JCꢀP
=
4.6 Hz), 16.2 (d, JCꢀP = 3.8 Hz); HRMS (ESI+) calcd for C15H20O5P
(M + H+), 311.1048; found, 311.1053.
Imine Formation12. The (3-oxopropyl)phosphonate derivative
(1 equiv) was dissolved in ethanol. O-Benzylhydroxylamine hydrochlor-
ide (1.5 equiv) and pyridine were added, and the reaction was stirred for
the time indicated below. The reaction mixture was coevaporated with
toluene three times.
Reduction of the Imine12. The crude imine product was dissolved
in methanol, and NaBH3CN (3 equiv) was added. After the reaction
mixture was stirred at room temperature for 45 min, it was cooled in an
ice bath (0 °C), and aqueous HCl (37%) was added dropwise over
45 min. The reaction mixture was stirred for an additional 2 h. The reaction
mixture was basified with aqueous NaOH (10% w/w) and extracted with
DCM. The combined organic layers were dried with MgSO4 and
evaporated. The crude material was used without further purification.
Acetylation12. The crude product from reductive amination
was dissolved in DCM. Triethylamine (3 equiv) and acetyl chloride
(2 equiv) were added, and the reaction mixture was stirred for the time
indicated below. After the reaction was finished, H2O was added, and the
reaction mixture was extracted with DCM. The combined organic layers
were dried with MgSO4 and evaporated. The product was purified by
column chromatography on silica gel (ethyl acetate).
Diethyl (1-(Benzo[d][1,3]dioxol-5-yl)-3-(N-(benzyloxy)ace-
tamido)propyl)phosphonate (11a). Reagents: 10a (0.34 g, 1.08
mmol) was dissolved in ethanol (6 mL). O-Benzylhydroxylamine hydro-
chloride (0.262 g, 1.64 mmol) and pyridine (4.5 mL). Time: 2.75 h.
Reagents: NaBH3CN (0.208 g, 3.31 mmol), methanol (14 mL), HCl
(37%, 1.6 mL). Time: 2 h. Reagents: Triethylamine (0.327 g, 3.23 mmol),
acetyl chloride (0.180 g, 2.29 mmol) and DCM (6 mL). Time: 2.5 h. 11a
(0.145 g, 0.312 mmol) was isolated as an oil in 39% yield. 1H NMR (400
MHz, CDCl3) δ 7.29ꢀ7.35 (m, 3H), 7.22ꢀ7.28 (m, 2H), 6.80 (d, J = 0.9
Hz, 1H), 6.69 (s, 2H), 5.89 (s, 2H), 4.62ꢀ4.71 (m, 2H), 3.92ꢀ4.06 (m,
2H), 3.82ꢀ3.91 (m, 1H), 3.67ꢀ3.79 (m, 1H), 3.48ꢀ3.61 (m, 1H),
3.34ꢀ3.46 (m, 1H), 2.93 (ddd, J = 3.5, 11.6, 22.9 Hz, 1H), 2.29ꢀ2.43 (m,
1H), 2.05ꢀ2.19 (m, 1H), 1.99 (s, 3H), 1.21 (t, J = 7.0 Hz, 3H), 1.07 (t, J =
7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.2, 147.8 (d, JCꢀP = 2.2
Hz), 146.8 (d, JCꢀP = 3.7 Hz), 134.3, 129.1, 128.9, 128.7 (d, JCꢀP = 7.4
Hz), 128.6, 122.7 (d, JCꢀP = 8.1 Hz), 109.3 (d, JCꢀP = 5.9 Hz), 108.2 (d,
JCꢀP = 2.2 Hz), 101.0, 76.3, 62.5 (d, JCꢀP = 6.6 Hz), 61.9 (d, JCꢀP = 7.4
Hz), 43.7, 41.7 (d, JCꢀP = 140.1 Hz), 27.1, 20.4, 16.4 (d, JCꢀP = 5.9 Hz),
16.3 (d, JCꢀP = 5.9 Hz); HRMS (ESI+) calcd for C23H31NO7P (M + H+),
464.1838; found, 464.1836.
Diethyl (3-(N-(Benzyloxy)acetamido)-1-(naphthalen-2-yl)-
propyl)phosphonate (11b). Reagents: 10b (0.28 g, 0.87 mmol)
was dissolved in ethanol (5 mL). O-Benzylhydroxylamine hydrochloride
(0.213 g, 1.33 mmol) and pyridine (3 mL). Time: 3.5 h. Reagents:
NaBH3CN (0.165 g, 2.63 mmol), methanol (11 mL), HCl (37%,
1.2 mL). Time: 2 h. Reagents: Triethylamine (0.265 g, 2.62 mmol),
acetyl chloride (0.157 g, 2.00 mmol) and DCM (5 mL). Time: 3 h. 11b
(0.41 g, 0.86 mmol) was isolated as an oil in 99% yield. 1H NMR (400
MHz, CDCl3) δ 7.72ꢀ7.87 (m, 4H), 7.41ꢀ7.53 (m, 3H), 7.25ꢀ7.35
(m, 3H), 7.17ꢀ7.24 (m, 2H), 4.56ꢀ4.73 (m, 2H), 3.94ꢀ4.13 (m, 2H),
3.79ꢀ3.93 (m, 1H), 3.54ꢀ3.75 (m, 2H), 3.39ꢀ3.54 (m, 1H), 3.24 (ddd,
J = 3.9, 11.3, 22.8 Hz, 1H), 2.47ꢀ2.59 (m, 1H), 2.31ꢀ2.47 (m, 1H), 1.99
8993
dx.doi.org/10.1021/jo201715x |J. Org. Chem. 2011, 76, 8986–8998

The Journal of Organic Chemistry
ARTICLE
Synthesis of Biaryl Compounds by Suzuki Reaction. Meth-
od A:62 a 2ꢀ5 mL microwave vial was charged with 11d (0.050 g, 0.10
mmol), boronic acid (0.50 mmol), Pd(PPh3)2Cl2 (7.0 mg, 0.010 mmol),
Na2CO3 (2 M, 0.15 mL), DME (2.4 mL), and ethanol (95%, 0.6 mL).
The vial was sealed, and the reaction mixture was irradiated for 30 min at
120 °C. After the reaction was finished the solvent was evaporated, and
the compound was purified on silica gel (100% EtOAc).
136.5 (d, JCꢀP = 6.9 Hz), 134.3, 130.0 (d, JCꢀP = 6.1 Hz), 129.1, 128.9,
128.6, 127.0 (d, JCꢀP = 3.1 Hz), 121.4, 76.4, 62.6 (d, JCꢀP = 6.9 Hz), 62.1
(d, JCꢀP = 7.7 Hz), 43.8, 41.9 (d, JCꢀP = 138.8 Hz), 26.8 (d, JCꢀP
=
2.3 Hz), 20.4, 16.4 (d, JCꢀP = 6.1 Hz), 16.2 (d, JCꢀP = 5.4 Hz);
HRMS (ESI+) calcd for C27H34N2O5P (M + H+), 497.2205; found,
497.2202.
Diethyl (3-(N-(Benzyloxy)acetamido)-1-(4-(thiophen-3-yl)-
phenyl)propyl)phosphonate (11i). Compound 11i was prepared
according to method A, and the synthesis was repeated two times.
Reagents: 11d (0.048 g, 0.097 mmol), thiophen-3-ylboronic acid (0.068
g, 0.53 mmol), Pd(PPh3)2Cl2 (9.2 mg, 0.013 mmol). 11i (0.0594 g, 0.118
mmol) was isolated as an oil in an average yield of 61%. 1H NMR (400
MHz, CDCl3) δ 7.55 (d, J = 7.6 Hz, 2H), 7.42ꢀ7.46 (m, 1H), 7.37ꢀ7.40
(m, 2H), 7.31ꢀ7.37 (m, 5H), 7.25ꢀ7.31 (m, 2H), 4.69 (s, 2H), 3.96ꢀ
4.11 (m, 2H), 3.84ꢀ3.95 (m, 1H), 3.68ꢀ3.79 (m, 1H), 3.54ꢀ3.67 (m,
1H), 3.43ꢀ3.54 (m, 1H), 3.08 (ddd, J = 3.9, 11.4, 22.9 Hz, 1H), 2.40ꢀ
2.53 (m, 1H), 2.21ꢀ2.36 (m, 1H), 2.01 (m, 3H), 1.26 (t, J = 7.0 Hz, 3H),
1.10 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.3, 141.9 (d,
JCꢀP = 1.5 Hz), 134.9 (d, JCꢀP = 3.8 Hz), 134.4, 134.1 (d, JCꢀP = 6.9 Hz),
129.8 (d, JCꢀP = 6.9 Hz), 129.2, 129.0, 128.8, 126.6 (d, JCꢀP = 2.3 Hz),
126.4, 126.3, 120.3 (d, JCꢀP = 1.5 Hz), 76.4, 62.8 (d, JCꢀP = 6.9 Hz), 62.1
(d, JCꢀP = 6.9 Hz), 44.0, 42.0 (d, JCꢀP = 138.8 Hz), 26.9, 20.6, 16.5 (d,
JCꢀP = 6.1 Hz), 16.4 (d, JCꢀP = 6.1 Hz); HRMS (ESI+) calcd for
C26H33NO5PS (M + H+), 502.1817; found, 502.1819.
Method B:63 a 2ꢀ5 mL microwave vial was charged with 11d (0.05 g,
0.10 mmol), boronic acid (0.60 mmol), Pd(OAc)2 (0.02 mmol), [HP(t-
Bu)3]BF4 (0.04 mmol), K2CO3 (0.60 mmol), DME (2 mL), and H2O
(0.6 mL). The vial was sealed, and the reaction mixture was irradiated for
15 min at 100 °C. After the reaction was finished, it was filtered through a
Celite plug, and the compound was purified on silica gel (100% EtOAc).
Diethyl (3-(N-(Benzyloxy)acetamido)-1-(4-(pyridin-3-yl)-
phenyl)propyl)phosphonate (11f). Compound 11f was prepared
according to method A, and the synthesis was repeated three times.
Reagents: 11d (0.048 g, 0.096 mmol), 3-pyridinylboronic acid (0.068 g,
0.55 mmol), Pd(PPh3)2Cl2 (7.4 mg, 0.011 mmol). 11f (0.128 g, 0.259
mmol) was isolated as an oil in an average yield of 90%. 1H NMR (400
MHz, CDCl3) δ 9.06 (s, 1H), 8.75 (d, J = 4.9 Hz, 1H), 8.39 (d, J = 8.2
Hz, 1H), 7.83 (dd, J = 5.4, 8.0 Hz, 1H), 7.54ꢀ7.61 (m, 2H), 7.45ꢀ7.53
(m, 2H), 7.35ꢀ7.40 (m, 3H), 7.28ꢀ7.34 (m, 2H), 4.74 (s, 2H),
4.00ꢀ4.15 (m, 2H), 3.90ꢀ4.00 (m, 1H), 3.77ꢀ3.90 (m, 1H), 3.46ꢀ
3.66 (m, 2H), 3.09ꢀ3.23 (m, 1H), 2.42ꢀ2.59 (m, 1H), 2.20ꢀ2.37 (m,
1H), 2.02 (s, 3H), 1.42 (d, J = 12.9 Hz, 1H), 1.28 (t, J = 7.1 Hz, 6H), 1.15
(t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.6, 161.7 (d,
JCꢀP = 38.3 Hz), 141.7 (d, JCꢀP = 38.3 Hz), 140.7, 139.6, 137.7 (d,
JCꢀP = 6.9 Hz), 134.3, 133.5 (d, JCꢀP = 3.1 Hz), 130.8 (d, JCꢀP = 6.9
Hz), 129.3, 129.2, 128.9, 127.4 (d, JCꢀP = 2.3 Hz), 126.3, 76.6, 63.1 (d,
JCꢀP = 7.7 Hz), 62.7 (d, JCꢀP = 6.9 Hz), 43.7, 42.0 (d, JCꢀP = 138.8 Hz),
29.0, 26.9, 20.5, 16.5 (d, JCꢀP = 6.1 Hz), 16.4 (d, JCꢀP = 6.1 Hz); HRMS
(ESI+) calcd for C27H34N2O5P (M + H+), 497.2205; found, 497.2201.
Diethyl (3-(N-(Benzyloxy)acetamido)-1-(30-methyl-[1,10-
biphenyl]-4-yl)propyl)phosphonate (11g). Compound 11g
was prepared according to method B, and the synthesis was repeated
three times. Reagents: 11d (0.050 g, 0.10 mmol), m-tolylboronic acid
(0.084 g, 0.62 mmol), Pd(OAc)2 (4.2 mg, 0.019 mmol), [HP(t-
Bu)3]BF4 (0.012, 0.040 mmol), K2CO3 (0.088 g, 0.64 mmol). 11g
(0.133 g, 0.262 mmol) was isolated as an oil in an average yield of 87%.
1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.7 Hz, 2H), 7.27ꢀ7.43 (m,
10H), 7.13ꢀ7.18 (m, 1H), 4.70 (s, 2H), 3.97ꢀ4.13 (m, 2H), 3.85ꢀ3.97
(m, 1H), 3.70ꢀ3.81 (m, 1H), 3.56ꢀ3.69 (m, 1H), 3.45ꢀ3.56 (m, 1H),
3.11 (ddd, J = 4.0, 11.3, 23.4 Hz, 1H), 2.43ꢀ2.55 (m, 1H), 2.39ꢀ2.43
(m, 3H), 2.24ꢀ2.38 (m, 1H), 2.02 (s, 3H), 1.27 (t, J = 7.3 Hz, 3H), 1.11
(t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.3, 140.6, 140.3
(d, JCꢀP = 3.1 Hz), 138.4, 134.4, 134.2 (d, JCꢀP = 6.9 Hz), 129.7 (d,
Diethyl (3-(N-(Benzyloxy)acetamido)-1-(4-(3,5-dimethyli-
soxazol-4-yl)phenyl)propyl)phosphonate (11j). Compound
11j was prepared according to method A, and the synthesis was repeated
two times. Reagents: 11d (0.048 g, 0.097 mmol), (3,5-dimethylisoxazol-
4-yl)boronic acid (0.074 g, 0.52 mmol), Pd(PPh3)2Cl2 (11 mg, 0.016
mmol). 11j (0.0920 g, 0.179 mmol) was isolated as an oil in an average
1
yield of 92%. H NMR (400 MHz, CDCl3) δ 7.31ꢀ7.40 (m, 5H),
7.26ꢀ7.31 (m, 2H), 7.18 (d, J = 7.8 Hz, 2H), 4.65ꢀ4.76 (m, 2H), 3.96ꢀ
4.11 (m, 2H), 3.83ꢀ3.95 (m, 1H), 3.70ꢀ3.82 (m, 1H), 3.45ꢀ3.66 (m,
2H), 3.08 (ddd, J = 3.9, 11.1, 23.1 Hz, 1H), 2.40ꢀ2.54 (m, 1H), 2.36 (s,
3H), 2.24ꢀ2.33 (m, 1H), 2.23 (s, 3H), 1.99 (s, 3H), 1.25 (t, J = 7.0 Hz,
3H), 1.07 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.7,
165.2, 158.6, 134.7 (d, JCꢀP = 6.9 Hz), 134.4, 129.8 (d, JCꢀP = 6.1 Hz),
129.5 (d, JCꢀP = 3.8 Hz), 129.2, 129.1, 129.0, 128.7, 116.2 (d, JCꢀP = 1.5
Hz), 76.4, 62.7 (d, JCꢀP = 6.9 Hz), 62.1 (d, JCꢀP = 7.7 Hz), 43.8, 42.0 (d,
JCꢀP = 138.8 Hz), 26.9 (d, JCꢀP = 2.4 Hz), 20.5, 16.4 (d, JCꢀP = 5.4 Hz),
16.2 (d, JCꢀP = 5.4 Hz), 11.7, 10.9; HRMS (ESI+) calcd for
C27H36N2O6P (M + H+), 515.2311; found, 515.2309.
Diethyl (3-(N-(Benzyloxy)acetamido)-1-(4-morpholino-
phenyl)propyl)phosphonate (11k).64. A 2ꢀ5 mL microwave
vial was charged with 11d (0.097 g, 0.19 mmol), morpholine (0.20 g, 2.3
mmol), Pd(OAc)2 (1.3 mg, 5.8 μmol), [HP(t-Bu)3]BF4 (1.3 mg, 4.5
μmol), NaO-t-Bu (0.028 g, 0.29 mmol), and anhydrous toluene (2 mL).
The vial was sealed and purged with N2(g), and the reaction mixture was
irradiated for 30 min at 100 °C. The reaction was repeated three times.
After the reaction was finished, the mixture was filtered through a Celite
plug, and the compound was purified on silica gel (DCM/methanol,
95/5). A mixture of the product and the deacetylated product was
obtained, so the crude product mixture was further reacted with acetyl
chloride (0.07 mL, 0.08 mmol), triethylamine (0.21 mL, 0.15 mmol) in
DCM (5 mL) for 2 h at room temperature. H2O (10 mL) was added, and
the reaction mixture was extracted with DCM (2 ꢁ 10 mL) dried with
MgSO4 and purified on silica gel (100% EtOAc). 11k (0.098 g, 0.19
mmol) was obtained as an oil in 33% yield. 1H NMR (400 MHz, CDCl3)
δ 7.30ꢀ7.36 (m, 3H), 7.23ꢀ7.29 (m, 2H), 7.13ꢀ7.21 (m, 2H), 6.82
(d, J = 8.5Hz, 2H), 4.67 (s, 2H), 3.90ꢀ4.05 (m, 2H), 3.76ꢀ3.90 (m, 5H),
3.61ꢀ3.74 (m, 1H), 3.49ꢀ3.61 (m, 1H), 3.36ꢀ3.48 (m, 1H),
3.05ꢀ3.15 (m, 4H), 2.95 (ddd, J = 3.8, 11.2, 23.1 Hz, 1H), 2.31ꢀ2.46
(m, 1H), 2.09ꢀ2.23 (m, 1H), 1.98 (s, 3H), 1.22 (t, J = 7.7 Hz, 3H),
1.06 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.0, 150.4
JCꢀP = 6.1 Hz), 129.2, 129.0, 128.7 (d, JCꢀP = 3.8 Hz), 128.0 (d, JCꢀP
=
29.9 Hz), 127.3 (d, JCꢀP = 3.1 Hz), 124.1, 76.4, 62.7 (d, JCꢀP = 6.9 Hz),
62.1 (d, JCꢀP = 6.9 Hz), 43.9, 41.9 (d, JCꢀP = 138.0 Hz), 26.9, 21.6, 20.5,
16.5 (d, JCꢀP = 6.1 Hz), 16.3 (d, JCꢀP = 6.1 Hz); HRMS (ESI+) calcd for
C29H37NO5P (M + H+), 510.2409; found, 510.2410.
Diethyl (3-(N-(Benzyloxy)acetamido)-1-(4-(pyridin-4-yl)-
phenyl)propyl)phosphonate (11h). Compound 11h was pre-
pared according to method A, and the synthesis was repeated two
times. Reagents: 11d (0.048 g, 0.097 mmol), 4-pyridinylboronic acid
(0.071 g, 0.58 mmol), Pd(PPh3)2Cl2 (10 mg, 0.014 mmol). 11h (0.0731
g, 0.147 mmol) was isolated as an oil in an average yield of 76%. 1H NMR
(400 MHz, CDCl3) δ 8.59ꢀ8.66 (m, 2H), 7.54ꢀ7.62 (m, 2H),
7.46ꢀ7.50 (m, 2H), 7.38ꢀ7.45 (m, 2H), 7.31ꢀ7.36 (m, 3H),
7.24ꢀ7.31 (m, 2H), 4.64ꢀ4.75 (m, 2H), 3.97ꢀ4.11 (m, 2H), 3.84ꢀ3.97
(m, 1H), 3.70ꢀ3.83 (m, 1H), 3.41ꢀ3.66 (m, 2H), 3.11 (ddd, J = 3.6, 11.0,
22.5 Hz, 1H), 2.40ꢀ2.55 (m, 1H), 2.19ꢀ2.38 (m, 1H), 1.99 (s,
3H), 1.25 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.3 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 172.1, 150.3, 147.7, 137.0 (d, JCꢀP = 3.8 Hz),
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(d, JCꢀP = 3.1 Hz), 134.4, 130.0 (d, JCꢀP = 6.9 Hz), 129.1, 128.9, 128.6,
126.0 (d, JCꢀP = 6.9 Hz), 115.7 (d, JCꢀP = 2.3 Hz), 76.3, 66.8, 62.6
(d, JCꢀP = 7.7 Hz), 61.9 (d, JCꢀP = 7.7 Hz), 49.1, 43.8, 41.1 (d, JCꢀP = 140.3
Hz), 26.6, 20.5, 16.4 (d, JCꢀP = 6.1 Hz), 16.3 (d, JCꢀP = 5.4 Hz); HRMS
(ESI+) calcd for C26H38N2O6P (M + H+), 505.2468; found, 505.2460.
Deprotection of the Benzyl Group. Method C:12 The acety-
lated product was dissolved in methanol, and Pd/C (10%) was added.
The reaction mixture was stirred under H2 (g) at atmospheric pressure
while the reaction was monitored by TLC (ethyl acetate 100% and
DCM/methanol, 95/5). After the reaction was finished, the mixture was
filtered through a Celite plug, and the solvent was removed by evapora-
tion. The product was purified by column chromatography on silica gel
(DCM/methanol, 95/5).
NMR (400 MHz, CDCl3) δ 9.55 (br. s., 1H), 7.42 (d, J = 8.1 Hz, 2H),
7.08ꢀ7.21 (m, 2H), 3.66ꢀ4.10 (m, 5H), 3.23ꢀ3.61 (m, 1H), 2.96ꢀ
3.16 (m, 1H), 2.33ꢀ2.88 (m, 2H), 1.98ꢀ2.19 (s, 3H), 1.22 (t, J = 6.9 Hz,
3H), 1.15 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.4,
135.0 (d, JCꢀP = 7.7 Hz), 131.8, 130.9 (d, JCꢀP = 6.9 Hz), 121.5 (d,
JCꢀP = 3.8 Hz), 63.2 (d, JCꢀP = 6.9 Hz), 62.7 (d, JCꢀP = 7.7 Hz), 46.1 (d,
JCꢀP = 13.8 Hz), 41.4 (d, JCꢀP = 138.0 Hz), 27.5, 20.6, 16.4 (d, JCꢀP
=
16.4 Hz), 16.3 (d, JCꢀP = 16.3 Hz); HRMS (ESI+) calcd for
C15H24BrNO5P (M + H+), 408.0575; found, 408.0580.
Diethyl (1-(Benzofuran-2-yl)-3-(N-hydroxyacetamido)pro-
pyl)phosphonate (12e). Compound 12e was prepared by method
C. Reagents: 11e (0.135 g, 0.294 mmol), Pd/C (10%, 0.037 g), and
methanol (5 mL). Time: 1.5 h. 12e (0.101 g, 0.274 mmol) was isolated
as an oil in 93% yield. 1H NMR (400 MHz, CDCl3) δ 9.60 (br. s., 1H),
7.37ꢀ7.53 (m, 2H), 7.14ꢀ7.25 (m, 2H), 6.65 (d, J = 3.7 Hz, 1H),
3.81ꢀ4.13 (m, 5H), 3.39ꢀ3.54 (m, 2H), 2.24ꢀ2.51 (m, 2H), 2.07 (s,
3H), 1.26 (t, J = 7.0 Hz, 3H), 1.19 (t, J = 7.0 Hz, 3H); 13C NMR (101
Method D:52 The acetylated product was stirred in dry DCM at
ꢀ50 °C under N2. BCl3 (4 equiv) was added. The reaction was stirred
for the time indicated. After the reaction was finished NaHCO3 (satd)
was added, and the mixture was extracted with DCM, dried with MgSO4,
filtered, and purified by column chromatography on silica gel (DCM/
methanol, 95/5).
MHz, CDCl3) δ 172.4, 154.8, 152.2 (d, JCꢀP = 9.2 Hz), 128.4 (d, JCꢀP
=
2.3 Hz), 124.1, 122.9, 120.9, 111.0, 105.5 (d, JCꢀP = 7.7 Hz), 63.4 (d,
JCꢀP = 6.9 Hz), 63.0 (d, JCꢀP = 6.9 Hz), 46.3 (d, JCꢀP = 13.0 Hz), 36.3
(d, JCꢀP = 141.1 Hz), 25.9, 20.5, 16.3 (d, JCꢀP = 5.4 Hz, 2C, confirmed
by HSQC); HRMS (ESI+) calcd for C17H25NO6P (M + H+), 370.1420;
found, 370.1408.
Diethyl (1-(Benzo[d][1,3]dioxol-5-yl)-3-(N-hydroxyaceta-
mido)propyl)phosphonate (12a). Compound 12a was prepared
by method C. Reagents: 11a (0.14 g, 0.30 mmol), Pd/C (10%, 0.035 g),
and methanol (15 mL). Time: 4 h. 12a (0.087 g, 0.23 mmol) was
isolated as an oil in 77% yield. 1H NMR (400 MHz, CDCl3)
δ 9.21ꢀ9.94 (m, 1H), 6.65ꢀ6.85 (m, 3H), 5.85ꢀ5.99 (m, 2H), 3.70ꢀ
4.10 (m, 5H), 3.30ꢀ3.42 (m, 1H), 2.92ꢀ3.09 (m, 1H), 2.40 (d, J = 4.0
Hz, 1H), 2.02ꢀ2.13 (m, 4H), 1.20ꢀ1.32 (m, 3H), 1.15 (t, J = 6.7 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 172.2, 147.9, 147.0, 129.3 (d,
JCꢀP = 7.4 Hz), 122.7 (d, JCꢀP = 8.1 Hz), 109.3 (d, JCꢀP = 5.9 Hz),
108.4, 101.2, 63.1 (d, JCꢀP = 6.6 Hz), 62.6 (d, JCꢀP = 5.9 Hz), 46.3 (d,
JCꢀP = 14.7 Hz), 41.6 (d, JCꢀP = 139.3 Hz), 27.8, 20.6, 16.4, 16.3; HRMS
(ESI+) calcd for C16H25NO7P (M + H+), 374.1369; found, 374.1359.
Diethyl (3-(N-Hydroxyacetamido)-1-(naphthalen-2-yl)-
propyl)phosphonate (12b). Compound 12b was prepared by
method C. Reagents: 11b (0.4 g, 0.85 mmol), Pd/C (10%, 0.102 g),
and methanol (25 mL). Time: 7 h. 12b (0.198 g, 0.52 mmol) was
isolated as an oil in 61% yield. 1H NMR (400 MHz, CDCl3) δ 9.68 (br.
s., 1H), 7.69ꢀ7.83 (m, 4H), 7.37ꢀ7.48 (m, 3H), 3.90ꢀ4.04 (m, 2H),
3.60ꢀ3.88 (m, 3H), 3.19ꢀ3.43 (m, 2H), 2.44ꢀ2.57 (m, 1H),
2.26ꢀ2.42 (m, 1H), 2.03 (s, 3H), 1.16ꢀ1.24 (m, 3H), 1.04 (t, J = 7.0
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.1, 133.3 (d, JCꢀP = 2.2
Hz), 133.0 (d, JCꢀP = 8.1 Hz), 132.6, 128.3, 128.2, 127.8, 127.6, 126.8 (d,
JCꢀP = 4.4 Hz), 126.2, 126.0, 63.0 (d, JCꢀP = 7.4 Hz), 62.4 (d, JCꢀP = 7.4
Hz), 46.3 (d, JCꢀP = 15.5 Hz), 42.1 (d, JCꢀP = 137.9 Hz), 27.4, 20.4, 16.3
(d, JCꢀP = 5.2 Hz), 16.2 (d, JCꢀP = 5.2 Hz); HRMS (ESI+) calcd for
C19H27NO5P (M + H+), 380.1627; found, 380.1624.
Diethyl (1-([1,10-Biphenyl]-4-yl)-3-(N-(benzyloxy)acetamido)-
propyl)phosphonate (12c). Compound 12c was prepared by method
C. Reagents: 11c (0.35 g, 0.71 mmol), Pd/C (10%, 0.074 g), and
methanol (20 mL). Time: 2.25 h. 12c (0.231 g, 0.569 mmol) was isolated
as an oil in 80% yield. 1H NMR (400 MHz, CDCl3) δ 9.71 (br. s., 1H),
7.46ꢀ7.63 (m, 4H), 7.15ꢀ7.45 (m, 5H), 3.92ꢀ4.10 (m, 2H), 3.81ꢀ3.92
(m, 1H), 3.67ꢀ3.81 (m, 2H), 3.32ꢀ3.48 (m, 1H), 3.03ꢀ3.24 (m, 1H),
2.36ꢀ2.54 (m, 1H), 2.17ꢀ2.35 (m, 1H), 2.05 (s, 2H), 1.17ꢀ1.33 (m,
3H), 1.08 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.0,
140.3, 140.1, 134.3 (d, JCꢀP = 7.4 Hz), 129.5 (d, JCꢀP = 6.6 Hz), 128.7,
127.3, 127.1, 126.8, 63.0, 62.4 (d, JCꢀP = 7.4 Hz), 46.2 (d, JCꢀP = 16.2
Hz), 41.6 (d, JCꢀP = 139.3 Hz), 27.2, 20.4, 16.3 (d, JCꢀP = 5.2 Hz), 16.1
(d, JCꢀP = 5.2 Hz); HRMS (ESI+) calcd for C21H29NO5P (M + H+),
406.1783; found, 406.1774.
Diethyl (3-(N-Hydroxyacetamido)-1-(4-(pyridin-3-yl)phe-
nyl)propyl)phosphonate (12f). Compound 12f was prepared by
method C. Reagents: 11f (0.149 g, 0.300 mmol), Pd/C (10%, 0.039 g),
and methanol (10 mL). Time: 20 h. 12f (0.0842 g, 0.207 mmol) was
isolated as an oil in 69% yield. 1H NMR (400 MHz, CDCl3) δ 10.06 (br.
s., 1H), 8.75 (s, 1H), 8.51 (d, J = 4.1 Hz, 1H), 7.81ꢀ7.89 (m, 1H),
7.47ꢀ7.56 (m, 2H), 7.40 (dd, J = 1.9, 8.2 Hz, 2H), 7.34 (dd, J = 4.9, 7.8
Hz, 1H), 3.74ꢀ4.11 (m, 5H), 3.38ꢀ3.50 (m, 1H), 3.10ꢀ3.24 (m, 1H),
2.43ꢀ2.59 (m, 1H), 2.16ꢀ2.34 (m, 1H), 2.05ꢀ2.12 (m, 3H), 1.23 (t, J =
7.0 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
172.3, 148.2, 147.8, 136.6, 136.3, 136.2 (d, JCꢀP = 6.9 Hz), 134.6, 130.0
(d, JCꢀP = 6.9 Hz), 127.3, 123.8, 63.0 (d, JCꢀP = 6.9 Hz), 62.6 (d, JCꢀP
=
6.9 Hz), 46.3 (d, JCꢀP = 14.6 Hz), 41.7 (d, JCꢀP = 138.0 Hz), 27.6, 20.6,
16.4, 16.3; HRMS (ESI+) calcd for C20H28N2O5P (M + H+), 407.1736;
found, 407.1733.
Diethyl (3-(N-Hydroxyacetamido)-1-(30-methyl-[1,10-biphe-
nyl]-4-yl)propyl)phosphonate (12g). Compound 12g was pre-
pared by method C. Reagents: 11g (0.166 g, 0.326 mmol), Pd/C (10%,
0.043 g) and methanol (5 mL). Time: 1.5 h. 12g (0.114 g, 0.272 mmol)
was isolated as an oil in 82% yield. 1H NMR (400 MHz, CDCl3) δ 9.60
(br. s., 1H), 7.48ꢀ7.62 (m, 2H), 7.27ꢀ7.43 (m, 5H), 7.15 (d, J = 7.2 Hz,
1H), 3.70ꢀ4.14 (m, 5H), 3.35ꢀ3.65 (m, 1H), 3.08ꢀ3.23 (m, 1H),
2.45ꢀ2.68 (m, 1H), 2.41 (s, 3H), 2.19ꢀ2.35 (m, 1H), 2.12 (s, 3H),
1.23ꢀ1.34 (m, 3H), 1.15 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 172.3, 140.5, 140.5 (d, JCꢀP = 3.1 Hz), 138.5, 134.9 (d, JCꢀP
=
7.7 Hz), 129.6 (d, JCꢀP = 6.9 Hz), 128.8, 128.2, 127.8, 127.4, 124.1, 63.2
(d, JCꢀP = 6.9 Hz), 62.7 (d, JCꢀP = 7.7 Hz), 46.4 (d, JCꢀP = 13.0 Hz),
41.8 (d, JCꢀP = 137.3 Hz), 27.8, 21.6, 20.7, 16.4, 16.3; HRMS (ESI+)
calcd for C22H31NO5P (M + H+), 420.1940; found, 420.1943.
Diethyl (3-(N-Hydroxyacetamido)-1-(4-(pyridin-4-yl)phe-
nyl)propyl)phosphonate (12h). Compound 12h was prepared
by method C. Reagents: 11h (0.073 g, 0.15 mmol), Pd/C (10%,
0.028 g), and methanol (5 mL). Time: 3 h. 12h (0.040 g, 0.098 mmol)
was isolated as an oil in 67% yield. 1H NMR (400 MHz, CDCl3) δ 9.90
(br. s., 1H), 8.43ꢀ8.75 (m, 2H), 7.54ꢀ7.66 (m, 2H), 7.35ꢀ7.52 (m,
4H), 3.79ꢀ4.12 (m, 5H), 3.35ꢀ3.66 (m, 1H), 3.11ꢀ3.25 (m, 1H),
2.46ꢀ2.67 (m, 1H), 2.18ꢀ2.39 (m, 1H), 2.07ꢀ2.17 (m, 3H),
1.22ꢀ1.28 (m, 3H), 1.19 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 172.4, 150.0, 147.9, 137.6 (d, JCꢀP = 7.7 Hz), 136.8, 130.0 (d,
JCꢀP = 6.1 Hz), 127.1, 121.5, 63.0 (d, JCꢀP = 8.4 Hz), 62.6 (d, JCꢀP = 6.9
Hz), 46.2 (d, JCꢀP = 13.0 Hz), 41.7 (d, JCꢀP = 137.3 Hz), 29.2, 20.6,
Diethyl (1-(4-Bromophenyl)-3-(N-hydroxyacetamido)pro-
pyl)phosphonate (12d). Compound 12d was prepared by method
D. Reagents: 11d (0.0975 g, 0.196 mmol), BCl3 (0.8 mL, 1 M). Time: 2
1
h. 12d (0.061 g, 0.149 mmol) was isolated as an oil in 76% yield. H
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16.31, 16.26; HRMS (ESI+) calcd for C20H28N2O5P (M + H+),
407.1736; found, 407.1735.
δ 7.79ꢀ7.85 (m, 4H), 7.52 (ddd, J = 1.5, 1.5, 8.7 Hz, 1H), 7.40ꢀ7.49 (m,
2H), 3.54ꢀ3.68 (m, 1H), 3.45 (s, 1H), 3.24 (ddd, J = 3.5, 11.4, 22.8 Hz,
1H), 2.46ꢀ2.61 (m, 1H), 2.27ꢀ2.44 (m, 1H), 1.95ꢀ2.09 (m, 3H); 13
C
Diethyl (3-(N-Hydroxyacetamido)-1-(4-(thiophen-3-yl)-
phenyl)propyl)phosphonate (12i). Compound 12i was prepared
by method D. Reagents: 11i (0.059 g, 0.12 mmol), BCl3 (0.5 mL, 1 M).
Time: 1 h. 12i (0.024 g, 0.058 mmol) was isolated as an oil in 49% yield.
1H NMR (400 MHz, CDCl3) δ 9.52 (br. s., 1H), 7.51ꢀ7.63 (m, 2H),
7.27ꢀ7.49 (m, 5H), 3.71ꢀ4.14 (m, 5H), 3.33ꢀ3.65 (m, 1H), 3.06ꢀ
3.22 (m, 1H), 2.44ꢀ2.68 (m, 1H), 2.19ꢀ2.39 (m, 1H), 2.07ꢀ2.18 (m,
3H), 1.23ꢀ1.34 (m, 3H), 1.08ꢀ1.21 (m, 3H); 13C NMR (101 MHz,
CDCl3) δ 13C NMR (101 MHz, CDCl3) δ = 172.5, 141.8, 135.2, 135.0
(d, JCꢀP = 8.4 Hz), 129.7, 126.7 (d, JCꢀP = 6.1 Hz), 126.5, 126.3, 120.5,
63.2 (d, JCꢀP = 6.9 Hz), 62.8 (d, JCꢀP = 6.9 Hz), 46.4 (d, JCꢀP = 11.5
Hz), 41.8 (d, JCꢀP = 138.0 Hz), 28.1, 20.7, 16.4, 16.3; HRMS (ESI+)
calcd for C19H27NO5PS (M + H+), 412.1348; found, 412.1344.
Diethyl (1-(4-(3,5-Dimethylisoxazol-4-yl)phenyl)-3-(N-hy-
droxyacetamido)propyl)phosphonate (12j). Compound 12j
was prepared by method C. Reagents: 11j (0.104 g, 0.202 mmol), Pd/
C (10%, 0.025 g), and methanol (5 mL). Time: 3 h. 12j (0.0822 g, 0.194
mmol) was isolated as an oil in 96% yield. 1H NMR (400 MHz, CDCl3)
δ 9.58 (br. s., 1H), 7.31ꢀ7.40 (m, 2H), 7.15ꢀ7.23 (m, 2H), 3.75ꢀ4.12
(m, 5H), 3.32ꢀ3.47 (m, 1H), 3.05ꢀ3.21 (m, 1H), 2.44ꢀ2.66 (m, 2H),
2.37 (s, 3H), 2.20ꢀ2.26 (m, 3H), 2.10 (s, 3H), 1.20ꢀ1.29 (m, 3H), 1.15
(t, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.5, 165.4, 158.6,
135.4 (d, JCꢀP = 7.7 Hz), 134.4, 129.7 (d, JCꢀP = 6.9 Hz), 129.2, 116.2,
63.1 (d, JCꢀP = 7.7 Hz), 62.7 (d, JCꢀP = 6.9 Hz), 46.2 (d, JCꢀP = 13.8
Hz), 41.7 (d, JCꢀP = 138.0 Hz), 27.8, 20.6, 16.4, 16.3, 11.7, 10.9; HRMS
(ESI+) calcd for C20H30N2O6P (M + H+), 425.1842; found, 425.1846.
Diethyl (3-(N-Hydroxyacetamido)-1-(4-morpholinophenyl)-
propyl)phosphonate (12k). Compound 12k was prepared by method
C. Reagents: 11k (0.098 g, 0.19 mmol), Pd/C (10%, 0.023 g), and
methanol (5 mL). Time: 3 h. 12k (0.057 g, 0.14 mmol) was isolated as
an oil in 71% yield. 1H NMR (400 MHz, CDCl3) δ 9.62 (br. s., 1H), 7.16
(dd, J = 2.2, 8.8 Hz, 2H), 6.82 (d, J = 8.3 Hz, 2H), 3.65ꢀ4.07 (m, 9H),
3.24ꢀ3.57 (m, 1H), 3.07ꢀ3.15 (m, 4H), 2.91ꢀ3.06 (m, 1H), 2.62ꢀ2.76
(m, 1H), 2.30ꢀ2.49 (m, 1H), 2.01ꢀ2.18 (m, 3H), 1.18ꢀ1.28 (m, 3H),
1.12 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.2, 150.5,
129.9 (d, JCꢀP = 6.9 Hz), 126.5 (d, JCꢀP = 7.7 Hz), 115.7, 66.9, 63.0 (d,
JCꢀP = 6.9 Hz), 62.5 (d, JCꢀP = 6.9 Hz), 49.2, 46.2 (d, JCꢀP = 14.6 Hz), 41.0
(d, JCꢀP = 137.3 Hz), 27.7, 20.6, 16.4, 16.3; HRMS (ESI+) calcd for
C19H32N2O6P (M + H+), 415.1998; found, 415.2005.
NMR (101 MHz, CD3OD) δ 173.6, 135.5 (d, JCꢀP = 7.7 Hz), 134.9
(d,JCꢀP = 2.3 Hz), 134.1 (d, JCꢀP = 2.3 Hz), 129.4 (d, JCꢀP = 8.4 Hz), 128.9,
128.6 (d, JCꢀP = 22.2 Hz), 128.4 (d, JCꢀP = 4.6 Hz), 126.9 (d, JCꢀP = 29.9
Hz), 47.5 (d, JCꢀP = 18.4 Hz), 44.4 (d, JCꢀP = 136.5 Hz), 28.2, 20.1; HRMS
(ESI+) calcd for C15H19NO5P (M + H+), 324.1001; found, 324.1003.
(1-([1,10-Biphenyl]-4-yl)-3-(N-hydroxyacetamido)propyl)-
phosphonic Acid (13c). Reagents: 12c (0.08 g, 0.2 mmol), TMSBr
(0.10 mL, 0.76 mmol), and DCM (5 mL). Time: 5 h. Purification:
gradient 5ꢀ45%, 70 min, 5 mL/min. 13c (38 mg, 0.11 mmol) was
1
isolated as a white lyophilized material in 56% yield. H NMR (400
MHz, CD3OD) δ 7.54ꢀ7.63 (m, 4H), 7.38ꢀ7.47 (m, 4H), 7.28ꢀ7.35
(m, 1H), 3.56ꢀ3.67 (m, 1H), 3.42ꢀ3.51 (m, 1H), 3.11 (ddd, J = 3.1,
11.5, 23.1 Hz, 1H), 2.41ꢀ2.55 (m, 1H), 2.19ꢀ2.35 (m, 1H), 2.04 (s,
3H); 13C NMR (101 MHz, CD3OD) δ 173.6, 142.1, 141.2 (d, JCꢀP
=
3.1 Hz), 137.1 (d, JCꢀP = 6.9 Hz), 131.0 (d, JCꢀP = 6.9 Hz), 129.8, 128.3,
128.0 (d, JCꢀP = 2.3 Hz), 127.9, 47.5 (d, JCꢀP = 17.6 Hz), 44.0 (d, JCꢀP
=
136.5 Hz), 28.2 (d, JCꢀP = 2.3 Hz), 20.2; HRMS (ESI+) calcd for
C17H21NO5P (M + H+), 350.1157; found, 350.1151.
(1-(4-Bromophenyl)-3-(N-hydroxyacetamido)propyl)-
phosphonic Acid (13d). Reagents: 12d (0.0608 g, 0.149 mmol),
TMSBr (0.10 mL, 0.76 mmol), and DCM (5 mL). Time: 9 h. Puri-
fication: gradient 5ꢀ45%, 60 min, 5 mL/min. 13d (50 mg, 0.14 mmol)
was isolated as a white lyophilized material in 96% yield. 1H NMR (400
MHz, CD3OD) δ 7.47 (d, J = 8.2 Hz, 2H), 7.27 (dd, J = 2.3, 8.5 Hz, 2H),
3.51ꢀ3.62 (m, 1H), 3.37ꢀ3.49 (m, 1H), 3.04 (ddd, J = 3.4, 11.4, 23.1
Hz, 1H), 2.37ꢀ2.52 (m, 1H), 2.11ꢀ2.27 (m, 1H), 2.00ꢀ2.06 (m, 3H);
13C NMR (101 MHz, CD3OD) δ 173.6, 137.4 (d, JCꢀP = 7.7 Hz), 132.4,
132.4, 121.8 (d, JCꢀP = 3.8 Hz), 47.3 (d, JCꢀP = 17.6 Hz), 43.7 (d, JCꢀP
=
136.5 Hz), 28.1, 20.1; HRMS (ESI+) calcd for C11H16BrNO5P (M +
H+), 351.9949; found, 351.9961.
(1-(Benzofuran-2-yl)-3-(N-hydroxyacetamido)propyl)-
phosphonic Acid (13e). Reagents: 12e (0.10 g, 0.27 mmol), TMSBr
(0.30 mL, 2.3 mmol), and DCM (5 mL). Time: 19 h. Purification:
gradient 0ꢀ40%, 80 min, 5 mL/min. 13e (72 mg, 0.23 mmol) was
1
isolated as a white lyophilized material in 85% yield. H NMR (400
MHz, CD3OD) δ 7.52 (d, J = 7.4 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H),
7.13ꢀ7.28 (m, 2H), 6.70 (d, J = 3.6 Hz, 1H), 3.65ꢀ3.78 (m, 1H),
3.50ꢀ3.63 (m, 1H), 3.39 (ddd, J = 3.5, 11.1, 23.3 Hz, 1H), 2.24ꢀ2.53
(m, 2H), 1.96ꢀ2.07 (m, 3H); 13C NMR (101 MHz, CD3OD) δ 173.8,
156.3, 155.1 (d, JCꢀP = 9.2 Hz), 130.1 (d, JCꢀP = 3.1 Hz), 124.7, 123.7,
121.6, 111.8, 106.0 (d, JCꢀP = 8.4 Hz), 47.4 (d, JCꢀP = 16.1 Hz), 38.7
(d, JCꢀP = 138.8 Hz), 26.9, 20.1; HRMS (ESI+) calcd for C13H17NO6P
(M + H+), 314.0794; found, 314.0790.
Deprotection of the Phosphate Ethyl Ester12. TMSBr was
added to a stirred solution of the phosphonate diethyl ester in dry DCM
under N2 at room temperature. After the indicated time, the volatiles
were removed in vacuo to give the phosphonic acid derivative. The
product was purified by preparative HPLC.
(1-(Benzo[d][1,3]dioxol-5-yl)-3-(N-hydroxyacetamido)pro-
pyl)phosphonic Acid (13a). Reagents: 12a (0.041 g, 0.11 mmol),
TMSBr (0.10 mL, 0.76 mmol), and DCM (5 mL). Time: 3 h.
Purification: gradient 0ꢀ30%, 60 min, 5 mL/min. 13a (33 mg, 0.10
(3-(N-Hydroxyacetamido)-1-(4-(pyridin-3-yl)phenyl)pro-
pyl)phosphonic Acid (13f). Reagents: 12f (0.0842 g, 0.207 mmol),
TMSBr (0.12 mL, 0.91 mmol), and DCM (5 mL). Time: 4 h. Puri-
fication: gradient 0ꢀ30%, 60 min, 5 mL/min. 13f (69 mg, 0.20 mmol)
was isolated as a white lyophilized material in 95% yield. 1H NMR (400
MHz, CD3OD) δ 8.53ꢀ8.69 (m, 3H), 7.95 (dd, J = 5.6, 7.9 Hz, 1H),
7.50ꢀ7.63 (m, 4H), 3.55ꢀ3.66 (m, 1H), 3.40ꢀ3.51 (m, 1H), 3.17 (ddd,
J = 3.0, 11.4, 22.7 Hz, 1H), 2.48ꢀ2.64 (m, 1H), 2.22ꢀ2.37 (m, 1H), 2.04
(s, 3H);13C NMR (101 MHz, CD3OD) δ173.6, 143.1, 141.7, 141.6, 141.0,
140.3, 133.4 (d, JCꢀP = 3.1 Hz), 131.9 (d, JCꢀP = 6.1 Hz), 128.1, 127.8, 47.4
(d, JCꢀP = 16.9 Hz), 44.6 (d, JCꢀP = 133.4 Hz), 28.3, 20.2; HRMS (ESI+)
calcd for C16H20N2O5P (M + H+), 351.1110; found, 351.1112.
(3-(N-Hydroxyacetamido)-1-(30-methyl-[1,10-biphenyl]-4-
yl)propyl)phosphonic Acid (13g). Reagents: 12g (0.114 g, 0.300
mmol), TMSBr (0.15 mL, 1.14 mmol), and DCM (5 mL). Time: 5 h.
Purification: gradient 5ꢀ45%, 70 min, 5 mL/min. 13g (53 mg, 0.15 mmol)
was isolated as a white lyophilized material in 54% yield. 1HNMR(400 MHz,
CD3OD) δ 7.52ꢀ7.61 (m, 2H), 7.34ꢀ7.46 (m, 4H), 7.29 (t, J = 7.6 Hz,
1
mmol) was isolated as a white lyophilized material in 95% yield. H
NMR (400 MHz, CD3OD) δ 6.86 (dd, J = 1.7, 1.7 Hz, 1H), 6.72ꢀ6.81
(m, 2H), 5.91 (s, 2H), 3.52ꢀ3.63 (m, 1H), 3.35ꢀ3.46 (m, 1H), 2.96
(ddd, J = 3.4, 11.5, 22.8 Hz, 1H), 2.34ꢀ2.46 (m, 1H), 2.07ꢀ2.19 (m,
1H), 2.05 (s, 3H); 13C NMR (101 MHz, CD3OD) δ 173.7, 149.2, 148.0,
131.5 (d, JCꢀP = 7.7 Hz), 123.9 (d, JCꢀP = 7.7 Hz), 110.4 (d, JCꢀP = 6.1
Hz), 109.0 (d, JCꢀP = 2.3 Hz), 102.3, 47.4 (d, JCꢀP = 18.4 Hz), 43.8 (d,
JCꢀP = 137.3 Hz), 28.5 (d, JCꢀP = 1.5 Hz), 20.2; HRMS (ESI+) calcd for
C12H17NO7P (M + H+), 318.0743; found, 318.0742.
(3-(N-Hydroxyacetamido)-1-(naphthalen-2-yl)propyl)-
phosphonic Acid (13b). Reagents: 12b (0.072 g, 0.19 mmol),
TMSBr (0.10 mL, 0.76 mmol), and DCM (5 mL). Time: 4 h. Purification:
gradient 5ꢀ40%, 70 min, 5 mL/min. 13b (42 mg, 0.19 mmol) was isolated
as a white lyophilized material in 68% yield. 1H NMR (400 MHz, CD3OD)
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dx.doi.org/10.1021/jo201715x |J. Org. Chem. 2011, 76, 8986–8998

The Journal of Organic Chemistry
ARTICLE
1H), 7.14 (d, J = 7.5 Hz, 1H), 3.56ꢀ3.67 (m, 1H), 3.41ꢀ3.52 (m, 1H),
3.10 (ddd, J = 3.2, 11.1, 22.7 Hz, 1H), 2.42ꢀ2.56 (m, 1H), 2.39 (s, 3H),
2.19ꢀ2.35 (m, 1H), 2.04 (s, 3H); 13C NMR (101 MHz, CD3OD) δ
173.6, 142.1, 141.3 (d, JCꢀP = 3.1 Hz), 139.5, 136.9 (d, JCꢀP = 6.9 Hz),
130.9 (d, JCꢀP = 6.1 Hz), 129.7, 128.9, 128.5, 128.0 (d, JCꢀP = 2.3 Hz),
for 6i and 13aꢀ13k. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: mats.larhed@orgfarm.uu.se.
125.0, 47.5 (d, JCꢀP = 18.4 Hz), 44.0 (d, JCꢀP = 136.5 Hz), 28.2 (d, JCꢀP
=
2.3 Hz), 21.6, 20.2; HRMS (ESI+) calcd for C18H23NO5P (M + H+),
364.1314; found, 364.1319.
(3-(N-Hydroxyacetamido)-1-(4-(pyridin-4-yl)phenyl)pro-
pyl)phosphonic Acid (13h). Reagents: 12h (0.040 g, 0.098 mmol),
TMSBr (0.6 mL, 4.9 mmol), and DCM (5 mL). Time: 46 h. Purification:
gradient 0ꢀ30%, 60 min, 5 mL/min. 13h (34 mg, 0.096 mmol) was
’ ACKNOWLEDGMENT
We would like to thank the Swedish Foundation for Strategic
Research (SSF), the Swedish Research Council (VR), Knut and
Alice Wallenberg’s foundation, and the EU Sixth Framework
Program NM4TB CT:01892 for financial support.
1
isolated as a white lyophilized material in 98% yield. H NMR (400
MHz, CD3OD) δ 8.69 (d, J = 6.1 Hz, 2H), 8.27 (d, J = 6.6 Hz, 2H), 7.87
(d, J = 8.2 Hz, 2H), 7.60 (dd, J = 1.9, 8.3 Hz, 2H), 3.55ꢀ3.66 (m, 1H),
3.41ꢀ3.53 (m, 1H), 3.20 (ddd, J = 3.2, 11.6, 22.8 Hz, 1H), 2.47ꢀ2.64
(m, 1H), 2.22ꢀ2.38 (m, 1H), 2.03 (s, 3H); 13C NMR (101 MHz,
CD3OD) δ 173.7, 158.3, 143.7, 142.9, 134.0, 132.0 (d, JCꢀP = 6.1 Hz),
128.9, 125.0, 47.3 (d, JCꢀP = 17.6 Hz), 44.6 (d, JCꢀP = 133.4 Hz), 28.1, 20.2;
HRMS (ESI+) calcd for C16H20N2O5P (M + H+), 351.110; found,
351.1111.
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1
mmol) was isolated as a white lyophilized material in 69% yield. H
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C15H19NO5PS (M + H+), 356.0722; found, 356.0725.
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1
mmol) was isolated as a white lyophilized material in 78% yield. H
NMR (400 MHz, CD3OD) δ 7.47 (dd, J = 2.0, 8.2 Hz, 2H), 7.30 (d, J =
8.0 Hz, 2H), 3.55ꢀ3.67 (m, 1H), 3.41ꢀ3.53 (m, 1H), 3.12 (ddd, J = 3.0,
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=
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3.51ꢀ3.61 (m, 1H), 3.35ꢀ3.48 (m, 5H), 3.07 (ddd, J = 3.2, 11.5, 22.8 Hz,
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’ ASSOCIATED CONTENT
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Supporting Information. 1H and 13C NMR spectra for
S
b
compound 6aꢀ6n, 10aꢀ10e, 11aꢀ11k, 12aꢀ12k, 13aꢀ13k as
well as GCꢀMS spectra for 6bꢀ6k, 6jꢀ6n and LC-MS spectra
8997
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ARTICLE
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dx.doi.org/10.1021/jo201715x |J. Org. Chem. 2011, 76, 8986–8998