Synthesis of Allylic Amide Functionalized 2H-Chromenes and Coumarins Using a One-Pot Overman Rearrangement and Gold(I)-Catalyzed Hydroarylation

Article abstract of DOI:10.1021/acs.joc.6b01881

A four-step synthesis of allylic trichloroacetimidates bearing a 2-proparyloxyaryl group has been developed from readily available 2-hydroxybenzaldehydes, and these have been used for the preparation of allylic amide derived 2H-chromenes using an Overman rearrangement and a 6-endo-dig hydroarylation. High yields of the 2H-chromenes were achieved using a stepwise approach involving an Overman rearrangement under thermal conditions followed by a hydroarylation reaction with a gold(I) triflimide catalyst. An alternative method where both reactions were performed as a one-pot process was also developed and instead used a gold(I) chloride catalyst activated by silver(I) hexafluoroantimonate for the cycloisomerization step. The allylic amide derived 2H-chromenes were converted to the corresponding coumarin analogues by a pyridinium dichromate (PDC)-mediated chemoselective allylic oxidation.

Full text of DOI:10.1021/acs.joc.6b01881

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Article
Synthesis of Allylic Amide Functionalized 2H-
Chromenes and Coumarins Using a One-Pot Overman
Rearrangement and Gold(I)-Catalyzed Hydroarylation
Salaheddin A. I. Sharif, Ewen D. D. Calder, Alexander H. Harkiss, Marie Maduro, and Andrew Sutherland
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01881 • Publication Date (Web): 28 Sep 2016
Downloaded from http://pubs.acs.org on September 30, 2016
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The Journal of Organic Chemistry
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Synthesis of Allylic Amide Functionalized 2Hꢀ
Chromenes and Coumarins Using a OneꢀPot Overman
Rearrangement and Gold(I)ꢀCatalyzed Hydroarylation
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Salaheddin A. I. Sharif, Ewen D. D. Calder, Alexander H. Harkiss, Marie Maduro and Andrew
Sutherland*
WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow,
Glasgow G12 8QQ, United Kingdom.
Andrew.Sutherland@glasgow.ac.uk
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
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Abstract: A fourꢀstep synthesis of allylic trichloroacetimidates bearing a 2ꢀproparyloxyaryl group has
been developed from readily available 2ꢀhydroxybenzaldehydes and these have been used for the
preparation of allylic amide derived 2Hꢀchromenes using an Overman rearrangement and a 6ꢀendoꢀdig
hydroarylation. High yields of the 2Hꢀchromenes were achieved using a stepwise approach involving an
Overman rearrangement under thermal conditions followed by a hydroarylation reaction with a gold(I)
triflimide catalyst. An alternative method where both reactions were performed as a oneꢀpot process was
also developed and instead used a gold(I) chloride catalyst activated by silver(I) hexafluoroantimonate
for the cycloisomerization step. The allylic amide derived 2Hꢀchromenes were converted to the
corresponding coumarin analogues by a PDCꢀmediated chemoselective allylic oxidation.
Keywords: 2Hꢀchromenes, coumarins, Overman rearrangement, gold catalysis, hydroarylation.
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INTRODUCTION
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Hꢀ1ꢀBenzopyrans, commonly known as 2Hꢀchromenes are an important class of heterocyclic
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compound found in a wide array of natural products. These include the αꢀmonomethyl 2Hꢀchromene 1
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from the leaf essential oil of Calyptranthes tricona and tephrowatsin B (2), a flavonoid from Tephrosia
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watsoniana (Figure 1). Many 2Hꢀchromenes also display significant pharmacological activity such as
the natural product, cannabichromene (3), which has analgesic, antiꢀinflammatory and antiviral
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properties. Various synthetic 2Hꢀchromenes have also been developed for medicinal applications and
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include iclaprim (4), an antibiotic used for skin infections, and the 6ꢀfluoro 2Hꢀchromene 5 which, is a
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high affinity antagonist for the 5ꢀHT receptor.
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Figure 1. Structures of 2Hꢀchromene natural products (1, 2 and 3) and pharmacologically active
compounds (4 and 5).
Due to their structural diversity and wideꢀranging pharmacological activities, a variety of methods
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have been reported for the synthesis of 2Hꢀchromenes. One key approach has been formation of the
pyran ring by intramolecular hydroarylation of aryl propargyl ethers. While this 6ꢀendoꢀdig
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cycloisomerization can be performed under thermal conditions, recent efforts have shown that this
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transformation can also be catalyzed using platinum(IV), indium(III), mercury(II), palladium(II)
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and various gold(I) complexes. This wide range of mild metalꢀcatalyzed methods for the synthesis of
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Hꢀchromenes has allowed the preparation of highly functional derivatives that have found use in
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various applications including laser dyes, organic light emitting devices and fluorescent probes.
We have recently reported a series of oneꢀpot multireaction processes using benzannulated alkene
derived allylic alcohols for the rapid and efficient synthesis of aminoꢀsubstituted indenes,
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dihydronaphthalenes, 1ꢀbenzoxepines and 1ꢀbenzoazepines. We were interested in developing a novel
oneꢀpot multistep process involving an Overman rearrangement and 6ꢀendoꢀdig cyclization process for
the preparation of allylic amide derived 2Hꢀchromenes (Scheme 1). It was proposed that these
compounds could then be used in a chemoselective oxidation for the synthesis of coumarin analogues.
Compounds with this coumarin core structure (see box, Scheme 1) have shown bactericidal effects
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against Mycobacterium tuberculosis. However, previous routes to this class of coumarin derivatives
installed the 8ꢀaminopropyl group using low yielding Friedel–Crafts acylation (<20%) and reductive
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amination steps (23–47%).
It was proposed that use of allylic trichloroacetimidates bearing a 2ꢀ
propargyloxyaryl group in combination with an optimized oneꢀpot multibond forming process would
allow access to these coumarin structures more efficiently.
Scheme 1. Proposed Approach to Allylic Amine Derived 2H-Chromenes and Coumarins
We now report the facile preparation of (E)ꢀ(2ꢀpropargyloxy)cinnamyl alcohols from readily available
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ꢀhydroxybenzaldehydes and demonstrate that these compounds are effective substrates for the
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synthesis of allylic amide derived 2Hꢀchromenes using either a stepwise approach or a oneꢀpot twoꢀstep
process. We also describe the preparation of the corresponding coumarin derivatives by the
chemoselective oxidation of the allylic amine derived 2Hꢀchromenes.
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RESULTS AND DISCUSSION
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Our studies began with the development of a short synthetic route for the preparation of cinnamyl
alcohols bearing a 2ꢀpropargyloxy group (Scheme 2). Initially, a series of commercially available 2ꢀ
hydroxybenzaldehydes 6a–e were alkylated with propargyl bromide and potassium carbonate. This was
followed by a HornerꢀWadsworthꢀEmmons reaction with triethyl phosphonoacetate (TEPA) under
MasamuneꢀRoush conditions and gave (E)ꢀpropargyl derived cinnamic esters 8a–e in essentially
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quantitative yields over the two steps. Analysis of the H NMR spectra of the crude reaction mixtures
for this transformation showed exclusive Eꢀalkene formation. DIBALꢀH reduction under standard
conditions then gave cinnamyl alcohols 9a–e in 89–96% yield.
Before developing the oneꢀpot process, the optimal reagents and conditions for the hydroarylation
step needed to be established. Therefore, cinnamyl alcohols 9a–e were converted to the corresponding
allylic trichloroacetamides 10a–e by first conversion to the allylic trichloroacetimidate using
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trichloroacetonitrile and catalytic DBU and then Overman rearrangement under thermal conditions.
In general, the rearrangements were complete after 18 hours and gave excellent yields over the two
steps (84–98%). It should be noted that longer reaction times for the rearrangement step were required
for the two substrates with electronꢀwithdrawing substituents (R = 5ꢀCl, 48 h; R = 5ꢀNO , 72 h).
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a
Scheme 2. Synthesis of Allylic Trichloroacetamides 10a–e
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Isolated yields are shown.
Having prepared a series of propargyloxy derived allylic trichloroacetamides, optimal conditions for
the subsequent hydroarylation reaction were next investigated. During the development of the Overman
rearrangement and using extended reaction times for some of the substrates, low amounts (<10%) of the
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Hꢀchromenes were detected by H NMR spectroscopy in the crude reaction mixtures. Based on this
observation, initial attempts at converting allylic trichloroacetamide 10a to the corresponding 2Hꢀ
chromene 11a focused on a thermally mediated 6ꢀendoꢀdig cycloisomerization (Table 1). It was
proposed that a successful hydroarylation reaction under these conditions would allow the development
of a oneꢀpot synthesis of the 2Hꢀchromenes from the corresponding allylic trichloroacetimidate where
both the rearrangement and cycloisomerization steps were performed simply by heating. As only small
amounts of 2Hꢀchromenes were observed at 140 ºC during the Overman rearrangement, the initial
hydroarylation reaction was performed at a higher temperature of 160 ºC (entry 1). However, after
heating for four days, only 35% conversion was observed. A higher temperature of 180 ºC was next
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investigated but, after five days, this gave a modest conversion of 50%. It was proposed that microwave
heating might allow a more efficient hydroarylation reaction with a shorter reaction time (entries 3 and
4). While a temperature of 200 ºC did show 91% conversion after two hours (entry 4), the 34% isolated
yield of 11a indicated that decomposition was an issue when using very high temperatures. Gold(I)ꢀ
catalysts were next studied for the cycloisomerization reaction. Using chloro(triphenylphosphine)gold(I)
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(
2.5 mol %), activated by silver(I) hexafluoroantimonate (2.5 mol %) at 80 ºC, gave 85% conversion
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after four hours (entry 5). However, using Ph PAuNTf (2.5 mol %),
which requires no activation,
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gave complete conversion after only four hours under similar conditions (entry 6). Furthermore, the H
NMR spectrum of the crude reaction mixture indicated a clean transformation and the exclusive
formation of 6ꢀendoꢀdig product 11a.
Table 1.
Optimization of the Hydroarylation Reaction
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reaction conditions
160 ºC
time (h) conversion (%)
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MW, 180 ºC
MW, 200 ºC
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Conversions were measured using H NMR spectroscopy.
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With conditions for an optimized hydroarylation reaction identified, the scope of this transformation
for the preparation of a range of allylic amide substituted 2Hꢀchromenes was explored (Scheme 3). For
substrates 10a–d, the reactions were complete after four hours, at 80 ºC and gave the products 11a–d in
essentially quantitative yields. The ability of this procedure for multigram synthesis of 2Hꢀchromenes
was also studied using aryl propargyl ether 10a. On scaleꢀup (2–3 g), and using the same reaction time
and temperature, it was found that the catalyst loading could be lowered to 1 mol % to give 2Hꢀ
chromene 11a in quantitative yield.
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Under the same conditions as for substrates 10a–d, nitro derivative 10e gave 2Hꢀchromene 11e in
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6% isolated yield (Scheme 3). Analysis of the H NMR spectrum of the crude reaction mixture
indicated a number of additional minor products, including 2ꢀmethylbenzofuran 11f, which is formed
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via an orthoꢀallenyl phenolate intermediate and a subsequent 5ꢀexoꢀdig cyclization. This propensity of
aryl propargyl ethers with electron deficient substituents to undergo sideꢀreactions during gold(I)ꢀ
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catalyzed cycloisomerization reactions has been observed in other studies.
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Scheme 3. Gold(I)-Catalyzed Synthesis of 2H-Chromenes 11a–e
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Isolated yields are shown.
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The next stage of this project investigated the combination of the optimized Overman rearrangement
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and gold(I)ꢀcatalyzed hydroarylation reaction for the oneꢀpot synthesis of 2Hꢀchromenes 11a–e
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(
Scheme 4). Initially, the Overman rearrangement was performed for each substrate at 140 ºC and the
same reaction time as previously described (Scheme 2). Surprisingly, addition of Ph PAuNTf (2.5 mol
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%) to the completed Overman rearrangement reactions and heating of the mixtures to 80 ºC gave none
of the hydroarylation product for any of the substrates. These results indicated that the highly active
Ph PAuNTf complex was not stable under the conditions of the oneꢀpot process. To confirm this, the
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oneꢀpot process for the formation of 2Hꢀchromene 11a was repeated using a combination of Ph PAuCl
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and AgNTF (to form Ph PAuNTf in situ) for the hydroarylation step. Again, no conversion to 2Hꢀ
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chromene 11a was observed, providing further evidence that this issue is due to the active catalyst.
Instead, the use of Ph PAuCl, activated by AgSbF was investigated for the hydroarylation step as
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part of the oneꢀpot process. Initial trials showed that this catalytic system was compatible with the
conditions of the Overman rearrangement and gave high conversions (>90%) to the 2Hꢀchromenes. On
optimization of the oneꢀpot process, it was found for the majority of substrates, that a higher catalyst
loading of both complexes (7.5 mol %) and a longer reaction (48 h) was required, compared to the
single step cycloisomerization catalyzed by Ph PAuNTf (2.5 mol %). Despite the longer reaction times
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for this stage, high yields (76–91%) were obtained for the oneꢀpot synthesis of 2Hꢀchromenes 11a–d
over the three steps (Scheme 4). As observed with the Ph PAuNTf complex, the Ph PAuCl/AgSbF
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catalyzed hydroarylation of electronꢀdeficient 5ꢀnitroaryl propargyloxy ether 10e again produced a
number of minor byꢀproducts. However, by increasing the catalyst loading (10 mol %), the oneꢀpot
synthesis of 11e could be achieved in 54% overall yield.
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a
Scheme 4. One-pot Synthesis of 2H-Chromenes 11a–e
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Isolated yields are shown. The hydroarylation step was complete after 4 h. The Overman
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rearrangement was complete after 48 h. The Overman rearrangement was complete after 72 h and the
hydroarylation step was done using 10 mol % of both complexes and was complete after 65 h.
Following the development of the two approaches for the preparation of allylic amide derived 2Hꢀ
chromenes 11a–e, we wanted to demonstrate their potential as synthetic building blocks. A
transformation that has been investigated in this study is the chemoselective allylic oxidation to give the
corresponding coumarins, a structural motif found in many natural products and used as fluorescent
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probes to investigate various biological systems. On searching the literature, there are relatively few
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The only general method, reported by Schmidt and coꢀworkers,
showed that following ring closing metathesis of 2ꢀallyoxystyrenes to give 2Hꢀchromenes, subsequent
addition of tertꢀbutyl hydroperoxide as part of a oneꢀpot process resulted in allylic oxidation and the
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7
formation of coumarins in yields of 30–63%. Therefore, our initial attempts at the chemoselective
oxidation of 2Hꢀchromene 11a investigated the use of tertꢀbutyl hydroperoxide as the oxidant.
However, coumarin 12a could only be isolated in 34% yield. While the allylic oxidation of 2Hꢀ
chromenes to coumarins is rare, a similar transformation to convert 5,6ꢀdihydropyrans to the
1
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7
8
9
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1
1
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1
1
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6
2
8,29
corresponding 5,6ꢀdihydropyranꢀ2ꢀones using chromium(VI) reagents is known.
As such, the
0
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0
oxidation of 11a was next investigated using pyridinium dichromate (PDC) (Scheme 5). On
investigating various temperatures for this reaction, it was found that room temperature (20 °C) gave the
cleanest, most selective transformation. While the reaction did take six days to go to completion,
coumarin 12a was isolated in 65% yield. Some of the other 2Hꢀchromenes were then oxidized using this
general procedure (room temperature, 4–6 days) and this gave the corresponding coumarins 12b–d in
42–62% yields.
a
Scheme 5. Chemoselective Oxidation of 2H-Chromenes to Coumarins
a
Isolated yields are shown.
CONCLUSIONS
In summary, a rapid and efficient approach has been developed for the synthesis of allylic amide
functionalized 2Hꢀchromenes from readily available 2ꢀhydroxybenzaldehydes using an Overman
rearrangement and a gold(I)ꢀcatalyzed cycloisomerization as the key steps. Two different approaches
involving stepwise rearrangement and hydroarylation with a gold(I) triflimide complex or a oneꢀpot
twoꢀstep process using a more robust gold(I)ꢀchloride catalyst activated by silver(I)
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hexafluoroantimonate has been presented. A PDC oxidation was developed for the conversion of the
Hꢀchromenes to the corresponding 8ꢀ(2ꢀamidopropenyl)coumarins, which are structurally related to
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1
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1
1
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1
1
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2
2
2
2
2
2
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3
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5
5
5
5
5
5
5
5
6
2
compounds that are bactericidal against M. tuberculosis. Work is currently underway to investigate
other applications of allylic amide functionalized 2Hꢀchromenes and coumarins, as well as the
development of new oneꢀpot multistep reaction processes.
0
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0
EXPERIMENTAL SECTION
All reagents and starting materials were obtained from commercial sources and used as received. All
dry solvents were purified using a solvent purification system. All reactions were performed under an
atmosphere of argon unless otherwise mentioned. Brine refers to a saturated solution of sodium
chloride. Flash column chromatography was performed using silica gel 60 (35–70 ꢀm). Aluminiumꢀ
backed plates preꢀcoated with silica gel 60F254 were used for thin layer chromatography and were
1
visualized with a UV lamp or by staining with potassium permanganate. H NMR spectra were recorded
on a NMR spectrometer at either 400 or 500 MHz and data are reported as follows: chemical shift in
ppm relative to tetramethylsilane or the solvent as the internal standard (CDCl , δ 7.26 ppm),
3
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or overlap of nonequivalent
13
resonances, integration). C NMR spectra were recorded on a NMR spectrometer at either 101 or 126
MHz and data are reported as follows: chemical shift in ppm relative to tetramethylsilane or the solvent
as internal standard (CDCl , δ 77.0 ppm), multiplicity with respect to hydrogen (deduced from DEPT
3
experiments, C, CH, CH or CH ). Infrared spectra were recorded on a FTIR spectrometer;
2
3
–
1
wavenumbers are indicated in cm . Mass spectra were recorded using electron impact, chemical
ionization or electrospray techniques. HRMS spectra were recorded using a dualꢀfocusing magnetic
analyzer mass spectrometer. Melting points are uncorrected.
3
0
2
-Propargyloxybenzaldehyde (7a). Propargyl bromide (3.34 mL, 30.0 mmol) was added to a
stirred solution of 2ꢀhydroxybenzaldehyde (6a) (3.00 g, 25.0 mmol) and potassium carbonate (7.00 g,
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5
0.0 mmol) in N,N'ꢀdimethylformamide (120 mL) and heated to 70 °C for 3 h. The reaction mixture was
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
cooled to room temperature, diluted with 5% aqueous lithium chloride solution (20 mL) and extracted
with diethyl ether (3 × 50 mL). The organic layer was washed with 5% aqueous lithium chloride
solution (3 × 50 mL), brine (50 mL), dried (MgSO ), filtered and concentrated in vacuo. Purification by
4
column chromatography (diethyl ether/petroleum ether, 1:4) gave 2ꢀpropargyloxybenzaldehyde (7a)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
0
(3.94 g, 100%) as a white solid. Mp 69–70 °C (lit. 69–70 °C); R = 0.65 (diethyl ether/petroleum ether
f
1
=
1:1); H NMR (500 MHz, CDCl )
δ
2.57 (t, J = 2.5 Hz, 1H), 4.81 (d, J = 2.5 Hz, 2H), 7.06 (br t, J =
3
7.5 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 7.54 (ddd, J = 8.5, 7.5, 1.9 Hz, 1H), 7.83 (dd, J = 7.5, 1.9 Hz,
13
1
H), 10.46 (br d, J = 0.6 Hz, 1H); C NMR (126 MHz, CDCl )
δ
56.4 (CH ), 76.5 (CH), 77.7 (C),
3
2
113.2 (CH), 121.7 (CH), 125.4 (C), 128.5 (CH), 135.7 (CH), 159.7 (C), 189.5 (CH); MS (EI) m/z 160
+
(M , 30), 131 (100), 121 (49), 109 (40), 83 (47), 65 (30), 39 (34).
31
5
-Methoxy-2-propargyloxybenzaldehyde (7b). The reaction was carried out as described for the
synthesis of 2ꢀpropargyloxybenzaldehyde (7a) using 2ꢀhydroxyꢀ5ꢀmethoxybenzaldehyde (6b) (0.152 g,
.00 mmol). Purification by column chromatography (diethyl ether/petroleum ether, 1:4) gave 5ꢀ
methoxyꢀ2ꢀpropargyloxybenzaldehyde (7b) (0.190 g, 100%) as a white solid. Mp 60–62 °C; R = 0.91
1
f
3
1 1
(diethyl ether/petroleum ether = 1:1); Spectroscopic data was consistent with the literature. H NMR
(500 MHz, CDCl3) 2.55 (t, J = 2.4 Hz, 1H), 3.81 (s, 3H), 4.78 (d, J = 2.4 Hz, 2H), 7.08 (d, J = 9.1 Hz,
δ
1
3
1H), 7.14 (dd, J = 9.1, 3.3 Hz, 1H), 7.34 (d, J = 3.3 Hz, 1H), 10.44 (s, 1H); C NMR (126 MHz,
CDCl3) 55.8 (CH ), 57.4 (CH ), 76.4 (CH), 77.9 (C), 110.4 (CH), 115.7 (CH), 123.2 (CH), 126.2 (C),
126.2 (C), 154.5 (C), 189.4 (CH); MS (ESI) m/z 213 (MNa , 100).
δ
3
2
+
3
1
4
-Methoxy-2-propargyloxybenzaldehyde (7c). The reaction was carried out as described for the
synthesis of 2ꢀpropargyloxybenzaldehyde (7a) using 2ꢀhydroxyꢀ4ꢀmethoxybenzaldehyde (6c) (0.152 g,
1.00 mmol). Purification by column chromatography (diethyl ether/petroleum ether, 1:4) gave 4ꢀ
31
methoxyꢀ2ꢀpropargyloxybenzaldehyde (7c) (0.188 g, 99%) as a white solid. Mp 82–84 °C (lit. 76–78
1
°
C); R = 0.41 (diethyl ether/petroleum ether = 1:1); H NMR (500 MHz, CDCl )
δ
2.58 (t, J = 2.4 Hz,
f
3
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1
H), 3.87 (s, 3H), 4.80 (d, J = 2.4 Hz, 2H), 6.58–6.61 (m, 2H), 7.81–7.84 (m, 1H), 10.29 (br d, J = 0.6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
Hz, 1H); C NMR (126 MHz, CDCl )
δ 55.7 (CH ), 56.4 (CH ), 76.6 (CH), 77.6 (C), 99.5 (CH), 106.9
3 2
3
+
(CH), 119.6 (C), 130.6 (CH), 161.5 (C), 165.9 (C), 188.1 (CH); MS (ESI) m/z 213 (MNa , 100).
31
5
-Chloro-2-propargyloxybenzaldehyde (7d). The reaction was carried out as described for the
synthesis of 2ꢀpropargyloxybenzaldehyde (7a) using 2ꢀhydroxyꢀ5ꢀchlorobenzaldehyde (6d) (1.57 g,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
0
0.0 mmol). Purification by column chromatography (diethyl ether/petroleum ether, 1:4) gave 5ꢀchloroꢀ
3
1
ꢀpropargyloxybenzaldehyde (7d) (1.93 g, 99%) as a white solid. Mp 74–75 °C (lit. 74–76 °C); R =
f
1
.58 (diethyl ether/petroleum ether = 1:1); H NMR (500 MHz, CDCl )
δ 2.59 (t, J = 2.4 Hz, 1H), 4.82
3
(d, J = 2.4 Hz, 2H), 7.08 (d, J = 8.9 Hz, 1H), 7.50 (dd, J = 8.9, 2.8 Hz, 1H), 7.80 (d, J = 2.8 Hz, 1H),
1
3
10.40 (s, 1H); C NMR (126 MHz, CDCl )
δ
56.8 (CH ), 76.9 (C), 77.2 (CH), 115.0 (CH), 126.5 (C),
3
2
+
1
27.5 (C), 128.1 (CH), 135.2 (CH), 158.1 (C), 188.2 (CH); MS (ESI) m/z 217 (MNa , 100).
3
2
5
-Nitro-2-propargyloxybenzaldehyde (7e). The reaction was carried out as described for the
synthesis of 2ꢀpropargyloxybenzaldehyde (7a) using 2ꢀhydroxyꢀ5ꢀnitrobenzaldehyde (6e) (2.75 g, 16.5
mmol). Purification by column chromatography (diethyl ether/petroleum ether, 1:4) gave 5ꢀnitroꢀ2ꢀ
3
2
propargyloxybenzaldehyde (7e) (3.31 g, 98%) as a white crystalline solid. Mp 90–91 °C (lit. 91.5–93
1
°
C); R = 0.32 (diethyl ether/petroleum ether = 1:1); H NMR (400 MHz, CDCl )
δ
2.71 (t, J = 2.4 Hz,
f
3
1
H), 5.01 (d, J = 2.4 Hz, 2H), 7.32 (d, J = 9.2 Hz, 1H), 8.45 (dd, J = 9.2, 2.9 Hz, 1H), 8.69 (d, J = 2.9
1
3
Hz, 1H), 10.45 (s, 1H); C NMR (101 MHz, CDCl )
δ
57.2 (CH ), 76.3 (C), 77.9 (CH), 113.8 (CH),
3
2
+
1
24.5 (CH), 125.2 (C), 130.4 (CH), 142.2 (C), 163.4 (C), 187.3 (CH); MS (EI) m/z 205 (M , 16), 176
(53), 167 (100), 137 (34), 120 (36), 92 (27), 65 (46).
Ethyl (2E)-3-(2'-Propargyloxyphenyl)prop-2-enoate (8a). Lithium chloride (4.20 g, 98.4 mmol)
was added to a solution of triethyl phosphonoacetate (16.6 mL, 83.6 mmol) and 1,8ꢀ
diazabicyclo[5.4.0]undecꢀ7ꢀene (12.5 mL, 83.6 mmol) in acetonitrile (100 mL) and stirred at room
temperature for 0.5 h. 2ꢀPropargyloxybenzaldehyde (7a) (3.94 g, 24.6 mmol) was added and the
solution was stirred at room temperature for 3.5 h. The reaction was quenched by the addition of a
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saturated solution of ammonium chloride (10 mL), concentrated to half volume in vacuo and extracted
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9
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2
2
2
2
2
2
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6
with diethyl ether (3 × 50 mL). The combined organic layers were washed with water (100 mL), brine
(100 mL), dried (MgSO ), filtered and concentrated in vacuo. Purification by column chromatography
4
(diethyl ether/petroleum ether, 1:10) yielded ethyl (2E)ꢀ3ꢀ(2'ꢀpropargyloxyphenyl)propꢀ2ꢀenoate (8a)
(
5.67 g, 100%) as a colorless oil. R = 0.70 (diethyl ether/petroleum ether = 1:1); IR (neat) 2983, 1701,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
f
−
1 1
1
632, 1486, 1316, 1220, 1175, 1022, 750, 731 cm ; H NMR (400 MHz, CDCl )
δ
1.34 (t, J = 7.1 Hz,
3
3
H), 2.53 (t, J = 2.4 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.78 (d, J = 2.4 Hz, 2H), 6.51 (d, J = 16.2 Hz,
1H), 7.01 (br t, J = 7.6 Hz, 1H), 7.05 (br d, J = 8.3 Hz, 1H), 7.35 (ddd, J = 8.3, 7.6, 1.6 Hz, 1H), 7.53
13
(
dd, J = 7.6, 1.6 Hz, 1H), 8.00 (d, J = 16.2 Hz, 1H); C NMR (101 MHz, CDCl )
δ
14.4 (CH ), 56.1
3
3
(CH ), 60.4 (CH ), 76.1 (CH), 78.2 (C), 112.7 (CH), 119.1 (CH), 121.6 (CH), 124.1 (C), 128.8 (CH),
2
2
+
1
31.2 (CH), 139.6 (CH), 156.1 (C), 167.3 (C); MS (EI) m/z 230 (M , 38), 201 (44), 185 (39), 157 (40),
+
1
47 (46), 118 (100), 103 (14), 91 (66); HRMS (EI) calcd for C H O (M ), 230.0943, found 230.0944.
1
4
14
3
Ethyl (2E)-3-(5'-Methoxy-2'-propargyloxyphenyl)prop-2-enoate (8b). The reaction was carried
out as described for the synthesis of ethyl (2E)ꢀ3ꢀ(2'ꢀpropargyloxyphenyl)propꢀ2ꢀenoate (8a) using 5ꢀ
methoxyꢀ2ꢀpropargyloxybenzaldehyde (7b) (0.167 g, 0.880 mmol). Purification by column
chromatography (diethyl ether/petroleum ether, 1:10) gave ethyl (2E)ꢀ3ꢀ(5'ꢀmethoxyꢀ2'ꢀ
propargyloxyphenyl)propꢀ2ꢀenoate (8b) (0.225 g, 99%) as a colorless oil. R = 0.60 (diethyl
f
−
1 1
ether/petroleum ether = 1:1); IR (neat) 3020, 1701, 1633, 1494, 1288, 1214, 1179, 1043, 752 cm ; H
NMR (400 MHz, CDCl3) 1.34 (t, J = 7.1 Hz, 3H), 2.51 (t, J = 2.4 Hz, 1H), 3.80 (s, 3H), 4.27 (q, J =
.1 Hz, 2H), 4.72 (d, J = 2.4 Hz, 2H), 6.48 (d, J = 16.2 Hz, 1H), 6.91 (dd, J = 9.0, 3.1 Hz, 1H), 7.01 (d,
δ
7
1
3
J = 9.0 Hz, 1H), 7.06 (d, J = 3.1 Hz, 1H), 7.98 (d, J = 16.2 Hz, 1H); C NMR (126 MHz, CDCl )
δ
14.4
3
(
CH ), 55.7 (CH ), 57.0 (CH ), 60.4 (CH ), 75.8 (CH), 78.5 (C), 112.9 (CH), 114.7 (CH), 116.9 (CH),
3
3
2
2
+
119.3 (CH), 125.0 (C), 139.4 (CH), 150.5 (C), 154.3 (C), 167.2 (C); MS (ESI) m/z 283 (MNa , 100);
+
HRMS (ESI) calcd for C H NaO (MNa ), 283.0941, found 283.0932.
1
5
16
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Ethyl (2E)-3-(4'-Methoxy-2'-propargyloxyphenyl)prop-2-enoate (8c). The reaction was carried out
as described for the synthesis of ethyl (2E)ꢀ3ꢀ(2'ꢀpropargyloxyphenyl)propꢀ2ꢀenoate (8a) using 4ꢀ
methoxyꢀ2ꢀpropargyloxybenzaldehyde (7c) (1.73 g, 9.07 mmol). Purification by column
chromatography (diethyl ether/petroleum ether, 1:10) gave ethyl (2E)ꢀ3ꢀ(4'ꢀmethoxyꢀ2'ꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
propargyloxyphenyl)propꢀ2ꢀnoate (8c) (2.35 g, 100%) as a colorless oil. R = 0.46 (diethyl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
f
−
1 1
ether/petroleum ether = 1:1); IR (neat) 2984, 1704, 1605, 1258, 1161, 1021, 970 cm ; H NMR (400
MHz, CDCl3) 1.32 (t, J = 7.1 Hz, 3H), 2.54 (t, J = 2.5 Hz, 1H), 3.83 (s, 3H), 4.24 (q, J = 7.1 Hz, 2H),
δ
4.75 (d, J = 2.5 Hz, 2H), 6.40 (d, J = 16.1 Hz, 1H), 6.54 (dd, J = 8.6, 2.4 Hz, 1H), 6.60 (d, J = 2.4 Hz,
13
1
H), 7.46 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 16.1 Hz, 1H); C NMR (101 MHz, CDCl )
δ
14.4 (CH3),
3
55.5 (CH ), 56.4 (CH ), 60.2 (CH ), 76.2 (CH), 78.0 (C), 99.9 (CH), 106.4 (CH), 116.5 (CH), 117.1 (C),
3
2
2
+
1
30.2 (CH), 139.5 (CH), 157.6 (C), 162.4 (C), 167.7 (C); MS (ESI) m/z 283 (MNa , 100); HRMS (ESI)
+
calcd for C H NaO (MNa ), 283.0941, found 283.0935.
1
5
16
4
Ethyl (2E)-3-(5'-Chloro-2'-propargyloxyphenyl)prop-2-enoate (8d). The reaction was carried out
as described for the synthesis of ethyl (2E)ꢀ3ꢀ(2'ꢀpropargyloxyphenyl)propꢀ2ꢀenoate (8a) using 5ꢀ
chloroꢀ2ꢀpropargyloxybenzaldehyde (7d) (0.120 g, 0.620 mmol). Purification by column
chromatography (diethyl ether/petroleum ether, 1:10) gave ethyl (2E)ꢀ3ꢀ(5'ꢀchloroꢀ2'ꢀ
propargyloxyphenyl)propꢀ2ꢀenoate (8d) (0.163 g, 100%) as a colorless oil. R = 0.60 (diethyl
f
−
1 1
ether/petroleum ether = 1:1); IR (neat) 3020, 1705, 1635, 1480, 1216, 1181, 1024, 747 cm ; H NMR
400 MHz, CDCl3) 1.33 (t, J = 7.1 Hz, 3H), 2.54 (t, J = 2.4 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.76 (d,
J = 2.4 Hz, 2H), 6.47 (d, J = 16.4 Hz, 1H), 6.99 (d, J = 8.9 Hz, 1H), 7.29 (dd, J = 8.9, 2.6 Hz, 1H), 7.49
(
δ
1
3
(
d, J = 2.6 Hz, 1H), 7.90 (d, J = 16.4 Hz, 1H); C NMR (101 MHz, CDCl ) δ 14.3 (CH ), 56.4 (CH ),
3 3 2
6
0.6 (CH ), 76.4 (CH), 77.8 (C), 114.2 (CH), 120.4 (CH), 125.7 (C), 126.8 (C), 128.2 (CH), 130.6
2
+
(CH), 138.1 (CH), 154.6 (C), 166.9 (C); MS (ESI) m/z 287 (MNa , 100); HRMS (ESI) calcd for
35
+
C H ClNaO (MNa ), 287.0445, found 287.0434.
14
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Ethyl (2E)-3-(5'-Nitro-2'-propargyloxyphenyl)prop-2-enoate (8e). The reaction was carried out as
described for the synthesis of ethyl (2E)ꢀ3ꢀ(2'ꢀpropargyloxyphenyl)propꢀ2ꢀenoate (8a) using 5ꢀnitroꢀ2ꢀ
propargyloxybenzaldehyde (7e) (0.140 g, 0.680 mmol). Purification by column chromatography (diethyl
ether/petroleum ether, 1:10) gave ethyl (2E)ꢀ3ꢀ(5'ꢀnitroꢀ2'ꢀpropargyloxyphenyl)propꢀ2ꢀenoate (8e)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
0.183 g, 98%) as a white solid. Mp 95–96 °C; R = 0.45 (diethyl ether/petroleum ether = 1:1); IR (neat)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
f
−
1 1
2
986, 1701, 1581, 1514, 1343, 1270, 1233, 1016, 750 cm ; H NMR (400 MHz, CDCl )
δ
1.34 (t, J =
3
7
.1 Hz, 3H), 2.61 (t, J = 2.4 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.90 (d, J = 2.4 Hz, 2H), 6.60 (d, J = 16.4
Hz, 1H), 7.15 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 16.4 Hz, 1H), 8.25 (dd, J = 9.2, 2.8 Hz, 1H), 8.43 (d, J =
13
2
.8 Hz, 1H); C NMR (101 MHz, CDCl )
δ
14.3 (CH ), 56.7 (CH ), 60.8 (CH ), 76.7 (CH), 77.4 (C),
3
3
2
2
112.5 (CH), 121.9 (CH), 124.0 (CH), 124.9 (C), 126.4 (CH), 137.1 (CH), 142.0 (C), 160.2 (C), 166.5
+
+
(
C); MS (ESI) m/z 298 (MNa , 100); HRMS (ESI) calcd for C H NNaO (MNa ), 298.0686, found
14 13 5
2
98.0672.
(2E)-3-(2'-Propargyloxyphenyl)prop-2-en-1-ol (9a). Diisobutylaluminium hydride (54.0 mL, 54.0
mmol, 1 M in hexane) was added dropwise with stirring to a solution of ethyl (2E)ꢀ3ꢀ(2'ꢀ
propargyloxyphenyl)propꢀ2ꢀenoate (8a) (5.66 g, 24.6 mmol) in dichloromethane (100 mL) at −78 °C.
The solution was stirred at −78 °C for 2 h and then allowed to return to room temperature over 2 h. The
reaction was quenched with 10% aqueous potassium sodium tartrate solution (10 mL), extracted with
diethyl ether (2 × 50 mL), washed with water (100 mL), brine (100 mL), dried (MgSO ), filtered and
4
concentrated in vacuo. Purification by column chromatography (diethyl ether/petroleum ether, 1:2) gave
(
2E)ꢀ3ꢀ(2'ꢀpropargyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (9a) (4.30 g, 93%) as a colorless oil. R = 0.25 (diethyl
f
−
1 1
ether/petroleum ether = 1:1); IR (neat) 3304, 2870, 1598, 1487, 1217, 1024, 974, 748 cm ; H NMR
400 MHz, CDCl3) 2.02 (br s, 1H), 2.51 (t, J = 2.4 Hz, 1H), 4.30 (br d, J = 5.7 Hz, 2H), 4.70 (d, J =
2.4 Hz, 2H), 6.36 (dt, J = 16.2, 5.7 Hz, 1H), 6.92 (d, J = 16.2 Hz, 1H), 6.95–6.99 (m, 2H), 7.19–7.24
(
δ
1
3
(
m, 1H), 7.44 (dd, J = 8.0, 1.3 Hz, 1H); C NMR (101 MHz, CDCl ) δ 56.2 (CH ), 64.1 (CH ), 75.7
3 2 2
(CH), 78.7 (C), 112.7 (CH), 121.7 (CH), 125.8 (CH), 126.5 (C), 127.1 (CH), 128.6 (CH), 129.7 (CH),
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54.7 (C); MS (EI) m/z 188 (M , 38), 149 (46), 131 (100), 121 (55), 91 (84), 77 (43), 65 (13); HRMS
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
(
EI) calcd for C H O (M ), 188.0837, found 188.0838.
1
2
12
2
(2E)-3-(5'-Methoxy-2'-propargyloxyphenyl)prop-2-en-1-ol (9b). The reaction was carried out as
described for the synthesis of (2E)ꢀ3ꢀ(2'ꢀpropargyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (9a) using ethyl (2E)ꢀ3ꢀ(5'ꢀ
methoxyꢀ2'ꢀpropargyloxyphenyl)propꢀ2ꢀenoate (8b) (1.87 g, 7.17 mmol). Purification by column
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
chromatography
(diethyl
ether/petroleum
ether,
1:2)
gave
(2E)ꢀ3ꢀ(5'ꢀmethoxyꢀ2'ꢀ
propargyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (9b) (1.39 g, 89%) as a colorless oil. R = 0.13 (diethyl
f
ether/petroleum ether = 1:1); IR (neat) 3288, 2920, 1583, 1492, 1286, 1202, 1041, 1021, 970, 803, 751
−1
1
cm ; H NMR (400 MHz, CDCl )
δ
1.59 (br s, 1H), 2.50 (t, J = 2.4 Hz, 1H), 3.79 (s, 3H), 4.34 (dd, J =
3
5
6
.8, 1.6 Hz, 2H), 4.67 (d, J = 2.4 Hz, 2H), 6.37 (dt, J = 16.0, 5.8 Hz, 1H), 6.78 (dd, J = 8.9, 3.1 Hz, 1H),
1
3
.92 (dt, J = 16.0, 1.6 Hz, 1H), 6.95 (d, J = 8.9 Hz, 1H), 7.02 (d, J = 3.1 Hz, 1H); C NMR (101 MHz,
CDCl3)
δ
55.7 (CH ), 57.3 (CH ), 64.1 (CH ), 75.4 (CH), 78.9 (C), 112.1 (CH), 113.7 (CH), 114.9
3
2
2
+
(CH), 125.7 (CH), 127.7 (C), 129.9 (CH), 149.2 (C), 154.5 (C); MS (ESI) m/z 241 (MNa , 100); HRMS
+
(
ESI) calcd for C H NaO (MNa ), 241.0835, found 241.0829.
1
3
14
3
(
2E)-3-(4'-Methoxy-2'-propargyloxyphenyl)prop-2-en-1-ol (9c). The reaction was carried out as
described for the synthesis of (2E)ꢀ3ꢀ(2'ꢀpropargyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (9a) using ethyl (2E)ꢀ3ꢀ(4'ꢀ
methoxyꢀ2'ꢀpropargyloxyphenyl)propꢀ2ꢀenoate (8c) (2.48 g, 9.40 mmol). Purification by column
chromatography
(diethyl
ether/petroleum
ether,
1:2)
gave
(2E)ꢀ3ꢀ(4'ꢀmethoxyꢀ2'ꢀ
propargyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (9c) (1.99 g, 92%) as a white solid. Mp 66–68 °C; R = 0.16 (diethyl
f
−
1 1
ether/petroleum ether = 1:1); IR (neat) 3302, 2929, 1608, 1503, 1258, 1194, 1161, 750 cm ; H NMR
(500 MHz, CDCl3) 1.86 (br s, 1H), 2.53 (t, J = 2.4 Hz, 1H), 3.80 (s, 3H), 4.28 (dd, J = 6.1, 1.1 Hz,
H), 4.69 (d, J = 2.4 Hz, 2H), 6.26 (dt, J = 16.0, 6.1 Hz, 1H), 6.51 (dd, J = 8.5, 2.4 Hz, 1H), 6.56 (d, J =
δ
2
13
2.4 Hz, 1H), 6.82 (br d, J = 16.0 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H); C NMR (126 MHz, CDCl )
δ
55.4
3
(
CH ), 56.3 (CH ), 64.3 (CH ), 75.8 (CH), 78.5 (C), 100.0 (CH), 106.2 (CH), 119.3 (C), 125.8 (CH),
3
2
2
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27.4, (CH), 127.9 (CH), 155.8 (C), 160.3 (C); MS (ESI) m/z 241 (MNa , 100); HRMS (ESI) calcd for
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
C H NaO (MNa ), 241.0835, found 241.0830.
13
14
3
(2E)-3-(5'-Chloro-2'-propargyloxyphenyl)prop-2-en-1-ol (9d). The reaction was carried out as
described for the synthesis of (2E)ꢀ3ꢀ(2'ꢀpropargyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (9a) using ethyl (2E)ꢀ3ꢀ(5'ꢀ
chloroꢀ2'ꢀpropargyloxyphenyl)propꢀ2ꢀenoate (8d) (2.48 g, 9.40 mmol). Purification by column
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
chromatography
(diethyl
ether/petroleum
ether,
1:2)
gave
(2E)ꢀ3ꢀ(5'ꢀchloroꢀ2'ꢀ
propargyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (9d) (1.95 g, 93%) as a white solid. Mp 67–68 °C; R = 0.25
f
−
1 1
(diethyl ether/petroleum ether = 1:1); IR (neat) 3285, 2929, 1480, 1222, 1025, 963, 795 cm ; H NMR
500 MHz, CDCl3) 2.20 (br s, 1H), 2.53 (t, J = 2.5 Hz, 1H), 4.30 (br d, J = 5.4 Hz, 2H), 4.68 (d, J =
.5 Hz, 2H), 6.34 (dt, J = 16.1, 5.4 Hz, 1H), 6.84 (dt, J = 16.1, 1.5 Hz, 1H), 6.89 (d, J = 8.9 Hz, 1H),
(
δ
2
7
1
3
.15 (dd, J = 8.9, 2.7 Hz, 1H), 7.39 (d, J = 2.7 Hz, 1H); C NMR (126 MHz, CDCl ) δ 56.5 (CH ), 63.7
2
3
(
CH ), 76.1 (CH), 78.2 (C), 114.0 (CH), 124.3 (CH), 126.8 (CH), 126.8 (C), 128.0, (CH), 128.2 (C),
2
+
35
131.0 (CH), 153.2 (C); MS (ESI) m/z 245 (MNa , 100); HRMS (ESI) calcd for C H ClNaO2
1
2
11
+
(
MNa ), 245.0340, found 245.0333.
(
2E)-3-(5'-Nitro-2'-propargyloxyphenyl)prop-2-en-1-ol (9e). The reaction was carried out as
described for the synthesis of (2E)ꢀ3ꢀ(2'ꢀpropargyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (9a) using ethyl (2E)ꢀ3ꢀ(5'ꢀ
nitroꢀ2'ꢀpropargyloxyphenyl)propꢀ2ꢀenoate (8e) (1.25 g, 4.54 mmol). Purification by column
chromatography (diethyl ether/petroleum ether, 1:2) gave (2E)ꢀ3ꢀ(5'ꢀnitroꢀ2'ꢀpropargyloxyphenyl)propꢀ
2
1
1
6
ꢀenꢀ1ꢀol (9e) (1.02 g, 96%) as a white solid. Mp 92–93 °C; R = 0.16 (diethyl ether/petroleum ether =
f
−
1 1
:1); IR (neat) 3299, 2917, 1584, 1514, 1343, 1230, 1011, 747 cm ; H NMR (400 MHz, CDCl )
δ
3
.56 (t, J = 5.6 Hz, 1H), 2.59 (t, J = 2.4 Hz, 1H), 4.39 (td, J = 5.6, 1.7 Hz, 2H), 4.85 (d, J = 2.4 Hz, 2H),
.51 (dt, J = 16.1, 5.6 Hz, 1H), 6.92 (dt, J = 16.1, 1.7 Hz, 1H), 7.08 (d, J = 9.1 Hz, 1H), 8.15 (dd, J =
13
9.1, 2.8 Hz, 1H), 8.36 (d, J = 2.8 Hz, 1H); C NMR (101 MHz, CDCl )
δ 56.5 (CH ), 63.6 (CH ), 76.9
2 2
3
(
C), 77.1 (CH), 112.0 (CH), 122.6 (CH), 123.3 (CH), 124.2 (CH), 127.4 (C), 132.6 (CH), 142.1 (C),
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59.0 (C); MS (ESI) m/z 256 (MNa , 100); HRMS (ESI) calcd for C H NNaO (MNa ), 256.0580,
1
2
11
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
found 256.0570.
3-(2'-Propargyloxyphenyl)-3-(2'',2'',2''-trichloromethylcarbonylamino)prop-1-ene (10a). (2E)ꢀ3ꢀ
2'ꢀPropargyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (9a) (0.20 g, 1.1 mmol) was dissolved in dichloromethane (16
(
mL) and cooled to 0 °C under argon with stirring. Trichloroacetonitrile (0.16 mL, 1.6 mmol) was added
to the solution, followed by 1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene (0.08 mL, 0.54 mmol) and the reaction
mixture was allowed to warm to room temperature over 2 h. The mixture was filtered through a short
pad of alumina (neutral, Brockman V) with diethyl ether (150 mL) and concentrated in vacuo to yield
the crude allylic trichloroacetimidate as a yellow oil which was used without further purification. The
allylic trichloroacetimidate was transferred to a dry Schlenk tube containing a stirrer bar and potassium
carbonate (15 mg, 3 mg/mL) to which pꢀxylene (5 mL) was then added. The tube was purged with
argon, sealed and heated to 140 °C for 18 h. The reaction mixture was concentrated in vacuo and
purified by column chromatography (diethyl ether/petroleum ether, 1:20) to give 3ꢀ(2'ꢀ
propargyloxyphenyl)ꢀ3ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)propꢀ1ꢀene (10a) (0.33 g, 97%) as a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
white solid. Mp 46–48 °C; R = 0.72 (diethyl ether/petroleum ether = 1:1); IR (neat) 3410, 3297, 1707,
f
−
1
1
1502, 1489, 1223, 1020, 818, 751 cm ; H NMR (500 MHz, CDCl )
δ
2.53 (t, J = 2.4 Hz, 1H), 4.77
3
(d, J = 2.4 Hz, 2H), 5.16–5.26 (m, 2H), 5.56–5.65 (m, 1H), 6.06 (ddd, J = 17.1, 10.3, 5.4 Hz, 1H), 6.98–
1
3
7
.07 (m, 2H), 7.27 (dd, J = 7.7, 1.6 Hz, 1H), 7.30–7.37 (m, 1H), 7.93 (br d, J = 7.9 Hz, 1H); C NMR
(101 MHz, CDCl3)
δ
56.0 (CH), 56.0 (CH ), 76.2 (CH), 77.8 (C), 92.9 (C), 112.6 (CH), 116.1 (CH ),
2
2
1
22.1 (CH), 127.1 (C), 129.5 (CH), 129.7 (CH), 135.8 (CH), 155.1 (C), 160.8 (C); MS (EI) m/z 331
+
(M , 5), 296 (90), 260 (22), 186 (29), 171 (41), 131 (100), 114 (61), 103 (68), 77 (75); HRMS (EI) calcd
35
12
+
for C H Cl NO (M ), 330.9934, found 330.9937.
1
4
3
2
3
-(5'-Methoxy-2'-propargyloxyphenyl)-3-(2'',2'',2''-trichloromethylcarbonylamino)prop-1-ene
(10b). The reaction was carried out as described for the synthesis of 3ꢀ(2'ꢀpropargyloxyphenyl)ꢀ3ꢀ
2'',2'',2''ꢀtrichloromethylcarbonylamino)propꢀ1ꢀene (10a) using (2E)ꢀ3ꢀ(5'ꢀmethoxyꢀ2'ꢀ
(
propargyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (9b) (0.302 g, 1.38 mmol). Flash column chromatography (diethyl
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The Journal of Organic Chemistry
ether/petroleum
ether,
1:10)
gave
3ꢀ(5'ꢀmethoxyꢀ2'ꢀpropargyloxyphenyl)ꢀ3ꢀ(2'',2'',2''ꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
trichloromethylcarbonylamino)propꢀ1ꢀene (10b) (0.441 g, 88%) as a yellow oil. R = 0.43 (diethyl
f
−
1 1
ether/petroleum ether = 1:1); IR (neat) 3404, 3298, 2917, 1707, 1493, 1205, 1041, 817, 709 cm ; H
NMR (400 MHz, CDCl3) 2.51 (t, J = 2.4 Hz, 1H), 3.78 (s, 3H), 4.71 (d, J = 2.4 Hz, 2H), 5.15–5.30
δ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(m, 2H), 5.52–5.61 (m, 1H), 6.04 (ddd, J = 17.1, 10.3, 5.4 Hz, 1H), 6.78–6.87 (m, 2H), 6.92–6.99 (m,
13
1
H), 7.95 (br d, J = 8.4 Hz, 1H); C NMR (101 MHz, CDCl )
δ
55.9 (CH ), 56.2 (CH), 56.8 (CH ),
3
3
2
7
6.1 (CH), 78.2 (C), 93.1 (C), 113.9 (CH), 114.2 (CH), 115.7 (CH), 116.4 (CH ), 128.4 (C), 135.9
2
+
(CH), 149.3 (C), 154.7 (C), 161.0 (C); MS (CI) m/z 362 (MH , 33), 328 (42), 292 (10), 236 (11), 201
35
+
(100), 163 (5); HRMS (CI) calcd for C H Cl NO (MH ), 362.0118, found 362.0116.
1
5
15
3
3
3-(4'-Methoxy-2'-propargyloxyphenyl)-3-(2'',2'',2''-trichloromethylcarbonylamino)prop-1-ene
(10c). The reaction was carried out as described for the synthesis of 3ꢀ(2'ꢀpropargyloxyphenyl)ꢀ3ꢀ
(2'',2'',2''ꢀtrichloromethylcarbonylamino)propꢀ1ꢀene
(10a)
using
(2E)ꢀ3ꢀ(4'ꢀmethoxyꢀ2'ꢀ
propargyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (9c) (0.100 g, 0.459 mmol). Flash column chromatography (diethyl
ether/petroleum ether, 1:10) gave 3ꢀ(4'ꢀmethoxyꢀ2'ꢀpropargyloxyphenyl)ꢀ3ꢀ(2'',2'',2''ꢀ
trichloromethylcarbonylamino)propꢀ1ꢀene (10c) (0.142 g, 84%) as a yellow oil. R = 0.46 (diethyl
f
ether/petroleum ether = 1:1); IR (neat) 3416, 3305, 3018, 1709, 1614, 1500, 1197, 1162, 1025, 820, 751
−
1 1
cm ; H NMR (400 MHz, CDCl )
δ 2.54 (t, J = 2.4 Hz, 1H), 3.81 (s, 3H), 4.73 (d, J = 2.4 Hz, 2H),
3
5.17–5.22 (m, 2H), 5.52–5.59 (m, 1H), 6.04 (ddd, J = 17.0, 10.4, 5.3 Hz, 1H), 6.53 (dd, J = 8.4, 2.4 Hz,
13
1
H), 6.60 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.80 (br d, J = 8.3 Hz, 1H); C NMR (101 MHz,
CDCl3)
δ 55.4 (CH ), 55.5 (CH), 56.1 (CH ), 76.3 (CH), 77.7 (C), 93.0 (C), 100.6 (CH), 105.6 (CH),
3 2
1
15.8 (CH ), 119.5 (C), 130.3 (CH), 136.1 (CH), 156.1 (C), 160.8 (C), 160.8 (C); MS (ESI) m/z 384
2
+
35
+
(
MNa , 55); HRMS (ESI) calcd for C H Cl NNaO (MNa ), 383.9931, found 383.9914.
15 14 3 3
3-(5'-Chloro-2'-propargyloxyphenyl)-3-(2'',2'',2''-trichloromethylcarbonylamino)prop-1-ene
(10d). The reaction was carried out as described for the synthesis of 3ꢀ(2'ꢀpropargyloxyphenyl)ꢀ3ꢀ
(2'',2'',2''ꢀtrichloromethylcarbonylamino)propꢀ1ꢀene
(10a)
using
(2E)ꢀ3ꢀ(5'ꢀchloroꢀ2'ꢀ
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propargyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (9d) (0.10 g, 0.45 mmol). The Overman rearrangement was heated
to 140 °C for 48 h. Flash column chromatography (diethyl ether/petroleum ether, 1:10) gave 3ꢀ(5'ꢀ
chloroꢀ2'ꢀpropargyloxyphenyl)ꢀ3ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)propꢀ1ꢀene (10d) (0.16 g,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
9
8%) as a white solid. Mp 64–66 °C; R = 0.56 (diethyl ether/petroleum ether = 1:1); IR (neat) 3422,
f
−
1 1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3306, 2931, 1713, 1504, 1486, 1215, 1022, 749 cm ; H NMR (400 MHz, CDCl )
3
δ
2.54 (t, J = 2.2 Hz,
1
1
H), 4.75 (d, J = 2.2 Hz, 2H), 5.15–5.35 (m, 2H), 5.55–5.65 (m, 1H), 6.03 (ddd, J = 17.0, 10.4, 5.3 Hz,
1
3
H), 6.96 (d, J = 8.6 Hz, 1H), 7.20–7.40 (m, 2H), 7.70 (br d, J = 8.3 Hz, 1H); C NMR (101 MHz,
CDCl3)
δ
55.1 (CH), 56.4 (CH ), 76.6 (CH), 77.3 (C), 92.8 (C), 113.9 (CH), 116.8 (CH ), 127.1 (C),
2
2
+
1
28.9 (C), 129.1 (CH), 129.5 (CH), 135.0 (CH), 153.6 (C), 160.9 (C); MS (ESI) m/z 388 (MNa , 45);
35
11
+
HRMS (ESI) calcd for C H Cl NNaO (MNa ), 387.9436, found 387.9424.
1
4
4
2
3
-(5'-Nitro-2'-propargyloxyphenyl)-3-(2'',2'',2''-trichloromethylcarbonylamino)prop-1-ene
10e). The reaction was carried out as described for the synthesis of 3ꢀ(2'ꢀpropargyloxyphenyl)ꢀ3ꢀ
(2'',2'',2''ꢀtrichloromethylcarbonylamino)propꢀ1ꢀene (10a) using (2E)ꢀ3ꢀ(5'ꢀnitroꢀ2'ꢀ
(
propargyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (9e) (0.100 g, 0.429 mmol). The Overman rearrangement was
heated to 140 °C for 72 h. Flash column chromatography (diethyl ether/petroleum ether, 1:10) gave 3ꢀ
(5'ꢀnitroꢀ2'ꢀpropargyloxyphenyl)ꢀ3ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)propꢀ1ꢀene (10e) (0.155 g,
9
6%) as a white crystalline solid. Mp 140–142 °C; R = 0.30 (diethyl ether/petroleum ether = 1:1); IR
f
−
1 1
(neat) 3422, 3305, 2926, 1708, 1516, 1343, 1263, 1010, 821, 751 cm ; H NMR (400 MHz, CDCl )
δ
3
2
.60 (t, J = 2.3 Hz, 1H), 4.88 (d, J = 2.3 Hz, 2H), 5.30 (d, J = 17.1 Hz, 1H), 5.33 (d, J = 10.3 Hz, 1H),
.71–5.82 (m, 1H), 6.05 (ddd, J = 17.1, 10.3, 5.4 Hz, 1H), 7.14 (d, J = 9.0 Hz, 1H), 7.44 (br d, J = 8.3
5
1
3
Hz, 1H), 8.22 (d, J = 2.7 Hz, 1H), 8.26 (dd, J = 9.0, 2.7 Hz, 1H); C NMR (101 MHz, CDCl )
δ
54.1
3
(
CH), 56.8 (CH ), 76.5 (CH), 77.4 (C), 92.5 (C), 112.5 (CH), 117.9 (CH ), 124.7 (CH), 125.6 (CH),
2
2
+
128.6 (C), 134.2 (CH), 142.1 (C), 159.7 (C), 161.0 (C); MS (ESI) m/z 399 (MNa , 48); HRMS (ESI)
35
11
+
calcd for C H Cl N NaO (MNa ) 398.9677, found 398.9662.
1
4
3
2
4
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The Journal of Organic Chemistry
8
-[1'-(2'',2'',2''-Trichloromethylcarbonylamino)-2'-propenyl]-2H-chromene
(11a).
3ꢀ(2'ꢀ
1
2
Propargyloxyphenyl)ꢀ3ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)propꢀ1ꢀene (10a) (0.82 g, 2.5 mmol)
was dissolved in pꢀxylene (10 mL) under argon followed by
bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold(I) (2:1) toluene adduct (0.097 g, 0.062
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
[
mmol) and the mixture was heated to 80 °C for 4 h. The reaction mixture was concentrated in vacuo and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
purified by column chromatography (diethyl ether/petroleum ether, 1:15) to give 8ꢀ[1'ꢀ(2'',2'',2''ꢀ
trichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀchromene (11a) (0.82 g, 100%) as a colorless oil. R =
f
0.67 (diethyl ether/petroleum ether = 1:1); IR (neat) 3418, 2930, 1707, 1700, 1507, 1215, 821, 747
−1
1
cm ; H NMR (500 MHz, CDCl )
δ
4.86 (dd, J = 3.6, 1.9 Hz, 2H), 5.18–5.24 (m, 2H), 5.55 (ddt, J =
.2, 5.4, 1.7 Hz, 1H), 5.82 (dt, J = 9.9, 3.6 Hz, 1H), 6.03 (ddd, J = 17.1, 10.4, 5.4 Hz, 1H), 6.45 (dt, J =
.9, 1.9 Hz, 1H), 6.88 (t, J = 7.6 Hz, 1H), 6.96 (dd, J = 7.6, 1.7 Hz, 1H), 7.06 (dd, J = 7.6, 1.7 Hz, 1H),
3
8
9
7
1
3
.94 (br d, J = 8.2 Hz, 1H); C NMR (126 MHz, CDCl )
δ 55.4 (CH), 65.7 (CH ), 93.0 (C), 116.0
2
3
(CH ), 121.8 (CH), 122.0 (CH), 123.1 (C), 124.5 (CH), 125.3 (C), 126.8 (CH), 128.9 (CH), 135.9 (CH),
2
+
1
51.4 (C), 160.8 (C); MS (EI) m/z 331 (M , 24), 296 (47), 260 (22), 224 (10), 196 (7), 170 (100), 128
3
5
+
(
35), 115 (30), 77 (10); HRMS (EI) calcd for C H Cl NO (M ), 330.9934, found 330.9939.
14 12 3 2
6
-Methoxy-8-[1'-(2'',2'',2''-trichloromethylcarbonylamino)-2'-propenyl]-2H-chromene
The reaction was carried out as described for the synthesis of 8ꢀ[1'ꢀ(2'',2'',2''ꢀ
trichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀchromene (11a) using 3ꢀ(5'ꢀmethoxyꢀ2'ꢀ
(11b).
propargyloxyphenyl)ꢀ3ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)propꢀ1ꢀene (10b) (0.060 g, 0.17 mmol).
Purification by column chromatography (diethyl ether/petroleum ether, 1:15) gave 6ꢀmethoxyꢀ8ꢀ[1'ꢀ
(2'',2'',2''ꢀtrichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀchromene (11b) (0.060 g, 100%) as a
colorless oil. R = 0.60 (diethyl ether/petroleum ether = 1:1); IR (neat) 3404, 2955, 1708, 1503, 1472,
f
−1 1
1
203, 818 cm ; H NMR (400 MHz, CDCl )
δ
3.75 (s, 3H), 4.78 (dd, J = 3.6, 1.9 Hz, 2H), 5.18–5.24
3
(m, 2H), 5.49 (ddt, J = 8.6, 5.4, 1.6 Hz, 1H), 5.86 (dt, J = 9.9, 3.6 Hz, 1H), 6.01 (ddd, J = 17.1, 10.3, 5.4
Hz, 1H), 6.41 (dt, J = 9.9, 1.9 Hz, 1H), 6.53 (d, J = 2.9 Hz, 1H), 6.62 (d, J = 2.9 Hz, 1H), 8.01 (br d, J =
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1
3
8
.6 Hz, 1H); C NMR (101 MHz, CDCl ) δ 55.7 (CH ), 55.7 (CH), 65.5 (CH ), 92.9 (C), 111.9 (CH),
3 3 2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
113.9 (CH), 116.1 (CH ), 123.1 (CH), 124.1 (C), 124.6 (CH), 126.0 (C), 135.7 (CH), 145.1 (C), 154.2
2
+
(
C), 160.8 (C); MS (CI) m/z 362 (MH , 42), 328 (5), 290 (4), 243 (4), 201 (100), 85 (4); HRMS (CI)
3
15
5
+
calcd for C H Cl NO (MH ), 362.0118, found 362.0113.
1
5
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5-Methoxy-8-[1'-(2'',2'',2''-trichloromethylcarbonylamino)-2'-propenyl]-2H-chromene
The reaction was carried out as described for the synthesis of 8ꢀ[1'ꢀ(2'',2'',2''ꢀ
trichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀchromene (11a) using 3ꢀ(4'ꢀmethoxyꢀ2'ꢀ
(11c).
propargyloxyphenyl)ꢀ3ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylꢀamino)propꢀ1ꢀene (10c) (0.025 g, 0.070
mmol). Purification by column chromatography (diethyl ether/petroleum ether, 1:15) gave 5ꢀmethoxyꢀ8ꢀ
[
1'ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀchromene (11c) (0.025 g, 99%) as a
colorless oil. R = 0.53 (diethyl ether/petroleum ether = 1:1); IR (neat) 3421, 2928, 1707, 1492, 1215,
f
−
1 1
1
109, 821, 747 cm ; H NMR (400 MHz, CDCl )
δ
3.82 (s, 3H), 4.78 (dd, J = 3.6, 1.6 Hz, 2H), 5.16–
5.22 (m, 2H), 5.49 (ddt, J = 8.4, 5.3, 1.6 Hz, 1H), 5.77 (dt, J = 10.0, 3.6 Hz, 1H), 6.02 (ddd, J = 17.0,
0.4, 5.3 Hz, 1H), 6.44 (d, J = 8.6 Hz, 1H), 6.77 (dt, J = 10.0, 1.6 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H),
3
1
1
3
7.85 (br d, J = 8.4 Hz, 1H); C NMR (101 MHz, CDCl ) δ 55.3 (CH ), 55.7 (CH), 65.2 (CH ), 93.0 (C),
3 2
3
1
03.8 (CH), 112.5 (C), 115.7 (CH ), 118.2 (C), 119.4 (CH), 119.9 (CH), 129.0 (CH), 136.2 (CH), 152.1
2
+
35
(
C), 155.3 (C), 160.7 (C); MS (ESI) m/z 384 (MNa , 51); HRMS (ESI) calcd for C H Cl NNaO
15 14 3 3
+
(MNa ), 383.9931, found 383.9916.
-Chloro-8-[1'-(2'',2'',2''-trichloromethylcarbonylamino)-2'-propenyl]-2H-chromene (11d). The
reaction was carried out as described for the synthesis of 8ꢀ[1'ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)ꢀ
'ꢀpropenyl]ꢀ2Hꢀchromene (11a) using 3ꢀ(5'ꢀchloroꢀ2'ꢀpropargyloxyphenyl)ꢀ3ꢀ(2'',2'',2''ꢀ
trichloromethylcarbonylꢀamino)propꢀ1ꢀene (10d) (0.062 g, 0.17 mmol). Purification by column
chromatography (diethyl ether/petroleum ether, 1:10) gave 6ꢀchloroꢀ8ꢀ[1'ꢀ(2'',2'',2''ꢀ
trichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀchromene (11d) (0.061 g, 98%) as a white solid. Mp
6
2
6
2–64 °C; R = 0.68 (diethyl ether/petroleum ether = 1:1); IR (neat) 3418, 2927, 1713, 1504, 1466,
f
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The Journal of Organic Chemistry
−1 1
1
214, 821, 748 cm ; H NMR (400 MHz, CDCl )
δ
4.86 (dd, J = 3.6, 1.9 Hz, 2H), 5.20–5.26 (m, 2H),
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5.52 (ddt, J = 8.6, 5.3, 1.6 Hz, 1H), 5.86 (dt, J = 9.9, 3.6 Hz, 1H), 6.00 (ddd, J = 17.0, 10.4, 5.3 Hz, 1H),
6
1
.38 (dt, J = 9.9, 1.9 Hz, 1H), 6.94 (d, J = 2.5 Hz, 1H), 7.04 (d, J = 2.5 Hz, 1H), 7.72 (br d, J = 8.6 Hz,
1
3
H); C NMR (101 MHz, CDCl )
δ 54.6 (CH), 65.9 (CH ), 92.8 (C), 116.7 (CH ), 123.4 (CH), 123.6
2 2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(CH), 124.4 (C), 126.3 (CH), 126.5 (C), 127.0 (C), 128.2 (CH), 135.1 (CH), 149.9 (C), 160.8 (C); MS
+
35
+
(
ESI) m/z 388 (MNa , 42); HRMS (ESI) calcd for C H Cl NNaO (MNa ), 387.9436, found
14 11 4 2
3
87.9419.
-Nitro-8-[1'-(2'',2'',2''-trichloromethylcarbonylamino)-2'-propenyl]-2H-chromene (11e). The
reaction was carried out as described for the synthesis of 8ꢀ[1'ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)ꢀ
2'ꢀpropenyl]ꢀ2Hꢀchromene (11a) using 3ꢀ(5'ꢀnitroꢀ2'ꢀpropargyloxyphenyl)ꢀ3ꢀ(2'',2'',2''ꢀ
trichloromethylcarbonylꢀamino)propꢀ1ꢀene (10e) (0.15 g, 0.40 mmol). Purification by column
chromatography (diethyl ether/petroleum ether, 1:10) gave 6ꢀnitroꢀ8ꢀ[1'ꢀ(2'',2'',2''ꢀ
trichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀchromene (11e) (0.098 g, 66%) as a yellow solid. Mp
38–140 °C; R = 0.48 (diethyl ether/petroleum ether = 1:1); IR (neat) 3418, 2924, 1710, 1518, 1338,
6
1
f
−
1 1
1216, 837, 754 cm ; H NMR (500 MHz, CDCl )
δ
5.05 (dd, J = 3.4, 2.0 Hz, 2H), 5.28 (dd, J = 17.2,
.7 Hz, 1H), 5.33 (dd, J = 10.4, 1.7 Hz, 1H), 5.68 (ddt, J = 8.3, 5.4, 1.7 Hz, 1H), 5.93 (dt, J = 10.1, 3.4
Hz, 1H), 6.03 (ddd, J = 17.2, 10.4, 5.4 Hz, 1H), 6.47 (dt, J = 10.1, 2.0 Hz, 1H), 7.41 (br d, J = 8.3 Hz,
3
1
13
1H), 7.83 (d, J = 2.7 Hz, 1H), 8.00 (d, J = 2.7 Hz, 1H); C NMR (126 MHz, CDCl )
δ
53.5 (CH), 67.1
3
(
CH ), 92.5 (C), 117.7 (CH ), 122.0 (CH), 122.6 (C), 123.0 (CH), 123.8 (CH), 124.1 (CH), 126.5 (C),
2
2
+
134.3 (CH), 141.7 (C), 156.6 (C), 160.9 (C); MS (ESI) m/z 399 (MNa , 51); HRMS (ESI) calcd for
35
+
C H Cl N NaO (MNa ), 398.9677, found 398.9665.
14
11
3
2
4
8
-[1'-(2'',2'',2''-Trichloromethylcarbonylamino)-2'-propenyl]-2H-chromene (11a). (2E)ꢀ3ꢀ(2'ꢀ
Propargyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (9a) (0.050 g, 0.27 mmol) was dissolved in dichloromethane (4.0
mL) and cooled to 0 °C under argon with stirring. Trichloroacetonitrile (0.040 mL, 0.040 mmol) was
added to the solution, followed by 1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene (0.020 mL, 0.13 mmol) and the
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mixture was allowed to warm to room temperature over 2 h. The reaction mixture was filtered through a
short pad of alumina (neutral, Brockman V) with diethyl ether (100 mL) and concentrated in vacuo to
yield the crude allylic trichloroacetimidate as a yellow oil which was used without further purification.
The allylic trichloroacetimidate was transferred to a dry Schlenk tube containing a stirrer bar and
potassium carbonate (12 mg, 3 mg/mL) to which toluene (4 mL) was then added. The tube was purged
with argon, sealed and heated to 140 °C for 18 h. The reaction mixture was allowed to cool to room
temperature and chloro(triphenylphosphine)gold(I) (0.012 g, 0.020 mmol) and silver(I)
hexafluoroantimonate (0.006 g, 0.020 mmol) were added. The reaction mixture was heated to 80 °C for
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
h. The reaction mixture was concentrated in vacuo and purified by column chromatography (diethyl
ether/petroleum ether, 1:15) to give 8ꢀ[1'ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀ
chromene (11a) (0.069 g, 80%) as a colorless oil. Spectroscopic data was as described above.
6
-Methoxy-8-[1'-(2'',2'',2''-trichloromethylcarbonylamino)-2'-propenyl]-2H-chromene
The reaction was carried out as described for the synthesis of 8ꢀ[1'ꢀ(2'',2'',2''ꢀ
trichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀchromene (11a) using (2E)ꢀ3ꢀ(5'ꢀmethoxyꢀ2'ꢀ
(11b).
propargyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (9b) (0.10 g, 0.46 mmol), chloro(triphenylphosphine)gold(I) (0.017
g, 0.035 mmol) and silver(I) hexafluoroantimonate (0.008 g, 0.035 mmol). The hydroarylation step was
heated to 80 °C for 48 h. Purification by column chromatography (diethyl ether/petroleum ether, 1:15)
gave 6ꢀmethoxyꢀ8ꢀ[1'ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀchromene (11b) (0.15
g, 91%) as a colorless oil. Spectroscopic data was as described above.
5
-Methoxy-8-[1'-(2'',2'',2''-trichloromethylcarbonylamino)-2'-propenyl]-2H-chromene
The reaction was carried out as described for the synthesis of 8ꢀ[1'ꢀ(2'',2'',2''ꢀ
trichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀchromene (11a) using (2E)ꢀ3ꢀ(4'ꢀmethoxyꢀ2'ꢀ
(11c).
propargyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (9c) (0.10 g, 0.46 mmol), chloro(triphenylphosphine)gold(I) (0.017
g, 0.035 mmol) and silver(I) hexafluoroantimonate (0.008 g, 0.035 mmol). The hydroarylation step was
heated to 80 °C for 48 h. Purification by column chromatography (diethyl ether/petroleum ether, 1:15)
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gave 5ꢀmethoxyꢀ8ꢀ[1'ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀchromene (11c) (0.13
g, 78%) as a colorless oil. Spectroscopic data was as described above.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6-Chloro-8-[1'-(2'',2'',2''-trichloromethylcarbonylamino)-2'-propenyl]-2H-chromene (11d). The
reaction was carried out as described for the synthesis of 8ꢀ[1'ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)ꢀ
2
'ꢀpropenyl]ꢀ2Hꢀchromene (11a) using (2E)ꢀ3ꢀ(5'ꢀchloroꢀ2'ꢀpropargyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (9d)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(0.11 g, 0.47 mmol), chloro(triphenylphosphine)gold(I) (0.018 g, 0.035 mmol) and silver(I)
hexafluoroantimonate (0.009 g, 0.035 mmol). The Overman rearrangement was heated to 140 °C for 48
h. The hydroarylation step was heated to 80 °C for 48 h. Purification by column chromatography
(diethyl ether/petroleum ether, 1:15) gave 6ꢀchloroꢀ8ꢀ[1'ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)ꢀ2'ꢀ
propenyl]ꢀ2Hꢀchromene (11d) (0.13 g, 76%) as a white solid. Spectroscopic data was as described
above.
6
-Nitro-8-[1'-(2'',2'',2''-trichloromethylcarbonylamino)-2'-propenyl]-2H-chromene (11e). The
reaction was carried out as described for the synthesis of 8ꢀ[1'ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)ꢀ
2'ꢀpropenyl]ꢀ2Hꢀchromene (11a) using (2E)ꢀ3ꢀ(5'ꢀnitroꢀ2'ꢀpropargyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (9e)
(0.085 g, 0.36 mmol), chloro(triphenylphosphine)gold(I) (0.018 g, 0.036 mmol) and silver(I)
hexafluoroantimonate (0.009 g, 0.036 mmol). The Overman rearrangement was heated to 140 °C for 72
h. The isomerisation step was heated to 80 °C for 65 h. Purification by column chromatography (diethyl
ether/petroleum ether, 1:10) gave 6ꢀnitroꢀ8ꢀ[1'ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ
2Hꢀchromene (11e) (0.074 g, 54%) as a white solid. Spectroscopic data was as described above.
8
-[1'-(2'',2'',2''-Trichloromethylcarbonylamino)-2'-propenyl]-2H-chromen-2-one
(12a).
Pyridinium dichromate (0.070 g, 0.19 mmol) was added to a stirred solution of 8ꢀ[1'ꢀ(2'',2'',2''ꢀ
trichloromethylcarbonylamino)ꢀ2’ꢀpropenyl]ꢀ2Hꢀchromene (11a) (0.030 g, 0.090 mmol) in
dichloromethane (1 mL) and stirred at room temperature for 6 days. The reaction mixture was
concentrated in vacuo and purified by column chromatography (diethyl ether/petroleum ether, 1:1) to
give 8ꢀ[1'ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀchromenꢀ2ꢀone (12a) (0.020 g,
6
5%) as a white solid. Mp 136–138 °C; R = 0.13 (diethyl ether/petroleum ether = 1:1); IR (neat) 3424,
f
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−
1 1
2
926, 1711, 1604, 1505, 1117, 907, 833, 726 cm ; H NMR (400 MHz, CDCl )
δ
5.23–5.34 (m, 2H),
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5.83 (ddt, J = 8.4, 5.7, 1.6 Hz, 1H), 6.16 (ddd, J = 17.1, 10.3, 5.7 Hz, 1H), 6.44 (d, J = 9.6 Hz, 1H), 7.29
(t, J = 7.7 Hz, 1H), 7.46 (dd, J = 7.7, 1.6 Hz, 1H), 7.52 (dd, J = 7.7, 1.6 Hz, 1H), 7.73 (d, J = 9.6 Hz,
1
3
1
H), 7.80 (br d, J = 8.4 Hz, 1H); C NMR (101 MHz, CDCl ) δ 54.9 (CH), 92.5 (C), 116.8 (CH), 117.9
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
CH ), 119.4 (C), 124.6 (CH), 126.6 (C), 128.2 (CH), 131.4 (CH), 134.6 (CH), 143.7 (CH), 151.8 (C),
2
+
35
+
1
59.2 (C), 161.1 (C); MS (ESI) m/z 368 (MNa , 51); HRMS (ESI) calcd for C H Cl NNaO (MNa ),
14 10 3 3
3
67.9618, found 367.9606.
-Methoxy-8-[1'-(2'',2'',2''-trichloromethylcarbonylamino)-2'-propenyl]-2H-chromen-2-one
12b). The reaction was carried out as described for the synthesis of 8ꢀ[1'ꢀ(2'',2'',2''ꢀ
6
(
trichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀchromenꢀ2ꢀone (12a) using 6ꢀmethoxyꢀ8ꢀ[1'ꢀ(2'',2'',2''ꢀ
trichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀchromene (11b) (0.066 g, 0.18 mmol). The reaction
mixture was allowed to stir at room temperature for 4 days. Purification by column chromatography
(diethyl ether/petroleum ether, 7:3) gave 6ꢀmethoxyꢀ8ꢀ[1'ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)ꢀ2'ꢀ
propenyl]ꢀ2Hꢀchromenꢀ2ꢀone (12b) (0.042 g, 62%) as a white solid. Mp 135–138 °C; R = 0.15 (diethyl
f
ether/petroleum ether = 2:1); IR (neat) 3247, 2967, 1714, 1702, 1584, 1537, 1462, 1303, 1175, 1117,
−
1 1
9
21, 827 cm ; H NMR (500 MHz, CDCl )
δ
3.85 (s, 3H), 5.24–5.35 (m, 2H), 5.72–5.81 (m, 1H), 6.14
3
(ddd, J = 16.5, 10.5, 6.0 Hz, 1H), 6.43 (d, J = 9.6 Hz, 1H), 6.89 (d, J = 2.8 Hz, 1H), 7.10 (d, J = 2.8 Hz,
13
1H), 7.66 (d, J = 9.6 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H); C NMR (126 MHz, CDCl )
δ
55.0 (CH), 56.0
3
(
CH ), 92.6 (C), 110.3 (CH), 117.3 (CH), 118.2 (CH ), 119.0 (CH), 120.0 (C), 127.9 (C), 134.6 (CH),
3
2
+
143.6 (CH), 146.1 (C), 156.1 (C), 159.6 (C), 161.2 (C); MS (ESI) m/z 398 (MNa , 51); HRMS (ESI)
3
12
5
+
calcd for C H Cl NNaO (MNa ), 397.9724, found 397.9715.
1
5
3
4
6
-Chloro-8-[1'-(2'',2'',2''-trichloromethylcarbonylamino)-2'-propenyl]-2H-chromen-2-one (12c).
The reaction was carried out as described for the synthesis of 8ꢀ[1'ꢀ(2'',2'',2''ꢀ
trichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀchromenꢀ2ꢀone (12a) using 6ꢀchloroꢀ8ꢀ[1'ꢀ(2'',2'',2''ꢀ
trichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀchromene (11d) (0.036 g, 0.099 mmol). The reaction
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mixture was allowed to stir at room temperature for 6 days. Purification by column chromatography
diethyl ether/petroleum ether, 1:1) gave 6ꢀchloroꢀ8ꢀ[1'ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)ꢀ2'ꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
propenyl]ꢀ2Hꢀchromenꢀ2ꢀone (12c) (0.015 g, 42%) as a white solid. Mp 150–153 °C; R = 0.15 (diethyl
f
ether/petroleum ether = 1:1); IR (neat) 3322, 2945, 1726, 1704, 1598, 1573, 1512, 1222, 1174, 1122,
−
1 1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1098, 823 cm ; H NMR (400 MHz, CDCl )
3
δ
5.31 (dd, J = 17.1, 1.6 Hz, 1H), 5.35 (dd, J = 10.3, 1.6
Hz, 1H), 5.78 (ddt, J = 7.5, 5.8, 1.6 Hz, 1H), 6.14 (ddd, J = 17.1, 10.3, 5.8 Hz, 1H), 6.48 (d, J = 9.6 Hz,
1
3
1
H), 7.45 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.60–7.70 (m, 2H); C NMR (101 MHz, CDCl )
3
δ
54.5 (CH), 92.4 (C), 118.1 (CH), 118.9 (CH ), 120.6 (C), 127.4 (CH), 128.7 (C), 130.1 (C), 131.1
2
+
(
CH), 134.0 (CH), 142.6 (CH), 150.3 (C), 158.7 (C), 161.3 (C); MS (ESI) m/z 402 (MNa , 49); HRMS
3
9
5
+
(ESI) calcd for C H Cl NNaO (MNa ), 401.9229, found 401.9222.
1
4
4
3
6
-Nitro-8-[1'-(2'',2'',2''-trichloromethylcarbonylamino)-2'-propenyl]-2H-chromen-2-one (12d).
The reaction was carried out as described for the synthesis of 8ꢀ[1'ꢀ(2'',2'',2''ꢀ
trichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀchromenꢀ2ꢀone (12a) using 6ꢀnitroꢀ8ꢀ[1'ꢀ(2'',2'',2''ꢀ
trichloromethylcarbonylamino)ꢀ2'ꢀpropenyl]ꢀ2Hꢀchromene (11e) (0.038 g, 0.10 mmol). The reaction
mixture was allowed to stir at room temperature for 4 days. Purification by column chromatography
(diethyl ether/petroleum ether, 7:3) gave 6ꢀnitroꢀ8ꢀ[1'ꢀ(2'',2'',2''ꢀtrichloromethylcarbonylamino)ꢀ2'ꢀ
propenyl]ꢀ2Hꢀchromenꢀ2ꢀone (12d) (0.023 g, 58%) as a white solid. Mp 61–64 °C; R = 0.18 (diethyl
f
ether/petroleum ether = 2:1); IR (neat) 3332, 3087, 1739, 1703, 1612, 1531, 1345, 1177, 1112, 908, 822
−
1 1
cm ; H NMR (400 MHz, CDCl )
δ
5.37 (dd, J = 17.1, 1.5 Hz, 1H), 5.43 (dd, J = 10.3, 1.5 Hz, 1H),
3
5
.92 (ddt, J = 6.8, 6.0, 1.5 Hz, 1H), 6.16 (ddd, J = 17.1, 10.3, 6.0 Hz, 1H), 6.60 (d, J = 9.7 Hz, 1H), 7.49
1
3
(
d, J = 6.8 Hz, 1H), 7.81 (d, J = 9.7 Hz, 1H), 8.39 (d, J = 2.6 Hz, 1H), 8.41 (d, J = 2.6 Hz, 1H); C
NMR (126 MHz, CDCl3) 53.9 (CH), 92.2 (C), 118.9 (CH), 119.5 (C), 119.9 (CH ), 123.6 (CH), 125.3
(CH), 129.1 (C), 133.3 (CH), 142.7 (CH), 144.0 (C), 155.3 (C), 157.8 (C), 161.4 (C); MS (ESI) m/z 413
δ
2
+
35
+
(
MNa , 51); HRMS (ESI) calcd for C H Cl N NaO (MNa ), 412.9469, found 412.9459.
14 9 3 2 5
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