Wolff rearrangement of β-alkynyl-α-diazo-β-ketoesters: Light-induced acetylene-allene isomerization and its use for activation of enediynes

Article abstract of DOI:10.1002/poc.1875

Irradiation of β-phenylethynyl-α-diazo-β-ketoester with 300 or 350nm light results in efficient and regioselective Wolff rearrangement producing only the product of alkynyl group migration. Addition of alcohols to the resulting α-oxoketene yields α-phenylethynyl-β-diester, which undergoes rapid (τ<1min) tautomerization to 1,1-dicarbalkoxyallene. The latter then adds second molecule of alcohol in Michael fashion to form the final product, 2-(1-alkoxy-2-phenylvinyl)malonic ester. α-Phenylethynyl- β-ketoacid produced from the ketene in aqueous solutions does not isomerize to an allene but rather undergoes decarboxylation to give β,γ- acetylenic ester. Introduction of o-(3-hydroxy-1-propynyl) fragment in the structure of the parent α-diazo-β-ketoester allowed us to achieve two goals simultaneously: ring closure by intramolecular nucleophilic attack of propargyl alcohol on photo-generated ketene and the subsequent acetylene-allene rearrangement. The resulting enyne-allene undergoes spontaneous Myers-Saito cycloaromatization generating 1,4-biradical. In alcohol solutions, however, ketene reaction with solvent outcompetes the intramolecular process.

Full text of DOI:10.1002/poc.1875

Research Article
Received: 08 March 2011,
Revised: 13 April 2011,
Accepted: 14 April 2011,
Published online in Wiley Online Library: 21 June 2011
(wileyonlinelibrary.com) DOI 10.1002/poc.1875
Wolff rearrangement of β‐alkynyl‐α‐diazo‐β‐
ketoesters: light‐induced acetylene–allene
isomerization and its use for activation
of enediynes
Natalia G. Zhegalovaa and Vladimir V. Popika*
Irradiation of β‐phenylethynyl‐α‐diazo‐β‐ketoester with 300 or 350 nm light results in efficient and regioselec-
tive Wolff rearrangement producing only the product of alkynyl group migration. Addition of alcohols to the
resulting α‐oxoketene yields α‐phenylethynyl‐β‐diester, which undergoes rapid (τ < 1 min) tautomerization to
1,1‐dicarbalkoxyallene. The latter then adds second molecule of alcohol in Michael fashion to form the final product,
2‐(1‐alkoxy‐2‐phenylvinyl)malonic ester. α‐Phenylethynyl‐β‐ketoacid produced from the ketene in aqueous solutions
does not isomerize to an allene but rather undergoes decarboxylation to give β,γ‐acetylenic ester. Introduction of
o‐(3‐hydroxy‐1‐propynyl) fragment in the structure of the parent α‐diazo‐β‐ketoester allowed us to achieve two
goals simultaneously: ring closure by intramolecular nucleophilic attack of propargyl alcohol on photo‐generated
ketene and the subsequent acetylene–allene rearrangement. The resulting enyne–allene undergoes spontaneous
Myers–Saito cycloaromatization generating 1,4‐biradical. In alcohol solutions, however, ketene reaction with
solvent outcompetes the intramolecular process. Copyright © 2011 John Wiley & Sons, Ltd.
Keywords: acetylene–allene rearrangement; diazo compounds; Myers–Saito cyclization; photochemistry; Wolff rearrangement
rapid cycloaromatization.[25,29,30] We have developed two meth-
INTRODUCTION
ods for the photochemical activation of 10‐membered ring
The extreme cytotoxicity of natural enediyne antibiotics[1] is
attributed to the ability of the (Z)‐3‐hexene‐1,5‐diyne (en-
ediyne)[2] and (Z)‐1,2,4‐heptatrien‐6‐yne (enyne–allene)[3–5]
fragments to cyclize, producing DNA‐damaging aromatic
biradicals.[1,6–9] From a mechanistic point of view, enediyne
cycloaromatization, known as the Bergman cyclization, permits
access to the unique family of σ,σ‐1,4‐biradicals, p‐benzynes. A
similar cyclization of (Z)‐hexa‐1,2,4‐heptatrien‐6‐ynes yields
σ,π‐1,4‐biradicals (Myers–Saito cyclization).[3–5] Although natural
enediynes are very powerful dDNA‐cleaving machines, the lack
of anti‐tumor selectivity results in a very high general toxicity,
which hampers clinical applications of natural enediyne
antibiotics.[10–19] Photo‐triggering of the cycloaromatization
reaction opens the possibility for the selective treatment of
cancerous tissues in a fashion similar to photodynamic
therapy.[20–22] Our group has developed several strategies for
the photochemical activation of enediynes.[23] We have de-
signed enediyne precursors, which are stable in the dark but are
efficiently converted into reactive form upon irradiation with
UV–Vis[22–26] or near‐infrared (NIR)[27] light. However, the rate of
the Bergman cyclization of even highly strained nine‐membered
ring enediynes (τ25°C ~ 2 h)[22] is not fast enough to allow for the
spatial resolution of p‐benzyne generation in biological systems.
In order to enhance the rate of the formation of cytotoxic 1,4‐
diradicals, we turned our attention to enyne–allenes. Acyclic
enyne–allenes usually undergo spontaneous cyclization under
ambient conditions.[28] Cyclic enyne–allenes are virtually un-
known, apparently because of their ability to undergo very
enyne–allenes: unmasking of a triple bond in precursor 1[31] and
Wolff rearrangement of acetylenic α‐diazo‐β‐diketone 5[25]
(Scheme 1).
Enyne–allene 2 undergoes facile spontaneous cyclization
under ambient conditions but produces diradical intermediate
only in non‐polar solvents. In water or alcohols, it yields O–H
insertion product 4, apparently via a polar intermediate (e.g.,
3).[31] Cycloaromatization of β‐ketoester 6a proceeds via rate‐
limiting tautomerization to enyne–allene 7, which rapidly
cyclizes (τ25°C < 0.1 s) to produce 1,4‐biradical 8 even in alcohol
or aqueous solutions.[25] The complete suppression of O–H
insertion in this case is apparently explained by the destabili-
zation of the polar intermediate (analogous to 3) by electron‐
withdrawing carbonyl groups. Unfortunately, the enyne–allene
producing β‐ketoester 6a is only a minor isomer formed in
the Wolff rearrangement of α‐diazo‐β‐diketone 5. The major
β‐ketoester 6b undergoes relatively slow Bergman cyclization.[25]
We hypothesized that with proper selection of substituents at
the α‐diazo‐β‐dicarbonyl fragment, we can achieve selective
formation of the tautomerizable regioisomer of acetylenic
β‐oxoester. Because the migratory aptitude of oxygen in the
* Correspondence to: V. V. Popik, Department of Chemistry, University of
Georgia, Athens, GA 30602, USA.
E‐mail: vpopik@uga.edu
a N. G. Zhegalova, V. V. Popik
Department of Chemistry, University of Georgia, Athens, GA 30602, USA
J. Phys. Org. Chem. 2011, 24 969–975
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N. G. ZHEGALOVA AND V. V. POPIK
Scheme 1. Photochemical generation of cyclic eneyne‐allenes
photochemical Wolff rearrangment is much lower than that of
the carbon atom,[32,33] irradiation of acetylenic α‐diazo‐β‐
ketoester 10 is expected to induce exclusive or predominant
migration of alkynyl substituent to give ketene 11. It would
rapidly add alcohol‐producing β‐diester 12, which, in turn,
should isomerize into allene 13 (Scheme 2).
We also planned to explore whether nucleophilic addition
of alcohol to ketene 11 can be achieved intramolecularly for
the simultaneous cyclization of stable acyclic enediyne into a
10‐membered ring and the induction of acetylene–allene
isomerization.
(IBX) oxidation[35,36] of hydroxy group in 14 gave the target α‐
diazo‐β‐ketoester 10 in excellent yield. It is important to note
that pyridinium chlorochromate (PCC) oxidation of 14 led to
rapid decomposition of the diazo compound (Scheme 3).
Synthesis of enediyne 20
Sonogashira coupling of o‐diiodobenzene with two‐fold excess
of propargyl alcohol produced quantitative yield of diol 15.
Mono‐acylation of the latter, followed by a PCC oxidation,
gave aldehyde 17. DBU‐catalyzed coupling of 17 with ethyl
diazoacetate resulted in the formation of α‐diazo‐β‐hydroxyester
18. IBX oxidation of the hydroxy group in 18, followed by
saponification of an acetate protection, produced the target
acyclic enediyne 20 (Scheme 4).
RESULTS AND DISCUSSION
Synthesis of α‐diazo‐β‐ketoester 10
Phenylpropynal was prepared by the carbonylation of lithium
salt of phenylacetylene with dimethylformamide. Condensation
of the aldehyde with ethyl diazoacetate catalyzed by
1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) produced α‐diazo‐β‐
hydroxyester 14. The use of sodium hydride as a base for this
aldol‐type reaction, as recommended in the literature,[34] results
in significantly lower yields of the product. 2‐Iodoxybenzoic acid
Photochemical reactivity of α‐diazo‐β‐ketoester 10
The UV spectrum of 10 shows an intense absorbance band at
303 nm (log ε = 4.3), which can be assigned to the diazodicarbonyl
fragment (solid line in Fig. 1). Irradiation of the ~0.1‐mM methanol
solution of α‐diazo‐β‐ketoester 10 with 300‐nm light for 1 min
resulted in the bleaching of this band (dashed line in Fig. 1).
O
C
OEt
OR
O
OEt
C
O
OEt
OR
O
O
ROH
h
OEt
O
N2
O
O
11
13
12
10
Scheme 2. Photo‐Wolff reaction and subsequent isomerization of α‐diazo‐β‐ketoester 10.
O
OH
O
O
CHO
b
OEt
OEt
c
a
N2
N2
14
10
Scheme 3. Synthesis of α‐diazo‐β‐ketoester 10. Reagents and conditions: (a) (i) n‐BuLi, DMF, THF −78 °C; (ii) KH2PO4 0 °C; (b) N2CHCO2Et, DBU, CH3CN;
(c) IBX, DMSO
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LIGHT‐INDUCED ACETYLENE–ALLENE ISOMERIZATION
I
OAc
O
OH
OH
c
a
OAc
OH
b
I
17
15
16
d
OH
OAc
N2
OAc
N2
e
f
N2
OEt
OEt
OEt
O
O
20
18
O
O
OH
O
19
Scheme 4. Synthesis of enediyne 20. Reagents and conditions: (a) propargyl alcohol, Pd(PPh3)2Cl2, CuI, Et2NH, THF; (b) AcCl, DMAP, CH2Cl2; (c) PCC,
CH2Cl2; (d) N2CHCO2Et, DBU, CH3CN; (e) IBX, DMSO; (f) K2CO3, MeOH
The formation of 2‐phenylethynylmalonate 12a can be by-
passed altogether if proton transfer to γ‐(acetylenic) carbon is
faster than protonation of β‐(vinyl) position in 22a.
O
O
OEt
The second molecule of the solvent can, in principle, add
across the triple bond of 12a to give 21a directly. We believe
that this is highly unlikely. First of all, the inductive effect of two
carbonyl groups in propargylic position is not strong enough to
make the triple bond susceptible to nucleophilic attack. On the
other hand, electrophilic addition of methanol across the triple
bond should produce a different regioisomer. Secondly,
analogous β‐oxoacid 12b and ethyl 4‐phenyl‐3‐butynoate 23
do not react with hydroxylic solvents. The latter even withstands
aqueous acid.[40] We also do not think that addition of
alcohol occurs at the enol 22a stage because electronically
analogous enol 6a does not add solvent in aqueous, methanol,
or 2‐propanol solutions.[25] Similar products are formed when
photolyses of 10 is conducted in ethanol (21c) and 2‐propanol
(21d, Scheme 5).
Irradiation of diazo compound 10 in aqueous acetonitrile
unexpectedly produced ethyl 4‐phenyl‐3‐butynoate 23 as a
major product (Scheme 6). The same ester was obtained in the
presence of 0.1 M of benzyl azide and in aqueous dimethyl
sulfoxide (DMSO). No traces of allene 13b or allene‐derived
products were detected in the photolysates. Unisomerized ester
23 is apparently formed by the decarboxylation of β‐oxoacid
12b (Scheme 6). The thermal or photochemical decarboxylation
of 12b is a facile process: HPLC analysis of the reaction mixture
right after the photolysis shows only the presence of ester 23 in
addition to two minor products, which are stable under ambient
conditions.
N2
1.0
0.5
0.0
10
h
MeOH
O
OMe
OEt
O
OMe
21
250
300
λ /nm
350
400
Figure 1. UV spectra of ~6 × 10−5 M solutions of the α‐diazo‐β‐ketoester
10 (solid line) and the photoproduct 21a (dashed line) in methanol
High‐performance liquid chromatography (HPLC) analysis of
the photolysate confirmed complete conversion of the
diazocompound 10 into a single product. The same result was
obtained in the photolysis using 350‐nm lamps; only the full
conversion required longer time (~20 min). The mass spectrum
of the photolysis product, however, did not correspond to the
expected 13a or 12a (Scheme 2, R = Me) but indicated that loss of
nitrogen was accompanied by the addition of two solvent
molecules (MW = 278). Preparative photolysis of 10 allowed us to
isolate 1‐ethyl 3‐methyl 2‐(1‐methoxy‐2‐phenylvinyl)malonate
(21a) in 82% yield. High stability of starting α‐diazo‐β‐ketoester
10 in methanol solutions in the dark and the rearranged
skeleton of the adduct 21a indicate that it is formed upon the
Wolff rearrangement of 10. Formation of 21a is a facile process,
which is complete in less than a minute after photolysis. There
are no changes observed in the UV spectrum recorded right after
the photolysis (Fig. 1), and HPLC analysis of the photolysate
shows no changes in the composition of the reaction mixture
with time.
Exclusive formation of 12b in the presence of water
apparently suggests that α‐alkynyl‐β‐dicarbonyl compounds
12 are kinetic products in tautomerization of 22. α‐Alkynyl‐
β‐oxoester 12a isomerizes into a thermodynamically more
stable 13a, whereas the decarboxylation of 12b prevents its
isomerization.
Photolyses of enediyne 20
Efficient isomerization of α‐alkynyl‐β‐oxoesters 12 into allenes
13 permits the use of photo‐Wolff reaction for the generation of
enyne–allenes. The photochemically triggered acetylene–allene
isomerization can be coupled with intramolecular addition of
alcohol to ketene moiety in the intermediate 24 to provide a
strategy for simultaneous ring closure and tautomerization
producing very reactive cyclic enyne–allenes, such as 29
(Scheme 7).
α‐Oxoketene 11 formed upon loss of nitrogen and migration
of alkynyl group is expected to react very rapidly with the
solvent (104–105 s−1 [37–39]
producing enol 22. Such α‐oxoenol
)
compounds usually ketonize to β‐dicarbonyl tautomer at
somewhat slower pace (100–102 s−1).[37–39] Diester 12a under-
goes tautomerization to allene 13a, which then apparently
reacts with methanol to yield the final product 21a (Scheme 5).
J. Phys. Org. Chem. 2011, 24 969–975
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N. G. ZHEGALOVA AND V. V. POPIK
O
OEt
OR
O
OEt
C
O
O
O
OEt
OR
OH
ROH
h
OEt
O
O
N2
12
11
22
OR
OEt
10
O
OEt
OR
O
R= (a) Me, (b) H, (c) Et, (d) i-Pr
C
O
O
OR
13
21
Scheme 5. Photolyis of α‐diazo‐β‐ketoester 10 in alcohols
O
OEt
O
OEt
OH
OH
CO2Et
h
H2O
CO2H
11
10
23
12b
22b
Scheme 6. Photolyis of α‐diazo‐β‐ketoester 10 in aqueous solutions
Scheme 7. Photolysis of enediyne 20 in 2‐propanol and aqueous solutions
The UV spectrum and photochemical reactivity of enediyne
20 are very similar to that of 10. One minute of 300‐nm
irradiation of ~0.1‐mM 2‐propanol solution of diazo compound
20 results in complete consumption of the starting material.
Only a single product 27 can be detected in the reaction mixture
by chromatographic analysis. This compound is apparently
formed by the sequential addition of two molecules of 2‐
propanol to ketene 24 (Scheme 7). This observation indicates
that intramolecular addition of propargylic alcohol to ketene
moiety is slower than the nucleophilic attack of the solvent
molecules. Results of the photolyses in non‐hydroxylic solvents
support this conclusion. After 1 min exposure of a tetrahydro-
furan (THF or THF/hexane) solution of 20 to 300‐nm light,
analysis of the reaction mixture confirms the formation of
naphthalene derivative 30 as the major product (~65–70%).
Lactone 30 is an apparent product of the Myers–Saito cyclization
of the intermediate enyne–allene 29.
rearrangement. Addition of alcohols to the resulting α‐oxoketenes
gives α‐alkynyl‐β‐diesters, which undergo rapid isomerization to
1,1‐dicarbalkoxyallene. Intramolecular version of this reaction
allowed us to achieve two goals in one step: cyclization of acyclic
enediyne, which is accomplished by the reaction between hydroxy
and ketene groups, and isomerization of relatively stable enediyne
into very reactive enyne–allene. Although this strategy works well
in non‐polar solvents, in hydroxylic solvents, the nucleophilic
addition of solvent molecules outcompetes the intramolecular
ketene reaction. We are currently exploring two approaches to the
solution of this problem: replacement of the hydroxy group with
more nucleophilic thiol or/and using steric compression to
enhance the rate of intramolecular reaction.
EXPERIMENTAL SECTION
General methods
All organic solvents were dried and freshly distilled before use.
All oxygen‐sensitive and moisture‐sensitive reactions were
carried out under an inert atmosphere in the oven‐dried
glassware. Solvents for moisture‐sensitive reactions were dis-
tilled prior to usage. Flash chromatography was performed using
40–63‐µm silica gel. All NMR spectra were recorded in CDCl3
CONCLUSIONS
We have demonstrated that photochemical reaction of β‐
alkynyl‐α‐diazo‐β‐ketoesters is regioselective, producing only the
product of the migration of alkynyl group in the Wolff
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LIGHT‐INDUCED ACETYLENE–ALLENE ISOMERIZATION
and referenced to tetramethylsilane unless otherwise noted.
Photolyses of diazo compounds 10 and 20 were conducted at
ambient temperatures using mini‐Rayonet photochemical reac-
tor equipped with eight fluorescent UV lamps (4 W, 300 or
350 nm) in quartz cuvettes (for HPLC/gas chromatography–mass
spectrometry (GC/MS) analyses) or tubular flow system (prepar-
ative irradiation). Reaction mixtures after photolysis were
analyzed by HPLC and GC/MS using pure substrates as
references. In the case of preparative photolyses, reaction
mixtures were separated on a silica gel; pure compounds were
characterized by NMR, GC/MS, and high‐resolution mass
spectrometry (HRMS) analyses.
120.00, 85.52, 76.72, 61.80, 14.41. DIP/MS: 242 (M+, 25), 214 (3),
142 (25), 129 (100), 114 (37), 101 (13). High res. EI‐HRMS: Found
242.0693, Calc. 242.0691.
o‐Bis(3‐hydroxy‐1‐propynyl)benzene (15)
Bis(triphenylphosphine)palladium dichloride (1 g, 1.4 mmol) was
added to a stirred solution of o‐diiodobenzene (5 g, 15.2 mmol)
in dry degassed THF (100 mL) under inert atmosphere. The
solution was degassed with a flow of argon, and powdered
copper(I) iodide (6 mol%, 17.3 mg, 0.91 mmol) was added to the
mixture. After 5 min of stirring, propargyl alcohol (3.4 g,
60.6 mmol, 3.5 mL) was added to the mixture, followed by
diethyl amine (10 mL). The reaction vessel was purged with
argon, sealed, and left with overnight stirring at r.t. Another two
equivalents of propargyl alcohol and 5 mL of diethyl amine were
added to the reaction mixture. After two more days of stirring,
the reaction mixture was filtered through a 3‐cm layer of silica gel
(5% ethyl acetate in hexanes); fractions containing the desired
product were combined, and solvents were evaporated under
reduced pressure. The crude product was purified by column
chromatography (30% to 50% of ethyl acetate in hexanes to 30%
of ethyl acetate in dichloromethane) yielding 2.82 g (quant.) of
15[41] as yellowish oil. 1H NMR: 7.40–7.38 (dd, J1 = 3.4 Hz,
J2 = 5.6 Hz, 2H), 7.25–7.23 (dd, J1 = 3.4 Hz, J2 = 5.6 Hz, 2H), 4.54
(s, 4H), 4.05 (br s, 2H). 13C NMR: 131.59, 128.28, 125.59, 92.01,
84.43, 51.65. DIP/MS: 186 (M+, 9), 168 (10), 139 (100), 128 (34),
115 (24), 102 (6), 89 (11).
Materials
All commercially available materials were purchased from VWR
or Sigma‐Aldrich and used as received unless otherwise stated.
Ethyl 2‐diazo‐3‐hydroxy‐5‐phenylpent‐4‐ynoate (14)
n‐Butyllithium (1.13 mL, 1.8 mmol, 1.6 M in hexane) was added to
a stirred solution of phenylacetylene (186 mg, 1.8 mmol) in 5 mL
of THF at −78 °C under nitrogen atmosphere, followed by a
dropwise addition of dimethylformamide (263 mg, 3.6 mmol,
0.28 mL) over 10 min. The reaction mixture was warmed to room
temperature (r.t.), stirred for 30 min at the temperature, and then
poured into a mixture of 5 mL of diethyl ether and 10 mL of 10%
aqueous KH2PO4 pre‐cooled to 0 °C. The reaction mixture was
stirred at 0 °C for 30 min, warmed up to r.t., organic layers were
separated, and aqueous phase was washed with ether. The
combined organic layers were dried over magnesium sulfate,
and solvents were evaporated under reduced pressure to give
234 mg of crude 3‐phenylpropiolaldehyde, which was used in
the next reaction without further purification because of its
instability.
1,8‐Diazabicyclo[5.4.0]undec‐7‐ene (54 μL, 0.36 mmol) and a
solution of 3‐phenylpropioaldehyde (234 g, 1.8 mmol) in anhy-
drous CH3CN (3 mL) were added to a solution of ethyl
diazoacetate (0.23 mL, 2.16 mmol) in anhydrous CH3CN (7 mL).
The reaction mixture was stirred overnight at r.t. and then
concentrated in vacuum. The residue was purified chromatog-
raphy (10% to 30% of ethyl acetate in hexanes) to give 200 mg
(46% over two steps) of ethyl 2‐diazo‐3‐hydroxy‐5‐phenylpent‐
4‐ynoate (14) as yellow oil. 1H NMR: 7.46–7.44 (m, 2H), 7.33–7.31
(m, 3H), 5.76 (s, 1H), 4.32–4.26 (q, J = 7 Hz, 2H), 1.68 (br s, 1H),
1.33–1.30 (t, J = 7 Hz, 3H). IR spectrum: 3412, 2981, 2098, 1668,
1490. DIP/MS: 216 (M+–N2, 18), 200 (6), 188 (9), 171 (16), 151
(36), 137 (15), 129 (100), 114 (32), 102 (34).
1‐(3‐Acetoxypropynyl)‐2‐(3‐hydroxypropynyl)benzene (16)
Acetyl chloride (1.07 μL, 15.1 mmol) was added to a solution of
15 (2.8 g, 15.1 mmol) in dichloromethane (100 mL), followed by
4‐dimethylaminopyridine (310 mg). The reaction mixture was
left with stirring at r.t., the solvent was evaporated, and the
residue purified by column chromatography (10% to 30% of
ethyl acetate in hexanes) to give 1.57 g (46%) of 16 as brownish
oil and 1.28 g of the diacetate by‐product. 1H NMR: 7.45–7.41
(m, 2H), 7.31–7.25 (m, 2H), 4.93 (s, 2H), 4.54 (s, 2H), 2.96 (br s, 1H),
2.15 (s, 3H). 13C NMR: 171.25, 132.22, 131.81, 128.84, 128.28,
126.19, 124.93, 92.32, 87.07, 85.01, 83.95, 53.29, 51.77, 21.15. MS:
228 (M+, 2), 210 (6), 195 (8), 168 (36), 139 (100), 127 (10), 115
(21), 91 (40).
Ethyl 5‐(2‐(3‐acetoxyprop‐1‐ynyl)phenyl)‐2‐diazo‐3‐hydoxypent‐
4‐ynoate (18)
Pyridinium chlorochromate (1.6g, 7.2mmol) was added to a
stirred suspension of celite in a solution of 16 (1.1 g, 4.8 mmol) in
dichloromethane (60 mL) at r.t. Three hours later, the reaction
mixture was filtered through a 3‐cm layer of silica gel with 1:1
ethyl acetate/hexanes as eluant. The solvents were evaporated
under reduced pressure producing 1.08 g of crude 3‐(2‐
(3‐acetoxyprop‐1‐ynyl)phenylpropiolaldehyde) (17), which was
not further purified but immediately introduced into the next
reaction.
A solution of DBU (143 μL, 0.96 mmol) and 17 (1.08 g, 4.8 mmol)
in anhydrous CH3CN (10 mL) were added to a solution of ethyl
diazoacetate (0.608 mL, 5.76 mmol) in anhydrous CH3CN (40 mL).
The reaction mixture was stirred overnight at r.t. and then
concentrated in vacuum. The residue was purified by column
chromatography (20% to 40% of ethyl acetate in hexanes)
producing 0.78 g (46% over two steps) of 18 as yellowish oil.
Ethyl 2‐diazo‐3‐oxo‐5‐phenylpent‐4‐ynoate (10)
A solution of 14 (200 mg, 0.82 mmol) in DMSO (3 mL) was added
to a solution of IBX (344 mg, 1.23 mmol) in DMSO (5 mL), and the
mixture was stirred for 3 h at r.t. The reaction mixture was
poured into water (20 mL) and extracted with dichloromethane
(2 × 20 mL). The combined organic layers were dried over
sodium sulfate and concentrated under reduced pressure. The
residue was purified by flash chromatography (15% to 20% of
ethyl acetate in hexanes) yielding 163 mg (82%) of pure ethyl
1
2‐diazo‐3‐oxo‐5‐phenylpent‐4‐ynoate (10) as yellow crystals. H
NMR: 7.65–7.64 (d, J = 7.2 Hz, 2H), 7.49–7.45 (m, 1H), 7.42–7.38
(t, J = 7.2 Hz, 2H), 4.40–4.34 (q, J = 7 Hz, 2H), 1.38–1.34 (t, J = 7 Hz,
3H). 13C NMR: 180.7, 160.02, 133.07, 130.96, 128.64, 128.35,
J. Phys. Org. Chem. 2011, 24 969–975
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N. G. ZHEGALOVA AND V. V. POPIK
1H NMR: 7.47–7.43 (m, 2H), 7.32–7.27 (m, 2H), 5.76–5.74 (d, J=6.4 Hz,
1H), 4.97–4.89 (m, 2H), 4.32–4.26 (m, 2H), 3.91 (br s, 1H), 2.14
(s, 3H), 1.33–1.30 (t, J= 7Hz, 3H). 13C NMR: 171.30, 165.41, 132.39,
132.20, 128.85, 125.14, 125.08, 88.72, 87.44, 85.18, 84.79, 61.55,
58.85, 53.34, 21.05, 14.68. DIP/MS: 312 (M+‐N2, 13), 270 (22), 241
(35), 224 (32), 197 (16), 181 (45), 167 (23), 155 (37), 139 (47), 127
(58), 115 (37), 86 (40), 61 (69), 45 (100). IR (neat, cm−1): 3447,
2984, 2359, 2342, 2099, 1744, 1689, 1558, 1481, 1442.
126.48, 104.30, 61.82, 55.64, 53.86, 52.79, 14.02. MS: 278 (M+, 53),
219 (7), 205 (9), 174 (37), 159 (12), 145 (100), 131 (39), 115 (34),
103 (45). ESI‐HRMS: Found 279.1233, Calc.(M + H+) 279.1227.
In CH3CN: A solution of diazo compound 10 (20 mg, 0.083 mmol)
in 200 mL of aqueous acetonitrile was irradiated as described
earlier. The solvent was evaporated under reduced pressure,
and the residue was separated by column chromatography
(10% to 30% of ethyl acetate in hexanes) affording 9.4 mg
(61%) of ethyl 4‐phenylbut‐3‐ynoate (23).[42] 1H NMR: 7.46–7.43
(m, 2H), 7.31–7.29 (m, 3H), 4.25–4.21 (q, J = 7.2 Hz, 2H), 3.51 (s, 2H),
1.33–1.29 (t, J = 7.2 Hz, 3H). MS: 188 (M+, 21), 160 (7), 144 (5), 115
(100), 89 (12). EI‐HRMS: Found 188.0833, Calc. 188.0837.
Ethyl 5‐(2‐(3‐acetoxyprop‐1‐ynyl)phenyl)‐2‐diazo‐3‐oxopent‐
4‐ynoate (19)
A solution of 18 (0.78 g, 2.3 mmol) in DMSO (3 mL) was added to
a solution of IBX (966 mg, 3.45 mmol) in DMSO (7 mL) and stirred
for 5 h. The reaction mixture was poured into water (20 mL) and
extracted with dichloromethane (2 × 20 mL). Combined organic
layers were dried over sodium sulfate and concentrated under
reduced pressure. The residue was purified by column
chromatography (20% of ethyl acetate in hexanes) to yield
718 mg (93%) of 19 as yellowish oil. 1H NMR: 7.66–7.64 (d, J = 7.8,
1H), 7.53–7.51 (d, J = 7.8, 1H), 7.43–7.34 (m, 2H), 4.99 (s, 2H), 4.38–
Photolysis of ethyl 2‐diazo‐5‐(2‐(3‐hydroxyprop‐1‐yn‐1‐yl)
phenyl)‐3‐oxopent‐4‐ynoate (20)
Approximately 0.1‐mM solution of 20 was irradiated for 1 min
using 300‐nm lamps. UV spectrum of photolysate and HPLC
analysis showed the complete consumption of the starting
material. The composition of the reaction mixture was analyzed
using HPLC and GC/MS.
4.33 (q, J = 7.2 Hz, 2H), 2.14 (s, 3H), 1.37–1.33 (t, J = 7.2 Hz, 2H). 13
C
NMR: 180.67, 170.50, 160.11, 133.88, 132.74, 130.70, 128.83,
126.25, 122.94, 88.80, 88.52, 84.11, 62.02, 53.08, 20.97, 14.56. DIP/
MS: 338 (M+, 5), 281 (53), 240 (34), 222 (18), 211 (30), 194 (20),
183 (46), 150 (100), 139 (91), 127 (48), 115 (15). IR (neat,
cm−1):2984, 2207, 2133, 1724, 1669, 1600, 1481, 1442.
1‐Ethyl 3‐isopropyl 2‐(2‐(2‐(3‐hydroxyprop‐1‐yn‐1‐yl)phenyl)‐
1‐isopropoxyvinyl) malonate (27)
MS: 388 (M+, 16), 346 (13), 328 (25), 286 (7), 279 (24), 241 (15),
223 (26), 197 (20), 169 (45), 149 (89), 141 (39), 115 (73), 70 (67),
57 (58), 45 (100).
Ethyl 2‐diazo‐5‐(2‐(3‐hydroxyprop‐1‐ynyl)phenyl)‐3‐oxopent‐
4‐ynoate (20)
Ethyl 3‐oxo‐3,4‐dihydro‐1 H‐benzo[g]isochromene‐4‐carboxylate (30)
Potassium carbonate (15.2 mg, 0.11 mmol) was added to a
solution of 19 (37.7 mg, 0.11 mmol), in aqueous methanol (5 mL),
stirred for 5 min, and poured into a mixture of 10% of aqueous
KH2PO4 and diethyl ether. After 15 min of vigorous stirring,
layers were separated, and the aqueous layer was extracted with
ether. Combined organic layers were dried over sodium sulfate,
solvents were removed under reduced pressure, and the residue
was purified by column chromatography (10% to 30% of ethyl
acetate in hexanes) to give 17 mg (76%) of pure 20 and 12 mg
(31%) of starting acetate 19. 1H NMR: 7.67 (d, J = 7.2 Hz, 1H),
7.48–7.40 (m, 2H), 7.36–7.32 (m, 1H), 4.54 (s, 2H), 4.38–4.33 (q,
J = 7.2 Hz, 2H), 1.76 (br s, 1H), 1.39–1.35 (t, J = 7.2 Hz, 3H). 13C
NMR: 160.64, 154.92, 133.04, 131.95, 130.28, 128.36, 127.92,
122.76, 93.97, 89.09, 85.82, 83.51, 62.29, 53.17, 14.46. DIP/MS: 296
(M+, 1), 268 (1), 239 (12), 211 (16), 196 (10), 183 (23), 168 (21),
150 (30), 139 (100), 127 (67), 115 (20).
MS: 270 (M+, 7), 243 (20), 229 (12), 213 (11), 197 (41), 169 (44),
157 (32), 141 (36), 128 (37), 115 (10), 71 (100).
Acknowledgement
The authors thank the Georgia Cancer Coalition for the support
of this project.
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