Intramolecular trapping of allenylzincs by carbonyl groups

Article abstract of DOI:10.1021/jo4022293

Allenylzinc formed via oxygen-promoted zinc/iodine exchange between propargyl iodides and diethylzinc can be trapped by intramolecular reaction with various electrophiles such as aldehydes, ketones, esters, carbamates, and imides. Potentially useful build

Full text of DOI:10.1021/jo4022293

Article
pubs.acs.org/joc
Intramolecular Trapping of Allenylzincs by Carbonyl Groups
Suribabu Jammi, Julien Maury, Jean-Simon Suppo, Michele P. Bertrand,* and Laurence Feray*
̀
́
Aix-Marseille Universite, CNRS, Institut de Chimie Radicalaire UMR 7273, Equipe CMO, 13397 Cedex 20 Marseille, France
S
* Supporting Information
ABSTRACT: Allenylzinc formed via oxygen-promoted zinc/
iodine exchange between propargyl iodides and diethylzinc can
be trapped by intramolecular reaction with various electrophiles
such as aldehydes, ketones, esters, carbamates, and imides.
Potentially useful building blocks were obtained in high yields.
Scheme 1. Reactivity of aldehyde 1b, and ketones 3a,b and 5
INTRODUCTION
■
The reaction of allenylmetals with different types of electro-
philes has widely been investigated.1 Whereas examples of intra-
molecular reactions are documented in the case of allenylsilanes,
allenylstannanes,1c,2 and allenylindium,3 little is known about
the intramolecular trapping of nucleophilic allenylzinc re-
agents.1c,d Our interest in reactions involving oxygen-promoted
zinc/iodine exchange and in subsequent tandem radical/polar
reactions,4,5 recently led us to investigate the mechanism of
formation of allenylzincs from propargyl iodides and dieth-
ylzinc.6,7 Our attention was focused on the reactivity of chelated
allenylzinc species with regard to carbonyl groups.7
In the continuity of these studies, the reactivity of structurally
related allenylzincs bearing an internal electrophilic partner
was explored. We report herein, the results of intramolecular
trapping of allenylzincs with classical partners such as aldehydes
and ketones. Acylation was observed when using esters and
carbamates, which are not usual electrophilic partners for
organozinc compounds. This reactivity was exploited in tandem
processes for the synthesis of more complex structures.
The metallotropic exchange between allenyl and propargyl
zinc species was shown to be rather fast with respect to
bimolecular nucleophilic addition to carbonyl groups.7 It is
largely admitted that allenylation proceeds through a six-
membered transition state involving the propargylzinc tautomer
(SE2′). The structures of the starting iodides can easily
accommodate such formally polycyclic transition structures.
The behavior of esters 7a and 7b was more interesting since
esters are not commonly used as electrophilic partners for
organozinc reagents (Scheme 2). Ester 7a led exclusively to
ketone 8a when the reaction was performed in the presence of
more than a 5-fold excess of diethylzinc. Conversely when only
1.5 equiv of diethylzinc was used, 7a led to aldol 9a which was
isolated after workup as a single diastereomer in 48% yield.
(The yield was calculated with respect to 7a; 8a was formed in
trace amount according to the 1H NMR spectrum of the crude
mixture.)
RESULTS AND DISCUSSION
■
The reactivity of aldehyde 1b and ketones 3a,b was investigated
first. As expected, the corresponding cyclic secondary (2b)
and tertiary (4a,b) allenyl alcohols were isolated in high yields
(Scheme 1). All reactions were performed at room temper-
ature, under argon atmosphere, but in nondegassed dichloro-
methane, so that a free radical zinc/iodine exchange could be
promoted.6,7 As discussed later on in Scheme 3, the allenylzinc
formed in this process evolved through regioselective
nucleophilic addition to the carbonyl group. It is worth noting
that substrates bearing a more flexible aliphatic substrate like
ketone 5 behaved similarly (Scheme 1). This outcome is very
similar to the outcome of related allenylindiums.3
As shown in Scheme 3, in all likelihood, ketone 12a results
from the displacement of ethylzinc methoxide from the fastly
Received: October 7, 2013
Published: November 19, 2013
© 2013 American Chemical Society
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Scheme 2. Reactivity of esters 7a,b and 10
Scheme 4. In-mediated reactions
No cyclization was observed when iodide 7b was reacted with
In(0). Allene 13b was isolated as the only product in 50% yield
(Scheme 4).
The absence of nucleophilic reactivity of the intermediate
allenylindium with regard to the ester carbonyl group might be
considered as surprising since the C−In bond should be more
polar than the C−Zn bond according to the Pauling electro-
negativity scale (1.78 for In; 1.65 for Zn), but the protic
medium is likely to be responsible for this anomalous reactivity.
Conversely, even in the presence of AcOH, the allenylindium
derived from ketone 3b led to alcohol 4b in 57% yield (Scheme 4).
Zinc Barbier reactions should lead to similar results. They were
not investigated because these reactions are typically performed
in aqueous medium in the presence of NH4Cl.12
These results emphasize that esters react far slower than
aldehydes with allenyl metals. The absence of cyclization products
when 7a and 7b were reacted with Et2Zn in the presence of
2 equiv of benzaldehyde is consistent with this statement.7
In order to delineate the scope and limitation of these cycliza-
tion processes regarding the nature of electrophilic carbonyl
groups that could be used as internal traps for allenylzinc
reactive intermediates, the series of substrates was completed
with carbamates 16a−c and imide 24. The results are reported
in Schemes 5, 6 and 8.
interconverting intermediates B and C. Owing to the reactivity
of the conjugated allenyl moiety, ketone 12a cannot be isolated,
and the reaction with another equivalent of diethylzinc generates
E. In nondegassed medium, the mechanism rather proceeds via
ethyl radical addition followed by homolytic substitution at zinc.
Direct nucleophilic conjugate addition of diethylzinc, which is
not represented for the sake of clarity, cannot be excluded.
Enolate E is protonated upon workup to give 8a when the
reaction is performed in the presence of a large excess of
diethylzinc. When only 1.5 equiv is used, 12a is not rapidly
consumed by the assumed ethyl radical addition, and enolate E
adds to 12a to give the dimeric product 9a via conjugate addition
followed by intramolecular aldol condensation.
No dimer was formed in the reaction of ester 7b with
diethylzinc under the same experimental conditions, as if the
conjugated allene 12b was a better radical acceptor than 12a
(Scheme 3).8 Ketone 8b was isolated as the only product in
85% (the yield was optimized by increasing the amount of
Et2Zn up to 2 equiv) (Scheme 2). Ester 10 reacted similarly
to give ketone 11 in quantitative yield according to the same
mechanism (Scheme 2).9
Bis-carbamate 16a was electrophilic enough to undergo
nucleophilic substitution by the corresponding intermediate
allenylzinc. It led to lactam 17 in quantitative yield in the
presence of a 5-fold excess of Et2Zn (Scheme 5).13
The comparative reactivity of carbamate 16b deserves being
discussed. No cyclization was observed. This behavior might be
rationalized as follows:
The exclusive formation of the E- isomer10 might result from
the fast equilibration between the zinc enolate and its chelated
tautomer possessing a carbon−zinc bond.11
− Zinc/iodine exchange should be fast in all cases. In the
case of 16b, subsequent intramolecular proton transfer
from the NH group would prevent further cyclization
and explain the formation of 18 and 19 after hydrolysis.
It is worth noting that the behavior of the intermediate
allenylmetal derivative is specific to its mode of formation.
Scheme 3. Mechanistic proposal for the formation of 9a from 7a
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Scheme 5. Reactivity of carbamates 16a,b
Scheme 7. Mechanistic proposal for the formation of 22
and 23
of intermediate I on iodide 16c (or its conjugated base) via
SN2′ mechanism.
Scheme 6. Reactivity of carbamate 16c
Eventually, intramolecular addition to the carbonyl group of
the imide function in 24 was achieved. It led to the one pot
formation of product 25 in 89% yield. The latter possesses the
skeleton of tetrahydroisoquinolinone alkaloids (Scheme 8).17
Scheme 8. Reactivity of imide 24
The activation of intramolecular transfer upon chelation
was recently discussed in the reaction of diethylzinc with
silazanes.14
CONCLUSION
■
In summary, the intramolecular trapping of allenylzincs by
electrophilic carbonyl groups was shown to open a route to a
large variety of polycyclic scaffolds ranging from bicyclic allenyl
alcohols, to bicyclic conjugated ketones, up to tetracyclic
alkaloids. Owing to the great reactivity of conjugated allenes
in nondegassed medium, cascade radical/polar reactions are
plausible pathways. The trapping by carbamates, which are not
currently used as electrophilic partners for organozinc
derivatives, strongly depends on the presence and the position
of acidic protons on the nitrogen atom of the carbamoyl group.
These preliminary results delineate how the various parameters
can influence the outcome of the reaction. Further inves-
tigations will be reported in due course. Simple phthalimido
derivatives were shown to provide a very simple route to
tetrahydroisoquinoline alkaloids scaffolds.
− The formation of a mixture of homopropargyl alcohol 20
and allenyl alcohol 21 in the presence of benzaldehyde
proved that the expected allenylzinc was formed in the
medium. Thus, proton migration is necessarily slower
than intermolecular addition of the metalated species to
benzaldehyde.
− In the absence of benzaldehyde, no cyclized product
was detected from 16b, even after waiting 14h before
quenching the reaction. This means that even if de-
protonation is not operative, the electrophilicity of the
carbamate unit cannot be compared to that of the
carboxylate.
Carbamate 16c presents a different chemoselectivity. In the
presence of an excess of diethylzinc, indole 22 was formed
as the only product (Scheme 6).15 When only 1.5 equiv of
diethylzinc was used, the consumption of the starting material was
slow enough to enable the formation of the spiranic dimer 23.
A possible rationale for the formation of products 22 and 23
is depicted in Scheme 7. Substrate 16c is more acidic than
its homologue 16b. Internal proton transfer would generate
intermediate H. Subsequent nucleophilic addition of the
metalated carbamate onto the allene16 would lead to the
nucleophilic indolic species I which itself would give 22 after
hydrolysis, when the reaction is performed in the presence of a
large excess of diethylzinc. In the presence of only 1.5 equiv of
diethylzinc, the consumption of iodide 16c would be slowed
down, and product 23 would originate from nucleophilic attack
EXPERIMENTAL SECTION
■
General. Commercially available dichloromethane (synthesis
grade - stabilized with ethanol 0.1−0.4% m/m) was stored on molecular
sieves and used without further purification. The commercially available
diethylzinc solutions were 1 M in heptane. Analytical thin layer
1
chromatography was performed on precoated silica gel plates. H and
13C NMR spectra were recorded at 400 MHz (1H) and 100 MHz (13C)
using CDCl3 as the solvent. Chemical shifts (δ) are reported in ppm.
Signals of the residual protonated solvent or of the deuterated solvent
served as the internal standard to calibrate the spectra (1H NMR,
CHCl3, 7.26 ppm; 13C NMR, CDCl3, 77.16 ppm). Multiplicity is
indicated by one or more of the following: s (singlet), d (doublet),
t (triplet), q (quartet), quint (quintet), hept (heptuplet), m (multiplet),
br (broad). The J values are given in Hz. High resolution MS
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experiments were performed with a mass spectrometer equipped with an
electrospray ionization source operated in the positive ion mode. In this
hybrid instrument, ions were measured using an orthogonal acceleration
time-of-flight mass analyzer.
Synthesis of Substrates. 3-(2-(3-Iodoprop-1-ynyl)phenyl)-
propanal (1b). To a solution of 3-(2-iodophenyl)propanal 1i (1 g,
11.16 mmol, 1.5 equiv), and iodine (2.82 g, 11.16 mmol, 1.5 equiv).
The reaction mixture was stirred at 0 °C and monitored by TLC.
After completion, the excess of iodine was removed by washing with
sat. aqueous Na2S2O3, and the organic layer was dried over MgSO4,
filtered, and concentrated in vacuo. The residue was quickly purified
through flash column chromatography using pentane/diethylether
1
(9/1) as the eluent to give 3a as a yellow oil (quantitative). H NMR
(400 MHz, CDCl3) δ: 2.15 (s, 3H), 3.81 (s, 2H), 3.90 (s, 2H), 7.09−
7.26 (m, 3H), 7.37 (d, J = 7.3, 1H). 13C NMR (100 MHz, CDCl3) δ:
−17.8 (CH2), 29.8 (CH3), 49.3 (CH2), 83.9 (C), 90.5 (C), 122.7
(C), 127.2 (CH), 129.1 (CH), 130.1 (CH), 132.2 (CH),
137.2 (C), 205.7 (CO). HRMS (ESI): m/z: calcd for [MNa]+
C12H11INaO+: 320.9747; found: 320.9746.
3.84 mmol, 1 equiv) in dry tetrahydrofuran/triethylamine (20/10 mL),
was added Pd(PPh3)4 (0.132 g, 0.115 mmol, 0.03 equiv) followed by
CuI (0.043 g, 0.23 mmol, 0.06 equiv) and propargyl alcohol (0.645 g,
11.52 mmol, 3 equiv), under argon atmosphere. The solution was
stirred at 40 °C, and the reaction was monitored by TLC. After
completion, the reaction mixture was concentrated in vacuo, and the
crude residue was dissolved in diethylether and filtered through a short
pad of silica gel column chromatography using diethylether as the
eluent. The filtrate was concentrated to obtain the residue containing
3-(2-(3-hydroxyprop-1-ynyl)phenyl)propanal 1j (0.70 g, 61%). To a
light-protected solution (covered with an aluminum foil) of residue
containing 3-(2-(3-hydroxyprop-1-ynyl)phenyl)propanal (0.70 g,
2.34 mmol, 1 equiv) in dry CH2Cl2 (20 mL) under argon atmosphere
at 0 °C were added imidazole (0.239 g, 3.52 mmol, 1.5 equiv), tri-
phenylphosphine (0.393 g, 3.52 mmol, 1.5 equiv), and iodine (0.379 g,
3.52 mmol, 1.5 equiv). The reaction mixture was stirred at 0 °C and
monitored by TLC. After completion, the excess of iodine was removed
by washing with sat. aqueous Na2S2O3, and the organic layer was dried
over MgSO4, filtered, and concentrated in vacuo. The residue was
quickly purified through flash column chromatography using pentane/
diethylether (9/1) as the eluent to give 1b as a yellow oil (0.40 g, 58%).
1H NMR (400 MHz, CDCl3) δ: 2.74 (t, J = 7.5, 2H), 3.00 (t, J = 7.5,
4-(2-(3-Iodoprop-1-ynyl)phenyl)butan-2-one (3b). 4-(2-(3-Hy-
droxyprop-1-ynyl)phenyl)butan-2-one (3j). To a solution of
4-(2-iodophenyl)butan-2-one 3i (2.2 g, 8 mmol, 1 equiv) in dry
tetrahydrofuran/triethylamine (40/20 mL), was added Pd(PPh3)4
(0.277 g, 0.24 mmol, 0.03 equiv) followed by CuI (0.091 g, 0.48
mmol, 0.06 equiv) and propargyl alcohol (1.344 g, 24 mmol, 3 equiv),
under argon atmosphere. The solution was stirred at 40 °C, and the
reaction was monitored by TLC. After completion, the reaction
mixture was concentrated in vacuo, and the crude residue was purified
through flash column chromatography using pentane/diethylether
(1/1) as the eluent, to give the title product as a yellow oil (1.4 g,
1
88%). H NMR (400 MHz, CDCl3) δ: 2.16 (s, 3H), 2.79 (t, J = 7.5,
2H), 2.82−2.99 (br s, 1H), 3.04 (t, J = 7.5, 2H), 4.52 (s, 2H), 7.12−
7.27 (m, 3H), 7.40 (d, J = 7.5, 1H). 13C NMR (100 MHz, CDCl3) δ:
28.9 (CH2), 30.1 (CH3), 44.2 (CH2), 51.5 (CH2), 83.8 (C), 91.9
(C), 122.1 (C), 126.3 (CH), 128.7 (CH), 128.8 (CH),
132.4 (CH), 143.1 (C), 209.1 (CO). HRMS (ESI): m/z: calcd
2H), 3.90 (s, 2H), 7.05−7.20 (m, 3H), 7.31 (d, J = 7.5, 1H), 9.77 (t, J =
1.3, 1H). 13C NMR (100 MHz, CDCl3) δ: −17.4 (CH2), 27.2 (CH2),
44.6 (CH2), 83.9 (C), 90.5 (C), 121.9 (C), 126.5 (CH),
129.1 (2×CH), 123.5 (CH), 143.0 (C), 201.7 (HCO).
HRMS (ESI): m/z: calcd for [M + Na]+ C12H11OINa+: 320.9747;
found: 320.9745.
+
for [MNa]+ C13H14NaO2 : 225.0885; found: 225.0886.
4-(2-(3-Iodoprop-1-ynyl)phenyl)butan-2-one (3b). To a light-
protected solution (covered with an aluminum foil) of 4-(2-(3-
hydroxyprop-1-ynyl)phenyl)butan-2-one (1.36 g, 6.73 mmol, 1 equiv)
in dry CH2Cl2 under argon atmosphere at 0 °C were added imidazole
(0.686 g, 10.09 mmol, 1.5 equiv), triphenylphosphine (2.64 g, 10.09
mmol, 1.5 equiv), and iodine (2.55 g, 10.09 mmol, 1.5 equiv). The
reaction mixture was stirred at 0 °C and monitored by TLC. After
completion, the excess of iodine was removed by washing with sat.
aqueous Na2S2O3, and the organic layer was dried over MgSO4,
filtered, and concentrated in vacuo. The residue was quickly purified
through flash column chromatography using pentane/diethylether
(9/1) as the eluent to give the title product as a yellow oil (quantitative).
1H NMR (400 MHz, CDCl3) δ: 2.20 (s, 3H), 2.82 (t, J = 7.5, 2H), 3.04
(t, J = 7.3, 2H), 4.01 (s, 2H), 7.14−7.28 (m, 3H), 7.40 (d, J = 7.5, 1H).
13C NMR (100 MHz, CDCl3) δ: −17.2 (CH2), 28.7 (CH2), 30.2
1-(2-(3-Iodoprop-1-ynyl)phenyl)propan-2-one (3a). 1-(2-(3-Hy-
droxyprop-1-ynyl)phenyl)propan-2-one (3j). To a solution of
1-(2-iodophenyl)propan-2-one (2.2 g, 8.49 mmol, 1 equiv) in dry
tetrahydrofuran/triethylamine (60/30 mL), was added Pd(PPh3)4
(0.293 g, 0.25 mmol, 0.03 equiv) followed by CuI (0.096 g, 0.50
mmol, 0.06 equiv) and propargyl alcohol (1.42 g, 25.5 mmol, 3 equiv),
under argon atmosphere. The solution was stirred at 40 °C, and the
reaction was monitored by TLC. After completion, the reaction
mixture was concentrated in vacuo, and the crude residue was purified
through flash column chromatography using pentane/diethylether
(1/1) as the eluent, to obtain the product as a yellow oil (1.4 g, 87%).
1H NMR (400 MHz, CDCl3) δ: 2.08 (s, 3H), 2.97−3.31 (br s, 1H),
3.78 (s, 2H), 4.39 (s, 2H), 7.09−7.24 (m, 3H), 7.36 (d, J = 7.5, 1H).
13C NMR (100 MHz, CDCl3) δ: 29.5 (CH3), 49.7 (CH2), 51.2 (CH2),
83.5 (C), 92.4 (C), 123.0 (C), 127.2 (CH), 128.8 (CH),
130.1 (CH), 132.3 (CH), 136.7 (C), 207.2 (CO). HRMS
(CH3), 44.5 (CH2), 84.1 (C), 90.2 (C), 121.8 (C), 126.2 (
CH), 129.0 (CH), 129.1 (CH), 132.4 (CH), 143.6 (C),
207.9 (CO). HRMS (ESI): m/z: calcd for [MH]+ C13H14IO+:
313.0084; found: 313.0082.
9-Iodonon-7-yn-2-one (5). 9-(Tetrahydro-2H-pyran-2-yloxy)non-
7-yn-2-one (5i). A mixture of 2-(6-iodohex-2-ynyloxy)tetrahydro-2H-
+
(ESI): m/z: calcd for [MNa]+ C12H12NaO2 : 211.0730; found:
211.0729.
1-(2-(3-Iodoprop-1-ynyl)phenyl)propan-2-one (3a). To a light-
protected solution (covered with an aluminum foil) of 1-(2-(3-
hydroxyprop-1-ynyl)phenyl)propan-2-one (1.3 g, 7.44 mmol, 1 equiv)
in dry CH2Cl2 (50 mL) under argon atmosphere at 0 °C, were added
imidazole (0.75 g, 11.16 mmol, 1.5 equiv), triphenylphosphine (2.92 g,
pyran 5h (5 g, 16.2 mmol, 1 equiv), pentane-2,4-dione (1.78 g, 17.8
mmol, 1.1 equiv), potassium carbonate (2.45 g, 17.8 mmol, 1.1 equiv),
and ethanol (50 mL) was heated at reflux for 24 h. Ethanol was
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evaporated, and the residue was dissolved in dichloromethane and
washed with water. The combined organic layers were dried over
MgSO4 and filtered, and the filtrate was concentrated under vacuo.
The residue was purified through flash column chromatography with
pentane/Et2O (1/1 mixture) to give the title compound as a colorless
dry CH2Cl2 (15 mL) under argon atmosphere at 0 °C, were added
imidazole (0.25 g, 3.69 mmol, 1.2 equiv), triphenylphosphine (0.96 g,
3.69 mmol, 1.2 equiv), and iodine (0.93 g, 3.69 mmol, 1.2 equiv). The
reaction mixture was stirred at 0 °C and monitored by TLC. After 2 h,
the excess of iodine was removed by washing with sat. aqueous
Na2S2O3, and the organic layer was dried over MgSO4, filtered, and
concentrated in vacuo. The residue was quickly purified through flash
column chromatography using pentane/diethylether (4/1) as the
1
liquid (3.0 g, 80%). H NMR (400 MHz, CDCl3) δ: 1.45−1.89 (m,
10H), 2.13 (s, 3H), 2.19−2.26 (m, 2H), 2.43 (t, J = 7.3, 2H), 3.46−
3.56 (m, 1H), 3.77−3.89 (m, 1H), 4.23 (AB pattern, J = 15.3, Δυ = 35,
2H), 4.78 (t, J = 3.2, 1H). 13C NMR (100 MHz, CDCl3) δ: 18.8
(CH2), 19.2 (CH2), 23.1 (CH2), 25.5 (CH2), 28.1 (CH2), 30.0 (CH3),
30.4 (CH2), 43.3 (CH2), 54.7 (CH2), 62.1 (CH2), 76.33 (C), 86.1
(C), 96.8 (CH), 208.8 (CO). HRMS (ESI): m/z: calcd for
1
eluent to give 7a as a yellow oil (0.75 g, 80%). H NMR (400 MHz,
CDCl3) δ: 3.73 (s, 3H), 3.82 (s, 2H), 3.97 (s, 2H), 7.32−7.21 (m,
3H), 7.43 (d, J = 7.5, 1H). 13C NMR (100 MHz, CDCl3) δ: −17.8
(CH2), 39.8 (CH2), 52.3 (CH3), 83.6 (C), 90.8 (C), 122.9
(C), 127.3 (CH), 129.1 (CH), 130.0 (CH), 132.4 (CH),
136.7 (C), 171.6 (OC). HRMS (ESI): m/z: calcd for [MH]+
+
[MNH4]+ C14H26NO3 : 256.1907; found: 256.1906.
9-Hydroxynon-7-yn-2-one (5j). To a solution of 9-(tetrahydro-2H-
pyran-2-yloxy)non-7-yn-2-one 5i (1.4 g, 5.88 mmol, 1 equiv) in ethanol
(50 mL) was slowly added pyridinium p-toluenesulfonate (1.47 g,
5.88 mmol, 1 equiv) at room temperature over 30 min. After addition
completion, the reaction mixture was heated at 50 °C for 12 h. Ethanol
was evaporated, and the residue was purified through flash column
chromatography to give the title product as a colorless liquid (0.74 g,
82%). 1H NMR (400 MHz, CDCl3) δ: 1.50 (quint, J = 7.0, 2H), 1.67
(quint, J = 7.2, 2H), 1.79−1.95 (br s, 1H), 2.13 (s, 3H), 2.18−2.27 (m,
2H), 2.44 (t, J = 7.3, 2H), 4.23 (s, 2H). 13C NMR (100 MHz, CDCl3)
δ: 18.7 (CH2), 23.0 (CH2), 28.1 (CH2), 30.0 (CH3), 43.2 (CH2), 51.4
(CH2), 79.0 (C), 85.9 (C), 209.0 (CO). HRMS (ESI): m/z:
calcd for [MNa]+ C9H14NaO2+: 177.0886; found: 177.0886.
9-Iodonon-7-yn-2-one (5). To a light-protected solution (covered
with an aluminum foil) of 9-hydroxynon-7-yn-2-one (0.74 g, 4.8 mmol,
1 equiv) in dry CH2Cl2 (50 mL) under argon atmosphere at 0 °C, were
added imidazole (0.489 g, 7.2 mmol, 1.5 equiv), triphenylphosphine
(1.88 g, 7.2 mmol, 1.5 equiv), and iodine (1.82 g, 7.2 mmol, 1.5 equiv).
The reaction mixture was stirred at 0 °C and monitored by TLC. After
completion, the excess of iodine was removed by washing with sat.
aqueous Na2S2O3, and the organic layer was dried over MgSO4, filtered,
and concentrated in vacuo. The residue was quickly purified through
flash column chromatography using pentane/diethylether (4/1) as the
eluent to give the title product as a yellow oil (quantitative). 1H NMR
(400 MHz, CDCl3) δ: 1.45−1.52 (m, 2H), 1.62−1.69 (m, 2H), 2.13 (s,
3H), 2.18−2.22 (m, 2H), 2.44 (t, J = 7.3, 2H), 3.68 (t, J = 2.3, 2H). 13C
NMR (100 MHz, CDCl3) δ: −16.8 (CH2), 19.1 (CH2), 23.0 (CH2),
27.9 (CH2), 30.0 (CH3), 43.2 (CH2), 77.6 (C), 86.2 (C), 208.2
(CO). HRMS (ESI): m/z: calcd for [M + H]+ C9H14IO+: 265.0084;
found: 265.0084.
+
C12H12IO2 : 314.9877; found: 314.9871.
Methyl 3-(2-(3-Iodoprop-1-ynyl)phenyl)propanoate (7b). Methyl
3-(2-(3-Hydroxyprop-1-ynyl)phenyl)propanoate (7l). To a solution
of methyl 3-(2-iodophenyl)propanoate 7k (1.20 g, 4.13 mmol,
1 equiv) in dry tetrahydrofuran/triethylamine (20/10 mL), was
added Pd(PPh3)4 (0.147 g, 0.123 mmol, 0.03 equiv) followed by CuI
(0.047 g, 0.247 mmol, 0.06 equiv) and propargyl alcohol (0.68 g, 12.39
mmol, 3 equiv), under argon atmosphere. The solution was stirred
at 40 °C, and the reaction was monitored by TLC. After completion,
the reaction mixture was concentrated in vacuo, and the crude residue
was purified through flash column chromatography using pentane/
diethylether (1/1) as the eluent, to obtain the title product as a yellow
1
oil (0.820 g, 91%). H NMR (400 MHz, CDCl3) δ: 2.20 (br s, 1H),
2.66 (t, J = 8.0, 2H), 3.10 (t, J = 7.8, 2H), 3.68 (s, 3H), 4.52 (s, 2H),
7.27−7.15 (m, 3H), 7.40 (d, J = 7.5, 1H). 13C NMR (100 MHz,
CDCl3) δ: 30.3 (CH2), 35.0 (CH2), 51.7 (CH2), 51.9 (CH3), 83.9
(C), 92.0 (C), 122.2 (C), 126.5 (CH), 128.8 (CH),
128.9 (CH), 132.3 (CH), 142.7 (C), 174.0 (OC). HRMS
+
(ESI): m/z: calcd for [MNH4]+ C13H18NO3 : 236.1281; found:
236.1281.
Methyl 3-(2-(3-Iodoprop-1-ynyl)phenyl)propanoate (7b). To a
light-protected solution (covered with an aluminum foil) of methyl
3-(2-(3-hydroxyprop-1-ynyl)phenyl)propanoate (0.80 g, 3.66 mmol,
1 equiv) in dry CH2Cl2 (15 mL) under argon atmosphere at 0 °C,
were added imidazole (0.37 g, 5.50 mmol, 1.5 equiv), triphenylphos-
phine (1.40 g, 5.50 mmol, 1.5 equiv), and iodine (1.40 g, 5.50 mmol,
1.5 equiv). The reaction mixture was stirred at 0 °C and monitored by
TLC. After 2 h, the excess of iodine was removed by washing with sat.
aqueous Na2S2O3, and the organic layer was dried over MgSO4,
filtered, and concentrated in vacuo. The residue was quickly purified
through flash column chromatography using pentane/diethylether
(4/1) as the eluent to give the title product as a yellow oil (0.75 g,
Methyl 2-(2-(3-Iodoprop-1-ynyl)phenyl)acetate (7a). Methyl 2-(2-
(3-Hydroxyprop-1-ynyl)phenyl)acetate (7j). To a solution of methyl
1
2-(2-iodophenyl)acetate 7i (1 g, 3.63 mmol, 1 equiv) in dry
tetrahydrofuran/triethylamine (20/10 mL), was added Pd(PPh3)4
(0.125 g, 0.108 mmol, 0.03 equiv) followed by CuI (0.041 g, 0.217
mmol, 0.06 equiv) and propargyl alcohol (0.6 g, 10.89 mmol, 3 equiv),
under argon atmosphere. The solution was stirred at 40 °C, and the
reaction was monitored by TLC. After completion, the reaction
mixture was concentrated in vacuo, and the crude residue was purified
through flash column chromatography using pentane/diethylether (1/1)
as the eluent, to obtain the title product as a yellow oil (0.650 g, 87%).
1H NMR (400 MHz, CDCl3) δ: 1.94 (br s, 1H), 3.70 (s, 3H), 3.82 (s,
2H), 4.49 (s, 2H), 7.32−7.21 (m, 3H), 7.43 (d, J = 7.5, 1H). 13C NMR
(100 MHz, CDCl3) δ: 40.3 (CH2), 51.7 (CH2), 52.3 (CH3), 83.9
(C), 92.4 (C), 123.0 (C), 127.3 (CH), 128.9 (CH), 130.0
(CH), 132.1 (CH), 136.5 (C), 172.1 (OC). HRMS (ESI):
m/z: calcd for [MNH4]+ C12H16NO3+: 222.1125; found: 222.1125.
Methyl 2-(2-(3-Iodoprop-1-ynyl)phenyl)acetate (7a). To a light-
protected solution (covered with an aluminum foil) of methyl 2-(2-(3-
hydroxyprop-1-ynyl)phenyl)acetate (0.63 g, 3.08 mmol, 1 equiv) in
56%). H NMR (400 MHz, CDCl3) δ: 2.68 (t, J = 8.3, 2H), 3.08 (t,
J = 7.5, 2H), 3.68 (s, 3H), 3.99 (s, 2H), 7.27−7.14 (m, 3H), 7.39 (d,
J = 7.8, 1H). 13C NMR (100 MHz, CDCl3) δ: −17.4 (CH2), 29.9
(CH2), 34.9 (CH2), 51.8 (CH3), 83.9 (C), 90.4 (C), 122.0
(C), 126.5 (CH), 129.0 (CH), 129.1 (CH), 132.5 (CH),
143.1 (C), 173.4 (OC). HRMS (ESI): m/z: calcd for [MH]+
+
C13H14IO2 : 329.0033; found: 329.0025.
Ethyl [2-(3-Iodoprop-1-yn-1-yl)phenyl]methyl Carbonate (10).
Ethyl (2-Iodophenyl)methyl carbonate:18 1H NMR (400 MHz,
CDCl3) δ: 1.31 (3H, t, J = 7.0), 4.28 (2H, q, J = 7.0), 4.70 (2H, s),
6.69−6.81 (2H, m), 7.23−7.36 (1H, m), 7.78−7.85 (1H, m).
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13C NMR (100 MHz, CDCl3) δ: 14.3 (CH3), 61.6 (CH2), 66.6 (CH2),
86.6 (C), 112.6 (CH), 123.7 (CH), 129.5 (CH), 140.0
(CH), 156.9 (C), 168.4 (CO).
in dry CH2Cl2 (60 mL) under argon atmosphere at 0 °C were added
imidazole (1.60 g, 22.80 mmol, 2 equiv), triphenylphosphine (6 g,
22.80 mmol, 2 equiv), and iodine (5.75 g, 22.80 mmol, 2 equiv). The
reaction mixture was stirred at 0 °C during 1 h. After completion, the
excess of iodine was removed by washing with sat. aqueous Na2S2O3,
and the organic layer was dried over MgSO4, filtered, and concentrated
in vacuo. After purification by flash chromatography on silica gel
(pentane/AcOEt from 100/0 to 90/10), 14 was isolated (3 g, 92%).
1H NMR (400 MHz, CDCl3) δ: 3.47 (s, 3H), 4.00 (s, 2H), 4.61 (s,
2H), 7.23 (dt, J = 1.0, 7.5, 1H), 7.34 (dt, J = 1.3, 7.5, 1H), 7.42 (m,
2H). 13C NMR (100 MHz, CDCl3) δ: −17.5 (CH2), 58.7 (CH3), 72.6
(CH2), 83.3 (C), 90.7 (C), 121.2 (C), 127.4 (CH), 127.7
(CH), 129.0 (CH), 132.2 (CH), 140.7 (C). HRMS: Calcd
for C11H15INO (MNH4)+ 304.0192, Found 304.0192.
Ethyl [2-(3-Hydroxyprop-1-yn-1-yl)phenyl]methyl Carbonate
(10j). To a solution of ethyl (2-iodophenyl)methyl carbonate 10i
(2 g, 4.23 mmol, 1 equiv) in dry tetrahydrofuran/triethylamine
(30/30 mL), was added Pd(PPh3)4 (196 mg, 0.17 mmol, 0.04 equiv)
followed by CuI (65 mg, 0.34 mmol, 0.08 equiv) and propargyl alcohol
(0.94 mL, 12.7 mmol, 3 equiv), under argon atmosphere. The solution
was stirred at 40 °C during 2 h. After completion, the layers were
separated, and the aqueous layer was extracted twice with CH2Cl2.
The combined organic phases were dried over MgSO4, filtered, and
concentrated in vacuo. After purification by flash chromatography
on silica gel (pentane/Et2O from 100/0 to 60/40) ethyl [2-(3-
hydroxyprop-1-yn-1-yl)phenyl]methyl carbonate was isolated as a
Ethyl N-(Ethoxycarbonyl)-N-{[2-(3-iodoprop-1-yn-1-yl)phenyl]-
1
methyl}carbamate (16a). Ethyl N-(Ethoxycarbonyl)carbamate:19
solid (333 mg, 34%). Mp (°C) = 61.7−62.7. H NMR (400 MHz,
CDCl3) δ: 1.29 (3H, t, J = 7.0), 2.21 (1H, br s), 4.26 (2H, q, J = 7.0),
4.52 (2H, s), 4.69 (2H, s), 6.72−6.80 (1H, m), 6.92−6.99 (1H, m),
7.22−7.30 (1H, m), 7.38−7.46 (1H, m). 13C NMR (100 MHz,
CDCl3) δ: 14.3 (CH3), 51.9 (CH2), 61.6 (CH2), 66.3 (CH2), 81.7
(C), 92.2 (C), 112.7 (CH), 112.9 (C), 121.8 (CH),
129.9 (CH), 133.9 (CH), 158.6 (C), 168.9 (CO). HRMS
+
(ESI): m/z: calcd for [MNa+] C13H14NaO4 : 257.0784; found:
257.0783.
1H NMR (400 MHz, CDCl3) δ: 1.29 (6H, t, J = 7.0), 4.23 (4H, q, J =
Ethyl [2-(3-Iodoprop-1-yn-1-yl)phenyl]methyl Carbonate (10).
To a light-protected solution (covered with an aluminum foil) of
ethyl [2-(3-hydroxyprop-1-yn-1-yl)phenyl]methyl carbonate (290 mg,
1.24 mmol, 1 equiv) in dry CH2Cl2 (8.5 mL) under argon atmosphere
at 0 °C were added imidazole (101 mg, 1.49 mmol, 1.2 equiv), tri-
phenylphosphine (390 mg, 1.49 mmol, 1.2 equiv), and iodine (377 mg,
1.49 mmol, 1.2 equiv). The reaction mixture was stirred at 0 °C during
1 h. After completion, the excess of iodine was removed by washing
with sat. aqueous Na2S2O3, and the organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. After purification by flash
chromatography on silica gel (pentane/AcOEt from 100/0 to 90/10),
ethyl [2-(3-iodoprop-1-yn-1-yl)phenyl]methyl carbonate was isolated
(290 mg, 59%). 1H NMR (400 MHz, CDCl3) δ: 1.30 (3H, t, J = 7.0),
4.01 (2H, s), 4.27 (2H, q, J = 7.0), 4.70 (2H, s), 6.71−6.80 (1H, m),
6.91−7.01 (1H, m), 7.19−7.30 (1H, m), 7.37−7.44 (1H, m). 13C NMR
(100 MHz, CDCl3) δ: −16.9 (CH2), 14.3 (CH3), 61.6 (CH2), 66.5
(CH2), 81.5 (C), 90.8 (C), 112.6 (C), 113.0 (CH), 121.9
(CH), 130.1 (CH), 134.1 (CH), 158.8 (C), 168.8 (CO).
HRMS (ESI): m/z: calcd for [MNH4]+ C13H17INO3+: 362.0248;
found: 362.0250.
7.0), 4.50−4.74 (1H, br s).
Ethyl N-(Ethoxycarbonyl)-N-[(2-iodophenyl)methyl]carbamate
(16i). To a solution of 2-iodobenzyl alcohol (2.9 g, 12.4 mmol,
1 equiv) and triphenylphosphine (3.6 g, 13.64 mmol, 1.1 equiv) in dry
THF (206 mL) was added ethyl N-(ethoxycarbonyl)carbamate (2 g,
12.4 mmol, 1 equiv). The reaction mixture was cooled to 0 °C, and
DEAD (2.5 mL, 13.64 mmol, 1.1 equiv) was added dropwise. The
mixture was stirred for 18 h. The organic layer was diluted with ether
and successively washed with water and brine. The ethereal layer was
dried over MgSO4, filtered, and concenterd under reduced pressure.
After purification by flash chromatography on silica gel (pentane/
AcOEt from 100/0 to 50/50), N-(ethoxycarbonyl)-N-[(2-iodophenyl)-
methyl]carbamate was isolated as an oil (1.5 g, 55%). 1H NMR
(400 MHz, CDCl3) δ: 1.25 (6H, t, J = 7.0), 4.25 (4H, q, J = 7.0), 4.88
(2H, s), 6.90−6.98 (1H, m), 7.03−7.10 (1H, m), 7.27−7.33 (1H, m),
7.80−7.86 (1H, m). 13C NMR (100 MHz, CDCl3) δ: 14.3 (CH3), 54.9
(CH2), 63.5 (CH2), 97.3 (C), 126.1 (CH), 128.5 (CH), 128.8
(CH), 139.5 (CH), 139.6 (C), 153.6 (CO). HRMS (ESI):
m/z: calcd for [MH+] C13H17INO4+: 378.0197; found: 378.0197.
Ethyl N-(Ethoxycarbonyl)-N-{[2-(3-hydroxyprop-1-yn-1-yl)-
phenyl]methyl}carbamate (16j). To a solution of ethyl
N-(ethoxycarbonyl)-N-[(2-iodophenyl)methyl]carbamate (2.5 g, 6.02
mmol, 1 equiv) in dry tetrahydrofuran/triethylamine (29:29 mL) was
added Pd(PPh3)4 (280 mg, 0.24 mmol, 0.04 equiv) followed by CuI
(92 mg, 0.48 mmol, 0.08 equiv) and propargyl alcohol (1.3 mL, 18.1
mmol, 3 equiv), under argon atmosphere. The solution was stirred at
40 °C during 2 h. After completion, the layers were separated and the
aqueous layer was extracted twice with CH2Cl2. The combined organic
phases were dried over MgSO4, filtered, and concentrated in vacuo.
After purification by flash chromatography on silica gel (pentane/
AcOEt from 100/0 to 50/50) ethyl N-(ethoxycarbonyl)-N-{[2-(3-
hydroxyprop-1-yn-1-yl)phenyl]methyl}carbamate was isolated as a
solid (1.5 g, 82%). Mp (°C) = 74.0−74.2. 1H NMR (400 MHz,
CDCl3) δ: 1.25 (6H, t, J = 7.3), 4.25 (4H, q, J = 7.3), 4.33 (1H, s),
4.50 (2H, s), 5.07 (2H, s), 7.16−7.31 (3H, m), 7.39−7.45 (1H, m).
13C NMR (100 MHz, CDCl3) δ: 14.3 (CH3), 48.6 (CH2), 51.8 (CH2),
1-(3-Iodoprop-1-ynyl)-2-(methoxymethyl)benzene (14). 3-(2-
(Methoxymethyl)phenyl)prop-2-yn-1-ol (14j). To a solution of
1-iodo-2-(methoxymethyl)benzene (3.20 g, 13.00 mmol, 1 equiv) in
dry tetrahydrofuran/triethylamine (60/30 mL) was added Pd(PPh3)4
(0.45 g, 0.39 mmol, 0.03 equiv) followed by CuI (0.15 g, 0.78 mmol,
0.06 equiv) and propargyl alcohol (2.18 g, 39.00 mmol, 3 equiv),
under argon atmosphere. The solution was stirred at 40 °C, and the
reaction was monitored by TLC. After completion, the reaction mixture
was concentrated in vacuo, and the crude residue was purified through
flash column chromatography using pentane/diethylether (1/1) as the
eluent, to obtain the title product as a yellow oil (2 g, 88%). 1H NMR
(400 MHz, CDCl3) δ: 2.41 (br s, 1H), 3.43 (s, 3H), 4.52 (d, J = 5, 2H),
4.62 (s, 2H), 7.24 (t, J = 7.5, 1H), 7.33 (t, J = 7.5, 1H), 7.43 (m, 2H).
13C NMR (100 MHz, CDCl3) δ: 51.7 (CH2), 58.5 (CH3), 72.8 (CH2),
83.3 (C), 92.0 (C), 121.5 (C), 127.5 (CH), 127.8 (CH),
128.8 (CH), 132.4 (CH), 140.0 (C). HRMS: Calcd for
63.4 (CH2), 83.4 (C), 92.5 (C), 121.0 (C), 126.5 (CH),
127.1 (CH), 128.8 (CH), 132.6 (CH), 139.5 (C), 154.0
+
(CO). HRMS (ESI): m/z: calcd for [MNa+] C16H19NNaO5 :
328.1155; found: 328.1155.
Ethyl N-(Ethoxycarbonyl)-N-{[2-(3-iodoprop-1-yn-1-yl)phenyl]-
methyl}carbamate (16a). To a light-protected solution (covered
with an aluminum foil) of ethyl N-(ethoxycarbonyl)-N-{[2-(3-
hydroxyprop-1-yn-1-yl)phenyl]methyl} carbamate (1.5 g, 4.91 mmol,
1 equiv) in dry CH2Cl2 (33 mL) under argon atmosphere at 0 °C were
added imidazole (400 mg, 5.90 mmol, 1.2 equiv), triphenylphosphine
+
C11H12O2Na (MNa)+ 199.0729, Found 199.0729.
1-(3-Iodoprop-1-ynyl)-2-(methoxymethyl)benzene (14). To a
light-protected solution (covered with an aluminum foil) of 3-(2-
(methoxymethyl)phenyl)prop-2-yn-1-ol (2.00 g, 11.36 mmol, 1 equiv)
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+
(1.55 g, 5.90 mmol, 1.2 equiv), and iodine (1.50 g, 5.90 mmol, 1.2 equiv).
The reaction mixture was stirred at 0 °C during 1 h. After completion,
the excess of iodine was removed by washing with sat. aqueous Na2S2O3,
and the organic layer was dried over MgSO4, filtered, and concentrated in
vacuo. After purification by flash chromatography on silica gel (pentane/
AcOEt from 100/0 to 80/20), ethyl N-(ethoxycarbonyl)-N-{[2-(3-
iodoprop-1-yn-1-yl)phenyl]methyl}carbamate was isolated as a solid
157.2 (CO). HRMS (ESI): m/z: calcd for [MH+] C12H13INO2 :
329.9985; found: 329.9984.
Methyl N-[2-(3-Iodoprop-1-yn-1-yl)phenyl]carbamate (16c).
Methyl N-[2-Iodophenyl]carbamate (16m):21 1H NMR (400 MHz,
1
(1 g, 49%). Mp (°C) = 39−40. H NMR (400 MHz, CDCl3) δ: 1.26
(6H, t, J = 7.3), 4.00 (2H, s), 4.25 (4H, q, J = 7.3), 5.06 (2H, s), 7.11−
7.43 (4H, m). 13C NMR (100 MHz, CDCl3) δ: −17.7 (CH2), 14.3
(CH3), 48.0 (CH2), 63.4 (CH2), 83.1 (C), 91.3 (C), 120.8 (C),
125.4 (CH), 126.9 (CH), 129.1 (CH), 132.4 (CH), 140.2
(C), 153.8 (CO). HRMS (ESI): m/z: calcd for [MH+]
C16H19INO4+: 416.0353; found: 416.0354.
CDCl3) δ: 3.81 (3H, s), 6.72 (1H, dt, J = 1.5 and 7.8), 6.95 (1H, br s),
7.28 (1H, dt, J = 1.5 and 7.8), 7.75 (1H, dd, J = 1.5 and 8.0), 8.04 (1H,
d, J = 8.0). 13C NMR (100 MHz, CDCl3) δ: 52.7 (CH3), 89.0 (C),
120.4 (CH), 125.3 (CH), 129.4 (CH), 138.5 (C), 139.0
(CH), 154.0 (CO).
Methyl N-{[2-(3-Iodoprop-1-yn-1-yl)phenyl]methyl}carbamate
(16b). Methyl N-[(2-Iodophenyl)methyl]carbamate (16k).20 To a
Methyl N-[2-(3-Hydroxyprop-1-yn-1-yl)phenyl]carbamate (16n).
To a solution of methyl N-[2-iodophenyl]carbamate (1 g, 3.61 mmol,
1 equiv) in dry tetrahydrofuran/triethylamine (15/15 mL), was added
Pd(PPh3)4 (166 mg, 0.144 mmol, 0.04 equiv) followed by CuI (55 mg,
0.288 mmol, 0.08 equiv) and propargyl alcohol (0.8 mL, 10.83 mmol,
3 equiv), under argon atmosphere. The solution was stirred at 40 °C
during 2 h. After completion, the layers were separated, and the
aqueous layer was extracted twice with CH2Cl2. The combined organic
phases were dried (MgSO4), filtered, and concentrated in vacuo. After
purification by flash chromatography on silica gel (pentane/AcOEt
from 100/0 to 50/50) methyl N-[2-(3-hydroxyprop-1-yn-1-yl)phenyl]-
carbamate was isolated as an oil (650 mg, 88%). 1H NMR (400 MHz,
CDCl3) δ: 1.80 (1H, br s), 3.80 (3H, s), 4.57 (2H, s), 6.98 (1H, dt, J =
1 and 7.6), 7.31 (1H, dt, J = 1 and 7.6), 7.36 (1H, dd, J = 1.5 and 7.8),
7.36 (1H, br s), 8.12 (1H, d, J = 7.8). 13C NMR (100 MHz, CDCl3) δ:
51.7 (CH2), 52.6 (CH3), 81.0 (C), 94.5 (C), 110.9 (C), 118.0
(CH), 122.7 (CH), 130.1 (CH), 132.2 (CH), 139.3 (C),
solution of (2-iodophenyl)methanamine (2.75 g, 11.8 mmol, 1 equiv)
were added K2CO3 (3.6 g, 25.96 mmol, 2.2 equiv) and methyl chloro-
formate (34 mL) at 0 °C. The reaction mixture was stirred at 0 °C
during 1 h. After completion, the layers were separated, and the
aqueous layer was extracted twice with CH2Cl2. The combined organic
phases were dried over MgSO4, filtered, and concentrated in vacuo.
Methyl N-[(2-iodophenyl)methyl]carbamate was isolated as an oil
(3.0 g, 87%). H NMR (400 MHz, CDCl3) δ: 3.69 (3H, s), 4.38
(2H, d, J = 6.3), 5.11−5.33 (1H, br s), 6.93−7.03 (1H, m), 7.28−7.42
(2H, m), 7.79−7.86 (1H, m).
Methyl N-{[2-(3-Hydroxyprop-1-yn-1-yl)phenyl]methyl}-
carbamate (16l). To a solution of methyl N-[(2-iodophenyl)methyl]-
carbamate (1.7 g, 5.84 mmol, 1 equiv) in dry tetrahydrofuran/
triethylamine (28/28 mL) was added Pd(PPh3)4 (270 mg, 0.23 mmol,
0.04 equiv) followed by CuI (89 mg, 0.47 mmol, 0.08 equiv) and pro-
pargyl alcohol (1.3 mL, 17.5 mmol, 3 equiv), under argon atmosphere.
The solution was stirred at 40 °C during 2 h. After completion, the
layers were separated, and the aqueous layer was extracted twice with
CH2Cl2. The combined organic phases were dried over MgSO4,
filtered, and concentrated in vacuo. After purification by flash chromato-
graphy on silica gel (pentane/AcOEt from 100/0 to 40/60), methyl
N-{[2-(3-hydroxyprop-1-yn-1-yl)phenyl]methyl}carbamate was isolated
as an oil (1.1 g, 87%). 1H NMR (400 MHz, CDCl3) δ: 3.01−3.12 (1H,
br s), 3.61 (3H, s), 4.37−4.47 (4H, m), 5.07−5.18 (1H, br s), 7.13−7.27
(3H, m), 7.33−7.38 (1H, m). 13C NMR (100 MHz, CDCl3) δ: 44.2
(CH2), 51.5 (CH2), 52.5 (CH3), 83.4 (C), 92.8 (C), 122.4 (C),
127.8 (CH), 128.7 (CH), 128.8 (CH), 132.3 (CH), 140.4
(C), 157.5 (CO). HRMS (ESI): m/z: calcd for [MNa+]
C12H13NNaO3+: 242.0787; found: 242.0788.
1
+
153.8 (CO). HRMS (ESI): m/z: calcd for [MNa+] C11H11NNaO3 :
228.0631; found: 228.0631.
Methyl N-[2-(3-Iodoprop-1-yn-1-yl)phenyl]carbamate (16c). To a
light-protected solution (covered with an aluminum foil) of methyl
N-[2-(3-hydroxyprop-1-yn-1-yl)phenyl]carbamate (1 g, 4.88 mmol,
1 equiv) in dry CH2Cl2 (65 mL) under argon atmosphere at 0 °C were
added imidazole (400 mg, 5.85 mmol, 1.2 equiv), triphenylphosphine
(1.53 g, 5.85 mmol, 1.2 equiv), and iodine (1.48 g, 5.85 mmol, 1.2 equiv).
The reaction mixture was stirred at 0 °C during 1 h. After completion,
the excess of iodine was removed by washing with sat. aqueous Na2S2O3
and the organic layer was dried over MgSO4, filtered, and concentrated in
vacuo. After purification by flash chromatography on silica gel (pentane/
AcOEt from 100/0 to 80/20), methyl N-[2-(3-iodoprop-1-yn-1-yl)-
1
phenyl]carbamate was isolated as an oil (1.09 g, 71%). H NMR (400
MHz, CDCl3) δ: 3.81 (3H, s), 4.00 (2H, s), 6.97 (1H, t, J = 7.5), 7.29−
7.36 (3H, m), 8.11 (1H, m). 13C NMR (100 MHz, CDCl3) δ: −18.4
(CH2), 52.7 (CH3), 80.8 (C), 93.5 (C), 110.8 (C), 118.1
(CH), 122.8 (CH), 130.4 (CH), 132.2 (CH), 139.7 (C),
153.9 (CO). HRMS (ESI): m/z: calcd for [MH+] C11H11INO2+:
315.9829; found: 315.9829.
Methyl N-{[2-(3-Iodoprop-1-yn-1-yl)phenyl]methyl}carbamate
(16b). To a light-protected solution (covered with an aluminum
foil) of methyl N-{[2-(3-hydroxyprop-1-yn-1-yl)phenyl]methyl}-
carbamate (1.1 g, 5 mmol, 1 equiv) in dry CH2Cl2 (33 mL) under
argon atmosphere at 0 °C were added imidazole (410 mg, 6 mmol,
1.2 equiv), triphenylphosphine (1.58 g, 6 mmol, 1.2 equiv), and iodine
(1.53 g, 6 mmol, 1.2 equiv). The reaction mixture was stirred at 0 °C
during 1 h. After completion, the excess of iodine was removed by
washing with sat. aqueous Na2S2O3 and the organic layer was dried
over MgSO4, filtered, and concentrated in vacuo. After purification
by flash chromatography on silica gel (pentane/AcOEt from 100/0 to
70/30), methyl N-{[2-(3-iodoprop-1-yn-1-yl)phenyl]methyl}-
carbamate was isolated as a solid (1.1 g, 67%). Mp (°C) = 69.3−
70.3. 1H NMR (400 MHz, CDCl3) δ: 3.69 (3H, s), 3.99 (2H, s), 4.48
(2H, d, J = 6.3), 5.12−5.29 (1H, br s), 7.19−7.26 (1H, m), 7.28−7.44
(3H, m). 13C NMR (100 MHz, CDCl3) δ: −17.7 (CH2), 43.8 (CH2),
52.4 (CH3), 83.3 (C), 91.2 (C), 121.6 (C), 127.6 (CH),
128.5 (CH), 129.2 (CH), 132.5 (CH), 140.9 (C),
2-{[2-(3-Iodoprop-1-yn-1-yl)phenyl]methyl}-2,3-dihydro-1H-iso-
indole-1,3-diione (24). 2-[(2-Iodophenyl)methyl]-2,3-dihydro-1H-
isoindole-1,3-diione (24i). To a solution of 2-iodobenzyl alcohol
(2 g, 8.55 mmol, 1 equiv) and triphenylphosphine (2.69 g, 10.3 mmol,
1.2 equiv) in dry THF (25 mL) and dichloromethane (5 mL) was
added phthalimide (1.5 g, 10.3 mmol, 1.2 equiv). The reaction mixture
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was cooled to 0 °C, and DEAD (1.6 mL, 10.3 mmol, 1.2 equiv) was
added dropwise. The reaction mixture was stirred for 18 h. The
organic layer was diluted with ether and successively washed with
water and brine. The ethereal layer was dried over MgSO4, filtered,
and concenterd under reduced pressure. After purification by flash
chromatography on silica gel (pentane/AcOEt from 100/0 to 90/10),
2-[(2-iodophenyl)methyl]-2,3-dihydro-1H-isoindole-1,3-diione was
isolated as an oil (1.1 g, 38%). 1H NMR (400 MHz, CDCl3) δ:
4.89 (2H, s), 6.95 (1H, td, J = 7.8 and 1.5), 7.06 (1H, dd, J = 7.8 and
1.6), 7.25 (1H, td, J = 7.8 and 1.0), 7.71−7.77 (2H, m), 7.84 (1H, dd,
J = 7.8 and 1.0), 7.86−7.92 (2H, m). 13C NMR (100 MHz, CDCl3) δ:
46.7 (CH2), 97.7 (C), 123.6 (2 = CH), 127.3 (CH), 128.5
(CH), 129.2 (CH), 132.0 (C), 134.3 (2 = CH), 137.9 (C),
139.7 (CH), 167.9 (CO). HRMS (ESI): m/z: calcd for [MH+]
1,2,3,4-Tetrahydro-1-vinylidenenaphthalen-2-ol (2b). 3-(2-(3-Io-
doprop-1-ynyl)phenyl)propanal, 1b (0.298 g, 1 mmol, 1 equiv),
diethylzinc (1.5 mL, 1.5 mmol, 1.5 equiv), and dichloromethane
(5 mL, 0.2 M) were kept under general procedure for 14 h to obtain
the title compound as a colorless liquid (0.15 g, 87%). 1H NMR
(400 MHz, CDCl3) δ: 1.93−2.06 (br s superimposed, 1H), 1.90−2.05
(m, 1H), 2.06−2.18 (m, 1H), 2.83 (ddd, J = 5.3, 8.3 and 16.6, 1H),
3.02 (ddd, J = 5.3, 7.0 and 16.8, 1H), 4.57−4.65 (m, 1H), 5.25−5.45
(m, 2H), 7.21−7.11(m, 3H), 7.47 (d, J = 7.0, 1H). 13C NMR (100
MHz, CDCl3) δ: 26.3 (CH2), 30.7 (CH2), 67.7 (CH), 82.2 (CH2),
107.1 (C), 126.4 (CH), 127.1 (CH), 127.4 (CH), 129.0
(CH), 129.4 (C), 135.5 (C), 205.6 (C). HRMS (ESI):
m/z: calcd for [MH]+ C12H13O+: 173.0961; found: 173.0961.
2,3-Dihydro-2-methyl-1-vinylidene-1H-inden-2-ol (4a). 1-(2-(3-
Iodoprop-1-ynyl)phenyl)propan-2-one, 3a (0.298 g, 1 mmol, 1 equiv),
diethylzinc (1.5 mL, 1.5 mmol, 1.5 equiv), and dichloromethane (5 mL,
0.2 M) were reacted under the conditions described in the general
procedure for 14 h to obtain the title compound as a colorless liquid
(0.14 g, 82%). 1H NMR (400 MHz, CDCl3) δ: 1.48 (s, 3H), 2.00 (br s,
1H), 3.07 (AB pattern, J = 16.6, Δυ = 16, 2H), 5.28 (AB pattern, J = 13,
Δυ = 8.6, 2H), 7.22−7.10 (m, 4H). 13C NMR (100 MHz, CDCl3) δ:
27.9 (CH3), 47.6 (CH2), 79.7 (C), 83.2 (CH2), 115.7 (C), 123.3
(CH), 125.3 (CH), 127.4 (CH), 128.2 (CH), 136.8 (C),
140.2 (C), 203.2 (C). HRMS (ESI): m/z: calcd for [MNa]+
C12H12NaO+: 195.0780; found: 195.0780.
+
C15H11INO2 : 363.9829; found: 363.9828.
2-{[2-(3-Hydroxyprop-1-yn-1-yl)phenyl]methyl}-2,3-dihydro-1H-
isoindole-1,3-diione (24j). To a solution of 2-[(2-iodophenyl)methyl]-
2,3-dihydro-1H-isoindole-1,3-diione (1.1 g, 3.03 mmol, 1 equiv) in dry
tetrahydrofuran/triethylamine (15:15 mL) was added Pd(PPh3)4
(140 mg, 0.12 mmol, 0.04 equiv) followed by CuI (46 mg, 0.24 mmol,
0.08 equiv) and propargyl alcohol (0.66 mL, 9.09 mmol, 3 equiv), under
argon atmosphere. The solution was stirred at 40 °C during 2 h. After
completion, the layers were separated, and the aqueous layer was extracted
twice with CH2Cl2. The combined organic phases were dried over
MgSO4, filtered, and concentrated in vacuo. After purification by flash
chromatography on silica gel (pentane/AcOEt from 100/0 to 60/40)
2-{[2-(3-hydroxyprop-1-yn-1-yl)phenyl]methyl}-2,3-dihydro-1H-isoin-
dole-1,3-diione was isolated as a solid (0.55 g, 62%). Mp (°C) = 116−117.
1H NMR (400 MHz, CDCl3) δ: 4.34 (1H, s), 4.49 (2H, s), 5.03 (2H, s),
1,2,3,4-Tetrahydro-2-methyl-1-vinylidenenaphthalen-2-ol (4b).
4-(2-(3-Iodoprop-1-ynyl)phenyl)butan-2-one, 3b (0.156 g, 0.5 mmol,
1 equiv), diethylzinc (0.75 mL, 0.75 mmol, 1.5 equiv), and
dichloromethane (2.5 mL, 0.2 M) were reacted under the conditions
described in the general procedure for 14 h to obtain the title
7.20−7.34 (2H, m), 7.39−7.43 (1H, m), 7.48−7.53 (1H, m), 7.69−7.75
(2H, m), 7.81−7.89 (2H, m). 13C NMR (100 MHz, CDCl3) δ: 41.1
(CH2), 51.8 (CH2), 83.7 (C), 93.2 (C), 122.2 (C), 123.5 (2 =
CH), 128.0 (CH), 128.7 (CH), 130.1 (CH), 132.0 (C), 132.4
(CH), 134.3 (2 = CH), 137.7 (C), 168.4 (CO). HRMS (ESI):
m/z: calcd for [MNa+] C18H13NNaO3+: 314.0788; found: 314.0786.
2-{[2-(3-Iodoprop-1-yn-1-yl)phenyl]methyl}-2,3-dihydro-1H-iso-
indole-1,3-diione (24). To a light-protected solution (covered with an
aluminum foil) of 2-{[2-(3-hydroxyprop-1-yn-1-yl)phenyl]methyl}-
2,3-dihydro-1H-isoindole-1,3-diione (530 mg, 1.89 mmol, 1 equiv) in
dry CH2Cl2 (13 mL) under argon atmosphere at 0 °C were added
imidazole (154 mg, 2.27 mmol, 1.2 equiv), triphenylphosphine (594 mg,
2.27 mmol, 1.2 equiv), and iodine (575 mg, 2.27 mmol, 1.2 equiv). The
reaction mixture was stirred at 0 °C during 1 h. After completion, the
excess of iodine was removed by washing with sat. aqueous Na2S2O3,
and the organic layer was dried over MgSO4, filtered, and concentrated
in vacuo. After purification by flash chromatography on silica gel
(pentane/AcOEt from 100/0 to 90/10), 2-{[2-(3-iodoprop-1-yn-1-
yl)phenyl]methyl}-2,3-dihydro-1H-isoindole-1,3-diione was isolated as a
1
compound as a colorless liquid. (0.086 g, 93%). H NMR (400 MHz,
CDCl3) δ: 1.47 (s, 3H), 1.85−1.97 (br s superimposed, 1H), 1.91
(ddd, J = 5.5, 8.5 and 13.3, 1H), 2.04 (ddd, J = 5.3, 6.8 and 13.1, 1H),
2.81 (ddd, J = 6.2, 6.3 and 16.8, 1H), 3.06 (ddd, J = 5.5, 8.3 and 16.8,
1H), 5.34 (s, 2H), 7.13−7.20 (m, 3H), 7.47 (d, J = 7.6, 1H). 13C NMR
(100 MHz, CDCl3) δ: 26.5 (CH2), 28.5 (CH3), 36.3 (CH2), 69.2 (C),
82.5 (CH2), 110.6 (C), 126.4 (CH), 126.9 (CH), 127.6 (
CH), 129.0 (CH), 129.8 (C), 135.1 (C), 205.3 (C).
HRMS (ESI): m/z: calcd for [MNa]+ C13H14NaO+: 209.0937; found:
209.0937.
1-Methyl-2-vinylidenecyclohexanol (6). 9-Iodonon-7-yn-2-one
5 (0.132 g, 0.5 mmol, 1 equiv), diethylzinc (0.75 mL, 0.75 mmol,
1.5 equiv), and dichloromethane (2.5 mL, 0.2 M) were submitted to
the conditions described in the general procedure for 14 h to give
the title compound as a colorless liquid (quantitative). 1H NMR
(400 MHz, CDCl3) δ: 1.35 (s, 3H), 1.45−1.82 (m, 7H), 2.08−2.22
(m, 1H), 2.30−2.44 (m, 1H), 4.74−4.82 (m, 2H). 13C NMR (100
MHz, CDCl3) δ: 22.9 (CH2), 26.7 (CH2), 28.1 (CH3), 28.7 (CH2),
40.8 (CH2), 69.8 (C), 77.1 (CH2), 108.7 (C), 201.7 (C).
HRMS (ESI): m/z: calcd for [MNa]+ C9H14NaO+: 161.0937; found:
161.0937
1
solid (620 mg, 82%). Mp (°C) = 150.5−151.5. H NMR (400 MHz,
CDCl3) δ: 4.01 (2H, s), 5.03 (2H, s), 7.17−7.30 (3H, m), 7.38−7.47
(1H, m), 7.69−7.77 (2H, m), 7.84−7.92 (2H, m). 13C NMR (100
MHz, CDCl3) δ: −17.5 (CH2), 40.4 (CH2), 83.0 (C), 92.0 (C),
121.6 (C), 123.6 (2 = CH), 123.7 (C), 127.6 (CH), 127.9
(CH), 129.0 (CH), 132.3 (C), 132.7 (CH), 134.2 (2 = CH),
138.2 (C), 168.4 (CO). HRMS (ESI): m/z: calcd for [MH+]
C18H13INO2+: 401.9986; found: 401.9988.
(E)-1-(Butan-2-ylidene)-1H-inden-2(3H)-one (8a). Methyl 2-(2-(3-
iodoprop-1-ynyl)phenyl)acetate, 7a (0.314 g, 1 mmol, 1 equiv), diethylzinc
(5 mL, 5 mmol, 5 equiv), and dichloromethane (5 mL, 0.2 M) were
reacted under the conditions described in the general procedure for 2 h
to give the title compound as a colorless oil. (0.149 g, 80%). 1H NMR
(400 MHz, CDCl3) δ: 1.28 (t, J = 7.7, 3H), 2.47 (s, 3H), 2.64 (q, J =
7.7, 2H), 3.50 (s, 2H), 7.24−7.36 (m, 3H), 7.60 (d, J = 7.6, 1H). 13C
NMR (100 MHz, CDCl3) δ: 11.3 (CH3), 21.2 (CH3), 30.8 (CH2),
43.2 (CH2), 124.0 (CH), 125.2 (CH), 127.3 (CH), 127.4
(CH), 130.7 (C), 136.9 (C), 140.3 (C), 155.6 (C), 205.5
General Procedure for Radical Reactions with Diethylzinc.
Reactions of Propargyl Iodides with Diethylzinc. A light-protected
round-bottom flask (covered with an aluminum foil) was loaded
with ortho-substituted 3-phenylalkynyl iodide (0.5 mmol, 1 equiv) and
dry CH2Cl2 (2.5 mL, 0.2 M) under argon atmosphere. Diethylzinc
(0.75 mL, 1.5 equiv) (1 M solution in heptane) was added to the
solution, and the resulting mixture was stirred at room temperature.
After completion, the reaction was quenched with saturated aqueous
NH4Cl. The two layers were separated, the aqueous layer was
extracted twice with dichloromethane (2 × 5 mL), and the combined
organic layers were evaporated in vacuo. The crude residue was
purified through flash column chromatography using pentane/
diethylether as the eluent to give the products.
+
(CO). HRMS (ESI): m/z: calcd for [MH+] C13H15O : 187.1123;
found: 187.1121.
(E)-1-(Butan-2-ylidene)-3,4-dihydronaphthalen-2(1H)-one (8b).
Methyl 3-(2-(3-iodoprop-1-ynyl)phenyl)propanoate, 7b (0.163 g,
0.5 mmol, 1 equiv), diethylzinc (1.1 mL, 1.1 mmol, 2.2 equiv), and
dichloromethane (2.5 mL, 0.2 M) were reacted under the conditions
described in the general procedure for 14 h to obtain the title
1
compound as a colorless oil. (0.085 g, 85%). H NMR (400 MHz,
CDCl3) δ: 1.09 (t, J = 7.4, 3H), 2.10 (s, 3H), 2.24 (q, J = 7.6, 2H),
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2.41 (t, J = 6.9, 2H), 2.80 (t, J = 6.5, 2H), 7.07−7.17 (m, 4H). 13C
NMR (100 MHz, CDCl3) δ: 13.3 (CH3), 20.1 (CH3), 27.9 (CH2),
29.6 (CH2), 38.5 (CH2), 126.2 (CH), 127.0 (CH), 127.1
(CH), 128.7 (CH), 133.4 (C), 135.5 (C), 138.6 (C),
149.5 (C), 204.5 (CO). HRMS (ESI): m/z: calcd for [MH]+
C14H17O+: 201.1273; found: 201.1274.
91.0 (2×C), 122.7 (2×C), 127.7 (2×CH), 128.1 (2×CH),
128.2 (2×CH), 132.3 (2×CH), 139.9 (2×C). HRMS (ESI):
m/z: calcd for [MNH4]+ C26H34NO3+: 408.2533; found: 408.2532.
Ethyl 4-(But-1-en-2-yl)-3-oxo-1,2,3,4-tetrahydroisoquinoline-2-
carboxylate (17). Ethyl N-(ethoxycarbonyl)-N-{[2-(3-iodoprop-1-yn-
1-yl)phenyl]methyl}carbamate, 16a (100 mg, 0.24 mmol, 1 equiv),
diethylzinc (1.2 mL, 5 equiv), and dichloromethane (1.2 mL, 0.2 M)
were reacted under the conditions described in the general procedure
for 14 h to give ethyl 4-(but-1-en-2-yl)-3-oxo-1,2,3,4-tetrahydroiso-
quinoline-2-carboxylate, 17, isolated as an oil (65 mg, quantitative). 1H
NMR (400 MHz, CDCl3) δ: 1.01 (3H, t, J = 7.3), 1.29 (3H, t, J = 7.3),
2.07 (2H, q, J = 7.3), 4.25 (1H, s), 4.27 (2H, q, J = 7.3), 4.42 (1H, d,
J = 1.3), 4.59 (1H, d, J = 15.6), 4.90 (1H, d, J = 1.3), 4.98 (1H, d, J =
15.6), 7.03−7.11 (1H, m), 7.14−7.29 (3H, m). 13C NMR (100 MHz,
CDCl3) δ: 12.3 (CH3), 14.3 (CH3), 27.2 (CH2), 48.2 (CH2), 58.0
(CH), 63.5 (CH2), 111.9 (CH2), 125.9 (CH), 127.5 (CH),
128.0 (CH), 128.3 (CH), 132.3 (C), 134.6 (C), 145.3
(C), 153.8 (CO), 169.7 (CO). HRMS (ESI): m/z: calcd for
4-Ethyl-9a-hydroxy-2-methylidene-1′,2,3, 3′,9,9a-
hexahydrospiro[fluorine-1,2′-indene]-3′-one (9a). Methyl 2-(2-(3-
iodoprop-1-ynyl)phenyl)acetate 7a (0.314 g, 1 mmol, 1 equiv), diethyl-
zinc (1.5 mL, 1.5 mmol, 1.5 equiv), and dichloromethane (5 mL,
0.2 M) were reacted under the conditions described in the general
procedure for 24 h to give the product as light-pink gummy foam.
1
(0.60 g, 48%). H NMR (400 MHz, CDCl3) δ: 1.32 (t, J = 7.8, 3H),
2.45−2.57 (m, 1H), 2.67 (AB parttern, JAB = 16.0, Δν = 26.6, 2H), 2.70
(superimposed m, 1H), 3.66 (d, A part of an AB pattern, J = 21.7, 1H),
3.88 (d, B part of an AB pattern, J = 22.6, 1H), 4.84 (m, 2H), 5.09 (m,
1H), 7.09−7.19 (m, 4H), 7.19−7.25 (m, 2H), 7.34 (d, J = 7.5, 1H),
7.62 (d, J = 8.0, 1H). 13C NMR (100 MHz, CDCl3) δ: 12.0 (CH3),
26.2 (CH2), 36.7 (CH2), 41.8 (CH2), 44.5 (CH2), 65.4 (C), 82.9 (C),
111.7 (CH2), 124.6 (CH), 125.3 (CH), 125.7 (CH), 125.8
(CH), 126.9 (CH), 127.5 (CH), 127.9 (CH), 128.3
(CH), 135.9 (C), 136.7 (C), 136.8 (C), 138.5 (C),
142.2 (C), 143.1 (C), 144.5 (C), 221.9 (CO). HRMS (ESI):
m/z: calcd for [MNa]+ C24H22NaO2+: 365.1512; found: 365.1512.
4-(But-1-en-2-yl)-3,4-dihydro-2H-1-benzopyran-3-one (11). Ethyl
[2-(3-iodoprop-1-yn-1-yl)phenyl]methyl carbonate 10 (100 mg, 0.29
mmol, 1 equiv), diethylzinc (0.58 mL, 2 equiv), and dichloromethane
(1.45 mL, 0.2 M) were reacted under the conditions described in the
general procedure for 14 h to give 4-(but-1-en-2-yl)-3,4-dihydro-2H-1-
+
[MH+] C16H20NO3 : 274.1438; found: 274.1437.
Methyl N-{[2-(prop-1-yn-1-yl)phenyl]methyl}carbamate (18) and
Methyl N-{[2-(propa-1,2-dien-1-yl)phenyl]methyl}carbamate (19).
Methyl N-{[2-(3-iodoprop-1-yn-1-yl)phenyl]methyl}carbamate (16b)
(100 mg, 0.3 mmol, 1 equiv), diethylzinc (0.45 mL, 1.5 equiv), and
dichloromethane (1.5 mL, 0.2 M) were reacted under the conditions
described in the general procedure for 14 h to give, after purification
by flash chromatography on silica gel (pentane/AcOEt from 100/0 to
50/50), a mixture of methyl N-{[2-(propa-1,2-dien-1-yl)phenyl]-
methyl}carbamate, 19, and methyl N-{[2-(prop-1-yn-1-yl)phenyl]-
methyl}carbamate, 18, isolated in a 70:30 ratio as an oil (0.043 g,
+
benzopyran-3-one, isolated as an oil (58 mg, quantitative). H NMR
71% overall yield). HRMS (ESI): m/z: calcd for [MH+] C12H14NO2 :
1
(400 MHz, CDCl3) δ: 1.24 (3H, t, J = 7.5), 2.28 (3H, s), 2.40 (2H, q,
J = 7.5), 4.42 (2H, s), 7.03−7.12 (2H, m), 7.20−7.29 (2H, m). 13C
NMR (100 MHz, CDCl3) δ: 13.2 (CH3), 20.6 (CH3), 30.2 (CH2),
73.9 (CH2), 118.0 (CH), 122.8 (CH), 125.4 (C), 127.3
(C), 128.7 (CH), 129.0 (CH), 153.5 (C), 155.3 (C),
204.1019; found: 204.1019.
18: 1H NMR (400 MHz, CDCl3) δ: 2.09 (3H, s), 3.68 (3H, s), 4.48
(2H, d, J = 6.0), 5.05−5.25 (1H, br s), 7.14−7.46 (4H, m). 13C NMR
(100 MHz, CDCl3) δ: 4.6 (CH3), 44.0 (CH2), 52.3 (CH3), 84.8
(C), 91.0 (C), 125.7 (C), 128.2 (CH), 129.6 (CH),
132.4 (2×CH), 134.7 (C), 156.9 (CO).
+
201.1 (CO). HRMS (ESI): m/z: calcd for [MH+] C13H15O2 :
1
203.1066; found: 203.1061.
19: H NMR (400 MHz, CDCl3) δ: 3.67 (3H, s), 4.42 (2H, d, J =
Methyl 3-(2-(propa-1,2-dienyl)phenyl)propanoate (13b). Methyl
3-(2-(3-iodoprop-1-ynyl)phenyl)propanoate 7b (0.082 g, 0.25 mmol,
1 equiv), In (0.057 g, 0.5 mmol, 2 equiv), and acetic acid (0.060,
1 mmol, 4 equiv) were stirred at room temperature for 14 h in a
DMF/H2O mixture (1 mL/0.125 mL). After this time, the reaction
mixture was filtered, and the filtrate was evaporated. The residue was
purified through flash column chromatography to give the title product
as a colorless oil. (25 mg, 50%). 1H NMR (400 MHz, CDCl3) δ: 2.60
(t, J = 8.3, 2H), 3.03 (t, J = 7.8, 2H), 3.7 (s, 3H), 5.13 (d, J = 6.9, 2H),
6.37 (t, J = 6.9, 1H), 7.10−7.25 (m, 3H), 7.41 (d, J = 7.3, 1H). 13C
NMR (100 MHz, CDCl3) δ: 28.6 (CH2), 35.3 (CH2), 51.8 (CH3),
78.3 (CH2), 90.8 (CH), 126.9 (CH), 127.3 (CH), 128.0
(CH), 129.8 (CH), 131.9 (C), 137.4 (C), 173.4 (CO),
5.52), 4.85−5.03 (1H, br s), 5.13 (2H, d, J = 6.8), 6.38 (1H, t, J = 6.8),
7.14−7.46 (4H, m). 13C NMR (100 MHz, CDCl3) δ: 43.2 (CH2),
52.3 (CH3), 78.3 (CH2), 90.6 (CH), 125.7 (C), 127.3 (CH),
127.4 (CH), 128.1 (CH), 128.2 (CH), 140.1 (C), 156.9
(CO), 210.7 (C).
Methyl N-{[2-(4-Hydroxy-4-phenylbut-1-yn-1-yl)phenyl]methyl}-
carbamate (20) and Methyl N-{[2-(1-Hydroxy-1-phenylbuta-2,3-
dien-2-yl)phenyl]methyl}carbamate (21). To a light-protected
round-bottom flask (covered with an aluminum foil), loaded with
methyl N-{[2-(3-iodoprop-1-yn-1-yl)phenyl]methyl}carbamate, 16b
(100 mg, 0.3 mmol, 1 equiv), and dry CH2Cl2 (1.5 mL, 0.2 M)
under argon atmosphere was added benzaldehyde (61 μL, 0.6 mmol,
2 equiv). Diethylzinc (0.45 mL, 1.5 equiv) was added to the solution,
and the resulting mixture was stirred at room temperature for 14 h.
After that time, the reaction was quenched with saturated aqueous
NH4Cl. The two layers were separated, the aqueous layer was
extracted twice with dichloromethane, and the combined organic
layers were evaporated in vacuo After purification by flash chromato-
graphy on silica gel (pentane/AcOEt from 100/0 to 90/10), a mixture
of methyl N-{[2-(1-hydroxy-1-phenylbuta-2,3-dien-2-yl)phenyl]-
methyl}carbamate, 21, and methyl N-{[2-(4-hydroxy-4-phenylbut-1-
yn-1-yl)phenyl]methyl}carbamate, 20, was isolated in a 61:35 ratio as
an oil (0.074 g, 76% overall yield). HRMS (ESI): m/z: calcd for
+
210.7 (C). HRMS (ESI): m/z: calcd for [MH]+ C13H15O2 :
203.1066; found: 203.1066.
1,7-bis[2-(methoxymethyl)phenyl]-4-propylhepta-1,6-diyn-4-ol
(15). Light-protected round-bottom flask (covered with an aluminum
foil) was loaded with 1-(3-iodoprop-1-yn-1-yl)-2-(methoxymethyl)-
benzene, 14 (143 mg, 0.5 mmol, 1 equiv), ethyl butanoate (290 mg,
2.5 mmol, 5 equiv), and dry CH2Cl2 (2.5 mL, 0.2 M) under argon
atmosphere. Diethylzinc (1.1 mL, 2.2 equiv) (1 M solution in heptane)
was added to the solution, and the resulting mixture was stirred at room
temperature for 14 h. After that time, the reaction was quenched with
saturated aqueous NH4Cl. The two layers were separated, the aqueous
layer was extracted twice with dichloromethane, and the combined
organic layers were evaporated in vacuo. 1,7-Bis[2-(methoxymethyl)-
phenyl]-4-propylhepta-1,6-diyn-4-ol was isolated as an oil (60 mg,
61%). 1H NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.3), 1.39−1.53
(2H, m), 1.68−1.76 (2H, m), 2.75 (4H, AB pattern, J = 16.6, Δυ =
15.4), 3.04−3.13 (1H, br s), 3.32 (6H, s), 4.55 (AB pattern, J = 12.6,
Δυ = 7.8, 4H), 7.12−7.26 (4H, m), 7.28−7.40 (4H, m). 13C NMR
(100 MHz, CDCl3) δ: 14.8 (CH3), 17.0 (CH2), 31.1 (2×CH2),
41.2 (CH2), 58.2 (2×CH3), 73.2 (2×CH2), 74.0 (C), 81.3 (2×C),
+
[MNa+] C19H19NNaO3 : 332.1257; found: 332.1255.
20: 1H NMR (400 MHz, CDCl3) δ: 2.86 (2H, d, J = 6.0), 3.61 (3H,
s), 4.32−4.40 (2H, m), 4.87−4.97 (1H, m), 5.57−5.66 (1H, br s),
7.02−7.45 (10H, m). 13C NMR (100 MHz, CDCl3) δ: 30.5 (CH2),
44.1 (CH2), 52.5 (CH3), 72.8 (CH), 80.7 (C), 91.6 (C), 122.9
(C), 125.9 (CH), 127.7 (CH), 128.1 (CH), 128.4 (CH),
128.9 (CH), 129.4 (CH), 134.2 (C) 140.7 (C), 157.4 (CO).
21: 1H NMR (400 MHz, CDCl3) δ: 3.01−3.39 (1H, br s),
3.61 (3H, s), 4.13−4.31 (2H, m), 4.88 (2H, s), 4.99−5.10 (1H, br s),
5.45 (1H, s), 7.02−7.45 (10H, m). 13C NMR (100 MHz, CDCl3)
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Article
δ: 42.7 (CH2), 52.3 (CH3), 75.3 (CH), 78.2 (CH2), 107.3 (C),
126.7 (2CH), 127.6 (CH), 128.0 (CH), 128.2 (CH), 128.4
(CH), 128.7 (2CH), 129.5 (CH), 137.4 (C), 141.9 (C),
143.1 (C), 157.5 (CO), 205.8 (C).
REFERENCES
■
(1) For reviews, see: (a) Yamamoto, Y. In Comprehensive Organic
Synthesis; Trost, B. M, Ed.; Pergamon Press: Oxford, 1991, 2, 81−98.
(b) Marshall, J. A. Chem. Rev. 2000, 100, 3163. (c) Marshall, J. A.;
Gung, B. W.; Grachan, M. L. Synthesis and Reactions of Allenyl
Compounds. In Modern Allene Chemistry; Krause, N.; Hashmi, A. S. K.,
Eds.; Wiley-VCH: Weinheim, 2004; pp 493−592. (d) Marshall, J. A.
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509.
Methyl 2-Methyl-1H-indole-1-carboxylate (22). Methyl N-[2-(3-
iodoprop-1-yn-1-yl)phenyl]carbamate, 16c (100 mg, 0.32 mmol,
1 equiv), diethylzinc (1.6 mL, 5 equiv), and dichloromethane (1.6 mL,
0.2 M) were reacted under the conditions described in the general
procedure for 14 h to give methyl 2-methyl-1H-indole-1-carboxylate,
1
isolated as an oil (41 mg, 67%). H NMR (400 MHz, CDCl3) δ: 2.61
(3H, bd, J = 1.0), 4.04 (3H, s), 6.35 (1H, br s), 7.17−7.28 (2H, m),
7.41−7.49 (1H, m), 8.10 (1H, d, J = 8.0). 13C NMR (100 MHz, CDCl3)
δ: 16.8 (CH3), 53.5 (CH3), 108.7 (CH), 115.6 (CH), 119.7 (
CH), 123.1 (CH), 123.5 (CH), 129.7 (C), 136.5 (C), 137.9
(C), 152.8 (CO). HRMS (ESI): m/z: calcd for [MH]+
C11H12NO2+: 190.0863; found: 190.0863.
Methyl 2′-Methylidene-3-oxo-1,1′,2′,3′-tetrahydrospiro[benzo-
[b]pyrrolizine-2,3′-indole]-1′-carboxylate (23). Methyl N-[2-(3-iodo-
prop-1-yn-1-yl)phenyl]carbamate 16c (100 mg, 0.32 mmol, 1 equiv),
diethylzinc (0.48 mL, 1.5 equiv) in dichloromethane (1.6 mL, 0.2 M)
were reacted under the conditions described in the general procedure
for 14 h to give methyl 2′-methylidene-3-oxo-1,1′,2′,3′-tetrahydrospiro-
[benzo[b]pyrrolizine-2,3′-indole]-1′-carboxylate, isolated as an oil
(32 mg, 58%). 1H NMR (400 MHz, CDCl3) δ: 3.62 (2H, AB pattern,
J = 17.3, Δυ = 25.0), 3.99 (3H, s), 4.69 (1H, d, J = 2.0), 5.86 (1H, d,
J = 2.0), 6.46 (1H, s), 6.96−7.12 (2H, m), 7.27−7.39 (3H, m), 7.53−
7.62 (1H, m), 7.86−7.92 (1H, m), 7.12−8.13 (1H, m). 13C NMR (100
MHz, CDCl3) δ: 39.2 (CH2), 53.3 (CH3), 62.6 (C), 96.3 (CH2),
101.9 (CH), 114.2 (CH), 116.4 (CH), 121.0 (CH), 122.6
(CH), 124.0 (CH), 124.6 (CH), 124.9 (CH), 129.8
(CH), 130.5 (C), 131.3 (C), 135.6 (C), 139.9 (C),
142.4 (C), 148.7 (C), 153.0 (CO), 170.0 (CO). HRMS
(ESI): m/z: calcd for [MH]+ C21H17N2O3+: 345.1234; found: 345.1232.
12-Ethenelidene-12a-hydroxy-5H,7H,12H,12aH-isoindolo[2,1-b]-
isoquinolin-5-one (25). 2-{[2-(3-Iodoprop-1-yn-1-yl)phenyl]methyl}-
2,3-dihydro-1H-isoindole-1,3-diione, 24 (100 mg, 0.25 mmol, 1 equiv),
diethylzinc (0.50 mL, 2 equiv), and dichloromethane (1.3 mL, 0.2 M)
were reacted under the conditions described in the above general
procedure for 14 h to give, after purification by flash chromatography
on silica gel (pentane/AcOEt from 100/0 to 50/50), 12-ethenelidene-
12a-hydroxy-5H,7H,12H,12aH-isoindolo[2,1-b]isoquinolin-5-one, 25,
(3) Kang, H.-Y.; Kim, Y.-T.; Yu, Y.-K.; Cha, J. H.; Cho, Y. S.; Koh, H.
Y. Synlett 2004, 45.
(4) (a) Bazin, S.; Feray, L.; Vanthuyne, N.; Siri, D.; Bertrand, M. P.
Tetrahedron 2007, 63, 77. (b) Maury, J.; Feray, L.; Perfetti, P.;
Bertrand, M. P. Org. Lett. 2010, 12, 3590. (c) Maury, J.; Feray, L.;
Bertrand, M. P. Org. Lett. 2011, 13, 1884. (d) Maury, J.; Mouysset, D.;
Feray, L.; Marque, S. R. A.; Siri, D.; Bertrand, M. P. Chem.Eur. J.
2012, 18, 3241 and previous references cited therein.
(5) For reviews on organozincs radical chemistry, see: (a) Bazin, S.;
Feray, L.; Bertrand, M. P. Chimia 2006, 60, 260. (b) Akindele, T.;
Yamada, K.-I.; Tomioka, K. Acc. Chem. Res. 2009, 42, 345. (c) Knochel,
P. Synlett 1995, 393.
(6) Maury, J.; Jammi, S.; Vibert, F.; Marque, S. R. A.; Siri, D.; Feray,
L.; Bertrand, M. P. J. Org. Chem. 2012, 77, 9081.
(7) Jammi, S.; Mouysset, D.; Siri, D.; Bertrand, M. P.; Feray, L. J. Org.
Chem. 2013, 78, 1589.
(8) Alternatively, the nucleophilic addition leading to intermediate F
might be slowed down in case b.
(9) It is worth noting that the allenylzinc resulting from Zn/I
exchange between Et2Zn and propargyl iodide 14 was shown to react
like a classical Grignard reagent with ethyl butanoate. It led to the
tertiary bis-homopropargylic alcohol 15. For pioneering studies, with
contradictory observation, see: Couffignal, R.; Gaudemar, M. Bull. Soc.
Chim. 1969, 3157.
1
isolated as an oil (61 mg, 89%). H NMR (400 MHz, CDCl3) δ:
4.29 (1H, br s), 4.44 (1H, d, J = 16.8), 5.12 (1H, d, J = 16.8), 5.15 (1H,
d, J = 12.8), 5.40 (1H, d, J = 13.0), 7.21−7.29 (3H, m), 7.39−7.50 (2H,
m), 7.54−7.63 (2H, m), 7.77−7.84 (1H, m). 13C NMR (100 MHz,
CDCl3) δ: 38.6 (CH2), 83.4 (CH2), 85.5 (C), 103.3 (C), 123.3
(CH), 124.2 (CH), 126.5 (CH), 127.3 (C), 127.4 (CH),
127.5 (CH), 127.6 (CH), 129.6 (CH), 130.4 (C), 130.7
(C), 131.9 (CH), 145.9 (C), 165.7 (CO), 207.6 (C).
HRMS (ESI): m/z: calcd for [MH+] C18H14NO2+: 276.1019; found:
276.1018.
(10) The configuration of the double bond in 8a, 8b, and 11 was
assigned from NOESY experiments showing cross-peaks between the
signals of the proton of the ethyl group and the signals of the aromatic
protons (see: Supporting Information).
ASSOCIATED CONTENT
(11) Tautomeric forms of enolate E
■
S
* Supporting Information
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
■
(12) (a) Bieber, L. W.; Da Silva, M. F.; Da Costa, R. C.; Silva, L. O. S.
Corresponding Authors
*michele.bertrand@univ-amu.fr
*laurence.feray@univ-amu.fr
Tetrahedron Lett. 1998, 39, 3655. (b) Jogi, A.; Maeorg, U. Molecules
̈
̈
2001, 6, 964.
(13) It was necessary to use an excess of diethylzinc for the reaction
to be completely chemoselective.
(14) Colquhoun, V. P.; Unkelbach, C.; Strohmann, C. Chem.
Notes
The authors declare no competing financial interest.
Commun. 2012, 48, 5034.
(15) For recent review on indole synthesis, see: (a) Taber, D. F.;
ACKNOWLEDGMENTS
■
Tirunahari, P. K. Tetrahedron 2011, 67, 7195. (b) Cacchi, S.; Fabrizi,
G. Chem. Rev. 2011, 111, PR215.
We thank the ANR (D2R2 project) for financial support and
Aix-Marseille Universite
́
for the postdoctoral grant of S.J.
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(16) Ma, S. In Modern Allene Chemistry; Krause, N., Hashmi, S. K.,
Eds.; Wiley-VCH: Weinheim, 2004, Vol. 2, p 595.
(17) See: Selvakumar, J.; Ramanathan, C. R. Org. Biomol. Chem.
2011, 9, 7643 and references cited therein.
(18) Portscheller, J. L.; Malinakova, H. C. Org. Lett. 2002, 4, 3679.
(19) Takeuchi, Y.; Nabetani, M.; Takagi, K.; Hagi, T.; Koizumi, T. J.
Chem. Soc., Perkin Trans. 1 1991, 49.
(20) Chrich, D.; Krishnamurthy, V. Tetrahedron 2006, 62, 6830.
(21) Chakraborty, A.; Sinha, S. Tetrahedron Lett. 2011, 52, 6635.
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