Theoretical support for the involvement of a radical pathway in the formation of allenylzincs from propargyl iodides and dialkylzincs: Influence of zinc coordination

Article abstract of DOI:10.1021/jo302704g

Propargyl iodides are good precursors for allenylzincs via reaction with diethylzinc, even in nondegassed medium. These reactions proceed via zinc/iodine exchange. Owing to the previously reported detection of propargyl radical by ESR experiments, in this process a radical mechanism was suspected. Calculations of the C-Zn BDEs in allenyl- and propargylzinc species were performed with the CBS-QB3 method to demonstrate that propargyl radicals could undergo homolytic substitution at zinc. The stabilization of allenylzinc derivatives by chelation, made possible by the selection of appropriate ortho-substituted 3-phenylalkynyl iodides as precursors, was shown to influence the regioselectivity of their addition to aldehydes and ketones. The more stabilized the chelated allenylzinc intermediate, the higher the ratio of homopropargylic alcohols.

Full text of DOI:10.1021/jo302704g

Article
pubs.acs.org/joc
Theoretical Support for the Involvement of a Radical Pathway in the
Formation of Allenylzincs from Propargyl Iodides and Dialkylzincs:
Influence of Zinc Coordination
Suribabu Jammi,† Dominique Mouysset,† Didier Siri,*,‡ Michele P. Bertrand,*,† and Laurence Feray*,†
̀
†
‡
́
Aix-Marseille Universite, CNRS, Institut de Chimie Radicalaire, UMR 7273, Equipes CMO and CT, 13397 Cedex 20,
Marseille, France
S
* Supporting Information
ABSTRACT: Propargyl iodides are good precursors for allenyl-
zincs via reaction with diethylzinc, even in nondegassed medium.
These reactions proceed via zinc/iodine exchange. Owing to the
previously reported detection of propargyl radical by ESR exper-
iments, in this process a radical mechanism was suspected. Calcula-
tions of the C−Zn BDEs in allenyl- and propargylzinc species were
performed with the CBS-QB3 method to demonstrate that
propargyl radicals could undergo homolytic substitution at zinc.
The stabilization of allenylzinc derivatives by chelation, made pos-
sible by the selection of appropriate ortho-substituted 3-phenylalkynyl
iodides as precursors, was shown to influence the regioselectivity
of their addition to aldehydes and ketones. The more stabilized the chelated allenylzinc intermediate, the higher the ratio of
homopropargylic alcohols.
reactivity of propargyl radicals have scarcely been investigated,
and little synthetic applications have been developed for these
short-lived species.16 The treatment of propargyl iodides with
diethylzinc in the presence of a catalytic amount of oxygen was
recently shown to produce propargyl radical on the ground of
electron paramagnetic resonance (EPR) experiments.17 As a
consequence, a radical chain mechanism might be proposed for
the formation of allenylzincs which would imply homolytic
displacement at diethylzinc by propargyl radical. However,
owing to the great sensitivity and specificity of EPR technique
in detecting free radicals, the detection of propargyl radicals is
necessary but not sufficient to demonstrate that the formation
of allenylzinc derivatives follows a radical pathway. Theoretical
calculations were undertaken to better understand the driving
force for this homolytic reaction. Such a displacement should
be facilitated by the coordination of zinc atom with a basic
directing group.18
Chelation is known to influence the stereochemical outcome
of reactions of alkylzinc derivatives.19 This is the reason why
we decided to investigate the possibility to initiate by oxygen
the formation of chelated allenylzinc species, and to explore the
impact of a coordinated directing group on the competition
between propargylation and allenylation of electrophiles like
aldehydes and ketones. It is generally admitted that a SE2′
mechanism is operative (Scheme 1).2
INTRODUCTION
■
The reactivity of allenylzincs and other allenyl metals, stimu-
lated by the synthetic potential of acetylenic and allenic linkages,
has widely been investigated.1 Little rationale can help in predic-
ting the reactivity of these organometallic species with electro-
philes.
Different methodologies have been explored for the specific
production of organozinc compounds:2,3 transmetalation of
organo-lithiated derivatives in the presence of ZnX2,4 boron/Zn
exchange from boronates,5 palladozincation of propargyl ben-
zoates or mesylates,6 direct zincation of propargyl halides,7
Zn-mediated Barbier reactions8 and Brook rearrangement.9 Com-
paratively, procedures involving iodine/Zn exchange from the
corresponding propargyl iodides10 or allenyl iodides have
scarcely been exploited.11 Closely related In-mediated reactions
have also been reported.12 In most of these reactions, allenylzinc
derivatives, supposed to be in equilibrium with the isomeric
propargylzincs, behave as propargylation reagents when reacting
with aldehydes or ketones via six-membered ring transition
states.13 This behavior affords valuable stereoselective synthetic
routes to homopropargyl alcohols.2,4−6,9,10 However, the regio-
selectivity of reactions of allenylmetal compounds with electro-
philes depends on numerous parameters like the nature of the
substituents at the α- and γ- positions in the alkynyl system, the
metal, and the nature of the electrophile. It is often related to
steric effects. As an example allenylzinc reagents derived from
TMS and most of all TIPS and TBDMS protected alkynes lead
to the quasi exclusive formation of homopropargyl alcohols.2,4,14
Our group has been involved in radical reactions promoted
by dialkylzincs over the past decade.15 The generation and the
Chelated allenylzincs of variable ring-size were prepared
from o-substituted 3-phenylpropargyl iodides of type 1b−d and
Received: December 12, 2012
Published: January 13, 2013
© 2013 American Chemical Society
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The global exchange in eq 3 implies the simultaneous for-
mation of ethyl iodide through iodine atom transfer from the
Scheme 1. General Reaction of Allenylzincs with Aldehydes
8a−c. The influence of the basic oxygen atom of ether and ester
groups on the regioselectivity of their reactions with selected
electrophiles is discussed in the following (Schemes 4, 5, 6).
propargylic iodide to ethyl radical (eq 1). As the C−I bond is
much stronger in ethyl iodide than in propargyl iodide, the
iodine atom transfer favors the generation of propargyl radical
(ΔH = −50.9 kJ mol−1 when R1 = H, according to experimental
C−I BDE values).23 Therefore the exothermicity of the first
propagation step largely counter-balance the endothermicity of
the second one (eq 2). Enthalpic factors are therefore favorable
to the formation of allenylzincs through two successive SH2
processes (global exothermicity −45.9 kJ mol−1 when R1 = H).
Both reversible and irreversible tautomerization of metal
η1-allenyl species, are known.24 The theoretical studies were com-
pleted by investigating the isomerization of monomeric ethyl
propargylzinc into the corresponding allenylzinc (Scheme 3).
As stated above, the optimization of both species led to two
distinct stable structures.25 The less stable propargylzinc readily
converts into its isomer via a concerted pathway. The reaction
profiles were calculated in three cases. The transition states
were located at the level of theory used in the optimization step
of the CBS-QB3 procedure (B3LYP/6-311G(2d,d,p)) and con-
firmed by the Intrinsic Reaction Coordinate (IRC) approach.
The calculations of their free energy performed at the CBS-
QB3 level allowed the estimation of reaction barriers and of
approximate reaction rates.
RESULTS AND DISCUSSION
■
Theoretical calculations of the C−Zn bond dissociation
enthalpy (BDE) in isomeric propargyl- and allenylzinc
derivatives were performed at the CBS-QB3 level of theory.20,21
An equilibrium promoted by a metallotropic rearrangement
is often used to represent allenylzinc and propargylzinc species
(Scheme 1). In the absence of substituent on the allenyl moiety,
allenylzinc species are reputedly thermodynamically more stable
than their propargylic isomers. Unsubstituted propargylzinc-,
3-phenylpropargylzinc-, and the corresponding isomeric allenylzinc
species, were taken as models for this theoretical study. The
bond dissociation enthalpy of the C−Zn bond in each of these
monomeric species was calculated, and the relative stability of
the two regio-isomers was compared in both cases. The data are
reported in Table 1.
Table 1. C−Zn BDEs in Propargylzinc and Allenylzinc
Species, Calculated at the CBS-QB3 Level of Theory
Theoretical calculations at the CBS-QB3 level of theory
show that the rearrangement of monomeric propargylzinc into
allenylzinc has an activation barrier ranging between 30 (iii) to
33.5 kJ mol−1 (ii) for X = Et. The structures of the transition
states are shown in Scheme 3.
As expected when the stabilization of the allenylzinc in-
creases with chelation, the activation barrier for the reverse
reaction reaches 70 kJ mol−1. Therefore, in the case of allenylzinc
B (Figure 1), the reverse process should be dramatically slowed
down. According to the calculated values, the rate constant for
the rearrangement of propargylzinc derivatives in the isomeric
allenylzincs would be extremely fast, ranging between 9 to
17 × 105 s−1 at 298 K.
The rate constant for the reverse isomerization would be
nearly 2 orders of magnitude slower in cases (i) and (ii), that is,
k− = 4−20 × 103 s−1 (which still remains very fast), whereas in
the case of the chelated enolate B (iii), the conversion of the
allenylzinc back to the propargylzinc would be 5 orders of mag-
nitude slower (k−= 1.3 s−1). This should influence the reactivity
of these organometallic species with respect to electrophiles.
Ether Oxygen Atoms as Intramolecular Coordinating
Agents. Our goal was to investigate how coordinating sub-
stituents in position ortho on the aromatic ring might influence
the regioselectivity of the trapping of allenylzinc species by
electrophiles. To this end, a series of 3-phenylpropargyl iodides
In a process initiated with oxygen, X can either be an ethyl
group or an ethoxy group in RZnX species (Scheme 2). Even
though the former is more likely in the presence of a catalytic
amount of oxygen,22 the C−Zn BDEs were calculated for both
types of monomeric propargyl- and allenylzinc species. These
values clearly indicate that the C−Zn bond is stronger in the
allenylzinc derivative. When X = Et, allenylzincs are more stable
by 16 kJ mol−1 (bare allenyl frame) and 11 kJ mol−1
(phenylsubstituted allene), than the corresponding propargyl-
zincs. At room temperature, the equilibrium between propargyl-
and allenylzinc derivatives, postulated in Scheme 1, should be
completely, or quasi completely, shifted toward the latter.
It must be noted that the C−Zn bond (Table 1) is either
lower by 5 kJ.mol−1 (R = CHCCH2) or 16 kJ.mol−1 (R =
C(Ph)CCH2) in allenylzinc derivatives than the C−Zn
bond in Et2Zn (277 kJ mol−1 at the same level of theory). This
means that the transfer of EtZn group should be endothermic.
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Scheme 2. Radical Route to Allenylzincs and Subsequent Trapping by Benzaldehyde
bearing methoxy or ω-methoxyalkyl groups in position ortho
relative to the triple bond were prepared and reacted with di-
ethylzinc in the presence of benzaldehyde in nondegassed medium.
The results compared to those obtained from 3-phenylpropargyl
iodide are given in Scheme 5. Blank experiments performed in
the absence of aldehyde by simply quenching the reaction with
aqueous NH4Cl, led to the data reported in Scheme 4. A trace
amount of the alkyne resulting from nucleophilic substitution of
the iodine atom by an ethyl group, was detected in the case of
iodide 1b. This is consistent with iodide becoming a better
leaving group as regard to nucleophilic displacement, owing to
the electronic effect of the o-methoxy group.
It is worth noting that the role of oxygen was even more
striking when more oxygen was allowed to interact with the
solution by several cycles of shaking/reopening the NMR tube
just before registering the spectrum (Figure 2). The formation
of allenylzinc B and EtI became quasi instantaneous.27 The
formation of allenylzinc C exhibited the very same behavior. A
closely related behavior was also observed when monitoring the
reaction of diethylzinc with 1d. (see Supporting Information).
It was interesting to compare the reactivity of iodide 1a to
that of 1b. In the case of 1a (Figure 3), no clearly distinct
signals could be assigned to the protons of either allenylzinc A
or its propargylic isomeric form, even though the signals cor-
responding to EtI were strong. Only a hardly visible very broad
singlet appeared at 2.65 ppm. That signal gradually increased
with the amount of EtI in the reaction medium. However, the
quenching of the reaction led to clean signals corresponding
to the expected allene and alkyne in a 55:45 ratio, exactly
matching the amount of EtI, as in the other experiments.
This observation would be consistent with a polymeric nature of
these organozinc species, as suggested by Utimoto, who reported
that the depolymerization of the latter could be induced by
the addition of diethyl ether to the reaction medium.10 The
involvement of a radical mechanism in alkenes carbozincation
has already been proposed.28 However, covalent bonding is not
necessarily implied in the formation of polymeric species, co-
ordination of Zn(II) with π bonds has already been demonstrated.29
The broadening of the signal suggests an alternative rationale, it
might result of a dynamic process with allenyl- and propargylzinc
species fastly interconverting at room temperature at an inter-
mediate rate with respect to the NMR time-scale.
Clearly no incidence of the possible chelation of allenylzinc
intermediates B−D (Figure 1) was detected on the regio-
selectivity of the protonation. This is in good agreement with
the lack of significant difference in Mulliken net atomic charges
on the two extreme carbons of the allenyl (or propargyl) sys-
tem in the isomeric metalated derivatives (Table 2).
1
The formation of allenylzincs was monitored by H NMR
(nondegassed solvent).26 As shown in Figure 2, in the case of
iodide 1b, nearly no evolution was detected unless the NMR
tube was shaken so that the two reagents interact with each
other. Only the starting material was detected (the methylene
protons and the methyl protons gave rise to two singlets at 3.95
and 3.80 ppm, respectively).
After shaking the solution, which clearly evidenced the
influence of the nondegassed medium (Figure 2), the signal of
EtI grew regularly while new signals appeared that were
assigned to allenylzinc B (☆) (1:1 ratio with respect to EtI; the
CH2 group was assigned the singlet at 4.31 ppm and the
protons in the CH3O group exhibited a singlet at 3.89 ppm). It
is to be noted that trace amount of 2b (▲) and 3b (■)
together with the alkyne resulting from the nucleophilic sub-
stitution of iodine by an ethyl group (ArCCCH2CH2CH3)
were detected. After completion, the quenching of the reaction
by addition of a drop of water led to the disappearance of the
signals corresponding to allenylzinc B, and concomitantly to
the increase of the signals of both 2b and 3b (60:40 ratio)
resulting from its protonation. Only trace amount of signals
corresponding to ethoxy groups could be detected at 3.70 ppm
under these conditions.
As expected from the estimate of the isomerization rate
constant, the coordinated methoxy group in B (and in all
likelihood in C) would slow down the interconversion process
so that only the most stable allenylzinc species are detected by
NMR. The rate of interconversion would be too fast in the case
1
of A. No effect was observed on the H NMR spectrum by
lowering the temperature down to 200 K.
The reaction of diethylzinc with oxygen is likely to promote a
radical chain reaction, as proposed in Scheme 2. Propargyl
radical can be represented by the contribution of two canonical
forms. It should rapidly interconvert into the slightly geometrically
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Scheme 3. Isomerization of Propargylzinc Derivatives in
Isomeric Allenylzincs
Figure 1. Structure of allenylzincs A−D.
Scheme 4. Protonation of Allenylzincs A−D
C−H and the C−Car bonds are 467 and 257 cm−1, in propargyl
and phenylpropargyl radicals, respectively, which indicates a
very low barrier to the geometrical change.30 As already stated,
owing to the substitution of Et−Zn bond by a slightly weaker
C−Zn bond and the replacement of the propargyl-I bond by a
much stronger C−I bond, the allenyl radical can displace an ethyl
group from diethylzinc. This displacement is even more favored in
the presence of a coordinating substituent on the aromatic ring.
Visualization of Natural Bond Orbitals31 (performed on
geometries calculated at the B3LYP/6-31+G(d,p)) showing the
orbital overlaps that probes the interaction between the oxygen
lone pair and zinc in the chelated allenylzincs B and D is given
in Figure 4. Even in the case of the most flexible arm in position
ortho (-(CH2)2OMe) (D), the NBO analysis shows that the
overlap of the lone pair of the oxygen atom with the vacant p
orbital at zinc contributes to the stabilization of the allenylzinc
species (by approximately 18 and 17 kcal mol−1, respectively).
The influence of the chelating arms on the aromatic ring on
the relative stabilities of allenylzincs B, C, D, as compared to
the corresponding propargylzinc species, was calculated. The
results of these theoretical calculations are given in Table 3. It
must be noted that the stability of the most stable conformers
of the chelated allenylzinc species shown in Figure 5 was found
superior by 26−30 kJ mol−1 to that of the nonchelated, torsionless,
released conformers. This supports the easy formation of chelated
species.
The presence of coordinating agents in the medium strongly
influences the reactivity of alkylzinc species.
The reactions reported in Scheme 5, performed in the
presence of benzaldehyde, were compared to the reaction
performed with propargyl iodide which can be used as standard
(eq 4). Under completely similar experimental conditions, the
allenylzinc formed from propargyl iodide led to the highly
regioselective formation of the expected homopropargyl alcohol.
This result is obviously different from the data obtained from
nonsubstituted 3-phenyl-propargyl iodide 1a which led to a
different allenyl radical. This vibrational motion is accompanied
by the rehybridation of the initially sp hybridized carbon atom
into a sp2 carbon. The calculated bending frequencies of the
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Table 2. Mulliken Net Atomic Charges in Propargyl and Allenylzinc Species Calculated at B3LYP/6-311G(2d,d,p)
1
Figure 2. H NMR monitoring (between 2.0 and 5.4 ppm) of the formation of organometallic species from 1b.
52:48 ratio of allenylation to propargylation (Scheme 5). This
experimental observation correlates with the relative stabilities
of propargyl/allenylzinc species in both cases. However, no
assumption could be made about the rate constant for the
bimolecular reaction of each species with benzaldehyde.
In the presence of benzaldehyde, a clear influence of the
nature of the substituent in position ortho on the aromatic ring
is observed. The size of the intermediate chelated allenylzinc
governs the regioselectivity and the overall yield of the reaction
(Scheme 5).
It must be noted that reactions were performed under inert
atmosphere but without degassing the solvent in order for a
catalytic amount of oxygen to be present in the medium to
initiate a radical chain process. Very good yields could be reached
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1
Figure 3. H NMR monitoring (between 2.0 and 5.4 ppm) of the formation of organometallic species from 1a.
Table 3. Relative Energies of Propargylzinc and Chelated
Allenylzinc Species Calculated at the CBS-QB3 Level of
Theory
Figure 4. NBO visualization of the interaction between the oxygen
lone pair and the metal in B and D.
despite the presence of oxygen.9,32 Even when air was added
(20 mL) to the reaction medium in dichloromethane, the
overall yield from iodide 1d was only lowered to 78%. The ratio
of isomeric products was essentially the same, and trace amount
of propargylic alcohol was detected. This argues in favor of a
radical mechanism for the formation of the reactive species,
whatever the experimental conditions.
observed in the In(0)-mediated reaction (97:3 in favor of
the allenylation product), however, the latter experiment was
performed at room temperature in the presence of a chiral
amino-alcohol.11d A completely different ratio was also reported
by Tamaru and co-workers for the Pd-catalyzed zincation of 1a
which led to a 18:82 ratio in favor of the homopropargylic
alcohol at the same temperature.6a It is hardly believable that
It is noteworthy that the lack of regioselectivity in the
reaction of 1a (Scheme 5) is completely different from that
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Table 4. Parameters Influencing the Ratio of Allenyl/
Homopropargyl Alcohol Starting from 1d
entry T (° C)
solvent
time
14 h
yield
products
ratio
1
2
3
4
5
6
7
8
9
25
25
CH2Cl2
Toluene
THF
90%
56%
51%
84%
64%
96%
87%
70%
73%
4d:5d
4d:5d
4d:5d
4d:5d
4d:5d
4d:5d
6d:7d
8d:9d
10d:11d
72:28
75:25
75:25
74:26
72:28
7:93
14 h
14 h
14 h
16 h
40 min
14 h
14 h
14 h
25
25
DMF
−10
80
CH2Cl2
(CH2Cl)2
CH2Cl2
CH2Cl2
CH2Cl2
Figure 5. Calculated most stable conformers of chelated allenyl species
B, C, and D and the corresponding propargylzincs.
25
<1:>99
66:34
25
a
Scheme 5. Reaction of Allenylzincs A−D with Benzaldehyde
25
9:91
a
Trace amount of the propargylic alcohol corresponding to the
1
starting material was detected from the H NMR spectrum of the
crude mixture.
The lowering of the temperature down to −10 °C did not
increase the amount of allenyl alcohol (entry 5). Conversely,
increasing the temperature up to 80 °C led to a 7:93 regio-
isomers ratio in favor of the homopropargylic alcohol (entries 6)
which is the thermodynamic product. When an isolated 69:31
mixture of allenyl- and homopropargyl- alcohols 4d and 5d was
allowed to react with diethylzinc at 80 °C, 5d was isolated as
the only product in quantitative yield. This is an additional
evidence for the reversibility of the addition reaction that had
previously been assumed.2a Conversely allenyl alcohol 4a
prepared in 72% from 1a by the indium methodology (In(0),
AcOH, in DMF)11 was recovered unchanged after treatment by
diethylzinc at room temperature. This demonstrated that the
reaction is irreversible at room temperature.
the same type of reactive intermediate could be involved in
these reactions.
The presence of the ortho-substituent influences the ratio of
allenylation to propargylation. Increasing the size of the ring in
the chelated allenylzincs, which are likely to be involved in
these reactions, contributes to increase the ratio of allenyl
alcohol. It is generally admitted that propargyl- and allenylzincs
react through six-membered transition states to give alleny-
lation and propargylation products, respectively.2 Therefore the
more stabilized is the allenylmetal, the higher the ratio of
homopropargyl versus allenyl alcohol should be. The frame
giving rise to the most stabilized chelate leads to the highest
relative amount of homopropargyl alcohol (Figure 1). Never-
theless, it is difficult to exclude from these data, the parti-
cipation of a SE2 mechanism in these reactions. Only the
determination of the activation barriers of SE2′ reactions of
allenyl- and propargylzinc species with aldehydes would help in
clarifying this point. The knowledge of thermodynamic data is
not sufficient to predict the kinetics of competitive reactions.
Since most methods involving organozincs, as reminded above,
are selective in the formation of homopropargyl alcohols, we tried
to displace the reaction in the opposite direction. We searched
how to improve the amount of allenylation by testing various
experimental conditions in the most favorable case, that is,
taking 1d as substrate. The influence of parameters like the
solvent, the temperature, and the nature of the electrophile are
reported in Table 4.
Theoretical calculations of the zinc alkoxides, precursors of
4a and 5a were performed to confirm that homopropargylic
alkoxides were more stable than the isomeric allenyl alkoxides
(Figure 6). The homopropargylic zinc alkoxide is more stable
Figure 6. Relative stability of the most stable conformers of the zinc
alkoxides precursors of 4a and 5a in (CBS-QB3 level).
by 20.3 kJ mol.−1 than the isomeric allenyl zinc alkoxide.
Alcohol 5a is clearly the thermodynamic product.
Finally it can be noted that replacing benzaldehyde by the
more crowded and less reactive acetophenone led to the ex-
clusive formation of the corresponding propargylation product
No significant change in the regioisomers ratio was detected
when changing the nature of the solvent (entries 1−3). However,
yields were lower in toluene and THF than in DCM. Temperature
has a large incidence on the ratio of the two regioisomers.
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Scheme 6. Reaction of Allenylzincs E−G with Benzaldehyde
7d (entry 7). Propanaldehyde led to a 66:34 ratio of 8d to 9d
(entry 8), while acetone, as acetophenone, led to
the quasi exclusive formation of homopropargylic alcohol 11d
(entry 9). This clearly confirms the incidence of steric hindrance
which slows down the rate of formation of allenyl alcohol.
Ester Carbonyl Groups as Intramolecular Coordinat-
ing Agents. The introduction of a methyl carboxylate as
coordinating group in position ortho relative to the triple bond
was also investigated starting from iodides 8a−c. The results of
their reaction with diethylzinc in the presence of benzaldehyde
at room temperature are given in Scheme 6.
Scheme 7. Reaction of Iodides 12a,b with Benzaldehyde
CONCLUSION
■
In this case varying the alkyl chain spacer induces the pos-
sibility to compare the reactivity of 6-, 7-, and 8-membered
chelated allenyl zinc E, F, and G, respectively (Figure 7).
In conclusion, we have shown that the formation of allenylzincs
could be promoted by diethylzinc, in the presence of oxygen,
via the generation of propargyl radicals from propargyl iodides.
The involvement of a radical chain mechanism had already
been suspected from the detection of propargyl radicals by
EPR.16 Its validity was attested by theoretical calculations of
dissociation enthalpies of C−Zn and C−I bonds, performed at
the CBS-QB3 level. The relative stability of isomeric propargyl-
and allenylzincs was also confirmed in this study. The reactivity
of ortho-substituted 3-phenylpropargyl iodides clearly indicated
that the possibility to stabilize allenylzincs by chelation in-
fluences the regioselectivity of their addition to aldehydes.
Increasing the stability of the reactive allenylzinc intermediate
by reducing the chelate ring size led to improve the ratio of
homopropargyl-/allenyl- alcohols. However, the knowledge of
thermodynamic data is only indicative. It does not allow the
kinetics of competitive reactions to be predicted. Monitoring
the formation of allenylzinc by 1H NMR brought new evidence
for the importance of ligation on the stabilization and on the
reactivity of organozinc species and most of all for the acceleration
of the formation of allenylzinc by oxygen.
Figure 7. Structure of allenylzincs E−G.
Increasing the size of the ring in the chelated allenylzinc
again favors the ratio of allenyl alcohols 10 (and (or) the
resulting lactones 9) to homopropargyl alcohols 11. Again,
rising the temperature of the reaction increased the ratio of the
thermodynamic product 11b formed from 8b at 80 °C. This is
in good agreement with the trend previously observed with the
series of aromatic ethers. The difference resides in this case in
further lactonization of the allenyl alcohol.
Behavior of Aliphatic Derivative 12. The reactivity of
iodide 12a was studied by comparison to 12b. The results are
given in Scheme 7. They confirm the absence of influence of
the flexible methoxylated tether on the regioselectivity of the
reaction with benzaldehyde. It must be noted that comparing
12a to 1a shows a dramatic influence of conjugation with the
aromatic ring in 1a on the ratio of regio-isomeric products.
EXPERIMENTAL SECTION
■
General. Commercially available dichloromethane (pure for synthesis
and stabilized with ethanol 0.1−0.4% m/m) was stored on molec-
ular sieves, and used without further purification. The commercially
available dialkylzinc solutions were 1 M in heptane. Analytical thin
layer chromatography was performed on precoated silica gel plates.
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(CH), 128.7 (CH), 126.4 (CH), 122.5 (C), 91.3 (C),
84.1 (C), 72.7 (CH2), 58.7 (CH3), 51.6 (CH2), 34.8 (CH2).
HRMS: Calcd for C12H15O2+ (M + H)+ 191.1067, Found 191.1068.
Methyl 2-(3-hydroxyprop-1-ynyl)benzoate (5y). The compound
5y was obtained from methyl 2-iodobenzoate (5x) (1 g, 3.8 mmol,
1 equiv) Propargyl alcohol (0.638 g, 11.49 mmol, 3 equiv), Pd(PPh3)4
(0.131 g, 0.11 mmol, 0.03 equiv), CuI (0.043 g, 0.229 mmol, 0.06
equiv) in THF/Et3N (20:10 mL) were mixed according to the general
procedure A for 3 h to give 5y as a yellow oil in 66% yield (0.476 g).
1H NMR (400 MHz, CDCl3) δ: 7.92 (d, J = 7.8, 1H), 7.54 (d, J = 7.8,
1H), 7.45 (t, J = 7.5 1H), 7.36 (t, J = 7.5 1H), 4.55 (s, 2H), 3.91 (s,
3H), 2.37 (br s, 1H). 13C NMR (100 MHz, CDCl3) δ: 166.7 (OC),
134.3 (CH), 132.0 (CH), 131.8 (C), 130.5 (CH), 128.2
(CH), 123.4 (C), 92.9 (C), 84.3 (C), 52.4 (CH3), 51.8 (CH2).
1H 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 abbreviations:
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 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 mea-
sured using an orthogonal acceleration time-of-flight mass analyzer.
General Procedure for the Synthesis of Orthosubstituted 3-
Phenylalkynyl iodides 1a−d and 8a−c. General Procedure A,
Sonogashira Cross-coupling.33 To a solution of orthosubstituted
phenyl iodide (2x−7x) in a 2:1 mixture of dry tetrahydrofuran/
triethylamine was added Pd(PPh3)4 (6 mol %) followed by CuI
(3 mol %) and propargyl alcohol (3 equiv), under argon atmosphere.
The above solution was stirred at 40 °C and the reaction progress was
monitored by CCM. After completion, the reaction mixture was
concentrated in vacuo and the crude residue was purified through flash
column chromatography using a 1:1 pentane/diethylether mixture as
the eluent, to obtain the cross-coupled products 2y−7y.
+
HRMS: Calcd for C11H14NO3 (M + NH4)+ 208.0974, Found
208.0975.
Methyl 2-(2-(3-hydroxyprop-1-ynyl)phenyl)acetate (6y). Methyl
2-(2-iodophenyl)acetate (6x) (1 g, 3.63 mmol, 1 equiv), propargyl
alcohol (0.60 g, 10.89 mmol, 3 equiv), Pd(PPh3)4 (0.125 g, 0.108
mmol, 0.03 equiv), CuI (0.041 g, 0.217 mmol, 0.06 equiv), and THF/
Et3N (20:10 mL) were subjected to the conditions mentioned in the
general procedure A for 16 h to get compound 6y as a yellow oil in
87% yield (0.650 g). 1H NMR (400 MHz, CDCl3) δ: 7.43 (d, J = 7.5,
1H), 7.32−7.21 (m, 3H), 4.49 (s, 2H), 3.82 (s, 2H), 3.70 (s, 3H), 1.94
(br s, 1H). 13C NMR (100 MHz, CDCl3) δ: 172.1 (OC), 136.5
(C), 132.1 (CH), 130.0 (CH), 128.9 (CH), 127.3 (CH),
123.0 (C), 92.4 (C), 83.9 (C), 52.3 (CH3), 51.7 (CH2), 40.3
(CH2).
+
HRMS: Calcd for C12H16NO3 (M + NH4)+ 222.1125, Found
222.1125.
Methyl 3-(2-(3-Hydroxyprop-1-ynyl)phenyl)propanoate (7y).
Methyl 3-(2-iodophenyl)propanoate (7x) (1.20 g, 4.13 mmol, 1 equiv),
propargyl alcohol (0.69 g, 12.39 mmol, 3 equiv), Pd(PPh3)4 (0.147 g,
0.123 mmol, 0.03 equiv), CuI (0.047 g, 0.247 mmol, 0.06 equiv), and
THF/Et3N (20:10 mL) were subjected to the conditions depicted in
the general procedure A for 21 h to obtain compound 7y as a yellow
3-(2-Methoxyphenyl)prop-2-yn-1-ol (2y):34 1-Iodo-2-methoxyben-
zene (2x) (1 g, 4.27 mmol, 1 equiv), propargyl alcohol (0.72 g,
12.81 mmol, 3 equiv), Pd(PPh3)4 (0.15 g, 0.13 mmol, 0.03 equiv), CuI
(0.049 g, 0.26 mmol, 0.06 equiv), and THF/Et3N (20:10 mL) were
reacted under the conditions mentioned in the general procedure A for
12 h to obtain compound 2y as a yellow oil in 79% yield (0.55 g).
1H NMR (400 MHz, CDCl3) δ: 7.41 (dd, J = 7.5, 1.5, 1H), 7.30 (td,
J = 8.2, 1.5, 1H), 6.95−6.83 (m, 2H), 4.54 (s, 2H), 3.81 (s, 3H), 1.72
(br s, 1H). 13C NMR (100 MHz, CDCl3) δ: 160.1 (C), 133.9 (CH),
130.1 (CH), 120.6 (CH), 111.7 (C), 110.7 (CH), 91.5 (C), 82.1
(C), 55.9 (OCH3), 52.03 (OCH2).
1
oil in 91% yield (0.820 g). H NMR (400 MHz, CDCl3) δ: 7.40 (dd,
J = 7.5, 0.75, 1H), 7.27−7.15 (m, 3H), 4.52 (s, 2H), 3.68 (s, 3H), 3.10
(t, J = 7.8, 2H), 2.66 (t, J = 8.0, 2H), 2.20 (s, 1H). 13C NMR (100
MHz, CDCl3) δ: 174.0 (OC), 142.7 (C), 132.3 (CH), 128.9
(CH), 128.8 (CH), 126.5 (CH), 122.2 (C), 92.0 (C),
83.9 (C), 51.9 (CH3), 51.7 (CH2), 35.0 (CH2), 30.3 (CH2).
+
HRMS: Calcd for C13H18NO3 (M + NH4)+ 236.1281, Found
236.1281.
General Procedure B, Iodination Reaction.35 To a light-
protected solution (flask wrapped in an aluminum foil) of phenyl
propargyl alcohol derivative (1y−7y) in dry CH2Cl2 under argon
atmosphere at 0 °C, were added imidazole (1.5 equiv), triphenyl-
phosphine (1.5 equiv) and iodine (1.5 equiv). The reaction mixture
was stirred at 0 °C and monitored by CCM. After completion of the
reaction, the excess of iodine was removed by washing with sat. aqueous
Na2S2O3 solution and the organic layer was dried with MgSO4, filtered
and concentrated in vacuo. The resultant residue was quickly purified
through flash column chromatography using pentane/diethylether
mixture (9:1) as the eluent to give the ortho-substituted 3-phenylalkynyl
iodides (1a-d and 8a-c).
+
HRMS: Calcd for C10H14NO2 (M + NH4)+ 180.1019, Found
180.1021.
3-(2-(Methoxymethyl)phenyl)prop-2-yn-1-ol (3y). 1-Iodo-2-
(methoxymethyl)benzene (3x) (3.20 g, 13.00 mmol, 1 equiv),
propargyl alcohol (2.18 g, 39.00 mmol, 3 equiv), Pd(PPh3)4 (0.45 g,
0.39 mmol, 0.03 equiv), CuI (0.15 g, 0.78 mmol, 0.06 equiv), and
THF/Et3N (60:30 mL) were subjected to the conditions depicted in
the general procedure A for 3 h to obtain compound 3y as a yellow oil
in 88% yield (2 g). 1H NMR (400 MHz, CDCl3) δ: 7.43 (2xd, J = 7.7,
2H), 7.33 (t, J = 7.5, 1H), 7.24 (t, J = 7.5, 1H), 4.62 (s, 2H), 4.52
(d, J = 5.0, 2H), 3.43 (s, 3H), 2.41 (br s, 1H). 13C NMR (100 MHz,
CDCl3) δ: 140.0 (C), 132.4 (CH), 128.8 (CH), 127.8
(CH), 127.5 (CH), 121.5 (C), 92.0 (C), 83.3 (C), 72.8
(CH2), 58.5 (CH3), 51.7 (CH2).
1-(3-Iodoprop-1-ynyl)benzene (1a). 3-Phenylprop-2-yn-1-ol (1y)
(1 g, 7.6 mmol, 1 equiv), imidazole (0.772 g, 11.36 mmol, 1.5 equiv),
triphenylphosphine (2.97 g, 11.36 mmol, 1.5 equiv) and iodine (2.87 g,
11.36 mmol, 1.5 equiv) were mixed in dry CH2Cl2 (40 mL) according to
the general procedure B for 3 h to afford 74% of the titled compound 1a
as a yellow viscous liquid (1.4 g). 1H NMR (400 MHz, CDCl3) δ: 7.44−
7.41 (m, 2H), 7.33−7.29 (m, 3H), 3.96 (s, 2H). 13C NMR (100 MHz,
CDCl3) δ: 139.9 (CH), 128.8 (CH), 128.4 (CH), 122.7 (C),
86.4 (C), 85.5 (C), −17.3 (CH2).
HRMS: Calcd for C11H12O2Na+ (M + Na)+ 199.0729, Found
199.0729.
3-(2-(2-Methoxyethyl)phenyl)prop-2-yn-1-ol (4y). The compound
4y was obtained from 1-Iodo-2-(2-methoxyethyl)benzene (4x) (1 g,
3.83 mmol, 1 equiv). Propargyl alcohol (0.643 g, 11.49 mmol,
3 equiv), Pd(PPh3)4 (0.128 g, 0.11 mmol, 0.03 equiv), CuI (0.044 g,
0.229 mmol, 0.06 equiv) in THF/Et3N (20:10 mL) were mixed
according to the general procedure A for 3 h to give 4y as a yellow oil
HRMS: Calcd for C9H7IAg+ (M + Ag)+ 348.8638, Found 348.8633.
1-(3-Iodoprop-1-ynyl)-2-methoxybenzene (1b). 3-(2-
Methoxyphenyl)prop-2-yn-1-ol (2y) (1 g, 3.67 mmol, 1 equiv), imidazole
(0.375 g, 5.51 mmol, 1.5 equiv), triphenylphosphine (1.44 g, 5.51 mmol,
1.5 equiv) and iodine (1.39 g, 5.51 mmol, 1.5 equiv) were mixed in dry
1
in 52% yield (0.378 g). H NMR (400 MHz, CDCl3) δ: 7.43 (d, J =
7.3, 1H), 7.30−7.22 (m, 2H), 7.21−7.15 (m, 1H), 4.53 (s, 2H), 3.65
(t, J = 7.3, 2H), 3.39 (s, 3H), 3.09 (t, J = 7.3, 2H), 2.60 (br s, 1H).
13C NMR (100 MHz, CDCl3) δ: 140.8 (C), 132.8 (CH), 129.5
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CH2Cl2 (25 mL) according to the general procedure B for 3 h to afford
compound 1b as a yellow viscous liquid (71%, 1.06 g). H NMR (400
(CH), 126.5 (CH), 122.0 (C), 90.4 (C), 83.9 (C), 51.8
(CH3), 34.9 (CH2), 29.9 (CH2), −17.4 (CH2).
HRMS: Calcd for C13H14O2I+ (M + H)+ 329.0033, Found
329.0025.
Synthesis of Aliphatic Propargyliodides 12a, 12b and
Propargyliodides.
1
MHz, CDCl3) δ: 7.39 (dd, J = 7.5, 1.5, 1H), 7.32 (td, J = 8.5, 1.5, 1H),
6.88 (td, J = 7.5, 0.8, 1H), 6.86 (d, J = 8.5, 1H), 4.05 (s, 2H), 3.90
(s, 3H). 13C NMR (100 MHz, CDCl3) δ: 160.3 (C), 133.9 (CH),
130.3 (CH), 120.6 (CH), 111.8 (C), 110.8 (CH), 90.3 (C),
82 (C), 56 (CH3), −16.5 (CH2).
HRMS: Calcd for C10H10OI+ (M + H)+ 272.9770, Found 272.9770.
1-(3-Iodoprop-1-ynyl)-2-(methoxymethyl)benzene (1c). The com-
pound 1c was obtained from 3-(2-(Methoxymethyl)phenyl)prop-2-yn-1-
ol (3y) (2.00 g, 11.36 mmol, 1 equiv), 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) in dry CH2Cl2 (60 mL) according to the
general procedure B. Compound 1c was isolated after 3 h as a yellow
oil in 92% yield (3 g). 1H NMR (400 MHz, CDCl3) δ: 7.42 (m, 2H),
7.34 (dt, J = 1.3, 7.5, 1H), 7.23 (dt, J = 1.0, 7.5, 1H), 4.61 (s, 2H), 4.00
(s, 2H), 3.47 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 140.7 (C),
132.2 (CH), 129.0 (CH), 127.7 (CH), 127.4 (CH), 121.2
(C), 90.7 (C), 83.3 (C), 72.6 (CH2), 58.7 (CH3), −17.5 (CH2).
HRMS: Calcd for C11H15NOI (M + NH4)+ 304.0192, Found
304.0192.
1-Iodooct-2-yne (12a). Oct-2-yn-1-ol (9z)36 (2 g, 16 mmol, 1 equiv),
imidazole (1.63 g, 24 mmol, 1.5 equiv), triphenylphosphine (6.28 g, 24
mmol, 1.5 equiv) and iodine (6.07 g, 24 mmol, 1.5 equiv) were reacted
in dry CH2Cl2 (15 mL) according to the general procedure B for 2 h
1
to afford product 12a as a yellow liquid (68%, 2.6 g). H NMR (400
MHz, CDCl3) δ: 3.70 (t, J = 2.5, 2H), 2.21−2.15 (m, 2H), 1.54−1.45
(m, 2H), 1.40−1.25 (m, 4H), 0.89 (t, J = 7.0, 3H). 13C NMR (100
MHz, CDCl3) δ: 87.0 (C), 77.1 (C), 31.1 (CH2), 28.2 (CH2),
22.3 (CH2), 19.2 (CH2), 14.1 (CH3), −16.5 (CH2).
HRMS: Calcd for C8H13IAg+ (M + Ag)+ 342.9107, Found
342.9109.
1-(3-Iodoprop-1-ynyl)-2-(2-methoxyethyl)benzene (1d). 3-(2-(2-
Methoxyethyl)phenyl)prop-2-yn-1-ol (4y) (2.20 g, 11.57 mmol, 1 equiv),
imidazole (1.18 g, 17.35 mmol, 1.5 equiv), triphenylphosphine (4.50 g,
17.35 mmol, 1.5 equiv) and iodine (4.40 g, 17.35 mmol, 1.5 equiv)
were mixed in dry CH2Cl2 (80 mL) under the general procedure B for
3 h to afford compound 1d as a yellow oil (88%, 3 g). 1H NMR (400
MHz, CDCl3) δ: 7.40 (d, J = 7.3, 1H), 7.30−7.22 (m, 2H), 7.18−7.14
(m, 1H), 4.00 (s, 2H), 3.64 (t, J = 7.2, 2H), 3.39 (s, 3H), 3.05 (t, J =
7.3, 2H). 13C NMR (100 MHz, CDCl3) δ: 141.4 (C), 132.5 (CH),
129.7 (CH), 128.9 (CH), 126.4 (CH), 122.3 (C), 89.9 (C),
84.3 (C), 72.7 (CH2), 58.8 (CH3), 34.8 (CH2), −17.2 (CH2).
HRMS: Calcd for C12H14OI+ (M + H)+ 301.0083, Found 301.0085.
Methyl 2-(3-Iodoprop-1-ynyl)benzoate (8a). Methyl 2-(3-hydrox-
yprop-1-ynyl)benzoate (5y) (2.00 g, 10.52 mmol, 1 equiv), imidazole
(1.07 g, 15.78 mmol, 1.5 equiv), triphenylphosphine (4.10 g, 15.78
mmol, 1.5 equiv) and iodine (4.00 g, 17.35 mmol, 2 equiv) were
stirred in dry CH2Cl2 (40 mL) according to the general procedure B
2-(7-Methoxyhept-2-ynyloxy)-tetrahydro-2H-pyran (8y):37 To a
solution of THP protected propargyl alcohol (4.25g, 30.37 mmol, 1 equiv)
in 50 mL of dry THF at −78 °C was added n-BuLi (13 mL, 30.37 mmol,
1 equiv, 2.34 M solution in hexane) over 30 min. After the completion
of the addition, the mixture was warmed to room temperature and
then substrate 8x38 (6.5g, 30.37 mmol, 1 equiv) was added over
10 min. The resulting mixture was heated at 55 °C for 24 h. The
cooled mixture was diluted in ethylacetate and sequentially washed
with ice−water, water and brine. The organic extract was dried over
MgSO4 and concentrated. The residue was purified through flash
column chromatography to give product 8y (5.5 g, 80% yield) as
colorless liquid. 1H NMR (400 MHz, CDCl3) δ: 4.79 (t, J = 3.3, 1H), 4.27
(dt, J = 15.3, 2.0, 1H), 4.17 (dt, J = 15.3, 2.0, 1H), 3.82 (m, 1H), 3.52 (m,
1H), 3.37 (t, J = 6.5, 2H), 3.31 (s, 3H), 2.24 (tt, J = 2.0, 7.0, 2H), 1.90−
1.44 (m, 10H). 13C NMR (100 MHz, CDCl3) δ: 96.8 (CH), 86.4 (C),
76.2 (C), 72.3 (CH2), 62.1 (CH2), 58.7 (CH3), 54.7 (CH2), 30.4 (CH2),
28.9 (CH2), 25.5 (CH2), 25.4 (CH2), 19.3 (CH2), 18.8 (CH2).
1
for 3 h to give compound 8a as a yellow oil (90%, 2.83 g). H NMR
(400 MHz, CDCl3) δ: 7.94 (dd, J = 7.9, 1.6, 1H), 7.53 (dd, J = 7.5, 1.0,
1H), 7.46 (td, J = 7.5, 1.3, 1H), 7.37 (td, J = 7.5, 1.0, 1H), 4.02
(s, 2H), 3.96 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 166.5 (OC),
134.2 (CH), 132.0 (C), 131.7 (CH), 130.5 (CH), 128.3
(CH), 123.0 (C), 91.1 (C), 84.0 (C), 52.4 (CH3), −17.3
(CH2).
HRMS: Calcd for C11H10O2I+ (M + H)+ 300.9720, Found
300.9716.
+
HRMS: Calcd for C13H22NaO3 (M + Na)+ 249.1461, Found
Methyl 2-(2-(3-iodoprop-1-ynyl)phenyl)acetate (8b). Methyl 2-(2-
(3-hydroxyprop-1-ynyl)phenyl)acetate (6y) (0.63 g, 3.08 mmol, 1 equiv),
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) were
stirred in dry CH2Cl2 (15 mL) according to the general procedure B
249.1459.
7-Methoxyhept-2-yn-1-ol (8z):39 To a solution of 2-(7-methoxy-
hept-2-ynyloxy)-tetrahydro-2H-pyran (8y) (2.42 g, 10.7 mmol) in
100 mL of ethanol was added pyridinium p-toluenesulfonate (2.68 g,
10.7 mmol) slowly 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 resulted residue was purified through flash
column chromatography to get product 8z as colorless liquid in 80%
1
for 2 h to give compound 8b as a yellow oil (80%, 0.75 g). H NMR
(400 MHz, CDCl3) δ: 7.43 (d, J = 7.5, 1H), 7.32−7.21 (m, 3H), 3.97
(s, 2H), 3.82 (s, 2H), 3.73 (s, 3H). 13C NMR (100 MHz, CDCl3) δ:
171.6 (OC), 136.7 (C), 132.4 (CH), 130.0 (CH), 129.1
(CH), 127.3 (CH), 122.9 (C), 90.8 (C), 83.6 (C), 52.3
(CH3), 39.8 (CH2), −17.8 (CH2).
1
yield (1.2 g): H NMR (400 MHz, CDCl3) δ: 4.19 (br s, 2H), 3.35
(t, J = 6.3, 2H), 3.29 (s, 3H), 2.21 (tt, J = 2.3, 7.0, 2H), 1.86 (br s, 1H),
1.67−1.60 (m, 2H), 1.57−1.50 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ: 86.2 (C), 78.8 (C), 72.4 (CH2), 58.7 (CH3), 51.4
(CH2), 28.8 (CH2), 25.4 (CH2), 18.7 (CH2).
HRMS: Calcd for C12H12O2I+ (M + H)+ 314.9877, Found
314.9871.
+
HRMS: Calcd for C8H14NaO2 (M + Na)+ 165.0886, Found
Methyl 3-(2-(3-Iodoprop-1-ynyl)phenyl)propanoate (8c). Methyl
3-(2-(3-hydroxyprop-1-ynyl)phenyl)propanoate (7y) (0.80 g, 3.66
mmol, 1 equiv), imidazole (0.37 g, 5.50 mmol, 1.5 equiv),
triphenylphosphine (1.40 g, 5.50 mmol, 1.5 equiv) and iodine (1.40
g, 5.50 mmol, 1.5 equiv) were reacted in dry CH2Cl2 (15 mL)
according to the general procedure B for 2 h to afford product 8b as a
yellow oil (56%, 0.75 g). 1H NMR (400 MHz, CDCl3) δ: 7.39 (dd, J =
7.8, 1.0, 1H), 7.27−7.14 (m, 3H), 3.99 (s, 2H), 3.68 (s, 3H), 3.08 (t,
J = 7.5, 2H), 2.68 (t, J = 8.3, 2H). 13C NMR (100 MHz, CDCl3) δ:
173.4 (OC), 143.1 (C), 132.5 (CH), 129.1 (CH), 129.05
165.0883.
1-Iodo-7-methoxyhept-2-yne (12b). 7-Methoxyhept-2-yn-1-ol
(8z) (1.2 g, 8.45 mmol, 1 equiv), imidazole (0.86 g, 12.6 mmol, 1.5
equiv), triphenylphosphine (3.3 g, 12.6 mmol, 1.5 equiv) and iodine
(3.18 g, 12.6 mmol, 1.5 equiv) were reacted in dry CH2Cl2 (15 mL)
according to the general procedure B for 2 h to afford product 12b as a
yellow liquid (75%, 1.6 g). 1H NMR (400 MHz, CDCl3) δ: 3.69 (t, J =
2.5, 2H), 3.38 (t, J = 6.0, 2H), 3.32 (s, 3H), 2.25−2.19 (m, 2H),
1.70−1.50 (m, 4H). 13C NMR (100 MHz, CDCl3) δ: 86.5 (C),
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77.4 (C), 72.3 (CH2), 58.7 (CH3), 28.8 (CH2), 25.2 (CH2), 19.0
(CH2), −16.7 (CH2).
127.8 (CH), 127.1 (CH), 126.9 (CH), 91.0 (CH), 78.2
(CH2), 73.1 (CH2), 58.8 (CH3), 33.7 (CH2).
HRMS: Calcd for C8H13INaO+ (M + Na)+ 274.9903, Found
274.9903.
HRMS: Calcd for C12H14ONa+ (M + Na)+ 197.0936, Found
197.0932.
3-Iodoprop-1-yne:40 Prop-2-yn-1-ol (2.5 mL, 43 mmol, 1 equiv),
imidazole (4.4 g, 64.5 mmol, 1.5 equiv), triphenylphosphine (16.8 g,
64.5 mmol, 1.5 equiv) and iodine (16.3 g, 64.5 mmol, 1.5 equiv) were
reacted in dry CH2Cl2 (100 mL) according to the general procedure B
for 3 h to afford the expected product as a yellow liquid (43%, 3 g)
(3d): 1H NMR (400 MHz, CDCl3) δ: 7.30 (d, J = 7.5, 1H), 7.15−
7.04 (m, 3H), 3.56 (t, J = 7.0, 2H), 3.31 (s, 3H), 2.99 (t, J = 7.3, 2H),
2.02 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 140.5 (C), 132.4
(CH), 129.4 (CH), 127.8 (CH), 126.3 (CH), 123.9 (C),
89.5 (C), 78.3 (C), 72.8 (CH2), 58.7 (CH3), 34.8 (CH2), 4.6
(CH3).
1
together with trace amount of the isomeric allenyliodide. H NMR
(400 MHz, CDCl3) δ: 3.64 (d, J = 2.5, 2H), 2.41 (t, J = 2.5, 1H). 13
C
HRMS: Calcd for C12H14ONa+ (M + Na)+ 197.0936, Found
197.0929.
NMR (100 MHz, CDCl3) δ: 80.6 (C), 73.5 (C), −19.5 (−CH2).
1
Characteristic signals of iodoallene: H NMR (400 MHz, CDCl3)
General Procedure D, Radical Reactions with Diethylzinc
and Electrophiles. Reactions of Propargyl Iodides, with Dieth-
ylzinc and Electrophiles. Light-protected round-bottom flask (covered
with an aluminum foil) was loaded with ortho-substituted 3-phenyl-
alkynyl iodide (1a−d and 8a−c) (0.25 mmol, 1 equiv), electrophile
(aldehydes or ketones) (0.5 mmol, 2 equiv) and kept under argon
atmosphere. The above reagents were dissolved in nondegassed
solvent and diethylzinc was injected through a syringe in the solution
(see the tables and schemes for the solvent and the number of equiv of
diethylzinc). The reaction mixture was stirred at the temperature and
during the time mentioned in tables and schemes. After that time, the
reaction was quenched with saturated NH4Cl aqueous solution. The
two layers were separated, the aqueous layer was extracted with
dichloromethane (2 × 5 mL) and the combined organic layers were
evaporated in vacuo. The crude residue was then purified via flash
column chromatography using pentane/diethylether mixtures to afford
the products.
δ:5.70 (t, J = 6.3, IH), 4.62 (d, J = 6.3, 2H). 13C NMR (100 MHz,
CDCl3) δ: 208.7 (C), 78.6 (CH2), 29.8 (CH).
HRMS: could not be obtained owing to the volatility of the product.
General Procedure C, Radical Reactions with Diethylzinc.
Reactions of Propargyl Iodides with Diethylzinc. Light-protected
round-bottom flask (covered with an aluminum foil) was loaded with
ortho-substituted 3-phenylalkynyl iodide (0.5 mmol, 1 equiv) and
nondegassed 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 above solution and the resulting mixture was stirred at room
temperature for 14 h. Then, the reaction was quenched with a
saturated NH4Cl aqueous solution. The two layers were separated
and 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 mixture as the eluant to give the products.
The NMR data of 1-(propa-1,2-dienyl)benzene (2a),41 1-(prop-1-
ynyl)benzene (2b),42 1-methoxy-2-(propa-1,2-dienyl)benzene (3a),43
and 1-methoxy-2-(prop-1-ynyl)benzene (3b)44 are in agreement with
those previously reported in the literature.
The NMR spectra of 1,4-diphenylbut-3-yn-1-ol (4a) and 1,2-
diphenylbuta-2,3-dien-1-ol (5a)45 were in agreement with the
literature data.
2-(2-Methoxyphenyl)-1-phenylbuta-2,3-dien-1-ol (4b) and 4-(2-
Methoxyphenyl)-1-phenylbut-3-yn-1-ol (5b). 1-(3-Iodoprop-1-ynyl)-
2-methoxybenzene (1b) (0.068 g, 0.25 mmol, 1 equiv), benzaldehyde
(0.053 g, 0.5 mmol, 2 equiv), diethylzinc (0.375 mL, 0.375 mmol, 1.5
equiv) (1 M solution in heptane) and nondegassed dry CH2Cl2 (1.25
mL, 0.2 M) were reacted according to the general procedure D to
afford products 4b and 5b in a 35:65 ratio, as colorless oil (overall
yield 72%, 0.045 g). The two products could not be fully separated
from each other, a pure isolated chromatographic fraction of 5b was
used to assign the NMR signals of 4b. The ratio was determined from
the relative integration of the protons of the methoxy groups.
1-(Methoxymethyl-2-(propa-1,2-dienyl)benzene (2c) and 1-(Me-
thoxymethyl)-2-(prop-1-ynyl)benzene (3c). 1-(3-Iodoprop-1-ynyl)-2-
(methoxymethyl)benzene (1c) (0.143 g, 0.50 mmol, 1 equiv),
diethylzinc (0.75 mL, 0.75 mmol, 1.5 equiv) (1 M solution in
heptane) and nondegassed dry CH2Cl2 (2.5 mL, 0.2 M) were reacted
according to the general procedure C to give the products 2c and 3c as
colorless oil (overall yield 66%, 0.053 g). The two products could not
fully separated from each other, pure isolated chromatographic
fractions were used for NMR.
1
(2c): H NMR (400 MHz, CDCl3) δ: 7.40 (d, J = 7.5, 1H), 7.24−
1
(4b): H NMR (400 MHz, CDCl3) δ: characteristic signals 6.93
7.18 (m, 2H), 7.11 (dt, J = 1.0, 7.5, 1H), 6.39 (t, J = 6.8, 1H), 5.05 (d,
J = 6.8, 2H), 4.44 (s, 2H), 3.32 (s, 3H). 13C NMR (100 MHz, CDCl3)
δ: 210.6 (C), 134.5 (C), 132.8 (C), 129.6 (CH), 128.4
(CH), 127.7 (CH), 126.9 (CH), 90.6 (CH), 78.3 (CH2),
73.0 (CH2), 58.2 (CH3).
(dd, J = 7.3, 1.5) 1H), 6.76 (td, J = 7.5, 1.0, 1H), 5.57 (br s, 1H),
4.93−4.85 (AB part of an ABX spectrum, JAB = 11.6, 2H), 3.73
(s, 3H), 3.13 (br s, 1H). 13C NMR (100 MHz, CDCl3) δ: 207.7
(C), 156.4 (C), 142.5 (C), 131.3 (CH), 129.0 (CH),
128.0 (CH), 127.3 (CH), 126.5 (CH), 124.3 (C), 121.1
(CH), 111.2 (CH), 108.2 (C), 77.9 (CH2), 73.9 (CH), 55.7
(CH3).
HRMS: Calcd for C11H12ONa+ (M + Na)+ 183.0780, Found
183.0782.
(3c): 1H NMR (400 MHz, CDCl3) δ: 7.35−7.30 (m, 2H), 7.22 (dt,
J = 1.3, 7.5, 1H), 7.13 (dt, J = 1.3, 7.5, 1H), 4.54 (s, 2H), 3.37 (s, 3H),
2.03 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 139.9 (C), 132.2
(CH), 127.9 (CH), 127.4 (CH), 127.3 (CH), 122.8 (C),
90.5 (C), 77.6 (C), 72.9 (CH2), 58.6 (CH3), 4.6 (CH3).
HRMS: Calcd for C11H12ONa+ (M + Na)+ 183.0780, Found
183.0781.
1
(5b): H NMR (400 MHz, CDCl3) δ: 7.36 (2 × d, J = 7.5, 2H),
7.29−7.08 (m, 5H), 6.81 (td, J = 7.5, 1.0, 1H), 6.79 (br d, J = 7.5, 1H),
4.93−4.85 (dd, J = 5.3, 7.5, 1H), 3.77 (s, 3H), 2.95 (br s, 1H) 2.85−
2.74 (AB part of an ABX spectrum, JAB = 16.8, 2H). 13C NMR (100
MHz, CDCl3 ) δ: 160.2 (C), 142.8 (C), 133.2
(CH), 129.5 (CH), 128.5 (CH), 127.9 (CH), 125.9
(CH), 120.6 (CH), 112.4 (C), 110.6 (CH), 90.6 (C),
80.1 (C), 72.5 (CH), 55.8 (CH3), 31.3 (CH2).
1-(2-Methoxyethyl)-2-(propa-1,2-dienyl)benzene (2d) and 1-(2-
Methoxyethyl)-2-(prop-1-ynyl)benzene (3d). 1-(3-Iodoprop-1-ynyl)-
2-(2-methoxyethyl)benzene (1d) (0.150 g, 0.50 mmol, 1 equiv) and
diethylzinc (0.75 mL, 0.75 mmol, 1.5 equiv) (1 M solution in heptane)
were mixed in nondegassed dry CH2Cl2 (2.5 mL, 0.2 M) according to
the general procedure C to give the products 2d and 3d as colorless oil
(overall yield 86%, 0.075 g). The two products could not be fully
separated from each other, pure isolated chromatographic fractions
were used for NMR.
HRMS: Calcd for C17H16O2Na (M + Na)+ 275.1043, Found
275.1043.
2-(2-(Methoxymethyl)phenyl)-1-phenylbuta-2,3-dien-1-ol (4c)
and 4-(2-(Methoxymethyl)phenyl)-1-phenylbut-3-yn-1-ol (5c). 1-
(3-Iodoprop-1-ynyl)-2-(methoxymethyl)benzene (1c) (0.071 g, 0.25
mmol, 1 equiv), benzaldehyde (0.053 g, 0.5 mmol, 2 equiv),
diethylzinc (0.375 mL, 0.375 mmol, 1.5 equiv) (1 M solution in
heptane) and nondegassed dry CH2Cl2 (1.25 mL, 0.2 M) were mixed
according to the general procedure D to give the products 4c and 5c in
a 44:56 ratio isolated as colorless oil (overall yield 75%, 0.050 g). The
two products could not be separated from each other. Their ratio was
(2d): 1H NMR (400 MHz, CDCl3) δ: 7.34 (d, J = 7.5, 1H), 7.13−
7.04 (m, 3H), 6.34 (t, J = 6.8, 1H), 5.04 (d, J = 6.8, 2H), 3.49 (t, J =
7.3, 2H), 3.29 (s, 3H), 2.89 (t, J = 7.5, 2H). 13C NMR (100 MHz,
CDCl3) δ: 210.6 (C), 135.6 (C), 132.2 (C), 130.5 (CH),
1599
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Article
determined from the relative integration of the protons of the methoxy
groups.
1H NMR (400 MHz, CDCl3) δ: 7.50−7.43 (m, 2H), 7.33−7.24 (m,
3H), 7.23−7.02 (m, 4H), 3.51−3.39 (m, AA′ part of an AA′XX′
pattern, 2H), 3.22 (s, 3H), 3.04 (s, 1H), 2.97 (d, A part of an AB
pattern, JAB = 16.6, 1H), 2.86 (d, B part of an AB pattern, JAB = 16.6,
1H), 2.87−2.74 (m, XX′ part of an AA′XX′ pattern, 2H), 1.60 (s, 3H).
13C NMR (100 MHz, CDCl3) δ: 147.0 (C), 141.3 (C), 132.3
1
(4c): H NMR (400 MHz, CDCl3) δ: 7.45−7.20 (m, 8H), 6.90
(dd, J = 7.5, 1.5, 1H), 5.56−5.47 (m, 1H), 4.92 (d, J = 2.0), 4.46
(s, 2H), 4.02 (br m, 1H), 3.41 (s, 3H).
HRMS: Calcd for C18H18O2Na (M + Na)+ 289.1199, Found
289.1197.
(CH), 129.4 (CH), 128.4 (CH), 128.2 (CH), 127.1
(CH), 126.3 (CH), 125.0 (CH), 123.4 (C), 89.8 (C),
82.5 (C), 73.8 (C), 73.3 (CH2), 58.8 (CH3), 35.8 (CH2),
35.0 (CH2), 29.8 (CH3).
1
(5c): H NMR (400 MHz, CDCl3) δ: 7.48−7.20 (m, 9H), 5.02−
4.93 (m, 1H), 4.56 (AB part of an AB spectrum, JAB = 12.5, 2H), 3.38
(s, 3H), 3.31 (br m, 1H), 2.93 (AB part of an ABX pattern, JAB = 17.0,
2H).
HRMS: Calcd for C20H22O2Na+ (M + Na)+ 317.1512, Found
317.1512.
13C NMR (100 MHz, CDCl3) for the two products, δ: 205.1 (
C), 142.7 (C), 142.2 (C), 139.7 (C), 136.1 (C), 134.4
(C), 132.0 (CH), 129.6 (CH), 129.4 (CH), 128.5 (CH),
128.4 (CH), 128.2 (CH), 128.0 (CH), 127.9 (CH), 127.8
(CH), 127.6 (CH), 127.5 (CH), 127.4 (CH), 126.9
(CH), 126.4 (CH), 125.8 (CH), 122.5 (C), 107.2 (C),
91.2 (C), 81.1 (C), 76.7 (CH2), 74.9 (CH), 73.1 (CH2),
72.9 (CH2), 72.6 (CH), 58.2 (CH3), 57.9 (CH3), 30.8 (CH2).
HRMS: Calcd for C18H18O2Na (M + Na)+ 289.1199, Found
289.1197.
4-(2-(2-Methoxyethyl)phenyl)hexa-4,5-dien-3-ol (8d) and 6-(2-
(2-Methoxyethyl)phenyl)hex-5-yn-3-ol (9d). 1-(3-Iodoprop-1-ynyl)-
2-(2-methoxyethyl)benzene (1d) (0.075 g, 0.25 mmol, 1 equiv),
propionaldehyde (0.029 g, 0.5 mmol, 2 equiv), diethylzinc (0.375 mL,
0.375 mmol, 1.5 equiv) (1 M solution in heptane) and nondegassed
dry CH2Cl2 (1.25 mL, 0.2 M) were kept under the general procedure
D to furnish the products 8d and 9d in a 66:34 ratio, isolated as a
colorless oil (overall yield 70%, 0.041 g). The two products could not
be separated from each other. Their ratio was determined from the
relative integration of the protons of the methoxy groups.
2-(2-(2-Methoxyethyl)phenyl)-1-phenylbuta-2,3-dien-1-ol (4d)
and 4-(2-(2-Methoxyethyl)phenyl)-1-phenylbut-3-yn-1-ol (5d). 1-
(3-Iodoprop-1-ynyl)-2-(2-methoxyethyl)benzene (1d) (0.075 g,
0.25 mmol, 1 equiv), benzaldehyde (0.053 g, 0.5 mmol, 2 equiv),
diethylzinc (0.375 mL, 0.375 mmol, 1.5 equiv) (1 M solution in
heptane) and nondegassed dry CH2Cl2 (1.25 mL, 0.2 M) were reacted
according to the general procedure D to afford products 4d and 5d in
a 72:28 ratio as colorless oil (overall yield 90%, 0.063 g). The two
products could not be fully separated from each other, a pure isolated
chromatographic fraction of 5d was used to assign the NMR signals of
4d. Their ratio was determined from the relative integration of the
protons of the methoxy groups. A pure sample of 5d was obtained
from this mixture upon reaction with diethylzinc at 80 °C, see below.
(4d): 1H NMR (400 MHz, CDCl3) δ: 7.32−7.00 (m, 8H), 6.94 (d,
J = 7.8, 1H), 5.39 (dt, J = 7.0, 2.5, 1H), 4.84 (AB part of an ABX
spectrum, JAB = 11.3, 2H), 3.45−3.36 (m, AA′ part of an AA′XX′
pattern, 2H), 3.34 (d, J = 4.5, 1H), 3.21 (s, 3H), 2.87−2.74 (m, XX′
part of an AA′XX′ pattern, 2H). 13C NMR (100 MHz, CDCl3) δ:
205.7 (C), 142.3 (C), 137.9 (C), 134.8 (C), 129.8 (
CH), 129.3 (CH), 127.8 (CH), 127.6 (CH), 126.6 (CH),
126.2 (CH), 108.0 (C), 78.0 (CH2), 75.2 (CH), 73.9 (CH2),
58.7 (CH3), 33.0 (CH2).
1
(8d): H NMR (400 MHz, CDCl3) δ: 7.30−7.12 (m, 4H), 5.00−
4.92 (AB part of an ABX spectrum, JAB = 11.8, 2H), 4.29 (tt, J = 7.5,
2.5, 1H), 3.68−3.59 (t, J = 7.3, 2H), 3.32 (s, 3H), 3.12−3.02 (dt, J =
13.8, 7.0, 1H), 2.98−2.88 (dt, J = 13.8, 7.3, 1H), 2.45 (br s, 1H),
1.80−1.53 (m, 2H), 1.00 (d, J = 7.3, 3H).
(9d): 1H NMR (400 MHz, CDCl3) δ: 7.40 (d, J = 7.5, 1H), 7.30−
7.12 (m, 3H), 3.80−3.78 (m, 1H), 3.68−3.56 (m, AA′ part of an
AA′XX′ pattern, 2H), 3.35 (s, 3H), 3.12−3.02 (m, 2H), 2.73 (dd, J =
4.5, 16.8, 1H), 2.59 (dd, J = 6.8, 16.8, 1H), 2.45 (br s, 1H), 1.80−1.53
(m, 2H), 1.00 (t, J = 7.3, 3H).
13C NMR (100 MHz, CDCl3) for the two products, δ: 205.5
(C), 140.9 (C), 137.6 (C), 135.8 (C), 132.2 (CH),
129.8 (CH), 129.4 (CH), 129.1 (CH), 128.1 (CH), 127.7
(CH), 126.5 (CH), 126.3 (CH), 123.5 (C), 107.4 (C),
90.4 (C), 81.5 (C), 77.8 (CH2), 74.0 (CH), 73.8 (CH2), 73.2
(CH2), 71.8 (CH), 58.8 (2xCH3), 35.2 (CH2), 33.2 (CH2), 29.4
(CH2), 28.7 (CH2), 28.2 (CH2), 10.3 (CH3), 10.2 (CH3).
+
HRMS: Calcd for C15H21O2 (M+H)+ 233.1536, Found 233.1538.
3-(2-(2-Methoxyethyl)phenyl)-2-methylpenta-3,4-dien-2-ol (10d)
and 5-(2-(2-Methoxyethyl)phenyl)-2-methylpent-4-yn-2-ol (11d). 1-
(3-Iodoprop-1-ynyl)-2-(2-methoxyethyl)benzene (1d) (0.075 g, 0.25
mmol, 1 equiv), acetone (0.029 g, 0.5 mmol, 2 equiv), diethylzinc
(0.375 mL, 0.375 mmol, 1.5 equiv) (1 M solution in heptane) and
nondegassed dry CH2Cl2 (1.25 mL, 0.2 M) were mixed according to
the general procedure D to afford products 10d and 11d in a 9:91
ratio, isolated as a colorless oil (overall yield 73%, 0.042 g, products
could not be separated from each other, and a trace amount of
propargyl alcohol (7y) corresponding to the starting material (1d) was
also detected in the mixture of the products).
1
(5d): H NMR (400 MHz, CDCl3) δ: 7.36 (br d, J = 8.8, 2H),
7.29−7.04 (m, 8 H), 4.88 (t, J = 6.3, 1H), 3.54−3.45 (m, AA′ part of
an AA′XX′ pattern, 2H), 3.23 (s, 3H), 3.11 (br s, 1H), 2.90−2.86 (m,
XX′ part of an AA′XX′ pattern, 2H), 2.86−2.78 (AB part of an ABX
spectrum, JAB = 16.8, 2H). 13C NMR (100 MHz, CDCl3) δ: 143.0 (C),
141.1 (C), 132.2 (CH), 129.4 (CH), 128.6 (CH), 128.2 (CH),
127.9 (CH), 126.3 (CH), 125.9 (CH), 123.4 (C), 90.1 (C),
81.8 (C), 73.2 (CH2), 72.7 (CH), 58.8 (CH3), 35.0 (CH2), 30.9 (CH2).
HRMS: Calcd for C19H20O2Na+ (M + Na)+ 303.1356, Found
303.1355.
4-(2-(2-Methoxyethyl)phenyl)-1-phenylbut-3-yn-1-ol (5d). Mix-
ture of 4d and 5d (100 mg, 0.35 mmol, 1 equiv, 4d/5d 69:31) was
dissolved in nondegassed dry 1,2-dichloroethane and kept under argon
atmosphere. Diethylzinc (0.525 mL, 0.525 mmol, 1.5 equiv, 1 M
solution in heptane) was injected to the above solution and stirred for
2 h at 80 °C. After this time, the reaction was quenched with saturated
aqueous NH4Cl solution. The layers were separated and the aqueous
layer was washed with CH2Cl2 (2 × 5 mL) and the combined organic
layers were evaporated in vacuo. The crude mixture showed that 5d
was the only product formed in quantitative yield.
(10d): 1H NMR (400 MHz, CDCl3) δ: 7.23−7.04 (m, 4H), 4.76 (s,
2H), 3.24 (s, 3H), 3.01 (t, J = 7.0, 2H), 2.91 (t, J = 6.8, 2H), 2.48 (br s,
1H), 1.36 (s, 6H). 13C NMR (100 MHz, CDCl3) δ: 204.8 (C),
138.0 (C), 135.5 (C), 132.5 (CH), 130.3 (CH), 129.5
(CH), 127.7 (C), 126.0 (CH), 110.8 (C), 76.5 (CH2),
73.4 (CH2), 71.2 (C), 58.7 (CH3), 34.8 (CH2), 29.8 (CH3).
(11d): 1H NMR (400 MHz, CDCl3) δ: 7.33 (d, J = 7.5, 1H), 7.23−
7.04 (m, 3H), 3.55 (t, J = 7.0, 2H), 3.26 (s, 3H), 3.00 (t, J = 7.0, 2H),
2.56 (s, 2H), 2.48 (br s, 1H), 1.31 (s, 6H). 13C NMR (100 MHz,
CDCl3) δ: 140.9 (C), 132.3 (CH), 129.4 (CH), 128.1
(CH), 126.4 (CH), 123.5 (C), 90.4 (C), 82.0 (C), 73.2
(CH2), 70.3 (C), 58.8 (CH3), 35.4 (CH2), 35.2 (CH2), 28.9 (CH3).
HRMS: Calcd for C15H21O2+ (M + H)+ 233.1536, Found 233.1538.
3,4-Dihydro-3-phenyl-4-vinylideneisochromen-1-one (9a) and
Methyl 2-(4-Hydroxy-4-phenylbut-1-ynyl)benzoate (11a). Methyl
2-(3-iodoprop-1-ynyl)benzoate (8a) (0.108 g, 0.36 mmol, 1 equiv),
benzaldehyde (0.078 g, 0.7 mmol, 2 equiv), diethylzinc (0.55 mL, 0.55
mmol, 1.5 equiv) (1 M solution in heptane) and nondegassed dry
CH2Cl2 (1.25 mL, 0.2 M) were reacted according to the general
5-(2-(2-Methoxyethyl)phenyl)-2-phenylpent-4-yn-2-ol (7d). 1-(3-
Iodoprop-1-ynyl)-2-(2-methoxyethyl)benzene (1d) (0.075 g, 0.25
mmol, 1 equiv), acetophenone (0.060 g, 0.5 mmol, 2 equiv),
diethylzinc (0.375 mL, 0.375 mmol, 1.5 equiv) (1 M solution in
heptane) and nondegassed dry CH2Cl2 (1.25 mL, 0.2 M) were reacted
according to the general procedure D to give product 7d as a colorless
oil (overall yield 87%, 0.063 g).
1600
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procedure D to give product 9a (4 mg, 4% yield) isolated as a white
solid and product 11a (82 mg, 82% yield isolated as a colorless oil
(overall yield 86%, overall allene:propargyl ratio, 5:95).
M) were mixed according to the general procedure D to give products
10c and 11c in a 84:16 ratio isolated as colorless oil (overall yield 80%,
0.061 g). The two products could not be separated from each other.
Their ratio was determined from the relative integration of the protons
of the methoxy groups.
1
(9a): H NMR (400 MHz, CDCl3) δ: 8.15 (dd, J = 7.8, 0.8, 1H),
7.59 (td, J = 7.8, 1.0, 1H), 7.46 (d, J=7.8, 1H), 7.42−7.29 (m, 6H),
1
(10c): H NMR (400 MHz, CDCl3) δ: 7.41−7.13 (m, 8H), 7.09
6.18 (t, J = 3.0, 1H), 5.34−5.20 (AB part of an ABX spectrum, JAB
=
13.3, 2H). 13C NMR (100 MHz, CDCl3) δ: 206.9 (C), 164.3
(OC), 137.9 (C), 134.6 (C), 134.3 (CH), 130.6 (CH),
128.8 (CH), 128.5 (CH), 128.4 (CH), 127.0 (CH), 126.0
(CH), 123.4 (C), 100.1 (C), 82.1 (CH2), 79.8 (CH).
HRMS: Calcd for C17H13O2+ (M + H)+ 249.0910, Found 249.0910.
(11a): 1H NMR (400 MHz, CDCl3) δ: 7.92 (dd, J = 7.8, 1.0, 1H),
7.57 (td, J = 7.8, 1.3, 1H), 7.49 (d, J = 7.3, 2H, plus superimposed td,
J = 7.8, 1.3, 7.5, 1.3, 1H), 7.42−7.35 (m, 3H), 7.31 (tt, J = 7.3, 1.3, 1H),
5.07 (dd, J = 8.3, 4.0, 1H), 4.38 (br s, 1H), 3.85 (s, 3H), 2.93 (dd, J =
4.0, 16.8, A part of an ABX pattern, 1H), 2.85 (dd, J = 8.5, 16.8, B part
of an ABX pattern,1H). 13C NMR (100 MHz, CDCl3) δ: 166.7 (OC),
142.9 (C), 133.8 (CH), 132.2 (CH), 131.4 (C), 130.7
(CH), 128.5 (CH), 127.8 (CH), 127.7 (CH), 125.8
(CH), 124.5 (C), 92.8 (C), 82.6 (C), 72.5 (CH), 52.6
(CH3), 31.8 (CH2).
(dd, J = 1,0, 7.3, 1H), 5.47 (br s, 1H), 5.07−4.99 (AB part of an ABX
spectrum, JAB = 11.1, 2H), 3.67 (s, 3H), 2.95−2.84 (m, AA′ part of an
AA′XX′ pattern, 2H), 2.71 (br s, 1H), 2.54−2.34 (m, XX′ part of
an AA′XX′ pattern, 2H). 13C NMR (100 MHz, CDCl3) δ: 205.2
(C), 173.8 (OC), 141.8 (C), 139.4 (C), 134.1 (C),
129.5 (CH), 129.3 (CH), 128.3 (CH), 128.0 (CH), 127.9
(CH), 126.7 (CH), 126.3 (CH), 108.0 (C), 78.9 (CH2),
75.2 (CH), 51.7 (CH3), 35.3 (CH2), 28.2 (CH2).
(11c): 1H NMR (400 MHz, CDCl3) δ: characteristic signals 7.49−
7.47 (m, 2H), 7.42−7.37 (m, 3H), 7.41−7.13 (m, 4H), 5.02−4.98 (m,
1H), 3.67 (s, 3H), 3.07 (t, J = 7.8, 2H), 3.05 (br s, 1H), 2.95−2.84 (m,
2H), 2.63 (pseudo t, J = 6.5, 2H). 13C NMR (100 MHz, CDCl3) δ:
173.8 (OC), 143.0 (C), 142.4 (C), 132.5 (CH), 128.8 (CH),
128.5 (CH), 128.3 (CH), 127.9 (CH), 126.4 (CH), 125.9
(CH), 122.9 (C), 90.6 (C), 81.2 (C), 72.7 (CH), 51.8
(CH3), 35.0 (CH2), 30.8 (CH2), 30.2 (CH2).
+
HRMS: Calcd for C18H20NO3 (M + NH4)+ 298.1438, Found
HRMS: Calcd for C20H20O3Na+ (M + Na)+ 331.1304, Found
331.1304.
298.1438.
4,5-Dihydro-4-phenyl-5-vinylidenebenzo[d]oxepin-2(1H)-one
(9b), Methyl 2-(2-(1-Hydroxy-1-phenylbuta-2,3-dien-2-yl)phenyl)-
acetate (10b) and Methyl 2-(2-(4-Hydroxy-4-phenylbut-1-ynyl)-
phenyl)acetate (11b). Methyl 2-(2-(3-iodoprop-1-ynyl)phenyl)-
acetate (8b) (0.115 g, 0.37 mmol, 1 equiv), benzaldehyde (0.078 g,
0.74 mmol, 2 equiv), diethylzinc (0.55 mL, 0.55 mmol, 1.5 equiv)
(1 M solution in heptane) and nondegassed dry CH2Cl2 (1.25 mL,
0.2 M) were mixed according to the general procedure D to give
product 9b (15 mg, 15% yield) isolated as a white solid and products
10b and 11b (85 mg, 80% yield) isolated as an unseparable mixture of
colorless oils (overall yield 95%, overall allene/propargyl ratio, 58:42
(the ratio is based on the integration of the characteristic signals at
5.42 and 4.91 ppm)).
1-Phenyl-2-vinylideneheptan-1-ol (13a) and 1-Phenylnon-3-yn-
1-ol (14a). 1-Iodooct-2-yne (12a) (0.059 g, 0.25 mmol, 1 equiv),
benzaldehyde (0.053 g, 0.5 mmol, 2 equiv), diethylzinc (0.375 mL,
0.375 mmol, 1.5 equiv) (1 M solution in heptane) and nondegassed
dry CH2Cl2 (1.25 mL, 0.2 M) were reacted according to the general
procedure D to give products 13a and 14a in a 73:27 ratio isolated as a
colorless oil (overall yield 89%, 0.048 g). The two products could not
be separated from each other. Their ratio was determined from the
relative integration of characteristic signals at 5.02 and 4.73 ppm.
(13a): 1H NMR (400 MHz, CDCl3) δ: 7.32−7.18 (m, 5H), 5.02 (t,
J = 2.2, 1H), 4.95−4.88 (m, 2H), 2.15 (br s, 1H), 1.80−164 (m, 2H),
1.44−1.10 (m, 6H), 0.76 (t, J = 6.8, 3H). 13C NMR (100 MHz,
CDCl3) δ: 204.2 (C), 142.3 (C), 128.4 (CH), 127.9 (CH),
126.8 (CH), 108.4 (C), 79.9 (CH2), 74.2 (CH), 31.6 (CH2),
28.0 (CH21), 27.2 (CH2), 22.6 (CH2), 14.1 (CH3).
1
(9b): H NMR (400 MHz, CDCl3) δ: 7.48 (dd, J = 1.3, 8.0, 1H),
7.38 (m, 2H), 7.33−7.25 (m, 3H), 7.21 (td, J = 7.8, 1.5, 1H), 7.16 (td,
J = 7.8, 1.5, 1H), 7.09 (br d, J = 7.3, 1H), 6.39 (t, J = 2.8, 1H), 5.03−
4.90 (AB part of an ABX spectrum, JAB = 13.5, 2H), 4.56 (d, J = 15.3,
1H), 3.76 d, J = 15.3, 1H). 13C NMR (100 MHz, CDCl3) δ: 210.5
(C), 171.0 (OC), 137.4 (C), 131.6 (C), 131.3 (CH),
129.1 (CH), 128.6 (CH), 128.3 (CH), 128.2 (CH), 128.2
(CH), 128.0 (C), 127.3 (CH), 106.8 (C), 81.7 (CH2),
79.4 (CH), 42.0 (CH2).
(14a): H NMR (400 MHz, CDCl3) δ: 7.30−7.18 (m, 5H), 4.73
(dd, J = 5.3, 7.6, 1H), 2.59−2.46 (m, 2H), 2.38 (br s, 1H), 2.08 (tt, J =
2.3, 7.0, 2H), 1.44−1.10 (m, 6H), 0.82 (t, J = 7.0, 3H). 13C NMR (100
MHz, CDCl3) δ: 142.9 (C), 128.5 (CH), 127.8 (CH), 125.9
(CH), 83.8 (C), 76.0 (C), 72.7 (CH), 31.2 (CH2), 30.2
(CH2), 28.7 (CH2), 22.3 (CH2), 18.9 (CH2), 14.1 (CH3).
HRMS: Calcd for C15H20ONa+ (M + Na)+ 239.1406, Found
239.1405.
+
HRMS: Calcd for C18H15O2 (M+H)+ 263.1067, Found 263.1067.
1
(10b): H NMR (400 MHz, CDCl3) δ: 7.38−7.11 (m, 8H), 7.02
(d, J = 8.0, 1H), 5.42 (t, J = 2.8, 1H), 4.87−4.80 (AB part of an ABX
spectrum, JAB = 11.3, 2H), 3.58 (AB spectrum, JAB = 16.3, 2H), 3.61 (s,
3H), 3.02 (br s, 1H).
8-Methoxy-1-phenyl-2-vinylideneoct-3-yn-1-ol (13b) and 8-Me-
thoxy-1-phenyloct-3-yn-1-ol (14b). 1-Iodo-7-methoxyhept-2-yne
(12b) (0.063 g, 0.25 mmol, 1 equiv), benzaldehyde (0.053 g, 0.5
mmol, 2 equiv), diethylzinc (0.375 mL, 0.375 mmol, 1.5 equiv) (1 M
solution in heptane) and dry CH2Cl2 (1.25 mL, 0.2 M) were reacted
according to the general procedure D to afford products 13b and 14b
in a 72:28 ratio, isolated as a colorless oil (overall yield 92%, 0.053 g).
The two products could not be separated from each other. Their ratio
was determined from the relative integration of characteristic signals at
5.03 and 4.71 ppm.
1
(11b): H NMR (400 MHz, CDCl3) δ: 7.38−7.11 (m, 9H), 4.91
(dd, J = 5.2, 7.3, 1H), 3.70 (AB spectrum, JAB = 15.1, 2H), 3.61 (s,
3H), 3.29 (br s, 1H), 2.84 (dd, J = 5.2, 16.8, AB part of an ABX
pattern, 1H), 2.85 (dd, J = 7.3, 16.8, AB part of an ABX pattern, 1H).
13C NMR (100 MHz, CDCl3) mixture of the two products, δ: 205.5
(C), 172.9 (OC), 172.2 (OC), 142.8 (C), 141.9 (C),
136.1 (C), 134.6 (C), 133.0 (C), 132.2 (CH), 131.0 (CH),
130.0 (CH), 129.2 (CH), 128.6 (CH), 128.4 (CH), 128.1
(CH), 128.0 (CH), 127.7 (CH), 127.6 (CH), 127.3
(CH), 127.2 (CH), 126.6 (CH), 125.9 (CH), 123.7 (C),
107.9 (C), 91.5 (C), 81.2 (C), 78.5 (CH2), 75.0 (CH), 72.6
(CH), 52.4 (CH3), 52.3 (CH3), 40.5 (CH2), 38.8 (CH2), 31.1 (CH2).
1
(13b): H NMR (400 MHz, CDCl3) δ: 7.30−7.18 (m, 5H), 5.03
(br s, 1H), 4.95−4.85 (m, 2H), 3.21 (t, J = 6.3, 2H), 3.20 (s, 3H), 2.40
(br s, 1H), 1.82−1.69 (m, 2H), 1.49−1.32 (m, 4H). 13C NMR (100
MHz, CDCl3) δ: 204.3 (C), 142.2 (C), 128.3 (CH), 127.7
(CH), 126.7 (CH), 108.0 (C), 79.8 (CH2), 74.3 (CH), 72.7
(CH2), 58.6 (CH3), 29.2 (CH2), 27.6 (CH2), 24.1 (CH2).
(14b): 1H NMR (400 MHz, CDCl3) δ: 7.30−7.18 (m, 5H), 4.71 (t,
J = 6.3, 1H), 3.29 (t, J = 6.3, 2H), 3.24 (s, 3H), 2.59 (br s, 1H), 2.55−
2.45 (m, 2H), 2.13−2.09 (tt, J = 7.0, 2.3, 2H), 1.59−1.52 (m, 2H),
1.49−1.32 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 143.0 (C),
128.4 (CH), 127.8 (CH), 125.9 (CH), 83.0 (C), 76.5 (C),
72.7 (CH), 72.3 (CH2), 58.6 (CH3), 30.1 (CH2), 28.8 (CH2), 25.6
(CH2), 18.6 (CH2).
+
HRMS: Calcd for C19H22NO3 (M + NH4)+ 312.1594, Found
312.1596.
Methyl 3-(2-(1-hydroxy-1-phenylbuta-2,3-dien-2-yl)phenyl)-
propanoate (10c) and methyl 3-(2-(4-hydroxy-4-phenylbut-1-ynyl)-
phenyl)propanoate (11c). Methyl 3-(2-(3-iodoprop-1-ynyl)phenyl)-
propanoate (8c) (0.082 g, 0.25 mmol, 1 equiv), benzaldehyde (0.053
g, 0.5 mmol, 2 equiv), diethylzinc (0.375 mL, 0.375 mmol, 1.5 equiv)
(1 M solution in heptane) and nondegassed dry CH2Cl2 (1.25 mL, 0.2
1601
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The Journal of Organic Chemistry
Article
HRMS: Calcd for C15H20O2Li+ (M + Li)+ 239.1618, Found
239.1621.
Normant, J. F. J. Am. Chem. Soc. 2001, 123, 4639−4640. (c) Louvel, J.;
Botuha, C.; Chemla, F.; Demont, E.; Ferreira, F.; Per
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ez-Luna, A. Eur. J.
ez-Luna, A.;
Ferreira, F.; Botuha, C.; Chemla, F. Org. Lett. 2009, 11, 931−934.
(e) Seguin, C.; Ferreira, F.; Botuha, C.; Chemla, F.; Perez-Luna, A. J.
Org. Chem. 2009, 74, 6986−6992.
NMR Experiment. The propargylic iodide (0.1 mmol) was put in a
dry NMR tube closed with rubber septum. Nondegassed CDCl3 (0.5 mL)
was injected through septum using a syringe. Diethylzinc (0.15 mL
of a 1 M solution in heptane) was injected into the above solution with
a syringe through septum. After the addition, the septum was replaced
with the NMR tube cap and the reaction was monitored using
NMR spectroscopy. No evolution was observed unless the solution
was shaken, so that reactants were mixed and the solution becomes
homogeneous. After evolution, the reaction mixture was quenched
with a drop of water.
Org. Chem. 2010, 16, 2921−2926. (d) Voituriez, A.; Per
́
́
́
(5) (a) Fandrick, D. R.; Fandrick, K. R.; Reeves, J. T.; Tan, Z.;
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C. H. Org. Lett. 2011, 13, 5616−5619.
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The evolution was instantaneous when the NMR tube was
reopened and shaken several times just before the spectrum was
recorded.
COMPUTATIONAL DETAILS
■
All calculations were performed with Gaussian 09 package.46 The
geometries of all species were calculated with the CBS-QB319
composite method in order to obtain accurate thermodynamic data.
During the CBS-QB3 procedure, vibrational frequencies were
calculated and the nature of stationary points were confirmed (0 or
1 imaginary frequency for a minimum or a transition state,
respectively). All transition state geometries were confirmed by
intrinsic reaction coordinate (IRC) calculations at the B3LYP/6-
311G(2d,d,p) level of theory. The NBO calculations for figure 4 were
performed at the B3LYP/6-31+G(d,p) level of theory.
(8) (a) Bieber, L. W.; Da Silva, M. F.; Da Costa, R. C.; Silva, L. O. S.
Tetrahedron Lett. 1998, 39, 3655−3658. (b) Jogi, A.; Maeorg, U.
̈
̈
Molecules 2001, 6, 964−968.
ASSOCIATED CONTENT
* Supporting Information
(9) Unger, R.; Weisser, F.; Chinkov, N.; Stanger, A.; Cohen, T.;
Marek, I. Org. Lett. 2009, 11, 1853−1856.
(10) Trost, B. M.; Ngal, M.-Y.; Dong, G. Org. Lett. 2011, 13, 1900−
1903.
■
S
EPR spectra for all new compounds, computational details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) (a) Shinokubo, H.; Miki, H.; Yokoo, T.; Oshima, K.; Utimoto,
K. Tetrahedron 1995, 51, 11681−11692. (b) Lin, M. H.; Tsai, W. S.;
Lin, L. Z.; Hung, S. F.; Chuang, T. H.; Su, Y. J. J. Org. Chem. 2011, 76,
8518−8523.
AUTHOR INFORMATION
Corresponding Author
*E-mail: michele.bertrand@univ-amu.fr; laurence.feray@univ-amu.
fr; didier.siri@univ-amu.fr.
■
(12) It must be noted that Indium-mediated reactions and In(cat)/
Ga-mediated reactions using propargyl bromides as the precursors of
organometallic species have also been investigated, see: (a) Hirayama,
L. C.; Dunham, K. K.; Singaram, B. Tetrahedron Lett. 2006, 47, 5173−
5176. (b) Lee, P. H.; Kim, H.; Lee, K. Adv. Synth. Catal. 2005, 347,
1219−1222. (c) Lin, M.-J.; Loh, T.-P. J. Am. Chem. Soc. 2003, 125,
13042−13043. (d) Loh, T.-P.; Lin, M.-J.; Tan, K.-L. Tetrahedron Lett.
2003, 44, 507−509. (e) Hua, X.-G.; Mague, J. T.; Li, C.-J. Tetrahedron
Lett. 1998, 39, 6837−6840. (f) Miao, W.; Lu, W.; Chan, T. H. J. Am.
Chem. Soc. 2003, 125, 2412−2413. (g) Xu, B.; Hammond, G. B.
Chem.Eur. J. 2008, 14, 10029−10035. (h) Gu, C. Z.; Li, Q. R.; Yin,
H. Chin. Chem. Lett. 2005, 16, 1573−1576. For the reactivity of
related organoaluminum, see: (i) Daniels, R. G.; Paquette, L. A.
Tetrahedron Lett. 1981, 22, 1579−1582. (j) Guo, L.-N.; Gao, H.;
Mayer, P.; Knochel, P. Chem.Eur. J. 2010, 16, 9829−9834.
(13) (a) Gung, B. W.; Xue, X.; Knatz, N.; Marshall, J. A.
Organometallics 2003, 22, 3158−3163. (b) Bejjani, J.; Botuha, C.;
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank Aix-Marseille Universite
doctoral fellowship of Dr S. Jammi. Calculation facilities were
■
́
for funding the post
provided by the “Centre Reg
́ ́
ional de Competences en
Modelisation Moleculaire” (Marseille, France).
́
́
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(30) These data support the proposal of the ready formation of an
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allenylzincs, see ref 10.
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