Regio- and stereoselective synthesis of 2,3,5-trienoates by palladium-catalyzed alkoxycarbonylation of conjugated enyne carbonates

Article abstract of DOI:10.1021/jo5014993

Palladium-catalyzed carbonylation of 2,4-enyne carbonates in an alcohol and under balloon pressure of CO proceeds through 1,5-substitution to yield (E)-2,3,5-trienoates. The olefin geometry of the substrate is important to control the overall stereochemistry of this alkoxycarbonylation method. The reaction proceeds through successive formation of π-allylpalladium with an R³ group oriented syn and σ-allenyl palladium complexes.

Full text of DOI:10.1021/jo5014993

Article
pubs.acs.org/joc
Regio- and Stereoselective Synthesis of 2,3,5-Trienoates by
Palladium-Catalyzed Alkoxycarbonylation of Conjugated Enyne
Carbonates
Ezgi Şule Karagoz, Melih Kus,̧ Gurkan Eray Akpınar, and Levent Artok*
̈
̈
Department of Chemistry, Faculty of Science, Izmir Institute of Technology, Urla 35430, Izmir Turkey
S
* Supporting Information
ABSTRACT: Palladium-catalyzed carbonylation of 2,4-enyne
carbonates in an alcohol and under balloon pressure of CO
proceeds through 1,5-substitution to yield (E)-2,3,5-trienoates.
The olefin geometry of the substrate is important to control
the overall stereochemistry of this alkoxycarbonylation
method. The reaction proceeds through successive formation
of π-allylpalladium with an R3 group oriented syn and σ-allenyl
palladium complexes.
vinylic group exclusively in the (E) configuration. However, no
INTRODUCTION
■
indication of chirality transfer from center-to-axial could be
demonstrated for these reactions since the palladium-catalyzed
reactions of enantiopure enyne carbonate substrates under the
established conditions all led to racemic vinylallene prod-
ucts.11,12
In that report, we have concluded that only (Z)-isomers of
the enyne carbonate substrates were capable of taking part in
this carbonylation reaction because the methoxycarbonylation
of the substrate (E)-1a under the conditions established therein
led to a complex mixture and consequently gave a low yield of
the expected product 2aa (Scheme 2).11 Repetitive trials by
different hands has also resulted in similar failures.
We have realized later that the incompatibility of the
established methodology is specifically peculiar to (E)-1a. We
have found upon further study that, as reported herein, (E)-
enyne carbonates are also applicable substrates.11 Moreover, a
good to excellent level of center-to-axial chirality transfer would
be possible upon modification of the reaction conditions. In
addition, observed stereoselectivity of the process, as well as
structural features of various byproducts identified during
several reactions, provided more information for the mecha-
nism underlying the method.
It should also be noted that the results obtained here
override our previously proposed notion that the reaction is
promoted via the cooperative coordination of palladium with
both alkynyl and carbonate moieties11 because (E)-enyne
carbonates, which proved high activity toward palladium
catalysis as a means to synthesize vinylallenes as presented
here and elsewhere,12 are not capable of taking part in such a
dual interaction due to geometrical constraints.
The development of synthetic methods for the construction of
allenes with diverse arrangements of functional groups,1
particularly in an enantioselective manner,2 has been of long-
standing interest because allenes are widely utilized as building
blocks,3 for translating axial chirality to central chirality, and as a
considerable number of naturally occurring and biopotent
compounds contain allene units.1,4
Pd(0)-catalyzed reactions of propargylic reagents usually
afford σ-allenyl palladium species,5 and the formation of this
intermediate has been a strategy widely applied for the
synthesis of functionalized allenyl structures.2a,b,4a,6 Moreover,
enantiomerically enriched propargyl reagents with relatively
good leaving groups such as cyclic carbonate,7 mesylate,4a,8
phosphate,9 and oxirane10 have been found to translate the
chirality center to the three carbon axis of the allenyl products
with good enantiomeric excesses (ee). In addition, only
recently have successful examples of asymmetric carbonylation
of racemic propargylic carbonates that led to access optically
active 2,3-allenoates with fairly high ee been demonstrated.2b
We have reported in our preliminary communication that the
Pd(0)-catalyzed carbonylation of carbonates of secondary (Z)-
2-en-4-yne alcohols also proceeds through the involvement of
an π-allenylpalladium intermediate, furnishing 2,3,5-trienoates
in high yields (Scheme 1).11 The method is completely
diastereoselective, with donated vinylallene products with a
Scheme 1. Alkoxycarbonylation of (Z)-Enyne Carbonates11
Received: July 21, 2014
Published: September 4, 2014
© 2014 American Chemical Society
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Scheme 2. Methoxycarbonylation of (E)-1a
was butyl ((E)-1k, 76%) or isopropyl ((E)-1l, 92%) groups
(entries 9 and 10).
RESULTS AND DISCUSSION
■
At the outset of this study, the applicability of (E)-enyne
carbonates toward alkoxycarbonylation reactions were eval-
uated using the conditions previously employed for (Z)-
configured enyne carbonates, that is, Pd2dba3·CHCl3 (1% Pd),
2% PPh3, 5 mL of alcohol, at 50 °C and under a CO-filled
balloon. First, (E)-1b was subjected to alkoxycarbonylation
reactions with several alcohols under these conditions. The
results obtained from the alkoxycarbonylation reactions of (E)-
1b with MeOH and primary C2−C4 alcohols all proved to be
comparable to those obtained with (Z)-1b; the high yield of the
desired vinylallene ester products (2ba−bd, 80−91%) were
obtained in each case (Table 1, entries 1−4). However, a
moderate yield (67%) of 2be was recovered from the reaction
of (E)-1b and isopropyl alcohol (entry 5).
It is worthy of note that in contrast to the activity of (Z)-
configured enyne carbonates the (E)-enyne carbonates showed
much less reactivity dependence on the size of substituents; a
longer reaction time or a higher reaction temperature was
required for complete conversion of the (Z)-isomer as it is
endowed with bulkier groups.11 This lower tolerance of the
method on larger substituents on (Z)-isomers may be related to
their overall more sterically congested structure as compared to
their (E)-configured counterparts.
The methoxycarbonylation of an enyne carbonate of a
primary alcohol (R3 = H) led to a mixture of vinylallene
product 2ma and ester functionalized 2-en-4-yne (3ma′)
byproduct (entry 11).
The method is also not suitable for an enyne carbonate
substrate that bears a phenyl group on the allylic position,
which resulted in a pair of allylic ethers and no traces of any
carbonylative product was observed to form (entry 12).
Another substrate that failed to yield the desired vinylallene
product carried a methyl group on the alkenyl carbon that is
distal to the alkynyl moiety ((E)-1o), which led to intricate
mixture during the methoxycarbonylation reaction (Scheme 3).
Having revealed the scope and limitation of the method, next
we attempted to explore its stereoselectivity using the
carbonates of enantiopure secondary enynols which were
prepared from corresponding racemic enynols by employing
Sharpless’s kinetic resolution method (Scheme 4).14
a
Table 1. Alkoxycarbonylation of (E)-Enyne Carbonate 2b
b
entry
ROH
product
yield (%)
1
2
3
4
5
MeOH
EtOH
2ba
2bb
2bc
2bd
2be
88
81
91
80
PrOH
BuOH
i-PrOH
c
67
The outcome of a methoxycarbonylation reaction of an
enantioenriched enyne carbonate (R,E)-1b under the afore-
mentioned optimal conditions was rather frustrating; the
vinylallene product (S)-2ba was obtained with fairly low ee
(Table 3, entry 1, ∼17% ee).15 Application of the reaction at 26
°C and at a higher catalyst loading level (2 mol % Pd and 4 mol
% PPh3) offered only a slight improvement for the ee (entry 2).
Nevertheless, it was encouraging to observe that doubling the
ligand-to-palladium ratio to 4:1 improved the ee up to 54%,
although it required a longer reaction period for the complete
conversion of (S)-2ba when the reaction was performed at 26
°C (entry 3). The coordinative saturation of palladium with the
phosphine ligand probably brought about a decrease in the
reactivity of the metal center toward the oxidative addition step,
leading to a π-allylpalladium complex16 that led to a decrease in
the reaction rate yet proved useful in regard to the
enantiomeric grade of the product.17
Replacement of the in situ formed a palladium−phosphine
catalyst system with a preprepared catalyst Pd(PPh3)4 showed
no beneficial effect on either the reactivity or enantiocontrol
ability of the method (entry 4).
Keeping the P/Pd ratio at 4:1, several mono- and bidentate
ligands were also surveyed in an attempt to improve the
stereoselectivity of this alkoxycarbonylation method. The
conversion of (R,E)-1b at 26 °C was incomplete when an
electron-poor ligand was used, thus giving rise to a low yield of
2ba (entry 5). Electron-rich bidentate phosphine ligands
a
Substrate 1b (0.3 mmol), ROH (5 mL), CO (balloon pressure), 1
b
c
mol % of Pd, 2 mol % of PPh3. Isolated yield. 6 h.
The carbonylation reactions were also performed with an
array of (E)-enyne carbonates in methanol (Table 2). The
conversions of enyne carbonate substrates, with 2,3,5-trienoates
identified as the sole products, were generally complete within
4−6 h regardless of the size and electronic nature of the
substituents. The method is perfectly suitable for enynes
bearing a methyl (1c), phenyl (1d), cyclohexyl (1e), or highly
cumbersome tert-butyl (1f) groups on the alkynyl moiety (R1),
providing the desired products in moderate to high yields
(entries 1−4). The methodology can also tolerate without
problem the enyne carbonate with disubstituted alkenyl moiety
(R2 = H) or those bearing butyl or phenyl groups on the
alkenyl carbon (R2) that is proximal to the alkynyl moiety,
affording the desired products 2ga−ia within the range of 77−
90% yields (entries 5−7). In contrast, however, an (E) and (Z)
isomeric mixture of the substrate 1j, where the R2 position is
occupied by a bulky tert-butyl group which favored the
formation of an allylic carbonylation (3ja) and methoxylation
(4ja)13 products, afforded, therefore, the expected trienoate
product (2ja) in a negligible amount (entry 8).
The effect of variation of allylic substitution (R3) on the
activity of the enyne carbonate was also assessed. The method
was rather successful also for the enyne substrates in which R3
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a
Table 2. Pd(0)-Catalyzed Methoxycarbonylation of (E)-Enyne Carbonates
a
b
c
Substrate 1 (0.3 mmol), MeOH (5 mL), CO (balloon pressure), 1 mol % of Pd, 2 mol % of PPh3. Isolated yield. Isomeric ratio was determined
d
e
by 1H NMR. 2 mol % of Pd, 4 mol % of PPh3, 22 h. 13% of 1j was recovered with an E/Z ratio of 1:2. The conversion was incomplete after 24 h.
Nevertheless, the most dramatic impact on both the reactivity
and the stereoselectivity of the method was observed by the use
of DPEphos ligand; the reaction rate was significantly
accelerated in the presence of this ligand in the reaction
medium, which allowed the formation of (S)-2ba with 90%
yield and 72% ee after 4 h of reaction at 26 °C (entry 7).
Elevation of the reaction temperature was detrimental for the
selectivity of the method (entry 8). However, further
Scheme 3. Pd(0)-Catalyzed Methoxycarbonylation of (E)-1o
Scheme 4. Synthesis of Enantiopure 2,4-Enynols by the
Sharpless Method
improvement was still possible (82% ee, [α]22 = +14.7 (c =
D
0.68, CH2Cl2)) by performing the reaction at 10 °C (entry 9),
but no benefit was gained from further lowering the reaction
temperature to 0 °C (entries 10 and 11).
Molander et al. reported that vinylallenes are relatively
reactive components toward enantiomerization under palla-
dium-mediated conditions.9b To test such a possibility, the
enantioenriched vinylallene compound (S)-2ba (82% ee) was
subjected to a methoxycarbonylation process at both 26 and 10
resulted in a better performance; the use of Xanthphos enabled
the formation of (S)-2ba with 62% ee and 93% yield (entry 6).
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reaction cycle, not due to the Pd-promoted enantiomerization
of the product vinylallene.
Table 3. Palladium-Catalyzed Methoxycarbonylation of
(R,E)-1b
a
The chirality transfer test was also attempted for (R,Z)-1b
substrate; the reaction with (R,Z)-1b proceeded more
sluggishly, and the reaction period was lengthened to 48 h
for complete conversion, yielding the vinylallene product in
opposite configuration ((R)-2ba, 79% ee) as compared to that
obtained from the substrate (R,E)-1b (Scheme 5, eq 1). These
results suggest that the stereoselectivity depends on the olefin
geometry of enyne carbonate.
It was intriguing to verify that there appears to be a direct
relation between the enantiocontrol ability of the method and
the size of the group on the alkynyl terminus (Scheme 5).18
Whereas methoxycarbonylation of an enantioenriched enyne
carbonate (R,E)-1p with a terminal alkynyl group proceeded
with partial racemization (44% ee, 90% yield) (eq 2), an
excellent level of chirality transfer could be attained during the
reaction of the enyne carbonate (R,E)-1f carrying a tert-butyl
group on the alkynyl terminus, which delivered (S)-2fa with
89% yield and 96% ee, albeit with longer reaction time and
higher Pd loading to complete the reaction (eq 3). To our
knowledge, this catalytic reaction has been the first example of
Pd-catalyzed coupling reaction proceeding with an efficient
remote stereocontrol for conjugated enyne structures with a
leaving group on the allylic carbon.19
b
Pd
T
time
(h)
ee
yield
entry
(%)
ligand (%)
PPh3 (2)
(°C)
(%)
(%)
1
2
3
4
5
6
7
8
1
2
2
2
2
2
2
1
2
2
5
50
26
26
26
26
26
26
50
10
0
4
9
17
21
54
50
58
62
72
64
82
77
70
90
91
90
91
PPh3 (4)
PPh3 (8)
20
40
25
27
4
Pd(PPh3)4
c
P(4-CF3C6H4)3 (8)
Xantphos (4)
DPEphos (4)
DPEphos (2)
DPEphos (4)
DPEphos (4)
DPEphos (10)
56
93
90
91
93
84
93
3
d,e
9
13
45
21
d
d
10
11
0
a
Substrate (R,E)-2b (0.1 mmol), MeOH (1.7 mL), CO (balloon
pressure), Xanthphos (4,5-bis(diphenylphosphino)-9,9-dimethylxan-
thene), DPEphos (bis-[2-(diphenylphosphino)phenyl] ether). Iso-
lated yield. The reactant was recovered by 31%. (R,E)-1b (0.3
b
c
d
e
mmol), MeOH (5 mL). For the product of this reaction, [α]22
+14.7 (c = 0.68, CH2Cl2).
=
D
In regard to the reaction mechanism, the catalytic cycle
should begin with oxidative addition of (R,E)-1 and (R,Z)-1 to
Pd(0) in order to afford π-allylpalladium complexes 5 and 6,
respectively, by displacement of the leaving group with
inversion (Scheme 6).16,21 The R3 group on both complexes
is oriented syn with respect to the middle allylic C−H in order
to furnish vinylallene products ultimately in the (E)
configuration. However, while R2 is inherently anti oriented
on the initially formed intermediate 5, it is syn in the case of 6.
Furthermore, the π-allylpalladium complexes 5 and 6 may be
°C using a Pd/DPEphos combination under the conditions
given for entry 9. Indeed, the substrate (S)-2ba underwent
partial racemization to give product of 58% ee after 8 h of
treatment at 26 °C, whereas no marked variation in
enantiopurity of (S)-2ba could be determined after 24 h of
treatment at 10 °C, indicating that at the lower reaction
temperature employed any loss of stereoselectivity during the
transformation of 1 to 2 chiefly takes place in the course of the
Scheme 5. Methoxycarbonylation of Enantiopure Enyne Carbonates20
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Scheme 6. Mechanism of Alkoxycarbonylation of 2-En-4-yne Carbonates
Scheme 7. Formation of Byproducts from the Methoxycarbonylation Reactions of 1j,m,n
converted crosswise into the enantiomers of each other,
enantio-6 and enantio-5, respectively, via the well-known the
π−σ−π interconversion.22
8, 11, and 12) are well in line with the proposed mechanism;
the conversion of these substrates to nonallenic products also
should involve π -allylpalladium intermediates. The formation
of a relatively stable primary σ-allylpalladium intermediate
should be responsible for the formation of the enyne ester
byproduct 3ma′ (Scheme 7, eq 1). The relatively higher
electrophilic nature and greater stability of π-allyl intermediate
where the allylic system is conjugated to the phenyl substituent
in comparison to its alkyl-substituted analogues unfavors the
palladium shift to generate σ-allenylpalladium complex but
rather undergoes methanol attack to give 4na and 4na′ (eq
2).23
Subsequently, all these intermediates may undergo a
palladium shift to the distal alkynyl carbon mainly by retention
of the configuration with accompanying isomerization of π-
electrons to afford σ-allenyl palladium complexes (S)-7 and
(R)-7. While both 5 and enantio-6 are able to lead to (S)-7,
(R)-7 could be derived from both 6 and enantio-5. The favored
position of R2 and alkynyl groups (syn or anti) on π-
allylpalladium intermediate, which will involve in the next
step of the mechanism, would probably be determined by the
thermodynamic stability of the allylic ligand.16a,b,21 Finally, the
(S)-7 and (R)-7 undergo sequential CO insertion followed by
reductive elimination to furnish vinylallene products (S)-2 and
(R)-2, respectively.
The substrate 1j contains a bulky tert-butyl group on the
alkenyl group that hinders the migration of the π-allyl
coordinated palladium to the alkynyl side, hence partly
undergoing allylic methoxycarbonylation (eq 3).
The formation of allylic substituted byproducts from the
corresponding reactions of 1j, 1m, and 1n (see Table 2, entries
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(16.5 mg, 0.085 mmol) was stirred in 70 mL of Et3N for 3 min at 50
°C under Ar, and then to this mixture was added 10 mL of Et3N
solution of S1 (∼17 mmol). The mixture was again stirred at 50 °C for
3 h. At the end of the reaction, water was added to the resulting
mixture and then extracted with Et2O. The combined organic layers
were dried over MgSO4. The solvent was evaporated in vacuo, and the
product (E)-3-methyl-5-phenylpent-2-en-4-yn-1-ol (S2d) was purified
by column chromatography on silica gel (hexane/ethyl acetate, 2.5 g,
85%). S2d was oxidized to the corresponding enyne aldehyde
structure and then subjected to Grignard reaction with MeMgBr
following the procedures as described previously12,13 to obtain (E)-4-
methyl-6-phenylhex-3-en-5-yn-2-ol (S3d) compound (1.75 g, 65%).
Carbonate derivatization of S3d was performed via a prescribed
method (0.88 g, 50%).25 The spectrometric data of this starting
material can be found elsewhere.12
CONCLUSION
■
In this report, a scope of alkoxycarbonylation reactions of
carbonates of (E)-2-en-4-yne alcohols leading to 2,3,5-
trienoates with an exclusively (E)-configuration is presented.
It has been found on the basis of the reactions, which were
performed over enantiopure reagents, that the geometry of the
alkenyl moiety ((E) or (Z)) controls the stereoselectivity of the
process. It was also observed that the extent to which center-to-
axis chirality transfer occurs is remarkably dependent on the
size of the substituent on the alkynyl terminus. On the basis of
the stereochemical outcome of the process, as well as structural
features of byproducts identified, we have envisaged that the
reactions should involve successive formations of π-allylpalla-
dium with an R3 group located syn with respect to the middle
allylic C−H and σ-allenylpalladium complexes for generating
the (E)-2,3,5-trienoates.
Synthesis of Substrates (E)-1e,f,h−j. Syntheses of these enyne
substrates involve palladium-catalyzed conjugate addition of terminal
alkynes to alkynyl esters through two established methods.
EXPERIMENTAL SECTION
■
General Methods. Tetrahydrofuran (THF) and dichloromethane
(DCM) solvents were all purified by a solvent purification system.
Et2O was distilled from benzophenone ketyl under argon prior to use.
Methanol and ethanol were dried over Mg turnings in the presence of
iodine and stored on 3A molecular sieves under Ar. Drying of 1-
propanol and 2-propanol were performed first by stirring over
anhydrous CaO and then refluxing over Mg turnings in the presence of
iodine. 1-Butanol was dried first by stirring over anhydrous MgSO4
and followed by refluxing over Mg turnings in the presence of iodine.
The Pd2(dba)3−CHCl3 complex was synthesized in the laboratory.24
All of the synthesized reactants and carbonylation products were
isolated by column chromatography using a hexane−ethyl acetate
eluent and analyzed by GC−MS, NMR, and FTIR techniques. NMR
(400 MHz) spectra were recorded in CDCl3 or C6D6. Infrared spectra
were obtained by the ATR method with neat samples. High-resolution
mass spectral analyses of new compounds were performed using an EI-
high resolution double focusing magnetic sector (ionization mode: 70
eV, emission current: 1 mA, source temperature: 160 °C, resolution:
10000 (10% valley definition)), ESI-LTQ Orbitrap (source voltage:
+3.8 kV, capillary voltage: 41 V, capillary temperature: 275 °C, tube
lens voltage: 140 V, system resolution: 60000 (10% valley definition)),
and ESI-Q-TOF (capillary voltage: 4.5 V, fragmentor voltage: 175 V,
gas temperature 325 °C, resolution: 4 GHz) mass spectrometers.
Synthesis of Substrates (E)-1a−c,k−m,p. The synthesis
procedure and spectrometric data of the starting material compounds
(E)-1a−c,k,l can be found elsewhere.11,12
Method A. A mixture of terminal alkyne (S4) (50 mmol), alkynoic
ester (S5) (25 mmol), CuBr (225 mg, 1.25 mmol), and PdCl2(PPh3)2
(465 mg, 0.625 mmol) in 50 mL water was stirred at 60 °C under Ar
for 48 h. After the starting material was consumed as monitored by
TLC (24 h when R1 = Me or Cy, 48 h when R1 = t-Bu), the reaction
mixture was extracted with Et2O. The combined extracts were dried
over MgSO4, filtered, and concentrated under reduced pressure. The
product was purified by column chromatography on silica gel (hexane/
ethyl acetate, yields, (S6): R1= Cy, R2= Me, 4.7 g, 85%; R1 = t-Bu, R2 =
Me, 3.6 g, 75%; R1 = Bu, R2 = Bu, 5.3 g, 90%; R1 = Bu, R2 = Ph, 4.8 g,
84%).26
(E)-Enyne esters S6 was converted to corresponding enyne
aldehydes (S7) following a described method,12 and conversion of
S7 to the corresponding enyne carbonates was performed as specified
for (E)-1d. All synthesized substrates appeared colorless oils ((E)-1e:
0.44 g, 18%; (E)-1f: 0.47 g 19%; (E)-1h: 0.5 g 20%; (E)-1i: 0.51 g,
20%)
1
(E)-1e: H NMR (400 MHz, CDCl3) δ 5.97 (d, J = 8.8 Hz, 1H),
5.48−5.41 (m, 1H), 3.75 (s, 3H), 2.48−2.43 (m, 1H), 1.88 (s, 3H),
1.84−1.77 (m, 2H), 1.74−1.66 (m, 2H), 1.51−1.39 (m, 3H), 1.36−
1.25 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 155.3, 133.7, 122.5,
93.6, 82.5, 71.7, 54.7, 32.8, 29.7, 26.0, 25.0, 20.5, 18.4; FTIR (νmax
/
cm−1): 3423, 2931, 2855, 2217, 1744, 1443, 1327, 1257, 1151, 1036,
939, 864, 791; MS (EI, m/z) 250 (4, M+), 191 (45), 175 (36), 159
(29), 145 (24), 131 (54), 117 (42), 109 (100), 105 (74), 91 (93), 81
(44), 79 (47), 77 (40), 55 (34) 43 (55); HRMS (EI) calcd for
C15H22O3 250.1564, found 250.1557.
The substrates (E)-1m (25% over six steps, 3.9 g) and (E)-1p (64%
over three steps, 1.08 g) were prepared following our previous report
starting from (E)-3-methylpent-2-en-4-yn-1-ol reagent,12 which
appeared as a colorless oil.
1
(E)-1m: H NMR (400 MHz, CDCl3) δ 5.83 (t, J = 7.2 Hz, 1H),
1
(E)-1f: H NMR (400 MHz, CDCl3) δ 5.66 (dd, J = 9.2, 1.2 Hz,
4.67 (d, J = 7.2 Hz, 2H), 3.77 (s, 3H), 2.29 (t, J = 6.8 Hz, 2H), 1.85 (s,
3H), 1.53 (quint, J = 7.2 Hz, 2H), 1.41 (sext, J = 7.2 Hz, 2H), 0.91 (t, J
= 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 155.8, 127.9, 124.9,
90.1, 82.5, 64.1, 54.9, 30.9, 22.1, 19.1, 18.2, 13.7; FTIR (νmax/cm−1)
2958, 2933, 2873, 2219, 1748, 1442, 1378, 1329, 1254, 943, 791; MS
(EI, m/z) 210 (2, M+), 168 (16), 151 (22), 135 (30), 119 (8), 109
(16), 105 (20), 95 (71), 92 (100), 91 (71), 81(30), 79 (53), 77 (42);
HRMS (EI) calcd for C12H18O3 210.1251, found 210.1257.
1H), 5.44 (dq, J = 9.2, 6.4 Hz, 1H), 3.75 (s, 3H), 1.87 (s, 3H), 1.34 (d,
J = 6.4 Hz, 3H), 1.22 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 155.3,
133.7, 122.5, 97.7, 81.0, 71.7, 54.7, 31.1, 27.9, 20.5, 18.4; FTIR (νmax
/
cm−1) 2969, 2929, 2902, 2868, 2205, 1744, 1442, 1327, 1255, 1150,
1038, 948, 938, 864, 791; MS (EI, m/z) 224 (6, M+), 165 (98), 167
(23), 149 (53), 133 (74), 123 (32), 121 (41), 107 (54), 105 (100), 93
(44), 91 (96), 79 (41), 77 (42), 43 (90); HRMS (EI) calcd for
C13H20O3 224.1407, found 224.1403.
1
(E)-1p: H NMR (400 MHz, C6D6) δ 5.84 (dq, J = 8.0, 6.5 Hz,
1
(E)-1h: H NMR (400 MHz, CDCl3) δ 5.66 (d, J = 9.4, 1H), 5.46
1H), 5.56 (d, J = 8.0 Hz, 1H), 3.34 (s, 3H), 2.80 (s, 1H), 1.58 (d, J =
1.2 Hz, 3H), 1.26 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, C6D6) δ
(dq, J = 9.2, 6.5 Hz, 1H), 3.74 (s, 3H), 2.28 (t, J = 6.8 Hz, 2H), 2.24−
2.10 (m, 2H), 1.53−1.27 (m, 11H), 0.9 (t, J = 7.6 Hz, 6H); 13C NMR
(101 MHz, CDCl3) δ 155.2, 133.5, 127.8, 90.2, 81.5, 71.4, 54.7, 31.5,
30.94, 30.75, 22.4, 22.1, 20.8, 19.1, 14.1, 13.7; FTIR (νmax/cm−1) 2957,
2932, 2862, 2219, 1744, 1441, 1259, 1151, 1036, 941, 866, 791; MS
(EI, m/z) 266 (1, M+), 207 (24), 191 (14), 161 (9), 148 (14), 119
(29), 105 (55), 91 (83), 77 (50), 55 (52), 43 (100); HRMS (ESI)
calcd for C16H27O3 (MH+) 267.1956, found 267.1955.
155.6, 138.0, 120.4, 83.4, 81.4, 73.8, 54.1, 22.7, 20.2; FTIR (λmax
/
cm−1) 2957, 2931, 2860, 2244, 146 1441, 1258, 1033, 944, 791, 762,
697; MS (EI, m/z) 168 (2, M+), 153 (4), 109 (100), 91 (77), 77 (44);
HRMS (EI) calcd for C9H12O3 168.0781, found 168.0780.
Synthesis of Substrate (E)-1d. (E)-3-Methylpent-2-en-4-yn-1-ol
(S1) was phenylated by the Sonogashira method: A mixture of phenyl
iodide (19 mmol), PdCl2(PPh3)2 (105.3 mg, 0.15 mmol), and CuI
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1
(E)-1i: 1H NMR (400 MHz, CDCl3) δ 7.37−7.29 (m, 5H), 5.99 (d,
J = 5.6 Hz, 1H), 5.33 (dq, J = 9.6, 6.4 Hz, 1H), 3.73 (s, 3H), 2.32 (t, J
= 7.2 Hz, 2H), 1.55−1.40 (m, 4H), 1.37 (d, J = 6.8 Hz, 3H), 0.91 (t, J
= 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 154.9, 137.4, 135.1,
128.48, 128.43, 128.1, 127.3, 91.7, 81.5, 72.3, 54.7, 30.8, 22.1, 20.8,
19.2, 13.7; FTIR (νmax/cm−1) 3019, 2957, 2933, 2873, 1744, 1442,
1258, 1154, 1029, 941, 866, 791, 772, 736, 699; MS (EI, m/z) 286 (2,
M+), 227 (25), 211 (20), 195 (18), 185 (14), 171 (23), 168 (51), 167
(39), 153 (35), 141 (24), 129 (22), 115 (21), 105 (8), 91 (22), 81
(21), 77 (13), 43 (100); HRMS (ESI) calcd for C18H23O3 (MH+)
287.1647, found 287.1642.
(E)-1g: colorless oil; H NMR (400 MHz, CDCl3) δ 5.98 (dd, J =
16.0, 6.8 Hz, 1H), 5.72 (d, J = 16 Hz, 1H), 5.19 (quint, J = 6.8 Hz,
1H), 3.76 (s, 3H), 2.29 (t, J = 6.8 Hz, 2H), 1.53- 1.39 (m, 4H), 1.36
(d, J = 6.4 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 155.1, 139.6, 113.1, 92.6, 78.0, 74.6, 54.8, 30.8, 22.1, 20.2,
19.2, 13.7; FTIR (νmax/cm−1) 2958, 2934, 2873, 2217, 1745, 1441,
1256, 1154, 1036, 942, 868, 791; MS (EI, m/z) 210 (2, M+), 168 (8),
151 (66), 135 (34), 119 (11), 109 (27), 105 (22), 95 (61), 91 (100),
79 (52), 77 (38), 65 (33), 43 (67); HRMS (EI) calcd for C12H18O3
210.1251, found 210.1250.
Synthesis of Substrate (E)-1o. A dry, two-necked, round-
bottomed 250 mL flask equipped with a reflux condenser and an Ar
gas inlet was filled with 75 mL of anhydrous absolute ethanol. Metallic
sodium (3.48 g, 150 mmol) was cut into small pieces and added into
the ethanol and stirred. After all sodium was dissolved, diethyl
malonate (23 mL, 150 mmol) was added to the solution. The reaction
mixture was treated with iodomethane (9.8 mL, 157,5 mmol) by
dropwise addition using a syringe and heated until the mixture reached
its boiling point. After 4 h, the reaction mixture was concentrated
under reduced pressure and diluted with diethyl ether and water.
Following phase separation, the aqueous layer was extracted with
ether, and the combined extracts were dried over MgSO4, filtered, and
evaporated in vacuo. The crude product diethyl 2-methylmalonate
(S8) was used in the next step.31
The crude S8 (∼50 mmol) was slowly added to the solution of
NaH (25 g, 52 mmol) in 63 mL of dry Et2O via syringe, and the
reaction mixture was refluxed again for 2.5 h. CHI3 (19.8 g, 50 mmol)
was added in one portion, and the mixture was refluxed for 20 h. After
the mixture was cooled to 0 °C, hydrochloric acid solution (18 mL,
10%) was added, and the resulting mixture was stirred for ∼10 min.
The organic phase was decanted, dried over MgSO4, filtered, and
concentrated under a reduced pressure. The remaining residue was
diluted with petroleum ether, and precipitated iodoform was removed
by filtration. The product diethyl 2-(diiodomethyl)-2-methylmalonate
(S9) was purified by distillation at 130 °C and 12 bar (yield = 14.3 g,
65%).32
The solution of S9 (∼33 mmol) and KOH (5.6 g, 0.1 mol) in
EtOH/H2O (3:1, 45 mL) was refluxed for 24 h and cooled to room
temperature. The reaction mixture was concentrated under reduced
pressure, diluted with an aqueous solution of K2CO3 (27 mL, %10),
and washed with dichloromethane (2 × 9 mL). The basic solution was
acidified with HCl (aq) (12 M), and the aqueous phase was extracted
with dichloromethane (7 × 7 mL). The combined organic phases were
dried over MgSO4, filtered, and concentrated under vacuum. (E)-3-
Iodo-2-methylacrylic acid (S10) was purified from the residue by
crystallization with petroleum ether (yield = 12.9 g 89%).32
Lithium aluminum hydride (1.1 g, 29 mmol) was slowly added to
the solution of S10 (∼29 mmol) in 48 mL of dry THF at 0 °C
temperature under Ar. The reaction mixture was allowed to warm to
room temperature and stirred for 3 h. The reaction mixture was
recooled to 0 °C and quenched with saturated aqueous Na2SO4 by
dropwise addition. The mixture was diluted with ether, and 40 mL of
aqueous H2SO4 (2 M) was added. The organic phase was decanted,
and the aqueous phase was extracted with DCM. The combined
organic phases were washed with 10 mL of aqueous K2CO3 (10%),
and the aqueous phase was extracted with DCM. The combined
organic phases were dried over MgSO4 and filtered, and the solvent
was removed under vacuum. The product (E)-3-iodo-2-methylprop-2-
en-1-ol (S11) was purified by column chromatography on silica gel
(hexane/ethyl acetate; yield 3.7 g, 65%).32
Method B. BuLi (6.9 mL, 2.5 M in hexane, 17.1 mmol) was added
to a solution of tert-butylacetylene (2 mL, 16.3 mmol) in dry THF (40
mL) at −78 °C, and the solution was stirred for 45 min at this
temperature. Methyl chloroformate (1.4 mL, 1.71 mmol) was added
subsequently, and the reaction mixture was allowed to warm slowly to
23 °C overnight. The reaction was quenched with H2O (20 mL), and
the mixture was extracted with Et2O (2 × 50 mL). The organic layers
were then combined, washed with brine (40 mL), and dried over
MgSO4. The solution of methyl 4,4-dimethylpent-2-ynoate (S5j) was
concentrated in vacuo and was directly used in the next step.27
S5j (2.8 g, 20 mmol) and 1-hexyne (1.64 g, 20 mmol) were
successively added to a mixture of Pd(OAc)2 (90 mg, 2 mol %) and
tris(2,6-dimethoxyphenyl)phosphine (180 mg, 2 mol %) in THF (30
mL). The resulting mixture was stirred at room temperature until the
reaction was judged complete by GC analysis. The mixture was
concentrated and filtered through a short column with silica gel using
hexane/EtOAc. The reaction produced the desired enyne ester S6j
compound along with its regioisomer in 1:1 ratio (overall yield: 4.5 g,
95%).28 The mixture of S6j and its regioisomer (Z)-ethyl 2-(2,2-
dimethylpropylidene)oct-3-ynoate was reduced to the corresponding
primary enyne alcohols as specified previously.11,12 The enyne alcohol
of desired isomeric form S2j could be separated from its regioisomer
by silica gel column chromatrography (hexane/ethyl acetate, yield: 1.8
g, 48%). S2j was oxidized to yield the corresponding enyne aldehyde
S7j in 77% (1.4 g), and S7j was then subjected to Grignard reaction
with MeMgBr following the procedures as described previously.11,12
The Grignard process partially isomerized the alkenyl moiety to
produce 4-tert-butyldec-3-en-5-yn-2-ol (S3j) in 76% yield (1.18 g)
with an E/Z ratio of 1.4:1. The carbonate functionalization of S3j was
performed by following a specified method (hexane/ethyl acetate,
colorless oil, yield: 1.3 g, 81%, (E)/(Z) ratio: 1.4/1).25
1
1j: H NMR (400 MHz, CDCl3) δ 5.90−5.82 (m, 1H, E), 5.69−
5.61 (m, 3H), 3.76 (s, 3H, Z), 3.76 (s, 3H, E), 2.38 (t, J = 7.2 Hz, 2H,
Z), 2.30 (t, J = 6.4 Hz, 2H, E), 1.59−1.39 (m, 8H), 1.36 (d, J = 6.4 Hz,
3H, Z), 1.35 (d, J = 6.4 Hz, 3H, E), 1.25 (s, 9H, E), 1.10 (s, 9H, Z),
0.93 (t, J = 7.2 Hz, 3H, E), 0.91 (t, J = 7.6 Hz, 3H, Z); 13C NMR (100
MHz, CDCl3) δ (E): 155.1, 133.9, 129.8, 89.7, 82.1, 71.8, 54.6, 35.7,
30.9, 29.0, 21.99, 21.1, 18.9, 13.59; (Z) 155.0, 136.3, 134.8, 103.2, 98.1,
74.9, 54.5, 36.2, 30.8, 29.0, 21.98, 20.4, 19.2, 13.57. MS (EI, m/z) 266
(2, M+), 207 (8), 135 (4), 133 (14), 91 (20), 65 (40), 59 (62), 57
(52), 43 (69), 41 (100); HRMS (ESI) calcd for C16H27O3 (MH+)
267.1956, found 267.1986.
Synthesis of Substrate (E)-1g. (Z)-Methyl 3-iodoacrylate, which
was synthesized by hydroiodation of methyl propiolate using a
reported procedure (3.4 g, 84%),29 was isomerized to its (E)-
configured form ((E)/(Z); 96:4).30 Then, (E)-methyl 3-iodoacrylate
was subjected to palladium-catalyzed coupling with 1-hexyne: The
mixture of (E)-methyl 3-iodoacrylate (∼25 mmol) in crude form,
PdCl2(PPh3)2 (151.2 mg, 0.23 mmol), and CuI (23.5 mg, 0.13 mmol)
in 100 mL of Et3N was stirred for 10 min at room temperature under
Ar. 1-Hexyne (28.8 mmol) was added to the resulting mixture and
stirred at room temperature for 3 h. At the end of the reaction, water
was added to the mixture and extracted with Et2O. The combined
organic layers were dried over MgSO4. The solvent was evaporated in
vacuo, and the enyne ester product (S6g) was purified by column
chromatography on silica gel (hexane/ethyl acetate, yield: 2.3 g, 88%).
S6g (10 mmol) was converted to (E)-1g (0.59 mg, 25%) as specified
for (E)-1e.
S11 was subjected to Sonogashira reaction with 1-hexyne. The
Sonogashira product (E)-2-methylnon-2-en-4-yn-1-ol (yield: 86%) was
oxidized to (E)-2-methylnon-2-en-4-ynal and then subjected to
Grignard reaction with MeMgBr following the procedures as described
previously11,12 to obtain (E)-3-methylhept-3-en-5-yn-2-ol (yield:
45%). Carbonate derivatization of this secondary was performed via
a prescribed method (hexane/NEt3 (1 vol %), colorless oil, yield = 1 g,
62%).25
1
(E)-1o: H NMR (400 MHz, CDCl3) δ 5.55 (s, 1H), 5.16 (q, J =
6.4 Hz,1H), 3.76 (s, 3H), 2.34 (td, J = 6.8,1.6 Hz, 2H), 1.87 (s, 3H),
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1.54−1.48 (m, 2H), 1.47−1.40 (m, 2H), 1.36 (d, J = 6.8 Hz, 3H), 0.92
(t, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 155.1, 147.0,
107.9, 95.8, 77.9, 77.3, 54.8, 31.1, 22.1, 19.4, 19.2, 14.9, 13.7; FTIR
(νmax/cm−1) 2982, 2957, 2934, 2861, 2215, 1746, 1441, 1328,
1256,1067, 938, 871, 853, 791; MS (EI, m/z) 224 (4, M+), 165
(31), 149 (15), 148 (12), 119 (13), 109 (25), 106 (37), 105 (50), 93
(26), 91 (100), 79 (32), 77 (31), 43 (40); HRMS (ESI) calcd for
C13H20O3 (MH+) 225.1486, found 225.1485.
125.6, 104.3, 87.3, 52.0, 18.4, 14.6; FTIR (νmax/cm−1) 2952, 1944,
1720, 1437, 1261, 1152, 1031, 961, 834; MS (EI, m/z) 152 (20, M+),
137 (20), 109 (40), 93 (48), 91 (95), 77 (99), 59 (100); HRMS (ESI)
calcd for C9H13O2 (MH+) 153.0916, found 153.0911.
General Procedure for Alkoxycarbonylation of Enantiopure
Enyne Carbonates. A palladium compound, phosphine ligand, and
an alcohol (0.5 mL) were added successively to a Schlenk apparatus
that is attached to an Ar line, and the mixture was stirred magnetically
for about 1 h. The reaction flask was adjusted to the reaction
temperature, and 1.2 mL of a methanol solution of a substrate was
added to the reaction flask. A balloon filled with CO was fixed to the
reaction vessel, and the mixture was stirred magnetically at a
prescribed temperature. Purification of the samples were performed
as mentioned for those of racemic substrates. Enantiomeric exesses of
(S)- and (R)-2ba and (S)-2fa vinylallene products were determined by
HPLC methods. For (S)-2ba, HPLC conditions: OJ-H column,
Preparation of Enantiopure Enyne Carbonates.14 For the
preparation of corresponding enantiopure enynols of (E)- and (Z)-1b
and (E)-1p; 1.0 equiv of Ti(O-i-Pr)4 and 1.2 equiv of diisopropyl
tartarate (DIPT) were stirred in dry DCM (10 mL/mmol of allylic
alcohol) for 10 min between the temperatures of −25 and −30 °C
(−20 °C for the enynol of (Z)-1b). A dry DCM (5 mL) solution of
1.0 equiv of 2,4-enynol was added dropwise. After the mixture was
stirred at the same temperature for 30 min, 2 equiv of anhydrous
TBHP (ca. 4−4.5 M in toluene) was added, and the homogeneous
reaction mixture was maintained at −20 °C (in a freezer) for 13 h.
After completion, 10% aqueous solution tartaric acid (2.5 mL/mmol of
allylic alcohol) was added to the reaction mixture at −20 °C while
stirring, allowing the aqueous layer to solidify. After 30 min, the
cooling bath was removed, and stirring was continued at room
temperature until the aqueous layer became clear. After separation of
the aqueous layer, the organic layer was washed once with water, dried
with MgSO4, and concentrated to yield colorless oil. This oil was
diluted with ether, the resulting solution was cooled in an ice bath, and
then 1 M sodium hydroxide solution (3 mL/mmol of allylic alcohol)
was added. The mixture was stirred for 30 min, and the organic phase
was recovered and washed with brine, dried with MgSO4,
concentrated, and purified by column chromatography on silica gel
(hexane/EtAc) to give a clear oil in 42% (0.35 g), 48% (0.37 g), and
46% (0.38) yield, respectively. The enantiomeric purity of the enynols
was determined by GC analysis using using a Hydodex-β-3P column
(25 m, 0.25 mm ID). Their hydroxyl groups were modified to
carbonate as described above. For (R,E)-1b: 98% ee, [α]18D = +37.0 (c
hexane = 0.4 mL/min, λ = 250 nm, tR (major) = 11.9 min, tR
=
(minor) 12.9 min. For (R)-2ba, HPLC conditions: OJ-H column,
hexane/i-PrOH = 200/1, 0.4 mL/min, λ = 250 nm, tR (minor) = 10.5
min, tR = (major) 11.2 min. For (S)-2fa, HPLC conditions: Regis (S,S)
Whelk-O1 column, hexane/i-PrOH = 200/1, 0.4 mL/min, λ = 250
nm, tR (major) = 26.1 min, tR = (minor) 28.2 min. Enantiomeric purity
of (S)-2pa was determined by a chiral GC method using a Hydodex-β-
3P column (25 m, 0.25 mm i.d.).
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C spectra of (E)-1d−i,m,o,p, (E,Z)-1j, and 2pa and
chromatograms of enantioenriched compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: leventartok@iyte.edu.tr
■
= 7.75, CH2Cl2); for (R,Z)-1b: 99% ee, [α]22 = −14.6 (c = 3.92,
D
Notes
CH2Cl2); for (R,E)-1p: 98% ee, [α]22 = +31.3 (c = 4.79, CH2Cl2).
D
The authors declare no competing financial interest.
For the preparation of the enynol of (R,E)-1f, 0.3 equiv of Ti(O-i-
Pr)4 and 0.36 equiv of DIPT were stirred in dry DCM (10 mL/mmol
of allylic alcohol) at −55 °C. After the mixture was stirred for 10 min,
1.0 equiv of enynol in 5−6 mL of dry DCM was added dropwise. After
the mixture was stirred at the same temperature for 30 min, 2 equiv of
anhydrous TBHP (ca. 4−4.5 M in toluene) was added, and the
homogeneous reaction mixture was stirred at the same temperature for
4 days and at −35 °C for 1 day. After completion, the treatment and
purification procedures were performed as described above (hexane/
EtAc, yield: 20%, 45 mg). Determination of its enantiomeric purity
and carbonate derivatization were performed as described above.
ACKNOWLEDGMENTS
■
The financial support of the Scientific and Technological
Research Council of Turkey and Federal Ministry of Education
and Research (Germany) via the Intensified Cooperation
Program (210T092) is gratefully acknowledged. We thank the
Salih Research Group, SAREG, of the Chemistry Department
of Hacettepe University and Mass Spectrometry Laboratory of
Dortmund University of Technology for HRMS analyses.
(R,E)-1f: 98% ee, [α]27 = +79.4 (c = 1.13, CH2Cl2).
D
DEDICATION
Dedicated to the memory of Dr. Ritchie C. Eanes.
General Procedure for Alkoxycarbonylation of Racemic
Enyne Carbonates. The substrate, a palladium compound, ligand,
and an alcohol (5 mL) were added successively to a Schlenk apparatus
that was attached to an Ar line. A CO balloon was fixed to the reaction
vessel, and the mixture was stirred magnetically in a preheated oil bath.
The course of the reaction was followed by TLC and GC analyses.
The solvent was evaporated at the end of the reaction, and the residue
was purified by column chromatography on silica gel (hexane/EtOAc),
affording the product. All of the vinylallene products appeared as
colorless oils, and coupling constants of olefinic protons and NOE
studies confirm (E)-configured structures. Except for 2pa, spectro-
metric data of vinylallene products can be found elsewhere (see Tables
1 and 2 for yield percentages; (E)-2ba, 54.9 mg; (E)-2bb, 53.9 mg;
(E)-2bc, 64.4 mg; (E)-2bd, 60.0 mg; (E)-2be, 47.4 mg; (E)-2ca, 32.9
mg; (E)-2da, 55.4 mg; (E)-2ea, 58.3 mg; (E)-2fa, 41.8 mg; (E)-2ga,
51.8 mg; (E)-2ha, 67.5 mg; (E)-2ia, 62.4 mg; (E)-2ka, 49.9 mg; (E)-
2la, 47.7 mg).11
■
REFERENCES
■
(1) (a) Krause, N.; Hashimi, A. S. K. Modern Allene Chemistry; Wiley-
VCH: Weinheim, 2004. (b) Hoffman-Roder, A.; Krause, N.
Tetrahedron 2004, 60, 11671. (c) Yu, S.; Ma, S. Chem. Commun.
2011, 47, 5384.
̈
(2) (a) Mikami, K.; Yoshida, A. Angew. Chem., Int. Ed. Engl. 1997, 36,
858. (b) Wang, Y.; Zhang, W.; Ma, S. J. Am. Chem. Soc. 2013, 135,
11517. (c) Krause, N.; Purpura, M. Angew. Chem., Int. Ed. 2000, 39,
435. (d) Cai, F.; Pu, X.; Qi, X.; Lynch, V.; Radha, A.; Ready, J. M. J.
Am. Chem. Soc. 2011, 133, 18066. (e) Nishimura, T.; Makino, H.;
Nagaosa, M.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 12865.
(f) Ogasawara, M. Tetrahedron: Asymmetry 2009, 20, 259. (g) Miura,
T.; Shimada, M.; Ku, S.-Y.; Tamai, T.; Murakami, M. Angew. Chem.,
Int. Ed. 2007, 46, 7101. (h) Crouch, I. T.; Neff, R. K.; Frantz, D. E. J.
Am. Chem. Soc. 2013, 135, 4970.
2pa: yield 90% (13.7 mg); 1H NMR (400 MHz, CDCl3) δ 5.98 (dt,
J = 15.6, 0.8 Hz, 1H), 5.77−5.69 (m, 1H), 5.68−5.66 (m, 1H), 3.72 (s,
3H), 1.89 (d, J = 2.8 Hz, 3H), 1.80 (dd, J = 6.8, 1.6 Hz, 3H), 1.26 (d, J
= 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 215.7, 166.3, 127.4,
(3) (a) Ma, S. Acc. Chem. Res. 2003, 36, 701. (b) Ma, S. Chem. Rev.
2005, 105, 2829.
9229
dx.doi.org/10.1021/jo5014993 | J. Org. Chem. 2014, 79, 9222−9230

The Journal of Organic Chemistry
Article
(4) (a) Marshall, J. A.; Wolf, M. A. J. Org. Chem. 1996, 61, 3238.
Sciano, G. T.; Costa, M.; Chiusoli, G. P. Tetrahedron Lett. 1997, 38,
6877.
(24) Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnet, J. J.; Ibers, J. A. J.
(b) Hoffman-Roder, A.; Krause, N. Angew. Chem., Int. Ed. 2004, 43,
̈
1196. (c) Ma, S.; Wu, S. Chem. Commun. 2001, 441. (d) Volz, F.;
Krause, N. Org. Biomol. Chem. 2007, 5, 1519. (e) Sun, T.; Deutsch, C.;
Krause, N. Org. Biomol. Chem. 2012, 10, 5965. (f) Volz, F.; Wadman,
Organomet. Chem. 1974, 65, 253.
(25) Chen, L.; Li, C. Tetrahedron Lett. 2004, 45, 2771.
(26) Zhao, S.; Ji, K.; Lu, L.; He, T.; Zhou, A.; Yan, R.; Ali, S.; Liu, X.;
Liang, Y. J. Org. Chem. 2012, 77, 2763.
(27) Rooke, D. A.; Ferreira, E. M. Angew. Chem., Int. Ed. 2012, 51,
3225.
(28) Rubina, M.; Conley, M.; Gevorgyan, V. J. Am. Chem. Soc. 2006,
128, 5818.
(29) Piers, E.; Wong, T.; Coish, P. D.; Rogers, C. Can. J. Chem. 1994,
72, 1816.
(30) Garrais, S.; Turkington, J.; Goldring, W. P. D. Tetrahedron 2009,
65, 8418.
S. H.; Hoffmann-Roder, A.; Krause, N. Tetrahedron 2009, 65, 1902.
̈
(g) Miura, T.; Shimada, M.; de Mendoza, P.; Deutsch, C.; Krause, N.;
Murakami, M. J. Org. Chem. 2009, 74, 6050.
(5) (a) Elsevier, C. J.; Kleijn, H.; Ruitenberg, K.; Vermeer, P. J. Chem.
Soc., Chem. Commun. 1983, 1529. (b) Elsevier, C. J.; Kleijn, H.;
Boersma, J.; Vermeer, P. Organometallics 1986, 5, 716. (c) Wouters, J.
M. A.; Klein, R. A.; Elsevier, C. J. Organometallics 1994, 13, 4586.
(d) Canty, A. J.; Jin, H.; Penny, J. D. J. Organomet. Chem. 1999, 573,
3035.
(6) (a) Tsuji, J.; Mandai, T. Angew. Chem., Int. Ed. Engl. 1995, 34,
2589. (b) Ma, S. Eur. J. Org. Chem. 2004, 1175.
(7) Dixneuf, P. H.; Guyot, T.; Nessb, M. D.; Roberts, S. M. Chem.
Commun. 1997, 2083.
(31) Weiner, N. Org. Synth. 1937, 17, 56.
(32) Baker, R.; Castro, J. L. J. Chem. Soc., Perkin Trans. 1 1990, 47.
(8) Marshall, J. A.; Wolf, M. A.; Wallace, E. M. J. Org. Chem. 1997,
62, 367.
(9) (a) Elsevier, C. J.; Stehouwer, P. M.; Westmijze, H.; Vermeer, P.
J. Org. Chem. 1983, 48, 1103. (b) Molander, G. A.; Sommers, E. M.;
Baker, S. R. J. Org. Chem. 2006, 71, 1563.
(10) (a) Piotti, M. E.; Alper, H. J. Org. Chem. 1997, 62, 8484.
(b) Yoshida, M.; Ueda, H.; Ihara, M. Tetrahedron Lett. 2005, 46, 6705.
(c) Yoshida, M.; Hayashi, M.; Shishido, K. Org. Lett. 2007, 9, 1643.
̈
̧ M.; Ucu̧ ncu, M.; Karakus,̧ E.; Artok, L. Org.
̈ ̈
(11) Akpınar, G. E.; Kus,
Lett. 2011, 13, 748.
(12) An extended version of the method involves the reaction of
enyne carbonates and organoboronic acids, which yields aryl
̈
vinylallenes: Ucu̧ ncu, M.; Karakus,̧ E.; Kus,̧ M.; Akpınar, G. E.;
̈ ̈
̈
Aksın-Artok, O.; Krause, N.; Karaca, S.; Elmacı, N.; Artok, L. J. Org.
Chem. 2011, 76, 5959.
(13) This SN2-type product was also determined to form in the
absence of the palladium catalyst.
(14) (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda,
M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237. (b) Kitano, Y.;
Matsumoto, T.; Sato, F. J. Chem. Soc., Chem. Commun. 1986, 1323.
(15) The Lowe−Brewster rule was used to correlate the sign of
optical rotation with the absolute configuration of the allene:
(a) Lowe, G. Chem. Commun. 1965, 411. (b) Brewster, J. H. Top.
Stereochem. 1967, 2, 33.
(16) (a) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1978, 100,
3435. (b) Hayashi, T.; Hagihara, T.; Konishi, M.; Kumada, M. J. Am.
Chem. Soc. 1983, 105, 7767. (c) Granberg, K. L.; Jan-E. Backvall, J.-E. J.
̈
Am. Chem. Soc. 1992, 114, 6858.
(17) All our attempts to convert a secondary 2-en-4-yne alcohol to its
corresponding mesylate4a,8 and phosphate9 derivatives in order to
implement a better leaving group to the structure failed due to
decomposition.
(18) Such a trend was also observed for the alkoxycarbonylation
reactions of conjugated enyne oxiranes: Kus,
in preparation.
̧ M.; Artok, L. Manuscript
(19) Reactions of enantiopure 2-en-4-yne acetates and organo-
cuprates is the only example of the 1,5-substitution type reaction of
conjugated enyne systems hitherto reported in the literature: Krause,
N.; Hoffman-Roder, A. Angew. Chem., Int. Ed. 2000, 39, 4355.
̈
(20) For the reaction of (R,E)-1f, the catalyst was added in two
portions: 6 mol % of Pd and 12 mol % of ligand in 1.7 mL of MeOH
initially, and the remaining portion was added in 0.5 mL of MeOH
after 48 h of reaction.
(21) (a) Trost, B. M.; Verhoeven, T. R. J. Org. Chem. 1976, 41, 3215.
(b) Hayashi, T.; Yamamoto, A.; Hagihara, T. J. Org. Chem. 1986, 51,
723.
(22) Faller, J. W.; Thomsen, M. E.; Mattina, M. J. J. Am. Chem. Soc.
1971, 93, 2642.
(23) Similarly, a palladium-catalyzed carbonylative reaction of a
phenyl-substituted secondary enynol in methanol was also shown to
undergo allylic etherification: Gabriele, B.; Salerno, G.; De Pascali, F.;
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