One-Pot Conversion of Aldehydes and Ketones into 1-Substituted and 1,4-Disubstituted 1,3-Enynes

Article abstract of DOI:10.1055/s-0037-1610197

Sequential treatment of 2,3-dichloropropene with magnesium and n -BuLi generates the operational equivalent of 1,3-dilithiopropyne, which upon treatment with aldehydes or ketones, produces the corresponding alkoxy lithium acetylide intermediates. Reaction of this alkoxide with tosyl chloride, and t -BuLi produces 1-substituted, or 1,1-disubstituted 1,3-enynes in a one-pot reaction. When this lithium acetylide intermediates, obtained by this procedure, were used to perform palladium-catalyzed cross-coupling reactions, followed by addition of thionyl chloride and pyridine, 1,4-disubstituted or 1,1,4-trisubstituted 1,3-enynes were obtained in a one-pot protocol.

Full text of DOI:10.1055/s-0037-1610197

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–O
feature
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J. A. Cabezas et al.
Feature
Synthesis
One-Pot Conversion of Aldehydes and Ketones into 1-Substituted
and 1,4-Disubstituted 1,3-Enynes
Jorge A. Cabezas*
Rebeca R. Poveda
José A. Brenes
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7-
5
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needle
balloon
Escuela de Química, Universidad de Costa Rica, San José,
2060, Costa Rica
O
jorge.cabezas@ucr.ac.cr
R
R'
Ar-X / Pd
This article is dedicated to Professor Cam Oehlschlager,
senior supervisor and friend
SOCl2 / Py
Cl
R'
4
Ar
Cl
1
3
THF
R
2
n-BuLi
–78 °C
Mg
H
H
H
H
17 examples, 18–71%
•
Received: 01.06.2018
Accepted after revision: 05.06.2018
Published online: 23.07.2018
is due to the cleavage of DNA in cells,10 provoked by this
chromophoric moiety (its protein component is essential in
transporting and stabilizing the drug).10c Kedarcidin chro-
mophore (5) is a chromoprotein isolated from the fermen-
tation broth of an actinomycete;11,12 the potent antitumor
agent dynemicin A (6)13 was isolated from the bacteria
Micromonospora chersina;14 and the potent antitumor
DOI: 10.1055/s-0037-1610197; Art ID: ss-2018-m0034-fa
Abstract Sequential treatment of 2,3-dichloropropene with magne-
sium and n-BuLi generates the operational equivalent of 1,3-dilithiopro-
pyne, which upon treatment with aldehydes or ketones, produces the
corresponding alkoxy lithium acetylide intermediates. Reaction of this
alkoxide with tosyl chloride, and t-BuLi produces 1-substituted, or 1,1-
disubstituted 1,3-enynes in a one-pot reaction. When this lithium
acetylide intermediates, obtained by this procedure, were used to per-
form palladium-catalyzed cross-coupling reactions, followed by addi-
tion of thionyl chloride and pyridine, 1,4-disubstituted or 1,1,4-trisub-
stituted 1,3-enynes were obtained in a one-pot protocol.
15
agent calicheamicin γ1 (7) is derived from the bacterium
Micromonospora echinospora, which has been marketed as
targeted therapy against non-solid tumors of acute myeloid
leukemia. Other interesting examples are histrionicotoxins
(8),16 gephyrotoxin (9),17 and N-methyldecahydroquinoline
alkaloids,18 found in the skin of poison frogs from the family
Dendrobatidae (Dendrobates histrionicus), as well as xerulin
(10), an inhibitor of cholesterol biosynthesis, isolated from
cultures of Xerula melanotricha Dörfelt.19
Key words 1,3-dilithiopropyne, lithium acetylides, 1,3-enynes, palla-
dium catalysis, cross-coupling, propargylation
The 1,3-enyne framework is also present in some im-
portant pharmaceutical compounds. Terbinafine (11), com-
mercially known as lamisil, was the first pharmaceutical
agent to contain an (E)-1,3-enyne in its chemical struc-
ture.20 It was discovered in 1984,21 as a synthetic modifica-
tion of naftifine (Exoderil), and it has been used commer-
cially since 1996, in oral and topical treatment of skin and
toenail infections (onychomycosis) caused by dermato-
phytes such as Trichophyton rubrum22 and Trichopyton
mentagrophytes.22 Another important example is oxamfla-
tin (12), a growth inhibitor of various cancer cells.23 It has
been found that oxamflatin has in vitro antiproliferative ac-
tivity against various mouse and human tumor cell lines,
and in vivo antitumor activity against B16 melanoma.
1,3-Enynes are also used as important building blocks in
organic synthesis.24 Numerous methods for the preparation
of 1,3-enynes have been developed,25 and, among those,
palladium-catalyzed Sonogashira cross-coupling26 of termi-
Introduction
1,3-Enynes are found widely in many natural products
and exhibit diverse biological activities. Some examples of
these are the marine natural products phorbasides A (1)
and B–E, highly cytotoxic macrolides isolated from the
Western Australian marine sponge Phorbas sp.,1 and the
structurally related (–)-callipeltosides A, B (2), and C (Figure
1). These are active against human bronchopulmonary non-
small-cell lung carcinoma (NSCLC-N6 and P388 cell lines),2
and were first isolated in 1996 from the New Caledonian
lithistida sponge Callipelta sp.3 Additionally, the 1,3-enyne
pyrrhoxanthin (3) has been isolated from the chloroplasts
of dinoflagellates Gyrodinium resplendens,4 Gymnodinium
nelsoni,5 and a natural bloom of Ceratium spp.6 Other exam-
ples of natural products containing the 1,3-enyne moiety
are the enediynes: neocarzinostatin (4) is the first enediyne
antitumor antibiotic, isolated in 1965 from a culture of
Streptomyces carzinostaticus,7,8 whose antitumor activity9
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

B
J. A. Cabezas et al.
Feature
Synthesis
nal acetylenes with vinyl halides is widely used.27 Other
methods include palladium-catalyzed alkynylation28 and
the direct transition-metal-catalyzed coupling of alkynes.29
We report herein a new method for the efficient, one-
pot conversion of aldehydes and ketones into 1,3-enynes.
gyl alcohols 17 in very good yields. Since the high cost of
allene 13 considerably restricts the use of this methodolo-
gy, we later developed a procedure to prepare the above
dianion 14 by treatment of propargyl bromide (18) with n-
BuLi, in the presence of TMEDA (method B).31 The organo-
metallic intermediate 14 thus generated reacts with alde-
hydes and ketones, producing the corresponding homo-
propargyl alcohols 17 in excellent yields.31 Recently we
showed that this dianion 14 (or its equivalent) could be pre-
pared in the absence of TMEDA, by sequential treatment of
2,3-dichloropropene (19) with magnesium and n-BuLi, and
it also reacted with aldehydes and ketones in similar yields
(method C).32
Results and Discussion
We previously reported that treatment of allene 13 with
two equivalents of n-BuLi produced the operational equiva-
lent of 1,3-dilithiopropyne (14; Scheme 1, method A).30 This
dianion 14 added regiospecifically to aromatic aldehydes
and ketones 15 to produce, after protonolysis, homopropar-
Biographical Sketches
Jorge A. Cabezas was born in
San José, Costa Rica, and stud-
ied chemistry at the University
of Costa Rica, where he ob-
tained B.Sc. and Licentiate de-
grees in chemistry. He obtained
his Ph.D. in chemistry (1990–
1994) at Simon Fraser Universi-
ty (SFU), British Columbia, Can-
ada, under the supervision of
Professor Cam Oehlschlager,
where he worked on mechanis-
tic, spectroscopic, and synthetic
aspects of the stannylcupration
of acetylenic ethers. After fin-
ishing his Ph.D., he spent one
more year (1994–1995) at SFU
as a postdoctoral fellow working
on the synthesis of phero-
mones. He returned to the Uni-
versity of Costa Rica and in
1996 was promoted to Associ-
ate Professor and became Full
Professor in 1999. He is the re-
cipient of several awards:
‘TWAS-CONICIT for Young Sci-
entists’ (1998) from the Nation-
al Council of Scientific and
Technological Research, ‘Contri-
butions to Creativity and Excel-
lence’ (2002) from the Florida
Ice & Farm, ‘National Prize in
the Government of Costa Rica,
and ‘Chemist of the Year’
(2007) from the National Asso-
ciation of Chemists of Costa Ri-
ca. Also, he has been frequently
recognized for excellence in
teaching. His research interests
involve the development of new
synthetic methodologies, or-
ganometallic chemistry, and the
synthesis of pheromones. His
hobbies include nature photog-
raphy, arts, drawing, music,
high-end audio, home-studio
acoustics design, literature, and
long walks with his Rottweilers.
Science
Clodomiro
Picado
Twight’ (2006) from the Minis-
try of Science and Technology
and the Ministry of Culture of
Rebeca Poveda was born in
Cartago, Costa Rica. She is fin-
ishing her undergraduate stud-
ies at the School of Chemistry,
University of Costa Rica, where
she has worked as a teaching as-
sistant in analytical and organic
chemistry lab courses. Current-
ly, she works as a research assis-
tant, under the supervision of
Professor Cabezas, on new syn-
thetic methodologies using or-
ganometallics
and
its
application to the synthesis of
enynes and antitumor com-
pounds.
José Á. Brenes was born in
Cartago, Costa Rica, in 1993. He
obtained his B.Sc. degree at the
University of Costa Rica. He car-
ried out his M.Sc. thesis re-
search under the guidance of
Prof. Cabezas on new method-
ologies for the organometallic
synthesis of enynes and their
application in total synthesis of
antifungal molecules. Also
during this period he worked as
an instructor at the UCR. Re-
cently, he joined Chem-Tica In-
ternational, where he works on
the synthesis of insect phero-
mones for the biological control
of plagues. He likes cooking,
hiking, club culture, dancing,
Japanese culture, ufology, read-
ing, and traveling to new places.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

C
J. A. Cabezas et al.
Feature
Synthesis
OH
R1
R2
O
O
MeO
OH
O
O
OMe
O
O
O
O
O
O
O
AcO
3, Pyrrhoxanthin
R3
O
O
H
OH
O
OH
MeO
O
MeHN
HO
O-i-Pr
n
O
R4
R5
MeO
MeO
H
OH
4, Neocarzinostatin chromophore
1, Phorbaside A, R1 = OH, R2 = H, R3 = Me, R4 = Cl, R5 = H, n = 1
2, Callipeltoside B, R1 = H, R2 = NHCHO, R3 = H, R4 = H, R5 = Cl, n = 2
OH
HN
O
N
Cl
H
HN
CO2H
O
O
OH
OH
O
O
O
O
OH
HO
OMe
O
O
H
H
O
OH
OH
O
O
6, Dynemicin A
5, Kedarcidin
NMe2
O
HO
NH
O
O
MeSSS
H
OMe
O
I
H
S
H
O
H
N
O
N
H
N
O
OMe
HO
O
H
OH
O
HO
OMe
O
H
HO
O
EtHN
MeO
HO
9, Gephyrotoxin
OH
MeO
7, Calicheamicin γ1
8, Histrionicotoxin 283 A
O
NHOH
Me
N
12, Oxamflatin
NH
O
10, Xerulin
11, Terbinafine
S
O
O
O
Figure 1 Examples of some biologically active compounds containing the 1,3-enyne framework
We envisioned that the lithium alkoxide intermediate
16 formed in the above protocols could be selectively react-
ed with a trapping agent (T.A.) at the alkoxide over the
acetylide terminus, to convert it into a good leaving group,
as in 20, to obtain, after basic treatment and protonolysis,
the corresponding 1,3-enyne 22 (Scheme 1). An additional
advantage of this methodology is that the lithium acetylide
intermediate 21 obtained through this methodology could
be reacted with an electrophile (E+) to produce 4-substitut-
ed enynes 23 in a one-pot reaction.
Synthesis of 1,3-Enynes Type 22
Initial reactions involved treatment of propargyl bro-
mide (18) with n-BuLi in the presence of TMEDA (Scheme 1,
method B), followed by addition of benzophenone 24 to
produce the corresponding lithium alkoxide intermediate
25 (Scheme 2). Subsequent reaction of intermediate 25
with ethyl chloroformate was not selective, resulting in
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

D
J. A. Cabezas et al.
Feature
Synthesis
Cl
Cl
19
O
Ph
Ph
OLi
Li
n-BuLi (2 equiv)
24
Li
Br
Ph
TMEDA, –78 °C
Li
18
14
Ph
25
1. Mg
Method C
Method B
2. n-BuLi (2 equiv), –78 °C
1. ClCO(OEt)
2. H3O+
H
n-BuLi (2 equiv)
n-BuLi (2 equiv)
Li
H
•
Br
O
H
–78 °C
TMEDA, –78 °C
Li
14
O
H
13
18
O
Ph
O
O
base
Method A
Method B
O
O
O
Ph
Ph
27
26
Ph
R
R`
15
Scheme 2 Initial synthesis of enyne 27 from benzophenone 24 and
dianion 14
OH
OLi
Li
H3O+
R
R
R´
R´
16
Table 1 Effect of Base on the Synthesis of 27 from 26
17
O
O
T.A.-X
O
Ph
O
O
base
O
O
O-TA
Li
Ph
Ph
Ph
26
27
R
R´
Entry
Base
Yield (%) of 27
20
1
2
3
LDA
10
42
87
base
KOH/MeOH
t-BuLi
R'
Li
R
21
treatment with KOH in ethanol (Scheme 3). In this case, the
expected enyne 27 was not obtained. Instead, a mixture of
the corresponding homopropargyl alcohol 28, benzhydrol
(29), carbonate 30, and unreacted benzophenone (24) was
obtained (Scheme 3; Table 2, entry 1). Benzhydrol 29 is ob-
tained from reduction of benzophenone 24 and its reaction
with ethyl chloroformate produces carbonate 30. We have
previously observed this type of reduction in this reaction
system.32
H3O+
E+
R'
R'
E
R
R
22
23
Scheme 1 Methods for preparation of dianion 14, and its application
to the synthesis of 1,3-enynes 22 and 23
C- and O-carbonylation, forming acetylenic ester 26. The
presence of TMEDA probably enhances the nucleophilicity
of the acetylide in 25, favoring C-carbonylation.
O
Acetylenic ester 26 was isolated, dissolved in THF, and
treated with LDA to obtain the corresponding substituted
enyne 27 in only 10% yield (Table 1, entry 1). Using KOH in
MeOH improved the yield to 42% (entry 2). The use of t-Bu-
Li, as a base for this elimination step, improved the yield of
27 to 87 % (entry 3). Surprisingly, several attempts to per-
form this transformation on benzophenone 24 to give
enyne 27 in a one-pot reaction resulted in very poor yields.
Perhaps the presence of TMEDA interferes in the elimina-
tion.
Cl
Ph
Ph
OLi
Ph
Li
1. Mg
24
Li
Cl
Ph
Li
2. n-BuLi
(2 equiv)
–78 °C
19
14
25
1. ClCO(OEt)
2. KOH, EtOH
Method C
O
OH
O
O
OH
O
+
+
+
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
28
36%
24
2%
29
20%
30
42%
We decided to prepare dianion 14 from 2,3-dichloro-
propene (19) and then treat it with benzophenone (24), fol-
lowed by sequential addition of ethyl chloroformate and
Scheme 3 Initial reactions of benzophenone 24 with dianion 14, gen-
erated from 2,3-dichloropropene 19
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

E
J. A. Cabezas et al.
Feature
Synthesis
Table 2 Effect of Reaction Conditions on Synthesis of Enyne 31
Cl
Ph
OLi
Ph
Li
24
1. Mg
1. T.A.
Cl
14
+
30
+
29
+
24
Ph
2. n-BuLi (2 equiv)
2. base
19
Ph
31
25
–78 °C
Entry
Trapping agent (T.A.)
Base
Yield (%)a
31
30
29
28
24
1
2
3
4
5
ClC(O)(OEt)
ClC(O)(OEt)
ClP(O)(OEt)2
TsCl/HMPA
TsCl/HMPA
KOH/EtOH
t-BuLi
–
–
42
47
20
36
2
13
4
5
4
35
16
14
34
t-BuLi
46
KOH/MeOH
t-BuLi
40
66
30
–
a Yields were determined by GC.
To determine the best reaction conditions for perform-
ing this transformation in a one-pot process, we studied
different alkoxide trapping reagents and different bases. As
described above, when ethyl chloroformate was used as a
trapping reagent, and KOH/EtOH as the base for the elimi-
nation step, no enyne 31 was obtained (Table 2, entry 1).
Furthermore, the use of t-BuLi, for the elimination step, did
not produce the desired product (entry 2). When interme-
diate 25 was reacted with diethyl chlorophosphate, fol-
lowed by elimination with t-BuLi, terminal enyne 31 was
obtained in 46% yield (entry 3). Use of tosyl chloride, as the
alkoxide trapping agent, and KOH in methanol, as base, af-
forded the desired enyne 31 in 40% yield (entry 4). When
this reaction was repeated using the stronger base t-BuLi,
enyne 31 was obtained in 66% isolated yield (entry 5).
Apparently, the reaction of intermediate 25 (prepared
from 19) with diethyl chlorophosphate or tosyl chloride
was regioselective, and only reaction at the oxygen oc-
curred. This was corroborated by the formation of only the
non-substituted enyne 31 (Table 2, entries 3–5). This be-
havior contrast with the preliminary results obtained when
dianion 14 was prepared from propargyl bromide (18) in
TMEDA (Scheme 2, Table 1). One advantage of the latter
methodology is that the corresponding lithium acetylide in-
termediate 21 could be derivatized in situ, producing 4-sub-
stituted enynes 23.
To demonstrate the reproducibility of this methodology
under the best reaction conditions developed (Table 2, en-
try 5), several 1,3-enynes were prepared from diverse alde-
hydes and ketones (Table 3). When aldehydes 32, 36, and 38
were used as the carbonyl component, mixtures of trans-
and cis-enynes, largely favoring the trans isomer, were ob-
tained (entries 2, 4, and 5). The use of acetophenone (34)
and cyclopropyl phenyl ketone (40) produced mixtures of E
and Z isomers. In both cases, the E isomers were obtained
as the major isomers (entries 3 and 6).
Table 3 Conversion of Aldehydes and Ketones into 1,3-Enynes
O
Cl
R
E
OLi
R
Li
R
Li
E+
TsCl
t-BuLi
1. Mg
R
R
Cl
14
R
R
19
–78 °C to r.t.
HMPA
–10 °C
R
2. n-BuLi
(2 equiv)
16
21
Entry
1
Aldehyde or Ketone
Electrophile (E+)
H3O+
Product(s)
Yield (%)a
66
O
Ph
Ph
31
24
Ph
O
+
Ph
2
H3O+
68
H
33a
33b
32
(trans/cis 78:22)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

F
J. A. Cabezas et al.
Feature
Synthesis
Table 3 (continued)
Entry
Aldehyde or Ketone
Electrophile (E+)
Product(s)
Yield (%)a
61
Ph
O
+
Ph
3
H3O+
35a
35b
34
(E/Z 84:16)
O
+
H
4
5
6
H3O+
58
53
40
O
O
O
36
O
O
37a
37b
O
(trans/cis 73:27)
O
+
H
H3O+
Me2N
Me2N
39a
39b
38
Me2N
(trans/cis 88:12)
Ph
O
+
H3O+
Ph
41a
41b
40
(E/Z 90:10)
O
Ph
OH
7
8
(CH2O)n
64
32
Ph
43
24
O
Ph
Me
MeI
Ph
44
24
OH
O
H
9
(CH2O)n
20
18
Me2N
38
Me2N
45a
46a
(trans/cis 99:1)
O
O
N
O
H
+
Me2N
H
10
Me2N
38
46b
Me2N
H
O
O
H
(trans/cis 87 : 13)
a Yields are of isolated products, purified by column chromatography.
Synthesis of 4-Substituted 1,3-Enynes
benzophenone (24) with dianion 14 under the above reac-
tion conditions was repeated and the final intermediate 42
was quenched with paraformaldehyde, instead of NH4Cl,
acetylenic alcohol 43 was obtained in 64% overall yield in a
one-pot reaction (Scheme 4, Table 3, entry 7). When same
intermediate 42 was quenched with methyl iodide, enyne
44 was obtained in 32% overall yield (Scheme 4, Table 3, en-
try 8).
As stated before, one of the advantages of this method-
ology is that the lithium acetylide intermediate 21, ob-
tained after addition of dianion 14 to aldehydes or ketones,
and elimination reaction, can be derivatized, by addition of
an electrophile, to obtain a 1,3-enyne substituted at posi-
tion 4, in a one-pot reaction (Scheme 1). When reaction of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

G
J. A. Cabezas et al.
Feature
Synthesis
O
Cl
Ph
Ph
OLi
Ph
Li
1. Mg
Cl
24
Li
Ph
2. n-BuLi (2 equiv)
Li
19
14
25
–78 °C
Me
I
Method C
1. TsCl, HMPA
48
2. t-BuLi
–10 °C
(Ph3P)2Cl2Pd
CuI
(CH2O)n
Ph
Ph
OH
64%
Ph
Li
43
Ph
Ph
Me
32%
42
MeI
Ph
Me
44
Me
I
OLi
48
Ph
Ph
(Ph3P)2Cl2Pd
CuI
49
X
Me
Ph
Ph
47
Scheme 4 Synthesis of 1,4-disubstituted 1,3-enynes in a one-pot reaction
Particularly important are the reactions where p-(dime-
thylamino)benzaldehyde 38 was reacted with dianion 14
and, after the elimination reaction, paraformaldehyde or N-
formylmorpholine was added as a second electrophile. In
these cases, highly functionalized trans-enynes 45 and 46
were obtained, respectively, which are not easily accessible
by other methodologies (Table 3, entries 9 and 10). Al-
though formylation with N-formylmorpholine gives a low
yield, the highly functionalized aldehyde 46 is obtained in a
one-pot reaction.
ported that the palladium-catalyzed cross-coupling reac-
tion between lithium acetylides and aromatic halides, in
the presence of catalytic amounts of the palladium complex
(without CuI), produces only very low yields of the desired
alkynylation products.28 Thus, the desired reaction is diffi-
cult to achieve, probably because the highly nucleophilic
alkynyllithiums act as catalyst poisons by displacing the li-
gands (i.e., PPh3, Cl) from the palladium complex, forming
lithium palladates 50 that do not exhibit catalytic activity
(Scheme 5).33 This coupling reaction can be achieved if a
stoichiometric amount of Pd complex is used.28,33 This
probably explains why palladium-catalyzed couplings be-
tween lithium acetylide 42 and o-iodotoluene (48) were
unsuccessful under these conditions. We reacted acetylide
25 with o-iodotoluene (48) in the presence of [Pd-
Cl2(PPh3)2], but without CuI, and no product was obtained.
This result is in agreement with Negishi’s results (Scheme
5).33
Palladium-Catalyzed Cross-Coupling Reactions of
Acetylenic Intermediates. Synthesis of 1,4-Disubsti-
tuted and 1,1,4-Trisubstituted 1,3-Enynes
Our final objective was to perform in situ palladium-
catalyzed cross-coupling reactions on lithiated acetylenic
intermediates such as 42 (Scheme 4), to obtain 1,3-enynes
substituted at the terminal acetylenic carbon with an aro-
matic group (e.g., 47). Initial reactions of intermediate 42,
prepared as outlined in Scheme 4, with o-iodotoluene (48)
in the presence of catalytic amounts of [PdCl2(PPh3)2] and
CuI failed to produce enyne 47.
Pd(PPh3)2Cl2
+
4
R
Pd(Li)2 + 2 PPh3 + 2 LiCl
R
Li
4
50
Scheme 5 Poisoning of palladium complex by an excess of lithium
acetylide
We considered that a highly coordinating solvent such
HMPA, used in the tosylation of intermediate 25, might
strongly coordinate with palladium, interfering with its cat-
alytic function. We have previously observed this type of
behavior with TMEDA.32 On the other hand, it has been re-
To overcome these difficulties, we decided to perform
first the palladium cross coupling, on the lithium acetylide
intermediate 25 to obtain lithium alkoxide 49 (Scheme 4).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

H
J. A. Cabezas et al.
Feature
Synthesis
In this way, the palladium cross coupling would be per-
formed without HMPA. Thus, when acetylide 25 was react-
ed with o-iodotoluene (48) in the presence of catalytic
amounts of [PdCl2(PPh3)2] and CuI, conditions used in the
Sonogashira reaction, the alkoxide intermediate 49 was
successfully obtained, as verified by GC-MS analysis of a
quenched aliquot of the reaction mixture. Surprisingly, ad-
dition of tosyl chloride and HMPA to this mixture, followed
by reaction with t-BuLi, failed to produce the desired enyne
47 (Table 4, entry 1).
We decided to treat alkoxide 49 with trimethylsilyl
chloride, to prepare the corresponding silyl ether, followed
by treatment with t-BuLi (Table 4, entry 2). We envisioned
the removal of a propargylic proton and generation of con-
ditions similar to the Peterson olefination.34 In this case,
enyne 47 was not obtained. Reaction of intermediate 49
with diethyl chlorophosphate, followed by treatment with
t-BuLi, also failed to produce enyne 47 (entry 3). We at-
tempted reaction of 49 with DEAD and Ph3P (Mitsunobu
conditions),35 trying to produce triphenylphosphine oxide
as driving force for the elimination reaction, but also in this
case enyne 47 was not produced (entry 4). Finally, treat-
ment of intermediate 49 with pyridine, followed by addi-
tion of thionyl choride, afforded the desired enyne 47 in
very good overall yield (entry 5).
Treatment of intermediate 25 with 4-iodo-1-nitroben-
zene (51) and o-iodoanisole (52) under the above devel-
oped reaction conditions produced enynes 53 and 54 re-
spectively (Table 5, entries 2 and 3). It is unclear why, under
our reaction conditions (catalytic amounts of Pd and Cu),32
the coupling reaction of acetylide intermediates (i.e., 25)
with aromatic iodides was very successful (entries 1–3)
when compared with the conditions described in Scheme 5.
Perhaps the presence of catalytic amounts of CuI (5–10%)
account for this success. A possible explanation is that
transmetalation of lithium intermediates (i.e., 25) with CuI
and the subsequent palladium catalytic cycle is much faster
than the poisoning of the palladium complex.
Table 4 Conversion of Alkoxide Intermediate 49 into Enyne 47
OLi
Ph
Ph
Ph
Ph
49
47
Entry
Reaction conditions
Yield (%)a
1
2
3
4
5
TsCl/HMPA, –78 °C to r.t., then t-BuLi, –10 °C
Me3SiCl, then t-BuLi
0
0
ClP(O)(OEt)2, then t-BuLi
DEAD, Ph3P
0
0
pyridine, then SOCl2
75
a Yield based on total conversion from benzophenone.
Table 5 Synthesis of 1,4-Disubstituted and 1,1,4-Trisubstituted 1,3-Enynes
O
R
Ar
OLi
R
Ar
OLi
R
Li
R
R
ArI
Li
A
B
R
Li
R
R
14
Entry
1
Carbonyl compound
ArI
Conditions
Product(s)
Yield (%)a
Me
Me
O
I
A. Pd(PPh3)4, CuI
B. SOCl2, py
71
24
47
48
NO2
O
I
A. Pd(PPh3)4, CuI
B. SOCl2, py
2
3
68
60
NO2
24
51
53
54
OMe
O
I
A. Pd(PPh3)4, CuI
B. SOCl2, py
OMe
24
52
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

I
J. A. Cabezas et al.
Feature
Synthesis
Table 5 (continued)
Entry
Carbonyl compound
ArI
Conditions
Product(s)
Yield (%)a
53
O
I
A. H2O (1 equiv), Et3N, [PdCl2(PPh3)2], CuI
B. PhSO2Cl
4
H
32
56
trans (59a)/cis (59b) 1:1
I
H
A. H2O (1 equiv), Et3N, [PdCl2(PPh3)2], CuI
B. PhSO2Cl
5
6
35
25
S
60
O
56
trans (61a)/cis (61b) 1:1
S
O
S
A. H2O (1 equiv), Et3N, [PdCl2(PPh3)2], CuI
B. PhSO2Cl
H
I
I
S
S
62
38
Me2N
trans (63a)/cis (63b) 7:3
Me2N
O
A. H2O (1 equiv), Et3N, [PdCl2(PPh3)2], CuI
B. PhSO2Cl
S
7
43
62
24
64
a Overall yields of isolated compounds, after purification by chromatography.
We decided to explore the palladium coupling reaction
under different conditions, and thus transmetalation of
lithium acetylide intermediate 55 was performed (Scheme
6). We attempted the palladium-catalyzed cross coupling
step under Negishi conditions.36 Thus, treatment of benzal-
dehyde 32 with dianion 14 (generated from 2,3-dichloro-
propene (19) according to Scheme 4) produced the corre-
sponding alkoxyalkyne 55, which was treated with an ethe-
real solution of ZnCl2 (2 equiv). This was followed by
addition of iodobenzene (56) and a catalytic amount of
Pd(PPh3)4. Surprisingly, this reaction sequence failed to pro-
duce any coupling product. We attempted this reaction
adding CuCN·2LiCl (1 and 2 equiv) to intermediate 55 in-
stead of ZnCl2, followed by addition of iodobenzene (56)
and Pd(PPh3)4. In this case, no coupling product was ob-
served either (Scheme 6). This reaction was repeated sever-
al times without any positive result.
In a typical Sonogashira reaction,26 an acetylene is con-
verted, by means of an amine, into a copper acetylide in
catalytic amounts (~5% CuI). Under our reaction conditions,
we were coupling an alkoxy lithium acetylide intermediate
(i.e., 55), presumably through a copper acetylide, under pal-
ladium catalysis, with an aromatic iodide. We envisioned
that lithium acetylide intermediate in 55 could be selective-
ly protonated over the lithium alkoxide moiety, because of
the pKa differences (pKa RC≡CH ~25; pKa ROH ~16) of the
I
56
O
PdCl2(Ph3P)2
OLi
H
Ph
H
OLi
H
Li
ZnCl2 or
CuI
X
32
Li
Ph
Ph
Li
CuCN·2LiCl
57
14
55
H2O (1 equiv)
I
PhSO2Cl
56
OLi
H
H
PdCl2(Ph3P)2
Ph
CuI
58
Et3N
Ph
59
Scheme 6 Transmetalation reactions of intermediate 55 and synthesis of enyne 59
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

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J. A. Cabezas et al.
Feature
Synthesis
conjugated acids. Reaction of lithium acetylide with water
(pKa ~16) should be largely favored (Keq ~109) over reaction
of alkoxide with water (pKa ~1). Thus, we intended to pro-
tonate lithium acetylide selectively to perform a palladium
cross-coupling reaction under Sonogashira conditions.
Dianion 14 was prepared by reaction of allene 13 gener-
ated from excess of 2,3-dichloropropene 19 (20 mmol) with
n-BuLi (1.70 mmol). Assuming a quantitative reaction, then
1,3-dilithiopropyne (14; 0.85 mmol) should react with
benzaldehyde (32; 0.60 mmol) (Scheme 6). After this reac-
tion, intermediate 55 (0.60 mmol) should be produced and
a portion of dianion 14 (0.25 mmol) should remain unre-
acted. To protonate unreacted dianion 14 and the lithium
acetylide part in 55, water (1.10 mmol, 20 μL) should be
used.
Benzaldehyde 32 was reacted with 14 at –78 °C and the
mixture was warmed to room temperature over 3 hours;
the addition of water (10–20 μL) in THF (5 mL) followed
(Scheme 6). After stirring for 5 minutes, a THF solution (5
mL) of iodobenzene (56) and [PdCl2(PPh3)2], triethylamine,
and CuI were sequentially added. After stirring at room
temperature overnight, intermediate 55 was consumed and
cross-coupling product 57 was obtained. This was verified
by GC-MS of a quenched aliquot of the reaction mixture.
The mixture was treated with benzenesulfonyl chloride to
obtain, after aqueous workup, a mixture of cis- and trans-
enyne 59 (Table 5, entry 4). Treatment of thiophene-2-car-
boxaldehyde (60) under same reaction conditions produced
an isomeric mixture of enyne 61 (entry 5). Also p-(dime-
thylamino)benzaldehyde (38) was sequentially reacted
with dianion 14 and 2-iodothiophene (62) under identical
conditions, to provide a cis/trans mixture of enyne 63 (en-
try 6). Finally, treatment of benzophenone (24) under the
above reaction conditions and coupling with 2-iodothio-
phene (62) gave product 64 (entry 7). When aldehydes are
used instead of ketones as starting materials, the final elim-
ination step has to be performed using PhSO2Cl instead of
SOCl2/py. The latter gave the corresponding chlorides by a
substitution reaction on the alkoxide carbon.
yields than the conditions where a controlled protonolysis
was intended. Probably in the latter case, a small excess of
water can also protonate the alkoxide in intermediate 16,
lowering the yield of the subsequent elimination step. As
far as we know, these are the first palladium cross cou-
plings reported on these lithium alkoxy acetylide interme-
diates and their application in the synthesis of 1,3-enynes.
All glassware and syringes were dried in an oven overnight at 140 °C,
assembled while hot, flamed and flushed and cooled under N2 imme-
diately prior to use. Transfers of reagents were performed with sy-
ringes equipped with stainless-steel needles. All reactions were car-
ried out under a positive pressure of N2. N2 was passed through a
Drierite gas drying unit prior to use. Et2O and THF were refluxed and
freshly distilled from sodium and potassium/benzophenone ketyl re-
spectively, under a N2 atmosphere. Hexane was distilled from sodium
and collected and kept over activated molecular sieves. Pd(PPh3)4,
[PdCl2(PPh3)2], and CuI were weighed in a glovebox under N2. n-BuLi
was titrated according to the method of Watson and Eastham.37 1H
NMR and 13C NMR spectra were recorded on a 400 MHz NMR Bruker
spectrometer. Low-resolution mass spectra were obtained on an Agi-
lent Technologies 7820A GC coupled to a mass spectrometer 5977E
unit using electron impact at 70 eV. High resolution mass spectra
were measured on a Waters Synapt HMDS G1, Q-TOF. IR spectra were
recorded on a Perkin Elmer FT-IR Spectrum 1000.
1,3-Dilithiopropyne (14)
An oven-dried, 100 mL, three-necked, round-bottomed flask was
equipped with a magnetic stirring bar and a Liebig condenser bearing
a glycerin bubbler at the top (Figure 2). The exit of the bubbler, bear-
ing a septum, was punctured with a double-tipped needle, whose
other end was inserted, through a rubber septum, into a two-necked
flask equipped with a magnetic stirring bar, and capped by a rubber
septum bearing a needle attached to a balloon. All joints were greased
and secured with Parafilm. The three-necked flask was charged with
Mg turnings (1.55 g, 64 mmol), a small crystal of I2 and THF (25 mL). A
small amount (~0.5 mL) of a THF solution (5 mL) of 2,3-dichloropro-
pene (19; 2.22 g, 20 mmol) was added to the Mg and the mixture was
stirred for about 10 min; a very exothermic reaction ensued after
slight warming of the reaction flask. The allene gas, generated, was
Conclusion
In summary, we have developed a protocol for the con-
version of aldehydes and ketones into 1-substituted and
1,1-disubstituted enynes in a one-pot reaction in good
yields. The advantage of this methodology is that the lithi-
um acetylide intermediate formed in this procedure can be
further functionalized, by the addition of an electrophile to
obtain highly functionalized enynes. We have also devel-
oped experimental conditions to perform palladium-cata-
lyzed cross-coupling reactions on lithium alkoxy acetylide
intermediates to obtain 1,4-disubstituted and 1,1,4-trisub-
stituted enynes in one-pot reactions. Original conditions
developed for the palladium cross coupling gave better
Figure 2 Glassware used for the generation of allene 13 and its conver-
sion into dianion 14
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

K
J. A. Cabezas et al.
Feature
Synthesis
bubbled into a solution of n-BuLi in hexane (2.6 M, 0.65 mL, 1.70
mmol) in anhyd Et2O (5 mL) and anhyd hexanes (4.35 mL),38 at –78 °C,
in a two-necked flask, under a N2 atmosphere. The remaining THF
solution of 2,3-dichloropropene was added in small portions, in order
to maintain a vigorous generation of allene. It is important to keep a
positive pressure of allene during the whole process, otherwise a
drop in pressure in the three-necked flask would produce a vacuum
in the second flask. To avoid loss of material, during the process of
generation of allene, the valve connected to the manifold, in the sec-
ond flask containing the n-BuLi, was kept closed, and the allene was
collected in a balloon. After generation of allene stopped, the cannula
was removed from the flask, and the n-BuLi/allene solution was
stirred at –78 °C for 1 h.
HRMS (ESI, V+): m/z [M + H]+ calcd for C16H13: 205.1017; found:
204.1014.
trans-1-Phenylbut-1-en-3-yne (33a)
Yield: 0.052 g of mixture of isomers (68%).
1H NMR (400 MHz, CDCl3): δ = 7.39 (m, 2 H), 7.33 (m, 3 H), 7.05 (d, J =
16.5 Hz, 1 H), 6.13 (dd, J = 2.35, 16.5 Hz, 1 H), 3.05 (d, J = 2.35 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 143.29, 136.00, 129.06, 128.88,
126.48, 107.15, 79.33, 81.04.
MS (EI, 70 eV): m/z (%) = 51 (10), 78 (8), 102 (21), 127 (26), 128 (100).
HRMS (ESI, V+): m/z [M + H]+ calcd for C10H9: 129.0704; found:
129.0702.
1,1-Diphenylbut-1-en-3-yne (31); Typical Procedure
cis-1-Phenylbut-1-en-3-yne (33b)
An Et2O solution (3 mL) of benzophenone (24; 0.109 g, 0.60 mmol)
was added to a cold (–78 °C) solution of 1,3-dilithiopropyne (14; pre-
pared as described above, presumably 0.85 mmol; prepared from 1.70
mmol n-BuLi). The mixture was slowly warmed to r.t over 3 h, and a
THF solution (2 mL) of TsCl (0.270 g, 1.4 mmol) and HMPA (0.8 mL, 4.6
mmol) was added and the solution was stirred at r.t. overnight. After
this time, the temperature was lowered to 0 °C and a 1.7 M pentane
solution of t-BuLi (2.0 mL, 3.4 mmol) was added dropwise. At this
point a color change to dark green was observed and, due to the exo-
thermic reaction, the mixture spontaneously refluxed. The reaction
was allowed to reach r.t. in 2 h and a sat. aq NH4Cl solution (3–5 mL)
was added. The crude reaction mixture was extracted with Et2O (3 × 5
mL) and the organic phase was washed several times with H2O. The
ethereal phase was dried over Na2SO4 and the solvent was evaporated
in vacuo. The residue was purified by column chromatography (Et2O–
hexanes) to give 31.
Yield: 0.052 g of mixture of isomers (68%).
1H NMR (400 MHz, CDCl3): δ = 7.33 (m, 5 H), 6.72 (d, J = 12.0 Hz, 1 H),
5.69 (dd, J = 2.7, 12.1 Hz, 1 H), 3.35 (d, J = 2.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 140.73, 136.21, 128.88, 128.55,
128.42, 106.45, 84.24, 82.15.
MS (EI, 70 eV): m/z (%) = 51 (10), 78 (8), 102 (21), 127 (26), 128 (100).
HRMS (ESI, V+): m/z [M + H]+ calcd for C10H9: 129.0704; found:
129.0702.
(E)-2-Phenylpent-2-en-4-yne (35a)
Yield: 0.052 g, of mixture of isomers (61%).
1H NMR (400 MHz, CDCl3): δ = 7.45 (m, 2 H), 7.35 (m, 3 H), 5.88 (dq,
J = 1.0, 2.4 Hz, 1 H), 3.28 (d, J = 2.4 Hz, 1 H), 2.35 (d, J = 1.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 190.52, 140.72, 128.57, 128.45,
125.60, 106.66, 82.89, 82.31, 18.76.
Yield: 0.081 g (66%).
MS (EI, 70 eV): m/z (%) = 77 (11), 89 (5), 115 (47), 126 (5), 141 (100),
142 (62).
1,1-Diphenyl-4-(2-tolyl)but-1-en-3-yne (47); Typical Procedure
An Et2O solution (3 mL) of benzophenone (24; 0.109 g, 0.60 mmol)
was added to a cold (–78 °C) 1,3-dilithiopropyne (14; prepared as de-
scribed above, presumably 0.85 mmol; prepared from 1.70 mmol n-
BuLi). The mixture was slowly warmed to r.t. over 3 h and a THF solu-
tion (5 mL) of 2-iodotoluene (48; 0.196 g, 0.9 mmol) and Pd(PPh3)4
(0.070 g, 0.06 mmol) was added, followed by addition of a suspension
of CuI (0.006 g) in THF (4 mL); then the resulting mixture was stirred
overnight. The reaction was quenched by the addition of a sat. aq
NH4Cl solution (4 mL) and extracted with Et2O (2 × 20 mL). The organ-
ic phase was dried over MgSO4 and concentrated in vacuo. The resi-
due was purified by column chromatography (hexane, then 5% Et2O–
hexane) to give 47.
HRMS (ESI, V+): m/z [M + H]+ calcd for C11H11: 143.0861; found:
143.0866.
(Z)-2-Phenylpent-2-en-4-yne (35b)
Yield: 0.052 g, of mixture of isomers (61%).
1H NMR (400 MHz, CDCl3): δ = 7.63 (m, 2 H), 7.35 (m, 3 H), 5.63 (dq,
J = 1.1, 2.6 Hz, 1 H), 2.90 (d, J = 2.6 Hz, 1 H), 2.19 (d, J = 1.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 190.35, 139.86, 128.25, 128.09,
127.64, 106.35, 79.45, 77.36,15.42.
MS (EI, 70 eV): m/z (%) = 77 (11), 89 (5), 115 (47), 126 (5), 141 (100),
142 (62).
Yield: 0.125 g (71%); pale-yellow solid; mp 78.1–80.5 °C.
HRMS (ESI, V+): m/z [M + H]+ calcd for C11H11: 143.0861; found:
143.0866.
The product was obtained as a mixture of cis and trans (and E and Z)
isomers; we did not separate them.
trans-1-(3,4-Dioxymethylenephenyl)but-1-en-3-yne (37a)
1,1-Diphenylbut-1-en-3-yne (31)
Yield: 0.060 g of mixture of isomers (58%).
Yield: 0.081 g (66%).
1H NMR (400 MHz, CDCl3): δ = 6.95 (d, J = 16.42 Hz, 1 H), 6.91 (d, J =
1.69 Hz, 1 H), 6.83 (dd, J = 1.70, 8.04 Hz, 1 H), 6.76 (d, J = 8.06 Hz, 1 H),
5.99 (s, 2 H), 5.95 (dd, J = 2.30, 16.40 Hz, 1 H), 3.02 (d, J = 2.36 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 148.53, 148.33, 142.87, 130.53,
121.95, 108.55, 106.33, 106.15, 101.45, 83.18, 78.90.
1H NMR (400 MHz, CDCl3): δ = 7.46 (dd, J = 2.0, 7.9 Hz, 2 H), 7.35 (m, 4
H), 7.29 (m, 4 H), 6.02 (d, J = 2.6 Hz, 1 H), 3.00 (d, J = 2.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 154.64, 141.26, 139.01, 130.06,
128.44, 128.11, 128.08, 106.13, 82.58, 81.60.
MS (EI, 70 eV): m/z (%) = 51 (6), 76 (8), 101 (21), 126 (8), 176 (6), 202
(85), 203 (100), 204 (67).
MS (EI, 70 eV): m/z (%) = 88 (26), 102 (4), 114 (100), 127 (5), 142 (5),
171 (78), 172 (83).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

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J. A. Cabezas et al.
Feature
Synthesis
HRMS (ESI, V+): m/z [M + H]+ calcd for C11H9O2: 173.0603; found:
13C NMR (100 MHz, CDCl3): δ = 129.63, 127.89, 127.60, 106.72, 82.53,
173.0602.
77.36, 14.19, 6.69.
MS (EI, 70 eV): m/z (%) = 77 (14), 91 (12), 115 (23), 128 (29), 139 (28),
152 (90), 165 (57), 167 (100), 168 (53).
cis-1-(3,4-Dioxymethylenephenyl)but-1-en-3-yne (37b)
HRMS (ESI, V+): m/z [M + H]+ calcd for C13H12: 168.0939; found:
Yield: 0.060 g of mixture of isomers (58%).
1H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 1.7 Hz, 1 H), 7.17 (dd, J = 1.7,
8.0 Hz, 1 H), 6.79 (d, J = 8.0 Hz, 1 H), 6.60 (d, J = 12.1 Hz, 1 H), 5.98 (s, 2
H), 5.56 (dd, J = 2.7, 12.05 Hz, 1 H), 3.37 (d, J = 2.7 Hz, 1 H).
168.0938.
5,5-Diphenylpent-4-en-2-yn-1-ol (43)
13C NMR (100 MHz, CDCl3): δ = 148.06, 147.67, 140.17, 130.79,
Yield: 0.090 g (64%).
124.30, 108.21, 108.18, 104.33, 101.35, 84.36, 82.17.
1H NMR (400 MHz, CDCl3): δ = 7.43 (m, 2 H), 7.34 (m, 4 H), 7.27 (m, 4
H), 6.03 (t, J = 2.2 Hz, 1 H), 4.29 (d, J = 2.2 Hz, 2 H), 1.62 (s, 1 H).
MS (EI, 70 eV): m/z (%) = 88 (26), 102 (4), 114 (100), 127 (5), 142 (5),
171 (78), 172 (83).
HRMS (ESI, V+): m/z [M + H]+ calcd for C11H9O2 173.0603; found:
13C NMR (100 MHz, CDCl3): δ = 153.23, 141.33, 139.16, 130.06,
128.54, 128.42, 128.35, 128.10, 128.04, 106.52, 91.47, 84.84, 51.91.
173.0602.
MS (EI, 70 eV): m/z (%) = 77 (28), 128 (45), 165 (39), 178 (25), 190
(34), 203 (81), 215 (100), 234 (92).
HRMS (ESI, V+): m/z [M + H]+ calcd for C17H15O: 235.1123; found:
235.1123.
4-(trans-But-1-en-3-ynyl)-N,N-dimethylaniline (39a)
Yield: 0.054 g of mixture of isomers (53%).
1H NMR (400 MHz, CDCl3): δ = 7.28 (d, J = 8.9 Hz, 2 H), 6.97 (d, J = 16.3
Hz, 1 H), 6.65 (d, J = 8.9 Hz, 2 H), 5.93 (dd, J = 2.3, 16.3 Hz, 1 H), 2.99 (s,
1 H), 2.98 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 151.02, 143.51, 127.72, 124.29,
112.20, 101.80, 84.21, 77.69, 40.43.
1,1-Diphenylpent-1-en-3-yne (44)
Yield: 0.042 g (32%).
1H NMR (400 MHz, CDCl3): δ = 7.44 (dd, J = 1.8, 7.9 Hz, 2 H), 7.32 (m, 4
H), 7.24 (m, 4 H), 5.97 (q, J = 2.6 Hz, 1 H), 1.89 (d, J = 2.6 Hz, 3 H).
MS (EI, 70 eV): m/z (%) = 77 (12), 115 (8), 127 (37), 128 (8), 141 (3),
155 (15), 171 (100).
HRMS (ESI, V+): m/z [M + H]+ calcd for C12H14N: 172.1126; found:
172.1124.
13C NMR (100 MHz, CDCl3): δ = 151.20, 141.93, 139.47, 130.10,
128.32, 128.07, 127.96, 127.93, 108.03, 90.66, 78.73, 4.84.
MS (EI, 70 eV): m/z (%) = 63 (8), 101 (13), 176 (5), 202 (100), 203 (80),
215 (45), 216 (19), 217 (48), 218 (95).
HRMS (ESI, V+): m/z [M + H]+ calcd for C17H15: 219.1174; found:
219.1172.
4-(cis-But-1-en-3-ynyl)-N,N-dimethylaniline (39b)
Yield: 0.054 g of mixture of isomers (53%).
1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.8 Hz, 2 H), 6.68 (d, J = 8.8
Hz, 2 H), 6.59 (d, J = 11.9 Hz, 1 H), 5.42 (dd, J = 2.62, 11.9 Hz, 1 H), 3.32
(dd, J = 0.89, 2.8 Hz, 1 H), 2.98 (s, 6 H),.
13C NMR (100 MHz, CDCl3): δ = 40.43, 77.36, 83.01, 101.12, 111.67,
130.26, 140.80.
trans-5-[4-(N,N-Dimethylamino)phenyl]pent-4-en-2-yn-1-ol
(45a)
Yield: 0.015 g (20%).
1H NMR (400 MHz, CDCl3): δ = 7.27 (d, J = 8.8 Hz, 2 H), 6.91 (d, J = 16.2
Hz, 1 H), 6.65 (d, J = 8.8 Hz, 2 H), 5.97 (dt, J = 2.21, 16.2 Hz, 1 H), 4.46
(dd, J = 2.1, 6.1 Hz, 2 H), 3.00 (s, 6 H).
MS (EI, 70 eV): m/z (%) = 77 (12), 115 (8), 127 (37), 128 (8), 141 (3),
155 (15), 171 (100).
HRMS (ESI, V+): m/z [M + H]+ calcd for C12H14N: 172.1126; found:
13C NMR (100 MHz, CDCl3): δ = 142.44, 140.95, 127.69, 124.47,
112.23, 87.88, 86.17, 52.06, 40.44.
172.1124.
MS (EI, 70 eV): m/z (%) = 77 (5), 115 (11), 128 (26), 157 (17), 170 (16),
184 (15), 201 (100).
HRMS (ESI, V+): m/z [M + H]+ calcd for C13H16NO: 202.1232; found:
202.1230.
(E)-1-Cyclopropyl-1-phenylbut-1-en-3-yne (41a)
Yield: 0.040 g of mixture of isomers (40%).
1H NMR (400 MHz, CDCl3): δ = 7.57 (m, 2 H), 7.36 (m, 2 H), 7.30 (m, 1
H), 5.47 (dd, J = 0.98, 2.48 Hz, 1 H), 2.85 (d, J = 2.48 Hz, 1 H), 1.70 (m, 1
H), 0.84 (m, 2 H), 0.61 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 156.65, 139.41, 128.25, 128.07,
128.00, 102.54, 82.23, 80.10, 18.26, 7.30.
trans-5-[4-(N,N-Dimethylamino)phenyl]pent-4-en-2-ynal (46a)
Yield: 0.021 g of mixture of isomers (18%).
(1H NMR (400 MHz, CDCl3): δ = 9.31 (d, J = 1.2 Hz, 1 H), 7.35 (d, J = 9.0
Hz, 2 H), 7.25 (d, J = 16.1 Hz, 1 H), 6.65 (d, J = 9.0 Hz, 2 H), 6.03 (dd, J =
1.2, 16.1 Hz, 1 H), 3.03 (s, 6 H).
MS (EI, 70 eV): m/z (%) = 77 (14), 91 (12), 115 (23), 128 (29), 139 (28),
152 (90), 165 (57), 167 (100), 168 (53).
HRMS (ESI, V+): m/z [M + H]+ calcd for C13H12: 168.0939; found:
13C NMR (100 MHz, CDCl3): δ = 176.58, 170.65, 150.32, 147.24,
129.10, 123.15, 111.95, 98.58, 91.09, 40.26.
168.0938.
MS (EI, 70 eV): m/z (%) = 77 (9), 115 (7), 127 (26), 128 (26), 140 (4),
155 (18), 170 (38), 198 (30), 199 (100).
HRMS (ESI, V+): m/z [M + H]+ calcd for C13H13NO: 200.1075; found:
200.1076.
(Z)-1-Cyclopropyl-1-phenylbut-1-en-3-yne (41b)
Yield: 0.040 g of mixture of isomers (40%).
1H NMR (400 MHz, CDCl3): δ = 7.33 (m, 5 H), 5.61 (dd, J = 0.70, 2.51
Hz, 1 H), 3.25 (d, J = 2.50 Hz, 1 H), 2.16 (m, 1 H), 0.90 (m, 4 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

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cis-5-[4-(N,N-Dimethylamino)phenyl]pent-4-en-2-ynal (46b)
13C NMR (100 MHz, CDCl3): δ = 141.4, 138.8, 136.7, 136.5, 131.7,
131.6, 128.9, 128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 126.4, 123.6,
123.5, 108.3, 107.5, 96.0, 91.9, 89.0, 88.3.
Yield: 0.021 g of mixture of isomers (18%).
1H NMR (400 MHz, CDCl3): δ = 9.40 (d, J = 1.4 Hz, 1 H), 7.79 (d, J = 9.0
Hz, 2 H), 6.87 (d, J = 12.0 Hz, 1 H), 6.69 (d, J = 8.9 Hz, 2 H), 5.53 (dd, J =
1.4, 12.0 Hz, 1 H), 2.94 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 172.24, 171.46, 152.01, 131.39,
111.58, 98.77, 97.68, 40.26.
MS (EI, 70 eV): m/z (%) = 204 (100), 126 (7), 103 (1), 102 (9), 101 (17),
77 (3).
HRMS (ESI, V+): m/z [M – 1]+ calcd for C16H11: 203.0861; found:
203.0855.
MS (EI, 70 eV): m/z (%) = 77 (9), 115 (7), 127 (26), 128 (26), 140 (4),
155 (18), 170 (38), 198 (30), 199 (100).
4-Phenyl-1-(2-thienyl)but-1-en-3-yne (61)
Yield: 0.0044 g (35%).
HRMS (ESI, V+): m/z [M + H]+ calcd for C13H13NO: 200.1075; found:
1H NMR (400 MHz, CDCl3): δ = 7.62–7.57 (m, 2 H), 7.49–7.44 (m, 2 H),
7.41–7.27 (m, 8 H), 7.22 (d, J = 4.9 Hz, 1 H), 7.15 (d, J = 15.8 Hz, 1 H),
7.08–6.94 (m, 4 H), 6.21 (d, J = 15.8 Hz, 1 H), 5.78 (d, J = 10.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 141.3, 140.6, 133.8, 132.0, 131.3,
131.2, 129.5, 128.2, 128.1, 128.0, 127.6, 126.9, 126.8, 126.2, 125.3,
123.3, 123.2, 107.1, 104.5, 98.5, 91.9, 88.5, 88.3, 65.7.
200.1076.
1,1-Diphenyl-4-o-tolylbut-1-en-3-yne (47)
Yield: 0.125 g (71%); pale-yellow solid; mp 78.1–80.5 °C).
1H NMR (400 MHz, CDCl3): δ = 7.51 (m, 2 H), 7.43–7.27 (m, 9 H), 7.20–
7.05 (m, 3 H), 6.33 (s, 1 H), 2.20 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 152.2, 141.3, 140.1, 139.4, 131.9,
130.1, 129.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 125.4, 123.4,
107.4, 92.9, 92.7, 20.5.
MS (EI, 70 eV): m/z (%) = 210 (100), 178 (7), 165 (54), 153 (3), 152 (2),
126 (5), 83 (1).
HRMS (ESI, V+): m/z [M – 1]+ calcd for C14H9S: 209.0425; found:
209.0418.
MS (EI, 70 eV): m/z (%) = 294 (100), 279 (24), 265 (10), 252 (8), 203
(17), 202 (25), 179 (2), 217 (21), 215 (60), 115 (7), 91 (9).
HRMS (ESI, V+): m/z [M – 1]+ calcd for C23H17: 293.1330; found:
293.1330.
N,N-Dimethyl-4-[4-(2-thienyl)but-1-en-3-ynyl]aniline (63)
Yield: 0.038 g (25%).
1H NMR (400 MHz, CDCl3): δ = 7.86–7.80 (m, 1 H), 7.32 (m, 2 H), 7.25–
7.17 (m, 2 H), 7.03–6.94 (m, 1 H), 6.74–6.64 (m, 3 H), 6.15 (d, J = 16.0,
1 H), 5.66 (d, J = 12.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 151.2, 142.1, 139.4, 131.6, 131.5,
130.6, 128.1, 127.6, 127.5, 127.4, 127.0, 125.6, 125.0, 124.6, 112.5,
112.0, 102.8, 102.0, 94.4, 93.9, 88.5, 83.7, 40.7.
4-(p-Nitrophenyl)-1,1-diphenylbut-1-en-3-yne (53)
Yield: 0.133 g (68%).
1H NMR (400 MHz, CDCl3): δ = 8.17–8.09 (m, 2 H), 7.54–7.48 (m, 2 H),
7.47–7.40 (m, 3 H), 7.39–7.31 (m, 7 H), 6.26 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 155.4, 147.7, 140.8, 139.1, 131.9,
130.6, 130.1, 129.9, 128.9, 128.6, 128.4, 128.3, 128.1, 128.0, 127.9,
123.6, 106.0, 94.9, 91.6.
MS (EI, 70 eV): m/z (%) = 253 (100), 237 (12), 223 (10), 209 (25), 165
(12), 152 (4), 139 (2), 126 (9), 104 (10), 77 (1).
HRMS (ESI, V+): m/z [M – 1]+ calcd for C16H14NS: 252.0847; found:
252.0842.
MS (EI, 70 eV): m/z (%) = 325 (1), 293 (2), 281 (20), 207 (37), 167 (40),
141 (86), 125 (28), 106 (19), 90 (11), 77 (100).
HRMS (ESI, V+): m/z [M + H]+ calcd for C22H16NO2: 326.1181; found:
326.1183.
1,1-Diphenyl-4-(2-thienyl)but-1-en-3-yne (64)
Yield: 0.074 g (43%).
1H NMR (400 MHz, CDCl3): δ = 7.55–7.51 (m, 2 H), 7.44–7.37 (m, 3 H),
7.35–7.33 (s, 5 H), 7.23 (dd, J = 5.1, 1.1 Hz, 1 H), 7.07 (dd, J = 3.6, 1.1
Hz, 1 H), 6.95 (dd, J = 5.1, 3.6 Hz, 1 H), 6.23 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 152.3, 141.1, 138.9, 131.3, 129.9,
128.2, 128.1, 128.0, 127.9, 127.7, 127.1, 126.9, 123.6, 106.5, 93.0, 86.7.
4-(o-Methoxyphenyl)-1,1-diphenylbut-1-en-3-yne (54)
Yield: 0.112 g (60%).
1H NMR (400 MHz, CDCl3): δ = 7.62–7.56 (m, 2 H), 7.44–7.36 (m, 3 H),
7.34–7.32 (m, 5 H), 7.25–7.18 (m, 2 H), 6.89–6.80 (m, 2 H), 6.30 (s, 1
H), 3.83 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 159.7, 151.7, 141.5, 139.0, 133.4,
133.2, 130.1, 129.3, 128.7, 128.1, 128.0, 127.9, 127.8, 127.5, 120.3,
112.7, 110.4, 107.4, 93.0, 90.1, 55.5.
MS (EI, 70 eV): m/z (%) = 286 (100), 271 (7), 252 (49), 239 (17), 226
(11), 209 (7), 202 (14), 184 (8), 163 (7), 77 (2).
HRMS (ESI, V+): m/z [M – 1]+ calcd for C20H13S: 285.0738; found:
285.0733.
MS (EI, 70 eV): m/z (%) = 310 (100), 295 (8), 294 (10), 233 (7), 204
(27), 203 (25), 178 (7), 119 (58), 91 (40).
HRMS (ESI, V+): m/z [M – 1]+ calcd for C23H17O: 309.1279; found:
309.1274.
Acknowledgment
Preliminary results were presented at the Third Iberoamerican Sym-
posium on Organic Chemistry (SIBEAQO-III), Porto, Portugal, Septem-
ber 2016. We thank the University of Costa Rica for financial support,
Sistema de Estudios de Posgrado (SEP-UCR) for a stipend to J.A.B., Lo-
rena Hernández of CIPRONA-UCR for high resolution mass spectra de-
termination, and the School of Chemistry for NMR determination.
1,4-Diphenylbut-1-en-3-yne (59)
Yield: 0.065 g (53%).
1H NMR (400 MHz, CDCl3): δ = 7.97–7.90 (m, 2 H), 7.54–7.27 (m, 18
H), 7.05 (d, J = 16.1 Hz, 1 H), 6.71 (d, J = 12.0, 1 H), 6.40 (d, J = 16.1 Hz,
1 H), 5.93 (d, J = 12.0 Hz).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

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Feature
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O