Palladium-Catalyzed One-Pot Conversion of Aldehydes and Ketones into 4-Substituted Homopropargyl Alcohols and 5-En-3-yn-1-ols ?

Article abstract of DOI:10.1021/acs.joc.7b01529

Sequential treatment of 2,3-dichloropropene with magnesium and n-BuLi generated the equivalent of 1,3-dilithiopropyne, which adds regiospecifically to aldehydes and ketones to produce homopropargyl alcohols. The lithium acetylide intermediate formed in this protocol can be further reacted with aromatic and vinyl halides, under palladium catalysis, to produce 4-substituted homopropargyl alcohols and 5-en-3-yn-1-ols, respectively, in one-pot with good overall yields.

Full text of DOI:10.1021/acs.joc.7b01529

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Article
Palladium-Catalyzed One-Pot Conversion of Aldehydes and Ketones
Into 4-Substituted Homopropargyl Alcohols and 5-En-3-yn-1-ols
Christian A Umaña, and Jorge A. Cabezas
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01529 • Publication Date (Web): 25 Aug 2017
Downloaded from http://pubs.acs.org on August 26, 2017
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Palladium-Catalyzed One-Pot Conversion of Aldehydes and Ketones
Into 4-Substituted Homopropargyl Alcohols and 5-En-3-yn-1-ols1
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Christian A. Umaña and Jorge A. Cabezas*
Escuela de Química, Universidad de Costa Rica
San José, 2060, Costa Rica
Abstract
Sequential treatment of 2,3ꢀdichloropropene with magnesium and nꢀBuLi
generated the equivalent of 1,3ꢀdilithiopropyne, which adds regiospecifically to
aldehydes and ketones to produce homopropargyl alcohols. The lithium acetylide
intermediate, formed in this protocol, can be further reacted with aromatic and
vinyl halides, under palladium catalysis, to produce 4ꢀsubstituted homopropargyl
alcohols and 5ꢀenꢀ3ꢀynꢀ1ꢀols respectively, in oneꢀpot with good overall yields.
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Introduction
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Homopropargyl alcohols are useful building blocks in the synthesis of a wide
variety of organic compounds of natural2 and synthetic origin3. Their synthesis
usually involves reaction of monoanionic propargyl, 1, or allenyl, 2,
organometallic reagents, with a carbonyl compound. The major drawback of this
methodology comes from the tendency of such ambident nucleophiles to produce
mixtures of both, homopropargyl, 3, and allenic, 4, alcohols, which are difficult to
separate (Scheme 1). These mixtures are normally obtained because, the
allenic, 2, and propargylic, 1, organometallic species generally coꢀexist in
equilibrium.4
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Numerous methods for synthesis of homopropargyl alcohols have been
developed using organometallic reagents,5 based on metals such as Zn,5a,b Al,5c
Mg,5d Sn,5e,f Ti,5g,h Zr,5i Sm,5j Ba,5k In,5l Pd,5m and Li5n and metalloids such as
Si6a,b and B,6cꢀe however, in many of these methodologies, the regiochemistry of
the product is highly dependent upon steric hindrance, substitution of the
organometallic, as well as solvation and nature of the metal. Allenyllithium
reagents, for example, react with aliphatic ketones producing mainly allenyl
alcohols,5n whereas reaction with aromatic carbonyl compounds generates
homopropargyl alcohols in poor yields. 7 Zinc and magnesium propargylic
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derivatives couple with aromatic or aliphatic aldehydes to produce mixtures of
allenic and homopropargyl alcohols.8a Addition of 1ꢀtrimethylsilylpropyneꢀ3ꢀzinc
bromide to aldehydes and ketones produces mainly homopropargyl alcohols, but
addition of the corresponding aluminum derivative produces the allenyl alcohol.8b
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The regiochemistry of the reaction using propargylic titanium reagents is highly
,
dependent upon the substitution of the organometallic.5g 9
Propargylation, a threeꢀcarbon homologation, is a very useful chemical
transformation often employed in isoprenoidꢀrelated syntheses.10 However, it is
frequently difficult to accomplish cleanly, and mixtures of allenic and acetylenic
products are generally obtained.11 An indirect procedure employing 3ꢀlithioꢀ1ꢀ
trimethylsilylpropyne initially produces the trimethylsilylꢀprotected acetylene, from
which the required homologated alkyne is liberated by reaction with ethanolic
silver nitrate followed by sodium cyanide.12
We previously reported 13 preparation of the operational equivalent of the
propargyl dianion, 5, from treatment of allene, 6, with two equivalents of nꢀBuLi
(Scheme 2). This dianion, 5, regiospecifically reacted with aromatic aldehydes
and ketones to produce homopropargyl alcohols, 3, in very good yields (Scheme
2, Method A).14 An additional advantage of this methodology is that the initiallyꢀ
formed lithium acetylide intermediate, 7, may be further transformed, in situ, into
other derivatives, 8, by adding electrophiles such as paraformaldehyde,
iodomethane, trimethylsilyl chloride and ethyl chloroformate.13, 15
When this methodology was used with aliphatic aldehydes or ketones, mixtures
of allenic and acetylenic isomers, favoring the latter (2:8), were obtained.
Fortunately we found that these mixtures of allenyl and homopropargyl alcohols
can be quantitatively converted to the corresponding homopropargyl alcohols by
a zipperꢀreaction.16
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Although this method (Scheme 2, Method A) produces homopropargyl alcohols,
3, in very good yields the high cost of allene, 6, restricts its use. To overcome this
inconvenience, we developed a new procedure15 for the preparation of dianion,
5. We envisioned that 1,3ꢀdilithiopropyne, 5, (or its equivalent) could be prepared
from reaction of propargyl bromide, 9, with nꢀbutyllithium at ꢀ78o C; thus acidꢀ
base reaction of acetylenic proton of 9, followed by halogenꢀmetal exchange
would produce 5 (Scheme 2, Method B). We found that this halogenꢀmetal
exchange requires the presence of tetramethylethylenediamine (TMEDA). We
prepared a series of homopropargyl alcohols by this methodology (Method B)15
and found that results were comparable with those previously obtained (Method
A).14
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Scheme 2. Our previous methods for the synthesis of homopropargyl alcohols
Our previous work:
H
H
nꢀBuLi (2 eq.)
nꢀBuLi (2 eq.)
Li
H
H
Br
•
ꢀ78 oC
Li
TMEDA, ꢀ78 ºC
6
5
9
Method A
Method B
O
R
R`
OH
E
OLi
R´
Li
OH
E+
H+
R
R
R
R´
R´
3
7
8
This procedure (Method B)15 has been successfully applied by others in the
synthesis of biologically active compounds such as Amphidinol 3,17 Landomycin
A,18,19 coenzyme Qꢀ10,20 and other pharmacologically active compounds.21 We
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have successfully used this methodology to prepare homopropargyl15 and
bishomopropargyl alcohols,16 1,5ꢀdiynes,22 and insect pheromones.22
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9
One of our interests has been to use lithium acetylide intermediate, 7, to perform,
in situ, palladiumꢀcatalyzed crossꢀcoupling chemistry. Thus, reaction of
intermediate, 7, with aromatic or vinyl halides, under palladiumꢀcatalysis, would
produce 4ꢀsubstituted homopropargyl alcohols in a oneꢀpot reaction.
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We report herein a modified procedure for a smallꢀscale synthesis of allene, 6,
the development of a new protocol for the preparation of dianion, 5, its highly
regioselective reaction with aldehydes and ketones to produce homopropargyl
alcohols, 3, and the efficient palladium crossꢀcoupling reaction of lithium
acetylide intermediate, 7, to produce acetyleneꢀsubstituted homopropargyl
alcohols, 8, in very good yields and in a oneꢀpot reaction.
Results and Discussion
Initial palladium crossꢀcoupling reactions were performed with acetylide
intermediate 11 (Scheme 3). Thus, benzophenone, 10, was reacted with dianion,
5, generated from propargyl bromide, 9, and nꢀBuLi in the presence of TMEDA,
at ꢀ78o C (Method B)15 and the reaction mixture was warmed to room
temperature to obtain intermediate 11 (Scheme 3). A THF solution of
bromobenzene, 12, and tetrakis triphenylphosphine palladium (0) was added to
this reaction mixture, followed by addition of copper iodide and the mixture stirred
overnight at room temperature. After stirring for 18 hours, a mixture of the
desired crossꢀcoupling product, 13, (27%) and the homopropargyl alcohol, 14,
(73%) was obtained (Scheme 3, Table 1, entry 1). The reaction was repeated
using a longer reaction time for the palladium crossꢀcoupling and, after stirring at
room temperature for 72 hours, the yield of product, 13, did not improve (25%)
(Table 1, entry 2).
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Scheme 3. Preliminary cross-coupling reactions between 11 and 12
5
6
O
7
8
10
9
nꢀBuLi (2 eq.)
Li
Br
10
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TMEDA, ꢀ78 ºC
Li
9
5
Method B
Br
OH
OH
OLi
Li
12
+
Pd(PPh3)4
CuI
13
14
11
nꢀBuLi (2 eq.)
12
11
Pd(PPh3)4
CuI
Several examples of chelate complexes between palladium and TMEDA and its
derivatives have been reported 23 . In our case, it is possible that TMEDA
coordinates so strongly with palladium, that the latter is not able to undergo an
efficient oxidative addition with bromobenzene, 12. In fact, a chelate complex
between palladium (II) chloride with one equivalent of TMEDA is commercially
available: dichloro (N,N,N´,N´ꢀtetramethylethylenediamine) palladium (II).
To determine if the presence of TMEDA was adversely affecting the palladium
crossꢀcoupling reaction, model reactions were performed. First, homopropargyl
alcohol, 14, was treated with nꢀBuLi (2 equivalents) to generate lithium acetylide
intermediate, 11, and this was reacted sequentially with copper iodide,
bromobenzene, 12, and Pd(PPh3)4 (Scheme 3) in the presence of TMEDA, with
overnight stirring at room temperature (Table 1, entry 3). After aqueous workꢀup,
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the unreacted alcohol 14, was recovered. In another reaction, intermediate 11,
was prepared from alcohol 14 as described, and the above crossꢀcoupling
reaction (Table 1, entry 3) was repeated in the absence of TMEDA. After stirring
at room temperature overnight and aqueous workꢀup, 1,1,4ꢀtriphenylꢀ3ꢀbutynꢀ1ꢀ
ol, 13, was obtained in 13% yield (Table 1, entry 4).
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Table 1. Preparation of 1,1,4-triphenyl-3-butyn-1-ol, 13, from 11.
Entry
Preparation of 11
Time
14
13
(hours)
(%)
(%)
9 + nꢀBuLi (2 equiv.) + TMEDA (method B)
9 + nꢀBuLi (2 equiv.) + TMEDA (method B)
14 + nꢀBuLi (2 equiv.) + TMEDA
18
72
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18
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27
25
0
73
75
1
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6
100
87
14 + nꢀBuLi (2 equiv.)
13
20
0
14 + PhBr, Pd(PPh3)4, CuI, Et3Na
80
14 + nꢀBuLi (2 equiv.) + PhBr, Pd(PPh3)4
100
a
Sonogashira conditions
We alternatively explored synthesizing alcohol 13 through a classical
Sonogashira approach. Thus, reaction of acetylenic alcohol, 14, with
bromobenzene, 12, generated product 13 in only 20% yield (Table 1, entry 5). By
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comparison, reaction of intermediate, 11, (prepared from treatment of 14 with 2
equivalents of nꢀBuLi), with bromobenzene, 12, and Pd(PPh3)4, in absence of
CuI, failed to yield product 13, and only homopropargyl alcohol, 14, was
recovered (Table 1, entry 6).
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From these experiments (Table 1, entries 1ꢀ4) it was concluded that palladiumꢀ
catalyzed crossꢀcoupling reaction of intermediate 11, was not clean because of
the tendency of TMEDA to form a chelate with palladium. Furthermore, it was
noticed that a catalytic amount of CuI is needed for the crossꢀcoupling to occur
(Table 1, entries 5ꢀ6).
To overcome this difficulty, a new protocol for the preparation of dianion 5,
without the presence of TMEDA, was developed.
New protocol for preparation of dianion, 5.
It was envisioned that a 2,3ꢀdihalopropene (15 or 16) could be a starting material
for the preparation of dianion, 5. Thus 2,3ꢀdibromopropene, 16, (or 2,3ꢀ
dichloropropene, 15) was treated with tertꢀBuLi, at ꢀ78o C, to promote metalꢀ
halogen exchange and generate 2ꢀbromoꢀ3ꢀlithiopropene, 17, (or 3ꢀbromoꢀ2ꢀ
lithiopropene) that could undergo 1,2ꢀelimination to generate allene, 6, whose
treatment with nꢀBuLi was expected to produce 1,3ꢀdilithiopropyne, 5, as in
method A (Scheme 2). The efficiency of this procedure was indirectly
corroborated by reacting intermediate, 5, with benzophenone, 10, to obtain the
corresponding homopropargyl alcohol 14 (Scheme 4)
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Scheme 4. Preparation of dianion, 5, from 2,3-dihalopropenes 15 and 16.
5
6
7
This work:
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9
Method C
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X
X
H
H
tꢀBuLi, ꢀ78º C
nꢀBuLi
H
H
Li
X
•
M
or
(2 equiv.)
Li
5
6
Mg/THF
15, X= Cl
16, X= Br
17, X= Br, M= Li
18, X= Cl, M= Li
19, X= Br, M=MgBr
20, X= Cl, M= MgCl
O
10
OH
OLi
Li
H3O+
14
11
This protocol was performed under different conditions, all of which produced
alcohol, 14, in very poor yields (Table 2). In all cases, reduction of
benzophenone, 10, to produce benzhydrol, 21, was a major byꢀproduct (Table
2). An additional common byꢀproduct was 1,1ꢀdiphenylpentanꢀ1ꢀol, 22, obtained
from the addition of remnant nꢀBuLi to benzophenone, 10. The presence of the
latter compound, 22, was an indication of incomplete metallation of allene, 6, with
nꢀBuLi, or incomplete metalꢀhalogen exchange of 16 (or 15) with tꢀBuLi, that
would result in a low yield of allene, 6 (Scheme 4).
Using different amounts of tertꢀBuLi and nꢀBuLi did not improve the yield of
alcohol 14 beyond 21% (Table 2, entry 7). Surprisingly, treatment of 16, with 1 or
2 equivalents of tertꢀBuLi, followed by addition of benzophenone, 10, did not
produce alcohol, 14, in appreciable amounts (Table 2, entries 2ꢀ3). Increasing
amounts of nꢀBuLi slightly improved the yield of alcohol 14 (Table 2, entries 4ꢀ5).
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In almost all reactions unidentified byꢀproducts were obtained in yields ranging
from 2ꢀ13% (by G.C.)
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Table 2. Production of homopropargyl alcohol 14, from 2,3ꢀdihalopropenes 15
and 16 by treatment with tertꢀBuLi and nꢀBuLi
Yield(%)
Entry
Dihalopropene
(equiv.)
tꢀBuLi
nꢀBuLi
PhCOPh
(equiv.)
(equiv.)
10 (equiv.)
14
21
22
1
2
3
4
5
6
7
15 (2.85)
16 (2.85)
16 (2.85)
16 (2.85)
16 (5.88)
16 (2.85)
16 (2.85)
5.70
2.85
5.70
5.70
11.76
2.86
5.71
2.00
0
1.00
1.00
1.00
1.00
1.00
1.00
1.00
2
0
68
98
91
85
44
48
60
24
0
0
5
0
1.00
4.12
1.00
2.00
0
10
36
24
12
7
18
21
Lithiation of 2,3ꢀdihalopropene 15 and 16 with tertꢀBuLi was complex. Apparently
the use of TMEDA is needed for complete metallation24. An alternative metalꢀ
halogen exchange methodology might be using an excess of lithium powder with
25
a catalytic amount of an arene, such as naphthalene
butylbiphenyl (DTBB).26
or 4,4´ꢀdiꢀtertꢀ
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It is known that allene, 6, can be prepared from 2,3ꢀdichloropropene, 15, and
excess zinc dust in refluxing ethanol.27 In this procedure,27 2,3ꢀdichloropropene
was added dropwise over a refluxing suspension of zinc dust in 95% ethanol and
water in a 5:1 ratio. The same report27 indicated that allene, prepared by this
methodology, contained up to 3% of 2ꢀchloropropene. In an alternative method,
2,3ꢀdichloropropene was reacted with tellurium in the system hydrazine hydrateꢀ
KOH.28
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We did not use the above procedure due to the possibility of generating allene
containing traces of water and ethanol. In our protocol, the allene is reacted with
nꢀBuLi and thus, presence of water and ethanol would be detrimental. Moreover,
the presence of high levels of 2ꢀchloropropene as impurity is likely to generate
sideꢀproducts under our reaction conditions. Rather we decided to use a more
simple approach employing magnesium instead of zinc, and dry tetrahydrofuran
as solvent. We envisioned that Grignard reagent, 19, (or 20) could undergo a βꢀ
elimination to produce allene, 6, (Scheme 4), which in turn could be directly
metallated with nꢀBuLi, as in our previous procedure.13 The starting Grignard
reagent can be easily prepared at room temperature without any external
heating.
Initial reactions of 2,3ꢀdibromopropene, 16, with magnesium, to form Grignard,
19, followed by treatment with nꢀBuLi and addition of benzophenone, 10,
(Scheme 4) resulted in formation of alcohol, 14, in 4 % yield (Table 3, entry 1)
accompanied by several unidentified byꢀproducts. This reaction was performed in
the same flask, equipped with a dryꢀice condenser to avoid loss of allene. We
decided to prepare allene, 6, by this procedure but bubbling this gas into a
different flask containing a mixture of nꢀBuLi in diethyl ether, at ꢀ78o C, and follow
this by addition of benzophenone, 10. Using these conditions, the yield of
homopropargyl alcohol, 14, increased to 20 % (Table 3, entry 2). A large excess
of 2,3ꢀdibromopropene, 16, did not improve the yield of 14, instead benzhydrol,
21, was obtained in 63 % (Table 3, entry 3).
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Table 3. Preparation of homopropargyl alcohol 14, from 2,3ꢀdihalopropenes 15
and 16.
7
8
9
OH
OH
OH
1. Mg, THF
2. nꢀBuLi
3. 10
X
10
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20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
+
X
15, X= Cl
16, X= Br
Method C
14
21
22
Yield(%)
Entry
Dihalopropene
Mg
nꢀBuLi
PhCOPh,
Ratio
(equiv.)
(equiv.)
(equiv.) 10(equiv.)
5/10
14
21a
22a
1
2
3
4
5
6
7
8
9
16 (6.1)
18.2
17.6
4.2
4.1
4.7
8.4
8.4
8.4
4.2
2.1
2.8
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.1
2.1
2.3
4.2
4.2
4.2
2.1
1.1
1.4
4
54
48
63
60
33
0
42
32
15
22
15
0
16 (5.9)
20
16 (33.3)
15 (36.4)
15 (36.4)
15 (121.0)
15 (45.4)
15 (15.3)
15 (33.3)
20.0
22
60.6
18
60.6
52
388.0
193.9
50.4
95
100
98
0
0
0
0
106.7
100
0
0
a Compounds 21 and 22 were not isolated. They were identified by comparison with authentic samples.
Yields were calculated by 1HꢀNMR and capillary GC analysis.
Formation of Grignard, 19, from 2,3ꢀdibromopropene, 16, was a vigorous and
exothermic reaction, therefore to prevent loss of allene, 6, we used a less
reactive starting material, 2,3ꢀdichloropropene, 15, to form related Grignard 20.
When dichloropropene, 15, was treated sequentially with magnesium, nꢀBuLi and
benzophenone, 10, homopropargyl alcohol, 14, was obtained in 18% (Table 3,
entry 4).
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6
It was surprising that a significant amount of 1,1ꢀdiphenylꢀpentanꢀ1ꢀol, 22, was
obtained in all previous reactions (15ꢀ42%, Table 3, entries 1ꢀ4).
7
8
9
We initially presumed that a large excess of allene, 6, was being generated from
2,3ꢀdihalopropenes 15 and 16, but significant amounts of nꢀBuLi were unreacted
by the time benzophenone, 10, was added (yield of 22 = 15ꢀ42 %, Table 3,
entries 1ꢀ4). We then considered it likely that either allene, 6, might either not be
formed in significant amounts or was being lost.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To corroborate the formation of allene, 6, a gas sample was taken from the
allene generation flask, and analyzed by GCꢀMS. This analysis showed the
presence of allene, 6, (M+= 40.1) (Figure 1), that gave a spectrum in agreement
with the NIST database29 . The peak at m/z 32.1 corresponds to molecular
oxygen.
Figure 1. Mass spectrum of gas sample taken from the allene generator.
In the previous reactions (Table 3, entries 1ꢀ4) allene, 6, generated from the 2,3ꢀ
dihalopropenes, (15 and 16) was bubbled into a second flask, containing nꢀBuLi
in a mixture hexanes:ether at ꢀ78o C, and this flask was equipped with a dryꢀice
condenser connected to a vacuum manifold and a glycerin bubbler. The reaction
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was repeated under identical conditions used in entry 4 (Table 3), but the dryꢀice
condenser was connected to a balloon, instead of a manifold. The balloon
inflated due to allene generation and as allene was bubbled into the nꢀBuLi
solution. The reaction was stirred at ꢀ78o C for 1 hour, by which time the balloon
deflated. Benzophenone, 10, dissolved in ether, was added to this reaction
mixture, followed by warming to room temperature, as in all previous
experiments. In this case, yield of 14, marginally improved to 52% (Table 3, entry
5).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
When the reaction was repeated using larger amounts of magnesium and the
ratio between dianion, 5 and benzophenone, 10 was lowered the homopropargyl
alcohol, 14 was obtained in excellent yields (95ꢀ100%, Table 3, entries 6ꢀ9). The
most reproducible results were obtained when a ratio 5 / 10 of 1.4 was used
(Table 3, entry 9).
Homopropargyl Alcohols
To demonstrate the reproducibility of this methodology (method C), and to
compare its efficiency against the previous protocols (methods A and B) several
homopropargyl alcohols were prepared (Table 4). Alcohols prepared by this
procedure were obtained in comparable (Table 4, entries 3 ꢀ 4), or higher (Table
4, entries 1 ꢀ 2) yields than with our previous methods.
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Table 4. Conversion of Aldehydes and Ketones into Homopropargyl Alcohols
5
6
7
8
9
1. Mg, THF
2. nꢀBuLi
Cl
OH
R
Method C
Cl
R
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15
3.
R
R
% Yield
Method A14 Method B16 Method C
Entry
1
Starting Material
Product
99
90
96
2
3
93
90
86
96
95
94
4
5
93
ꢀ
83
94
99
ꢀ
6
7
99
69
ꢀ
ꢀ
ꢀ
82
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When dianion, 5, was reacted with hexanal, 31, a mixture of the corresponding
homopropargyl, 32, (91%) and allenyl, 33, (9%) alcohols was obtained (Table 4,
entry 6). This result is in agreement with our previous findings14,16 that as the
carbonyl group, of the aldehyde or ketone, becomes “harder” (aromatic vs
aliphatic), a significant amount of allenic derivative is obtained, presumably as a
result of the nucleophilic addition from the “harder” end of the isomeric form of
the ambident dianion, 5 (Scheme 5).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Fortunately, when this crude reaction was treated with potassium 3ꢀ
aminopropylamide (KAPA), allenyl alcohol, 33, was completely isomerized to
homopropargyl alcohol, 32. This result validates mechanism of the “zipper”
reaction,30 where isomerization of internal acetylenes to terminal acetylenes
proceeds via a series of deprotonation, allenylꢀpropargyl rearrangements, and an
allenyl species has been proposed as an intermediate31 (Scheme 6).
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As previously established, the advantage of this methodology is that the initially
formed lithium acetylide, 11, can be further reacted with a second electrophile.
Thus, addition of a second electrophile, such as paraformaldehyde, to the lithium
acetylide intermediate, 11, resulted in the formation of 69 % of diol, 34, in a oneꢀ
pot reaction (Table 4, entry 7).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In situ synthesis of substituted homopropargyl alcohols
The main objective of this project was to use lithium acetylide intermediates (e.g.
11) to perform, in situ, palladiumꢀcatalyzed crossꢀcoupling chemistry, and to
prepare 4ꢀ(substituted) homopropargyl alcohols in a oneꢀpot reaction. Thus,
benzophenone, 10, was reacted at ꢀ78º C, with 1,3ꢀdilithiopropyne, 5, prepared
from 2,3ꢀdichloropropene, 15, as previously described (method C). The reaction
was allowed to warm to room temperature and a THF solution of bromobenzene,
12, and Pd(PPh3)4 added, followed by addition of copper iodide. The reaction
was stirred at room temperature overnight, and after aqueous workꢀup, and
column chromatography, 1,1,4ꢀtriphenylꢀ3ꢀbutynꢀ1ꢀol, 13, was obtained, in 45 %
yield (Table 5, entry 1). As expected, the use of chlorobenzene, 35, gave a lower
yield (33%, Table 5, entry 2). When the above palladiumꢀcatalyzed crossꢀ
coupling between intermediate, 11, with bromobenzene, 12, was attempted
without CuI product, 13, was obtained in only 7% and alcohol 14 was recovered
in 81% yield. This result is consistent with the previous crossꢀcoupling attempted
without copper (Table 1, entry 6).
To show the wide applicability of this protocol, tolerance to diverse functional
groups, and its application to the synthesis of highly substituted homopropargyl
alcohols, several compounds were prepared (Table 5). To favor the palladium
oxidative addition step, we used aromatic iodides. Thus, addition of 1,3ꢀ
dilithiopropyne, 5, (prepared by Method C, Tables 3 and 4) to acetophenone, 23,
followed by addition of oꢀiodotoluene, 36, PdCl2(PPh3)2 and CuI resulted, after
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stirring overnight and column chromatography, in the production of 5ꢀ(oꢀtolyl)ꢀ2ꢀ
phenylꢀ4ꢀpentynꢀ2ꢀol, 37, in 80 % (Table 5, entry 3). Treatment of acetophenone,
23, under identical conditions and using 2ꢀiodoanisole, 38, as electrophile, and
Pd(PPh3)4 resulted in the formation of 5ꢀ(oꢀmethoxyphenyl) 2ꢀphenylꢀ4ꢀpentynꢀ2ꢀ
ol, 39, in 96% in a oneꢀpot reaction (Table 5, entry 4). Reaction of acetophenone,
23, with dianion, 5, followed by treatment with pꢀiodo nitrobenzene, 40, and
palladium catalysis, generated 5ꢀ(pꢀnitrophenyl)ꢀ2ꢀphenylꢀ4ꢀpenynꢀ2ꢀol, 41, in
89% (Table 5, entry 5).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Particularly interesting was the preparation of the highly substituted 4ꢀ(4´, 4´ꢀ
diphenyl, 4´ꢀhydroxyꢀ1´ꢀbutynyl) acetophenone, 43, in 63% overall yield (Table 5,
entry 6). In this case crossꢀcoupling reaction of acetylide intermediate, 11, with
4´ꢀiodoacetophenone, 42, was very successful and no addition to the carbonyl
group was observed.
Reaction of lithium acetylide intermediate, 11, with 2ꢀiodothiophene, 44, under
palladiumꢀcatalysis, yielded 4ꢀ(2´ꢀthiophenyl)ꢀ1, 1ꢀdiphenylꢀ3ꢀbutynꢀ1ꢀol, 45, in
69% overall yield (Table 5, entry 7).
This procedure is particularly useful in the synthesis of highly functionalized
conjugated enynes. Palladiumꢀcatalyzed coupling of intermediate, 11, with transꢀ
1ꢀiodoꢀ1ꢀpentene, 46, yielded transꢀ1,1ꢀdiphenylꢀ5ꢀnonenꢀ3ꢀynꢀ1ꢀol, 47, in 55%
overall yield from benzophenone (Table 5, entry 8). Coupling of acetophenone,
23, with 5, followed by treatment with cisꢀdichloroethene, 48, under palladium
catalysis, led to the formation of cisꢀ7ꢀchloroꢀ2ꢀphenylꢀ6ꢀheptenꢀ4ꢀynꢀ2ꢀol, 49, in
62% (Table 5, entry 9).
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Table 5. OneꢀPot Conversion of Aldehydes and Ketones into 4ꢀSubstitutedꢀ
5
6
Homopropargyl Alcohols
7
8
9
This work:
O
nꢀBuLi
(2 eq.)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
R´
R´´
OLi
R´
Li
Cl
R´´
X
Mg
R
R´
Cl
R
R
ꢀ78 oC
Pd(PPh3)4 or
Pd(PPh3)2Cl2
THF
Method C
CuI
Entry Carbonyl Compound
1
RꢀX
Catalyst
Product
% Yield
45
Pd
(
PPh
)
3 4
2
3
4
33
80
96
Pd
(
PPh
)
3 4
PdCl2(PPh )
3 2
Pd
(
PPh )
3 4
5
6
89
63
Pd
(
(
PPh
PPh
)
3 4
Pd
)
3 4
7
8
69
55
PdCl2
PdCl2
(
(
PPh )
3 2
PPh )
3 2
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62
PdCl2(PPh3)2
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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27
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31
32
33
34
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37
38
39
40
41
42
43
44
45
46
47
48
49
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59
60
Conclusions
In summary, we have further developed and improved a method for the synthesis
of allene, from treatment of 2,3ꢀdichloropropene with magnesium in dry THF. In
contrast to the previous method27, our preparation of allene can be executed
easily, under milder conditions and dry atmosphere. Thus, the allene generated
through our methodology, can be metallated without any further purification. This
represent a vast improvement on the previously reported27 procedure, which is
performed under aqueous conditions. We then used the allene, generated using
our protocol, to develop a new TMEDAꢀfree procedure for the preparation of one
operational equivalent of propargyl dianion, 5, that can be used for the
conversion of aldehydes and ketones into homopropargyl alcohols (Method C).
This new procedure, has an economic advantage over our previous method A,
which uses allene gas to prepare dianion, 5. Preparation of 5, using method C is
about 2.5 times cheaper than using method A. Furthermore, our new method C
represents an improvement over our previous method B because it is TMEDAꢀ
free, enabling further palladiumꢀcatalyzed functionalization of lithium acetylide
intermediates. Thus, the lithium acetylide intermediates obtained in this
procedure can be further reacted, under palladium catalysis, to obtain highly
functionalized acetylene diꢀsubstituted homopropargyl alcohols in oneꢀpot
reaction. This synthetic methodology tolerates the presence of different
functionalities such as ethers, carbonyl or nitro groups in the palladium crossꢀ
coupling reaction. This procedure can also be applied in the oneꢀpot synthesis of
highly substituted enynes.
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EXPERIMENTAL SECTION
5
6
7
8
9
General Information. All glassware and syringes were dried in an oven
overnight at 140º C and flushed with nitrogen immediately prior to use. Transfers
of reagents were performed with syringes equipped with stainlessꢀsteel needles.
All reactions were carried out under a positive pressure of nitrogen. Nitrogen was
passed through a Drierite gasꢀdrying unit prior to use. Diethyl ether and
tetrahydrofuran were refluxed and freshly distilled from sodium and potassium
/benzophenone ketyl respectively, under nitrogen atmosphere. Hexane was
distilled from sodium and collected and kept over activated molecular sieves. nꢀ
Butyllithium was titrated according to the method of Watson and Eastham.32
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Pd(PPh3)4, PdCl2(PPh3)2 and CuI were transferred in a glove box. HꢀNMR and
13CꢀNMR spectra were recorded on a 400 MHz Bruker spectrometer. Low
resolution mass spectra were obtained on a Agilent Technologies 7820A GC
coupled to a mass spectrometer 5977E unit using electron impact at 70 eV. High
resolution mass were measured on a Waters Synapt HMDS G1, QꢀTOF. Infrared
spectra were recorded on a Perkin Elmer FTꢀIR Spectrum 1000.
General procedure for the synthesis of 4-(substituted) homopropargyl
alcohols.
Preparation of 1,3-dilithiopropyne (5).
An ovenꢀdried, 100 mL, threeꢀnecked, roundꢀbottomed flask was equipped with a
magnetic stirring bar and a Liebig condenser bearing a glycerinꢀbubbler at the
top. The exit of the glycerin bubbler was connected, by means of tygon tubing to
a doubleꢀtipped needle. The other end of this needle was inserted, through a
rubber septum, into a singleꢀnecked flask equipped with a magnetic stirring bar,
and capped by a rubber septum bearing a needle attached to a balloon. The
threeꢀnecked flask was charged with magnesium turnings (1.55g, 64 mmol), a
small crystal of iodine and THF (25 mL). A small amount (~0.5 mL) of a THF
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solution (3 mL) of 2,3ꢀdichloropropene (2.22 g, 20 mmol) was added to the
magnesium, the mixture was stirred for about 10 min. and a very exothermic
reaction ensued after slightly warming the reaction flask. The allene gas,
generated, was bubbled into a solution of nꢀBuLi (0.65 mL, 1.70 mmol) in dry
diethyl ether (5 mL) and dry hexanes (4.35 mL)33, at ꢀ78o C, in a singleꢀnecked
flask, under nitrogen atmosphere. The remaining THF solution of 2,3ꢀ
dichloropropene was added in small portions, in order to maintain a vigorous
generation of allene. After generation of allene stopped, the canula was removed
from the singleꢀnecked flask, and the nꢀBuLiꢀallene was stirred at ꢀ78o C for 1
hour.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of 5-[(o-methoxy)phenyl]-2-phenyl-4-pentyn-2-ol (39)
An ether solution (3 mL) of acetophenone, 23, (0.085 g, 0.60 mmol) was added
to a cold (ꢀ78o C) 1,3ꢀdilithiopropyne, 5, solution prepared as above, and
assumed to be 0.85 mmol of 5, (prepared from 1.70 mmol of nꢀBuLi). The
mixture was slowly warmed to room temperature over 3 hours, and a mixture of
2ꢀiodoanisole, 38, (0.210 g, 0.90 mmol) and Pd(PPh3)4 (0.069 g) in THF (5 mL)
was added, followed by addition of a suspension of CuI (0.006 g) in THF (3 mL),
and the resulting mixture stirred at room temperature for 18 h. The reaction was
quenched be addition of 10% ammonium acetate (3 mL) and extracted with ether
(2 x 20 mL). The organic phase was dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified by column chromatography
(Et2O : hexanes, 1:4) to give 0.152 g (96%) of alcohol 39.
1,1-diphenyl-3-butyn-1-ol (14). (0.132 g, 99%); IR (KBr): νmax 3410, 3292, 1493,
1448, 1168, 1054 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 7.45 (m, 4H), 7.33 (m, 4H),
13
7.25 (m, 2H), 3.16 (d, J = 2.7 Hz, 2H), 2.04 (t, J = 2.7 Hz, 1H); C NMR (100
MHz, CDCl3): δ 145.4, 128.2, 127.3, 126.1, 80.2, 77.1, 72.5, 33.4; MS (EI) m/z
(rel. intensity) 39.1 (5), 77.1 (72), 105.2 (100), 183.2 (85); HRMS (ESI, V+): m/z
[M + H]+ calc. for C16H15O 223.1121, found 223.1121; m.p = 58 – 59 °C.
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2-phenyl-4-pentyn-2-ol (24). (0.091 g, 95%); IR (film): νmax 3411, 3295, 2119,
1
1495, 1446, 1375, 1101 cmꢀ1; H NMR (400 MHz, CDCl3): δ 7.49 (m, 2H), 7.36
7
8
9
(m, 2H), 7.30 (m, 1H), 2.77 (dd, J = 2.6, 16.6 Hz, 1H), 2.69 (dd, J = 2.6, 16.6 Hz,
13
1H), 2.43 (broad singlet, 1H), 2.06 (t, J = 2.6, 1H), 1.65 (s, 3H); C NMR (100
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MHz, CDCl3): δ 146.3, 128.4, 127.2, 124.8, 80.5, 73.2, 71.7, 34.6, 29.2; MS (EI)
m/z (rel. intensity) 43.1 (92), 77.1 (35), 105.1 (25), 121.1 (100); HRMS (ESI, V+):
m/z [M + H]+ calc. for C11H13O 161.0966, found 161.0969.
1-cyclopropyl-1-phenyl-3-butyn-1-ol (26). (0.105 g; 94%); IR (film): νmax 3548,
3467, 3294, 1493, 1447, 1050 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 7.52 (m, 2H),
7.38 (m, 2H), 7.30 (m, 1H), 2.93 (dd, J = 2.6, 16.6 Hz, 1H), 2.85 (dd, J = 2.6, 16.6
Hz, 1H), 2.21 (s, 1H), 2.00 (t, J = 2.6 Hz, 1H), 1.40 ꢀ 1.33 (m, 1H), 0.59 – 0.50
(m, 2H), 0.44 – 0.38 (m, 1H,); 13C NMR (100 MHz, CDCl3): δ 145.0, 128.0, 127.1,
125.5, 80.3, 73.7, 71.1, 33.2, 21.2, 1.5, 0.9; MS (EI) m/z (rel. intensity) 39.1 (15),
77.1 (52), 105.1 (98), 147.1 (100); HRMS (ESI, V+): m/z [M + H]+ calc. for
C13H15O 187.1123, found 187.1126.
1-phenyl-3-butyn-1-ol (28). (0.082 g, 94%); IR (film): νmax 3367, 3310, 2121,
1
1493, 1453, 1053 cmꢀ1; H NMR (400 MHz, CDCl3): δ 7.41 ꢀ 7.35 (m, 4H), 7.33ꢀ
7.28 (m, 1H), 4.87 (ddd, J = 3.2, 6.3, 6.3 Hz, 1H), 2.65 (ddd, J = 2.7, 6.3, 6.3 Hz,
2H), 2.47 (s, J = 3.2 Hz, 1H), 2.09 (t, J = 2.7 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ 142.4, 128.5, 128.0, 125.7, 80.6, 72.3, 71.0, 29.4; MS (EI) m/z (rel.
intensity) 39.1 (5), 41.1 (5), 77.1 (42), 79.1 (75), 107.1 (100); HRMS (ESI, V+):
m/z [M + H]+ calc. for C10H11O 147.0810, found 147.0810.
1-[4-(dimethylamino)-phenyl]-3-butyn-1-ol (30). (0.112 g, 99%); IR (film): νmax
1
3370, 3311, 2119, 1955, 1465, 1348, 1163, 1048 cmꢀ1; H NMR (400 MHz,
CDCl3): δ 7.26 (m, 2H), 6.72 (m, 2H), 4.80 (dd, J = 5.6, 7.3 Hz, 1H), 2.96 (s, 6H),
2.70 – 2.63 (ddd, J = 2.7, 7.2, 16.1 Hz, 1H), 2.65 – 2.58 (ddd, J = 2.7, 5.6, 16.1
Hz, 1H), 2.26 (Broad singlet, 1H), 2.07 (t, J = 2.7, 1H); 13C NMR (100 MHz,
CDCl3): δ 150.6, 130.5, 126.7, 112.4, 81.2, 72.2, 70.5, 40.6, 29.1; MS (EI) m/z
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(rel. intensity) 39.1 (5), 77.1 (18), 150.1 (100), 171.0 (65), 189.0 (M+, 16); HRMS
(ESI, V+): m/z [M + H]+ calc. for C12H16NO 190.1232, found 190.1232.
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1,1-diphenyl-3-pentyn-1,5-diol (34). (0.104 g, 69%); IR (KBr): νmax 3338, 3257,
2916, 1446, 1188, 1049, 1009 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 7.44 (m, 4H),
7.33 (m, 4H), 7.26 (m, 2H), 4.17 (dd, J = 2.0 Hz, 2H), 3.20 (t, J = 2.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3): δ 145.5, 128.2, 127.3, 126.1, 82.7, 82.2, 77.4, 51.4,
33.8; MS (EI) m/z (rel. intensity) 39.1 (4), 77.1 (47), 105.0 (95), 183.1 (100);
HRMS (ESI, V+): m/z [M + Na]+ calc. for C17H16O2Na 275.1048, found 275.1052;
m.p = 82 – 83 °C.
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1-nonyn-4-ol (32). (0.083, 99%); IR (film): vmax 3349, 3311, 2931, 2119, 1460,
1425, 1078, 1037; 1H NMR (400 MHz, CDCl3): δ 3.66 (m, 1H), 2.42 (ddd, J = 2.7,
4.7, 16.8 Hz, 1H), 2.31 (ddd, J = 2.7, 6.8, 16.8 Hz, 1H), 2.04 (t, 1H), 1.53 (m, 2H),
1.40 – 1.25 (m, 6H), 0.88 (t, 3H); 13C NMR (100 MHz, CDCl3): δ 81.1, 70.9, 70.0,
36.3, 31.9, 27.5, 25.4, 22.7, 14.1; MS (EI) m/z (rel. intensity) 39.0 (27), 41.1 (47),
55.0 (96), 83.1 (100), 101.0 (38); HRMS (ESI, V+): m/z [M + H]+ calc. for C9H17O
141.1279, found 141.1279.
2-phenyl-5-(o-tolyl)-4-pentyn-2-ol (37). (0.120 g, 80%); IR (film): νmax 3554,
3429, 2222, 1601, 1485, 1446, 1069 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 7.55 (m,
2H), 7.38 (m, 2H), 7.32 (m, 1H), 7.28 (m, 1H), 7.18 (m, 1H), 7.15 (m, 1H), 7.10
(m, 1H), 3.06 (d, 1H, J = 16.6 Hz), 2.96 (d, 1H, J = 16.6 Hz), 2.51 (s, 1H), 2.26 (s,
3H), 1.71 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 146.7, 140.3, 132.1, 129.5,
128.4, 128.1, 127.2, 125.6, 125.0, 123.1, 89.8, 82.9, 73.8, 36.0, 29.6, 20.8; MS
(EI) m/z (rel. intensity) 43.1 (78), 77.1 (15), 115.1 (10), 121.1 (100), 130 (57),
HRMS (ESI, V+): m/z [M + H]+ calc. for C18H18O 250.1358, found 250.1352.
5-(o-methoxyphenyl)-2-phenyl-4-pentyn-2-ol (39). (0.153 g, 96%); IR (film):
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3504, 2233, 1492, 1463, 1102 νmax cmꢀ1; H NMR (400 MHz, CDCl3): δ 7.55 (m,
2H), 7.37 (m, 2H), 7.30 (m, 1H), 7.27 (m, 1H), 7.24 (m, 1H), 6.88 (m, 1H), 6.85
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(m, 1H), 3.87 (s, 3H), 3.00 (d, 1H, J = 16.6 Hz), 2.94 (d, 1H, J = 16.6 Hz), 1.72 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 160.4, 146.8, 133.0, 129.5, 128.3, 127.0,
124.9, 120.5, 112.5, 110.6, 90.5, 80.6, 73.6, 55.9, 36.3, 29.4; MS (EI) m/z (rel.
intensity) 43.1 (78), 77.1 (21), 115.1 (20), 121.1 (95), 131.1 (33), 146.1 (100);
HRMS (ESI, V+): m/z [M + H]+ calc. for C18H19O2 267.1385, found 267.1390.
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5-(p-nitrophenyl)-2-phenyl-4-pentyn-2-ol (41). (0.150 g, 89%); IR (KBr): νmax
1
3546, 3412, 2223, 1593, 1493, 1446, 1107 cmꢀ1; H NMR (400 MHz, CDCl3): δ
8.13 (m, 2H), 7.53 (m, 1H), 7.45 (m, 2H), 7.39 (m, 2H), 7.30 (m, 1H), 3.02 (d, 1H,
J = 16.9 Hz), 2.94 (d, 1H, J = 16.9 Hz), 2.34 (Broad singlet, 1H), 1.73 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 147.0, 146.3, 132.5, 130.4, 128.5, 127.4, 124.9,
123.6, 92.3, 82.3, 73.9, 36.0, 29.4; MS (EI) m/z (rel. intensity) 43.1 (58), 77.1
(10), 121.1 (100), 161.1 (5), 122.1 (10); HRMS (ESI, V+): m/z [M + H]+ calc. for
C17H16NO3 282.1130, found 282.1125.
p-(4-hydroxy-4,4-diphenyl-1-butynyl)acetophenone (43). (0.129 g, 63%); IR
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(KBr): νmax 3498, 2225, 1670, 1598, 1267 cmꢀ1; H NMR (400 MHz, CDCl3): δ
7.83 (d, 2H, J = 8.4 Hz), 7.49 (m, 4H), 7.35 (m, 4H), 7.32 (d, 2H, J = 8.4 Hz),
13
7.28 (m, 2H), 3.40 (s, 2H), 2.56 (s, 3H); C RMN (100 MHz, CDCl3): δ 197.3,
145.5, 136.1, 131.8, 128.2, 128.1, 128.0, 127.4, 126.2, 89.5, 83.3, 77.6, 34.6,
26.6; MS (EI) m/z (rel. intensity) 43.1 (9), 77.1 (48), 105.1 (85), 158.1 (28), 183.1
(100), 322.2 (M+ ꢀH2O, 10); HRMS (ESI, V+): m/z [M + H]+ calc. for C24H21O2
341.1542, found 341.1541; m.p = 123 – 124 °C.
(E)-1,1-diphenyl-5-en-3-nonyn-1-ol (47). (0.095 g, 55%); IR (film): νmax 3500,
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3082, 1968, 1599, 1447 cmꢀ1; H NMR (400 MHz, CDCl3): δ 7.45 (m, 4H), 7.32
(m, 4H), 7.24 (m, 2H), 6.00 (m, 1H, J = 1.6, 7.1, 16.0 Hz), 5.37 (m, 1H, J = 1.7,
7.1, 16.0 Hz), 3.25 (d, 2H, J = 1.7 Hz), 2.61 (s, 1H), 2.02 (m, 2H, J = 1.6, 7.1,
16.0 Hz), 1.37 (m, 2H), 0.88 (t, 3H); 13C NMR (100 MHz, CDCl3): δ 145.9, 144.8,
128.2, 127.3, 126.3, 109.4, 83.7, 83.6, 77.4, 35.1, 34.5, 22.0, 13.8; MS (EI) m/z
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(rel. intensity) 51.1 (10), 77.1 (5), 108.1 (20), 183.1 (85), 262.1 (100); HRMS
(ESI, V+): m/z [M + H]+ calc. for C22H25O 305.1905, found 305.1905.
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1,1-diphenyl-4-(2-tiophenyl)-3-butyn-1-ol (45). (0.126 g, 69%); IR (KBr): νmax
3525, 3470, 2219, 1447, 1425, 1341 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 7.49 (m,
4H), 7.35 (m, 4H), 7.27 (m, 2H), 7.17 (dd, 1H, J = 1.2, 5.2 Hz), 7.05 (dd, 1H, J =
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1.2, 3.7 Hz), 6.90 (dd, 1H, J = 3.7, 5.2 Hz), 3.39 (s, 2H), 2.96 (s, 1H); C NMR
(100 MHz, CDCl3): δ 145.7, 131.9, 128.3, 127.4, 126.9, 126.8, 126.4, 123.2,
89.9, 77.9, 77.6, 34.9; MS (EI) m/z (rel. intensity) 51.0 (8), 77.0 (50), 105.0 (82),
122.0 (14), 183.0 (100), 286.0 (M+ ꢀH2O, 10); HRMS (ESI, V+): m/z [M + H]+ calc.
for C20H17OS 305.1000, found 305.1005. m.p = 68 – 70 °C.
1,1,4-triphenyl-3-butyn-1-ol (13). (0.059 g, 33%); IR (KBr): νmax 3560, 1487,
1
1446, 1347, 1278, 1167 cmꢀ1; H NMR (400 MHz, CDCl3): δ 7.49 (m, 4H), 7.34
(m, 4H), 7.28ꢀ7.24 (m, 7H), 3.37 (s, 2H), 3.00 (s, 1H); 13C NMR (100 MHz,
CDCl3): δ 145.8, 131.8, 128.3, 128.3, 128.2, 127.4, 126.4, 34.6; MS (EI) m/z (rel.
intensity) 51.0 (8), 77.0 (43), 105.0 (78), 115.0 (13), 183.0 (100), 280.0 (M+ ꢀH2O,
10); HRMS (ESI, V+): m/z [M + H]+ calc. for C22H19O 299.1436, found 299.1431.
(Z)-7-chloro-2-phenyl-6-en-4-heptyn-2-ol (49). (0.104 g, 62%); IR (KBr): γmax
3401, 2214, 1601, 1494, 1446, 1098 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 7.51 (m,
2H), 7.36 (m, 2H), 7.27 (m, 1H), 6.34 (d, 1H, J = 7.4 Hz), 5.83 (dt, 1H, J = 2.2,
7.4 Hz), 2.95 (dd, 1H, J = 2.2, 16.9 Hz), 2.89 (dd, 1H, J = 2.2, 16.9 Hz), 2.50 (s,
1H), 1.69 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 146.5, 128.4, 128.3, 127.2,
124.9, 112.1, 94.8, 78.1, 73.6, 36.1, 29.4; MS (EI) m/z (rel. intensity) 43.1 (76),
77.1 (15), 99.0 (4), 105.1 (8), 121.1 (100), 183.2 (M+ ꢀHCl, 10) HRMS (ESI, V+):
m/z [M+ ꢀ HCl]+ calc. for C13H13O 185.0966, found 185.0968.
Acknowledments
We thank the University of Costa Rica for financial support, Sistema de Estudios
de Posgrado (SEPꢀUCR) for a stipend to C.U., CIPRONAꢀUCR for high
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resolution mass spectra determination, Prof. Cam Oehlschlager for reading the
manuscript and useful suggestions and Dr. Albán Pereira for useful suggestions.
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ASSOCIATED CONTENT
Supporting Information
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Diagram of glassware used and copies of HꢀNMR and CꢀNMR spectra of all
compounds prepared in Tables 4 and 5 are provided.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: jorge.cabezas@ucr.ac.cr
ORCID
Jorge A. Cabezas: 0000ꢀ0002ꢀ7571ꢀ6914
Notes
The authors declare no competing financial interest.
References
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