Regio- and Stereoselective Synthesis of 2-Hydroxymethyl-1,3-enynes by Rhodium-Catalyzed Decarboxylative C?C Coupling

Article abstract of DOI:10.1002/adsc.201901013

A regio- and stereoselective protocol for rhodium(I)-catalyzed decarboxylative C?C coupling between propiolic acids and propargyl alcohols has been achieved. This efficient catalytic approach could facilitate the preparation of a diversity of synthetically valuable 2-hydroxymethyl-1,3-enynes with high Z-stereoselectivity. Notably, non-terminal alkynes were smoothly transformed into the target products that show intriguing synthetic utility. (Figure presented.).

Full text of DOI:10.1002/adsc.201901013

Title: Regio- and Stereoselective Synthesis of 2-Hydroxymethyl-1,3-
enynes by Rhodium-Catalyzed Decarboxylative C–C Coupling
Authors: Shi-Chao Lu, Zhi-Xin Chang, Yu-Liang Xiao, and Hong-
Shuang Li
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901013
Link to VoR: http://dx.doi.org/10.1002/adsc.201901013

10.1002/adsc.201901013
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Regio- and Stereoselective Synthesis of 2-Hydroxymethyl-1,3-
enynes by Rhodium-Catalyzed Decarboxylative C–C Coupling
Shi-Chao Lu,+b,c Zhi-Xin Chang,+a Yu-Liang Xiao,a and Hong-Shuang Lia,*
a
Institute of Pharmacology, School of Pharmaceutical Sciences, Shandong First Medical University & Shandong
Academy of Medical Sciences, 619 Changcheng Road, Taian 271016, People’s Republic of China
Phone: +86 538 6229755; Fax: +86 538 6229751; E-mail: lihongshuang8625@163.com
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, People’s Republic of
b
China
c
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, and Beijing Key Laboratory of
Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical
Sciences and Peking Union Medical College, 2A Nanwei Road, Xicheng District, Beijing 100050, People’s Republic
of China
+
These authors contribute equally.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. A regio- and stereoselective protocol for
rhodium(I)-catalyzed decarboxylative C–C coupling
between propiolic acids and propargyl alcohols has been
achieved. This efficient catalytic approach could facilitate
the preparation of a diversity of synthetically valuable 2-
hydroxymethyl-1,3-enynes with high Z-stereoselectivity.
Notably, non-terminal alkynes were smoothly
transformed into the target products that show intriguing
synthetic utility.
synthesis of 2-hydroxymethyl-1,3-enynes relying on
nickel and palladium catalysis, respectively.
Subsequently, Miura and co-workers reported an
interesting homocoupling of 1,1-disubstituted 3-aryl-
2-propyn-1-ols in company with the cross-coupling
reactions of the same components with
bis(trimethylsilyl)acetylene to give rise to E-selective
enynes.[5b,c] In 2017, Hirano, Uchiyama, and co-
workers
alkynylboration of propargylic alcohols with
subsequent protodeboration to deliver 2-
achieved
the
first
trans-selective
Keywords: Wilkinson’s catalyst; Decarboxylative C–C
coupling; 2-Hydroxymethyl-1,3-enyne; Regioselective
synthesis; Z-stereoselectivity
hydroxymethyl-(E)-enynes.[9] Very recently, a dual
Ni/Cu-catalyzed protocol for the regioselective
synthesis of gem-1,3-enynes was accomplished by Xia,
Lee, and co-workers.[4d] However, the substrates were
limited to terminal alkynes as well as aryl-substituted
propiolic acids. To the best of our knowledge, regio-
and stereoselective synthesis of 2-hydroxymethyl-(Z)-
enynes from two different non-terminal alkynes by
transition metal catalysis remains elusive.
The 1,3-Enynes of which versatile functionalized
molecules are composed can be ubiquitously found in
naturally occurring products[1] and medicinally
relevant compounds,[2] and they are also important
precursors in materials science.[3] Consequently,
extensive efforts have been dedicated to transition-
metal-catalyzed coupling reactions of terminal alkynes
to control the regio- and stereoselectivity and provide
head-to-tail and Z- and E-head-to-head conjugated
enynes.[4] Among abundant enyne compounds, 2-
hydroxymethyl-1,3-enynes have recently received
considerable attention due to their potential
application in the preparation of dihydrofuran
derivatives with fluorescent properties.[5] Besides
conventional multistep synthesis of 2-hydroxymethyl-
1,3-enynes involving the Sonogashira cross-coupling
reaction as the key procedure,[6] the groups of Sato[7]
and Trost[8] independently developed regioselective
The evolution of transition-metal-catalyzed
decarboxylative transformations has always been a
fascinating research topic in the field of
organometallic chemistry because of its step-economy
and regioselective reaction sequence.[10] Propiolic
acids, which are simple and sufficiently available
feedstocks, can achieve a rapid elaboration of
structural complexity through decarboxylative C–C
coupling reactions.[11] Typically, the initially formed
metal propiolate undergoes decarboxylation to
produce the alkynylmetal species, which usually
participates in a subsequent coupling reaction. In terms
1
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10.1002/adsc.201901013
Advanced Synthesis & Catalysis
of availability of the starting materials and a wide
range of applications in organic synthesis, it would be
highly desirable and still challenging to use the
decarboxylative coupling reactions of propiolic acids
in achieving regio- and stereocontrol.
This chemistry was initiated by choosing
phenylpropiolic acid (1a) and 1-(prop-1-yn-1-
yl)cyclobutan-1-ol (2a) as model substrates to evaluate
the reaction conditions (Table 1). When the coupling
reaction
was
conducted
with
the
On the basis of our experience with the rhodium-
catalyzed functionalization of benzylic alcohols and
allylic alcohols,[12] we envisioned that the combination
of elaborated designed non-terminal alkynes bearing a
chelation-assisting group with alkynoic acids under
rhodium catalysis may address the regioselective
synthesis of 2-hydroxymethyl-1,3-enynes, and control
the stereoselectivity to obtain one isomer
predominantly. This method described herein also
aims to use alkynoic acids with diverse substitution
patterns which would broaden the scope of
decarboxylative C–C coupling reactions substantially.
[Rh(COD)Cl]2/PPh3/K2CO3 catalytic system in dry
toluene at 100 ℃for 12 h, (Z)-1-(1-phenylpent-3-en-1-
yn-3-yl)cyclobutan-1-ol (3aa) was provided in 45%
yield in a regioisomeric ratio of 7.8:1 (Table 1, entry
1). Further screening of the other two rhodium(I)
catalysts demonstrated that Wilkinson’s catalyst was
the best choice (Table 1, entry 2–3). The yield was
increased gradually by decreasing the reaction time,
indicating that the product may be unstable to
prolonged heating (Table 1, entry 4–5). Lowering the
temperature to 80 ℃ resulted in an inferior yield and
slightly improved regioselectivity (Table 1, entry 6).
Among the bases tested (Table 1, entry 7–9),
potassium tert-butoxide delivered a yield comparable
to that achieved with K2CO3. Using KF (1.0 equiv.) as
an additive decreased the yield considerably (Table 1,
entry 10). Furthermore, switching toluene to other dry
solvents such as DCE, THF, and p-xylene proved to be
inefficient to promote the reaction and decreased the
regioselectivity (Table 1, entry 11–13). To our delight,
an enhancement in base loading had a positive effect
on the reaction turnover, and 2-hydroxymethyl-(Z)-
enyne 3aa was produced with the highest yield (Table
1, entry 14). Under the optimal conditions, the ratio of
(Z)-isomer to (E)-isomer was 88:12, as determined by
1H NMR integration of the crude mixture. Control
experiments demonstrated that the RhCl(PPh3)3/PPh3
catalytic couple was essential for the reaction (Table 1,
entry 15), and the absence of the ligand or the base led
to lower yields of the product (Table 1, entry 16–17).
After identifying the optimized reaction conditions,
we evaluated the decarboxylative C–C coupling
reactions of a series of propiolic acids with alkynyl
cycloalkanol 2a (Scheme 1). Propiolic acids bearing
electron-donating groups on the benzene ring, such as
alkyl (3ba–3ca) and alkoxy (3da–3fa) groups,
underwent the coupling reactions smoothly to provide
the 2-hydroxymethyl-(Z)-enynes in satisfactory yields
and regioselectivities. The reactions of aryl-substituted
propiolic acids with 2a gave the corresponding enynes
(3ga–3ha) in 61% and 58% yield, respectively. It was
found that the substrates with fluoro (3ia), chloro (3ja),
trifluoromethyl (3ka), and ester (3la) groups were also
compatible with the catalytic system. To our delight,
3-(benzo[b]thiophen-2-yl)propiolic acid successfully
engaged in the decarboxylative addition to furnish the
desired compound 3ma, albeit with low
Table 1. Evaluation of the Reaction Conditions for the
Synthesis of 2-Hydroxymethyl-1,3-enynes.[a]
time yield
entry Rh
base
solvent
rr[c]
(h) (%)[b]
toluene 12
7.8:1
1
2
3
4
[Rh(COD)Cl]2 K2CO3
[Rh(COD)OH]2 K2CO3
45
toluene 12 36
toluene 12 58
6.9:1
10.4:1
10.1:1
RhCl(PPh3)3
RhCl(PPh3)3
K2CO3
K2CO3
K2CO3
K2CO3
toluene
toluene
toluene
6
62
4
10.9:1
5
6[d]
7
8
9
RhCl(PPh3)3
RhCl(PPh3)3
RhCl(PPh3)3
RhCl(PPh3)3
RhCl(PPh3)3
69
44
56
53
68
24
42
51
40
74
0
4
4
4
4
4
4
4
4
4
4
4
4
12.2:1
9.8:1
7.6:1
8.3:1
10.6:1
5.4:1
9.5:1
8.7:1
11.3:1
-
Na2CO3 toluene
Cs2CO3 toluene
t-BuOK toluene
10[e] RhCl(PPh3)3
11
12
K2CO3
K2CO3
K2CO3
K2CO3
toluene
DCE
THF
RhCl(PPh3)3
RhCl(PPh3)3
RhCl(PPh3)3
13
14[f]
15[g]
p-xylene
RhCl(PPh3)3 K2CO3 toluene
\
K2CO3
K2CO3
\
toluene
toluene
toluene
16[f,g] RhCl(PPh3)3
47
41
11.1:1
10.3:1
17
[a]
RhCl(PPh3)3
Unless noted otherwise, all reactions were performed
using 1a (0.3 mmol, 1 equiv.), 2a (1.5 equiv.), [Rh]
catalyst (5 mol %), PPh3 (10 mol %), and base (10 mol %)
in 1.5 mL of solvent at 100 ℃.
[b] Yield denotes isolated (Z)-isomer.
[c] Regioisomeric ratio (rr) of combined (Z)- and (E)-3aa to
1
3aa′ was determined by H NMR analysis of the crude
mixture.
[d] 80 ℃.
[e] 1.0 equiv. of KF was added.
[f]
regioselectivity.
However,
pyridyl-substituted
20 mol % of K2CO3 was used.
[g] Without PPh3.
alkynoic acid did not react. Furthermore, exposure of
the substrates bearing methyl and trimethylsilyl groups
to the reaction conditions produced the corresponding
1,3-enynes (3na–3oa) in moderate yields, thus
2
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10.1002/adsc.201901013
Advanced Synthesis & Catalysis
group at the γ-position were suitable substrates to
produce the anticipated molecules (3ac, 3af).
However, 2-methylbut-3-yn-2-ol (2h) exhibited lower
reactivity toward phenylpropiolic acid (1a). This
unique protocol could be utilized to the preparation of
the 2-hydroxymethyl-(Z)-enynes (3ai–3aj) bearing an
aromatic ring at the γ-position of the hydroxyl group,
complementing the reported methods for constructing
the corresponding (E)-isomers.[5b,9] Moreover, the
present catalytic system was observed to be effective
for the coupling reactions of 2-phenylbut-3-yn-2-ol
(2k) and 3-phenylprop-2-yn-1-ol (2l) with 1a to
provide the regiospecific products (3ak–3al). 1,1-
Diphenyl-substituted substrate participated in the
decarboxylative C–C coupling reaction sluggishly
(3am) because of the steric hindrance. Finally, when
3-alkyl-substituted propargyl alcohols were treated
with 1a in the presence of the rhodium catalyst, the
desired 2-hydroxymethyl-(Z)-enynes (3an–3ao) were
afforded in yields of 45% and 52%, respectively.
expanding the scope of the decarboxylative C–C
coupling reactions compared with the recently
developed method with only aryl-substituted alkynoic
acids as the coupling partner.[4d] It needs to be pointed
out that only the (Z)-isomer was isolated as the major
product from these reactions.
Scheme 1. Scope of Propiolic Acids for the Synthesis of 2-
Hydroxymethyl-(Z)-enynes.
As shown in Scheme 2, a myriad of terminal and
non-terminal alkynes were then examined for the
decarboxylative C–C coupling reactions with
propiolic acids. For example, the conversion of
terminal alkynes bearing different kinds of
carbocycles regioselectively delivered gem-1,3-
enynes (3ab, 3ae, 3je, 3ag) with the yield varying
from 54% to 75%. In addition to γ-methylated
propargyl alcohol 2d, the alkynes bearing a phenyl
Scheme 2. Scope of Alkynes for the Synthesis of 2-
Hydroxymethyl-1,3-enynes.
3
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10.1002/adsc.201901013
Advanced Synthesis & Catalysis
To confirm the regio- and stereoselectivity of this
protocol, we turned to use an unambiguous route to
prepare the representative compound (Scheme 3).
phenylacetylene exhibited poor reactivity toward 2e
under the standard conditions and that oxidative
addition of the acetylene C–H bond to the metal with
subsequent hydroalkynylation is unlikely to occur in
our catalytic system.[4c,15] While performing the
coupling reactions of phenylpropiolic acid (1a) with
terminal alkynes bearing different substituents (4, 5) in
the absence of a vicinal hydroxymethyl group (Scheme
4b), inferior regioselectivities were detected. The
result highlighted the importance of the hydroxy group
in assisting chelation to the rhodium intermediates.
Moreover, the coupling of the homologue of propargyl
alcohol to 1a provided gem-1,3-enyne 9 in 26% yield
with a relatively low regioselectivity (Scheme 4c),
suggesting that the chelation of the hydroxyl group and
the alkyne moiety to rhodium(I) may require an
appropriate steric distance.
Initially,
palladium-catalyzed
stereospecific
hydrostannation of 2-octyn-1-ol (2o) followed by
treatment with iodine[13a] produced the (E)-vinyl iodide
2o′ (81% overall yield), which is a known
compound.[13b] The Sonogashira cross-coupling
reaction was successfully achieved by treating the
intermediate with phenylacetylene (4),[14] leading to
the corresponding product in 73% yield. 1H NMR, 13C
NMR, and NOESY analyses of the product were in
agreement with those of 3ao, which was synthesized
by rhodium-catalyzed decarboxylative C–C coupling.
Scheme 3. An Unambiguous Route to Confirm the Structure.
Scheme 5. Proposed Catalytic Cycle.
Based on the depicted mechanistic evidence, we
propose that the 2-hydroxymethyl-1,3-enyne might be
formed by the catalytic mechanism illustrated in
Scheme 5. After generation of rhodium propiolate I,
decarboxylation proceeds readily to afford
unstabilized alkynylrhodium species II. The alkyne
moiety of propargyl alcohol 2 is activated by
electrophilic rhodium(I) to form π-complex III[16] with
the strong chelation assistance of the hydroxyl group,
which upon regioselective insertion of the alkyne into
the Rh–C bond provides vinylrhodium species IV.[5b]
This unusual regioselectivity of the carbometallation
step has been reported to be mainly attributed to steric
factors.[5b,8a] The successive protonation preferentially
produces target molecule (Z)-3 and regenerates the
active rhodium(I) catalyst. Note that the
stereochemical isomerization of intermediate IV to V
Scheme 4. Mechanistic Investigations.
To probe the mechanism of this rhodium-catalyzed
decarboxylative C–C coupling reaction, several
control experiments were carried out (Scheme 4). To
form as few isomers as possible, the incorporation of
ethynyl cyclopentanol (2e) to phenylacetylene (4)
instead of phenylpropiolic acid (1a) was investigated,
resulting in 3ae in 4% isolated yield along with (E)-
isomer 3ae′ in 13% isolated yield (Scheme 4a). The
low yield and regioselectivity indicated that
4
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10.1002/adsc.201901013
Advanced Synthesis & Catalysis
through a zwitterionic form[17] allows the production
of (E)-3, which was detected by 1H NMR.
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In summary, we have developed a rhodium(I)-
catalyzed regio- and stereoselective synthesis of 2-
hydroxymethyl-1,3-enynes from readily accessible
aryl-, alkyl-, and trimethylsilyl-substituted propiolic
acids and propargyl alcohols through decarboxylative
C–C bond formation. This research highlights the
employment of non-terminal alkynes for the coupling
reactions, which predominantly deliver a diversity of
(Z)-enynes. The subject of our ongoing studies will
focus on further elucidation of the Z-stereochemistry
and synthetic applications of this attractive approach.
Experimental Section
To an oven-dried sealed tube (20 mL) equipped with a
stirrer bar was added RhCl(PPh3)3 (13.9 mg, 0.015 mmol, 5
mol %), PPh3 (7.9 mg, 0.03 mmol, 10 mol %), K2CO3 (8.3
mg, 0.06 mmol, 20 mol %), phenylpropiolic acid 1a (43.8
mg, 0.3 mmol, 1.0 equiv.), and 1-(prop-1-yn-1-
yl)cyclobutan-1-ol 2a (49.6 mg, 0.45 mmol, 1.5 equiv.)
under ambient atmosphere. Dry toluene (1.5 mL, 0.2 M) was
then added. After the reaction mixture was stirred at room
temperature for 15 min, the resulting mixture was heated at
100 ℃ for 4 h. Upon completion, the reaction mixture was
concentrated under reduced pressure and the residue was
purified by silica gel chromatography (petroleum
ether/EtOAc) to obtain the desired product 3aa.
Acknowledgements
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[9] M. Nogami, K. Hirano, M. Kanai, C. Wang, T. Saito, K.
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This work was supported by the Natural Science Foundation of
Shandong Province (ZR2019MB003), the Key Research and
Development Program of Shandong Province (2018GGX109010),
the Natural Science Foundation of China (21602256, 81671395),
the CAMS Innovation Fund for Medical Sciences (CIFMS, 2017-
I2M-2-004), the State Key Laboratory of Natural and Biomimetic
Drugs (K20170205), and the High-Level Project Cultivation
Program of TSMC (2018GCC16).
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