Highly stereocontrolled synthesis of trans-enediynes via carbocupration of fluoroalkylated diynes

Article abstract of DOI:10.3762/bjoc.8.249

Treatment of readily prepared (Z)-6-benzyloxy-1,1,1,2-tetrafluoro-6-methyl- 2-hepten-4-yne with 1.5 equiv of LHMDS in -78 °C for 1 h gave the corresponding trifluoromethylated diyne in an excellent yield. This diyne was found to be a good substrate for th

Full text of DOI:10.3762/bjoc.8.249

Highly stereocontrolled synthesis of trans-enediynes
via carbocupration of fluoroalkylated diynes
Tsutomu Konno*, Misato Kishi and Takashi Ishihara
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 2207–2213.
Department of Chemistry and Materials Technology, Kyoto Institute of
Technology, Matsugasaki, Sakyo-ku, Kyoto 606-0962, Japan
doi:10.3762/bjoc.8.249
Received: 31 October 2012
Accepted: 05 December 2012
Published: 19 December 2012
Email:
Tsutomu Konno* - konno@chem.kit.ac.jp
* Corresponding author
This article is part of the Thematic Series "Carbometallation chemistry".
Guest Editor: I. Marek
Keywords:
carbocupration; carbometallation; diyne; enediyne; fluorine; highly
regioselective; highly stereoselective
© 2012 Konno et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Treatment of readily prepared (Z)-6-benzyloxy-1,1,1,2-tetrafluoro-6-methyl-2-hepten-4-yne with 1.5 equiv of LHMDS in −78 °C
for 1 h gave the corresponding trifluoromethylated diyne in an excellent yield. This diyne was found to be a good substrate for the
carbocupration with various higher-ordered cyanocuprates to give the corresponding vinylcuprates in a highly regio- and stereose-
lective manner. The in situ generated vinylcuprates could react very smoothly with an excess amount of iodine, the vinyl iodides
being obtained in high yields. Thus-obtained iodides underwent a very smooth Sonogashira cross-coupling reaction to afford
various trans-enediynes in high yields.
Introduction
trans-Enediynes (trans-hex-3-ene-1,5-diynes), as shown in building blocks because they are frequently utilized for the syn-
Figure 1, are well-recognized as one of the most important thesis of π-conjugated polymers, which have attracted much
attention in the fields of electronic and photonic materials
science [1-3].
While numerous synthetic approaches to non-fluorinated trans-
enediynes have been reported so far, there has been quite a
limited number studies on the preparation of fluoroalkylated
trans-enediynes [4-7], although the introduction of fluorine
atom(s) into organic molecules very often changes their phys-
ical as well as chemical characteristics significantly, resulting in
the discovery of new materials with unique physical properties
Figure 1: trans-Enediyne.
[8-14].
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Beilstein J. Org. Chem. 2012, 8, 2207–2213.
Scheme 1: Synthetic strategy for the preparation of trifluoromethylated diynes.
In this paper we report a convenient and efficient access to tri- of 3a with 1.5 equiv of potassium tert-butoxide (t-BuOK) in
fluoromethylated enediynes by the highly regio- and stereose- THF at room temperature for 2 h. Very surprisingly, the desired
lective carbocupration reaction of trifluoromethylated diyne trifluoromethylated diyne 4a was not detected at all and the
with various organocuprates (Scheme 1).
addition–elimination product 5a was obtained quantitatively.
Therefore, we examined the reaction conditions for the β-elimi-
nation of 3a in detail (Table 1). As shown in Table 1, entries 2
Results and Discussion
Our initial studies began with the preparation of trifluoro- and 3, the reactions with t-BuOK in various solvents, such as
methylated diyne derivatives [15-22]. Thus, treatment of 1,4-dioxane and ether, were found to be fruitless, leading to a
2,3,3,3-tetrafluoro-1-iodo-1-propene (1), which could be easily quantitative formation of 5a. Changing the base from t-BuOK
prepared from 2,2,3,3,3-pentafluoropropanol in three steps [23], to KOH brought about better results (Table 1, entries 4–6).
with 1.2 equiv of terminal alkynes 2 and 1.5 equiv of Et3N in Thus, the reaction with 1.5 equiv of KOH at the reflux tempera-
the presence of 5 mol % of Pd(OAc)2 and 10 mol % each of ture of THF produced the desired diyne 4a in ca. 10%, while no
PPh3 and CuI in DMF at room temperature for 24 h, gave the desired product was given at room temperature. On the other
corresponding Sonogashira cross-coupling products 3a–e in hand, a dramatic change could be observed when the amide
good to high yields [24-26] (Scheme 2).
bases were used. The use of lithium diisopropylamide (LDA) in
THF at −78 °C for 2 h resulted in a significant increase of the
yield from 10% to 46% (Table 1, entry 7). Switching LDA into
lithium hexamethyldisilazide (LHMDS) led to a further
improvement of the yield (Table 1, entry 8). Finally, the best
yield was obtained when the reaction was carried out in THF at
−78 °C for 1 h by using LHMDS. In this case the desired diyne
4a was generated in 74% 19F NMR yield as a sole product.
Unfortunately, 4a was found to be somewhat thermally
unstable, and a partial decomposition was observed in silica-gel
column chromatography, 4a being isolated in very low yield.
Additionally, such a partial decomposition of 4a was also
observed even when 4a was kept in a freezer.
With the thus-obtained optimum reaction conditions, we next
investigated the β-elimination reaction of various enynes as
described in Table 2. As shown in Table 2, entry 2, changing a
phenyl group into an anisyl group in R1 resulted in a significant
increase of the yield from 74% to a quantitative yield. In this
case, it was found that 4b was slightly thermally stable,
compared to 4a, while it could not be isolated in a pure form. In
the case of the enyne having an n-C6H13 group as R1, on the
other hand, the starting material was not completely consumed,
and an inseparable mixture of the desired diyne 4c and the
Scheme 2: Preparation of various enynes.
Subsequently, 3a was subjected to the usual β-elimination enyne 3c was given (Table 2, entry 3). In addition, the reaction
conditions according to the literature [23,27-29], i.e., treatment proceeded very sluggishly in the enyne having CH2OBn as R1,
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Beilstein J. Org. Chem. 2012, 8, 2207–2213.
Table 1: Investigation of the reaction conditions.
entry base
solvent
temp. (°C)
time (h)
yielda (% of 4a)
yielda (% of 5a)
recoverya (% of 3a)
1
2
3
4
5
6
7
8
9
t-BuOK
THF
rt
2
2
2
2
2
2
2
2
1
0
quant.
quant.
quant.
—
0
t-BuOK
t-BuOK
KOH
1,4-dioxane
Et2O
THF
rt
0
0
rt
0
0
rt
0
quant.
KOH
THF
reflux
reflux
−78
−78
−78
9
—
83
47
0
KOH
THF
10
46
69
74
—
LDA
THF
—
LHMDS
LHMDS
THF
—
0
THF
—
0
aDetermined by 19F NMR.
Table 2: β-Elimination of various enynes.
entry
R1
yielda (% of 4)
recoverya (/% of 3)
1
Ph (a)
74
0
2
p-MeOC6H4 (b)
n-C6H13 (c)
CH2OBn (d)
quant.
48
0
3b
4
35
13
3
quant.
(95)
5
CMe2OBn (e)
0
aDetermined by 19F NMR. Value in parentheses is of isolated yield. bCarried out for 24 h.
and neither 3d nor 4d could be obtained in high yields (Table 2, reaction with saturated aqueous NH4Cl, gave the corresponding
entry 4). Interestingly, the enyne 3e having a CMe2OBn group carbocupration product 5 in 46% yield as a sole product (it is
as R1 was found to be a good substrate, the desired diyne 4e well known that the carbocupration reaction of fluoroalkylated
being obtained quantitatively (Table 2, entry 5). Additionally, alkynes with cuprates proceeds in a highly cis-selective manner
4e was so thermally stable that it could be obtained in 95% [30,31]), together with a slight recovery of the starting material
isolated yield after the silica-gel column chromatography.
(Table 3, entry 1). In this case, the reaction proceeded in a
highly regio- and stereoselective manner and the other isomers
With the substrate 4e in hand, our interest was next directed 6–12 were not detected at all (Figure 2). It was especially note-
toward the carbocupration reaction of 4e. First of all, we worthy that only the triple bond possessing a CF3 group, not the
attempted the investigation of the reaction conditions for the triple bond having a CMe2OBn group, was subjected to the
carbocupration reaction of 4e, as described in Table 3. Thus, carbocupration reaction. As shown in Table 3, entry 2, raising
treatment of 4e with 1.2 equiv of higher-ordered cyanocuprate the reaction temperature from −78 to −45 °C led to a signifi-
(n-Bu)2CuLi·LiCN, which was prepared from CuCN and cant increase in the yield. We also examined the reaction with
2 equiv of n-BuLi, at −78 °C for 2 h, followed by quenching the the cuprate prepared from Grignard reagent, n-BuMgBr. As
2209

Beilstein J. Org. Chem. 2012, 8, 2207–2213.
Table 3: Investigation of the reaction conditions in carbocupration.
copper reagenta
(R22CuM·MCN)
entry
x (equiv)
temp. (°C)
time (h)
yieldb (% of 5)
recoveryb (% of 4e)
1
2
3
4
5
6
7
(n-Bu)2CuLi·LiCN
1.2
1.2
1.2
1.2
1.2
1.5
1.5
−78
−45
−45
−78
−78
−78
−78
2
1
1
1
2
1
2
46
61
38
44
44
85
57
7
0
0
3
0
0
0
(n-Bu)2CuLi·LiCN
(n-Bu)2CuMgBr·MgBrCN
(n-Bu)2CuMgBr·MgBrCN
(n-Bu)2CuMgBr·MgBrCN
(n-Bu)2CuMgBr·MgBrCN
(n-Bu)2CuMgBr·MgBrCN
aCopper reagents were prepared from 1 equiv of CuCN and 2 equiv of R2Li or R2MgBr. bDetermined by 19F NMR.
result, the desired product being obtained in 85% yield, though
the yield was somewhat eroded in the reaction for 2 h.
With the optimum reaction conditions in hand, we next investi-
gated the carbocupration reaction by using various copper
reagents. In all cases, iodine was employed as an electrophile
instead of aqueous NH4Cl. The results are summarised in
Table 4. As shown in Table 4, entries 1 and 2,
(n-Bu)2CuLi·LiCN and Me2CuLi·LiCN could participate in the
reaction to give the corresponding iodide 13a,b in good yields.
Furthermore, the cuprates prepared from alkyl Grignard
reagents, such as n-Bu, Me, and cyclohexylmagnesium bro-
mide, reacted smoothly (Table 4, entries 3–5). Switching the
cuprate from dialkylcuprate into diarylcuprate did not bring
about any influence on the yields at all (Table 4, entries 6
and 7).
A proposed reaction mechanism is outlined in Scheme 3. Based
on the accumulated studies on the chemistry of fluoroalkylated
alkynes, it appears possible that the copper reagent coordinates
to the triple bond proximate to the CF3 group (Int-A), rather
than the alternative one (Int-B), due to high reactivity of the
fluoroalkylated alkyne. Then, CuI adds oxidatively to the alkyne
to form the intermediate Int-C, not Int-D. Since a CF3 group
has a very strong electron-withdrawing ability, the
CF3Cα—CuIII bond may be stronger than CuIII—Cβ. (In the
hydrometalation and the carbometalation reaction of fluoroalky-
lated alkynes, the same regioselectivity was observed [32-35].)
Accordingly, a transfer of the R2 group on CuIII to the olefinic
Figure 2: Regio- and stereoisomers.
summarised in Table 3, entries 3–5, a significant decrease of the
yield was observed when the reaction was performed by using
1.2 equiv of cuprate. Very interestingly, the use of 1.5 equiv of
the higher-ordered cyanocuprate realized the most satisfactory
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Beilstein J. Org. Chem. 2012, 8, 2207–2213.
Table 4: Carbocupration with various cuprates.
copper reagenta
entry
x (equiv)
temp. (°C)
product
yieldb (% of 13)
(R22CuM·MCN)
1
2
3
4
5
6
7
(n-Bu)2CuLi·LiCN
1.2
1.2
1.5
1.5
1.5
1.5
1.5
−45
−45
−78
−78
−78
−78
−78
13a
13b
13a
13b
13c
13d
13e
54
55
60
59
44
55
49
Me2CuLi·LiCN
(n-Bu)2CuMgBr·MgBrCN
Me2CuMgBr·MgBrCN
Cy2CuMgBr·MgBrCN
Ph2CuMgBr·MgBrCN
(p-MeOC6H4)2CuMgBr·MgBrCN
aCopper reagents were prepared from 1 equiv of CuCN and 2 equiv of R2Li or R2MgBr. bIsolated yield.
Scheme 3: A proposed reaction mechanism.
carbon distal to a CF3 group may take place preferably, with Finally, we attempted the Sonogashira cross-coupling reaction
vinylcopper intermediate Int-E, not Int-F, being produced of the obtained iodide 13a (Scheme 4). Thus, treatment of 13a
exclusively. As a result, vinyl iodide 13 can be given in a highly with 1.2 equiv of terminal alkynes and 40 equiv of Et3N in the
regio- and stereoselective manner.
presence of 10 mol % each of Pd(PPh3)4 and CuI in THF at
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Beilstein J. Org. Chem. 2012, 8, 2207–2213.
Scheme 4: Synthesis of trans-enediynes. aDetermind by 19F NMR. Values in parentheses are of isolated yield.
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Supporting Information File 1
Experimental, characterization details, and NMR spectra of
synthesized compounds, 4e, 13a–e, and 14a–c.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-249-S1.pdf]
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