n-Butyllithium-promoted regioselective elimination of vicinal bis-triflate having an adjacent ether oxygen

Article abstract of DOI:10.1016/j.tetlet.2017.09.036

Regioselective elimination of a vicinal bis-triflate having an adjacent ether oxygen functional group has been developed. Considered in the context of our studies of the regioselective elimination of vicinal dibromide, the key to the mechanism involves the electron-withdrawing inductive effect of the neighboring oxygen functional group. Aliphatic vinyl triflate was shown to be effective in Suzuki–Miyaura cross coupling compared with corresponding aliphatic vinyl bromide.

Full text of DOI:10.1016/j.tetlet.2017.09.036

Tetrahedron Letters xxx (2017) xxx–xxx
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Tetrahedron Letters
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n-Butyllithium-promoted regioselective elimination of vicinal
bis-triflate having an adjacent ether oxygen
b
b
b,
Noriki Kutsumura a,b, , Kota Shibuya , Hitoshi Yamaguchi , Takao Saito
⇑
⇑
a International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
b Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Regioselective elimination of a vicinal bis-triflate having an adjacent ether oxygen functional group has
been developed. Considered in the context of our studies of the regioselective elimination of vicinal
dibromide, the key to the mechanism involves the electron-withdrawing inductive effect of the neighbor-
ing oxygen functional group. Aliphatic vinyl triflate was shown to be effective in Suzuki–Miyaura cross
coupling compared with corresponding aliphatic vinyl bromide.
Received 11 August 2017
Revised 7 September 2017
Accepted 14 September 2017
Available online xxxx
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
Vinyl triflate
Regioselective elimination
Vicinal bis-triflate
Electron-withdrawing inductive effect
Neighboring-group effect
Introduction
problem to overcome.1e,i,7c,d,9 Additionally, other examples of
regio- and stereoselective synthesis of vinyl triflates are rarely used
Vinyl triflates are useful building blocks in a wide range of tran-
sition-metal catalyzed C–C bond formations, such as Suzuki–
Miyaura coupling, Sonogashira coupling, and Negishi coupling.1
In consequence of their high reactivity, vinyl triflates are often uti-
lized as the first choice of alternative substrates2 when bond-form-
ing reactions using vinyl bromides as the coupling partner do not
work well. In some cases, both vinyl triflates and vinyl bromides
can be used quite chemoselectively, depending on the synthetic
demands, by choosing a suitable catalyst.2a,3 In addition, vinyl
triflates, which display excellent elimination ability, have also
been utilized as precursors for elimination reactions,4 nucleophilic
substitution reactions,5 or fragmentation reactions.6 Therefore,
vinyl triflates have a great deal of potential in total synthesis of
natural products and modern drug discovery research.
Despite the usefulness of vinyl triflates in organic chemistry,
there are few effective versatile synthetic methods. The most pop-
ular synthetic routes are transformations from ketones through the
corresponding enolate intermediates1e,i,7 or from diols through the
geminal bis-triflate intermediate.1e,i,8 In these pathways, regio- and
stereocontrol of the double bond in vinyl triflates is a major
in complex molecules because they require harsh reaction
conditions.9b,10
Recently, we reported the synthesis of 2-bromo-1-alkenes
under mild basic conditions that used the DBU-promoted regiose-
lective HBr-elimination of vicinal dibromides having an adjacent
oxygen functional group.11 The key to the high yield and regiose-
lectivity of the HBr-elimination reaction was attributed to the elec-
tron-withdrawing inductive effect of the neighboring oxygen
substituent, which enhanced the acidity of the hydrogen at the
C2 position, along with the electron-withdrawing inductive effects
of both bromine atoms (Scheme 1, eq. 1).11a,e,h Based on this
research background, we envisioned regioselective synthesis of
vinyl triflates from vicinal bis-triflates having an adjacent oxygen
functional group. In the course of our work, we discovered the
curious reaction conditions that afforded 2-triflate-1-alkenes
(Scheme 1, eq. 2). Herein, we describe the results in detail.
Results and discussion
Based on our previous research results,11 we started our study
using a benzyl-protected bis-triflate 1a as a substrate and 1,8-diaz-
abicyclo[5.4.0]undec-7-ene (DBU) as a base (Table 1, Entries 1–5).
However, the DBU-promoted elimination resulted in unsatisfac-
tory results, particularly in terms of low selectivity of vinyl triflates
2a and 3a under the attempted conditions. Some other bases, such
⇑
Corresponding authors at: International Institute for Integrative Sleep Medicine
(WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
(N. Kutsumura).
E-mail addresses: kutsumura.noriki.gn@u.tsukuba.ac.jp (N. Kutsumura), tsaito@
rs.kagu.tus.ac.jp (T. Saito).
https://doi.org/10.1016/j.tetlet.2017.09.036
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kutsumura N., et al. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.09.036

2
N. Kutsumura et al. / Tetrahedron Letters xxx (2017) xxx–xxx
Previouswork
To confirm the generality of the regioselective synthesis of
2-triflate-1-alkenes 2, we examined the elimination reaction of
a variety of vicinal bis-triflates 1 under the optimal conditions
(Table 2). First, the reactions of the bis-triflates 1 having an adja-
cent substituted benzyloxy (1b and 1c), phenoxy (1d and 1e),
and alkoxy (1f and 1g) groups proceeded smoothly to afford
the corresponding 2-triflates 2b–g as the sole product (Entries
1–6), while the reaction of 1h was relatively slow (Entry 7). In
addition, the reaction of the silyl-protected 1i did not give the
desired vinyl triflate, although the reason is still under investiga-
tion (Entry 8). The regioselective elimination of internally syn-
and anti-bis-triflates 1j and 1k proceeded with high cis–trans
selectivity as a consequence of the trans elimination (Entries 9
and 10). Moreover, the reaction of cyclic vicinal bis-triflates 1l
and 1m also succeeded to give the expected 2l and 2m, respec-
tively (Entries 11 and 12). Finally, to confirm the importance of
the neighboring oxygen functional group’s participation, bis-tri-
flate 1n was examined (Entry 13). In comparison with the elim-
ination of 1d (Entry 3), it is clear that the adjacent oxygen
functional group is important in determining the elimination
reactivity and selectivity.
As mentioned above, both vinyl triflates and vinyl bromides can
be synthesized chemoselectively by choosing appropriate reaction
conditions.3 However, to our knowledge, there have been almost
no reports comparing the reactivity of aliphatic vinyl triflates with
that of aliphatic vinyl bromides.12 Thus, the competition experi-
ment in Suzuki–Miyaura cross coupling was studied using phenyl-
boronic acid (Scheme 2). An equimolar mixture of 2a, vinyl
bromide 5, and phenylboronic acid was treated in the presence
of 5 mol% of tetrakis(triphenylphosphine)palladium and 5 equiva-
lents of potassium carbonate in DMF/H2O (5/1) at room tempera-
weak base
Br
Br
Br
OR
OR
(1)
(2)
+
+
Br
OR
OR
H
acidity
enhancement
major
minor
minor
This work
OTf
nBuLi (1.5 equiv)
OTf
TfO
OR
TfO
OR
CH2Cl2
–78 ºC, 10 min
major
Scheme 1. Regioselective HBr-elimination of vicinal dibromide (previous work)
and this work.
as 1,4-diazabicyclo[2.2.2]octane (DABCO), NaOAc, K2CO3, and KOH,
were also examined, but these reactions showed complicated
results even at room temperature (Entries 6–9). This outcome
seemed to be due to the reaction sensitivity of 1a at ambient tem-
perature. Therefore, we next evaluated a variety of strong bases at
À78 °C for the elimination reaction of 1a. Interestingly, 2-triflate 2a
was obtained as a single product with 70% yield by using potas-
sium bis(trimethylsilyl)amide (KHMDS, in toluene solution) in
dichloromethane, while 2a, 3a, and the overreaction product,
alkyne 4a, were obtained by using lithium bis(trimethylsilyl)amide
(LHMDS, in THF solution) in the same solvent (Entries 10 and 11).
In addition, when nBuLi in hexane solution was used in diethyl
ether, 2-triflate 2a was obtained in 51% yield together with 4a
(Entry 12). These results suggested that the solvent effect was
involved to a large degree of the elimination reactivity. Hence,
nBuLi-promoted eliminations of 1a in THF, toluene, or dichloro-
methane were carried out (Entries 13–15). As a result, the com-
pound 2a was solely produced when toluene or dichloromethane
was used as a solvent, whereas the reaction system in THF was
complicated. The difference of the reactivity and selectivity of the
elimination could be caused by the different degrees of association
and coordination of nBuLi in the solvent. Thus, we selected the
optimal conditions as shown in Entry 15.
ture. After 45 min, the reaction system afforded
5 and the
coupling product 6 in good yields along with the recovered 5, while
2a was completely consumed. This result implied that aliphatic
vinyl triflate 2 might be a better coupling substrate than aliphatic
vinyl bromide 5, without any side-reactions resulting from forma-
Table 1
Optimization of reaction conditions.
Entry
Base (X equiv)
Solv.
Temp. (°C)
Time (min)
Obtained Product Yield (%)
1
2
3
4
5
6
7
8
DBU (1.1)
DBU (1.1)
DBU (1.1)
DBU (1.1)
DMF
THF
RT
RT
RT
À40
À78
RT
RT
RT
10
10
60
60
60
15
25
20
10
10
10
10
10
10
10
66 (2a/3a = 1.0/2.7)d
71 (2a/3a = 1.0/1.3)d
77 (2a/3a = 1.0/2.0)d, 17 (1a)
57 (2a/3a = 1.0/2.4)d, 15 (1a)
25 (2a/3a = 1.0/2.1)d, 48 (1a)
Decomp.
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
DMF
DMF
CH2Cl2
CH2Cl2
Et2O
DBU (1.1)
DABCO (1.1)
NaOAc (2.0)
K2CO3 (2.0)
KOH (4.0)
Decomp.
Decomp.
Decomp.
70 (2a)
9
RT
10
11
12
13
14
15
KHMDS (1.5)a
LHMDS (1.5)b
nBuLi (1.5)c
nBuLi (1.5)c
nBuLi (1.5)c
nBuLi (1.5)c
À78
À78
À78
À78
À78
À78
18 (2a/3a = 1.3/1.0)d, 46 (4a)
51 (2a), 18 (4a)
THF
Toluene
CH2Cl2
44 (2a/3a = 1.0/1.1)d, 18 (1a), 16 (4a)
82 (2a)
94 (2a)
a
b
c
0.5 M in toluene solution.
1.3 M in THF solution.
1.6 M in hexane solution.
d
Ratio of 2a/3a was determined by 1H NMR.
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N. Kutsumura et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
Table 2
Regioselective elimination of vicinal bis-triflate 1.a
Entry
1
Bis-triflate 1
Obtained Product Yields (%)
85
87
2
3
85
58
83
4
5
6
7
76
54b
8
9
N.D.c
89d
10
11
84e
94
12f
13
60
5g
OTf
TfO
2n
3n
a
b
c
d
e
f
nBuLi (1.5 equiv, 1.6 M in hexane solution)/CH2Cl2, À78 °C, 10 min.
1h was recovered (27%).
2i was not detected, and 1i was recovered (76%).
1-(Benzyloxy)hexane-2-one was obtained as a byproduct (9%).
2j was obtained as a byproduct (4%).
nBuLi (2.0 equiv, 1.6 M in hexane solution)/CH2Cl2, À78 °C, 20 min.
g
The ratio of 2n/3n was 2/3 determined by 1H NMR and 1n was recovered (80%).
tion of
p-allyl palladium complex by the transition metal under
OTf
these reaction conditions.11g,12,13
OBn
OTf
PhB(OH)2 (1 equiv)
K2CO3 (5 equiv)
Pd(PPh3)4 (5 mol%)
2a
OBn
OBn
(0%)
2a
Conclusion
Br
OBn
(86%)
Ph
DMF/H2O (5/1)
RT, 45 min
We have developed a new and unique approach to the synthesis
of vinyl triflate 2 in high yield and selectivity. The regioselective
elimination of vicinal bis-triflate 1 also involved the electron-with-
drawing inductive effect of the neighboring ether oxygen func-
tional group. These synthetic studies including our previous
research11 should be applicable to the total synthesis of natural
products and for use in modern drug-discovery research.
5
Br
OBn
5
6 (86%)
Scheme 2. Competition experiment in the Suzuki–Miyaura cross coupling.
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4
N. Kutsumura et al. / Tetrahedron Letters xxx (2017) xxx–xxx
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