Indium Tribromide Catalyzed Coupling Reaction of Enol Ethers with Silyl Ketene Imines toward the Synthesis of β,γ-Unsaturated Nitriles

Article abstract of DOI:10.1002/chem.201503414

Herein, a coupling reaction of enol ethers with silyl ketene imines in the presence of catalytic amounts of InBr₃ and Me₃SiBr is described. Kinetic studies have revealed that an indium catalyst and Me₃SiBr accelerated the coupling process and the regeneration of the catalyst, respectively. Various types of enol ethers and silyl ketene imines are applicable. In addition, a formal synthesis of verapamil was achieved by using this novel coupling reaction. Let's get together: The coupling reaction of enol ethers with silyl ketene imines in the presence of a catalytic amount of InBr₃ and Me₃SiBr is shown (see scheme, TBS=tert-butyl dimethylsilyl). Kinetic studies revealed that an indium salt and Me₃SiBr accelerated the coupling process and the regeneration of the catalyst. Several enol ethers and silyl ketene imines are applicable to this strategy.

Full text of DOI:10.1002/chem.201503414

DOI: 10.1002/chem.201503414
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&
Coupling Reactions
Indium Tribromide Catalyzed Coupling Reaction of Enol Ethers
with Silyl Ketene Imines toward the Synthesis of b,g-Unsaturated
Nitriles
Yoshihiro Nishimoto,*[a, b] Takashi Nishimura,[a] and Makoto Yasuda*[a]
Abstract: Herein, a coupling reaction of enol ethers with
silyl ketene imines in the presence of catalytic amounts of
InBr3 and Me3SiBr is described. Kinetic studies have revealed
that an indium catalyst and Me3SiBr accelerated the coupling
process and the regeneration of the catalyst, respectively.
Various types of enol ethers and silyl ketene imines are ap-
plicable. In addition, a formal synthesis of verapamil was
achieved by using this novel coupling reaction.
nucleophiles includes only alkyl- and arylmetals.[1] Recently,
Heck reactions and direct CÀO/CÀH cross-coupling reactions
by using heteroarenes and carbonyl compounds have been ac-
complished.[2,3] However, the scope of suitable nucleophiles re-
mains narrow compared with that of traditional cross-coupling
reactions by using organic halides. In particular, a cyanoalkyl
anion that could be used to construct nitrile moieties would
be desirable for the synthesis of valuable b,g-unsaturated ni-
triles and a-aryl nitriles, which are the frameworks for many
natural products and biologically active agents.[4,5] As far as we
could ascertain, the reactions of enol and arenol derivatives
with a cyanoalkyl anion have never been established.[6] The
use of cyanoalkyl anions in general transition-metal-catalyzed
coupling reactions is difficult because the reductive elimination
of a coupling product from a cyanoalkyl–transition metal inter-
mediate is slowed down by the electron-withdrawing effect of
the cyano group.[7]
Introduction
Cross-coupling reactions by using enol and arenol derivatives
toward the transformation of C(sp2)ÀOR bonds have attracted
rising attention in the field of organic synthesis due to their
low toxicity and readily availability in contrast to commonly
used organic halides (Scheme 1). Although many types of tran-
sition-metal-catalyzed coupling reactions by using enol and
arenol derivatives have been reported, the employable list of
Recently, we developed a GaBr3-catalyzed coupling reaction
between enol ethers and ketene silyl acetals.[8] This coupling
reaction proceeds through an addition–elimination mechanism
that includes anti carbogallation among GaBr3, an enol ether,
and a ketene silyl acetal in sharp contrast to a transition-metal-
catalyzed coupling through oxidative addition/reductive elimi-
nation. Therefore, we envisioned applying a cyanoalkyl nucleo-
phile to this reaction system. Herein, we report the InBr3-cata-
lyzed coupling reaction of enol ethers with silyl ketene imines
(SKIs) as cyanoalkyl nucleophiles by using Me3SiBr as a co-cata-
lyst toward the synthesis of b,g-unsaturated nitriles. Silyl
ketene imines are the most useful cyanoalkyl anion equiva-
lents.[9] SKIs have a higher chemoselectivity than the corre-
sponding a-lithiated nitriles, and various types of reactions
have been developed, which use a SKI as a nucleophile. How-
ever, the application to carbonÀcarbon bond forming reactions
has been limited to aldol and Mannich reactions and there
have been no reports of coupling reactions, which use SKIs,
which are thought to be too unstable to tolerate harsh condi-
tions. Recently reactions involving trifluoromethylation with
the reagent of Togni[10] and a [3+2] annulation with enol diazo-
Scheme 1. Cross-coupling reaction by using enol and arenol derivatives
toward the transformation of C(sp2)ÀOR bonds (mt=metal).
[a] Dr. Y. Nishimoto, T. Nishimura, Prof. Dr. M. Yasuda
Department of Applied Chemistry
Graduate School of Engineering, Osaka University
Suita, Osaka 565-0871 (Japan)
E-mail: nishimoto@chem.eng.osaka-u.ac.jp
yasuda@chem.eng.osaka-u.ac.jp
[b] Dr. Y. Nishimoto
Frontier Research Base for Young Researchers
Graduate School of Engineering, Osaka University
Suita, Osaka 565-0871 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503414.
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acetates have been achieved.[11] In our reaction system, the
moderate Lewis acidity of InBr3 created mild coupling reaction
conditions that allowed the use of SKIs.
Table 1. Optimization of the reaction conditions[a]
Entry
Catalyst
Additive
Yield [%][b]
Results and Discussion
1
2
GaBr3
InBr3
none
none
21
29
Optimization of the reaction conditions
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
GaBr3
InBr3
none
InBr3
InBr3
InBr3
InBr3
InBr3
InCl3
InI3
In(OTf)3
BF3·OEt2
AlCl3
ZnBr2
Sc(OTf)3
Me3SiBr
Me3SiBr
Me3SiBr
Me3SiCl
Me3SiI
64
Initially, we investigated the effect of the catalysts in the reac-
tion between butyl vinyl ether (1a) and tert-butyldimethylsilyl
phenylmethylketene imine (2a) (Table 1). GaBr3 and InBr3 af-
forded the corresponding b,g-unsaturated nitrile 3aa in only
21 and 29% yield, respectively, although these catalysts are ef-
fective in coupling reactions using ketene silyl acetals[8]
(Table 1, entries 1 and 2). Interestingly, the addition of
20 mol% Me3SiBr accelerated the catalytic reaction, and partic-
ularly the combination of InBr3 with Me3SiBr afforded an excel-
lent yield of compound 3aa (Table 1, entries 3 and 4). The use
of Me3SiBr alone did not accelerate the coupling reaction,
which indicated the importance of the combination of InBr3
with Me3SiBr (Table 1, entry 5). Me3SiCl and Me3SiI were less ef-
fective than Me3SiBr (Table 1, entries 6 and 7). The use of
Et3SiBr instead of Me3SiBr led to a somewhat lower yield
(Table 1, entry 8). The addition of tBuMe2SiBr did not improve
the yield (Table 1, entry 9). When employing Bu4NBr as a Br
anion source, no product was observed (Table 1, entry 10).
Among other indium halides examined, InCl3 and InI3 had
lower catalytic effects than InBr3 (Table 1, entries 11 and 12).
In(OTf)3 (Tf=triflate) was ineffective for this reaction (Table 1,
entry 13) and representative Lewis acids such as BF3·OEt2, AlCl3,
ZnBr2, and Sc(OTf)3 showed no catalytic ability (Table 1, en-
tries 14–17).
82 (81)[c]
0
76
68
68
32
0
80
50
2
2
2
11
0
Et3SiBr
tBuMe2SiBr
Bu4NBr
Me3SiBr
Me3SiBr
Me3SiBr
Me3SiBr
Me3SiBr
Me3SiBr
Me3SiBr
[a] Compound 1a (1 mmol), compound 2a (1.5 mmol), catalyst
(0.1 mmol), additive (0.2 mmol), ClCH2CH2Cl (2 mL), 808C, 2 h. [b] Yields
were determined by GC. [c] Yield of the isolated product.
ditions to afford product 3aa, TBSBr, and InBr(OBu)2 (5). On the
other hand, the coupling reaction in the presence of Me3SiBr
was completed to give product 3aa in 95% yield and afforded
TBSBr, TBSOBu, and Me3SiOBu as byproducts [Eq. (3)]. There-
fore, InBr2(OBu) (4) was an effective catalyst under heating con-
ditions, and Me3SiBr was the co-catalyst that led to a regenera-
tion of compound 4 through transmetallation between InBr(O-
Bu)2 (5) and TBSBr [Eq. (4)].
Effect of Me3SiBr
An observation of the byproducts in the control ex-
periments was conducted to gain insight into the
effect of Me3SiBr.[12] When the coupling reaction at
room temperature was catalyzed by 20 mol% of
InBr3 in the absence of Me3SiBr, product 3aa was not
obtained beyond the amount of the loaded InBr3,
which meant that the process was not catalytic. In
fact, the reaction at room temperature afforded prod-
uct 3aa in only 24% yield [Eq. (1)]. Under heating
conditions, product 3aa was obtained in 44% yield,
which was as much as twice the amount of the
loaded InBr3 [Eq. (2)]. These results suggested that
the coupling occurred without Me3SiBr. What is more
remarkable is that TBSOBu (TBS=tert-butyl dimethyl-
silyl) was not observed and TBSBr was produced in
yields equal to product 3aa in both reactions given
in Equations (1) and (2). Therefore, InBr2(OBu) (4) and
InBr(OBu)2 (5) would be generated and InBr3 was not
regenerate. Obtaining product 3aa in a yield that
was twice the amount of loaded InBr3 in the reaction
given in Equation (2) suggested that InBr2(OBu) (4)
accelerated the coupling reaction under heating con-
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Kinetic study
yield (0.051m) within one minute. Shortly thereafter, the reac-
tion rate was drastically decreased (condition a, Figure 1A).
When increasing the loading amount of InBr3 to 15 mol%
(0.038m) (condition b, Figure 1A ), the reaction rapidly gave
product 3aa in 37% yield (0.089m), and then the rate was
slowed similar to the use of condition a. It is noteworthy that
To determine the turnover-limiting step, the reaction progress
was monitored. Under standard conditions (condition a: [1a]=
0.25m, [2a]=0.38m, [InBr3]=0.025m (10 mol%), [Me3SiBr]=
0.05m (20 mol%), 808C), product 3aa was produced in 20%
Figure 1. Reaction profiles. Conditions a (standard conditions): [1a]=0.25m, [2a]=0.38m, InBr3 (10 mol%, 0.025m), Me3SiBr (20 mol%, 0.05m). Conditions b:
InBr3 (15 mol%, 0.038m), Me3SiBr (20 mol%, 0.05m). Conditions c: InBr3 (10 mol%, 0.025m) without Me3SiBr. Conditions d: Conditions a + product 3aa
(10 mol%, 0.025m). Conditions e: Condition a + TBSOBu (10 mol%, 0.025m). Conditions f: Me3SiBr (30 mol%, 0.075m). Conditions g: Me3SiBr (10 mol%,
0.025m). Conditions h: Without Me3SiBr, 208C. Conditions i: Me3SiBr (20 mol%, 0.05m), 208C. Yields were determined by GC analysis.
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the reaction rates for both conditions a and b were reduced
after product 3aa was obtained in yields that were as much as
twice the amount of the loaded InBr3 in a very short time
(cutout of Figure 1A). In the absence of Me3SiBr, the reaction
by using an amount of 10 mol% of InBr3 furnished product
3aa in 19% yield (0.045m) within one minute, although the
catalytic coupling hardly proceeded (condition c, Figure 1A).
This reaction profile of condition c is consistent with the reac-
tion given in Equation (2). In order to reveal the cause of the
drastic reduction in the reaction rate, we evaluated the effects
of product 3aa and of the side product TBSOBu (Figure 1B).
The addition of these compounds had no influence on the re-
action profile (conditions e and d, Figure 1B), so they did not
disturb the catalytic cycle. Next, we investigated the influence
of Me3SiBr on the reaction rate (Figure 1C). The rate of the
coupling reaction depended greatly on the concentration of
Me3SiBr, although the profiles showing that the rate was ex-
tremely decreased in the early stage of the reaction were un-
changed. In fact, an elevation of the reaction rate after one
minute was observed as the concentration of Me3SiBr was in-
creased (conditions a, c, f, and g, Figure 1C). The effect of tem-
perature is shown in Figure 1D. At 208C, both the coupling re-
actions in the presence and absence of Me3SiBr showed nearly
identical kinetic profiles (conditions h and i, Figure 1D). Prod-
uct 3aa was quickly obtained in a yield almost equal to the
amount of loaded InBr3, and then the reaction was almost
static (cutout of Figure 1D). Therefore, the regeneration of the
catalyst mediated by Me3SiBr did not occur at room tempera-
ture. The reaction yields at 208C were half that at 808C in the
absence of Me3SiBr (conditions c and h, Figure 1D). These re-
sults were consistent with the reactions given in Equations (1)
and (2). Finally, the influence of the substrates, that is, enol
ether 1a and SKI 2a, on the reaction rate was investigated
(Figure 2). The increase in the concentrations of the enol ether
1a and the SKI 2a reduced the reaction rate. Therefore, Fig-
ures 1 and 2 suggested that the regeneration of the catalyst
by Me3SiBr is the turnover-limiting step, and substrates 1a and
2a disturbs this step.
Figure 2. Reaction profiles. [1a]=0.1–0.36m, [2a]=0.15–0.4m, InBr3
(10 mol%, 0.02m), Me3SiBr (20 mol%, 0.04m), 808C.
Proposed reaction mechanism
Based on the kinetic studies and the control experiments, we
can propose a plausible mechanism for the coupling reaction
between vinyl ether 1 and the SKIs 2 (Schemes 2 and 3). In the
present reaction, InBr3 accelerates the coupling reaction at the
initial stage (Scheme 2), and In(OR1)Br2 works as a catalyst in
the catalytic cycle (Scheme 3). First, the double bond of com-
pound 1 coordinates to InBr3 to form complex 6 (Scheme 2A ).
Then, a regioselective carboindation by the nucleophilic attack
of compound 2 to complex 6 from the opposite side of InBr3
affords the alkylindium intermediate 7 and TBSBr (Scheme 2B),
which is supported by the fact that carboindation reactions of
alkynes and alkenes by using ketene silyl acetals usually occurs
in an anti-addition fashion.[13–15] This regioselectivity is due to
the stabilization of a positive charge by the OR1 group in the
transition state 8. A syn elimination of InBr2 and the OR1
groups from the alkylindium 7 occurs to furnish the b,g-unsa-
Scheme 2. Plausible mechanism for the initial reaction of vinyl ethers 1 with
the SKIs 2.
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Investigation of the scope of the SKIs and the enol ethers
With optimized conditions by using InBr3 and Me3SiBr, the
scope and limitations of the SKIs 2 was investigated (Table 2).
Various alkyl,aryl-substituted SKIs were applicable to this reac-
tion system. SKIs bearing electron-donating and -withdrawing
groups on the aryl moieties smoothly afforded the correspond-
ing products 3ab, 3ac, 3ad, and 3ae (Table 2, entries 1–4).
The reaction by using the mesityl-substituted SKI 2 f did not
occur due to considerable steric hindrance (Table 2, entry 5).
On the other hand, the bulky alkyl-substituted SKI 2g gave the
product 3ag in 71% yield (Table 2, entry 6). The heteroaryl-
substituted SKIs 2h and 2i were found to be applicable nu-
cleophiles (Table 2, entries 7 and 8).[17] The diphenyl-substituted
SKI 2j also reacted with compound 1a to furnish the product
Scheme 3. Plausible catalytic cycle for the coupling reaction of enol ethers
1 with the SKIs 2.
turated nitrile 3 and In(OR1)Br2 (4) (Scheme 2C).[16] The pro-
posed anti addition/syn elimination is supported by the D-la-
beled experiment shown in Equation (5); the E isomer of the
deuterated phenyl vinyl ether [D]1b reacted with the SKI 2a in
the presence of InBr3 and Me3SiBr to exclusively furnish the (E)-
b,g-unsaturated nitrile [D]3aa with the retention of the stereo-
chemical configuration of compound [D]1b. This result would
suggest that the coupling reaction by using a vinyl ether
occurs stereospecifically. At room temperature, the regenera-
tion of InBr3 by the transmetallation between In(OR1)Br2 (4)
and TBSBr would not occur even in the presence of Me3SiBr,
and In(OR1)Br2 has no catalytic ability. Therefore, the coupling
reaction would terminate under non-heating conditions
(Figure 1D, conditions h and i). Under heating conditions,
In(OR1)Br2 (4) works as a catalyst to complete the catalytic
cycle in the presence of Me3SiBr (Scheme 3). As in the case of
the initial reaction, anti carboindation followed by syn elimina-
tion among In(OR1)Br2 (4), vinyl ethers 1, and the SKIs 2 takes
place to afford product 3, TBSBr, and In(OR1)2Br (5). The trans-
metallation between In(OR1)2Br (5) and Me3SiBr regenerates
In(OR1)Br2 (4) with the production of Me3SiOBu. The anion ex-
change between TBSBr and Me3SiOBu furnishes TBSOBu and
Me3SiBr, which has actually been confirmed [Eq. (6)]. The kinet-
ic studies suggest that the catalyst regeneration is the turn-
over-limiting step. The subdued effect of bulky bromosilanes
such as Et3SiBr and TBSBr (Table 1, entries 8 and 9) is due to
the interference of the transmetallation between In(OR1)2Br (5)
and bromosilane by the steric hindrance. The vinyl ethers
1 and the SKIs 2 coordinate to In(OR1)2Br (5) to disturb the in-
teraction of compound 5 with Me3SiBr, which would be the
cause of the inhibition effect of compounds 1 and 2 shown in
Figure 2.
Table 2. Scope of the silyl ketene imines.[a,b]
Entry
SKI 2
Product 3
Yield [%][c]
1
2
3
4
X=Me (2b)
3ab
3ac
3ad
3ae
92
73
89
59
X=OMe (2c)
X=Cl (2d)
X=F (2e)
5
0
6
7
71
56[c]
8
66
9
40[d]
85
10
11
86
12
68
[a] Compound 1a (1 mmol), compound 2 (1.5 mmol), InBr3 (0.1 mmol),
Me3SiBr (0.2 mmol), ClCH2CH2Cl (2 mL), 808C, 2 h. [b] Yields of the isolated
products were shown. [c] Yield determined by 1H NMR analysis.
[d] Me3SiBr (0.05 mmol).
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3aj, although the yield was moderate (Table 2, entry 9). The di-
alkyl-substituted SKIs 3ak and 3al were also suitable for this
reaction system (Table 2, entries 10 and 11). The a-silylated SKI
2m effectively afforded the corresponding a-cyanoallylsilane
3am (Table 2, entry 12).
Applicable a-substituted enol ethers are shown in Table 3.
The reaction of the a-methyl enol ether 1c with the SKI 2a
smoothly proceeded to give the corresponding product 3ca in
Table 3. Reactions of a-substituted enol ethers.[a]
Scheme 4. Proposed anti-addition/anti-elimination mechanism for reaction
of 1,2-dihydrofuran (1 f).
11 because of the large degree of steric repulsion between the
R1 and Nu groups (Nu=nucleophile) in the transition state of
anti elimination (Scheme 5A).[18] In the case of the Z-enol ether,
the steric repulsion between the R1 and Nu groups on the alky-
lindium intermediate disturbs the syn-elimination orientation
12 so that the Z product, generated through the anti-elimina-
tion transition state 13, is the major result (Scheme 5B).
Entry
1
Enol Ether 1
Product 3
Yield [%][b]
78
2
3
57
60
[a] Compound 1 (1 mmol), compound 2a (1.5 mmol), InBr3 (0.1 mmol),
Me3SiBr (0.2 mmol), ClCH2CH2Cl (2 mL), 808C, 2 h. [b] Yields of the isolated
products were shown.
78% yield (Table 3, entry 1). The primary alkyl-substituted enol
ether 1d was also found to be a suitable substrate (Table 3,
entry 2). The enyne ether 1e effectively reacted with the SKI
2a to produce ester 3ea in 60% yield (Table 3, entry 3).
Next, the coupling reaction of b-substituted enol
ethers was investigated. Unexpectedly, the reaction
of a (Z)-cyclic enol ether, that is, 1,2-dihydrofuran
(1 f), with the SKI 2a exclusively produced the E
alkene 3 fa with an inversion of the steric configura-
tion (Scheme 4A). This stereoselectivity was ex-
plained by an anti-addition/anti-elimination mecha-
nism (Scheme 4B). An anti-carboindation reaction
among InBr3, compound 1 f, and the SKI 2a afforded
the corresponding alkylindium 9, and then no syn
but anti elimination from compound 9 occurred due
to the rigid cyclic structure of compound 9.
As with the reaction of the vinyl ether [D]1b illus-
trated in Equation (5), the reaction of the (E)-acyclic
enol ether 1g only afforded the (E)-b,g-unsaturated
nitrile 3ga in 62% yield with the retention of the ste-
reochemistry [Eq. (7)]. On the other hand, the (Z)-acy-
clic enol ether 1g gave a mixture of (E)- and (Z)-3ga
in 50% yield [Eq. (8)]. The stereoselectivity of the re-
actions given in Equations (7) and (8) were a result of
the steric repulsion on the elimination step. In the
case of an E-enol ether, the syn-elimination structure
Scheme 5. Explanation for the stereoselectivity of reactions of acyclic b-substituted enol
10 is preferred over the anti-elimination orientation ethers.
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Application to the formal synthesis of verapamil
ies have been conducted, and the following conclusions con-
cerning the reaction mechanism have been revealed:
We applied this methodology to the formal synthesis of vera-
pamil (14), which is one of the antiarrhythmic agents
(Scheme 6).[7b,19,20] The alkylation of commercially available 3,4-
dimethoxyphenylnitrile (15) with isopropylbromide and NaH
led to nitrile 16. Nitrile 16 was transformed to the SKI 2n
through the conventional method with lithium diisopropyl-
amide and TBSCl. The InBr3-catalyzed coupling of the SKI 2n
with enol ether 1a under optimized conditions afforded the
b,g-unsaturated nitrile 17, which is the key intermediate of the
total synthesis of verapamil (14).
1) In(OR1)Br2 is the catalyst in the catalytic cycle, rather than
InBr3.
2) Me3SiBr works as a co-catalyst to regenerate In(OR1)Br2.
Experimental Section
General procedure for the coupling reaction of an enol
ether with a ketene silyl acetal (Table 1, entry 4)
To a suspended solution of InBr3 (0.1 mmol, 0.038 g), silyl ketene
imine 2a (1.5 mmol, 0.366 g), and trimethylsilyl bromide (0.2 mmol,
0.033 g) was added butyl vinyl ether (1a) (1.0 mmol, 0.102 g). The
mixture was stirred at 808C for 2 h and then the reaction was
quenched by the addition of 1m aqueous HCl solution. The mix-
ture was extracted with diethyl ether. The collected organic layer
was dried over MgSO4. The solvent was removed under reduced
pressure to afford the crude product. The crude product was puri-
fied by column chromatography (hexane/ethyl acetate=96:4) to
give the desired product (0.13 g, 81%).
Acknowledgements
This work was supported by Grants-in-Aid for Scientific Re-
search of the Ministry of Education, Culture, Sports, Science,
and Technology (Japan). We thank the Tonen General Sekiyu
Research and Development Encouragement Foundation and
the Tokuyama Science Foundation for financial support. Y.N. ac-
knowledges support from the Frontier Research Base for
Global Young Researchers, Osaka University, on the Program of
MEXT.
Scheme 6. Formal synthesis of verapamil (14). [a] Compound 15, isopropyl
bromide, NaH, 81%; [b] lithium diisopropylamide, TBSCl, 54%; [c] compound
1a (1 mmol), compound 17 (1.5 mmol), InBr3 (0.1 mmol), Me3SiBr (0.2 mmol),
ClCH2CH2Cl (2 mL), 808C, 2 h.
Keywords: cross-coupling · enol ethers · indium · silicon · silyl
ketene imines
Conclusion
We accomplished an InBr3-catalyzed coupling reaction of enol
ethers with silyl ketene imines to establish a novel synthetic
method for b,g-unsaturated nitriles. The combination of InBr3
with Me3SiBr was found to be the most suitable catalyst. Vari-
ous types of alkyl,aryl-, dialkyl-, and diaryl-substituted silyl
ketene imines were applicable to this reaction system. Hetero-
aryl groups were compatible with the reaction conditions so
that silyl ketene imines with indolyl and thiophenyl groups
smoothly afforded the desired products. With regard to the
scope of enol ethers, not only vinyl ether but also substituted
enol ethers smoothly reacted with silyl ketene imines. Finally,
we demonstrated the application of this novel synthetic
method to a formal synthesis of verapamil.
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