Electroreductive radical cyclization of ethyl 2-bromo-3-allyloxy- and -3-(propargyloxy)propanoates catalyzed by (tetramethylcyclam)nickel(I) electrogenerated at carbon cathodes in dimethylformamide

Article abstract of DOI:10.1002/ejoc.200500478

Reductive intramolecular cyclization of ethyl 2-bromo-3-(3′,4′- methylenedioxyphenyl)-3-(propargyloxy)propanoate (1) and ethyl 3-allyloxy-2-bromo-3-(3′,4′-dimethoxyphenyl)-propanoate (2) promoted by (1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane)nickel(I), [Ni(tmc)]⁺, electrogenerated at glassy-carbon cathodes in dimethylformamide containing tetraalkylammonium salts, has been investigated. Cyclic voltammograms for reduction of [Ni(tmc)]²⁺ in the presence of 1 and 2 reveal that [Ni(tmc)]⁺ catalytically reduces these two compounds at potentials significantly more positive than those required for direct reduction of the bromo esters. During controlled-potential electrolyses of solutions of [Ni(tmc)]²⁺ in the presence of 1 and 2, catalytic reduction of each substrate proceeds by one-electron cleavage of the carbon-bromine bond to form a radical intermediate that undergoes cyclization to afford, respectively, ethyl 2-(3′,4′-methylenedioxyphenyl)-4- methylenetetrahydrofuran-3-carboxylate (3) and ethyl 2-(3′,4′- dimethoxyphenyl)-4-methyltetrahydrofuran-3-carboxylate (6). A mechanistic Scheme is proposed to account for the formation of each major product. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500478

FULL PAPER
Electroreductive Radical Cyclization of Ethyl 2-Bromo-3-allyloxy- and
-3-(propargyloxy)propanoates Catalyzed by (Tetramethylcyclam)nickel(
I
)
Electrogenerated at Carbon Cathodes in Dimethylformamide
Ana P. Esteves,[a] Danielle M. Goken,[b] Lee J. Klein,[b] Luis F. M. Leite,[a]
Maria J. Medeiros,[a] and Dennis G. Peters*[b]
Keywords: Electroreduction / Intramolecular cyclization / Redox catalysis / (Tetramethylcyclam)nickel(i) / Bromo propar-
gyloxy ester / Bromo allyloxy ester
Reductive intramolecular cyclization of ethyl 2-bromo-3-
(3Ј,4Ј-methylenedioxyphenyl)-3-(propargyloxy)propanoate
(1) and ethyl 3-allyloxy-2-bromo-3-(3Ј,4Ј-dimethoxyphenyl)-
propanoate (2) promoted by (1,4,8,11-tetramethyl-1,4,8,11-
esters. During controlled-potential electrolyses of solutions of
[Ni(tmc)]2+ in the presence of 1 and 2, catalytic reduction of
each substrate proceeds by one-electron cleavage of the car-
bon–bromine bond to form a radical intermediate that un-
dergoes cyclization to afford, respectively, ethyl 2-(3Ј,4Ј-
tetraazacyclotetradecane)nickel(I
), [Ni(tmc)]+, electrogener-
ated at glassy-carbon cathodes in dimethylformamide con- methylenedioxyphenyl)-4-methylenetetrahydrofuran-3-car-
taining tetraalkylammonium salts, has been investigated.
boxylate (3) and ethyl 2-(3Ј,4Ј-dimethoxyphenyl)-4-methyl-
tetrahydrofuran-3-carboxylate (6). A mechanistic Scheme is
Cyclic voltammograms for reduction of [Ni(tmc)]2+ in the
presence of 1 and 2 reveal that [Ni(tmc)]+ catalytically re- proposed to account for the formation of each major product.
duces these two compounds at potentials significantly more
positive than those required for direct reduction of the bromo
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
less toxic and easier to remove by conventional work-up
procedures than Bu3SnH. In addition, 1-ethylpiperidinium
hypophosphite and hypophosphorous acid can serve as ef-
fective reducing agents for organic halides.[8,9] For processes
involving radicals, a recent advance has been the introduc-
tion of solid-phase organic synthesis,[10–12] for which the
radical precursor is attached to a resin and the Bu3SnH
used in the reaction is removed by simple washing of the
resin after the intramolecular cyclization is complete; thus,
the desired product can be obtained easily and in a highly
pure state.
Another convenient way to initiate radical reactions is to
employ a nickel(i) complex as an electron-transfer media-
tor.[13] Reports pertaining to electrogenerated nickel(i) spe-
cies as catalysts for the reductive radical cyclization of vari-
ous organic halides,[14] bromoacetals possessing electron-
deficient olefinic moieties,[15] and 2-haloaryl ethers contain-
ing unsaturated side chains[16] have demonstrated that the
electrochemical method is an excellent alternative to the use
of organometallic reagents. Reductive intramolecular cycli-
zation of 6-iodo- and 6-bromo-1-phenyl-1-hexyne, cata-
lyzed by electrogenerated (salen)nickel(i), affords benzyl-
idenecyclopentane in 84–95% yield;[17] (salen)nickel(i)-cata-
lyzed reduction of 6-bromo-1-hexene involves homolytic
scission of the carbon–bromine bond to give the 5-hexen-1-
yl radical which cyclizes intramolecularly to form methylcy-
clopentane as well as dimeric species arising from coupling
of both cyclic and acyclic radicals.[18] In other investi-
Introduction
Carbon–carbon bond formation by radical cyclization
has been an important tool in organic chemistry, especially
for the total synthesis of complex natural products.[1,2] Until
relatively recently, most synthetically useful radical-medi-
ated carbon–carbon bond-forming reactions have been car-
ried out by use of tri-n-butyltin hydride (Bu3SnH);[2–4] this
approach ordinarily requires an excess of Bu3SnH along
with a small amount of radical initiator, usually azobis(iso-
butyronitrile) (AIBN). For example, Roy and Adhikari[5]
utilized such a procedure for the highly stereocontrolled to-
tal synthesis of paulownin (a furofuran lignan), a key reac-
tion being the intramolecular radical cyclization of ethyl 2-
bromo-3-(3Ј,4Ј-methylenedioxyphenyl)-3-(propargyloxy)pro-
panoate (1) to afford ethyl 4-methylene-2-(3Ј,4Ј-methylene-
dioxyphenyl)tetrahydrofuran-3-carboxylate (3).
Unfortunately, triorganotin hydrides are toxic, and sepa-
ration of tin-containing residues from the desired products
is a time-consuming operation. As substitutes for Bu3SnH,
tri-n-butylgermanium hydride (Bu3GeH) was employed by
Dolbier et al.[6] and tris(trimethylsilyl)silane [(Me3Si)3SiH]
was used by Quirante and co-workers;[7] both reagents are
[a] Centro de Química, Universidade do Minho,
Largo do Paço, 4704-553 Braga, Portugal
[b] Department of Chemistry, Indiana University,
Bloomington, Indiana 47405, USA
E-mail: peters@indiana.edu
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DOI: 10.1002/ejoc.200500478
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Electroreductive Radical Cyclization Reactions
FULL PAPER
gations,[19–21] it was reported that electrogenerated nickel(i) panoate at a glassy-carbon electrode, we conclude that the
complexes catalyze the reduction of unsaturated halides to first sharp spike is associated with irreversible two-electron
yield alkenyl radicals, which react intramolecularly to give reductive cleavage of the carbon–bromine bond of 1 and 2,
carbocyclic products. Finally, the use of nickel(i) complexes and that the second, third, and fourth peaks are due to
as mediators for radical cyclization has been applied to the subsequent reduction of trans-3-(3Ј,4Ј-methylenedioxy-
synthesis of substituted tetrahydrofurans, for which the fur- phenyl)prop-2-enoate and trans-3-(3Ј,4Ј-dimethoxyphenyl)-
ofuran moiety is an important subunit in a wide range of
biologically active natural products.[22,23]
In this research we have examined the reductive intra-
molecular cyclizations of ethyl 2-bromo-3-(3Ј,4Ј-methylene-
dioxyphenyl)-3-(propargyloxy)propanoate (1) and ethyl 3-
allyloxy-2-bromo-3-(3Ј,4Ј-dimethoxyphenyl)propanoate (2)
that are promoted by electrogenerated (1,4,8,11-tet-
ramethyl-1,4,8,11-tetraazacyclotetradecane)nickel(i), [Ni-
(tmc)]+. Cyclic voltammetry has been used to ascertain if
bromo esters 1 and 2 undergo catalytic reduction as well as
to find the optimal conditions for preparative-scale con-
trolled-potential electrolyses. Experimental parameters,
such as the initial ratio of parent nickel(ii) complex to
bromo ester and the effects of an added proton donor
(1,1,1,3,3,3-hexafluoro-2-propanol) and of an added hydro-
gen atom donor (diphenylphosphane), have been investi-
gated to ascertain how these variables affect the yield and
identity of cyclic products.
Figure 1. Cyclic voltammograms recorded with a glassy-carbon
electrode (area = 0.077 cm2) at 100 mV s–1 in DMF containing
0.10 m TEABF4: (A) 1.0 mm 1; (B) 2.0 mm [Ni(tmc)]Br2; (C) 2.0 mm
[Ni(tmc)]Br2 and 20.0 mm 1. For curve A, the scan goes from +0.70
to –2.00 to +0.70 V; for curves B and C, the scan goes from +0.70
to –0.50 to +0.70 V.
Results and Discussion
Cyclic Voltammetric Behavior of Ethyl 2-Bromo-3-(3Ј,4Ј-
methylenedioxyphenyl)-3-(propargyloxy)propanoate (1) and
Ethyl 3-Allyloxy-2-bromo-3-(3Ј,4Ј-dimethoxyphenyl)-
propanoate (2)
Cyclic voltammograms recorded at a scan rate of 100 mV
s–1 for the direct reduction of 1 and 2 are shown in Figure 1
(curve A) and Figure 2 (curve A) , respectively, at a glassy-
carbon electrode in DMF containing 0.10 m TEABF4. Ex-
cept for the values of peak potentials, both compounds ex-
hibit the same cyclic voltammetric characteristics: an initial
irreversible sharp spike, followed by three irreversible peaks
at more negative potentials (the first actually appearing to
be an unresolved double peak, and the third being a shoul-
der preceding the final current rise). For compound 1, these
four voltammetric features have peak potentials of –0.69,
Figure 2. Cyclic voltammograms recorded with a glassy-carbon
electrode (area = 0.077 cm2) at 100 mV s–1 in DMF containing
0.10 m TEABF4: (A) 2.0 mm 2; (B) 2.0 mm [Ni(tmc)]Br2; (C) 2.0 mm
[Ni(tmc)]Br2 and 4.0 mm 2; (D) 2.0 mm [Ni(tmc)]Br2 and 20.0 mm
2. For curve A, the scan goes from +0.70 to –2.00 to +0.70 V; for
–1.11, –1.51, and –1.83 V, whereas for compound 2 the cor-
responding four peak potentials are –0.80, –1.22, –1.57
and –1.94 V. On the basis of our earlier detailed investiga-
tion[24] of the cyclic voltammetric behavior of ethyl 2-
bromo-3-(3Ј,4Ј-dimethoxyphenyl)-3-(propargyloxy)pro- curves B–D, the scan goes from +0.70 to –0.50 to +0.70 V.
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D. G. Peters et al.
FULL PAPER
prop-2-enoate, which arise, respectively, during the first TEABF4, for different bromo ester/Ni(tmc)]2+ ratios, where
stage of reduction of 1 and 2.
(Ipc)c is the cathodic peak current in the presence of bromo
ester, and (Ipc)d is the cathodic peak current in its absence.
From these results, it can be concluded that, for a fixed
initial concentration of [Ni(tmc)]2+, the extent of the cata-
lytic reaction increases when the concentration of bromo
ester is larger, and the effect is greater in the case of 2 than
in the case of 1. However, it is obvious that the peak current
ratio, (Ipc)c/(Ipc)d, does not increase linearly with the bromo
ester/[Ni(tmc)]2+ ratio. These findings indicate that the effi-
ciency of electrogenerated [Ni(tmc)]+ is diminished as it en-
gages in repetitive catalytic cycles, presumably due to slug-
gish regeneration of [Ni(tmc)]2+. Similar results were ob-
tained in our previous work dealing with the [Ni(tmc)]+-
catalyzed electroreductive intramolecular cyclization of
ethyl 2-bromo-3-(3Ј,4Ј-dimethoxyphenyl)-3-(propargyloxy)-
propanoate.[21]
Behavior of (1,4,8,11-Tetramethyl-1,4,8,11-tetraazacyclo-
tetradecane)nickel(II) Bromide, [Ni(tmc)]Br2, in Cyclic
Voltammetry and Controlled-Potential Electrolysis
Experiments
Cyclic voltammograms were recorded at a series of scan
rates (v) between 20 and 200 mV s–1 at a glassy-carbon elec-
trode for 2.0 mm solutions of [Ni(tmc)]Br2 in DMF contain-
ing 0.10 m TEABF4. Representative cyclic voltammograms
obtained at 100 mV s–1 for the reversible one-electron re-
duction of [Ni(tmc)]2+ to [Ni(tmc)]+ are shown in curve B
of both Figure 1 and Figure 2. From an analysis of these
cyclic voltammograms, we found that the separation of
cathodic and anodic peak potentials (ΔEp = Epc – Epa) is
close to 60 mV, the ratio of the peak currents (Ipc/Ipa) is
unity, and Ipc/v1/2 is independent of the scan rate. In ad-
Table 1. Peak-current ratios obtained from cyclic voltammograms
of solutions of DMF containing 0.10 m TEABF4, 2 mm
[Ni(tmc)]2+, and various concentrations of 1 at 100 mV s–1.
dition, the formal potential for the reversible [Ni(tmc)]2+
/
[Ni(tmc)]+ couple was determined to be –0.15 V, and no
further electron-transfer process involving the nickel com-
plexes occurs within the potential range of the medium.
Controlled-potential electrolyses were performed at po-
tentials approximately 150 mV more negative than the peak
potential for reduction of [Ni(tmc)]2+, and the coulometric
n value was 1.0. Thus, [Ni(tmc)]+ is stable on the time scale
of a bulk electrolysis. Furthermore, the electron added to
[Ni(tmc)]2+ is known to be nickel-centered, and the elec-
tron-transfer process is fast and is known to occur without
significant changes in the geometry of the complex.[25–29]
Concentration of 1 [mm]
2
4
20
40
[a]
(Ipc)c/(Ipc)d
1.62
2.89
3.68
3.80
[a] (Ipc)c = catalytic peak current in the presence of substrate and
(Ipc)d = diffusion peak current in the absence of substrate.
Table 2. Peak-current ratios obtained from cyclic voltammograms
of solutions of DMF containing 0.10 m TEABF4, 2 mm
[Ni(tmc)]2+, and various concentrations of 2 at 100 mV s–1.
Concentration of 2 [mm]
4
10
20
28
Cyclic Voltammetric Behavior of [Ni(tmc)]Br2 in the
Presence of Ethyl 2-Bromo-3-(3Ј,4Ј-methylenedioxyphenyl)-
3-(propargyloxy)propanoate (1) and Ethyl 3-Allyloxy-2-
bromo-3-(3Ј,4Ј-dimethoxyphenyl)propanoate (2)
[a]
(Ipc)c/(Ipc)d
4.09
9.81
10.90
12.24
[a] (Ipc)c = catalytic peak current in the presence of substrate and
(Ipc)d = diffusion peak current in the absence of substrate.
Cyclic voltammograms were recorded for reduction of
2.0 mm [Ni(tmc)]Br2 at a glassy-carbon electrode in DMF
containing 0.10 m TEABF4 and different concentrations of
each bromo ester. Figure 1 (curve C) and Figure 2 (curve
C) show the cyclic voltammetric behavior of [Ni(tmc)]Br2
in the presence of 20.0 mm 1 and 4.0 mm 2, respectively, at
a scan rate of 100 mV s–1.
Controlled-Potential Reduction of [Ni(tmc)]Br2 in the
Presence of Ethyl 2-Bromo-3-(3Ј,4Ј-methylenedioxyphenyl)-
3-(propargyloxy)propanoate (1) and Ethyl 3-Allyloxy-2-
bromo-3-(3Ј,4Ј-dimethoxyphenyl)propanoate (2)
Even in the presence of a relatively low concentration of
Controlled-potential reductions of [Ni(tmc)]2+ in the
bromo ester, the reduction of [Ni(tmc)]2+ becomes com- presence of either 1 or 2 were performed at either platinum
pletely irreversible; although the cathodic peak increases in or reticulated vitreous carbon cathodes in DMF containing
height upon addition of substrate, the anodic peak vanishes 0.10 m TEABF4; the potential was 100 mV more negative
because electrogenerated [Ni(tmc)]+ is consumed by the than the peak potential for reduction of [Ni(tmc)]2+ in the
substrate. When the initial concentration of bromo ester is presence of each bromo ester. Several substrate/[Ni(tmc)]2+
increased, the cathodic peak current grows, but not in pro- ratios were employed; in each experiment, current–time
portion to the concentration of the substrate. Furthermore, data were used to calculate the number of electrons (n)
with progressive increases in the concentration of bromo transferred to a molecule of bromo ester. At the end of an
ester, the cathodic peak potential shifts toward more nega- electrolysis, the current dropped to a steady and low value,
tive values (as a comparison of curves C and D in Figure 2 all of the starting material was consumed, and the products
reveals). Table 1 and Table 2 provide a compilation of data were separated, identified, and quantitated with the aid of
obtained from experiments carried out in DMF–0.10 m gas chromatography.
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Electroreductive Radical Cyclization Reactions
FULL PAPER
Table 3. Coulometric data and product distributions for catalytic reduction of 1 by [Ni(tmc)]+ electrogenerated at platinum and reticulated
vitreous carbon cathodes in DMF containing 0.10 m TEABF4.
Product distribution [%][a]
Entry
[Ni(tmc)]2+
[mM]
[1]
[mM]
[HFIP]
[mM][b]
[DPP]
n[d]
3
4
5
Total
[mM][c]
1[e]
2[f]
3[f]
4[e]
5[e]
6[e]
7[e]
8[e]
0.5
0.4
0.2
0.5
0.5
0.5
0.5
0.5
1
2
2
1
1
1
2.5
5
–
–
–
4
10
–
–
–
–
–
–
–
4
10
20
0.9
0.9
0.8
0.9
0.8
0.8
0.8
0.9
81
74
79
Ͻ1
Ͻ1
63
66
67
23
26
17
89
85
11
10
4
–
–
–
–
−
11
104
100
96
90
86
85
87
85
11
14
–
[a] % = yield expressed as the percentage of 1 incorporated into each product. [b] HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol. [c] DPP =
diphenylphosphane. [d] Number of electrons per molecule of starting material. [e] Platinum gauze cathode. [f] Reticulated vitreous carbon
cathode.
Catalytic Reduction of Ethyl 2-Bromo-3-(3Ј,4Ј-methylene-
dioxyphenyl)-3-(propargyloxy)propanoate (1)
ence on the product distribution. An interpretation of these
observations will be presented in the following mechanistic
section.
Table 3 presents coulometric data and product distribu-
tions obtained from the catalytic reduction of 1; each Entry
is an average of two or three individual experiments. Two
general conclusions can be drawn from the results: (i) An n
value of essentially 1 was observed, indicating that catalytic
reduction of 1 is a one-electron process which leads to for-
mation of a radical intermediate; (ii) the product distribu-
tion and coulometric n value do not depend on the initial
concentration of [Ni(tmc)]2+, as revealed by Entries 1–3 of
Table 3.
Entries 1–3 in Table 3 show that, in the absence of a de-
liberately added proton source or hydrogen atom donor,
catalytic reduction of 1 by electrogenerated [Ni(tmc)]+ gives
rise to two major products: ethyl 4-methylene-2-(3Ј,4Ј-
methylenedioxyphenyl)tetrahydrofuran-3-carboxylate (3),
formed in 74–81% yield, and ethyl 4-methyl-2-(3Ј,4Ј-
methylenedioxyphenyl)-2,5-dihydrofuran-3-carboxylate (4),
obtained in 17–26% yield. Although the sum of the yields
of 3 and 4 accounts for less than 100% of the original start-
ing material in some experiments, we found no evidence
(e.g., additional gas chromatographic peaks) for any other
product.
In a study of the homogeneous interaction of alkyl ha-
lides with the (octaethylisobacteriochlorin)nickel(i) anion,
[NiIOEiBC]–, generated through reduction with a sodium
amalgam in DMF, Helveston and Castro[30] investigated the
influence of hydrogen atom donors on the behavior of the
system. To determine the source of the hydrogen atom in
methane derived from methyl iodide, various proton and
hydrogen atom donors were added to the reaction medium.
It was found that, when diphenylphosphane was added to
the reaction mixture, the yield of methane was greatly en-
hanced, an observation leading to the conclusion that di-
phenylphosphane acts as a hydrogen atom donor and not
as an acid (pKa = 23.7 in DMF[31,32] at 25 °C). Further-
more, Ozaki and co-workers reported that reduction of a
vinyl bromide[33] or a bromo amide[34,35] mediated by elec-
trogenerated nickel(i) species in the presence of diphenyl-
phosphane led to a significant enhancement in the yield of
the desired cyclic product as well as that of an acyclic pro-
duct. Thus, in an effort to maximize the formation of 3, we
surveyed what effect would result from the addition of a
hydrogen atom donor (diphenylphosphane) to the system.
We carried out a series of electrolyses of DMF/0.10 m
TEABF4 solutions containing 0.50 mm [Ni(tmc)]Br2 and
three different concentrations of 1, along with diphenyl-
phosphane at a concentration level four times that of 1.
Entries 6–8 of Table 3 list the coulometric n values and
product distributions for these experiments. It can be seen
(in comparison with Entries 1–3 of Table 3) that diphenyl-
phosphane does not exert a major effect on the ratio of
yields of 3 and 4. However, the absolute yields of these two
cyclic products are diminished, due to the accompanying
To probe the effect of an added proton donor, solutions
of 1.0 mm 1, 0.50 mm [Ni(tmc)]Br2, and 1,1,1,3,3,3-hexa-
fluoro-2-propanol (HFIP) in DMF containing 0.10 m
TEABF4 were electrolyzed. Entries 4 and 5 of Table 3 show
that increasing amounts of HFIP lead to no change in the
coulometric n value. On the other hand, the product distri-
bution is significantly altered; 4 is obtained almost quanti-
tatively, whereas 3 is formed in trace amounts only. Thus, a
deliberately added proton donor exerts a profound influ-
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D. G. Peters et al.
FULL PAPER
formation of ethyl 3-(3Ј,4Ј-methylenedioxyphenyl)prop-2- Halcrow and Christou,[36] who published an extensive re-
enoate (5) in 11–14% yield.
view of catalytic processes involving nickel(i) complexes and
alkyl halides, a nickel(i) species can transfer one electron to
an alkyl halide through an inner-sphere mechanism, and an
alkylnickel intermediate might be formed; the subsequent
decomposition of which could generate alkyl radicals. Once
produced, 7 and 9 would be expected to undergo rapid in-
tramolecular cyclization to yield the carbocyclic radicals 8
and 10, respectively, which, after abstracting a hydrogen
atom from DMF, will afford 3 [reaction (2)] and 6 [reaction
(3)], respectively. Considerable evidence exists that DMF
can act as a hydrogen atom donor.[37–40]
An inevitable consequence of electrolytic reductions in
DMF is that small quantities of electrogenerated bases are
produced.[41] Under such conditions, 3 can undergo depro-
tonation, due to the acidity of the proton adjacent to the
carbonyl moiety, to give the corresponding resonance-stabi-
lized carbanion 11; protonation of this carbanion results in
the formation of 4 [reaction (4)]. This process is in agree-
ment with that described in our previous work.[21]
Catalytic Reduction of Ethyl 3-Allyloxy-2-bromo-3-(3Ј,4Ј-
dimethoxyphenyl)propanoate (2)
Summarized in Table 4 are coulometric data and product
distributions, obtained from the reduction of compound 2
by electrogenerated [Ni(tmc)]+ in DMF/0.10 TEABF4. As
expected, the [Ni(tmc)]+-catalyzed reduction of 2 is a one-
electron process, which implies the intermediacy of an alkyl
radical. At the end of the electrolyses, two major products
− both isomers of ethyl 2-(3Ј,4Ј-dimethoxyphenyl)-4-meth-
yltetrahydrofuran-3-carboxylate (6) − were found by means
of gas chromatographic analysis. In the absence of a proton
donor, the product distributions are not sensitive to the ini-
tial concentration of [Ni(tmc)]2+ (Table 4, Entries 1–3).
Moreover, when a proton donor (HFIP) is introduced into
the system (Table 4, Entry 4), neither the coulometric n
value nor the product distribution is altered.
As shown by Entries 4 and 5 of Table 3, when HFIP is
added to the catholyte prior to the start of an experiment,
4 is formed almost exclusively, whereas 3 is detected in trace
amounts only. Similar results, observed in our earlier
work,[21] suggest that the enhanced isomerization of 3 to 4
occurs because the conjugate base of HFIP (arising from
its reaction with electrogenerated base) can deprotonate 3,
whereas HFIP itself can readily protonate 11. In a sense,
HFIP acts as a buffer to facilitate the isomerization.
To account for the formation of the acyclic product 5
[obtained when 1 is catalytically reduced in the presence of
diphenylphosphane (Entries 6–8 of Table 3)], it is reason-
able to assert that 7 can abstract a hydrogen atom from
diphenylphosphane, followed by deprotonation to give the
carbanion 12 [reaction (5)]. Then, as soon as 12 is formed,
it could eliminate the propargyloxy anion, leading to the
formation of 5 [reaction (6)]. This latter process is termed
an E1cB mechanism, which is most likely to be encountered
with substrates containing acidic hydrogen atoms or poor
leaving groups, or when the carbanion is stabilized by reso-
nance.[42] In previous work[24] dealing with direct electro-
chemical reduction of ethyl 2-bromo-3-(3Ј,4Ј-dimeth-
oxyphenyl)-3-(propargyloxy)propanoate at a vitreous car-
bon cathode in DMF, we rationalized the formation of a
cinnamic acid ester by means of the same process.
Table 4. Coulometric data and product distributions for catalytic
reduction of 2 mm 2 by [Ni(tmc)]+ electrogenerated at reticulated
vitreous carbon cathodes in DMF containing 0.10 m TEABF4.
Product distribution
[%][a]
En-
try
[Ni(tmc)]2+
[mM]
[HFIP]
n[c]
6 (dr)[d]
[mm][b]
1
2
3
4
1
−
−
−
8
1.2
1.2
1.1
1.0
100 (92:8)
96 (92:8)
107 (92:8)
104 (92:8)
0.4
0.2
0.4
[a] % = yield expressed as the percentage of 2 incorporated into
each product. [b] HFIP 1,1,1,3,3,3-hexafluoro-2-propanol.
=
[c] Number of electrons per molecule of starting material. [d] Dia-
stereomeric (cis-to-trans) ratio.
Finally, with respect to the stereochemistry of the two
starting materials and the various cyclic products, it should
be noted that the original trans-ester-to-aryl group orienta-
tion of compounds 1 and 2 is retained in 3, 4, and 6. How-
ever, as revealed in Table 4, the electroreductive ring closure
of 2 to 6 affords a mixture of isomers in which the ester
Mechanistic Aspects of the [Ni(tmc)]+-Catalyzed
Reductions of Ethyl 2-Bromo-3-(3Ј,4Ј-methylenedioxyphen-
yl)-3-(propargyloxy)propanoate (1) and Ethyl 3-Allyloxy-2-
bromo-3-(3Ј,4Ј-dimethoxyphenyl)propanoate (2)
To account for the various products that arise from the and methyl groups are cis and trans to each other in a 92:8
[Ni(tmc)]+-catalyzed reductions of 1 and 2, the mechanistic ratio. A review chapter by Renaud[43] discusses the factors
steps outlined in Scheme 1 are proposed. After [Ni(tmc)]2+ that govern the stereochemistry of radical cyclization reac-
is reversibly reduced to [Ni(tmc)]+ [reaction (1)], the latter tions.
species transfers an electron to a bromo ester, cleaving the
In conclusion, we have shown that the method described
carbon–bromine bond homolytically, to give radical inter- here can afford a desired cyclized product in good yield
mediates 7 [reaction (2)] and 9 [reaction (3)]. According to through the use of a catalytic amount of an appropriate
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Electroreductive Radical Cyclization Reactions
FULL PAPER
Scheme 1.
procedures were carried out with zero-grade argon (Air Products).
electrogenerated metal complex under mild experimental
conditions at room temperature starting from bromo esters
1 and 2, which makes this procedure an attractive alterna-
tive to other synthetic methods.
Published procedures were employed for the preparation of
[44]
[Ni(tmc)]Br2
and of ethyl 2-bromo-3-(3Ј,4Ј-methylenedioxy-
phenyl)-3-(propargyloxy)propanoate (1) and ethyl 3-allyloxy-2-
bromo-3-(3Ј,4Ј-dimethoxyphenyl)propanoate (2).[5]
A method described by McCague et al.[9] provided the basis for the
syntheses of ethyl 4-methylene-2-(3Ј,4Ј-methylenedioxyphenyl)-
tetrahydrofuran-3-carboxylate (3), ethyl 4-methyl-2-(3Ј,4Ј-methyl-
enedioxyphenyl)-2,5-dihydrofuran-3-carboxylate (4), and ethyl
2-(3Ј,4Ј-dimethoxyphenyl)-4-methyltetrahydrofuran-3-carboxylate
(6). We identified the compounds by means of 1H NMR spectrome-
try with a Varian Unity Plus 300-MHz instrument.
Experimental Section
Reagents: Each of the following chemicals was used as received:
Nickel(ii) bromide (Aldrich, 98%), 1,4,8,11-tetramethyl-1,4,8,11-
tetraazacyclotetradecane (tetramethylcyclam, tmc, Fluka, 97%),
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP, Aldrich, 99.8+%), di-
phenylphosphane (Aldrich, 95%), n-tetradecane (Aldrich, 99+%),
and n-hexadecane (Aldrich, 99+%). Dimethylformamide (DMF),
“distilled-in-glass” reagent from Aldrich, was used as received. We
obtained tetraethylammonium tetrafluoroborate (TEABF4) with a
purity of 98.5% from GFS Chemicals; this electrolyte was stored
in a vacuum oven at 80 °C to remove traces of water. Deaeration
3: 1H NMR (CDCl3): δ = 1.28 (t, J = 7.2 Hz, 3 H, OCH2CH3),
3.42–3.47 (m, 1 H, 3-H), 4.21 (qABq, J = 11.0, 7.2 Hz, 2 H,
OCH2CH3), 4.49 (apparent dq, J = 13.0, 2.4 Hz, 1 H, 5-H), 4.63
(br. apparent d, J = 13.0 Hz, 1 H, 5-H), 5.10 (apparent q, J =
2.4 Hz, 1 H, =CH), 5.15 (d, J = 8.7 Hz, 1 H, 2-H), 5.18 (apparent
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D. G. Peters et al.
q, J = 2.4 Hz, 1 H, =CH), 5.96 (s, 2 H, OCH2O), 6.77 (d, J = cies. Due to uncertainties in various analytical measurements (i.e.,
FULL PAPER
8.0 Hz, 1 H, 5Ј-H), 6.88 (dd, J = 8.0, 1.8 Hz, 1 H, 6Ј-H), 6.90 (d,
J = 1.8 Hz, 1 H, 2Ј-H) ppm.
quantities of internal standards and starting materials as well as
gas chromatographic peak areas and response factors), the absolute
error in the average yield of each product is typically 3–4%. Con-
sequently, it is not surprising that, for several Entries in Tables 3
and 4, the total recovery of products slightly exceeds 100%. Such
analytical results are not uncommon in electrochemical studies in-
volving gas chromatographic determinations of product distribu-
tions.[21,40,49–52]
4: 1H NMR (CDCl3): δ = 1.16 (t, J = 7.2 Hz, 3 H, OCH2CH3),
2.18 (apparent d, J = 1.2 Hz, 3 H, 4-CH3), 4.09 (qABq, J = 10.8,
7.2 Hz, 2 H, OCH2CH3), 4.71 (apparent ddd, J = 15.0, 3.5, 1.0 Hz,
1 H, 5-H), 4.87 (apparent ddd, J = 15.0, 5.0, 1.0 Hz, 1 H, 5-H),
5.83–5.87 (m, 1 H, 2-H), 5.94 (s, 2 H, OCH2O), 6.76 (d, J = 8.0 Hz,
1 H, 5Ј-H), 6.77 (d, J = 1.8 Hz, 1 H, 2Ј-H), 6.82 (dd, J = 8.0,
1.8 Hz, 1 H, 6Ј-H) ppm.
6: 1H NMR (CDCl3): δ = 1.07 (d, J = 6.9 Hz, 2.55 H, 4-CH3), 1.18
(d, J = 6.6 Hz, 0.45 H, 4-CH3), 1.25 (t, J = 7.0 Hz, 0.45 H,
OCH2CH3), 1.28 (t, J = 7.2 Hz, 2.55 H, OCH2CH3), 2.55 (apparent
t, J = 9.0, 8.7 Hz, 0.15 H, 3-H), 2.70–2.85 (m, 1 H, 4-H), 3.00
(apparent dd, J = 9.0, 7.8 Hz, 0.85 H, 3-H), 3.66 (apparent dd, J
= 8.7, 6.6 Hz, 1 H, 5-Ha), 3.87 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3),
4.12–4.24 (m, 2 H, OCH2CH3), 4.28 (dd, J = 8.4 and 6.6 Hz, 1 H,
5-Hb), 5.05 (d, J = 9.0 Hz, 0.15 H, 2-H), 5.19 (d, J = 7.8 Hz, 0.85
H, 2-H), 6.83 (d, J = 9.0 Hz, 1 H, 5Ј-H), 6.88–6.92 (m, 2 H, 2Ј-H
and 6Ј-H) ppm. These compounds were utilized as standards for
the determination of gas chromatographic response factors.
Identities of the products were confirmed with the aid of a Hew-
lett–Packard 5890 Series II gas chromatograph coupled to a Hew-
lett–Packard 5971 mass-selective detector: 3: MS (70 eV): m/z =
276 (35) [M+], 247 (3) [M – C2H5]+, 202 (18) [M – CO2C2H5
–
H]+, 149 (45) [CH2O2C6H3CO]+, 126 (59) [H5C2O2CC4H5]+, 98
(100) [C5H6O2]+. 4: MS (70 eV): m/z = 276 (100) [M+], 261 (17)
[M – CH3]+, 247 (34) [M – C2H5]+, 202 (82) [M – CO2C2H5
–
H]+, 149 (64) [CH2O2C6H3CO]+, 77 (7) [C6H5]+, 29 (22) [COH]+.
5: MS (70 eV): m/z = 220 (100) [M+], 205 (1) [M – CH3]+, 192 (16)
[M – C2H4]+, 175 (69) [M – C2H5O]+, 145 (39) [H5C7O2CϵC]+,
117 (17) [C6H5OCϵC]+, 89 (36) [C7H5]+, 29 (9) [COH]+. 6: MS
(70 eV): m/z = 294 (84) [M+], 279 (26) [M – CH3]+, 265 (69) [M –
C2H5]+, 220 (10) [M – CO2C2H5 – H]+ , 205 (35) [M – CO2C2H5 –
CH3 – H]+, 165 (100) [(CH3O)2C6H3CO]+, 29 (16) [COH]+. These
identifications were checked by comparison of gas chromato-
graphic retention times for the suspected products, under carefully
controlled conditions, with those of the authentic compounds pre-
pared above.
Electrodes: For cyclic voltammetry we fabricated a planar, circular
working electrode with an area of 0.077 cm2 by press-fitting a short
length of 3-mm-diameter glassy-carbon rod (Grade GC-20, Tokai
Electrode Manufacturing Company, Tokyo, Japan) into a Teflon
shroud. Working electrodes for controlled-potential electrolyses
were of two kinds: (i) platinum gauze (area of 2.4 cm2) and (ii)
disks (0.4 cm in thickness, 2.4 cm in diameter, and approximately
200 cm2 in geometric area) sliced from reticulated vitreous carbon Acknowledgments
logs (RVC, 2X1–100S, Energy Research and Generation, Oakland,
CA). Procedures for the cleaning and handling of reticulated vitre-
ous carbon electrodes have been described previously.[45] All poten-
tials are quoted with respect to a reference electrode consisting of
a cadmium-saturated mercury amalgam in contact with DMF satu-
rated with both cadmium chloride and sodium chloride.[46,47] This
electrode has a potential of –0.76 V vs. the aqueous saturated calo-
mel electrode (SCE) at 25 °C.
Most of this research was conducted while M. J. M. was a Visiting
Scholar at Indiana University. In addition, we are grateful to the
Fundação Calouste Gulbenkian, CRUP and FCT for partial finan-
cial support of this work. During the course of this work, D. M.
G. was the holder of a Government Assistance in Areas of National
Need (GAANN) Fellowship awarded by Indiana University.
Cells and Instrumentation: Cells for cyclic voltammetry[48] and for
controlled-potential electrolysis[49] have been described in earlier
publications. Cyclic voltammograms were obtained with the aid of
a Princeton Applied Research Corporation (PARC) model 175 uni-
versal programmer coupled to a PARC model 173 potentiostat–
galvanostat and were recorded with a Yokogawa model 3023 X–Y
plotter. Controlled-potential electrolyses were carried out by means
of the above-mentioned potentiostat–galvanostat equipped with a
PARC model 176 current-to-voltage converter. Electrolyses were
programmed and current–time curves were acquired, stored, and
integrated with the aid of locally written software, which controlled
a data acquisition board installed in a personal computer.
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Received: June 28, 2005
Published Online: September 27, 2005
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4859