Formal alkylation of allenes through highly selective radical cyclizations of allene-enes

Article abstract of DOI:10.1002/anie.201107747

Something radical: The first example of alkene-to-allene radical cyclization of allene-enes is reported. The highly chemoselective intermolecular radical addition reaction of the alkene and subsequent, exclusive exo-radical addition to the allene was real

Full text of DOI:10.1002/anie.201107747

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Angewandte
Communications
DOI: 10.1002/anie.201107747
Heterocycles
Formal Alkylation of Allenes through Highly Selective Radical
Cyclizations of Allene-enes**
Rong Zeng, Chunling Fu,* and Shengming Ma*
In the last few decades, radical-based transformations have
become one of the most powerful ways to form carbon–
carbon bonds in organic synthesis.[1] However, the radical
reactions of allenes are largely unknown.[2,3] Particularly, in
contrast to the radical cyclization reactions of dienes[4] and
enynes,[4k–m,5] the inter- and intramolecular tandem radical
addition/cyclization reactions of allene-enes[6] has not been
extensively explored. All the reported reactions proceed in an
“allene-to-alkene” fashion,[6] which is consistent with the
traditional notion that allenes are more reactive than alkenes
towards radicals (Scheme 1). Herein, we report a reaction
a 1:1 mixture of 4-phenylbuta-1,2-diene (1) and 1-octene (2)
afforded a mixture of both addition products, namely the
alkenyl iodide 3 and (perfluoroalkyl)alkyl iodide 4, in 76%
and 93% yields, respectively, thus demonstrating a poor
selectivity [Eq. (1)].
To avoid using a large amount of Na2S2O4 and NaHCO3,
we started to explore a general catalytic or subcatalytic
radical initiation system for the reaction of a simple allene,
that is, 4-phenylbuta-1,2-diene (1) with 5a to possibly obtain
a better selectivity. The investigation on the reaction of 1 with
5a was conducted under the known reaction conditions for
the radical addition of alkenes:[8] 1.0 equivalent of 1 and
1.5 equivalents of 5a reacted in the presence of 20 mol%
trifluoroacetic acid (TFA) when using 10 mol% zinc powder
as the catalyst at room temperature. Unfortunately, less than
5% product was formed with the recovery of 1 being 92%
(see Table S1, entry 1 in the Supporting Information). After
some optimization, we were happy to observe that the radical
addition reaction may be conducted with 40 mol% of zinc in
the presence of 20 mol% of HOAc (Scheme 2; for details see
Table S1).
Scheme 1. Radical cyclizations of allene-enes.
that proceeds in an “alkene-to-allene” fashion, starting with
the alkene moiety to afford products of type A exclusively.
It has been shown that a stoichiometric amount of
Na2S2O4 may promote the radical addition reaction of olefins
and allenes with perfluoroalkyl iodides in the presence of
NaHCO3.[7] It is interesting to observe that the corresponding
radical addition reaction of perfluorobutyl iodide (5a) with
[*] R. Zeng, Prof. C. Fu, Prof. S. Ma
Laboratory of Molecular Recognition and Synthesis
Department of Chemistry, Zhejiang University
Hangzhou 310027, Zhejiang (P.R. China)
E-mail: masm@sioc.ac.cn
Scheme 2. Zinc-initiated radical addition reactions of allene 1 with 5a.
Reported yield is for the isolated product. Bn=benzyl.
[**] Financial support is acknowledged from the National Basic
Research Program of China (No. 2011CB808700) and the National
Natural Science Foundation of China (No. 21072167). S.M. is a Qiu
Shi Adjunct Prof. at Zhejiang University. We thank Weiming Yuan in
this group for reproducing the results presented in entries 9 and 11
in Table 1 and compound 13a in Scheme 3.
We started to study the radical cyclization by using the
allene-ene 6a as a model substrate. Disappointingly, some
typical radical initiators such as Et3B,[9] AIBN,[10] and zinc
powder[8] failed to catalyze the cyclization reaction of the
allene-ene 6a with 5a [Eqs. (3)–(5)]. Gladly, we found that
the radical addition reaction of the allene-ene 6a with 5a was
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107747.
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indeed be promoted by 50 mol% of zinc powder in the
presence of 20 mol% HOAc at 408C, thus forming two
products exclusively. Upon analyzing the spectroscopic data,
including 1H, 13C, and 19F NMR spectra, as well as IR, MS, and
HRMS data, for the two products, we found that both the
allene and alkene moieties in allene-ene 6a had been
converted: 5a was incorporated into the product with the Rf
group linked to a methylene group; there were no olefinic
protons present in the product. Thus, by comparing the data
with the possible radical cyclization products of allene-enes
shown in Scheme 1, we reasoned that the two compounds
should be a pair of diastereomers arising from an A-type
cyclization to give the product 7a, which must be formed
highly chemoselectively through the alkene-to-allene addi-
tion and exo cyclization. This result indicates a favored
selectivity towards the alkene over the allene [compare with
the results shown in Eqs. (1) and (2–5)], which is different
from what has been previously reported.[6] Thus, 7a was
formed in 73% yield as determined by NMR spectroscopy
and 56% yield upon isolation [Eq. (5)]. With 40 mol% of
zinc, 6a was recovered (8%). These reaction conditions had
shown obvious advantages as compared to the reported ones
for allenes:[7] 1) the reaction proceeds under mild reaction
conditions and is very practical; 2) both the zinc powder and
HOAc are cheap, nontoxic, user-friendly, and readily avail-
able.
the typical results are summarized in Table 1. Differently
substituted allene-enes (6a,b and 6d–g) were successfully
applied in the radical addition/cyclization reaction to afford
the corresponding products 7a–d and 7g–7n in moderate to
good yields. The products were were directly converted into
the formal alkylation products of the allene moiety, that is, 3-
(1-alkenylidene)tetrahydrofurans 8a–d and 8g–n, in good to
excellent yields by using the dehydroiodination approach.
The substituents R1 and R2 could be either different alkyl
groups or a carbon chain forming a ring (Table 1). Compared
with the other substrates, when R1 = R2 = Me, the reaction
afforded the lowest yield (Table 1, entries 5 and 6). Further-
more, the reactions of substrates in which R3 was a methyl
group (Table 1, entries 11 and 12) gave even better results
than those obtained when R3 = H (Table 1, entries 3 and 4).
The different perfluoroalkyl iodides, such as n-C4F9I or
n-C6F13I, could be used in the reactions with the similar
results.
Table 1: The scope of the radical addition/cyclization and elimination
reaction of allene-enes.
Entry
6
Rf
Yield [%][a]
R1
R2
R3
7[b]
8
1
2
3
4
5
6
7
8
–(CH2)5–
–(CH2)5–
–(CH2)11–
–(CH2)11–
H (6a)
H (6a)
H (6b)
H (6b)
H (6d)
H (6d)
H (6e)
H (6e)
H (6 f)
H (6 f)
Me(6g)
Me(6g)
n-C4F9
n-C6F13
n-C4F9
n-C6F13
n-C4F9
n-C6F13
n-C4F9
n-C6F13
n-C4F9
n-C6F13
n-C4F9
n-C6F13
56 (7a)
60 (7b)
77 (7c)
60 (7d)
59 (7g)
53 (7h)
86 (7i)
80 (7j)
57 (7k)
74 (7l)
79 (7m)
80 (7n)
92 (8a)
95 (8b)
93 (8c)
98 (8d)
83 (8g)
83 (8h)
96 (8i)
Me
Me
Bn
Me
Me
Bn
Bn
Bn
88 (8j)
9
Me
Me
iBu
iBu
83 (8k)[c]
90 (8l)[c]
97 (8m)
99 (8n)[d]
10
11
12
-(CH2)11-
-(CH2)11-
[a] Yield of isolated product. [b] All the products were mixtures of
diastereomers. [c] 2.5 equiv of TBAF·3H2O were used. [d] 2.9 equiv of
TBAF·3H2O were used.
Inspired by this observation, we proposed to develop
a base-promoted elimination of HI from the two diastereo-
mers to regenerate the allene moiety,[11] a reaction that would
additionally confirm that the two isomers are indeed a pair of
diastereomers. After some experimentation, we were happy
to observe that the dehydroiodination of 7a with 2.1 equiv-
alents of TBAF·3H2O in toluene at 808C afforded 8a in 96%
yield [Eq. (6), for details see Table S2 in the Supporting
Information]. Thus, these reaction conditions were defined as
the standard reaction conditions.
Moreover, the allene-ene 6c having an adamantanyl
group as a terminal substituent on the allene yielded the
exo-cyclization product 7e–f in moderate yield. The allene-
ene 9a having NBn and the allene-ene 12a having C-
(COOMe)2 as tethers instead of the oxygen atom yielded
the exo-cycliclization product 10a and 13a,b, respectively, in
moderate to good yields (Scheme 3).
Thus, a possible mechanism of the radical addition/
cyclization was proposed in Scheme 4: 1) the initiation of
the reaction with Zn forms the perfluoroalkyl radical; 2) the
formed perfluoroalkyl radical attacks the alkene moiety of
allene-ene 6 to form the radical intermediate E; 3) an
intramolecular radical exo-cyclization process yields the
intermediate F; 4) atom transfer releases the product 7 and
regenerates the perfluoroalkyl radical.
We then studied the scope of the radical addition/
cyclization reaction and the subsequent dehydroiodination
reaction of allene-enes with perfluoroalkyl iodides. Some of
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(see the Supporting Information). The product 7a was used in next
step without further characterization.
TBAF.3H2O (130.3 mg, 0.42 mmol), 7a (104.0 mg, 0.2 mmol),
and toluene (2.0 mL) were added to a dried Schlenk tube equipped
with a Teflon-coated magnetic stirring bar. The tube was then
submerged in an oil bath that was preheated to 808C. After 7 h, the
reaction was complete as monitored by TLC. The crude reaction
mixture was filtered through a short column of silica gel and
evaporation afforded a residue, which was purified by flash column
chromatography on silica gel (eluent: 30–608C petroleum ether/
diethyl ether= 80:1) to afford 8a (72.2 mg, 92%) as a liquid. 1H NMR
(300 MHz, CDCl3): d = 4.37 (dd, J1 = 11.7 Hz, J2 = 1.2 Hz, 1H, one
proton of CH2O), 4.30–4.16 (m, 2H, 2 ꢀ (one proton of CH2O)), 3.50
(t, J = 8.6 Hz, 1H, one proton of CH2O), 3.18–3.04 (m, 1H, CH), 2.50–
2.24 (m, 1H, one proton of CH2Rf), 2.22–1.93 (m, 5H, one proton of
CH2Rf and 2 ꢀ CH2), 1.75–1.44 ppm (m, 6H, 3 ꢀ CH2); 13C NMR
(75 MHz, CDCl3): d = 188.1, 110.3, 102.1, 74.0 (d, J = 4.3 Hz), 68.5,
35.9 (d, J = 2.6 Hz), 33.1 (t, J = 21.6 Hz), 32.1, 31.5, 27.9, 27.7,
26.0 ppm; 19F NMR (282 MHz, CDCl3): d = ꢀ81.0 ꢁ (ꢀ81.1) (m,
3F), ꢀ111.9 (dm, J = 276 Hz, 1F), ꢀ114.5 (dm, J = 276 Hz, 1F),
ꢀ124.5 ꢁ (ꢀ124.7) (m, 2F), ꢀ125.9 ꢁ (ꢀ126.2) ppm (m, 2F); IR
Scheme 3. Radical addition/cyclizations of allene-enes 6c, 9a, and
12a.
~
(neat): n = 2932, 2856, 1970, 1449, 1433, 1352, 1235, 1134, 1066,
1020 cmꢀ1; MS (EI, 70 eV) m/z (%) 396 [M+, 100]; HRMS calcd for
C16H17OF9 [M+]: 396.1136. Found: 396.1144.
Received: November 3, 2011
Published online: March 6, 2012
Keywords: alkylation · allenes · cyclization · elimination ·
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radical reactions
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Scheme 4. The mechanism.
In conclusion, we have developed the first example of
radical addition/cyclization reactions of allene-enes in an
alkene-to-allene fashion using zinc powder as a cheap, readily
available, efficient, and mild initiator to afford the highly
selective formation of exo-cyclization products in moderate to
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Experimental Section
Typical procedure: Zinc powder (48.0 mg, 0.74 mmol), 6a (264.7 mg,
1.49 mmol), CH2Cl2 (1 mL), perfluorobutyl iodide (0.39 mL, d = 2.01,
0.7839 g, 2.3 mmol), HOAc (18.9 mg, 0.32 mmol), and CH2Cl2 (1 mL)
were added sequentially under a nitrogen atmosphere at room
temperature to a dried Schlenk tube equipped with a Teflon-coated
magnetic stirring bar. The tube was then submerged in an oil bath that
was preheated to 408C. After 12 h, the reaction was complete as
monitored by GC. The crude reaction mixture was filtered through
a short column of silica gel and evaporation of the solvent afforded
a residue, which was purified by column chromatography on silica gel
(eluent: 30–608C petroleum ether/diethyl ether= 80:1!40:1) to
afford 7a (437.4 mg, 56%) as a liquid. Because of the presence of
two diastereomers, the 1H and 19F NMR spectra are very complicated
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