A radical cascade reaction of aza-1,6-enyne compounds using allyltributyltin

Article abstract of DOI:10.1016/j.tet.2016.04.078

The radical cascade reaction of allyltin with aza-1,6-enyne compounds was studied. Optically active aza-1,6-enynes underwent a radical cascade process in the presence of a high concentration of allyltributyltin to give stannolanes as the major isomer. Piperidines were also observed in small amounts when an allylic unit was introduced stereoselectively to the trans-position of the aryl group at the C2 position. The yield of the products dramatically decreased with concentrations of tin reagent. The E/Z selectivity at the exomethylene group in piperidine depended on the reaction temperature, and it almost doubled when the reaction was carried out at 30 °C. In this study, the reaction mechanism of the radical cascade is discussed.

Full text of DOI:10.1016/j.tet.2016.04.078

Tetrahedron xxx (2016) 1e5
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Tetrahedron
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A radical cascade reaction of aza-1,6-enyne compounds using
allyltributyltin
,
a
a
b
Akio Kamimura a , Koichiro Miyazaki , Takuji Kawamoto , Hidemitsu Uno
*
a Department of Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University, Ube 755-8611, Japan
b Department of Chemistry, Graduate School of Science and Engineering, Ehime University, Matsuyama 790-8577, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The radical cascade reaction of allyltin with aza-1,6-enyne compounds was studied. Optically active aza-
1,6-enynes underwent a radical cascade process in the presence of a high concentration of allyltributyltin
to give stannolanes as the major isomer. Piperidines were also observed in small amounts when an allylic
unit was introduced stereoselectively to the trans-position of the aryl group at the C2 position. The yield
of the products dramatically decreased with concentrations of tin reagent. The E/Z selectivity at the
exomethylene group in piperidine depended on the reaction temperature, and it almost doubled when
the reaction was carried out at 30 ꢀC. In this study, the reaction mechanism of the radical cascade is
discussed.
Received 31 March 2016
Received in revised form 26 April 2016
Accepted 28 April 2016
Available online xxx
Keywords:
Radical addition
Radical cyclization
Radical substitution reaction
Stannolane
Ó 2016 Elsevier Ltd. All rights reserved.
Piperidine
1. Introduction
radical cascade process to mainly give stannolanes, and piperidine
formation occurs as a minor process. As the E/Z ratios depends on
Radical reactions occupy an important position in organic
chemistry.1 Radical cascades are those in which the key step con-
stitutes a radical reaction and they provide a useful route for the
preparation of carbocyclic and heterocyclic compounds through
radical cyclization reactions.2 Recently, we reported an interesting
radical cascade with 1,6-enyne compounds3 wherein a tin radical
the reaction temperature, we believe that the reaction progressed
through the addition of tin radical to the -unsaturated end fol-
a,b
lowed by cyclization reaction with the terminal alkyne unit to give
an intermediate vinyl radical that attacks the tin atom to give
stannolane or an alkyl radical intermediate. The product ratio be-
tween stannolane and piperidine reflects a rough ratio between
radical substitution reaction in tin from back-side and front-side
modes.
underwent
a radical additionecyclizationedirect substitution
(SHi)4 reaction to give high yields of bicyclic stannolanes;5 stereo-
selectivity was very high during the cyclization process. We also
estimated the kinetic parameter of the direct substitution reaction
on a tin atom.6 A radical cascade reaction of similar compounds was
reported by Kim and Shanmugam, but they did not observe any
stannolane formation.7 They reported that the radical cascade re-
action of oxy-1,6-enynes gave tetrahydropyrane derivatives. Addi-
tionally, Kim reported that aza-1,6-enynes underwent cyclization
triggered by allyltributyltin to give piperidine in moderate yields.8
This contradicted our findings, which showed that the same aza-
1,6-enynes resulted in an exclusive formation of stannolanes by
treatment with Bu3SnH.5
2. Results and discussion
We first examined the reaction of compound 1a with allyl-
tributyltin at various concentrations (Scheme 1). The results are
summarized in Table 1.
The present study aims to understand the differences in these
results and investigate the reactions that occur in the presence of
allyltin compounds. We disclose that aza-1,6-enynes undergoes
Scheme 1. Reaction of 1a with allyltributyltin.
* Corresponding author. E-mail address: ak10@yamaguchi-u.ac.jp (A. Kamimura).
http://dx.doi.org/10.1016/j.tet.2016.04.078
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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2
A. Kamimura et al. / Tetrahedron xxx (2016) 1e5
Table 1
Radical cascade reaction of 1a with allyltributyl tin
Entry Solventb Conc. 2a; Yield 3a; Yield 2a/3a 3; E/Za 1a; Recovery
(M)
(%)a
(%)a
(%)a
1
2
3
4
5
d
3.2
1.0
0.8
0.3
0.1
47 (49)
50
51
18
5.4
26 (15)
19
30
9
1.5
1.8
2.6
1.7
2
51/49
53/47
52/48
50/50
59/41
0
0
0
46
75
BTF
BTF
BTF
BTF
3.6
a
NMR yields estimated by 1H NMR integration. Isolated yields are in parentheses.
BTF¼CF3C6H5.
b
The aza-1,6-enyne 1a underwent radical cascade reaction on
treatment with allyltributyltin under no solvent conditions at 80 ꢀC
(entry 1). The starting material was consumed smoothly and two
major products were formed. One was stannolane 2a that was ob-
tained in 47% yield. The structure of 2a was determined by com-
parison with an authentic sample prepared in our previous
method.5 It is noteworthy that stannolane 2a was isolated as a single
isomer and the other stereoisomer was not observed in the reaction
mixture. The other product 3a was also isolated in 26% by purifi-
cation using a recycle GPC apparatus. It was a mixture of E/Z isomers
whose ratio was approximately 1:1. This diastereomeric difference
was caused by the difference in the configuration at the exo-
methylene unit and not by the stereochemistry of the piperidine
ring. The stereochemistries of E-3a and Z-3a were determined by
the NOESY spectra, where a cross peak between 5.87 (SneCH]) and
4.19 (eNCH2e) was observed in E-3a whereas a cross peak between
5.78 (SneCH]) and 2.52 (eCH2ꢁC(CO2R)e) was observed in Z-3a.
The E/Z ratio slightly improved when the reaction was performed
under lower concentration conditions (entry 5). The tributyltin
group was removed by an acidic treatment to give exomethylene
piperidine 4a, the structure of which was unambiguously de-
termined by X-ray crystallographic analysis (Scheme 2).9
Scheme 3. The reaction of allyltributyltin with various aza-1,6-enynes 1.
Our results clearly show that stannolane 2, which was always
obtained as a single diastereomer, was the main products when 1,6-
enyne 1 was exposed to allyltributyltin. The yield of piperidine 3
was around 10%, indicating its formation was only a minor process.
The Bu3Sn group in piperidines 3 was readily removed by treatment
with a concentrated aqueous HCl to give compound 4.
From all the abovementioned results, the reaction mechanism
is proposed as shown in Scheme 4. The precursor 1 undergoes
a radical addition of the tin radical to give an intermediate A
which then attacks the terminal alkyne unit in 5-exo-dig mode,
leading to the formation of a vinyl radical B. The intermediate B
can undergo two possible reaction pathways; one is the radical
substitution reaction to produce butyl radical and stannolane 2,
and the other is the radical substitution reaction to give a CH2
radical C. The former pathway is believed to be a fast reaction step
because its kinetic parameter was estimated to be around
4.23ꢂ108 sꢁ1 6
. Thus, most of the radical B gives stannolane 2.
However, there is no source of hydrogen to trap B in order to give
the exomethylene product 5; therefore radical B has a chance of
undergoing the latter reaction pathway to give radical C by the SHi
process in retention configuration, which is a relatively slower
Scheme 2. Structural elucidation of piperidine 3a and 4a.
As yield of 2a and 3a decreased with concentration of allyl-
tributyltin. For example, the yields of 2a and 3a were 50% and 19%
yield, respectively, when the reaction was performed at 1 M con-
centration whereas the yields dropped down to 5.4% and 1.5%, re-
spectively, when 1a was treated at 0.1 M concentration (entries 2
and 5). At low concentration (0.1 M), the percentage recovery of
compound 1a was 75%. This was contrary to the result obtained
during the reaction of 1a with Bu3SnH, where the yield of stan-
nolane 2a was 80%.5 However, the product ratios between 2a and
3a were not affected by reaction conditions; the values ranged
between 1.7 and 3.6, and their average was calculated to be 2.3.
The results obtained in our study were found to be significantly
different from those reported by Kim et al., in which they obtained
exomethylene piperidines at yields higher than 60%.8 To validate
our results, we examined the reaction of various aza-1,6-enyne
substrates 1 under similar reaction conditions. The results are
summarized in Scheme 3. The reaction was performed under no
solvent conditions.
Scheme 4. The reaction pathway.
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A. Kamimura et al. / Tetrahedron xxx (2016) 1e5
3
process. The radical substitution reaction from B to C is believed
to be irreversible because radical C is alkyl radical in nature and
hence thermodynamically more stable than the vinyl radical B.10
investigation gives useful information about radical substitution
reactions. Further work focused on the improvement of the piper-
idine synthesis in radical cascade is underway and will be reported
in due course.
Once radical
C is formed, a rearrangement through cyclo-
propylmethyl radical D progresses to give piperidine radical E,
which is trapped by the allyl group of allyltributyltin to give the
tin radical and product 3. There is another possibility for the
formation of radical C through radical F, which is formed by
radical addition to the terminal alkyne unit. However, this is less
4. Experimental section
4.1. General
likely to occur because the addition of a tin radical to an
a
,
b
-un-
All 1H and 13C NMR spectra were recorded on JEOL lamda-500 or
JNM-ECA 500 Delta2 (500 MHz for 1H and 126 MHz for 13C) spec-
trometer. Allyltributyltin was purchased from TCI. 1,6-enynes 1
were prepared by the previous reported method.3 All the reactions
in this paper were performed under nitrogen atmosphere unless
otherwise mentioned. High resolution mass spectra (HRMS) were
was measured by JEOL JMS T-100LP LC-ESI mass spectrometer.
saturated ester is much faster than the addition to an alkyne
unit.11 Also, it is very difficult to produce product 2 through this
route, which is the major product of the reaction. In all the radical
cascade reactions of 1,6-enynes 1, we observed the addition oc-
curred exclusively from the
from the alkyne unit.
a,b-unsaturated ester unit and not
To check the abovementioned assumption, we examined the
same reaction at 30 ꢀC, and found that the E/Z ratio of 3a improved
to 65/35 although the total yields of 2a and 3a decreased (Scheme
5). Thus, E-3a became a major product of the reaction as long as
a low temperature reaction condition was employed. A similar re-
sult was observed in the reaction with Bu2PhSnH.6 We believe that
the free rotation of the carbonecarbon single bond in intermediate
D is suppressed under lower temperature conditions and E-3a
should be the main product as long as the intermediate radical C is
generated through radical substitution reaction of B to C. Con-
versely, if the intermediate radical C is formed through F to C, the
formation of 3a should occur in a non-stereoselective manner and
not be affected by the change in reaction temperature.12 This result
supports the assumption that the intermediate radical is mainly
produced from the radical substitution process of B to C and not
from the radical cyclization of F to C.
4.2. The reaction of 1a with allyltributyltin (Table 1, entry 1)
A mixture of 1a (212 mg, 0.50 mmol), allyltributyltin (662 mg,
2.00 mmol), and AIBN (81.8 mg, 0.50 mmol) was heated at 80 ꢀC for
1 h. The reaction mixture was directly subjected flash chromatog-
13
raphy (silica gel-K2CO3 9:1/hexane then hexane-EtOAc 15:1 v/v)
to give to 2a in 49% yield (159 mg, 0.24 mmol) along with 3a in 15%
yield (57 mg, 0.075 mmol).
4.3. Conversion of 3a to 4a (Scheme 2)
A biphasic solution of 3a (30.6 mg, 0.04 mmol) in ether (0.4 mL)
and conc. HCl (0.04 mL) was stirred at room temperature for 1 h.
Concentrated crude product was purified through flash chroma-
tography (silica gel/hexane then hexane-EtOAc 10:1 v/v) to give 4a
in 58% yield (10.6 mg, 0.023 mmol).
Other compound 2 and 4 were prepared in a similar manner.
4.3.1. (3S,3aS)-tert-Butyl 5,5-dibutyl-3-phenyl-2-tosyl-1,2,3,3a,4,5-
hexahydrostannolo[3,4-c]pyrrole-3a-carboxylate (2a). Colorless oil;
[a
]
D þ7.7 (c 1.04, CHCl3); nmax (neat) 1720, 1367, 1348, 1161 cmꢁ1
; dH
(500 MHz CDCl3) 7.41 (d, J¼8.1 Hz, 2H), 7.20e7.09 (m, 3H), 7.06 (d,
J¼8.0 Hz, 2H), 6.97e6.90 (m, 2H), 6.55 (s, 1H), 5.44 (s, 1H), 4.15 (dd,
J¼12.9, 2.2 Hz, 1H), 4.01 (d, J¼12.9 Hz, 1H), 2.31 (s, 3H), 1.51e1.42
(m, 2H), 1.37 (d, J¼2.1 Hz, 9H), 1.29e1.19 (m, 4H), 1.13e0.95 (m, 6H),
0.90 (d, J¼13.5 Hz, 1H), 0.83 (t, J¼7.3 Hz, 3H), 0.73 (t, J¼7.0 Hz, 3H),
0.23 (d, J¼12.6 Hz, 1H); dC (126 MHz, CDCl3) 173.8, 158.3, 142.6,
139.6, 136.6, 129.1 (2C), 128.1 (br, 2C), 128.1 (2C), 128.0, 127.5, 127.3
(2C), 81.6, 69.7, 68.6, 50.6, 29.0, 28.7, 27.8 (3C), 27.1, 27.0, 23.5, 21.5,
13.7, 13.1, 12.9, 12.3; HRMS (ESI-TOF, HCO2Na): MNaþ, found
682.1975. C32H45NNaO4S120Sn requires 682.1989.
Scheme 5. The reaction of 1a with allyltributyltin at 30 ꢀC.
Finally, a rough kinetic estimation was performed for the SHi
process in retention configuration, i.e., the process from radical B to
C. Although the kinetic parameter for the radical substitution re-
action of B to product 2 was already estimated to be 4.23ꢂ108 sꢁ1
,
this value was calculated at 30 ꢀC, and therefore cannot be used to
estimate and absolute value for the kinetic parameter of B to C.
However, an average of the product ratios between 2a and 3a was
found to be 2.3, which was unaffected by reaction conditions. Thus,
we believe that the rate constant of the SHi process in retention
configuration (B to C) should be 2.3 times smaller then that of the
SHi process in inversion configuration (B to 2). This is in good
agreement with our previous results in which the radical cascade
driven by PhBu2SnH produced a piperidine as a minor product.
4.3.2. (2S,3S)-tert-Butyl 3-allyl-2-phenyl-5-methylene-1-
tosylpiperidine-3-carboxylate
123.0e124.0 ꢀC; [
þ23.3 (c 0.06, CHCl3); nmax (neat) 1730, 1370,
1223 cmꢁ1
dH (500 MHz CDCl3) 7.29 (d, J¼6.3 Hz, 2H), 7.25e7.11 (m,
(4a). Colorless
solid;
mp
a]
D
;
5H), 6.97 (d, J¼8.5 Hz, 2H), 5.66e5.51 (m, 1H), 5.13 (s, 1H),
5.12e5.03 (m, 3H), 4.93 (d, J¼1.6 Hz, 1H), 4.15 (d, J¼14.1 Hz, 1H),
3.63 (d, J¼14.1 Hz, 1H), 2.92 (d, J¼15.7 Hz, 1H), 2.67 (dd, J¼14.2,
9.1 Hz,1H), 2.54 (dd, J¼13.6, 6.9 Hz,1H), 2.47 (d, J¼15.4 Hz,1H), 2.28
(s, 3H), 1.10 (s, 9H); dC (126 MHz, CDCl3) 171.8, 142.7, 137.5, 137.1,
136.2, 132.6, 130.0 (2C), 129.0 (2C), 128.2 (2C), 128.0, 127.2 (2C),
119.3, 114.2, 81.4, 77.4, 63.0, 50.5, 47.2, 40.7, 32.1, 27.6 (3C), 21.4;
HRMS (ESI-TOF, HCO2Na): MNaþ, found 490.2023. C27H33NNaO4S
requires 490.2028.
3. Conclusion
In conclusion, the present study reveals the reaction pathway
between aza-1,6-enynes and allyltributyltin, which made confusion
because of inconsistent results reported in literature. It is clearly
shown that the tin radical dominantly attacks from the
a,b-un-
saturated ester side and radical cascade reactions, including SHi
process progresses, occurs. The product ratio gives a rough esti-
mation of the difference in rate constants of the SHi process be-
tween the back-side attack (normal) and the front-side attacks.
Although the yields of the piperidine were rather low, this
4.3.3. (3S,3aS)-Methyl 5,5-dibutyl-3-(p-chlorophenyl)-2-tosyl-1,2,3,
3a,4,5-hexahydrostannolo[3,4-c]pyrrole-3a-carboxylate
(2b). Colorless oil; [
a
]
D
þ16.7 (c 1.03, CHCl3); nmax (neat) 1728,
Please cite this article in press as: Kamimura, A.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.04.078

4
A. Kamimura et al. / Tetrahedron xxx (2016) 1e5
1348, 1161 cmꢁ1
;
dH (500 MHz CDCl3) 7.51 (d, J¼7.7 Hz, 2H), 7.17 (d,
12.2; HRMS (ESI-TOF, HCO2Na): MNaþ, found 696.2131.
C
J¼7.2 Hz, 2H), 7.15 (d, J¼7.7 Hz, 2H), 6.94 (d, J¼7.8 Hz, 2H), 6.63 (s,
1H), 5.39 (s, 1H), 4.14e4.05 (m, 2H), 3.44 (s, 3H), 2.37 (s, 3H),
1.53e1.33 (m, 2H), 1.30e0.96 (m, 10H), 0.90 (d, J¼12.9 Hz, 1H), 0.83
(t, J¼7.3 Hz, 3H), 0.76 (t, J¼7.1 Hz, 3H), 0.16 (d, J¼13.1 Hz, 1H); dC
(126 MHz, CDCl3) 174.8, 157.2, 143.1, 138.5, 136.0, 133.5, 129.5,
129.4e129.3 (m, 2C), 129.3 (2C), 128.4 (2C), 127.5 (2C), 68.9, 67.9,
52.8, 50.6, 28.9, 28.8, 27.1, 27.0, 21.5, 13.7, 13.7, 13.7, 13.1, 12.5; HRMS
(ESI-TOF, HCO2Na): MNaþ, found 674.1113. C29H38ClNNaO4S120Sn
requires 674.1130.
33H47NNaO4S120Sn requires 696.2146.
4.3.8. (2S,3S)-tert-Butyl 3-allyl-2-(m-tolyl)-5-methylene-1-
tosylpiperidine-3-carboxylate
125.0e126.0 ꢀC; [
þ12.7 (c 0.22, CHCl3); nmax (neat) 1737, 1727,
1385, 1352, 1228, 1217, 1158 cmꢁ1
(4d). Colorless
solid;
mp
a
]
D
;
dH (500 MHz CDCl3) 7.23 (d,
J¼8.2 Hz, 2H), 7.07 (d, J¼7.4 Hz, 1H), 7.03e6.93 (m, 5H), 5.66e5.53
(m, 1H), 5.13e5.03 (m, 4H), 4.93 (s, 1H), 4.19 (d, J¼14.0 Hz, 1H), 3.66
(d, J¼13.3 Hz, 1H), 2.90 (d, J¼15.3 Hz, 1H), 2.68 (dd, J¼13.6, 8.5 Hz,
1H), 2.54 (dd, J¼13.8, 5.1 Hz, 1H), 2.46 (d, J¼15.3 Hz, 1H), 2.28 (s,
3H), 2.19 (s, 3H), 1.11 (s, 9H); dC (126 MHz, CDCl3) 171.8, 142.6, 137.6,
137.5, 136.8, 136.2, 132.7, 131.1, 128.9 (2C), 128.6, 128.0, 127.2 (2C),
126.6, 119.2, 114.2, 81.3, 63.1, 50.6, 47.4, 40.6, 32.0, 27.7 (3C), 21.4,
21.4; HRMS (ESI-TOF, HCO2Na): MNaþ, found 504.2182.
4.3.4. (2S,3S)-Methyl 3-allyl-2-(4-chlorophenyl)-5-methylene-1-
tosylpiperidine-3-carboxylate
158.0e159.0 ꢀC; [
ꢁ11.4 (c 0.14, CHCl3); nmax (neat) 1730, 1370,
1223 cmꢁ1
dH (500 MHz CDCl3) 7.22 (d, J¼8.1 Hz, 2H), 7.10 (d,
(4b). Colorless
solid;
mp
a
]
D
;
J¼8.1 Hz, 2H), 7.06 (dd, J¼8.3, 1.9 Hz, 2H), 7.00 (d, J¼7.0 Hz, 2H),
5.62e5.45 (m, 1H), 5.16 (s, 1H), 5.12e5.00 (m, 3H), 4.97 (q, J¼1.8 Hz,
1H), 4.29 (dt, J¼13.8, 1.4 Hz, 1H), 3.71 (d, J¼13.9 Hz, 1H), 3.41 (d,
J¼1.4 Hz, 3H), 2.81 (dt, J¼15.1, 2.0 Hz, 1H), 2.71e2.61 (m, 1H),
2.61e2.52 (m,1H), 2.48 (d, J¼15.2 Hz,1H), 2.32 (s, 3H); dC (126 MHz,
CDCl3) 173.0, 143.2, 136.5, 135.7, 135.7, 134.1, 132.3, 130.6 (2C), 129.1
(2C), 128.3 (2C), 127.1 (2C), 119.6, 114.9, 62.2, 51.8, 51.1, 47.5, 39.8,
31.2, 21.5; HRMS (ESI-TOF, HCO2Na): MNaþ, found 482.1177.
C28H35NNaO4S requires 504.2185.
4.3.9. (3S,3aS)-Methyl 5,5-dibutyl-3-(p-tolyl)-2-tosyl-1,2,3,3a,4,5-
hexahydrostannolo[3,4-c]pyrrole-3a-carboxylate (2e). Colorless oil;
[a]
þ15.5 (c 1.20, CHCl3); nmax (neat) 1728, 1344, 1161 cmꢁ1
; dH
D
(500 MHz CDCl3) 7.50 (d, J¼7.9 Hz, 2H), 7.13 (d, J¼7.9 Hz, 2H), 6.98 (d,
J¼7.7 Hz, 2H), 6.87 (d, J¼7.6 Hz, 2H), 6.60 (s,1H), 5.38 (s,1H), 4.13 (dd,
J¼13.0, 2.1 Hz, 1H), 4.09 (d, J¼14.2 Hz, 1H), 3.43 (s, 3H), 2.35 (s, 3H),
2.27 (s, 3H), 1.71 (s, 2H), 1.42 (dp, J¼16.6, 8.6, 8.0 Hz, 2H), 1.28e0.95
(m, 8H), 0.90 (d, J¼13.1 Hz, 1H), 0.82 (t, J¼7.4 Hz, 3H), 0.74 (t,
J¼7.0 Hz, 3H), 0.25 (d, J¼13.0 Hz, 1H); dC (126 MHz, CDCl3) 175.1,
157.8, 142.7, 137.2, 136.8, 136.2, 129.1 (2C), 128.9 (2C), 127.9 (2C), 127.5
(2C), 121.5, 69.0, 68.4, 52.7, 50.6, 39.4, 29.0, 28.8, 27.0, 25.2, 23.5, 21.5,
21.2, 13.7, 13.0, 12.4.; HRMS (ESI-TOF, HCO2Na): MNaþ, found
654.1666. C30H41NNaO4S120Sn requires 654.1676.
C
24H26ClNNaO4S requires 482.1169.
4.3.5. (3S,3aS)-tert-Butyl 5,5-dibutyl-3-(p-trifluoromethylphenyl)-2-
tosyl-1,2,3,3a,4,5-hexahydrostannolo[3,4-c]pyrrole-3a-carboxylate
(2c). Colorless oil; [
a]
D þ3.2 (c 1.06, CHCl3); nmax (neat) 1716, 1325,
1161 cmꢁ1
;
dH (500 MHz CDCl3) 7.46e7.41 (m, 2H), 7.38 (d, J¼7.8 Hz,
2H), 7.07 (d, J¼7.9 Hz, 4H), 6.60 (s, 1H), 5.47 (s, 1H), 4.13 (d,
J¼12.4 Hz,1H), 4.06 (d, J¼12.9 Hz,1H), 2.30 (s, 3H),1.46 (q, J¼8.0 Hz,
2H), 1.34 (s, 9H), 1.22 (dt, J¼14.4, 7.1 Hz, 4H), 1.15e0.94 (m, 6H), 0.90
(d, J¼13.1 Hz, 1H), 0.82 (t, J¼8.2, 6.4 Hz, 3H), 0.69 (t, J¼7.0 Hz, 3H),
0.09 (d, J¼12.4 Hz, 1H); dC (126 MHz, CDCl3) 173.3, 157.5, 144.0,
143.0, 136.2, 129.6 (q, J¼32.5 Hz), 129.2 (2C), 128.8, 128.4 (m), 128.2,
127.2 (2C), 125.0 (q, J¼3.7 Hz), 81.9, 69.5, 67.9, 50.7, 28.9, 28.7, 27.7
(3C), 27.1, 26.8, 23.4, 21.4, 13.7, 13.4, 13.2, 12.7, 12.2; HRMS (ESI-TOF,
HCO2Na): MNaþ, found 750.1872. C33H44F3NNaO4S120Sn requires
750.1863.
4.3.10. (2S,3S)-Methyl 3-allyl-2-(p-tolyl)-5-methylene-1-
tosylpiperidine-3-carboxylate
154.0e155.0 ꢀC; [
þ4.7 (c 0.21, CHCl3); nmax (neat) 1737, 1365,
1354, 1228, 1217, 1205 cmꢁ1
(4e). Colorless
solid;
mp
a]
D
;
dH (500 MHz CDCl3) 7.20 (d, J¼8.0 Hz,
2H), 7.05 (d, J¼7.3 Hz, 2H), 6.95 (d, J¼8.2 Hz, 2H), 6.89 (d, J¼7.7 Hz,
2H), 5.55 (dddd, J¼19.2, 10.6, 6.2, 1.6 Hz, 1H), 5.16 (s, 1H), 5.11e5.01
(m, 3H), 4.94 (s, 1H), 4.25 (dd, J¼13.7, 2.0 Hz, 1H), 3.73 (d, J¼13.3 Hz,
1H), 3.40 (s, 3H), 2.90 (d, J¼14.8 Hz, 1H), 2.68 (dd, J¼13.8, 7.9 Hz,1H),
2.58 (dd, J¼14.6, 6.4 Hz, 1H), 2.47 (d, J¼15.6 Hz,1H), 2.29 (s, 3H), 2.25
(s, 3H).; dC (126 MHz, CDCl3) 173.2, 142.7, 137.7, 137.1, 135.9, 134.1,
132.6, 129.1 (2C), 128.9 (2C), 128.8 (2C), 127.2 (2C), 119.3, 114.5, 62.7,
51.7, 51.2, 47.5, 39.8, 31.3, 21.5, 21.0.; HRMS (ESI-TOF, HCO2Na): MNaþ,
found 462.1713. C25H29NNaO4S requires 462.1715.
4.3.6. (2S,3S)-tert-Butyl 3-allyl-2-(p-trifluoromethylphenyl)-5-
methylene-1-tosylpiperidine-3-carboxylate (4c). Colorless solid;
mp 151.0e152.0 ꢀC; [
a
]
þ10.4 (c 0.17, CHCl3); nmax (neat) 1724,
D
1325, 1161 cmꢁ1
;
dH (500 MHz CDCl3) 7.42e7.31 (m, 4H), 7.25 (d,
J¼8.7 Hz, 2H), 6.99e6.93 (m, 2H), 5.63e5.52 (m, 1H), 5.17e5.04 (m,
4H), 4.96 (s, 1H), 4.27 (d, J¼12.9 Hz,1H), 3.65 (d, J¼14.3 Hz,1H), 2.83
(d, J¼15.0 Hz, 1H), 2.65 (dd, J¼14.8, 6.6 Hz, 1H), 2.54 (dd, J¼14.3,
6.1 Hz, 1H), 2.50 (d, J¼15.4 Hz, 1H), 2.27 (s, 3H), 1.11 (s, 9H); dC
(126 MHz, CDCl3) 171.4, 143.2, 141.0, 136.8, 135.8, 132.2, 130.2 (2C),
129.1 (2C), 127.0 (2C), 124.9 (2C, q, J¼3.4 Hz), 122.9 (q, J¼91.7 Hz),
122.8, 119.6, 114.8, 81.9, 62.5, 50.5, 47.5, 40.6, 31.9, 27.7 (3C), 21.3;
HRMS (ESI-TOF, HCO2Na): MNaþ, found 558.1899. C28H32F3NNaO4S
requires 558.1902.
Supplementary data
Supplementary data (Spectroscopic charts for compounds 2 and
4.) associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2016.04.078.
References and notes
1. Recent reviews, see: (a) Zimmerman, J.; Halloway, A.; Sibi, M. P. In Handbook of
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D
ꢀ
793; (f) Barrero, A. F.; Quílez del Moral, J. F.; Sanchez, E. M.; Arteaga, J. F. Eur. J.
(500 MHz CDCl3) 7.42e7.36 (m, 2H), 7.05 (d, J¼8.0 Hz, 2H), 7.01 (d,
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(m, 1H), 5.39 (s, 1H), 4.16 (dd, J¼12.9, 2.2 Hz, 1H), 3.99 (d, J¼12.9 Hz,
1H), 2.31 (s, 3H), 2.15 (s, 3H), 1.54e1.42 (m, 2H), 1.37 (s, 9H),
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(126 MHz, CDCl3) 173.9, 158.5, 142.5, 139.3, 137.5, 136.6, 129.0 (2C),
128.8e128.4 (br), 128.2, 127.9, 127.8, 127.3 (2C), 125.3, 81.6, 69.7,
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12. If an equilibrium process dominates in the formation of intermediate radical F,
Z-configuration in intermediated
C should be much preferred because of
avoiding steric hindrance caused between they methylene radical and the
Bu3Sn group in C. However, E-C intermediate is mainly formed in the reaction
performed at lower temperature (Scheme 5). In addition, we observed tin
radical always attacks the alkene unit first to form intermediate B in the pre-
vious results. See refs. 5 and 6.
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Please cite this article in press as: Kamimura, A.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.04.078