Facile Preparation of Functionalized 1-Substituted Cycloalkenes via an Iodine Atom Transfer Radical Addition-Elimination Process

Article abstract of DOI:10.1055/s-0035-1560555

An efficient and scalable two-step one-pot procedure for the preparation of cycloalkenes substituted with a functionalized alkyl side chain is reported. This method is based on a triethylborane-mediated iodine atom transfer radical addition (ATRA) of 1-io

Full text of DOI:10.1055/s-0035-1560555

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, 745–748
cluster
745
D. Meyer et al.
Cluster
Synlett
Facile Preparation of Functionalized 1-Substituted Cycloalkenes
via an Iodine Atom Transfer Radical Addition–Elimination Process
Daniel Meyer
Et3B, air
then DBU
CN
Estelle Vin
+
NC
I
93%
Benjamin Wyler
Guillaume Lapointe
Philippe Renaud*
EWG
n = 1–4, EWG = CO2Et, CN, SO2Ph
13 examples, 42–93% yield
endo/exo 84:16 to >98:2
University of Bern, Department of Chemistry and Biochemistry,
Freiestrasse 3, 3012 Bern, Switzerland
( )
n
philippe.renaud@dcb.unibe.ch
Received: 23.10.2015
Accepted after revision: 16.11.2015
Published online: 23.12.2015
In order to study this chemistry, an efficient access to 1-
(3-hydroxyprop-1yl)cycloalkenes was needed. Initially, we
focused our attention on transition-metal-catalyzed cross-
coupling reactions. Indeed, palladium- or nickel-catalyzed
Suzuki–Miyaura or Kumada cross-coupling reactions as
well as reactions involving higher order cuprates are pow-
erful methods for the construction of C–C bonds starting
from vinyl triflates.3,4 This approach was tested with the cy-
clohexenyl triflate derived from cyclohexanone and a tert-
butyl-protected 3-hydroxypropyl organometallic species
(Scheme 2). Suzuki and Kumada cross-couplings gave either
low yield or no product (Scheme 2, eq. 1 and 2). Better re-
sults were obtained with a higher-order cuprate (Scheme 2,
eq. 3). However, scaling up this reaction and removal of the
tert-butyl protecting group (the only protecting group that
gave good results) proved to be difficult. Finally, the high
price of N-(5-chloro-2-pyridyl)bis(trifluoromethanesul-
fonimide) (Comins reagent) used for the formation of the
alkenyl triflate led us to abandon this route and to find a
more convenient and scalable method.
DOI: 10.1055/s-0035-1560555; Art ID: st-2015-r0837-c
Abstract An efficient and scalable two-step one-pot procedure for the
preparation of cycloalkenes substituted with a functionalized alkyl side
chain is reported. This method is based on a triethylborane-mediated
iodine atom transfer radical addition (ATRA) of 1-iodoesters and related
compounds to methylenecycloalkanes followed by treatment of the in-
termediate tertiary iodide with 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) to promote a selective endo elimination.
Key words radical reaction, cycloalkenes, endo elimination, triethyl-
borane, methylenecycloalkene
Recently, our group has developed the anti-Mar-
kovnikov hydroazidation of alkenes.1 The azides resulting
from the hydroazidation of 1-(3-hydroxyprop-1yl)cy-
cloalkenes are potential precursors of indolizidine and re-
lated alkaloids via an intramolecular Schmidt reaction
(Scheme 1).2
As an alternative approach, a radical addition of 1-io-
doester to methylenecycloalkenes (easily available through
methylenation of the corresponding ketones) under iodine
atom transfer radical addition (ATRA) conditions followed
by a base-induced endo-selective elimination could solve
the problem (Scheme 3). Interestingly, Curran and cowork-
ers reported a spontaneous HI elimination during the reac-
tion between dimethyl methyliodomalonate and methy-
lenecyclohexane.5 A mixture of alkenes was obtained in low
yields (25%) but encouraging endo selectivity (Scheme 3, eq.
1). More recently, we described that the product resulting
from iodine ATRA to 4-phenylmethylenecyclohexane af-
fords selectively the endo-alkene upon treatment with ben-
zyl azide (Scheme 3, eq. 2).6 Curran and coworkers reported
intramolecular
Schmidt reaction
( )n
X
( )n
N
(X = OH)
ref. 2
N3
hydroazidation
ref. 1
X
( )n
Scheme 1 Retrosynthetic approach for the preparation of indolizidines
and related alkaloid skeletons from 1-alkylcycloalkenes
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 745–748

746
D. Meyer et al.
Cluster
Synlett
EtOH–H2O as solvent system we were able to increase the
yield of 3a to 70% with an increased regioselectivity for the
elimination reaction (endo/exo = 96:4).
R2B
Ot-Bu
OTf
Pd(dppf)Cl2 (10 mol%)
3 M Cs2CO3 aq, DMF
Ot-Bu
(1)
Ph
Ph
BR2 = 9-BBN
Et3B (0.5 equiv)
O2, r.t.
35%
CO2Et
then DBU (3 equiv)
+
EtO2C
I
BrMg
Ot-Bu
Ni(dppe) (5 mol%)
benzene
OTf
OTf
3a
1a
2 (2 equiv)
(2)
yield
17%
70%
no reaction
solvent
endo/exo
Ph
Ph
benzene
EtOH–H2O
91:9
96:4
BrMg
S
Ot-Bu
Scheme 4 Iodine ATRA reaction of ethyl 2-iodoacetate (2) to methy-
lenecyclohexane (1a) followed by DBU-promoted elimination
Cu(CN)Li
Ot-Bu
(3)
THF, HMPA
–78 to –20 °C
Ph
These optimized reaction conditions were then tested
for an iodine ATRA–elimination sequence using iodoester 2
and several methylenecycloalkenes9,10 1a–g (Scheme 5).11
First, the influence of the ring size was examined. The five-,
seven-, and eight-membered rings (1b–d) afforded the de-
sired product in 49–82% yield. The endo/exo selectivities
ranging from 84:16 (seven-membered ring) to 89:11 (eight-
membered ring) were obtained. The higher endo selectivity
obtained for the six-membered ring is ascribed to the per-
fect antiperiplanar diaxial arrangement of the iodine/hy-
drogen atoms in the chair conformation that favor the E2
elimination leading to the endo product 3a. Next, we inves-
tigated the reaction of substituted methylenecyclohexanes
1e and 1f. The 4-phenylmethylenecyclohexane (1e) gave
the alkene 3e in good yield (76%) and excellent regioselec-
tivity (endo/exo = 94:6). The dioxolanyl acetal 1f gave the
product in moderate yield (48%) and regioselectivity (en-
do/exo = 82:18). Finally, the reaction with 2-methylenein-
dane (1g) afforded the desired product 3g in 52% yield as a
single endo isomer.
90%
Scheme 2 Initial attempts to prepare 1-alkylcyclohexane from cyclo-
hexanone via cross-coupling reaction
during their pioneering work with dimethyl iodomethyl-
malonate5 that a β-substituted styrene could be prepared
by iodine ATRA onto styrene followed by treatment with
1,8-diazabicycloundec-7-ene (DBU) as a base to promote
the elimination of HI (Scheme 3, eq. 3).
1) ATRA
CO2Et
2) elimination
+
EtO2C
I
( )n
( )n
(Bu3Sn)2, hν
Me
CO2Me
CO2Me
65–85 °C
MeO2C
MeO2C
+
I
25%
(endo/exo 8:1)
Me
I
(1)
CO2Et
(2)
CO2Et
BnN3 (1 equiv)
72%
In order to demonstrate the scalability of the reaction,
we prepared 3a on multigram scale starting from 60 mmol
of olefin 1a. The alkene 3a was obtained in 74% yield as a
endo/exo mixture with a ratio of 96:4.12 For the scale-up, a
3:1 EtOH–H2O mixture was used as a solvent in order to
form a homogenous solution.
Ph
Ph
Me
(Bu3Sn)2, hν
CO2Me
CO2Me
(3)
Me
then DBU
MeO2C
MeO2C
+
70%
I
Finally, we turned our attention to the use of other io-
dides as precursors for the iodine ATRA–elimination se-
quence. Under the same reaction conditions, 2-iodoacetoni-
trile (4) and the iodomethyl phenyl sulfone (5)13 were test-
ed (Scheme 6). Reactions with nitrile 4 gave yields and
regioselectivities similar or higher than the corresponding
esters 3. The reaction of the iodomethyl phenyl sulfone (5)
with olefin 1e showed the highest endo/exo selectivity
(>98:2) of all iodides investigated with this substrate.
Scheme 3 Atom transfer addition followed by DBU-promoted elimina-
tion by Curran et al.
Our initial investigation started with the triethylborane-
induced reaction of methylenecyclohexane (1a) and ethyl
2-iodoacetate (2) followed by elimination with DBU in ben-
zene as solvent (Scheme 4). We obtained the corresponding
ester 3a in 17% yield with an endo/exo selectivity of 91:9.
Oshima and coworkers reported excellent results by run-
ning iodine ATRA reactions in aqueous media.7,8 By using
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 745–748

747
D. Meyer et al.
Cluster
Synlett
Acknowledgment
Et3B (0.5 equiv), O2, r.t.
EtOH–H2O
then DBU (3 equiv)
CO2Et
We thank the Swiss National Science Foundation (Project
200020_152782) for generous financial support. We are also grateful
to BASF Corporation for generous gift of Et3B.
+
EtO2C
I
( )n
( )n
1
2 (2 equiv)
CO2Et
endo-3
CO2Et
CO2Et
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560555.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
3b 49%b
endo/exo 88:12
3a 70% (74%)a
endo/exo 96:4
3c 53%
endo/exo 84:16
References and Notes
CO2Et
CO2Et
(1) Kapat, A.; König, A.; Montermini, F.; Renaud, P. J. Am. Chem. Soc.
2011, 133, 13890.
Ph
(2) Kapat, A.; Nyfeler, E.; Giuffredi, G. T.; Renaud, P. J. Am. Chem. Soc.
2009, 131, 17746.
3e 76%
endo/exo 94:6
3d 82%
endo/exo 89:11
(3) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(4) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1980, 21, 4313.
(5) Curran, D. P.; Chen, M. H.; Spletzer, E.; Seong, C. M.; Chang, C. T.
J. Am. Chem. Soc. 1989, 111, 8872.
(6) Maury, J.; Feray, L.; Bertrand, M. P.; Kapat, A.; Renaud, P. Tetra-
hedron 2012, 68, 9606.
(7) Yorimitsu, H.; Shinokubo, H.; Matsubara, S.; Oshima, K.; Omoto,
K.; Fujimoto, H. J. Org. Chem. 2001, 66, 7776.
(8) Yorimitsu, H.; Shinokubo, H.; Oshima, K. Synlett 2002, 674.
(9) Fitjer, L.; Quabeck, U. Synth. Commun. 1985, 15, 855.
(10) Yan, T.-H.; Tsai, C.-C.; Chien, C.-T.; Cho, C.-C.; Huang, P.-C. Org.
Lett. 2004, 6, 4961.
CO2Et
CO2Et
O
O
3g 52%b
3f 48%
endo/exo 82:18
endo/exo >98:2
Scheme 5 Atom transfer reactions with ethyl 2-iodoacetate 2. Elimina-
tion selectivity was determined by 1H NMR spectroscopy [endo:
(C=CHCH2) δ = ca. 5.5 ppm; exo (C=CHCH2) δ = ca. 3 ppm]. a 60 mmol
scale reaction. b EtOH–H2O (3:1) as solvent.
(11) General Procedure for Iodine ATRA–Elimination Reaction
A solution of Et3B (0.5 mL, 1.0 M in EtOH, 0.5 mmol) was added
over 2 h by syringe pump to a stirred mixture of the iodide 2, 4,
or 5 (2.0 mmol) and olefin 1 (1 mmol) in EtOH–H2O (1:1, 10 mL)
in the dark and open to air. After complete addition, the brown
mixture was allowed to stir for 1 h at r.t. DBU (457 mg, 3 mmol)
was added at 0 °C, and the mixture was stirred at r.t. overnight.
After addition of a sat. aq solution of NH4Cl (50 mL), the mixture
was extracted with Et2O (20 and 10 mL), and the organic phases
were washed with brine (10 mL). The combined organic layers
were dried over Na2SO4 and concentrated. The crude product
was purified by column chromatography.
In conclusion, we have developed an iodine ATRA–elim-
ination process that converts readily available methy-
lenecycloalkenes into functionalized 1-substituted cy-
cloalkenes. This method does not require the use of any
transition metal and afforded the desired product in 48–
93% yield and endo/exo selectivities ranging from 82:18 to
>98:2. The applicability of the method to multigram syn-
thesis has been demonstrated.
Et3B (0.5 equiv), O2, r.t.
EtOH–H2O
then DBU (3 equiv)
EWG
Ethyl 3-{1,2,3,6-Tetrahydro-[1,1′-biphenyl]-4-yl}propanoate
(3e)
+
EWG
I
4,6: EWG = CN
5,7: EWC = SO2Ph
( )n
( )n
Colorless and clear oil; 76% yield; endo/exo = 94:6. 1H NMR (300
MHz, CDCl3): δ = 7.34–7.15 (m, 5 H), 5.54–5.48 (m, 1 H), 4.14 (q,
J = 7.1 Hz, 2 H), 2.80–2.67 (m, 1 H), 2.47–2.40 (m, 2 H), 2.35–
2.21 (m, 3 H), 2.20–1.91 (m, 4 H), 1.82–1.68 (m, 1 H), 1.26 (t,
J = 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 173.5, 147.1,
136.1, 128.3 (2 C), 126.9, 126.8, 126.0, 121.2, 60.3, 40.1, 33.4,
32.9, 32.6, 30.0, 28.9, 14.3. IR (neat): 3043, 2915, 2087, 1731,
1602, 1493, 1160, 916. HRMS (ESI-TOF): m/z calcd for C17H23O2
[M + H]+: 259.1693; found: 259.1691.
4,5 (2 equiv)
1
endo-6,7
CN
CN
CN
6b 50%a
6d 52%
6a 93%
endo/exo 93:7
SO2Ph
endo/exo >98:2
endo/exo 94:6
CN
CN
3-{1,2,3,6-Tetrahydro-[1,1′-biphenyl]-4-yl}propanenitrile
(6e)
O
Ph
Ph
O
Colorless and clear oil; 70% yield; endo/exo = 94:6. 1H NMR (300
MHz, CDCl3): δ = 7.32–7.26 (m, 2 H), 7.25–7.16 (m, 3 H), 5.67–
5.61 (m, 1 H), 2.83–2.70 (m, 1 H), 2.51–2.47 (m, 2 H), 2.40–2.27
(m, 3 H), 2.26–2.10 (m, 2 H), 2.08–1.93 (m, 2 H), 1.85–1.71 (m, 1
H). 13C NMR (100 MHz, CDCl3): δ = 146.6, 133.9, 128.4 (2 C),
126.9 (2 C), 126.1, 123.6, 119.6, 39.8, 33.3, 33.0, 29.8, 28.5, 16.1.
IR (neat): 3025, 2919, 2836, 2248, 1602, 1494, 1436, 908, 729,
7e 68%
endo/exo >98:2
6e 70%
endo/exo 94:6
6f 42%
endo/exo 91:9
Scheme 6 Atom transfer reactions with α-iodoacetonitrile (4) and io-
domethyl phenyl sulfone (5). The endo/exo regioselectivity was deter-
mined by 1H NMR spectroscopy. a EtOH–H2O (3:1) as solvent.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 745–748

748
D. Meyer et al.
Cluster
Synlett
699. HRMS (ESI-TOF): m/z calcd for C15H18N [M + H]+: 212.1434;
found: 212.1427.
4-[2-(Phenylsulfonyl)ethyl]-1,2,3,6-tetrahydro-1,1′-biphenyl
(7e)
5.77 g, 60 mmol) in EtOH–H2O (3:1, 60 mL) in the dark and open
to air. After complete addition, the brown mixture was allowed
to stir for 2 h at r.t. DBU (27.40 g, 180 mmol) was added at
<10 °C, and the mixture was stirred at r.t. overnight. After addi-
tion of a sat. aq solution of NH4Cl (150 mL), the mixture was
extracted with pentane (150 and 75 mL), and the organic
phases were washed with H2O (75 mL), dried over Na2SO4, and
concentrated. The crude product was purified by column chro-
matography (Et2O–pentane, 5:95) to provide 3a (8.06 g, 74%) as
a colorless and clear oil. 1H NMR (300 MHz, CDCl3): δ = 5.45–
5.37 (m, 1 H), 4.12 (q, J = 7.1 Hz, 2 H), 2.45–2.33 (m, 2 H), 2.25 (t,
J = 7.7 Hz, 2 H), 2.02–1.87 (m, 4 H), 1.67–1.47 (m, 4 H), 1.25 (t,
J = 7.1 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 173.6, 136.1,
121.6, 60.2, 33.1, 33.0, 28.3, 25.2, 22.9, 22.4, 14.3. IR (neat):
2925, 1733, 1445, 1368, 1340, 1288, 1248, 1157, 1081, 1038,
919, 856, 838 cm–1. HRMS (ESI-TOF): m/z calcd for C11H18O2Na
[M + Na]+: 205.1199; found: 205.1193.
Amorphous white solid; 68% yield; endo/exo >98:2; mp 80–
1
82 °C. H NMR (300 MHz, CDCl3): δ = 8.01–7.88 (m, 2 H), 7.72–
7.52 (m, 3 H), 7.32–7.26 (m, 2 H), 7.32–7.25 (m, 3 H), 5.53–5.46
(m, 1 H), 3.28–3.18 (m, 2 H), 2.72–2.58 (m, 1 H), 2.46–2.37 (m, 2
H), 2.28–2.16 (m, 1 H), 2.15–2.00 (m, 2 H), 1.99–1.85 (m, 2 H),
1.75–1.57 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ = 146.6, 139.3,
133.7, 133.4, 129.3, 128.4, 128.1, 126.8, 126.1, 123.2, 54.8, 39.7,
33.3, 30.3, 29.7, 28.8. IR (neat): 2939, 2892, 2831, 1495, 1446,
1305, 1283, 1147, 1139, 1121, 1088, 887. HRMS (ESI-TOF): m/z
calcd for C20H23O2S [M + H]+: 327.1413; found: 327.1404.
(12) Scale-up Experiment for Ethyl 3-(Cyclohex-1-en-1-yl)propa-
noate (3a)
A solution of Et3B (30 mL, 1.0 M in EtOH, 30 mmol) was added
over 2 h by syringe pump to a stirred solution of ethyl 2-iodoac-
etate (2, 25.68 g, 120 mmol) and methylenecyclohexane (1a,
(13) Jończyk, A.; Pytlewski, T. Synthesis 1978, 883.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 745–748