Ruthenium-catalyzed synthesis of 1,5-dichlorides by sequential intermolecular Kharasch reactions

Article abstract of DOI:10.1002/ejoc.201001213

Sequential intermolecular atom transfer radical addition reactions of activated dichlorides Cl₂CRR′ (R = CN, CO₂Et, R′ = H, CN, CO₂Et) with two olefins catalyzed by [Cp*RuCl₂(PPh₃)] in the presence Mg

Full text of DOI:10.1002/ejoc.201001213

FULL PAPER
DOI: 10.1002/ejoc.201001213
Ruthenium-Catalyzed Synthesis of 1,5-Dichlorides by Sequential
Intermolecular Kharasch Reactions
Katrin Thommes,[a] Mariano A. Fernández-Zúmel,[a] Charlotte Buron,[a] Aurélien Godinat,[a]
Rosario Scopelliti,[a] and Kay Severin*[a]
Keywords: Radical reactions / Ruthenium / Sequential reactions
Sequential intermolecular atom transfer radical addition re- products are interesting synthetic precursors as demon-
actions of activated dichlorides Cl2CRRЈ (R = CN, CO2Et, RЈ
H, CN, CO2Et) with two olefins catalyzed by
[Cp*RuCl2(PPh3)] in the presence Mg allow the synthesis of
linear 1,5-dichlorides. Different olefins can be employed in
the first and in the second addition reaction. The reaction
strated by the synthesis of two cyclopentanes by Mg-induced
dechlorination. The structure of trans-3,4-diphenylcyclopen-
tanecarbonitrile was determined by single-crystal X-ray dif-
fraction.
=
Kharasch reactions of 1,6-dienes with CXCl3 (X = Br, Cl)
have been investigated by several groups.[5b,6c,11] These reac-
tions provide cyclopentanes (3) as a mixture of stereo-
isomers (Scheme 1, d). Formally, these reactions can be re-
garded as ATRA-ATRC sequences, but the reactions pro-
ceed likely via a single ATRA step which is intercepted by
an intramolecular radical cyclization.
Introduction
The anti-Markovnikov addition of halogenated com-
pounds to olefins via a radical mechanism (Kharasch reac-
tion)[1] can be achieved by photochemical activation, with
radical initiators, or with transition metal catalysts.[2] The
latter method is particularly appealing because the reac-
tions can be carried out under mild conditions with good
selectivity. Numerous transition metal complexes are able
to catalyze atom transfer radical addition (ATRA) reac-
tions. The best performance is typically observed for Cu[3]
and Ru[4] catalysts, in particular if the catalysts are used in
conjunction with reducing agents such as diazo initiators[5]
or Mg.[6]
An interesting feature of ATRA reactions is that they
can be performed in a sequential fashion. The ultimate se-
quential reaction is a polymerization (Scheme 1, a). Atom
transfer radical polymerization (ATRP) reactions have been
studied extensively over the last years because they allow to
obtain polymers with good control over molecular weight,
structure, and composition.[7] In the context of synthetic
organic chemistry, sequential ATRA reactions have been
used to build complex molecules. The group of Itoh, for
example, has shown that a bicyclic lactam (1) can be ob-
tained by double atom transfer radical cyclizations (ATRC)
followed by elimination of HCl (Scheme 1, b).[8,9] The intra-
molecular cyclization can also be combined with an inter-
molecular ATRA reactions as demonstrated the successful
synthesis of lactam 2 (Scheme 1, c).[10] Intermolecular
[a] Institut des Sciences et Ingénierie Chimiques,
École Polytechnique Fédérale de Lausanne (EPFL),
1015 Lausanne, Switzerland
Scheme 1. Sequential atoms transfer radical addition (ATRA) and
cyclization (ATRC) reactions.
Fax: +41-21-693-9305
E-mail: kay.severin@epfl.ch
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Table 1. Sequential ATRA reactions catalyzed by [Cp*RuCl2(PPh3)] in the presence of Mg.[a]
[a] Reaction conditions: [chlorinated substrate] 0.50 m, [olefin] 1.50 m, [Ru] 5.0 mm (1.0 mol-%), [Mg] 30 equiv. with respect to the chlori-
nated substrate, toluene, 60 °C. [b] Isolated yields with respect to the chlorinated substrate. [c] Ratio [styrene]/[Cl2CHCO2Et] 2.5:1. [d]
Conditions: [Cl2C(CN)2] 0.30 m, [2-vinylnaphthalene] 0.90 m, [Ru] 3.0 mm (1.0 mol-%), [Mg] 30 equiv.
Below we report that it is possible to perform double
Kharasch reactions with dichlorinated compounds in a
purely intermolecular fashion (Scheme 1, e). The ATRA-
ATRA reaction sequence can be performed with one or
with two types of olefins allowing the efficient preparation
of structurally diverse 1,5-dichlorides. The latter are inter-
esting synthetic precursors as demonstrated by the synthesis
if cyclopentanes by Mg-induced reductive coupling
(Table 1).
Scheme 2. Regio- and chemoselectivity need to be controlled for
sequential ATRA reactions.
Results and Discussion
Double ATRA reactions involving 1,1-dichlorides face of the intermediate 1,3-dichloride. Furthermore, they
two synthetic challenges (Scheme 2). On one hand, oligo- should render the intermediate 1,3-dichloride more reactive
merization has to be suppressed, i.e. the reaction has to be than the 1,5-dichloride product, which would allow to avoid
stopped after two ATRA steps. The second difficulty is to problems with oligomerization.
achieve a good regioselectivity. The reaction product after
The addition of dichloroacetonitrile to styrene was used
the first ATRA is a 1,3-dichloride and both halides could as a test reaction. As a catalyst, we decided to employ the
react in the second step.
Ru complex [Cp*RuCl2(PPh3)] in combination with Mg.
We hypothesized that it should be possible to solve both Mg reduces the RuIII precursor in situ to a catalytically
problems by using appropriate electron-withdrawing sub- active RuII species, and it helps to avoid the accumulation
stituents on the dichlorinated substrate. These substituents of undesired RuIII complexes during the course of the reac-
(R2 and R3) should selectively activate the adjacent chloride tion.[6a] Screening of different reaction conditions revealed
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Ruthenium-Catalyzed Synthesis of 1,5-Dichlorides
that the double Kharasch adduct 4 could be obtained in nation in THF.[6b] We were thus interested to see whether
91% isolated yield when styrene and dichloroacetonitrile 1,5-dichlorides could be cyclized in a similar fashion to give
were used in a ratio of 3:1 (Table 1, entry 1). The high yield cyclopentanes. It should be noted that the reductive cycliza-
of the desired 1,5-dichloride shows that the second ATRA tion of alkyl 1,5-dihalides has been reported before, but pre-
reaction proceeds with good regioselectivity at the chloro vious attempts have focused on the more reactive bromides
atom next to the electron-withdrawing nitrile group. The and iodides.[12]
one-pot reaction proceeds in a step-wise fashion via an 1,3-
When a mixture of 4-chloro-2-(2-chloro-2-phenylethyl)-
dichloride intermediate. The latter could be identified when 4-phenylbutanenitrile (4), Mg (10 equiv., activated with
reaction mixtures were analyzed after shorter times by gas 5 mol-% of DIBAL-H) and LiCl[13] in THF was stirred for
chromatography (GC). p-Chloro- and p-fluorostyrene could 2 h at room temperature, the desired cyclopentane 15 could
be coupled in a similar fashion to give the chlorinated ni- indeed be detected by GC–MS (Scheme 3, a). In a reaction
triles 5 and 6 in good yields after 48 h (Table 1, entries 2 on preparative scale, 15 was obtained with an isolated yield
and 3). Clean reactions were observed as well with the dou- of 49% as a mixture of three stereoisomers (ratio: 4:1:1).
bly activated chlorides Cl2C(CN)2 and Cl2C(CN)(CO2Et) Interestingly, the entire ATRA-ATRA-dechlorination reac-
(Table 1, entries 4–6). For the reaction of styrene with tion sequence could also be performed in one pot
Cl2C(CO2Et)2, however, a lower yield of 70% was obtained (Scheme 3, b). After the second ATRA reaction had com-
due to the formation of side products, which were hard to pleted, the toluene solution was diluted with THF contain-
separate (Table 1, entry 7). For all cases listed in Table 1, ing LiCl to induce cyclization. The yield for this one-pot
the products were obtained as a mixture of two or more reaction was 60%, which is higher than what was obtained
diastereoisomers. The isomer ratios are given in the experi- in the two-step procedure (presumably because only one
mental part.
isolation step was involved). A similar behavior was ob-
Next, we have investigated the possibility to perform served for 4-chloro-2-[2-chloro-2-(4-fluorophenyl)ethyl]-4-
double ATRA reactions with two different olefins. First, the (4-fluorophenyl)butanenitrile (6). A Mg-induced cyclization
less reactive olefin (1.1 equiv.) was allowed to react with gave cyclopentane 16 in 39% yield as a mixture of isomers.
Cl2C(CN)2 to give the mono Kharasch adduct. After time A one-pot reaction according to Scheme 3 (b) gave slightly
t1, olefin 2 was added to the mixture and the reaction was better results (42%). Attempts to cyclize more reactive dicy-
stirred for another period t2. Using this one-pot, two-step ano compounds such as 7 were not successful.
procedure it was possible to obtain the corresponding 1,5-
dichlorides 11–14 as a mixture of stereoisomers in moderate acterized by single-crystal X-ray crystallography. The two
to good yield (Table 2). phenyl groups of 15C show a trans configuration (Figure 1),
The main isomer of 15 (15C, see Exp. Section) was char-
We have recently reported that cyclopropanes can be syn- which is expected to be more stable than the cis configura-
thesized from 1,3-dichlorides (the reaction products of sin- tion because repulsive interactions between the phenyl rings
gle ATRA and ATRC reactions) by Mg-induced dechlori- are minimized.
Table 2. Sequential ATRA reactions with two different olefins catalyzed by [Cp*RuCl2(PPh3)] in the presence of Mg.[a]
[a] Reaction conditions: [olefin 1] 0.55 m, [chlorinated substrate] 0.50 m, [olefin 2] 1.00 m, [Ru] 5.0 mm (1.0 mol-%), [Mg] 30 equiv. with
respect to the chlorinated substrate, toluene, 60 °C. [b] Isolated yields with respect to the chlorinated substrate. [c] Conditions: [olefin 1]
0.44 m, [chlorinated substrate] 0.40 m, [olefin 2] 0.80 m, [Ru] 4.0 mm (1.0 mol-%), [Mg] 30 equiv.
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FULL PAPER
powder was agitated by a stirring bar under an atmosphere of dry
dinitrogen for 5 d before use. LiCl was dried under vacuum at
140 °C for 5 h.[13] Catalyst [Cp*RuCl2(PPh3)][15] and the substrates
[16]
Cl2C(CO2Et)CN[16] and Cl2C(CO2Et)2 were synthesized accord-
ing to literature procedures. The 1H and 13C spectra were recorded
on a Bruker Avance DPX 400 spectrometer with the residual sol-
vents as internal standards. All spectra were recorded at room tem-
perature. Column chromatography was performed using Silica Gel
60 (230–400 mesh, 0.04–0.063 nm) from Fluka. Plates with Silica
Gel 60 F245 from Merck were used for thin-layer chromatography.
Elemental analyses were performed on a EA 1110 CHN instru-
ment.
General Procedure for Sequential ATRA Reactions with One Olefin:
Mg powder (30 equiv.) and toluene were added to a flask contain-
ing the desired amount of the Ru catalyst. The olefin (3.0 or
2.5 equiv.) and the chlorinated substrate (1.0 equiv.) were added
([chlorinated substrate] 0.5 m) and the mixture was stirred at 60 °C.
After the given time, the crude reaction mixture was filtered and
the solvent was removed under reduced pressure. The product was
purified by flash chromatography.
Scheme 3. Regio- and chemoselectivity for sequential ATRA reac-
tions.
General Procedure for Sequential ATRA Reactions with Two Dif-
ferent Olefins: Mg powder (30 equiv.) and toluene were added to a
flask containing the desired amount of the Ru catalyst. Olefin 1
(1.1 equiv.) and the chlorinated substrate (1.0 equiv.) were added
([chlorinated substrate]final 0.5 m) and the mixture was stirred at
60 °C. After time t1, olefin 2 (2.0 equiv.) was added and the reaction
was stirred again at 60 °C. After time t2, the crude reaction mixture
was filtered and the solvent was removed under reduced pressure.
The product was purified by flash chromatography.
Figure 1. Molecular structure of cyclopentane 15C in the crystal,
shown with 40% thermal probability ellipsoids. Selected bond
lengths [Å] and angles [°]: N1–C6 1.139(4), C1–C6 1.471(5), C1–
C2 1.542(4), C1–C5 1.547(4), C2–C3A 1.522(6), C3A-C4A
1.543(7), C4A–C5 1.554(6); C6–C1–C2 112.5(3), C6–C1–C5
113.3(3), N1–C6–C1 178.9(5).
General Procedure for Mg-Induced Reductive Cyclopentanations.
Method A: Mg powder (231 mg, 10 equiv.), LiCl (201 mg, 5 equiv.)
and DIBAL-H (48 μL of a 1 m solution in hexanes, 5 mol-% with
respect to substrate) were added to a flask containing THF (5 mL).
The mixture was stirred for 5 min and then a THF solution
(4.5 mL) of the chlorinated substrate (0.95 mmol) was added
([chlorinated substrate]final 0.5 m). After stirring for 2 h at room
temp., the reaction mixture was filtered under an inert atmosphere
and Et2O and a saturated aqueous solution of NH4Cl were added.
After biphasic separation, the aqueous phase was extracted again
with Et2O. The organic phases were mixed, washed with brine,
dried with MgSO4, and the solvents were removed under reduced
pressure.
Conclusions
We have demonstrated that it is possible to perform se-
quential intermolecular atom transfer radical addition reac-
tions of activated dichlorides to olefins with the help of a
Ru catalyst.[14] Different chlorinated substrates and olefins
can be used to give selectively 1,5-dichlorides in good yields.
The stereo-control of the reactions is poor, which is not
unexpected for this type of radical addition reaction. How-
ever, this one-pot three-component reaction provides easy
access to a diverse set of linear 1,5-dichlorides, which are
difficult to prepare otherwise. An interesting perspective is
the utilization of 1,5-dichlorides as precursors for cyclopen-
tanes. The successful synthesis of compounds 15 and 16
demonstrates that a reductive coupling is possible, but fur-
ther optimization of the reaction conditions is needed to
improve yields and substrate scope.
Method B: Mg powder (1.82 g, 30 equiv.) and toluene were added
to a flask containing the Ru catalyst (14.2 mg, 1 mol-%). The olefin
(3.0 equiv.) and dichloroacetonitrile (200 μL, 1.0 equiv.) were added
([Cl2CHCN]final 0.5 m) and the mixture was stirred at 60 °C. After
48 h, the reaction mixture was cooled to room temperature and
diluted to four times the original volume using a 0.5 m solution of
LiCl in THF. After stirring for 2 h at room temp. the mixture was
filtered under an inert atmosphere and Et2O and a saturated aque-
ous solution of NH4Cl were added. After biphasic separation, the
aqueous phase was extracted again with Et2O. The organic phases
were mixed, washed with brine, dried with MgSO4, and the solvents
were removed under reduced pressure. In both cases (Methods A
and B) the product was purified by flash chromatography.
Experimental Section
General: All reactions were performed under an atmosphere of dry
dinitrogen using a glovebox or standard Schlenk and vacuum-line
techniques. The solvents and liquid substrates were distilled from
appropriate drying agents according to the literature and stored
under nitrogen. The olefinic substrates were stored at a temperature
of –18 °C. The solvents and the chlorinated esters as well as the
Characterization of Products: All products except for 16 were ob-
tained as a mixture of isomers. For the assignment of the 1H NMR
spectra, the different isomers were labeled as A, B, and C. Due to
solids were kept at room temperature. Before use, commercial overlap of peaks in the 13C NMR spectra, the correct number of
chemicals were put under an atmosphere of dry nitrogen. The Mg
peaks could not always be observed.
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Ruthenium-Catalyzed Synthesis of 1,5-Dichlorides
115.90–116.34 (m, aromatic), 119.70, 119.74, 119.86 (CN), 128.58–
136.12 (m, aromatic), 161.55–164.16 (m, C-F). C18H15Cl2F2N
(354.23): calcd. C 61.03, H 4.27, N 3.95; found C 61.05, H 4.33, N
4.01.
2,2-Bis(2-chloro-2-phenylethyl)malononitrile (7): Flash chromatog-
raphy on silica gel: hexane/ethyl acetate, 88:12. The product (1.51 g,
88%) was obtained as a mixture of 2 diastereoisomers (ratio from
GC: A:B = 1.0:1.1). 1H NMR (CDCl3, 400 MHz): δ = 2.60–2.83
(m, CH2, 8 H, A, B), 5.15–5.21 (m, CHCl, 4 H, A, B), 7.35–7.50
(m, aromatic, 20 H, A, B). 13C NMR (CDCl3, 100 MHz): δ = 34.08
[C(CN)2], 47.12, 47.19 (CH2), 57.83, 57.88 (CHCl), 112.49, 113.23,
114.05 (CN), 127.24 (br), 129.28 (br), 129.82 (br), 138.45 (aro-
matic). C19H16Cl2N2 (343.26): calcd. C 66.48, H 4.70, N 8.16;
found C 66.36, H 4.78, N 8.17.
2,2-Bis[2-chloro-2-(naphthalen-2-yl)ethyl]malononitrile (8): Flash
chromatography on silica gel: hexane/ethyl acetate, 88:12. The
product (2.00 g, 90%) was obtained as a mixture of 2 diastereoiso-
mers (ratio from GC: A:B = 1.0:1.0). 1H NMR (CDCl3, 400 MHz):
δ = 2.64–2.94 (m, CH2, 8 H, A, B), 5.33–5.38 (m, CHCl, 4 H, A, B),
7.43–7.57 (m, aromatic, 6 H, A, 6 H, B), 7.77–7.90 (m, aromatic, 8
H, A, 8 H, B). 13C NMR (CDCl3, 100 MHz): δ; 34.23 [C(CN)2],
46.76, 46.86 (CH2), 58.26, 58.35 (CHCl), 112.66, 113.44, 114.23
(CN), 123.80, 123.84, 126.86, 126.91, 127.01, 127.22, 127.86,
128.26, 128.28, 129.58, 129.59, 132.91, 133.66, 135.52, 135.60 (aro-
matic). C27H20Cl2N2 (443.38): calcd. C 73.14, H 4.55, N 6.32;
found C 72.84, H 4.54, N 6.29.
4-Chloro-2-(2-chloro-2-phenylethyl)-4-phenylbutanenitrile (4): Flash
chromatography on silica gel: hexane/ethyl acetate, 9:1. The prod-
uct (1.45 g, 91%) was obtained as a mixture of 3 diastereoisomers
1
1
(ratio from H NMR: δ = A:B:C = 1.0:1.0:1.8). H NMR (CDCl3,
400 MHz): δ = 2.19–2.41 (m, CH2, 7 H, A, B, 3 H, C), 2.47–2.62
(m, CH2, 1 H, A or B, 1 H, C, CHCN, 1 H, A or B), 2.87–2.97
(m, CHCN, 1 H, C), 3.52–3.62 (m, CHCN, 1 H, A or B), 4.99–
5.15 (m, CHCl, 6 H, A, B, C), 7.25–7.39 (m, aromatic, 30 H, A, B,
C). 13C NMR (CDCl3, 100 MHz): δ = 27.33, 27.99, 28.71 (CHCN),
41.10, 41.89, 41.94, 42.41 (CH2), 59.33, 59.36, 60.58, 60.80 (CHCl),
119.92, 120.02, 120.09 (CN), 126.81, 126.83 (br), 126.94 (br),
127.01, 129.04 (br), 129.12, 129.21 (br), 129.28, 139.10, 139.21,
140.091, 140.24 (aromatic) ppm. C18H17Cl2N (318.25): calcd. C
67.93, H 5.38, N 4.40; found C 68.05, H 5.32, N 4.46.
Ethyl 4-Chloro-2-(2-chloro-2-phenylethyl)-2-cyano-4-phenylbutano-
ate (9): Flash chromatography on silica gel: hexane/ethyl acetate,
85:15. The product (1.77 g, 90%), was obtained as a mixture of 3
diastereoisomers (ratio from 1H NMR A:B:C = 1.0:2.0:3.0). 1H
NMR (CDCl3, 400 MHz): δ = 0.87, (t, J = 7.2 Hz, CH3, 3 H, B),
1.16 (dd, J = 7.2, 7.2 Hz, CH3, 3 H, C), 1.43 (t, J = 7.2 Hz, CH3,
3 H, A), 2.26–2.31 (m, CH2, 2 H, A), 2.43–2.47 (m, CH2, 1 H, B),
2.52–2.57 (m, CH2, 1 H, B), 2.67–2.72 (m, CH2, 2 H, B), 2.84–3.00
(m, CH2, 2 H, A, 4 H, C, OCH2, 2 H, B), 3.57–3.84 (m, OCH2, 2
H, C), 4.36 (q, J = 7.2 Hz, OCH2, 2 H, A), 5.08–5.18 (m, CHCl, 6
H, A, B, C), 7.24–7.45 (m, aromatic, 30 H, A, B, C). 13C NMR
(CDCl3, 100 MHz): δ = 13.17, 13.53, 13.82 (CH3), 46.86 (CH2),
46.97 (CCN), 47.09 (CH2), 47.31 (CCN), 47.51 (CH2), 47.55
(CCN), 47.82 (CH2), 58.49, 58.62, 58.93, 58.96 (CHCl), 62.93,
63.26, 63.66 (OCH2), 116.93, 117.11, 117.21 (CN), 126.92, 127.8,
127.89, 128.60, 128.69, 128.99, 129.03, 129.11, 129.14, 129.18,
129.21, 138.6, 138.7, 140.2 (aromatic), 166.26, 167.06, 167.79 (CO-
4-Chloro-2-[2-chloro-2-(4-chlorophenyl)ethyl]-4-(4-chlorophenyl)-
butanenitrile (5): Flash chromatography on silica gel: hexane/ethyl
acetate, 9:1. The product (1.75 g, 90%) was obtained as a mixture
of 3 diastereoisomers (ratio from 1H NMR A:B:C = 1.0:1.7:2.3).
1H NMR (CDCl3, 400 MHz): δ = 2.19–2.40 (m, CH2, 3 H, A, 4 H,
B, 3 H, C), 2.43–2.59 (m, CH2, 1 H, A, 1 H, C, CHCN, 1 H, A),
2.85–2.94 (m, CHCN, 1 H, C), 3.50–3.58 (m, CHCN, 1 H, B), 4.93–
5.09 (m, CHCl, 6 H, A, B, C), 7.25–7.41 (m, aromatic, 24 H, A, B,
C) ppm. 13C NMR (CDCl3, 100 MHz): δ = 27.20, 27.91, 28.63
(CHCN), 40.89, 41.77, 41.86, 42.35 (CH2), 58.30, 58.36, 59.63,
59.84 (CHCl), 119.63, 119.67, 119.78 (CN), 128.16, 128.18, 128.31,
128.37, 129.23 (br), 129.35, 129.44, 134.87, 134.89, 135.14, 135.15,
137.51, 136.64, 138.50, 138.66 (aromatic) ppm. C18H15Cl4N
(387.14): calcd. C 55.84, H 3.91, N 3.62; found C 55.76, H 3.94, N
3.57.
OEt). IR (film): ν = 1737 (C=O) cm–1. C H Cl NO (390.31):
˜
21 21
2
2
calcd. C 64.92, H 5.42, N 3.59; found C 65.03, H 5.70, N 3.58.
Diethyl 2,2-Bis(2-chloro-2-phenylethyl)malonate (10): Flash
chromatography on silica gel: hexane/ethyl acetate, 9:1. The prod-
uct (1.23 g, 70%) was obtained as a mixture of 2 diastereoisomers
(ratio from 1H NMR: A:B = 1.0:1.4). 1H NMR (CDCl3, 400 MHz):
δ = 1.14 (t, J = 7.1 Hz, CH3, 3 H, B), 1.18 (dd, J = 7.1, 7.1 Hz,
CH3, 6 H, A), 1.28 (t, J = 7.1 Hz, CH3, 3 H, B), 2.83–3.05 (m,
CH2, 8 H, A, B), 3.84–4.03 (m, OCH2, 4 H, A, 2 H, B), 4.16 (q, J
= 7.14 Hz, OCH2, 2 H, B), 4.86–4.90 (m, CHCl, 2 H, A), 4.97–
5.00 (m, CHCl, 2 H, B), 7.29–7.41 (m, aromatic, 20 H, A, B). 13C
NMR (CDCl3, 100 MHz): δ = 13.58, 13.79, 13.82, 13.92 (CH3),
42.03, 42.19 (CH2), 55.72, 55.74 [C(CO2Et)2], 58.86, 59.07 (CHCl),
61.64, 61.83, 61.91 (OCH2), 127.06, 127.16, 128.65, 128.71, 128.75,
128.76, 141.39, 141.56 (aromatic), 169.54, 169.81, 170.40 (COOEt).
4-Chloro-2-[2-chloro-2-(4-fluorophenyl)ethyl]-4-(4-fluorophenyl)-
butanenitrile (6): Flash chromatography on silica gel: hexane/ethyl
acetate, 9:1. The product (1.31 g, 92%)was obtained as a mixture
1
of 3 diastereoisomers (ratio from H NMR: A:B:C = 1.0:1.7:2.3).
1H NMR (CDCl3, 400 MHz): δ = 2.17–2.37 (m, CH2, 3 H, A, 4 H,
B, 3 H, C), 2.44–2.60 (m, CH2, 1 H, A, 1 H, C, CHCN, 1 H, A),
2.85–2.94 (m, CHCN 1 H, C), 3.48–3.59 (m, CHCN, 1 H, B), 4.96–
5.07 (m, CHCl, 6 H, A, B, C), 7.25–7.41 (m, aromatic, 24 H, A, B,
IR (film): ν = 1728 (C=O) cm–1. C H Cl O (437.36): calcd. C
˜
23 26
2
4
63.16, H 5.99; found C 63.37, H 6.47.
C). 13C NMR (CDCl3, 100 MHz): δ = 27.24, 27.97, 28.69 (CHCN), 2-(1-Chloro-2,3-dihydro-1H-indan-2-yl)-2-(2-chloro-2-phenylethyl)-
41.06, 41.95, 42.02, 42.49 (CH2), 58.39, 58.45, 59.75, 59.93 (CHCl), malononitrile (11): Flash chromatography on silica gel: hexane/ethyl
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K. Severin et al.
(16): Flash
FULL PAPER
acetate, 4:1. The product (1.06 g, 75%) was obtained as a mixture
of 2 diastereoisomers (ratio from NMR: A:B = 1.0:1.0). δ = 2.76–
2.80 (m, CH2, 1 H), 2.90–3.02 (m, CH2, 2 H), 3.06–3.31 (m, CH2,
5 H), 3.42–3.58 (m, CH, 2 H), 5.24–5.34 (m, CHCl, 2 H), 5.45 (d,
J = 6.7 Hz, CHCl, 1 H), 5.50 (d, J = 6.8 Hz, CHCl, 1 H), 7.20–
7.60 (m, aromatic, 20 H, A, B). 13C NMR (CDCl3, 100 MHz): δ =
3,4-Bis(4-fluorophenyl)cyclopentanecarbonitrile
chromatography on silica gel: hexane/ethyl acetate, 12:1. The prod-
uct (68 mg, 39% by method A; 140 mg, 42% by method B) was
obtained as a single diastereoisomer. 1H NMR (CDCl3, 400 MHz):
δ = 2.20–2.32 (m, CH2, 2 H), 2.56–2.63 (m, CH2, 1 H), 2.67–2.75
(m, CH2, 1 H), 3.05–3.12 (m, CHAr, 1 H), 3.16–3.24 (m, CHCN,
35.10, 35.8 [C(CN)2], 39.35, 39.46 (CH2Ar), 45.11, 45.14 1 H), 3.28–3.36 (m, CHAr, 1 H), 6.92–7.09 (m, aromatic, 9 H). 13
(CH2CCl), 56.39, 56.44 (CHCCl), 58.47 (br) (CHClCH2), 62.04, NMR (CDCl3, 100 MHz): δ = 26.56 (CHCN), 39.16, 39.14 (CH2),
C
62.10 (CHClCH), 112.50, 112.95, 113.48, 113.70 (CN), 124.54,
125.3, 127.36, 127.4, 128.42, 129.33, 129.36, 129.83, 129.93, 137.76,
137.80, 138.41, 138.61, 140.31 (Ph). C20H16Cl2N2 (355.27): calcd.
C 67.62, H 4.54, N 7.89; found C 67.35, H 4.68, N 7.82.
52.2, 53.33 (CHPh), 115.38–115.61 (m, aromatic), 123.11 (CN),
128.56–136.51 (m, aromatic), 160.48–162.95 (m, C-F). C18H15F2N
(283.32): calcd. C 76.31, H 5.34, N 4.94; found C 76.62, H 5.63, N
4.56.
Crystallographic Analyses: Single crystals of 15C were obtained by
slow evaporation of a CH2Cl2/hexane solution. Intensity data for
15C were collected using an Oxford Diffraction KM-4 CCD dif-
fractometer having kappa geometry and using graphite monochro-
matized Mo-Kα radiation (λ = 0.71073 Å) at low temperature. A
summary of the crystallographic data, the data collection param-
eters, and the refinement parameters are given in Table 3. Data
reduction was carried out with CrysAlis PRO.[17] Structure solution
and refinement were performed with the SHELXTL software pack-
age.[18] The structures were refined using the full-matrix least-
squares routines on F2. All non-hydrogen atoms were refined with
anisotropic displacement parameters. H atoms were included to the
models in calculated positions using the riding model. Disorder
problems have been observed for the carbon atoms next to the
phenyl groups (C3 and C4).
2-[2-Chloro-2-(naphthalene-2-yl)ethyl]-2-(2-chloro-2-phenylethyl)-
malononitrile (12): Flash chromatography on silica gel: hexane/ethyl
acetate, 4:1. The product (1.20 g, 76%) was obtained as a mixture
of 2 diastereoisomers (ratio from GC: A:B = 1.0:1.0). 1H NMR
(CDCl3, 400 MHz): δ = 2.56–2.98 (m, CH2, 8 H), 5.14–5.21 (m,
CHCl, 2 H), 5.36–5.42 (m, CHCl, 2 H), 7.32–7.58 (m, aromatic, 8
H, A, 8 H, B), 7.80–7.94 (m, aromatic, 4 H, A, 4 H, B). 13C NMR
(CDCl3, 100 MHz): δ = 34.16 [C(CN)2], 46.83, 46.92, 47.07, 47.16
(CH2), 57.84, 57.91, 58.24, 58.31 (CHCl), 112.57, 113.31, 113.34,
114.13 (CN), 123.78, 123.83, 126.90, 126.93,127.02, 127.22, 127.87,
128.25, 129.26, 129.28, 129.61, 129.79, 132.92, 133.69, 135.53,
135.56, 138.43, 138.48 (aromatic). C23H18Cl2N2 (393.32): calcd. C
70.24, H 4.61, N 7.12; found C 70.39, H 4.33, N 7.18.
2-[2-Chloro-2-(4-fluorophenyl)ethyl]-2-(2-chloro-2-phenylethyl)-
malononitrile (13): Flash chromatography on silica gel: hexane/ethyl
acetate, 12:1. The product (501 mg, 70%) was obtained as a mix-
ture of 2 diastereoisomers (ratio from GC: A:B = 1.0:1.5). 1H
NMR (CDCl3, 400 MHz): δ = 2.57–2.90 (m, CH2, 8 H, A, B),
5.19–5.24 (m, CHCl, 4 H, A, B), 7.10–7.14 (m, aromatic, 2 H, A, 2
H, B), 7.42–7.46 (m, aromatic, 7 H, A, 7 H, B). 13C NMR (CDCl3,
100 MHz): δ = 34.01 [C(CN)2], 47.04, 47.11, 47.18 (CH2), 57.13,
57.16, 57.84, 57.90 (CHCl), 112.51, 113.19, 114.01 (CN), 116.24–
116.46 (m, aromatic), 127.23–138.48 (m, aromatic), 162.06–164.55
(m, C-F). C24H15Cl2FN2 (421.30): calcd. C 63.17, H 4.19, N 7.75;
found C 63.16, H 4.67, N 7.40.
Table 3. Crystallographic data for cyclopentane 15C.
Formula
FW
C18H17N
247.33
0.20ϫ0.11ϫ0.09
orthorhombic
Pbca
Crystal size [mm3]
Crystal system
Space group
a [Å]
b [Å]
5.981(2)
18.648(6)
c [Å]
24.581(7)
90
2741.7(15)
8
1.198
α = β = γ [°]
V [A3]
2-[2-Chloro-2-(4-chlorophenyl)ethyl]-2-(2-chloro-2-phenylethyl)-
malononitrile (14): Flash chromatography on silica gel: hexane/ethyl
acetate, 15:1. The product (709 mg, 72%) was obtained as a mix-
ture of 2 diastereoisomers (ratio from GC: A:B = 1.0:1.2). 1H
NMR (CDCl3, 400 MHz): δ = 2.57–2.90 (m, CH2, 8 H, A, B),
5.14–5.21 (m, CHCl, 4 H, A, B), 7.34–7.38 (m, aromatic, 9 H, A,
B). 13C NMR (CDCl3, 100 MHz): δ = 34.01 [C(CN)2], 46.84, 46.92,
47.08, 47.15 (CH2), 57.06, 57.11, 57.84, 57.88 (CHCl), 112.52,
113.19, 113.26, 113.99 (CN), 127.24, 128.65, 129.31, 129.33, 129.50,
129.54, 129.86, 135.71, 136.95, 136.96, 138.43 (aromatic).
C24H15Cl3N2 (437.76): calcd. C 60.42, H 4.00, N 7.42; found C
60.01, H 4.06, N 7.04.
Z
ρ calcd. [gcm–3]
T [K]
140(2)
θ range [°]
3.31 to 26.36
22582
2805
semiempirical
1.00000 / 0.47460
2805 / 21 / 179
0.934
R1 = 0.0922, wR2 = 0.0683
R1 = 0.2845, wR2 = 0.0994
0.182 / –0.152
Reflections collected
Independent reflections
Absorption correction
Max. / min. transmission
Data / restraints / parameters
Goodness of fit on F2
Final R indices [IϽ2σ(I)]
R indices (all data)
Max. peak / hole [eÅ–3]
3,4-Diphenylcyclopentanecarbonitrile (15): Flash chromatography
on silica gel: hexane/ethyl acetate, 9:1. The product (115 mg, 49%
by method A; 371 mg, 60% by method B) was obtained as a mix-
ture of 3 diastereoisomers (ratio from GC: A:B:C = 1.0:1.0:4.0).
The NMR spectroscopic data of the main product (C) is given. H
NMR (CDCl3, 400 MHz): δ = 2.22–2.35 (m, CH2, 2 H), 2.56–2.63
CCDC-790832 contains the supplementary crystallographic data
for 15C. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
1
(m, CH2, 1 H), 2.67–2.74 (m, CH2, 1 H), 3.10–3.22 (m, CHCN or
CHPh, 1 H), 3.35–3.43 (m, CHCN or CHPh, 2 H), 7.07–7.26 (m, Acknowledgments
aromatic, 10 H). 13C NMR (CDCl3, 100 MHz): δ = 26.56 (CHCN),
39.16, 39.14 (CH2), 52.2, 53.33 (CHPh), 123.32 (CN), 126.80,
126.85, 127.29, 127.38, 128.59, 128.61, 141.08, 141.37 (aromatic).
C18H17N (247.34): calcd. C 87.41, H 6.93, N 5.51; found C 87.42,
H 6.84, N 5.66.
This work was supported by the Swiss National Science Founda-
tion and by the École Polytechnique Fédérale de Lausanne
(EPFL). We thank Dr. E. Solari for help with the crystallographic
measurement.
254
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 249–255

Ruthenium-Catalyzed Synthesis of 1,5-Dichlorides
tauer, Eur. J. Inorg. Chem. 2008, 563–571; f) W. T. Eckenhoff,
T. Pintauer, Inorg. Chem. 2007, 46, 5844–5846; g) L. Quebatte,
K. Thommes, K. Severin, J. Am. Chem. Soc. 2006, 128, 7440–
7441.
[1] a) M. S. Kharasch, E. V. Jensen, W. H. Urry, Science 1945, 102,
128–128; b) M. S. Kharasch, W. H. Urry, E. V. Jensen, J. Am.
Chem. Soc. 1945, 67, 1626–1626.
[6]
[7]
a) M. A. Fernández-Zúmel, K. Thommes, G. Kiefer, A. Sienk-
iewicz, K. Pierzchala, K. Severin, Chem. Eur. J. 2009, 15,
11601–11607; b) K. Thommes, G. Kiefer, R. Scopelliti, K. Se-
verin, Angew. Chem. Int. Ed. 2009, 48, 8115–8119; c) J. M.
Muñoz-Molina, T. R. Belderraín, P. J. Pérez, Adv. Synth. Catal.
2008, 350, 2365–2372; d) J. Wolf, K. Thommes, O. Briel, R.
Scopelliti, K. Severin, Organometallics 2008, 27, 4464–4474; e)
K. Thommes, B. Içli, R. Scopelliti, K. Severin, Chem. Eur. J.
2007, 13, 6899–6907.
a) M. Ouchi, T. Terashima, M. Sawamoto, Chem. Rev. 2009,
109, 4963–5050; b) N. V. Tsarevsky, K. Matyjaszewski, Chem.
Rev. 2007, 107, 2270–2299; c) R. Poli, Angew. Chem. Int. Ed.
2006, 45, 5058–5070; d) M. Kamigaito, T. Ando, M. Sawam-
oto, Chem. Rev. 2001, 101, 3689–3745; e) K. Matyjaszewski, J.
Xia, Chem. Rev. 2001, 101, 2921–2990.
[2] a) W. T. Eckenhoff, T. Pintauer, Catal. Rev. 2010, 52, 1–59; b)
T. Pintauer, K. Matyjaszewski, Chem. Soc. Rev. 2008, 37, 1087–
1097; c) K. Severin, Curr. Org. Chem. 2006, 10, 217–224; d) L.
Delaude, A. Demonceau, A. F. Noels, Top. Organomet. Chem.
2004, 11, 155–171; e) H. Nagashima, in: Ruthenium in Organic
Synthesis (Ed.: S.-I. Murahashi), Wiley-VCH, Weinheim, 2004,
p. 333–343; f) A. J. Clark, Chem. Soc. Rev. 2002, 31, 1–11; g)
K. I. Kobrakov, A. V. Ivanov, J. Heterocycl. Chem. 2001, 37,
529–539; h) R. A. Gossage, L. A. van de Kuil, G. van Koten,
Acc. Chem. Res. 1998, 31, 423–431; i) J. Iqbal, B. Bhatia, N. K.
Nayyar, Chem. Rev. 1994, 94, 519–564; j) F. Minisci, Acc.
Chem. Res. 1975, 8, 165–171.
[3] For selected examples, see: a) J. Muñoz-Molina, T. R. Belder-
raín, P. J. Pérez, Inorg. Chem. 2010, 49, 642–645; b) M. Patta-
rozzi, F. Roncaglia, V. Giangiordano, P. Davoli, F. Prati, F.
Ghelfi, Synthesis 2010, 694–700; c) A. J. Clark, P. Wilson, Tet-
rahedron Lett. 2008, 49, 4848–4850; d) J. A. Bull, M. G. Hutch-
ings, C. Luján, P. Quayle, Tetrahedron Lett. 2008, 49, 1352–
1356; e) R. N. Ram, N. Kumar, Tetrahedron Lett. 2008, 49,
799–802; f) J. A. Bull, M. G. Hutchings, P. Quayle, Angew.
Chem. Int. Ed. 2007, 46, 1869–1872; g) A. J. Clark, J. V. Geden,
S. Thom, P. Wilson, J. Org. Chem. 2007, 72, 5923–5926; h)
J. M. Muñoz-Molina, A. Caballero, M. M. Díaz-Requejo, S.
Trofimenko, T. R. Belderraín, P. J. Pérez, Inorg. Chem. 2007,
46, 7725–7730; i) C. V. Stevens, E. Van Meenen, K. G. R. Mas-
schelein, Y. Eeckhout, W. Hooghe, B. DЈhondt, V. N. Nemykin,
V. V. Zhdankin, Tetrahedron Lett. 2007, 48, 7108–7111.
[4] For selected examples, see: a) R. J. Lundgren, M. A. Rankin,
R. McDonald, M. Stradiotto, Organometallics 2008, 27, 254–
258; b) B. Dutta, E. Solari, R. Scopelliti, K. Severin, Organo-
metallics 2008, 27, 423–429; c) Y. Borguet, A. Richel, S.
Delfosse, A. Leclerc, L. Delaude, A. Demonceau, Tetrahedron
Lett. 2007, 48, 6334–6338; d) Y. Motoyama, S. Hanada, K.
Shimamoto, H. Nagashima, Tetrahedron 2006, 62, 2779–2788;
e) L. Quebatte, E. Solari, R. Scopelliti, K. Severin, Organome-
tallics 2005, 24, 1404–1406; f) Y. Motoyama, S. Hanada, S.
Niibayashi, K. Shimamoto, N. Takaoka, H. Nagashima, Tetra-
hedron 2005, 61, 10216–10226; g) L. Quebatte, M. Haas, E.
Solari, R. Scopelliti, Q. T. Nguyen, K. Severin, Angew. Chem.
Int. Ed. 2005, 44, 1084–1088; h) L. Quebatte, R. Scopelliti, K.
Severin, Eur. J. Inorg. Chem. 2005, 3353–3358; i) L. Quebatte,
R. Scopelliti, K. Severin, Angew. Chem. Int. Ed. 2004, 43,
1520–1524; j) B. T. Lee, T. O. Schrader, B. Martín-Matute,
C. R. Kauffman, P. Zhang, M. L. Snapper, Tetrahedron 2004,
60, 7391–7396; k) O. Tutusaus, S. Delfosse, A. Demonceau,
A. F. Noels, C. Viñas, F. Teixidor, Tetrahedron Lett. 2003, 44,
8421–8425; l) O. Tutusaus, C. Viñas, R. Núñez, F. Teixidor, A.
Demonceau, S. Delfosse, A. F. Noels, I. Mata, E. Molins, J.
Am. Chem. Soc. 2003, 125, 11830–11831; m) B. de Clercq, F.
Verpoort, Tetrahedron Lett. 2002, 43, 4687–4690; n) F. Simal,
L. Wlodarczak, A. Demonceau, A. F. Noels, Eur. J. Org. Chem.
2001, 14, 2689–2695; o) F. Simal, L. Wlodarczak, A. De-
monceau, A. F. Noels, Tetrahedron Lett. 2000, 41, 6071–6074.
[5] a) M. N. C. Balili, T. Pintauer, Inorg. Chem. 2010, 49, 5642–
5649; b) C. Ricardo, T. Pintauer, Chem. Commun. 2009, 3029–
3031; c) T. Pintauer, W. T. Eckenhoff, C. Ricardo, M. N. C. Ba-
lili, A. B. Biernesser, S. T. Noonan, M. T. Taylor, Chem. Eur. J.
2009, 15, 38–41; d) M. N. C. Balili, T. Pintauer, Inorg. Chem.
2009, 48, 9018–9026; e) W. T. Eckenhoff, S. T. Garrity, T. Pin-
[8]
[9]
H. Nagashima, H. Wakamatsu, N. Ozaki, T. Ishii, M. Watan-
abe, T. Tajima, K. Itoh, J. Org. Chem. 1992, 57, 1682–1689.
For a more recent example of an intramolecular Kharasch re-
action of a 1,5-diene, see: D. Yang, Y.-L. Yan, B.-F. Zheng, Q.
Gao, N.-Y. Zhu, Org. Lett. 2006, 8, 5757–5760.
S. Iwamatsu, H. Kondo, K. Matsubara, H. Nagashima, Tetra-
hedron 1999, 55, 1687–1706.
[10]
[11]
a) A. E. Díaz-Álvarez, P. Crochet, M. Zablocka, C. Duhayon,
V. Cadierno, J.-P. Majoral, Eur. J. Inorg. Chem. 2008, 786–794;
b) N. Huther, P. T. McGrail, A. F. Parsons, Eur. J. Org. Chem.
2004, 1740–1749; c) B. De Clercq, F. Verpoort, J. Organomet.
Chem. 2003, 672, 11–16; d) B. De Clercq, F. Verpoort, Catal.
Lett. 2002, 83, 9–13; e) B. C. Gilbert, W. Kalz, C. I. Lindsay,
P. T. McGrail, A. F. Parsons, D. T. E. Whittaker, J. Chem. Soc.
Perkin Trans. 1 2000, 8, 1187–1194; f) D. Derouet, J. C. Brosse,
Eur. Polym. J. 1991, 27, 1125–1140; g) R. Grigg, J. Devlin, A.
Ramasubbu, R. M. Scott, P. Stevenson, J. Chem. Soc. Perkin
Trans. 1 1987, 1515–1520.
a) F. O. Ginah, T. A. Donovan, S. D. Suchan, D. R. Pfennig,
G. W. Ebert, J. Org. Chem. 1990, 55, 584–589; b) M. Mitani,
H. Takeuchi, K. Koyama, Chem. Lett. 1986, 2125–2126; c)
W. F. Bailey, R. P. Gagnier, J. J. Patricia, J. Org. Chem. 1984,
49, 2098–2107; d) W. F. Bailey, R. P. Gagnier, Tetrahedron Lett.
1982, 23, 5123–5126.
[12]
[13] For the activation of Mg with LiCl and DIBAL-H, see: a)
F. M. Piller, A. Metzger, M. A. Schade, B. A. Haag, A. Gavryu-
shin, P. Knochel, Chem. Eur. J. 2009, 15, 7192–7202; b) F. M.
Piller, P. Appukkuttan, A. Gavryushin, M. Helm, P. Knochel,
Angew. Chem. Int. Ed. 2008, 47, 6802–6806.
[14] For a review about sequential reactions with Ru catalysts, see:
C. Bruneau, S. Dérien, P. H. Dixneuf, Top. Organomet. Chem.
2006, 19, 295–326.
[15] T. Arliguie, C. Border, B. Chaudret, J. Devillers, R. Poilblanc,
Organometallics 1989, 8, 1308–1314.
[16] G. H. Hakimelahi, G. Just, Tetrahedron Lett. 1979, 20, 3643–
3644.
[17] CrysAlis PRO, Oxford Diffraction Ltd., Abingdon OX14 1
RL, Oxfordshire, UK, 2008.
[18] G. M. Sheldrick, University of Göttingen, Germany, 1997;
SHELXTL, rel. 6.1.4, Bruker AXS Inc., Madison, Wisconsin
53719, USA, 2003.
Received: August 27, 2010
Published Online: November 5, 2010
Eur. J. Org. Chem. 2011, 249–255
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
255