An Atom-Economic and Stereospecific Access to Trisubstituted Olefins through Enyne Cross Metathesis Followed by 1,4-Hydrogenation

Article abstract of DOI:10.1055/s-0036-1591528

The combination of intermolecular enyne cross metathesis and subsequent 1,4-hydrogenation opens a stereocontrolled and atom-economic access to trisubstituted olefins. By investigating different combinations of functionalized alkyne and alkene substrates, we found that the outcome (yield, E / Z ratio) of the Grubbs II-catalyzed enyne cross-metathesis step depends on the substrate's structure, the amount of the alkene (used in excess), and the (optional) presence of ethylene. In any case, the 1,4-hydrogenation, catalyzed by 1,2-dimethoxybenzene-Cr(CO) ₃, proceeds stereospecifically to yield exclusively the E -products from both the E- and Z- 1,3-diene intermediates obtained by metathesis. A rather broad scope and functional group compatibility of the method is demonstrated by means of 15 examples.

Full text of DOI:10.1055/s-0036-1591528

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–H
letter
A
en
F. Ratsch, H.-G. Schmalz
Letter
Synlett
An Atom-Economic and Stereospecific Access to Trisubstituted
Olefins through Enyne Cross Metathesis Followed by
1,4-Hydrogenation
Friederike Ratsch
H
H
(Ar)Cr(CO)3
H2
R
H
Hans-Günther Schmalz*
0
0
0
0
0-
0
0
3
0-
4
8
9
1-
8
2
7
Ru cat.
R
R'
R
R'
+
enyne
metathesis
University of Cologne, Department of Chemistry,
Greinstraße 4, 50939 Köln, Germany
schmalz@uni-koeln.de
CH3
stereospecifically E
1,4-hydrogenation
CH2
R'
H2C
R = funct. alkyl, aryl
R' = funct. alkyl
15 examples, up to 72% overall yield
Received: 24.10.2017
Accepted after revision: 10.12.2017
Published online: 15.01.2018
H2
R
(Ar)Cr(CO)3
(cat.)
R
R'
cat. Ru
1
R
R'
DOI: 10.1055/s-0036-1591528; Art ID: st-2017-b0785-l
1,4-hydrogenation
R'
3
4
enyne
Abstract The combination of intermolecular enyne cross metathesis
and subsequent 1,4-hydrogenation opens a stereocontrolled and atom-
economic access to trisubstituted olefins. By investigating different
combinations of functionalized alkyne and alkene substrates, we found
that the outcome (yield, E/Z ratio) of the Grubbs II-catalyzed enyne
cross-metathesis step depends on the substrate’s structure, the
amount of the alkene (used in excess), and the (optional) presence of
ethylene. In any case, the 1,4-hydrogenation, catalyzed by 1,2-di-
methoxybenzene-Cr(CO)3, proceeds stereospecifically to yield exclu-
sively the E-products from both the E- and Z-1,3-diene intermediates
obtained by metathesis. A rather broad scope and functional group
compatibility of the method is demonstrated by means of 15 examples.
2
metathesis
Scheme 1 Envisioned two-step reaction sequence
A literature search revealed (almost surprisingly) that
such a sequence has never been described in the litera-
ture9,10 and we therefore decided to explore the feasibility
of this concept. We herein report the results of our study,
which has indeed led to the development of a facile two-
step protocol for the stereospecific synthesis of trisubstitut-
ed olefins of type 4.
To investigate the scope and limitations of the envi-
sioned sequence we selected the set of alkyne and alkene
building blocks shown in Figure 1.
Key words Ru catalysis, enyne cross metathesis, 1,4-hydrogenation,
synthesis of alkenes, diastereoselectivity, 1,3-dienes
The development of new synthetic strategies for the ste-
reoselective synthesis of trisubstituted olefins, a wide-
spread structural motif of natural products, is a topic of
high interest in synthetic organic chemistry. This is because
most of the established methods, such as olefination,1
cross-coupling,2 or carboalumination/cross-coupling3, also
have drawbacks – in spite of their usefulness. For instance,
the laborious synthesis of functionalized building blocks
(e.g. for cross-couplings4) or a lack of E/Z-stereoselectivity5
may hamper the applicability of the existing protocols,
most of which are also far from being atom-efficient.6 Thus,
the search for novel atom-economic methods for the syn-
thesis of trisubstituted olefins still represents a relevant
challenge.
Alkynes:
O
OPG
OBn
2
1a
1b: PG = Bn
1c: PG = Bz
1d: PG = TBDPS
R
NHBoc
1e: R = H
1f: R = OMe
1g
Alkenes:
OPG
n
n
2a: n = 5
2b: n = 3
2c: n = 2, PG = C(O)Et
2d: n = 1, PG = Bz
2e
2i
O
X
3
NHBoc
2f: X = Br
2g: X = CN
2h
Against this background, we reasoned that the inter-
molecular cross metathesis7 of an alkyne 1 and an alkene 2
followed by 1,4-hydrogenation8 of the resulting 1,3-diene
intermediate 3 should open a general access to E-olefins 4
(Scheme 1).
Figure 1 Alkyne and alkene building blocks used in this study
As a positive influence of ethylene on enyne metathesis,
discovered by Mori,11 is well documented in the literature,12
we chose the ethylene-promoted procedure of Lee et al.13 to
test and optimize the enyne-metathesis step. At first, we
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–H

B
F. Ratsch, H.-G. Schmalz
Letter
Synlett
performed a brief catalyst screening employing substrates
1a and 2a and four different commercially available ruthe-
nium catalysts 5–814 (Scheme 2). The Grubbs II14c (6) and
the Hoveyda–Grubbs14d catalyst (7) delivered comparably
good results (Table 1) and we therefore used the less expen-
sive catalyst 6 for all further experiments. On a small scale
(about 1 mmol) we generally performed the reactions with
10 mol% of catalyst while at larger scales (>1.5 mmol) the
catalyst amount could be slightly reduced (7–8 mol%). Low-
er catalyst loadings (<5%) usually resulted in incomplete
conversion even after prolonged reaction times (50 h).
We next tested the scope and limitations of the cross-
metathesis protocol by employing the different alkynes and
alkenes depicted in Figure 1. In all cases, a solution of the
alkyne (1 equiv), the alkene (10 equiv), and the catalyst 6
(7–10 mol%) in CH2Cl2 was stirred under an ethylene atmo-
sphere until complete consumption of the alkyne (24–
72 h). Table 2 shows 17 successful examples, in which the
expected products were formed in moderate to good yield.
As a trend, the propargyl benzoate 1c gave rise to higher
yields than the corresponding propargyl benzyl ether 1b
(Table 2, entries 2, 3 and 12, 13, respectively). Remarkably,
mixtures of E/Z-diastereomers were obtained in the case of
alkene substrates with ester, keto, or cyano functionalities
(i.e., 2c–e,g), while virtually pure E-products were formed
in the case of unfunctionalized olefins, such as 2a,b,i. The
cyano-substituted diene 3n (formed in only 34% yield as an
E/Z mixture) could be better synthesized by SN2 chemistry15
from the bromide 3m (see below), which was obtained in
61% as a pure E-isomer – in contrast to 3l (with an OBn in-
stead of an OBz unit), which was isolated as an E/Z-mixture
in lower yield. Here, an unexpected and subtle dependency
of the diastereoselectivity on the substrate structure be-
came apparent.
BnO
cat. [Ru]
ethylene (1 atm)
O
BnO
C5H11
1a (1 equiv)
+
CH2Cl2
0 °C to r.t.
O
C5H11
3a
2a (10 equiv)
N
N
N
N
Mes
Mes
Mes
Mes
PCy3
Cl
Cl
Cl
Cl
Ru
Ru
Ru
Cl
Cl
PCy3
PCy3
O
R
5
6
7 (R = H)
8 (R = NO2)
Table 2 Outcome of the Enyne Cross Metathesis with Different
Substrates
Scheme 2 Test reaction and catalysts screened (see Table 1)
Entry Substrates Product
(time)
Yield
(%)
E/Z
The reactions were carried out in CH2Cl2 as solvent un-
der an atmosphere of ethylene (1 atm) and run until com-
plete consumption of the alkyne starting material (GC–MS
monitoring, 24–72 h). The product 3a was then isolated af-
ter flash chromatography and the E/Z ratio determined by
means of 1H NMR spectroscopy.
BnO
1a + 2a
(72 h)
1
2
3
4
5
66
66
75
73
40
>99:1
C6H13
3a
O
1b + 2a
(24 h)
BnO
BzO
BzO
>99:1
>99:1
>99:1
>99:1
C6H13
C6H13
C4H9
3b
3c
3d
Table 1 Results of the Catalyst Screening According to Scheme 2
Entry
Catalyst
Loading
(mol%)
Reaction time Isolated yield E/Za
(h) (%)
1c + 2a
(72 h)
1
2
3
4
5
6
7
8
5
6
6
6
7
7
8
8
10
10
8
72
48
50:50
>99:1
>99:1
>99:1
n.d.
24
48
72
24
48
24
48
51
57
66
1c + 2b
(72 h)
10
5
b
–
1d + 2a
(48 h)
TBDPSO
C6H13
10
1
60
>99:1
n.d.
3e
c
–
O
10
43
>99:1
1c + 2c
(72 h)
BzO
6
7
54
56
62:38
79:21
a Determined by 1H NMR spectroscopy.
b Only 40 % conversion (GC–MS).
O
Et
3f
c < 2% conversion (GC–MS and NMR).
1c + 2d
(72 h)
BzO
OBz
3g
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–H

C
F. Ratsch, H.-G. Schmalz
Letter
Synlett
Table 2 (continued)
Grubbs II
ethylene
(1 atm)
Entry Substrates Product
(time)
Yield
(%)
E/Z
R'
R'
+
R
R
+
R
CH2Cl2
0 °C to r.t.
3
9
1
2
(excess)
up to 16%
1e + 2b
(24 h)
8
9
55
64
36
>99:1
Ph
C4H9
Scheme 3 Formation of side products of type 9 during enyne cross
metathesis in the presence of ethylene
3h
1f + 2b
(24 h)
>99:1
79:21
selectivity of the metathesis reaction (Table 2). As already
mentioned, the dienes 3 were formed with high E-selectivi-
ty (>95:5) in the majority of the examples, while rather low
E/Z ratios (in the range of 4:1 to 1:1) were observed in other
cases, in accordance with literature reports.13
Using the reaction of 1c with 2a as a model system we
could show that the stereoselectivity (as well as the yield)
depends on the amount of the alkene used in excess. The
highest yield and E-selectivity (dr >99:1) was achieved with
10 equivalents of 2a while both the yield and the E/Z ratio
dropped significantly when only 5 or 3 equivalents of 2a
were used (Table 3).
4-MeOC6H4
C4H9
3i
1b + 2e
(24 h)
BnO
10
3j
O
O
1c + 2e
(72 h)
BzO
11
12
13
14
15
16
17
61
54
61
84:16
60:40
>99:1
52:48
>99:1
>99:1
>95:5
3k
1b + 2f
(48 h)
BnO
Br
Br
3l
Table 3 Dependence of Yield and Stereoselectivity on the Excess of
1c + 2f
(48 h)
BzO
Alkene
3m
Grubbs II
(10 mol%)
ethylene
OBz
C6H13
BnO
C5H11
1c + 2g
(24 h)
34
BzO
CN
(+ 23)a
CH2Cl2
0 °C to r.t.
72 h
3n
1c
2a
3c
1g + 2a
(24 h)
BocHN
Entry
Alkene (equiv)
Yield (%)
E/Z
>99:1
40
54
57
C6H13
3o
1
2
3
10
5
75
57
38
77:23
55:45
1c + 2h
(24 h)
BzO
NHBoc
3
3p
We also investigated the influence of ethylene on the
yield and the diastereoselectivity of the enyne cross
metathesis by performing reactions of 2a with three differ-
ent alkynes 1a–c both in the presence and the absence of
ethylene. As the results shown in Table 4 indicate, a virtual-
ly complete E-selectivity was achieved for alkynes 1a and
1c also in the absence of ethylene (Table 4, entries 2 and 7),
and in the case of 1a the product 3a was formed even in im-
proved yield (Table 4, entry 2). For substrate 2b, however,
the diastereoselectivity was completely lost in the absence
of ethylene and the yield dropped to 25% (Table 4, entry 4).
This demonstrates that certain enyne cross-metathesis re-
actions indeed benefit from the presence of ethylene while
others do not. In any case, the use of a large (typically ten-
fold) excess of the alkene component is recommended to
promote both yield and E-selectivity.
1a + 2i
(48 h)
BnO2C
3
3q
a With slight impurities.
Table 2 reflects the general usefulness of the enyne-
metathesis protocol used. Noteworthy, small amounts of
monosubstituted 1,3-butadienes of type 9 were also
formed (Scheme 3), especially in some of the highly E-selec-
tive reactions. These byproducts arising from reaction of
the alkyne with ethylene were separated off by chromato-
graphy on AgNO3-doped silica16 and only isolated if formed
in larger amounts (16% in entry 1; 21% in entry 3, 10% in
entry 4; 14% in entry 9).
Although both the E- and the Z-isomers of the enyne-
metathesis products of type 3 can be employed in the fol-
lowing 1,4-hydrogenation step to deliver the same product
(see below), we were puzzled by the ‘fluctuating’ diastereo-
Noteworthy, the reaction time also had an important in-
fluence on the yield (Table 4, compare entries 5 and 6). Even
though the alkyne starting material 1c was completely con-
sumed after 24 h (GC–MS control), the yield of the cross-
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D
F. Ratsch, H.-G. Schmalz
Letter
Synlett
Table 4 Influence of Ethylene on the Yield and Diastereoselectivity of
the Reaction of 2a with Alkynes 1a–c
via an ‘ene-first’ mechanism,18 and Lippstreu and Straub
also suggested (based on DFT calculations) that an ‘ene-
first’ pathway should be energetically favored, with the
alkyne insertion being the only irreversible and therefore
regioselectivity-determining step.19
Entry
Alkyne
(1 equiv)
Alkene
(10 equiv)
Ethylene Reaction Yield
E/Zb
time (h)
(%)a
1
2
3
4
5
6
7
1a
1a
1b
1b
1c
1c
1c
2a
2a
2a
2a
2a
2a
2a
yes
no
72
72
24
48
24
72
24
66
78
66
25
53
75
55
>99:1
However, in other cases reactions were shown to pro-
ceed via the ‘yne-first’ pathway,17 and our observation of
side products of type 9 also indicates the involvement of
intermediate IV.20 On the other hand, only the ‘ene-first’
mechanism should selectively afford the E-product, because
the alkyne insertion is expected to generate the E-configu-
rated intermediate III only.19 In contrast, both diastereo-
mers can arise from the ‘yne-first’ route as the formation of
cycloadduct V does not necessarily proceed in a stereo-
selective fashion. Thus, we suggest that the highly E-selec-
tive enyne metathesis reactions (see Table 2) proceed via
the ‘ene-first’ mechanism (cycle A), which is kinetically
fostered by a large excess of the alkene. The detrimental
effect of polar donor functionalities in the alkene unit (as
part of R1) on the diastereoselectivity may be explained by
assuming a chelate coordination to the Ru atom in II and
thus a kinetic retardation of the alkyne insertion in cycle A.
As a result, such reactions will proceed (at least partly) via
cycle B and, accordingly, with reduced stereoselectivity.
Fortunately, the configuration of dienes 3 was not im-
portant for our study (Scheme 1) because both isomers
were expected to yield the same E-configurated 1,4-hydro-
genation product 4. The (arene)Cr(CO)3-catalyzed 1,4-hy-
drogenation of conjugated dienes, first reported in 1968 by
Frankel, proceeds regio- and stereospecifically and presum-
ably involves a ‘synchronous’ transfer of the two hydrogen
atoms to the ends of the diene unit kept in a s-cis conforma-
tion by η4-complexation (Scheme 5).21,22
>99:1
>99:1
50:50
>99:1
>99:1
>99:1
yes
no
yes
yes
no
a Isolated yield.
b Determined by 1H NMR spectroscopy.
metathesis product 3c increased from 53% to 75% upon pro-
longing the reaction time from 24 h to 72 h in this case. This
is possibly due to a slow conversion of the side product 9
(see Scheme 3) to the desired product 3c through diene-ene
cross metathesis. In the absence of ethylene, none or only
negligible amounts of 9 were formed.
All these results let us rethink the mechanism of the in-
termolecular enyne metathesis, which is still the subject of
debate.17 Two mechanistic pathways have been proposed,
which are depicted in Scheme 4. In the ‘ene-first’ pathway
(cycle A) the catalyst I first reacts reversibly with the alkene
2, and the new Ru carbene II then fuses with the alkyne 1 to
generate the vinylcarbene III, which finally may react ei-
ther with ethylene or directly with the next molecule of the
alkene 2. In both cases, the catalytic cycle would be closed
under formation of the product 3. In the ‘yne-first’ pathway
(cycle B) the catalyst I reacts first with the alkyne to gener-
ate the intermediate IV, which then combines with the
alkene via the metallacyclobutane V to release the product
under regeneration of the catalyst.
Hydrogenation experiments were performed according
to the procedure of Le Maux,23 however, higher tempera-
tures and longer reaction times were needed to achieve full
conversion. After testing four catalysts available in our labo-
ratory (Table 5) we selected (veratrole)Cr(CO)3 (10) for all
further experiments.
On the basis of a Hammett analysis Diver et al. found
that the Grubbs II catalyzed metathesis of substituted
styrenes with 1-butyn-3-yl benzoate appears to proceed
A: Ene-first
B: Yne-first
[Ru]
[Ru]
R2
R2
R1
R1
R2
2
1
1
II
R2
[Ru]
[Ru]
R1
[Ru]=CH2
[Ru]=CH2
3
2
R2
R2
I
9
IV
I
R1
R1
R1
[Ru]
R1
[Ru]
R2
2
R2
R2
3
3
R1
R2
III
V
E-product
E/Z-mixture
Scheme 4 The two possible mechanistic pathways of enyne cross metathesis
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–H

E
F. Ratsch, H.-G. Schmalz
Letter
Synlett
the cases of the Boc-protected amine 4o (54%, Table 6, entry
15) and the phenyl-substituted product 4h (43%, Table 6,
entry 8).
H2
Δ
solvent
(e.g. THF)
[solv]
H
[solv]
H
OC
OC
[solv]
[solv]
OC
OC
Cr
Cr
CO
CO
R
Table 6 Outcome of the 1,4-Hydrogenation of Various Substrates
Cr(CO)3
R
R'
3
R'
10 (5 mol%)
R'
H
2 (41–60 bar)
H
4
R
R'
R'
OC
OC
R
R
Cr
THF
H
120 °C, 15–20 h
3
4
CO
Scheme 5 Proposed mechanism of the (arene)Cr(CO)3-catalyzed
Entry
1
Substrate
Product
Yield (%)a
88
1,4-hydrogenation20,21
BnO
3a
C6H13
Typically, a solution of the substrate (3) and 5 mol% of
10 in THF was stirred in an autoclave at 50–60 bar H2 at
120 °C for 24 h. Under these optimized conditions, the
(arene)Cr(CO)3-catalyzed 1,4-hydrogenation was performed
with all seventeen dienes obtained before by enyne meta-
thesis (Table 6).
4a
O
BnO
2
3
4
5
3b
3c
3d
3e
65
96
C6H13
4b
4c
4d
BzO
BzO
C6H13
Table 5 Results of the Catalyst Screening in the 1,4-Hydrogenationa
Me
Cr(CO)3
OMe
Cr(CO)3
OMe
Cr(CO)3
O
Cr(CO)3
OMe
>99
78b
C4H9
O
MeO
OMe
10
11
12
13
TBDPSO
BzO
C5H11
4e
Entry
Catalyst
Substrate Temp (°C) Conversion (%)b Yield (%)
O
1
2
3
4
5
6
10
11
12
13
10
11
3a
3a
3a
3a
3c
3c
100
100
100
100
120
120
100
100
100
83
96
6
7
3f
61
O
Et
84
4f
n.d.
n.d.
85
c
BzO
OBz
3g
–
4g
100
100
76
a Reaction conditions: 5 mol% (Ar)Cr(CO)3, H2 (50–55 bar), THF, 17–20 h.
b Determined by GC–MS.
8
9
3h
3i
43d
90d
Ph
C4H9
4h
As Table 6 shows, the 1,4-hydrogenation of the dienes 3
proceeded smoothly in most cases to afford the desired tri-
substituted olefins of type 4 as single isomers, as analyzed
by GC–MS and NMR spectroscopy. The expected E-configu-
ration was confirmed through H,H-NOESY experiments.
Particularly good results were achieved for dienes 3a–e and
3h,i, respectively, which all carry long aliphatic side chains
(Table 6, entries 1–5 and 9). In a similar manner substrate
3q (carrying a branched ‘terpenoid’ side chain) delivered
the 1,4-hydrogenated product 4q in excellent yield (91%, Ta-
ble 6, entry 17). Functional groups on the ‘western’ (alkyne-
derived) terminus of the molecules were generally well tol-
erated, albeit the O-benzyl-protected substrates again per-
formed slightly worse in comparison to the corresponding
O-benzoyl-protected analogues (Table 6, entries 2, 3 and 10,
11, respectively). Somewhat lower yields were obtained in
4-MeOC6H4
BnO
C4H9
4i
4j
10
11
12
13
3j
68
89
O
O
BzO
BnO
BzO
3k
3l
4k
Br
Br
e
–
4l
3m
24b
4m
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–H

F
F. Ratsch, H.-G. Schmalz
Letter
Synlett
Table 6 (continued)
cannot be directly prepared under the standard conditions.
As an example, the cyano-substituted alkene 4n was syn-
thesized in good overall yield from the readily available
starting materials 1c and 2f via the three-step sequence
shown in Scheme 7. Thus the feasibility of the concept was
proven and we are optimistic that it will find application in
organic synthesis in the future.
Entry
Substrate
Product
Yield (%)a
74f
BzO
CN
14
3n
4n
4o
BocHN
BzO
15
16
3o
3p
54
23
C6H13
O
Et
O
Et
BzO
BzO
BzO
BzO
H2
cat. 10
E-3f
4f
O
O
+
+
NHBoc
4p
O
Et
O
Et
14
Z-3f
O
O
BnO
17
3q
91d
3
BzO
OBz
BzO
OBz
4q (rac)
O
H2
cat. 10
4g
+
E-3g
a Isolated yield.
+
b 20 mol% of catalyst 10 were used.
BzO
15
BzO
c ca. 40 % of an inseparable mixture were obtained.
d 10 mol% of catalyst 10 were used.
BzO
OBz
Z-3g
e No product detected, starting material re-isolated.
f The diene 3n synthesized from 3m was employed.
Scheme 6 Isomerization in case of allylic (3f) and homoallylic (3g)
substrates
Br
cat. [Ru]
ethylene
BzO
In contrast, functional groups on the ‘eastern’ (i.e., the
alkene-derived) side of the substrates had a more pro-
nounced influence on the outcome of the 1,4-hydrogena-
tion. While the propionate 4f, the ketones 4j,k, as well as
the nitrile 4n were formed in good yields, the benzoate 4g,
the bromides 4l,m, as well as the carbamate 4p could not be
isolated in useful yields and/or purities. Noteworthy, the es-
ter-functionalized substrates 3f and 3g, which were both
employed as E/Z-diastereomeric mixtures, led also to the
formation of the isomerized side products 14 and 15, re-
spectively (Scheme 6). Similar Cr-catalyzed isomerizations
of Z-configurated dienes had been described by Shibasaki et
al.24 While pure 4f was obtained in 61% yield after chro-
matographic separation, 4g was isolated only as a constitu-
ent of an inseparable mixture also containing the isomeri-
zation product 15 (resulting from Z-3g through a Cr-assist-
ed 1,5-H shift)24 and remaining starting material 3g.
Obviously, the bromides 3l and 3m do not represent suit-
able substrates for the 1,4-hydrogenation (Table 6, entries
12 and 13).
In conclusion, we have demonstrated that the combina-
tion of enyne cross metathesis and a subsequent 1,4-hydro-
genation opens a straightforward, atom-economic, and ste-
reospecific access to a variety of functionalized triple-sub-
stituted alkenes of type 4 as pure E-isomers.25 Despite their
broad general applicability, both the Ru-catalyzed enyne
cross metathesis and the arene-Cr(CO)3-catalyzed hydroge-
nation fail for certain particular substrates. However, the
interconversion of functional groups at the stage of the
diene intermediates 3 allows the application of the meth-
odology also for the synthesis of ‘difficult’ products, which
1c
BzO
61%
Br
3m
2f
NaCN, DMF
60 °C, 2 h
99%
CN
H2
CN
cat. 9
BzO
BzO
74%
4n
3n
Scheme 7 Overall synthesis of the functionalized E-alkene 4n
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591528.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
(1) (a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863. (b) van
Staden, L. F.; Gravestock, D.; Ager, D. J. Chem. Soc. Rev. 2002, 31,
195. (c) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002,
2563.
(2) (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed.
2005, 44, 4442. (b) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem.
Rev. 2011, 111, 1417.
(3) (a) Zweifel, G.; Miller, J. A. In Organic Reactions 32; John Wiley
and Sons: Hoboken, NJ, 1984. (b) Huang, Z.; Tan, Z.; Novak, T.;
Zhu, G.; Negishi, E.-I. Adv. Synth. Catal. 2007, 349, 539. (c) Van
Horn, D. E.; Negishi, E.-I. J. Am. Chem. Soc. 1978, 100, 2252.
(4) Buchanan, G. S.; Cole, K. P.; Li, G.; Tang, Y.; You, L.-F.; Hsung, R.
P. Tetrahedron 2011, 67, 10105.
(5) Zhou, Y.; Murphy, P. V. Tetrahedron Lett. 2010, 51, 5262.
(6) Sheldon, R. A. Pure Appl. Chem. 2000, 72, 1233.
(7) Storm Poulsen, C.; Madsen, R. Synthesis 2003, 1.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–H

G
F. Ratsch, H.-G. Schmalz
Letter
Synlett
(8) Sodeoka, M.; Shibasaki, M. Synthesis 1993, 643.
(9) A single example of ethylene-alkyne metathesis followed by
1,4-hydrogenation to generate a tetrasubstituted olefin was
reported by: Vasil'ev, A. A.; Engman, L.; Serebryakov, E. P. Men-
deleev Commun. 2000, 10, 101.
(10) For an unsuccessful attempt to 1,4-hydrogenate a substrate
obtained by enyne ring-closing metathesis, see: Cho, J.; Lee, Y.
M.; Kim, D.; Kim, S. J. Org. Chem. 2009, 74, 3900.
(11) (a) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63,
6082. (b) Tonogaki, K.; Mori, M. Tetrahedron Lett. 2002, 43,
2235.
(12) (a) Diver, S. T.; Griffiths, J. R. In Olefin Metathesis: Theory and
Practice; John Wiley and Sons: Hoboken, NJ, 2014. (b) Diver, S.
T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317.
chromatography on SiO2/AgNO3 (cHex/EtOAc) to afford the
diene 3 as colorless oil.
Analytical Data of Selected Dienes
Compound 3a: 1H NMR (500 MHz, CDCl3): δ = 7.38–7.30 (m, 5
H,), 6.04 (d, 3JH,H = 15.8 Hz, 1 H), 5.72 (dt, 3JH,H = 15.8 Hz, 6.9 Hz,
1 H), 5.12 (s, 2 H), 4.90 (s, 1 H), 4.84 (s, 1 H), 2.56 (m, 4 H), 2.11–
2.06 (m, 2 H), 1.41–1.35 (m, 2 H), 1.32–1.25 (m, 6 H), 0.88 (t,
3JH,H = 6.9 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 173.2,
144.6, 136.1, 131.5), 130.9, 128.7, 128.3, 113.6, 66.4, 33.3, 33.0,
31.8, 29.4, 29.0, 27.4, 22.7, 14.2 ppm. HRMS (ESI): m/z calcd
[M+H]+ for C20H28O2: 301.21621; found: 301.21666.
Compound 3d: 1H NMR (500 MHz, CDCl3): δ = 8.08–8.06, 7.58–
3
7.54 (m, 1 H), 7.46–7.43 (m, 2 H), 6.12 (d, JH,H = 16.0 Hz, 1 H),
5.81 (dt, 3JH,H = 16.0 Hz, 6.9 Hz, 1 H), 5.22 (s, 1 H), 5.14 (s, 1 H),
(13) Lee, H.-Y.; Kim, B. G.; Snapper, M. L. Org. Lett. 2003, 5, 1855.
(14) Ru-Catalysts were purchased from Sigma-Aldrich. For selected
references, see: (a) Vougioukalakis, G. C.; Grubbs, R. H. Chem.
Rev. 2010, 110, 1746. Grubbs I: (b) Schwab, P.; France, M. B.;
Ziller, J. W.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1995, 34,
2039. Grubbs II: (c) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H.
Org. Lett. 1999, 1, 953–956. Hoveyda–Grubbs: (d) Garber, S. B.;
Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2000, 122, 8168. Nitro-Grela: (e) Michrowska, A.; Bujok, R.;
Harutyunyan, S.; Sashuk, V.; Dolgonos, G.; Grela, K. J. Am. Chem.
Soc. 2004, 126, 9318.
4.99 (s, 2 H), 2.14–2.10 (m, 2 H), 1.42–1.36 (m, 2 H), 1.35–1.30
3
(m, 2 H), 0.89 (t, JH,H = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 166.4, 140.7, 133.1, 132.1, 130.3, 129.8, 129.3, 128.5,
115.4, 64.8, 32.8, 31.5, 22.3, 14.0 ppm. HRMS (ESI): m/z calcd [M
+ H]+ for C16H20O2: 245.15361; found: 245.15396.
Compound 3i: 1H NMR (500 MHz, CDCl3): δ = 7.26–7.24 (m, 2
H), 6.88–6.85 (m, 2 H), 6.28 (d, 3JH,H = 15.6 Hz, 1 H), 5.67 (dt, 3JH,H
= 15.6 Hz, 7.0 Hz, 1 H), 5.11 (d, 4JH,H = 1,4 Hz, 1 H), 5.01 (d, 3JH,H
=
1.8 Hz, 1 H), 3.81 (s, 3 H), 2.14–2.10 (m, 2 H), 1.40–1.28 (m, 4 H),
0.89 (t,3JH,H = 7.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 159.1,
147.7, 134.5, 133.3, 131.6, 129.4, 113.7, 113.6, 55.4, 32.7, 31.6,
22.4, 14.1 ppm.
(15) Zhang, C.; Santiago, C. B.; Kou, L.; Sigman, M. S. J. Am. Chem. Soc.
2015, 137, 7290.
General Procedure for 1,4-Hydrogenation
(16) den Boer, F. C. Angew. Chem., Int. Ed. Engl. 1964, 3, 760.
(17) Li, J.; Lee, D. In Handbook of Metathesis: Applications in Organic
Under argon atmosphere, 1.00 equiv of the diene were dis-
solved in dry THF (4.0 ml/mmol diene) in a glass reaction vial.
Then 0.05 equiv of the (arene)Cr(CO)3 catalyst were added, and
the vial was placed in a Parr autoclave. After sealing the auto-
clave and purging it three times with hydrogen (30 bar), the
hydrogen pressure was set to 41–59 bar, and the temperature
raised to 120 °C for 15–20 h (overnight). After cooling to r.t., the
solvent was evaporated under reduced pressure, and the crude
product was dissolved in EtOH (4.0 ml/mmol diene). To oxidize
the remaining catalyst, 1.0 equiv of anhydrous FeCl3 were
added, and nitrogen was bubbled through the mixture for 30
min. Then, water was added, and the mixture was extracted 3
times with petrol ether or cyclohexane. The combined organic
layers were dried over Na2SO4 under reduced pressure, and the
crude product was purified by column chromatography on
silica (cHex/EtOAc).
Synthesis;
2
V
o.
l
Grubbs, R. H.; O’Leary, D. J., Eds.; Wiley-VCH: Wein-
heim, 2015.
(18) Giessert, A. J.; Diver, S. T. Org. Lett. 2005, 7, 351.
(19) Lippstreu, J. J.; Straub, B. F. J. Am. Chem. Soc. 2005, 127, 7444.
(20) The pathway leading to 9 must necessarily be the one shown as
an exit of cycle B. The fact that this side reaction is especially
observed for the E-selective reactions (proceeding via cycle A)
indicates that in these cases cycle B is much slower and does not
go beyond intermediate IV. The exit pathway to form 9 then just
regenerates the catalyst for the (faster) cycle A.
(21) (a) Frankel, E. N.; Selke, E.; Glass, C. A. J. Am. Chem. Soc. 1968, 90,
2446. (b) Cais, M.; Frankel, E. N.; Rejoan, A. Tetrahedron Lett.
1968, 16, 1919.
(22) For reviews on the application of 1,4-hydrogenation in organic
synthesis, see ref. 8 and: Vasil'ev, A. A.; Serebryakov, E. P. Russ.
Chem. Bull. Int. Ed. 2002, 51, 1341.
(23) Le Maux, P.; Jaouen, G.; Saillard, J. Y. J. Organomet. Chem. 1981,
212, 193.
(24) Sodeoka, M.; Yamada, H.; Shibasaki, M. J. Am. Chem. Soc. 1990,
112, 4906.
(25) Detailed experimental procedures and characterization data are
given in the Supporting Information.
Analytical Data of Selected Trisubstituted Olefins
Compound 4a: 1H NMR (300 MHz, CDCl3): δ = 7.37–7.30 (m, 5
H), 5.16–5.13 (m, 1 H), 5.10 (s, 2 H), 2.48–2.45 (m, 2 H), 2.33–
2.31 (m, 2 H), 1.96–1.93 (m, 2 H), 1.59 (s, 3 H), 1.32–1.23 (m, 10
H), 0.88 (t, 3JH,H = 7.0 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 173.4, 136.2, 133.1, 128.7, 128.3, 128.3, 125.9, 66.2, 34.8, 33.4,
32.0, 29.9, 29.4, 29.4, 28.0, 22.8, 16.0, 14.3 ppm. HRMS (EI): m/z
calcd [M]+ for C20H30O2: 302.2245; found: 302.232.
1
General Procedure for Enyne Metathesis
Compound 4d: H NMR (500 MHz, CDCl3): δ = 8.07–8.05 (m, 2
A Schlenk flask was filled under argon with 0.1 equiv of catalyst
6, cooled to 0 °C and flushed with ethylene. Then, dry CH2Cl2
(2.0 ml/mmol alkyne), 1.0 equiv of the alkyne (1) and 10 equiv
of the alkene 2 were added, and the reaction mixture was
stirred at r.t. for 24–72 h. The catalyst was removed by stirring
the reaction mixture with active charcoal. The suspension was
then filtered over silica, and the solvent was evaporated under
reduced pressure. The crude product was purified by column
H), 7.57–7.53 (m, 1 H), 7.45–7.42 (m, 2 H), 5.58–5.55 (m, 1 H),
4.71 (s, 2 H), 2.09–2.04 (m, 2 H), 1.74 (s, 3 H), 1.41–1.35 (m, 2
H), 1.34–1.27 (m, 4 H), 0.89 (t, 3JH,H = 7.0 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 166.6, 133.0, 130.6, 130.3, 130.0, 129.7,
128.5, 70.9, 31.7, 29.1, 27.9, 22.7, 14.2, 14.2 ppm. HRMS (ESI):
m/z calcd [M + Na]+ for C16H22O2: 269.15120; found: 269.15154.
Compound 4i: 1H NMR (500 MHz, CDCl3): δ = 7.33–7.30 (m, 2
H), 6.86–6.83 (m, 2 H), 5.72–5.69 (m, 1 H), 3.80 (s, 3 H), 2.17 (q,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–H

H
F. Ratsch, H.-G. Schmalz
Letter
Synlett
3JH,H = 7.3 Hz, 2 H), 2.00 (s, 3 H), 1.47–1.41 (m, 2 H), 1.34–1.31
129.7, 128.7, 128.5, 70.5, 43.1, 30.1, 27.1, 23.4, 14.2 ppm.
Compound 4n: H NMR (300 MHz, CDCl3): δ = 8.07–8.04 (m, 2
3
1
(m, 4 H), 0.90 (t, JH,H = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 158.5, 136.8, 133.9, 127.4, 126.7, 113.6, 55.4, 31.8,
H), 7.59–7.54 (m, 1 H), 7.47–7.42 (m, 2 H), 5.53 (t, 3JH,H = 7.2 Hz,
1 H), 4.71 (s, 2 H), 2.35 (t, 3JH,H = 6.9 Hz, 2 H), 2.13 (‘q’, 3JH,H = 7.2
Hz, 2 H), 1.74 (s, 3 H), 1.71–1.64 (m, 2 H), 1.61–1.51 (m, 2 H)
ppm.13C NMR (75 MHz, CDCl3): δ = 166.5, 133.1, 131.3, 130.5,
129.7, 128.5, 128.3, 119.8, 70.5, 28.4, 27.0, 25.1, 17.2, 14.2 ppm.
HRMS (EI): m/z calcd [M]+ for C16H19NO2: 257.1416; found:
257.143.
29.6, 28.9, 22.8, 15.9, 14.3 ppm.
1
Compound 4k: H NMR (300 MHz, CDCl3): δ = 8.06–8.05 (m, 2
H), 7.57–7.54 (m, 1 H), 7.46–7.43 (m, 2 H), 5.54–5.51 (m, 1 H),
3
4.71 (s, 2 H), 2.44 (t, JH,H = 7.4 Hz, 2 H), 2.14 (s, 3 H), 2.09 (‘q’,
3JH,H = 7.6 Hz, 2 H), 1.73 (s, 3 H), 1.68 (‘p’, 3JH,H = 7.4 Hz) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 208.9, 166.5, 133.0, 131.2, 130.5,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–H