Direct synthesis of Z-alkenyl halides through catalytic cross-metathesis

Article abstract of DOI:10.1038/nature17396

Olefin metathesis has had a large impact on modern organic chemistry, but important shortcomings remain: for example, the lack of efficient processes that can be used to generate acyclic alkenyl halides. Halo-substituted ruthenium carbene complexes decompose rapidly or deliver low activity and/or minimal stereoselectivity, and our understanding of the corresponding high-oxidation-state systems is limited. Here we show that previously unknown halo-substituted molybdenum alkylidene species are exceptionally reactive and are able to participate in high-yielding olefin metathesis reactions that afford acyclic 1,2-disubstituted Z-alkenyl halides. Transformations are promoted by small amounts of a catalyst that is generated in situ and used with unpurified, commercially available and easy-to-handle liquid 1,2-dihaloethene reagents, and proceed to high conversion at ambient temperature within four hours. We obtain many alkenyl chlorides, bromides and fluorides in up to 91 per cent yield and complete Z selectivity. This method can be used to synthesize biologically active compounds readily and to perform site- and stereoselective fluorination of complex organic molecules.

Full text of DOI:10.1038/nature17396

ARTICLE
doi:10.1038/nature17396
Direct synthesis of Z-alkenyl halides
through catalytic cross-metathesis
Ming Joo Koh1, Thach T. Nguyen1, Hanmo Zhang1, Richard R. Schrock2 & Amir H. Hoveyda1
Olefin metathesis has had a large impact on modern organic chemistry, but important shortcomings remain: for example,
the lack of efficient processes that can be used to generate acyclic alkenyl halides. Halo-substituted ruthenium carbene
complexes decompose rapidly or deliver low activity and/or minimal stereoselectivity, and our understanding of the
corresponding high-oxidation-state systems is limited. Here we show that previously unknown halo-substituted
molybdenum alkylidene species are exceptionally reactive and are able to participate in high-yielding olefin metathesis
reactions that afford acyclic 1,2-disubstituted Z-alkenyl halides. Transformations are promoted by small amounts
of a catalyst that is generated in situ and used with unpurified, commercially available and easy-to-handle liquid
1,2-dihaloethene reagents, and proceed to high conversion at ambient temperature within four hours. We obtain many
alkenyl chlorides, bromides and fluorides in up to 91 per cent yield and complete Z selectivity. This method can be used
to synthesize biologically active compounds readily and to perform site- and stereoselective fluorination of complex
organic molecules.
Olefins with a halogen substituent are a mainstay in chemistry. Alkenyl would have several other advantages, as follows: (1) strong oxidants
chlorides and bromides are found in biologically active natural prod- (for example, Br2), toxic mercury salts23 and/or the more difficult to
ucts (for example, the recently isolated Z-alkenyl chloride contain- prepare and use alkenylboronic acids24 (compared to B(pin) deriv-
ing neuromodulator janthielamide A1 or bromine-containing fatty atives) would not be needed; (2) severely basic conditions for (pin)
acids that are adipogenesis stimulators2) or can be used in some of B-to-halogen exchange and reactive halide sources (for example, iodine
the most central transformations in chemistry (for example, catalytic monochloride), which may be detrimental to certain functionality (for
cross-coupling3). Alkenyl fluorides are valued because of the impor- example, sulphides25 or indoles26), would not be necessary; (3) prod-
tance of organofluorine compounds in medicine4, agrochemicals5 and uct purification would be more practical—organic halide reagents are
materials development6. A fluoro-substituted olefin can influence the more easily removable (sufficiently volatile) and do not afford pinacol
properties of a molecule; an example is the Z-fluoroalkene derivative of by-product that can be difficult to separate from the desired product;
γ-aminobutyric acid (GABA) transaminase inhibitor7, which is more and (4) access to multifunctional molecules with an alkenyl–B(pin) as
active than its E isomer8 yet similarly potent and with a distinct mode well as an alkenyl halide would be more feasible27.
of action compared to the parent non-fluorinated alkene (vigabatrin).
Fluoro-olefins may be used as substrates in synthesis of fluorine- The potential and challenge of alkenyl halide CM
containing building blocks9. And yet the number of approaches for A catalytic CM protocol that converts an alkene to an alkenyl halide
accessing alkenyl halides is limited; many entail multi-step sequences directly would be complementary to the existing methods (it would
demanding prior synthesis of alkenylboron10, alkenylsilane11 or an offer a distinct synthesis strategy) and especially advantageous if a
organometallic species12,13, followed by conversion of the C–B, C–Si commercially available, easy-to-handle (that is, liquid at ambient
or C–metal unit to a carbon–halogen bond (for a more extensive list, conditions) and relatively inexpensive reagent could be used in a highly
see Supplementary Information). Reactions might begin with the stereoselective process (Fig. 1a). For instance, a transition metal com-
more costly and less widely available (compared to alkenes) alkyne plex that catalyses CM of an abundant substrate such as methyl oleate
substrates13, at times proceed with moderate stereoselectivity10, or and an easily accessible organo-chloride reagent would afford separable
are not sufficiently general11,12. Methods for preparation of 1,2-disub- Z-alkenyl halide compounds (Fig. 1a); one (1b) could be converted to
stituted Z-halo-alkenes with high stereoselectivity are even fewer in anti-inflammatory agent (S)-coriolic acid methyl ester28 by an ensuing
number10–13. One option is a Wittig reaction of an aldehyde with a catalytic cross-coupling. Ring-opening/cross-metathesis (ROCM) of
halogen-substituted phosphonium salt14,15, but stereoselectivities are cyclooctene with an alkenyl bromide would deliver Z,Z-dibromoalkene
variable and, at times, toxic hexamethylphosphoramide and/or severely 2, an intermediate used to access anti-tumour and immunosuppressive
low temperatures are needed for high Z:E ratios16. Approaches to agent tetrahydrosiphonodiol29 (Fig. 1a). The feasibility of a CM that
synthesis of 1,2-disubstituted Z-alkenyl fluorides are scarce15,17,18 and furnishes alkenyl fluorides would allow for late-stage fluorination30 of
none has reasonable scope.
complex molecules, such as potassium channel activator isopimaric
Certain 1,2-disubstituted Z-alkenyl halides can be prepared via stereo- acid31 in a catalytic, chemo- and stereoselective fashion (3, Fig. 1a).
defined alkenyl–B(pin) (pin, pinacolato) compounds19,20, acces-
Development of efficient alkenyl halide-generating CM reactions
is however not straightforward. Unlike Ru carbenes or Mo or W alky-
sible by catalytic cross-metathesis (CM) with vinyl–B(pin)21,22
.
If direct CM were able to deliver halogen-substituted olefins in a single lidenes with alkyl, aryl, boryl or alkoxy substituents, those bearing
catalytic reaction from a terminal olefin without the need for use and/or a halogen atom are either unstable (Ru), their transformations
synthesis of (at times expensive) organoboron reagents, such a reaction inefficient (Ru)32–34 or there is little known about them (Mo/W).
1Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA. 2Department of Chemistry, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, USA.
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RESEARCH ARTICLE
a
Representative applications to synthesis of valuable organic molecules
b State-of-the-art in alkenyl halide CM with Ru-based complexes
C7H15
Cl
MesN
Cl
NMes
Cl
MesN
NMes
Cl
MesN
NMes
MesN
Cl
NMes
Cl
O
Oleꢀn metathesis
catalyst
1a
MeO
Cl
+
PCy3
–
X
Ru
Ru
Ru
Ru
O
Ph
X
Cl
Cl
C7H15
MeO
Alkenyl–Cl reagent
X = Cl, Br, or F
PCy3
Cl
PCy3
Ru-1d
Methyl oleate
Cl
Ru-1a
Ru-1b
Ru-1c
Fischer-type carbene,
low activity
Decomposition products
with X = Cl and Br
1b
n-Bu
n-Bu
Cl
Br
O
With Z-dichloroethene,
5.0 mol%, 50 °C, 3 h:
>98%conv., yield ND,
Z:E = 60:40
With Z/E-dibromoethene,
5.0 mol%, 50 °C, 3 h:
16% conv., yield ND,
Z:E = 33:66
OMe
Cross-coupling
MesN
NMes
Cl
C5H11
catalyst
G
HO
+
Ru
C5H11
Cl
PhS
HO
F
X
i-PrO
(S)-coriolic acid methyl ester
With vinyl ꢀuoride,
X(or H)
B(pin)
Ru-2
(anti-inꢀammatory)
5.0 mol%, 23 °C, 24 h:
<5%conv., yield NA,
Z:E = NA
Oleꢀn metathesis
catalyst
Br
Br
c
Possible pathways for Z-selective CM with alkenyl halides and high-oxidation-state complexes
Alkenyl–Br reagent
X
X
X
G
RN
N
2
G
X
X = Cl, Br or F?
X
M
NR
M
N
Ph
OAr
iii
ArO
i
Ref. 29
OH
G
RN
RN
N
NR
OH
N
N
G
G
X
G
Tetrahydrosiphonodiol
(anti-tumour, immunosuppressant)
M
M
M
X
OAr
G
ArO
ii
v
iv
X
OAr
Ph
RN
G
N
Me
Me
X
M
Oleꢀn metathesis
catalyst
HE
HE
Me
Me
HZ
F
M = Mo or W
vi OAr
H
H
RN
NR
M
Alkenyl–F reagent
G
N
N
X
G
H
Me
H
Me
MeO2C
MeO2C
M
3
OAr
ArO
From isopimaric acid
(potassium channel activator)
viii
vii
Figure 1 | Designing catalytic CM reactions that afford Z-alkenyl
b, Ru complexes cannot promote efficient CM reactions of alkenyl halides
because of the low reactivity and instability of the derived halo-substituted
carbenes. c, The pathways that might allow a Mo or W species to promote
CM transformations that generate alkenyl halides, despite the fleeting
nature of the corresponding halo-substituted alkylidenes. Attempts to
generate and examine Cl-substituted alkylidenes (iv, shown red, with
X =Cl) were unsuccessful. Abbreviations: Conv., conversion; M, transition
metal; X, halogen; Mes, 2,4,6-(Me)3C6H2; G or R, various functional
groups; Ar, aryl group; NA, not applicable; ND, not determined.
halides. a, Potential applications of Z-selective CM reactions that afford
alkenyl halides include a concise synthesis of an anti-inflammatory agent
(top) and a ring-opening/CM (ROCM) process that delivers a compound
with two Z-alkenyl bromide bonds formerly employed in the preparation
of an immunosuppressant (middle). The ability to perform late-stage
stereoselective fluorination of complex molecules is another notable
and high impact advantage (bottom). In each case, a readily accessible,
easy-to-use and inexpensive halogen-containing reagent is involved,
shown blue; alkenyl-Cl (top), alkenyl-Br (middle) and alkenyl-F (bottom).
Fluoro-, chloro-, or bromo-substituted Fischer-type Ru complexes any data on the structure, stability or reactivity of a halo-substituted
show negligible activity (Ru-1b, Fig. 1b)34. With phosphine-containing Mo or W alkylidene. Adding to the uncertainty is a computational
systems (for example, Ru-1a) inactive species such as phosphoni- study suggesting that fluoro-substituted Mo alkylidenes would be
omethylidene Ru-1c and carbide Ru-1d32 are produced. There is some less stable than even the methylidenes36. Equally discouraging were
improvement with phosphine-free complexes (for example, Ru-2, the outcome of our attempts to prepare halo-substituted alkylidenes
Fig. 1b)33,34, but reactions are low yielding and minimally stereose- of Mo monoaryloxide pyrrolide (MAP) species (compare iv, Fig. 1c)
lective despite elevated temperatures (for example, 50°C) and long by using Z-dichloroethene (4a). Subjection of a neophylidene MAP
reaction times (for example, 24h).
complex (compare i) with two equivalents of 4a resulted in <2% trans-
formation (4h, 22°C; 400MHz 1H NMR analysis). The more reactive
methylidene (generated from ethylene) was consumed completely, but
Identification of an effective catalyst
The central issue, therefore, was whether high-oxidation-state (Mo/W) a halo-substituted alkylidene was not found spectroscopically. Our
halo-substituted alkylidene complexes would be sufficiently robust yet remaining hope was that, although undetected, the putative complex
appropriately reactive. Since alkoxy-substituted Mo alkylidenes are might be sufficiently long-lived to fuel the catalytic cycles (compare iv,
more active than the related Ru carbenes35, we hoped that the same Fig. 1c). If so, reaction of a neophylidene with a terminal alkene
might apply to halogen-containing olefins, but we did not know of could generate the less congested ii, which in turn might react with a
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ARTICLE RESEARCH
none of the alternative E isomer being observable (1H NMR analysis,
4h, 22°C; entry 8). We then reasoned that a larger aryloxide ligand,
although likely to be less active, might translate into longer catalyst
lifetime and better efficiency; we therefore examined the CM with
Mo-4b, but, while high stereochemical control could be retained (98:2 Z:E),
conversion and yield were reduced (62% conversion, 40% yield; entry 9).
After 12 h, 5a was isolated in 84% yield (95% conversion; entry 10) but
with some diminution in stereoisomeric purity (93:7 Z:E), probably
caused by post-metathesis isomerization. To achieve a better balance
between robustness and reaction rate without forfeiting stereocontrol, we
examined 2,4,6-triethyl-substituted aryloxide complex Mo-4c (entry 11);
5a could thus be secured in 75% yield and >98:2 Z:E selectivity after
four hours at room temperature.
Table 1 | Examination of complexes for CM
NMes
Cl
MesN
H
N
MesN
O
N
N
N
S
W
Ph
Mo
O
Ph
O
N
Ru
Ru
F3
C
O
O
O
O
Br
S
Br
F3
C
i-PrO
Cl
TBSO
CF3
F3C
Ru-3
Ru-4
Mo-1
W-1
F
F
F
F
F
N
N
N
N
N
N
Mo
Mo
Mo
O
Ph
Ph
Ph
O
O
Br
G
G
Br
Br
Br
G
G
TBSO
TBSO
Synthesis of Z-alkenyl chlorides and bromides
Mo-4aG = Me
Mo-4b G = i-Pr
Mo-4cG = Et
G
G
Mo-2
Mo-3
An array of Z-alkenyl chlorides can be prepared; yields were in the
50%–91% range with uniformly high stereoselectivity (95:5 to >98:2
Z:E; Fig. 2); the dichloroethene reagent (4a) was used without purifi-
cation. Commonly occurring and versatile functional groups such as a
silyl ether (5b, Fig. 2a), a sulphide (5c), an alkyne (5d), an epoxide (5e),
an ester (5f) or a phthalimide (5g) were tolerated. An aryl or a heteroaryl
moiety at the allylic position did not hinder the CM process (5j, k),
but reactions with styrenes (regardless of its electronic attributes) were
inefficient; this is probably due to steric hindrance within the requisite
trisubstituted all-syn metallacyclobutane intermediate (compare iii,
Fig. 1c) and the relatively facile homocoupling of aryl olefins. Hence,
stilbenes, which do not re-enter the catalytic cycle easily (compared
to the homocoupling product of an aliphatic alkene), were produced
predominantly (see below for further discussion); however, in the
reactions with α-branched aliphatic alkenes, which do not undergo
homocoupling as rapidly for steric reasons, CM is efficient. Z-Selective
synthesis of polycyclic compound 5n demonstrates applicability to
alkenes with a homoallylic quaternary carbon centre.
Cl
3.0–5.0 mol%
complex
Br
Br
Cl
Cl
+
benzene
4a
Z-5a
(5.0 equiv.;
used withoutpuriꢀcation)
Entry
number
Complex;
Time (h);
Conversion (%)*;
loading (mol%)
Ru-2; 5.0
Ru-3; 5.0
Ru-4; 5.0
Mo-1; 5.0
W-1; 5.0
temperature (°C) yield (%)†
Z:E‡
1
4; 50
4; 50
4; 50
4; 22
4; 22
4; 22
4; 22
4; 22
4; 22
12; 22
4; 22
82; 59
10; <5
<10; <5
67; <5
45; <10
43; <5
60; 27
87; 60
62; 40
95; 84
90; 75
58:42
NA
2
3
NA
4
NA
5
ND
6
Mo-2; 5.0
Mo-3; 5.0
Mo-4a; 5.0
Mo-4b; 5.0
Mo-4b; 5.0
Mo-4c; 3.0
NA
7
>98:2
>98:2
98:2
93:7
>98:2
8
Allylboronate 5o (Fig. 2b) was isolated in 66% yield and >98:2 Z:E
selectivity; this product, similar to allyltin compound 5h and allylsilane
product 5i, may be used as a reagent for C–C bond formation. Two
representative cases are shown; in one, allyl chloride 6a was obtained
in >98% γ- and diastereoselectivity, and in the other, performed in the
presence of 10mol% aminophenol 739, alkenyl chloride 6b was gen-
erated with high α-selectivity without any loss in Z:E ratio (>98:2).
As noted, access to several of the aforementioned CM products (such
as sulphide 5c, stannane 5h, indole 5k as well as allyl boron com-
pound 5o) by means of the two-step protocol involving vinyl–B(pin)
CM/boron-to-halogen exchange would be problematic.
9
10
11
Here we show the performance of various complexes (shown above the table) used for CM of a
terminal alkene with Z-1,2-dichloroethene (reaction highlighted in grey). Reactions were carried
out under a nitrogen atmosphere; see Supplementary Information for details. NA, not applicable;
ND, not determined.
*Conversion was based on the disappearance of the limiting reagent (8-bromo-1-octene) and
determined by analysis of the 1H NMR spectra of the unpurified mixtures; the variance of values
is estimated to be < 2%.
†Yield of isolated and purified product (Z/E mixture); the variance of values is estimated to be < 5%.
‡Z/E ratios were determined by 1H NMR analysis of unpurified mixtures; the variance of values is
estimated to be < 2%. See Supplementary Information for details.
Z-Disubstituted alkenes are effective substrates. Treatment of com-
Z-dihaloalkene (compared to the more volatile vinyl halide), affording mercially available Z-5-decene and Z-dichloroethene with 1.0mol%
the desired product and halo-substituted alkylidene (iv) via all-syn Mo-4c for two hours followed by the addition of alkyne 8 (5.0mol%
metallacyclobutane iii. Complex iv and the olefin could then com- PdCl2(PhCN)2, 10mol% CuI, piperidine, 15h), afforded 9 in 67% over-
bine to afford v, which would in turn release alkylidene ii and vinyl all yield and 97:3 Z:E selectivity. These processes were performed with-
halide. Alternatively, the halo-substituted alkylidene could react with out the need for isolation of volatile Z-alkenyl chloride 5p (Fig. 2b), and
another substrate molecule to furnish, by means of vi, the Z-alkenyl the enyne product has been used in the synthesis of marine metabolite
halide product and methylidenes vii and viii, which are precursors to ii. clathculin B40. Reactions can be easily carried out on a gram scale: CM
We probed the ability of several complexes to effect Z-selective CM of methyl oleate and 4a in the presence of 3.0mol% Mo-4c afforded
between 8-bromo-1-octene and commercially available and easy to Z-alkenyl chlorides 1a and 1b in 86% and 91% yield and with 97:3 Z:E
handle Z-dichloroethene 4a (boiling point 60°C versus –13°C for vinyl selectivity, respectively (Fig. 2b). Subsequent catalytic cross-coupling
chloride). Reaction with dichloro complex Ru-2 required 50°C to reach with alkenylboronate 10, obtained from site- and E-selective catalytic
82% conversion after four hours (Table 1, entry 1), affording 5a as a protoboryl addition of the commercially available propargyl alcohol41,
near equal mixture of stereoisomers; there was no transformation with completed the two-step synthesis of (S)-coriolic acid methyl ester28
Z-selective Ru-337 or Ru-438 (entries 2, 3). Use of bis-alkoxide Mo-1 from a renewable resource in 65% overall yield and 97:3 Z:E selectivity
led to ~70% conversion (4h, 22°C) but mostly to the corresponding (compared to five steps previously; see Supplementary Information
homocoupling product without any detectable alkenyl halide (entry 4). for bibliography).
Experiments with complexes W-1 and Mo-2 were similarly disappoint-
Z-Selective synthesis of alkenyl bromides brings with it the added
ing (entries 5, 6) as again there was only alkene homocoupling (<2% 5a). complication that stereoisomerically pure Z-dibromoethene (4b) is
Adamantylimido Mo-3 provided the first hopeful data: we isolated 5a not readily available and difficult to prepare, but a 64:36 Z:E mixture
in 27% yield and >98% Z selectivity (entry 7). Efficiency improved with can be purchased at relatively low cost (Fig. 3a). Although MAP com-
perfluoroimido complex Mo-4a: Z-5a was obtained in 60% yield with plexes prefer to react with Z-1,2-disubstituted alkene isomers42, our
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RESEARCH ARTICLE
Representative applications involving Z-alkenyl chlorides obtained by catalytic CM
b
a
Preparation of Z-alkenyl chlorides through catalytic CM
HO
Ph
Cl
10 equiv. PhCHO
G
Cl
Cl
3.0–5.0 mol% Mo-4c
G
Cl
+
toluene, 22 °C, 48 h
6a
benzene, 22 °C, 4 h
4a
64% yield, >98:2
>98:2 d.r.
:
(5.0 equiv.,
used as received)
(pin)B
Cl
10 mol%
i-Pr
N
Cl
Cl
Cl
N
5o
With 5.0 mol% Mo-4c,
90% conv. (4 h), 66% yield,
H
O
BnS
OH
TBSO
HO
(i-Pr)3Si
rac-7
5c
5d
t-Bu
Cl
5b
>98:2 Z:E
With 5.0 mol% Mo-4c,
94% conv., 71% yield,
>98:2 Z:E
With 3.0 mol% Mo-4c,
97% conv., 89% yield,
>98:2 Z:E
Ph
With 3.0 mol% Mo-4c,
88% conv., 80% yield,
>98:2 Z:E
2.0 equiv. PhCHO,
12.5 mol%NaOt-Bu,
1.5 equiv. MeOH,
6b
92% yield, 95:5
:
>98:2 Z:E
toluene, 22 °C, 24 h
O
Cl
Cl
n-Bu
n-Bu
N
Cl
MeO2C
O
1.0 mol% Mo-4c
benzene, 22 °C, 2 h
O
n-Bu
Cl
5e
5f
5g
Cl
Cl
With 5.0 mol% Mo-4c,
91% conv., 68% yield,
>98:2 Z:E
With 3.0 mol% Mo-4c,
90% conv., 65% yield,
>98:2 Z:E
With 3.0 mol% Mo-4c,
81% conv., 65% yield,
>98:2 Z:E
5p
5.0 mol% PdCl2(PhCN) 2,
10 mol% CuI
4a
Not isolated
(5.0 equiv.)
OH
8
Ph3Sn
Cl
MeO
MeO
Cl
(i-Pr)3Si
Cl
piperidine, 22 °C, 15 h
Ref. 40
5h
5j
5i
n-Bu
n-Bu
With 3.0 mol% Mo-4c,
97% conv., 89% yield,
>98:2 Z:E
With 3.0 mol% Mo-4c,
88% conv., 61% yield,
>98:2 Z:E
With 5.0 mol% Mo-4c,
90% conv., 84% yield,
96:4 Z:E
NMe
OH
9
MeHN
Clathculin B
67% overall yield
97:3 Z:E
(marine metabolite)
Cl
Cl
Cl
Cl
n-oct
HN
5m
5k
5l
n-oct
1a
With 3.0 mol% Mo-4c,
>98%conv., 78% yield,
96:4 Z:E
With 3.0 mol% Mo-4c,
86% conv., 50% yield,
95:5 Z:E
With 3.0 mol% Mo-4c,
96% conv., 75% yield,
>98:2 Z:E
86% yield, 97:3 Z:E
3.0 mol% Mo-4c
MeO2C
Cl
Cl
Cl
benzene, 22 °C, 4 h
94% conv.
4a
(5.0 equiv.)
MeO2C
Cl
1b
91% yield, 97:3 Z:E
Me
OTBS
H
H
10 mol% Pd(OAc)2,
20 mol% SPhos
HO
n-pent
H
H
OH
5n
MeO2C
(pin)B
n-pent
With 5.0 mol% Mo-4c,
75% conv., 70% yield,
95:5 Z:E
71% yield, 97:3 Z:E
(S)-coriolic acid methyl ester
(anti-in‰ammatory)
10
KOH, THF/H2O, 65 °C, 12 h
X-ray structure of 5n
Figure 2 | Synthesis of Z-alkenyl chlorides and applications. a, Many
Z-alkenyl chlorides (5b–5n) can be prepared with Mo-4c and unpurified
one gram scale) further underscores utility. Abbreviations: G, functional
groups; TBS, t-butyldimethylsilyl; Bn, benzyl; pin, pinacolato; Ac, acetyl;
SPhos, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl. Reactions
were performed under N2. Conversions and Z:E ratios were measured
by analysis of 1H NMR spectra of unpurified mixtures; the variance of
values is estimated to be < 2%. Yields correspond to isolated and
purified products and represent an average of at least three runs ( 5%).
See Supplementary Information for experimental details and spectroscopic
analyses.
Z-dichloroethene (4a; see boxed reaction at top); each product 5b–5n has
synthesis conditions shown under. Useful functional units are tolerated,
among them a sulphide, an allyl stannane, an indole and an allylboron.
The X-ray structure of 5n confirms the predominant formation of the Z isomer.
b, Chloro-substituted allylboron compounds for use in catalytic C–C bond
forming transformations. Top, synthesis of 6a, b. Application to synthesis
of clathculin B (middle) and (S)-coriolic acid methyl ester (bottom, on a
concern was possible interference by E-4b, leading to diminution in
The present strategies are applicable to ROCM; two instances are
stereoselectivity. It was also unclear whether the more sizeable dibro- depicted in Fig. 3b. Dibromoalkene 2 was obtained in 88% yield
moethene would cause significant lowering of efficiency. In the event, and 89:11 Z,Z:Z,E selectivity (10 mol% Mo-4c, 1 h); as mentioned
a range of Z-alkenyl bromides were obtained in 57%–83% yield and (compare Fig. 1a), diene 2 has been used in the preparation of
87:13–91:9 Z:E selectivity (11a–f, Fig. 3a). With the more volatile vinyl tetrahydrosiphonodiol29. The need for larger amounts of the more active
bromide (versus 4b), yields were significantly lower (<25%) because pentafluoroimido Mo-4c is so that maximum amounts of the
the increased amount of ethylene boosts the concentration of the com- ring-opening polymerization (ROMP) by-product can be converted
paratively unstable methylidene complexes (compare vii, viii, Fig. 1c). to monomeric 2. Z,Z-Dichloroalkene 12 was isolated in 75% yield as a
The lower Z selectivity in the case of bromoalkene products (versus single stereoisomer; adamantylimido complex Mo-3 proved optimal, as
alkenyl chlorides) may be attributed to a minor pathway involving this less active catalyst (compared to Mo-4c) is sufficient for the faster
metallacyclobutanes derived from the E isomer of the dibromo-alkene ROCM involving the less hindered Z-dichloroethene to compete with
reagent (see Supplementary Information for details).
ROMP for attaining maximal Z selectivity. When the milder Mo-3 was
4 6 2
| N A T U R E | V O L 5 3 1 | 2 4 M A R C H 2 0 1 6
© 2016 Macmillan Publishers Limited. All rights reserved

ARTICLE RESEARCH
a Preparation of Z-alkenyl bromides through catalyticCM
b Preparation of a Z,Z-bis(alkenyl) bromide and chloride by ROCM
Br
10 mol% Mo-4c
5.0 mol% Mo-4c
G
Br
Br
G
Br
Br
Br Br
+
+
benzene, 22 °C, 1 h
benzene, 22 °C, 4 h
Br
4b
64:36 Z:E
(8.0 equiv.)
Br
4b
2
64:36 Z:E
(8.0 equiv., used as received)
>98%conv., 88% yield,
89:11 Z,Z:Z,E
O
Br
Br
N
Br
OH
OH
O
Ref. 29
TBSO
(i-Pr)3Si
11b
11a
11c
98% conv., 83% yield,
95% conv., 63% yield,
92% conv., 67% yield,
Tetrahydrosiphonodiol
(anti-tumour, immunosuppressant)
87:13 Z:E
88:12 Z:E
87:13 Z:E
O
Br
Br
Cl
Me
TBSO
Me
Me
5.0 mol% Mo-3
O
NBn2
Br
Cl
Cl
+
benzene, 22 °C, 2 h
NBoc
Cl
12
11d
11f
4a
11e
90% conv., 66% yield,
74% conv., 57% yield,
>98:2 Z:E
(5.0 equiv.)
84% conv., 66% yield,
>98%conv., 75% yield,
>98:2 Z,Z:Z,E
88:12 Z:E
91:9 Z:E
87:13 Z:E
Figure 3 | Z-Alkenyl bromides through catalytic CM and ROCM.
a, Stereoisomeric mixture of 1,2-dibromoethene (4b) can be used in
preparation of Z-alkenyl bromides 11a–11f via the reaction shown boxed
at the top. b, The protocol is applicable to ROCM processes with readily
accessible cyclic alkenes; Z,Z-bis(alkenyl)bromide has been employed in
the preparation of anti-tumour agent tetrahydrosiphonodiol (top).
The corresponding dichloride was synthesized in 75% yield and with
complete Z selectivity (bottom). Abbreviations: G, various functional
groups; Ar, aryl group; TBS, t-butyldimethylsilyl; Bn, benzyl; Boc,
t-butyloxycarbonyl. Reactions were performed under N2. Conversions
and Z:E ratios were measured as in Fig. 2, with the same variance; yields
were also measured as in Fig. 2. See Supplementary Information for
experimental details and spectroscopic analyses.
used in the more demanding transformation leading to bromo-alkene 2, of fluorine with G in the all-syn metallacyclobutane) versus the larger
there was >98:2 Z,Z:Z,E selectivity but with less conversion to the chlorine and bromine atoms, such that CM with 4c competes better
desired product (~35%, ~20% ROMP). Control experiments indi- with homocoupling of styrene. To the best of our knowledge, there
cated that post-metathesis isomerization is minimal.
are no reports regarding the synthesis of aryl-substituted Z-alkenyl
fluorides by catalytic cross-coupling of 4c, and such transformations
(for example, 13e, f) would probably suffer from chemoselectivity com-
Synthesis of Z-alkenyl fluorides
Development of Z-selective CM reactions that afford organofluo- plications. The present processes would offer an attractive pathway for
rine products posed a new complication (Fig. 4). Vinyl fluoride has accessing a variety of organofluorine compounds43. Z-Alkenyl fluoride
a very low boiling point (–72 °C versus –13 °C for vinyl chloride); 13g has been converted to the aforementioned GABA transaminase
Z-difluoroethene is expensive, similarly difficult to handle as well as inhibitor 147; product 13g was obtained in 55% overall yield and >98:2
explosive (Fig. 4a). We thus envisioned using Z-bromo-fluoroethene fluoro:bromo and Z:E selectivity by CM with the silyl-amide substrate
(4c), a commercially available, economically viable and substantially followed by deprotection. There was <5% conversion with the parent
less volatile organohalide (boiling point, +36°C), an option that raises amide probably due to internal association of the Lewis basic amide
a selectivity problem: the bromo-fluoroethene compound must inter- with the Mo centre in the intermediate alkylidene complex44.
act with a Mo alkylidene according to the regiochemical mode of addi-
tion I in Fig. 4a. If the transformation were to proceed through II, Z-selective complex molecule fluorination
a Z-alkenyl bromide would be formed. We reasoned that reaction A corollary to the present approach is the possibility of implementing
via I might be preferred for two reasons. First, the 1H NMR spectrum net stereoselective olefinic C–H/C–F bond exchange within a com-
(CDCl3) of 4c contains a significantly more upfield signal for the pro- plex molecule; this would allow rapid access and screening of well-
ton at the base of the C–Br bond, indicating that electron density is defined fluorine-tagged derivatives for possible desirable properties.
greater at this carbon (stronger π donation and σ withdrawing induc- In this context (Fig. 4c), formation of Z-alkenyl fluoride 15 (>98:2
tive effect by fluorine), favouring its association with the Lewis acidic fluoro:bromo, 63% yield, >98:2 Z:E) demonstrates relevance to
Mo centre (compare I versus II). Additionally, the metallacyclobutane processes involving a relatively hindered allylic ether45. Tricyclic prod-
generated via II would suffer from steric repulsion between the more uct 3 (94:6 fluoro:bromo, 70% yield in the pure form, 96:4 Z:E) is derived
sizeable halogen and the alkylidene substituent (G). The catalytic CM from the challenging CM with the isopimaric acid31 methyl ester
affording Z-alkenyl fluoride 13a indeed generated bromide 11b as (compare Fig. 1a); here, the alkene is next to a sterically demanding
the minor product (72:28 fluoro:bromo; Fig. 4b). Consistent with the all-carbon quaternary centre.
suggested model (I versus II), with an α-branched terminal alkene,
The findings summarized in Fig. 4d illustrate that the method is
the product mixture was less contaminated by the corresponding tolerant of a range of functional units commonly found in biologi-
bromoalkene: pure 13b, formed from a CM reaction that proceeded cally active molecules. Z-alkenyl fluoride 16 (from anti-depressant
with 96:4 fluoro:bromo selectivity, was isolated in 70% yield and >98:2 perphenazine46) was obtained efficiently and stereoselectively (91:9
Z:E ratio after purification.
fluoro:bromo, 78% yield, >98:2 Z:E), underscoring tolerance towards
Contrary to transformations of styrenes with dichloro- or dibro- aryl or alkyl amines and aryl sulphides. Synthesis of Z-fluoro-alkene
moethene (4a, b), CM with 4c and aryl olefins proceeded readily 17 (from β-lactamase inhibitor sulbactam47) by the two-step sequence
and stereoselectively: β-(Z)-fluorostyrenes 13c–f were obtained in of Z-selective CM with vinyl–B(pin)21 followed by conversion of
93:7–96:4 fluoro:bromo selectivity, 64%–72% yield of the pure Z-alkenyl the C–B unit to a C–F bond, according to the only available reported
fluoride and 93:7–97:3 Z:E selectivity. These variations in efficiency procedure48, led to outright substrate decomposition. The first step
might be associated with the lower steric repulsion (eclipsing interaction afforded the Z-alkenyl–B(pin) compound as expected (22°C, 24h, 70%
2 4 M A R C H 2 0 1 6
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RESEARCH ARTICLE
a
b
Identifying a practical and effective alkenyl ꢀuoride reagent
Br
Preparation of Z-alkenyl ꢀuorides through catalytic CM
F
F
F
5.0 mol% Mo-4c
benzene, 22 °C, 4 h
G
G
F
Br
F
Difꢀcult to handle,
explosive,
4c
+
Easier to handle,
much less costly
4c
(5.0 equiv.,
expensive
used as received)
+
Br
F
Br
F
H
1 and H2
–
assigned on basis
of H–F coupling
MeO
AcO
H2
5.61 p.p.m.
H1
H2
H1
Me
Me
TBSO
Me
7.08 p.p.m.
F
F
F
F
F
F
F
(i-Pr)3Si
F
F
13a
13b
F
F
F
13c
13d
>98%conv., 72:28 F:Br,
64% yield of ꢀuoride,
>98:2 Z:E
>98%conv., 96:4 F:Br,
70% yield of ꢀuoride,
>98:2 Z:E
>98%conv., 93:7 F:Br,
71% yield of ꢀuoride,
95:5 Z:E
84% conv., 96:4 F:Br,
72% yield of ꢀuoride,
94:6 Z:E
F
F
N
+
–
N
+
N
N
Cl
Br
–
O
Mo
Mo
G
G
O
O
+
More
steric
repulsion
NH3
HN
F
F
Br
O
O
HCl
–
F
F
F
Ar
Ar
F
Br
–
+
–
Ref. 7
+
13g
Ar
Ar
14
13e
13f
(CM of TBS-amide/
deprotection)
60% conv., >98:2 F:Br,
55% overall yield of ꢀuoride,
>98:2 Z:E
Electronically
mismatched
GABA transaminase inhibitor
exhibits higher potency versus E isomer
and unique mode of action
78% conv., 96:4 F:Br,
64% yield of ꢀuoride,
97:3 Z:E
88% conv., 95:5 F:Br,
66% yield of ꢀuoride,
93:7 Z:E
I
II
c
Z-Selective “ꢀuorine insertion” involving complex molecules
d Demonstration of functional group compatibility
O
O
H
Me
N
S
Me
Me Me
N
O
O
Me
N
Me
O
F
Bn
O
Cl
N
S
H
O
O
F
F
Me
O
X-ray structure of 15
MeO2C
H
PMP
F
Me
Me
15
3
16
17
80% conv., >98:2 F:Br,
63% yield of ꢀuoride,
>98:2 Z:E
83% conv., 94:6 F:Br,
70% yield of ꢀuoride,
96:4 Z:E
88% conv., 91:9 F:Br,
78% yield of ꢀuoride,
>98:2 Z:E
86% conv., >98:2 F:Br,
80% yield of ꢀuoride,
>98:2 Z:E
(from intermediate in
synthesis of baconipyrone C)
(from isopimaric acid,
K channel activator)
(from perphenazine,
anti-depressant)
(from sulbactam,
-lactamase inhibitor)
Figure 4 | Z-alkenyl fluorides and late-stage fluorination. a, Z-Bromo-
fluoroethene (4c, top) can be used for synthesis of Z-alkenyl fluorides.
Based on electronic and steric factors, reactions probably proceed
via I (versus II). b, An array of products (13a–14) can be accessed
using the general reaction shown boxed, including those with an aryl
substituent. c, Stereoselective late-stage fluorination of complex molecules
can be performed, giving, for example 15, 3. d, A variety of widely
occurring heteroatom-containing functional units are tolerated, giving,
for example, 16, 17. Abbreviations: G, various functional groups;
Ar, aryl group; PMP, p-methoxyphenyl; Ac, acetyl; Bn, benzyl; TBS,
t-butyldimethylsilyl. Reactions were performed under N2. Conversions
and Z:E ratios were measured as in Fig. 2, with the same variance; yields
were also measured as in Fig. 2. For 13a, 3.0 mol% Mo-4c was used, and
for 3, 13g and 15, 10 mol% Mo-4c was used (40 °C, 12 h for 13g).
See Supplementary Information for details.
conversion, >98:2 Z:E); but attempts to generate 17 by treatment with the costly and impractical fluoro-olefin alternatives (for example, vinyl
NaOH and AgOTf and then Selectfluor yielded an unidentifiable mix- fluoride or Z-1,2-difluoroethene).
ture of compounds, probably due to sensitivity of the substrate’s bicyclic
The advances outlined here serve as the foundation for future
core49. In contrast, Z-alkenyl fluoride 17 was obtained through direct CM progress involving this intriguing set of halogen-containing Mo
in 80% yield (>98:2 fluoro:bromo) as a single stereoisomer (>98% Z).
alkylidenes. The transformations should facilitate considerably the
preparation of an assortment of desirable molecules for research in
chemistry, biology and medicine, particularly since easy-to-handle (no
Conclusions
We have introduced halo-substituted Mo alkylidenes as highly reactive glove box needed) paraffin-wrapped MAP complexes are becoming
and difficult-to-detect but viable intermediates in olefin metathesis. commercially accessible.
The matter of efficiency is especially noteworthy because, regardless
Received 10 December 2015; accepted 2 February 2016.
of stereochemical control, there did not exist previously a catalytic CM
protocol that generated halo-alkenes in useful yields. The ability of
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4 6 4
| N A T U R E | V O L 5 3 1 | 2 4 M A R C H 2 0 1 6
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Author Contributions M.J.K., T.T.N. and H.Z. were involved in the discovery,
design and development of the new Z-selective cross-metathesis strategies
and their applications. A.H.H., M.J.K., T.T.N. and H.Z. conceived the research
programme. A.H.H. designed and directed the investigations. A.H.H. and R.R.S.
conceived the studies that led to the development of Mo MAP complexes.
A.H.H. wrote the manuscript with revisions provided by M.J.K., T.T.N. and H.Z.
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Author Information Reprints and permissions information is available at
www.nature.com/reprints. The authors declare competing financial interests:
details are available in the online version of the paper. Readers are welcome to
comment on the online version of the paper. Correspondence and requests for
materials should be addressed to A.H.H. (amir.hoveyda@bc.edu).
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