E- and Z-, di- and tri-substituted alkenyl nitriles through catalytic cross-metathesis

Article abstract of DOI:10.1038/s41557-019-0233-x

Nitriles are found in many bioactive compounds, and are among the most versatile functional groups in organic chemistry. Despite many notable recent advances, however, there are no approaches that may be used for the preparation of di- or tri-substituted alkenyl nitriles. Related approaches that are broad in scope and can deliver the desired products in high stereoisomeric purity are especially scarce. Here, we describe the development of several efficient catalytic cross-metathesis strategies, which provide direct access to a considerable range of Z- or E-di-substituted cyano-substituted alkenes or their corresponding tri-substituted variants. Depending on the reaction type, a molybdenum-based monoaryloxide pyrrolide or chloride (MAC) complex may be the optimal choice. The utility of the approach, enhanced by an easy to apply protocol for utilization of substrates bearing an alcohol or a carboxylic acid moiety, is highlighted in the context of applications to the synthesis of biologically active compounds.

Full text of DOI:10.1038/s41557-019-0233-x

Articles
https://doi.org/10.1038/s41557-019-0233-x
E- and Z-, di- and tri-substituted alkenyl nitriles
through catalytic cross-metathesis
YuchengMuꢀ ꢀ1, ThachT.Nguyen1, MingJooKohꢀ ꢀ1, RichardR.Schrock2 and AmirH.Hoveydaꢀ ꢀ1*
Nitriles are found in many bioactive compounds, and are among the most versatile functional groups in organic chemistry.
Despite many notable recent advances, however, there are no approaches that may be used for the preparation of di- or tri-
substituted alkenyl nitriles. Related approaches that are broad in scope and can deliver the desired products in high stereoiso-
meric purity are especially scarce. Here, we describe the development of several efficient catalytic cross-metathesis strategies,
which provide direct access to a considerable range of Z- or E-di-substituted cyano-substituted alkenes or their corresponding
tri-substituted variants. Depending on the reaction type, a molybdenum-based monoaryloxide pyrrolide or chloride (MAC)
complex may be the optimal choice. The utility of the approach, enhanced by an easy to apply protocol for utilization of sub-
strates bearing an alcohol or a carboxylic acid moiety, is highlighted in the context of applications to the synthesis of biologi-
cally active compounds.
itrile compounds are important to chemistry, medicine1 and
There are catalytic approaches for the stereoselective preparation
materials research2. Cyano-substituted alkenes are particu- of tri-substituted alkenyl nitriles, but these are confined to aryl- or
larly attractive, as these robust and highly polarized alkenes3 polyaryl-substituted products21,24,34–37 or demand forcing conditions
N
may be the source of biological activity, or provide a site for irre- (≥120°C)38,39. In some instances, high loadings of precious metal
versible and covalent inhibition4. Alkenyl nitriles may be readily salts39,40 or excess amounts (2.0equiv.) of a strong Lewis acid (BCl3)36
modified at the olefin site (for example, catalytic enantioselective are needed. To synthesize aliphatic tri-substituted alkenyl nitriles,
hydrogenation5–7 or conjugate additions8) and/or the nitrile moi- expensive reagents must be used, slight structural variations can
ety. Z- and E-di-substituted variants can be used in the stereose- result in low stereoselectivity28 or the substrates are valuable stereo-
lective preparation of medicinally relevant compounds, such as chemically defined tri-substituted alkenyl iodides27.
LR5182 (Fig. 1a)9. A nitrile unit can be the key component of a
The large majority of the above protocols, regardless of the
biologically active molecule, examples being the anti-HIV reverse degree of substitution in the product olefin, require an acetylenic
transcriptase inhibitors rilpivirine10 and fosdevirine11 (Fig. 1a). compound as the starting material22,23,25,29,35–40. Methods that involve
Stereochemically defined tri-substituted alkenyl nitriles are found alkenes as substrates would be strategically distinct and especially
within the anticancer agents CC-507912,13, phorboxazoles and their desirable, as olefins are more abundant and less costly.
analogues14,15, where the alkenyl oxazole moiety may also be gener-
Catalytic cross-metathesis represents an attractive strategy
ated by modification of a cyano-substituted olefin16,17 and calyculin for the preparation of stereochemically defined alkenyl nitriles.
A18 (Fig. 1b). Sequential addition of two different nucleophiles may However, such methods are scarce. The first examples were dis-
be induced to occur to an alkenyl nitrile at the CN bond, generating closed more than two decades ago by Crowe and Goldberg, who
N–H amines19 without oxidation-state adjustments or protection/ showed that Mo bis-alkoxide complexes can be used to synthesize
deprotection schemes.
Z-1,2-di-substituted alkenyl nitriles41. Later studies with Ru-based
There are catalytic protocols for the synthesis of di-substituted complexes led to protocols that are either similarly42,43 or less ste-
alkenyl nitriles involving palladium-20,21, nickel-22,23, iron-24, gal- reoselective44. Regardless of the catalyst type, Z:E ratios were vari-
lium-25, copper-26,27,28 or rhodium-based29 complexes. Major short- able, depended on the olefin type and did not exceed 90:10. What is
comings remain to be addressed, however. Toxic24,25 or costly more, only reactions of unhindered n-alkyl-substituted olefins were
reagents28 or catalysts bearing a precious metal20,21,29 are required reasonably efficient. There are only three reported instances where a
in several cases. Some reactions produce hydrogen cyanide21,27,29
.
tri-substituted alkenyl nitrile has been prepared by cross-metathesis
Limitation in scope is another significant issue, as methods that (again, from n-alkyl olefins)45–47, and stereoselectivity was minimal
furnish alkyl-substituted alkenyl nitriles are uncommon21,23,27,29
in every case (for example, 66:34 Z:E).
.
Effective control of stereochemistry can be problematic. Wittig-30,31
and Peterson-type reactions32,33 have been used to obtain Z-alkenyl Results
nitriles, but stereoselectivities can be moderate30,32, and stoichiomet- Key challenges and their origins. Because the cyano group is small,
ric amounts of a strong base (that is, n-butyllithium or hexamethyl- development of a highly stereoselective cross-metathesis that generates
disilazide) and cryogenic conditions (–78°C)30,33 are often needed. alkenyl nitriles is especially challenging. The energy difference between
Only two reported procedures offer access to a cyano-substituted Z the isomers of cyano-propene has been calculated by Wiberg and col-
olefin selectively21,27, and these require a stereochemically defined leagues48 to be just 0.26 0.04kcalmol−1 in favour of the Z isomer
Z-alkenyl bromide or iodide, the stereoselective synthesis of which (61:39 Z:E). It is thus not surprising that, whereas most cross-metathesis
is non-trivial.
reactions generate E isomers preferentially, cyano-substituted alkenes
1Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA, USA. 2Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, MA, USA. *e-mail: amir.hoveyda@bc.edu
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a
Cl
b
CN
O
Cl
Cl
NMe2
OH
CN
MeO
MeO
OMe
N
Cl
O
Me
OMe
OH
LR5182
O
O
CC-5079
(anticancer)
(used for cocaine abuse treatment)
Me
NC
O
Me
O
CN
O
Me
NC
O
Hemi-phorboxazole A
(anticancer)
CN
NH
Me
MeO
N
H
NMe2 OH
N
MeO
O
P
Me
Me
N
Cl
(HO)2OP
O
HN
CONH2
Me
Me
O
N
H
Me
CN
Me
Me
Me
N
Rilpivirine
Fosdevirine
O
OH
(anti-HIV, reverse transcriptase inhibitors)
Me
Me
OH
OH
OMe
Calyculin A
(anticancer)
Fig. 1 | Biologically active compounds with an alkenyl nitrile or a related moiety. a, Stereoisomerically pure 1,2-di-substituted olefins bearing a nitrile
substituent may be used to prepare medicinally relevant agents, such as LR5182, a polycyclic tertiary amine used to battle cocaine abuse. Furthermore,
stereochemically defined alkenyl nitriles reside in a range of biologically active molecules. Examples are rilpivirine and fosdevirine, entities relevant to the
fight against AIDS. b, Stereoisomerically pure tri-substituted alkenyl nitriles are also desirable. These moieties are found in biologically active entities,
represented by anticancer agents CC-5079, various phorboxazoles and calyculin A. In the case of phorboxazoles, the oxazole ring and its adjacent olefin
may also be generated from an alkenyl nitrile.
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
CN
N
N
N
N
N
N
N
δ–
N
δ+
N
CN
NC
Ar
Mo
Mo
Cl
Mo
Mo
CN
δ+
δ–
δ–
δ–
NC
O
O
O
O
Ar
Ar
Ar
δ–
Ar
δ+
Ar
Ar
Ar
I
II
III
IV
Less stabilized alkylidene:
more reactive
More stabilized alkylidene:
less reactive
Highly polarized alkylidene
Metallacyclobutane
and alkene: strong coordination
for non-productive process
Fig. 2 | Challenges in designing reactions that deliver stereodefined alkenyl nitriles. Unlike other types of Mo alkylidene, such as those that contain
a chlorine atom (i), a nitrile-substituted variant (ii) is more strongly stabilized due to electronic factors, and is therefore less reactive. The higher
polarizability of the Mo=C bond of a CN-substituted alkylidene and the alkene of acrylonitrile facilitates reaction via iii, generating metallacyclobutane iV
and causing non-productive olefin metathesis. Ar, aryl.
are formed with low to moderate Z selectivity, an attribute that was matters, as these factors favour reaction via the electronically
recently attributed to stereoelectronic factors49.
matched III (Fig. 2), which is precursor to the symmetrical metalla-
Another complication originates from the strongly electron- cyclobutane IV, an intermediate for non-productive self-metathesis.
withdrawing nature of a nitrile unit. With an alkenyl halide50,51 the
electron-withdrawing effect of a C–halogen bond is partially offset Z-di-substituted alkenyl nitriles. We began by examining a model
by electron–electron repulsion caused by the halide’s non-bonding transformation that could generate a Z-alkenyl nitrile, opting to
electrons and the accumulated electron density at the carbon atom use a terminal alkene (1a) and commercially available acrylonitrile
of a strongly polarized Mo alkylidene (see I, Fig. 2). In contrast, the (Fig. 3a). To minimize homo-metathesis of 1a, we initially used
presence of a cyano moiety has one overarching effect: stabilization excess acrylonitrile (that is, 3.0 equiv.). Among the Mo monoarylox-
of electron density at the alkylidene carbon (II), which translates ide pyrrolide (MAP) complexes, Mo-1a emerged as the most effec-
to diminished catalyst activity. The small size of a nitrile group and tive. Z-alkenyl nitrile 2a was formed with complete stereochemical
the strongly polarized C=C bond in acrylonitrile further complicate control (<2% E isomer), but there was only 45% consumption
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a
Br
Br
5.0 mol % Mo-1a
With 3.0 equiv. acrylonitrile:
Benzene, 22 °C, 4 h
45% conv., 40% yield, >98:2 Z:E
CN
+
With 1.0 equiv. acrylonitrile:
CN
81% conv., 71% yield, >98:2 Z:E
(equimolar amounts)
1a
2a
O
MeS
CN
O
CN
(i -Pr)3Si
CN
TBSO
CN
BnS
O
NHBoc
CN
2b
2c
2d
2e
2f
82% conv., 77% yield,
64% conv., 63% yield,
80% conv., 70% yield,
>98:2 Z:E
83% conv., 78% yield,
>98:2 Z:E
83% conv., 73% yield,
>98:2 Z:E
>98:2 Z:E
>98:2 Z:E
O
Me3Si
Ph3Sn
TBSO
N
O
BnO2C
CN
CN
CN
CN
CN
2g
2h
2i
2j
2k
71% conv., 63% yield,
89% conv., 86% yield,
>98:2 Z:E
Conv. ND, 74% yield,
>98:2 Z:E
84% conv., 71% yield,
>98:2 Z:E
70% conv., 42% yield,
>98:2 Z:E
>98:2 Z:E
MeO
HN
Me
(pin)B
TESO
CN
CN
CN
2m
CN
CN
2l
2n
2o
2p
<2% conv.
(see below)
70% conv., 41% yield,
>98:2 Z:E
56% conv., 46% yield,
>98:2 Z:E
75% conv., 69% yield,
>98:2 Z:E
<2% conv.
(see below)
b
5.0 mol % Mo-2a
Benzene, 22 °C, 4 h
(pin)B
(pin)B
+
CN
CN
R
CN
(R = Me,
comm. avail.)
Z-3
(1.5 equiv.)
2l
95% conv., 64% yield,
>98:2 Z:E
Ph
Ph
(t-Bu)Ph2SiO
Bn2N
BocN
2s (R = Me)
CN
CN
Me
2r (R = Me)
CN
CN
Me
CN
CN
2q (R = Me)
2t (R = Et)
2u (R = Me)
2v (R = Me)
87% conv., 82% yield,
76% conv., 70% yield,
95% conv., 90% yield,
>98% conv., 96% yield,
91% conv., 66% yield,
87% conv., 57% yield,
>98:2 Z:E
>98:2 Z:E
>98:2 Z:E
>98:2 Z:E
98:2 Z:E
>98:2 Z:E
CN
CN
CN
CN
CN
F3C
F
Br
I
2p (R = Me, 40 °C)
>98% conv., 84% yield,
>98:2 Z:E
2w (R = Me, 40 °C)
>98% conv., 77% yield,
2x (R = Me, 40 °C)
>98% conv., 66% yield,
2y (R = i-Pr, 40 °C)
Conv. ND, 63% yield,
98:2 Z:E
2z (R = i -Pr, 40 °C)
Conv. ND, 56% yield,
98:2 Z:E
>98:2 Z:E
97:3 Z:E
MeO
F
Me
CN
CN
N
Boc
CN
S
CN
CN
OMe
2aa (R = Me, 40 °C)
98% conv., 79% yield,
>98:2 Z:E
2ab (R = Me, 40 °C)
>98% conv., 75% yield,
>98:2 Z:E
2ac (R = Me, 40 °C)
>98% conv., 98% yield,
93:7 Z:E
2ad (R = Me, 40 °C)
>98% conv., 92% yield,
92:8 Z:E
2ae (R = Me, 40 °C)
80% conv., 55% yield,
96:4 Z:E
Fig. 3 | A broadly applicable approach to Z-di-substituted alkenyl nitriles. a, In the presence of Mo-1a, Z-selective cross-metathesis between a terminal
alkene and acrylonitrile may be performed efficiently and with high stereoselectivity. Transformations are more efficient with equimolar amounts of the
alkene substrates (versus excess acrylonitrile), probably because non-productive metathesis is minimized. The method is applicable to an assortment
of α-olefins. However, reactions with sterically demanding olefins are severely inefficient (for example, 2l and 2p). b, The latter shortcoming may be
addressed by stereoretentive processes involving easily accessible Z-di-substituted alkenes and maleonitrile (Z-3), and a monoaryloxide chloride (MAC)
catalyst (Mo-2a). See Supplementary Information section 3 for experimental and analytical details. comm. avail, commercially available; Bn, benzyl; pin,
pinacolato; Boc, tert-butoxycarbonyl; TBS, tert-butyldimethylsilyl; TES, triethylsilyl; ND, not determined.
of 1a after 4 h at ambient temperature, with no further progress conversion, especially in kinetically Z-seletive52,53 or E-selective51,54
after extended periods. On the basis of the hypothesis vis-à-vis cross-metathesis.
the adventitious influence of non-productive self-metathesis (via
Various linear alkenes were transformed to the corresponding
IV, Fig. 2), we probed the effect of lower acrylonitrile concentra- Z-alkenyl nitriles under the conditions used to access 2a (Fig. 3a).
tion on efficiency. With equimolar amounts of the two olefin sub- Products bearing a sulfide (2b–c), an epoxide (2d), an alkyne (2e),
strates, there was 81% conversion to 2a, which was isolated in 71% a silyl ether (2f) or a Lewis basic carbonyl unit (2g–h) were iso-
yield as the pure Z isomer (Fig. 3a). It is noteworthy that, typi- lated in 63–86% yield. Linear alkenes wherein a relatively long
cally, an excess amount of one reaction partner is needed for high C–Si or C–Sn bond separates a large substituent and the alkene were
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similarly efficient (2i–j). A bulky and/or an electron-withdrawing the steric pressure that probably exists within the corresponding
olefin substituent, however, had an adverse effect on efficiency. tert- metallacyclobutane intermediate.
Butyl(dimethyl)silyl ether 2k was isolated in 42% yield (compared
Nevertheless, a set of substrates that we were unable to efficiently
to 74% and 71% yields for 2i and 2j, respectively), and there was transform to their corresponding alkenyl nitriles were allylic ethers,
no conversion to allylic boronate 2l. This last finding underscores regardless of the nature of the Mo complex used or the nature of
the greater difficulty associated with the formation of alkenyl nitrile the protecting unit (for example, tert-butyldimethyl silyl, benzyl).
products in comparison to alkenyl halides, because Mo-1a, despite This shortcoming is reflected in the yield with which primary allyl
bearing a bulkier 2,6-bis(2,4,6-triethylphenyl)phenoxy ligand, was silyl ether 2k was obtained (42% yield); unlike other instances men-
effective in generating Z-γ-chloroallyl boronates (5.0mol% loading, tioned above (Fig. 3b), the efficiency did not improve in the cor-
22°C, 4h, 66% yield, >98:2 Z:E)50. β-Branched secondary homoal- responding stereoretentive process involving a MAC complex. The
lyl silyl ether 2m, and 2n, containing a benzylic substituent, were steric hindrance imposed by the allylic substituent together with
isolated in 41% and 46% yields, respectively. While 2o, a Z-alkenyl diminution of alkene Lewis basicity, caused by the adjacent C–O
nitrile with an unprotected indole, was obtained in 69% yield, bond, and the relative stability of a CN-substituted Mo alkylidene
there was <2% conversion when styrene was used as the substrate. (see Fig. 2) are probably responsible for the lack of reactivity.
Complete Z selectivity was observed in all cases (<2% E; more
on this later).
E-alkenyl nitriles. Next, we investigated reactions that would gen-
erate an E-di-substituted alkenyl nitrile (Fig. 4). As in the past, we
The more challenging Z-alkenyl nitriles. To address the limita- chose to focus on stereoretentive51 processes (versus stereoselec-
tions in scope noted above, we turned to Mo monoaryloxide chlo- tive). To identify an effective catalyst, we studied the reaction of
ride (MAC) complexes55, recently demonstrated to exhibit greater aryl olefin E-4a with commercially available fumaronitrile (E-3;
reactivity than the MAP systems. Because MAC species decompose Fig. 4a). The transformation with pentafluorophenyl imido MAP
readily in the presence of a terminal alkene55, a Z-alkene must be complexes Mo-1a and Mo-1b, while highly stereoretentive (>98:2
used as the starting material. We have shown that many such sub- E:Z), were moderately efficient, despite the elevated temperature
strates can be prepared readily and in high yield by single-vessel (47% and 52% conv. to E-4a, respectively, at 80°C). To improve
operations, often involving an efficient catalytic cross-coupling of efficiency, we again turned to MAC alkylidenes, mindful that this
an alkenyl boronate. Furthermore, a mixture of easily separable class of complexes were not formerly used for reactions that gen-
fumaronitrile and maleonitrile (E- and Z-3) can be obtained by erate E alkenes. We began with Mo-2a, which proved effective for
treatment of the commercially available E isomer with 5.0mol% the processes with hindered alkyl- and aryl-substituted olefins and
iodine (160°C, 6h)55. Therefore, subjecting commercially available leading to Z-alkenyl nitriles (Fig. 3b). Although there was only 20%
Z-crotyl–B(pin) to 1.5equiv. of maleonitrile and 5.0mol% Mo-2a conversion to E-5a, we were encouraged for several reasons. First,
afforded cyano-substituted Z-allyl–B(pin) product 2l (Fig. 3b) in the reaction was completely stereoretentive. Second, the transfor-
64% yield and >98:2 Z:E ratio after 4h at ambient temperature. mation was more efficient than when a MAP species was used, as
When the same transformation was carried out with Mo-1a, under a considerably greater portion of the product mixture consisted
otherwise identical conditions, the major product was derived of the desired product (22% conv., 20% to E-5a compared to 82%
from self-metathesis of Z-crotyl-B(pin) (72% conv.) while 2l was conv., 52% to E-5a for Mo-1b). Third, whereas Mo-1b is already a
the minor component (25% conv., >98:2 Z:E). This is probably pentafluoro-imido complex, Mo-2a is an adamantyl imido deriva-
because, unlike Mo-2a, Mo-1a is unable to react with the severely tive, leaving room for the possibility of achieving better efficiency
electron-deficient maleonitrile (Z-3). The approach is applicable to through incorporation of an activating polyfluoroaryl imido ligand.
α-branched alkenes (2q–s), which are among the most challenging
Topromotecross-metathesisbetweenE-3andE-4a,weprobedthe
ability of the pentafluoro-imido MAC alkylidenes derived from Mo-
substrates in cross-metathesis.
Unlike when MAC complex Mo-2a was used, attempts to gener- 2b, most efficiently prepared and isolated as a dimethylphenylphos-
ate amine 2t, 1,3-diene 2u and 1,4-diene 2v with a MAP species phine complex56. We used 15mol% tris(pentafluorophenyl)borane
(Mo-1a) led to much less favourable results (<30% conv. to the as the additive to generate the active four-coordinate species (after
desired product). Intramolecular N→Mo chelation may be respon- loss of the phosphine) and to cap the hydroxy group of residual free
sible for the diminished conversion to 2t, whereas the MAC cata- 2,6-(2,4,6-triisopropyl)phenol (remainder from catalyst synthesis),
lyst is probably reactive enough that even a low concentration of a strategy that we would later use to address another important issue
the active four-coordinate alkylidene species can be sufficient for (see below). After 12h at 40°C, there was 67% consumption of E-4a,
efficient cross-metathesis. When a MAP complex was used to pre- with 49% conversion to E-5a, representing a notable boost in reac-
pare 1,3-diene 2u, there was <2% conversion to the desired product. tivity. Unexpectedly, however, there was significant diminution in
In the case of diene 2v, significant amounts of by-products from the E:Z ratio (88:12). Usually, the reason for lower product stereo-
transformation at the substrate’s E-alkene could be observed. As isomeric purity in stereoretentive olefin metathesis is adventitious
noted previously55, MAC complexes react with Z alkene isomers isomerization of the starting alkene. We surmised that E-3, an
preferentially.
exceedingly electrophilic reagent, might interconvert with its simi-
Equally notable are the transformations that generate different larly favoured Z isomer (as noted above) through an addition/elim-
aryl- and heteroaryl-substituted Z-alkenyl nitriles (2p–2ae; Fig. 3b). ination sequence. The likely nucleophilic promoter for this event,
Thus, regardless of the position or the electronic attributes of the considering the complete retention of stereochemistry with the
aryl substituent, the desired products were isolated in 55–98% yield acetonitrile complex Mo-2a, would be an uncoordinated dimeth-
and 92:8 to >98:2 Z:E ratio. In certain cases, slight heating to 40°C ylphenylphosphine. This led us to subject E-3 to 5.0mol% of tri-
led to a higher yield, but the duration of all transformations was cyclohexylphosphine (easier to handle than PhMe2P) and 15mol%
just 4h. Two additional points merit note: (1) with a MAC species, (C6F5)3B (22°C, 4h), which resulted in just 3% isomerization (that
reaction with unprotected indole-containing substrate (cf. 2ad) did is, from >98:2 to 97:3 E-3:Z-3). This might seem insignificant, but,
not lead to any significant conversion (<5%); (2) this set of products considering that Z alkenes generally react faster with this catalyst
(Fig. 3b) is not in the purview of any existing cross-metathesis meth- class55, particularly with a larger aryloxide ligand, this could indeed
ods, where a more traditional Mo-41 or Ru-based42 complex is used. be the source of the 12% loss in stereochemical purity. To con-
The case of ortho-tolyl-substituted alkenyl nitrile 2ac, which was firm, we prepared Mo-2c, a complex that bears a less nucleophilic
secured in 98% yield (93:7 Z:E), is especially noteworthy, considering 3-bromopyridyl ligand, and, under otherwise identical conditions
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a
Me
CN
5.0 mol% Mo complex
CN
+
NC
MeO
MeO
E-4a
5a
E-3
(5.0 equiv.)
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
N
N
N
Br
N
N
O
N
Me2PhP
Ph
N
N
N
Ph
Ph
Mo
Mo
Mo
Mo
Mo
Ph
Ph
Cl
Cl
Cl
O
O
O
O
Mo-1a
(tol., 80 °C, 12 h)
Mo-1b
(tol., 80 °C, 12 h)
Mo-2a
(C6H6, 40 °C, 12 h)
Mo-2b
Mo-2c
(C6H6, 15 mol% (C6F5)3B, 40 °C, 12 h)
67% conv., 49% conv. to 5a,
88:12 E:Z
(C6H6, 6.0 mol% (C6F5)3B, 40 °C, 12 h)
>98% conv., 84% conv. to 5a,
78% yield, 96:4 E:Z
54% conv., 47% conv. to 5a,
>98:2 E:Z
82% conv., 52% conv. to 5a,
>98:2 E:Z
22% conv., 20% conv. to 5a,
>98:2 E:Z
b
F
Me
CN
Br
CN
CN
CN
MeO2C
5b (with Mo-2c)
62% conv., 54% yield,
90:10 E:Z
5c (with Mo-2d)
54% conv., 50% yield,
5d (with Mo-2c)
77% conv., 73% yield,
97:3 E:Z
5e (with Mo-2c)
75% conv., 71% yield,
97:3 E:Z
96:4 E:Z
CN
CN
CN
CN
S
F3C
Ph
I
5f (with Mo-2c)
64% conv., 54% yield,
96:4 E:Z
5g (with Mo-2c)
75% conv., 62% yield,
5h (with Mo-2c)
88% conv., 81% yield,
97:3 E:Z
5i (with Mo-2c)
95% conv., 87% yield,
96:4 E:Z
96:4 E:Z
c
5.0 mol% Mo-2c
Ph
CN
CN
+
Alkyl
Alkyl
NC
6.0 mol% (C6F5)3B,
C6H6, 40 °C, 12 h
E-5
E-3
6
(5.0 equiv.)
O
CN
CN
F
CN
BnO
OTs
N
F
F
F
6a
76% conv., 75% yield,
O
6b
96:4 E:Z
70% conv., 69% yield,
F
6c
93:7 E:Z
70% conv., 69% yield,
Br
N
N
93:7 E:Z
Ph
Mo
Me
CN
5.0 mol% Mo-2d
6.0 mol% (C6F5)3B, C6H6, 40 °C, 12 h
Cl
O
CN
+
NC
NC
NC
E-7
E-3
6d
(comm. avail.)
(5.0 equiv.)
62% conv., 60% yield,
Mo-2d
97:3 E:Z
Fig. 4 | E-di-substituted alkenyl nitriles. a, Cross-metathesis between an E-di-substituted olefin and fumaronitrile was more efficient with Mo-2b, but E:Z
ratios were low compared to when Mo-1b or Mo-2a were used (88:12 versus >98:2, respectively). Control experiments indicated that this is probably due
to isomerization of E-3 to Z-3, catalysed by the released PMe2Ph by Mo-2b. Thus, with Mo-2c (3-bromopyridine ligand), 4a was obtained with 96:4 E:Z
selectivity. b, The approach can be used to access aryl-substituted E-alkenyl nitriles. c, E-β-alkyl-styrenyl precursors can be converted to E-alkyl-substituted
alkenyl nitriles. With a bulky aliphatic alkene higher efficiency was observed with Mo-2d (smaller aryloxide ligand). See Supplementary Information section 3
for experimental and analytical details. Bn, benzyl; Ts, para-toluenesulfonyl; tol., toluene.
as used for Mo-2b, we isolated 5a in 78% yield and 96:4 E:Z ratio of o-tolyl-substituted 5c, with the substrate bearing a particularly
after 12h at 40°C (6.0mol% (C6F5)3B was used as there was less hindered substituent, the reaction was much more efficient when
contaminating phenol remaining from preparation of the Mo-2b). the less sterically demanding Mo-2d was employed (50% yield, 96:4
Control experiments indicated that there is no post-metathesis E:Z; compared to 34% conv., 84:16 E:Z with Mo-2c).
alkene isomerization.
The E-alkenyl nitriles with an n-alkyl substituent were most
The method is applicable to E-aryl-substituted and E-heteroaryl- efficiently generated by catalytic stereoretentive reactions with E-β-
substituted alkenes of disparate steric and/or electronic properties alkyl styrenes (Fig. 4c)51; 6a–c were thus obtained in 69–75% yield
(5b–i, Fig. 4b); products were obtained in up to 87% yield, with and 93:7–96:4 E:Z ratio. As in the case of sterically hindered 5c, the
stereoselectivity ranging from 90:10 to 97:3 E:Z ratio. In the case reaction of α-branched alkene E-7 to generate 6d was more efficient
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Me
Me
a
Me
NC
H
5.0 mol% Mo-2b
Me
Me
H
OTBS
OTBS
+
NC
CN
15 mol% (C6F5)3B,
Benzene, 40 °C, 4 h
H
H
H
H
H
H
X-ray of 9a
8
Z-3
(1.5 equiv.)
9a
Prepared from allylestrenol
in 2 steps (81% overall yield)
67% conv., 66% yield,
92:8 E:Z
Me
CN
Me
CN
Me
Me
CN
Bn2N
CN
S
(i-Pr)3Si
9b
9c
9d
9e
60% conv., 53% yield,
92:8 E:Z
86% conv., 86% yield,
85% conv., 82% yield,
92:8 E:Z
60% conv., 58% yield,
92:8 E:Z
93:7 E:Z
b
c
MeO
MeO
MeO
Me
NBn2
Me
Me
Me
As above
BnO2C
MeO
CN
CN
Me
CN
10a
Prepared by cross-coupling
11a
11b
11c
91% conv., 91% yield,
80% conv., 77% yield,
86% conv., 75% yield,
with Z-2-bromobutene (75% yield)
89:11 Z:E
88:12 Z:E
90:10 Z:E
F
F
F
F
F
F
F
F
F
F
Me
Me
N
Br
N
N
Cl
Me
NC
CN
CN
Ph
Me
CN
+
Me
Mo
Mo
MeO
MeO
Cl
O
Ar
O
12a
Z-3
(1.5 equiv.)
13a
Prepared in one step
60% conv., 57% yield,
from comm. avail. materials
(80% yield)
93:7 E:Z
10 mol % Mo-2e
12 mol% B(C6F5)3, tol., 80 °C, 4 h
mcb-1
Me
CN
Me
Me
CN
Me
Cl
CN
CN
O
N
O
O
Me
13ba
13ca
13d
13e
55% conv., 51% yield,
91:9 E:Z
60% conv., 59% yield,
56% conv., 54% yield,
75% conv., 47% yield,
89:11 E:Z
90:10 E:Z
87:13 E:Z
Fig. 5 | E- and Z-tri-substituted alkenyl nitriles. a, Readily accessible stereochemically defined E-tri-substituted alkenes, bearing a relatively diminutive
methyl group terminus, can be converted in the presence of Mo-2b and Z-3 to the corresponding E-alkenyl nitriles. The method is applicable to various
alkyl-substituted olefins (9a–e). b, Z-tri-substituted alkenyl nitriles can be obtained similarly. c, An even more difficult process is one that might deliver a
tri-substituted alkenyl nitrile with a sizeable aryl unit. This may be accomplished with 10ꢀmol% Mo-2e at 80ꢀ°C (via mcb-1 to give 13a-e). a15.0ꢀmol% Mo-2e
and 18ꢀmol% B(C6F5)3 were used. See Supplementary Section 3 for experimental and analytical details.
with Mo-2d (60% yield, 97:3 E:Z compared to 20% conv., 54:46 E:Z released 3-bromopyridine, can become more competitive, especially
with Mo-2c); the smaller aryloxide ligand might better accommo- at 40°C, and diminution in E:Z product ratios ensues. This scenario
date the sizeable alkyl moiety, which would be projected towards it is supported by the finding that more Z-alkenyl nitrile is generated
in the corresponding metallacyclobutane.
when the more sterically demanding ortho-substituted substrates
The stereoisomeric purity of the E-alkenyl nitrile products, are used (that is, 84:16–90:10 E:Z for 5b–c when Mo-2c was used).
although generally high, is slightly lower than the related Z isomers In the case of less hindered alkyl-substituted alkenyl nitriles (6a–c),
accessed through stereoretentive cross-metathesis (Fig. 3b); this dif- substrate self-metathesis and E-to-Z isomerization are probably
ferencemaybeattributedtoincreasedstericpressurebetweenanE-di- more facile, and stereoisomeric purity suffers.
substituted alkene and the large aryloxide ligand of a Mo complex
(for example, Mo-2c). Consequently, fumaronitrile-to-maleonitrile Tri-substituted E- and Z-alkenyl nitriles. We then turned to deter-
isomerization (E-3→Z-3), despite the lower nucleophilicity of the mining whether a catalytic method for stereoretentive synthesis of
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a
1.
OH
Me
Cl
15
OAc
OAc
(1.2 equiv., comm. avail.)
CN
Cl
Ag2CO3 (1.2 equiv.), 5.0 mol% I2,
O
O
AcO
AcO
AcO
AcO
O
CH2Cl2, 22 °C, 20 h (65% yield)
2. 5.0 mol% Mo-2a, Z-3 (3.0 equiv.),
BPh3 (1.0 equiv.), C6H6, 40 °C, 12 h
2af
OAc
AcO
CN
Br
(precursor to LR5182; see Fig. 1a)
>98% conv., 98% yield,
97:3 Z:E
14
(comm. avail.)
Alliarinoside peracetate
87% conv., 60% yield,
>98:2 Z:E
1. n-BuLi (2.6 equiv.), THF;
1-Br-4-pentene (2.6 equiv.)
–78→22 °C, 24 h
(98% yield)
S
S
N
O
n-Bu
N
H
CN
n-Bu
S
S
2. 7.5 mol% Mo-1a,
Acrylonitrile (2.0 equiv.),
Benzene, 40 °C, 4 h
CN
CN
CN
CN
OH
(Comm.avail.)
16
Perhydrohistrionicotoxin
2ag
90% conv., 57% yield,
>98:2 Z,Z:Z,E
b
OMe
MeO
Cl
Cl
Catalytic Heck
Cl
MeO
CN
5.0 mol % Pd(OAc)2,
3,4-(MeO)2C6H3I (1.9 equiv.),
5o
CN
Cl
62% conv., 60% yield,
MeO
(n-Bu)4NBr (1.1 equiv.),
KOAc (2.5 equiv.),
DMF, 80 °C, 48 h
17
97:3 E:Z
OMe
(>98% stereospecificity)
CN
OMe
5n
95% conv., 82% yield,
95:5 E:Z
CC-5079
NHMe
78% yield, 97:3 Z:E
Cl
Cl
Indatraline
c
1.1 equiv. HB(pin), Z-3 (1.5 equiv.),
Benzene, 22 °C, 15 min; 5.0 mol% Mo-2a
HO
HO
O
B
n-Oct
CN
H
Benzene, 22 °C, 4 h;
Silica gel chromatography
O
Oleyl alcohol
2ah
H(pin)
88% conv., 85% yield,
>98:2 Z:E
1.1 equiv. HB(trip)2, Z-3 (1.5 equiv.),
Benzene, 22 °C, 15 min; 5.0 mol% Mo-2a,
i-Pr
i-Pr
HO2C
n-Oct
HO2C
CN
HB
i-Pr
Benzene, 22 °C, 4 h;
Silica gel chromatography
2
Oleic acid
2ai
82% conv., 60% yield,
HB(trip)2
>98:2 Z:E
Fig. 6 | utility of the method in chemical synthesis. a, The possibility of synthesizing aryl- or alkyl-substituted Z-alkenyl nitriles by catalytic cross-
metathesis is likely to have a notable impact on the efficiency with which many bioactive compounds can be prepared. Representative cases are the agent
for cocaine abuse treatment LR5182, agrochemical agent alliarinoside and perhydrohistrionicotoxin (step 2ag to 1661), which has been used for probing the
mechanisms of neuromuscular impulses. b, The E-alkenyl nitriles are crucial for stereoselective generation of a variety of bio-active molecules. Anticancer
agent CC-5079 and antidepressant indatraline are two examples. 50 to 17, catalytic Heck reaction6. c, In situ protection/deprotection of a neighbouring
hydroxy and carboxylic acid group may be carried out, significantly enhancing the scope of the method. See Supplementary Information sections 4–9 for
experimental and analytical details. pin, pinacolato; trip, 2,4,6-triisopropylphenyl; Ac, acetyl.
tri-substituted alkenyl nitriles is feasible. What distinguishes this set for details). Subjection of 8 to Mo-2b (5.0mol%), 15mol% (C6F5)3B
of transformations, other than the involvement of a more congested and Z-3 (1.5equiv.) afforded 9a in 66% yield and 92:8 E:Z selec-
metallacyclobutane, is that they probably involve a cyano-substi- tivity (Fig. 5a). The E:Z ratio was the same with 3-bromopyridine-
tuted alkylidene exclusively, as opposed to a 1,1-di-substituted vari- containing MAC complex Mo-2c, in line with the predominant
ant arising from initial reaction with a tri-substituted olefin. This intermediacy of the cyano-substituted syn-alkylidene, regardless of
means that reaction with either Z- or E-3 should lead to the same whether E- or Z-3 is involved. Assorted aliphatic E-tri-substituted
degree of stereochemical purity, although, as already noted, reaction alkenyl nitriles were accessed similarly (9b–e, in 53–86% yield
involving the former isomer would probably be more efficient.
and 92:8–93:7 E:Z). The approach is applicable to the preparation
Tri-substituted alkene 8 was prepared in a single-vessel operation of Z-tri-substituted alkenyl nitriles (see 11a–c). A rationale for the
from a silyl ether of allylestrenol (see Supplementary Information lower stereochemical control in the formation of the Z isomers was
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provided recently in connection with the synthesis of tri-substituted as 80:20 E:Z mixtures by Wittig-type reactions6,13, and removal of
alkenyl chlorides and bromides57.
stoichiometric amounts of the phosphine-oxide side product often
Perhaps the most challenging aspect of this study was designing required difficult chromatographic procedures.
efficient reactions between relatively stabilized cyano-substituted
We then set out to address another major shortcoming, namely
alkylidenes and hindered tri-substituted alkenes; particularly dif- the instability of such species to an alcohol or a carboxylic acid moi-
ficult would be processes involving an aryl olefin. Yet again, in the ety. In the case of a substrate that bears a hydroxy group, we find that
case of alkenyl chlorides, the corresponding products were obtained by simply treating the alkenes with 1.1equiv. of commercially avail-
when MAP complex Mo-1b57 was used. However, the same strategy able HB(pin) (pin, pinacolato) at ambient temperature for 15min
was ineffective when applied to reactions proceeding via a more and then the requisite amount of the Mo complex for 4h, followed
stabilized/less reactive cyano-substituted alkylidene species (com- by silica gel chromatography, the desired alkenyl nitrile product can
pare I to II, Fig. 2). There was <2% conversion to 13a with MAC be obtained in high yield and stereochemical purity. The conver-
complex Mo-2c or Mo-2d. To address this issue, we synthesized sion of oleyl alcohol to 2ah is a case in point (85% yield, >98:2 Z:E;
Mo-2e (Fig. 5c), which bears an aryloxide with 3,5-di-t-butylphe- Fig. 6c). For a starting material containing a carboxylic acid moi-
nyl groups at its C2 and C6 sites. We expected reduced steric pres- ety, the most effective approach is to use HB(trip)2 (trip, 2,4,6-tri-
sure in the corresponding metallacyclobutane (mcb-1). Through isopropylphenyl)63, a reagent that can be prepared easily on a gram
the use of 10mol% Mo-2e and 12mol% (C6F5)3B, and at 80°C for scale from commercially available materials in two steps (70–75%
4h, we were able to isolate 13a in 57% yield and 93:7 E:Z selectiv- overall yield). Transformation of oleic acid to alkenyl nitrile 2ai is
ity. As indicated by the synthesis of 13b–e, the approach is appli- representative (60% yield, >98:2 Z:E versus 47% yield, >98:2 Z:E
cable to different aryl alkenes. Reactions were slower with the more with HB(pin)). This development promises to expand the practical
electron-withdrawing aryl alkenes, as synthesis of 13b–c required utility of Mo-based catalysts considerably.
15mol% Mo-2e and 18mol% (C6F5)3B to reach 55–60% conversion
(with 10mol% Mo-2e: 36% and 41% conv., 32% and 35% yield, 91:9 Conclusions
and 89:11 E:Z, respectively).
We have developed a broadly applicable set of catalytic methods for
Under the same conditions and with a Z-tri-substituted aryl the preparation of Z- and E-di-substituted and tri-substituted alke-
olefin, there was only about 20% conversion to the desired alkenyl nyl nitriles in high stereoisomeric purity. We have shown that, by
nitrile, formed with minimal stereoisomeric purity (~60:40 Z:E). considering the various attributes of the Mo-based complex (MAP
Development of a more effective solution to these important but or MAC) and the electronic and steric attributes of the intermedi-
difficult cross-metathesis reactions is a goal of future investigations. ate alkylidenes and metallacyclobutanes, catalysts providing access
to stereoisomerically enriched alkenyl nitriles, from those that
Utility. The present advance provides a convenient entry to many bear a linear aliphatic substituent to those that contain a hindered
otherwise difficult to prepare stereochemically defined alkenyl α-branched or aryl moiety, can be identified. Similarly notable is
nitriles, facilitating the synthesis of a large variety of biologically that an equimolar amount of the two cross partners is not only
active compounds. 3,4-Dichloroaryl-substituted Z-alkenyl nitrile sufficient, but is optimal, for achieving high efficiency in a cross-
2af (Fig. 6a), obtained in 98% yield and 97:3 Z:E ratio, is an inter- metathesis reaction. We introduce the use of easily accessible boron
mediate en route to LR5182 (Fig. 1). The cross-metathesis approach hydride compounds for in situ temporary protection of the hydroxy
is more efficient than the previously utilized Knoevenagel conden- and carboxylic acid groups, which can otherwise quickly deactivate
sation (aryl aldehyde and cyano acetic acid)/decarboxylation at a Mo-based catalyst. The ability to access an alkenyl nitrile isomer
elevated temperature, which generated an 80:20 Z:E mixture9.
with high stereochemical purity allows for significant enhance-
The union of glycosyl bromide 14 and allylic alcohol 15, both ment in the efficiency with which many biologically active entities
commercially available, followed by catalytic stereoretentive cross- are prepared.
metathesis delivered alliarinoside peracetate in 39% overall yield
as a single olefin isomer (>98:2 Z:E) (Fig. 6a). Previously reported Data availability
X-ray crystallographic data for compound 9a, are freely available from the
protocols either generate a near-equal mixture of alkene isomers
Cambridge Crystallographic Data Centre (CCDC 1861573). Copies of the data
(Horner–Wadsworth–Emmons-type processes)58,59 or demand
can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.
initial generation of a Z-alkenyl iodide (catalytic cross-coupling),
All other data in support of the findings of this study are available within the
requiring at least two additional operations27. Also noteworthy
Article and its Supplementary Information or from the corresponding author
upon reasonable request.
is bis-alkenyl nitrile 2ag, accessed by a double-cross-metathesis
in 57% yield and >98:2 Z,Z’:Z,E’ (Fig. 6a), and utilized in the
total synthesis of perhydrohistrionicotoxin (via 16)60. This com-
pound was formerly accessed by a route that included synthesis
of an alkene via the corresponding bis-aldehyde, the preparation
of which necessitated an additional deprotection step (acetal
removal), while the highly toxic hexamethylphosphoramide was
required to facilitate alkylation.
Received: 13 September 2018; Accepted: 12 February 2019;
Published: xx xx xxxx
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Author contributions
Y.M., T.T.N. and M.J.K. identified the optimal catalyst and conditions, developed the
method and performed the experiments to demonstrate utility. The Mo complexes
used in this study were designed and developed as part of a long-standing collaboration
between the research groups of R.R.S. and A.H.H. A.H.H. directed the investigations and
composed the manuscript with revisions provided by the other authors.
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Competing interests
The authors declare no competing interests.
Additional information
Supplementary information is available for this paper at https://doi.org/10.1038/
s41557-019-0233-x.
Reprints and permissions information is available at www.nature.com/reprints.
Correspondence and requests for materials should be addressed to A.H.H.
Acknowledgements
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
This research was supported by a grant from the National Institutes of Health (GM-
59426). T.T.N. was supported as a John LaMattina Graduate Fellow in Chemical
Synthesis. The authors thank S. Torker for helpful discussions.
© The Author(s), under exclusive licence to Springer Nature Limited 2019
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