Traceless Protection for More Broadly Applicable Olefin Metathesis

Article abstract of DOI:10.1002/anie.201901132

An operationally simple in situ protection/deprotection strategy that significantly expands the scope of kinetically controlled catalytic Z- and E-selective olefin metathesis is introduced. Prior to the addition of a sensitive Mo- or Ru-based complex, treatment of a hydroxy- or a carboxylic-acid-containing olefin with commercially available HB(pin) or readily accessible HB(trip)₂ (pin=pinacolato, trip=2,4,6-tri(isopropyl)phenyl) for 15 min is sufficient for efficient generation of a desired product. Routine workup leads to quantitative deprotection. A range of stereochemically defined Z- and E-alkenyl chlorides, bromides, fluorides, and boronates or Z-trifluoromethyl-substituted alkenes with a hydroxy or carboxylic acid group were thus prepared in 51–97 % yield with 93 to >98 % stereoselectivity. We also show that, regardless of whether a polar functional unit is present or not, a small amount of HB(pin) may be used to remove residual water, significantly enhancing efficiency.

Full text of DOI:10.1002/anie.201901132

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Traceless Protection for More Broadly Applicable Olefin
Metathesis
Authors: Amir H. Hoveyda, Yucheng Mu, Thach T. Nguyen, Farid W.
van der Mei, and Richard R. Schrock
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901132
Angew. Chem. 10.1002/ange.201901132
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10.1002/anie.201901132
Angewandte Chemie International Edition
Traceless Protection for More Broadly Applicable Olefin Metathesis
Yucheng Mu,† Thach T. Nguyen,† Farid W. van der Mei, Richard R. Schrock, and Amir H.
Hoveyda*
[*]
Prof. R. R. Schrock, Prof. A. H. Hoveyda, Y. Mu, T. T. Nguyen, F. W. van der Mei
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467 (USA)
Prof. R. R. Schrock
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 (USA)
† These authors contributed equally.
E-mail: amir.hoveyda@bc.edu
Abstract: An operationally simple in situ protection/deprotection strategy that significantly
expands the scope of kinetically controlled catalytic Z- and E-selective olefin metathesis is introduced. We
demonstrate that, prior to the addition of a sensitive Mo- or Ru-based complex, treatment of a hydroxy-
or a carboxylic acid-containing olefin with commercially available HB(pin) or readily accessible HB(trip)2
(pin = pinacolato, trip = 2,4,6-tri(iso-propyl)phenyl) for 15 minutes is sufficient for efficient generation of a
desired product. Routine workup leads to quantitative deprotection. A range of stereochemically defined
Z- or E-alkenyl chlorides, bromides, fluorides, and boronates or Z-trifluoromethyl-substituted alkenes with
a hydroxy- or a carboxylic acid group were thus prepared in 51–97% yield and 93% to >98%
stereoselectivity. The substrates, HB(pin), and cross-partners were used as received. We also show that,
regardless of whether a polar functional unit is present or not, a small amount of HB(pin) (e.g., 10 mol %)
may be used to remove residual water, significantly enhancing efficiency (i.e., lower catalyst loading).
The colossal impact of olefin metathesis on modern chemistry is largely due to the
complementary nature of Mo-based alkylidenes and Ru-based carbenes,[1] an attribute more recently
manifested in the recently introduced methods for Z- or E-selective processes (Scheme 1a).[2] While only
monoaryloxide pyrrolide (MAP)[3] Mo-1 and monoaryloxide chloride (MAC)[4] Mo-2 can be used to
generate Z- or E-alkenyl halides,[5] and synthesis of Z-trifluoromethyl-substituted alkenes is confined to
reactions with Mo-2,[4] a hydroxy or a carboxylic acid unit decompose the derived catalysts rapidly.
Reactions with Ru-1[6] can involve hydroxy-containing substrates, but efficiency is lower with an allylic
alcohol,[7] and, as with Mo-based catalysts, a carboxylic acid is not tolerated.[7] Unsaturated organic
compounds bearing an alcohol and/or a carboxylic acid,[8-9] are suitable substrates for Ru-2; however,
unlike Mo-1 and Ru-1, and similar to Mo-2, monosubstituted alkenes cannot be used.[10]
Unsaturated hydrocarbons with a hydroxy or a carboxylic acid group are an important class of
compounds in chemistry.[11] Many are renewable raw materials, including animal fats and vegetable oils,
inexpensive and viable substitutes for the dwindling petrochemicals,[11] and others are biologically active.
The ability to synthesize stereochemically defined alkenyl halide derivatives[5] of the aforementioned
molecules by cross-metathesis without protection/deprotection sequences or rigorous purification would
be highly advantageous. In this context, stereochemically defined alkenes with a fluoro or a
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Scheme 1. Complexes used for kinetically controlled olefin metathesis and the objectives of this study.
trifluoromethyl substituent would be especially attractive products. Such entities are vital to future
advances in medicine,[12] and the corresponding chlorides or bromides may be transformed to many
valuable entities with high stereospecificity by catalytic cross-coupling.[13]
The above considerations led us to envision a traceless protecting group strategy (Scheme 1b)
that would offer the following features: a) efficient and rapid protection of an alcohol or a carboxylic acid
under mild conditions; b) readily accessible and mild reagent; c) transient derivatives that are not too
basic or nucleophilic (e.g., a metal alkoxide); d) easily removable and innocuous byproducts with no
adverse influence on catalyst activity; e) umasking by a simple, efficient, and mild protocol. Herein, we
disclose the realization of the above objective.
The negative impact of a Lewis basic amide or amine on the efficiency of olefin metathesis
reactions with Ru-based catalysts has been formerly addressed by the addition of an appropriate additive
(e.g., a Ti-based complex[14] or a BrØnsted acid[15]). In 2005 we reported a case where chelation of a Mo
alkylidene with a nearby secondary amine may be circumvented by pre-treatment of the substrate with
freshly distilled catecholborane (12 h, 22 °C), releasing H2. Ensuing subjection to aqueous NaOH
regenerated the product free amine.[16] We thus chose to identify another boron–hydride reagent which,
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while readily available and inert towards addition to alkenes, can react with a hydroxy group to afford a
boronate[17] more quickly (e.g., 1 vs. 12 h) and without the need for initial purification/drying. These
deliberations led us to pinacolborane (HB(pin)), a robust, mild and commercially available reagent.
Whether the strategy would be applicable to carboxylic acids remained to be established.
To probe the feasibility of the approach, we treated a mixture of oleyl alcohol and Z-
dichloroethene with 1.1 equivalent of HB(pin) for just 15 minutes at room temperature, affording boronic
ester 1 (observable by 1H and 11B NMR spectroscopy; Scheme 2a); Mo-2 (3.0 mol % in benzene) was then
added. After four hours and routine silica gel chromatography, we isolated Z-alkenyl chlorides 2a and 3 in
87% and 78% yield, respectively (>98% Z). Similarly, we synthesized Z-alkenyl bromide 2b (69% yield, >98:2
Z:E), and Z-F3C-substituted alkene 2c (72% yield, >98:2 Z:E). The approach is amenable to gram-scale
operations (Scheme 2b) and the use of a complex confined in a paraffin pellet [18] (Scheme 2c). Regardless
of the cross-partner or the conditions used, we were able to obtain the alkyl-substituted alkenyl halide
a. Traceless protection: Practical, efficient, and scalable:
OH
HB(pin)
(1.1 equiv.; used as received)
C8H17
Cl
Cl
15 min, 22 °C
Oleyl alcohol
(used as received)
comm. avail.
(5.0 equiv.;
used as received)
<2% conv. to 2a and 3 without pretreatment with HB(pin)
3.0 mol % Mo-2,
benzene, 4 h, 22 °C;
OH
OB(pin)
C8H17
H17C8
Cl
Cl
silica gel chromatography
3
1
2a
78% yield,
(detected by 1H and 11
B
87% conv., 87% yield,
>98:2 Z:E
NMR spectroscopy)
>98:2 Z:E
OH
OH
CF3
Br
F3C
CF3
Br
Br
2b
comm. avail.
(5.0 equiv.;
2c
comm. avail.
(5.0 equiv.;
used as received)
(5.0 mol % Mo-2)
89% conv., 69% yield,
>98:2 Z:E
(2.0 mol % Mo-2)
89% conv., 72% yield,
>98:2 Z:E
used as received)
b. A reaction performed on gram scale:
Oleyl alcohol
HB(pin)
(1.0 g;
used as received)
(1.1 equiv.;
used as received)
Mo-1b (1.0 mol %)
benzene, 1 h, 22 °C;
2a
Cl
Cl
[ 1 ]
>98% conv.,
97% yield,
95:5 Z:E
15 min, 22 °C
comm. avail.
(3.0 equiv.;
silica gel chromatography
used as received)
c. In combination with a catalyst in paraffin tablet:
Oleyl alcohol
HB(pin)
(used as received)
(1.1 equiv.;
Mo-1b
(5.0 mol %)
2a
used as received)
Cl
Cl
>98% conv.,
97% yield,
93:7 Z:E
[ 1 ]
comm. avail.
(5.0 equiv.;
15 min, 22 °C
benzene, 4 h, 50 °C;
silica gel chromatography
used as received)
Scheme 2. Traceless protection of an alcohol substrate with HB(pin) is practical, efficient, and scalable. Conversion was determined
by 1H NMR analysis of unpurified product mixtures; see the Supporting Information for details.
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(cf. 3) or trifluoromethyl co-products with identical stereochemical purity as the component bearing a
primary alcohol but in slightly lower yields (volatile). The oleyl alcohol, the halogen-containing reagents,
and HB(pin), all commercially available, were used as received.
Different unsaturated alcohols and cross partners are suitable substrates (Table 1). Kinetically Z- or E-
selective transformations with substrates with a primary aliphatic (entry 1), a primary or secondary allylic
(entries 2–3), or a tertiary alcohol (entries 4–6) were efficient, affording 1,2-disubstituted alkenyl
boronates (5 and 10b) or alkenyl halides (7, 9, 10a, and 11) in 59–93% yield and with high stereoselectivity.
[a]Reactions were performed under N2 atm. [b] Determined by analysis of 1H NMR spectra of unpurified product mixtures. [c] Yield of isolated and purified
product. See the Supporting Information for details.
The strategy is applicable to more challenging reactions, involving trisubstituted alkenes (Scheme
3a). Citronellol was converted to Z-alkenyl fluoride 12a with 94:6 fluoro:bromo selectivity, in 90% yield
(pure fluoride) and >98:2 Z:E selectivity. The transformation to E-alkenyl chloride 12b was as efficient and
stereoretentive (80% yield, 95:5 E:Z). Z-Alkenyl fluoride 13 was prepared from natural product bisabolol
in 87% yield (pure fluoride) and 98:2 Z:E selectivity. In light of the prevalence of compounds that contain
an isoprenyl group along with a polar (e.g., hydroxy) group, the approach provides a cost-effective and
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Scheme 3. Transient protection in cross-metathesis reactions involving trisubstituted alkenes as products or substrates.
stereoselective method for synthesis of an assortment of valuable and/or easily functionalizable
derivatives. Traceless protection may be used in reactions that convert readily available trisubstituted
alkenes to those that are less easily accessible (Scheme 3b),[19] including alkenyl chlorides, bromides, and
olefins that contain three C-based substituents (15a-b[20] and 18, respectively). The high yield (80–90%)
and stereoisomeric purity (95% to >98% of one isomer) with which 12a-b and 13 (Scheme 3a) are formed
is noteworthy because, generally, alkenyl halides bearing an unhindered (linear) alkyl substituent cannot
be obtained efficiently from a terminal or a 1,2-disubstituted olefin. Homocoupling and/or isomerization
of the 1,2-disubstituted olefin is a complication with these less substituted alkenes, and fluoro:bromo or
E:Z selectivity is typically lower (~70:30).[5]
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Commercially available eugenol was converted to alkenyl chloride 19a in 79% yield and 96:4 Z:E
selectivity (Scheme 4). The reaction generating ortho-substituted 19b (55% yield, 95:5 Z:E) was somewhat
less efficient, perhaps due to internal OMo chelation.[21] When we applied the same procedure to
synthesis of E-styrenyl halides 20a and 20b, there was <5% conversion. This might be for two reasons:
reduced Lewis basicity of the styrenyl phenol, resulting in slower boronate formation, a scenario that is
supported by analysis of the relative rates of boronate formation (1H NMR), [22] and lower rate of olefin
metathesis due to the sterically more hindered alkenes. Therefore, with 2.0 equivalents of HB(pin) 20a
and 20b were isolated in 78% and 75% yield, respectively (>98:2 E:Z). With more borane present, brief
Scheme 4. Traceless protection in cross-metathesis with phenolic alkenes.
subjection of the solution to mild vacuum (5 min, 2 torr) is needed to ensure maximum efficiency (e.g.,
without vacuum: 40% conv. with natural product eugenol); this shows that excess HB(pin) and/or its long
term exposure to a Mo MAP or MAC complex can have an adverse impact (more on this below).
With oleic acid (Scheme 5), 2.0 equivalents of HB(pin) were needed and Z-alkenyl bromide 21a was
isolated in 66% yield (>98% Z). The need for excess borane was not surprising in light of the earlier data
(cf. 20a-b) and the lower Lewis basicity of a carboxylic acid. More disconcerting were the boron containing
byproducts; one was confirmed to be (pin)BOB(pin) (11B NMR,  21.7 ppm),[23] arising from bimolecular
disproportionation of in situ generated carboxyl boryl compounds (to give a carboxylic anhydride).[24]
We therefore examined the effectiveness of HB(trip)2. We surmised that this more sizeable
alternative might be less susceptible to disproportionation and react less readily with a Mo alkylidene
complex; although, boronate formation could be too slow as well. In the event, we prepared HB(trip)2, a
robust reagent that can be accessed in multi-gram quantities in two straightforward steps and 70-75%
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Scheme 5. Transient protection in cross-metathesis with unsaturated carboxylic acids.
overall yield.[22] When pre-treatment with HB(trip)2 was applied (1.1 equiv.), under otherwise identical
conditions, we were able to isolate 21a in 80% yield (vs. 66% with HB(pin); >98% Z). There was no
byproducts and subjection to mild vacuum was not necessary. Synthesis of Z-alkenyl chloride 21b and Z-
F3C-substituted alkene 21c further highlight utility. The smaller difference in yields for alkenyl chloride 21b
might be attributed to the faster pace of this particular reaction, compared to those involving the less
reactive Z-1,2-dibromoethene (cf. 21a) or Z-1,1,1,4,4,4-hexafluoro-2-butene (cf. 21c), which in turn
implies that, as cross-metathesis rate is reduced, there is stronger likelihood that a borane reacts with a
Mo complex.[25] The conversion of aryl olefin 22 to Z-alkenyl chloride 23, carried out in the presence of
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anti-malarial agent artesunate,[26] demonstrates applicability to relatively sensitive functional groups.
Whereas trisubstituted alkene of citronellic acid was converted to Z-alkenyl fluoride 24 in the presence of
1.1 equivalents of HB(trip)2 (85% yield, 96:4 Z:E), there was <5% conversion when HB(pin) was used or
when the combination of the more sensitive Mo-2 and HB(trip)2 was employed (<5% conv.).
The present strategy may be used to improve reactions with Ru-based catalysts that, although
effective with terminal alkenes (i.e., Ru-1 vs. Ru-2),[10] do not tolerate a carboxylic acid. Whereas there
was no conversion to 26 under a typical set of conditions (Scheme 6), the desired product was obtained
in 70% yield when the mixture was charged with 5.0 mol % Ru-1 after brief initial treatment with HB(trip)2.
There was <5% conversion with HB(pin), indicating that, similar to Mo-based systems, this class of Ru
carbenes is susceptible to decomposition[27] when subjected to a reactive boron hydride. This example
underscores a key advantage of the transient protection strategy, as 26 is a type of acid/ester compound,
which would be difficult to access efficiently by site-selective hydrolysis of a diester. While stereocontrol
is not optimal with Ru-1, the strategy should be germane to transformations with the more selective
variants.[28]
Scheme 6. The traceless protection strategy expands the scope of reactions catalyzed by Ru-based complexes.
The approach can be applied conveniently to removing residual moisture or other debilitating
impurities, allowing for improved efficiency (Scheme 7). Subjection of Z-crotyl–B(pin) to Z-1,2-
dichloroethene and 3.0 mol % Mo-2 led to minimal conversion; only after the addition of another 2.0 mol
% Mo-2 were we able to isolate 27 in 75% yield (>98:2 Z:E). In contrast, with 4.0 gram of Z-crotyl–B(pin),
after initial treatment with just 10 mol % HB(pin) for 15 minutes at room temperature before addition of
Scheme 7. Commercially available HB(pin) may be used to remove residual moisture, allowing for enhanced efficiency.
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just 1.6 mol % Mo-2 for one hour, we obtained 4.3 grams of 27 (96% yield) as a single stereoisomer after
distillation.
In closing, we present a practical solution to several key problems in the state-of-the-art in
catalytic olefin metathesis, which are likely to have an immediate impact on stereoselective chemical
synthesis. Development of additional traceless protection approaches that are applicable to other
sensitive functional groups is in progress.
Acknowledgements. Financial support was provided by the NIH (GM-59426 and GM-130395). T.T.N. gratefully
acknowledges a LaMattina Graduate Fellowship. We thank J. del Pozo, F. Romiti, and M. J. Koh for helpful discussions.
Keywords: alkenes, catalysis, cross-metathesis, stereoselectivity, synthesis
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