Stereospecific Allylic Functionalization: The Reactions of Allylboronate Complexes with Electrophiles

Article abstract of DOI:10.1021/jacs.7b10240

Allylboronic esters react readily with carbonyls and imines (π-electrophiles), but are unreactive toward a range of other electrophiles. By addition of an aryllithium, the corresponding allylboronate complexes display enhanced nucleophilicity, enabling addition to a range of electrophiles (tropylium, benzodithiolylium, activated pyridines, Eschenmoser's salt, Togni's reagent, Selectfluor, diisopropyl azodicarboxylate (DIAD), MeSX) in high regio- and stereocontrol. This protocol provides access to key new functionalities, including quaternary stereogenic centers bearing moieties such as fluorine and the trifluoromethyl group. The allylboronate complexes were determined to be 7 to 10 orders of magnitude more reactive than the parent boronic ester.

Full text of DOI:10.1021/jacs.7b10240

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Communication
Stereospecific Allylic Functionalization: The Reactivity
of Allylboronate Complexes with Electrophiles
Cristina García-Ruiz, Jack L. -Y. Chen, Christopher Sandford, Kathryn Feeney,
PAULA LORENZO, Guillaume BERIONNI, Herbert Mayr, and Varinder K. Aggarwal
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b10240 • Publication Date (Web): 13 Oct 2017
Downloaded from http://pubs.acs.org on October 13, 2017
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Stereospecific Allylic Functionalization: The Reactivity of Al-
lylboronate Complexes with Electrophiles
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Cristina García-Ruiz†, Jack L.-Y. Chen†, Christopher Sandford†, Kathryn Feeney†, Paula Lorenzo†,
Guillaume Berionni‡, Herbert Mayr‡, and Varinder K. Aggarwal*,†
†School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, United Kingdom
‡Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5–13, 81377 München, Germany
Supporting Information Placeholder
ABSTRACT: Allylboronic esters react readily with carbonyls and
imines (π-electrophiles), but are unreactive towards a range of other
electrophiles. By addition of an aryl organolithium, the correspond-
ing allylboronate complexes display enhanced nucleophilicity, en-
abling addition to a range of electrophiles (tropylium, benzodithi-
olylium, activated pyridines, Eschenmoser’s salt, Togni’s reagent,
Selectfluor, DIAD, MeSX) in high regio- and stereocontrol. This
protocol provides access to key new functionalities, including qua-
ternary stereogenic centers bearing moieties such as fluorine and
the trifluoromethyl group. The allylboronate complexes were de-
termined to be 7 to 10 orders of magnitude more reactive than the
parent boronic ester.
Scheme 1. Reactions of (A) Allylboronic esters and (B) Al-
kylboronate complexes. (C) This work – The reactivity of
Allylboronate complexes.
The reaction of allylmetals with electrophiles represents a cor-
nerstone in organic synthesis.1 The field is dominated by reactions
of allylborons with carbonyls and imines (π-electrophiles) because
(i) it leads to synthetically useful products with high and predicta-
ble selectivity and (ii) enantioenriched allylborons are easily avail-
able or chiral catalysts have been developed to promote the reac-
tion.2,3 However, reactions of allylborons with a broader range of
electrophiles are virtually unknown; their unique reactivity with
π-electrophiles stems from the simultaneous activation of both the
boron atom and the carbonyl group in the closed transition state
(Scheme 1A).4 In order to address this shortcoming, more nucleo-
philic allylmetals have been explored, e.g. allylsilanes5 and al-
lylstannanes,6 but the chiral versions are often difficult to prepare
with high selectivity7 and the latter are toxic and labile towards
1,3-transposition.
We began our study by investigating the tropylium cation as a
model electrophile for addition to boronate complexes, selecting
trisubstituted allylic boronic ester 1 to explore the formation of qua-
ternary stereogenic centers, incorporating a reporter stereogenic
center in order to assess the stereospecificity of the reaction. When
the parent boronic ester 1 was subjected to the tropylium cation in
THF, no reaction was observed (Table 1, entry 1), demonstrating
the low reactivity of allylboronic esters even with highly reactive
electrophiles. However, after addition of aryllithium 2, the al-
lylboronate complex reacted readily to afford the allylation product
5, albeit with moderate regiocontrol between γ- and α- addition
(87:13), and poor diastereocontrol (56:44, entry 2). The selectivity
was found to be improved by lowering the reaction temperature to
–78 °C, although the dr was still moderate (88:12, entry 4). In all
cases, the reaction gave complete E-selectivity (>95:5). In our pre-
vious studies of boronate complexes, we had observed that elec-
tron-deficient aryllithiums improved the stereospecificity of the re-
action,10a and they were examined here too. Using the electron-de-
ficient aryllithium 3 did indeed result in improved diastereocontrol
(>95:5, entry 5). Interestingly, through screening various aryllithi-
ums, we discovered that naphthyllithium (4) also gave very high
Allylborons would be ideal reagents since they are configura-
tionally stable, easily accessible in high ee3h,8 and unlike most other
allylmetals do not undergo 1,3-transposition,9 but their low nucle-
ophilicity has limited their broader use. We considered separating
the activation mode of boron by converting the allylic boronic ester
into a more nucleophilic boronate complex. Previously, we have
shown that the addition of an aryl organolithium to an alkylboronic
ester creates a configurationally stable nucleophilic boronate com-
plex which can react with electrophiles through an enantiospecific
SE2inv pathway (Scheme 1B).10 We reasoned that the addition of
an organolithium to an allylboronic ester might also ‘switch on’ the
reactivity of these species, enabling SE2’ reactions with a much
more diverse array of electrophiles (Scheme 1C). Herein, we report
the successful realization of this strategy, providing access to an
array of stereodefined tertiary and quaternary allylic products.
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Page 2 of 5
selectivity (entry 6), which proved beneficial in some cases with
Table 1. Optimization of the Formation of Quaternary Ste-
reogenic Centers with Tropylium Tetrafluoroboratea
alternative electrophiles (vide infra).11
1
2
3
4
5
6
7
8
9
Having identified conditions under which the allylboronate com-
plex derived from 1 reacted with high regio- and stereoselectivity,
we explored the electrophile scope in the formation of both tertiary
and quaternary stereogenic centers (Scheme 2). We used 3 as the
standard nucleophilic activator, but if lower selectivity was ob-
served we also tested 4. Pleasingly, the reactions of boronate com-
plexes derived from 1 and 6 were successfully extended to benzo-
dithiolylium (to afford 8 and 15), activated pyridines (9 and 16)10b
and Eschenmoser’s salt (10 and 17). In all of these C–C bond form-
ing cases, high regio- and stereospecificity and complete E-selec-
tivity was observed.
Temp. /
°C
Yieldb
/ %
Entry
ArLi
γ/αc
drc / %
10
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1
2
3
4
5
6
None
25
25
0
–
–
The allylboronate complex derived from 6 could also be trifluo-
romethylated using Togni’s reagent as an electrophilic source of
CF3, providing access to 11 in 50% yield, >95:5 γ/α and 90:10 dr.
In comparison to alternative allylmetal species, Gouverneur and co-
workers have reported the trifluoromethylation of analogous al-
lylsilanes, which proceeds with similar selectivity under photore-
dox catalysis.12 It is of particular note that the allylboronate com-
plex from 1 could also be trifluoromethylated in 59% yield, >95:5
γ/α and >95:5 dr (18) – the trifluoromethylation of an allylmetal to
form a quaternary stereogenic center has, to the best of our
knowledge, not previously been reported.
2
2
2
3
4
62
48
52
81d
95
87:13
86:14
>95:5
>95:5
>95:5
56:44
55:45
88:12
>95:5
93:7
0
–78
–78
–78
aReactions conducted with 0.10 mmol 1, 1.2 eq ArLi and 1.2 eq
tropylium tetrafluoroborate. b 1HNMR yield using 0.33 eq of 1,3,5-
c
trimethoxybenzene as internal standard. dr of γ-attack product 5,
determined by GCMS. dIsolated yield.
Scheme 2. Scope of Electrophiles added to Allylboronate Complexesa
aSee the Supporting Information for more details; yields of isolated material; γ/α ratio and dr determined by GCMS, 1H NMR or 19F NMR.
bTropylium tetrafluoroborate added at –78°C. c1,3-benzodithiolylium tetrafluoroborate added at –78°C. dN,N-diethylnicotinamide and Troc-
Cl added at –78°C. Relative stereochemistry of dihydropyridine based on previous model,10b but not confirmed. eN,N-dimethylmethylenei-
minium iodide added at –78°C. fAte complex solution added to solution of 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one in THF at –78°C.
gDimethyl(methylthio)sulfonium tetrafluoroborate added at –78°C. Diisopropyl azodicarboxylate added at –78°C, and the reaction main-
h
tained at –78°C for 16 h. iAte complex solution in MeCN added to solution of Selectfluor in MeCN at –40°C, and the reaction maintained at
–40°C for 16 h. j 1H NMR yield using 0.33 eq of 1,3,5-trimethoxybenzene as internal standard due to product instability.
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Electrophiles which create new carbon–heteroatom bonds could
1
2
3
4
5
6
7
8
also be utilized in conjunction with the allylboronate complexes,
enabling the formation of C–S, C–N and C–F bonds at tertiary (12–
14) and quaternary stereocenters (19–21). The electrophilic fluori-
nation of boronate complexes10c provides access to medicinally rel-
evant chiral allylic fluorides which are otherwise challenging to ob-
tain from allylmetals.13 Whilst allylsilanes undergo successful ste-
reospecific fluorination,14 access to enantioenriched acyclic tertiary
allylfluorides from an allylmetal has not previously been reported.
Pleasingly, the reaction of 1 with aryllithium 4, and subsequent
fluorination with Selectfluor in MeCN at –40 °C, was found to af-
ford allylfluoride 21 in 76% yield, >95:5 γ/α and >95:5 dr. To de-
termine the absolute configuration and demonstrate that there were
no matched/mismatched effects in operation, we also synthesized
the alternative diastereomer of fluoride 14 from the opposite anti
diastereomer of 6.15
33d
5
4
32
31
30
33c
33b
3
33a
2
33g
log k2
29
1
28
9
33f
33e
0
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-1
-2
-9 -7 -5 -3 -1
1
Electrophilicity E
We next chose to develop the fluorination of allylboronate com-
plexes because of the importance of incorporating fluorine stere-
oselectively into organic molecules (Scheme 3). It was found that
changing the alkyl substituent at R1 to either a sterically bulky iso-
propyl (22) or a benzyl group (23) afforded the desired allylfluo-
rides in high yield and selectivity. Fluorination of allylboronates
derived from cyclic alkenes also occurred in good yield, albeit with
slightly reduced regioselectivities (24 and 25). Pleasingly, the re-
action tolerated a range of functional groups including carbamates
(25), tert-butyl esters (26) and tert-butyldiphenylsilyl protected al-
cohols (27). Owing to the facile synthesis of the starting al-
lylboronic esters through lithiation–borylation between a vinyl-
boronic ester and alkylbenzoate,3k,16 an array of allylfluorides can
now be formed with high selectivity.
Figure 1. Correlation of the second-order rate constants k2 for the
reactions of allylboron compounds 28–32 (for structures, see Fig.
2) with benzhydrylium ions 33 (see Supporting Information) to-
ward the electrophilicity parameters E of the benzyhdrylium ions.
intercepts on the abscissa of the correlation lines in Fig. 1. Addition
of an aryllithium to allylboronic ester 28 increases the nucleophilic-
ity by 7 to 10 orders of magnitude.18 Thus, the anionic allylboronate
complexes 30–32 are significantly more nucleophilic than al-
lylsilanes, allylstannanes and allyltrifluoroborate 29, all of which
are more nucleophilic than the parent boronic ester 28. The previ-
ously reported N parameter of benzylboronate complex 34,19 which
reacts in an SE2 mode with electrophiles, is two logarithmic units
smaller than of 30. In line with this ordering, allylboronates 30–32
react with high γ-selectivity (SE2’), in preference to reaction at the
α-position (SE2).
Scheme 3. Scope of the Fluorination Reactiona
aAll boronic esters have dr > 95:5. Yields of isolated material; γ/α
ratio and dr determined by GCMS or 19F NMR.
In order to quantify the change of nucleophilicity of the allyl
moiety upon addition of an organolithium to an allylboronic ester
(28), we measured the kinetics of the reactions of allylboron com-
pounds 28–32 with benzhydrylium ions 33, following previously
published methods (Figures 1 and 2).17 Figure 1 demonstrates that
the measured second-order rate constants correlate linearly with the
electrophilicity parameters E of the reference benzhydrylium ions,
which allows us to employ eq. (1) for calculating the nucleophilic-
ity parameters N and susceptibilities sN of 28–32.
Figure 2. Comparison of nucleophilicity parameters N (suscepti-
bility parameters sN in parentheses) of allylmetal reagents. Boro-
nate complexes and allyltrifluoroborate determined in CH3CN,
other nucleophiles in CH2Cl2.
log k2 (20 °C) = sN(N + E)
(1)
Although Figure 1 shows that the relative reactivities of the al-
lylboron compounds somewhat depend on the nature of the elec-
trophiles (because of the different slopes (sN) of the correlation
lines), a rough ordering of the nucleophilic reactivities is given by
their N parameters (Figure 2), which correspond to the negative
In conclusion, by addition of an organolithium we have con-
verted weakly nucleophilic allylic boronic esters into potent nucle-
ophiles which now react with a broad range of carbon- and heteroa-
tom-based electrophiles with very high -selectivity and essentially
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53, 10992. (l) Hesse, M. J.; Essafi, S.; Watson, C. G.; Harvey, J. N.; Hirst,
complete stereospecificity. Indeed, the addition of an organolith-
ium to form a boronate complex increases the nucleophilicity of the
stable boronic ester by 7 to 10 orders of magnitude. Importantly,
this process provides access to a broad array of functionalities, in-
cluding quaternary all-carbon stereocentres and allylic fluoro- and
trifluoromethyl moieties. We envisage that the continued applica-
tion of boronate complexes10e will provide access to an array of new
enantioenriched functionalities which are otherwise difficult to ob-
tain.
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ASSOCIATED CONTENT
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Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Detailed experimental procedures, kinetics data, and
characterization data for new compounds (PDF).
AUTHOR INFORMATION
Corresponding Author
*v.aggarwal@bristol.ac.uk
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank EPSRC (EP/I038071/1), ERC (670668) and Deutsche
Forschungsgemeinschaft (SFB 749, project B1) for financial sup-
port. C.G.-R. thanks the Ramón Areces Foundation and P.L. thanks
Xunta de Galicia for postdoctoral fellowships. C.S. thanks the Uni-
versity of Bristol for a PhD scholarship and K.F. thanks the EPSRC
Bristol Chemical Synthesis Doctoral Training Centre for a student-
ship (EP/L015366/1). We thank E. M. Wöllner and P. Gänsheimer
for initial kinetic results, and A. R. Ofial for helpful discussions.
(11) More electron rich boronate complexes are more prone to SET path-
ways than polar pathways (see ref 10a) which could account for the higher
selectivity observed with 3,5-(CF3)2C6H3Li and naphthylLi vs 4-
MeOC6H4Li.
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