Activation of alkynes with B(C6F5)3 - Boron allylation reagents derived from propargyl esters

Article abstract of DOI:10.1021/ja4110842

Novel allyl boron compounds are readily synthesized via rearrangement reactions between Lewis acidic B(C₆F₅)₃ and propargyl esters. These reactions proceed through an initial cyclization followed by ring-opening and concurrent C₆F₅-group migration. In the absence of disubstitution adjacent to the ester oxygen atom, an allyl boron migration rearrangement leads to formal 1,3-carboboration products. These allyl boron compounds act as allylation reagents with aldehydes introducing both a C₃-allyl fragment and a C₆F ₅-unit as a single anti-diastereomer. In these reactions, B(C ₆F₅)₃ activates the alkynes, prompting the rearrangement processes and enabling installations of C₆F₅ and R-groups.

Full text of DOI:10.1021/ja4110842

Article
pubs.acs.org/JACS
Activation of Alkynes with B(C6F5)3 − Boron Allylation Reagents
Derived from Propargyl Esters
Max M. Hansmann,†,§ Rebecca L. Melen,‡,§ Frank Rominger,† A. Stephen K. Hashmi,*,†
and Douglas W. Stephan*,‡
†Organisch-Chemisches Institut, Ruprecht-Karls-Universitat Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
̈
‡Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada
§Chemistry Department, Faculty of Science, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia
S
* Supporting Information
ABSTRACT: Novel allyl boron compounds are readily
synthesized via rearrangement reactions between Lewis acidic
B(C6F5)3 and propargyl esters. These reactions proceed
through an initial cyclization followed by ring-opening and
concurrent C6F5-group migration. In the absence of
disubstitution adjacent to the ester oxygen atom, an allyl
boron migration rearrangement leads to formal 1,3-carbobora-
tion products. These allyl boron compounds act as allylation
reagents with aldehydes introducing both a C3-allyl fragment
and a C6F5-unit as a single anti-diastereomer. In these
reactions, B(C6F5)3 activates the alkynes, prompting the
rearrangement processes and enabling installations of C6F5
and R-groups.
previously reported analogous intramolecular reactions of
propargyl amides with the Lewis acid B(C6F5)3,16 which afford
stable zwitterionic 5-alkylidene-4,5-dihydrooxazolium borate
species (III) via an intramolecular 5-exo oxyboration reaction.
This can, in some cases (R′ = H), aromatize to afford oxazole
products (IV) (Scheme 1).16 Herein, we exploit this initial π-
activation mode to uncover a novel synthetic route to
functionalized boron allylation reagents from propargyl esters.
These reagents are subsequently utilized as allylation reagents
INTRODUCTION
■
Allylation and crotylation reactions have gained a prominent
position as tools in organic synthesis for the construction of
carbon−carbon bonds.1 Traditionally, η1-allyl-transfer reagents
are derived from main group compounds such as allylboron,2
allylsilane,3 or allylstannanes.4 The allyl or crotyl-boron
reagents are generally less toxic and more reactive than the
silicon and tin counterparts. The allyl additions of organoboron
reagents to carbonyl compounds are highly diastereoselective
and enantioselective when chiral boranes are employed. These
reagents have found widespread applications in organic
chemistry and natural product synthesis.5 Synthetic routes to
such boron allylation reagents include hydroboration, transition
metal-catalyzed borylation of allylic compounds with bis-
(pinacolato)diboron, or the addition of reactive allyl lithium,
allyl magnesium, and allyl potassium reagents to a borinic or
boric ester.6
Scheme 1. Cyclization Pathways of Propargyl Amides with
the π-Lewis Acid B(C6F5)3
The Lewis acid B(C6F5)3 was first reported in the 1960s7 and
has found widespread applications in organometallic and
organic chemistry,8,9 olefin polymerization,10 and hydro-
silylation.11 In recent years, B(C6F5)3 has been exploited as
the Lewis acid component in frustrated Lewis pair (FLP)
chemistry.12 FLPs, first described in 2006,13 consist of Lewis
acids and bases that act in concert to activate a wide range of
small molecules or to effect catalysis.12 For example, suitable
combinations of Lewis bases (including amines,14 phosphines,15
amides,16 and pyrroles17) and B(C6F5)3 undergo 1,2-addition
reactions to C−C π-bonds of olefins or alkynes. We have
Received: October 30, 2013
© XXXX American Chemical Society
A
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with aldehydes enabling the installation of C6F5 and R-groups,
opening a new route to highly functionalized organic
compounds.
2e (Figure 1 and Supporting Information), which exhibited
similar geometric parameters. X-ray diffraction analysis also
RESULTS AND DISCUSSION
■
The 1:1 stoichiometric reaction of the propargyl ester 1a with
B(C6F5)3 in CH2Cl2 at 45 °C results in the rapid and clean
formation of the cyclic allyl boron compound 2a (Scheme 2) in
Scheme 2. Synthesis of Allyl Boron Reagents via a Propargyl
a
Rearrangement
Figure 1. POV-ray depictions of the molecular structure of 2d. C,
black; O, red; F, pink; B, yellow-green. Analogous structures of 2a, 2c,
and 2e are deposited in the Supporting Information.
confirmed the Z-configuration about the CC double bond in
2c and 2d. Efforts to employ other boranes (including BPh3
and BF3·OEt2) in this rearrangement reaction gave no
conversion even at elevated temperatures (50 °C) for 24 h.
These reactions are thought to proceed via a reactive
zwitterionic intermediate (3) (Scheme 2), which rapidly
rearranges to yield compounds of type 2 by a C6F5 group
migration. This migration is enabled as a result of the
carboxylate group to act as a good leaving group. Attempts to
observe the intermediate en route to 2a (Scheme 2) by in situ
11B NMR spectroscopy revealed a sharp signal at δ = −17.1
ppm during the first few minutes of the reaction at 25 °C. This
chemical shift suggested B−C bond formation concurrent with
the quaternization of boron yielding a borate intermediate.
While normally the reactions to afford 2 were homogeneous in
CH2Cl2, 1a and B(C6F5)3 gave single crystals of 3a immediately
after mixing, which were suitable for X-ray diffraction analysis
(Figure 2). This structure confirms the proposed reaction
a
Isolated yields are indicated.
which C6F5-group migration from boron to carbon has
occurred. It is noteworthy that direct 1,1-carboboration of
terminal alkynes is known to afford vinyl-boranes;18 this is not
seen in the case of the present reactions, as the propargyl
rearrangement process is significant faster.
This reaction between 1a and B(C6F5)3 was found to be
strongly solvent dependent with no evidence of reaction in
coordinating solvents such as d8-THF or d3-MeCN. Nonethe-
less, the reaction was rapid and clean in CD2Cl2 and slower in
d8-toluene, d6-benzene, and d5-bromobenzene. The analogous
reactions of 1b−e with B(C6F5)3 afforded the corresponding
compounds 2b−e in high conversions and yields. The reactions
of 1c and 1d were particularly rapid giving the allyl boron
compounds 2c and 2d in less than 15 min at room temperature.
These cyclizations are much faster than those previously
described for propargyl amides,16 presumably a result of poorer
coordination ability of the ester carbonyl in comparison to the
propargyl amide fragment,19 enabling faster π-alkyne activation.
These stoichiometric reactions were scaled up to afford the
products 2a−e in good to high yields (in most cases
quantitative by in situ NMR), which were fully characterized
Figure 2. POV-ray depiction of the molecular structure of 3a. C, black;
O, red; F, pink; B, yellow-green.
mechanism. It is interesting to note the similarity between this
reactivity and that of Lewis acidic transition metals such as gold
or platinum.20 These transition metals undergo a similar initial
1,2-acyl-oxy shift with terminal alkynes leading to electrophilic
metal-carbenoids, although such intermediates have never been
isolated.20 In this respect, the isolation of 3a represents the first
1
by H, 13C, 19F, and 11B NMR spectroscopy. In the case of
compounds 2c and 2d, the Z-isomer was exclusively formed. X-
ray crystallography was also used to characterize 2a, 2c, 2d, and
B
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crystallographic characterization of an intermediate in such
acyl−oxy shift reactions.
room temperature with benzaldehyde to afford the allylation
product 5 as a single diastereomer (Scheme 4). While the clean
Furthermore, we investigated the propargyl rearrangement
process utilizing the enantiomerically pure (S)-1c propargyl
ester and observed the formation of the racemic allyl boron
compound 2c by chiral HPLC−MS (see the Supporting
Information).21 Temperature-dependent chiral HPLC measure-
ments indicate no racemization of the allyl boron compound
itself up to 60 °C. This loss in chirality transfer is suggesting a
nonconcerted mechanism in which ring-opening of 3 proceeds
prior to C6F5 group migration (Scheme 2).
Scheme 4. Tandem Rearrangement−Addition Process
Leading to α,β-Unsaturated Ketones
Interestingly, these allyl boron compounds (2) are quite
stable in contrast to other compounds incorporating C(sp3)−B
bonds.2 For example, compound 2a could be purified by an
aqueous workup with 3 M NaOH, even in the presence of
hydrogen peroxide, under air and is a bench stable white solid.
This stability can be attributed to the steric shielding of the
boron center and the intramolecular ester-boron chelate.
Subsequent heating of compounds 2a or 2b at 45 °C resulted
in an irreversible allyl boron migration affording the
compounds 4a and 4b, respectively (Scheme 3), as evidenced
formation of 5 was consistent with in situ NMR studies (see the
Supporting Information), the isolation of 5 proved challenging.
Nonetheless, treatment of the reaction mixture under oxidative
conditions (NaOH/H2O2) generated the hydrolyzed sensitive
β-hydroxy ketone 6a. This species eliminates water upon
column chromatography to generate the α,β-unsaturated
ketone 7 (see the Supporting Information). The molecular
structure of compound 7a was confirmed by an X-ray
diffraction study (Figure 4). In a similar fashion, the α,β-
Scheme 3. 1,3-Allyl Shift Products
Figure 4. POV-ray depiction of the molecular structure of 7a. C, black;
O, red; F, pink.
unsaturated ketone analogues 7b−f were also prepared
(Scheme 4) from the reactions of 1b and B(C6F5)3 with a
variety of aldehydes, thus demonstrating the broad scope of the
allylation reactions. The high yielding, multistep reactions to 7
represent a facile route to trisubstituted alkenes with exclusive
E-configuration. Interestingly, in the absence of aldehyde,
species 4b is converted to the α-C6F5 substituted ketone 8
when subjected to column chromatography. In this reaction,
three processes have taken place including (i) ester hydrolysis,
(ii) enol−keto tautomerization, and (iii) protonation of the C−
B bond.
The corresponding reaction of 2c (generated in situ) with
aldehydes resulted in the selective and clean formation of the
formal trans-crotylation products 9 (Scheme 5). After oxidative
aqueous workup, the β-hydroxy enol esters 10 could be isolated
as single diastereomer. This reaction provides a route to the
rapid synthesis of β-hydroxy enol esters (10a−10f) as a single
diasteromer (Scheme 5). The relative stereochemistry and the
Figure 3. POV-ray depiction of the molecular structure of 4a. C, black;
O, red; F, pink; B, yellow-green. The analogous structure of 4c is
deposited in the Supporting Information.
by spectroscopic data and confirmed by a crystallographic study
of 4a (Figure 3). Compound 4c could also be synthesized from
the reaction of the corresponding propargyl ester with
B(C6F5)3 and was structurally characterized (see the Support-
ing Information). While 2a required prolonged heating to be
converted to 4a, the acetate compound (2b) undergoes a clean
1,3-allyl boron shift within 24 h at 45 °C. These 1,3-boron allyl-
shifts are reminiscent of the conversion of allyl boranes to the
more thermodynamically stable isomers in which the boron
atom is located on the least substituted carbon atom.22
The applications of these novel allyl boron compounds in
organic synthesis were subsequently investigated. In situ
generated compound 4b reacted cleanly, and in <5 min, at
C
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a
the combination of aldehyde, propargyl ester, and B(C6F5)3 in a
1:1:1.1 ratio with heating to 50 °C generated the expected
intermediate (2c) as evidenced by NMR spectroscopy. These
signals ultimately collapse to the final crotylation product 9,
which afforded 10a on workup (Scheme 6). B(C6F5)3
coordination to the aldehyde significantly diminishes the rate
of the boron propargyl-allyl rearrangement as a result of
reduced free B(C6F5)3 available for alkyne activation (the
equilibrium constant for adduct formation between B(C6F5)3
and an aldehyde is 102 times stronger than that with an ester19).
However, it is found that B(C6F5)3 synergistically accelerates
the allylation process because it both enables the irreversible
formation of the allyl boron compound 2c and activates the
aldehyde to nucleophilic attack yielding 9 (Scheme 6).23
By simply changing the R-group on the propargyl ester, a
straightforward route to access various allylation products is
possible in a single one-pot transformation. For example,
reactions of in situ generated allyl boron compounds 2 with
benzaldehyde yield a single diastereomer of the species 12a−c
when purified by column chromatography on silica, while
purification on neutral aluminum oxide provides the corre-
sponding rearranged ketones 13a−13c in good isolated yields
(Scheme 7). Spectroscopic data clearly support the formulation
of these products, and the structure of 13b was also confirmed
by X-ray diffraction (Figure 6).
Scheme 5. Diastereoselective Crotylation Reactions
a
Reactions performed on a 0.50 mmol scale (0.2 M in CH2Cl2). (A)
H2O2/NaOH; SiO2; (B) H2O2/NaOH; neutral aluminum oxide.
enol ester geometry were unambiguously confirmed by an X-
ray crystallographic analysis of 10a (Figure 5). Interestingly,
Scheme 7. Diastereoselective Allylation by Propargyl-Allyl
a
Rearrangement
Figure 5. POV-ray depiction of the molecular structure of 10a. C,
black; O, red; F, pink.
purification by column chromatography on silica gel allowed
the isolation of the enol esters (10), whereas use of neutral
aluminum oxide cleanly gave the rearranged product 11. The
formation of 11 arises from an intramolecular 1,3-acyl shift
(transesterification) reaction concurrent with an enol−keto
tautomerization, presumably triggered by Lewis-acidic sites on
the neutral aluminum oxide.
The aforementioned allylation reactions were sequential one-
pot processes in which the first step (formation of the allyl
boron compound) was monitored before aldehyde addition.
The formation of 10a was also achieved in a one-pot process by
mixing all components at the start of the reaction (Scheme 6);
a
Performed on a 0.50 mmol scale (0.2 M in CH2Cl2). (A) H2O2/
NaOH; SiO2; (B) H2O2/NaOH; neutral aluminum oxide.
Scheme 6. Dual Role of B(C6F5)3 − One-Pot Crotylation
Sequence from the Aldehyde/Propargyl Ester Mixture
Figure 6. POV-ray depiction of the molecular structure of 13a. C,
black; O, red; F, pink.
D
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While boron-allylation reactions normally proceed via a
closed six-membered Zimmermann−Traxler transition state,5
in this case, the boron allylation appears to represent a unique
example of an open transition state addition as the intra-
molecular ester chelate presumably inhibits the aldehyde
coordination. Nonetheless, open transition state allylation
reactions seen with tin or silicon allylation reagents normally
result in only poor diastereoselectivities;5c the present reactions
afford exclusive anti-addition stereochemistry. This is a result of
the exclusive formation of only one (Z)-enol ester diastereomer
in the initial boron rearrangement process. It is proposed that
the R-group of the aldehyde is placed in an antiperiplanar
position to the bulky ester group, maximizing the dipole−
dipole interactions of the two C−O bonds, thus fixing the
resulting geometry (Scheme 8). While opening of the boron
rearrangements in organic chemistry is the target of continued
efforts.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details for the synthesis of starting materials and
new compounds, NMR spectra, and crystallographic informa-
tion files in CIF format. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
dstephan@chem.utoronto.ca
hashmi@hashmi.de
Author Contributions
§These authors contributed equally.
Scheme 8. Stereochemical Rationale for the anti-Allylation
Product
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
NSERC of Canada is thanked for financial support. D.W.S. is
grateful for the award of a Canada Research Chair. M.M.H. is
grateful to the Fonds der chemischen Industrie for a
Chemiefonds scholarship and the Studienstiftung des deut-
schen Volkes. We thank Dr. Alan J. Lough (Toronto) for the X-
ray characterization of compound 4c. We thank Dr. Matthias
Rudolph (Heidelberg) for helpful discussions. We thank
Alexander F. Siegle and Prof. Oliver Trapp (Heidelberg) for
the chiral HPLC/MS experiments.
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CONCLUSIONS
■
We have demonstrated the synthesis of a variety of novel allyl
boron compounds from the reactions of Lewis acidic B(C6F5)3
with propargyl esters. These reactions proceed via a rearrange-
ment process consisting of (i) cyclization via an intramolecular
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(19) Parks, D. J.; Piers, W. E.; Parvez, M.; Atencio, R.; Zaworotko, M.
J. Organometallics 1998, 17, 1369.
(20) For transition metal-catalyzed propargyl-rearrangement, see:
(a) Mauleon, P.; Toste, F. D. In Modern Gold Catalyzed Synthesis;
Hashmi, A. S. K., Toste, F. D., Eds.; Wiley: New York, 2012; p 74.
(b) Marion, N.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2750.
(c) Marco-Contelles, J.; Soriano, E. Chem.Eur. J. 2007, 13, 1350.
(d) Correa, A.; Marion, N.; Fensterbank, L.; Malacria, M.; Nolan, S. P.;
Cavallo, L. Angew. Chem., Int. Ed. 2008, 47, 718. (e) Wang, S.; Zhang,
G.; Zhang, L. Synlett 2010, 692. (f) Hashmi, A. S. K.; Yang, W.; Yu, Y.;
Hansmann, M. M.; Rudolph, M.; Rominger, F. Angew. Chem., Int. Ed.
2013, 52, 1329. (g) Nosel, P.; dos Santos Comprido, L. N.;
̈
Lauterbach, T.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. J. Am.
Chem. Soc. 2013, 135, 15662. (h) Shiroodi, R. K.; Gevorgyan, V. Chem.
Soc. Rev. 2013, 42, 4991. (i) Yang, W.; Yu, Y.; Zhang, T.; Hansmann,
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̈
2037−2043.
(21) We rule out a racemization process of the chiral propargyl ester
by B(C6F5)3 prior to cyclization, as we subjected the 2:1 reaction
mixture of propargyl ester and B(C6F5)3 onto the chiral HPLC and
could not detect racemization of the remaining propargyl ester.
(22) (a) Jutzi, P.; Seufert, A. Chem. Ber. 1979, 112, 2481. (b) Kramer,
G. W.; Brown, H. C. J. Organomet. Chem. 1977, 132, 9. (c) Bubnov, Y.
N. Pure Appl. Chem. 1987, 59, 895.
(23) It is interesting to highlight that B(C6F5)3 also found application
as a Lewis acid in allylstannation of aldehydes, see: (a) Ooi, T.;
Uraguchi, D.; Kagushima, N.; Maruoka, K. J. Am. Chem. Soc. 1998,
120, 5327. For a mechanistic study showing that the boron source acts
as an initiator to generate a tin-Lewis acid, see: (b) Blackwell, J. M.;
F
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