Facile Synthesis of α-N-Heterocyclic Carbene-Boryl Ketones from N-Heterocyclic Carbene-Boranes and Alkenyl Triflates

Article abstract of DOI:10.1021/jacs.9b05547

Reactions of readily available alkenyl triflates with N-heterocyclic carbene (NHC)-boranes in the presence of diisopropyl ethyl amine provided about three dozen stable α-NHC-boryl ketones. Isolated yields were typically 40-56% for B-unsubstituted NHC-boranes (NHC-BH₃), and somewhat lower for NHC-boranes with B-substituents (NHC-BH₂R). The requisite alkenyl triflates can be made separately or prepared in situ from either ketones or alkynes. The experimental evidence supports a radical chain mechanism that involves the following: (1) addition of an NHC-boryl radical to the alkenyl triflate, (2) fragmentation to give the α-NHC-boryl ketone, SO₂, and trifluoromethyl radical, and (3) hydrogen abstraction by trifluoromethyl radical from the starting NHC-borane to return the NHC-boryl radical along with trifluoromethane. Reactions 1 and 3 are both new and evidently rather fast.

Full text of DOI:10.1021/jacs.9b05547

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Article
Facile synthesis of #-NHC-boryl ketones
from NHC-boranes and alkenyl triflates
Wen Dai, Steven J. Geib, and Dennis P. Curran
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 11 Jul 2019
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Journal of the American Chemical Society
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Facile synthesis of -NHC-boryl ketones from NHC-boranes and
alkenyl triflates
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Wen Dai, Steven J. Geib and Dennis P. Curran*
Department of Chemistry, University of Pittsburgh, Pittsburgh PA, USA 15208
ABSTRACT: Reactions of readily available alkenyl triflates with NHC-boranes in the presence of diisopropyl ethyl amine
provided about three-dozen stable -NHC-boryl ketones. Isolated yields were typically 40–56% for B-unsubstituted
NHC-boranes (NHC-BH3), and somewhat lower for NHC-boranes with B-substituents (NHC-BH2R). The requisite alkenyl
triflates can be made separately or prepared in situ from either ketones or alkynes. The experimental evidence supports
a radical chain mechanism that involves: (1) addition of an NHC-boryl radical to the alkenyl triflate, (2) fragmentation to
give the -NHC-boryl ketone, SO2 and trifluoromethyl radical, and (3) hydrogen abstraction by trifluoromethyl radical
from the starting NHC-borane to return the NHC-boryl radical along with trifluoromethane. Reactions (1) and (3) are
both new and evidently rather fast.
INTRODUCTION
coworkers have made various benzyl-substituted -
NHC-boryl esters and amides by radical hydroboration
of cinnamic esters and amides.8 Finally, Zhou and
coworkers have introduced gold-catalyzed reactions of
carbenes generated from alkynes rather than diazo
Boron enolates of various types are readily available
and have a rich chemistry.1 Until recently, their -boryl
carbonyl isomers (sometimes called C-boron enolates)
have been the poorer cousins of the family. But that
situation is changing.2
compounds.9
These transformations starting from
alkynes are oxidative (8-isopropylquinoline-N-oxide is
the oxidant), and serve well to make amine-borane
analogs of 3 (X = R) but not N-heterocyclic carbene
analogs.
Recent work has shown that strong electron donating
substituents on boron tend to favor the -boryl carbonyl
form, as shown by the examples in Figure 1a. Classes of
-boryl carbonyls in the boronic acid oxidation state
include N-methyliminodiacetic acid (MIDA) boronates 13
and pinacol boranes 2.4 In the borane oxidation state,
various classes of ligated boranes 3 are known with
amine, phosphine and N-heterocyclic carbene (NHC)
ligands.5 Trivalent pinacol boranes 2 are moisture
sensitive, but the tetravalent species 1 and 3 tend to be
robust compounds, stable to air, water and
chromatography.
To date, most ligated -boryl carbonyl compounds 3
have been made by transition metal catalyzed B–H bond
insertion reactions between -diazocarbonyl compounds
4 and ligated boranes (L–BH3), see Figure 1b.5 On the
plus side, these are one-step reactions that often give
good yields and selectivities due to the hydridic nature
of the B–H bonds in L–BH3.6 On the minus side,
diazocarbonyl compounds are potentially hazardous and
transition metals catalysts can be expensive.
Recently, we have described reactions between 4 (X =
OR) and NHC-boranes that are catalyzed by borenium
ions rather than transition metals,7 and Wang and
Figure 1. -Boryl carbonyl compounds
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Here we describe a new route to -NHC-boryl ketones
ClCH2CH2Cl), the -NHC-boryl ketone 10a was formed,
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that does not start from a diazo-carbonyl compound and
does not require either a catalyst or an oxidant. This
method was inspired by recent independent discoveries
of Li10 and Kamimura11 that alkenyl triflates 5 rearrange
to -trifluoromethyl ketones 6 under radical conditions
(Figure 2a). (Alkenyl triflates are also commonly called
vinyl triflates and enol triflates.) Under Kamimura’s
conditions, for example, an alkenyl triflate 5 is simply
but only in small amounts according to 11B NMR analysis.
However, we soon found that the target reaction
proceeded rather smoothly when all the other reagents
were replaced by a simple tert-amine (Scheme 1). For
example, heating of NHC-borane 8, alkenyl triflate 9a
(1.3 equiv) and diisopropyl ethyl amine (iPr2NEt, 0.8
equiv) in THF at 66 ˚C for 3 h provided -NHC-boryl
ketone 10a in 66% yield according to 11B NMR analysis
of the reaction mixture. Solvent evaporation and flash
chromatography provided pure 10a in 50% yield as a
stable white solid.
9
treated with Et3B and O2 to initiate chains.
A
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trifluoromethyl radical (CF3•)12 is thought to add to 5,
followed by -fragmentation to give 6, SO2 and CF3•.13
We hypothesized that addition of an NHC-borane
(NHC-BH3) to an alkenyl triflate would result in an
interrupted reaction wherein an NHC-boryl radical would
add to the alkenyl triflate rather than the trifluoromethyl
radical, as shown in Figure 2b. Supporting this idea, Kim
and coworkers have described interrupted reactions of
alkenyl triflates with various ethers and alkanes, which
result in -alkylation.14 B–H bonds of NHC-boranes are
weaker than most C–H bonds and therefore more prone
to abstraction. Still, even if NHC-boryl radicals are
formed as projected, it is unclear whether they will add
rapidly to alkenyl triflates.
Scheme 1.
Preferred reaction conditions for
synthesis of -NHC-boryl ketone 10a
We now report that reactions of alkenyl triflates 5,
NHC-boranes and diisopropyl ethyl amine provide
various stable -NHC-boryl ketones 7 in good yields.
Evidence suggests that these are radical transformations
that occur without the need for a traditional radical
initiator.
The results of other optimization experiments with 8
and 9a are summarized in Table S1 of the Supporting
Information. Briefly, various other amines (Et3N, Bu3N,
MeN(c-C6H11)2) gave about the same yield as iPr2NEt.
The amount of amine could be varied somewhat, but no
reaction occurred if it was omitted. THF was superior to
other solvents surveyed (CH2Cl2, CHCl3, ClCH2CH2Cl,
dioxane). And a reaction time of about 1–3 h was
sufficient; shorter times (<1 h) gave lower yields and
longer times gave about the same yield.
formation of the product 10a was blocked by addition of
the radical inhibitor TEMPO ((2,2,6,6-
tetramethylpiperidin-1-yl)oxyl, 2 equiv).
Finally,
The results of a scope study with readily available
alkenyl triflates are summarized in Figure 3, which shows
structures of -boryl ketone products, 11B NMR yields,
and isolated yields (in parentheses) of the various
products that were prepared. The standard procedure
from Scheme 1 was used in all of these experiments (0.1
mmol NHC-borane 8; alkenyl triflate, 1.3 equiv; iPr2NEt,
0.8 equiv, THF, 66 ˚C, 3 h). A quick glance at the
Figure 2. (a) Known conversion of alkenyl triflates to -
trifluoromethyl ketones, and (b) proposed conversion to -
NHC-boryl ketones
RESULTS AND DISCUSSION
products in Figure
3 shows that many common
The results of preliminary experiments were
discouraging. Reactions of NHC-borane 8 and alkenyl
triflate 9a under the conditions of Li10 (AgNO3,
(NH4)2S2O8, tBuOH/H2O) provided no target product 10a.
Further, the added NHC-borane spoiled the default
reaction – the -trifluoromethyl ketone was not formed
either. Under Kamimura’s conditions11 (Et3B, ambient air,
functional groups are tolerated in the reaction.
Products 10b–g with assorted 4-substituents (Br, CF3,
CN, esters, sulfone) on the aromatic ring were isolated in
yields ranging from 41–56%.
Products with 3-
substituents were isolated in somewhat lower yields. For
example, 3-chloro product 10h was isolated in 40%
whereas the 4-isomer 10a was isolated in 50% yield.
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Likewise, the yields of 3-bromo and 3-cyano products
yield shows that the activating group does not have to
be aryl. Related ketoester 10t was isolated in 19% yield.
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10i and 10j (38% and 40%) were a somewhat lower than
the corresponding 4-isomers 10b and 10d (41% and
56%). The 3,4- and 3,5-dichlorophenyl products 10k and
10l were isolated on 51% and 42% yield, respectively.
Again the 4-Cl isomer was formed in somewhat higher
yield. The reaction with 9k was also conducted on a 1
mmol scale and gave marginally improved results; the
NMR yield of 10k was 64% and the isolated yield was
55%.
For most of the products in Figure 3, the 11B NMR yield
exceeds the isolated yield by about 10–20%, suggesting
that there may be some decomposition during flash
chromatography. This problem is most acute with -
ketoesters 10s (NMR yield, 67%) and 10t (NMR yield,
70%), where the NMR yield exceeds the isolated yield by
40–50%. Once isolated, however, the pure products are
stable to storage and handling under ambient lab
conditions.
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Alkenyl triflates bearing heteroaryl groups were also
viable substrates. -NHC-boryl ketones bearing pyridine
(10m) and substituted pyridine (10n, 10o) rings were
isolated in yields of 30%, 40% and 41%, respectively, and
a 2-cyanothiophene analog (10p) was isolated in 52%
yield.
The 3,4-dichlorophenyl -NHC-boryl ketone 10k was
nicely crystalline. Its X-ray structure was solved, and two
views of the structure are shown in Figure 4. The left
view approximates a Newman projection looking down
the CH2–C(O)Ar bond. Notice that the CH2–B bond is
roughly orthogonal to the carbonyl group (the B–C–C=O
torsion angle is 93˚). NHC-boryl groups are among the
In contrast, alkenyl triflates with two or three alkyl
substituents (9q and 9r) were inert and did not provide
-NHC-boryl ketones. This shows that some kind of
activating group is needed on the triflate. However, the
formation of -NHC-boryl keto ester 10s in 25% isolated
+
strongest known -electron donors, with p for 1,3-
dimethylimidazol-2-ylidine boryl estimated at +0.48.15
So this orientation might result due to hyperconjugation
of the CH2–BH2NHC group with the carbonyl group.
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a) results of a 1 mmol scale experiment, 2 equiv iPr2NEt, THF, 66 ˚C, 8 h; b) at 40 ˚C for 1 h
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Figure 3. Results of scope study with NHC-borane 8 with about twenty additional alkenyl triflates under standard conditions
(0.1 mmol 8, 1.3 equiv alkenyl triflate, 0.8 equiv iPr2NEt, THF, 66 ˚C, 3 h)
The right view of the crystal structure in Figure 4 is an
approximate Newman projection looking down the BH2–
CH2 bond of 10k. This bond is approximately staggered,
but the ketone on the carbon atom and the NHC ring on
the boron atom are oriented gauche rather than anti.
The NHC–B–C–C(O)Ar torsion angle is 69˚. This is
somewhat larger than a perfect gauche angle (60˚),
doubtless due to some steric repulsion between the two
gauche substituents.
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Figure 4. Two views of the X-ray crystal structure of 10k
(ORTEP at 50% probability level); right, approximate
Newman projection of the CH2–C(O)Ar bond; left,
approximate Newman projection of the BH2–CH2 bond.
We next surveyed variation of the NHC-borane
component with alkenyl triflate partner fixed as 9d.
Reactions were conducted under the standard
conditions, and Figure 5 shows product structures and
Figure 5. Variation of substituents on the NHC ring and the
boron; products and isolated yields (0.1 mmol NHC-borane,
1.3 equiv 9d, 0.8 equiv iPr2NEt, THF, 66 ˚C, 3 h)
isolated yields.
Products 11–16 with various N-
substituents (R1, R2 = Me, iPr, Bu, Bu, Bn, allyl) were
isolated in yields ranging from 42–56%. Products 17 and
18 with two additional substituents on the NHC ring (Me
and Cl, respectively) were both isolated in 42% yield.
Many of these products have C–H bonds that are
susceptible to abstraction by trifluoromethyl radicals,13a-
t
Alkenyl triflates are reactive molecules that can be
inconvenient to handle (depending on substituents). So
we next studied several one-pot reactions where the
alkenyl triflate was generated in situ and then directly
converted to an -NHC-boryl ketone. Two convenient
ways to make alkenyl triflates are base-promoted
triflation of ketones16 and addition of triflic acid to
alkynes,17 so one-pot variants of each where studied.
c,14
and the tight range of yields indicates that B–H bond
abstraction is preferred in all cases.
Adding a substituent on boron dented the isolated
yields, but products were still isolated in all five of the
reactions studied. The hindered B-alkyl borane 19 was
isolated in 28% yield, while the B-aryl borane 20 was
produced in 18% yield. An -boryl ester and ketone
produced the corresponding products 21 and 22 in 26%
and 20% yields. Finally, a B-cyanoborane produced
product 23 in only 9% yield. This poor result could be
because the cyano group retards the B–H abstraction
reaction due to a polarity mismatch, or because the
resulting radical (NHC-B(•)HCN) is too stable.
In the standard ketone triflation procedure (Figure
6a),18 ketone 24 (0.25 mmol), triflic anhydride (1.4 equiv)
and Na2CO3 (1.3 equiv) were stirred in CH2Cl2 at rt for 24
h to make the alkenyl triflate.
The CH2Cl2 was
evaporated, then THF, NHC-borane 8 (0.1 mmol), and
iPr2NEt (0.1 mmol) were added. The resulting mixture
was heated at 70 ˚C for 1.5 h, then cooled and
concentrated
again.
Purification
by
flash
chromatography gave existing product 10k in 44% yield.
Two new products were also made; naphthyl ketone 25
gave 10u in 30% yield, and biphenyl ketone 26 gave 10v
in 25% yield. These one-pot yields are about the same
as the two-step yields, but the procedure is more
convenient.
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The one-pot procedure starting from alkynes is even
appeared.
So typical amine- and phosphine- and
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more convenient (Figure 6b). Trifluoromethane sulfonic
acid (1.4 equiv) was added to 4-chlorophenylethyne 27
(1.3 equiv) in CH2Cl2.17 After 10 min at rt, the solvent was
removed and THF, NHC-borane 8 (0.1 mmol), and
iPr2NEt (0.1 mmol) were added. Heating at 70 ˚C for 1 h,
followed by cooling, concentration and chromatography,
provided 10a in 41% yield. Likewise, 4-trifluoromethyl
analog 10c was prepared in one pot starting from 4-
trifluoromethylphenylethyne 28 in 39% yield.
amidine-boranes are not viable partners, at least under
these conditions.
Figure 7 shows a suggested radical chain mechanism
for this transformation, starting from the trifluoromethyl
radical (CF3•).
In the transformations of Li9 and
Kamimura10 (Figure 1a), this radical adds to the alkenyl
triflate to ultimately provide an -trifluoromethyl ketone.
However, this reaction is interrupted by the addition of
the NHC-borane 8 to the medium. Now the faster
reaction of trifluoromethyl radical is abstraction of a
hydrogen atom from a B–H bond of 8 to provide
trifluoromethane (CF3H) and NHC-boryl radical 29. This
is an unknown reaction that we projected would be fast
because it is exothermic by roughly 25 kcal/mol (the C–H
bond dissociation energy12b of CF3–H is about 107 kcal
mol–1 while the B–H bond dissociation energy21 of NHC-
BH2–H is about 80–82 kcal mol–1.) In addition, it is
polarity matched; NHC-boranes electron rich and
trifluoromethyl radicals are electrophilic.12 Reactions of
NHC-boranes with alkoxyl radicals have similar features
(highly exothermic, polarity matched), and indeed these
reactions have high rate constants (~108 M–1 s–1).22
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In turn, the NHC-boryl radical 29 then adds to the
alkenyl triflate 9 to give 30, which undergoes -
fragmentation to give the NHC-boryl ketone 10, SO2 and
trifluoromethyl radical. The addition step is also a
previously unknown reaction, but NHC-boryl radicals are
known to add to electron poor alkenes (such as
acrylates22b,23) and to phenyl-substituted alkenes and
alkynes.8,24 The final fragmentation step is expected
based on prior radical additions to alkenyl triflates.10–12
Figure 6. One-pot synthesis of -NHC-boryl ketones from
(a) ketones and (b) alkynes
To close the scope aspects of the study, we conducted
reactions of alkenyl triflate 9k (3,4-diClC6H3C(OTf)=CH2)
with four different ligated boranes under the standard
conditions (9k, 1.3 equiv; ligated borane, 1 equiv, iPr2NEt,
0.8 equiv, THF, 70 ˚C, 3 h). Reactions were conducted
with the following ligated boranes: Et3N–BH3, Ph3P–BH3,
DMAP-BH3 (DMAP is 4-dimethylamino-pyridine)19 and
DBU-BH3 (DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene).20
Reaction progress was followed by 11B NMR
spectroscopy, but in each case the resonance of the
starting borane remained and no new resonances
Figure 7. Propagation steps of a proposed radical chain
mechanism are H-transfer, addition and fragmentation
The function of the amine is somewhat speculative at
this point, but two roles seem sensible. First, no reaction
occurs if the amine is omitted, so it may function in the
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initiation step (for example, electron transfer to an
NHC-boryl ketones. Isolated yields were typically 40–
56% for B-unsubstituted NHC-boranes (NHC-BH3), and
somewhat lower for NHC-boranes with B-substituents
(NHC-BH2R). No catalyst is needed for this reaction, and
a traditional high energy initiator (for example Et3B, AIBN
or tBuOOtBu) is not needed either.
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alkenyl triflate could make an amine radical cation and
trifluoromethyl radical). In addition, it likely functions as
an acid scavenger. Standard (undried) THF is used in this
reaction, and the residual water is expected to add to
SO2 to make H2SO3 (sulfurous acid). This is a strong acid
(pKa1 = 1.8) that will be neutralized by the amine.
The requisite alkenyl triflates can be made separately,
or more conveniently, prepared in situ either from
ketones (by triflation with triflic anhydride) or from
alkynes (by ionic addition of triflic acid). Following the
triflate-forming reaction, the NHC-borane and amine are
added directly and the products are isolated as usual.
The yields for the one-pot, two-step reactions are about
the same as when the two steps are conducted
separately with purification of the alkenyl triflate in
between.
The features of the reaction are broadly consistent
with the chain mechanism in Figure 7. First, the reaction
needs an initiator (the amine) and is shut down by an
inhibitor (TEMPO). Second, the scope is also broadly
consistent with the reaction being limited by the step of
addition of the NHC-boryl radical to the alkenyl triflate.
Specifically, an additional activating group on C2 of the
alkene is needed besides OTf (either aryl or carbonyl),
and terminal alkenes are preferred substrates.
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In addition, the mechanism in Figure 7 was further
supported by an isotope effect experiment, the results of
which are shown in Figure 8. Alkenyl triflate 9e was
reacted with an excess of NHC-borane 9 and its labeled
analog 9-d3 (2 equiv each) under the standard
conditions. The isolated product was a mixture of 10e
and 10e-d2 in a ratio of about 2.6/1 according to MS
analysis. This result indicates a significant primary
isotope effect caused by the hydrogen atom abstraction
reaction, and the value is reasonable given that this
reaction is exothermic and therefore has an early
transition state.
The substrate scope and the results of mechanistic
experiments support a radical chain mechanism in which
the propagation steps are: (1) addition of an NHC-boryl
radical to the alkenyl triflate, (2) fragmentation of the
resulting -triflyloxy radical to give the -NHC-boryl
ketone, SO2 and trifluoromethyl radical, and (3) hydrogen
abstraction by trifluoromethyl radical from the starting
NHC-borane to return the NHC-boryl radical along with
trifluoromethane.
The mild conditions and broad substituent tolerance
suggest that the new method will be useful for making
various types of -NHC-boryl ketones. In addition, the
results show for the first time that trifluoroalkyl radicals
rapidly abstract hydrogen atoms from NHC-boranes, and
therefore suggest that other new chain reactions that
can be designed with this reaction as a key step.
ASSOCIATED CONTENT
Supporting Information
Contains full experimental and compound characterization
details, copies of NMR spectra (1H, 11B and 13C) of all new
compounds, and the details of the crystal structure.
The Supporting Information is available free of charge on
the ACS Publications website.
Figure 8. Results of an isotope effect experiment with D-
labeled NHC-borane
Experimental, compound characterization and copies of
spectra (PDF)
CONCLUSIONS
We have described a fundamentally new approach to
making -NHC-boryl ketones.
Most previous
Details of X-ray structure (cif)
approaches are based on carbene B–H insertion
reactions and require both a diazocarbonyl precursor
and a transition metal catalyst.
AUTHOR INFORMATION
In a complementary approach, we reacted readily
available alkenyl triflates with NHC-boranes in the
presence of diisopropyl ethyl amine in refluxing THF for
Corresponding Author
* curran@pitt.edu
ORCID
several hours.
Solvent evaporation and flash
Wen Dai: 0000-0002-9098-5215
chromatography provided about three dozen stable -
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Journal of the American Chemical Society
10. Su, X.; Huang, H.; Yuan, Y.; Li, Y., Radical desulfur-
Steven J. Geib: 0000-0002-9160-7857
Dennis P. Curran: 0000-0001-9644-7728
1
2
3
fragmentation and reconstruction of enol triflates: Facile access
to α-trifluoromethyl ketones. Angew. Chem. Int. Ed. 2017, 56,
1338-1341.
ACKNOWLEDGMENT
11. Kawamoto, T.; Sasaki, R.; Kamimura, A., Synthesis of α-
trifluoromethylated ketones from vinyl triflates in the absence
of external trifluoromethyl sources. Angew. Chem. Int. Ed. 2017,
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We thank the US National Science Foundation for support
of this work through grant CHE-1660927.
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