Difluoromethane as a precursor to difluoromethyl borates

Article abstract of DOI:10.1039/c9cc01565e

Difluoromethane (CF₂H₂) is an ecologically-friendly refrigerant which holds promise as a source of CF₂H^-. However, the weak acidity (pK_a = 35-41) and low stability of the conjugate base have prevented its utilization as a chemical feedstock. In this manuscript, we use a Lewis pair approach to deprotonate CF₂H₂ and capture CF₂H^- as R₃B-CF₂H^- adducts. One reagent can be used as a base-free Suzuki reagent in palladium-mediated difluoromethylation, where CF₂H^- transfer is templated by precoordination to an azaborine derived R₃B-CF₂H^- reagent..

Full text of DOI:10.1039/c9cc01565e

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Difluoromethane as a precursor to difluoromethyl
borates†
Cite this:DOI: 10.1039/c9cc01565e
Jacob B. Geri,‡ Ellen Y. Aguilera and Nathaniel K. Szymczak
*
Received 24th February 2019,
Accepted 1st April 2019
DOI: 10.1039/c9cc01565e
rsc.li/chemcomm
Difluoromethane (CF2H2) is an ecologically-friendly refrigerant
which holds promise as a source of CF2Hꢀ. However, the weak
acidity (pKa = 35–41) and low stability of the conjugate base have
prevented its utilization as a chemical feedstock. In this manuscript,
we use a Lewis pair approach to deprotonate CF2H2 and capture
CF2Hꢀ as R3B–CF2Hꢀ adducts. One reagent can be used as a base-free
Suzuki reagent in palladium-mediated difluoromethylation, where
CF2Hꢀ transfer is templated by precoordination to an azaborine
derived R3B–CF2Hꢀ reagent.
Fig. 1 Conceptual outline of the Lewis acid/base strategy to enable
CF2Hꢀ capture/transfer from H2CF2.
When incorporated into biologically active molecules, the difluoro-
methyl group acts as a metabolically stable lipophilic bioisostere of
Furthermore, if CF2Hꢀ is generated in the presence of a
OH or SH groups.1–3 As a result of these desirable properties, fluorophilic cation such as Li+, immediate defluorination occurs.17
molecules containing –CF2H groups are routinely investigated in If the Li+ is replaced with [Cs(18-crown-6)2]+, a cation with low Fꢀ
drug development.4–6 Many of the commonly used CF2H transfer affinity, the corresponding [CF2H]ꢀ is highly basic and deproto-
reagents (such as SiMe3CF2H and Zn(CF2H)2) are prepared from nates THF. For these reasons, CF2H2 has not been used to prepare
halofluoromethanes (XCF2H;
X =
Cl, Br, F) and their synthetically useful CF2Hꢀ equivalents. These problems may be
derivatives,7–12 compounds with high ozone depleting potential.13 mitigated by deprotonating CF2H2 in the presence of a Lewis acid
In contrast, difluoromethane (CF2H2) would represent an attractive (LA) that can capture CF2Hꢀ as a LA–CF2Hꢀ adduct, and then later
source of the difluoromethyl group if it could be deprotonated to release CF2Hꢀ in a subsequent reaction. To realize this strategy,
reveal nucleophilic CF2Hꢀ fragments. It is nontoxic, has no ozone- selection of an appropriate Brønsted base and Lewis acid is critical,
depleting potential, and is already manufactured on a large scale because the Lewis acid and base must be strong enough to
as a refrigerant.14 However, no approaches for nucleophilic deprotonate CF2H2 and to stabilize CF2Hꢀ while also avoiding
difluoromethylation from difluoromethane have been reported.
the formation of inert acid–base adducts.18 We previously
Despite the attractive properties of CF2H2 as a source of described a compatible Lewis acid/base approach that can
CF2Hꢀ, challenges associated with deprotonation and capture resolve categorically similar issues with ArCF2H substrates;19
have prevented its use as a chemical synthon (Fig. 1). In addition the acid/base partners mediate CF2Phꢀ generation, capture, and
to its low acidity (gas phase proton affinity: 389 kcal molꢀ1 15
;
release. In this communication, we report the direct synthesis of
HCF3: 376 kcal molꢀ1),16 free CF2Hꢀ is unstable to a-fluoride R3B–CF2Hꢀ adducts from difluoromethane and their ability to
elimination.17
serve as nucleophilic sources of CF2Hꢀ.
We hypothesized that an appropriate Lewis pair for difluoro-
methane deprotonation/CF2Hꢀ capture must satisfy several key
criteria. The base must be sufficiently strong to deprotonate
CF2H2 and not contain fluorophilic cations such as Li+ and Na+.
The Lewis acid must be sufficiently strong to stabilize CF2Hꢀ
against a-fluoride elimination but weak enough to release CF2Hꢀ
nucleophiles. In addition to these requirements, the Lewis acid/
base pairs must not quench their respective reactivities through
Department of Chemistry, University of Michigan Ann Arbor, 930 N. University,
Ann Arbor, MI 48109, USA. E-mail: nszym@umich.edu;
Web: http://www.umich.edu/Bszymlab
† Electronic supplementary information (ESI) available. CCDC 1897944 and
1897945. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c9cc01565e
‡ Current address: Merck Center for Catalysis at Princeton University, Washington
Road, Princeton, NJ 08544, USA.
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the formation of irreversible adducts.18 We selected KCH2Ph as an even under forcing conditions (24 h, 80 1C in THF). The lack
initial base for experimental evaluation because of its high basicity of reactivity and the shorter B–CF2H bond relative to analogous
(pKa = 42 (DMSO)),20 straightforward preparation,21 and potassium –CF3 and CF2Phꢀ adducts alluded to a stronger B–CF2H bond
ꢀ
countercation. Hexamethylborazine (B3N3Me6) was selected as the preventing CF2H transfer. We confirmed this hypothesis in silico
initial Lewis acid partner because it forms a reversible adduct with and found that the calculated affinity of B3N3Me6 for CF2Hꢀ
KCH2Ph and is known to stabilize fluoroalkyl nucleophiles (ꢀ33 kcal molꢀ1) was 10 kcal higher than for CF3ꢀ (ꢀ23 kcal molꢀ1
)
(CF3 and CF2Arꢀ).19,22,23
at the M062X/6-31g(d,p) level of theory.
ꢀ
When CH2F2 gas was added to a deep red THF solution
One option to lower the kinetic barrier to CF2H transfer is
containing a 1 : 1 : 1 ratio of KCH2Ph, B3N3Me6, and 18-crown-6 via pre-coordination to an adjacent ligand donor group. To imple-
at 0 1C, the solution became colorless after 90 minutes. ment this design principle for CF2Hꢀ transfer, we targeted two
19F NMR spectroscopy revealed the formation of a new species [6,6]-fused 1,2-azaborine rings that either contain (1,2,3,4-
2
1
at ꢀ128.23 ppm exhibiting J11B–19F and J1H–19F coupling (32, tetrahydro-[1,2]azaborinino[1,2-a][1,2]azaborinine)26 or omit
49 Hz) consistent with a B–CF2H unit.24 Trituration with pentane (octahydro-[1,2]azaborinino[1,2-a][1,2]azaborinine)27 a p-system.
afforded a white solid in 95% yield, which was characterized by Their calculated CF2Hꢀ affinities (M062X/6-31g(d,p)) are similar
1
1H, 11B, 13C, and 19F NMR spectroscopy. The H NMR spectrum to that of B3N3Me6 (ꢀ33 (2) and ꢀ34 (3) vs. ꢀ33 (1) kcal molꢀ1),
revealed the loss of symmetry of the B3N3Me6 unit with four –CH3 making these adducts suitable candidates to test our hypothesis.
resonances (2.51, 2.49, 0.05, ꢀ0.39 ppm), as well as a new –CF2H Adducts between these Lewis acids and CF2Hꢀ would present
resonance at 5.20 ppm with 1J1H–19F coupling (51 Hz). The 11B-NMR nucleophilic –C and/or –N nucleophilic sites proximal to the
spectrum revealed one broad (32.3 ppm) and one sharp resonance CF2Hꢀ group, and could serve to direct CF2Hꢀ transfer. When a
(ꢀ5.7 ppm) integrating in a 2 : 1 ratio. These data are consistent with solution of either of the [6,6]-fused 1,2-azaborine Lewis acids,
a dearomatized B3N3Me6 unit containing one tetrahedral boron KCH2Ph, and 18-crown-6 was treated with CH2F2 and CF2Hꢀ
atom and two planar boron atoms, enabling assignment of adducts analogous to 1 (K(18-crown-6) (2: 1,2,3,4-tetrahydro-
the isolated compound as K(18-crown-6)B3N3Me6(CF2H) (1). [1,2]azaborinino[1,2-a][1,2]azaborinine)(CF2H); 3: K(18-crown-6)-
Importantly, in the absence of B3N3Me6, no tractable reaction (octahydro-[1,2]azaborinino[1,2-a][1,2]azaborinine)(CF2H)) were
products were observed.
Crystals suitable for X-ray diffraction were obtained by 3 was increased to 78% by substituting KN(iPr)2 for KCH2Ph.
allowing pentane to diffuse into a concentrated solution of 1
The 19F-NMR spectrum of 2 exhibited two resonances
obtained as solids in 62% and 34% yield (Fig. 3). The yield of
28
2
1
2
in THF at ꢀ35 1C. The solid-state structure revealed a CF2Hꢀ (ꢀ127.10 and 131.96 ppm) with J19F–19F, J1H–19F, and J11B–19F
anion coordinated to a dearomatized B3N3Me6 unit, capped with coupling (311, 54, and 20 Hz), while the 11B-NMR spectrum
a K(18-crown-6)+ cation (Fig. 2b). The B–CF2H bond is elongated showed a sharp peak at ꢀ10.22 ppm. These data are consistent
relative to the other B–CH3 bonds (1.640(5) vs. 1.621(5), 1.612(7), with a B–CF2H unit containing diastereotopic fluorine units.
1
and 1.594(7) Å), consistent with its lower bond strength (vide 3 exhibited a single 19F resonance (127.04 ppm, J1H–19F and
infra). The structure is largely homologous with other fluoroalkyl– 2J11B–19F = 51 and 18 Hz), a sharp 11B-NMR resonance at ꢀ12.4 ppm,
borazine adducts K(18-crown-6)B3N3Me6(CF3) and K(18-crown- and C2-symmetric 1H and 13C NMR resonances. A single crystal
6)B3N3Me6(CF2Ph), which also exhibit elongated B-–C distances of 3 was grown by allowing pentane to diffuse into a THF
of 1.656(4) and 1.670(6) Å.19,22
solution at ꢀ35 1C, and the solid state structure revealed that
1 is the first structurally characterized R3B–CF2Hꢀ adduct.25 3 exhibits a bent geometry of the azaborine unit, similar to that of
Organoboronate complexes of this type are the active forms of the hydrocarbon decalin, capped with a B–CF2H group. The B–CF2H
commonly used Suzuki reagents in palladium-catalyzed cross bond in 3 (1.633(3) Å) is within error of that in 1 (1.640(5) Å), and
coupling, and the known ability of K(18-crown-6)B3N3Me6(CF3) is consistent with their similarly calculated CF2Hꢀ affinities and
and K(18-crown-6)B3N3Me6(CF2Ph) to transfer fluoroalkyl anions B–CF2H bond lengths (1.633 and 1.638 Å).
to Pd(II) centers such as Pd(TMEDA)(Ph)I (TMEDA = tetramethyl-
To assess whether pre-coordination could provide a more
ethylenediamine) suggested that 1 may be able to promote similar kinetically accessible pathway for CF2Hꢀ transmetalation,
reactivity. Unfortunately, 1 did not react with Pd(TMEDA)(Ph)I we evaluated the reactivity of 2 and 3 with Pd(TMEDA)(Ph)I.
Fig. 2 (a) Synthesis of 1 from H2CF2. (b) X-ray crystal structure of 1. The
K(18-c-6)(THF)+ counterion is omitted for clarity.
Fig. 3 (a) Synthesis of 2 and 3 from CF2H2. (b) X-ray structure of 3. The
K(18-c-6)(THF) counterion is omitted for clarity.
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Fig. 4 (a) Transmetalation of 1–3 to Pd(TMEDA)(Ph)I and subsequent reaction with 1,10-bis(diphenylphosphino)ferrocene (DPPF). (b) Computed pathway
for transmetalation using 2 (M06L2X/6-31g(d,p)). Hydrogen atoms are omitted for clarity.
Heating a mixture of 2 and 1.5 equivalents Pd(TMEDA)(Ph)I (4) isomers, the isomer with Pd–C3 coordination was more stable by
at 80 1C afforded a 1 : 1 ratio of Pd(TMEDA)(CF2H)2 (5)29 and ꢀ1.3 kcal molꢀ1 and the calculated NMR shifts32 more closely
Pd(TMEDA)(CF2H)(Ph) (6)30 in 55% combined yield as identified resembled the experimental values ((C1–C4)–H: 5.40, 5.01,
by 19F-NMR spectroscopy. Addition of two equiv. DPPF followed by 3.15, 8.20 vs. 2.58, 7.63, 5.29, 6.26), allowing us to assign the
heating to 80 1C for 2 h triggered reductive elimination of connectivity of 7 as depicted in Fig. 4.
difluoromethylbenzene in 28% combined yield over both steps.31
An associative mechanism for CF2Hꢀ transmetalation from
In contrast, 3 or 1, which do not contain a p-system, afforded 2 to 4 via 7 was then computationally evaluated (M06L2X/6-
Pd(TMEDA)(CF2H)2 in only trace quantities; further reaction with 31g(d,p)). In the first step, Iꢀ is displaced by 2 to form the observed
DPPF did not yield PhCF2H.
prereactive complex 7 in an exothermic process (ꢀ3.8 kcal molꢀ1).
These experiments highlight ring unsaturation as a key Rotation of the ring positions the CF2Hꢀ group in close proximity
structural element that can be used to direct CF2Hꢀ transfer to the Pd(II) center (8: +1.3 kcal molꢀ1). CF2Hꢀ transfer occurs
and suggest that precoordination of the R3B–CF2Hꢀ adduct may through b-alkyl elimination (transition state 9) to form product
facilitate transmetalation. We assessed this hypothesis using a 6 and the free azaborine Lewis acid with a net barrier of
combined experimental/theoretical approach. Combination of 2 34.7 kcal molꢀ1. These computational and experimental data
and 4 at 25 1C afforded a deep red species (7) with new NMR support our hypothesis that an associative mechanism for
resonances. Titration of 2 with 4 identified 7 as a 1 : 1 adduct of CF2Hꢀ transmetalation to Pd(II) is operative for reagent 2.
2 and 4. Alternative reagents 3 and 1, which lack a p-system, did
In conclusion, we have developed the first strategy to repurpose
not form observable adducts when combined with 4. Heating 7 at CF2H2, a widely available refrigerant, into a –CF2Hꢀ building
80 1C for 2 hours afforded Pd(TMEDA)(CF2H)(Ph) (6), establishing block. A compatible Lewis acid/base pair approach enabled the
7 as an intermediate formed prior to CF2Hꢀ transfer. 1H–1H COSY preparation of a family of three boron–CF2Hꢀ adducts (1–3)
and 1H–13C HSQC spectra allowed a partial structural assignment following difluoromethane deprotonation. Of these reagents,
1
for 7. Notably, H-NMR resonances associated with the sp2 C–H only 2 can transmetalate CF2Hꢀ to palladium(II), a challenging
groups in the azaborine fragment (C1–H: 4.89, C2–H: 4.85, C3–H: transformation which has not been demonstrated using B–CF2Hꢀ
4.07, C4–H: 7.86) are significantly shifted with respect to those sources.29,30,33,34 We have identified that templated coordination
found in unbound 2, suggesting a Pd–p interaction in 7. To through the p-system of 2 is required to facilitate –CF2Hꢀ transfer,
augment the assignment, DFT analyses were used to identify two and used the resulting difluoromethylpalladium complex to prepare
structural isomers of 7 as energetic minima, in which the closest PhCF2H. We anticipate that this conceptual approach to difluoro-
Pd–C contact is at either the C3 or the C1 position. Of these two methane activation and transfer may be applied to other reactive
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This work was supported by the University of Michigan
Department of Chemistry, a Rackham Predoctoral Fellowship
(JBG), and an NSF CAREER (grant CHE-1350877). X-ray diffracto-
meters used were funded by the NSF (CHE 1625543). N. K. S. is a
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