Design considerations for chiral frustrated Lewis pairs: B/N FLPs derived from 3,5-bicyclic aryl piperidines

Article abstract of DOI:10.1039/C8DT04070B

Herein, 3,5-bicyclic aryl piperidines are derivatized to generate chiral B/N FLPs. Initially, the twofold symmetric amine C₆H₂F₂(C₅H₈NiPr) 1 was converted in a series of synthetic steps to the styrene-derivative C₆HF₂(C₅H₈NiPr)(CH═CH₂) 4. Efforts to hydroborate the vinyl fragment proved challenging as a result of the strongly basic nitrogen, although the species C₆HF₂(C₅H₈N(H)iPr)(CH₂CH₂B(OH)(C₆F₅)₂) 5 was crystallographically characterized. Modification of the system was achieved by conversion of the amine C₆H₂F₂(C₅H₈NH) 6 to C₆HF₂(C₅H₈NPh)(CH═CH₂) 9. Hydroboration of 9 with 9-BBN or HB(C₆F₅)₂ gave C₆HF₂(C₅H₈NPh)(CH₂CH₂BBN) 10 or C₆HF₂(C₅H₈NPh)(CH₂CH₂B(C₆F₅)₂) 11, respectively. The latter species was derivatized by complexation of PPh₃ to give C₆HF₂(C₅H₈NPh)(CH₂CH₂B(C₆F₅)₂)(PPh₃) 12. The Lewis acidities of 10 and 11 were assessed by the Gutman-Beckett test and by computations of the FIA and GEI. While 10 did not effect HD scrambling or hydrogenation of N-phenylbenzylimine, 11 was effective in HD scrambling. Despite this, no reduction of N-t-butylbenzylimine or N-phenylbenzylimine was achieved. These data demonstrate that 10 lacks the threshold combination of Lewis acidity and basicity to activate H₂, while 11 lacks the steric demands about boron to preclude classical Lewis acid-base bond formation with imine substrates.

Full text of DOI:10.1039/C8DT04070B

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PAPER
Design considerations for chiral frustrated Lewis
pairs: B/N FLPs derived from 3,5-bicyclic aryl
piperidines†
Cite this: Dalton Trans., 2019, 48, 133
Jolie Lam,a Susanna Sampaolesi,b James H. W. LaFortune,a Jotham W. Coe*b and
a
Douglas W. Stephan
*
Herein, 3,5-bicyclic aryl piperidines are derivatized to generate chiral B/N FLPs. Initially, the twofold sym-
metric amine C6H2F2(C5H8NiPr) 1 was converted in a series of synthetic steps to the styrene-derivative
C6HF2(C5H8NiPr)(CHvCH2) 4. Efforts to hydroborate the vinyl fragment proved challenging as a result of
the strongly basic nitrogen, although the species C6HF2(C5H8N(H)iPr)(CH2CH2B(OH)(C6F5)2) 5 was crystal-
lographically characterized. Modification of the system was achieved by conversion of the amine
C6H2F2(C5H8NH) 6 to C6HF2(C5H8NPh)(CHvCH2) 9. Hydroboration of 9 with 9-BBN or HB(C6F5)2 gave
C6HF2(C5H8NPh)(CH2CH2BBN) 10 or C6HF2(C5H8NPh)(CH2CH2B(C6F5)2) 11, respectively. The latter
species was derivatized by complexation of PPh3 to give C6HF2(C5H8NPh)(CH2CH2B(C6F5)2)(PPh3) 12. The
Lewis acidities of 10 and 11 were assessed by the Gutman–Beckett test and by computations of the FIA
and GEI. While 10 did not effect HD scrambling or hydrogenation of N-phenylbenzylimine, 11 was
effective in HD scrambling. Despite this, no reduction of N-t-butylbenzylimine or N-phenylbenzylimine
was achieved. These data demonstrate that 10 lacks the threshold combination of Lewis acidity and basi-
city to activate H2, while 11 lacks the steric demands about boron to preclude classical Lewis acid–base
bond formation with imine substrates.
Received 10th October 2018,
Accepted 21st November 2018
DOI: 10.1039/c8dt04070b
rsc.li/dalton
Far and away the most successful systems known for asym-
metric FLP reductions have been developed by the Du group in
Introduction
Since the advent of frustrated Lewis pair (FLP) hydrogenations, China. These authors have developed a series of in situ-gener-
several groups have explored the potential of chiral systems to ated catalysts derived from hydroboration of bis-allylbi-
effect asymmetric reductions. The first of such efforts,
reported by Chen and Klankermayer,1 provided a low enantio-
meric excess using the chiral borane (α-pinenyl)B(C6F5)2 as the
catalyst. Subsequent modifications using camphor-templated
boranes (Fig. 1)1–4 effectively catalyzed ketimine reductions
affording ee of 70–76%. Erker et al.5 separated diastereomers
of a chiral ferrocene-templated FLP zwitterion (Fig. 1) and
used it to hydrogenate six ketimines, achieving ee ranging
from 42–69%. In 2015, Repo and co-workers6 described the
design of an intramolecular B/N FLP system based on a
binapthyl backbone (Fig. 1). The resulting catalyst was effective
for the asymmetric hydrogenation of enamines and unhin-
dered imines with stereoselectivities ranging from 32–99%.
aDepartment of Chemistry, University of Toronto, 80 St George St, Toronto, M5S3H6,
Canada. E-mail: dstephan@chem.utoronto.ca
bPfizer, Groton, CT, USA
†Electronic supplementary information (ESI) available: Spectral and crystallo-
graphic data. CCDC 1868691–1868693 for compounds: 12, 5 and 10, respectively.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c8dt04070b
Fig. 1 Examples of chiral FLP catalysts for hydrogenations.
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naphthalene species with HB(C6F5)2 (Fig. 1). Such catalysts
have been used to reduce ketamines,7 silyl enol ethers,8 2,4-
and 2,3-disubstituted quinolines,9 2,3,4-trisubstituted quino-
lines,10 2,3,4-trisubstituted quinoxalines,11 and 3-phenyl-1,4-
benzoxazines.12 Similar catalysts have been derived from chiral
binaphthyl-based diynes,13 while chiral catalysts derived from
the reaction of Piers’ borane and (S)-t-butylsulfinamide
(Fig. 1)14 have been used to mediate the hydrogenation and
transfer hydrogenation of imines and 2,3-disubstituted quin-
oxalines.15 Very recently, Wang has developed a C2-symmetric
bis-borane (Fig. 1) that is highly selective, affording imine
reductions with up to 95% ee.16
Scheme 1 Synthesis of 1–5, (a) n-BuLi, THF, −78 °C, oxirane, BF3·OEt2;
(b) MeSO2Cl, NEt3, DCM; (c) KOtBu, THF.
Efforts to hydroborate 4 with 9-BBN proceeded slowly and
required use of multiple equivalents of borane to consume the
starting material. Successive washes with n-heptane removed
excess 9-BBN, affording 1H NMR data that confirmed the
absence of vinyl proton signals. This suggests the formation of
C6HF2(C5H8NiPr)(CH2CH2BBN), however it was not possible to
isolate this species in pure form.
In our early efforts,17 we employed B(C6F5)3 to catalyze the
hydrogenation of chiral imines with diastereoselectivity. More
recently, in collaboration with the groups of Crudden and
Melen, we described the synthesis of asymmetric borenium
cations exploiting chiral substituents directly on B or on a
donor ligand (Fig. 1).18 While some of these species were com-
petent hydrogenation catalysts, enantioselectivities were gener-
ally poor. That work demonstrated the steric dilemma,
wherein using less hindered cations gave limited selectivity
while bulkier systems reduced reactivity.
In the present efforts, we noted the interesting chiral tri-
cyclic amines developed during a drug discovery program at
Pfizer.19 In such 3,5-bicyclic aryl piperidines, the geometry
forces the substituent on the nitrogen to assume the favoured
equatorial position in the chair conformation of the piperidine
ring, thus placing the amine nitrogen atom in a chiral pocket
(Fig. 2).20 Herein, we derivatize such amines to prepare asym-
metric intramolecular FLPs. The reactivities of these systems
are probed. These investigations illuminate some design fea-
tures that require consideration for the construction of new
chiral FLP hydrogenation catalysts.
Similar efforts to hydroborate 4 using HB(C6F5)2 under
various conditions from 25–80 °C afforded mixtures of pro-
ducts as evidenced by 11B NMR spectroscopy. In a typical case,
among the peaks observed, a singlet at −12.4 ppm and a
doublet at −24.9 ppm with a coupling constant of 84 Hz were
ascribed to a borane–amine adduct and the [HB(C6F5)3] anion,
respectively. We speculated that hydride abstraction from the
iPr group by HB(C6F5)2 would generate the iminium cation
and the [H2B(C6F5)2] anion. The latter anion is known to
scramble its substituents to generate the stable anion
[HB(C6F5)3]. Serendipitously, from this mixture of products, a
few crystals suitable for X-ray crystallography were
isolated. Crystallographic data confirmed this species to be
C6HF2(C5H8N(H)iPr)(CH2CH2B(OH)(C6F5)2) 5 (Fig. 3), indicating
that hydroboration of 4 had occurred, however subsequent
reaction with water led to the protonation of the nitrogen atom
and provided hydroxide to the boron center. The resulting B–O
bond distance was found to be 1.498(3) Å. It is clear from
these results that the combination of a strongly basic nitrogen
atom and a Lewis acidic, yet sterically accessible boron center,
undermines the synthetic protocol.
Results and discussion
To initially establish a synthetic protocol, procedures were
These observations prompted synthetic modifications of
the amine to reduce the basicity at nitrogen by the introduc-
tion of a phenyl group on nitrogen. To this end, the primary
amine C6H2F2(C5H8NH) 6 was prepared and a Buchwald–
developed
using
the
twofold
symmetric
amine
C6H2F2(C5H8NiPr) 1. Incorporation of an ethyl alcohol frag-
ment was achieved in THF using n-BuLi, oxirane, and BF3 to
give almost complete conversion. Subsequent chromatography
gave C6HF2(C5H8NiPr)(CH2CH2OH) 2 in 68% isolated yield.
Mesylation gave C6HF2(C5H8NiPr)(CH2CH2OSO2Me) 3 and sub-
sequent treatment with KOtBu gave the styrene-derivative
C6HF2(C5H8NiPr)(CHvCH2) 4 (Scheme 1).
Fig. 3 POV-ray depiction of 5; hydrogen atoms have been omitted for
Fig. 2 Geometry of chiral 3,5-bicyclic aryl piperidines.
134 | Dalton Trans., 2019, 48, 133–141
clarity. B: yellow-green; C: black; N: blue; F: pink; H: white.
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These data are consistent with the presence of a three-
coordinate boron center and the formulation of 11 as
C6HF2(C5H8NPh)(CH2CH2B(C6F5)2). Subsequent reaction of 11
with PPh3 afforded 12, albeit in modest yield of 34%. The 31P
NMR spectrum of 12 showed a single resonance at 10.1 ppm.
The corresponding 11B NMR signal at −6.2 ppm and the 19F
NMR spectrum with a doublet of doublets at −141.0 ppm,
doublet at −146.9 ppm, and signals for the C6F5 rings at
−127.1, −157.2, and −163.5 ppm, are consistent with a four-
coordinate boron center and the formation of the B–P adduct
C6HF2(C5H8NPh)(CH2CH2B(C6F5)2)(PPh3) 12. Single crystals
suitable for X-ray crystallography were isolated by slow
diffusion of n-pentane into a cold CH2Cl2 saturated solution of
12. The crystallographic characterization of 12 (Fig. 5) con-
firmed the above formulation and revealed B–P and B–Calkyl
distances of 2.083(5) Å and 1.634(6) Å, respectively.
Scheme 2 Synthesis of 6–12 (a) bromobenzene, Pd(dba)2, Q-Phos,
NaOtBu, Tol; (b) nBuLi, THF, −78 °C, I2; (c) pinacol vinylboronate,
Pd(PPh3)4, Na2CO3, DMF/H2O; (d) for 10 9-BBN; for 11 HB(C6F5)2, (e) PPh3.
Lewis acidity
Hartwig cross-coupling21 afforded the N-phenylated species
C6H2F2(C5H8NPh) 7 in 96% yield. Lithiation and iodination
gave the species C6HIF2(C5H8NPh) 8, installing iodine in the
position ortho to fluorine. Pd-mediated cross-coupling with
vinylborate gave C6HF2(C5H8NPh)(CHvCH2) 9 in 86% yield
(Scheme 2).
The Gutmann–Beckett test was performed on 10 and 11. This
involved exposure to Et3PO and monitoring by 31P{H} NMR
spectroscopy. The adduct formed from 10 and Et3PO resulted
in a resonance at 52.4 ppm while that from 11 gave a peak at
73.4 ppm. When comparing the adduct formed from 10 to the
chemical shift of free Et3PO (δ = 52.1 ppm), the small shift
(Δδ = 0.2 ppm) suggests that 10 is weakly Lewis acidic. In con-
trast, the adduct formed from 11 displays significantly greater
Lewis acidity, with a Δδ from free Et3PO of 21.3 ppm. In fact,
this is only slightly less than that seen for the more common
Lewis acid B(C6F5)3 (Δδ = 26.5 ppm).
Hydroboration of 9 with 9-BBN proceeded successfully to
afford 10 in 69% yield. The 11B NMR spectrum showed a
single broad peak at 88 ppm, while the 19F NMR spectrum
showed two resonances; a doublet at −149.6 ppm and a
3
doublet of doublets at −146.9 ppm. The JFF was 19 Hz while
3
the latter signal also showed a JFH of 7 Hz. Single crystals of
Computations related to the Lewis acidity of 10 and 11 were
carried out. Geometry optimizations and frequency calcu-
lations were performed using the BP86 functional and the
def2-TZVP basis set. Frequency calculations on the optimized
structures showed the absence of imaginary frequencies con-
firming that minima on the potential energy hypersurfaces
were located. Energies for fluoride ion affinity (FIA) were calcu-
lated using the MP2 functional and the def2-TZVPP basis
set,22,23 as previously described using the experimental FIA of
carbonyl difluoride.24 The global electrophilicity index (GEI)
was calculated using the B3LYP25,26,39,40 functional and the
def2-TZVP basis set, as previously described.27,28 Natural bond
10 suitable for X-ray crystallography were isolated and the sub-
sequent crystallographic study confirmed the formulation as
C6HF2(C5H8NPh)(CH2CH2BBN) (Fig. 4). The boron atom
exhibited typical three-coordinate trigonal planar geometry.
While the N atom is oriented above the aromatic ring, the
boron is positioned at 6.947 Å from the N atom, consistent
with no intramolecular interaction.
Similarly, hydroboration of 9 with HB(C6F5)2 gives a yellow
oil 11. NMR spectroscopy showed a 11B NMR signal at
72.5 ppm, while the 19F NMR spectrum showed a doublet at
−145.7 ppm and a doublet of doublets at −139.9 ppm corres-
ponding to the piperidine backbone as well as resonances at
−130.1 ppm, −146.4 ppm, and −160.7 ppm for the C6F5 rings.
Fig. 4 POV-ray depiction of 10; hydrogen atoms have been omitted for
Fig. 5 POV-ray depiction of 12; hydrogen atoms have been omitted for
clarity. B: yellow-green; C: black; N: blue; F: pink.
clarity. B: yellow-green; C: black; N: blue; P: orange; F: pink.
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orbital and natural population analyses were performed using N-phenylbenzylimine resulted from exposure of these imines
the M062X basis set29 and def2-TZVPP functional using NBO to 11 and 4 atm of H2, even upon heating to 40 °C. The inde-
6.0.30 NBO analysis showed that the expected HOMOs reside pendent combination of 11 and N-t-butylbenzylimine revealed
on the N atom, while the LUMOs are centered on the boron for a peak at −12.6 ppm in the 11B NMR spectrum, suggesting
both 10 and 11 (Fig. 6).
coordination of the imine to the boron centre.
The GEI and FIA values of compound 10 are lower than that
The Lewis acid B(C6H3F2)3 shows no interaction with 1, con-
seen for 11, consistent with the presence of the electron-with- sistent with the generation of an FLP. Subjecting this to 4 atm
drawing groups on 11. Interestingly, in comparisons to other of HD gas at 80 °C resulted in isotopic scrambling, generating
systems, the GEI of 10 is lower than that of BPh3, although the a mixture of H2, HD, and D2 as evidenced by 1H NMR spec-
FIA of 10 is computed to be slightly higher than that of BPh3. troscopy. Despite this evidence of H2 activation, addition of
Likewise, both Gutmann Beckett and FIA of 11 suggest a 10 equivalents of N-t-butylbenzylimine did not lead to
higher Lewis acidity than B(C6H3F2)3, yet 11 exhibits a lower hydrogenation.
GEI value (Table 1). These discrepancies among the measured
These data infer that 10 lacks the threshold combination of
and computed Lewis acidities appear to arise from variations Lewis acidity and basicity to activate H2. On the other hand, 11
in the steric environments about the boron centers in the di- and 1/B(C6H3F2)3 surpass the apparent threshold and effect H2
and triaryl boron derivatives. This points to the need for activation. In the case of 11, it lacks the steric demands about
careful scrutiny of such comparisons and to the need for the boron to preclude classical Lewis acid–base bond formation
use of several methods to provide a clearer picture of Lewis with imine substrates that impedes hydrogenation. In contrast,
acidity.
the basicity of the amine in 1 precludes protonation of the
imine thus prevents hydrogenation.
Activation of HD
Compound 10 was exposed to 4 atm of HD. Even at 70 °C,
no evidence of HD scrambling was observed by NMR
Conclusions
spectroscopy.
Similarly,
combination
of
10
and
Collectively, the present results provide access to new chiral
intramolecular FLP systems. While one of these systems acti-
vates H2, these species proved to be ineffective hydrogenation
catalysts. This work thus illustrates the need for careful selec-
tion of the basicity and Lewis acidity combination as well as
the need for a balancing of steric environment about these
centers. Clearly, donor–acceptor interactions are to be avoided
but moreover, the base and acid sites must be sufficiently reac-
tive to effect H2 activation and yet allow for facile hydride and
proton delivery. While computational methods can provide
some guidance in predicting relative Lewis acidity, the method
and its limitations should be judiciously considered. We are
continuing to develop new FLP systems targeting intra-
molecular species that will provide active catalysts for asym-
metric reductions.
N-phenylbenzylimine under H2 showed no evidence of imine
reduction. In sharp contrast, exposure of 11 to 4 atm of HD at
room temperature leads to the formation of the isotopomeric
mixtures of H2, HD, and D2 as evidenced by 1H NMR spec-
troscopy. Despite this demonstration of the reversible acti-
vation of dihydrogen, no reduction of N-t-butylbenzylimine or
Experimental section
General considerations
Fig. 6 Surface contour plot (isovalue 0.02) of the HOMO and LUMO
of 11.
All manipulations were carried out under dry, O2-free N2 using
an MBraun glovebox and a Schlenk vacuum-line. n-Pentane
and dichloromethane were collected from a Grubbs-type
column system manufactured by Innovative Technology and
into thick-walled glass Schlenk bombs with Young-type Teflon
valve stopcocks. Chloroform-d was obtained from Cambridge
Isotope Laboratories, dried over CaH2, and vacuum-transferred
into Young bombs. Toluene-d8 and benzene-d6 were obtained
from Sigma-Aldrich, dried over Na/benzophenone, and
vacuum-transferred into Young bombs. All solvents were
degassed after purification and stored over 4 Å molecular
sieves. B(C6F5)3 was purchased from Boulder Scientific and
Table 1 Experimental and computational measures of Lewis acidity
Compound
Gutmann–Beckett (Δδ)
GEI (eV)
FIA (kJ mol−1
)
10
BPh3
B(C6H3F2)3
11
B(C6F5)3
0.18a
21.1
24.6
27.8
30.0
1.00
2.04
2.56
3.45
3.78
350.1
328.3
362.3
441.4
452.6
All values were obtained from experiments performed in C6D6 excepta
CDCl3. All computations were calculated in the gas phase.
136 | Dalton Trans., 2019, 48, 133–141
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used without further purification for the synthesis of bis (per- showed very little remaining starting material (3 : 1 ethyl
fluorophenyl)borane.31 N-t-Butylbenzylimine was purchased acetate : heptane, starting material Rf = 0.9, product Rf = 0.55).
from Sigma-Aldrich and dried and stored over 4 Å molecular The crude was then filtered on a silica pad, with an eluent
sieves. Hydrogen gas (Grade 5.0) was obtained from Linde and solution 3 : 1 ethyl acetate : heptane. Used as a crude in the
1
purified through a Matheson Nanochem WeldAssure™ gas next step. Oil. H NMR (CDCl3, 500 MHz) δ: 6.75 (dd, J = 9.4,
purifier column prior to use. Deuterium hydride (extent of lab- 7.0 Hz, 1H), 3.60–3.73 (m, 2H), 3.11 (dd, J = 7.8, 3.9 Hz, 1H),
elling: 96 mol% HD, 98 atom% D) was purchased from Sigma 2.97 (dd, J = 8.1, 4.4 Hz, 1H), 2.72–2.88 (m, 3H), 2.66 (br. dd,
Aldrich. 1·HCl was received from Pfizer and used without J = 10.1, 1.6 Hz, 1H), 2.41–2.52 (m, 3H), 2.13 (s, 1H), 1.59 (d,
further purification. (E)-N-Phenylbenzylimine,32 and tris (2,6- J = 10.0 Hz, 1H), 0.82 ppm (dd, J = 6.6, 1.2 Hz, 6H). 13C NMR
difluorophenyl)borane33 were prepared according to literature (CDCl3, 126 MHz) δ: 149.1 (dd, J = 244, 14.3 Hz), 148.0
methods.
(dd, J = 243.2, 13.5 Hz), 141.4, 121.6 (d, J = 13.5 Hz), 108.9
NMR spectra were recorded on a Bruker Avance 400 MHz (d, J = 18.5 Hz), 61.9, 53.9, 51.9, 51.0, 44.4, 41.3, 39.1 (d, J =
spectrometer or a Varian Mercury Plus 400 MHz spectrometer 1.7 Hz), 30.5, 18.4, 18.2 ppm. 19F NMR (CDCl3, 376 MHz)
at 25 °C. Chemical shifts are given relative to SiMe4 and refer- δ: −141.74 (dd, J = 20.4, 9.5 Hz, 1F), −146.94 ppm (dd, J = 19.1,
enced to the residual solvent signal (1H, 13C) or relative to an 6.8 Hz, 1F). GC-MS (EI, 70 eV) m/z: 266 (100%), 235, 191, 177,
external standard (11B: 15% (Et2O)BF3, 31P: 85% H3PO4, 19F: 164, 86.
CFCl3). Chemical shifts are reported in ppm and coupling con-
Synthesis of C6HF2(C5H8NiPr)(CH2CH2OSO2Me) 3. To a stir-
stants as scalar values in Hz. Mass spectrometry was carried ring solution of 2 (1540 mg, 5.474 mmol) in dichloromethane
out using an AB/Sciex QStar mass spectrometer with an ESI (25 mL), triethylamine (1990 mg, 19.7 mmol, 2.69 mL) was
source or on a Hewlett-Packard GC/MS 6890 N that works with added. Then, a solution of methanesulfonyl chloride (60.1 mg,
the EI technique (70 eV). Elemental analyses (C, H, N) were 0.5250 mmol, 0.0406 mL) in dichloromethane (1 mL) was
performed in-house with a PerkinElmer 2400 Series II CHNS dropped into the reaction mixture. Reaction was monitored by
Analyzer.
TLC (100% ethyl acetate, starting material Rf = 0.52, product
Synthesis of C6H2F2(C5H8NiPr) 1. 30 mg of 1·HCl (0.1 mmol, Rf = 0.84). Once the reaction was finished, water was poured
1 eq.) and 18 mg of Na2CO3 (0.17 mmol, 1.7 eq.) were added to into the reaction flask, the 2 phases were separated, and the
1 mL of water. Diethyl ether was added, extracted and dried organic layer was washed with water and a saturated solution
with Na2SO4. The organic extract was then filtered through Celite of sodium bicarbonate. At the end, all the organic phases were
and dried to a clear orange oil. Yield: 18 mg, 76%; 1H NMR combined and dried. The product was purified on isolera
3
(CDCl3, 400 MHz, 298 K): 6.91 (t, JHF = 9 Hz, 2H, FCCH), 3.03 biotage with a ramp 0–50% of ethyl acetate in heptane. Yield
3
2
(d, JHH = 4 Hz, 2H, NCH2CH), 2.70 (d, JHH = 10 Hz, 2H, 65% over 2 steps. 1H NMR (CDCl3, 500 MHz) δ: 6.77 (t, J =
3
2
NCHeq), 2.55 (septet, JHH = 7 Hz, 1H, iPr-CH), 2.54 (d, JHH
10 Hz, 2H, NCHax), 2.23 (dt, JHH = 10 Hz, JHH = 5 Hz, 1H, 1H), 2.99–3.08 (m, 2H), 2.97 (br. s., 1H), 2.73 (s, 3H), 2.69 (d,
=
8.2 Hz, 1H), 4.25–4.33 (m, 2H), 3.35 (br. s., 1H), 3.13 (br. s.,
2
3
2
NCH2CHCHeq) 1.65 (d, JHH = 10 Hz, 1H, NCH2CHCHax), 0.87 J = 9.8 Hz, 1H), 2.62 (d, J = 8.8 Hz, 1H), 2.43–2.54 (m, 2H),
3
(d, JHH = 7 Hz, 6H, CH3); 13C{H} NMR (CDCl3, 125 MHz, 2.09–2.16 (m, 1H), 1.60 (d, J = 10.5 Hz, 1H), 0.74–0.85 ppm (m,
298 K): 149.0 (dd, JCF = 149 Hz, JCF = 15 Hz, CF), 142.5 (t, 6H). 13C NMR (CDCl3, 126 MHz) δ: 148.7 (dd, J = 244.9,
1
2
3JCF = 5 Hz, p-C6F2H2), 110.7 (dd, JCF = 12 Hz, JCF = 7 Hz, 13.5 Hz), 147.6 (dd, J = 242.3, 14.3 Hz), 142.3, 141.9, 118.9 (d,
C2H2C4F2), 53.6 (iPr-CH), 51.6 (NCH2), 44.6 (NCH2CHCH2), J = 13.5 Hz), 109.4 (d, J = 17.7 Hz), 68.9, 53.2, 51.1, 50.7, 44.3,
41.2 (NCH2CH), 18.4 (CH3); 19F NMR (CDCl3, 376 MHz, 298 K): 41.3, 39.1, 36.7 (d, J = 2.5 Hz), 26.7, 18.4, 17.5 ppm. 19F NMR
2
3
−142.2 (t, JHF = 9 Hz); MS (ESI) m/z: 238 [M + H]+; HR-MS (CDCl3, 376 MHz) δ: −141.23 (dd, J = 19.1, 9.5 Hz, 1F),
3
(ESI): C14N17F2N [M + H]+ m/z (calc.) 238.1402, m/z (obs.) −147.21 ppm (dd, J = 19.1, 6.8 Hz, 1F). HR-MS Calcd for
238.1402.
[C17H23F2NO3S + H]+: 360.1439. Found: 360.1431 (100%).
Synthesis of C6HF2(C5H8NiPr)(CH2CH2OH) 2. A stirring
Synthesis of C6HF2(C5H8NiPr)(CHvCH2) 4. To a stirring
solution of 1 (4003 mg, 16.87 mmol) in THF (42 mL) was solution of 3 (35 mg, 0.097 mmol) in THF (1.0 mL), potassium
cooled to −78 °C and then treated dropwise with nBuLi tert-butoxide (37 mg, 0.33 mmol) was added at room tempera-
(1190 mg, 18.6 mmol, 6.87 mL, 2.7 M). The solution did not ture. The reaction mixture was stirred for 1 h, then it was
appear to change. After 1 h at −78 °C, oxirane (892 mg, checked by TLC (eluent ethyl acetate : hexane 1 : 1) and it
20.2 mmol, 8.10 mL, 2.5 M) was added followed by boron tri- showed complete consumption of the starting material (Rf =
fluoride ethyl ether complex (5510 mg, 38.8 mmol, 4.79 mL). 0.67) and the presence of a very active UV and permanganate
During the addition of the boron trifluoride, the reaction color spot with Rf = 0.85. To the reaction was added a 1 N aqueous
started to lighten. After 3 hours and a half, the reaction was solution of HCl and the water phase was washed with ethyl
allowed to warm to room temperature, then it was quenched acetate. Then the water phase was basified to pH 10 and back
with a saturated aqueous solution of sodium carbonate and extracted with dichloromethane. The dichloromethane phase
stirred for 20 minutes. The two phases were separated, and the was then washed with brine and dried, yielding the pure
aqueous phase was extracted with ethyl acetate (30 mL), then product. Yield 67%. Yellow oil. 1H NMR (CDCl3, 500 MHz)
an acid–base wash was performed and the organic phase was δ: 6.69 (dd, J = 9.3, 7.1 Hz, 1H), 6.56 (dd, J = 18.1, 11.7 Hz, 1H),
dried over sodium sulfate, filtered and stripped to an oil. TLC 5.75 (d, J = 17.9 Hz, 1H), 5.38 (dt, J = 11.7, 1.6 Hz, 1H), 3.15 (d,
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J = 3.9 Hz, 1H), 2.89 (t, J = 4.0 Hz, 1H), 2.62–2.66 (m, 1H), 2.56–2.64 (m, 1H), 2.07 ppm (d, J = 10.8 Hz, 1H). 13C NMR
2.55–2.59 (m, 1H), 2.40–2.46 (m, 3H), 2.05–2.11 (m, 1H), 1.53 (CDCl3, 126 MHz) δ: 150.6, 149.4 (dd, J = 249.9, 15.1 Hz), 148.0
(d, J = 10.3 Hz, 1H), 0.75 ppm (d, J = 6.6 Hz, 6H). 13C NMR (dd, J = 243.2, 15.1 Hz), 146.0 (d, J = 3.4 Hz), 141.8 (d, J = 3.4
(CDCl3, 101 MHz) δ: 149.3 (dd, J = 243.6, 13.9 Hz), 147.8 (dd, Hz), 129.3, 118.0, 112.9, 111.6 (d, J = 18.5 Hz), 79.8 (d, J = 22.5
J = 247.2, 13.9 Hz), 141.6, 140.3, 128.5 (d, J = 10.3 Hz), 120.4, Hz), 51.5, 49.5, 44.5, 42.4, 41.0 ppm. 19F NMR (CDCl3,
109.7, 51.3, 50.5, 43.9, 41.1, 39.3, 29.7, 18.2, 18.1 ppm. 376 MHz) δ: −120.41 (dd, J = 21.8, 6.8 Hz, 1F), −135.30 ppm
19F NMR (CDCl3, 376 MHz) δ: −141.84 (br. s., 1F), (dd, J = 21.8, 9.5 Hz, 1F). GC-MS (EI, 70 eV) m/z: 397 (molecular
−145.85 ppm (br. s., 1F). GC-MS (EI, 70 eV) m/z: 263 (molecular ion), 292, 276, 268, 164, 120 (100%), 104, 91, 77, 65, 51. LC-MS
ion), 248 (100%), 204, 177, 164, 151, 115, 86, 56. HR-MS Calcd (ESI+): 398 [M + H]+.
for [C16H19F2N + H]+: 264.1558. Found: 264.1548 (100%).
Synthesis of C6HF2(C5H8NPh)(CHvCH2) 9. To a vial con-
Synthesis of C6H2F2(C5H8NPh) 7. To a dry vial containing taining 8 (768 mg, 1.93 mmol), sodium carbonate (1440 mg,
bromobenzene (173 mg, 1.10 mmol) and sodium tert-butoxide 11.6 mmol) and tetrakis(triphenylphosphine) palladium (0)
(99.1 mg, 1.00 mmol), a solution of 6 (201 mg, 1.00 mmol) (55.3 mg, 0.0478 mmol) were added and the vial was flushed
in toluene (6.0 mL) was added. The resulting solution with nitrogen flow for 15 min. Then, previously degassed DMF
was degassed with 3 vacuum-nitrogen cycles and then bis(di- (20 mL) and water (4 mL) were added to the vial and the reac-
benzylideneacetone)palladium(0) (5.75 mg, 0.0100 mmol) tion mixture was treated with 3 vacuum-nitrogen flow cycles.
and 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)-ferrocene At the end, 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxoborolane
(14.2 mg, 0.0200 mmol) were added to the solution. The reac- (1070 mg, 6.77 mmol, 1.29 mL) was added and the reaction
tion mixture was heated to 100 °C for 24 hours. After 24 h the mixture was heated to 80 °C for 1 h. Then, it was cooled down
reaction was finished, so it was cooled down and then the and it was filtered through a pad of Celite, washing with
crude was filtered on a Celite pad to remove the black precipi- diethyl ether. The biphasic system was poured inside a separ-
tate. Then the filtrate was stripped down, and product was pur- ating funnel and the water phase was extracted with ethyl
ified on isolera biotage with a ramp 0–20% of ethyl acetate in acetate for 3 times. Then combined organic layers were
heptane. Yield 96%. Off-white solid. 1H NMR (CDCl3, washed with water and brine, dried over sodium sulfate, fil-
500 MHz) δ: 7.11 (dd, J = 8.8, 7.3 Hz, 2H), 6.94 (t, J = 8.6 Hz, tered and the volatiles evaporated. The product was purified
2H), 6.60–6.66 (m, 3H), 3.53 (ddd, J = 10.8, 2.9, 1.5 Hz, 2H), on isolera biotage with a ramp 0–15% of ethyl acetate in
3.24 (dt, J = 5.0, 2.5 Hz, 2H), 3.08 (dd, J = 10.8, 2.4 Hz, 2H), heptane. Yield 86%, 92% product purity. Yellowish solid. 1H
2.33 (dtt, J = 10.5, 5.2, 1.7 Hz, 1H), 1.84 ppm (d, J = 10.5 Hz, NMR (CDCl3, 500 MHz) δ: 7.04–7.12 (m, 1H), 6.81 (ddd, J = 9.1,
1H). 13C NMR (CDCl3, 126 MHz) δ: 150.6, 149.5 (dd, J = 247.4, 6.8, 2.7 Hz, 1H), 6.56–6.65 (m, 5H), 5.83 (dd, J = 17.9, 4.4 Hz,
15.1 Hz), 141.7 (t, J = 4.2 Hz), 129.1, 117.5, 112.5, 111.3 (dd, J = 1H), 5.46–5.52 (m, 1H), 3.53 (dd, J = 10.8, 1.5 Hz, 1H), 3.50 (dd,
13.5, 5.9 Hz), 51.5, 41.7, 40.3 ppm. 19F NMR (CDCl3, 376 MHz) J = 12.8, 1.8 Hz, 1H), 3.44 (br. s., 1H), 3.18 (br. s., 1H), 3.02
δ: −140.45 ppm (t, J = 8.2 Hz, 2F). LC-MS (ESI+): 272 [M + H]+. (dd, J = 10.6, 2.1 Hz, 2H), 2.23–2.29 (m, 1H), 1.79 ppm (d, J =
GC-MS (EI, 70 eV) m/z: 271 (molecular ion), 170, 151, 120 10.5 Hz, 1H). 13C NMR (CDCl3, 100 MHz) δ: 150.5, 149.8 (dd,
(100%), 91, 86.
J = 245.8, 13.9 Hz), 148.3 (dd, J = 249.4, 13.9 Hz), 141.0 (m),
Synthesis of C6HIF2(C5H8NPh) 8. Compound 7 (485 mg, 139.6 (br, s), 129.1, 128.0 (d, J = 2.9 Hz), 122.0 (d, J = 9.5 Hz),
1.79 mmol) was stirred in THF (10 mL) in a dried 20 mL vial 121.2 (d, J = 10.3 Hz), 117.6, 112.5, 110.0 (d, J = 19.1 Hz), 51.4,
under nitrogen at −78 °C. To this light amber solution, nBuLi 50.3, 41.2, 40.4, 38.6 ppm. 19F NMR (CDCl3, 376 MHz)
(172 mg, 2.68 mmol, 0.993 mL, 2.7 M) was added dropwise δ: −140.09 (dd, J = 18.4, 8.9 Hz, 1F), −144.20 ppm (dd, J = 17.7,
over 5 minutes. The solution was stirred 1.5 h at −78 °C, then 6.8 Hz, 1F). LC-MS (ESI+): 298 [M + H]+ GC-MS (EI, 70 eV) m/z:
iodine (681 mg, 2.68 mmol) was added in one lot from a vial. 297 (molecular ion), 177, 151, 120 (100%), 91, 77. HR-MS
The mixture was stirred in the cold bath, iodine was consumed Calcd for [C19H17F2N + H]+: 298.1402 (100%). Found: 298.139
in 1 hour, but the reaction was stirred for 3 hours and then (100%).
removed from the bath and allowed to warm to approximately
0 °C, then it was quenched with a saturated aqueous solution (0.0849 mmol,
Synthesis of C6HF2(C5H8NPh)(CH2CH2BBN) 10. 25 mg of 9
eq.) and 10.5 mg of 9-BBN dimer
1
of sodium bicarbonate and allowed to stir to achieve ambient (0.0425 mmol, 0.5 eq.) were dissolved in 4 mL DCM. The col-
temperature. The reaction was then poured with ethyl acetate ourless solution formed was stirred overnight. The solution
and saturated aqueous sodium carbonate solution into a sep- was then concentrated, layered with pentane and stored in the
arating funnel. The two layers were separated and the aqueous freezer. Colourless crystals were formed, and the excess solvent
was back extracted (2 × 20 mL) with ethyl acetate. Combined was pipetted out. The solids were washed with cold pentane
organic layers were then washed with brine, dried over anhy- and dried. Single crystals suitable for X-ray crystallography were
drous sodium sulfate, filtered and dried under vacuum. Yield formed by slow diffusion of pentane into a cold saturated solu-
98%. White solid. TLC Rf = 0.30 with eluent mixture 1 : 9 tion of 12. Yield: 24.4 mg, 69%. 1H NMR (CDCl3, 400 MHz,
toluene : heptane. 1H NMR (CDCl3, 500 MHz) δ: 7.43 (t, J = 298 K): 7.21–7.15 (m, 2H, m-C6H5), 6.85 (dd, 3JHF = 9 Hz, 3JHF
=
7.9 Hz, 2H), 7.14 (dd, J = 8.4, 7.2 Hz, 1H), 6.98 (t, J = 7.2 Hz, 7 Hz, 1H, FCCH), 6.71–6.65 (m, 3H, m-C6H5, p-C6H5), 3.61 (dt,
4
1H), 6.94 (d, J = 8.3 Hz, 2H), 3.92 (d, J = 10.8 Hz, 1H), 3.76 (d, 3JHH = 10 Hz, JHH = 5 Hz, 2H, NCH2eq), 3.44 (s, br, 1H,
2
J = 10.5 Hz, 1H), 3.59 (d, J = 7.8 Hz, 2H), 3.20–3.30 (m, 2H), NCH2CH), 3.29 (s, br, 1H, NCH2CH), 3.14 (dt, JHH = 11 Hz,
138 | Dalton Trans., 2019, 48, 133–141
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Paper
2
3
4JHH = 3 Hz, 2H, NCH2ax), 2.95–2.75 (m, 2H, BCH2), 2.42–2.32 (m, 2H), 3.00 (dd, JHH = 11 Hz, JHH = 2.6 Hz, 1H, NCHeq),
2
2
3
(m, 1H, NCH2CHCHax), 1.90 (d, JHH = 10 Hz, NCH2CHCHeq), 2.50 (td, JHH = 13.0 Hz, JHH = 4 Hz, 1H, CH2Ph), 2.38 (td,
1.94–1.83 (m, 7H, 9-BBN), 1.85–1.75 (m, 2H, BCH2CH2), 2JHH = 13.0 Hz, 3JHH = 4 Hz, 1H, CH2Ph), 2.30 (dt, 2JHH = 10 Hz,
1.75–1.64 (m, 5H, 9-BBN), 1.28–1.23 (m, 2H, 9-BBN); 13C NMR 3JHH = 5 Hz, 1H, NCH2CHCHeq), 1.85 (d, JHH = Hz, 1H,
2
1
(CDCl3, 125 MHz, 298 K): 150.7 (BCH2CH2C), 140.0 (d, JCF
=
NCH2CHCHax), 1.70–1.50 (m, 2H, CH2CH2Ph); 13C NMR
2
153 Hz, FC) 129.2 (m-C6H5), 117.6 (p-C6H5), 112.6 (m-C6H5), (CDCl3, 125 MHz, 298 K): 150.8 (d, JCF = 14 Hz, CCF), 148.4
108.5 (d, JCF = 19 Hz, FCCH), 51.7 (NCH2), 51.0 (NCH2), 41.6 (dd, JCF = 249 Hz, JCF = 14 Hz, CF), 140.6 (CFCC), 140.0
(NCH2CHCH2), 40.7 (NCH2CH), 38.5 (NCH2CH), 33.4 (9-BBN), (CFCHC), 137.3 (dd, JCF = 254 Hz, JCF = 20 Hz, FCCF), 134.3
2
1
2
1
2
2
31.4 (s, br, BCH2CH2), 29.0 (9-BBN), 23.4 (9-BBN), 21.7 (BCH2), (d, JCP = 10 Hz, PPh3), 131.5 (PPh3), 129.2 (m-C6H5), 128.7 (d,
quaternary carbon in phenyl rings were not observed; 11B NMR 3JCP = 10 Hz, PPh3), 117.4 (p-C6H5), 112.4 (o-C6H5), 108.3 (d,
(CDCl3, 128 MHz, 298 K): 88.0 (s, br); 19F NMR (CDCl3, 2JCF
=
19 Hz, CFCH), 51.7 (NCH2), 50.7 (NCH2), 41.6
376 MHz, 298 K): −140.6 (dd, 3JFF = 19 Hz, 3JHF = 10 Hz, FCCF), (NCH2CHC), 40.7 (NCH2CH) 38.3 (NCH2CH), (25.3 (s, br,
−146.9 (dd, 3JFF = 19 Hz, 3JHF = 7 Hz, FCCH).
BCH2), 24.4 (BCH2CH2). C–F carbons in C6F5 and quaternary
Synthesis of C6HF2(C5H8NPh)(CH2CH2B(C6F5)2) 11. 10 mg carbon in C6H5 ring were not observed. 11B NMR (CDCl3,
(0.0336 mmol, 1 eq.) and 11.6 mg of HB(C6F5)2 128 MHz, 298 K): −6.2 (s, br); 19F NMR (CDCl3, 376 MHz, 298 K):
of
9
3
3
3
(0.0336 mmol, 1 eq.) were dissolved in 1 mL benzene. A clear −127.1 (d, JFF = 24 Hz, Fo), −141.0 (dd, JFF = 19 Hz, JHF = 10
yellow solution was formed and dried to a orangish-yellow oil. Hz, FCCH), −146.93 (d, 3JFF = 17 Hz, FCCFCH) −157.2 (t, JFF
=
3
The oil is freshly generated and used immediately in sub- 21 Hz, Fp), −163.5 (td, JFF = 23 Hz, JFF = 8 Hz, Fm); 31P NMR
3
3
sequent experiments.
(CDCl3, 162 MHz, 298 K): 10.1 (s, br); MS (DART) m/z: 263.1
Yield: 18 mg, 83%; 1H NMR (C6D6, 400 MHz, 298 K): [PPh3 + H]+, 644.1 [M − PPh3 + H]+; HRMS (ESI): C18H16P
3
7.20–7.16 (m, 2H, m-C6H5), 6.77 (t, JHH = 7 Hz, 1H, p-C6H5), [PPh3
+
H]+ m/z (calc.) 263.0990, m/z (obs.) 263.0992,
3
3
6.65 (d, JHH = 8 Hz, 2H, o-C6H5), 6.55 (t, JHF = 8, 1H, FCCH), C31H18BF12N [M − PPh3 + H]+ m/z (calc.) 644.1411, m/z (obs.)
2
2
3.46 (d, JHH = 11 Hz, 1H, NCHeq), 3.25 (d, JHH = 11 Hz, 1H, 644.1414. Anal. Calcd for C49H33BF12NP: C 64.99%, H 3.67%,
3
2
NCHax), 3.01 (d, JHH = 4 Hz, 1H, NCH2CH), 2.82 (d, JHH = 11 N 1.55%. Found C 62.82%, H 4.15%, N 1.47%
3
Hz, 1H, NCHax), 2.76–2.71 (m, 1H, NCHeq), 2.69 (d, JHH = 10
Hz, 2H, BCH2CH2), 2.64 (d, JHH = 6 Hz, 1H, NCH2CH), common to the HD experiments conducted. In the glovebox,
2.29–2.08 (m, 2H, BCH2), 2.00 (dt, JHH = 11 Hz, JHH = 5 Hz, the necessary reagents were added to 1 mL of solvent. The
HD scrambling experiments. The following procedure is
3
2
3
2
1H, NCH2CHCHeq), 1.43 (d, JHH = 11 Hz, 1H, NCH2CHCHax); reaction mixture was then transferred into an oven-dried
13C NMR (C6D6, 125 MHz, 298 K): 151.1 (CCF), 150.0 (dd, Teflon screw cap J-young tube. The reaction tube was degassed
2
1
1JCF = 246 Hz, JCF = 14 Hz, FCCH), 149.7 (dd, JCF = 240 Hz, by 3 cycles of freeze–pump–thaw and then filled with HD
2JCF = 13 Hz, FCCFCH), 147.5 (d, JCF = 249 Hz, o-C6F5), 143.8 (4 atm) at −196 °C. The reaction was then heated to the
1
(d, 1JCF = 262 Hz, p-C6F5), 141.6 (CHCC), 139.6 (CHC), 137.7 (d, respectively temperature and monitored regularly by H NMR
1
1JCF = 259 Hz, m-C6F5), 129.3 (m-C6H5), 118.4 (p-C6H5), 113.0 spectroscopy.
(o-C6H5), 109.6 (2JCF = 18 Hz, FCCH), 51.7 (NCH2), 51.0 (NCH2),
Hydrogenation experiments. In the glovebox, the necessary
41.7 (NCH2CHCH2), 40.7 (NCH2CH), 38.6 (NCH2CH), 31.6 reagents were added to 1 mL of solvent. The reaction mixture
(BCH2), 22.1 (BCH2CH2). Quaternary carbon in C6H5 and C6F5 was then transferred into an oven-dried Teflon screw cap
ring were not observed. 11B NMR (C6D6, 128 MHz, 298 K): 72.5 J-young tube. The reaction tube was degassed by 3 cycles of
3
(s, br); 19F NMR (C6D6, 376 MHz, 298 K): −130.1 (d, JFF = 18 freeze–pump–thaw and then filled with H2 (4 atm) at −196 °C.
3
3
Hz, Fo), −139.9 (dd, JFF = 16 Hz, JHF = 9 Hz, FCCH), −145.7 The reaction was then heated to the respectively temperature
3
3
(d, JFF = 16 Hz, FCCFCH), −146.4 (t, JFF = 21 Hz, Fp), −160.7 and monitored regularly by 1H NMR spectroscopy.
(td, 3JFF = 14 Hz, 3JFF = 7 Hz, Fm) MS (DART) m/z: 644.1 [M + H]+
HRMS (ESI): [M + H]+ m/z (calc.) 644.1411, m/z (obs.) 644.1409.
Computational details. Electronic structure calculations,
including geometry optimizations and frequency calculations,
Synthesis of C6HF2(C5H8NPh)(CH2CH2B(C6F5)2)(PPh3) 12. were performed using Gaussian 16.34 Geometry optimizations
30 mg of 11 (0.1 mmol, 1 eq.) and 35.8 mg of HB(C6F5)2 and frequency calculations were performed using the BP8635,36
(0.1 mmol, 1 eq.) were dissolved in 1 mL benzene. The clear functional and the def2-TZVP basis set.34,35,37,38 X-ray coordi-
yellow solution formed was stirred for 5 min and was added to nates were used as the starting geometries. Frequency calcu-
26.2 mg of PPh3 (0.1 mmol, 1 eq.). The solution was then lations on the optimized structures showed the absence of
dried, re-dissolved in DCM and stored in freezer with slow imaginary frequencies confirming that minima on the poten-
diffusion of pentane. Colourless crystals were formed, and the tial energy hypersurfaces were located. Energies for fluoride
excess solvent was pipetted out. The crystals were washed with ion affinity (FIA) were calculated using the MP2 22,39,40 func-
pentane and dried. Yield: 31 mg, 34%; 1H NMR (CDCl3, tional and the def2-TZVPP basis set, as previously described
400 MHz, 298 K): 7.56–7.47 (m, 3H), 7.48–7.25 (m, 12H), using the experimental FIA of carbonyl difluoride.24 The
7.19–7.12 (m, 2H, m-C6H5), 6.80 (dd, JHF = 9, JHF = 7 Hz, 1H), global electrophilicity index (GEI)27,28 was calculated using the
3
4
3
3
6.71 (t, JHH = 7 Hz, 1H, p-C6H5), 6.63 (d, JHH = 8 Hz, 2H, B3LYP25,26,41,42 functional and the def2-TZVP basis set, as pre-
2
2
o-C6H5), 3.61 (d, JHH = 10 Hz, 1H, NCHax), 3.42 (d, JHH = 11 viously described. Natural bond orbital and natural population
Hz, 1H, NCHax), 3.26 (d, JHH = 5 Hz, 1H, NCH2CH), 3.17–3.07 analyses were performed using the M062X basis set29 and
3
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def2-TZVPP functional using NBO 6.0.30 The Cartesian coordi- 14 S. L. Li, G. Li, W. Meng and H. F. Du, J. Am. Chem. Soc.,
nates of the optimized structures are collected in Tables S4–9.† 2016, 138, 12956–12962.
This work was made possible by the facilities of the Shared 15 S. Li, W. Meng and H. F. Du, Org. Lett., 2017, 19, 2604–
Hierarchical Academic Research Computing Network
(SHARCNET: http://www.sharcnet.ca) and Compute Canada.
X-ray diffraction studies. Single crystals were coated with
paratone oil, mounted on a cryoloop, and frozen under a
2606.
16 X.-S. Tu, N.-N. Zeng, R.-Y. Li, Y.-Q. Zhao, D.-Z. Xie, Q. Peng
and X.-C. Wang, Angew. Chem., Int. Ed., 2018, 57, 15096–
15100.
stream of cold nitrogen. Data were collected on a Bruker Apex2 17 Z. M. Heiden and D. W. Stephan, Chem. Commun., 2011,
X-ray diffractometer at 150(2) K for all crystals using graphite 47, 5729–5731.
monochromated Mo-Kα radiation (0.71073 Å). Data were col- 18 J. Lam, B. A. R. Gunther, J. M. Farrell, P. Eisenberger,
lected using Bruker APEX-2 software and processed using
B. P. Bestvater, P. D. Newman, R. L. Melen, C. M. Crudden
SHELX and an absorption correction applied using multi-scan
and D. W. Stephan, Dalton Trans., 2016, 45, 15303–15316.
within the APEX-2 program. All structures were solved and 19 J. F. Cryan, F. Gasparini, G. Van Heeke and A. Markou,
refined by direct methods within the SHELXTL package.
Drug Discovery Today, 2003, 8, 1025–1034.
20 J. W. Coe, P. R. Brooks, M. C. Wirtz, C. G. Bashore,
K. E. Bianco, M. G. Vetelino, E. P. Arnold, L. A. Lebel,
C. B. Fox, F. D. Tingley, D. W. Schulz, T. I. Davis,
S. B. Sands, R. S. Mansbach, H. Rollema and B. T. O’Neill,
Bioorg. Med. Chem. Lett., 2005, 15, 4889–4897.
Conflicts of interest
There are no conflicts to declare.
21 N. Kataoka, Q. Shelby, J. P. Stambuli and J. F. Hartwig,
J. Org. Chem., 2002, 67, 5553–5566.
22 M. J. Frisch, M. Head-Gordon and J. A. Pople, Chem. Phys.
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Acknowledgements
D. W. S. gratefully acknowledges the financial support from 23 S. A. Sæbø and J. Almlöf, Chem. Phys. Lett., 1989, 154, 83–89.
NSERC Canada and the award of Canada Research 24 K. O. Christe, D. A. Dixon, D. McLemore, W. W. Wilson,
Chair. D. W. S. is also grateful for the award of an Einstein
Fellowship at TU Berlin.
J. A. Sheehy and J. A. Boatz, J. Fluorine Chem., 2000, 101,
151–153.
25 A. D. Becke, J. Chem. Phys., 1993, 98, 5648.
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28 A. R. Jupp, T. C. Johnstone and D. W. Stephan, Inorg.
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