9-Borabicyclo[3.3.l]nonane-induced Friedel-Crafts benzylation of arenes with benzyl fluorides

Article abstract of DOI:10.1039/c9ob00912d

Friedel-Crafts benzylation of arenes with benzyl fluorides using 9-borabicyclo[3.3.l]nonane (9-BBN) as a mediator has been developed. This provides a simple and cheap route to the activation of C-F bonds to synthesize 1,1-diarylmethanes in good to excellent yields (up to 98%) under mild conditions. Functional group tolerance and the mechanism are considered.

Full text of DOI:10.1039/c9ob00912d

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9-Borabicyclo[3.3.l]nonane-induced Friedel–Crafts benzylation of
arenes with benzyl fluorides
Jing Guo,a Karlee L. Bamforda and Douglas W. Stephan*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Friedel–Crafts benzylation of arenes with benzyl fluorides using 9- boryldefluorination, without
borabicyclo[3.3.l]nonane (9-BBN) as mediator has been demonstrated that the more highly electrophilic
a
catalyst.28 These results
a
developed. This provides a simple and cheap route to the activation hydridoboranes were more reactive towards fluoroalkanes.
of C-F bonds to synthesize 1,1-diarylmethanes in good to excellent Despite these advances, the development of Friedel–Crafts
yield (up to 98%) under mild conditions. Functional group tolerance coupling reactions of arenes and benzyl fluorides via a practical
and the mechanism are considered.
and simple method remains a meaningful pursuit.
Carbon-fluorine bonds are among the strongest single bonds
involving carbon and their selective activation and
transformation under mild conditions remains a challenge.1-13
Due to potential applications in synthetic organic chemistry and
the prevalence of fluorinated environmental contaminants,14-18
C-F bond activation has attracted the attention of organic,
inorganic and organometallic chemists alike.19-20 There have
been a number of synthetic strategies developed for the use of
benzyl fluorides in Friedel-Crafts benzylation (Scheme 1). In
2013, Kemnitz and co-workers reported heterogeneous C-F
bond activation of benzyl fluoride and fluoromethane
substrates using nanoscopic aluminium chlorofluoride (ACF) in
the presence of Et3SiH.21 In 2014, Paquin et al. detailed the in
situ generation of HF acid for benzyl fluoride activation
promoted by HFIP (hexafluoro-2-propanol).22 The Paquin group
subsequently described an improved methodology using HFIP
and the Brønsted acid trifluoroacetic acid (TFA) as an initiator
for HF-promoted Friedel-Crafts benzylation from benzylic
fluorides.23-25 In 2016, our group described the coupling of
benzyl fluorides with arenes and allylic silanes, catalysed by the
a) Hydrogen fluoride
HF formation in situ
or TFA
F
R1
R2
R2
R1
+
DCM/HFIP
b) Electrophilic Phosphonium Cation
[(C6F5)3PF][B(C6F5)4]
F
R2
R1
R1
R2
+
+
Et3SiH
DCM
- H2, Et3SiF
c) Piers’ Borane
F
HB(C6F5)2
DCM
R2
R1
R1
R2
+
- FB(C6F5)2
d) This work: convenient and commercially available 9-BBN
F
9-BBN
R2
R1
R1
R2
+
DCM
- 9-F-BBN
Scheme 1 Recent methods for C-F bond activation of benzyl fluorides in
Friedel–Crafts reaction (TFA = trifluoroacetic acid, HFIP = hexafluoro-2-
propanol).
In our previous work, we found that the cheap and
commercially available hydridoborane 9-BBN can activate the
C-F bonds of fluoroalkanes and a benzyl fluoride substrate. This
borane represents an attractive alternative to more exotic
boranes (e.g. HB(C6F5)2), highly reactive Lewis acid catalysts
(ACF, EPCs), or highly corrosive Brønsted acids (HF) for C-F bond
activation. Herein, we describe the use of the readily available
9-BBN in Friedel–Crafts benzylation of arenes with benzyl
fluorides. These reactions provide facile access to 1,1-
electrophilic
fluorophosphonium
catalyst
(EPC)
[(C6F5)3PF][B(C6F5)4], under mild conditions and with short
reaction times.26-27 In 2018, our group further reported that
combination of hydridoboranes (e.g. catecholborane,
pinacolborane, Piers’ borane) and fluoroalkanes effected
hydrodefluorination,
dehydrofluorination,
or
a. Department of Chemistry, University of Toronto, 80 St. George Street, Toronto,
Ontario M5S 3H6, Canada, E-mail: dstephan@chem.utoronto.ca
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
diarylmethanes, offering
a
potential strategy to simple
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synthetic building blocks reminiscent of those found in natural HB(C6F5)2 in place of 9-BBN led to complete reacVtiieownAroticfletOhnelisnee
products and medicinal chemistry.29-30
deactivated benzyl fluoride substrates.
DOI: 10.1039/C9OB00912D
The corresponding reactivity of arenes with 4-tert-butyl
benzyl fluoride was also surveyed (Table 2). The Friedel–Crafts
reaction of benzyl fluorides with benzene or electron-rich
arenes (toluene, toluene-d8, anisole, p-xylene, 1,4-
dimethoxybenzene, mesitylene, 1,2,4,5-tetramethylbenzene)
in the presence of 9-BBN dimer (0.5 equiv) proceeded in 10
minutes to 3 hours at room temperature. These reactions
afforded the corresponding diarylmethanes (11−18) in good to
excellent yields (80–98 %). The ratio of regioisomers was
determined by 1H NMR spectroscopic analysis. In the case of the
electron-deficient fluorobenzene, the reaction afforded three
isomers of the products 19 in 80% yield and 17:2:1 ratio for the
para-, ortho- and meta-fluoro-substituted products. The
desired Friedel–Crafts benzylated products were not observed
Table 1 Reactions of benzyl fluorides with C6D6.a
D
D
D
D
D
D
D
D
D
9-BBN (0.5 equiv)
DCM, rt
- 9-F-BBN
F
R1
R1
+
HD
+
D
D
1-10
H
B
B
H
9-BBN
Me
D
D
D
D
D
D
D
D
D
D
D
D
tBu
D
D
D
1
2
3
10 min, 95% yield
12 h, 92% yield
12 h, 91% yield
when
deactivated
electron-deficient
arenes
(1,2-
difluorobenzene, and 1,2-dichlorobenzene) were used. In these
instances, only polymerization of benzyl fluoride was observed.
However, the corresponding Friedel-Crafts reactions with
heterocycles 1-tert-butyl-1H-pyrrole, furan and thiophene
proceeded smoothly, affording the corresponding products 20–
22 in good yields (90–96%).
D
D
Ph
D
Me
D
D
MeO
D
D
D
D
D
D
D
D
D
D
4
5
6
12 h, 86% yield
12 h, 90% yield
12 h, 89% yield
Table 2 Reactions of tert-butylbenzyl fluorides with arenes and heterocycles.a
D
D
D
Br
D
D
D
D
D
F
9-BBN (0.5 equiv)
DCM, rt
- 9-F-BBN
R1
R1
+
+
H2 or HD
D
D
D
F
D
D
Ph
D
D
7
tBu
tBu
11-22
8
9
H
traceb, 96% yieldc
B
B
30 min, 90% yield
24 h, 80% yield
D
H
9-BBN
D
D
D
F3C
D
D
D
D
D
tBu
tBu
Me
tBu
D
, traceb 99% yieldc
10
D
D
11
10 min, 92% yield
13
12
a All reactions were performed with benzyl fluorides (0.05 mmol, 1.0 equiv), excess
C6D6 (0.2 mL) and 9-BBN dimer (0.025 mmol, 6.2 mg) in DCM (0.4 mL) at 25 oC for
the specified reaction time. Isolated yield. b At 50 oC for 2 days. Using HB(C6F5)2
10 min, 96% yield (4.2 : 1)b
10 min, 98% yield (4.2 : 1)b
Me
OMe
c
(0.05 mmol, 17.3 mg) instead of 9-BBN dimer.
tBu
OMe
tBu
tBu
OMe
16
10 min, 86% yieldc
Me
The reactivity of benzyl fluorides with excess C6D6 in DCM
solution in the presence of 0.5 equivalents of 9-BBN dimer was
investigated (Table 1). Various electron-rich benzyl fluorides (R
= 4-tBu, H, 2-Me, 3-Me, 3-MeO, 2-Ph and 4-Ph) reacted to
provide Friedel–Crafts benzylation resulting in the
corresponding diarylmethanes 1−7 in good to excellent yield
(80−95 %) in 10 minutes to 12 hours at room temperature. At
the same time, the bubbling of HD was observed, and 9-F-BBN
was detected by 19F and 11B NMR spectroscopy as one of by-
products (see ESI). The position of the substituents on the
benzyl fluoride appear to have no effect on the yield of this
reaction. Substitution of the benzyl fluoride with a weakly
electron-withdrawing substituent (4-fluoro 8) slowed the
observed reactivity and lead to significantly longer reaction
times. Interestingly, almost no reaction was observed when
more electron-deficient benzyl fluorides (3-bromo 9, 4-
trifluoromethyl 10) were used. Only traces of the anticipated
products were seen and even upon raising the reaction
temperature to >50 °C, the benzyl fluoride starting materials
persisted. In contrast, use of the more electrophilic borane
14
15
10 min, 98% yielda (1.2 : 1)b
30 min, 96% yield
Me
Me
Me
tBu
Me
Me
tBu
Me
tBu
F
Me
17
3 h, 96% yield
19
10 min, 80% yield (17 : 2 : 1)d
18
3 h, 80% yieldc
tBu
N
S
O
tBu
tBu
tBu
20
21
22
1 h, 87% yielde (2:1)f
12 h, 93% yielde
48 h, 96% yielde (2.5:1)f
a
All reactions were performed with 1-(tert-butyl)-4-(fluoromethyl)benzene (0.05
mmol, 1.0 equiv), excess arene (0.2 mL) and 9-BBN dimer (0.025 mmol, 6.2 mg) in
DCM (0.4 mL) at 25 oC for the specified reaction time. Isolated yield. b Ratio of the
c
para: ortho isomers.
1-(tert-Butyl)-4-(fluoromethyl)benzene (0.05 mmol, 1.0
equiv) and arene (1.1 equiv). Ratio of the para: ortho: meta isomers. e 1-(tert-
Butyl)-4-(fluoromethyl)benzene (0.05 mmol, 1.0 equiv) and arene (0.1 mL). f Ratio
of the 2-: 3-isomers.
d
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These facile Friedel-Crafts reactions were shown to be viable tolerant of the presence of triethylsilane, nitrile, ketone, alkyne,
View Article Online
DOI: 10.1039/C9OB00912D
on a gram-scale. To this end, 4-(fluoromethyl)-1,1'-biphenyl tertiary amine, olefin, CF3-species and silylether (Table 3,
(0.93 g, 5.0 mmol) was reacted with p-xylene (10 mL) In the entries 1−12). The yields are further reduced to less than 60% in
presence of 9-BBN dimer (0.62 g, 2.5 mmol), to give the product the presence of secondary amine, phenol, imine, phosphine or
PhC6H4CH2(C6H3Me2) 23 (1.05 g, 77% yield) as a white solid amide (Table 3, entries 13−18). Lewis basic additives such as
(Scheme 2).
aniline, pyridine, pyridine N-oxide, water, phosphine-oxide or
alcohol precluded the benzylation completely (Table 3, entries
19−24), presumably as a result of coordination of such donors
to 9-BBN. The catalyst-free dehydrocoupling of 9-BBN and
protic species, such as amines and alcohols, has been previously
described.33
Me
Me
9-BBN (0.5 equiv)
F
+
+
H2
20 mL DCM, rt
- 9-F-BBN
Ph
Ph
Me
Me
23
The mechanism of these benzylation is thought to be related
to that proposed in our previous studies of C-F bond
hydrodefluorination.28 In that case, computations revealed that
HB(C6F5)2 interacts with the C-F bond to generate a benzyl-
cation hydridofluoroborate anion pair which is quenched by
arene. The arenium cation subsequently releases proton and H2
is generated upon its combination with the hydridofluoroborate
anion. In the present case, similar generation of the benzyl
cation by 9-BBN prompts Friedel–Crafts chemistry and affords
the diarylmethane products with liberation of H2. Support for
this reaction pathway were derived from NMR spectroscopy.
While the evolution of HD in the formation is visible (see SI), the
corresponding 1H and 2H{1H} NMR resonances were also
observed (δ(1H): 4.37 (1:1:1, t) ppm; δ(2H{1H}): 4.5 (s) ppm).
Similarly, the formation of 9-F-BBN was affirmed by 19F NMR
and 11B NMR spectra (δ(19F): -46.9 ppm; δ(11B): 63.9 ppm).
Interesting, multinuclear NMR spectroscopy reveals the
liberation of HD is subsequent to the formation of the
diarylmethane. We speculate that the protic arenium cation
reacts with the transient anion, [FHBBN]- to give initially the
kinetic product of B-C bond cleavage, which gradually releases
HD yielding the thermodynamically favoured 9-F-BBN (see ESI).
H
5 mmol, 0.93 g 10 mL
1.05g, 77% yield
B
B
H
9-BBN
Scheme 2 Gram-scale synthesis of 23.
Table 3 Examining functional group compatibility.
D
D
D
9-BBN (0.5 equiv)
additive (1.0 equiv)
D
D
D
D
F
HD
+
+
DCM, rt
- 9-F-BBN
tBu
tBu
D
D
D
D
1
Entrya
1
2
3
4
5
6
7
8
Additive
-
Et3SiH
PhC≡N
Ph2CO
PhC≡CPh
PhC≡CH
Ph3N
Yield of 1 b
95 c
88
84
75
74
65
68
66
62
73
69
66
56
56
42
33
23
10
0
Ph2C=CH2
C6H10 (cyclohexene)
TMSCF3
PhCF3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
While this use of 9-BBN provides
a facile avenue to
Me3SiOPh
Ph2NH
Ph2O
diarylmethane product formation, we note that it is
insufficiently Lewis acidic to activate the electron-deficient
benzyl fluorides, whereas the more Lewis acidic HB(C6F5)2 is
effective.
PhOH
PhCH=NPh
P(o-MeC6H4)3
PhC(O)N(H)CH2Ph
PhNH2
Conclusions
C5H5N
C5H5NO
H2O
Ph3PO
Ph3COH
0
0
0
0
In summary, we have reported a simple and cheap strategy for
the activation of C-F bonds affording the Friedel–Crafts
benzylation of arenes with benzyl fluorides. A variety of 1,1-
diarylmethanes were obtained in good to excellent yield under
these mild reaction conditions and the method was amenable
to larger, gram-scale reactions. Thus, this is an attractive and
simple protocol for the preparation of various 1,1-
diarylmethanes from benzyl fluorides using a commonly
available and easy to handle borane, 9-BBN. We are continuing
to explore the utility of main group catalysts for applications in
organic synthesis.
0
a The standard reaction was done in the presence of 1.0 equiv of the given additive.
b GC-MS yields were determined after a 24 h reaction time using diphenylmethane
as standard. c Isolated yield.
To probe the functional group tolerance of this methodology,
a standard reaction was investigated in the presence of
additives incorporating various functional groups. Our group31
as well as that of Glorius32 have exploited this screening method
in the past. The reaction of p-tBuC6H4CH2F with C6D6 mediated
by 9-BBN dimer, which gave the product 1 in 95% isolated yield
(Table 3, entry 1), was used as the model. Generally, while the
yields diminish to some extent, the benzylation reaction is
Conflicts of interest
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There are no conflicts to declare.
24.
25.
26.
27.
28.
R. Hemelaere, P. A. Champagne, J. Desroches and J.-F.
View Article Online
Paquin, J. Fluorine Chem., 2016, 190, 1.
DOI: 10.1039/C9OB00912D
N. S. Keddie, P. A. Champagne, J. Desroches, J.-F. Paquin
and D. O'Hagan, Beilstein J. Org. Chem., 2018, 14, 106.
J. Zhu, M. Pérez, C. B. Caputo and D. W. Stephan, Angew.
Chem. Int . Ed., 2016, 55, 1417-1421.
J. T. Zhu, M. Pérez and D. W. Stephan, Angew. Chem. Int .
Ed., 2016, 55, 8448-8451.
Acknowledgements
NSERC of Canada is thanked for financial support. D.W.S is
grateful for the award of a Canada Research Chair and a Visiting
Einstein Fellowship at TU Berlin. K.L.B is grateful for the award
of an NSERC CGS-D scholarship. The authors thank Prof. Sophie
Rousseaux and Nick Michel (University of Toronto) for
assistance with GC-MS.
K. L. Bamford, S. S. Chitnis, Z.-w. Qu and D. W. Stephan,
Chem. Eur. J., 2018, 24, 16014.
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M. W. P. Bebbington, Chem. Soc. Rev., 2017, 46, 5059.
D. W. Stephan, S. Greenberg, T. W. Graham, P. Chase, J. J.
Hastie, S. J. Geier, J. M. Farrell, C. C. Brown, Z. M. Heiden,
G. C. Welch and M. Ullrich, Inorg. Chem., 2011, 50, 12338–
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DOI: 10.1039/C9OB00912D
9-borabicyclo[3.3.l]nonane dimer (9-BBN) mediates the Friedel–
Crafts benzylation of arenes with benzyl fluorides, affording a series
of 1,1-diarylmethanes under mild conditions.
H
B
B
H
9-BBN
F
R1
+
R1
R
H2
R
+
DCM, rt
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