Transition Metal Catalyst-Free, Base-Promoted 1,2-Additions of Polyfluorophenylboronates to Aldehydes and Ketones

Article abstract of DOI:10.1002/anie.202103686

A novel protocol for the transition metal-free 1,2-addition of polyfluoroaryl boronate esters to aldehydes and ketones is reported, which provides secondary alcohols, tertiary alcohols, and ketones. Control experiments and DFT calculations indicate that both the ortho-F substituents on the polyfluorophenyl boronates and the counterion K⁺ in the carbonate base are critical. The distinguishing features of this procedure include the employment of commercially available starting materials and the broad scope of the reaction with a wide variety of carbonyl compounds giving moderate to excellent yields. Intriguing structural features involving O?H???O and O?H???N hydrogen bonding, as well as arene-perfluoroarene interactions, in this series of racemic polyfluoroaryl carbinols have also been addressed.

Full text of DOI:10.1002/anie.202103686

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Accepted Article
Title: Transition Metal Catalyst-Free, Base-Promoted 1,2-Additions of
Polyfluorophenylboronates to Aldehydes and Ketones
Authors: Zhiqiang Liu, Goutam Kumar Kole, Yudha P. Budiman, Ya-
Ming Tian, Alexandra Friedrich, Xiaoling Luo, Stephen A.
Westcott, Udo Radius, and Todd B. Marder
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10.1002/anie.202103686
Angewandte Chemie International Edition
Transition Metal Catalyst-Free, Base-Promoted 1,2-Additions of
Polyfluorophenylboronates to Aldehydes and Ketones
Zhiqiang Liu,[a] Dr. Goutam Kumar Kole,[a,b] Dr. Yudha P. Budiman,[a,c] Dr. Ya-Ming Tian,[a]
Dr. Alexandra Friedrich,[a] Prof. Dr. Xiaoling Luo,*[d] Prof. Dr. Stephen A. Westcott,[e] Prof.
Dr. Udo Radius,*[a] and Prof. Dr. Todd B. Marder*[a]
[a]
Institute of Inorganic Chemistry and Institute for Sustainable Chemistry & Catalysis with
Boron, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
E-mail: u.radius@uni-wuerzburg.de; todd.marder@uni-wuerzburg.de
[b]
Department of Chemistry, College of Engineering and Technology, SRM Institute of
Science and Technology, SRM Nagar, Kattankulathur, Tamil Nadu 603203, India
[c]
Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas
Padjadjaran, 45363 Jatinangor, Indonesia
[d]
Chongqing Key Laboratory of Inorganic Functional Materials, College of Chemistry,
Chongqing Normal University, Chongqing, 401331, China
E-mail: xiaolingluo@cqnu.edu.cn
[e] Department of Chemistry and Biochemistry, Mount Allison University, Sackville, NB E4L
1G8 Canada
1
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Abstract: A novel protocol for the transition metal-free 1,2-addition of polyfluoroaryl
boronate esters to aldehydes and ketones is reported, which provides secondary alcohols,
tertiary alcohols, and ketones. Control experiments and DFT calculations indicate that both
the ortho-F substituents on the polyfluorophenyl boronates and the counterion K+ in the
carbonate base are critical. The distinguishing features of this procedure include the
employment of commercially available starting materials and the broad scope of the reaction
with a wide variety of carbonyl compounds giving moderate to excellent yields. Intriguing
structural features involving O−H···O and O−H···N hydrogen bonding, as well as
arene-perfluoroarene interactions, in this series of racemic polyfluoroaryl carbinols have
also been addressed.
Over the past few decades, the transition metal catalyzed 1,2-addition of organometallic
reagents to the C=O functionality of aldehydes and ketones has developed as a useful method
for the synthesis of substituted secondary and tertiary alcohols.[1] Numerous reagents have
been used for these reactions, including organomagnesium,[2] organozinc,[1,3] organolithium,[4]
organosilane,[5] organostannane,[6] organocerium[7] and organoboron compounds.[8] In
particular, organoboronate reagents offer significant advantages such as air and moisture
stability, low toxicity, good functional group tolerance, and availability.[8] In 1998, Miyaura
and co-workers[9] first reported the addition of arylboronic acids to aldehydes using a Rh
catalyst. In subsequent studies, other rhodium,[10] palladium,[11] platinum,[12] nickel,[13]
copper,[14] iron,[15] cobalt,[16] and ruthenium[17] complexes have been developed as
precatalysts for such reactions. However, transition metals can be expensive, toxic, and
difficult to remove completely from the corresponding product. A transition metal-free
strategy would be highly desirable for these useful transformations. The reaction products for
the addition of arylboronic acids to ketones, after hydrolysis, are tertiary alcohols, which are
important building blocks for the synthesis of pharmaceuticals, agrochemical compounds,
and natural products.[18] However, the nucleophilic addition of organometallic reagents to
ketones can be challenging due to the inherent steric congestion around the carbonyl group,
frequently resulting in the generation of products arising from side reactions such as
2
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10.1002/anie.202103686
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reduction and aldol condensation.[19] Therefore, the development of an efficient, general, and
convenient protocol for the synthesis of tertiary alcohols is of considerable interest.
Moreover, an ideal strategy to synthesize ketones, important and ubiquitous structural
motifs,[20] lies in the transition metal-catalyzed replacement of an aldehyde’s C(O)−H group
with a carbon electrophile.[21] Recently, Zheng and co-workers demonstrated the direct
functionalization of aldehyde C−H bonds with aryl halides, using a precious metal palladium
catalyst, which has proven to be a viable method to generate the corresponding ketone
products.[22]
Scheme 1. Approaches to access polyfluoroaryl carbinols via the addition to aldehydes.
Polyfluoroarenes have gained extensive attention due to their important role in
pharmaceutical, agrochemical, and advanced materials.[23] Thus, identifying practical and
efficient concepts for the introduction of fluorine or fluorinated building blocks is highly
desirable. Several studies have been reported regarding the polyfluorophenylation of
aldehydes. For example, in 1999, Knochel and co-workers[24] used fluorinated aryl bromides
to perform pentafluorophenylation of aldehydes (Scheme 1a). More recently, Lam and
co-workers[25] used a copper catalyst (Scheme 1b) and Gu and co-workers[26] (Scheme 1b)
3
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used an N-heterocyclic carbene (NHC) organocatalyst to obtain fluorinated aryl carbinols
using polyfluorophenyl trimethylsilane as a nucleophile for the addition to aldehydes. In 2015,
Huang and co-workers[27] (Scheme 1c) reported a Mg-mediated polyfluoroaryl addition to
aldehydes. Although some advancements in this field have been reported, these methods
suffer from the requirement for highly flammable Grignard reagents, transition metals or
NHC catalysts. Moreover, methods reported by Lam and co-workers and Gu and co-workers
are limited to pentafluorophenyl trimethylsilane or 1,4-bis (trimethylsilyl) tetrafluorobenzene
as substrates.
Recently, we reported efficient methods to generate fluorinated arylboronic acid pinacol
esters (ArF-Bpin) via C-F borylation of fluoroarenes using NHC-ligated Ni complex[28a,b] and
C-Cl borylation of ArF-Cl using Pd catalyst under base free condition.[28c] Likewise, we
reported optimized conditions for the Suzuki-Miyaura cross-coupling reaction of ArF-Bpin
compounds with ArX (X = Br, I) using a combination of CuI and 1,10-phenanthroline as a
catalyst precursor.[28d] Furthermore, we reported the palladium-catalyzed homocoupling of
fluorinated arylboronates,[28e] and the copper-catalyzed oxidative cross-coupling of
electron-deficient polyfluorophenyl boronate esters with terminal alkynes.[28f] We report
herein the transition metal-free polyfluorophenylation of ketones and aldehydes with
fluorinated aryl boronates, which provides a convenient and novel strategy for the synthesis
of alcohols and ketones.
Addition of arylboronic acids to aldehydes using transition metal catalysts has been well
developed. We expected that the use of more Lewis acidic pentafluorophenyl-Bpin with a
base would generate a nucleophilic intermediate in the absence of a transition metal. To
verify our hypothesis, we initially examined the reaction of pentafluorophenyl-Bpin (1a) and
benzaldehyde (2a) as a model reaction. As shown in Table 1, secondary alcohol 3a was
observed as the addition product after hydrolysis when the mixture of 1a and 2a was heated
in the presence of KOMe as the base (Table 1, entry 1). Encouraged by this first result, we
screened the reaction parameters, including the base and the solvent, to improve the
4
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10.1002/anie.202103686
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performance of the reaction. The employment of K2CO3 as the base dramatically increased
the yield to 92% (Table 1, entry 6). The experimental results revealed that heating is required
as the room temperature reaction only afforded 3a in trace amounts (Table 1, entry 7). Low
conversions were observed when reactions were conducted in coordinating solvents such as
DMF, THF, and 1,4-dioxane (Table 1, entries 8, 10, 11), and the lowest yield was obtained
when CH3CN was used as the solvent (Table 1, entry 9). In addition, the reaction exhibited
very poor performance under aerobic conditions (Table 1, entry 12). Interestingly, increasing
the amount of K2CO3 to 3 equiv. only led to a moderate increase in yield (Table 1, entry 13).
Decreasing the amount of K2CO3 (0.8 equiv.) did not impact the performance of the reaction
(Table 1, entry 14). No reaction took place when K2CO3 was absent (Table 1, entry 15),
indicating that K2CO3 as the base is important for this reaction. Not surprisingly, adventitious
water quenched the reaction (Table 1, entries 16-17). However, under anhydrous conditions,
the transition metal-free polyfluorophenylation of benzaldehyde with pentafluorophenyl-Bpin
is feasible and leads to high yields of the desired product.
Table 1: Optimization of the reaction conditions.[a]
Entry
Base
Solvent
Yield (%)[b]
1
2
3
4
5
6
7[c]
8
KOMe
KF
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
CH3CN
THF
1,4-Dioxane
Toluene
20
25
52
60
78
92
trace
50
15
88
79
35
tBuOLi
Cs2CO3
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
9
10
11
12[d]
5
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13[e]
14[f]
15
16[g]
17[h]
K2CO3
K2CO3
-
K2CO3
K2CO3
Toluene
Toluene
Toluene
Toluene
Toluene
83
92
0
66
25
[a] conditions: 1a (0.44 mmol), 2a (0.4 mmol), base (1.0 equiv), degassed and dried solvent
(3 mL), 60 °C, 36 h, under argon. [b] Yields were determined by GC-MS analysis vs. a
calibrated internal standard and are averages of two runs. [c] room temperature. [d] under air.
[e] K2CO3 (3 equiv). [f] K2CO3 (0.8 equiv). [g] K2CO3 (0.8 equiv), degassed wet toluene. [h]
K2CO3 (0.8 equiv), wet toluene. Moisture and air are detrimental to the yield due to the
instability of the fluorinated aryl boronate.[23g]
Using these optimized conditions, we evaluated the scope and the limitations of this
reaction. As shown in Table 2, a series of aldehydes bearing electron-withdrawing or
-donating substituents at the para-, meta-, or ortho-position all worked well with
pentafluorophenyl-Bpin to give the desired products (3b-3k). Notably, for reactions
employing aldehydes bearing electron-donating groups, increasing the reaction temperature
to 80 °C for 48 hours was required to generate the corresponding products in acceptable
yields. It should be noted that reactions using 4-(diethoxymethyl)benzaldehyde resulted in
cleavage of the diethoxymethyl group (3l). Furthermore, this methodology could be
successfully extended to more complex aldehydes, such as those incorporating naphthyl and
pyridyl groups (3m and 3n). The structures of compounds 3f, 3l, 3m and 3n were
unambiguously confirmed via single crystal X-ray analysis (vide infra). After a broad range
of aromatic aldehydes were examined, reactions with aliphatic aldehydes were investigated
using the optimized conditions. Gratifyingly, all reactions proceeded smoothly to afford the
corresponding products (3o-3q). Importantly, aldehydes containing ester groups, which are
well-known to be sensitive towards Grignard reagents, also afforded the desired alcohols in
excellent yield (3r).
Table 2: Scope of the reaction with respect to the different aldehyde substrates 2.[a,b]
6
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[a] conditions: 1a (0.44 mmol), 2 (0.4 mmol), K2CO3 (0.32 mmol), Toluene (3 mL), 60 °C,
36 h, Ar. [b] Isolated yields are reported. [c] 80 °C, 48 h.
Table 3: Scope of the reaction with respect to the different ketone substrates 2.[a,b]
[a] conditions: 1a (0.44 mmol), 2 (0.4 mmol), K2CO3 (0.32 mmol), Toluene (3 mL), 120 °C,
96 h, Ar. [b] Isolated yields are reported.
We then briefly investigated the scope using simple ketones (Table 3). When reactions
were performed at 120 °C and for prolonged reaction times, the corresponding products were
provided in moderate yields (3s-3u). Modest reaction yields were obtained when sterically
hindered benzophenone and (2-fluorophenyl)(phenyl)methanone were used (3v-3w).
Importantly, cyclohexanone proceeded to give the desired products in good yield (3x).
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Table 4: Scope of the reaction with respect to different polyfluorophenyl boronate substrates
1.[a,b]
[a] Reaction conditions: 1a (0.44 mmol), 2 (0.4 mmol), K2CO3 (0.32 mmol), toluene (3 mL),
80 °C, 48 h, Ar. [b] Isolated yields are reported. [c] t-BuOLi (0.32 mmol). [d] 120 °C, 96 h.
To explore further the utility of this reaction, we then examined the scope using other
less substituted polyfluorophenyl boronate esters with benzaldehyde (Table 4). The
compounds
2,3,5,6-tetrafluorophenyl-Bpin,
2,3,4,6-tetrafluorophenyl-Bpin,
and
2,4,6-trifluorophenyl-Bpin also proved to be effective in these reactions and afforded the
products in excellent yields (4a-4c). Furthermore, the reaction with 2,6-difluorophenyl-Bpin
proceeded to give the desired product in 80% yield (4d). However, these reaction conditions
were not suitable for the reaction of 2,5-difluorophenyl-Bpin and 2-fluorophenyl-Bpin with
benzaldehyde. Surprisingly, reactions with these substrates resulted in the formation of
ketones (4e and 4f) when a strong base was used. Tetrafluorophenyl-Bpin reacted readily
9
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with acetophenone to yield product 4g. Unfortunately, no reaction occurred when the
aryl-Bpin compound did not have an ortho-fluorine substituent (4h and 4i), as
3-fluorophenyl-Bpin, phenyl-Bpin, 4-CH3-phenyl-Bpin and 4-CN-phenyl-Bpin all failed to
provide any product. These results demonstrate that the ortho-fluorine group plays a key role
in related conversions.
Scheme 2. Preliminary mechanistic studies.
To gain further insight into the aforementioned reactions, several mechanistic studies were
conducted. The reaction of 2a with pentafluorobenzene 5 under standard conditions was
examined, yet 3a was not formed in any detectable amounts (Scheme 2a), indicating that the
C-Bpin moiety is essential and deprotonation of the fluoroarene or nucleophilic attack at the
fluoroarene by the base is not a plausible pathway. Interestingly, for the standard reaction
between 1a and 2a, the yield dropped dramatically if 18-crown-6 ether and K2CO3 were
added (Scheme 2b). This experimental result indicates that the presence of the potassium ion
plays a crucial role for the outcome of the reaction. Furthermore, if the reaction of 1a and 2a
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was performed in the presence of only a catalytic amount of K2CO3 (20 mol%) (Scheme 2c),
reaction rates were reduced, and a week was required to produce 3a in good, isolated yield.
This finding again indicates that the potassium ion (or the base) plays an important role in the
reaction. Substituting ortho-fluorines by ortho-chlorines, using either C6Cl5Bpin or
2,6-dichlorophenyl-1-Bpin as substrates, did not yield any product as shown by in situ GCMS
studies. Likewise, 2,3,4-trifluorophenylBpin and 3,4,5-trifluorophenylBpin substrates with
only one or no ortho-fluorine substituent also led to no detectable product formation. The
presence of an ortho-methoxy group on the aldehyde, however, did not inhibit the reaction.
Scheme 3. Proposed mechanism of the 1,2-addition of polyfluorophenylboronates to
aldehyde derivatives in the presence of K2CO3 as base.
Based on previous studies[28,29] and experimental observations, a mechanism for the
1,2-addition of polyfluorophenylboronates to aryl aldehydes in the presence of K2CO3 as base
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is proposed, as shown in Scheme 3. K2CO3 interacts with the Lewis-acidic Bpin moiety of
substrate 1 to generate base adduct A, which weakens the carbon-boron bond and ultimately
cleaves the B−C bond along with attachment of a potassium cation to the aryl group. The
-
resulting ArF anion adduct B undergoes nucleophilic attack at the aldehyde carbon atom of
substrate 2 to generate methanolate C. The methanolate oxygen atom then attacks the
electrophilic Bpin group to obtain compound D. Transfer of K2CO3 from intermediate D to
the boron atom of the more Lewis-acidic polyfluorophenyl-Bpin 1 finally closes the cycle
and regenerates complex A. Thus, the primary reaction product is the O-borylated addition
product E, which was detected by HRMS and NMR spectroscopy for the perfluorinated
derivative (see Supporting Information section VIII).
Figure 1. Free energy profile for the 1,2-addition of pentafluorophenyl-Bpin (1a) and
benzaldehyde (2a) in the presence of K2CO3 as the base, calculated at the M06/(6-311++G(d,
p), SMD)//B3LYP/(6-31+G(d)) level of theory. Relative free energies (G) are given in
kcal/mol, and bond lengths are given in Å.
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To corroborate this mechanism, a detailed DFT study was performed on the model
1,2-addition of 1a to 2a, the results of which are shown in Figure 1. In the initial step, K2CO3
coordinates to the Bpin moiety of 1a and gives rise to the pentafluorophenyl-Bpin-base
complex 6 with free energy decreasing by 27.2 kcal/mol. The energy of compound 6 is set as
-
the zero point of the energy profile. The pentafluorobenzene anion (ArF ) adduct 8 is formed
endothermically by cleavage of the B−C(ArF) bond via transition state 7-ts with an energy
barrier of 26.4 kcal/mol. In the optimized structures of 7-ts, K+ cations coordinate to C, O and
F atoms, whereas there is only K−O coordination in compound 6. Subsequent cleavage of the
-
B−C(ArF) bond can be facilitated by this pathway. The separated carbonate adduct and ArF
-
group in adduct 8 are connected and stabilized by K+ cations. Nucleophilic attack of ArF at
the aldehyde carbon atom via transition state 10-ts occurs to achieve the coupling
intermediate 11 with an energy of 17.6 kcal/mol. This low activation energy barrier can be
attributed to the coordination of K+ to the oxygen atom of the aldehyde, thus enhancing the
electrophilicity of the aldehyde carbon atom. Subsequently, the methanolate oxygen atom
attacks the Lewis-acidic boron atom to give the corresponding compound 13 irreversibly via
transition state 12-ts. The overall energy barrier for this step is 16.2 kcal/mol. Finally, K2CO3
in compound 13 coordinates to the boron of substrate 1a via transition state 14-ts, followed
by cleavage of a B−O bond to give 16-ts and eventually 17, regenerating the active species 6.
As shown in Figure 1, the energy barriers for these two steps are very low, indicating that
intermediate 13 transforms to product 17 swiftly. The step from pentafluorophenyl-Bpin-base
compound 6 to product 17 is calculated to be exergonic by 14.3 kcal/mol. The base-assisted
cleavage of Bpin and pentafluorophenyl (ArF) is calculated to be the rate determining step
(RDS) with a free energy of activation of 26.4 kcal/mol.
13
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Figure 2. Free energies of activation of the cleavage of Bpin and ArF step calculated at the
M06/(6-311++G(d, p), SMD)//B3LYP/(6-31+G(d)) level of theory. Relative free energies
(G) are given in kcal/mol.
As shown in Figure 1, the cation K+ bonds with one or two F atoms in these intermediates
and transition states, suggesting that the fluoride substituents possibly play an important role
in the 1,2-addition of polyfluorophenylboronates to aryl aldehydes. Therefore, we calculated
the activation free energies of the RDS using polyfluorophenylboronates with different
numbers and positions of fluorine substituents as the substrate. The results given in Figure 2
clearly show that the energy barrier rises with a reduction in the number of F substituents.
The position of the fluorine atoms also affects the energy barrier, and ortho fluorine has a
stronger effect on the barrier than F substituents at other positions. The barrier for 24, with an
ortho-F substituent, is higher than that of 22 by 2.6 kcal/mol, whereas that of 26 with a
para-F substituent rises to 39.0 kcal/mol. In fact, no reaction was observed under these
conditions when 26 was used as the substrate, which is consistent with our calculated results.
We conclude that the ortho-F substituent is vital in this reaction for interaction with K+ along
the reaction pathway, and that other F substituents also influence the reactivity for the
1,2-addition of polyfluorophenylboronates to aryl aldehydes via their electron-withdrawing
effect. Thus, stronger electron-withdrawing groups located at the para or meta carbons of
polyfluorophenylboronates may promote this reaction.
In order to ascertain the role of the K+ cation in these reactions, part of the free energy
profile without the cation was also calculated at the same level of theory, and the results are
given in Figure 3. Compared with the energy profile in Figure 1, in the absence of K+, the
process of the methanolate oxygen anion 33 attack at the Lewis-acidic boron in 30 becomes
improbable, with an activation barrier of 41.4 kcal/mol, although the initial cleavage of Bpin
and pentafluorophenyl (ArF) step has a lower free energy of activation. Upon addition of
18-crown-6 to the reaction, the yields drop dramatically. As a counterion, K+ clearly regulates
2-
the nucleophilicity of CO3 , and promotes the reactivity by interaction with oxygen or
fluorine atoms. Our DFT calculations indicate that both the ortho-F substituents on the
14
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polyfluorophenylboronates and the counterion K+ are essential for the 1,2-addition of
polyfluorophenylboronates to aryl aldehydes.
Figure 3. Free energy profile of 1,2-addition of polyfluorophenylboronates with aryl
aldehydes in the absence of K+ calculated by the M06/(6-311++G(d, p),
SMD)//B3LYP/(6-31+G(d)) level of theory. Relative free energies (G) are given in
kcal/mol, bond lengths are given in Å.
The structures of 3f, 3l, 3m, 3n, and 4d were unambiguously confirmed by single crystal
X-ray diffraction. While the molecular structures are chiral (Figure 4), all the compounds
represent racemic mixtures. Due to the presence of OH groups, the arrangement of the
molecules in the crystal structures of all compounds is primarily determined by O−HO or
O−HN hydrogen bonding (Supporting Information, Table S2). The presence of 
stacking interactions between pentafluorophenyl and bromophenyl or naphthyl moieties (3f
and 3m), respectively, is also observed in these examples (Table S3). Such an attractive
interaction between arenes and perfluorinated arenes results from the different
electronegativities of the hydrogen and fluorine atoms with respect to the carbon atoms of the
aromatic rings and, hence, from opposite multipole moments of the aromatic groups. It is
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called the arene–perfluoroarene interaction and can be applied as a supramolecular synthon in
crystal engineering.[30] This was previously confirmed by Marder and co-workers, who have
shown that this type of interaction leads to the formation of highly ordered -stacks of
alternating arene and perfluoroarene molecules in co-crystals of arenes and
perfluoroarenes.[30d,31]
.
Figure 4. Molecular structures of compounds 3f, 3l, 3m, 3n and 4d in the solid state at 100 K.
Atomic displacement ellipsoids are drawn with 50% probability. Only selected hydrogen
atoms are shown for clarity. Colour code: grey – carbon, red – oxygen, blue – nitrogen,
orange – bromine, green – fluorine, and white – hydrogen.
In the crystal structures of compounds 3f and 3m, the combination of both O−HO
hydrogen bonding and arene-perfluoroarene interaction leads to the intriguing formation of
4
[O−H]4 hydrogen-bonded cyclic tetramers with graph set R4 (8) (Figure 5, Table S2).[32]
The molecules of the tetramer interact via arene-perfluoroarene  stacking between the
bromophenyl or naphthyl and pentafluorophenyl moieties on the outside of the cyclic
[O−H]4 ring. The interplanar separations (3.281(7) – 3.687(14) Å) are typical for 
stacking interactions,[30,31] the angles between the interacting planes are 4.96(19) – 16.8(3)°
(Table S3). In the higher symmetry compound 3m (space group P21/c with Z' = 2, where Z'
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denotes the number of molecules in the asymmetric unit), arene-perfluoroarene interactions
are also present between the tetramers, in addition to C–H, C–HF, and FF interactions
(Figure S6). Each tetramer of 3m is centrosymmetric and, hence, contains molecules of
opposite chirality (RRSS), leading to a racemic mixture (Figure 5(b)). Tetramers are arranged
⃗
in sheets parallel to the 푏,푐-plane (Figure S6). In contrast, compound 3f crystallizes in the
non-centrosymmetric space group P1. There are 16 symmetry-independent molecules in the
asymmetric unit (Z' = 16) of 3f, which build up four symmetry-independent hydrogen-bonded
cyclic tetramers (Figure S1). Each tetramer is constituted by molecules of the same chirality
(RRRR or SSSS) (Figure 5(a)). Thus, the chirality of the four tetramers in the asymmetric unit,
i.e., (RRRR)(SSSS)(RRRR)(SSSS), leads to a racemic mixture, as shown in Figures 5(a), S1
⃗
and S3. Tetramers of mixed chirality are arranged in sheets parallel to the 푏,푐-plane with
bromine atoms all pointing up or down within the sheet (Figures S2 and S3). Parallel sheets
face each other either with the bromine atoms or without. In fact, crystals of 3f represent one
of the rare class of crystals for which Z' > 1.[33, 34] While searching for a structure of higher
symmetry, the cell parameters of 3f were also determined at 200 K. As this resulted in a
similar triclinic unit-cell metric as was observed at 100 K, the occurrence of a phase
transition at temperatures between 100 K and 200 K is unlikely.
17
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10.1002/anie.202103686
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Figure 5. Compounds (a) 3f and (b) 3m self-assemble to form tetramers via O‒H···O
4
hydrogen bonding and the corresponding graph set notation is R4 (8).31 π···π stacking
interactions between the bromophenyl or naphthyl and pentafluorophenyl groups,
respectively, within the tetrameric unit are indicated by close CC contacts (dashed lines). (a)
Each of the four symmetry-independent tetramers of 3f consists of molecules of the same
chirality (RRRR or SSSS). Only one tetramer (SSSS) is shown here. (b) In 3m, the tetramer is
centrosymmetric with (RRSS) chirality of the molecules.
18
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Contrary to 3f and 3m, the dominance of hydrogen bonding and absence of
̅
arene-perfluoroarene interactions in compounds 3l (space group P1), 3n and 4d (both space
group C2/c) resulted in the formation of one-dimensional hydrogen-bonded chains (Figure 6).
In 3l and 3n, the intermolecular O‒H···O and O–H···N hydrogen bonding interaction takes
place between the alcohol (O‒H, donor) and the carboxaldehyde (O, acceptor) and pyridyl (N,
acceptor) groups, respectively, the latter having a stronger hydrogen bond acceptor ability
compared to the alcohol group (Table S2). Depending on the position of the acceptor atom in
the molecule, hydrogen-bonded chains are straight (3l, Figure 6(a)) or zig-zag-like (3n,
Figure 6(b)). In 3l, each one-dimensional chain contains molecules of one particular chirality
(either R or S), and chains of opposite chirality exhibit extensive π-stacking interaction
between the phenyl groups. In this way, double-stranded linear chains projecting the C6F5
groups on both sides are formed, as shown in Figure 6(a). The C6F5 groups from neighboring
strands undergo interdigitation and exhibit partial offset π···π interactions between
fluorinated moieties and C‒F···π interactions between phenyl and pentafluorophenyl groups
(Figures S4 and S5, Table S3). In 3n, one-dimensional zig-zag chains are formed by
molecules of alternating chirality (RSRS…) (Figure 6(b)). The pyridyl rings lie coplanar and
the pentafluorophenyl groups interdigitate via partial offset π···π interactions to form a
parallel ribbon-like arrangement (Figure S7, Table S3). This structure exhibits a bilayer
architecture as there are alternating hydrophobic and hydrophilic regions (Figures S7 and
S8).[35] In 4d, corrugated one-dimensional chains are observed by the intermolecular O‒
H···O‒H···hydrogen bonding interactions between the alcohol groups (Table S2), and
molecules constituted of alternating pairs of same chirality (RRSSRRSS… as shown in Figure
6(c) and Figure S9). Other intermolecular interactions observed in 4d include C−H···F,
C−H···π, and very weak, strongly offset π···π interactions (Table S3).
19
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10.1002/anie.202103686
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Figure 6. One-dimensional hydrogen-bonded chains are present in (a) 3l (O−H···O), (b) 3n
(O−H···N), and (c) 4d (O−H···O). (a) In 3l, chains containing molecules of opposite chirality
stack parallel via π···π interaction between the phenylcarboxaldehyde groups. (b) A zig-zag
chain constituted by molecules of alternative chirality (RSRS…) is shown for compound 3n.
(c) Compound 4d exhibits corrugated chains with (RRSS…) chirality of the molecules.
Additional weak interactions (C−H···π and partial π···π stacking) are shown.
20
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Conclusion
We have demonstrated here the simple conditions for the 1,2-addition of aldehydes and
ketones with polyfluorophenylboronate compounds. This strategy has the following
advantages: (1) transition metal-free catalyst system; (2) a variety of aromatic and aliphatic
aldehydes were found to be suitable substrates for this reaction using pentafluorophenyl-Bpin
in moderate to excellent yields; and (3) sterically hindered ketones also worked well to
furnish the corresponding products. This method also introduces the use of
polyfluoropenyl-Bpin compounds instead of Grignard reagents for polyfluorophenylation of
arylaldehyde and ketone substrates. Further studies of the synthesis and applications of
polyfluorophenyl boronates are underway in our laboratory and will be reported in due
course.
Crystallographic details
Crystal data collection and processing parameters are given in the Supporting Information.
CCDC-2045652 (3f), 2045653 (3l), 2045654 (3m), 2045655 (3n), and 2045656 (4d) contain
the supplementary crystallographic data for this paper. These data are provided free of charge
by The Cambridge Crystallographic Data Centre.
Acknowledgments
Z.L. and Y.M.T. are grateful to the China Scholarship Council for providing Ph.D.
scholarships. X.L. is grateful to the China Scholarship Council for providing a sabbatical
leave fellowship. G.K.K. thanks the Alexander von Humboldt Foundation for a postdoctoral
fellowship. Y.P.B. thanks the Universitas Padjadjaran for an Academic Leadership Grant
(ALG). T.B.M. and U.R. thank the Julius-Maximilians-Universität Würzburg and the
Deutsche Forschungsgemeinschaft (DFG) for support. S.A.W. acknowledges support from
the Natural Science and Engineering Research Council of Canada. We thank AllyChem Co.
Ltd. for a generous gift of B2pin2.
21
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Conflict of interest
The authors declare no conflict of interest.
Keywords: boronate ester; transition metal-free; fluorine; fluoroarene; 1,2-addition reaction
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Graphical Abstract
Transposing B-flat to F: Herein we report a transition metal-free procedure for the
base-promoted 1,2-addition of polyfluorophenylboronates to aldehydes and ketones to
generate organofluorine alcohols in yields up to 93%.
28
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