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Synthesis 2022; 54(22): 4971-4978
DOI: 10.1055/a-1818-0576
special topic
Aryne Chemistry in Synthesis

3-Trifluoromethylbenzyne: Precise Orientation in Cycloaddition Reaction Enabled Regioselective Synthesis of Trifluoromethylated Triptycenes

Takayuki Iwata∗
a   Institute for Materials Chemistry and Engineering, Kyushu University, 6-1, Kasugako-en, Kasuga 816-8580, Japan
,
Mizuki Hyodo
b   Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1, Kasugako-en, Kasuga 816-8580, Japan
,
Takumi Fujiwara
b   Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1, Kasugako-en, Kasuga 816-8580, Japan
,
Ryusei Kawano
b   Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1, Kasugako-en, Kasuga 816-8580, Japan
,
Leah Kuhn
c   Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA
,
Igor V. Alabugin
c   Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA
,
Mitsuru Shindo  ∗
a   Institute for Materials Chemistry and Engineering, Kyushu University, 6-1, Kasugako-en, Kasuga 816-8580, Japan
› Author Affiliations

This work was partially supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant Nos. JP18H02557, JP18H04418, JP18H04624, JP20H04780, JP20K21198, and JP20K15283), Nagase Science Technology Foundation (M.S.), Asahi Glass Foundation (T.I.), and the Integrated Research Consortium on Chemical Sciences (IRCCS) Fusion Emergent Research Program (T.I.). This work was performed under the Cooperative Research Program ‘Network Joint Research Center for Materials and Devices’. L.K. acknowledges support by the National Science Foundation (Graduate Research Fellowship Grant No. 1449440).
› Further Information
 
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Abstract

The first regioselective addition reactions to 3-trifluoromethylbenzyne are reported. Triple cycloaddition of ynolates to the benzyne provided 1,8,13-tris(trifluoromethyl)triptycenes with high regioselectivity. 1-Trifluoromethyltriptycenes were regioselectively obtained by the Diels–Alder reaction of anthranoxides with the benzyne. These selectivities are attributed to the electron-acceptor nature of the trifluoromethyl group on the benzyne.


#

Key words

benzynes - trifluoromethyl group - triptycenes - regioselective synthesis - cycloaddition - negative hyperconjugation

Fluorine is unique, due to its high electronegativity and small atomic radius, among the elements of the 2nd period.[1] The C–F bond is strong and short and can participate in multiple electronic effects including the inductive effect (I-effect), stereoelectronic effects, such as hyperconjugation, and through-space electrostatic interactions. In medicinal chemistry, fluorine substitution improves metabolic stability, bioavailability, and binding affinity to biomolecules.[2] These unique properties are well-known and widely used in synthetic reactions. Therefore, a trifluoromethyl (CF3) group has properties that are distinctly different from the corresponding methyl group.[3] The electronegativity of the trifluoromethyl group is similar to that of oxygen (Pauling scale 3.5), while the hydrophobicity is much larger.[4] These properties and the related reactivity have been summarized in numerous reviews and books.[4] [5]

Triptycenes are highly symmetric organic molecules with a rigid strained barrelene skeleton, which is flanked by three benzene rings. They play an important role in the development of various materials, supramolecules, molecular machines, and polymers.[6] However, the efficient synthesis of triptycenes had been limited to a few methods, most including a Diels–Alder reaction of anthracenes. Recently, we have developed a novel synthetic approach to triptycenes via triple cycloaddition of ynolates[7] 1 with benzynes 2 (Scheme [1, a]).[8] It is noteworthy that using 3-methoxybenzyne[8a] and 3-silylbenzynes[8b] as reactants results in regioselective formation of functionalized triptycenes with substituents at the 1,8,13-positions.[9] In the case of 3-methoxybenzyne (2a), this high selectivity is derived from the presence of the methoxy group. Although this group generally behaves as a donor in reactions that involve the out-of-plane aromatic system, it displays its σ-CO-acceptor properties[10] in transformations of the in-plane π-orbital of the o-benzyne moiety. Each of the three nucleophilic addition steps are assisted by negative hyperconjugation from the developing aryl anion to the electron-deficient σ*C–O orbital.[11] This orbital interaction between the σ*C–O orbital and the π-orbital of the benzyne makes the C1 position more electrophilic (Scheme [1, b]). Additionally, regioselectivity of the Diels–Alder reaction of anthranoxide (intermediate 4) with the benzyne is assisted through both hyperconjugation and electrostatic interactions between the Li and MeO groups.[12]

The strategy utilizing a σ-electron-acceptor substituent on benzynes for the control of regioselectivity in cycloadditions can potentially be expanded to other suitable substituents. We considered a trifluoromethyl group as a promising choice to demonstrate the strategy. Although generation and reactions of trifluoromethylated benzynes have been reported by a few groups (Scheme [2, a]),[13] there have been no examples of regioselective reactions in these previous publications. Herein, we report stereoselective syntheses of trifluoromethyltriptycenes through the regioselective triple cycloaddition of ynolates (Scheme [2, b]).

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Scheme 1 (a) Triple cycloaddition of ynolates with benzynes with the formation of triptycenes; (b) Evolution of negative hyperconjugation in the reaction of 3-methoxybenzyne with a nucleophile.
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Scheme 2 Syntheses of trifluoromethylated triptycenes

The preparation of 3-trifluoromethylbenzyne (2b) was attempted from 1-chloro-2-trifluoromethylbenzene (5) according to Schlosser’s method,[13b] in which lithiated 1-chloro-2-trifluoromethylbenzene 6 in THF at –78 °C was transferred to a furan solution at 25 °C using a cannula. In our hands, however, the cycloadduct 7 was isolated only in a moderate yield (Scheme [3, a]). A simpler alternative protocol, in which n-butyllithium was added to a mixture solution of precursor 5 and furan, gave even poorer results (Scheme [3, b]).

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Scheme 3 Generation of 3-trifluoromethylbenzyne (2b) using Schlosser’s method

Table 1 Generation of 3-Trifluoromethylbenzyne from 1-Fluoro-3-trifluoromethylbenzene (8)

Entry

Base

Temp (°C)

Yield (%) 7

Yield (%) 9

1

MeLi

  0

33

2a

2

n-BuLi

  0

42

4a

3

s-BuLi

  0

10a

3a

4

t-BuLi

  0

11a

3a

5

PhLi

  0

31a

5a

6

Ph3MgLi

  0

15a

1a

7

n-BuLi

–78

–b

–b

8

n-BuLi

–20

–b

–b

9

n-BuLi

  rt

32a

4a

a The yields were calculated by 1H NMR.

b Not obtained.

Since our attempts to use the known benzyne precursor were unsuccessful, we turned our attention to alternative precursors. Since fluoroarenes are known to be good precursors for arynes due to their easy ortho-lithiation with organolithium reagents, we examined the formation of 3-trifluoromethylbenzyne from 1-fluoro-3-trifluoromethylbenzene (8) using furan to trap the benzyne (Table [1]). With methyllithium as a base (entry 1), the cycloadduct 7 was obtained in 33% along with a small amount of regioisomer 9. n-Butyllithium improved the yield of adduct 7 to 42% (entry 2), while sec- and tert-butyllithium, phenyllithium, and triphenylmagnesium lithium led to decreased yields (entries 3–6). In addition, reaction temperature was also found to be influential. When the reaction mediated by n-butyllithium was performed at a lower temperature (–78 and –20 °C), adduct 7 was not obtained at all (entries 7 and 8). The reaction at room temperature also had a lower yield (entry 9). Taken together, we decided to select entry 2 as the preferred conditions for the subsequent studies.

We then investigated the cycloaddition reaction of 3-trifluoromethylbenzyne with 2-methyl- and 2-methoxyfuran in order to examine the regioselectivity. As shown in Scheme [4], the reaction using 2-methylfuran provided a mixture of proximal and distal cycloadducts 10 in a ratio of 58:42. On the other hand, the ratio of proximal and distal cycloadducts 11 with 2-methoxyfuran was 80:20. These results matched with the earlier findings that benzynes bearing an inductive electron-withdrawing group such as F[14] or OMe[15] preferably form the proximal cycloadducts.

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Scheme 4 Regioselective cycloaddition of 3-trifluoromethylbenzyne with furans
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Scheme 5 Triple cycloaddition of ynolates to 3-trifluoromethylbenzyne
Zoom Image
Figure 1 X-ray crystallographic analysis of 13a. (a) Ball and stick model, (b) space-filling model. Units are in Å.

Based on these experiments, the triple cycloaddition reactions of 3-trifluoromethylbenzyne with lithium ynolates 1 were examined (Scheme [5]). The ynolate solution in THF, prepared from dibromo ester 12 and tert-butyllithium by our usual protocol,[16] was mixed with 1-fluoro-3-trifluoromethylbenzene (8). After, n-butyllithium was slowly added at 0 °C. In the case of methyl-substituted ynolate, 1,8,13-tris(trifluoromethyl)triptycene 13a was isolated in 49% yield. This product shows great regioselectivity with all the CF3 substituents and hydroxyl group on the same side of the triptycene. Although numerous side products are formed, we could not detect any regioisomers among the numerous side products in the crude mixture where 13a was the major product. In any case, this is the first highly regioselective cycloaddition of ynolate 1 with 3-trifluoromethylbenzyne (2b). Larger substituents (R = Et, n-Bu, n-Hex) on the ynolate also yielded the product 13b–d having the same stereochemistry, albeit in moderate yield. The stereochemistry was also confirmed by X-ray crystallographic analysis (Figure [1]). It is noteworthy that the nine fluorine atoms are densely set on one side of the triptycene scaffold; all of them are arranged in an almost equilateral triangle with a side length of approximately 7.2 Å. In addition, a H–F through-space coupling[17] was observed in the 1H NMR spectra of triptycenes 13 (see the Supporting Information). The peak of the OH group appeared as a multiplet with a splitting of about 3.7 Hz. This splitting disappeared in the 19F-decoupling experiments. Moreover, in the IR spectra, a sharp and intense free OH peak appeared at about 3660 cm–1, while the broad hydrogen-bonded peak was weak.[17c] This indicates that the intramolecular H–F interactions prevent the OH group from forming a hydrogen bond with water, as if it is a ‘water repellent’ OH group.

Because the triple cycloaddition reaction should proceed via an anthranoxide intermediate that undergoes a Diels–Alder reaction with the aryne to form the last cycle of the triptycene system, we have generated such a species independently by treatment of the corresponding stable anthrones 14 with base.[12] Indeed, the cycloaddition of anthranoxides 15, derived from anthrone and 10-methylanthrone, with 3-trifluoromethylbenzyne (2b) furnished 1-trifluoromethyltriptycenes 16 with high regioselectivity (Scheme [6]). No other regioisomers could be detected in both cases.

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Scheme 6 Synthesis of 1-trifluoromethyltriptycenes via the anthrone method

The high regioselectivity observed in both the ynolate and anthrone methods could be attributed to the polarization of the in-plane π-orbital due to the electronegative nature of the CF3 group. As is the case with methoxybenzyne,[8a] the addition of both lithium ynolate 1 and benzocyclobutenone enolate 3 to trifluoromethylbenzyne will selectively occur at the C1 position. These asynchronous cycloadditions start as nucleophilic additions to the alkyne moiety. The natural bond orbital (NBO) calculations revealed that the regioselectivity of this step is controlled by the polarization of the benzyne triple bond which is induced by the I-effect of the CF3 group (NBO charge at C1 is +0.11e vs –0.05e at C2) and by negative hyperconjugation between the σ*C–CF3 and π-orbitals (11.7 kcal/mol) (Figure [2]). For the benzyne in-plane πin*-orbital, that is directly involved in the Nu–C bond formation, the NBO polarization indicates clearly that nucleophilic attack will occur at C1 (57% at C1 vs 43% at C2).[18] It is well-documented that bent alkyne π-bonds are particularly strong electron donors.[19]

Zoom Image
Figure 2 DFT calculations on trifluoromethylbenzyne and the nucleophiles

In a similar way, as we have shown earlier,[8a] [12] the Diels–Alder reaction of anthranoxide and benzynes is noticeably asynchronous: nucleophilic addition of anthranoxide to the benzyne precedes the formation of the second C–C bond. Therefore, polarization of the trifluoromethylbenzyne triple bond would also play a significant role in this step. Additionally, because Li–O interaction was highly important to form precomplexes in the case of methoxybenzyne,[8a] one can suggest that Li–F noncovalent interactions[20] may also contribute to the regioselectivity of these trifluoromethylbenzyne cycloadditions.

In conclusion, we have developed a highly regioselective synthesis of 1-trifluoromethyl- and 1,8,13-tris(trifluoromethyl)triptycenes via the Diels–Alder reaction of 3-trifluoromethylbenzyne with anthranoxides and via the triple cycloaddition of this benzyne with ynolates, respectively. This regioselectivity originates from selective attack at the C1 atom in the highly polarized triple bond of 3-trifluoromethylbenzyne. Additionally, assistance from the F–Li noncovalent interactions may contribute to the observed regioselectivity. This is the first example of the regioselective cycloaddition of 3-trifluoromethylbenzyne. Detailed theoretical calculations are now in progress.

1H and 1H{19F} NMR spectra were measured in CDCl3 solution containing 0.01% TMS (reference: 0.00 ppm), or THF-d 8 solution (reference: 1.72 ppm), using JEOL JNM-ECA 600 (600 MHz) or JNM-ECZ 400 (400 MHz) spectrometers. 13C{1H, 19F} NMR spectra were measured in CDCl3 solution (reference: 77.0 ppm), or THF-d 8 solution (reference: 25.31 ppm), using JEOL JNM-ECA 600 (150 MHz) or JNM-ECZ 400 (100 MHz) spectrometers. 1H NMR and 13C NMR spectra were measured at room temperature unless otherwise noted. Peak multiplicities use the following abbreviations: s, singlet; d, doublet; dd, double doublet; t, triplet; q, quartet; m, multiplet; br, broad. IR spectra were recorded on a SHIMADZU IRPrestige-21 FT-IR spectrophotometer using a KBr disk or a NaCl plate. Column chromatography was performed on silica gel (spherical neutral, particle size 100–210 μm, Kanto Chemical Co.). TLC was performed on precoated plates (0.25 mm, silica gel Merck 60 F254). Mass spectra (MS) and high-resolution mass spectra (HRMS) were measured on a JEOL JMS-700 mass spectrometer. Melting points were measured with a Büchi 535 melting point apparatus and are uncorrected. X-ray crystallographic data were collected on a Rigaku FR-E+ Super Bright or a Rigaku XtaLAB Synergy-R/DW diffractometer.[21]

THF (anhydrous), CH2Cl2 (anhydrous), Et2O (anhydrous), and n-BuLi (1.6 M, n-hexane solution) were purchased from Kanto Chemical Co. Furan, 1-fluoro-3-(trifluoromethyl)benzene, 2-methylfuran, and NaH (60%, dispersion in paraffin liquid) were purchased from Tokyo Chemical Industry. EtOAc, hexane, benzene, CHCl3, EtOH, MeOH, NH4Cl, and MgSO4 were purchased from FUJIFILM Wako Pure Chemical Corporation. 2-Methoxyfuran was purchased from Sigma-Aldrich. Ethyl 2,2-dibromopropanoate,[16b] ethyl 2,2-dibromobutanoate,[16b] ethyl 2,2-dibromohexanoate,[16b] ethyl 2,2-dibromooctanoate,[16b] and 10-methylanthrone[22] were synthesized according to our previous reports. Reaction mixtures were stirred magnetically unless otherwise noted. n-BuLi solution was used after titrimetric determination of the concentration by the diphenylacetic acid method.[23] Furan, 2-methylfuran, 2-methoxyfuran, and 1-fluoro-3-(trifluoromethyl)benzene were distilled prior to use. All other chemicals and solvents were used without further purification unless otherwise noted.


#

5-(Trifluoromethyl)-1,4-dihydro-1,4-epoxynaphthalene (7)

To a solution of 1-fluoro-3-(trifluoromethyl)benzene (8; 171 mg, 1.00 mmol) and furan (freshly distilled, 0.75 mL, 10.0 mmol) in anhyd THF (4.0 mL) was added n-BuLi (0.85 mL, 1.2 mmol, 1.44 M in hexane) over 5 min at 0 °C under argon atmosphere. After stirring for 1 h, the reaction was quenched with sat. NH4Cl aq. The mixture was extracted with EtOAc. The combined organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (hexane/EtOAc, 20:1) to give the title compound (94.5 mg, 43%) as a colorless oil.

1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 6.9 Hz, 1 H), 7.18 (d, J = 7.8 Hz, 1 H), 7.11–7.03 (m, 3 H), 6.01 (s, 1 H), 5.78 (s, 1 H); NMR spectral data match that previously reported.[13b]


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1-Methyl-8-(trifluoromethyl)-1,4-dihydro-1,4-epoxynaphthalene (Proximal-10) and 1-Methyl-5-(trifluoromethyl)-1,4-dihydro-1,4-epoxynaphthalene (Distal-10)

To a solution of 1-fluoro-3-(trifluoromethyl)benzene (8; 130 mg, 0.792 mmol) and 2-methylfuran (freshly distilled, 0.70 mL, 7.92 mmol) in anhyd THF (3.2 mL) was added n-BuLi (0.85 mL, 1.2 mmol, 1.40 M in hexane) over 5 min at 0 °C under argon atmosphere. After stirring for 30 min, the reaction was quenched with sat. NH4Cl aq. The mixture was extracted with Et2O. The combined organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (hexane/Et2O, 10:1) to give a mixture of the title compounds (40.9 mg, 23%; proximal-10/distal-10 = 58:42) as a colorless oil. An analytical sample was further purified by preparative TLC (hexane/Et2O, 5:1, then hexane/Et2O, 4:1) to give proximal-10 as a colorless oil and distal-10 as a colorless oil. The stereochemistry was determined by NOE experiments.


#

Proximal-10

IR (NaCl): 3014, 1313 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.35 (d, J = 7.3 Hz, 1 H), 7.23 (d, J = 8.2 Hz, 1 H), 7.08–7.03 (m, 2 H), 6.80 (d, J = 5.5 Hz, 1 H), 5.67 (d, J = 2.3 Hz, 1 H), 2.03 (q, J = 1.8 Hz, 3 H).

13C{1H, 19F} NMR (100 MHz, CDCl3): δ = 153.0, 150.1, 145.4, 145.0, 125.3, 123.8, 123.7, 122.7, 121.7, 91.2, 81.1, 16.7.

MS (EI): m/z (%) = 226 (M+, 51), 200 (100).

HRMS (EI): m/z calcd for C12H9F3O: 226.0605; found: 226.0605.


#

Distal-10

IR (NaCl): 2933, 1323 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.30 (d, J = 6.9 Hz, 1 H), 7.17 (d, J = 7.8 Hz, 1 H), 7.10 (apparent t, J = 7.8 Hz, 1 H), 7.04 (dd, J = 5.2, 1.6 Hz, 1 H), 6.80 (d, J = 5.2 Hz, 1 H), 5.92 (d, J = 1.6 Hz, 1 H), 1.96 (s, 3 H).

13C{1H, 19F} NMR (100 MHz, CDCl3): δ = 152.7, 149.3, 146.1, 143.7, 125.6, 124.0, 123.2, 121.5, 120.9, 89.1, 80.9, 15.0.

MS (EI): m/z (%) = 226 (M+, 36), 200 (100).

HRMS (EI): m/z calcd for C12H9F3O: 226.0605; found: 226.0604.


#

4-Methoxy-5-(trifluoromethyl)naphthalen-1-ol (Proximal-11) and 4-Methoxy-8-(trifluoromethyl)naphthalen-1-ol (Distal-11)

To a solution of 1-fluoro-3-(trifluoromethyl)benzene (8; 254 mg, 1.58 mmol) and 2-methoxyfuran (freshly distilled, 0.70 mL, 7.92 mmol) in anhyd THF (6.3 mL) was added n-BuLi (1.34 mL, 1.90 mmol, 1.42 M in hexane) over 5 min at 0 °C under argon atmosphere. After stirring for 1 h, the reaction was quenched with sat. NH4Cl aq. The mixture was extracted with Et2O. The combined organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (hexane/EtOAc, 7:1 to 5:1) to give proximal-11 (83.2 mg, 22%) as colorless needles along with distal-11 (20.4 mg, 5%) as colorless needles. The stereochemistry was determined by X-ray crystallographic analysis. A single crystal suitable for X-ray analysis was obtained by recrystallization from CHCl3.[21]


#

Proximal-11

Mp 138–140 °C (CHCl3, hexane).

IR (KBr): 3251, 2956 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.45 (d, J = 8.7 Hz, 1 H), 8.01 (d, J = 7.8 Hz, 1 H), 7.52 (apparent t, J = 8.0 Hz, 1 H), 6.90–6.85 (m, 2 H), 5.02 (s, 1 H), 3.94 (s, 3 H).

13C{1H, 19F} NMR (100 MHz, CDCl3): δ = 149.5, 145.4, 127.0, 126.7, 126.6, 124.8, 124.7, 124.0, 122.6, 109.2, 108.3, 56.7.

MS (EI): m/z (%) = 242 (M+, 100), 227 (64).

HRMS (EI): m/z calcd for C12H9F3O2: 242.0555; found: 242.0554.


#

Distal-11

Mp 153–156 °C (CHCl3).

IR (KBr): 3379, 2956 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.54 (d, J = 8.7 Hz, 1 H), 8.00 (d, J = 7.3 Hz, 1 H), 7.50 (apparent t, J = 8.0 Hz, 1 H), 6.99 (d, J = 8.2 Hz, 1 H), 6.80 (d, J = 8.2 Hz, 1 H), 5.09 (s, 1 H), 3.98 (s, 3 H).

13C{1H, 19F} NMR (100 MHz, CDCl3): δ = 150.3, 143.6, 127.5, 127.2, 126.8, 124.9, 123.7, 123.6, 121.5, 114.2, 105.0, 55.9.

MS (EI): m/z (%) = 242 (M+, 43), 222 (31), 207 (100).

HRMS (EI): m/z calcd for C12H9F3O2: 242.0555; found: 242.0555.


#

9-Hydroxy-10-methyl-1,8,13-tris(trifluoromethyl)triptycene (13a)

To a solution of ethyl 2,2-dibromopropanoate (133 mg, 0.513 mmol) in anhyd THF (3.0 mL), cooled to –78 °C under argon, was added a solution of t-BuLi (1.30 mL, 2.00 mmol, 1.54 M in pentane) dropwise over 5 min. The resultant yellow solution was stirred for 30 min at –78 °C and then for another 30 min at 0 °C. After the ice bath was removed, a solution of 1-fluoro-3-(trifluoromethyl)benzene (8; 0.38 mL, 3.00 mmol) in anhyd THF (2.0 mL) was added. After that, a solution of n-BuLi (1.80 mL, 2.50 mmol, 1.40 M in hexane) was added dropwise over 5 min. After stirring for 30 min, the reaction was quenched with AcOH. The mixture was evaporated under reduced pressure to remove volatiles. The crude compound was suspended in water and the supernatant was removed after centrifugation. This suspension–centrifugation operation was further repeated two times using Et2O to give 97.0 mg of 13a and an impure mixture. The latter was further purified by reprecipitation from THF and MeOH to give 26.8 mg of 13a as colorless prisms; total yield: 123.8 mg (49%); mp >400 °C (THF, MeOH). A single crystal suitable for X-ray analysis was obtained by recrystallization from THF.[21]

IR (KBr): 3660 cm–1.

1H NMR (400 MHz, THF-d 8): δ = 7.77 (d, J = 8.0 Hz, 3 H), 7.59 (d, J = 8.0 Hz, 3 H), 7.31 (dd, J = 8.0, 8.0 Hz, 3 H), 5.06–5.01 (m, 1 H), 2.55 (s, 3 H).

13C{1H, 19F} NMR (100 MHz, CDCl3): δ = 148.9, 145.9, 127.4, 125.8, 125.7, 125.4, 83.5, 79.5, 49.4, 15.9.

MS (EI): m/z (%) = 488 (M+, 100), 468 (40), 453 (40), 399 (47).

HRMS (EI): m/z calcd for C24H13F9O: 488.0823; found: 488.0823.


#

10-Ethyl-9-hydroxy-1,8,13-tris(trifluoromethyl)triptycene (13b); Typical Procedure 1 (TP1)

To a solution of ethyl 2,2-dibromobutanoate (141 mg, 0.520 mmol) in anhyd THF (3.0 mL), cooled to –78 °C under argon, was added a solution of t-BuLi (1.30 mL, 2.00 mmol, 1.54 M in pentane) dropwise over 5 min. The resultant yellow solution was stirred for 30 min at –78 °C and then for another 30 min at 0 °C. After the ice bath was removed, a solution of 1-fluoro-3-(trifluoromethyl)benzene (8; 0.38 mL, 3.00 mmol) in anhyd THF (2.0 mL) was added. After that, a solution of n-BuLi (1.80 mL, 2.50 mmol, 1.40 M in hexane) was added dropwise over 5 min. After stirring for 30 min, the reaction was quenched with 3 M HCl aq. The mixture was extracted with CHCl3 and the combined organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated. The crude compound was roughly purified by silica gel column chromatography (hexane/CHCl3, 10:1). The obtained mixture was further purified by the suspension–centrifugation operation using MeOH to give 33.2 mg of 13b. The supernatant was again purified by silica gel column chromatography (hexane/CHCl3, 10:1) and the suspension–centrifugation operation using MeOH to give 1.7 mg of 13b; total yield: 34.9 mg (13%); colorless prisms; mp 279–281 °C (CHCl3, hexane).

IR (KBr): 3667, 2985 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.69–7.46 (m, 6 H), 7.25 (brs, 3 H), 5.12–5.05 (m, 1 H), 3.09 (q, J = 7.0 Hz, 2 H), 1.66 (t, J = 7.0 Hz, 3 H).

1H NMR (400 MHz, C2D2Cl4, 80 °C): δ = 7.64 (d, J = 7.8 Hz, 3 H), 7.56 (d, J = 8.2 Hz, 3 H), 7.24 (apparent t, J = 7.8 Hz, 3 H), 5.08–5.03 (m, 1 H), 3.09 (q, J = 7.0 Hz, 2 H), 1.67 (t, J = 7.0 Hz, 3 H).

13C{1H, 19F} NMR (100 MHz, C2D2Cl4, 80 °C): δ = 146.7, 145.9, 125.8, 125.5, 124.5, 124.1, 120.2, 82.4, 53.2, 20.7, 10.9.

MS (EI): m/z (%) = 502 (M+, 98), 453 (100), 384 (79).

HRMS (EI): m/z calcd for C25H15F9O: 502.0979; found: 502.0978.


#

10-Butyl-9-hydroxy-1,8,13-tris(trifluoromethyl)triptycene (13c)

The title compound was synthesized according to TP1 using ethyl 2,2-dibromohexanoate (1.50 g, 5.00 mmol). The crude compound was purified by silica gel column chromatography (hexane/CHCl3, 10:1) and the suspension–centrifugation operation using Et2O.

Yield: 348.3 mg (13%); colorless prisms; mp 216–218 °C (CHCl3, hexane).

IR (KBr): 3660, 2960 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.65–7.44 (m, 6 H), 7.27–7.10 (m, 3 H), 5.10–5.06 (m, 1 H), 2.97 (t, J = 7.5 Hz, 2 H), 2.07–1.99 (m, 2 H), 1.90–1.82 (m, 2 H), 1.17 (t, J = 7.3 Hz, 3 H).

13C{1H, 19F} NMR (100 MHz, CDCl3): δ = 145.8, 145.0, 126.4, 125.8, 125.5, 124.9, 124.1, 82.3, 52.5, 29.1, 27.4, 24.7, 14.3.

MS (EI): m/z (%) = 530 (M+, 45), 474 (66), 454 (100).

HRMS (EI): m/z calcd for C27H19F9O: 530.1292; found: 530.1292.


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10-Hexyl-9-hydroxy-1,8,13-tris(trifluoromethyl)triptycene (13d)

The title compound was synthesized according to TP1 using ethyl 2,2-dibromooctanoate (163.1 mg, 0.497 mmol). The crude compound was purified by silica gel column chromatography (hexane/EtOAc, 20:1) and the suspension–centrifugation operation using MeOH and hexane. A single crystal suitable for X-ray analysis was obtained by recrystallization from CHCl3 and MeOH.[21]

Yield: 36.8 mg (13%); colorless prisms; mp 250–252 °C (CHCl3, MeOH).

IR (KBr): 3662, 2957 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.63–7.46 (m, 6 H), 7.25 (s, 3 H), 5.10–5.04 (m, 1 H), 2.96 (t, J = 7.5 Hz, 2 H), 2.05–2.01 (m, 2 H), 1.86–1.78 (m, 2 H), 1.53–1.42 (m, 4 H), 1.00 (t, J = 7.1 Hz, 3 H).

13C{1H, 19F} NMR (100 MHz, CDCl3): δ = 145.9, 145.0, 126.4, 125.8, 125.5, 124.9, 124.2, 82.4, 52.6, 31.9, 31.3, 29.4, 25.2, 22.7, 14.1.

MS (EI): m/z (%) = 558 (M+, 100), 474 (83), 454 (96).

HRMS (EI): m/z calcd for C29H23F9O: 558.1605; found: 558.1603.


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9-Hydroxy-1-(trifluoromethyl)triptycene (16a); Typical Procedure 2 (TP2)

To a solution of anthrone (65.0 mg, 0.334 mmol) in anhyd THF (5.6 mL) was added NaH (22.1 mg, 0.500 mmol, 60%, dispersion in paraffin liquid) at room temperature under argon atmosphere. After the resulting orange solution was stirred for 10 min, 1-fluoro-3-(trifluoromethyl)benzene (8; 164 mg, 1.00 mmol) was added. To the resulting mixture, a solution of n-BuLi (0.85 mL, 1.22 mmol, 1.44 M in hexane) was added dropwise over 5 min at room temperature. After stirring for 1.5 h, 1-fluoro-3-(trifluoromethyl)benzene (8; 164 mg, 1.00 mmol) and a solution of n-BuLi (0.85 mL, 1.22 mmol, 1.44 M in hexane) was added to the mixture. After stirring for another 20 min, the reaction was quenched with sat. NH4Cl aq. The mixture was extracted with CHCl3. The combined organic phase was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (hexane/benzene, 2:1) and the suspension–centrifugation operation using Et2O to give the title compound (59.1 mg, 52%) as colorless prisms; mp 200–203 °C (CHCl3, MeOH).

IR (KBr): 3620, 3072 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 7.3 Hz, 2 H), 7.55 (d, J = 7.3 Hz, 1 H), 7.41–7.38 (m, 3 H), 7.15–7.05 (m, 5 H), 5.44 (s, 1 H), 3.86 (q, J = 4.3 Hz, 1 H).

13C{1H, 19F} NMR (100 MHz, CDCl3): δ = 147.2, 145.2, 145.0, 142.9, 127.3, 125.9, 125.5, 125.5, 124.4, 124.1, 123.4, 123.1, 120.0, 81.1, 53.3.

MS (EI): m/z (%) = 338 (M+, 100), 320 (46).

HRMS (EI): m/z calcd for C21H13F3O: 338.0918; found: 338.0919.


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9-Hydroxy-10-methyl-1-(trifluoromethyl)triptycene (16b)

The title compound was synthesized according to TP2 using 10-methylanthrone (125 mg, 0.600 mmol). The crude compound was purified by silica gel column chromatography (hexane/EtOAc, 20:1) and recrystallization (CHCl3, hexane).

Yield: 117.4 mg (56%); colorless prisms; mp 245–246 °C (CHCl3, hexane).

IR (KBr): 3630, 3431, 3070 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.65 (dd, J = 7.1, 1.1 Hz, 2 H), 7.55 (d, J = 7.8 Hz, 1 H), 7.40 (d, J = 7.8 Hz, 1 H), 7.37 (d, J = 6.9 Hz, 2 H), 7.16–7.08 (m, 5 H), 3.88 (q, J = 4.3 Hz, 1 H), 2.43 (s, 3 H).

13C{1H, 19F} NMR (100 MHz, CDCl3): δ = 149.2, 146.2, 146.1, 144.8, 125.7, 125.4, 125.1, 124.1, 123.6, 123.3, 120.4, 119.5, 80.2, 48.2, 13.9.

MS (EI): m/z (%) = 352 (M+, 100), 337 (86).

HRMS (EI): m/z calcd for C22H15F3O: 352.1075; found: 352.1076.


#
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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Mr. T. Matsumoto at IMCE, Kyushu University for his support with the X-ray crystallographic analyses.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1818-0576.
  • Supporting Information

Corresponding Authors

Takayuki Iwata
Institute for Materials Chemistry and Engineering, Kyushu University
6-1, Kasugako-en, Kasuga 816-8580
Japan   

Mitsuru Shindo
Institute for Materials Chemistry and Engineering, Kyushu University
6-1, Kasugako-en, Kasuga 816-8580
Japan   

Publication History

Received: 14 March 2022

Accepted after revision: 05 April 2022

Accepted Manuscript online:
05 April 2022

Article published online:
31 May 2022

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Zoom Image
Scheme 1 (a) Triple cycloaddition of ynolates with benzynes with the formation of triptycenes; (b) Evolution of negative hyperconjugation in the reaction of 3-methoxybenzyne with a nucleophile.
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Scheme 2 Syntheses of trifluoromethylated triptycenes
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Scheme 3 Generation of 3-trifluoromethylbenzyne (2b) using Schlosser’s method
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Scheme 4 Regioselective cycloaddition of 3-trifluoromethylbenzyne with furans
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Scheme 5 Triple cycloaddition of ynolates to 3-trifluoromethylbenzyne
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Figure 1 X-ray crystallographic analysis of 13a. (a) Ball and stick model, (b) space-filling model. Units are in Å.
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Scheme 6 Synthesis of 1-trifluoromethyltriptycenes via the anthrone method
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Figure 2 DFT calculations on trifluoromethylbenzyne and the nucleophiles