Difluoroketenimine: Generation from Difluorocarbene and Isocyanide and Its [3 + 2] Cycloadditions with Alkenes or Alkynes

Article abstract of DOI:10.1021/acs.joc.0c01120

Ketenimines have been explored as useful building blocks for the synthesis of heteroatom-containing cyclic compounds through the cycloaddition with polar multiple bonds. Herein, we report the cycloaddition of difluoroketenimine with nonpolar multiple bond

Full text of DOI:10.1021/acs.joc.0c01120

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Article
Difluoroketenimine: Generation from Difluorocarbene and
Isocyanide, and Its [3+2] Cycloadditions with Alkenes or Alkynes
Rui Zhang, Zhikun Zhang, Kang Wang, and Jianbo Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01120 • Publication Date (Web): 07 Jul 2020
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Difluoroketenimine: Generation from Difluorocarbene and
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Isocyanide, and Its [3+2] Cycloadditions with Alkenes or Alkynes
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Rui Zhang, Zhikun Zhang, Kang Wang and Jianbo Wang*
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Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry
and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing
100871, China
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
ABSTRACT. Ketenimines have been explored as useful building blocks for the synthesis of heteroatom
containing cyclic compounds through the cycloaddition with polar multiple bonds. Herein we report the
cycloaddition of difluoroketenimine with non-polar multiple bonds, namely the cycloaddition with
alkenes or alkynes. The difluoroketenimine is generated from the coupling of tert-butylisocyanide and
difluorocarbene, which is formed in situ from (bromodifluoromethyl)trimethylsilane. The
difluoroketenimine then reacts in situ with alkenes or alkynes to afford fluorinated pyrrolidines or
pyrroles. DFT study suggests that a fluorinated cyclic (alkyl)(amino)carbene is involved as the key
intermediate in these reactions.
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INTRODUCTION
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Ketenimines are a type of unique building blocks in organic synthesis, and are generally served as a 2π
species in cycloaddition reactions, due to the high reactivity of their cumulated double bonds.1 For
instance, ketenimines can undergo formal [2+2] reactions with imines2 and ketones,3 [3+2] reactions
with 1,3-dipolars4 and [4+2] reactions with azadienes5 (Scheme 1a). Conjugated vinyl/phenyl-
substituted ketenimines can also serve as 4π species in various [4+2] reactions.6 Despite these known
reaction modes, the cycloaddition reaction of ketenimines is still limited. In most cases, only the carbon-
carbon bond in ketenimines is involved in the cycloaddition process7 and another reaction component is
restricted in polar multiple bonds, such as imines or ketones. So far, the cycloaddition reactions between
ketenimines and nonpolar multiple bonds, especially those where both double bonds in ketenimines are
involved, still remain challenging and unexplored.
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On the other hand, fluorine-containing molecules have attracted significant attention in recent years,
due to their importance in life science, drug industry and material science.8 Consequently, various
fluorinated reagents have been developed to introduce fluorine atoms into complex molecules.9 We have
recently reported the in-situ generation of a new fluorinated intermediate, difluoroketenimine, via the
reaction between difluorocarbene and isocyanides.10 Difluoroketenimine can serve as the surrogate of
the highly unstable intermediate difluoroketene11 and undergoes [2+2] reaction with imines to give α,α-
difluoro-β-amino amides and α,α-difluoroazetidinimines (Scheme 1b). We also found that the
introduction of fluorine atoms would significantly enhance ketenimines’ reactivity in [2+2]
cycloadditions. To further explore the intriguing chemistry of the newly discovered difluoroketenimine
and its application in the synthesis of fluorine-containing molecules, we conceived to develop the [3+2]
cycloaddition reaction between difluoroketenimines and nonpolar multiple bonds (Scheme 1c). Herein
we report that the reaction leads to one-step synthesis of fluorinated multi-substituted pyrrolidines and
pyrroles, which are important backbones in various natural products and pharmaceuticals.12 Mechanistic
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study through DFT calculation reveals that a fluorinated cyclic (alkyl)(amino)carbene (CAAC) species is
likely involved as key intermediate.
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Scheme 1. Cylcoaddition Reactions of Ketenimines and Difluoroketenimines
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RESULTS AND DISCUSSIONS
To test our hypothesis, styrene 1a was chosen as the model substrate and reacted with tert-
butylisocyanide 2, (bromodifluoromethyl)trimethylsilane 3 and tetra-n-butylammonium bromide (TBAB)
under similar conditions which we have reported before. A pyrrolidine derivative 4a was obtained in
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29% H NMR yield (Table 1, entry 1), whose structure was determined unambiguously via X-ray
diffraction (see Supporting Information for details). Interestingly, the structure features an α-cyano
substitution, which indicates the participation of a second equivalent of isocyanide during the [3+2]
reaction. Satisfyingly, the reaction demonstrated excellent diastereoselectivity for the phenyl and cyano
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substituents, and we could only observe the syn-diastereomer via careful H and C NMR analysis of
the crude mixture. The yield slightly increased with less TBAB and higher temperature (Table 1, entries
2-3). Under 90 ℃, 2 and 3 was added dropwise to avoid side reactions of the in situ formed
difluoroketenimine and 4a was obtained in 46% yield (Table1, entry 4). With 3 equivalents of 2, we
further screened a series of solvents. Toluene and diglyme are superior choices to give 4a in 74% and
75% yield respectively (Table 1, entries 5-8). In consideration of that polar substrates always show
better solubility in diglyme, we finally choose diglyme as the solvent. Further increasing the amount of
4a to 4 equivalents gave the best result and 4a was isolated in 84% yield (Table 1, entry 9).
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Table 1. Optimization of the Reaction Conditionsa
entry ratio of 1a:2:3 TBAB (mol%) solvent
temp. (oC) yield (%)b
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1:2:2
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DCE
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toluene
PhCF3
diglyme
diglyme
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82(84)d
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aThe reactions were run on a 0.2 mmol scale. The concentration of 1a was 1.33M. The yields were
determined by 1H NMR with CH2Br2 as the internal standard. The dr value was determined by 1H NMR
analysis of the crude mixture. Under all circumstances, only the syn diastereomer was identified (dr >
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20:1). The solution of 2 and 3 in 0.5 mL solvent was added dropwise in 3 h. The reaction was run on
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0.4 mmol scale and the isolated yield was given. TBAB: tetra-n-butylammonium bromide
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Other isocycnides, including cyclohexyl isocyanide and 1,1,3,3-tetramethylbutyl isocyanide, were also
examined in the reaction. However, cyclohexyl isocyanide did not give the desired product according to
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the H NMR analysis of the crude product. The reaction with 1,1,3,3-tetramethylbutyl isocyanide gave
the corresponding product only in 22% isolated yields. From these results, it is concluded that the
secondary alkyl isocynides are not applicable in this reaction, and the efficiency of tertiary isocycnides
other than t-BuNC is relatively low.
With the optimized conditions in hand, we further evaluated the substrate scope of alkenes. As
illustrated in Scheme 2, styrenes with electron-withdrawing groups (4b-d, 4l) or electron-donating
groups (4e, 4f) are both well tolerated and give the corresponding products in excellent yields. Besides,
various functional groups, for instance, ester (4d), thioether (4f), nitro (4l) and boronic ester (4g) are
compatible under the reaction conditions. The yields for the substrates bearing an ortho-substituent (4i, j)
are not affected, indicating that the reaction is not sensitive to steric effects. Substrates with a meta-
substituent (4k-m) also react smoothly to give the products. Notably, the reaction could be scaled up to
gram-scale. We could obtain 1.00 g of 4l without significant loss of the yield.
Other aromatic groups, such as naphthalene (4n), furan (4o) and thiophene (4p), are also compatible
in this transformation. The reaction could also be applied in synthesizing the derivative of Raxatrigine
(4q), a voltage-gated sodium channel inhibitor13 currently under phase Ⅱ clinical trials for trigeminal
neuralgia and small fiber neuropathy. It is worth noting that the reaction scope is not restricted in
alkenes. Acrylate (4r), 1,3-dienes (4s) and vinyl ketones (4t) could give the corresponding products as
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well. However, alkenes without conjugated substitutions or multi-substituted alkenes stay inert under the
reaction conditions, possibly because of the low activity of double bonds or higher steric hindrance
respectively.
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Scheme 2. Scope of Alkenesa
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aReaction conditions: 1:2:3:TBAB = 0.4:1.6:0.8:0.12 (mmol), in 3 mL diglyme at 90 ℃ for 6 h. The
solution of 2 and 3 in 1 mL diglyme was added dropwise in 3 h. All the yields refer to the isolated
products after column chromatography on silica gel. The dr value was determined by 1H NMR.
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We further tested the reaction with alkynes, which are expected to be less reactive toward
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cycloaddition with difluoroketenimine. Under similar conditions (see Supporting Information for details
on reaction condition optimization), the reaction with phenylacetylene proceeded smoothly. After the
aforementioned [3+2] cycloaddition reaction, the pyrroline intermediate spontaneously eliminated a
hydrogen fluoride to give the mono-fluorinated pyrrole derivative 6a (Scheme 3). The structure of 6a
was determined unambiguously via X-ray diffraction (see Supporting Information for details).
Phenylacetylenes with electron-withdrawing groups (6b-e) gave the corresponding products in moderate
to good yields, while the electron-donating methoxy group (6f) led to diminished results. Steric hindered
(6g) or heterocycle (6h) substrates were also tolerated. Interestingly, ethyl acetylenecarboxylate gives the
product (6i) in excellent yields, which indicates that electron deficient multiple bonds are more active in
this transformation.
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Scheme 3. Scope of Alkynesa
aSubstrate scope of alkynes. Reaction conditions: 5:2:3:TBAB = 0.4:2.4:1.2:0.12 (mmol), in 3 mL
toluene at 80 ℃ for 6 h. All the yields refer to the isolated products after column chromatography on
silica gel.
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This unique three-component reaction raises intriguing mechanistic questions. In addition to the
details of the [3+2] cycloaddition, the origin of cyano group in the product and the high syn
diastereoselectivity are intriguing. To answer these questions, we conducted the following control
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experiments. First, to rule out the possible epimerization during the reaction, we have analyzed by H
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NMR the dr value of the product (4a) under the standard reaction conditions at intervals of 0.5 h, 1 h, 2
h, 4 h and 5 h, after the tert-butylisocyanide and TMSCF2Br were added dropwise to the reaction. The
diastereoselectivities of the product 4a remained almost unchanged (dr > 20:1), which indicated that
epimerization did not occur during the time-course of the reaction.
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Next, we observed that no corresponding product 4h was detected in the reaction with
difluorocyclopropane 714 as the substrate (Scheme 4a), which was completely recovered under the
standard conditions. This result rules out the possibility that the reaction is initiated by cyclopropanation
between styrenes and the difluorocarbene. Thus, it is more likely that the in situ generated
difluorocarbene is captured by the nucleophilic isocyanide to give difluoroketenimine, which afterwards
undergoes [3+2] cycloaddition with styrenes.
Furthermore, we envisioned that the [3+2] product 8 would feature a fluorinated cyclic
(alkyl)(amino)carbene (CAAC) structure. CAACs are a large group of singlet carbenes stabilized by the
adjacent amino group, which have attracted considerable attentions in recent years.15 We tried several
common strategies to trap the CAAC intermediate 8, for example, quenching the reaction with Se or
metal complexation.16 However, none of the them were proved successful, possibly because the
intermediate 8 is less sterically hindered and less nucleophilic comparing to traditional CAACs.17 The
intermediate 8 would be readily captured by the excess isocyanide in the reaction mixture, thus
rendering the mechanistic study further difficult. Fortunately, we managed to detect the N-H bond
insertion product of the intermediate with amines (Scheme 4b). Finally, to elucidate the origins of cyano
group and the α-proton, we conducted deuterium labeling experiments (Scheme 4c). The deuterium in
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additives18 is incorporated in the reaction and the α-proton in the final product is partly deuterated.
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While these control experiments provide some insights, the mechanistic details still remain elusive.
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Scheme 4. Control Experiments
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To further shed light on the mechanistic details of this transformation, we conducted DFT
calculations (Figure 1). All calculations were performed with Gaussian 09.19 First, the [3+2]
cycloaddition step goes through a concerted but asynchronous transition state TS1-b with a barrier of
27.6 kcal/mol. Other possible processes, for example, [3+2] reaction with 1,3-dipolar Int1-a are also
carefully considered and proved unfavored with the activation barrier of 42.5 kcal/mol. The calculation
further confirmed the existence of the CAAC-type intermediate 8, which is then attacked by the
nucleophilic isocyanide to give a ketenimine intermediate Int2. Ketenimines are known to undergo
facile decomposition when heating. Research has shown that N-benzyl ketenimines give the 1,3-
rearrangement products via homolytic cleavage and radical recombination.20 However, the
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decomposition of N-tert-butyl ketenimines requires higher temperature and yields nitrile products
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without alkyl migration, probably through a retro-ene transition state.21
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Figure 1. A) Energy Profile of the Reaction Pathways. B) Key Optimized Structures with Selected
Bond Lengths in Angstroms.
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For our ketenimine product Int2, the retro-ene mechanism TS3-a requires a high activation barrier
(36.1 kcal/mol) and shows moderate anti selectivity (the anti transition state favors by 1.1 kcal/mol),
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which is in sharp contrast to the excellent syn diastereoselectivity that we observed. Besides, this
intramolecular proton transfer mechanism cannot explain the incorporation of deuterium in our
mechanistic experiments. Then we speculated that Int2 could also be cleaved to give Int3 with the assist
of strong base, in our system for example, the anion of bromodifluoromethane generated by
decomposition of the difluorocarbene source 3.22 The step, with an activation barrier of 31.9 kcal/mol, is
responsible for the high temperature required for this transformation. Int3 is then protonated by proton
sources in the reaction mixture. This intermolecular proton transfer mechanism (TS3-b) has lower
activation barrier than the retro-ene process and the diastereoselectivity is controlled by the protonation
step. The sterically hindered proton sources tend to attack opposite to the bulky phenyl group, therefore
pushing the cyano and phenyl group to the syn position.23 The structures of syn and anti transition states
in the protonation step are shown in Figure 1B. The calculated 2.0 kcal/mol gap between anti and syn
transition states is consistent with our experimental observation.
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The role of fluorine substitution has also been considered by the calculation with ketenimine 12H
(Scheme 5). Without fluorine substitution, the activation barrier of the [3+2] reaction increased to 42.3
kcal/mol, and the Gibbs free energy of the reaction increased to 10.8 kcal/mol (see Supporting
Information for details). This result indicates that this [3+2] reaction is unfavored both kinetically and
thermodynamically. The fluorine atoms can not only activate the double bonds in ketenimines, but also
stabilize the carbene intermediate.
Scheme 5. Difluoroketenimine 12 vs Ketenimine 12H in [3+2] Cycloaddition
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CONCLUSION
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In summary, we have reported the first example of [3+2] cycloaddition reaction between
ketenimine and alkenes or alkynes. The reaction yields fluorinated pyrrolidines or pyrroles in excellent
yield and diastereoselectivity. Mechanistic experiments and DFT calculations have suggested the
existence of a cyclic (alkyl)(amino)carbene intermediate and further explained the origins of cyano
group and the high diastereoselectivity observed in this reaction. This work not only extends the reaction
mode of ketenimines, but also provides an efficient one-pot synthesis for fluorinated heterocycles.
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EXPERIMENTAL SECTION
General Methods. All the reactions were performed under nitrogen atmosphere with a flamed-
dried reaction tube. Oil bath was used for heating reactions. All solvents were distilled under nitrogen
atmosphere prior to use. THF, diethyl ether, toluene and 1,4-dioxane were dried by distillation over
sodium/benzophenone. DCE and CH3CN were distilled over CaH2. DMF and diglyme were available
from commercial sources without further purification. TLCs were performed on silica gel HS-GF 254
plates. For chromatography, 200-300 mesh silica gel was employed. Melting points were measured in
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open capillary vials. H NMR spectra were recorded on Bruker ARX 400 (400 MHz) or Brucker ARX
500 (500 MHz); 13C NMR spectra were recorded on Bruker ARX 400 (101 MHz). 19F NMR was
recorded at 470 MHz with Brucker ARX 500 spectrometer. The data for NMR spectra were reported as
follows: chemical shifts (δ) were reported in ppm using tetramethylsilane as internal standard when
using CDCl3 as solvent, and coupling constants (J) were in Hertz (Hz). IR spectra were recorded on
Nicolet 5MX–S infrared spectrometer and were reported in terms of frequency of absorption (cm−1).
HRMS were obtained on Bruker APEX IV FTMS. HRMS was detected through Bruker Solarix XR
FTMS by ESI.
PE: petroleum ether; EA: ethyl acetate; DCM: dichloromethane; DCE: 1,2-dichloroethane; DMF:
dimethylformamide; diglyme: TBAB: tetra-n-butylammonium bromide.
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Synthesis of the Substrates. The alkene substrates 1a-1c, 1h, 1k, 1n, 1s were purchased from
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commercial sources. 1d-1g, 1i, 1j, 1l, 1m, 1o, 1p were synthesized by Wittig reaction.
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1-Fluoro-2-((4-vinylphenoxy)methyl)benzene (1q). 1q was synthesized by the following method:
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Under a nitrogen atmosphere, 4-hydroxybenzaldehyde (1.28 g, 10.4 mmol, 1.0 equiv), 1-
(bromomethyl)-2-fluorobenzene (2.27 g, 12.0 mmol, 1.15 equiv), K2CO3 (3.32 g, 24 mmol, 2.3 equiv)
and 25 mL DMF were added to a 50 mL Schlenk flask and stirred at room temperature. The reaction
was monitored by TLC. After 4 h, the mixture was extracted by EA (50 mL × 3), washed by water (50
mL × 3) and 50 mL brine. The solvent was removed under reduced pressure and the crude product was
purified by column chromatography using PE/EA as solvents to give 2.32 g (96%) alkylation product 14.
White solid; mp 57-58 ℃; Rf = 0.20 (PE:EA = 10:1); 1H NMR (CDCl3, 400 MHz): δ 9.89 (s, 1H), 7.90–
7.80 (m, 2H), 7.49 (td, 1H, J = 7.5, 1.8 Hz), 7.34 (tdd, 1H, J = 7.5, 5.3, 1.8 Hz), 7.21–7.05 (m, 4H), 5.22
(s, 2H); 13C{1H} NMR (CDCl3, 101 MHz): δ 190.8, 163.5, 160.5 (d, J = 247.2 Hz), 132.0, 130.3 (d, J =
7.7 Hz), 130.2, 129.7 (d, J = 3.7 Hz), 124.4 (d, J = 3.7 Hz), 123.2 (d, J = 14.2 Hz), 115.5 (d, J = 21.2
Hz), 115.1, 64.0 (d, J = 4.5 Hz); 19F NMR (377 MHz, CDCl3): δ -118.5 (s, 1F); HRMS (ESI) m/z: [M +
H]+ Calcd for C14H12FO2 231.0821; Found 231.0816; IR (film): 2917, 2849, 1694, 1602, 1578, 1508,
1495, 1458, 1388, 1313, 1253, 1160, 1110, 1005, 833 cm-1.
Under a nitrogen atmosphere, methyltriphenylphosphonium bromide (2.79 g, 7.8 mmol, 1.3
equiv), 30 mL THF and a stir bar were added to a 100 mL Schlenk flask and cooled to -78 ℃. To this
solution was slowly added n-butyllithium (2.5 M, 2.9 mL, 1.2 equiv). The reaction mixture was then
allowed to slowly warm up to room temperature and stir for another 1 h. The flask was again cooled
down to -78 ℃ and 14 (1.38 g, 6.0 mmol, 1.0 equiv) was added. The mixture was slowly warmed up to
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room temperature. The reaction was monitored by TLC until 14 was fully consumed. Then, the reaction
was filtered through a short silica gel pad and washed with EA. The solvent was removed under reduced
pressure and the crude product was purified by column chromatography using PE/EA as solvents to give
1q (1.36 g, 99%). White solid; mp 58-59 ℃; Rf = 0.35 (PE); 1H NMR (CDCl3, 400 MHz) δ 7.49 (t, 1H,
J = 7.3 Hz), 7.39–7.24 (m, 3H), 7.14 (t, 1H, J = 7.4 Hz), 7.07 (t, 1H, J = 9.2 Hz), 6.93 (d, 2H, J = 8.4
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Hz), 6.65 (dd, 1H, J = 17.6, 10.9 Hz), 5.61 (d, 1H, J = 17.6 Hz), 5.17–5.03 (m, 3H); C{1H} NMR
(CDCl3, 101 MHz) δ 160.5 (d, J = 246.9 Hz), 158.4, 136.2, 130.9, 129.8 (d, J = 5.2 Hz), 129.7, 127.5,
124.3 (d, J = 3.5 Hz), 124.2 (d, J = 14.3 Hz), 115.4 (d, J = 21.1 Hz), 114.9, 111.9, 63.7 (d, J = 4.5 Hz);
19F NMR (471 MHz, CDCl3) δ -118.7 (s, 1F); HRMS (ESI) m/z: [M + H]+ Calcd for C15H14FO
229.1029; Found 229.1024; IR (film): 3047, 1607, 1509, 1493, 1458, 1384, 1306, 1242, 1115, 1013,
990, 902, 834 cm-1;
General Procedures for the [3+2] Cycloaddition with Alkene (1a-t). Under a nitrogen atmosphere,
the corresponding alkene 1a-t (0.4 mmol, 1.0 equiv), TBAB (38.6 mg, 0.12 mmol, 0.3 equiv) and
diglyme (2 mL) were added to a dry Schlenk tube successively. A solution of 2-isocyano-2-
methylpropane 2 (132.8 mg, 184 μL, 1.6 mmol, 4.0 equiv) and (bromodifluoromethyl)trimethylsilane 3
(162.4 mg, 124 μL, 0.8 mmol, 2.0 equiv), in diglyme (1 mL) was added dropwise in 3 h at 90 ℃. The
mixture was stirred at 90 ℃ for another 3 h. The solvent was removed under reduced pressure and the
residue was purified by chromatography on silica gel with PE-EA as the eluent to afford the products.
rac-(2S,5S)-1-(tert-Butyl)-3,3-difluoro-5-phenylpyrrolidine-2-carbonitrile (4a). Yield: 88.5 mg, 84%,
dr > 20:1; pale yellow oil; Rf = 0.31 (PE:EA = 30:1); 1H NMR (CDCl3, 400 MHz) δ 7.37 (d, 2H, J = 7.3
Hz), 7.26 (t, 2H, J = 7.5 Hz), 7.17 (t, 1H, J = 7.3 Hz), 4.30–4.20 (m, 2H), 2.58 (td, 1H, J = 13.8, 6.7 Hz),
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2.23 (dddd, 1H, J = 31.3, 14.0, 10.0, 7.0 Hz), 0.95 (s, 9H); C{1H} NMR (CDCl3, 101 MHz) δ 145.0,
128.8, 127.5, 126.1, 124.0 (dd, J = 263.9, 250.2 Hz), 117.5 (d, J = 14.3 Hz), 60.6 (d, J = 7.5 Hz), 57.1
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(dd, J = 38.4, 23.3 Hz), 56.3, 44.2 (dd, J = 22.5, 18.9 Hz), 27.2; F NMR (377 MHz, CDCl3) δ -101.3
(dddd, 1F, J = 227.2, 31.5, 16.3, 13.7 Hz), -107.2 (dd, 1F, J = 227.3, 7.0 Hz); HRMS(ESI) m/z: [M +
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H]+ Calcd for C15H19F2N2 265.1516; Found 265.1510; IR (film): 2976, 1493, 1456, 1399, 1373, 1332,
1255, 1220, 1161, 1128, 1087, 1030, 981, 920, 838 cm-1.
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rac-(2S,5S)-1-(tert-Butyl)-3,3-difluoro-5-(4-(trifluoromethyl)phenyl)pyrrolidine-2-carbonitrile (4b).
Yield: 112.1 mg, 85%, dr = 15:1; pale yellow oil; Rf = 0.21 (PE:EA = 30:1); 1H NMR (CDCl3, 500 MHz)
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δ 7.62–7.58 (m, 4H, J = 6.0 Hz), 4.45–4.39 (m, 1H), 4.36 (d, 1H, J = 15.7 Hz), 2.76–2.65 (m, 1H), 2.28
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(dddd, 1H, J = 30.7, 14.0, 9.6, 7.2 Hz), 1.04 (s, 9H); C{1H} NMR (CDCl3, 101 MHz) δ 149.2, 129.8
(q, J = 32.4 Hz), 126.5, 125.8 (q, J = 3.7 Hz), 127.8–121.1 (m, 1C, observe complexity due to F-C
coupling), 124.1 (q, J = 271.8 Hz), 117.25 (d, J = 13.6 Hz), 60.1 (d, J = 7.1 Hz), 57.0 (dd, J = 38.1, 23.3
19
Hz), 56.5, 43.8 (dd, J = 22.7, 19.7 Hz), 27.1; F NMR (CDCl3, 471 MHz) δ -62.5 (s, 3F), -101.5 (ddt,
1F, J = 228.3, 29.7, 14.5 Hz), -106.8 (dd, 1F, J = 227.5, 6.0 Hz); HRMS (ESI) m/z: [M + H]+ Calcd for
C16H18F5N2 333.1390; Found 333.1385; IR (film): 2971, 1620, 1471, 1374, 1325, 1206, 1161, 1107,
1067, 1018, 983, 920, 841 cm-1.
rac-(2S,5S)-1-(tert-Butyl)-5-(4-chlorophenyl)-3,3-difluoropyrrolidine-2-carbonitrile (4c). Yield: 79.6
1
mg, 75%, dr > 20:1; pale yellow oil; Rf = 0.24 (PE:EA = 30:1); H NMR (CDCl3, 400 MHz) δ 7.43–
7.27 (m, 4H), 4.39–4.25 (m, 2H), 2.66 (td, 1H, J = 13.6, 6.9 Hz), 2.37–2.15 (m, 1H), 1.02 (s, 9H);
13C{1H} NMR (CDCl3, 101 MHz) δ 143.6, 133.1, 128.98, 127.5, 123.9 (dd, J = 263.8, 250.5 Hz), 117.4
(d, J = 14.1 Hz), 59.9 (d, J = 7.3 Hz), 57.0 (dd, J = 38.2, 23.3 Hz), 56.4, 44.0 (dd, J = 22.6, 19.2 Hz),
27.2; 19F NMR (CDCl3, 471 MHz) δ -101.4 (ddt, 1F, J = 227.7, 30.1, 14.8 Hz), -106.9 (dd, 1F, J = 228.1,
7.2 Hz); HRMS (ESI) m/z: [M + H]+ Calcd for C15H18ClF2N2 299.1127; Found 299.1121; IR (film):
2974, 1490, 1399, 1373, 1330, 1254, 1220, 1182, 1161, 1130, 1014, 982, 920, 830 cm-1.
rac-Methyl 4-((2S,5S)-1-(tert-Butyl)-5-cyano-4,4-difluoropyrrolidin-2-yl)benzoate (4d). Yield: 115.8
mg, 90%, dr > 20:1; pale yellow oil; Rf = 0.10 (PE:EA = 30:1); 1H NMR (CDCl3, 400 MHz) δ 8.03 (d,
2H, J = 7.6 Hz), 7.54 (d, 2H, J = 7.6 Hz), 4.45–4.30 (m, 2H), 3.92 (s, 3H), 2.70 (td, 1H, J = 13.5, 7.0
13
Hz), 2.30 (ddt, 1H, J = 30.8, 15.7, 8.6 Hz), 1.03 (s, 9H); C{1H} NMR (CDCl3, 101 MHz) δ 166.8,
150.2, 130.2, 129.6, 126.1, 126.7–120.3 (m), 117.3 (d, J = 14.0 Hz), 60.3 (d, J = 7.3 Hz), 57.0 (dd, J =
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38.3, 23.3 Hz), 56.5, 52.1, 44.3–43.1 (m), 27.1; 19F NMR (CDCl3, 471 MHz) δ -101.4 (ddt, 1F, J =
228.0, 30.2, 14.7 Hz), -106.9 (dt, J = 228.0, 6.8 Hz); HRMS (ESI) m/z: Calcd for [M + H]+
C17H21F2N2O2 323.1571; Found 323.1558; IR (film): 2975, 1722, 1612, 1471, 1437, 1373, 1331, 1280,
1205, 1130, 1116, 1085, 1019, 912 cm-1.
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rac-(2S,5S)-1-(tert-Butyl)-3,3-difluoro-5-(4-methoxyphenyl)pyrrolidine-2-carbonitrile (4e). Yield:
84.0 mg, 71%, dr > 20:1; pale yellow oil; Rf = 0.27 (PE:EA = 30:1); 1H NMR (CDCl3, 400 MHz) δ 7.35
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(d, 2H, J = 8.3 Hz), 6.87 (d, 2H, J = 8.3 Hz), 4.36–4.23 (m, 2H), 3.80 (s, 3H), 2.63 (td, 1H, J = 14.1, 6.8
Hz), 2.28 (dddd, 1H, J = 31.4, 14.2, 9.8, 7.4 Hz), 1.02 (s, 9H); 13C{1H} NMR (CDCl3, 101 MHz) δ
158.9, 137.0, 127.2, 124.0 (dd, J = 263.9, 250.3 Hz), 118.0 (d, J = 14.3 Hz), 114.1, 60. 0 (d, J = 7.6 Hz),
57.1 (dd, J = 38.3, 23.2 Hz), 56.3, 55.3, 44.2 (dd, J = 22.3, 18.4 Hz), 27.2; 19F NMR (CDCl3, 471 MHz)
δ -100.9 – -101.7 (m, 1F), -107.0 (ddd, 1F, J = 227.3, 11.0, 6.7 Hz); HRMS (ESI) m/z: Calcd for [M +
H]+ C16H21F2N2O 295.1622; Found 295.1616; IR (film): 2975, 1613, 1513, 1467, 1441, 1373, 1246,
1221, 1182, 1127, 1085, 1036, 982 cm-1.
rac-(2S,5S)-1-(tert-Butyl)-3,3-difluoro-5-(4-(methylthio)phenyl)pyrrolidine-2-carbonitrile (4f). Yield:
99.9 mg, 80%, dr > 20:1; yellow oil; Rf = 0.27 (PE:EA = 30:1); 1H NMR (CDCl3, 400 MHz) δ 7.36 (d,
2H, J = 7.4 Hz), 7.22 (d, 2H), 4.38–4.24 (m, 2H), 2.65 (td, 1H, J = 13.8, 6.9 Hz), 2.48 (s, 3H), 2.27 (ddt,
1H, J = 31.2, 16.2, 8.5 Hz), 1.02 (s, 9H); 13C{1H} NMR (CDCl3, 101 MHz) δ 141.9, 137.5, 126.9,
126.7, 126.6–120.8 (m), 117.5 (d, J = 14.2 Hz), 60.1 (d, J = 7.5 Hz), 57.0 (dd, J = 38.3, 23.2 Hz), 56.4,
44.0 (dd, J = 22.5, 18.8 Hz), 27.2, 15.8; 19F NMR (CDCl3, 471 MHz): δ -100.9 – -101.8 (m, 1F), -106.9
(dt, 1F, J = 227.6, 5.6 Hz); HRMS (ESI) m/z: [M + H]+ Calcd for C16H21F2N2S 311.1394; Found
311.1388. IR (film): 2974, 2920, 2880, 1600, 1493, 1438, 1399, 1330, 1253, 1206, 1182, 1129, 1085,
1031, 981 cm-1.
rac-(2S,5S)-1-(tert-Butyl)-3,3-difluoro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl)pyrrolidine-2-carbonitrile (4g). Yield: 68.6 mg, 44%, dr > 20:1; yellow oil; Rf = 0.15 (PE:EA
= 30:1); 1H NMR (CDCl3, 400 MHz) δ 7.79 (d, 2H, J = 8.0 Hz), 7.45 (d, 2H, J = 8.0 Hz), 4.44–4.22 (m,
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2H), 2.65 (td, 1H, J = 12.7, 11.8, 6.8 Hz), 2.39–2.20 (m, 1H), 1.34 (s, 12H), 1.02 (s, 9H); 13C{1H} NMR
(CDCl3, 101 MHz) δ 148.1, 135.3, 125.5, 123.9 (dd, J = 264.1, 250.2 Hz), 117.39 (d, J = 14.4 Hz), 83.8,
60.7 (d, J = 7.4 Hz), 57.1 (dd, J = 38.4, 23.2 Hz), 56.4, 44.0 (dd, J = 22.7, 19.0 Hz), 27.2, 24.9; 19F
NMR (CDCl3, 471 MHz) δ -100.8 – -101.5 (m, 1F), -107.1 (dd, 1F, J = 227.5, 6.9 Hz); HRMS (ESI) m/z:
calcd [M + H]+ for C21H30BF2N2O2 391.2368; Found 391.2367; IR (film): 2978, 1611, 1470, 1362, 1328,
1273, 1220, 1129, 1087, 1020, 963, 859 cm-1.
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rac-(2S,5S)-5-([1,1'-Biphenyl]-4-yl)-1-(tert-butyl)-3,3-difluoropyrrolidine-2-carbonitrile (4h). Yield:
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117.7 mg, 86%, dr > 20:1; yellow oil; Rf = 0.43 (PE:EA = 30:1); H NMR (CDCl3, 400 MHz) δ 7.61–
7.54 (m, 4H), 7.50 (d, 2H, J = 8.2 Hz), 7.43 (t, 2H, J = 7.6 Hz), 7.33 (t, 1H, J = 7.3 Hz), 4.41–4.28 (m,
2H), 2.68 (td, 1H, J = 13.8, 6.8 Hz), 2.34 (dddd, 1H, J = 31.3, 14.0, 9.9, 7.1 Hz), 1.05 (s, 2H); 13C{1H}
NMR (CDCl3, 101 MHz) δ 144.1, 140.7, 140.4, 128.8, 127.5, 127.4, 127.1, 126.6, 126.8–121.3 (m),
117.5 (d, J = 14.3 Hz), 60.3 (d, J = 7.4 Hz), 57.1 (dd, J = 38.3, 23.2 Hz), 56.4, 44.1 (dd, J = 22.5, 18.9
Hz), 27.3; 19F NMR (CDCl3, 471 MHz,) δ -101.2 (ddt, 1F, J = 227.4, 30.8, 14.9 Hz), -106.99 (d, 1F, J =
227.4 Hz); HRMS (ESI) m/z: [M + H]+ Calcd for C21H23F2N2 341.1829; Found 341.1823; IR (film):
2975, 1487, 1399, 1373, 1329, 1252, 1220, 1161, 1129, 1084, 982, 911, 838 cm-1.
rac-(2S,5S)-5-(2-Bromophenyl)-1-(tert-butyl)-3,3-difluoropyrrolidine-2-carbonitrile (4i). Yield: 117.8
mg, 86%, dr > 20:1; yellow oil, Rf = 0.40 (PE:EA = 30:1); 1H NMR (CDCl3, 400 MHz) δ 7.87 (d, 1H, J
= 7.7 Hz), 7.47 (d, 1H, J = 7.9 Hz), 7.38 (t, 1H, J = 7.5 Hz), 7.12 (t, 1H, J = 7.5 Hz), 4.77 (t, 1H, J = 8.2
Hz), 4.37 (d, 1H, J = 15.1 Hz), 2.99–2.73 (m, 1H), 2.28–2.04 (m, 1H), 1.04 (s, 9H); 13C{1H} NMR
(CDCl3, 101 MHz) δ 143.5, 132.5, 129.0, 128.8, 128.3, 124.3 (dd, J = 263.3, 251.6 Hz), 121.4, 117.3 (d,
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J = 12.9 Hz), 59.4 (d, J = 6.8 Hz), 57.0 (dd, J = 37.8, 23.3 Hz), 56.4, 42.0–41.4 (m), 26.9; F NMR
(471 MHz, CDCl3) δ -100.8 (ddt, J = 229.3, 28.2, 14.3 Hz), -104.8 (ddd, J = 229.0, 8.1, 4.8 Hz); HRMS
(ESI) m/z: calcd [M + H]+ for C15H18BrF2N2 343.0621; Found 343.0625; IR (film): 2973, 1470, 1399,
1373, 1255, 1220, 1202, 1166, 1085, 1023, 981 cm-1.
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rac-(2S,5S)-5-([1,1'-Biphenyl]-2-yl)-1-(tert-butyl)-3,3-difluoropyrrolidine-2-carbonitrile (4j). Yield:
106.5 mg, 78%, dr > 20:1; yellow oil, Rf = 0.30 (PE:EA = 30:1); 1H NMR (CDCl3, 400 MHz) δ 7.94 (d,
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1H, J = 7.9 Hz), 7.48–7.37 (m, 4H), 7.28 (t, 1H, J = 7.1 Hz), 7.21 (d, 2H, J = 6.7 Hz), 7.12 (d, 1H, J =
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7.4 Hz), 4.32–4.18 (m, 2H), 2.56 (td, 1H, J = 14.0, 6.9 Hz), 2.43–2.22 (m, 1H), 0.88 (s, 9H); C{1H}
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NMR (CDCl3, 101 MHz) δ 142.3, 140.8, 139.79, 129.6, 128.8, 128.5, 128.4, 127.5, 127.0, 126.9, 124.1
(dd, J = 263.7, 250.3 Hz), 117.4 (d, J = 14.4 Hz), 57.1 (dd, J = 38.4, 23.1 Hz), 56.8 (d, J = 7.4 Hz), 56.3,
43.9 (dd, J = 22.6, 19.0 Hz), 27.0; 19F NMR (CDCl3, 471 MHz) δ -100.9 (ddt, 1F, J = 227.3, 31.0, 15.3
Hz), -106.6 (dd, 1F, J = 227.4, 7.3 Hz); HRMS (ESI) m/z: [M + H]+ Calcd for C21H23F2N2 341.1829;
Found 341.1831; IR (film): 2971, 1478, 1439, 1373, 1252, 1220, 1197, 1164, 1083, 1026, 981 cm-1.
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rac-(2S,5S)-1-(tert-Butyl)-5-(3-chlorophenyl)-3,3-difluoropyrrolidine-2-carbonitrile (4k). Yield: 92.8
mg, 78%, dr > 20:1; pale yellow oil; Rf = 0.24 (PE:EA = 30:1); 1H NMR (400 MHz, CDCl3) δ 7.37 (d,
2H, J = 7.3 Hz), 7.26 (t, 2H, J = 7.5 Hz), 7.17 (t, 1H, J = 7.3 Hz), 4.29–4.21 (m, 2H), 2.58 (td, 1H, J =
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13.8, 6.7 Hz), 2.23 (dddd, 1H, J = 31.3, 14.0, 10.0, 7.0 Hz), 0.95 (s, 9H); C{1H} NMR (CDCl3, 101
MHz) δ 147.2, 134.6, 130.2, 127.7, 126.2, 124.3, 123.9 (dd, J = 263.9, 250.5 Hz), 117.2 (d, J = 13.9 Hz),
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60.1 (d, J = 7.3 Hz), 57.0 (dd, J = 38.2, 23.2 Hz), 56.5, 43.9 (dd, J = 22.7, 19.4 Hz), 27.15; F NMR
(CDCl3, 471 MHz) δ -101.2 (ddt, J = 228.1, 30.2, 14.7 Hz), -106.9 (dd, J = 228.3, 7.2 Hz); HRMS (ESI)
m/z: [M + H]+ Calcd for C15H18ClF2N2 299.1127; Found 299.1122; IR (film): 2975, 1598, 1475, 1434,
1373, 1349, 1328, 1220, 1202, 1130, 1035, 983 cm-1.
rac-(2S,5S)-1-(tert-Butyl)-3,3-difluoro-5-(3-nitrophenyl)pyrrolidine-2-carbonitrile (4l). Yield: 111.2
mg, 90%, dr > 20:1; pale yellow oil, Rf = 0.09 (PE:EA = 30:1); 1H NMR (CDCl3, 400 MHz) δ 8.23 (s,
1H), 8.14 (d, 1H, J = 8.0 Hz), 7.96 (d, 1H, J = 7.7 Hz), 7.60 (t, 1H, J = 7.9 Hz), 4.52–4.46 (m, 1H), 4.40
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(d, 1H, J = 15.4 Hz), 2.84–2.71 (m, 1H), 2.41–2.22 (m, 1H), 1.06 (s, 9H); C{1H} NMR (CDCl3, 101
MHz) δ 148.4, 147.3, 132.4, 130.2, 123.8 (dd, J = 263.7, 251.0 Hz), 122.8, 121.0, 117.1 (d, J = 13.3 Hz),
59.9 (d, J = 7.0 Hz), 56.9 (dd, J = 37.8, 23.2 Hz), 56.7, 43.7 (t, J = 20.3, 19.7 Hz), 27.2; 19F NMR
(CDCl3, 471 MHz) δ -101.5 (ddt, 1F, J = 228.8, 28.8, 14.3 Hz), -106.4 (ddd, 1F, J = 228.9, 7.3, 3.1 Hz);
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HRMS (ESI) m/z: [M + H]+ Calcd for C15H18F2N3O2 310.1367; Found 310.1363. IR (film): 2974, 1531,
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1477, 1401, 1374, 1352, 1255, 1219, 1163, 1088, 984 cm-1.
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Gram scale synthesis of 4l:
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Under a nitrogen atmosphere, 1-nitro-3-vinylbenzene 1l (98% purity, 635.0 mg, 4.2 mmol, 1.0 equiv),
TBAB (403.1 mg, 1.3 mmol, 0.3 equiv) and diglyme (10 mL) were added to a dry 50 mL Schlenk flask
successively. A solution of 2-isocyano-2-methylpropane 2 (1.39 g, 16.7 mmol, 4.0 equiv) and
(bromodifluoromethyl)trimethylsilane 3 (1.69 g, 8.3 mmol, 2.0 equiv), in diglyme (22 mL) was added
dropwise in 3 h at 90 ℃. The mixture was stirred at 90 ℃ for another 3 h. The solvent was removed
under reduced pressure and the residue was purified by chromatography on silica gel with PE-EA as the
eluent to afford the products. Yield: 997.5 mg, 77%. Characterization data match those that were
reported in smaller scale synthesis.
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rac-(2S,5S)-5-(Benzo[d][1,3]dioxol-5-yl)-1-(tert-butyl)-3,3-difluoropyrrolidine-2-carbonitrile (4m).
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Yield: 74.4 mg, 60%, dr > 20:1; yellow oil; Rf = 0.30 (PE:EA = 30:1); H NMR (CDCl3, 400 MHz) δ
7.01 (d, 1H, J = 1.5 Hz), 6.84 (dd, 1H, J = 8.0, 1.5 Hz), 6.74 (d, 1H, J = 7.9 Hz), 5.96 (d, 2H, J = 2.5
Hz), 4.34–4.28 (m, 1H), 4.25 (dd, 1H, J = 9.9, 6.9 Hz), 2.62 (td, 1H, J = 13.8, 6.8 Hz), 2.27 (dddd, 1H, J
= 31.1, 14.0, 10.0, 7.0 Hz), 1.04 (s, 9H); 13C{1H} NMR (CDCl3, 101 MHz): δ 148.1, 146.9, 139.1,
123.9 (dd, J = 264.1, 250.2 Hz), 119. 1, 117.4 (d, J = 14.3 Hz), 108.2, 106.5, 101.1, 60.3 (d, J = 7.6 Hz),
57.0 (dd, J = 38.4, 23.2 Hz), 56.4, 44.5 – 43.8 (m), 27.2; 19F NMR (CDCl3, 471 MHz): δ -100.8 – -101.8
(m, 1F), -107.0 (dd, 1F, J = 227.5, 6.9 Hz); HRMS (ESI) m/z: [M + H]+ Calcd for C16H19F2N2O2
309.1415; Found 309.1405; IR (film): 2976, 2915, 1504, 1488, 1372, 1244, 1219, 1181, 1085, 1039,
983 cm-1.
rac-(2S,5S)-1-(tert-Butyl)-3,3-difluoro-5-(naphthalen-2-yl)pyrrolidine-2-carbonitrile (4n). Yield: 87.2
mg, 69%, dr > 20:1; yellow oil; Rf = 0.31 (PE:EA = 30:1); 1H NMR (CDCl3, 400 MHz) δ 7.90–7.74 (m,
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4H), 7.66 (d, 1H, J = 8.5 Hz), 7.52–7.41 (m, 2H), 4.55–4.44 (m, 1H), 4.35 (d, 1H, J = 16.3 Hz), 2.69 (td,
1H, J = 13.7, 6.8 Hz), 2.49–2.25 (m, 1H), 1.03 (s, 9H); 13C{1H} NMR (CDCl3, 101 MHz) δ 142.4,
133.4, 133.1, 129.0, 127.8, 126.4, 126.0, 124.8, 124.2, 124.0 (dd, J = 264.0, 250.1 Hz), 117.6 (d, J =
14.4 Hz), 60.8 (d, J = 7.5 Hz), 57.2 (dd, J = 38.4, 23.2 Hz), 56.5, 44.0 (dd, J = 22.6, 18.9 Hz), 27.3; 19F
NMR (CDCl3, 471 MHz) δ -101.0 (ddt, 1F, J = 227.4, 30.6, 15.0 Hz), -107.0 (ddd, 1F, J = 227.5, 30.6,
6.9 Hz); HRMS (ESI): m/z [M + H]+ Calcd for C19H21F2N2 315.1673; Found 315.1666. IR (film): 2974,
1507, 1469, 1399, 1371, 1252, 1219, 1125, 1085, 1037, 986 cm-1.
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rac-(2S,5S)-5-(5-Bromofuran-2-yl)-1-(tert-butyl)-3,3-difluoropyrrolidine-2-carbonitrile (4o). Yield:
86.2 mg, 65%, dr > 20:1; yellow oil; Rf = 0.27 (PE:EA = 30:1); 1H NMR (CDCl3, 400 MHz) δ 6.35 (d,
1H, J = 3.2 Hz), 6.25 (d, 1H, J = 3.3 Hz), 4.39 (t, 1H, J = 7.4 Hz), 4.26 (dd, 1H, J = 14.3, 2.8 Hz), 2.71–
2.47 (m, 2H), 1.11 (s, 9H); 13C{1H} NMR (CDCl3, 101 MHz) δ 158.3, 124.5 (dd, J = 261.9, 252.2 Hz),
120.5, 116.8 (d, J = 9.8 Hz), 112.3, 109.5, 56.3 (dd, J = 36.5, 23.5 Hz), 56.1, 53.6 (dd, J = 5.7, 2.6 Hz),
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40.6 (t, J = 22.7, 21.0 Hz), 26.8; F NMR (CDCl3, 471 MHz) δ -100.1 (ddt, 1F, J = 229.3, 21.6, 13.9
Hz), -102.7 (dtd, 1F, J = 229.4, 9.3, 3.5 Hz); HRMS (ESI) m/z: [M + H]+ Calcd for C13H16BrF2N2O
333.0414; Found 333.0418; IR (film): 2976, 1504, 1437, 1335, 1250, 1202, 1164, 1084, 1039, 1009,
985 cm-1.
rac-(2S,5S)-5-(3-Bromothiophen-2-yl)-1-(tert-butyl)-3,3-difluoropyrrolidine-2-carbonitrile (4p). Yield:
114.0 mg, 82%, dr > 20:1; yellow oil; Rf = 0.33 (PE:EA = 30:1); 1H NMR (CDCl3, 400 MHz) δ 7.23 (d,
1H, J = 5.3 Hz), 6.86 (d, 1H, J = 5.3 Hz), 4.67 (t, 1H, J = 8.0 Hz), 4.30 (d, 1H, J = 14.9 Hz), 2.88–2.72
(m, 2H), 2.40 (ddt, 1H, J = 27.5, 14.1, 8.3 Hz), 1.11 (s, 9H); 13C{1H} NMR (CDCl3, 101 MHz) δ 145.6,
129.8, 125.3, 124.1 (dd, J = 263.4, 251.7 Hz), 116.7 (d, J = 12.2 Hz), 105.9, 56.7, 56.9–56.0 (m), 55.4
(d, J = 7.8 Hz), 42.1 (dd, J = 22.6, 20.2 Hz), 26.8; 19F NMR (CDCl3, 471 MHz) δ -100.8 (ddt, J = 229.4,
27.9, 14.1 Hz), -104.8 (ddd, J = 229.0, 8.2, 4.8 Hz); HRMS (ESI) m/z: [M + H]+ Calcd for
C13H16BrF2N2S 349.0186; Found 349.0189; IR (film): 2973, 1525, 1469, 1438, 1374, 1271, 1253, 1195,
1160, 1085, 1026, 970 cm-1.
rac-(2R,5R)-1-(tert-Butyl)-3,3-difluoro-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carbonitrile
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(4q). Yield: 119.4 mg, 77%, dr > 20:1; yellow solid; mp 90-92 ℃; Rf = 0.30 (PE:EA = 30:1); 1H NMR
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(CDCl3, 400 MHz) δ 7.50 (t, 1H, J = 7.5 Hz), 7.36 (d, 2H, J = 8.6 Hz), 7.32–7.27 (m, 1H), 7.16 (t, 1H, J
= 7.5 Hz), 7.08 (t, 1H, J = 9.2 Hz), 6.95 (d, 2H, J = 8.7 Hz), 5.11 (s, 2H), 4.35–4.22 (m, 2H), 2.62 (td,
1H, J = 13.8, 6.8 Hz), 2.27 (dddd, 1H, J = 31.3, 14.0, 10.0, 7.0 Hz), 1.02 (s, 9H); 13C{1H} NMR
(CDCl3, 101 MHz) δ 160.5 (d, J = 247.0 Hz), 158.0, 137.6, 129.8 (d, J = 1.3 Hz), 129.8 (d, J = 5.7 Hz),
127.3, 129.0–121.4 (m), 124.3 (d, J = 3.6 Hz), 124.1 (d, J = 14.2 Hz), 117.6 (d, J = 14.3 Hz), 115.4 (d, J
= 21.2 Hz), 115.0, 63.8 (d, J = 4.4 Hz), 60.0 (d, J = 7.6 Hz), 57.1 (dd, J = 38.3, 23.2 Hz), 56.3, 44.2 (dd,
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J = 22.3, 18.5 Hz), 27.2; F NMR (CDCl3, 471 MHz) δ -101.3 (ddt, 1F, J = 227.2, 30.9, 15.0 Hz), -
107.0 (d, 1F, J = 227.2 Hz), -118.7 (s, 1F); HRMS (ESI) m/z: [M + H]+ Calcd for C22H24F3N2O
389.1841; Found 389.1835; IR (film): 2974, 2877, 1611, 1510, 1494, 1457, 1373, 1235, 1172, 1128,
1084, 1022, 982 cm-1.
rac-Phenyl (2S,5S)-1-(tert-butyl)-5-cyano-4,4-difluoropyrrolidine-2-carboxylate (4r). Yield: 117.1 mg,
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95%, dr > 20:1; yellow oil; Rf = 0.10 (PE:EA = 30:1); H NMR (CDCl3, 400 MHz) δ 7.39 (t, 2H, J =
7.9 Hz), 7.25 (t, 1H, J = 7.4 Hz), 7.10 (d, 2H, J = 7.7 Hz), 4.30 (d, 1H, J = 15.2 Hz), 4.09 (t, 1H, J = 8.1
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Hz), 2.87–2.61 (m, 2H), 1.21 (s, 9H); C{1H} NMR (CDCl3, 101 MHz) δ 171.6, 150.5, 129.6, 126.2,
124.2 (dd, J = 262.7, 251.3 Hz), 121.0, 116.3 (d, J = 12.0 Hz), 58.2 (d, J = 5.9 Hz), 56.2 (dd, J = 38.0,
23.8 Hz), 56.0, 37.9 (dd, J = 24.7, 23.0 Hz), 26.5; 19F NMR (CDCl3, 471 MHz) δ -99.7 – -100.5 (m, 1F),
-105.0 (ddd, 1F, J = 229.0, 7.7, 5.0 Hz); HRMS (ESI) m/z: [M + H]+ Calcd for C16H19F2N2O2 309.1415;
Found 309.1409; IR (film): 2957, 2928, 1778, 1593, 1459, 1374, 1258, 1223, 1163, 1135, 1088, 1025,
994 cm-1.
rac-(2S,5S)-1-(tert-Butyl)-3,3-difluoro-5-((E)-styryl)pyrrolidine-2-carbonitrile (4s). Yield: 55.4 mg,
48%, dr > 20:1; yellow oil; Rf = 0.27 (PE:EA = 30:1); 1H NMR (CDCl3, 400 MHz) δ 7.41–7.29 (m, 4H),
7.28–7.21 (m, 1H), 6.49 (d, 1H, J = 16.0 Hz), 6.23 (dd, 1H, J = 15.9, 7.7 Hz), 4.20 (d, 1H, J = 15.9 Hz),
3.98 (q, 1H, J = 7.8 Hz), 2.56–2.43 (m, 1H), 2.32 (ddt, 1H, J = 27.8, 13.8, 8.6 Hz), 1.16 (s, 9H); 13C{1H}
NMR (CDCl3, 101 MHz) δ 136.4, 133.6, 129.9, 128.7, 127.8, 126.4, 124.1 (dd, J = 262.5, 250.7 Hz),
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117.5 (d, J = 12.5 Hz), 58.7 (d, J = 6.9 Hz), 56.7 (dd, J = 37.7, 23.3 Hz), 56.1, 41.0 (dd, J = 22.5, 19.2
Hz), 27.5; 19F NMR (CDCl3, 471 MHz) δ -99.6 (ddt, 1F, J = 227.4, 28.1, 14.6 Hz), -104.8 (ddd, 1F, J =
227.4, 8.2, 4.3 Hz); HRMS (ESI) m/z: [M + H]+ Calcd for C17H21F2N2 291.1673; Found 291.1671; IR
(film): 2973, 2942, 1598, 1494, 1450, 1399, 1372, 1250, 1185, 1126, 1110, 1086, 1023, 965 cm-1.
rac-(2S,5S)-5-Benzoyl-1-(tert-butyl)-3,3-difluoropyrrolidine-2-carbonitrile (4t). Yield: 95.4 mg, 82%,
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dr = 10:1; yellow solid; Rf = 0.10 (PE:EA = 30:1); H NMR (CDCl3, 400 MHz) δ 8.18 (d, J = 8.2 Hz,
2H), 7.62 (t, 1H, J = 7.4 Hz), 7.52 (t, 2H, J = 7.7 Hz), 4.63 (dd, 1H, J = 10.5, 7.0 Hz), 4.36 (d, 1H, J =
16.7 Hz), 2.71 (td, 1H, J = 13.8, 6.9 Hz), 2.52 (dddd, 1H, J = 30.3, 13.7, 10.7, 7.1 Hz), 1.12 (s, 9H);
13C{1H} NMR (CDCl3, 101 MHz) δ 198.5, 134.5, 133.8, 129.0, 128.7, 123.9 (dd, J = 264.3, 250.0 Hz),
116.4 (d, J = 14.0 Hz), 62.4–61.7 (m), 56.5 (dd, J = 38.6, 23.7 Hz), 56.1, 38.5 (dd, J = 24.6, 22.0 Hz),
26.5; 19F NMR (CDCl3, 471 MHz) δ -98.8 (dddd, 1F, J = 228.0, 30.2, 16.7, 14.0 Hz), -105.8 (dd, 1F, J =
228.0, 6.9 Hz); HRMS (ESI) m/z: [M + H]+ Calcd for C16H19F2N2O 293.1465; Found 293.1462. IR
(film): 2974, 1702, 1597, 1449, 1400, 1372, 1332, 1254, 1192, 1177, 1136, 1085, 1004, 966 cm-1.
General Procedures for the [3+2] Cycloaddition with Alkyne (5a-i). Under a nitrogen atmosphere,
the corresponding alkyne 5a-i (0.4 mmol, 1.0 equiv), 2-isocyano-2-methylpropane 2 (199.2 mg, 276 μL,
2.4 mmol, 6.0 equiv) and (bromodifluoromethyl)trimethylsilane 3 (243.6 mg, 186 μL, 1.2 mmol, 3.0
equiv), TBAB (38.6 mg, 0.12 mmol, 0.3 equiv) and toluene (3 mL) were added to a dry Schlenk tube
successively. The mixture was stirred at 80 ℃ for 6 h. The solvent was removed under reduced pressure
and the residue was purified by chromatography on silica gel with PE-EA as the eluent to afford the
products 6a-i.
1-(tert-Butyl)-3-fluoro-5-phenyl-1H-pyrrole-2-carbonitrile (6a). Yield: 57.2 mg, 59%; white solid; Rf
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= 0.56 (PE:EA = 10:1); H NMR (CDCl3, 400 MHz) δ 7.43–7.25 (m, 5H), 5.71 (s, 1H), 1.55 (s, 9H);
13C{1H} NMR (CDCl3, 101 MHz) δ 159.6 (d, J = 259.8 Hz), 137.9 (d, J = 5.9 Hz), 135.1, 130.3, 128.8,
127.9, 113.6 (d, J = 4.2 Hz), 99.8 (d, J = 12.5 Hz), 89.8 (d, J = 22.8 Hz), 62.0, 32.3; 19F NMR (CDCl3,
471 MHz) δ -148.3 (s, 1F); HRMS (ESI) m/z: [M+H]+ Calcd for C15H16FN2 243.1298; Found 243.1290;
IR (film): 2973, 2960, 2212, 1561, 1480, 1451, 1372, 1358, 1330, 1212, 1034 cm-1.
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1-(tert-Butyl)-5-(4-chlorophenyl)-3-fluoro-1H-pyrrole-2-carbonitrile (6b). Yield: 62.1 mg, 54%; white
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solid; Rf = 0.52 (PE:EA = 10:1); 1H NMR (CDCl3, 400 MHz): δ 7.35 (d, 2H, J = 8.4 Hz), 7.24 (d, 2H, J
= 8.4 Hz), 5.72 (s, 1H), 1.55 (s, 9H); 13C{1H} NMR (CDCl3, 101 MHz): δ 159.5 (d, J = 260.2 Hz),
136.3 (d, J = 6.0 Hz), 135.1, 133.5 (d, J = 1.5 Hz), 131.6, 128.2, 113.3 (d, J = 4.3 Hz), 100.1 (d, J = 12.7
Hz), 90.3 (d, J = 22.6 Hz), 62.2, 32.4; 19F NMR (CDCl3, 471 MHz): δ -148.0 (s, 1F); HRMS (ESI) m/z:
[M + H]+ Calcd for C15H15ClFN2 277.0908; Found 277.0901; IR (film): 2962, 2930, 2207, 1654, 1560,
1478, 1397, 1326, 1214, 1087, 1017, 836 cm-1.
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1-(tert-Butyl)-3-fluoro-5-(4-nitrophenyl)-1H-pyrrole-2-carbonitrile (6c). Yield: 73.1 mg, 64%; white
solid; Rf = 0.31 (PE:EA = 10:1); 1H NMR (CDCl3, 400 MHz) δ 8.26 (d, 2H, J = 8.6 Hz), 7.54 (d, 2H, J
= 8.6 Hz), 5.79 (s, 1H), 1.58 (s, 9H); 13C{1H} NMR (CDCl3, 101 MHz) δ 159.3 (d, J = 260.9 Hz), 148.0,
141.7, 134.8 (d, J = 6.0 Hz), 131.2, 123.2, 112.8, 100.6 (d, J = 13.2 Hz), 91.4 (d, J = 22.5 Hz), 62.5,
32.4; 19F NMR (CDCl3, 471 MHz) δ -147.5 (s, 1F); HRMS (ESI) m/z: [M + H]+ Calcd for C15H15FN3O2
288.1148; Found 288.1142; IR (film): 3001, 2961, 2208, 1601, 1561, 1479, 1376, 1286, 1103, 1017, 864
cm-1.
1-(tert-Butyl)-3-fluoro-5-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2-carbonitrile (6d). Yield: 86.2 mg,
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69%; white solid; Rf = 0.52 (PE:EA = 10:1); H NMR (CDCl3, 400 MHz) δ 7.65 (d, 2H, J = 8.1 Hz),
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7.46 (d, 2H, J = 8.0 Hz), 5.75 (s, 1H), 1.56 (s, 9H); C{1H} NMR (CDCl3, 101 MHz) δ 159.4 (d, J =
260.4 Hz), 138.8, 135.9 (d, J = 6.0 Hz), 131.0 (q, J = 32.8 Hz), 130.7, 124.9 (q, J = 3.7 Hz), 123.8 (q, J
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= 272.4 Hz), 113.1 (d, J = 4.3 Hz), 100.3 (d, J = 13.0 Hz), 90.7 (d, J = 22.6 Hz), 62.3, 32.4; F NMR
(CDCl3, 471 MHz) δ -62.8 (s, 3F), -147.9 (s, 1F); HRMS (ESI) m/z: [M + H]+ Calcd for C16H15F4N2
311.1171; Found 311.1164; IR (film): 2988, 2215, 1621, 1567, 1481, 1364, 1215, 1169, 1167, 850 cm-1.
1-(tert-Butyl)-5-(4-cyanophenyl)-3-fluoro-1H-pyrrole-2-carbonitrile (6e). Yield: 74.0 mg, 69%; pale
yellow solid; Rf = 0.17 (PE:EA = 10:1); 1H NMR (CDCl3, 400 MHz) δ 7.69 (d, 2H, J = 8.2 Hz), 7.47 (d,
2H, J = 8.2 Hz), 5.76 (s, 1H), 1.56 (s, 9H); 13C{1H} NMR (CDCl3, 101 MHz) δ 159.4 (d, J = 260.7 Hz),
139.8, 135.3 (d, J = 5.9 Hz), 131.7, 131.0, 118.1, 112.9 (d, J = 4.3 Hz), 112.8, 100.4 (d, J = 13.2 Hz),
91.1 (d, J = 22.5 Hz), 62.4, 32.4; 19F NMR (CDCl3, 471 MHz) δ -147.6 (s, 1F); HRMS (ESI) m/z: [M +
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H]+ Calcd for C16H15FN3 268.1250; Found 268.1243; IR (film): 2962, 2215, 1610, 1481, 1376, 1325,
1215, 1168, 1108, 850 cm-1.
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1-(tert-Butyl)-3-fluoro-5-(4-methoxyphenyl)-1H-pyrrole-2-carbonitrile (6f). Yield: 50.3 mg, 46%;
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yellow oil; Rf = 0.33 (PE:EA = 10:1); H NMR (CDCl3, 400 MHz) δ 7.20 (d, 2H, J = 8.7 Hz), 6.88 (d,
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2H, J = 8.7 Hz), 5.70 (s, 1H), 3.84 (s, 3H), 1.54 (s, 9H); C{1H} NMR (CDCl3, 101 MHz) δ 159.9,
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159.6 (d, J = 259.8 Hz), 137.7 (d, J = 6.1 Hz), 131.5, 127.1, 113.7 (d, J = 4.2 Hz), 113.3, 99.9 (d, J =
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12.2 Hz), 89.6 (d, J = 22.6 Hz), 61.9, 55.3, 32.3; F NMR (CDCl3, 471 MHz) δ -148.4 (s, 1F); HRMS
(ESI) m/z: [M + H]+ Calcd for C16H18FN2O 273.1403; Found 273.1393; IR (film): 2956, 2838, 1613,
1529, 1481, 1441, 1324, 1249, 1216, 1109, 839 cm-1.
1-(tert-Butyl)-5-(2-chlorophenyl)-3-fluoro-1H-pyrrole-2-carbonitrile (6g). Yield: 75.1 mg, 68%; pale
yellow solid; Rf = 0.43 (PE:EA = 10:1); 1H NMR (CDCl3, 400 MHz) δ 7.45–7.25 (m, 4H), 5.69 (s, 1H),
13
1.55 (s, 9H); C{1H} NMR (CDCl3, 101 MHz) δ 159.5 (d, J = 259.9 Hz), 135.1, 134.4, 133.6 (d, J =
19
6.3 Hz), 132.2, 130.6, 129.4, 126.4, 113.3, 99.4 (d, J = 12.8 Hz), 90.2 (d, J = 22.7 Hz), 62.1, 31.3; F
NMR (CDCl3, 471 MHz) δ -147.7 (s, 1F); HRMS (ESI) m/z: [M + H]+ Calcd for C15H15ClFN2 277.0908;
Found 277.0899; IR (film): 2991, 2214, 1566, 1479, 1444, 1374, 1327, 1216, 1061, 1032, 798 cm-1.
1-(tert-Butyl)-3-fluoro-5-(thiophen-2-yl)-1H-pyrrole-2-carbonitrile (6h). Yield: 46.4 mg, 47%; yellow
solid; Rf = 0.48 (PE:EA = 10:1); 1H NMR (CDCl3, 400 MHz) δ 7.41 (dd, 2H, J = 5.1, 1.2 Hz), 7.06–6.99
(m, 4H), 5.89 (s, 1H), 1.62 (s, 9H); 13C{1H} NMR (CDCl3, 101 MHz) δ 159.0 (d, J = 259.8 Hz), 134.4,
130.6, 129.0 (d, J = 6.8 Hz), 127.6, 126.6, 113.1, 102.2 (d, J = 12.3 Hz), 91.2 (d, J = 22.4 Hz), 62.4,
31.8; 19F NMR (CDCl3, 471 MHz) δ -148.3 (s, 1F); HRMS (ESI) m/z: [M + H]+ Calcd for C13H14FN2S
249.0862; Found 249.0858; IR (film): 2975, 2214, 1706, 1653, 1547, 1480, 1372, 1205, 1092, 848 cm-1.
Ethyl 1-(tert-butyl)-5-cyano-4-fluoro-1H-pyrrole-2-carboxylate (6i). Yield: 88.8 mg, 93%; red oil; Rf
1
= 0.45 (PE:EA = 10:1); H NMR (CDCl3, 400 MHz) δ 6.41 (s, 1H), 4.32 (q, 2H, J = 7.1 Hz), 1.81 (s,
13
9H), 1.37 (t, 3H, J = 7.1 Hz); C{1H} NMR (CDCl3, 101 MHz) δ 161.4 (d, J = 2.6 Hz), 157.8 (d, J =
259.9 Hz), 127.3 (d, J = 5.0 Hz), 111.9 (d, J = 4.5 Hz), 103.4 (d, J = 13.7 Hz), 94.3 (d, J = 23.1 Hz),
62.8, 62.0, 30.9, 14.0; 19F NMR (CDCl3, 471 MHz) δ -148.5 (s, 1F); HRMS (ESI) m/z: [M + H]+ Calcd
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The Journal of Organic Chemistry
for C12H16FN2O2 239.1196; Found 239.1191; IR (film): 2990, 2220, 1729, 1559, 1467, 1342, 1210,
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1153, 822 cm-1.
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
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Corresponding Author
*Email: wangjb@pku.edu.cn.
ORCID
Jianbo Wang: 0000-0002-0092-0937
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The project is supported by NSFC (Grant 91956104).
Supporting Information
The Supporting Information is available free of charge at http://pubs.acs.org.
Optimization of reaction conditions for alkyne substrates; mechanistic experimental details; X-ray
crystallographic data for 4a and 6a; DFT calculation; and copies of H and 13C spectra for all
1
products.
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cycloaddition product was observed. Chloroform-d was less acidic and failed to give any deuterated
products.
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