Direct N-gem-difluorocyclopropylation of nitro-heterocycles by utilizing gem-difluorocyclopropyl tosylate

Article abstract of DOI:10.1016/j.cclet.2013.11.027

We have developed an efficient method to achieve N-gem- difluorocyclopropylation of N-heterocycles with the use of gem- difluorocyclopropyl tosylate as a building block under mild conditions. gem-Difluorocyclopropyl tosylates could be easily prepared on a large scale and exhibit great stability.

Full text of DOI:10.1016/j.cclet.2013.11.027

Accepted Manuscript
Title: Direct N-gem-difluorocyclopropylation of
nitro-heterocycles by utilizing gem-difluorocyclopropyl
tosylate
Author: Wei-Peng Gu Jin-Hong Lin Ji-Chang Xiao
PII:
S1001-8417(13)00525-1
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2013.11.027
CCLET 2774
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
2-9-2013
29-10-2013
8-11-2013
Please cite this article as: W.-P. Gu, J.-H. Lin, J.-C. Xiao, Direct
N-gem-difluorocyclopropylation
gem-difluorocyclopropyl tosylate,
http://dx.doi.org/10.1016/j.cclet.2013.11.027
of
nitro-heterocycles
Chinese Chemical
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(2013),
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Graphical Abstract
Direct N-gem-difluorocyclopropylation of nitro-heterocycles by utilizing gem-difluorocyclopropyl tosylate
Wei-Peng Gu, Jin-Hong Lin, Ji-Chang Xiao*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
R
X
R
Y
X
N
F
Y
F
N
H
O
S
F
NaH, HMPA
1 h, r.t.
O
+
F
or
or
O
O
O
F
F
NH
O
N
O
2a
3
4
N-gem-Difluorocyclopropylation of N-heterocycles with the use of gem-difluorocyclopropyl tosylate as building block under mild conditions
was described. gem-Difluorocyclopropyl tosylates could be easily prepared on a large scale and exhibit great stability.
Page 1 of 7

Original article
Direct N-gem-difluorocyclopropylation of nitro-heterocycles by utilizing gem-
difluorocyclopropyl tosylate
Wei-Peng Gu, Jin-Hong Lin, Ji-Chang Xiao∗
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
ARTICLE INFO
ABSTRACT
We have developed an efficient method to achieve N-gem-difluorocyclopropylation of N-
heterocycles with the use of gem-difluorocyclopropyl tosylate as a building block under mild
conditions. gem-Difluorocyclopropyl tosylates could be easily prepared on a large scale and
exhibit great stability.
Article history:
Received 2 September 2013
Received in revised form 29 October 2013
Accepted 8 November 2013
Available online
Keywords:
N-gem-Difluorocyclopropylation
N-Heterocycles
gem-Difluorocyclopropyl tosylate
Building block
1. Introduction
The sharp increase in the number of fluorine-containing pharmaceuticals and agrochemicals clearly demonstrates the exceptional
importance of fluorinated compounds [1-5]. As one of the important classes of fluorinated molecules, gem-difluorocyclopropanes have
attracted much attention due to the unique biological activities of the gem-difluorocyclopropyl group [6-16]. Since N-heterocycles are
valuable subunits of many pharmacologically active compounds, the incorporation of gem-difluorocyclopropyl moieties into N-
heterocycles might significantly improve the bioactivities of N-heterocycles [8]. Therefore, the synthesis of gem-difluorocyclopropyl
group substituted N-heterocylces continues to be an important goal of organic chemists [17-18]. Traditional method for the preparation of
gem-difluorocyclopropanes is [2+1] cycloaddition of difluorocarbene with alkenes [15-20]. Another largely unexplored approach
involves the use of building blocks [12, 21-23]. The second approach is very promising because it can construct unique molecules which
can not be easily obtained by [2+1] cycloaddition. As part of our continuing interest in gem-difluorocyclopropanes chemistry [24-28], we
described the design and synthesis of gem-difluorocyclopropane building blocks and the application of them to N-gem-
difluorocyclopropylation of N-heterocycles.
The reported gem-difluorocyclopropane building blocks include silyl, stannyl, vinyl and boron substituted gem-difluorocyclopropanes
(Scheme 1) [21-23, 12]. Silyl substituted building blocks could act as anion equivalents in the presence of a catalytic amount of fluoride
[21]. Stannyl and vinyl groups are valuable functionalities for transition-metal-catalyzed transformations such as alkene metathesis [22-
23]. The homologation of boron substituted gem-difluorocyclopropanes with lithium carbenoids and the subsequent oxidation was able to
afford a variety of gem-difluorocyclopropanes [12]. In this study, we found that gem-difluorocyclopropyl tosylate could act as a cation
equivalent to achieve N-gem-difluorocyclopropylation of nitro-heterocylces.
F
F
F
F
O
S
3
1
R
R
O
R
FG
2
R
O
FG = SiMe , SnBu , CH =CH-, B(pin)
3
3
2
This work
Known building blocks
Scheme 1. gem-Difluorocyclopropane building blocks.
∗ Corresponding author.
E-mail address: jchxiao@sioc.ac.cn
Page 2 of 7

2. Experimental
1H NMR spectra were recorded on a Bruker AM 300 (300 MHz) spectrometer with TMS as an internal standard (negative for upfield).
19F NMR spectra were recorded on a Bruker AM 300 (282 MHz) with CFCl3 as an external standard (negative for upfield). 13C NMR
spectra were recorded on a Bruker AM 400 (100 MHz) spectrometer with CDCl3 as an internal standard (negative for upfield). MS and
HRMS were recorded on a Hewlett–Packard HP-5989A spectrometer and a Finnigan MAT-8483 mass spectrometer. Elementary
analyses were obtained on a Perkin–Elmer 2400 Series II Elemental Analyzer. Infrared spectra were measured with a Perkin–Elmer 983
spectrometer. TLC analysis was performed on silica gel plates, column chromatography over silica gel (mesh 300–400). All solvents for
reactions were dried by standard methods.
2.1 General procedure for preparation of vinyl sulfonic esters (1a-c)
Into anhydrous THF (110 mL) was added n-BuLi (2.5 mol/L, 40 mL) under N2, and the mixture was stirred at 35 ºC for 4 h. After
being cooled to -78 ºC, the solution of sulfonyl chloride (80 mmol) in anhydrous THF (40 mL) was added dropwise in 0.5 h. The
resulting mixture was stirred at -78 ºC for 1 h and warmed to room temperature and stirred for another 1 h. The reaction system was
poured into water (150 mL) and extracted with ether (80 mL×4). The organic phase was wash with brine, dried over MgSO4, then
concentrated under reduced pressure. The residue was subjected to flash column chromatography to give the products 1a-c.
Vinyl 4-methylbenzenesulfonate 1a: colorless oil (48%). 1H NMR (300 MHz, CDCl3): δ 7.78 (d, 2H, J = 8.8 Hz), 7.35 (d, 2H, J = 8.8
Hz), 6.68 (dd, 1H, J = 13.4 Hz, J = 5.8 Hz), 4.89 (dt, 1H, J = 13.4 Hz, J = 2.4 Hz), 4.69 (dt, 1H, J = 5.8 Hz, J = 2.4 Hz) 2.45 (s, 3H).
1
Vinyl 4-nitrobenzenesulfonate 1b: colorless oil (46%). H NMR (300 MHz, CDCl3): δ 8.43 (d, 2H, J = 8.7 Hz), 8.13 (d, 2H, J = 8.7
Hz), 6.66 (dd, 1H, J = 13.3Hz, J = 5.9 Hz), 4.97 (dd, 1H, J = 13.3 Hz, J = 2.7 Hz), 4.81 (dd, 1H, J = 5.9 Hz, J = 2.7 Hz). 13C NMR (100
MHz, CDCl3): δ 151.1, 141.4, 141.2, 129.4, 124.5, 104.1. IR (cm-1): 3105, 3088, 3067, 1638, 1608, 1527, 1404, 1381, 1350, 1306, 1192,
1104, 1086. MS (EI) m/z: 186 (100.00), 165 (10.90), 122 (73.44), 92 (19.41), 76 (33.05), 75 (27.08), 74(10.26), 50 (22.33). Anal. Calcd.
for C8H7NO5S: C, 41.92; H, 3.08; N, 6.11. Found: C, 41.90; H, 3.16; N, 6.01.
Vinyl benzenesulfonate 1c: colorless oil (45%). 1H NMR (300 MHz, CDCl3): δ 7.92 (d, 2H, J = 7.3 Hz), 7.69 (t, 1H, J = 7.3 Hz), 7.57
(t, 2H, J = 7.3 Hz), 6.62 (dd, 1H, J = 13.7 Hz, J = 6.0 Hz), 4.90 (dd, 1H, J = 13.7 Hz, J = 2.3 Hz), 4.70 (dd, 1H, J = 6.0 Hz, J = 2.3 Hz).
2.2 General procedure for preparation of gem-difluorocyclopropyl sulfonic esters (2a-c)
Into the mixture of vinyl sulfonic esters 1a-c (50 mmol) and NaF (210 mg, 10 mol %) in xylene (5 mL) at 120 °C was added TFDA
(75 g, 6 equiv.) dropwise in 2 h. The resulting mixture was then stirred for 2 h at the same temperature. After being cooled to room
temperature, the solution was concentrated to remove the solvent. The residue was purified by chromatography on a silica gel to give 2a-
c.
2, 2-Difluorocyclopropyl 4'-methylbenzenesulfonate 2a: colorless oil (78%). 1H NMR (300 MHz, CDCl3): δ 7.82 (dd, 2H, J = 7.7 Hz,
J = 2.8 Hz), 7.38 (d, 2H, J = 7.7 Hz), 4.18-4.29 (m, 1H), 2.47 (d, 3H, J = 2.8 Hz), 1.54-1.80 (m, 2H). 19F NMR (282 MHz, CDCl3): δ -
132.5 (dm, 1F, J = 170 Hz), -144.9 (ddd, 1F, J = 170 Hz, J = 16.0 Hz, J = 7.0Hz). 13C NMR (100 MHz, CDCl3): δ 145.9, 132.0, 130.0,
128.2, 107.6 (t, J = 283.1 Hz), 54.5 (dd, J = 16.0 Hz, J = 9.0 Hz), 21.6, 17.9 (t, J = 6.8 Hz). IR (cm-1): 3067, 1930, 1597, 1474, 1368,
1311, 1233, 1196, 1120, 1092, 1018. EI-MS (m/z): 157 (3.72), 156 (13.08), 155 (56.64), 92 (12.83), 91 (100.00), 89 (6.27), 65 (22.80),
63 (5.12). Anal. Calcd. for C10H10F2O3S: C, 48.38; H, 4.06. Found: C, 48.45; H, 4.21.
2, 2-Difluorocyclopropyl 4'-nitrobenzenesulfonate 2b: colorless solid (80%). 1H NMR (300 MHz, CDCl3): δ 8.45 (d, 2H, J = 8.7 Hz),
8.16 (d, 2H, J = 8.7 Hz), 4.34-4.46 (m, 1H), 1.66-1.93 (m, 2H). 19F NMR (282 MHz, CDCl3): δ -132.0 (dm, 1F, J = 171.2 Hz), -144.9
(ddd, 1F, J = 171.2 Hz, J = 14.4 Hz, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3): δ 151.3, 140.8, 129.7, 124.6, 107.3 (t, J = 290.5 Hz), 55.1
(dd, J = 16.3 Hz, J = 9.6 Hz), 18.2 (t, J = 11.4 Hz). IR (cm-1): 3111, 3072, 3023, 2876, 1610, 1539, 1473, 1376, 1349, 1305, 1246, 1202,
1104, 1088, 988. MS (EI) m/z: 187 (31.99), 186 (100.00), 122 (77.93), 77 (58.04), 76 (62.85), 75 (42.23), 65 (42.73), 50 (36.54); Anal.
Calcd. for C9H7F2NO5S: C, 38.71; H, 2.53; N, 5.02. Found: C, 38.66; H, 2.70; N, 5.04.
2,2-Difluorocyclopropyl benzenesulfonate 2c: colorless oil (75%). 1H NMR (300 MHz, CDCl3): δ 7.96 (d, 2H, J = 7.8 Hz), 7.72 (t,
1H, J = 7.8 Hz), 7.60 (t, 2H, J = 7.8 Hz), 4.20-4.33 (m, 1H), 1.55-1.82 (m, 2H). 19F NMR (282 MHz, CDCl3): δ -132.3 (dm, 1F, J = 171.2
Hz), -144.7 (ddd, 1F, J = 171.2 Hz, J = 15.4 Hz, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3): δ 135.2, 134.6, 129.5, 128.3, 107.5 (t, J =
291.6 Hz), 54.6 (dd, J = 16.2 Hz, J = 9.6 Hz), 18.0 (t, J = 11.0 Hz). IR (cm-1): 3108, 3068, 1586, 1477, 1450, 1378, 1310, 1238, 1192,
1120, 1093, 1010, 986. MS (EI) m/z: 142 (16.28), 141 (54.31), 94 (3.74), 78 (22.45), 77 (100.00), 65 (6.23), 51 (26.12), 50 (7.82); Anal.
Calcd. for C9H8F2O3S: C, 46.15; H, 3.44. Found: C, 46.55; H, 3.69.
2.3 General procedure for the N-gem-difluorocyclopropylation of heterocycles (4a-g)
Into the suspension of sodium hydride (1 mmol) in anhydrous HMPA (1 mL) under N2 was added a solution of heterocycles 3a-g (1
mmol) in anhydrous HMPA (1 mL). The mixture was stirred for 1 h at room temperature. Then the solution of 2a (1.1 mmol) in
anhydrous HMPA (1 mL) was added dropwise in 15 minutes. The reaction system was stirred until the heterocycle was consumed
completely, as detected by TLC. The reaction mixture was poured into water (20 mL) and extracted with ether (15 mL×3).The organic
phase was washed with water (20 mL), dried over MgSO4, then concentrated under reduced pressure. The residue was subjected to flash
column chromatography to give the products 4a-g.
1-(2, 2-Difluorocyclopropyl)-indole 4a: colorless oil (57%). 1H NMR (300 MHz, CDCl3): δ 7.62 (d, 1H, J = 7.3 Hz), 7.41 (d, 1H, J =
7.3 Hz), 7.25 (t, 1H, J = 7.3 Hz), 7.15 (t, 1H, J = 7.3 Hz), 7.08 (s, 1H), 6.51 (s, 1H), 3.73-3.91 (m, 1H), 1.81-2.17 (m, 2H). 19F NMR (282
Page 3 of 7

MHz, CDCl3): δ -130.0 (dm, 1F, J = 166.0 Hz), -141.6 (ddd, 1F, J = 166.0 Hz, J = 14.4 Hz, J = 5.2Hz). 13C NMR (100 MHz, CDCl3): δ
137.1, 128.8, 127.4, 122.4, 121.2, 120.5, 110.4 (t, J = 284.2 Hz), 109.9, 102.9, 34.3 (dd, J = 16.6 Hz, J = 9.3 Hz), 18.5 (t, J = 10.7 Hz).
IR (cm-1): 3106, 3055, 3018, 2917, 1613, 1517, 1463, 1311, 1232, 1206, 1021, 969. MS (EI) m/z: 193 (M+, 100.00), 192 (70.43), 172
(48.31), 143 (56.55), 142 (20.51), 129 (16.60), 115 (17.78), 89 (19.52). Anal. Calcd. for C11H9F2N: C, 68.39; H, 4.70; N, 7.25. Found: C,
68.21; H, 4.54; N, 7.23.
1
1-(2, 2-Difluorocyclopropyl)-2-methyl-indole 4b: colorless oil (69%). H NMR (300 MHz, CDCl3): δ 7.50 (d, 1H, J = 6.9 Hz), 7.32
(d, 1H, J = 7.3 Hz), 7.01-7.25 (m, 2H), 6.27 (s, 1H), 3.60-3.73 (m, 1H), 2.46 (s, 3H), 1.91-2.28 (m, 2H). 19F NMR (282 MHz, CDCl3): δ -
130.8 (dm, 1F, J = 160.9 Hz), -141.6 (ddd, 1F, J = 160.9 Hz, J = 13.4 Hz, J = 5.1Hz). 13C NMR (100 MHz, CDCl3): δ 138.2, 137.4,
128.7, 121.2, 120.2, 120.1, 110.4 (t, J = 282.9 Hz), 109.8, 101.8, 33.1 (dd, J = 16.7 Hz, J = 9.7 Hz), 18.5 (t, J = 10.6 Hz), 12.78. IR (cm-
1): 3101, 3017, 2994, 2955, 1608, 1557, 1479, 1462, 1393, 1323, 1312, 1241, 1220, 1027, 965. MS (EI) m/z: 207 (M+, 100.00), 206
(46.43), 192 (61.53), 186 (49.25), 172 (37.69), 157 (29.01), 156 (45.29), 115 (46.46). Anal. Calcd. for C12H11F2N: C, 69.55; H, 5.35; N,
6.76. Found: C, 69.61; H, 5.47; N, 6.64.
1
1-(2, 2-Difluorocyclopropyl)-3-aceyl-indole 4c: colorless oil (63%). H NMR (300 MHz, CDCl3): δ 8.36 (m, 1H), 7.72 (s, 1H), 7.28-
7.45 (m, 3H), 3.84-3.99 (m, 1H), 2.50 (s, 3H), 2.12-2.31 (m, 1H), 1.91-2.01 (m, 1H). 19F NMR (282 MHz, CDCl3): δ -129.8 (dm, 1F, J =
162.9 Hz), -140.9 (ddd, 1F, J = 162.9 Hz, J = 14.5 Hz, J = 6.2Hz). 13C NMR (100 MHz, CDCl3): δ 193.09, 134.2, 126.1, 124.0, 124.0
123.2, 122.8, 118.3, 110.1, 109.5 (t, J = 286.3 Hz), 34.4 (dd, J = 16.6 Hz, J = 9.7 Hz), 27.6, 18.5 (t, J = 11.1 Hz). IR (cm-1): 3133, 3106,
3005, 1639, 1533, 1475, 1460, 1381, 1306, 1229, 1216, 1008, 915. MS (EI) m/z: 235 (M+, 59.76), 200 (48.11), 192 (74.05), 172 (100.00),
170 (91.98), 115 (38.60), 87 (55.43), 43 (40.09). Anal. Calcd. for C13H11F2NO: C, 66.38; H, 4.71; N, 5.95. Found: C, 66.53; H, 4.90; N,
5.94.
1
1-(2, 2-Difluorocyclopropyl)benzimidazole 4d: colorless oil (55%). H NMR (300 MHz, CDCl3): δ 7.97 (s, 1H), 7.83 (dm, 1H, J =
5.9Hz), 7.48 (d, 1H, J = 6.8Hz), 7.29-7.48 (m, 2H), 3.85-4.00 (m, 1H), 2.15-2.35 (m, 1H), 1.93-2.10 (m, 1H). 19F NMR (282 MHz,
CDCl3): δ -130.9 (dm, 1F, J = 161.8 Hz), -140.9 (dm, 1F, J = 161.8 Hz). 13C NMR (100 MHz, CDCl3): δ 143.3, 142.6, 134.2, 123.8,
122.8, 120.4, 110.0, 109.5 (t, J = 286.9 Hz), 32.3 (dd, J = 16.6 Hz, J = 10.0 Hz), 18.2 (t, J = 11.0 Hz). IR (cm-1): 3093, 3019, 1615, 1497,
1458, 1369, 1315, 1226, 1105, 1023. MS (EI) m/z: 194 (M+, 100.00), 193 (57.84), 167 (60.84), 144 (36.17), 103 (37.52), 77 (21.50), 76
(48.14), 50 (20.60). Anal. Calcd. for C10H8F2N2: C, 61.85; H, 4.15; N, 14.43. Found: C, 61.84; H, 4.44; N, 14.31.
1
1-(2, 2-Difluorocyclopropyl) -6-nitro-benzimidazole 4e: white solid (54%). H NMR (300 MHz, CDCl3): δ 7.51-8.79 (m, 4H), 3.95-
4.12 (m, 1H), 2.27-2.49 (m, 1H), 1.99-2.18 (m, 1H). 19F NMR (282 MHz, CDCl3): δ -130.3 (dm, 1F, J = 162.9 Hz), -140.9 (dm, 1F, J =
162.9 Hz). 13C NMR (100 MHz, CDCl3): δ 138.2, 137.4, 128.7, 121.1, 120.2, 120.0, 110.3 (t, J = 286.3 Hz), 109.7, 33.0 (dd, J = 16.8 Hz,
J = 9.4 Hz), 18.5 (t, J = 11.0 Hz). IR (cm-1): 3101, 3014, 1619, 1593, 1517, 1482, 1345, 1308, 1226, 1203, 1063, 1023, 966. MS (EI) m/z:
239 (M+, 94.16), 222 (100.00), 193 (43.36), 192 (51.91), 173 (39.64), 102 (28.53), 75 (53.67), 74 (26.49). Anal. Calcd. for C10H7F2N3O2:
C, 50.22; H, 2.95; N, 17.57. Found: C, 49.96; H, 3.22; N, 17.57.
N-(2, 2-Difluorocyclopropyl)phthalimide 4f: white solid (65%). 1H NMR (300 MHz, CDCl3): δ 7.84-7.92 (m, 2H), 7.72-7.79 (m, 2H),
3.22-3.32 (m, 1H), 2.02-2.24(m, 2H). 19F NMR (282 MHz, CDCl3): δ -134.0 (dm, 1F, J = 163.3 Hz), -142.7 (dm, 1F, J = 163.3 Hz).
1
1-(2, 2-Difluorocyclopropyl)benzotriazole 4g: colorless oil (60%). H NMR (300 MHz, CDCl3): δ 8.08 (d, 1H, J = 8.1 Hz), 7.63 (d,
1H, J = 8.1 Hz), 7.56 (dd, 1H, J = 8.1Hz, J = 6.9 Hz), 7.41 (dd, 1H, J = 8.1Hz, J = 6.9 Hz), 4.22-4.39 (m, 1H), 2.58-2.77 (m, 1H), 2.33-
2.52 (m, 1H). 19F NMR (282 MHz, CDCl3): δ -131.2 (dm, 1F, J = 162.8 Hz), -141.9 (ddd, 1F, J = 162.8 Hz, J = 13.5 Hz, J = 7.5 Hz). 13
C
NMR (100 MHz, CDCl3): δ 145.5, 133.6, 127.8, 124.1, 119.8, 108.9, 108.5 (t, J = 285.6 Hz), 34.7 (dd, J = 16.9 Hz, J = 10.3 Hz), 18.5 (t,
J = 11.2 Hz). IR (cm-1): 3109, 3029, 1614, 1495, 1478, 1454, 1316, 1233, 1178, 1099, 1021, 1008, 978. MS (EI) m/z: 166 (35.83), 148
(28.73), 140 (23.56), 103 (73.87), 173 (39.64), 91 (24.60), 76 (100.00), 50 (32.81). Anal. Cald. for C9H7F2N3: C, 55.39; H, 3.62; N,
21.53. Found: C, 55.22; H, 3.69; N, 21.45.
3. Results and discussion
Since tosylate was an excellent leaving group, we assumed gem-difluorocyclopropyl sulfonic esters could be used for direct N-
difluorocyclopylation via simple nucleophilic substitution. So the initial effort was directed towards the synthesis of these building
blocks. Fortunately, gem-difluorocyclopropyl sulfonic esters (2a-2c) could be easily obtained by gem-difluorocyclopropanation of vinyl
sulfonic esters 1a-c with trimethylsilyl fluorosulfonyldifluoroacetate (TFDA), which has proved to be an efficient difluorocarbene
reagent (Scheme 2) [19-20]. Slow addition of TFDA to vinyl sulfonic esters in xylene with a catalytic amount of NaF gave gem-
difluorocyclopyl tosylates in moderate to good yields. The desired products 2a-c could be prepared in gram scale and are stable to air and
water.
O
F
TFDA, NaF
xylene
F
O
S
O
S
R
O
R
O
O
2a: 78%
2b: 80%
2c: 75%
1a: R = Me
1b: R = NO2
1c: R = H
Scheme 2. The synthesis of gem-difluorocyclopropyl sulfonic esters.
Page 4 of 7

With these reagents in hand, we next explored N-gem-difluorocyclopropylation of indole with 2a. We believed the reaction would
proceed via the SN2 process instead of SN1 because the strong destabilization effect of β-fluorine and strain energy make it hard to form a
cation intermediate of cyclopropane. One of the issues for this nucleophilic substitution is the regioselectivity of indole because the C3-
position is also very reactive towards electrophiles. The problem could be solved by the addition of 2a solution into indole anion, which
is generated from the reaction of indole with strong base. The other issue is the decomposition of 2a in the presence of strong base due to
deprotonation followed by β-fluorine elimination. The decomposition should be able to be suppressed if the base is used without excess.
Indeed, this transformation in HMPA could give the desired product with excellent regioselectivity at room temperature with 1 equiv.
of sodium hydride (Table 1, entry 1). The further screening of the ratio of substrates and reaction time (entries 2-4) showed that
reasonable yield could be obtained with the use of 1.1 equiv. of 2a, the conversion of which was completed in 1 h (entry 2). Highly polar
solvent is favorable for the reaction (entries 5 and 6), but a less polar solvent resulted in no expected product (entry 7). It was found that
the yield was increased slightly by slowing down the addition rate of 2a solution (entry 8).
Table 1
Optimization of reaction conditions for N-difluorocyclopropylation of heterocycles.a
F
O
S
F
NaH (1 equiv.)
solvent, r.t.
N
+
O
N
O
F
H
F
4a
3a
2a
Entry
Solvent
HMPA
HMPA
HMPA
HMPA
DMF
DMSO
THF
HMPA
2a : 3ab Time (h)
Yield (%)c
1
2
3
4
5
6
7
8d
1.0 : 1
1.1 : 1
1.2 : 1
1.1 : 1
1.1 : 1
1.1 : 1
1.1 : 1
1.1 : 1
1
1
1
1.5
1
1
1
1
47
51
51
51
51
51
ND
58
a Reaction conditions: 2a solution (1 mL solvent) was added into the reaction system of indole (1 mmol) and NaH (1 mmol) in solvent (1 mL) at r.t.
b Molar ratio;
c Determined by 19F NMR with the use of trifluoromethyl benzene as internal standard;
d The addition of 2a solution was completed in 15 min.
The scope of substrates was explored (Table 2) under the optimized reaction conditions (Table 1, entry 8). Irrespective of whether the
indole was substituted by an electron-withdrawing or an electron-donating group, the conversion occurred smoothly to give the desired
gem-difluorocyclopropylation product in moderate yields (Table 2, entries 1-3). Similar results were obtained in the case of
benzimidazoles (entries 4 and 5). Phthalimide could also be converted well into the expected product (entry 6). For benzotriazole, the
reaction needs a higher temperature in order to get a reasonable yield due to the low nucleophilic ability of the corresponding anion
(entry 7).
Table 2.
gem-Difluorocyclopropylation of heterocycles.a
R
R
X
N
X
Y
Y
F
F
N
H
O
S
NaH, HMPA
1 h, r.t.
F
F
+
or
or
O
F
O
O
O
F
NH
O
2a
N
4
O
3
Entry
1
Substrate
Product
4, yields (%)b
N
4a, 57
N
H
F
F
F
F
N
2
3
4b, 69
4c, 63
N
H
COMe
O
N
N
H
F
F
Page 5 of 7

N
N
N
4
4d, 55
N
H
F
F
N
N
N
O N
2
5
4e, 54
4f, 65
4g, 60
N
H
O N
2
F
F
F
O
O
F
NH
N
6
O
O
N
N
N
N
7c
N
N
H
F
F
a Reaction conditions: 2a (1.1 mmol), N-heterocycle (1 mmol) and NaH (1 mmol) in HMPA (1 mL) at r.t.;
b Isolated yields;
c Reaction was performed at 80 ºC.
4. Conclusion
In summary, we have designed and synthesized some gem-difluorocyclopropane building blocks, gem-difluorocyclopropyl tosylates.
The tosylate could act as a cation equivalent to achieve N-gem-difluorocyclopropylation of N-heterocycles under mild conditions. Further
application of these building blocks into gem-difluorocyclopropylation of other compounds is currently under investigation in our
laboratory.
Acknowledgments
We thank the National Natural Science Foundation of China (Nos. 21032006, 21172240), the 973 Program of China (No.
2012CBA01200), the Chinese Academy of Sciences for financial support.
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