Continuous Flow Synthesis of Difluoroamine Systems
149
3.7, C-2). dF (376 MHz, CDCl3) ꢀ135.5–(ꢀ135.6) (m, 2F, F-2),
ꢀ160.7–(ꢀ160.9) (m, 2F, F-3). m/z (EIþ) 190 ([MH]þ, 100 %),
162 (20), 143 (24), 124 (18).
including the provision of calcium gluconate antidote gel.
Whilst fluorine is less toxic than widely used chlorine gas,[39]
appropriate safety precautions using standard research grade
fume cupboards are required.
2,3,5,6-Tetrafluoro-4-(trifluoromethyl)aniline 2b
Certain difluoroamine compounds are known to be sensitive
explosives.[14,38] Whilst no difficulties were encountered in this
work, appropriate precautions should be taken when handling
potentially explosive materials.
Octafluorotoluene 1b (3.0 g, 12.72 mmol), ammonium
hydroxide (12.0 mL, 120 mmol) and MeCN (10 mL), after
column chromatography on silica gel using hexane/ethyl acetate
4 : 1 as the eluent, gave 2,3,5,6-tetrafluoro-4-(trifluoromethyl)
aniline 2b (1.43 g, 48 %) as a clear orange oil. nmax (neat)/cmꢀ1
3600 and 3428 (NH2), 1127, 1330, 1506 and 1654. dH
(400 MHz, CDCl3) 4.38 (br, 2H, NH2). dC (176 MHz, CDCl3)
97.0 (qt, 2JCF 34.8, 2JCF 21.6, C-4), 121.8 (qm, 1JCF 272.7, CF3),
130.2 (tt, 2JCF 13.9, 3JCF 4.4, C-1), 136.3 (ddm, 1JCF 240.0, 2JCF
16.0, C-3), 144.9 (dm, 1JCF 255.3, C-2). dF (376 MHz, CDCl3)
Using the continuous flow device shown in Fig. 3, fluorine in
N2 (10 % v/v) was passed into the flow reactor channel via inlet 1
at an appropriate rate, which was controlled by a gas flow meter
(BrooksÒ) and, simultaneously, aniline derivative 2 in MeCN
was added via inlet 2 at a rate controlled by syringe pump over a
period of 30 min. All liquid products were collected in a vessel
containing water (25 mL), whilst excess gasses were vented
through a soda lime scrubber. The reactants were extracted from
the aqueous layer using DCM (3 ꢁ 25 mL) and the organic
extracts were dried (MgSO4), filtered and concentrated under
reduced pressure to yield the crude product as an orange oil.
Purification by column chromatography on silica gel gave the
difluoroamine 3.
4
ꢀ55.3 (t, 3F, JFF 21.1, CF3); ꢀ144.0–(ꢀ144.3) (m, 2F, F-3),
ꢀ162.0–(ꢀ162.2) (m, 2F, F-2). m/z (EIþ) 233 ([M]þ, 42 %), 214
(82), 183 (64), 117 (34), 69 (100); and as compared with
literature data.[34]
Tetrafluoro-4-nitroaniline 2c and Tetrafluoro-
6-nitroaniline 2d
4-(Difluoroamino)-2,3,5,6-tetrafluorobenzonitrile 3a
Pentafluoronitrobenzene 1c (2.3 g, 10.8 mmol), ammonium
hydroxide (2.2 mL, 22 mmol) and THF (20 mL), after column
chromatography on silica gel using hexane/ethyl acetate (2 : 1)
as eluent, gave 2c, 2d, and 2e. Tetrafluoro-4-nitroaniline 2c
(0.37 g, 15 %) as yellow crystals, mp 105–1068C (lit.[35] 106–
1088C). dH (400 MHz, CDCl3) 4.62 (br, 2H, NH2). dC (176 MHz,
F2 (10 % in N2, 6.0 mmol hꢀ1), MeCN (10.0 mL hꢀ1) and
4-amino-2,3,5,6-tetrafluorobenzonitrile 2a (0.283 g, 1.50 mmol,
10.0 mL hꢀ1, 1.0 mmol hꢀ1) in DCM (15.0 mL), after column
chromatography on silica gel using hexane/DCM (2 : 1) as the
eluent, gave 4-(difluoroamino)-2,3,5,6-tetrafluorobenzonitrile
3a (0.24 g, 71 %) as a clear oil. dC (126 MHz, CDCl3)
98.9 (tt, 2JCF 17.1, 3JCF 2.1, C-1), 106.1 (s, CN), 130.1 (t, 2JCF
8.9, C-4), 142.5 (dddd, 1JCF 267.9, 2JCF 21.5, 3JCF 14.3, 4JCF 8.1,
2
3
CDCl3) 119.6–120.2 (m, C-1), 131.2 (tt, JCF 13.9, JCF 4.1,
C-4), 135.3 (ddm, 1JCF 243.6, 2JCF 14.2, C-3), 142.1 (dddd, 1JCF
260.6, 2JCF 13.4, 3JCF 4.0, 4JCF 2.6, C-2). dF (376 MHz, CDCl3)
ꢀ147.6–(–147.8) (m, 2F, F-2), ꢀ161.6–(ꢀ161.8) (m, 2F, F-3).
m/z (EIþ) 210 ([M]þ, 80 %), 180 (67), 164 (57), 144 (42), 137
(100). Tetrafluoro-6-nitroaniline 2d (0.85 g, 37 %) as red crys-
tals, mp 45–468C (lit.[36] 43–448C). dH (400 MHz, CDCl3) 5.87
(br, 2H, NH2). dC (176 MHz, CDCl3) 120.7–121.1 (m, C-6),
132.12 (dddd, 1JCF 245.6, 2JCF 16.5, 3JCF 13.7, 4JCF 2.9, C-2),
132.3 (ddd, 2JCF 13.2, 3JCF 3.8, 4JCF 1.9, C-1), 136.2 (dddd, 1JCF
243.2, 2JCF 12.5, 3JCF 5.5, 4JCF 2.3, C-5), 143.7 (ddt, 1JCF 262.4,
1
2
C-2), 147.7 (ddm, JCF 268.0, JCF 12.6, C-3). dF (376 MHz,
4
3
CDCl3) 63.8 (t, JFF 10.3, 2F, NF2), ꢀ129.3 (ddm, JFF 20.8,
4JFF 10.4, 2F, F-3), ꢀ140.2 (ddm, 3JFF 20.3, 4JFF 10.3, 2F, F-2).
m/z (ASAP) 227 ([MH]þ, 5 %), 207 (100), 191 (40), 160 (17).
2,3,5,6-Tetrafluoro-4-(trifluoromethyl)difluoramine 3b
F2 (10 % in N2, 6.0 mmol hꢀ1), MeCN (10.0 mL hꢀ1) and
2,3,5,6-tetrafluoro-4-(trifluoromethyl)aniline
2b
(0.06 g,
3
1
2
2JCF 12.8, JCF 4.7, C-3 or C-4), 144.2 (dtd, JCF 260.2, JCF
0.25 mmol, 5.0 mL hꢀ1, 0.5 mmol hꢀ1) in DCM (2.5 mL), after
column chromatography on silica gel using hexane/DCM (2 : 1)
as the eluent, gave 2,3,5,6-tetrafluoro-4-(trifluoromethyl)
difluoramine 3b (0.04 g, 54 %) as a clear oil. dC (126 MHz,
CDCl3) 95.1 (tt, 2JCF 17.0, 3JCF 3.8, C-1), 103.1 (m, CF3), 129.0
(t, 2JCF 9.4, C-4), 143.8 (ddd, 1JCF 262.0, 2JCF 20.5, 3JCF 14.0,
3
13.9, JCF 4.6, C-4 or C-3). dF (376 MHz, CDCl3) ꢀ145.5 (dt,
3JFF 22.6, 4JFF 8.9, 1F, F-3 or F-4), ꢀ147.5 (td, 3JFF 21.4, 4JFF
8.9, 1F, F-3 or F-4), ꢀ160.5 (ddd, 3JFF 20.6, 4JFF 8.9, 5JFF 5.9,
1F, F-2 or F-5), ꢀ164.3 (td, 3JFF 22.4, 4JFF 5.8, 1F, F-2 or F-5).
m/z (EIþ) 207 ([M]þ, 81 %), 177 (50), 161 (58), 134 (100). 2,4,5-
Trifluoro-6-nitrobenzene-1,3-diamine 2e (0.42 g, 19 %) as yel-
low crystals, mp 145–1478C (lit.[35] 147–1488C). dH (400 MHz,
CDCl3) 4.48 (br, 2H, NH2), 5.86 (br, 2H, NH2). dC (176 MHz,
CDCl3) 113.6–113.9 (m, C-3), 131.8 (ddd, 1JCF 234.5, 2JCF 16.4,
3JCF 7.9, C-4), 133.0 (dm, 1JCF 226.2, C-2), 133.0 (td, 2JCF 15.0,
3JCF 4.5, C-3), 143.6 (ddd, 1JCF 254.8, 2JCF 12.9, 4JCF 3.2, C-5).
dF (376 MHz, CDCl3) ꢀ147.9 (dd, 3JFF 21.5, 4JFF 8.9, 1F, F-4),
ꢀ163.4 (dd, 4JFF 8.9, 5JFF 2.0, 1F, F-2), ꢀ172.2 (dd, 3JFF 21.5,
5JFF 2.0, 1F, F-5). m/z (EIþ) 207 ([M]þ, 81 %), 177 (50), 161
(58), 134 (100).
1
2
C-2), 147.7 (ddm, JCF 268.0, JCF 12.3, C-3). dF (376 MHz,
4
2
CDCl3) 64.0 (t, JFF 10.2, 2F, NF2), ꢀ57.1 (t, JFF 22.3, 3F,
CF3), ꢀ137.7 (ddm, 3JFF 22.1, 4JFF 9.4, 2F, F-2), ꢀ141.8 (ddm,
3JFF 19.3, JFF 9.7, 2F, F-3); m/z (ASAP) 270 ([MH]þ, 18 %),
217 (53).
4
2,3,5,6-Tetrafluoro-4-nitro-1-difluoramine 3c
F2 (10 % in N2, 6.0 mmol hꢀ1), MeCN (10.0 mL hꢀ1
)
and 2,3,5,6-tetrafluoro-4-nitroaniline 2c (0.21 g, 1.0 mmol,
10.0 mL hꢀ1, 2.0 mmol hꢀ1) in DCM (5.0 mL), after column
chromatography on silica gel using hexane/DCM (4 : 1) as the
eluent, gave 2,3,5,6-tetrafluoro-4-nitro-1-difluoramine 3c
(0.16 g, 65 %) as a yellow oil. dC (126 MHz, CDCl3) 128.3
Synthesis of Difluoramine Derivatives 3
General Procedure
2
1
CAUTION: Although 10 % v/v fluorine in nitrogen is rela-
tively easy to handle as described previously,[37] it is still a
potent oxidising agent and must be treated as such. Appropriate
precautions must also be taken with regards to HF handling,
(t, JCF 9.7, C-4), 133.0–133.4 (m, 1C, C-1), 140.4 (ddd, JCF
2
266.0, JCF 14.8, JCF 6.1, C-3), 142.9 (ddd, JCF 270.0, JCF
12.9, JCF 6.8, C-2). dF (376 MHz, CDCl3) 64.2 (t, JFF 10.0,
2F, NF2), ꢀ138.8–(ꢀ139.3) (m, 2F, F-2), ꢀ143.8–(ꢀ144.1)
3
1
2
3
4