Synthesis and X-ray information of substituted gem-difluoroallenyl amines

Article abstract of DOI:10.1016/S0022-1139(02)00158-6

An O to N substitution in 4,4-difluorobutadiene-2,3-ol-1 has been accomplished in very satisfactory yields, and without compromising the gem-difluoroallenyl integrity, using modified Mitsunobu conditions. Recrystallization of the resulting tosyl-substitut

Full text of DOI:10.1016/S0022-1139(02)00158-6

Journal of Fluorine Chemistry 117 (2002) 131–135
Synthesis and X-ray information of substituted
gem-difluoroallenyl amines
Qilong Shen, Chbun-Hsing Chen, Gerald B. Hammond*
Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth,
285 Old Westport Road, North Dartmouth, MA 02747, USA
Received 25 April 2002; received in revised form 13 May 2002; accepted 15 May 2002
Dedicated to Professor Lev M. Yagupolskii on the occasion of his 80th birthday.
Abstract
An O to N substitution in 4,4-difluorobutadiene-2,3-ol-1 has been accomplished in very satisfactory yields, and without compromising the
gem-difluoroallenyl integrity, using modified Mitsunobu conditions. Recrystallization of the resulting tosyl-substituted amines furnished the
first X-ray crystallographic analysis of difluoroallenes.
# 2002 Elsevier Science B.V. All rights reserved.
Keywords: Fluoroallenes; Recrystallization; Nucleophiles
1. Introduction
difluoroallenyl indium with aqueous formaldehyde [5]
(Eq. (1)). The readily available starting materials and mild
reaction conditions will make this process valuable for the
synthesis of other functionalized gem-difluoroallenes.
Herein, we report a convenient synthesis of gem-difluor-
oallenyl amines 2 and provide selected X-ray data for some
of them.
In recent years, considerable attention has been given to
the development of new methodologies for the introduction
of fluorine into organic molecules, since this modification
can bring dramatic changes in physical properties, chemical
reactivity and biological activity [1]. Fluoroallenes, despite
(1)
their potential as synthons in the preparation of alicyclic
fluorinated compounds, remain largely unexplored [2]. With
minor exceptions, most of the work involving the synthesis
and chemistry of fluorinated allenes, namely, tetrafluoroal-
lene, trifluoroallene, 1,1-difluoroallene, and 1,3-difluoroal-
lene, has been carried out in Dolbier’s group [3]. As
mechanistic probes, these fluoroallenes were extensively
investigated toward cycloaddition reactions. Xu has reported
the synthesis of alkyl-substituted gem-difluoroallenes, how-
ever, harsh reaction conditions were needed [4]. Recently,
the first functionalized gem-difluoroallenol 1 was synthe-
sized in our laboratory by treating a room-temperature stable
2. Results and discussion
Being interested in the synthesis of difluoroallenyl
amines, we turned our attention to the Mitsunobu reaction
(Eq. (2)). This reaction is a useful tool for replacing a
hydroxyl group with nucleophiles [6]. Various nitrogen
nucleophiles have been utilized in this procedure to afford
amino derivatives [7]. The starting gem-difluoroallenyl alco-
hol 1 was obtained by reacting TIPS-difluoropropargyl
bromide with indium in H2O/THF, followed by sonication
with excess aqueous formaldehyde at room temperature
overnight. The standard Mitsunobu redox system, diethyl
azodicarboxylate (DIAD)/triphenylphosphine, was tested
first, with disappointingly low yields. By decreasing the
temperature, switching to diisopropyl azodicarboxylate
* Corresponding author. Tel.: þ1-508-999-8865; fax: þ1-508-910-6918.
E-mail address: ghammond@umassd.edu (G.B. Hammond).
0022-1139/02/$ – see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 1 5 8 - 6

132
Q. Shen et al. / Journal of Fluorine Chemistry 117 (2002) 131–135
Table 1
Mitsnobou reaction of TIPS–difluoroallyl alcohol 1a
Entry
Substituted amine
Product
Yieldb
1
2a (83%)
2
3
2b (43%)
2c (44%)
4
5
2d (32%)
2e (51%)c
a All reaction were carried out with TIPS–difluoroallenyl alcohol (1 mmol) and PPh3 (1 eq.) and DIAD (1 eq.) in THF at 0 8C.
b Isolated yields.
c PPh3 (2 eq.) and DIAD (4 eq.) were used.
(DIAD)/triphenylphosphine, and controlling the order of
addition of reactants, we were able to get the desired
gem-difluoroallenyl amine in very good yield. A typical
experiment consisted in the dropwise addition of a solution
of DIAD in THF at 0 8C to a mixture of gem-difluoroallenyl
alcohol 1, triphenyl phosphine, and propargyl amine; the
reaction was left to stir at 0 8C for 2 h, after which standard
work-up and purification by flash chromatography afforded
2a in 83% yield.
showed a very complicated mixture. After experimenting
with different amounts of the reagents, we obtained the
desired product 3 in 61% yield using the conditions
described in the table footnote. The Boc-group in 3 was
easily removed using an excess of trifluoroacetic acid [8] to
yield 2e (entry 5).
(3)
(2)
The 19F-NMR chemical shifts of all products were
observed in the range d: 104–108 ppm. The recrystallization
of gem-difluoroallenyl amines 2a–c, e and their X-ray
analysis secured the difluoroallene structure (Table 2). As
shown in boldface, the bond lengths of carbons C(1), C(2)
and C(3) and its torsion angle provides evidence for the
allene presence, whereas the C–F bond length and F–C–F
angle lent experimental support to previous calculations on
the nature of bonds and bond angles in gem-difluoroallene
(recently, the X-ray of tetrafluorobutatriene was reported by
[9]) (Figs. 1 and 2).
We conducted the reaction of 1 with other amines in a
similar fashion (Table 1). As shown in the table, whereas, an
unsubstituted N-tosyl propargyl amine afforded the product
2a in high yield (entry 1), alkyl substitution on the triple
bond decreased the yield (entries 2 and 3). Use of an imide
substrate (entry 4) decreased the yield even further. When
the same Mitsunobu conditions were applied to a protected
sulfonamide (Eq. (3)) the 19F-NMR spectrum of crude 3

Q. Shen et al. / Journal of Fluorine Chemistry 117 (2002) 131–135
133
Table 2
as received. The reaction progress were monitored using one
of the following techniques: 19F-NMR, TLC and GC–MS.
Analytical TLC was performed using Macherey–Nagel
Polygram Sil G/UV254 precoated plastic plates and visua-
lized using phosphomolybdic acid (5% in methanol). Flash
chromatography (eluant: hexane/ethyl acetate) was per-
formed using silica gel 230–400 mesh, 40–63 mm (Lagand
Chemicals). IR spectra were recorded on a Bruker Vector, 22
Bond lengths and angles measured for allenes 2a–d
˚
Bond length (A)
Atom–atom
2a
2b
2c
2d
F(1)–C(1)
F(2)–C(1)
C(1)–C(2)
C(2)–C(3)
C(3)–C(4)
C(3)–Si(1)
1.347 (5)
1.292 (6)
1.270 (5)
1.299 (3)
1.518 (3)
1.905 (2)
1.339 (6)
1.287 (5)
1.277 (5)
1.294 (3)
1.515 (3)
1.906 (2)
1.311 (7)
1.308 (6)
1.280 (6)
1.299 (5)
1.517 (4)
1.898 (3)
1.327 (3)
1.327 (3)
1.286 (3)
1.305 (3)
1.513 (3)
1.9059 (2)
1
FT–IR spectrophotometer. H, 19F and 13C-NMR spectra
were recorded in CDCl3 at 300, 282 and 75 MHz, respec-
tively. 19F-NMR spectra were referenced against external
CFCl3 and were broadband decoupled from hydrogen
nuclei. Elemental analyses were performed by Atlantic
Microlab Inc., Norcross, GA.
Atom–atom–atom
Bond angle (8)
F(1)–C(1)–F(2)
F(1)–C(1)–C(2)
F(2)–C(1)–C(2)
C(1)–C(2)–C(3)
C(2)–C(3)–C(4)
C(2)–C(3)–Si(1)
C(4)–C(3)–Si(1)
108.9 (4)
123.9 (4)
127.2 (4)
178.4 (3)
119.3 (2)
107.69 (4) 107.5 (4)
108.16 (18)
126.2 (2)
127.1 (4)
125.3 (4)
173.6 (3)
121.1 (2)
126.3 (5)
126.2 (5)
178.4 (4)
120.3 (3)
125.7 (2)
175.2 (2)
4.1. Typical procedure for the synthesis of allenylamines
2a–d
120.71 (18)
117.72 (15)
121.35 (14)
120.24 (17) 118.92 (16) 119.6 (2)
120.48 (14) 119.96 (16) 120.1 (2)
To the solution of TIPS-a-hydroxy difluoroallene 1
(0.262 g, 1 mmol) in THF (2 ml) were added tosyl propargyl
amine (0.209 g, 1 mmol) and triphenylphosphine (0.262 g,
1 mmol) at 0 8C under argon. A solution of diisopropyl
azodicarboxylate (0.202 g, 1 mol) in THF (1 ml) was added
dropwise and the reaction mixture was stirred overnight,
concentrated in vacuo and the product was purified by flash
chromatography on silica gel (20/1, hexane/ethyl acetate).
3. Conclusion
We have successfully synthesized substituted gem-
difluoroallenyl amines using Mitsunobu conditions. In addi-
tion, X-ray crystallographic analysis of the difluroroallenyl
amine products demonstrated, for the first time, the validity
of theoretical predictions regarding the nature of bonds and
bond angles in fluoroallenes.
4.2. N-Tosyl-1,1-difluoro-3-triisopropylsilyl-5-aza-octa-
1,2-dien-7-yne 2a
3
4. Experimental
1H-NMR (CDCl3) d: 7.70 (d, JHH ¼ 8:3 Hz, 2H), 7.28
(d, 3JHH ¼ 8:4 Hz, 2H), 4.21 (t, 5JHF ¼ 5:8 Hz, 2H), 4.21 (d,
4
The solvents are reagent grade and used without purifica-
tion. The indium metal powder (100 mesh) and all other
commercial reagents were purchased from Aldrich and used,
4JHH ¼ 2:4 Hz, 2H), 2.42 (s, 3H), 2.10 (t, JHH ¼ 2:6 Hz,
1H), 1.21 (m, 3H), 1.07 (d, 3JHH ¼ 6:6 Hz, 18H) ppm; 19F-
NMR (CDCl3) d: À107.47 (s, 2F) ppm; 13C-NMR (CDCl3,
Fig. 1. ORTEP view of 2a. Displacement ellipsoids are shown at the 50% probability level.

134
Q. Shen et al. / Journal of Fluorine Chemistry 117 (2002) 131–135
Fig. 2. ORTEP view of 2b. Displacement ellipsoids are shown at the 50% probability level.
2
1
75 Hz) d: 179.41 (t, JCF ¼ 36:3 Hz), 159.61 (t, JCF
¼
72.80, 49.30, 36.65, 21.95, 21.68, 20.69, 18.65, 13.57,
11.53.
3
260:4 Hz), 143.91, 136.66, 130.42 (t, JCF ¼ 5:9 Hz),
129.82, 127.73, 76.93, 74.18, 49.45, 36.17, 21.74, 18.65,
11.53. Anal. Calc. for C23H33F2NO2SSi: C, 60.89; H, 7.33.
Found: C, 61.11; H, 7.27.
4.5. N-(2-triisopropylsilyl-4,4-difluoro-2,3-butyldienyl)
phthalimide 2d
4.3. N-Tosyl-1,1-difluoro-3-triisopropylsilyl-5-aza-nona-
1,2-dien-7-yne 2b
1H-NMR (CDCl3, 300 MHz) d: 7.87 (m, 2H), 7.74 (m,
5
2H), 4.52 (t, JHF ¼ 5:8 Hz, 2H), 1.28 (m, 3H), 1.16 (d,
3JHH ¼ 6:6 Hz, 18H) ppm; 19F-NMR (CDCl3, 282 MHz) d:
À106.96 (s, 2F) ppm; 13C-NMR (CDCl3, 75MHz) d: 177.05
3
1H-NMR (CDCl3, 300 MHz) d: 7.70 (d, JHH ¼ 7:5 Hz,
3
5
2
1
2H), 7.29 (d, JHH ¼ 8:2 Hz, 2H), 4.19 (t, JHF ¼ 5:7 Hz,
(t, JCF ¼ 33:8 Hz), 167.55, 159.33 (t, JCF ¼ 261:8 Hz),
134.35, 132,13, 130.98 (t, 3JCF ¼ 6:3 Hz), 123.60, 41.78 (t,
4JCF ¼ 4:1 Hz), 18.52, 11.37.
5
2H), 4.21 (q, JHH ¼ 2:2 Hz, 2H), 2.42 (s, 3H), 1.60 (t,
5JHH ¼ 2:4 Hz, 1H), 1.21 (m, 3H), 1.07 (d, JHH ¼ 6:6 Hz,
3
18H) ppm; 19F-NMR (CDCl3, 282MHz) d: À107.70 (s,
2F) ppm; 13C-NMR (CDCl3, 75 Hz) d: 179.40 (t, JCF
¼
4.6. N-Tosyl-N-Boc-1,1-difluoro-3-triisopropylsilyl-1,2-
butadienyl-4-amine 3
2
1
35:2 Hz), 159.61 (t, JCF ¼ 260:1 Hz), 143.59, 136.83,
3
130.57 (t, JCF ¼ 5:8 Hz), 129.64, 127.76, 82.18, 72.03,
49.45, 36.69, 21.69, 18.67, 11.30, 3.48. Anal. Calc. for
C24H35F2NO2SSi: C, 61.63; H, 7.54. Found: C, 61.80; H,
7.61.
To the solution of N-(t-Butoxycarbonyl)-p-toluenesulfo-
namide (0.44 g, 1.6 mmol) in THF (10 ml) was added PPh3
(0.85 g, 3.2 mmol). Followed by the addition of 1 (0.44 g,
1.6 mmol), and then DIAD (1.344 g, 6.7 mmol). The
resulted mixture was stirred at room temperature overnight.
Standard work-up gave a pale yellow oil, which was purified
by flash chromatography to give a solid in 60.5% yield.
4.4. N-Tosyl-1,1-difluoro-3-triisopropylsilyl-5-aza-undeca-
1,2-dien-8-yne 2c
3
1H-NMR (CDCl3, 300 MHz) d: 7.70 (d, JHH ¼ 7:5 Hz,
3
5
2H), 7.28 (d, JHH ¼ 8:2 Hz, 2H), 4.18 (t, JHF ¼ 5:8 Hz,
4.7. Cleavage of Boc-protected group
5
2H), 4.10 (t, JHH ¼ 2:1 Hz, 2H), 2.41 (s, 3H), 1.92 (tt,
3JHH ¼ 7:0 Hz, 4JHH ¼ 2:2 Hz, 2H), 1.30 (m, 2H), 1.17 (m,
To a solution of 3 (0.483 g, 0.94 mmol) in CH2Cl2 (15 ml)
was added trifluoroacetic acid (0.321 g, 2.8 mmol) at room
temperature. The mixture was stirred for 3 h. Standard work-
up gave a pale yellow crude product, which was then purified
by flash chromatography (Hex:E-Ac ¼ 30:1) to give 2e as a
solid in (0.323 g, 83%). Colorless crystals were obtained by
3
3
3H), 1.06 (d, JHH ¼ 6:6 Hz, 18H), 0.82 (t, JHH ¼ 7:4 Hz,
3H) ppm; 19F-NMR (CDCl3, 282MHz) d: À107.73 (s, 2F)
ppm; 13C-NMR (CDCl3, 75 Hz) d: 179.54 (t,
2JCF ¼ 36:4 Hz), 159.63 (t, JCF ¼ 260:4 Hz), 143.58,
1
3
136.85, 130.50 (t, JCF ¼ 6:0 Hz), 129.71, 127.75, 86.65,

Q. Shen et al. / Journal of Fluorine Chemistry 117 (2002) 131–135
135
3
˚
recrystallization from a mixture of hexane and ethyl acetate.
3
2303:32 (8) A ; Z ¼ 4; Dcalc ¼ 1:199 g cmÀ3; lðMo KaÞ ¼
1H-NMR (CDCl3) d: 7.72 (d, JHH ¼ 8:4 Hz, 2H), 7.29 (d,
0:71073 A; T ¼ 293:0 K; prismatic crystal 0:10 mmꢀ
˚
5
3JHH ¼ 8:0 Hz, 2H), 4.75 (s, 1H), 3.85 (t, JHF ¼ 5:7 Hz,
0:35 mm ꢀ 0:75 mm, R, wR, S 0.0487, 0.1360, 1.04.
3
2H), 2.41 (s, 3H), 1.18 (m, 3H), 0.97 (d, JHH ¼ 6:7 Hz,
18H) ppm; 19F-NMR (CDCl3) d: À104.81 (s, 2F) ppm; 13C-
NMR (CDCl3) 159.61 (t, 1JCF ¼ 263:2 Hz), 143.92, 136.78,
Acknowledgements
4
132.05 (3JCF ¼ 5:8 Hz),, 129.99, 127.40, 46.00 (t, JCF
¼
3:5 Hz), 21.69, 18.38, 10.98. Anal. Calc. for C20H31-
F2NO2SSi: C, 57.80; H, 7.52. Found: C, 57.67; H, 7.53.
The financial support of the Petroleum Research Fund
(PRF no. 36602-AC1) is acknowledged with gratitude. The
authors are grateful to Drs. James A. Golen, Department
of Chemistry and Biochemistry (UMass Dartmouth) and
A. Chandrasekaran (UMass Amherst), for supplying the
crystallographic data.
4.8. Crystal structure data
4.8.1. Crystal data for compound 2a
C23H33F2NO2SSi, M ¼ 453:67, triclinic, space group P1
(no. 2), a ¼ 9:88819ð2Þ, b ¼ 10:8511 (2), c ¼ 12:9294
References
˚
(3) A; a ¼ 108:1280ð7Þ, b ¼ 90:8731 (7), g ¼ 103:5254
3
(11); V ¼ 1276:03 (5) A ; Z ¼ 2; Dcalc ¼ 1:181 g cmÀ3
;
˚
[1] D. Lentz, S. Willemsen, Angew. Chem. Int. Ed. 40 (2001) 2087–2091;
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T. Hiyama, Organofluorine Compounds, Chemistry and Applications,
Springer, Berlin, 2000;
˚
lðMo KaÞ ¼ 0:71073 A; T ¼ 293:0 K; prismatic crystal
0:08 mm ꢀ 0:22 mm ꢀ 0:30 mm, R, wR, S 0.0512, 0.1417,
1.03.
D.P. Curran, S. Hadida, S.-Y. Kim, Z. Luo, J. Am. Chem. Soc. 121
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4.8.2. Crystal data for compound 2b
C24H35F2NO2SSi, M ¼ 467:70, triclinic, space group P1
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D. O’Hagan, H.S. Rzepa, J. Chem. Soc. Chem. Commun. (1997) 645–
652;
˚
(no. 2), a ¼ 9:2423 (1), b ¼ 11:3980 (1), c ¼ 14:1375 (2) A;
a ¼ 98:7602 (5), b ¼ 108:9314 (6), g ¼ 105:8472 (6); V ¼
3
1306:70 (5) A ; Z ¼ 2; Dcalc ¼ 1:189 g cmÀ3; lðMo KaÞ ¼
˚
S. Moran, R.X.-F. Ren, S. Rumney Jr, E.T. Kool, J. Am. Chem. Soc.
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˚
0:71073 A; T ¼ 293:0 K; prismatic crystal 0:40 mm ꢀ
I. Ojima, J.R. McCarthy, J.T. Welch (Eds.), Biomedical Frontiers of
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0:50 mm ꢀ 0:50 mm. R, wR, S 0.0493, 0.1429, 1.05.
4.8.3. Crystal data for compound 2d
C21H27F2NO2SSi, M ¼ 391:53, triclinic, space group P1
[2] A.B. Shtarov, P.J. Krusic, B.E. Smart, W.R. Dolbier Jr, J. Am. Chem.
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a ¼ 76:0452 (9), b ¼ 84:9547 (8), g ¼ 76:2805 (9)8; V ¼
3
1115:63 (5) A ; Z ¼ 2; Dcalc ¼ 1:166 g cmÀ3; lðMo KaÞ ¼
˚
˚
0:71073 A; T ¼ 293:0 K; prismatic crystal 0:40 mmꢀ
0:90 mm ꢀ 1:00 mm, R, wR, S 0.1053, 0.3258, 1.06.
[7] M.L. Edwards, D.M. Stemerick, J.R. McCarthy, Tetrahedron Lett. 131
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4.8.4. Crystal data for compound 2e
C20H31F2NO2SSi, M ¼ 415:62, monoclinic, space group
[9] D. Dixon, B. Smart, J. Phys. Chem. 93 (1989) 7772–7780;
A. Bash, D. Lentz, P. Luger, M. Messerschmidt, C. Olesch, M.
Patzschke, Angew. Chem. Int. Ed. 41 (2002) 296–299.
P21/n (no. 14), a ¼ 10:6123 (2), b ¼ 12:9595 (2),
˚
c ¼ 17:3623 A; a ¼ 90, b ¼ 105:3074 (7), g ¼ 908; V ¼