Ring-opening reactions of difluoro(methylene)cyclopropanes with halogens and amines

Article abstract of DOI:10.1021/jo801610t

(Chemical Equation Presented) The distal and proximal bond of difluoro(methylene)cyclopropanes (F₂MCPs) could be cleaved, respectively, under different conditions to give the corresponding ring-opening products. The reaction mechanisms are disc

Full text of DOI:10.1021/jo801610t

SCHEME 1. Reaction of 1a with Tin Radicals
Ring-Opening Reactions of
Difluoro(methylene)cyclopropanes with Halogens
and Amines
Xiao-Chun Hang, Qing-Yun Chen, and Ji-Chang Xiao*
Key Laboratory of Organofluorine Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032 China
t-BuLi-induced hydrogen abstraction, and retro-Diels-Alder
reaction.4 However, we found that the cycloadducts of F2MCPs
and nitrones could rearrange to give the ring-opened 3,3-
difluorinated tetrahydropyridinols at elevated temperature.5 As
an extension of our interest in the stability of the difluorocy-
clopropane rings in F2MCPs, we investigated their ring-opening
reactions under different conditions.
jchxiao@mail.sioc.ac.cn
ReceiVed July 21, 2008
Under thermal reaction conditions, nonfluorinated MCPs
could generate diradical intermediates by homolytic cleavage
of the cyclopropane rings.2c,6 In the case of 1,1-difluoro-2-
methylenecyclopropane, the simplest homologue of F2MCPs,
the similar ring-opening rearrangement was experimentally
investigated by Dolbier and computationally studied by Borden.7
They found that the presence of two fluorine atoms in the
cyclopropane ring improved the ring strain.7a,c Therefore, we
postulated that the difluorocyclopropane ring might be cleaved
under radical conditions. Herein, we present the results.
Treatment of F2MCPs 1a with n-Bu3SnH in the presence of
2,2′-azobisisobutyronitrile (AIBN) in toluene gave the ring-
opening product 2 in 42% yield (Scheme 1). The distal bond
of F2MCPs 1a was cleaved under this radical condition. In view
of the easy generation of halogen radicals under thermal
conditions, we reinvestigated the CuI-catalyzed ring-opening
reactions of F2MCPs 1a with I2.4a Unexpectedly, this reaction
can proceed smoothly even without the presence of CuI (Table
1, entries 2, 4, 6). Bromine was found to react equally well to
give the ring-opening products at lower temperature (entries 1,
3, 5), whereas in the case of ICl, the ring-opening product could
not be obtained and 1a was fully recovered (entry 7).
The distal and proximal bond of difluoro(methylene)cyclo-
propanes (F2MCPs) could be cleaved, respectively, under
different conditions to give the corresponding ring-opening
products. The reaction mechanisms are discussed.
Methylenecyclopropane derivatives (MCPs), which are rela-
tively stable but highly strained molecules, have been proved
to be useful building blocks in organic synthesis for their
remarkable chemical reactivity over the past decades.1 Among
the various reactions of MCPs, the reactions related to the ring-
opening process are most attractive to chemists,2 as one of the
fluorinated MCPs, difluoro(methylene)cyclopropanes (F2MCPs),
may possess many interesting properties derived from both steric
and electronic effects of the fluorinated cyclopropanes.3b
However, ring-opening reactions of F2MCPs are seldom dis-
closed due to the difficulty in their synthesis.3 Recently, we
found that F2MCPs could be readily prepared from the direct
difluorocyclopropanation of allenes.4a It was shown that the
difluorocyclopropane rings in F2MCPs are quite stable under
many reaction conditions, such as Pd-catalyzed Heck reaction,
To gain more insight into the reaction mechanism of F2MCPs
1 with halogen, inhibition experiment was carried out. Addition
of the free radical inhibitor hydroquinone (20 mol %) to the
reaction mixture of 1a and Br2 decreased the yield of 3a from
50% (entry 1) to 13% (entry 8). On the basis of these
experiments it appears that bromine radical was involved in the
reaction, suggesting a reaction mechanism as shown in Scheme
2. Homolytic cleavage of Br2 resulted in the formation of
(3) (a) Wang, R.; Ksebati, M. B.; Corbett, T. H.; Kern, E. R.; Drach, J. C.;
Zemlicka, J. J. Med. Chem. 2001, 44, 4019–4022. (b) Taguchi, T.; Okada, M. J.
Fluorine Chem. 2000, 105, 279–283. (c) Dolbier, W. R., Jr.; Burkholder, C. R.;
Chaves, A. L.; Green, A. J. Fluorine Chem. 1996, 77, 31–37. (d) Dolbier, W. R.,
Jr.; Seabury, M. J. Tetrahedron 1987, 43, 2437–2442. (e) Dolbier, W. R., Jr.; Seabury,
M.; Daly, D. J. Org. Chem. 1986, 51, 974–979. (f) Dolbier, W. R.; Sellers, S. F.;
Al-Sader, B. H; Fielder, T. H. J. Am. Chem. Soc. 1981, 103, 718–720.
(4) (a) Cheng, Z.-L.; Xiao, J.-C.; Liu, C.; Chen, Q.-Y. Eur. J. Org. Chem.
2006, 5581–5587. (b) Hang, X. -C; Chen, Q. -Y.; Xiao, J.-C. Eur. J. Org. Chem.
2008, 1101–1106.
(5) Hang, X.-C; Chen, Q.-Y.; Xiao, J.-C Synlett 2008, 1989–1992.
(6) (a) Creary, X. J. Org. Chem. 1978, 43, 1777–1783. (b) Creary, X. J. Am.
Chem. Soc. 1980, 102, 1611–1618.
(7) (a) Dolbier, W. R.; Gautriaud, E.; Cai, X. J. Fluorine Chem 2005, 126,
339–343. (b) Dolbier, W. R., Jr.; Fielder, T. H. J. Am. Chem. Soc. 1978, 100,
5577–5578. (c) Lewis, S. B.; Hrovat, D. A.; Getty, S. J.; Borden, W. T. J. Chem.
Soc., Perkin Trans. 2 1999, 2339–2347. (d) Wei, H.; Hrovat, D. A.; Borden,
W. T. J. Am. Chem. Soc. 2006, 128, 16676–2497.
(1) For recent reviews, see: (a) Goti, A.; Cordero, F. M.; Brandi, A. Top. Curr.
Chem. 1996, 178, 1–97. (b) Brandi, A.; Goti, A. Chem. ReV. 1998, 98, 589–635.
(c) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. ReV. 2003, 103, 1213–
1269. (d) Nakamura, I.; Yamamoto, Y. AdV. Synth. Catal. 2002, 344, 111–129. (e)
Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. ReV. 2007, 107, 3117–3179.
(2) Selected references: (a) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996,
96, 49–92. (b) Nakamura, E.; Yamago, S. Acc. Chem. Res. 2002, 35, 867–877. (c)
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Org. Chem. 2007, 11, 1135–1153. (e) Huang, X.; Zhou, H.-W. Org. Lett. 2002, 4,
4419–4422. (f) Kurahashi, T.; Meijere, A. Angew. Chem., Int. Ed. 2005, 44, 7881–
7884. (g) Fu¨rstner, A.; A¨ıssa, C. J. Am. Chem. Soc. 2006, 128, 6306–6307. (h)
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8598 J. Org. Chem. 2008, 73, 8598–8600
10.1021/jo801610t CCC: $40.75 2008 American Chemical Society
Published on Web 10/01/2008

TABLE 1. Ring-Opening Reaction of 1 with Halogens
TABLE 2. Reaction of F2MCPs 1a with Nucleophiles
entry
NuNa(H) (equiv) solvent T (°C)a t (h)b product (%)c
entry F2MCPs
R1/R2
X2 (equiv) T (°C)a product (%)b
1
2
3
4
5
6
7
8
EtONa (0.5)
EtONa (2)
EtOH
EtOH
EtOH
THFh
THF
rtg
rtg
80
50
50
50
50
50
1
5
6a (79)
6a (54)
d
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1a
1a
CH3/CH3
CH3/CH3
CH3/C2H5
CH3/C2H5
-(CH2)5-
-(CH2)5-
CH3/CH3
CH3/CH3
Br2 (2)
I2 (3)
50
80
50
80
50
80
80
50
3a (50)
4a (61)
3b (63)
4b (85)
3c (49)
4c (80)
c
EtONa (2)
2
2
4
2
1
1.5
6ae
Br2 (4)
I2 (3)
EtONa (1.2)
PhONa (1.2)
PhSNa (1.1)
6b (52)
6c (59)
6d (85)
7a (59)
Br2 (4)
I2 (3)
THF
C7H11O4Na f (1.2) THFh
ICl (4)
Br2 (2)
BnNH2 (1.2)
CHCl3
3a (13)d
a Temperature. b Time. c Isolated yield. d Reaction was complicated,
and no main product was isolated. e Only a trace of 6a was detected by
19F NMR. f Sodium salts of diethyl malonate. g Room temperature.
h Anhydrous THF that was distilled from sodium wires.
a Reaction temperature. b Isolated yield. c 1a was fully recovered.
d 20% hydroquinone was added, and the yield was determined by 19F
NMR.
TABLE 3. Reaction of F2MCPs 1a with Aminesa
SCHEME 2. Proposed Mechanism of 1a with Br2
entry
R1
R2
product
yield (%)b
bromine radical. Its attack on 1a led to the opening of the
difluorocyclopropane ring. Subsequent reaction with bromine
or bromine radical afforded the final product 3a.
1
2
3
4
5
6
7
H
H
CH3
PhCH2
C5H5Oc
CH3
7a
7b
7c
7d
7e
d
80
83
56
56
52
d
The distal bond of F2MCPs 1a was cleaved under radical
conditions, while the proximal bond remains intact. In an attempt
to increase the diversity of the ring opening of F2MCPs 1a, we
investigated their proximal bond-cleavage reactions. Kobayashi
found that the bond opposite to the difluorinated carbon can be
cleaved through an R-carbanion intermediate,8 which suggested
that the difluorocyclopropane ring of F2MCPs 1a might be
similarly opened. In order to obtain an R-carbanion intermediate,
we investigated the nucleophilic addition of 1a with several
nucleophiles.
CH2CH2CH2CH2
H
H
H
H
(CH3)3CH
Ph
d
d
a 2.5 equiv of amines was used. b Isolated yield. c Furfuryl. d No
reaction and 1a was recovered.
SCHEME 3. Proposed Mechanism of 1a with Benzylamine
Ethanol was first used as the nucleophile. Among various
conditions investigated, only the addition product 6a was formed
(Table 2, entries 1-4). Similar results were obtained when
phenolate, thiophenolate, or malonate anion were employed as
the nucleophiles (entries 5-7). However, the difluorocyclopro-
pane ring in F2MCPs 1a was opened in its reaction with
benzylamine, giving a monofluorinated butadiene derivative 7a
as the sole product (entry 8). The structure of 7a was assigned
1
by H and 19F NMR spectroscopy, mass spectrometry, and
elementary analysis and further comfirmed by X-ray crystal-
lography (see Supporting Information).
Although various solvents such as methanol, benzene, tet-
rahydrofuran could be used for the reaction, CHCl3 was found
to be the most suitable solvent. A series of amines were
applicable to the reaction in CHCl3 (Table 3). Primary amines
gave better yields than secondary amines and ammonia. No
desired products were obtained in the case of t-butylamine and
aniline, which might be a result of the steric hindrance of amines
(entries 6 and 7).
course showed an AB peak appearing at -147.1 and -150.0
1
ppm while being performed at -10 °C. Further H NMR and
mass spectral mesurements revealed the formation of simple
addition product similar to 6, which could be transformed to
7a at elevated temperature in the presence of excess amount of
benzylamine (see Supporting Information). Thus, the simple
nucleophilic adduct A was considered to be the intermediate of
the reaction (Scheme 3). Similar to R-carbanion promoted ring-
opening reaction of the difluorocyclopropane,8 the nitrogen lone
pair in A would initiate the proximal bond cleavage with
simultaneous removal of fluoride ion. Subsequent rearrangement
The reaction of benzylamine with 1a was chosen to probe
the reaction mechanism. 19F NMR measurement of the reaction
(8) Kobayashi, Y.; Morikawa, T.; Yoshizawa, A.; Takeo Taguchi, T.
Tetrahehdron 1981, 22, 5297–5300.
J. Org. Chem. Vol. 73, No. 21, 2008 8599

δ -99.1 (s, 2F). 13C NMR (100 MHz, CDCl3): δ 21.7, 29.3, 61.1
(t, JFC ) 28.5 Hz), 117.8 (t, JFC ) 254.9 Hz), 127.3 (m), 128.3,
130.0, 136.5, 140.2(t, JFC ) 5.9 Hz), 145.7. IR (film): 3036, 1597,
1466, 1394, 1333, 1213, 1152, 1110, 1086, 1063, 923, 879, 815,
558 cm-1. MS (ESI): m/z 449.9 [M + NH4+]. HRMS (ESI) calcd
for C13H14Br2F2O2S + Na+ 452.8942, found 452.8940.
of B in the presence of benzylamine resulted in the formation
of 7a, whereas for those adducts with ethanol, phenol, etc. (Table
2, entries 1-7), the lone electron pair on oxygen or sulfur in
6a-d could not cause the opening of the difluorocyclopropane
ring. Therefore, no further rearrangement occurred. However,
the cyclopropane ring in F2MCPs 1a was relatively easier to
open as compared with the nonfluorinated MCPs. It is often
necessary to use specific catalysts in the ring-opening reactions
of MCPs with nucleophiles.9
In summary, the distal bond of difluoro(methylene)cyclopro-
panes can be cleaved under radical reaction conditions, while
its proximal bond can be opened with the addition of amines.
As a result of the ready availability of F2MCPs and the ease of
operation of these ring-opening reactions, a number of fluorine-
containing compounds that were prepared with difficulty by the
traditional method might be synthesized in this way, making
them potential fluorine-containing building blocks. Efforts to
determine the scope and limitations of these reactions are
currently underway in this laboratory.
(Z)-N-Benzyl-3-fluoro-4-methyl-1-tosylpenta-1,3-dien-2-
amine (7a). A 5 mL sealed tube was charged with 1a (54 mg,
0.20 mmol), benzylamine (54 mg, 0.50 mmol), and chloroform (1
mL). The sample was stirred at 50 °C for 2 h. After cooling to
room temperature, the solvent was removed under reduced pressure.
The residue was directly purified by chromatography on a silica
gel column (petroleum ether/ethyl acetate ) 10:1) to yield 10a as
1
a white solid, 57 mg, 80%. H NMR (300 MHz, CDCl3): δ 1.46
(d, J ) 2.4 Hz, 3H), 1.66 (d, J ) 2.4 Hz, 3H), 2.42 (s, 3H), 4.30
(d, J ) 6.2 Hz, 2H), 4.88 (s, 1H), 7.11-7.44 (m, 7H), 7.71 (d, J
) 8.4 Hz, 2H). 19F NMR (282 MHz, CDCl3): δ -112.9 (s, 1F).
13C NMR (100 MHz, CDCl3) δ 15.8 (d, J ) 7.5 Hz), 18.2 (d, J )
3.0 Hz), 21.5, 48.4 (d, J ) 3.6 Hz), 95.4 (d, J ) 5.1 Hz), 118.0 (d,
J ) 15.4 Hz), 126.0, 127.1, 127.4, 128.6, 129.5, 138.6, 140.9, 143.2,
145.9 (d, J ) 243.5 Hz), 148.5 (d, J ) 25.5 Hz). IR (film): 3362,
3096, 2951, 2855, 1706, 1664, 1592, 1582, 1455, 1414, 1353, 1283,
1137, 1120, 1081, 1042, 834, 820, 665, 605, 540 cm-1. MS (ESI):
m/z 360.0 [M + H+]. Anal. Calcd for C20H22FNO2S: C 66.83, H
6.17, N, 3.90. Found: C 66.76, H 6.17, N, 3.68.
Experimental Section
(Z)-1-(3-Bromo-2-(bromodifluoromethyl)-3-methylbut-1-enyl-
sulfonyl)-4-methylbenzene (3a). A 5 mL sealed tube was charged
with 1 (54 mg, 0.20 mmol), bromine (96 mg, 0.40 mmol), and
acetonitrile (1.5 mL). The sample was stirred at 50 °C for 6 h.
After cooling to room temperature, the solvent was removed under
reduced pressure. The residue was directly purified by chromatog-
raphy on a silica gel column (petroleum ether/ethyl acetate ) 10:
Acknowledgment. We thank the Chinese Academy of
Sciences (Hundreds of Talents Program) and the National
Natural Science Foundation (20772147) for financial support.
1
Supporting Information Available: Experimental details,
characterization data for new compounds, and crystallographic
data in CIF format. This material is available free of charge via
the Internet at http://pubs.acs.org.
1) to yield 3a as a viscous oil, 43 mg, 50%. H NMR (300 MHz,
CDCl3): δ 1.84 (s, 6H), 2.45 (s, 3H), 7.37 (d, J ) 8.6 Hz, 2H),
7.56 (s, 1H), 7.88 (d, J ) 8.6 Hz, 2H). 19F NMR (282 MHz, CDCl3):
(9) (a) Shi, M.; Xu, B. Org. Lett. 2002, 4, 2145–2149. (b) Smolensky, E.;
Kapon, M.; Eisen, M. S. Organometallics 2007, 26, 4510–4527.
JO801610T
8600 J. Org. Chem. Vol. 73, No. 21, 2008