An efficient approach for monofluorination via aqueous fluorolactonization reaction of 2,3-allenoic acids with selectfluor

Article abstract of DOI:10.1021/jo702409y

(Chemical Equation Presented) We have developed a convenient method for the efficient monofluorination via the electrophilic fluorocyclization reaction of 2,3-allenoic acids with Selectfluor in MeCN in the presence of 10 equiv of H₂O or even in

Full text of DOI:10.1021/jo702409y

BF4) represents a major advance for electrophilic fluorination
since it is a reliable, mild, stable, inexpensive, yet effective
reagent.5 During our study on the chemistry of allenes,6 we
imagined that the fluorine chemistry of allenes, which has not
been well established,7 may be a nice way to introduce fluorine
atoms into organic molecules. In this paper, we wish to disclose
our recent observation on an effective monofluorination protocol
via the electrophilic fluorolactonization of easily available 2,3-
allenoic acids.8
In fact, we started our work by fluorinating a series of
substituted unsaturated carboxylic acids, such as 3-undecaynoic
acid or 4-phenyl-3-butenoic acid,9 which afforded complicated
mixtures (Scheme 1).
An Efficient Approach for Monofluorination via
Aqueous Fluorolactonization Reaction of
2,3-Allenoic Acids with Selectfluor
Chao Zhou,† Zhichao Ma,† Zhenhua Gu,‡
Chunling Fu,*,† and Shengming Ma*,†,‡
Laboratory of Molecular Recognition and Synthesis, Department
of Chemistry, Zhejiang UniVersity, Hangzhou 310027, Zhejiang,
P. R. China, and State Key Laboratory of Organometallic
Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P. R.
China
Further study indicates that although the fluorinating reaction
of 2,3-allenoic acid 2a with Selectfluor 1 in EtOH failed to
afford â-fluorobutenolide 3a (entry 1, Table 1), the reaction in
EtOH/H2O (20:1) afforded 3a in 50% yield together with some
byproducts (entry 2, Table 1), indicating the effect of H2O. The
reaction in DMF, DMA, or MeNO2 in the presence of 10 equiv
of H2O afforded 3a in 63-76% yields (entries 3-5, Table 1).
Further screening led to the observation that MeCN is the best
masm@mail.sioc.ac.cn
ReceiVed NoVember 8, 2007
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1992, 9. (b) Banks, R. E.; Lawrence, N. J.; Popplewell, A. L. Synlett 1994,
831. (c) Banks, R. E.; Besheesh, M. K.; Mohialdin-Khaffaf, S. N.; Sharif,
I. J. Chem. Soc., Perkin Trans. 1 1996, 2069. (d) Nyffeler, P. T.; Duron, S.
G.; Burkart, M. D.; Vincent, S. P.; Wong, C.-H. Angew. Chem., Int. Ed.
2005, 44, 192. (e) Singh, R. P.; Shreeve, J. M. Acc. Chem. Res. 2004, 37,
31.
We have developed a convenient method for the efficient
monofluorination via the electrophilic fluorocyclization reac-
tion of 2,3-allenoic acids with Selectfluor in MeCN in the
presence of 10 equiv of H2O or even in pure water to afford
â-fluorobutenolides in moderate to high yields.
(6) For reviews on the chemistry of allenes, see: (a) Zimmer, R.; Dinesh,
C.; Nandanan, E.; Khan, F. Chem. ReV. 2000, 100, 3067. (b) Marshall, J.
A. Chem. ReV. 2000, 100, 3163. (c) Hashmi, A. S. K. Angew. Chem., Int.
Ed. 2000, 39, 3590. (d) Bates, R.; Satcharoen, V. Chem. Soc. ReV. 2002,
31, 12. (e) Sydnes, L. Chem. ReV. 2003, 103, 1133. (f) Ma, S. Acc. Chem.
Res. 2003, 36, 701. (g) Brandsma, L.; Nedolya, N. A. Synthesis 2004, 735.
(h) Tius, M. A. Acc. Chem. Res. 2003, 36, 284. (i) Wei, L.-L.; Xiong, H.;
Hsung, R. P. Acc. Chem. Res. 2003, 36, 773. (j) Lu, X.; Zhang, C.; Xu, Z.
Acc. Chem. Res. 2001, 34, 535. (k) Wang, K. K. Chem. ReV. 1996, 96,
207. (l) Ma, S. Chem. ReV. 2005, 105, 2829. (m) Ma, S. Aldrichim. Acta
2007, 40, 91. For a monograph on the chemistry of allenes, see: Krause,
N.; Hashmi, A. S. K. Modern Allene Chemistry; Wiley-VCH: Weinheim,
2004. For a recent review on the synthesis of allenes: Brummond, K. M.;
DeForrest, J. E. Synthesis 2007, 795.
(7) The reports on the fluorination based on allenes are very limited.
For electrophilic monofluorination of 1,2- or 2,3-allenylsilanes, see: (a)
Carroll, L.; Pacheco, M. C.; Garcia, L.; Gouverneur, V. Chem. Commun.
2006, 4113. (b) Pacheco, M. C.; Gouverneur, V. Org. Lett. 2005, 7, 1267.
(8) For a most recent review on electrophilic cyclization of functionalized
allenes, see: Krause, N.; Hashmi, A. S. K. Modern Allene Chemistry; Wiley-
VCH: Weinheim, 2004; Chapter 10. For electrophilic halolactonization of
2,3-allenoic acids or 2,3-allenoates from this group, see: (a) Fu, C.; Ma, S.
Eur. J. Org. Chem. 2005, 2942. (b) Ma, S.; Shi, Z.; Yu, Z. Tetrahedron
Lett. 1999, 40, 2393. (c) Ma, S.; Wu, B.; Shi, Z. J. Org. Chem. 2004, 69,
1429.
(9) (a) For fluorolactonization of 4-phenyl-3-butenoic acid with Select-
fluor, see: Serguchev, Yu. A.; Lourie, L. F.; Shevchenko, G. V.; Chernega,
A. N. Zh. Org. ta Farm. Khim. 2005, 3, 28. (b) For fluorolactonization of
norbornenecarboxylic acids with Selectfluor and XeF2, see: Lourie, L. F.;
Serguchev, Y. A.; Shevchenko, G. V.; Ponomarenko, M. V.; Chernega, A.
N.; Rusanov, E. B.; Howard, J. A. K. J. Fluorine Chem. 2006, 127, 377.
(c) For fluorolactonization of 4-alkenoic acid derivatives with N-fluoro-
pentachloropyridinium triflate, see: Okada, M.; Nakamura, Y.; Horikawa,
H.; Inoue, T.; Taguchi, T. J. Fluorine Chem. 1997, 82, 157. In most cases
shown above, the reaction afforded a mixture of fluorine-containing lactones
with poor selectivity.
Although there are extremely rare organic fluorine metabolites
in nature, bioactive organofluorine compounds play a very
important role in modern medicinal chemistry;1 therefore, it is
not surprising that the development of new methods for the
efficient introduction of fluorine atom into organic compounds
is of current interest. Although fluorine itself is one of the most
powerful reagents, it is usually too reactive for controllable and
selective monofluorination reactions and definitely very danger-
ous.1,2 On the other hand, protocols for the introduction of
fluorine atom into organic molecules rely upon dozens of
different reagents;1,3 the most successful one is a new class of
electrophilic fluorinating reagents with the general structure of
R2N-F or R3N+-F.1,3,4 In this area, the development of the
reagent Selectfluor 1 (1-chloromethyl-4-fluoro-1,4-diazonia-
bicyclo[2.2.2]octane bis(tetrafluoroborate), also called F-TEDA-
* To whom correspondence should be addressed. Tel: 86-21-549-25147.
Fax: 86-21-641-67510.
† Zhejiang University.
‡ Chinese Academy of Sciences.
(1) Kirsch, P. Modern Fluoroorganic Chemistry, 1st ed.; Wiley-VCH:
Weinheim, 2004.
(2) (a) Rozen, S. Acc. Chem. Res. 1996, 29, 243. (b) Rozen, S. Acc.
Chem. Res. 1988, 21, 307.
(3) (a) Middleton, W. J. J. Org. Chem. 1975, 40, 574. (b) Barton, D. H.
R.; Godinho, L. S.; Hesse, R. H.; Pechet, M. M. Chem. Commun. 1968,
804. (c) Schack, C. J. K.; Christe, O. Inorg. Chem. 1979, 18, 2619. (d)
Tius, M. A. Tetrahedron 1995, 51, 6605. (e) Schmutzler, R. Angew. Chem.,
Int. Ed. 1968, 7, 440. (f) Rozen, S. Chem. ReV. 1996, 96, 1717.
10.1021/jo702409y CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/23/2007
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J. Org. Chem. 2008, 73, 772-774

TABLE 2. Selectfluor-Mediated Lactonization Reactions of
Different Substituted 2,3-Allenoic Acids
SCHEME 1. Fluorinating of Substituted Unsaturated
Carboxylic Acids
entry
R1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R2
R3
conditions isolated yield of 3 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Me Me (2a)
Me Me (2a)
A
81 (3a)
75 (3a)
81 (3b)
59 (3b)
86 (3c)
96 (3d)
94 (3e)
61 (3f)
70 (3f)
65 (3g)
39 (3h)
9b (3h)
49 (3h)
19 (3i)
64 (3i)
53 (3j)
34 (3j)
B
A
B
B
A
A
A
B
Et
Et
Et
Ph
Ph
n-Pr (2b)
n-Pr (2b)
Me (2c)
Me (2d)
n-Pr (2e)
Me H (2f)
Me H (2f)
TABLE 1. Selectfluor-Mediated Lactonization Reaction of
2,4-Dimethyl-4-phenyl- 2,3-butadienoic Acid 2a
Ph
H
H
H
H
H
H (2g)
A
n-Pr (2h)
n-Pr (2h)
n-Pr (2h)
Me (2i)
Me (2i)
Me (2j)
Me (2j)
Aa
B
Aa,c
B
Aa,d
A
(CH2)4
(CH2)4
Be
entry
solvent
EtOH
EtOH/H2O ) 20:1
DMA
CH3NO2
DMF
CH3CN
CH3CN
CH3CN
H2O
H2O (equiv) 1 (equiv) yield of 3aa (%)
a 1.5 equiv of Selectfluor 1 was used. b NMR yield; 52% of 2h was
recovered. c The reaction was conducted at 100 °C in a reaction tube with
a screw cap for 18 h. d The reaction was conducted at 95 °C in a reaction
tube with a screw cap. e 1.2 equiv of Selectfluor 1 was used.
1
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.1
1.1
no reaction
2b
3
50
63
69
76
85
71
86
78
10
10
10
10
4
5
6
7
the hydrogen bonding between Selectfluor and H2O may
facilitate the electrophilic fluorocyclization. Due to the easily
availability of 2,3-allenoic acids10 and Selectfluor as well as
the importance of butenolides11-14 and monofluorides,1,5 this
reaction may be useful in organic synthesis and medicinal
chemistry. Further studies in this area are being conducted in
our laboratory.
8
10
9c
a NMR yield. b Byproducts were also formed. c The reaction was con-
ducted at 90 °C.
Experimental Section
solvent (compare entry 6 with entry 8 in Table 1; the reaction
conditions of entry 8 are defined as conditions A). The reaction
in MeCN in the absence of H2O afforded 3a in a relatively lower
yield (entry 7, Table 1). Furthermore, the reaction may also be
performed in pure water with just 1.1 equiv of Selectfluor 1
(entry 9, Table 1, defined as conditions B).
Synthesis of 4-Fluoro-3,5-dimethyl-5-phenyl-2(5H)-furanone
(3a). Typical procedure for conditions A: To a solution of 2a (94.0
mg, 0.5 mmol) in 5.0 mL of MeCN was added subsequently 90
µL (10 equiv) of H2O and 194.5 mg (0.55 mmol) of Selectfluor 1.
After the reaction mixture was stirred at 80 °C for 10 h as monitored
by TLC, it was quenched with 10 mL of water, extracted with
diethyl ether (30 + 25 × 2 mL), washed with brine, and dried
over anhydrous Na2SO4. Evaporation and column chromatography
With the optimized reaction conditions A and B in hand, the
reaction of Selectfluor 1 with phenyl- and alkyl-substituted 2,3-
allenoic acids 2 producing the corresponding â-fluorobutenolide
derivatives was studied. It was observed that with at least one
phenyl group at the 4-position of the 2,3-allenoic acid, the
reaction of the fully substituted (entries 1-7, Table 2) and 4,4-
disubstituted (entries 8-10, Table 2) 2,3-allenoic acids afforded
the â-fluorobutenolides in good yields under conditions A and/
or B. With 2-alkyl-4-phenyl-2,3-allenoic acids 2h and 2i, when
conditions A or B were applied, the reaction at 90 °C was slow
and low-yielding (entries 11, 12, and 14, Table 2); thus, the
reaction of 2h and 2i in MeCN in the presence of 10 equiv of
H2O was conducted at 95-100 °C in a reaction tube with a
screw cap to afford the corresponding products 3h and 3i in
49% and 64% yields, respectively (entries 13 and 15, Table 2).
Conditions A are also applicable to fully alkyl-substituted
substrate 2j (compare entry 16 with entry 17, Table 2).
(10) (a) Ma, S.; Wu, S. J. Org. Chem. 1999, 64, 9314. (b) Clinet, J. C.;
Linstrumelle, G. Synthesis 1981, 875. (c) Marshall, J. A.; Wolf, M. A.;
Wallace, E. M. J. Org. Chem. 1997, 62, 367.
(11) For reviews on the synthesis of butenolides, see: (a) Negishi, E.;
Kotora, M. Tetrahedron 1997, 53, 6707. (b) Rao, Y. S. Chem. ReV. 1976,
76, 625. (c) Knight, D. W. Contemp. Org. Synth. 1994, 1, 287. (d) Bruckner,
R. Curr. Org. Chem. 2001, 5, 679. (e) Carter, N. B.; Nadany, A. E.;
Sweeney, J. B. J. Chem. Soc., Perkin Trans. 1 2002, 2324.
(12) For some of the most recent examples, see: (a) Marshall, J. A.;
Piettre, A.; Paige, M. A.; Valeriote, F. J. Org. Chem. 2003, 68, 1780. (b)
Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem. Soc.
2003, 125, 1192. (c) Linclau, B.; Boydell, A. J.; Clarke, P. J.; Horan, R.;
Jaequet, C. J. Org. Chem. 2003, 68, 1821. (d) Patil, S. N.; Liu, F. Org.
Lett, 2007, 9, 195. (e) Adrio, J.; Carretero, J. C. J. Am. Chem. Soc. 2007,
129, 778. (f) Maulide, N.; Marko, I. E. Org. Lett. 2006, 8, 3705. (g) Ma,
S.; Lu, L.; Lu, P. J. Org. Chem. 2005, 70, 1063. (h) Kong, K.; Romo, D.
Org. Lett. 2006, 8, 2909. (i) Marshall, J. A.; Sabatini, J. J. Org. Lett. 2006,
8, 3557.
In conclusion, we have developed a convenient method for
the efficient monofluorination via the electrophilic fluorocy-
clization reaction of 2,3-allenoic acids with Selectfluor 1 in
MeCN in the presence of 10 equiv of H2O or even in pure water.
Although the effect of water is not clear yet, we reasoned that
(13) For reviews on biological importance of butenolide derivatives,
see: (a) Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Synlett 1999,
1333. (b) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. ReV.
2000, 100, 1929. (c) Casiraghi, G.; Zanardi, F.; Rassu, G. Pure Appl. Chem.
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J. Org. Chem, Vol. 73, No. 2, 2008 773

on silica gel (petroleum ether/ethyl acetate ) 20:1) afforded 3a
on silica gel (petroleum ether/ethyl acetate ) 20:1) afforded 3a
(46.3 mg, 75%).
1
(83.1 mg, 81%): oil; H NMR (400 MHz, CDCl3) δ 7.46-7.41
(m, 2H), 7.40-7.32 (m, 3H), 1.89 (s, 3H), 1.80 (d, J ) 2.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 177.5 (d, J ) 297.6 Hz),
170.7 (d, J ) 21.8 Hz), 137.2 (d, J ) 3.2 Hz), 128.76, 128.73,
124.7, 103.1 (d, J ) 7.6 Hz), 82.2 (d, J ) 20.5 Hz), 24.0 (d, J )
3.1 Hz), 5.8 (d, J ) 2.7 Hz); 19F NMR (282 MHz, CDCl3) δ
-111.6; IR (neat) ν (cm-1) 1775, 1727, 1496, 1448, 1336, 1080,
1048; MS (70 eV, EI) m/z 206 (M+, 7.48), 163 (100); HRMS calcd
for C12H11O2F (M+) 206.0743, found 206.0753.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20572093), Major State
Basic Research and Development Program (2006CB8061007),
and the Cheung Kong Scholar Program is greatly appreciated.
This work was conducted at Zhejiang University. We thank
Zhao Fang in our group for reproducing the results presented
in entries 2, 4, and 16 of Table 2.
Typical procedure for conditions B: To a solution of 2a (56.5
mg, 0.3 mmol) in 3.0 mL of H2O was added with stirring 116.8
mg (0.33 mmol) of Selectfluor 1. After the reaction mixture was
stirred at 90 °C for 10 h as monitored by TLC, it was extracted
with diethyl ether (30 + 25 × 2 mL), washed with brine, and dried
over anhydrous Na2SO4. Evaporation and column chromatography
Supporting Information Available: Experimental procedures
1
and copies of H and 13C NMR spectra of all compounds. This
material is available free of charge via the Internet at http://pubs.
acs.org.
JO702409Y
774 J. Org. Chem., Vol. 73, No. 2, 2008