Functionalization of monofluoroallene and the synthesis of aryl-substituted conjugated fluorodienes

Article abstract of DOI:10.1021/ol026196k

(Matrix Presented) 4-Fluoroallenol 3a, prepared from 1, cyclized easily to 4 but preserved its fluoroallenyl integrity under oxidation and S_N2 displacement to yield aldehyde, amine, mesylate, and halide 6. Allylic isomerization yielded 2-halo-1

Full text of DOI:10.1021/ol026196k

ORGANIC
LETTERS
2002
Vol. 4, No. 14
2437-2439
Functionalization of Monofluoroallene
and the Synthesis of Aryl-Substituted
Conjugated Fluorodienes
Yunfeng Lan and Gerald B. Hammond*
Department of Chemistry and Biochemistry, UniVersity of Massachusetts Dartmouth,
285 Old Westport Road, North Dartmouth, Massachusetts 02747
ghammond@umassd.edu
Received May 16, 2002
ABSTRACT
4-Fluoroallenol 3a, prepared from 1, cyclized easily to 4 but preserved its fluoroallenyl integrity under oxidation and SN2 displacement to yield
aldehyde, amine, mesylate, and halide 6. Allylic isomerization yielded 2-halo-1-fluoro-1,3-butadiene 7, which underwent a Suzuki coupling to
give aryl-substituted conjugated diene 8.
Fluorinated allenes blend the unique stereoelectronic proper-
ties of fluorine with the well-known synthetic capabilities
of the allene moiety. This unique combination makes them
attractive building blocks for the synthesis of partially
fluorinated alicyclic compounds not accessible through
current fluorinating strategies. Their ring-forming capability
was showcased in our recently published regiospecific
synthesis of bicyclo- and heterobicyclo-gem-difluoro-
cyclobutene, via a novel Mo-catalyzed intramolecular [2 +
2] cycloaddition of a functionalized gem-difluoroallene.1 In
theory, a suitably functionalized monofluoroallene could also
be used to construct alicyclic monofluoro compounds. This
potentialsfirst recognized by Dolbier2shas not prospered
further because synthetic routes to substituted monofluoro-
allenes are painstakingly few. One such preparation involved
treating acetylenic alcohols with sulfur tetrafluoride.3 Later,
Castelhano and Krantz introduced the only other viable
route: reduction of a fluorochloropropargyl precursor with
aluminum hydride.4 We now report a practical, environmen-
tally benign synthesis of fluoroallenyl alcohol 3a, its cy-
clization to fluorodihydrofuran 4, and its functional group
interconversion to fluoroallenyl derivatives with desirable
synthetic handlesssuitable for chain extension or further
functionalizationssuch as aldehyde, amine, mesylate and
halide 6, and diene 7. The latter furnished 2-aryl-substituted
1,3-dienes 8 via Suzuki coupling.
Our group has reported the preparation of difluoroallenyl
indium 2b, in predominantly aqueous media (Scheme 1), and
its reaction with formaldehyde to yield allenyl alcohol 3b.5
This discovery encouraged us to investigate whether a
monofluorinated allenyl indium analogue 2a could be
similarly prepared from bromofluoropropyne 1a. Although
we could not isolate 2a using the same conditions as for 2b,
proof of its fleeting existence was the formation of TIPS-
* To whom correspondence should be addressed. Tel: 508-999-8865.
Fax: 508-910-6918.
(1) Shen, Q.; Hammond, G. B. J. Am. Chem. Soc. 2002, 124, 6534-
6535.
(4) Castelhano, A. L.; Krantz, A. J. Am. Chem. Soc. 1987, 109, 3491-
3493.
(5) Wang, Z.; Hammond, G. B. J. Org. Chem. 2000, 65, 6547-6552.
(2) Dolbier, W. R., Jr. Acc. Chem. Res. 1991, 24, 63-69.
(3) Dear, R. E.; Gilbert, E. E. J. Org. Chem. 1968, 33, 819-823.
10.1021/ol026196k CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/13/2002

Scheme 1. Synthesis and Cyclization of Fluoroallenol 3ba
Table 1. Chemical Modifications Derived from 3a
a Key: (i) In (1 equiv); (ii) 3a, HCHOaq, (5 equiv), THF, rt
o
(66%); (iii) TBAF, THF, -80 C, 15 min (62%); (iv) NaH, THF,
rt, 2 h (75%).
CHdCdCHF, accompanied by its propargylic isomer (1:1
ratio) and unreacted starting material. By eliminating water
as cosolvent in the reaction and trapping 2a with an excess
of aqueous formaldehyde, we obtained the desired 3a, this
time accompanied by 5a in a 7:1 ratio. The allene/propargyl
ratio was reversed when TIPS was replaced with TMS to
give a mixture of 5c/3c (2:1). In both cases, the only other
byproduct was the dimer (R3SiCtCCHF)2, easily separated
by chromatography because of its very low polarity. With
an expedient synthesis of 3a in hand, we proceeded to study
its chemistry. An attempted TBAF desilylation afforded
dihydrofuran 4, in 62% yield, by means of a 5-endo-trig
cyclization path. The same product could be isolated in better
yield using sodium hydride.6 A plausible reaction mechanism
involves the nucleophilic attack by oxygen on the distal
double bond of the allene, generating a negative charge on
the ring that is stabilized by a favorable â-effect of the silicon
atom.5 In contrast, the Ag(I)-catalyzed cyclization7 of 3a
resulted in the elimination of fluoride and the formation of
3-TIPS-furan (65%). Similarly, when 3a reacted with iodine
in THF at rt, the loss of fluoride was accompanied by iodo
substitution to give 3-TIPS-4-iodofuran (60% yield).
To find out if a functional group interconversion in 3a
could be carried out without compromising the integrity of
the fluoroallenyl moiety, we first probed the alcohol to
aldehyde oxidation in 3a. This oxidation, using Dess-
Martin8 conditions, resulted in a facile synthesis of 6a in
very good yield (entry 1, Table 1). Another functional group
interconversion, the replacement of O by N in 3a, was carried
out in high yield under Mitsunobu9 conditions with N-(tert-
butoxycarbonyl)-p-toluenesulfonamide (entry 2). Removal of
the BOC-protecting group in 6b afforded 6c (entry 3). Its
a Isolated yield, not optimized. b CFCl3 used as external reference; CDCl3
used as solvent. c Used without further purification in entry 7.
(6) Yamazaki, T.; Hiraoka, S.; Sakamoto, J.; Kitazume, T. J. Phys. Chem.
A 1999, 103, 6820-6824. Ichikawa, J.; Fujiwara, M.; Wada, Y.; Okauchi,
T.; Minami, T. J. Chem. Soc., Chem. Commun. 2000, 1887-1888.
(7) Marshall, J. A.; Wang, X. J. Org. Chem. 1991, 56, 4913-4918.
(8) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
(9) Hughes, D. L. Org. React. 1992, 42, 335.
recrystallization from hexane afforded X-ray quality crystals10
that provided the first crystallographic analysis of a mono-
fluorinated allene.11 The integrity of the fluoroallenyl moiety
2438
Org. Lett., Vol. 4, No. 14, 2002

was also maintained under bromination and mesylation12
conditions, although the resulting products 6d and 6e,
respectively, were obtained only in moderate to good yields
(entries 4 and 5).
1-Fluoro-1,3-butadiene has been extensively studied for
conformational stability,13 spectral characteristics,14 reactivity
in Diels-Alder reaction,15 and [2 + 2] cycloaddition.16 Its
substituted derivatives are less known, perhaps due to their
laborious synthesis. Our recent Pd-catalyzed preparation of
2-aryl- and 2-alkynyl-substituted 1,1-difluoro-1,3-buta-
dienes12 persuaded us to conduct a similar study with
monofluorovinyl iodide 7a. To our satisfaction, coupling 7a
with aryl boronic acids under Suzuki conditions afforded
substituted-1,3-butadienes 8a-d (entry 8), mostly in good
or very good yields, except when a strong electron-
withdrawing substituent was employed (8d). We have not
succeeded yet at elucidating the stereochemistry of the
fluorine-containing double bond in 8seither by scalar
coupling analysis or NOE experiments. Investigation is
ongoing. The spectral data of 8a-d showed that in each case
the chemical shifts of C-1 and H-1, as well as 1JHF and 1JCF
coupling constants, were in good agreement with the reported
values for E/Z 1-fluoro-1,3-butadiene.16 The chemical shift
of C-4 was assigned on the basis of a DEPT experiment,
but the 13C NMR signals of C-2 and C-3 are interchangeable
with the quaternary carbon of the aromatic ring bonded to
the diene moiety.
Interestingly, one sees allylic isomerization under certain
conditions. For example, treatment of 3a with methyl iodide
and Mitsunobu conditions produced the conjugated diene
isomer 7a (entry 6). Our hypothesis that an allene-containing
allylic halide (4-iodo-1,2-diene) (6, R ) CH2I) was generated
first via an SN2 mechanism but isomerized later to the
thermodynamically more stable 2-iodo-1,3-diene 7a was
confirmed by monitoring the progress of the reaction using
19F NMR. At room temperature, after a reaction time of only
5 min, the signal corresponding to the starting material (δ
-173) had decreased dramatically, and a new signal at δ
-176 ppm, believed to correspond to the 4-iodo-1,2-diene,
was observed, accompanied by two smaller signals of similar
intensity at δ -95 and -97, thought to correspond to E/Z
diastereomers of 7a.
As the reaction time lengthened, the intensity of the 19F
signals at δ -95 and -97 increased, while the δ -176 signal
decreased until its complete disappearance. The final signal
ratio of δ -95 to -97 was approximately 6:1. Decreasing
the temperature slowed the rate of isomerization, yet the
reaction did not take place at -78 °C. Alternatively, under
Finkelstein conditions (entry 7), a bromide attack on mesylate
6e produced a mixture of diene 7b and allene 6d in 3:1 ratio.
The fact that 6d was still present at the end of the reaction
discarded the possibility of a SN2′ allylic transposition,
suggesting instead an apparent SN2 course, followed by
partial allylic isomerization, as in 7a.
In sum, we have found a practical preparation of fluoro-
allenyl alcohol 3a and its derivatives such as aldehydes,
amines, halides, and aryl-substituted conjugated dienes. Their
chain extension reactions and metal-mediated cyclizations
are under study.
Acknowledgment. The Petroleum Research Fund (PRF
no. 36602-AC1) has partially financed this work. Drs. James
A. Golen (UMass Dartmouth) and A. Chandrasekaran
(UMass Amherst) supplied the crystallographic data, and Mr.
Qilong Shen provided helpful experimental advice.
(10) ORTEP view of 6c:
Supporting Information Available: Experimental pro-
cedures and spectroscopic and analytical data for 3a-8 and
CIF files for 6c. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL026196K
(13) Ribeiro-Claro, P. J. A. Chem. Phys. Lett. 1992, 188, 303-309.
(14) Cederbalk, P. Acta Chem. Scand., Ser. A 1980, A(34), 409-413.
Cederbalk, P. Acta Chem. Scand., Ser. A 1984, A(38), 15-21. Fueno, T.;
Yamaguchi, K. J. Am. Chem. Soc. 1972, 94, 1119-1125.
(15) Apeloig, Y.; Matzner, E. J. Am. Chem. Soc. 1995, 117, 5375-5376.
Imade, M.; Hirao, H.; Omoto, K.; Fujimoto, H. J. Org. Chem. 1999, 64,
6697-6701.
(11) For an analysis of bond lengths and angles in fluorinated allenes,
see: Dixon, D.; Smart, B. J. Phys. Chem. 1989, 93, 7772-7780.
(12) A similar but higher yielding SN2 mesylation was observed with
3b. See: Shen, Q.; Hammond, G. B. Org. Lett. 2001, 3, 2213-2215.
(16) Dolbier, W. R., Jr.; Gray, T. A.; Keaffaber, J. J.; Celewicz, L.;
Koroniak, H. J. Am. Chem. Soc. 1990, 112, 363-367.
Org. Lett., Vol. 4, No. 14, 2002
2439