C-F bond cleavage by intramolecular SN2 reaction of alkyl fluorides with O- and N-nucleophiles

Article abstract of DOI:10.1021/jo802819p

The nueleophilic substitution of alkyl fluorides was achieved in the intramolecular reactions with O- and N-nucleophiles. The intramolecular defluorinative cyclization reaction was influenced by the nature of nucleophiles, the size of the ring to be forme

Full text of DOI:10.1021/jo802819p

reactivity of four halides is known to be decreasing in the
following order: I- (30 000) > Br- (10 000) > Cl- (200) > F-
(1),6a which explains the difficulty of using primary alkyl
fluorides in conventional SN2 reactions. As a result, both inter-
and intramolecular SN2 reactions between alkyl fluorides and
nucleophiles are largely neglected in most organic chemistry
textbooks.6
C-F Bond Cleavage by Intramolecular SN2
Reaction of Alkyl Fluorides with O- and
N-Nucleophiles
Laijun Zhang, Wei Zhang, Jun Liu, and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Ling-Ling Road, Shanghai 200032, China
However, although alkyl fluorides are generally inert to SN2-
type nucleophilic displacement, some C(sp3)-F bonds can be
cleaved by hydroxide under enzyme-catalyzed conditions.7 The
acceleration of C-F bond cleavage by enzyme catalysis can
be explained by the proximity effect, that is, enzyme binds both
alkyl fluoride and a nucleophile (such as hydroxide) together
to make the reaction an intramolecular process.8,9 This indicates
that the nucleophilic substitution of an alkyl fluoride can be
significantly accelerated when the reaction proceeds as an
intramolecular process. Intramolecular SN2 reaction of alkyl
fluorides, however, did not attract much attention for a long
time probably due to the “common sense” that the C-F bond
is highly stable. In many early publications, some unexpected
intramolecular nucleophilic substitution reactions of the C-F
bond were observed, but most of these discoveries were
considered as undesirable and sometimes even as side reac-
tions.10 Although some early examples of these C-F cleavage
reactions were summarized by Hudlickly,10 there is still a lack
of detailed and systematic study of intramolecular nucleophilic
substitution of alkyl fluorides with different nucleophiles to
determine both the scope and chemical yields of the reactions.
In this Note, we wish to disclose our recent study on this topic,
which provides new insights into the intramolecular nucleophilic
substitutions of primary and secondary alkyl fluorides with
different nucleophiles.
jinbohu@mail.sioc.ac.cn
ReceiVed December 29, 2008
The nucleophilic substitution of alkyl fluorides was achieved
in the intramolecular reactions with O- and N-nucleophiles.
The intramolecular defluorinative cyclization reaction was
influenced by the nature of nucleophiles, the size of the ring
to be formed, and the comformational rigidity of the
precursors. Intermolecular nucleophilic substitution reactions
of alkyl fluorides under similar reaction conditions were
found to be difficult. The stereochemistry study of the current
C-F bond cleavage reaction showed a complete configu-
rational inversion, which supports an intramolecular SN2
reaction mechanism.
Previously, we reported an efficient nucleophilic fluoro-
alkylation-acylation of benzyne with PhSO2CFHC(O)Ph re-
agent, and further elaboration of the product gave [(2-fluoro-
methyl)phenyl](phenyl)methanol (1) in good yield.11 Interest-
The carbon-fluorine bond is commonly regarded as the
strongest single bond to carbon, and the selective C-F bond
activation and transformation have become an interesting
challenge in modern organic chemistry.1,2 In this context, C-F
bond cleavage mediated by transition metal complexes,3 reduc-
ing metals,4 and Lewis acids5have received substantial attention.
Furthermore, it is widely realized that, unlike other alkyl halides
(halogen ) iodine, bromine, and chlorine), alkyl fluorides do
not typically undergo SN2 reactions,6a or the SN2 reactions with
alkyl fluorides are very slow.6b The relative leaving group
(5) (a) Uneyama, K. Organofluorine Chemistry; Blackwell: Oxford, UK,
2006. (b) Olah, G. A.; Prakash, G. K. S.; Krishnamurthy, V. V. J. Org. Chem.
1983, 48, 5116. (c) Prakash, G. K. S.; Hu, J.; Simon, J.; Bellew, D. R.; Olah,
G. A. J. Fluorine Chem. 2004, 125, 595. (d) Terao, J.; Begum, S. A.; Shinohara,
Y.; Tomita, M.; Naitoh, Y.; Kambe, N. Chem. Commun. 2007, 855. (e) Douvris,
C.; Ozerov, O. V. Science 2008, 321, 1188.
(6) (a) McMurry, J. Organic Chemistry, 7th ed.; Brooks/Cole: New York,
2007. (b) Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. Organic Chemistry;
Oxford University Press: Oxford, UK, 2000. (c) Solomons, T. W. G.; Fryhle,
C. B. Organic Chemistry, 9th ed.; Wiley: New York, 2007. (d) Carey, F. Organic
Chemistry, 7th ed.; McGraw-Hill: New York, 2007. (e) Smith, M. B.; March, J.
March’s AdVanced Organic Chemistry. Reactions, Mechanisms, and Structures,
6th ed.; Wiley: New York, 2007. (f) Carey, F. A.; Sundberg, R. J. AdVanced
Organic Chemistry, 5th ed.,Parts A and B; Springer: New York, 2007.
(7) (a) Goldman, P.; Mine, G. W. A. J. Biol. Chem. 1966, 241, 5557. (b)
Goldman, P. J. Biol. Chem. 1965, 240, 3434.
(1) Smart, B. E. Fluorocarbons. In Chemistry of Functionalized Groups,
Supplement D; Patai, S., Rappoport, Z., Eds.; Wiley: New York, 1983..
(2) Organofluorine Compounds: Chemistry and Applications; Hiyama, T.,
Ed.; Springer: New York, 2000.
(8) (a) Menger, F. M. Acc. Chem. Res. 1985, 18, 128. (b) Menger, F. M.
Acc. Chem. Res. 1993, 26, 206.
(3) See reviews:(a) Kiplinger, J. L.; Richmond, T. G.; Osterberg, C. E. Chem.
ReV. 1994, 94, 373. (b) Perutz, R. N.; Braun, T. In ComprehensiVe Organome-
tallic Chemistry III; Mingos, M. D., Crabtree, R. H., Eds.; Elsevier: Amsterdam,
The Netherlands, 2007. (c) Burdeniuc, J.; Jedlicka, B.; Crabtree, R. H. Chem.
Ber. 1997, 130, 145. (d) Richmond, T. G. In Topics in Organometallic Chemistry;
Murai, S., Ed.; Springer: New York, 1999; Vol. 3. (e) Reade, S. P.; Mahon,
M. F.; Whittlesey, M. K. J. Am. Chem. Soc. 2009, 131, 1847.
(4) (a) Saunders, G. C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2615. (b)
Chakrabarti, N.; Jacobus, J. Macromolecules 1988, 21, 3011. (c) Uneyama, K.;
Amii, H. J. Fluorine Chem. 2002, 114, 127.
(9) Besides “proximity effect”, the rate acceleration by intramolecular reaction
and enzyme catalysis was also explained by other hypotheses such as “spa-
tiotemporal effect”, “transition state effect”, “near attack conformations”, and
“orbital steering”, among others. See:(a) Menger, F. M. Pure Appl. Chem. 2005,
77, 1873. (b) Houk, K. N.; Tucker, J. A.; Dorigo, A. E. Acc. Chem. Res. 1990,
23, 107. (c) Bruce, T. C.; Lightstone, F. C. Acc. Chem. Res. 1999, 32, 127. (d)
Anslyn, E. V.; Sougherty, D. A. Modern Physical Organic Chemistry; University
Science Books: New York, 2005.
(10) Hudlicky, M. Isr. J. Chem. 1978, 17, 80.
(11) Ni, C.; Zhang, L.; Hu, J. J. Org. Chem. 2008, 73, 5699.
2850 J. Org. Chem. 2009, 74, 2850–2853
10.1021/jo802819p CCC: $40.75 2009 American Chemical Society
Published on Web 03/05/2009

TABLE 1. Survey of Reaction Conditions
SCHEME 2. One-Pot Lithiation, Addition, and Cyclization
Reactions Between 3 and Ketonesa
entry
base (equiv)
solvent
temp (°C) time (h) yield (%)a
1
2
3
4
5
6
NaH (2.0)
NaH (2.0)
NaH (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
CH3OH
DMF
THF
DMF
DMF
25
25
25
25
80
25
24
24
24
4
2
24
83
90
98
NRb
trace
64
t-BuOK (2.0) DMF
a Isolated yield. b Starting material 1 was recovered.
SCHEME 1. One-Pot Lithiation, Addition, and Cyclization
Reactions between 3 and Aldehydesa b
,
a The data in paratheses are isolated yields of products 4a-j.
SCHEME 3. Intramolecular C-F Functionalizations with
O-, N-, S-, and C-Nucleophiles
a The data in paratheses are isolated yields of products 2a-j. b The
reaction time was extended to 12 h.
ingly, we noticed that compound 1 readily transformed to 1,3-
dihydroisobenzofuran 2a under basic conditions. For instance,
when 1 was stirred with NaH in methanol at room temperature,
product 2a was obtained in 83% isolated yield. Thereafter, we
examined the influence of base, solvent, and temperature on
the reaction, and the results are shown in Table 1. It turned out
that both NaH and t-BuOK were suitable bases to facilitate the
intramolecular nucleophilic substitution reaction, while the
basicity of potassium carbonate was not strong enough to
mediate the reaction (Table 1, entries 4 and 5). The best yield
(98%) of product 2a was obtained when starting material 1 was
treated with NaH in THF at room temperature (Table 1, entry
3). It should be mentioned that the addition of 1 equiv of 1,4-
dinitrobenzene in the reaction mixture (same as entry 3) did
not inhibit the cyclization reaction, which rules out the pos-
sibility of the involvement of a free radical reaction mechanism.
With the consideration that compound 1 and its derivatives
can be prepared from o-(fluoromethyl)phenyllithium (5) and
aldehydes, we carried out the one-pot lithiation-addition-
defluorinative cyclization cascade reactions, using 2-fluoro-
methylbromobenzene (3), n-BuLi, and aldehyde as the starting
materials (Scheme 1). Compound 3 was generally treated with
n-BuLi (1.1 equiv) in THF at -78 °C for 30 min, followed by
addition of aldehyde (0.9 equiv). The cascade reactions com-
pleted in around 10 h to give the desired products 2a-j in
61-95% isolated yields (Scheme 1). Similarly, the one-pot
three-step cascade reaction also worked well with ketones,
giving products 4a-j in 68-90% isolated yields (Scheme 2).
It should be mentioned that the reaction of o-bromo(or iodo)m-
ethylbromobenzene in place of 3 would give no or low chemical
yield due to undesired reactions such as metalation at the
benzylic position with n-BuLi.12
We also tried other compounds 6-10 to react with in situ
generated o-(fluoromethyl)phenyllithium (5) (Scheme 3). It was
found that both p-tolyl isocyanate and p-tolyl isothiocyanate
could react with intermediate 5, which resulted in the formation
of 2-(p-tolyl)isoindolin-1-one (11) and 2-(p-tolyl)isoindoline-
1-thione (12) in 85% and 36% yields, respectively (Scheme 3,
eqs 1 and 2). This indicates that besides oxygen-nucleophiles,
nitrogen-nucleophiles are also able to facilitate the C-F cleavage
via an intramolecular substitution process. When cyclohexene
(12) Parham, W. E.; Jones, L. D.; Sayed, Y. A. J. Org. Chem. 1976, 41,
1184.
J. Org. Chem. Vol. 74, No. 7, 2009 2851

SCHEME 4. Selected Intra- and Intermolecular C-F
Cleavage Reactions
SCHEME 5. Stereochemistry of the Intramolecular C-F
Functionalization Reaction
oxide 8 (0.5 equiv, along with 0.75 equiv of BF3-Et2O) was
used as substrate to react with 5, the in situ defluorinative
cyclization process proceeded smoothly to form a six-membered
ring, giving chromene derivative 13 in 70% yield (eq 3).
However, when cyclohexene sulfide (9) (instead of 8) was used
for the reaction, the defluorinative cyclization reaction was not
observed, only giving the uncyclized compound 14 in 65% yield
(eq 4). The Michael acceptor 10 was also used to react with 5
to generate stabilized carbanion intermediate, but the latter one
could not undergo intramocleular nucleophilic displacement of
fluorine atom. Instead, the uncyclized compound 15 was isolated
in excellent yield (eq 5). We also tried the reaction with methyl
cinnamate instead of 10, and similarly, no C-F bond cleavage
was observed. These results can be explained by using the hard
soft acids and bases (HSAB) principle,13 that is, alkyl fluorides
are hard electrophiles, which are favorable to react with hard
nucleophiles such as O- and N-anions, but less favorable to react
with soft nucleophiles such as S- and C-nucleophiles.
pyl)benzene (17) only gave uncyclized product 21 in 86% yield
(eq 7), which indicates that the intramolecular C-F cleavage
to form a 7-membered ring is unfavored (unlike the cases of
forming 5- and 6-membered rings). Furthermore, the defluori-
native cyclization of 2-(3-fluoropropyl)phenol (18) in the
presence of NaH in DMF proceeded at 80 °C to give chroman
22 in 82% yield (eq 8). Besides primary alkyl fluorides,
secondary fluoride was also found to be amenable to the
intramolecular nucleophilic substitution reaction with an O-
nucleophile. As a result, the one-pot lithiation-addition-defluori-
native cyclization process successfully transformed 1-bromo-
2-(1-fluoroethyl)benzene (19) to a 5-membered-ring-containing
product 23 in 84% yield (eq 9). We also found that the
comformational rigidity of the compounds plays an important
role in the intramolecular defluorinative cyclization reactions.
For instance, 4-fluoro-4-p-tolylbutan-1-ol (24), which bears a
linear and relatively flexible carbon skeleton, could not undergo
5-membered-ring formation under the treatment of NaH in THF
(eq 10). The effect of comformational rigidity on the cyclization
reactions can be well explained by several deviations of
“proximity effect” concept, such as “spatiotemporal effect”,
“transtion state effect”, and “near attack conformations” hy-
potheses.9 These hypotheses can also be used to explain the
remarkable intramolecularity: while the intramolecular cycliza-
tion proceeded smoothly as mentioned above, the similar
Thereafter, we examined the intramolecular cyclization reac-
tion with substrates bearing a nonbenzylic C-F bond such as
compounds 16-18 (Scheme 4). Under similar one-pot three-
step procedures as mentioned above, 1-bromo-2-(2-fluoroeth-
yl)benzene (16) was transformed to product 20 in 80% yield
(eq 6). However, the reaction with 1-bromo-2-(3-fluoropro-
(13) (a) Hard and Soft Acids and Bases; Pearson, R. G., Ed.; Dowden,
Hutchinson & Ross: Stroudsburg, PA, 1973. (b) Ho, T.-L. Hard and Soft Acids
and Bases Principle in Organic Chemistry; Academic: New York, 1977.
2852 J. Org. Chem. Vol. 74, No. 7, 2009

intermolecular reactions between compound 3 and alcohol 26
(or 27) failed (eq 11).
found to be difficult. The stereochemistry study of this C-F
bond cleavage reaction showed a complete configurational
inversion, which supports an intramolecular SN2 reaction
mechanism.
To gain some insights into the mechanism of the present
intramolecular defluorinative cyclization reactions, we investi-
gated the stereochemistry of the reaction (Scheme 5). We
Experimental Section
25
synthesized (R)-2-(2-fluoropropyl)phenol (30) (92% ee, [R]D
-11.5 (c, 1.2 in CHCl3)) via stereospecific preparation of 32,
fluorination with DAST,14 followed by deprotection with H2
(eq 12). The absolute configuration of 30 was determined by
the characterization of the X-ray crystal structure of its derivative
compound 37 (see the Supporting Information). Compound 30
was subjected to the treatment of NaH in THF or DMF at 70
°C. It was found that the reaction proceeded well to give product
31 in good yield and with high enantiospecificity [in THF, 89%
Typical Procedure for the Preparation of 2j. Under N2
atmosphere, into a 50-mL Schlenk flask containing 1-bromo-2-
(fluoromethyl)benzene (3; 2.0 mmol, 0.378 g) in THF (20 mL) at
-78 °C was added n-BuLi (2.2 mmol, 1.38 mL, 1.6 M in hexane).
The reaction mixture was stirred at -78 °C for 30 min, followed
by the addition of 2-naphthaldehyde (1.8 mmol, 0.281 g), then the
solution was stirred for 2 h at the same temperature. Next the
reaction mixture was warmed to room temperature and stirred for
12 h. After being quenched with brine, the reaction mixture was
extracted with Et2O (3 × 30 mL), and the combined organic phase
was dried over anhydrous MgSO4. The volatile solvents were
removed under vacuum, and the crude product was purified by silica
gel column chromatography (ethyl acetate/petroleum ether ) 1:
30 v/v) to afford 2j (0.336 g) in 76% yield.
25
yield, 91% ee, [R]D -13.3 (c, 1.2 in CHCl3); in DMF, 87%
25
yield, 93% ee, [R]D -17.2 (c, 1.0 in CHCl3)] (Scheme 5, eq
13). To determine the absolute configuration of compound 31,
(R)-1-(2-(benzyloxy)phenyl)propan-2-ol (32) was subjected to
palladium-catalyzed hydrogenolysis on carbon (Pd(OH)2/C),
leading to (R)-2-(2-hydroxypropyl)phenol (33) in 98% yield.
Compound 33 was treated under standard Mitsunobu inversion
condition to give (S)-2-methyl-2,3-dihydrobenzofuran (31) in
1H NMR δ 7.87-7.78 (m, 4H), 7.49-7.44 (m, 2H), 7.37 (d, J
) 8.4 Hz, 1H), 7.32-7.28 (m, 2H), 7.24-7.17 (m, 1H), 7.03 (d, J
) 7.5 Hz, 1H), 6.32 (s, 1H), 5.42 (dd, J ) 12.2, 2.4 Hz, 1H), 5.26
(d, J ) 12.3 Hz, 1H); 13C NMR δ 141.9, 139.5, 139.1, 133.3, 128.5,
128.0, 127.7, 127.5, 126.1, 126.0, 125.9, 124.9, 122.4, 120.9, 86.4,
73.4; MS (EI, m/z, %) 246 (100.00), 246 (100.00); IR (film) 2856,
1600, 1508, 1460, 1124, 1035, 819, 740 cm-1. Anal. Calcd for
C18H14O: C, 87.78; H, 5.73. Found: C, 87.57; H, 5.92.
24
68% yield and with 99% ee, [R]D -20.1 (c, 1.1 in CHCl3)
(Scheme 5, eq 14). The result in eq 14 shows that the product
31 in eq 13 is in the S-configuration, which supports that the
current defluorinative cyclization reaction proceeds via an
intramolecular SN2 reaction mechanism.
Acknowledgement. We thank the National Natural Science
Foundation of China (20772144; 20825209; 20832008) and the
Chinese Academy of Sciences (Hundreds-Talent Program and
Knowledge Innovation Program) for financial support.
In conclusion, we have shown that the nucleophilic substituion
of alkyl fluorides can be achieved in intramolecular reactions.
The intramolecular defluorinative cyclization reaction was
influenced by (a) the nature of nucleophiles (hard nucleophiles
such as O- and N-nucleophiles are favored), (b) the size of the
ring to be formed (5- and 6-membered rings are favored15), and
(c) the comformational rigidity of the precursors. Intermolecular
nucleophilic substitution reactions under similar conditions were
Supporting Information Available: General experimental
information and characterization data of the new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Although the fluorination of an alcohol with DAST usually gives the
fluorinated product with inversion of configuration, a neighboring group
participation mechanism sometimes leads to a product with retention of
configuration. For an example see: De´champs, I.; Pardo, D. G.; Cossy, J. Synlett
2007, 263.
JO802819P
(15) 3-Membered-ring formation via intramolecular nucleophilic substitution
of alkyl fluorides with O-nucleophiles is also known. See ref 10.
J. Org. Chem. Vol. 74, No. 7, 2009 2853