Preparation of CF3-containing 1,3-Di- and 1,1,3-trisubstituted allenes

Article abstract of DOI:10.1021/jo060909l

Novel synthetic pathway to access trifluoromethylated allenes with 1,3-di- as well as 1,1,3-trisubstitution patterns was developed from a variety of 4,4,4-trifluorobut-2-yn-1-ols which were then transformed into the corresponding vinylic iodides in highly

Full text of DOI:10.1021/jo060909l

SCHEME 1. Synthetic Routes to the CF3-Containing
Allenes 9
Preparation of CF3-Containing 1,3-Di- and
1,1,3-Trisubstituted Allenes
Takashi Yamazaki,* Takahiro Yamamoto, and
Ritsuko Ichihara
Strategic Research InitiatiVe for Future Nano-Science and
Technology, Institute of Symbiotic Science and Technology,
Tokyo UniVersity of Agriculture and Technology, 2-24-16,
Nakamachi, Koganei 184-8588, Japan
tyamazak@cc.tuat.ac.jp
ReceiVed May 2, 2006
effective modification toward their original properties. However,
despite such interest, only a limited number of methods can be
found in the literature allowing access to these types of
molecules.3 In this paper, we would like to describe our recent
development on the novel and simple preparative route to CF3-
possessing allenes starting from commercially available 2-bromo-
3,3,3-trifluoropropene 1 in only four easy steps. Especially,
emphasis should be placed on the fact that the present process
leads to construction of various allenes of type F3C-CHdCd
CHR whose methylated counterpart (RdCH3) is the only one
reported example to date.3e
Novel synthetic pathway to access trifluoromethylated allenes
with 1,3-di- as well as 1,1,3-trisubstitution patterns was
developed from a variety of 4,4,4-trifluorobut-2-yn-1-ols
which were then transformed into the corresponding vinylic
iodides in highly regio- and stereospecific manners, and zinc-
mediated â-elimination after trifluoroacetylation of the
hydroxyl group eventually realized the formation of the target
molecules in good to excellent overall yields in facile and
short steps.
Synthetic investigation of our target allenes was initiated by
the preparation of propargylic alcohols 2 totally in line with
our original technique (Scheme 1).4 Thus, treatment of com-
mercially available 2-bromo-3,3,3-trifluoropropene 1 with 2
equiv of LDA successively affected dehydrobromination and
then deprotonation of the terminal acetylenic hydrogen atom
from the resultant 3,3,3-trifluoropropyne intermediate. Addition
of appropriate carbonyl compounds to this reactive species
smoothly furnished propargylic alcohols 2 in good to excellent
chemical yields (Table 1). Transformation of 2 into the cor-
responding iodoalkenes 3 was performed by heating a mixture
of 2 in the presence of NaI in an acetic acid solvent by referring
to the protocol described by Qing et al.5 This process realized
the regio- as well as stereospecific formation of vinyl iodides 3
with (Z)-configuration in every instance.
It is well-documented that introduction of fluorine atoms into
organic molecules endows quite unique properties due to the
special electronic character of this particular element with
imposing only the slightest steric perturbation,1 and a wide
variety of fluorinated materials has been applied to such fine
chemicals as pharmaceuticals, optical devices, and so forth.
However, it is also this special character at least in part that
renders preparation of fluorine-containing substances difficult,
especially when appropriate building units with this atom around
the reaction sites were utilized as starting materials. In fact, it
is not rare to encounter chemical processes which do not proceed
at all just by entry of a single fluorine atom to substrates while
the corresponding nonfluorinated counterparts react smoothly.
For this reason, we should sometimes explore independent “fine-
tuned” methods for construction of the desired compounds with
this special atom.
(2) For the preparation of allenes, see the following recent reviews. (a)
Krause, N.; Hoffmann-Ro¨der, A. Tetrahedron 2004, 60, 11671. (b) Sydnes,
L. K. Chem. ReV. 2003, 103, 1133. For the synthetic application of allenic
compounds, see: Bates, R. W.; Satcharoen, V. Chem. Soc. ReV. 2002, 31,
12.
(3) (a) Mae, M.; Hong, J.-A.; Xu, B.; Hammond, G. B. Org. Lett. 2006,
8, 479. (b) Ogu, K.; Akazome, M.; Ogura, K. J. Fluorine Chem. 2004,
125, 429. (c) Konno, T.; Tanikawa, M.; Ishihara, T.; Yamanaka, H. Collect.
Czech. Chem. Commun. 2002, 67, 1421. (d) Shen, Q.-L.; Hammond, G. B.
J. Am. Chem. Soc. 2002, 124, 6534. (e) Burton, D. J.; Hartgraves, G. A.;
Hsu, J. Tetrahedron Lett. 1990, 31, 3699. (f) Dolbier, W. R., Jr.; Burkholder,
C. R.; Piedrahita, C. A. J. Fluorine Chem. 1982, 20, 637.
Taking the well-known importance of allenes in synthetic
organic chemistry2 into consideration, installation of fluorine
atoms or fluoroalkyl groups to this framework would offer
* Address correspondence to this author. Fax: +81-42-388-7038.
(1) (a) Smart, B. E. J. Fluorine Chem. 2001, 109, 3. (b) Hiyama, T.
Organofluorine Compounds. Chemistry and Applications; Springer-Ver-
lag: Berlin, Germany, 2000. (c) Kitazume, T.; Yamazaki, T. Experimental
Methods in Organic Fluorine Chemistry; Kodansha, Gordon and Breach:
Tokyo, Japan, 1998. (d) Smart, B. E. In Organofluorine Chemistry:
Principles and Commercial Applications; Banks, R. E., Smart, B. E., Tatlow,
J. C., Eds.; Plenum Press: New York, 1994; p 57.
(4) (a) Mizutani, K.; Yamazaki, T.; Kitazume, T. J. Chem. Soc., Chem.
Commun. 1995, 51. (b) Yamazaki, T.; Mizutani, K.; Kitazume, T. J. Org.
Chem. 1995, 60, 6046. See also the following: Katritzky, A. R.; Qi, M.;
Wells, A. P. J. Fluorine Chem. 1996, 80, 145.
10.1021/jo060909l CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/11/2006
J. Org. Chem. 2006, 71, 6251-6253
6251

TABLE 1. Preparation of Propargylic Alcohols 2, Vinyl Iodides 3,
and Hydroxy-Protected Materials 4-8
TABLE 2. Investigation of the Elimination Reaction of 5aa
isolated yield (%)
entry
compd
R1
R2
2
3
4 to 8
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
a
1-Naphthyl-
H
68
80
98 (4)
96 (5)
93 (6)
96 (4)
82 (5)
93 (7)
26 (8)
93 (4)
99 (5)
97 (6)
86 (4)
95 (4)
81 (5)
80 (4)
74 (5)
b
c
PhCH2CH2-
H
H
89
98
99
84
isolated yield (%)
X
(equiv)
time
(h)
entry
solvent
9a
5a
1
2
3
4
5
6
7
THF
THF
THF
Et2O
THF
Et2O
CH2Cl2
THF
THF
1.5
0
1.0
23.5
2.5
8.5
4.5
4.5
4.5
0.5
0.5
75
29
43
17
81
13
27
74
99
n-C12H25-
28
5
82
0.1
0.1
0.5
0.5
0.5
0
d
e
p-Br-C6H4-
o-CH3OC6H4-
H
H
85
90
85
81
87
63
8b
9b,c
f
Ph-
CH3-
90
72
0
a 1 mmol of 5a was treated with zinc powder (without any special
pretreatment or purification) in 5 mL of an appropriate solvent under reflux.
b Activated zinc powder was employed. c The corresponding trifluoroacetate
4a was employed as the starting material.
With the requisite (Z)-3 in hand, we turned our attention to
specify adequate reaction conditions for their conversion to our
targets, CF3-containing allenes 9. First of all, by using 3a (R1
) 1-naphthyl, R2 ) H) as the representative substrate, various
types of leaving groups were introduced at the hydroxy function.
Because of their prominent ability accepted widely, sulfonates
such as 7a and 8a were selected at the first stage but they were
proved quite unstable under the preparation conditions employed
presumably due to “double activation” of these sulfonate groups
at both the allylic and benzylic positions. On the other hand,
ester moieties were readily incorporated, and trifluoroacetate
4a and acetate 5a were synthesized under the usual method in
nearly quantitative yields. Compound 6a with a tetrahydropy-
ranyl protective group was also prepared for comparison despite
its lower leaving ability.
Our synthetic plan for the final step was to transform the
vinylic iodide Z-3 to the corresponding organozinc species6 for
effecting the desired â-elimination: organozinc was selected
because this species (i) is easy to handle, (ii) shows good
chemoselectivity (usually no reaction with esters), (iii) is
produced under heating condition (easily applicable to the larger
yield synthesis), and so on. A THF solution containing the model
acetate 5a (R1 ) 1-naphthyl, R2 ) H) and zinc powder without
any pretreatment nor purification was refluxed in the presence
of an appropriate amount of trimethylsilyl chloride (TMSCl,
Table 2).7 As described in entry 1, 1.5 equiv of TMSCl enabled
the smooth oxidative addition of zinc to the C-I bond in 5a
and the delivery of CH3CO2ZnI from the resultant intermediate
furnished the expected CF3-containing allene 9a in 75% yield.
The importance of TMSCl was clearly demonstrated by
comparison of the results in entries 2, 3, and 5 with those in
entry 1, and the highest yield among these examples was
recorded when 0.5 equiv of TMSCl was employed. The
experimental fact that even an excess amount of TMSCl did
not successfully capture the reactive intermediate would be the
reflection that elimination of an acetate group might simulta-
neously occur with organozinc formation. Et2O and CH2Cl2 were
TABLE 3. Preparation of CF3-Containing Allenes 9 under Various
Conditions
time
(h)
yield of
entry
substb
R1
R2
prodc
9a (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4a
5a
6a
3a
4b
4b
5b
7b
4c
5c
6c
4d
4f
1-Naphthyl-
H
0.5
2.0
23.0
19.0
0.5
0.5
7.0
0.25
0.5
4.0
5.0
0.5
0.5
2.0
1.0
1.0
9a
99
74
23
21d
98
92e
67
84
86
81
7
87
87
93
76
69
PhCH2CH2-
H
H
9b
9c
n-C12H25-
p-Br-C6H4-
o-CH3O-C6H4-
H
H
9d
9f
5f
4i
5i
Ph-
CH3-
9i
a Isolated yield. b Substrate. c Product. d Protodeiodination product of 3a
was obtained in 55% yield. e In the presence of 0.5 equiv of TMSCl.
also used for the construction of 9a (entries 4, 6, and 7), but
this molecule was obtained in only moderate yields in these
solvents probably due to the lower refluxing temperature. Entry
8 showed intriguing information that prewashing with dilute
HCl8 was quite effective in zinc activation and a similar yield
was attained in much shorter reaction time (0.5 h) without the
addition of TMSCl. Almost a quantitative yield was eventually
recorded when the substrate was changed to the corresponding
trifluoroacetate 4a with better leaving ability, and thus, we
determined the best conditions for the production of the
trifluoromethylated allenes 9 as treatment of trifluoroacetate 4
with 2 equiv of prewashed zinc powder in refluxing THF for
an appropriate time.
Table 3 summarized the results of the preparation of various
allenes 9 starting not only from trifluoroacetates 4 but also from
substrates possessing other leaving groups for comparison. In
general, trifluoroacetates 4 afforded better yields in a shorter
(5) Qing, F.-L.; Gao, W.-Z.; Ying, J.-W. J. Org. Chem. 2000, 65, 2003.
(6) Transformation of vinyl iodide to the corresponding organo-
magnesium species with the methyl protection of the OH group was affected
by the elimination to give the allenes. Alexakis, A.; Marek, I.; Mangeney,
P.; Normant, J. F. J. Am. Chem. Soc. 1990, 112, 8042.
(7) TMSCl was sometimes used as an activator of the Reformatsky
reaction. See, for example: Ikegami, R.; Koresawa, A.; Shibata, T.; Takagi,
K. J. Org. Chem. 2003, 68, 2195.
(8) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon: Oxford, UK, 1988; p 360.
6252 J. Org. Chem., Vol. 71, No. 16, 2006

1-(1-naphthyl)but-2-yn-1-ol (2a) is described as the representative
example.
reaction period than the case of the corresponding nonfluorinated
acetates 5 (entries 1 vs 2, 5 vs 7, 9 vs 10, and 15 vs 16).
Interesting enough was the conversion of unprotected 3a under
the same condition, furnishing the desired allene 9a in 21%
yield; however, the main process was, as our expectation,
reductive deiodination from 3a (55% yield). As shown in entry
6 of Table 1, sulfonate 7b from vinyl iodide 3b was significantly
smoothly transformed into 9b in 84% yield with complete
consumption of the starting 7b after only 15 min of reflux.
In this paper, we have described our successful results for
the construction of the CF3-containing allenes 9 in a simple four-
step process in good to excellent chemical yields. The advantage
of the present synthetic transformation was to offer the novel
as well as general pathway to access the 3-substituted 1-CF3-
allenes among which only one derivative has been reported thus
far.3e Further synthetic application of these fluorinated allenes
9 has being investigated in this laboratory.
A solution of NaI (6.385 g, 42.6 mmol) and 4,4,4-trifluoro-1-
(1-naphthyl)but-2-yn-1-ol 2a (6.98 g, 27.9 mmol) in AcOH (42
mL) was stirred at 70 °C for 8 h. The reaction mixture was added
to a beaker containing 50 mL of water, neutralized with 77.2 g
(0.728 mol) of Na2CO3, and extracted with AcOEt three times.
Concentration after drying over MgSO4 furnished a crude solid that
was purified by recrystallization from hexane to yield 8.508 g (22.5
mmol) of the desired 4,4,4-trifluoro-2-iodo-1-(1-naphthyl)but-2-
en-1-ol (3a). Yield 81%.
General Procedure for the Construction of 4,4,4-Trifluoro-
1-(1-naphthyl)-2,3-butadiene (9a). The reaction with 4,4,4-tri-
fluoro-2-iodo-1-(1-naphthyl)but-2-en-1-ol (3a) is described as the
representative example.
To a CH2Cl2 solution (5 mL) of 4,4,4-trifluoro-2-iodo-1-(1-
naphthyl)but-2-en-1-ol (0.7562 g, 2.00 mmol) was successively
added trifluoroacetic anhydride (0.42 mL, 3.0 mmol) and triethyl-
amine (0.41 mL, 3.0 mmol) at 0 °C and the whole mixture was
stirred for 5 h at that temperature. The usual workup furnished the
crude 4a, which was used for the next step without further
purification.
Experimental Section
General Procedure for the Construction of 4,4,4-Trifluo-
robut-2-yn-1-ols (2). The reaction with 1-naphthaldehyde is
described as the representative example.
To 1.307 g (20 mmol) of activated zinc powder in THF (10.0
mL) under argon atmosphere was added 4.619 g (9.7 mmol) of 4a
and the whole reaction mixture was refluxed for 30 min. After
removal of the excess zinc by filtration, the residue was extracted
three times with ether after addition of 30 mL of H2O. The usual
workup furnished a crude mixture that was purified by silica gel
chromatography to furnish 2.024 g (8.64 mmol) of the desired allene
9a. Yield 89%.
To a solution of diisopropylamine (5.61 mL, 40.0 mmol) in THF
(40 mL) at 0 °C was added dropwise a 1.60 M solution of n-BuLi
in hexane (25.0 mL, 40.0 mmol) and the mixture was stirred for
30 min at that temperature. The resultant LDA mixture was cooled
to -80 °C, and 2-bromo-3,3,3-trifluoropropene (2.08 mL, 20.0
mmol) in THF (10 mL) was slowly added at -80 °C. After the
solution was stirred for 5 min, 1-naphthaldehyde (2.72 mL, 20.0
mmol) was added and the whole was stirred for 1.5 h at that
temperature. The reaction mixture was quenched with 1 N HCl aq
(100 mL) and extracted with AcOEt three times. Concentration after
drying over MgSO4 furnished a crude solid that was purified by
recrystallization from petroleum ether to yield the desired 4,4,4-
trifluoro-1-(1-naphthyl)but-2-yn-1-ol (2a) (3.403 g, 13.6 mmol).
Yield 68%.
Acknowledgment. This work was financially supported by
the Iketani Science and Technology Foundation (0171011-A).
The authors thank TOSOH F-TECH, Inc. for the generous gift
of 2-bromo-3,3,3-trifluoropropene.
Supporting Information Available: Full experimental de-
tails and spectroscopic data for all new compounds synthesized.
This material is available free of charge via the Internet at
http://pubs.acs.org.
General Procedure for the Construction of (Z)-4,4,4-Tri-
fluoro-2-iodobut-2-en-1-ols (3).5 The reaction with 4,4,4-trifluoro-
JO060909L
J. Org. Chem, Vol. 71, No. 16, 2006 6253