A new and improved synthesis of trans-1,2-diiodoalkenes and their stereospecific and highly regioselective trifluoromethylation

Article abstract of DOI:10.1021/jo9816663

Reaction of terminal alkynes with iodine in the presence of CuI (5%) in acetonitrile under reflux for several hours gave the trans-1,2-diiodoalkenes in high yields. The trifluoromethylation of these diiodides using FSO₂CF₂CO₂Me/CuI/DMF proceeded in excellent yields in a stereospecific and highly regioselective manner.

Full text of DOI:10.1021/jo9816663

9486
J . Org. Chem. 1998, 63, 9486-9489
A New a n d Im p r oved Syn th esis of tr a n s-1,2-Diiod oa lk en es a n d
Th eir Ster eosp ecific a n d High ly Regioselective
Tr iflu or om eth yla tion
J ianxin Duan,† William R. Dolbier, J r.,*,† and Qing-Yun Chen‡
Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200, and
Shanghai Institute of Organic Chemistry, 354 Fenglin Lu, Shanghai, 200032, China
Received August 17, 1998
Reaction of terminal alkynes with iodine in the presence of CuI (5%) in acetonitrile under reflux
for several hours gave the trans-1,2-diiodoalkenes in high yields. The trifluoromethylation of these
diiodides using FSO2CF2CO2Me/CuI/DMF proceeded in excellent yields in a stereospecific and highly
regioselective manner.
Ta ble 1. Rea ction of I2 w ith Alk yn es in th e P r esen ce of
Cu I (5%) in CH3CN
In tr od u ction
Trifluoromethylated compounds remain of great inter-
est in the pharmaceutical and agrochemical industries.1
Trifluoromethyl-containing compounds are generally syn-
thesized via functional group transformation processes
or by use of synthetic building blocks that already contain
the trifluoromethyl group.2 The coupling reaction of the
in situ-generated trifluoromethylcopper reagent, CF3Cu,
with alkenyl and aryl halides has been reported to be
useful for direct introduction of CF3 into a molecule.2
Although there are a number of methods for generating
CF3Cu as well as studies of its reaction with organic
halides,3 the stereochemistry of the reaction has been less
studied. In this paper we report the results of the
stereospecific and highly regioselective trifluorometh-
ylation of trans-1,2-diiodoalkenes using the convenient
trifluoromethylating reagent FSO2CF2CO2Me/CuI/DMF.3c
A new and improved method of preparation of such
diiodides from terminal alkynes is also reported.
alkyne
R
temp (°C)
time (h)
2 (%)a
1a
1b
1c
1d
C6H5
p-MeC6H4
n-C4H9
60
60
80
80
3.5
3
5
2a (95)
2b (95)
2c (90)
2d (85)
CO2Et
10
a
Isolated yields based on the alkynes.
was reported to catalyze the iodination of electron rich
alkynes, i.e., 1-hexyne,6 but we found the reaction not to
work well for electron-deficient alkynes. For example,
when CHtCCO2H was allowed to react with I2 in hexane
in the presence of Al2O3, diiodide E-CHIdCICO2H was
obtained in only 23% yield.
We found cuprous iodide (CuI) to be a very good
catalyst for the iodination of terminal alkynes. Treatment
of alkynes 1 with 1.5 equiv of I2 in the presence of 5%
CuI in acetonitrile under appropriate reaction conditions
led to the formation of diiodides 2 in excellent yield (Table
1).
From the results given in Table 1, it can be seen that
both electron-rich and electron-deficient alkynes gave
very good yields, although the latter needed a longer
reaction time and higher temperature. It should be noted
that no over-iodinated products, i.e., RCI2CI2H or alkynyl
iodides, were detected. The presence of CuI was critical;
in its absence, the reaction was slow.
The trans structures of the diiodides were assigned on
the basis of their 1H NMR spectra. Such spectra were
identical to those reported in the literature for the
E-isomers.4
Resu lts a n d Discu ssion
Im p r oved Meth od for Syn th esizin g tr a n s-1,2-
Diiod oa lk en es fr om Ter m in a l Alk yn es. The iodina-
tion of alkynes has been reported to be stereospecific,
with only trans-adducts being obtained.4 Although the
iodination of alkynes using I2 in CHCl3 or chlorobenzene
has been reported to give the trans-diiodides in almost
quantitative yields,4 we found the reaction to be very
slow, with low conversion. A brief report of iodination of
terminal alkynes in methanol has also appeared.5 Al2O3
† University of Florida.
‡ Shanghai Institute of Organic Chemistry.
(1) (a) Filler, R.; Kobayashi, Y., Eds. Biomedicinal Aspects of
Fluorine Chemistry; Kodasha/Elsevier: New York, 1982. (b) Welch, J .
T. Tetrahedron 1987, 43, 3123. (c) Seebach, D. Angew. Chem., Int. Ed.
Engl. 1990, 29, 1320.
(2) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555.
(3) (a) Kobayashi, Y.; Kumadaki, I. Tetrahedron Lett. 1969, 47, 4095.
(b) Matsui, K.; Tobita, E.; Ando, M.; Kondo, K. Chem. Lett. 1981, 1719.
(c) Wiemers, D. M.; Burton, D. J . J . Am. Chem. Soc. 1986, 108, 832.
(d) Chen, Q.-Y.; Wu, S.-W. J . Chem. Soc. Chem. Commun. 1989, 705.
(e) Carr, G. E.; Chambers, R. D.; Holmes, T. F.; Parker, D. G. J . Chem.
Soc., Perkin Trans. 1 1988, 921. (f) Su, D.-B.; Duan, J .-X.; Chen, Q.-Y.
Tetrahedron Lett. 1991, 32, 7689. (g) Urata, H.; Fuchikami, T.
Tetrahedron Lett. 1991, 32, 91.
Mon otr iflu or om eth yla tion of tr a n s-1,2-Diiod oa lk -
en es. It was well-known that, in the reaction of CF3Cu
with alkenyl and aryl halides, the iodides are more
reactive than the corresponding bromides, and the bro-
mides are much more reactive than the corresponding
chlorides,3c but no one has studied the relative reactivities
(4) Hollins, R. A.; Campos, M. P. A. J . Org. Chem. 1979, 44, 3931.
(5) Heasley, V. L.; Shellhamer, D. F.; Heasley, L. E.; Yaeger, D. B.
J . Org. Chem. 1980, 45, 4649.
(6) Larson, S.; Luidhardt T.; Kabalka, G. W.; Pagni, R. M. Tetra-
hedron Lett, 1988, 29, 35.
10.1021/jo9816663 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/21/1998

Synthesis of trans-1,2-Diiodoalkenes
J . Org. Chem., Vol. 63, No. 25, 1998 9487
Ta ble 2. Rea ction of 1,2-Diiod oa lk en es 1a -d w ith 2.5
Equ iv of F SO2CF 2CO2Me in th e P r esen ce of Cu I (10%) in
DMF
PhCIdCHCF3 was carried out in AcOH/HCl (10:1(v/v))
using Zn/AgOAc as reducing agent, a stereospecific reduc-
tion of the C-I bond was observed, with only the Z-isomer
being obtained. On the basis of these results, the E-
configuration was assigned to product 4a .
diiodide
R
temp (°C)
time (h)
product (%)a
1a
1b
1c
1d
C6H5
p-Me-C6H4
n-C4H9
75-80
75-80
75-80
75-80
8
10
9
7a (91)
7b (90)
7c (80)
7d (72)
Similar results were obtained for diiodides 1b and 1d ,
as indicated above and below.
CO2Et
12
a
Isolated yields based on the diiodides.
of dihalides that have two identical halogen atoms in
different structural environments.
With diiodoalkenes of the general structure 2 now
readily available with iodine substituents at electroni-
cally distinctive positions, it was of interest to investigate
the possibility of selective trifluoromethylation. Structure-
reactivity relationships for vinylic iodine substitution by
trifluoromethylcopper reagents are not well defined. Thus
it was believed that a study of regioselectivity in our
series of diiodides might provide some mechanistic
insight into this reaction. Moreover, the products of such
monotrifluoromethylation, retaining one iodo substituent,
will be ideal substrates for further structural elaboration.
Reaction of 1.1 equiv of FSO2CF2CO2Me (3) with 1
equiv trans-R,â-diiodostyrene, 2a , in the presence of 10%
molar CuI in N,N-dimethylformamide under N2 atmo-
sphere at 75-80 °C gave a single trifluoromethylated
product in 90% yield. When the reaction was monitored
In contrast, when the E-1,2-diiodohex-1-ene (1c) was
allowed to react with 1.1 equiv of FSO2CF2CO2Me under
similar reaction conditions, the reaction lost its re-
giospecificity, with the two iodo substituents being
competitive in their respective reactions with CF3Cu.
Only monosubstitution was observed, with the terminal
iodo substituent still being more reactive than the
internal one (ratio ) 70:30).
Although it is reported that in the trifluoromethylation
of aryl or alkenyl iodides,3c either CuI or CuBr can be
used as catalyst, we have found that, in the present
examples, only CuI is effective as the reaction catalyst.
When CuBr was used as catalyst in the reactions, only
deiodination of the diiodides occurred to regenerate
alkyne. The observed ineffectiveness of CuBr in the
current study probably derives from the lower nucleo-
philicity of bromide versus iodide, which apparently slows
the formation of CF3Cu sufficiently to allow the competi-
tive deiodination to dominate in the reaction with CuBr,
but not in the reaction with CuI.
by 19F NMR, it was observed that as the signal at -103
ppm (FSO2CF2CO2Me) decreased, a new doublet (-58.2
ppm, J ) 7 Hz) increased, with no other fluorine signals
appearing during the reaction. The coupling constant of
3
the product (7 Hz) is a typical value for J F-H of PhCId
CHCF3; therefore, the product was assigned to be PhCId
CHCF3 (4a ). The configuration of the double bond was
designated E based on the coupling constant between the
cis-vinyl protons (3J H,H ) 12.3 Hz) of the reduced product
PhCH)CHCF3 (5a ). When product 4a was reduced to 5a
using Zn/AgOAc in DMF in the presence of acetic acid
(AcOH/DMF ) 1:10(v/v)), two isomers were obtained in
a ratio of Z/E ) 2:1. The configurations of the reduced
products were easily assigned based on the coupling
It should also be noted that although the reaction of
diiodides with CF3Cu reagent occurred with great ef-
ficiency and selectivity, when CH3Cu was used in the
reaction, no analogous coupling was observed. Thus,
when CH3Cu, prepared from MeLi and CuI, was allowed
to react with 2a at -78 °C, only (PhCtC)2 was obtained.
When catalysis by CuCN was attempted, no CF3Cu
chemistry was observed, probably again because of the
relatively low nucleophilicity of cyanide ion. Instead a
complicated reaction mixture was obtained, with nonse-
lective CN coupling being the major observed reaction.
P r ep a r a tion of Bis-tr iflu or om eth yla ted Alk en es.
Although only monotrifluoromethated products were
obtained when using 1.1 equiv of FSO2CF2CO2Me, the
remaining iodine substituent is by no means inert to
trifluoromethylcopper. When 2.5 equiv of FSO2CF2CO2-
Me was used in the reaction, both iodine substituents
were readily replaced, presumably stereospecifically, to
give a single product in each case.
constants of the two vinylic protons, comparing them with
those reported in the literature.7 (For the E-isomer, the
coupling constant of CH)CH is 16.1 Hz, whereas the
3
Z-isomer has a J H-H ) 12.3 Hz.) When the reduction of
(7) Fuchikami, T.; Yatabe, M.; Ojima, I. Synthesis 1981, 365.

9488 J . Org. Chem., Vol. 63, No. 25, 1998
Duan et al.
(E)-1,2-Diiod oh exen e (2d ):4 1H NMR δ: 0.93 (t, J ) 7.2
Hz, 3H), 1.35 (h, J ) 7.2 Hz, 2H), 1.51 (p, J ) 7.2 Hz, p, 2H),
2.49 (t, J ) 7.2 Hz, 2H), 6.78 (s, 1H).
The results given in Table 2 above indicate that all of
the diiodides are converted smoothly to the trans-1,2-bis-
trifluoromethylalkenes, 7a -d , in good to excellent yields.
Typ ica l P r oced u r e for t h e P r ep a r a t ion of Mon ot r i-
flu or om eth yla ted Com p ou n d s. Into a 50 mL three-necked,
round-bottomed flask, equipped with magnetic stirrer, ther-
mometer, and condenser with a gas outlet on the top was
added a mixture of dry DMF (20 mL), 2 (10 mmol), FSO2CF2-
CO2Me (11 mmol), and CuI (0.5 mmol). The mixture was then
heated to 75-80 °C with stirring. After the reaction was over
(monitored by 19F NMR), the reaction mixture was cooled to
room temperature and extracted with hexane (3 × 40 mL).
The combined hexane solution was then washed with brine
and dried over CaCl2. Distillation gave the desired products.
(E)-1-Iodo-1-ph en yl-3,3,3-tr iflu or opr open e (4a): bp 105-
Mech a n istic Discu ssion
The mechanism of generation of CF3Cu from FSO2CF2-
CO2Me has been discussed previously.3c Ambiguity exists
regarding the nature of specific intermediates formed
after decarboxylation and prior to formation of CF3Cu,
1
106 °C/25 mmHg. H NMR δ 6.49 (q, J ) 7.2 Hz, 1H), 7.19 (s,
5H); 19F NMR δ -58.27 (d, J ) 7.2 Hz). HRMS calcd for
C9H6F3I: 297.9466, found: 297.9461.
(E)-1-Iod o-1-(p -m et h ylp h en yl)-3,3,3-t r iflu or op r op en e
1
(4b): bp 123 °C/25 mmHg. H NMR δ 1.85 (s, 3H), 6.10 (q, J
although it is believed that CF3Cu is likely in equilibrium
with the CF2 carbene complex, (CF2dCu)+F-, and that
the reactivity of such species are dependent upon the
nature of the CuX counterion.8
In a study of the reaction of para-substituted aryl
iodides with CF3CO2Na/CuI, Chambers reported a F
value of +0.46, indicating that such reactions are assisted
by electron-withdrawing substituents on the substrate
aryl iodide.3d Our results are consistent with this general
picture, since the aryl and carbethoxy substituents of 1a ,
1b, and 1d are anion-stabilizing, whereas the n-Bu
substituent of 1c is not.
) 7.2 Hz, 1H), 6.64 (d, J ) 7.2 Hz, 2H), 6.73 (d, J ) 7.2 Hz,
2H). 19F NMR δ -58.16 ppm (d, J ) 7.2 Hz). HRMS calcd for
C
10H9F3I: 311.9623, found: 311.9588.
Eth yl (E)-2-iod o-4,4,4-tr iflu or obu t-2-en oa te (4d ): bp 50
1
°C/25 mmHg. H NMR δ 1.30 (t, J ) 7.2 Hz, 3H), 4.29 (q, J )
7.2 Hz, 2H), 6.49 (q, J ) 7.2 Hz, 1H); 19F NMR δ -61.92 (d, J
) 7.2 Hz). HRMS calcd for C6H6F3IO2: 293.9365, found:
293.9359.
(E)-3-Iod o-1,1,1-tr iflu or oh ex-2-en e (4c) a n d (E)-1-iod o-
2-(tr iflu or om eth yl)h exen e (6c). A mixture of (E)-CF3CHd
CIC4H9 (4c) and (E)-CHIdC(CF3)C4H9 (6c) was obtained from
the reaction (E)-CHIdCIC4H9 with FSO2CF2CO2Me: 1H NMR
for (E)-CF3CHdCIC4H9: δ 0.92 (t, J ) 7.2 Hz, 3H), 1.34 (m,
2H), 1.52 (m, 2H), 2.59 (t, J ) 7.5 Hz, 2H), 6.36 (q, J ) 7.8
1
Hz, 1H); 19F NMR δ -58.44 (d, J ) 7.8 Hz); H NMR for (E)-
Con clu sion s
CHIdC(CF3)C4H9 δ 0.93 (t, J ) 6.9 Hz, 3H), 1.25 (m, 2H), 1.43
(m, 2H), 2.23 (t, J ) 8.7 Hz, 2H), 7.16 (s, 1H); 19F NMR δ
-67.023(s). HRMS calcd for C7H10F3I: 277.9779, found: 277.970.
Red u ction of (E)-P h CIdCHCF 3 (4a ) in DMF . Into a 50
mL round-bottomed flask was added a mixture of DMF (10
mL), AcOH (1 mL), 4a (1.5 g), Zn dust (0.6 g), and AgOAc (0.1
g). The mixture was then stirred at room temperature under
N2 for 8 h. After the reaction was over, the reaction mixture
was filtered, and the filtrate was mixed with 30 mL of hexane
and 10 mL of H2O. The organic layer was separated, and the
water solution was extracted with hexane (20 mL × 3). The
combined organic solution was washed with water (10 mL ×
3), dried, and concentrated. Distillation (70 °C/25 mmHg) gave
0.7 g (81%) PhCHdCHCF3 ((Z)- and (E)-5a ) with the ratio of
Z/E ) 2:1).
A new and highly efficient, stereospecific synthesis of
trans-1,2-diiodoalkenes from terminal alkynes by addi-
tion of I2 in the presence of catalytic CuI in acetonitrile
has been presented. In cases where the diiodoalkene is
substituted by an aryl or carboethoxy group, as in 2a ,
2b, and 2d , it is possible to replace the iodo substituent
at the terminal position by a trifluoromethyl group in a
regio- and stereospecific manner, using the convenient
in situ CF3Cu reagent obtained from FSO2CF2CO2Me/
CuI/DMF. The reported chemistry provides synthetic
chemists with a new approach to preparing trans, vicinal
trifluoromethyl iodo alkenes, which are potentially useful
fluorinated synthetic intermediates.
(E)-1-P h en yl-3,3,3-tr iflu or op r op en e ((E)-5a ):7 1H NMR
δ -6.20 (dq, J ) 16.1 Hz, 7.3 Hz, 1H), 7.30 (m, 6H); 19F NMR
δ -62.81 (d, J ) 7.3z).
Exp er im en ta l Section
(Z)-1-P h en yl-3,3,3-tr iflu or op r op en e ((Z)-5a ): 1H NMR δ
5.75 (dq, J ) 7.1 Hz, 12.3z), 6.92 (d, J ) 12.3 Hz, 1H), 7.36
(m, 5H); 19F NMR δ -58.14 (d, J ) 7.1 Hz).
Red u ction of (E)-P h CIdCHCF 3 in AcOH. (E)-PhCId
CHCF3 (1.5 g, 5 mmol), Zn (1.2 g, 20 mmol), and AgOAc (0.1
g, 0.6 mmol) were mixed together in AcOH (10 mL). Under
vigorous stirring 1 mL of concentrated HCl (37%) was added
dropwise over a 5 min period. The mixture was further stirred
for 5 min. 19F NMR indicated the reaction was over, and only
a doublet at -58.2 ppm appeared. Normal workup gave pure
(Z)-PhCHdCHCF3 ((Z)-5a ) in 78% yield.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1,2-Bis-
(tr iflu or om eth yl)a lk en es 7a -d . Into a 50 mL three-necked,
round-bottomed flask, equipped with magnetic stirrer, ther-
mometer, and condenser with a gas outlet on the top, was
added a mixture of DMF (20 mL), diiodide (1a -d ) (10 mmol),
FSO2CF2CO2Me (25 mmol), and CuI (0.5 mmol). The mixture
was then heated to 75-80 °C under stirring. After the reaction
was over (monitored by 19F NMR), the reaction mixture was
distilled under reduced pressure (40 mmHg). The distillate was
added to 50 mL of ice-water, and an organic layer separated.
After the organic layer was separated, the water solution was
Typ ica l P r oced u r e for th e Iod in a tion of Alk yn es. Into
a 150 mL round-bottomed flask was added a mixture of
acetonitrile (50 mL), alkyne (50 mmol), I2 (75 mmol), and CuI
(2.5 mmol). The mixture was stirred vigorously under reflux
for 3-5 h. After the reaction was over, the mixture was poured
into 200 mL of hexane. The resulted solution was washed with
Na2S2O4 (10% aqueous solution) and then with brine to pH )
7, dried over CaCl2, and concentrated by rotoevaporation.
Purification by flash column chromatography gave the desired
product.
(E)-1,2-Diiod ostyr en e (2a ):4 1H NMR δ 7.25 (s, 5H), 7.16
(s, 1H).
(E)-1,2-Diiod o-p-m eth ylstyr en e (2b):4 1H NMR δ 2.39 (s,
3H), 7.20 (d, J ) 7.6 Hz, 2H), 7.26 (s, 1H), 7.31 (d, J ) 7.6 Hz,
2H).
Eth yl (E)-2,3-d iiod obu t-2-en oa te (2c):4 1H NMR δ 1.34
(t, J ) 7.2 Hz, 3H), 4.29 (q, J ) 7.2 Hz, 2H), 7.66 (s, 1H).
(8) Yang, Z.-Y.; Wiemers, D. M.; Burton, D. J . J . Am. Chem. Soc.
1992, 114, 4402.

Synthesis of trans-1,2-Diiodoalkenes
J . Org. Chem., Vol. 63, No. 25, 1998 9489
extracted with CH2Cl2 (5 mL × 3), and the combined organic
solution was washed with H2O (10 mL × 3) and dried.
Distillation gave the desired product (7a -d ).
(E)-1,1,1-Tr iflu or o-3-(tr iflu or om eth yl)h ep t-2-en e (7c):
bp 71-72 °C. H NMR δ 0.71 (t, J ) 7.3 Hz, 3H), 1.10 (h, J )
7.3 Hz, 2H), 1.32 (p, J ) 7.3 Hz), 2.13 (t, J ) 7.3 Hz, 2H), 5.87
(q, J ) 7.8 Hz, 1H); 19F NMR δ -59.67 (d, J ) 7.8 Hz, 3F),
69.09 (s, 3F). HRMS, M+ - 1 calcd for C8H9F6: 219.0608,
found: 219.0595.
1
(E)-1,1,1,4,4,4-Hexa flu or o-2-p h en ylbu t-2-en e (7a ): bp
1
58-60 °C/25 mmHg. H NMR δ 6.48 (q, J ) 7.2 Hz, 1H), 7.30
(t, J ) 7.2 Hz, 2H), 7.41 (m, 3H); 19F NMR δ -58.63 (d, J )
7.2 Hz, 3F), -68.87 (s, 3F). HRMS calcd for C10H6F6: 240.0373,
found: 240.0321.
Ack n ow led gm en t. Support of this work in part by
the National Science Foundation is acknowledged with
thanks.
Su p p or tin g In for m a tion Ava ila ble: 1H and 19F NMR
spectra of all previously unreported compounds (4a -d , 6c,
7a -d ) (16 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
(E )-1,1,1,4,4,4-H e xa flu or o-2-(p -m e t h ylp h e n yl)b u t -2-
en e (7b): bp 79-82 °C/25 mmHg. 1H NMR δ 1.87 (s, 3H), 5.94
(q, J ) 7.2 Hz, 1H), 6.66 (d, J ) 7.2 Hz, 2H), 6.71 (d, J ) 7.2
Hz, 2H); 19F NMR δ -58.57 (d, J ) 7.2 Hz, 3F), -68.89 (s,
3F). HRMS calcd for C11H9F6: 254.0530, found: 254.0550.
Eth yl (E)-4,4,4-tr iflu or o-2-(tr iflu or om eth yl)bu t-2-en oate
1
(7c): bp 112 °C. H NMR δ 1.33 (t, J ) 7.2 Hz, 3H), 4.35 (q, J
) 7.2 Hz, 2H), 6.44 (q, J ) 6.9 Hz); 19F NMR δ -61.99 (d, J )
6.9 Hz, 3F), 66.39 (s, 3F). HRMS, M+ - EtO calcd for
C5HF6O: 190.9932, found: 190.9936.
J O9816663