Copper-Mediated Halotrifluoromethylation of Unactivated Alkenes

Article abstract of DOI:10.1002/adsc.201500731

A copper-mediated halotrifluoromethylation of unactivated alkenes using Umemoto's reagent and copper(I) halide (CuX, X=Cl, Br, and I) was developed. The CuX species (CuI, CuBr, and CuCl) were chosen as the source for both copper and halides because of their benchtop stability, commercial availability, and relatively low cost. Simple exchange of the copper salt provided the desired simultaneous and regioselective incorporation of the halogen atom and of the CF₃ group to various alkenes. This protocol offers an efficient and practical route to various β-halotrifluoromethylated alkanes. Further modifications of the C-Br bond to C-B, C-N and C-S bonds were performed. These derivatizations show the feasibility of late-stage modifications.

Full text of DOI:10.1002/adsc.201500731

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DOI: 10.1002/adsc.201500731
Copper-Mediated Halotrifluoromethylation of Unactivated
Alkenes
Won An,+a,b Neul Ha,+a,c Hyun Myung Lee,a,c Yashwardhan R. Malpani,a,c
Duck-Hyung Lee,b Young-Sik Jung,a,c,* and Soo Bong Hana,c,*
a
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong, Daejeon
305-600, Republic of Korea
Fax: (+82)-42-860-7160; phone: (+82)-42-860-7133; e-mail: ysjung@krict.re.kr or sbhan@krict.re.kr
Department of Chemistry, Sogang University, 5 Baekbeom-ro, Mapo-gu, Seoul 121-742, Republic of Korea
Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 217 Gajeongro, Yuseong,
b
c
Daejeon 305-355, Republic of Korea
+
These authors contributed equally to this work.
Received: August 3, 2015; Revised: September 14, 2015; Published online: December 4, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500731.
Abstract: A copper-mediated halotrifluoromethyla- col offers an efficient and practical route to various
tion of unactivated alkenes using Umemotoꢀs reagent b-halotrifluoromethylated alkanes. Further modifica-
À
À
À
À
and copper(I) halide (CuX, X=Cl, Br, and I) was tions of the C Br bond to C B, C N and C S bonds
developed. The CuX species (CuI, CuBr, and CuCl) were performed. These derivatizations show the fea-
were chosen as the source for both copper and hal- sibility of late-stage modifications.
ides because of their benchtop stability, commercial
availability, and relatively low cost. Simple exchange
of the copper salt provided the desired simultaneous Keywords: copper-mediated reaction; halotrifluoro-
and regioselective incorporation of the halogen atom methylation; late stage modification; trifluoromethyl
and of the CF3 group to various alkenes. This proto- group (CF3); unactivated alkenes
Introduction
methods using active CF3-containing species, trifluor-
omethylation of alkenes has been extensively studied
Because of their unique properties, fluorine-contain- because, in many cases, at the same time a variety of
ing molecules are of great importance in pharmaceuti- functional groups are easily introduced into the b posi-
[6]
[7]
cal, agricultural, and materials science, and efforts tion to the CF3 group.[5] For example, C H, C C,
À
À
[8]
[9]
[10]
[11]
À
À
À
À
have been directed toward the development of new C N, C O, C S, or C X (X=halogen) bonds
organic transformations for the introduction of fluo- were simultaneously formed along with the C CF3
À
rine.[1] In particular, for many years, the introduction bond (Scheme 1). This strategy has many advantages
of a CF3 group has been one of the main focuses in from the synthetic point of view because it allows the
medicinal chemistry because of the great impact of preparation of various CF3-containing multi-function-
this moiety on biological properties such as lipophilic- al aliphatic derivatives from a common alkene inter-
ity, metabolic stability, and binding selectivity.[2] How- mediate. In particular, the halotrifluoromethylation of
ever, because of the characteristic chemical reactivity alkenes has been an important focus of study not only
of fluorine and the limited commercial availability of because of its versatility but also because halogen
the sources, conventional methods for introducing atoms are useful handles for further manipulations. In
CF3 groups showed limited application in the prepara- spite of the importance of the vicinal halotrifluorome-
tion of organofluorine compounds.[3] In order to over- thylation, most methodologies were directed towards
come these drawbacks, several new types of reactions the development of iodotrifluoromethylation. Only
have been developed and various sources of CF3 have a few methods introduce other halogen elements, with
been employed photochemically, oxidatively, reduc- narrow substrate scopes and harsh reaction condi-
tively, and electrochemically.[4] Among the synthetic tions.[9g,11b] Thus, a new reaction for incorporation of
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Figure 1. CF3 sources.
Togniꢀs reagent[14] I (1a), II (1b) and Umemotoꢀs re-
agent[15] (1c) (Figure 1).
Our hypothesized reaction design is described in
Scheme 3. When Cu(I)X activates the CF3 source,
e.g., Umemotoꢀs reagent (1c), Cu(I) will be oxidized
to Cu(II) species (I) and the CF3 radical will be
formed. This CF3 radical would be easily trapped by
an alkene to give an alkyl radical, which will recom-
Scheme 1. Various vicinal difunctionalizations of alkenes
(C H, C C, C N, C O, C S, and C X bond formation
along with the introduction of CF3).
À
À
À
À
À
À
different halogen atoms from a common intermediate
is needed. Our group previously reported the vicinal
chlorotrifluoromethylation of alkenes using CF3SO2Cl
and visible light catalysis [Eq. (1), Scheme 2].[11j] In
the course of this study, we assumed that the same
alkyl radical intermediate could be a new useful plat-
form for the incorporation of different halogen atoms.
In particular, we speculated that a transition metal
halide that can generate the active CF3 species and
serve as the halogen source would be a good candi-
date to address this issue [Eq. (2), Scheme 2].
Scheme 3. Hypothesized reaction scheme.
bine with Cu(II) to produce the Cu(III) species (II).
Reductive elimination will eventually generate the de-
sired product. On the basis of our hypothesis, we first
tested the bromotrifluoromethylation of alkene 2a
using the three different CF3 reagents (1a, 1b, and
1c). Pleasingly, using 1c, the desired product contain-
ing vicinal Br- and CF3 moieties was obtained regiose-
lectively in 80% yield (entry 3, Table 1). However
Togniꢀs reagents 1a and 1b showed little or no reactiv-
ity (entries 1 and 2). Solvent screening revealed that
MeCN was the optimal solvent (entries 3–5). To vali-
date our strategy of simply changing the Cu salt, CuI
was applied instead of CuBr. As expected, CuI
showed very high reactivity to generate the target io-
Scheme 2. Strategy for the transition metal-mediated halo-
trifluoromethylation of alkenes.
Results and Discussion
As a proof of concept, Cu(I)X species (CuI, CuBr, dotrifluoromethylated product (entry 6). However,
and CuCl) were chosen as the source for both copper when CuCl was employed, the desired product was
and halides because of their benchtop stability, com- obtained in only 40% yield (entry 7). In order to im-
mercial availability, and relatively low cost.[12a] More- prove the low efficiency of CuCl, various reaction pa-
over, CuX has been used as halide source in the Sand- rameters were screened. During investigation of the
meyer reaction.[13] In addition, these species generate effect of additives, 2,2’-bipyridyl was found to im-
a CF3 radical from commercial CF3 sources such as prove the reaction to 59% yield (entry 8). Encour-
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Copper-Mediated Halotrifluoromethylation of Unactivated Alkenes
Table 1. Optimization of halotrifluoromethylation of alk-
(2f) was well tolerated by this procedure (93%). Sur-
prisingly, the unprotected primary alcohol-containing
alkene 2g was smoothly converted into the desired
product 3g (70%). Moreover, alkenes bearing an
amide group (2h, 2i, and 2j) afforded the desired
products in high yields. Interestingly, aromatic halo-
gens, such as Cl, Br, and I, showed high stability
under the reaction conditions (81%, 74%, and 78%,
respectively). Thus, this transformation proved to be
highly tolerant of a variety of functional groups. Nota-
bly, this is the first report of vicinal bromotrifluoro-
methylation of unactivated alkenes with broad sub-
strate scope.[17] Because the bromo group is a very
useful functional handle for further manipulations,
the products could serve as building blocks for vari-
ous derivatizations.
enes.[a]
Next, in order to expand the scope of the reaction
CuI was employed using the optimized condition. The
same set of terminal alkenes 2a–j was employed. The
general reactivity of the reaction is similar to that of
CuBr. Iodotrifluoromethylated alkanes containing
OTs (4a, 90%), NHTs (4b, 88%), NHBoc (4c, 83%),
and phthalimide (4d, 64%) moieties were produced in
high yields and selectivity. Products containing alde-
hyde (4e, 99%), ester (4f, 85%), unprotected alcohol
(4g, 60%), and amide (4h–4j; 81%, 83%, and 82%,
respectively) moieties were obtained with comparable
functional group tolerance. This type of product in
[a]
The reactions were carried out under an N2 atmosphere
at 658C for 20 h using 2a (0.25 mmol), CuX (1.5 equiv.),
CF3 source (2 equiv.) and K2HPO4 (1 equiv.).
[b]
0.1 equiv.
Yields were determined by H NMR.
[c]
[d]
1
Isolated yield.
aged by this result, different additives were tested. In particular has been extensively produced in recently
the event, PCy3 and B2pin2 (10 mol%) were found to developed methodologies with the use of CF3I.[4]
be very efficient, producing the corresponding chloro- However, the handling of gaseous CF3I is inconven-
trifluoromethylated product in 75% and 84% yield, ient and problematic. The combination of CuI and
respectively (entries 9 and 10).
Umemotoꢀs reagent can therefore provide an alterna-
A similar ligand effect was found in related copper tive way to access the iodotrifluoromethylated prod-
chemistry.[16] When B2pin2 was applied with CuBr, the ucts. Finally, chlorotrifluoromethylation was per-
product yield increased from 80% to 93%, as expect- formed on the same substrates 2a–j using CuCl. The
ed (entry 11). This effect was consistent in the case of products 5a–j were obtained with similar yields and
CuI (from 89% to 95% yield; entry 12). Therefore, by selectivities.
simply changing the copper halide salt, after optimiza-
tion we achieved I-, Br-, and Cl-trifluoromethylation other types of alkenes, such as 1,1-disubstituted and
of the unactivated alkene 2a.[12b]
internal alkenes, were subjected to the reaction condi-
After the scope of terminal alkenes was explored,
With the optimized conditions in hand, we exam- tions (Table 3). The 1,1-disubstituted alkene 6a was
ined the scope of the bromotrifluoromethylation of converted into the corresponding halotrifluoromethy-
terminal alkenes. Various terminal alkenes showed lated products 7a (I, 71%), 8a (Br, 71%), and 9a (Cl,
high reactivity and regioselectivity under the opti- 74%) in high yields (entry 1) by simply changing the
mized conditions (Table 2). The O-tosylated alcohol copper halide source. (S)-Carvone 6b reacted smooth-
2a was converted into the corresponding bromotri- ly to afford the desired iodo- (7b, 68%), bromo- (8b,
fluoromethylated product 3a in very high yield 72%), and chloro- (9b, 63%) trifluoromethylated
(85%). Also, N-tosyl (2b) and Boc (2c) protected products. In addition, (S)-(À)-perillaldehyde 6c was
amine-containing alkenes were efficiently transformed easily transformed into the desired products 7c (I,
into the desired products in 77% (3b) and 83% (3c) 62%), 8c (Br, 64%), and 9c (Cl, 53%) in moderate
yield, respectively. Moreover, the phthalimide-con- yields (entry 3). These results showed the tolerance of
taining bromotrifluoromethylated product 3d was ob- a,b-unsaturated ketones (6b) and aldehydes (6c)
tained from the corresponding terminal alkene 2d under the optimized protocol. Moreover, a biologically
with comparable efficiency (74%). Notably, unpro- active natural compound (+)-nootkatone 6d was
tected aldehyde 2e participated smoothly in the reac- tested and the iodo- (7d, 84%), bromo- (8d, 71%),
tion (91%). In addition, the ester functional group and chloro- (9d, 69%) derivatives were formed in
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Table 2. Reaction scope of halotrifluoromethylation of terminal alkenes.[a]
[a]
The reactions were carried out under an N2 atmosphere for 20 h using 2a–j (0.25 mmol) in MeCN (0.125M).
Isolated yield.
[b]
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Copper-Mediated Halotrifluoromethylation of Unactivated Alkenes
Table 3. Reaction scope of 1,1-disubstituted and internal alkenes.[a]
[a]
The reactions were carried out under an N2 atmosphere for 20 h using 6a–e (0.25 mmol) in MeCN (0.125M).
[b]
Isolated yield.
[c]
The yields were determined by 1H NMR and the products decomposed during purification.
[d]
1
The dr was determined by H NMR.
high yields (entry 4). When the symmetric internal derivatization (Scheme 4). Under copper-catalyzed
alkene 6e was employed, in all cases, internal C CF3 borylation conditions,[18] 3d was efficiently converted
and C X bonds were formed simultaneously (7e, 8e, to boronic ester 10 (65% yield), which is a useful syn-
À
À
and 9e, entry 5). Notably, whereas tertiary bromo- thetic intermediate for transition metal-catalyzed
(8a–d) and chloro-containing products (9a–d) showed cross-coupling reactions. An azide group can be easily
high stability, tertiary iodo-containing compounds introduced in high yield by treatment with NaN3 (11,
(7a–d) were readily decomposed during purification. 90% yield), proving the efficient formation of a C N
Thus, investigation of the substrate scope (Table 2 bond. In addition, nucleophilic substitution reaction
À
À
and Table 3) showed that various alkenes were with NaSCN was performed to achieve C S bond for-
smoothly converted to the desired products by simple mation (12, 98%). Treatment of 3d with a base such
change of the Cu salt. Having established the scope of as DBU generated the elimination product 13 in high
the reaction, various modifications were performed yield (74%) and selectivity (E-alkene). These various
on the halotrifluoromethylated products to demon- derivatization examples showed the possibility of late-
strate the potential of the halogen atom for further stage modifications of the halotrifluoromethylated
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Scheme 4. Derivatization of the bromotrifluoromethylated product.
product, which can be highly valuable in medicinal recorded on a Varian 300 and Bruker 300 NMR spectropho-
tometer operating at 300 MHz and 500 MHz. High resolu-
tion mass spectra were obtained on a Varian 1200L quadru-
pole MS (EI) spectrophotometer. FT-IR spectra were ob-
tained using an FT-IR Smiths Identify IR. Melting points
were obtained on a Mettler Toledo MP50 apparatus and are
uncorrected.
chemistry.
Conclusions
We have developed a copper-mediated halotrifluoro-
methylation of alkenes using inexpensive and stable
CuX salts (X=Cl, Br, and I). This reaction provided
an efficient and practical route to various b-halotri-
fluoromethylated alkanes by simple change of CuX
salt. The regioselectivity and the wide substrate scope
make this protocol a very convenient strategy. In ad-
dition, the possibility of further manipulations of the
halogen group is highly attractive in the field of me-
dicinal chemistry.
Typical Experimental Procedure for
Halotrifluoromethylation Reactions of Alkenes and
Characterization for Selected Examples
In a 4-mL pre-dried screw-capped sealed tube, a suspension
of alkene (0.25 mmol), Umemotoꢀs reagent 1c (0.50 mmol),
CuX (0.38 mmol), B2pin2 (0.03 mmol) and K2HPO4
(0.25 mmol) in MeCN (0.125M) was stirred at 658C for 20 h
under an N2 atmosphere. The reaction mixture was concen-
trated under vacuum. Purification was achieved by column
chromatography on SiO2 gel using hexanes/ethyl acetate.
Experimental Section
5-Bromo-7,7,7-trifluoroheptyl
4-ethylbenzenesulfonate
1
(3a): Yield: 85%; H NMR (300 MHz, CDCl3): d=7.82 (d,
J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 4.13–4.05 (m, 3H),
2.79–2.59 (m, 2H), 2.48 (s, 3H), 1.89–1.61 (m, 5H), 1.51–
1.43 (m, 1H); 13C NMR (125 MHz, CDCl3): d=144.85,
132.98, 129.87, 127.88, 125.17 (q, J=276.4 Hz), 69.91, 44.33
(q, J=2.8 Hz), 42.96 (q, J=28.3 Hz), 37.62, 27.99, 23.25,
21.63; 19F NMR (470 MHz, CDCl3): d=À64.83 (t, J=
9.4 Hz); HR-MS: (EI): m/z=402.0120, calcd. for
C14H18Br1F3O3S1 [M]+: 402.0112; IR (neat): n=2926, 1354,
1253, 1173, 1143, 1094, 934, 908, 814, 778, 730, 662 cmÀ1.
General Remarks
All of the Cu reactions were carried out under an N2 atmos-
phere using pre-dried screw-capped sealed tubes. Chemical
reagents were purchased from Aldrich and TCI. Commer-
cially available alkenes were purified immediately prior to
use. Analytical thin-layer chromatography (TLC) was car-
ried out using 0.2 mm commercial silica gel plates (Merck
TLC Silica gel 60 F254). Flash chromatography was per-
formed on silica gel 60 (200–400 mesh). NMR spectra were
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Copper-Mediated Halotrifluoromethylation of Unactivated Alkenes
N-(3-Bromo-5,5,5-trifluoropentyl)-4-methylbenzenesulfo-
namide (3b): Yield: 77%; H NMR (300 MHz, CDCl3): d=
J=28.3 Hz), 35.32, 27.36; 19F NMR (470 MHz, CDCl3): d=
À64.83 (t, J=9.4 Hz); HR-MS (EI): m/z=278.0122, calcd.
for C8H14Br1F3O2 [M]+: 278.0129; IR (neat): n=3419, 2925,
2867, 1388, 1369, 1257, 1225, 1145, 1121, 1062, 889, 680 cmÀ1.
N-(7-Bromo-9,9,9-trifluorononyl)-4-chlorobenzamide (3h):
1
7.76 (d, J=8.2 Hz, 2H), 7.32 (d, J=8.2 Hz, 2H), 4.61 (t, J=
6.3 Hz, 1H), 4.21–4.12 (m, 1H), 3.23–3.08 (m, 2H), 2.83–
2.53 (m, 2H), 2.44 (s, 3H), 2.19–1.85 (m, 2H);13C NMR
(125 MHz, CDCl3): d=143.78, 136.44, 129.84, 127.05, 124.99
(q, J=276.5 Hz), 42.92 (q, J=28.5 Hz), 41.48 (q, J=2.6 Hz),
41.10, 38.09, 21.48; 19F NMR (470 MHz, CDCl3): d=À64.56
(t, J=9.4 Hz); HR-MS (EI): m/z=372.9957, calcd. for
C12H15Br1F3N1O2S1 [M]+: 374.9939; mp 60–628C; IR (neat):
n=3283, 2925, 1597, 1417, 1325, 1240, 1142, 938, 835, 811,
658 cmÀ1.
1
Yield: 81%; H NMR (300 MHz, CDCl3): d=7.74–7.70 (m,
2H), 7.44- 7.39 (m, 2H), 6.20 (br, 1H), 4.20–4.11 (m, 1H),
3.49–3.42 (m, 2H), 2.86–2.64 (m, 2H), 1.93–1.80 (m, 2H),
1.69–1.58 (m, 2H), 1.50–1.35 (m, 6H); 13C NMR (125 MHz,
CDCl3): d=166.45, 137.53, 133.04, 128.75, 128.26, 125.26 (q,
J=276.4 Hz), 42.03 (q, J=2.8 Hz), 42.96 (q, J=28.3 Hz),
40.02, 38.27, 29.49, 28.36, 26.98, 26.70; 19F NMR (470 MHz,
CDCl3): d=À64.80 (t, J=9.4 Hz); HR-MS (EI): m/z=
413.0367, calcd. for C16H20Br1Cl1F3N1O1 [M]+: 413.0369; mp
71–748C; IR (neat): n=3299, 2933, 2857, 1625, 1535, 1481,
1385, 1306, 1253, 1233, 1149, 1089, 1059, 1014, 842, 758, 726,
664 cmÀ1.
tert-Butyl (7-bromo-9,9,9-trifluorononyl)carbamate (3c):
1
Yield: 83%; H NMR (300 MHz, CDCl3): d=4.51 (br, 1H),
4.17–4.08 (m, 1H), 3.13–3.06 (q, J=6.5 Hz, 2H), 2.83–2.60
(m, 2H), 1.89–1.79 (m, 2H), 1.51–1.43 (m, 13H), 1.38–1.32
(q, J=8.2 Hz, 4H); 13C NMR (125 MHz, CDCl3): d=155.94,
125.28 (q, J=276.4 Hz), 79.03, 45.02 (q, J=2.5 Hz), 43.03 (q,
J=28.2 Hz), 40.43, 38.32, 29.93, 28.38, 27.00, 26.50;
19F NMR (470 MHz, CDCl3): d=À64.84 (t, J=9.4 Hz); HR-
MS (EI): m/z=375.1026, calcd. for C14H25Br1F3N1O2 [M]+:
375.1021; IR (neat): n=2975, 2930, 2859, 1696, 1510, 1365,
1252, 1164, 1147 cmÀ1.
N-(7-Bromo-9,9,9-trifluorononyl)-4-chlorobenzamide (3i):
1
Yield: 74%; H NMR (300 MHz, CDCl3): d=7.74–7.70 (m,
2H), 7.44–7.39 (m, 2H), 6.20 (br, 1H), 4.20–4.11 (m, 1H),
3.49–3.42 (m, 2H), 2.86–2.64 (m, 2H), 1.93–1.80 (m, 2H),
1.69–1.58 (m, 4H), 1.50–1.35 (m, 4H); 13C NMR (125 MHz,
CDCl3): d=166.51, 133.53, 131.77, 128.44, 126.01, 125.26 (q,
J=276.4 Hz), 45.01 (q, J=2.8 Hz), 42.98 (q, J=28.3 Hz),
40.04, 38.30, 29.52, 28.38, 26.99, 26.71; 19F NMR (470 MHz,
CDCl3): d=À64.80 (t, J=9.4 Hz); HR-MS (EI): m/z=
413.0367, calcd. for C16H20Br1Cl1F3N1O1 [M]+: 413.0369; mp
71–748C; IR (neat): n=3299, 2933, 2857, 1625, 1535, 1481,
1385, 1306, 1253, 1233, 1149, 1089, 1059, 1014, 842, 758, 726,
664 cmÀ1.
N-(7-Bromo-9,9,9-trifluorononyl)-4-iodobenzamide (3j):
Yield: 78%; 1H NMR (300 MHz, CDCl3): d=7.79 (d, J=
8.0 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H), 6.24 (br, 1H), 4.20–
4.11 (m, 1H), 3.47–3.41 (m, 2H), 2.89–2.60 (m, 2H), 1.92–
1.79 (m, 2H), 1.61–1.55 (m, 2H), 1.49–1.27 (m, 4H);
13C NMR (125 MHz, CDCl3): d=166.70, 137.70, 134.09,
128.44, 125.26 (q, J=276.4 Hz), 98.22, 45.01 (q, J=2.6 Hz),
43.02 (q, J=28.3 Hz), 40.02, 38.28, 29.48, 28.36, 26.98, 26.70;
19F NMR (470 MHz, CDCl3): d=À64.79 (t, J=9.4 Hz); HR-
MS (EI): m/z=504.8937, calcd. for C16H20Br1Cl1F3N1O1
[M]+: 504.9725; mp 78–808C; IR (neat): n=3303, 2929,
2852, 1632, 1585, 1539, 1413, 1367, 1313, 1259, 1235, 1143,
1123, 1079, 1062, 1002, 844, 670 cmÀ1.
4-Methyl-N-(5,5,5-trifluoro-3-iodopentyl)benzenesulfona-
mide (4b): Yield: 88%; 1H NMR (300 MHz, CDCl3): d=
7.89–7.83 (m, 2H), 7.77–7.70 (m, 2H), 4.20–4.12 (t, J=
6.3 Hz, 1H), 3.97–3.86 (m, 2H), 2.73–2.58 (m, 2H), 2.32–
2.08 (m, 2H); 13C NMR (125 MHz, CDCl3): d=143.81,
136.52, 129.86, 127.10, 125.28 (q, J=277.3 Hz), 44.79 (q, J=
28.4 Hz), 43.41, 39.20, 21.52, 17.03 (q, J=2.6 Hz); 19F NMR
(470 MHz, CDCl3): d=À64.62 (t, J=11.8 Hz); HR-MS (EI):
m/z=420.9801, calcd. for C12H15F3N1O2S1I1 [M]+: 420.9820;
IR (neat): n=3275, 2928, 1425, 1321, 1255, 1224, 1137, 1093,
1080, 941, 896, 857, 833, 813, 764, 705 cmÀ1.
2-(3-Bromo-5,5,5-trifluoropentyl)isoindoline-1,3-dione
1
(3d): Yield: 74%; H NMR (300 MHz, CDCl3): d=7.90–7.83
(m, 2H), 7.77–7.71 (m, 2H), 4.21–4.12 (m, 1H), 4.00–3.83
(m, 2H), 2.90–2.71 (m, 2H), 2.42–2.15 (m, 2H); 13C NMR
(125 MHz, CDCl3): d=168.15, 134.15, 131.92, 125.05 (q, J=
276.5 Hz), 123.42, 42.87 (q, J=28.5 Hz), 41.01 (q, J=
2.8 Hz), 36.84, 36.10; 19F NMR (470 MHz, CDCl3): d=
À64.61 (t, J=9.4 Hz); HR-MS (EI): m/z=348.9923, calcd.
for C13H11Br1F3N1O2 [M]+: 348.9925; mp 61–638C; IR
(neat): n=2921, 1767, 1700, 1391, 1356, 1260, 1237, 1174,
1145, 1084, 1042, 1000, 714 cmÀ1.
4-[(4-Bromo-6,6,6-trifluorohexyl)oxy]benzaldehyde (3e):
1
Yield: 91%; H NMR (300 MHz, CDCl3): d=9.88 (s, 1H),
7.83 (d, J=8.4 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H), 4.23 (br,
1H), 4.10 (t, J=4.8 Hz, 2H), 2.93–2.64 (m, 2H), 2.18–2.10
(m, 2H), 2.06–1.97 (m, 2H); 13C NMR (125 MHz, CDCl3):
d=190.77, 163.73, 132.00, 130.03, 125.18 (q, J=276.38),
114.67, 67.08, 44.40 (q, J=3.0 Hz), 43.11 (q, J=67.5 Hz),
35.04, 26.92; 19F NMR (470 MHz, CDCl3): d=À64.79 (t, J=
9.4 Hz); HR-MS (EI): m/z=338.0132, calcd. for
C13H14Br1F3O2 [M]+: 338.0129; IR (neat): n=2954, 2877,
2732, 1686, 1600, 1250, 1152, 1064, 937, 846, 769 cmÀ1.
5-Bromo-7,7,7-trifluoroheptyl benzoate (3f): Yield: 93%;
1H NMR (300 MHz, CDCl3): d=8.08–8.05 (m, 2H), 7.62–
7.56 (m, 1H), 7.47 (d, J=7.5 Hz, 2H), 4.37 (t, J=6.4 Hz,
2H), 4.37 (t, J=6.4 Hz, 2H), 4.24–4.15 (m, 1H), 2.89–2.66
(m, 2H), 2.03–1.74 (m, 5H), 1.71–1.61 (m, 1H); 13C NMR
(125 MHz, CDCl3): d=166.53, 132.91, 130.22, 129.50, 128.34,
125.22 (q, J=276.4 Hz), 64.41, 44.65 (q, J=2.8 Hz), 42.94 (q,
J=28.3 Hz), 37.95, 27.86, 23.81; 19F NMR (470 MHz,
CDCl3): d À64.78 (t, J=9.4 Hz); HR-MS (EI): m/z=
352.0285, calcd. for C14H16Br1F3O2 [M]+: 352.0286; IR
(neat): n=2953, 1714, 1451, 1388, 1313, 1270, 1255, 1174,
1143, 1113, 1069, 1026, 711, 687 cmÀ1.
tert-Butyl (9,9,9-trifluoro-7-iodononyl)carbamate (4c):
1
Yield: 83%; H NMR (300 MHz, CDCl3): d=4.51 (s, 1H),
4.18 (s, 1H), 3.10 (s, 2H), 2.90–2.79 (m, 2H), 1.76 (s, 2H),
1.44 (s, 13H), 1.32 (s, 4H);13C NMR (125 MHz, CDCl3): d=
155.95, 125.56 (q, J=277.0 Hz), 79.06, 44.88 (q, J=28.1 Hz),
40.46, 39.50, 29.96, 29.35, 28.41, 28.16, 26.52, 21.70 (q, J=
2.5 Hz); 19F NMR (470 MHz, CDCl3): d=À64.79 (t, J=
9.4 Hz); HR-MS (EI): m/z=423.0858, calcd. for
5-Bromo-7,7,7-trifluoroheptyl benzoate (3g): Yield: 70%;
1H NMR (300 MHz, CDCl3): d=4.24–4.15 (m, 1H), 3.73 (m,
2H), 3.56–3.48 (m, 4H), 2.87–2.64 (m, 2H), 1.91–1.83 (m,
4H); 13C NMR (125 MHz, CDCl3): d=125.25 (q, J=
276.3 Hz), 71.86, 70.03, 61.85, 44.79 (q, J=2.6 Hz), 43.12 (q,
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FULL PAPERS
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C14H25I1F3N1O2 [M]+: 423.0882 ; IR (neat): n=2973, 2928,
2857, 1697, 1509, 1365, 1251, 1169, 1145 cmÀ1.
4-Iodo-N-(9,9,9-trifluoro-7-iodononyl)benzamide
(4j):
Yield: 82%; 1H NMR (300 MHz, CDCl3)::d=7.80 (d, J=
8.0 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H), 6.12 (br, 1H), 4.25–
4.16 (m, 1H), 3.49–3.43 (m, 2H), 2.93–2.79 (m, 2H), 1.84–
1.74 (m, 2H), 1.66–1.62 (m, 2H), 1.49–1.33 (m, 6H);
13C NMR (125 MHz, CDCl3): d=166.67, 137.75, 134.11,
128.44, 125.51 (q, J=277.1 Hz), 98.24, 44.89 (q, J=28.0 Hz),
40.03, 39.45, 29.53, 29.33, 28.17, 26.71, 21.65 (q, J=2.2H);
19F NMR (470 MHz, CDCl3): d=À64.89 (t, J=9.4 Hz); HR-
MS (EI): m/z=552.9588, calcd. for C16H20F3I2N1O1 [M]+:
552.9587; mp 91–958C; IR (neat): n=3304, 2935, 2855, 1731,
1625, 1584, 1528, 1168, 1364, 1300, 1128, 1142, 1128, 1245,
1065, 1007, 879, 856, 768, 708, 663 cmÀ1.
2-(5,5,5-Trifluoro-3-iodopentyl)isoindoline-1,3-dione (4d):
1
Yield: 64%; H NMR (300 MHz, CDCl3): d=7.89–7.83 (m,
2H), 7.76–7.71 (m, 2H), 4.21–4.11 (m, 1H), 3.94–3.76 (m,
2H), 2.99–2.80 (m, 2H), 2.27–2.19 (m, 2H);13C NMR
(125 MHz, CDCl3): d=168.15, 134.15, 131.90, 125.35 (q, J=
277.5 Hz), 123.42, 44.67 (q, J=28.4 Hz), 38.14, 38.10, 15.49
(q, J=2.5 Hz); 19F NMR (470 MHz, CDCl3): d=À64.71 (t,
J=9.4 Hz); HR-MS (EI): m/z=396.9772, calcd. for
C13H11I1F3N1O1 [M]+: 396.9787; IR (neat): n=2941, 1771,
1709, 1432, 1396, 1257, 1187, 1145, 721 cmÀ1.
4-[(6,6,6-Trifluoro-4-iodohexyl)oxy]benzaldehyde
(4e):
1
5-Chloro-7,7,7-trifluoroheptyl 4-methylbenzenesulfonate
Yield: 99%; H NMR (300 MHz, CDCl3): d=9.91 (s, 1H),
7.88–7.85 (m, 2H), 7.12 (d, J=8.7 Hz, 2H), 4.31–4.27 (m,
1H), 4.14–4.08 (m, 2H), 3.04–2.80 (m, 2H), 2.17–1.95 (m,
4H); 13C NMR (125 MHz, CDCl3): d=190.79, 163.75,
132.00, 130.02, 125.48 (q, J=277.2 Hz), 114.68, 66.92, 44.93
(q, J=28.2 Hz), 36.20, 29.20, 20.57 (q, J=2.4 Hz); 19F NMR
(470 MHz, CDCl3): d=À64.85 (t, J=9.4 Hz); HR-MS (EI):
m/z=385.9988, calcd. for C13H14F3O2I1 [M]+: 358.9991; IR
(neat): n=2925, 2736, 1686, 1598, 1577, 1508, 1350, 1213,
1156, 1143, 1109, 1076, 831 cmÀ1.
1
(5a): Yield: 72%; H NMR (300 MHz, CDCl3): d=7.79 (d,
J=8.1 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 4.08–4.00 (m, 3H),
2.69–2.41 (m, 2H), 2.39 (s, 3H), 1.85–1.57 (m, 5H), 1.54–
1.39 (m, 1H); 13C NMR (125 MHz, CDCl3): d=144.85,
132.93, 129.85, 127.83, 125.11 (q, J=275.9 Hz), 69.93, 53.65
(q, J=2.8 Hz), 42.26 (q, J=28.3 Hz), 37.16, 28.05, 21.99,
21.57; 19F NMR (470 MHz, CDCl3): d=À64.81 (t, J=
9.4 Hz); HR-MS (EI): m/z=358.0616, calcd. for
C14H18Cl1F3O3S1 [M]+: 358.0617; IR (neat): n=2956, 1597,
13.56, 1268, 1188, 1175, 1145, 1097, 939, 910, 814, 733,
665 cmÀ1.
4-Chloro-N-(9,9,9-trifluoro-7-iodononyl)benzamide (4g):
1
Yield: 60%; H NMR (300 MHz, CDCl3): d=4.28–4.19 (m,
N-(3-Chloro-5,5,5-trifluoropentyl)-4-methylbenzenesulfo-
1H), 3.76–3.71 (m, 2H), 3.56–3.51 (m, 4H), 2.98–2.74 (m,
2H), 1.91–1.81 (m, 4H); 13C NMR (125 MHz, CDCl3): d=
125.52 (q, J=277.1 Hz), 71.87, 69.85, 61.84, 44.93 (q, J=
28.1 Hz), 36.50, 29.62, 21.18 (q, J=2.4 Hz); 19F NMR
(470 MHz, CDCl3): d=À64.92 (t, J=11.8 Hz); HR-MS (EI):
m/z=325.9959, calcd. for C8H14F3O2I1 [M]+: 325.9991; IR
(neat): n=6411, 2918, 2865, 1433, 1365, 1253, 1213, 1143,
1119, 1075, 1061, 889 cmÀ1.
4-Chloro-N-(9,9,9-trifluoro-7-iodononyl)benzamide (4h):
Yield: 81%; 1H NMR (300 MHz, CDCl3): d=7.70 (d, J=
7.8 Hz, 2H), 7.39 (d, J=7.8 Hz, 2H), 6.27 (br, 1H), 4.25–
4.11 (m, 1H), 3.46–3.40 (m, 2H), 2.94–2.71 (m, 2H), 1.90–
1.74 (m, 2H), 1.90–1.54 (m, 2H), 1.49–1.30 (m, 6H);
13C NMR (125 MHz, CDCl3): d=166.45, 137.49, 137.03,
128.71, 128.27, 125.51 (q, J=277.2 Hz), 44.81 (q, J=
28.0 Hz), 40.02, 39.41, 29.48, 29.29, 28.14, 26.69, 21.66 (q, J=
2.5 Hz); 19F NMR (470 MHz, CDCl3): d=À64.87 (t, J=
9.4 Hz); HR-MS (EI): m/z=461.0227, calcd. for
C16H20Cl1F3I1N1O1 [M]+: 461.0230; mp 72–758C; IR (neat):
n=3309, 2936, 2858, 1627, 1592, 1528, 1484, 1470, 1363,
1335, 1302, 1255, 1243, 1143, 1130, 1106, 1089, 1067, 1015,
843, 763, 726, 661 cmÀ1.
1
namide (5b): Yield: 75%; H NMR (300 MHz, CDCl3): d=
7.82 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 4.65 (t, J=
6.3 Hz, 1H), 4.21–4.12 (m, 1H), 3.21–3.14 (m, 2H), 2.65–
2.45 (m, 2H), 2.44 (s, 3H), 2.15–2.04 (m, 1H), 1.89–1.78 (m,
1H); 13C NMR (125 MHz, CDCl3): d=143.82, 136.51,
129.87, 127.07, 125.17 (q, J=276.4 Hz), 51.17 (q, J=2.2 Hz),
42.33 (q, J=28.3 Hz), 40.0, 37.73, 21.52; 19F NMR
(470 MHz, CDCl3): d=À64.83 (t, J=9.4 Hz); HR-MS (EI):
m/z=402.0120, calcd. for C14H18Br1F3O3S1 [M]+: 402.0112;
mp 87–898C; IR (neat): n=2926, 1354, 1253, 1173, 1143,
1094, 934, 908, 814, 778, 730, 662 cmÀ1.
N-(3-Chloro-5,5,5-trifluoropentyl)-4-methylbenzenesulfo-
1
namide (5c): Yield: 77%; H NMR (300 MHz, CDCl3): d=
4.51 (s, 1H), 4.11–4.04 (m, 1H), 3.13–3.07 (m, 2H), 2.60–
2.46 (m, 2H), 1.86–1.63 (m, 2H), 1.50–1.22 (m, 17H);
13C NMR (125 MHz, CDCl3): d=155.95, 125.24 (q, J=
275.9 Hz), 54.09 (q, J=2.5 Hz), 42.38 (q, J=28.1 Hz), 40.43,
37.89, 29.93, 28.47, 28.38, 26.52, 25.80; 19F NMR (470 MHz,
CDCl3): d=À64.83 (t, J=9.4 Hz); HR-MS (EI): m/z=
331.1519, calcd. for C14H25Cl1F3N1O2 [M]+: 331.1526; IR
(neat): n=2930, 2859, 1697, 1510, 1365, 1265, 1244, 1168,
1147 cmÀ1.
4-Bromo-N-(9,9,9-trifluoro-7-iodononyl)benzamide (4i):
Yield: 83%; 1H NMR (300 MHz, CDCl3): d=7.65 (d, J=
8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 6.20 (br, 1H), 4.25–
4.16 (m, 1H), 3.49–3.42 (m, 2H), 2.93–2.78 (m, 2H), 1.83–
1.75 (m, 2H), 1.69–1.50 (m, 3H), 1.50–1.29 (m, 5H);
13C NMR (125 MHz, CDCl3): d=166.54, 133.51, 131.69,
128.46, 125.94, 125.52 (q, J=277.1 Hz), 44.82 (q, J=
28.0 Hz), 40.03, 39.42, 29.48, 29.30, 28.15, 26.69, 21.64 (q, J=
2.3 Hz); 19F NMR (470 MHz, CDCl3): d=À64.87 (t, J=
9.4 Hz); HR-MS (EI): m/z=504.9732, calcd. for
C16H20Br1F3I1N1O1 [M]+: 504.9725; mp 85–888C; IR (neat):
n=3304, 2936, 2857, 1626, 1587, 1528, 1480, 1469, 1363,
1334, 1300, 1255, 1244, 1143, 1129, 1104, 1066, 1011, 840,
760, 711, 662 cmÀ1.
4-[(4-Chloro-6,6,6-trifluorohexyl)oxy]benzaldehyde (5e):
Yield: 81%; H NMR (300 MHz, CDCl3): d=9.89 (s, 1H),
1
7.84 (d, J=9 Hz, 2H), 6.99 (d, J=9 Hz, 2H), 4.24–4.17 (m,
1H), 4.10 (t, J=5.7 Hz, 2H), 2.64–2.55 (m, 2H), 2.14–2.07
(m, 2H), 2.02–1.90 (m, 2H); 13C NMR (125 MHz, CDCl3):
d=190.79, 163.74, 132.00, 130.03, 125.12 (q, J=275.9 Hz),
114.67, 67.20, 53.73 (q, J=2.0H), 42.48 (q, J=28.4 Hz),
34.62, 25.73; 19F NMR (470 MHz, CDCl3): d=À64.75 (t, J=
9.4 Hz); HR-MS (EI): m/z=294.0634, calcd. for
C13H14Cl1F3O2 [M]+; 294.0609; IR (neat): n=2955, 2878,
2841, 1687, 1603, 1578, 1245, 1146, 1115, 1031, 830 cmÀ1.
2-[(4-Chloro-6,6,6-trifluorohexyl)oxy]ethan-1-ol
Yield: 55%; H NMR (300 MHz, CDCl3): d=4.17–4.12 (m,
(5g):
1
1H), 3.76–3.71 (m, 2H), 3.56–3.50 (m, 4H), 2.66–2.50 (m,
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Copper-Mediated Halotrifluoromethylation of Unactivated Alkenes
2H), 1.93–1.75 (m, 4H); 13C NMR (125 MHz, CDCl3): d
125.19 (q, J=276.5 Hz), 71.83, 70.13, 61.83, 53.96 (q, J=
2.0H), 42.45 (q, J=28.3 Hz), 34.86, 26.16; 19F NMR
(470 MHz, CDCl3): d À64.81 (t, J=9.4 Hz); HRMS (EI):
m/z Calcd for C8H14Cl1F3O2 [M]+234.0634, found 234.0631;
IR (neat): 3419, 2922, 2867, 1389, 1263, 1243, 1145, 1119,
1063, 664 cmÀ1.
(125 MHz, CDCl3): d=137.98, 128.43, 127.69, 127.57, 125.07
(q, J=277.6 Hz), 73.17, 68.09, 60.84, 48.18 (q, J=28.6 Hz),
44.54, 32.13; 19F NMR (470 MHz, CDCl3): d=À61.46 (t, J=
9.4 Hz); HR-MS (EI): m/z=324.0326, calcd. for
C13H16Br1F3O1 [M]+: 324.0337; IR (neat): n=2927, 2859,
1453, 1363, 1255, 1207, 1140, 1100, 1027, 736, 698, 677 cmÀ1.
(S)-5-(2-Bromo-4,4,4-trifluorobutan-2-yl)-2-methylcyclo-
hex-2-en-1-one (8b): Yield: 72% (1.1:1 dr); 1H NMR
(300 MHz, CDCl3): d=6.78 (s, 1H), 3.06–2.87 (m, 2H),
2.77–2.70 (m, 1H), 2.59–2.51 (m, 3H), 2.25–2.19 (m, 1H),
1.98–1.86 (m, 3H), 1.83 (s, 3H); 13C NMR (125 MHz,
CDCl3): d=198.25, 197.91, 143.43, 143.30, 135.39, 124.90 (q,
J=278.1 Hz), 124.87 (q, J=278.1 Hz), 66.67, 66.61, 46.14 (q,
J=27.4 Hz), 46.09 (q, J=27.4 Hz), 45.16, 45.06, 40.99, 40.80,
29.85, 29.77, 28.82, 28.63, 15.52; 19F NMR (470 MHz,
CDCl3): d=À61.35 (t, J=9.4 Hz), À61.37 (t, J=9.4 Hz);
HR-MS (EI): m/z=298.0173, calcd for C16H20I1Cl1F3N1O1
[M]+: 298.0180; IR (neat): n=2925, 1671, 1433, 1365, 1252,
1177, 1137, 1115, 1076, 906, 733, 673 cmÀ1.
N-(7-Chloro-9,9,9-trifluorononyl)-4-chlorobenzamide
1
(5h): Yield: 72%; H NMR (300 MHz, CDCl3): d=7.70 (d,
J=8.6 Hz, 2H), 7.40 (d, J=8.6 Hz, 2H), 6.17 (br, 1H), 4.14–
4.06 (m, 1H), 3.47–3.40 (m, 2H), 2.68–2.47 (m, 2H), 1.89–
1.71 (m, 2H), 1.65–1.58 (m, 2H), 1.48–1.33 (m, 6H);
13C NMR (125 MHz, CDCl3): d=166.44, 137.55, 133.07,
128.77, 128.26, 125.22 (q, J=275.9 Hz), 54.08 (q, J=2.8 Hz),
42.39 (q, J=28.1 Hz), 40.03, 37.86, 29.51, 28.49, 26.72, 25.78;
19F NMR (470 MHz, CDCl3): d=À64.80 (t, J=9.4 Hz); HR-
MS (EI): m/z=369.0874, calcd. for C16H20Cl2F3N1O1 [M]+:
369.0813; mp 67–708C; IR (neat): n=3299, 2935, 2857, 1625,
1535, 1481, 1386, 1310, 1257, 1240, 1151, 1091, 1060, 1014,
861, 843, 758, 726, 665 cmÀ1.
(R)-4-(2-Bromo-4,4,4-trifluorobutan-2-yl)cyclohex-1-ene-
1-carbaldehyde (8c): Yield: 64% (1.1:1 dr); 1H NMR
(300 MHz, CDCl3): d=9.45 (s, 1H), 6.83–6.82 (m, 1H),
3.20–2.90 (m, 2H), 2.69–2.58 (m, 2H), 2.45–2.43 (m, 1H),
2.19–2.07 (m, 2H), 2.02–1.98 (m, 3H), 1.82–1.73 (m, 1H),
1.53–1.42 (m, 1H); 13C NMR (125 MHz, CDCl3): d=193.30,
148.88, 148.72, 141.19, 141.13, 126.16 (q, J=279.5 Hz),
123.94 (q, J=279.5 Hz), 67.41, 67.08, 46.36 (q, J=27.5 Hz),
46.30 (q, J=27.5 Hz), 44.31, 43.83, 30.41, 29.88, 29.54, 29.47,
24.65, 24.28, 21.61, 1.47; 19F NMR (470 MHz, CDCl3): d=
À61.27 (t, J=10.4 Hz), À61.51 (t, J=10.4 Hz); HR-MS (EI):
m/z=298.0176, calcd. for C11H14Br1F3O1 [M]+: 298.0180; IR
(neat): n=2928, 1682, 1648, 1434, 1359, 1252, 1102, 1197,
1132, 1083, 1026, 738, 679 cmÀ1.
N-(7-Chloro-9,9,9-trifluorononyl)-4-bromobenzamide (5i):
Yield: 71%; 1H NMR (300 MHz, CDCl3): d=7.63 (d, J=
8.6 Hz, 2H), 7.56 (d, J=8.6 Hz, 2H), 6.16 (br, 1H), 4.15–
4.06 (m, 1H), 3.47–3.40 (m, 2H), 2.68–2.49 (m, 2H), 1.87–
1.69 (m, 2H), 1.64–1.60 (m, 2H), 1.48–1.33 (m, 6H);
13C NMR (125 MHz, CDCl3): d=166.53, 133.53, 131.75,
128.45, 125.99, 125.24 (q, J=275.9 Hz), 54.09 (q, J=2.8 Hz),
42.39 (q, J=28.1 Hz), 40.04, 37.87, 29.50, 28.49, 26.73, 25.79;
19F NMR (470 MHz, CDCl3): d=À64.80 (t, J=9.4 Hz); HR-
MS (EI): m/z=413.0340, calcd. for C16H20Br1Cl1F3N1O1
[M]+: 413.0369; mp 67–708C; IR (neat): n=3296, 3055,
2934, 2856, 1625, 1590, 1535, 1479, 1387, 1307, 1258, 1241,
1150, 1095, 1070, 1005, 841, 665 cmÀ1.
N-(7-Chloro-9,9,9-trifluorononyl)-4-iodobenzamide (5j):
Yield: 68%; 1H NMR (300 MHz, CDCl3): d=7.80 (d, J=
8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 6.12 (br, 1H), 4.18–
4.08 (m, 1H), 3.49–3.42 (m, 2H), 2.70–2.49 (m, 2H), 1.89–
1.75 (m, 2H), 1.70–1.56 (m, 2H), 1.50–1.35 (m, 6H);
13C NMR (125 MHz, CDCl3): d=166.68, 137.75, 134.10,
128.43, 125.13 (q, J=275.9 Hz), 98.24, 54.08 (q, J=2.0 Hz),
42.40 (q, J=28.1 Hz), 40.02, 37.87, 29.51, 28.50, 26.72, 25.79;
19F NMR (470 MHz, CDCl3): d=À64.80 (t, J=9.4 Hz); HR-
MS (EI): m/z=461.0223, calcd. for C16H20I1Cl1F3N1O1 [M]+:
461.0230; mp 64–678C; IR (neat): n=3302, 3066, 2929, 2852,
1637, 1586, 1539, 1436, 1385, 1314, 1264, 1238, 1138, 1057,
1001, 885, 760, 667 cmÀ1.
(4R,4aS,6R)-6-(2-bromo-4,4,4-trifluorobutan-2-yl)-4,4a-di-
methyl-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one
(8d):
1
Yield: 71% (1:1 dr); H NMR (300 MHz, CDCl3): d=5.78
(s, 1H), 3.03–2.82 (m, 2H), 2.53–2.39 (m, 2H), 2.30–2.26 (m,
2H), 2.13–2.03 (m, 3H), 1.96–1.93 (m, 3H), 1.90–1.81 (m,
1H), 1.50–1.12 (m, 2H), 1.11–1.09 (m, 3H), 1.01–0.99 (m,
3H); 13C NMR (125 MHz, CDCl3): d=199.24, 199.21,
168.86, 168.75, 125.18 (q, J=278.1 Hz), 125.10 (q, J=
278.1 Hz), 124.78, 124.74, 67.57, 67.05, 46.29 (q, J=27.4 Hz),
46.07 (q, J=27.4 Hz), 43.69, 43.02, 41.94, 40.71, 40.60, 40.33,
40.29, 39.07, 32.15, 32.08, 30.59, 30.25, 28.87, 28.64, 15.01,
14.98; 19F NMR (470 MHz, CDCl3): d=À61.14 (t, J=
10.4 Hz), À61.15 (t, J=10.4 Hz); HR-MS (EI): m/z=
366.0805, calcd. for C16H22Br1F3O1 [M]+: 366.0806; IR
(neat): n=2962, 2938, 2881, 1663, 1619, 1434, 1370, 1355,
1304, 1254, 1190, 1137, 1100, 1080, 1028, 998, 886, 680,
661 cmÀ1.
(S)-2-Methyl-5-(4,4,4-trifluoro-2-iodobutan-2-yl)cyclohex-
1
2-en-1-one (7b): Yield: 68% (1:1 dr); H NMR (300 MHz,
CDCl3): d=6.74–6.76 (m, 1H), 3.02–3.21 (m, 2H), 2.66–2.72
(m, 1H), 2.53–2.61 (m, 1H), 2.34–2.44 (m, 2H), 2.17–1.81
(m, 3H), 1.80–1.81 (m, 3H), 1.09–1.20 (m, 1H); 13C NMR
(125 MHz, CDCl3): d=199.1, 198.7, 144.3, 144.1, 134.8,
124.95 (q, J=279.2 Hz), 53.97, 53.69, 48.49, 48.35, 45.38,
45.02, 43.54, 43.32, 33.33, 31.30, 31.04, 15.91, 15.89; 19F NMR
(470 MHz, CDCl3): d=À60.97 (t, J=11.8 Hz); HR-MS (EI):
m/z=346.0747, calcd. for C11H14F3O1I1 [M]+: 346.0042; IR
(neat): n=2978, 2927, 1670, 1358, 1249, 1222, 1194, 1172,
1134, 1115, 1073, 904, 673 cmÀ1.
(1-Bromo-3,3,3-trifluoropropane-1,2-diyl)dibenzene (8e):
Yield: 80% (1.5:1 dr); 1H NMR (300 MHz, CDCl3): d=
7.49–7.35 (m, 4H), 7.22–7.06 (m, 6H), 5.44–5.39 (m, 1H),
4.22–4.03 (m, 1H); 13C NMR (125 MHz, CDCl3): d=139.44,
138.86, 134.04, 132.39, 129.39, 128.93, 128.84, 128.62, 128.59,
128.41, 128.38, 128.31, 128.23, 128.20, 127.86, 126.69, 125.57
(q, J=280.4 Hz), 124.74 (q, J=281.0 Hz), 58.08 (q, J=
26.1 Hz), 58.24 (q, J=26.1 Hz), 52.10, 48.42; 19F NMR
(470 MHz, CDCl3): d=À64.45 (d, J=8.6 Hz), À64.69 (d, J=
8.6 Hz); HR-MS (EI): m/z=328.0080, calcd. for C15H12Br1F3
[M]+: 328.0074; mp 84–888C; IR (neat): n=1492, 1454,
{[(5,5,5-Trifluoro-3-bromo-3-methylpentyl)oxy]methyl}-
1
benzene (8a): Yield: 71%; H NMR (300 MHz, CDCl3): d=
7.41–7.32 (m, 5H), 4.55 (s, 2H), 3.85–3.78 (m, 2H), 3.00–
2.86 (m, 2H), 2.37–2.24 (m, 2H), 1.95 (s, 3H); 13C NMR
Adv. Synth. Catal. 2015, 357, 3949 – 3960
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FULL PAPERS
Won An et al.
1370, 1322, 1239, 1150, 1171, 1031, 1001, 939, 823, 774, 759,
670, 651 cmÀ1.
7.73 (m, 2H), 3.94–3.80 (m, 2H), 3.78–3.68 (m, 1H), 2.45–
2.31 (m, 2H), 2.03–1.83 (m, 2H); 13C NMR (125 MHz,
CDCl3): d=168.25, 134.20, 131.90, 123.45 (q, J=275.3 Hz),
54.75, 38.75 (q, J=28.1 Hz), 34.45, 33.56; 19F NMR
(470 MHz, CDCl3): d=À64.39 (t, J=9.9 Hz); HR-MS (EI):
m/z=284.0763, calcd. for C13H11F3N2O2 [MÀN2]+: 284.2377;
IR (neat): n=2925, 2118, 2018, 1395, 1379, 1282, 1258, 1138,
117, 719 cmÀ1.
2-(5,5,5-Trifluoro-3-thiocyanatopentyl)isoindoline-1,3-
dione (12): In a 4-mL pre-dried screw-capped sealed tube,
a suspension of 2-(3-bromo-5,5,5-trifluoropentyl)isoindoline-
1,3-dione (88 mg, 0.25 mmol), NaSCN (41 mg, 0.5 mmol),
and NaI (7.5 mg, 0.05 mmol) in DMF (2 mL, 0.125M) was
stirred at 808C for 4 h. The reaction mixture was cooled and
concentrated under vacuum. A white solid precipitated out
after addition of Et2O. The white solid was filtered and
dried to give the desired product as oily liquid; yield: 98%;
1H NMR (300 MHz, CDCl3): d=7.89–7.85 (m, 2H), 7.79–
7.74 (m, 2H), 3.97–3.89 (m, 2H), 3.32–3.22 (m, 1H), 2.82–
2.61 (m, 2H), 2.37–2.12 (m, 2H); 13C NMR (125 MHz,
CDCl3): d=168.26, 134.38, 131.71, 124.73 (q, J=272.7 Hz),
123.59, 109.21, 40.61, 39.56 (q, J=29.0 Hz), 34.96, 34.16;
19F NMR (470 MHz, CDCl3): d=À64.39 (t, J=9.4 Hz); HR-
MS (EI): m/z=328.0486, calcd. for C14H11F3N2O2S1 [M]+:
328.3092; IR (neat): n=2945, 2155, 1774, 1707, 1357, 1266,
1247, 1211, 1018, 715 cmÀ1.
{[(3-Chloro-5,5,5-trifluoro-3-methylpentyl)oxy]methyl}-
1
benzene (9a): Yield: 74%; H NMR (300 MHz, CDCl3): d=
7.41–7.31 (m, 5H), 4.54 (s, 2H), 3.83–3.71 (m, 2H), 2.89–
2.66 (m, 2H), 2.31–2.16 (m, 2H), 1.76 (s, 3H); 13C NMR
(125 MHz, CDCl3): d=137.98, 137.98. 128.43, 127.69, 127.57,
125.07 (q, J=277.0 Hz), 73.15, 66.69, 66.19, 46.93 (q, J=
27.5 Hz), 43.59, 30.41; 19F NMR (470 MHz, CDCl3): d=
À60.49 (t, J=10.6 Hz); HR-MS (EI): m/z=280.0842, calcd.
for C13H16Br1F3O1 [M]+: 280.0842; IR (neat): n=2864, 1453,
1355, 1293, 1258, 1208, 1176, 1142, 1101, 1027, 736, 699,
678 cmÀ1.
(1-Chloro-3,3,3-trifluoropropane-1,2-diyl)dibenzene (9e):
1
Yield: 73% (2:1 dr); H NMR (300 MHz, CDCl3): d=7.44–
7.37 (m, 3H), 7.20–7.03 (m, 7H), 5.45–5.35 (m, 1H), 4.08–
3.86 (m, 1H); 13C NMR (125 MHz, CDCl3): d=138.80,
138.34, 132.23, 132.17, 129.72, 129.35, 128.86, 128.78, 128.50,
128.44, 128.41, 128.39, 128.21, 127.85, 127.51, 125.66 (q, J=
280.3 Hz), 125.12 (q, J=280.3 Hz), 60.84, 59.46, 58.13 (q, J=
26.0 Hz), 58.09 (q, J=25.4 Hz); 19F NMR (470 MHz,
CDCl3): d=À64.24 (d, J=8.6 Hz), À65.34 (d, J=8.6 Hz);
HR-MS (EI): m/z=284.0554, calcd. for C15H12Cl1F3 [M]+:
284.0580; mp 73–768C; IR (neat): n=1491,1455, 1370, 1276,
1244, 1162, 1153, 1108, 1074, 761, 727, 697, 684 cmÀ1.
(E)-2-(5,5,5-Trifluoropent-3-en-1-yl)isoindoline-1,3-dione
(13): 2-(3-Bromo-5,5,5-trifluoropentyl)isoindoline-1,3-dione
(175 mg, 0.25 mmol) was dissolved in DCM (0.2M). The so-
lution was cooled to 08C and DBU (77 mg, 0.25 mmol) was
added. The reaction mixture was stirred at 08C for 1 h. H2O
was added to the reaction mixture. The solution was extract-
ed with Et2O and dried over Na2SO4. The crude was purified
by silica gel column chromatography (EtOAc:kexane=1:4)
Derivatization of the Bromotrifluoromethylated
Product
2-[5,5,5-Trifluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)pentyl]isoindoline-1,3-dione (10): 2-(3-Bromo-5,5,5-tri-
fluoropentyl)isoindoline-1,3-dione (175 mg, 0.50 mmol),
B2pin2(190.5 mg, 0.75 mmol), CuI (10.0 mg, 0.05 mmol),
PPh3 (17 mg, 0.065 mmol) and LiOEt (52.0 mg, 1.0 mmol)
were dissolved in DMF (4 mL, 0.125M). The reaction mix-
ture was stirred for 12 h at 378C. Then the mixture was
cooled to room temperature and poured into a separatory
funnel containing 50 mL of EtOAc and H2O (20 mL). The
aqueous layer was extracted with EtOAc (50 mL). The com-
bined organic layers were dried with Na2SO4 and concen-
trated under vacuum. Purification by column chromatogra-
phy on SiO2 gel (EtOAc : hexanes=2:8) gave the desired
1
to give the desired product as a solid; Yield: 74%; H NMR
(300 MHz, CDCl3): d=7.87–7.85 (m, 2H), 7.74–7.72 (m,
2H), 6.41–6.34 (m, 1H), 5.73–5.66 (m, 1H), 3.83 (t, J=
7.1 Hz, 2H), 2.59–2.54 (m, 2H); 13C NMR (125 MHz,
CDCl3): d=168.13, 136.29 (q, J=6.2 Hz), 134.13, 131.85,
123.38, 121.01 (q, J=34.8 Hz), 36.20, 30.62; 19F NMR
(470 MHz, CDCl3): d=À65.46 (d, J=4.0 Hz); HR-MS (EI):
m/z=269.0674, calcd. for C13H10F3N1O2 [M]+: 269.0664;
M.P.: 91.7–92.68C; IR (neat): n=2948, 2920, 2851, 1699,
1101, 872, 719 cmÀ1.
1
product as an oily liquid; yield: 65%; H NMR (300 MHz,
CDCl3): d=7.88–7.82 (m, 2H), 7.74–7.69 (m, 2H), 3.80–3.69
(m, 2H), 2.43–2.19 (m, 2H), 1.90–1.76 (m, 2H), 1.26–1.24
(m, 13H); 13C NMR (125 MHz, CDCl3): d=168.26, 133.88,
132.17, 127.27 (q, J=275.5 Hz), 123.18, 83.87, 36.77, 34.65
(q, J=27.9 Hz), 29.24, 24.67, 24.64; 19F NMR (470 MHz,
CDCl3): d=À65.72 (t, J=11.5 Hz); HR-MS (EI): m/z=
397.1663, calcd. for C14H16F3N1O2 [M]+: 397.1676; IR (neat):
n=2980, 2935, 1773, 1710, 1392, 1371, 1332, 1259, 1138,
1084, 721 cmÀ1.
Acknowledgements
This work was supported by Korea Research Institute of
Chemical Technology (Grant No. KK-1507-C03 and KK-
1503-C00).
N-{4-[(4-Azido-6,6,6-trifluorohexyl)oxy]pheny}acetamide
(11): In a 4-mL pre-dried screw-capped sealed tube, a sus- References
pension of 2-(3-bromo-5,5,5-trifluoropentyl)isoindoline-1,3-
dione (88 mg, 0.25 mmol), NaN3 (33 mg, 0.5 mmol), and NaI
(7.5 mg, 0.05 mmol) in DMF (2 mL, 0.125M) was stirred at
808C for 4 h. The reaction mixture was cooled and concen-
trated under vacuum. A white solid precipitated out after
addition of Et2O. The white solid was filtered and dried to
give the desired product as an oily liquid; yield: 90%;
1H NMR (300 MHz, CDCl3): d=7.89–7.85 (m, 2H), 7.77–
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