Facile preparation of CF3-Containing 1-bromoallenes

Article abstract of DOI:10.1055/s-0029-1218383

The novel synthetic method is described for preparation of not only 1-bromo- but 1,3-dibromo-1-trifluoromethylated allenes from the corresponding propargylic alcohols with a combination of CBr₄ and Ph₃P. Selection of the organic solv

Full text of DOI:10.1055/s-0029-1218383

3352
LETTER
Facile Preparation of CF3-Containing 1-Bromoallenes
C
CF
o-Containing
hPropargylic
Alcohols
i
u
nto Bromoal
k
lenes e Watanabe, Takashi Yamazaki*
Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology,
Koganei, Tokyo 184-8588, Japan
Fax +81(42)3887038; E-mail: tyamazak@cc.tuat.ac.jp
Received 17 September 2009
this halogenation of the alcohol 1a in other solvents (THF,
Et2O) afforded the bromoallene 3a only sluggishly, but in-
stead, the propargylic bromide 2a and the 1,3-dibromo-
allene 4a in moderate and irreproducible yields,
respectively. This CBr4–Ph3P reagent system was suc-
cessfully applied to a variety of CF3-containing propar-
gylic alcohols 1a–j in DMF at room temperature.
Although various types of arene-substituted alcohols 1a–
e were converted into allenes 3a–e in high yields (Table 1,
entries 1–5), 3e was the exception which could not be iso-
lated due to its instability towards silica gel at the purifi-
cation stage (entry 5).
Abstract: The novel synthetic method is described for preparation
of not only 1-bromo- but 1,3-dibromo-1-trifluoromethylated allenes
from the corresponding propargylic alcohols with a combination of
CBr4 and Ph3P. Selection of the organic solvent employed enabled
us to access to these two different allenes quite readily.
Key words: alkynes, allenes, fluorine, trifluoromethyl, bromina-
tion
Currently, organofluorine compounds have attracted an
enormous interest because of their remarkable properties
on the basis of the special electronic character of fluorine
which has contributed to their wide application to novel
pharmaceuticals, advanced materials, and so on.1 We have
recently demonstrated the transformation of propargylic
alcohols 1 into 3-mono- and 3,3-disubstituted allenes with
a CF3 group at the 1-position, CF3CH=C=CR1R2.2a Al-
lenes have been recognized as attractive and useful organ-
ic compounds and utilized as a variety of synthetic
building blocks or convenient intermediates.3 Such mate-
rials are also found in nature and panacene, isolated in
1977, is known as one of the representative allenes con-
taining a bromine atom.4 While nonfluorinated allenes en-
joy both utilization and wide application, there have been
only limited synthetic pathways for fluorinated counter-
parts,2i–2k especially the ones with a CF3 group.2b–2h In this
paper, we present the facile and straightforward conver-
sion of the corresponding propargylic alcohols 1 into tri-
fluoromethylated bromoallenes 3 by treatment with CBr4
and Ph3P.5
The aliphatic alcohols 1f–h were also transformed to 3f–
h successfully (entries 6–8), while the tertiary alcohols
Table 1 Transformation of 1 into 3
Ph3P (2.4 equiv)
CBr4 (1.2 equiv)
OH
R1
R2
Br
•
R1
R2
DMF, r.t., time
R3
R3
1
3
Entry R1
R2
R3
Time
(h)
3
Yield
(%)a
1
2
3
4
5
6
7
8
9c
Ph
H
H
H
H
H
H
H
H
Me
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
n-Bu
n-Bu
Ph
2
2
3a8
3b
3c
3d
3e
3f
85
1-Naphthyl
4-MeOC6H4
4-BrC6H4
2-furyl
93
2
74
4
85
6
67b
63
The combined reagent system CX4–Ph3P (X = Cl or Br)
has been employed for halogenation of primary and sec-
ondary hydroxyl groups under mild conditions which usu-
ally proceeds in an SN2 manner.6 When we applied this
method to the alcohol 1a, unexpected transformation to
the bromoallene 3a was observed along with formation of
a small amount of the corresponding ‘normal product’,
propargylic bromide 2a.
(E)-PhCH=CH
PhCH2CH2
c-Hex
24
14
14
55
90
4
3g
3h
3i
89
87
Ph
39
10
–(CH2)5–
Ph
3j
39
Brief investigation of the reaction conditions led to con-
clusion that Ph3P and CBr4 in DMF at ambient tempera-
ture were appropriate for the preparation of allenes with
such substituents as a trifluoromethyl group and bromine
at the geminal site and thus, we next examined generaliza-
tion of this reaction (Table 1). It is interesting to note that
11
12
13
H
H
H
3k
3l
86
PhCH2CH2
Ph
18
8
0 (44)d
e
3m
–
a Isolated yield.
b 19F NMR yield determined by PhCF3 as an internal standard.
c Ph3P (4.8 equiv) and CBr4 (2.4 equiv) were used.
d The value in the parenthesis was the yield of the corresponding pro-
pargylic bromide 2l.
SYNLETT 2009, No. 20, pp 3352–3354
x
x
.x
x
.2
0
0
9
Advanced online publication: 18.11.2009
DOI: 10.1055/s-0029-1218383; Art ID: U09409ST
© Georg Thieme Verlag Stuttgart · New York
e A complex mixture was obtained.

LETTER
Conversion of CF3-Containing Propargylic Alcohols into Bromoallenes
3353
PPh3
Br
Br
Br
Br
Ph3P CBr2
Br
Ph3P
Br CBr3
Ph3P Br
CX3
CX3
CX3
CBr3
Br
LUMO
LUMO+1
LUMO+2
Ph3P CBr2
Ph3P CBr2
Energy level (eV)
LUMO+1
Ph3P Br
LUMO+2
X
Compound
LUMO
–0.356
–0.869
–0.040
–0.367
H
F
5
6
–0.617
–2.021
OH
Br
Ph3P, CBr4
Br
R
R
R
Figure 1 Computation of 5 and 6 by Gaussian 03W using the
B3LYP/6-311++G** level of theory
– PPh3=O, – CHBr3
CF3
CF3
1
2
CF3
Br
In order to examine the synthetic utility of 3 thus obtained,
we further attempted the reaction with isobutyraldehyde
after conversion into the corresponding allenyllithium,
generated in situ by lithium–bromine exchange using bu-
tyllithium and the bromoallene 3a. The desired allenyl-
carbinols 7a and 7b,9 were readily obtained as a separable
diastereomer mixture and isolated in 34% and 55% yields,
respectively, after separation by silica gel column chro-
matography (Scheme 2).
Br
•
Br
CF3
Br
Br CBr3
CF3
R
•
3
H
R
4
2
CBr3
Scheme 1 Proposed mechanism for the conversion of 1 into bromo-
allenes 3 and 4
1i,j afforded the corresponding products only in low
yields probably because of their increased steric hin-
drance around the site where the first SN2-type attack was
occurred (entries 9 and 10). Among nonfluorinated alco-
hols used, only 1k recorded successful conversion into 3k
in an excellent yield which clearly demonstrated require-
ment of appropriate activation of substrates for this reac-
tion.
BuLi
(1.3 equiv)
CF3
H
•
+
i-PrCHO
Ph
Et2O, –105 °C, 2 h
Br
(1.3 equiv)
racemic
3a
AgNO3
(20 mol%)
CF3
CF3
H
•
acetone, r.t., 4 d
Ph
i-Pr
i-Pr
i-Pr
Ph
Ph
O
75%
Ha
Hb
The reaction mechanism is proposed as illustrated in
Scheme 1. At first, usual CBr4–Ph3P-promoted halogena-
tion of alcohols 1 would proceed to form propargylic bro-
mides 2 whose further bromination in an SN2¢ fashion led
to ready formation of bromoallenes 3 (Scheme 1). Excel-
lent conversion of the independently prepared propargylic
bromide 2g into the corresponding allene 3g with a cata-
lytic amount of the bromide source clearly supported this
mechanism (Equation 1).
HO
34%
7a
8a
+
CF3
AgNO3
(20 mol%)
CF3
H
•
acetone, r.t., 5 d
52%
Ph
i-Pr
O
Ha
Hb
HO
7b 55%
8b
Scheme 2 Preparation of dihydrofurans 8a and 8b
Br
Ph3P (0.2 equiv)
Relative stereochemistry of the minor adduct 7a was de-
termined by 1H NMR analysis after stereospecific conver-
sion into the corresponding diastereomerically pure 2,5-
dihydrofuran 8a10 by treatment with 20 mol% AgNO3 at
room temperature for 4 days (Scheme 2).7 The clear cor-
relation between Ha and Hb was observed only in the
NOESY spectrum of 8a, not in the one of 8b, which un-
ambiguously proved the 2,5-cis stereochemical relation-
ship of the former compound. Considering the Lewis
acidic role of AgNO3, this information also led to strong
anticipation of the three dimensional structure of 7a and
7b as shown in Scheme 2.
Br
CBr4 (0.2 equiv)
•
Ph(H2C)2
DMF, r.t., 16 h
83%
Ph(H2C)2
CF3
CF3
2g
3g
Equation 1 Isomerization of propargylic bromide 2g to the corre-
sponding allene 3g
We performed DFT calculation of the model compound 6
for obtaining MO information along with its nonfluorinat-
ed prototype 5. According to the result, compound 6 re-
vealed the significantly lower energy levels of LUMO
than 5, and the similar tendency was also noticed for
LUMO+1 and LUMO+2 (the depicted lobes are almost
perpendicular and parallel to the C–Br bond, respectively)
while the gap became smaller. These discrepancies would
clearly demonstrated higher electrophilicity of 6 relative
to 5 (Figure 1) and would be the primary reason why the
second attack of bromide ion was occurred smoothly only
in the case of trifluorinated substrates.
In conclusion, we have demonstrated that CF3-containing
bromoallenes 3 were produced in high yields directly
from alcohols 1 by way of the CBr4–Ph3P-mediated se-
quential bromination reactions. It was also appeared that
this method was applicable to the nonfluorinated propar-
gylic alcohol 1k with adequate activating substituents. Al-
lenyllithium derived from the bromoallene 3a as the
Synlett 2009, No. 20, 3352–3354 © Thieme Stuttgart · New York

3354
Y. Watanabe, T. Yamazaki
LETTER
chromatography (hexane–EtOAc, 20:1) to afford 3a (0.14 g,
0.51 mmol, 85%) as a pale yellow oil. Rf = 0.79 (CH2Cl2–
EtOAc, 1:1). 1H NMR (300 MHz, CDCl3): d = 6.71 (q,
J = 2.7 Hz, 1 H), 7.34–7.44 (m, 5 H). 13C NMR (75.5 MHz,
CDCl3): d = 82.5 (q, J = 45.3 Hz), 106.8, 119.8 (q, J = 271.7
representative example was conveniently transformed
into the carbonyl adducts 7a and 7b in excellent yield.
Further studies on expanding the scope of the substrates
are in progress.
Hz), 128.5, 129.2, 129.4, 129.9, 202.6 (q, J = 3.1 Hz). 19
F
NMR (283 MHz, CDCl3): d = –65.66 (s). IR (neat): 613, 653,
690, 720, 749, 819, 847, 897, 918, 951, 1003, 1029, 1045,
1075, 1119, 1267, 1293, 1313, 1397, 1459, 1496, 1597,
1736, 3034, 3066 cm–1. HRMS–FAB: m/z calcd for
C10H7F3Br [M + H]+: 262.9683; found: 262.9668.
(9) Procedure for the Preparation of the Allenylcarbinols 7a
and 7b
Acknowledgment
The authors are grateful to Tosoh F–Tech, Inc. for the generous gift
of 2-bromo-3,3,3-trifluoropropene.
References and Notes
To a solution of 3a (0.32 g, 1.20 mmol) and isobutyr-
aldehyde (142 mL, 1.6 mmol) in Et2O (5 mL) was added
BuLi (0.98 mL, 1.6 mmol, 1.6 M in hexane) at –105 °C. The
solution was stirred at that temperature for 2 h. The reaction
mixture was quenched with 1 M aq HCl solution (3 mL) and
extracted with EtOAc (3 × 20 mL). Usual workup and
purification by silica gel chromatography (hexane–EtOAc,
12:1) afforded 7a (0.087 g, 0.41 mol 34%) and 7b (0.14 g,
0.66 mmol 55%).
Compound 7a: colorless oil. Rf = 0.56 (hexane–EtOAc, 4:1).
1H NMR (300 MHz, CDCl3): d = 1.01 (d, J = 6.9 Hz, 6 H),
1.80 (br s, 1 H), 1.96 (oct, J = 6.6 Hz, 1 H), 4.12 (dd, J = 6.6,
1.5 Hz, 1 H), 6.73 (qd, J = 3.3, 1.5 Hz, 1 H), 7.26–7.38 (m,
5 H). 13C NMR (75.5 MHz, CDCl3): d = 17.0, 19.5, 32.7,
73.8, 103.0, 106.0 (q, J = 32.3 Hz), 123.1 (q, J = 274.1 Hz),
127.4, 128.6, 129.0, 131.1, 204.4 (q, J = 4.4 Hz). 19F NMR
(283 MHz, CDCl3): d = –62.44 (s). IR (neat): 692, 721, 747,
828, 920, 1001, 1029, 1074, 1127, 1210, 1273, 1369, 1387,
1411, 1462, 2874, 2934, 2963, 3429 cm–1. HRMS–FAB:
m/z calcd for C14H16OF3 [M + H]+: 257.1153; found:
257.1176.
Compound 7b: colorless oil. Rf = 0.47 (hexane–EtOAc,
4:1). 1H NMR (300 MHz, CDCl3): d = 1.00 (d, J = 6.6 Hz,
3 H), 1.01 (d, J = 6.6 Hz, 3 H), 1.88 (br s, 1 H), 1.96 (oct,
J = 6.6 Hz, 1 H), 4.12 (dd, J = 6.6, 1.2 Hz, 1 H), 6.78 (qd,
J = 3.3, 1.5 Hz, 1 H), 7.27–7.39 (m, 5 H). 13C NMR (75.5
MHz, CDCl3): d = 17.1, 19.6, 32.8, 73.6, 103.2, 106.1 (q,
J = 32.2 Hz), 123.2 (q, J = 272.9 Hz), 127.6, 128.6, 129.0,
131.1, 204.1 (q, J = 4.3 Hz). 19F NMR (283 MHz, CDCl3):
d = –62.52 (s). IR (neat): 692, 719, 747, 829, 920, 1000,
1029, 1074, 1123, 1210, 1274, 1369, 1388, 1411, 1462,
1715, 1961, 2876, 2933, 2967, 3036, 3410 cm–1. HRMS–
FAB: m/z calcd for C14H16OF3 [M + H]+: 257.1153; found:
257.1187.
(1) (a) Kitazume, T.; Yamazaki, T. Experimental Methods in
Organic Fluorine Chemistry; Kodansha Scientific: Tokyo,
1998. (b) Hiyama, T. Organofluorine Compounds:
Chemistry and Applications; Springer: Berlin, 2000.
(c) Shimizu, M.; Hiyama, T. Angew. Chem. Int. Ed. 2005,
44, 214. (d) Uneyama, K. Organofluorine Chemistry;
Blackwell: Oxford, 2006.
(2) (a) Yamazaki, T.; Yamamoto, T.; Ichihara, R. J. Org. Chem.
2006, 71, 6251. Other examples of trifluoromethyl-
substituted allenes: (b) Shimizu, M.; Higashi, M.; Takeda,
Y.; Jiang, G.; Murai, M.; Hiyama, T. Synlett 2007, 1163.
(c) Bosbury, P. W. L.; Fields, R.; Haszeldine, R. N.; Moran,
D. J. Chem. Soc., Perkin Trans. 1 1976, 1173. (d) Bosbury,
P. W. L.; Fields, R.; Haszeldine, R. N. J. Chem. Soc., Perkin
Trans. 1 1978, 422. (e) Hanzawa, Y.; Kawagoe, K.-i.;
Yamada, A.; Kobayashi, Y. Tetrahedron Lett. 1985, 26,
219. (f) Burton, D. J.; Hartgraves, G. A.; Hsu, J. Tetrahedron
Lett. 1990, 31, 3699. (g) Konno, T.; Tanikawa, M.; Ishihara,
T.; Yamanaka, H. Chem. Lett. 2000, 1360. (h) Han, H. Y.;
Kim, M. S.; Son, J. B.; Jeong, I. H. Tetrahedron Lett. 2006,
47, 209. Examples of fluorine-substituted allenes:
(i) Dolbier, W. R. Jr.; Burkholder, C. R.; Piedrahita, C. A.
J. Fluorine Chem. 1982, 20, 637. (j) Mae, M.; Hong, J. A.;
Xu, B.; Hammond, G. B. Org. Lett. 2006, 8, 479.
(k) Yokota, M.; Fuchibe, K.; Ueda, M.; Mayumi, Y.;
Ichikawa, J. Org. Lett. 2009, 11, 3994.
(3) For recent reviews, see: (a) Brummond, K. M.; DeForrest,
J. E. Synthesis 2007, 795. (b) Ma, S. Aldrichimica Acta
2007, 40, 91. (c) Modern Allene Chemistry, Vol. 1 and 2;
Krause, N.; Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim,
2004. (d) Hoffmann-Röder, A.; Krause, N. Angew. Chem.
Int. Ed. 2004, 43, 1196.
(4) (a) Kinnel, R.; Duggan, A. J.; Eisner, T.; Meinwald, J.
Tetrahedron Lett. 1977, 3913. Recent studies on
bromoallenes: (b) Tang, Y.; Shen, L.; Dellaria, B. J.; Hsung,
R. P. Tetrahedron Lett. 2008, 49, 6404. (c) Braddock, D.
C.; Bhuva, R.; Pérez-Fuertes, Y.; Pouwer, R.; Robers, C. A.;
Ruggiero, A.; Stokes, E. S. E.; White, A. J. P. Chem.
Commun. 2008, 1419.
(10) Procedure for the Preparation of the 2,5-Dihydrofuran
8a
To a solution of 7a (0.087 g, 0.41 mmol) in acetone (3 mL)
was added AgNO3 (12 mg, 0.082 mmol) at r.t. The solution
was protected from light and stirred at that temperature for 4
d. Concentration by rotary evaporator furnished a crude
mixture that was purified by silica gel chromatography
(hexane–EtOAc, 20:1) to afford 8a (0.066 g, 75%) as a pale
yellow oil; Rf = 0.77 (hexane–EtOAc, 4:1). 1H NMR (300
MHz, CDCl3): d = 0.94 (d, J = 6.9 Hz, 3 H), 1.13 (d, J = 6.9
Hz, 3 H), 2.03 (septd, J = 6.6, 1.2 Hz, 1 H), 5.18 (dq, J = 6.6,
0.9 Hz, 1 H), 5.83–5.88 (m, 1 H), 6.45 (sext, J = 1.8 Hz, 1
H), 7.26–7.44 (m, 5 H). 13C NMR (75.5 MHz, CDCl3): d =
14.5, 19.9, 32.0, 87.7 (q, J = 0.6 Hz), 89.3 (q, J = 0.6 Hz),
121.7 (q, J = 269.2 Hz), 126.4, 128.4, 128.7, 131.9 (q,
J = 33.5 Hz), 135.8 (q, J = 4.4 Hz), 140.0. 19F NMR (283
MHz, CDCl3): d = –64.13 (s). IR (neat): 698, 726, 760, 879,
917, 1009, 1051, 1068, 1126, 1158, 1242, 1265, 1281, 1334,
1360, 2876, 2935, 2970 cm–1. HRMS–FAB: m/z calcd for
C14H16OF3 [M]+: 256.1075; found: 256.1046.
(5) Transformation of a-arylpropargylic alcohols into
bromoallenes by treatment with CBr4 and Ph3P has recently
been reported, see: Sakai, N.; Maruyama, T.; Konakahara, T.
Synlett 2009, 2105.
(6) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801.
(7) Marshall, J. A.; Yu, R. H.; Perkins, J. F. J. Org. Chem. 1995,
60, 5550.
(8) Typical Procedure for the Preparation of the
Bromoallene 3a
To a solution of 1a (0.12 g, 0.60 mmol) and Ph3P (0.38 g, 1.4
mmol) in DMF (2.0 mL) was added CBr4 (0.24 g, 0.72
mmol) at r.t. The solution was stirred at that temperature for
2 h. The reaction mixture was quenched with H2O (20 mL)
and extracted with hexane–EtOAc (1:1, 3 × 15 mL).
Concentration by rotary evaporator after dried over Na2SO4
furnished a crude mixture that was purified by silica gel
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