Chemoselective isomerization of secondary-type propargylic alcohols to propargylic/allenic bromides, and brominated dienes with Appel-type reaction conditions

Article abstract of DOI:10.1055/s-0029-1217701

Herein is described the chemoselective isomerization of secondary-type propargylic alcohols to allenic bromides, propargylic bromides and brominated dienes under Appel-type reaction conditions containing Ph₃P, CBr ₄ and additives. Ge

Full text of DOI:10.1055/s-0029-1217701

LETTER
2105
Chemoselective Isomerization of Secondary-Type Propargylic Alcohols to
Propargylic/Allenic Bromides, and Brominated Dienes with Appel-Type
Reaction Conditions
Chemoselective
Is
o
omerization
r
S
econ
i
dary-T
o
A
lcohols toBr
S
omide
s
akai,* Tsukasa Maruyama, Takeo Konakahara
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI),
Noda, Chiba 278-8510, Japan
Fax +81(4)71239890; E-mail: sakachem@rs.noda.tus.ac.jp
Received 7 May 2009
we report that a somewhat of a substituted group on a pro-
pargylic alcohol effectively and selectively controls sev-
eral reaction paths, giving three different products; allenic
bromides, propargylic bromides, and brominated dienes.
Abstract: Herein is described the chemoselective isomerization of
secondary-type propargylic alcohols to allenic bromides, propar-
gylic bromides and brominated dienes under Appel-type reaction
conditions containing Ph3P, CBr4 and additives.
Key words: Appel reaction, propargylic alcohol, allene, diene, First, we attempted to improve the yield of allene deriva-
tive 2a, and the results are shown in Table 1.13 Addition of
isomerization
Et3N as a base was ineffective for this reaction at room
temperature, but increasing the reaction temperature to 50
°C increased the yield of allenic bromide 2a to 48% (en-
tries 2 and 3). In addition, use of more bulky tertiary
amine, i-Pr2NEt, gave the product in 68% yield (entry 4).
Moreover, when 10 mol% of (n-Bu)3P was added to the
reaction mixture, the reaction time was drastically re-
duced to less than two hours (entries 5 and 6).14 Finally, it
was found that refluxing in a toluene solution containing
i-Pr2NEt and (n-Bu)3P gave the best result (entry 7).15
Since allenes work as a basic building block to construct
naturally occurring products and biologically active sub-
stances,1 and are used as a key substrate in common
organic syntheses involving cyclizations, additions, cy-
cloadditions, and metal-catalyzed cross-couplings, the de-
velopment of a facile and practical preparation for their
skeletons is in high demand.2 On the other hand, we have
already reported on a highly effective method for the
deacetoxylation of secondary propargylic acetates by
Et3SiH in the presence of InBr3.3 During our ongoing in-
vestigations for functional inversion of propargylic deriv-
atives, we attempted the preparation of a propargylic
bromide from a propargylic alcohol with Appel reaction
conditions using CBr4 and PPh3.4,5 Against our expecta-
tions, we found that the selective formation of the allenic
bromide derivative could be obtained through an SN2¢
substitution path. In general, the conventional SN2¢ prepa-
rations from a propargylic compound of an allene deriva-
tive are integrated into the following methods: i)
substitution of propargylic derivatives with cuprate
reagents6 and with some organometallic compounds, such
as Grignard reagents, alkyl lithium reagents, and orga-
nozinc compounds in the presence of palladium,7 copper,8
nickel,9 and other metals;10 ii) intermolecular substitution
of some carbon nucleophiles with a synthetic gadget, a
tertiary alcohol-type propargylic derivative, in which an
SN2 substitution, back-side attack is entirely retarded due
to steric hindrance on the tertiary carbon;11 and, iii) in-
tramolecular displacement of propargylic derivatives con-
necting with a nucleophilic moiety.12 Those previous
results encouraged us to develop a facile preparation of an
allene derivative from a secondary alcohol-type propar-
gylic derivative under metal-free conditions. In this letter,
Table 1 Examination of the Preparation of Allene 2a
CBr4 (2 equiv)
OH
Ph3P (2 equiv)
base, additive
C6H13
Ph
Ph
PhH or PhMe
C6H13
Br
1a
2a
Entry Base
(equiv)
Additive
(equiv)
Temp Time Yield
(°C)
(h)
24
24
24
24
2
(%)a
1
2
3
4
5
6
7b
–
–
–
–
–
0
21
Et3N (1)
r.t.
50
14
Et3N (1)
48
i-Pr2NEt (2)
i-Pr2NEt (2)
i-Pr2NEt (2)
i-Pr2NEt (2)
50
68
(n-Bu)3P (0.1)
50
69
(n-Bu)3P (0.1)
(n-Bu)3P (0.1)
80
2
71
110
1
76
a NMR yield.
b Toluene was used as a solvent.
To extend the generality of this reaction, a substitution
with propargylic alcohols 1 (R = n-Hex and n-Bu, Ar =
Ph, 2-Naph and 3-Py) through an SN2¢-type reaction, was
then performed under the optimal conditions. The results
are summarized in Table 2. Most of the reaction with a
substrate having a benzene ring on the Ar group was com-
SYNLETT 2009, No. 13, pp 2105–2108
x
x
.x
x
.2
0
0
9
Advanced online publication: 16.07.2009
DOI: 10.1055/s-0029-1217701; Art ID: U04709ST
© Georg Thieme Verlag Stuttgart · New York

2106
N. Sakai et al.
LETTER
pleted within one hour to give the desired allene deriva- CH=CH2) produced enyne product 2j via an SN2¢ reaction
tives 2a–e in good yields. In addition, when the reaction in the vinyl moiety rather than the corresponding propar-
of a compound containing a naphthyl and pyridine ring gylic bromide.
was carried out, the yield of the corresponding allenes 2f
and 2g were reduced to 48% and 31% yields, respectively.
On the other hand, when a propargylic alcohol had an aryl
group (R = Ph) or no substituent group (R = H), next to the
triple bond, the desired substitution did not proceed; in-
stead, complex products were obtained. At the present
time, there is no clear explanation for this result.
Br
CBr4 (2 equiv)
Ph3P (2 equiv)
i-Pr2NEt (2 equiv)
(n-Bu)3P (0.1 equiv)
R
OH
C6H13
R
2h (R = n-Pr): 85%
2i (R = t-Bu): 75%
C6H13
1h (R = n-Pr)
1i (R = t-Bu)
1j (R = vinyl)
PhMe, reflux, 0.5 h
Table 2 Synthesis of Allene Derivatives 2a
Br
C6H13
CBr4 (2 equiv), Ph3P (2 equiv)
2j: 62%
OH
i-Pr2NEt (2 equiv)
(n-Bu)3P (0.1 equiv)
R
Ar
Scheme 1 Bromination of propargylic derivatives 1h–j
Ar
PhMe, reflux
R
Br
1a–g
2a–g
We performed several trials to improve the chemical yield
of allene derivative 2a, and found interesting results.
When a similar reaction using several propargylic alco-
hols (R = C6H13, Ar = Ph and Naph) was carried out under
the reaction conditions without i-Pr2NEt, diene derivative
3, rather than allene derivative 2, was stereoselectively
obtained as the main product.16,17 The stereochemistry
was found to be 1E,3E by an NMR measurement. Table 3
summarizes the dienes obtained via a skeletal isomeriza-
tion of propargylic alcohols. With no relationship to any
type of substituent group on the aromatic ring (Ar), this
type of conversion occurs cleanly to produce the corre-
sponding diene derivatives 3a–g.
Entry Product
Time (h)
1
Yield (%)
72
C6H13
Ph
Ph
1
Br
2a
C4H9
2
3
4
5
6
7
0.5
0.2
0.2
0.2
1
79
76
77
82
48
31
Br
2b
C6H13
Br
F
Br
I
2c
Isomerization from a propargylic alcohol to an allenic
bromide follows a typical Appel reaction mechanism, as
shown in Scheme 2.5,18 When a propargylic alcohol has an
alkyl group (path a), an SN2 process proceeds to give the
corresponding propargylic bromide. In contrast, with an
aryl group (path b) an SN2¢ process selectively occurs to
produce the corresponding allenic bromide derivative. Al-
though there currently is no clear explanation for the role
of the two additives, i-Pr2NEt and (n-Bu)3P, these re-
agents appear to promote improved reactivity of the bro-
mide anion in the final substitution step.
C6H13
Br
Br
2d
C6H13
2e
C6H13
Br
Br
2f
H
O
C6H13
0.5
+
CBr3
Br CBr3
Ph3P
Ph3PBr
– CHBr3
X
N
R
2g
a Isolated yield.
PPh3
X
path b
(X = aryl)
Ph3P Br
O
O
X
In contrast, when substrates 1h and 1i having an aliphatic
group (R = n-Pr and t-Bu) next to the hydroxy group were
used, the common SN2 reaction proceeded cleanly to pro-
duce propargylic bromides 2h and 2i in 85% and 75%
yields, respectively (Scheme 1), which were our original
products. At first, with propargylic alcohol 1i having a
more hindered t-Bu group, formation of an allenic bro-
mide through an SN2¢ path was expected, but propargylic
bromide 2i was produced instead. In addition, due to the
extension of a conjugated system, the reaction with prop-
argylic alcohol 1j having a terminal vinyl group (R =
R
R
– Ph3P=O
X
path a
Br
path b
(X = alkyl)
R
path a
– Ph3P=O
Br
Br
X
R
Scheme 2
Synlett 2009, No. 13, 2105–2108 © Thieme Stuttgart · New York

LETTER
Chemoselective Isomerization of Secondary-Type Alcohols to Bromides
2107
Table 3 Synthesis of Diene Derivatives 3a
Thus far, we have demonstrated that treatment of a sec-
ondary-type propargylic alcohol having an alkyl group
next to a hydroxy group with Appel-type reaction condi-
tions containing Ph3P, CBr4, (n-Bu)3P, and i-Pr2NEt, pro-
duces a propargylic bromide through an SN2 process. We
also found that employment of a similar propargylic alco-
hol with an aryl group selectively produces the corre-
sponding allenic bromide through an SN2¢ process.
Moreover, we found that under Appel-type reaction con-
ditions without a base, stereoselective formation of a
1E,3E-brominated diene preferentially occurs through an
allenic intermediate.
OH
CBr4 (2 equiv), Ph3P (2 equiv)
Br
(n-Bu)3P (0.1 equiv)
Ar
C5H11
PhMe, reflux
Ar
C5H11
1
3a–g
Entry Product
Compound
Time (h) Yield (%)
Br
Br
1
3a
1
72
C5H11
Ph
2
3
4
5
3b (X = F)
3c (X = Cl)
3d (X = Me) 0.5
1
1
51
43
39
52
Acknowledgment
C5H11
This work was partially supported by a fund for the ‘High-Tech Re-
search Center’ Project for Private Universities, a matching fund
subsidy from MEXT, 2000-2004, and 2005-2007, and by a grant
from the Japan Private School Promotion Foundation, 2008.
3e (X = OMe) 2
X
Br
References and Notes
C5H11
6
3f
1
35
37
(1) Hoffmann-Röder, A.; Krause, N. Angew. Chem. Int. Ed.
2004, 43, 1196.
(2) For selected recent books and reviews for allene chemistry,
see: (a) Krause, N.; Hashmi, A. S. K. In Modern Allene
Chemistry, Vol. 1; Wiley-VCH: Weinheim, 2004.
(b) Krause, N.; Hashmi, A. S. K. In Modern Allene
Chemistry, Vol. 2; Wiley-VCH: Weinheim, 2004.
(c) Kwong, C. K.-W.; Fu, M. Y.; Lam, C. S.-L.; Toy, P. H.
Synthesis 2008, 2307. (d) Ma, S. Chem. Rev. 2005, 105,
2829. (e) Miesch, M. Synthesis 2004, 746. (f) Krause, N.;
Hoffmann-Röder, A. Tetrahedron 2004, 60, 11671. (g) Lu,
X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535.
(3) Sakai, N.; Hirasawa, M.; Konakahara, T. Tetrahedron Lett.
2005, 46, 6407.
(4) (a) Das, B.; Damodar, K.; Bhunia, N.; Shashikanth, B.
Tetrahedron Lett. 2009, 50, 2072. (b) Das, B.; Kanth, B. S.;
Reddy, K. R.; Satyalakshmi, G.; Kumar, R. A. Chem. Lett.
2008, 37, 512.
(5) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801.
(6) (a) Alexakis, A.; Marek, I.; Mangeney, P.; Normant, J. F.
J. Am. Chem. Soc. 1990, 112, 8042. (b) Marek, I.;
Mangeney, P.; Alexakis, A.; Normant, J. F. Tetrahedron
Lett. 1986, 27, 5499. (c) Rona, P.; Crabbe, P. J. Am. Chem.
Soc. 1969, 91, 3289. (d) Rona, P.; Crabbe, P. J. Am. Chem.
Soc. 1968, 90, 4733.
Br
C5H11
O
7
3g
0.5
a Isolated yield
On the other hand, as shown in Scheme 3, a diene deriva-
tive is formed via the skeletal isomerization of an allene
derivative. Several groups have reported that a phosphine-
catalyzed isomerization from an alkyne derivative to a di-
ene skeleton proceeds through a proton shift via an allenic
intermediate.14 Under the conditions shown in Table 3, we
confirmed the isomerization of an isolated allene 2a to a
diene 3a (48% NMR yield) after refluxing in toluene for
24 hours. Steric repulsion between the aryl group and the
vinyl group preferentially formed the final E,E-structure.
(7) (a) Keinan, E.; Bosch, E. J. Org. Chem. 1986, 51, 4006.
(b) Elsevier, C. J.; Stehouwer, P. M.; Westmijze, H.;
Vermeer, P. J. Org. Chem. 1983, 48, 1103.
(8) (a) Moreau, J.-L.; Gaudemar, M. J. Organomet. Chem. 1976,
108, 159. (b) Alexakis, A.; Commercon, A.; Villiéras, J.;
Normant, J. F. Tetrahedron Lett. 1976, 2313.
R
R
PR3
H
Ar
– PR3
H
R
H
Br
Ar
Br
Br
Ar
(1Z,3E)
PR3
(9) Wenkert, E.; Leftin, M. H.; Michelotti, E. L. J. Org. Chem.
minor product
1985, 50, 1122.
(10) (a) Riveiros, R.; Rodriguez, D.; Perez Sestelo, J.;
Sarandeses, L. A. Org. Lett. 2006, 8, 1403. (b) Yoshida,
M.; Gotou, T.; Ihara, M. Tetrahedron Lett. 2004, 45, 5573.
(c) Lee, K.; Seomoon, D.; Lee, P. H. Angew. Chem. Int. Ed.
2002, 41, 3901. (d) Pasto, D. J.; Chou, S.-K.; Waterhouse,
A.; Shults, R. H.; Hennion, G. F. J. Org. Chem. 1978, 43,
1385.
R
R
PR3
H
PR3
H
H
Ar
– PR3
Ar
Ar
H
R
Br
(1E,3E)
major product
Br
H
Br
H
(11) (a) Sanz, R.; Miguel, D.; Martinez, A.; Alvarez-Gutierrez,
J. M.; Rodriguez, F. Org. Lett. 2007, 9, 727. (b) Huang, W.;
Scheme 3
Synlett 2009, No. 13, 2105–2108 © Thieme Stuttgart · New York

2108
N. Sakai et al.
LETTER
Wang, J.; Shen, Q.; Zhou, X. Tetrahedron 2007, 63, 11636.
(c) Ishikawa, T.; Aikawa, T.; Mori, Y.; Saito, S. Org. Lett.
2003, 5, 51. (d) Ishikawa, T.; Okano, M.; Aikawa, T.; Saito,
S. J. Org. Chem. 2001, 66, 4635.
1992, 114, 7933. (c) Trost, B. M.; Schmidt, T. J. Am. Chem.
Soc. 1988, 110, 2301. (d) Lu, X.; Ma, D. Pure Appl. Chem.
1990, 62, 723.
(15) When the same reaction was conducted with CCl4 instead of
CBr4, the corresponding chlorinated allene derivative was
obtained in 40% yield. For a selected paper on the SN2-type
chlorination of a primary alcohol using CCl4 and PPh3, see:
Lee, J. B.; Downie, I. M. Tetrahedron 1967, 23, 359.
(16) General Procedure for the Synthesis of Diene Derivatives
3: The same procedure as above without i-Pr2NEt gave the
diene derivative 3. However, formation of a quite small
amount of the (1Z,3E)-diene along with the (1E,3E)-diene
separable by column chromatography was observed by
NMR. Spectral data for selected compound: [(1E,3E)-3-
Bromo-1,3-nonadien-1-yl]benzene (3a): pale brown oil. 1H
NMR (300 MHz, CDCl3): d = 0.88 (t, 3 H, J = 7.2 Hz), 1.27
(m, 3 H), 1.35 (m, 1 H), 1.47 (m, 2 H), 2.35 (q, 2 H, J = 7.2
Hz), 6.08 (t, 1 H, J = 7.2 Hz), 6.73 (d, 1 H, J = 15.0 Hz), 6.89
(d, 1 H, J = 15.0 Hz), 7.23 (m, 1 H), 7.30 (m, 2 H), 7.42 (m,
2 H). 13C NMR (75 MHz, CDCl3): d = 13.9, 22.4, 28.1, 31.4,
31.7, 126.7, 126.9, 127.7, 127.9, 128.6, 128.7, 132.1, 135.3.
MS (EI): m/z = 279 [M+]. HRMS (FAB): m/z calcd for
C15H20Br: 279.0748; found: 279.0728. Stereochemistry
(1E,3E) of the isolated compound was determined by
the chemical shift and coupling constant of the related
compound. Specific peaks derived from (1Z,3E)-diene 3a
were observed by 1H NMR. 1H NMR: d = 5.87 (t, 1 H, J =
7.2 Hz), 6.76 (d, 2 H, J = 15.0 Hz), 6.94 (d, 1 H, J = 15.0 Hz).
Other peaks overlapped with those of the (1E,3E)-diene.
(17) We have no clear cause for the low yield of diene derivative
3; however, formation of several complex products, which
were probably derived from the starting propargylic alcohol,
was observed by an NMR measurement.
(12) (a) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118,
4492. (b) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984,
25, 3055. (c) Parker, K. A.; Petraitis, J. J. Tetrahedron Lett.
1977, 4561.
(13) General Procedure for the Synthesis of Allene
Derivatives 2: CBr4 (331 mg, 1.0 mmol), Ph3P (262 mg, 1.0
mmol), propargylic alcohol 1 (0.50 mmol), i-Pr2NEt (129
mg, 1.0 mmol), P(n-Bu)3 (10 mg, 0.05 mmol), and a freshly
distilled toluene (1 mL) were successively added into a
screw-capped vial, and the vial was sealed with a cap
containing a PTFE septum. The reaction mixture was stirred
at 100 °C, and monitored by TLC until the propargylic
alcohol 1 was consumed. To quench the reaction, H2O (2
mL) was added to the mixture. The mixture was extracted
with CH2Cl2 (3 ×), and the combined organic extracts were
dried over Na2SO4, filtered, and then evaporated under
reduced pressure. The crude product was purified by silica
gel chromatography(hexane) to produce the allene
derivative 2, and if necessary, was further purified by a
recycling preparative HPLC equipped with a GPC column
(chloroform as an eluent). Spectral data for selected
compound: 1-(3-Bromo-1,2-nonadien-1-yl)benzene (2a):
pale yellow oil. 1H NMR (300 MHz, CDCl3): d = 0.86 (t, 3
H, J = 7.2 Hz), 1.24–1.38 (m, 6 H), 1.50 (quint, 2 H, J = 7.2
Hz), 2.52 (td, 2 H, J = 7.2, 3.0 Hz), 6.19 (t, 1 H, J = 3.0 Hz),
7.23–7.27 (m, 1 H), 7.32–7.33 (m, 4 H). 13C NMR (75 MHz,
CDCl3): d = 13.9, 22.5, 27.9, 28.2, 31.4, 38.0, 96.1, 100.3,
127.7, 128.1, 128.7, 133.0, 199.8. MS (FAB): m/z (%) = 281
(100) [M+], 279 (40) [M+]. HRMS (FAB): m/z calcd for
C15H20Br: 279.0748; found: 279.0726.
(18) (a) Slagle, J. D.; Huang, T. T. S.; Franzus, B. J. Org. Chem.
1981, 46, 3526. (b) Jones, L. A.; Sumner, C. E.; Franzus, B.;
Huang, T. T. S.; Snyder, E. I. J. Org. Chem. 1978, 43, 2821.
(14) (a) Guo, C.; Lu, X. J. Chem. Soc., Perkin Trans. 1 1993,
1921. (b) Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc.
Synlett 2009, No. 13, 2105–2108 © Thieme Stuttgart · New York

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