Cyclic vinylogous triflate hemiacetals as new surrogates for alkynyl aldehydes

Article abstract of DOI:10.1016/j.tetlet.2006.06.040

Cyclic vinylogous triflate hemiacetals can serve as 'synthetic equivalents' for alkynyl aldehydes: treatment of a vinylogous triflate hemiacetal with excess amounts of Grignard reagents produces acyclic alkynyl alcohols in good to high yields. This transf

Full text of DOI:10.1016/j.tetlet.2006.06.040

Tetrahedron Letters 47 (2006) 5629–5632
Cyclic vinylogous triflate hemiacetals as new surrogates
for alkynyl aldehydes
Shin Kamijo and Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA
Received 22 April 2006; revised 31 May 2006; accepted 6 June 2006
Available online 27 June 2006
Abstract—Cyclic vinylogous triflate hemiacetals can serve as ‘synthetic equivalents’ for alkynyl aldehydes: treatment of a vinylogous
triflate hemiacetal with excess amounts of Grignard reagents produces acyclic alkynyl alcohols in good to high yields. This trans-
formation likely involves the Grob-type C–C bond cleaving fragmentation to form the alkynyl aldehyde in situ. Subsequent nucleo-
philic attack of the Grignard reagent furnishes secondary alkynols. Vinylogous triflate hemiacetals are easily prepared by DIBALH
reduction of vinylogous acyl triflates, which are derived from cyclic 1,3-diketones.
Ó 2006 Elsevier Ltd. All rights reserved.
Carbonyl moieties are ubiquitous components of impor-
tant molecules in a wide range of areas in chemistry.1
The diverse reactivity of carbonyl compounds presents
many options in organic synthesis, but the high reactiv-
ity of those compounds usually needs to be managed
effectively to achieve the desired transformations. Alde-
hydes, being generally more reactive than ketones and
esters, pose particular problems related to the myriad
reaction pathways in which aldehydes participate.
by reduction of lactones) into hydroxy alkenes via
in situ-generated aldehydes.3 Due to the stability of
many cyclic hemiacetals, their emergence as masked
aldehydes was almost inevitable. This convenient
approach obviates the need to prepare and handle the
labile aldehyde prior to the desired reaction.
This letter describes a new class of stable alkynyl alde-
hyde surrogate: cyclic vinylogous triflate hemiacetal 2.
Vinylogous hemiacetals 2 arise from DIBALH reduc-
tion of cyclic vinylogous ester derivatives 1, which in
turn are prepared from the corresponding 1,3-diketone
(Eq. 1).4 Subsequent treatment of 2 with excess amounts
of Grignard reagents directly affords alkynyl alcohols 3,
presumably through in situ generation of alkynyl alde-
hyde intermediate A. In contrast to ordinary cyclic
hemiacetals (lactols), vinylogous triflate hemiacetals 2
are not subject to reversible masking and unmasking
of the reactive aldehyde.
Protecting group strategies are often employed to con-
trol the reactivity of C@O bonds, with acetals of various
types being perhaps the most popular.2 Under a range of
mild hydrolytic conditions, acetals may be reversibly
converted into hemiacetals, which generally collapse to
reveal the underlying carbonyl group. Protecting groups
enable one to shuttle sensitive functionality through
harsh reaction sequences before the deprotection at the
appropriate stage.
Alternatively, masked carbonyls may be employed to
reveal the reactive ketone or aldehyde substrate during
the course of the desired reaction, rather than in a
previously mentioned protecting group manipulation.
For example, olefination conditions have been applied
to convert cyclic hemiacetals (lactols, usually prepared
O
OH
R'
R
R
DIBALH
excess R'MgX
OH
R
OTf
OTf
2
1
3
O
vinylogous triflate hemiacetals 2:
stable surrogate for
H
R
Keywords: Alkynyl aldehyde surrogate; C–C bond cleavage; Grignard
alkynyl aldehydes A
reagent; Vinylogous acyl triflate; Vinylogous triflate hemiacetal.
A
*
Corresponding author. Tel.: +1 850 644 2333; fax: +1 850 644
8281; e-mail: gdudley@chem.fsu.edu
ð1Þ
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.040

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S. Kamijo, G. B. Dudley / Tetrahedron Letters 47 (2006) 5629–5632
The tandem fragmentation/addition process (2 ! 3)
illustrated in Eq. 1 is made possible by the nucleofugacity
of the triflate group, which activates the r-bond frame-
work of 2 for the Grob-type fragmentation. We have
been studying the related tandem addition/fragmenta-
tion process that converts cyclic vinylogous acyl triflates
(1) into acyclic alkynyl ketones, amides, and related com-
pounds using various carbon and nitrogen nucleophiles.5
The synthesis of acyclic alkynyl aldehydes by the reaction
of 1 with an equimolar amount of hydride agent, how-
ever, could not bring about the desired aldehydes in
acceptable yield and purity, despite strong evidence that
they are generated efficiently in the reaction mixture (vide
infra). We concluded that the problem stems from the
high lability of alkynyl aldehydes under the reaction con-
ditions, which prompted the current efforts.
reduction of 1a was conducted with (i-Bu)2AlH (DI-
BALH; 2.2 equiv) as the hydride source in THF between
ꢀ78 and 60 °C within 80 min, vinylogous hemiacetal 2a
was formed selectively in almost quantitative yield (en-
try 3).6 Optimization of these reaction conditions re-
vealed that the excess DIBALH and mild heating were
unnecessary. Thus, vinylogous ester derivative 1a was
treated with an approximately equimolar amount of
DIBALH (1.1 equiv) at ꢀ78 °C to rt (within 50 min),
giving 2a in excellent yield (entry 4).7 Surprisingly, the
treatment of 1a with i-BuMgCl (2.2 equiv) furnished
acyclic secondary alkynol 3a in 59% isolated yield as
the sole product (entry 5). This result implies that half
of the Grignard reagent behaved as a hydride source
and the other half reacted as a carbon nucleophile.8
The DIBALH reduction of triflate 1b (derived from
1,3-cyclohexanedione) provided vinylogous hemiacetal
2b in 95% yield (Eq. 3).
During our research on the direct reductive ring opening
reaction of vinylogous acyl triflate 1a (derived from 2-
methyl-1,3-cyclohexanedione) to form the correspond-
ing acyclic primary alkynol 4a using a variety of reduc-
ing agents,5 we observed the formation of cyclic
vinylogous hemiacetal 2a along with the desired prod-
uct, 4a (Eq. 2, Table 1). The products ratios depended
on the sources of hydride species. Strong reducing
agents, such as LiBHEt3 (super hydride), furnished 4a
as the sole product (entry 1). Reduction using milder
borohydrides (e.g., LiBH4) predominantly afforded 2a
along with small amounts of 4a (entry 2). When the
O
OH
DIBALH (1.1 equiv)
THF
OTf
OTf
ð3Þ
-78 ˚C to rt
1b
2b
95%
Despite considerable efforts, we were unable to obtain
the corresponding alkynyl aldehyde (A, R = Me) in sat-
isfactory yield. We treated vinylogous hemiacetal 2a
with equimolar amounts of bases, such as LiBHEt3,9
n-BuLi,10 PhMgBr, LiHMDS, NaH, and NaOEt; in
most cases, a complex mixture of compounds was
formed, which included a small amount of aldehydes
Table 1. Reduction of vinylogous acyl triflate 1a using various
reducing agentsa,b
O
OH
OH
Me
Me
reducing agent
Me
+
ð2Þ
1
as determined by H NMR analysis of the crude mix-
OTf
OTf
tures. These observations—including the reaction of 1a
with excess amounts of i-BuMgCl to form secondary
alkynol 3a (entry 5 of Table 1)—prompted us to investi-
gate 2a as a novel alkynyl aldehyde surrogate; vinyl-
ogous triflate hemiacetal 2a was isolable (and in nearly
quantitative yield).
1a
2a
4a
Entry
Reducing agent
Yieldc (%)
2a
4a
1
2
3
4
5f
LiBHEt3
LiBH4
(i-Bu)2AlH
(i-Bu)2AlHe
i-BuMgCl
0
62
99d
97d
0
65d
9
0
0
We conducted a series of reactions between vinylogous
triflate hemiacetal 2a and excess amounts of diverse
Grignard reagents (Eq. 4, Table 2). Indeed, the reaction
of 2a with PhMgBr (2.2 equiv) in THF between ꢀ78 and
60 °C within 80 min furnished benzylic alcohol 3b in
84% yield (entry 1).11 The tandem fragmentation/addi-
tion reaction also took place using isopropenylmagne-
sium bromide to afford allylic alcohol 3c in high yield
(entry 2). Alkyl and allyl Grignard reagents gave rise
to the corresponding alcohols (3d and 3e, respectively)
in good yields (entries 3 and 4). Addition of the alkynyl-
magnesium chloride12 to the in situ-generated aldehyde
proceeded smoothly to furnish propargyl alcohol 3f in
high yield (entry 5). The reaction of vinylogous hemi-
acetal 2b with PhMgBr, however, afforded 3g in only
15% yield with a significant amount of recovered starting
material 2b under the same reaction conditions (entry 6).
0
a Standard reaction conditions: vinylogous acyl triflate 1a (0.5 mmol)
was treated with reducing agent (1.1 mmol) in 2 mL of THF at ꢀ78
to 60 °C within 80 min.
b Experiments described in entries 1–3 were originally conducted
enroute to an optimized procedure for the preparation of 4a (see Ref.
5). Aldehyde A (R = Me) was never isolated in acceptable yield or
purity.
c Estimated yield based on 1H NMR otherwise noted.
d Isolated yield.
e Vinylogous acyl triflate 1a (0.5 mmol) was treated with 0.55 mmol of
DIBALH at ꢀ78 °C to rt within 50 min.
f Secondary alkynol 3a was obtained in 59% isolated yield.
OH Me
The mechanistic pathway for the present stepwise ring
opening reaction of vinylogous acyl triflates 1—
3a

S. Kamijo, G. B. Dudley / Tetrahedron Letters 47 (2006) 5629–5632
5631
Table 2. Tandem fragmentation/addition reaction of vinylogous triflate hemiacetals 2 using various Grignard reagentsa
OH
R'
R'MgX (2.2 equiv)
R
OH
R
ð4Þ
THF
-78 to 60 °C
OTf
2
3
Entry
1
R0MgX
2
Product
3
Yieldb (%)
Ph
PhMgBr
2a (R = Me)
2a (R = Me)
2a (R = Me)
3b
84
OH Me
2
3
3c
3d
81
OH Me
OH Me
MgBr
Bu
n-BuMgCl
76c
MgBr
4
2a (R = Me)
3e
79
OH Me
Ph
5
6
Ph–C„C–MgCld
2a (R = Me)
2b (R = H)
3f
90
OH Me
OH
Ph
PhMgBr
3g
15e
a Vinylogous hemiacetal 2 (0.5 mmol) was treated with Grignard reagent (1.1 mmol) in 2 mL of THF at ꢀ78 to 60 °C within 80 min.
b Isolated yield.
c 2a was recovered in 19% yield.
d The alkynyl Grignard reagent was prepared from phenylacetylene (3 equiv) and n-BuMgCl (2.2 equiv) in THF at 60 °C for 30 min.
e 2b was recovered in 81% yield.
O
O
H
OM
DIBALH reduction of 1 and subsequent treatment of
vinylogous triflate hemiacetals 2 with excess amounts
of Grignard reagents—is proposed as shown in Scheme
1. The alkoxyaluminum intermediate (B-Al) is formed
by 1,2-reduction of 1 with (i-Bu)2AlH (DIBALH). This
species is apparently more stable with respect to frag-
mentation than the alkoxyboronate intermediate (B-B)
generated by LiBHEt3 reduction, and vinylogous hemi-
acetals 2 were formed upon aqueous workup. The Grob-
type C–C bond cleaving fragmentation13,14 occurs upon
treatment of 2 with excess Grignard reagents, presum-
ably via the alkoxymagnesium intermediate (B-Mg).15
In situ-generated alkynyl aldehydes A would then react
with the remaining Grignard reagent to furnish inter-
mediate C, and aqueous workup yields secondary alky-
nols 3. This stepwise procedure to reach 3 demonstrates
the utility of isolable vinylogous triflate hemiacetals 2 as
alkynyl aldehyde surrogates.
(i-Bu)2AlH
R
R
H
R
OTf
OTf
MOTf
B
A
1
R'MgX
H3O+
R'MgX
OH
OMgX
R'
R
R
OTf
2
C
H3O+
R'
OH
R
In conclusion, treatment of vinylogous hemiacetal 2a
with excess amounts of Grignard reagents produced
acyclic alkynols 3 in good to high yields. This transfor-
mation likely involves the Grob-type C–C bond cleav-
ing fragmentation to form alkynyl aldehyde A in situ,
and subsequent nucleophilic attack of the Grignard
3
Scheme 1. Proposed mechanistic pathway for the stepwise ring
opening reaction of vinylogous acyl triflates 1 through vinylogous
triflate hemiacetals 2.

5632
S. Kamijo, G. B. Dudley / Tetrahedron Letters 47 (2006) 5629–5632
layer was washed with water, dried (MgSO4), filtered, and
concentrated. The residue was purified by chromatography
on a silica gel column (hexanes/AcOEt = 20/1 to 2/1) to
give 2-methyl-3-(trifluoromethanesulfonyloxy)-2-cyclohexen-
1-ol (2a) in 97% yield (1.26 g). Colorless oil; 1H NMR
(300 MHz, CDCl3) d 1.60 (1H, t, J = 7.5 Hz), 1.71–1.90
(4H, m), 1.88 (3H, t, J = 2.1 Hz), 2.34 (2H, m), 4.22 (1H,
m); 13C NMR (75 MHz, CDCl3) d 13.7, 18.4, 27.7, 30.9,
69.2, 118.2 (1J(C,F) = 317 Hz), 128.0, 146.4; IR (neat) 3365
(br), 1703, 1415, 1208, 1140, 1034 cmꢀ1; HRMS (FAB)
Calcd for C8H11O4SF3Na ([M+Na]+) 283.0228. Found
283.0230.
reagent furnishes secondary alkynols 3. The vinylogous
triflate hemiacetals 2 are prepared by DIBALH reduc-
tion of vinylogous acyl triflates 1, derived from cyclic
1,3-diketones, and serve as surrogates for alkynyl
aldehydes.
Acknowledgments
This research was supported by a grant from the James
and Ester King Biomedical Research Program, Florida
Department of Health, the Donors of the American
Chemical Society Petroleum Research Fund, an award
from Research Corporation, and by the FSU Depart-
ment of Chemistry and Biochemistry. S.K. is a recipient
of the Postdoctoral Fellowship for Research Abroad
(2004) from the Japan Society for the Promotion of Sci-
ence (JSPS). We are profoundly grateful to all of these
agencies for their support. We thank Dr. Joseph Vaughn
for assistance with the NMR facilities, Dr. Umesh Goli
for providing the mass spectrometry data, and the Krafft
Lab for access to their FT-IR instrument. We thank
David Jones for conducting additional optimization
experiments.
8. (a) Wakefield, B. J. In Organomagnesium Methods in
Organic Synthesis; Academic Press: London, 1995; pp
111–130; (b) Krasovskiy, A.; Kopp, F.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 497.
9. The treatment of 2a with 2.2 equiv of LiBHEt3 gave the
corresponding primary alkynol, 5-heptynol (4a), in good
yield, see: Ref 5.
10. The reaction of 2a with 2.2 equiv of organolithium
reagents, such as n-BuLi or PhLi, gave a complex mixture
of compounds.
11. Standard experimental procedures for the tandem frag-
mentation/addition reaction of vinylogous hemiacetals 2
using Grignard reagents. To a THF solution (2.0 mL) of
2-methyl-3-(trifluoromethanesulfonyloxy)-2-cyclohexen-1-
ol (2a) (130.1 mg, 0.50 mmol) was slowly added PhMgBr
(0.37 mL, 1.1 mmol; 3.0 M solution in ether) at ꢀ78 °C
under an Ar atmosphere. The mixture was stirred at
ꢀ78 °C for 10 min, at 0 °C for 10 min, at rt for 30 min,
and then at 60 °C for 30 min. Saturated aqueous NH4Cl
solution was added to quench the reaction and the mixture
was extracted with ether. The organic layer was washed
with water, dried (MgSO4), filtered, and concentrated. The
residue was purified by chromatography on a silica gel
column (hexanes/ether = 50/1 to 3/1) to give 1-phenyl-5-
References and notes
1. (a) Brettle, R. In Comprehensive Organic Chemistry;
Barton, S. D., Ollis, W. D., Eds.; Pergamon: Oxford,
1979; pp 943–1015; (b) Waring, A. J. In Comprehensive
Organic Chemistry; Barton, S. D., Ollis, W. D., Eds.;
Pergamon: Oxford, 1979; pp 1017–1104; (c) Laird, T. In
Comprehensive Organic Chemistry; Barton, S. D., Ollis, W.
D., Eds.; Pergamon: Oxford, 1979; pp 1105–1160; (d)
Laird, T. In Comprehensive Organic Chemistry; Barton, S.
D., Ollis, W. D., Eds.; Pergamon: Oxford, 1979; pp 1161–
1211; (e) Modern Carbonyl Chemistry; Otera, J., Ed.;
Wiley-VCH: Weinheim, 2000.
1
heptyn-1-ol (3b) in 84% yield (79.5 mg). Colorless oil; H
NMR (300 MHz, CDCl3) d 1.33–1.60 (3H, m), 1.67 (3H, t,
J = 2.4 Hz), 1.72–1.87 (2H, m), 2.07 (2H, tq, J = 6.9,
2.4 Hz), 4.61 (1H, m), 7.16–7.23 (3H, m), 7.26–7.27 (2H,
m); 13C NMR (75 MHz, CDCl3) d 3.3, 18.5, 25.1, 38.0,
74.1, 75.8, 78.8, 125.8, 127.4, 128.3, 144.6; IR (neat) 3368
(br), 1603, 1493, 1453, 1331, 1205, 1065, 1025, 760,
700 cmꢀ1; HRMS (CI) Calcd for C13H17O ([M+H]+)
189.1279. Found 189.1281.
2. (a) Greene, T. W.; Wuts, P. G. M. In Protective Groups in
Organic Synthesis; Wiley: New York, 1999; pp 293–398;
´
(b) Kocienski, P. J. In Protecting Groups; Thieme: Stutt-
gart, 2000; pp 155–184.
12. The alkynyl Grignard reagent was prepared from phenyl-
acetylene and n-BuMgCl by mixing in THF at 60 °C for
30 min, see: Ref. 8a, pp. 46–48.
3. Representative example, see: Lawrence, N. J. In Prepara-
tion of Alkenes; Williams, J. M. J., Ed.; Oxford: Oxford,
1996; pp 31–32.
13. (a) Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed.
Engl. 1967, 6, 1; (b) Grob, C. A. Angew. Chem., Int. Ed.
Engl. 1969, 8, 535; Other reviews on the Grob-type
fragmentations, see: (c) Weyerstahl, P.; Marschall, H. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 6, pp 1041–1070;
(d) Hesse, M. In Ring Enlargement in Organic Chemistry;
VCH: Weinheim, 1991; pp 163–198.
4. For preparation, see: (a) Kamijo, S.; Dudley, G. B. J. Am.
Chem. Soc. 2005, 127, 5028; (b) Hori, M.; Mori, M. J.
Org. Chem. 1995, 60, 1480.
5. Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2006, 128,
6499, and references cited therein.
6. Similar reductions have been reported, see: (a) Yamano,
Y.; Mimuro, M.; Ito, M. J. Chem. Soc., Perkin. Trans. 1
1997, 2713; (b) von Zezschwitz, P.; Petry, F.; de Meijere,
14. Similar type of C–C bond cleavage reaction is observed in
Eschenmoser–Tanabe fragmentation, see: (a) Eschenmo-
ser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta 1967, 50,
708; (b) Felix, D.; Shreiber, J.; Ohloff, G.; Eschenmoser,
A. Helv. Chim. Acta 1971, 54, 2896; (c) Tanabe, M.;
Crowe, D. F.; Dehn, R. L. Tetrahedron Lett. 1967, 3943;
(d) Tanabe, M.; Crowe, D. F.; Dehn, R. L.; Detre, G.
Tetrahedron Lett. 1967, 3739.
15. Fragmentation (B ! A) should be accelerated by destabi-
lizing steric interactions in B. Increased A1,2-strain may
explain why 2a (R = Me) is a better substrate than 2b
(R = H). See Ref. 5 for more examples of fragmentations
that are consistent with this observation.
´
A. Chem. Eur. J. 2001, 7, 4035–4046; (c) Martınez, A. G.;
Alvarez, R. M.; Casado, M. M.; Subramanian, L. R.;
Hanack, M. Tetrahedron 1987, 43, 275.
7. Standard experimental procedures for DIBALH reduction
of vinylogous acyl triflates 1. To a THF solution (20 mL) of
2-methyl-3-(trifluoromethanesulfonyloxy)-2-cyclohexenone
(1a) (1.29 g, 5.0 mmol) was slowly added DIBALH
(5.5 mL, 5.5 mmol; 1.0 M solution in heptane) at ꢀ78 °C
under an Ar atmosphere. The mixture was stirred at ꢀ78 °C
for 10 min, at 0 °C for 10 min, and then at rt for 30 min.
Saturated aqueous NH4Cl solution was added to quench
the reaction, and the mixture was then treated with aqueous
NaOH solution (1 M) and extracted with ether. The organic