TBAF-mediated aldol reaction of β-allenoates: Regio- and stereoselective synthesis of (2E,4E)-4-carbinol alkadienoates

Article abstract of DOI:10.1021/jo900567m

(Chemical Equation Presented) The aldol reaction of β-allenoate with use of a commercial THF solution of tetrabutylammonium fluoride (TBAF) yielded polyfunctionalized (2E,4E)-4-carbinol alkadienoate - a valuable building block - in highly regio- and stereoselective fashion.

Full text of DOI:10.1021/jo900567m

SCHEME 1. Regio- and Stereoselective Considerations in
the Base-Mediated Reactions of ꢀ-Allenoate 1
TBAF-Mediated Aldol Reaction of ꢀ-Allenoates:
Regio- and Stereoselective Synthesis of
(2E,4E)-4-Carbinol Alkadienoates
Jose´ C. Aponte, Gerald B. Hammond, and Bo Xu*
Department of Chemistry, UniVersity of LouisVille,
LouisVille, Kentucky 40292
bo.xu@louisVille.edu
ReceiVed March 14, 2009
intrigued by the synthesis of the 4-regioisomer, where the
carbinol substituent is strategically placed in the diene moiety
(i.e., 2). Although an obvious disconnection for the synthesis
of 2 is the aldol reaction of an extended enolate A with an
aldehyde (E+ ) RCHO) (Scheme 1), this reaction is hitherto
unknown. Herein we report a new role of allenyl enolate A as
intermediate in the regio- and stereoselective synthesis of
(2E,4E)-4-carbinol alkadienoate 2, starting from a readily
available ꢀ-allenoate 1, under very mild conditions. To the best
of our knowledge, this is the first report where ꢀ-allenoate 1
has been functionalized through trapping of an allenyl enolate
with a carbon electrophile.
The aldol reaction of ꢀ-allenoate with use of a commercial
THF solution of tetrabutylammonium fluoride (TBAF)
yielded polyfunctionalized (2E,4E)-4-carbinol alkadienoatesa
valuable building blocksin highly regio- and stereoselective
fashion.
One advantage of using ꢀ-allenoate 1 as the starting material
is that it is readily synthesized by a Claisen rearrangement of a
propargylic alcohol and an ortho ester.4 If a strong enough base
is present, the deprotonation of 1 would produce allenyl enolate
A, which, in turn, could either isomerize to the corresponding
diene 4 (structure in Table 1 footnote) and react further, or it
could react with an electrophile E+, like an aldehyde or an imine,
to give R- or γ-products 2 or 3 (Scheme 1). Although some
reactions of allenyl enolates have been studied, most of these
derived from 1,6-additions of copper reagents to alkenynones
or alkenynoates.5 Reactions of these allenyl copper enolates with
aldehydes generally favor R-products.5,6
Functionalized 2,4-alkadienoates are important building blocks
in organic chemistry; they are widely used in synthesis and a
frequent motif in natural products.1,2 In this vein, carbinol
alkadienoates would be expected to enhance the synthetic value
of 2,4-alkadienoates; indeed carbinol alkadienoates have been
intermediates in natural product syntheses, but their preparation
needed multiple steps or showed low stereoselectivity.3 We were
The reactions of dienolates are important synthetic tools.7 But
our recent focus has been the chemistry of alkynyl enolates,
(1) Selected references on 1,3-dienes as building blocks: (a) Garigipati, R. S.;
Freyer, A. J.; Whittle, R. R.; Weinreb, S. M. J. Am. Chem. Soc. 1984, 106,
7861–7867. (b) DeBoef, B.; Counts, W. R.; Gilbertson, S. R. J. Org. Chem.
2007, 72, 799–804. (c) Marcus, A. P.; Lee, A. S.; Davis, R. L.; Tantillo, D. J.;
Sarpong, R. Angew. Chem., Int. Ed. 2008, 47, 6379–6383. (d) Enders, D.; Geibel,
G.; Osborne, S. Chem.sEur. J. 2000, 6, 1302–1309. (e) Vidari, G.; Ferrino, S.;
Grieco, P. A. J. Am. Chem. Soc. 1984, 106, 3539–3548. (f) Grieco, P. A.; Collins,
J. L.; Moher, E. D.; Fleck, T. J.; Gross, R. S. J. Am. Chem. Soc. 1993, 115,
6078–6093. (g) Walker, D. P.; Grieco, P. A. J. Am. Chem. Soc. 1999, 121, 9891–
9892. (h) Holland, H. L.; Viski, P. J. Org. Chem. 1991, 56, 5226–5229. (i)
Andrade, R. B.; Martin, S. F. Org. Lett. 2005, 7, 5733–5735.
(2) (a) Chang, H.-M.; Cheng, C.-H. J. Org. Chem. 2000, 65, 1767–1773.
(b) Fu, C.; Ma, S. Org. Lett. 2005, 7, 1707–1709. (c) Krause, N.; Gerold, A.
Angew. Chem., Int. Ed. 1997, 36, 186–204. (d) Nunomoto, S.; Yamashita, Y. J.
Org. Chem. 1979, 44, 4788–91. (e) Trost, B. M.; Pinkerton, A. B.; Seidel, M.
J. Am. Chem. Soc. 2001, 123, 12466–12476. (f) Soundararajan, R.; Li, G.; Brown,
H. C. J. Org. Chem. 1996, 61, 100–104. (g) Ma, S.; Yu, F. Tetrahedron 2005,
61, 9896–9901. (h) Oshima, M.; Yamazaki, H.; Shimizu, I.; Nisar, M.; Tsuji, J.
J. Am. Chem. Soc. 1989, 111, 6280–6287.
(3) (a) Stork, G.; Nakahara, Y.; Nakahara, Y.; Greenlee, W. J. J. Am. Chem.
Soc. 1978, 100, 7775–7777. (b) Seck, M.; Franck, X.; Seon-Meniel, B.;
Hocquemiller, R.; Figade`re, B. Tetrahedron Lett. 2006, 47, 4175–4180. (c) Lai,
M. T.; Li, D.; Oh, E.; Liu, H. W. J. Am. Chem. Soc. 1993, 115, 1619–1628. (d)
Yoshikawa, K.; Inoue, M.; Hirama, M. Tetrahedron Lett. 2007, 48, 2177–2180.
(e) Paquette, L. A.; Kreilein, M. M.; Bedore, M. W.; Friedrich, D. Org. Lett.
2005, 7, 4665–4667. (f) Li, X.; Zeng, X. Tetrahedron Lett. 2006, 47, 6839–
6842. (g) Smith, A. B., III.; Walsh, S. P.; Frohn, M.; Duffey, M. O. Org. Lett.
2005, 7, 139–142.
(4) (a) Henderson, M. A.; Heathcock, C. H. J. Org. Chem. 1988, 53, 4736–
4745. (b) Ma, S.; Yu, F.; Li, Y.; Gao, W. Chem.sEur. J. 2007, 13, 247–254.
(5) (a) Fredrick, M. A.; Hulce, M. Tetrahedron 1997, 53, 10197–10226. (b)
Krause, N.; Arndt, S. Chem. Ber. 1993, 126, 261–263. (c) Hohmann, M.; Krause,
N. Chem. Ber. 1995, 128, 851–860. (d) Laux, M.; Krause, N.; Koop, U. Synlett
1996, 87–88. (e) Krause, N. Liebigs Ann. Chem. 1993, 521–525. (f) Lee, S. H.;
Shih, M. J.; Hulce, M. Tetrahedron Lett. 1992, 33, 185–188. (g) Krause, N.;
Laux, M.; Hoffmann-Ro¨der, A. Tetrahedron Lett. 2000, 41, 9613–9616. (h)
Hoffmann-Ro¨eder, A.; Krause, N. Synthesis 2006, 2143–2146.
(6) Arndt, S.; Handke, G.; Krause, N. Chem. Ber. 1993, 126, 251–259.
(7) Selected references on reaction of dienolates: (a) Denmark, S. E.; John,
R.; Heemstra, J.; Beutner, G. L. Angew. Chem., Int. Ed 2005, 44, 4682. (b)
Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. ReV. 2000, 100,
1929–1972. (c) Sickert, M.; Schneider, C. Angew. Chem., Int. Ed. 2008, 47,
3631–3634. (d) Salvador Gonzalez, A.; Gomez Arrayas, R.; Rodriguez Rivero,
M.; Carretero, J. C. Org. Lett. 2008, 10, 4335–4337. (e) Giera, D. S.; Sickert,
M.; Schneider, C. Org. Lett. 2008, 10, 4259–4262. (f) Carswell, E. L.; Snapper,
M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2006, 45, 7230–7233.
(8) Selected references on the reactions of alkynyl enolates: (a) Xu, B.;
Hammond, G. B. Angew. Chem., Int. Ed 2008, 47, 689–692. (b) Wang, W.; Xu,
B.; Hammond, G. B. Org. Lett. 2008, 10, 3713–3716. (c) Liu, L.-P.; Xu, B.;
Hammond, G. B. Org. Lett. 2008, 10, 3887–3890. (d) Yang, H.; Xu, B.;
Hammond, G. B. Org. Lett. 2008, 10, 5589–5591. (e) Liu, L.-P.; Xu, B.; Mashuta,
M. S.; Hammond, G. B. J. Am. Chem. Soc. 2008, 130, 17642–17643. (f) Miesch,
L.; Rietsch, V.; Welsch, T.; Miesch, M. Tetrahedron Lett. 2008, 49, 5053–5055.
(g) Lepore, S. D.; He, Y.; Damisse, P. J. Org. Chem. 2004, 69, 9171–9175.
10.1021/jo900567m CCC: $40.75
Published on Web 05/18/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4623–4625 4623

TABLE 1. Optimization of Conditions for the Aldol Reaction of 1
TABLE 2. TBAF-Mediated Reaction of ꢀ-Allenoates with
Aldehydes
base temp time
equiv (°C) (h)
yield of
entry
base
2ae (%)
entry R1
R2
R3
R4
R
time (h) yield (%)b
1
2
3
4
5
6
7
8
t-BuOK
phosphazene (P1-t-Bu)
phosphazene (P2-Et)
LDA
TBAOH
K2CO3
K2CO3
K2CO3
DBU
TEA
KF
CsF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
0.2
0.2
0.2
1.0
0.2
0.2
2.0
2.0
0.2
0.2
0.2
0.2
0.2
0.5
1.0
1.5
2.0
2.0
2.0
0
0
0
-79
0
rt
rt
rt
0
0
0
0
0
0
0
0
0
4
4
4
4
4
4
4
complex mixtureb
complex mixtureb
complex mixtureb
complex mixtureb
1
2
3
4
5
6
7
8
H
H
H
H
H
H
C5H11
C5H11
H
H
H
H (1a) p-ClC6H4
CH3 (1b) p-ClC6H4
2
2
2
2
2
5
2
2
2
3
2
2
1
3
3
6
70 (2a)
66 (2b)
41 (2c)
84 (2d)
82 (2e)
49 (2f)
41 (2g)
89 (2h)
87 (2i)
68 (2j)
80 (2k)
44 (2l)
81 (2m)
36 (2n)
65 (2o)
37 (2p)
CH3 H (1c)
H
H
p-ClC6H4
p-ClC6H4
CH(CH3)2
CH(CH3)2
CH2CH3 CH3 H (1f)
H (1d)
25.0a b
,
CH3 (1e) p-ClC6H4
31.5a d
,
p-ClC6H4
p-ClC6H4
p-ClC6H4
43.9a d
,
(CH2)5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H (1g)
H (1h)
16 52.3a d
,
H
H
H
H
H
H
H
H
H
9
4
4
4
4
2
2
2
2
2
2
2
no reactionb
9
CH3 (1i) p-ClC6H4
CH3 (1i) C6H5
10
11
12
13
14
15
16
17
18
19
no reactionb
no reactionb
no reactionb
28.6a,b
10
11
12
13
14
15
16
CH3 (1i) p-BrC6H4
CH3 (1i) p-FC6H4
CH3 (1i) p-CF3C6H4
CH3 (1i) p-NO2C6H4
CH3 (1i) p-CNC6H4
CH3 (1i) p-OCH3C6H4
55.5a b
,
68.1a b
,
70.0a b
,
84.6a b
,
a TBAF, 1 M in THF. The reaction was conducted in the absence of
additional solvent. b Isolated yields.
0
0
64.0
70.9c
1H NMR yield. b Reaction ran with 1.5 mL of THF as solvent.
c With 1.0 equiv of aldehyde and 1.2 equiv of allene. d Reaction ran on
DMF as solvent. e In most cases, 4 was also isolated as byproduct.
a
2). The yields of aldol condensation were affected by the
substitution pattern of the ꢀ-allenoate. Monosubstitution at the
R-carbon (such as in 1a, 1b; 1d, 1e; and 1h, 1i) give good yields
(entries 1, 2; 4, 5; and 8, 9, Table 2). Terminal ꢀ-allenoates 1c
only give moderate yield (entry 3, Table 2). This may be due
to the fact that 1c was less stable and polymerized under the
basic conditions utilized. A ꢀ-allenoate disubstituted on the
δ-carbon (1g, entry 9, Table 2) appeared to be less reactive,
giving rise to the formation of its corresponding 2,4-alkadi-
enoates, due to the steric hindrance of the γ-carbon in this
molecule.2b Under similar conditions, the reaction of an aliphatic
aldehyde (hexanal) gave the 2,4-allenoate isomer product 4
exclusively.
It should be noted that all the reactions in Table 2 were highly
regio- and stereoselective. We did not detect either the formation
of the 4-carbinol alkadienoate sterereoisomer, the product 2 with
a (2Z)- and/or (4Z)-configuration, or other products arising from
the lactonization of (2Z)-2 in basic media.
The olefin stereochemistry of all products (2a-p) was
(2E,4E); this was confirmed by an inspection of their J coupling
constants, as well as NOESY NMR experiments. This selectivity
could be explained by invoking the argument of Ma and co-
workers2b that the steric repulsion between the bulky ester and
γ-vinyl groups favors a trans stereoselective orientation of the
alkadienoate. We monitored the reaction of 1a with p-chlo-
robenzaldehyde using in situ IR spectroscopy.10 The reaction
proceeded very fast, and reached its maximum conversion after
only 10 min.
starting from R-allenyl- or propargyl-ester precursors.8a-e This
research led to regioselective syntheses of carbinol allenoates,8a
R,R-disubstituted R-alkynyl esters,8b 2-alkynyl-substituted glu-
taric acid derivatives,8c and R-fluoro propargyl esters or
γ-iodoallenoates.8d In these syntheses, the Lewis acidity and
size of the base counterion played a critical role on the
regioselectivity. With this experience in mind, we screened
various inorganic and organic bases at different temperatures
to find the best conditions for the aldol reaction of ꢀ-allenoate
1a (Table. 1). Employing strong bases gave rise to a complex
mixture of products (entries 1-4, Table. 1), while weak bases
produced no reaction, or low yields (entries 5-12, Table. 1).
TBAF (commercially available as a 1 M solution in THF) at 0
°C gave the best results in the synthesis of carbinol alkadienoate
2a (entry 17, Table. 1). The main competition was the base-
promoted isomerization to 2,4-alkadienoate, 4. The isomeric
byproduct 4 has been prepared by sequential allenyl enolate
formation-protonation (EtONa in EtOH) or alumina-catalyzed
isomerization.9 Different solvents were also screened (data not
shown), showing that polar solvents, such as ethanol and
acetonitrile, promoted the unwanted 2,4-alkadienoate isomer-
ization, while in nonpolar solvents, such as toluene and DCM,
there was no reaction.
To further expand the scope of this protocol, we examined
the reaction of ꢀ-allenoate 1h with an imine electrophile,
p-toluenesulfonamide (p-TSA) (eq 1). Using a commercial 1
M THF solution of TBAF, we obtained only (2E,4E)-4-carbinol
alkadienoate 2h, probably because the sulfonamide hydrolyzed
With optimized experimental conditions in hand, we inves-
tigated the scope of the aldol reaction using various aldehydes
and ꢀ-allenoates 1 with different substitution patterns (Table
(9) (a) Amos, R. A.; Katzenellenbogen, J. A. J. Org. Chem. 1978, 43, 555–
560. (b) Tsuboi, S.; Masuda, T.; Mimura, S.; Takeda, A. Organic Syntheses;
Wiley: New York, 1993; Collect. Vol. VIII, pp 22-27. (c) Mori, K.; Maemoto,
S. Liebigs Ann. Chem. 1987, 10, 863–869. (d) Georgy, M.; Lesot, P.; Campagne,
J.-M. J. Org. Chem. 2007, 72, 3543–3549. (e) Passaro, L. C.; Webster, F. X.
Synthesis 2003, 8, 1187–1190.
(10) The reaction was conducted with the conditions in Table 2 and was
monitored by the changes in the aldehyde and alkadienoate 2a characteristic
absorption bands at 1743 and 1611 cm-1 (see the figure in the Supporting
Information).
4624 J. Org. Chem. Vol. 74, No. 12, 2009

t, J ) 7.5 Hz), 7.29 (4H, m), 7.58 (1H, d, J ) 16.0 Hz); 13C
NMR (CDCl3, 125 MHz) δ 14.2, 14.6, 22.7, 28.2, 29.4, 31.7,
60.7, 74.3, 119.8, 128.3, 128.3, 128.9, 128.9, 133.7, 136.3, 138.2,
140.8, 140.8, 167.5; MS (EI) m/z 336 (M+), 320, 291, 274, 263;
to the corresponding aldehyde in the presence of the water
present in commercial TBAF (∼3-5% H2O content). Dryer
conditions (K2CO3 in DMF) prevented the sulfonamide hy-
drolysis, and led to the synthesis of (2E,4E)-4-sulfonami-
domethly alkadienoate (5a), albeit in moderate yield.
IR (neat) ν 3435, 2956, 2857, 1709, 1691, 1489, 1282 cm-1
.
Anal. Calcd for C19H25ClO3: C, 67.75; H, 7.48. Found: C, 67.96;
H, 7.44.
(1)
Preparation of (2E,4E)-4-Sulfonamidomethyl Dienoate, 5a.
After K2CO3 (276.6 mg, 2.0 mmol) in 1.0 mL of DMF was stirred
for 3 h at room temperature, p-toluenesulfonamide (p-TSA, 259.4
mg, 1.0 mmol) was added together with an extra 0.5 mL of DMF.
Compound 1h (169.2 mg, 1.2 equiv) was added dropwise, then
the mixture was stirred at room temperature for 16 h. Saturated
NH4Cl solution (10 mL) was added to the resulting reddish mixture
and after 5 min of stirring, the solution was extracted with ether (3
× 20 mL). The organic layer was extracted with distilled H2O (3
× 20 mL) to remove the DMF and then dried over MgSO4. The
solvent was removed by reduced pressure and the crude product
was purified by flash silica gel column chromatography (9:1, 8:1,
6:1, 4:1, 2:1 hexanes:ethyl acetate) to give 5a (181.8 mg, 0.44
mmol, 44%) as a white solid (mp 111-113 °C). 1H NMR (CDCl3,
500 MHz) δ 1.26 (3H, t, J ) 7.0 Hz), 1.77 (3H, d, J ) 7.5 Hz),
2.42 (3H, s), 4.16 (2H, q, J ) 7.0 Hz), 5.04 (1H, d, J ) 7.5 Hz),
5.22 (1H, d, J ) 8.0 Hz), 5.64 (1H, d, J ) 16.0 Hz), 5.97 (1H, q,
J ) 7.5 Hz), 7.09 (2H, m), 7.24 (4H, m), 7.49 (1H, d, J ) 16.0
Hz), 7.63 (2H, d, J ) 16.0 Hz); 13C NMR (CDCl3, 125 MHz) δ
14.2, 14.5, 21.7, 59.6, 60.7, 119.6, 127.3, 127.3, 127.5, 127.5, 128.1,
129.0, 129.0, 129.7, 129.7, 134.1, 136.5, 137.6, 137.9, 139.2, 143.6,
167.2; MS (EI) m/z 398 (M+), 353, 324, 260, 229; IR (neat) ν 3275,
2981, 2926, 1710, 1281, 1160 cm-1. Anal. Calcd. for C22H25NO4S:
C, 66.14; H, 6.31. Found: C, 65.91; H, 6.29.
In summary, the regio- and stereoselective synthesis of a
functionalized 2,4-alkadienoate has been achieved through an
aldol reaction of ꢀ-allenoate. This simple base-mediated reaction
can yield hitherto unknown intermediates that could be further
utilized in a variety of transformations, such as oxidations,
reductions, and olefin cross-metathesis.
Experimental Section
Typical Procedure for the Preparation of (2E,4E)-4-Carbinol
Dienoates: Synthesis of 2a. p-Chlorobenzaldehyde (70.4 mg, 0.5
mmol) was dissolved in 1.0 mL of TBAF (1 M in THF, 2 equiv,
1 mmol). The mixture was stirred in an ice bath for 3 min before
compound 1a was added dropwise. The reddish solution was
stirred for 2 h. Then, saturated NH4Cl solution (10 mL) was
used to quench the reaction. After being stirred for 5 min at
room temperature, the mixture was extracted with ether (2 ×
20 mL). The organic layer was dried over MgSO4 and the filtrate
was concentrated in vacuo. The residue was purified by flash
silica gel column chromatography (9:1, 8:1, 6:1, 4:1, 2:1 hexanes:
ethyl acetate) to give 2a (119.4 mg, 0.35 mmol, 70%) as a
Acknowledgment. We are grateful to the National Science
Foundation for financial support (CHE-0809683).
Supporting Information Available: Experimental proce-
dures, characterization, spectroscopic spectra for 2 and 5, and
in situ IR spectroscopy (Figure SI1). This material is available
free of charge via the Internet at http://pubs.acs.org.
1
colorless oil. H NMR (CDCl3, 500 MHz) δ 0.90 (3H, t, J )
7.0 Hz), 1.26 (3H, t, J ) 7.0 Hz), 1.31-1.34 (4H, m), 1.46
(2H, m), 2.35 (2H, q, J ) 7.5 Hz), 2.61 (1H, br s), 4.16 (2H, q,
J ) 7.0 Hz), 5.42 (1H, s), 5.85 (1H, d, J ) 16.0 Hz), 6.14 (1H,
JO900567M
J. Org. Chem. Vol. 74, No. 12, 2009 4625