One-pot vinylogous aldol addition of β,γ-unsaturated esters under mild conditions

Article abstract of DOI:10.1039/c5nj00961h

We described a one-pot vinylogous aldol addition of methyl 3-butenoate to aromatic aldehydes in the presence of silver salts and the TMSCl-TBAF mixture. The reaction can be done simply by sequentially mixing reagents in situ, and it does not require any c

Full text of DOI:10.1039/c5nj00961h

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DOI: 10.1039/C5NJ00961H
One-Pot Vinylogous Aldol Addition of β,γ-Unsaturated Esters Under
Mild Conditions
Đsmail Akçok, and Ali Çağır*
A new methodology for the addition of β,γꢀunsaturated esters to aldehydes was developed in TMSCl,
Ag2CO3, and TBAF mixture.

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One-Pot Vinylogous Aldol Addition of β,γ-Unsaturated Esters
Under Mild Conditions†
Received 00th January 20xx,
Accepted 00th January 20xx
Đsmail Akçok and Ali Çağır*
DOI: 10.1039/x0xx00000x
www.rsc.org/
unsaturatedꢀδꢀlactones
We described a one-pot vinylogous aldol addition of methyl 3-
butenoate to aromatic aldehydes in the presence of silver salts
and TMSCl-TBAF mixture. The reaction can be done simply by
by sequential mixing reagents in situ, and it does not require any
catalyst or dienolate ether preparations prior to the reaction.
The aim of the study is to prepare 1ꢀmethoxyꢀ1ꢀ(trimethylsiloxy)ꢀ
1,3ꢀbutadiene (3) in situ via the reaction of methyl 3ꢀbutenoate (2)
and trimethylsilyl cation which can be simply generated from the
reaction between silver salts and TMSCl. Then the addition of
aldehyde would give the vinylogous aldol addition product (8). For
this purpose 1ꢀnaphthaldehyde (7) was chosen as a model aromatic
aldehyde for the optimization of reaction conditions (Scheme 2).
Preliminary studies showed that pretreatment of starting ester 2 with
silver carbonate and TMSCl for one hour followed by the addition of
TBAF and 1ꢀnaphhaldehyde gave compound 8 with 39% yield.
Interestingly, when the reaction was repeated in the absence of any
one of the reagents, silver carbonate, TMSCl or TBAF, the reaction
did not occur.
Synthesis of α,βꢀunsaturatedꢀδꢀlactones is of great importance to
scientists because of their valuable antitumor, antibacterial, and
antifungal activities.1, 2 Vinylogous aldol addition of esters (1 or 2)
to aldehydes (4) produces unsaturated esters (5) which are valuable
precursors for the synthesis of 6ꢀalkyl or 6ꢀaryl substituted 5,6ꢀ
4
dihydroꢀ2Hꢀpyranꢀ2ꢀone derivatives (6).3, In general, vinylogous
aldol addition reactions of esters (1 or 2) to aldehydes (4) are
performed by a twoꢀstep procedure. In the first step, starting esters (1
or 2) should be transferred to Oꢀsilyldienolate (3)5ꢀ9 and then purified
by unreacted LDA and formed diisopropylamine by distillation
before addition to aldehydes (Scheme 1).10 Such a distillation
procedure may not be preferred for expensive starting esters because
of their low yields. Alternatively, these reactions can be catalyzed by
simple Lewis acids11 and their complexes which can be prepared
prior to the reaction.12 Here we report a oneꢀpot vinylogous aldol
addition of β,γꢀunsaturated ester (2) with aromatic aldehydes under
mild conditions.
1) Ag2CO3, TMSCl,
OH
O
O
DMF, 0 oC, 1 h.
OMe
O
MeO
2)
TBAF, 24 h.
0 oC -> RT
2
8
7
Scheme 2 Oneꢀpot vinylogous aldol addition to 1ꢀnaphthaldehyde
To investigate the effect of choice of solvent on reaction yield,
reaction was carried out in 1.0 mL of THF, toluene, NMP, and DMF.
All reactions were terminated after 24 hours and products were
isolated. It seems that reaction proceeds faster in DMF and gives the
highest yield of 39%. When the amount of DMF was increased to
4.0 mL the yield of the reaction increased to 44% but further
dilutions of reactants in 10 mL of DMF slowed down the reaction
and resulted in only 28% yield (Table 1).
Table 1. Effect of solvent on the preparation of α,βꢀunsaturated ester (8)*
Entry
Solvent [Conc.]
THF [0.25M]
Toluene [0.25M]
NMP [0.25M]
DMF [0.25M]
DMF [0.0625M]
DMF [0.025M]
Yield (%)
1
2
3
4
5
6
17
16
16
39
44
28
Scheme 1 Vinylogous aldol addition products as precursors of α,βꢀ
[*] Isolated yield. All reactants used were 1.00 eq.
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COMMUNICATION
To better understand the role of silver carbonate in the reaction, Table 4 Vinylogous aldol addition to different aldehydes. Conditions: methyl
the reactions were carried out with different silver salts or sodium 3ꢀbutenoate (1 eq), TMSCl (1 eq), Ag2CO3 (0.5 eq), aldehyde (2 eq), TBAF
carbonate (Table 2). Again, all reactions were terminated in about 24 (1 eq)
hours, and products were purified. In the presence of a weak base of
silver triflate, silver nitrate, silver oxide or triethylamine, there were
either poor yields or no reaction. On the other hand, when reactions
were carried out with sodium carbonate or silver carbonate
comparable yields were obtained (44 and 39% respectively). These
findings imply that the basicity of the solution is quite important for
Aldehyde
Ar(R)
Yield* (%)
41
the outcome of the reactions. Among the tested silver salts silver
triflate was found to be the least effective. This might be because of
the formation of trifluoromethanesulfonic acid during the enolization
process. The presence of such a strong acid may shift the enolꢀketo
tautomerism toward the carbonyl isomer.
9
10
12
Table 2 Effect of silver source and base on the preparation of α,βꢀ
unsaturated ester (8)
11
67
NP
28
69
Entry
Silver source
(and base)
Ag2CO3
Solvent
[Conc.]
Time
(h)
24
Yield*
(%)
44
12
1
2
3
4
5
6
7
8
DMF [0.0625M]
NMP [0.0625M]
THF [0.0625M]
DMF [0.0625M]
DMF [0.0625M]
DMF [0.0625M]
DMF [0.0625M]
DMF [0.0625M]
AgOTf
AgOTf
AgOTf + Na2CO3
Na2CO3
24
24
24
24
NP
NP
6
13
14
39
AgOTf + Et3N
Ag2O
24
24
NP
19
AgNO3
24
2
[*] Isolated yield. All reactants used were 1.00 eq.
On the other hand, the reaction gave low yield in the presence of
silver nitrate, which can also produce a strong conjugate acid during
the enolization step. As shown in Table 1, the rate of the reactions
depends on the concentrations of the reagents. To further optimize
the reaction conditions, reactions were performed in the presence of
various amounts of aldehyde (7) and silver carbonate (Table 3).
After 24 hours, a reaction with only 0.5 equivalent of silver
carbonate for each aldehyde gave slightly better yield (55%).
Addition of two equivalents of aldehyde to the reactions increased
the yield up to 75%. When TBDMSCl was used as silyl source the
yield of the reaction decreased to 25%, and this clearly shows that
silyl group plays an effective role in the reaction mechanism.
[*] Isolated yield.
To test the effectiveness of the reaction mixture two different
acetate esters were used as an enolate source for aldol reactions
(Scheme 3). In neither trial was product formation observed. This
implies that the base is not strong enough to obtain acidic alphaꢀ
protons of acetates.
methylpyrrolidinone and no enolization was observed in this attempt
either.
A similar reaction was tried with Nꢀ
Table 3 Effect of the amount of Ag2CO3 and aldehyde on the preparation of
α,βꢀunsaturated ester (8)
Entry
Aldehyde 7 (eq.) Ag2CO3 (eq.)
DMF
(mL)
Yield
(%)
44
55
53
Scheme 3 Addition of acetate esters (21 and 22) to 1ꢀnaphthaldehyde
[Conc.]
[Conc.]
1
2
3
4
5
1.00 [0.0625 M]
1.00 [0.0625 M]
1.00 [0.025 M]
2.00 [0.125 M]
2.00 [0.05 M]
1.00 [0.0625M]
0.50 [0.03125M]
0.50 [0.0125M]
0.50 [0.03125M]
0.50 [0.0125M]
4 mL
4 mL
10 mL
4 mL
10 mL
Earlier it was mentioned that the aim was to prepare 1ꢀmethoxyꢀ1ꢀ
(trimethylsiloxy)ꢀ1,3ꢀbutadiene (3) in situ via the reaction of methyl
3ꢀbutenoate (2) and trimethylsilyl cation which can be simply
generated from the reaction between silver salts and TMSCl. To
identify such enol ether formation methyl 3ꢀbutenoate (2) was stirred
with silver carbonate in DMF for 24 hours but no detectable reaction
was observed. A similar preparation of silyl vinyl dienol ether (26)
was also studied, starting with ester 25 and TBDMSCl, but no Oꢀ
silyl dienol ether formation was observed. Additionally, vinylogous
aldol addition of compound 25 to 1ꢀnaphthaldehyde gave compound
27 as product in 51% yield (Scheme 4).
75
65
[*] Isolated yield. All other reagents used were 1.00 eq.
To check the applicability of the methodology, six different
aldehydes were used in optimized reaction conditions. As can be
seen in Table 4, yields of the reaction may be altered by the
substituents present on the aromatic ring. Although the electron
donating group causes a decrease, the electron withdrawing group
increases the yield. Enolizable aldehyde (12) gave no product
formation whereas corresponding styryl substituted aldehyde (13)
gave a product with 28% yield.
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Notes and references
1
P. Kasaplar, O. Yilmazer and A. Cagir, Bioorg. Med. Chem., 2009, 17,
311.
2
3
P. Kumar and S. V. Naidu, J. Org. Chem., 2006, 71, 3935.
M. Kumar, A. Kumar, M. Rizvi, M. Mane, K. Vanka, S. C. Taneja and
B. A. Shah, Eur. J. Org. Chem., 2014, 2014, 5247.
M. J. Aurell, L. Ceita, R. Mestres, M. Parra and A. Tortajada,
Tetrahedron, 1995, 51, 3915.
H.ꢀF. Chow and I. Fleming, J. Chem. Soc., Perkin Trans. 1, 1998, 17,
2651.
C. Camiletti, D. D. Dhavale, F. Donati and C. Trombini, Tetrahedron
Lett., 1995, 36, 7293.
4
5
6
7
L. Ratjen, P. GarciaꢀGarcia, F. Lay, M. E. Beck and B. List, Angew.
Chem., 2011, 50, 754.
8
9
P. Sawant and M. E. Maier, Eur. J. Org. Chem., 2012, 2012, 6576.
G. Bluet and J. M. Campagne, J. Org. Chem., 2001, 66, 4293.
Scheme 4 Preparation of dienol silyl ether
10 B. BazánꢀTejeda, G. Bluet, G. Broustal and J.ꢀM. Campagne, Chem. –
Eur. J., 2006, 12, 8358.
11 M. Christmann and M. Kalesse, Tetrahedron Lett., 2001, 42, 1269.
12 J. A. Gazaille and T. Sammakia, Org. Lett., 2012, 14, 2678.
Lastly, similar to aldehyde 12 all additions of dienolate to the
ketones (28-31) failed (Scheme 5). The current method cannot
tolerate any acidic proton on the α carbon of carbonyls.
1) TMSCl, Ag2CO3,
DMF,0 oC, 1h.
O
O
OH
(Ar)R
O
OMe
MeO
2) 28-31, TBAF, 24 h.
0 oC -> RT
2
32-35
O
O
O
28
29
30
31
Scheme 5 Addition of methyl 3ꢀbutenoate to different ketones
A new selective enolization methodology for β,γꢀunsaturated
esters was developed and used in vinylogous aldol addition
reactions. The exact reaction mechanism and the role of the reagents
in the reaction are not clear yet, but reaction cannot be carried out in
the absence of any one of the reagents, TMSCl, TBAF, and silver
carbonate. The methodology does not require large amounts of
starting materials, and it can be simply applied to small amounts of
valuable aldehydes or vinyl acetate derivatives.
This work was supported by the Scientific and Technological
Research Council of Turkey (TÜBĐTAK, 110T782).
Experimental Section
To a twoꢀnecked round bottom flask 34 mg of Ag2CO3 (0.125
mmol, 0.5 eq.) and 4 mL of anhydrous DMF were added. The
mixture was stirred about 20 minutes at room temperature and
cooled down to 0 ºC in ice bath. Then 28 ꢁL of methyl 3ꢀbutenoate
(0.25 mmol, 1 eq.) and 33 ꢁL of TMSCl (0.25 mmol, 1 eq.) were
added sequentially. After solution was stirred 1 h at 0 ºC, 72 ꢁL 1ꢀ
naphthaldehyde (0.5 mmol, 2 eq.) and 0.25 mL TBAF (1.0 in M
THF) (0.25 mmol, 1 eq.) were added to the reaction mixture. The
final mixture was allowed to warm to room temperature and stirred
for 24 h. The mixture was poured into 30 mL of water and extracted
with Et2O (3x40 mL). Combined organic phase was dried over
MgSO4 and excess solvent was removed under reduced pressure.
Purification of crude product on SiO2 column (1:6 ꢀ1:4;
EtOAc:Hexane) furnished 48 mg of (E)ꢀmethyl 5ꢀhydroxyꢀ5ꢀ
(naphthalenꢀ5ꢀyl)pentꢀ2ꢀenoate (8) as yellow oil in 75% yield.
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