4-(Dimethylamino)pyridine as a catalyst for the lactonization of 4-hydroxy-2-methylenebutanoate esters

Article abstract of DOI:10.1016/j.tetlet.2014.02.024

The catalytic action of 4-(dimethylamino)pyridine (DMAP) in lactonizing 4-hydroxy-2-methylenebutanoate esters to 2-methylene-γ-butyrolactones is described. The use of DMAP, which functions as an excellent complement to the more traditional acid-catalyzed lactonization protocol, allows for the synthesis of 2-methylene-γ-butyrolactones containing acid-sensitive groups under essentially neutral conditions.

Full text of DOI:10.1016/j.tetlet.2014.02.024

Tetrahedron Letters 55 (2014) 2075–2077
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
4-(Dimethylamino)pyridine as a catalyst for the lactonization
of 4-hydroxy-2-methylenebutanoate esters
⇑
Daniel R. Nicponski
Department of Chemistry, Purdue University, 560 Oval Dr., West Lafayette, IN 47907, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The catalytic action of 4-(dimethylamino)pyridine (DMAP) in lactonizing 4-hydroxy-2-methylenebut-
Received 14 January 2014
Revised 8 February 2014
Accepted 10 February 2014
Available online 20 February 2014
anoate esters to 2-methylene-
excellent complement to the more traditional acid-catalyzed lactonization protocol, allows for the
c-butyrolactones is described. The use of DMAP, which functions as an
synthesis of 2-methylene-
conditions.
c
-butyrolactones containing acid-sensitive groups under essentially neutral
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Lactonization
Cyclization
Esterification
Catalysis
Green chemistry
There has been a recent resurgence in consideration of the
-methylene- -butyrolactone scaffolding in synthetic and medici-
butanoates. Specifically, the development of a method that could
take place under essentially neutral conditions, thereby allowing
a higher degree of functional group tolerance, would be especially
welcome.
A recent disclosure by our research group of a novel aminolact-
onization reaction, was, by careful investigation of the mechanism,
a
c
nal chemistry. This is likely due to their common occurrence in
natural products and the wide range of biological activities
reported for such compounds.1 Some of these potentially useful
pharmacological effects include anti-malarial,2 anti-cancer,2,3
anti-bacterial,2 anti-fungal,2 anti-viral,2 anti-inflammatory,2 and
anthelmintic4 properties, along with other immune system
responses. More recently, they have been investigated for their
demonstrated to proceed through
a unique pathway which
involved a conjugate addition followed by an intramolecular pro-
ton transfer and subsequent lactonization.11 As the final step in
this mechanism occurs by way of a pericyclic proton transfer from
the 4-hydroxyl group to the enolate, it seemed reasonable that
such a lactonization could still occur if the conjugate addition were
reversible. Upon consideration of the Morita–Baylis–Hillman
(MBH) reaction, which proceeds by way of a reversible conjugate
addition and generation of a comparably incipient enolate, it
seemed natural that the use of similar catalysts could affect the
enolization–lactonization sequence, thereby providing an attrac-
tive alternative to the use of acid catalysts in the synthesis of these
lactones. The notion of performing intramolecular reactions with
these enolates is not a new one. For example, when made to
undergo conjugate addition onto a tethered Michael acceptor, the
reaction of these enolates is typically referred to as the
Rauhut–Currier reaction (Fig. 1).12
biological effects on the NF-jB pathway, which has been linked
to a variety of disorders, including diabetes, cancers, arthritis,
and Alzheimer’s disease.5
A
large amount of research into the production of this
important pharmacophore has been reported in the literature,
and a variety of methods for its synthesis has been developed.1
These methods include the Dreiding–Schmidt reaction,6 the
chloropalladation of acetylenic acids,7 the allylation of aldehydes
in the presence of Brønsted or Lewis acids,8 and the direct lacton-
ization of precursor butanoates. Typically, the latter approach
makes use of an acid-catalyzed lactonization, using promoters such
as trifluoroacetic acid9 or p-toluenesulfonic acid monohydrate.10
Unfortunately, a variety of acid-sensitive functional groups are
not well-tolerated by these acidic conditions. Accordingly,
there remains interest in developing an alternative method for
lactonization which makes use of these same precursor
It was discovered that 4-(dimethylamine)pyridine (DMAP)—a
common catalyst used for the MBH reaction13—was efficacious in
affecting this desired transformation. Indeed,
a very high
conversion was observed when the reaction was performed at
ambient temperature and in an ethanolic medium. In fact, the
model lactonization reaction of methyl syn-4-hydroxy-2-methy-
⇑
Tel.: +1 765 494 5317.
E-mail address: drn2@purdue.edu
http://dx.doi.org/10.1016/j.tetlet.2014.02.024
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2076
D. R. Nicponski / Tetrahedron Letters 55 (2014) 2075–2077
Rauhut-Currier Reaction:
R2
Nuc
O
OH
O
Aldehyde
DABCO
HBr/HOAc
R2 OH
R1
R2
O
O
R2
OMe
OMe
O
O
O
O
O
O
Aldehyde
In (powder)
R1
R1
Nuc
- Nuc
R1
O
R1
OMe
R1
OMe
n
n
n
n
THF/H2O
Nuc
Br
R2
O
Scheme 1. Route used for producing lactonization substrates.
R1
This work:
Table 2
Three-step route used for the production of substrates
O
OH
OH
-MeOH
- Nuc
O
OMe
O
OMe
O
OMe
R2 OH
Nuc
Aldehyde
O
O
O
Aldehyde HBr/HOAc In (powder)
O
OMe
DABCO
R1
No.
THF/H2O
OMe
Nuc
Nuc
Figure 1. Examples of intramolecular reactions of generated enolate ions.
Entry
1
Product
OH
Yielda (%)
14
O
3
4
OMe
lene-3,4-diphenylbutanoate could be catalyzed with catalytic load-
ings as low as 1 mol %, albeit, at extremely long reaction times
(Table 1). While DMAP has been reported to be an effective catalyst
for a variety of reactions, including azetidination,14 cyanation,15
intermolecular esterification,16 acylation,17 and for cycloadditions
such as aromatization,18 this appears to be the first such case in
which it catalyzes a lactonization reaction which functions by
way of an intramolecular proton transfer mechanism.
To test the generality of this new lactonization procedure, a
series of functionally complex 4-hydroxy-2-methylenebutanoate
esters which contained electronically and sterically diverse sub-
stituents were designed, then constructed through the three-step
process shown in Scheme 1. The compounds produced for this
methodology (Table 2) possessed a number of sensitive functional-
ities, including thiophenyl (entry 6), furyl (entries 8 and 9), indolyl
(entry 8), and acyloxy and benzyloxy groups (entry 11). Knowing
that an allylic bromide could be chemoselectively activated with
indium metal, then subsequently reacted with an electrophile,
while in the presence of an arylic bromide,19 several aryl bro-
mide-containing substrates were successfully constructed (entries
10 and 11). A naphthol group was also chosen for inclusion in this
methodology, as it was believed that this would potentially offer
an opportunity to demonstrate a ring size-selective formation of
a butyrolactone in lieu of a caprolactone.
OH
O
Ph
2
3
14
74
62
70
36
23
29
36
72
63
OMe
c-C6H11
OH
O
5
4-Me-Ph
3-F-Ph
OMe
OH
O
4
6
n-C3H7
OMe
OH
2-HO-1-Naph
O
5
7
n-C3H7
OMe
OMe
2-Thiophenyl
OH
O
6
8
E-Styryl
3,4,5-(MeO)3-Ph
OH
O
7
9
E-Styryl
OMe
N-Boc-3-Indolyl
OH
O
8
10
11
12
13
2-Furyl
OMe
4-CF3-Ph
OH
O
9
2-Furyl
OMe
The application of these lactonization conditions to these
substrates was then performed (Table 3). Due to the sluggish
nature of the reaction when using lower catalytic loadings, these
reactions were performed using 50 mol % DMAP catalyst.
As can be seen from the table, a variety of functionalities were
tolerated under these conditions. That the lactonization to form 15
4-CF3-Ph
OH
O
10
11
3-Br-Ph
OMe
OH
3-AcO-4-BnO-Ph
2-Br-Ph
O
OMe
a
Combined yield for three steps.
Table 1
Determination of catalytic turnover
Ph
OH
O
from tertiary alcohol 4 was not problematic, indicating that less
nucleophilic tertiary alcohols could also be cyclized by this
methodology, was especially gratifying. The exclusive formation
O
Ph
Ph
O
DMAP [mol %]
EtOH, 25 °C
Ph
OMe
1
2
of 18 indicated the preferred formation of
a butyrolactone.
Especially pleasing was the discovery that many of the sensitive
functionalities, including furyl and Boc-protected indolyl (entry
8), and acyloxy and benzyloxy groups (entry 13) were well-
tolerated. For reasons that are not clear at this time, the use of
the thiophene-containing 8 did not provide the expected butyro-
lactone, but rather the ethyl butanoate, presumably by means of
a base-catalyzed transesterification reaction.
Entry
DMAP (mol %)
Time (h)
Yield (%)
1
2
3
4
5
6
200
100
50
25
10
1
12
30
40
55
90
ꢀ165
>99
>99
>99
>99
>99
>99

D. R. Nicponski / Tetrahedron Letters 55 (2014) 2075–2077
2077
Table 3
Application of lactonization conditions to butanoate substrates
Supplementary data
Supplementary data (mass data, along with 1H, 13C, and 19F
NMR spectra) associated with this article can be found, in the on-
line version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.024.
R2 OH
O
R2
O
O
DMAP [50 mol%]
EtOH
R1
OMe
R1
Entry
1
Ester
Product
No.
Yield (%)
93
Time (h)
150
References and notes
O
O
3
4
14
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Angew. Chem., Int. Ed. 2009, 48, 9426; (b) Hoffmann, H. M. R.; Rabe, J. Angew.
Chem. 1985, 97, 96; (c) Hoffman, H.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985,
24, 94; (d) Picman, A. K. Biochem. Syst. Ecol. 1986, 14, 255; (e) Grieco, P. A.
Synthesis 1975, 67; (f) Sarma, J. C.; Sharma, R. P. Heterocycles 1986, 24, 441; (g)
Petragnani, N.; Ferraz, H. M. C.; Silva, G. V. J. Synthesis 1986, 157; (h) Collins, I. J.
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2008, 2353; (j) Elford, T. G.; Hall, D. G. Synthesis 2010, 6, 893.
O
O
Ph
2
3
15
16
>99
53
65
90
O
c-C6H11
O
O
5
6
2. (a) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985, 24, 94; (b)
Picman, A. K. Biochem. Syst. Ecol. 1986, 14, 255.
4-Me-Ph
3-F-Ph
O
3. (a) Holcomb, B. K.; Yip-Schneider, M. T.; Waters, J. A.; Beane, J. D.; Crooks, P. A.;
Schmidt, C. M. J. Gastrointest. Surg. 2012, 16, 1333; (b) Nasim, S.; Crooks, P. A.
Bioorg. Med. Chem. Lett. 2008, 18, 3870; (c) Shanmugam, R.; Kusumanchi, P.;
Appaiah, H.; Cheng, L.; Crooks, P.; Neelakantan, S.; Peat, T.; Klaunig, J.;
Matthews, W.; Nakshatri, H.; Sweeney, C. J. Int. J. Cancer 2011, 128, 2481; (d)
Lesiak, K.; Koprowska, K.; Zalesna, I.; Nejc, D.; Duchler, M.; Czyz, M. Melanoma
Res. 2010, 20, 21; (e) Huang, W.-C.; Chan, S.-T.; Yang, T.-L.; Tzeng, C.-C.; Chen,
C.-C. Carcinogenosis 2004, 25, 1925.
4
5
17
18
89
98
75
60
n-C3H7
O
O
2-HO-1-Naph
7
n-C3H7
O
2-Thiophenyl
O
4. Steurer, S.; Podlech, J. Eur. J. Org. Chem. 2002, 899.
a
6
7
8
9
19
20
21
22
23
24
—
28
25
90
19
45
26
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M.; Yamamoto, Y.; Wang, Q. M. Nat. Rev. Drug Disc. 2004, 3, 17.
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(b) Löffler, A.; Pratt, R. D.; Pucknat, J.; Gelbard, G.; Dreiding, A. S. Chimia 1969,
23, 413; (c) Löffler, A.; Pratt, R. J.; Rüesch, H. P.; Dreiding, A. S. Helv. Chim. Acta
1970, 53, 383.
E-Styryl
O
3,4,5-(MeO)3-Ph
O
51
49
22
62
88
E-Styryl
O
7. Dong, Y.; Guo, X.; Yu, Y. Y.; Liu, G. Mol. Divers. 2013, 17, 1.
N-Boc-3-Indolyl
O
8. (a) Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002, 124, 11586; (b)
Ramachandran, P. V.; Pratihar, D. Org. Lett. 2007, 9, 2087; (c) Ramachandran, P.
V.; Pratihar, D.; Biswas, D.; Srivastava, A.; Reddy, M. V. R. Org. Lett. 2004, 6, 481;
(d) Elford, T. G.; Arimura, Y.; Yu, S. H.; Hall, D. G. J. Org. Chem. 2007, 72, 1276; (e)
Chataigner, I.; Zammattio, F.; Lebreton, J.; Villiéras, J. Tetrahedron 2008, 64,
2441.
9. Lee, S. I.; Jang, J. H.; Hwang, G. S.; Ryu, D. H. J. Org. Chem. 2013, 78, 770.
10. Kim, K. H.; Lee, H. S.; Kim, S. H.; Lee, K. Y.; Lee, J.; Kim, J. N. Bull. Korean Chem.
Soc. 2009, 30, 1012.
8
10
11
12
13
2-Furyl
O
4-CF3-Ph
O
9
2-Furyl
O
4-CF3-Ph
O
10
11
3-Br-Ph
11. Ramachandran, P. V.; Nicponski, D. R. Aminolactonization: A Tandem Reaction
for the Highly Diastereoselective Synthesis of
Butyrolactones, manuscript submitted for publication.
a-(Aminomethyl)-c-
O
3-AcO-4-BnO-Ph
O
12. (a) Rauhut, M.; Currier, H. U.S. Patent American Cyanamide Co. 3074999, 1963;
(b) Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem.
Soc. 2002, 124, 2402; (c) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem.
Soc. 2002, 124, 2404; (d) Aroyan, C. E.; Dermenci, A.; Miller, S. J. Tetrahedron
2009, 65, 4069.
2-Br-Ph
Reactions were carried out at 0.1 M in EtOH and at 25 °C using 50 mol % DMAP.
Only the ethyl ester of the starting material was produced under the applied
conditions.
a
13. (a) Rezgui, F.; El Gaied, M. M. Tetrahedron Lett. 1998, 39, 5965; (b) Lee, K. Y.;
Gong, J. Y.; Kim, J. N. Bull. Korean Chem. Soc. 2002, 23, 659.
14. Meng, L.-G.; Cai, P.; Guo, Q.; Xue, S. J. Org. Chem. 2008, 73, 8491.
15. Aoki, S.; Kotani, S.; Sugiera, M.; Nakajima, M. Tetrahedron Lett. 2010, 51, 3547.
16. Sakakura, A.; Kawajiri, K.; Ohkubo, T.; Kosugi, Y.; Ishihara, K. J. Am. Chem. Soc.
2007, 129, 14775.
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4751.
Despite the relatively long reaction times required for the
completion of the lactonization reactions with DMAP catalysis, this
new methodology is an excellent complement to the acid-catalyzed
one. As one example, lactonization of the highly sensitive
compound 10 through the catalytic action of p-toluenesulfonic acid
monohydrate in methylene chloride provided lactone 21 in only
33% yield, compared to 49% with the present method.
In conclusion, the use of 4-(dimethylamino)pyridine as a unique
lactonization catalyst has been developed.20 This new methodol-
ogy, which offers an interesting alternative to the use of more
traditional catalysts, allows for the incorporation of acid-sensitive
18. (a) Yang, H.-T.; Ren, W.-L.; Miao, C.-B.; Dong, C.-P.; Yang, Y.; Xi, H.-T.; Meng, Q.;
Jiang, Y.; Sun, X.-Q. J. Org. Chem. 2013, 78, 1163; (b) Nair, V.; Vidya, N.; Biju, A.
T.; Deepthi, A.; Abhilash, K. G.; Suresh, E. Tetrahedron 2006, 62, 10136.
19. Ramachandran, P. V.; Nicponski, D. R.; Drolet, M. P.; Schmidt, C. M.; Yip-
Schneider, M. T. Future Med. Chem. 2013, 5, 633.
20. All new compounds gave satisfactory spectroscopic and analytical results.
Representative experimental procedure: Into a flask that had been charged with a
magnetic stir bar was added 1.0 equiv of butanoate ester. This material was
dissolved in enough EtOH to furnish a 0.1 M solution, whereafter 0.50 equiv of
DMAP was added. The reaction mixture was stirred until deemed complete by
TLC analysis, after which time, the solution was partitioned between deionized
water and CH2Cl2. The organic layer was separated, then the residual product
was further extracted from the aqueous layer with an additional portion of
CH2Cl2. The combined organic layers were subsequently washed with brine,
dried with Na2SO4, filtered, and concentrated. The crude organic product was
groups during the formation of c-butyrolactones from 4-hydroxy-
butanoate esters. Further work to develop this methodology is
ongoing, and will be reported in due course.
then purified via column chromatography to furnish the desired c-lactone.