A new method using 2-chloro-4,6-dimethoxy-1,3,5-triazine for facile elimination of dimethylamino group in Eschenmoser's methylenation for synthesis of α,β-unsaturated esters

Article abstract of DOI:10.1016/j.tetlet.2013.01.092

A facile one-step method for the elimination of the dimethylamino group in Eschenmoser's methylenation has been developed using a combination of 2-chloro-4,6-dimethoxy-1,3,5-triazine and triethylamine. The chemoselective elimination of the dimethylamino group occurred in compounds possessing either a diethylamino group or an alkylsulfanyl group.

Full text of DOI:10.1016/j.tetlet.2013.01.092

Tetrahedron Letters 54 (2013) 1758–1760
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Tetrahedron Letters
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A new method using 2-chloro-4,6-dimethoxy-1,3,5-triazine for facile
elimination of dimethylamino group in Eschenmoser’s methylenation
for synthesis of a,b-unsaturated esters
Kohei Yamada a, Kazumasa Masaki a, Yuri Hagimoto b, Seina Kamiya c, Munetaka Kunishima a,b,
⇑
a Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
b Cooperative Research Center of Life Sciences, Kobe Gakuin University, 1-1-3 Minatojima Chuo-ku, Kobe 655-8586, Japan
c Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima Chuo-ku, Kobe 655-8586, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile one-step method for the elimination of the dimethylamino group in Eschenmoser’s methylena-
tion has been developed using a combination of 2-chloro-4,6-dimethoxy-1,3,5-triazine and triethyl-
amine. The chemoselective elimination of the dimethylamino group occurred in compounds
possessing either a diethylamino group or an alkylsulfanyl group.
Received 24 December 2012
Revised 18 January 2013
Accepted 21 January 2013
Available online 30 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Eschenmoser’s methylenation
2-Chloro-4,6-dimethoxy-1,3,5-triazine
(CDMT)
a,b-Unsaturated esters
Introduction
(CDMT) as a reagent for the activation of the dimethylamino
group. CDMT is known to react with tertiary amines such as
Methylenation at the
reaction in organic synthesis as the resulting
bonyl groups occur in many natural products and are versatile
functional groups that can undergo further transformation.
Eschenmoser’s methylenation is a reliable and widely used method
a
-position of a carbonyl group is a useful
4-methylmorpholine and N,N-dimethylglycine esters to form
triazinylammonium salts that act as dehydrocondensing reagents
such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholini-
um chloride (DMT-MM).5 As these reactions complete within
30 min at room temperature,6 the reaction of a dimethylamino
group with CDMT is expected to proceed rapidly. In addition, the
elimination of the resulting triazinylammonio group is expected
to be faster than that of the trimethylammonio group because of
the strong electron-withdrawing nature of the triazinyl group.7
We have previously reported that when DMT-MM is suspended
in CH2Cl2 for 3 h at room temperature, DMT-MM completely
a
,b-unsaturated car-
for the introduction of a methylene group at the
a-position of a
carbonyl group.1,2 However, this is a three-step reaction that can
be both complicated and time consuming (Scheme 1). These steps
include the introduction of an N,N-dimethylaminomethyl group
using
a
base and N,N-dimethylmethyleneiminium iodide
(Eschenmoser’s salt) (STEP 1), conversion of the dimethylamino
group to a trimethylammonio group by excess iodomethane
(MeI)3 (reaction time of approximately 24 h) or to an N-oxide
(reaction time of approximately 10 min) using an oxidant such as
m-chloroperbenzoic acid4 (STEP 2), elimination of the trimethyl-
ammonio group by a strong base such as DBU, or that of N-oxide
by thermolysis (STEP 3).
Developing a method for the rapid conversion of a dimethyl-
amino group to a more reactive leaving group and enabling its sub-
sequent facile elimination would allow chemists to conduct
Eschenmoser’s methylenation with both ease and efficiency. For
this purpose, we chose 2-chloro-4,6-dimethoxy-1,3,5-triazine
⇑
Corresponding author. Tel./fax: +81 76 264 6201.
E-mail address: kunisima@p.kanazawa-u.ac.jp (M. Kunishima).
Scheme 1. Traditional Eschenmoser’s methylenation methods.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.092

Kohei Yamada et al. / Tetrahedron Letters 54 (2013) 1758–1760
1759
decomposes (96%) into 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)mor-
pholine (DMTM) by demethylation because of the high leaving
ability of DMTM.8 In this study, we report a facile method for the
elimination of a dimethylamino group in Eschenmoser’s methyle-
nation using CDMT.
decrease in the latter cases, the decomposition of 3a by the 1,4-
addition and/or polymerization due to its high reactivity might
be responsible for decreasing its yields. Next, we examined the ef-
fect of changing the base in the reaction using DMF as a solvent.
When the reaction was conducted with DBU, the yield of 3a de-
creased (80%, entry 7). The reaction with K2CO3 and 4-methylmor-
pholine afforded only moderate yields (53% (entry 8) and 55%
(entry 9), respectively). The reaction with pyridine or without the
addition of any bases resulted in poor yields and the other by-
product 5 was obtained (entries 10 and 11). The by-product 5
might be generated via a SN2 reaction of the chloride anion with
a methyl group attached to the nitrogen atom. Since deprotonation
Results and discussion
The reaction scheme that we have designed is illustrated in
Scheme 2. When a b-dimethylamino ester 1 is treated with CDMT,
the nucleophilic attack of the dimethylamino group proceeds to
form the triazinylammonium salt 2. Subsequent E2 or E1cB elimi-
nation of the resulting triazinylammonium salt 2 takes place to
at the
a-position of the carbonyl group hardly proceeded under
neutral or weakly basic conditions, an alternative competing
demethylation occurred in these cases (Scheme 3).
give the desired a,b-unsaturated ester 3 along with the formation
of co-product 4.
The effect of changing the chemical structure of the starting
compound on the reaction was examined (Table 2). When the reac-
tion was conducted in DMF with compound 1b, which possesses a
As expected, the reaction of benzyl 3-(dimethylamino)propionate
(1a) using CDMT and triethylamine (Et3N) as a base in CH2Cl2 at
room temperature for 15 min afforded benzyl acrylate (3a) in
84% yield, along with a formation of 77% yield of co-product 4
(Table 1, entry 1).9 The highest yield (94%) of 3a was achieved
when DMF was used as a solvent (entry 2). The reaction in MeCN
and 2-PrOH also gave good yields (entries 3 and 4), whereas those
in MeOH and THF gave somewhat lower yields (75% (entry 5) and
74% (entry 6), respectively). Because the yields of 4 did not
methyl group at the
competitive demethylation, which is probably because of the steric
hindrance of the -proton of the carbonyl group (entry 1). To avoid
a-position, the yield decreased (50%) owing to
a
this demethylation, we used 2-PrOH instead of DMF to decrease
the nucleophilicity of the chloride anion by solvation. As expected,
the demethylation was prevented and the yield was increased to
90% (entry 2). A lactone type compound 1c was converted into
product 3c in 77% yield (entry 3). Application to the compound
1d, which possesses an ethylsulfanyl group that is susceptible to
decomposition by electrophiles and oxidants, afforded 3d in 86%
yield (entry 4), whereas the reaction of 1d with MeI (1 equiv)
Scheme 3. Formation of by-product 5 from intermediate 2.
Scheme 2. Reaction scheme for the elimination of the dimethylamino group using
CDMT and a base.
Table 2
Elimination of the dimethylamino group by CDMT and Et3N
Table 1
List of solvent and base conditions
Entry
1
3
Solvent Yielda (%)
1
2
DMF
2-PrOH 90
50
Entry
Solvent
Base
3aa (%)
4a (%)
5 (%)
b
1
2
3
4
5
6
7
8
9
CH2Cl2
DMF
MeCN
2-PrOH
MeOH
THF
DMF
DMF
DMF
DMF
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DBU
K2CO3
84
94
89
85
75
74
80
53
55
15c
15c
77
93
92
95
91
88
61
70
71
16c
16c
—
3
2-PrOH 77b
b
—
b
—
b
—
b
—
b
4
5
DMF
86
93
—
b
—
—
—
b
b
4-Methylmorpholine
Pyridine
None
19c
15c
CH2Cl2
10
11
DMF
a
b
c
a
Isolated yields.
Not detected.
Isolated yields.
Because it was difficult to isolate 3c from 4, the yield of 3c was estimated by 1
b
H
Determined by 1H NMR.
NMR spectroscopy from a mixture of 3c and 4 after column chromatography.

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Kohei Yamada et al. / Tetrahedron Letters 54 (2013) 1758–1760
Acknowledgment
This work was financially supported in part by a Grant-in-Aid
for Research Activity Start-up (22890072) from the Ministry of
Education, Culture, Sports, Science, and Technology of Japan.
Supplementary data
Scheme 4. Eschenmoser’s methylenation using CDMT and Et3N.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
01.092.
followed by elimination with aq NaHCO3 gives 3d in only 60% yield
(Eq. 1). The reaction of 1e possessing a diethylamino group pro-
ceeded via chemoselective quaternization of a dimethylamino
group to give desired acrylate 3e in 93% yield (entry 5),10 whereas
the reaction of 1e with MeI (1 equiv) followed by elimination with
aq NaHCO3 affords 3e in only 26% yield (Eq. 2). We reported that at
least one methyl group is essential for the formation of triaziny-
lammonium salts in acyclic tertiary amines because a b-alkyl group
maintained in a gauche relationship with the nitrogen lone pair
hinders the approach of CDMT to nitrogen (the gauche b-alkyl
group effect).11 Therefore, the observed high chemoselectivity be-
tween the dimethylamino group and the diethylamino group is
attributed to the lower reactivity of the diethylamino group to
CDMT by the gauche repulsion.12
Finally, we introduced a methylene group into benzyl acetate
(6) using the Mannich reaction and demonstrated its subsequent
elimination by CDMT and Et3N (Scheme 4). The introduction of
the dimethylaminomethyl group with lithium diisopropylamide
(LDA) and Eschenmoser’s salt followed by the elimination of the
dimethylamino group by CDMT and Et3N afforded 3a in 60% over
all yield:
References and notes
1. Danishefsky, S.; Kitahara, T.; McKee, R.; Schuda, P. F. J. Am. Chem. Soc. 1976, 98,
6715–6717.
2. For recent examples in 2010–2011, see: (a) Andrews, R. S.; Becker, J. J.; Gagné,
M. R. Angew. Chem., Int. Ed. 2010, 49, 7274–7276; (b) Bradshaw, B.; Etxebarria-
Jardi, G.; Bonjoch, J. J. Am. Chem. Soc. 2010, 132, 5966–5967; (c) Tsuboi, K.;
Nakamura, T.; Suzuki, T.; Nakazaki, A.; Kobayashi, S. Tetrahedron Lett. 2010, 51,
1876–1879; (d) Bon, D. J.-Y. D.; Banwell, M. G.; Willis, A. C. Tetrahedron 2010,
66, 7807–7814; (e) Armstrong, A.; Bettati, M.; White, A. J. P. Tetrahedron 2010,
66, 6309–6320.
3. Tamelen, E. E. V.; Bach, S. R. J. Am. Chem. Soc. 1955, 77, 4683–4684.
4. Brand, M.; Drewes, S. E.; Roos, G. H. P. Synth. Commun. 1986, 16, 883–889.
5. (a) Kunishima, M.; Kawachi, C.; Morita, J.; Terao, K.; Iwasaki, F.; Tani, S.
Tetrahedron 1999, 55, 13159–13170; (b) Kunishima, M.; Yoshimura, K.;
Morigaki, H.; Kawamata, R.; Terao, K.; Tani, S. J. Am. Chem. Soc. 2001, 123,
10760–10761; (c) Kunishima, M.; Nakanishi, S.; Nishida, J.; Tanaka, H.;
Morisaki, D.; Hioki, K.; Nomoto, H. Chem. Commun. 2009, 5597–5599; (d)
Kunishima, M.; Hioki, K.; Moriya, T.; Morita, J.; Ikuta, T.; Tani, S. Angew. Chem.,
Int. Ed. 2006, 45, 1252–1255; (e) Kunishima, M.; Tokaji, M.; Matsuoka, K.;
Nishida, J.; Kanamori, M.; Hioki, K.; Tani, S. J. Am. Chem. Soc. 2006, 128, 14452–
14453; (f) Kunishima, M.; Imada, H.; Kikuchi, K.; Hioki, K.; Nishida, J.; Tani, S.
Angew. Chem., Int. Ed. 2005, 44, 7254–7257; (g) Kunishima, M.; Kikuchi, K.;
Kawai, Y.; Hioki, K. Angew. Chem., Int. Ed. 2012, 51, 2080–2083.
6. Actually the reaction should be much faster because we can see a formation of
the precipitate of DMT-MM within a couple of minutes.
7. Mascal, M.; Armstrong, A.; Bartberger, M. D. J. Am. Chem. Soc. 2002, 124, 6274–
6276.
8. Kunishima, M.; Kawachi, C.; Iwasaki, F.; Terao, K.; Tani, S. Tetrahedron Lett.
1999, 40, 5327–5330.
ð1Þ
9. General procedure for elimination reaction: To
3-(dimethylamino)propionate 1a (383 mg, 1.85 mmol) in DMF (9 mL) were
added CDMT (325 mg, 1.85 mmol) and Et3N (260 L, 1.85 mmol) at room
a solution of benzyl
l
temperature. After being stirred for 15 min, the reaction mixture was
partitioned between Et2O and brine. The aqueous phase was extracted with
Et2O three times and the combined organic phases were dried over anhydrous
magnesium sulfate. The solvent was removed under reduced pressure and the
residue was purified by flash column chromatography (hexane:ethyl
acetate = 15:1) to give benzyl acrylate 3a (281 mg, 94%) as a colorless oil.
10. Because the reaction could not be worked up with water due to high polarity of
3e, CH2Cl2 was used as a solvent. After the completion of the reaction, the
solvent was removed under reduced pressure and the residue was directly
purified by flash column chromatography.
11. Kunishima, M.; Ujigawa, T.; Nagaoka, Y.; Kawachi, C.; Hioki, K.; Shiro, M. Chem.
Eur. J. 2012, 18, 15856–15867.
12. For the same reason, Et3N can work as a base without reacting with CDMT.
13. To the best of our knowledge, there is no example of application of traditional
methods to the compounds possessing dialkylamino group.
ð2Þ
In summary, we have demonstrated the use of a new method
(the combination of CDMT and Et3N) for the elimination of the
dimethylamino group in Eschenmoser’s methylenation. The elimi-
nation of the dimethylamino group afforded the corresponding
a
,b-unsaturated esters in good yields in one step and with short
reaction times (15 min). This new method could also be applied
to the compounds possessing a N,N-dialkylamino group with ethyl
or larger alkyl substituents at the nitrogen atom, a structure to
which conventional organic synthetic methods are unsuitable.13