Synthesis of 2-(buta-1,3-diynyl)-N,N-dimethylanilines Using Reductive Methylation Step

Article abstract of DOI:10.1016/j.mencom.2014.03.013

Synthesis of 2-(buta-1,3-diynyl)-N,N-dimethylanilines based on reductive methylation of ortho-iodoanilines using CH2O-NaBH3CN and coupling with terminal diacetylens was developed. Altered sequence including dimethylation of 2-(buta-1,3-diynyl)anilines was

Full text of DOI:10.1016/j.mencom.2014.03.013

Mendeleev
Communications
Mendeleev Commun., 2014, 24, 102–104
Synthesis of 2-(buta-1,3-diynyl)-N,N-dimethylanilines
using reductive methylation step
Alexandra E. Kulyashova, Elena V. Mikheeva, Natalia A. Danilkina and Irina A. Balova*
Institute of Chemistry, St. Petersburg State University, 198504 St. Petersburg, Russian Federation.
Fax: +7 812 428 6733; e-mail: balova.irina@chem.spbu.ru
DOI: 10.1016/j.mencom.2014.03.013
Synthesis of 2-(buta-1,3-diynyl)-N,N-dimethylanilines based on reductive methylation of ortho-iodoanilines using CH2O–NaBH3CN
and coupling with terminal diacetylens was developed. Altered sequence including dimethylation of 2-(buta-1,3-diynyl)anilines was
also successfully achieved and gave higher overall yields in the case of anilines without acceptor substituent in the ring.
NH2
CH2O (30 equiv.),
NaBH3CN (4 equiv.),
MeCN, AcOH
NMe2
HNMe
Following the studies by Stephens and Castro who stated the
formation of indoles in a reaction of 2-iodoaniline with copper
acetylenides,1 intramolecular cyclization involving an amino
group and an ethynyl moiety became common to access various
indoles.2 The cyclization is catalysed by bases or transition metal
salts, among which Cu, Au or Pd ones proved to be the most
efficient and versatile with respect to the nature of the other
functional groups in starting substrates.3 The electrophilic cyclization
of N,N-dimethyl-2-ethynylanilines on treatment with elementary
iodine was employed in a synthesis of 3-iodoindoles4 and other
indole derivatives.5 Upon replacement of the ethynyl substituent
by the 1,3-diynyl moiety, the iodocyclization should result in
3-iodo-2-ethynyl-substituted heterocycles.We used this approach
as the key step in syntheses of enediyne systems fused to a
heterocyclic moiety.6
2-(Buta-1,3-diynyl)-N,N-dimethylanilines are usually used
as substrates in electrophilic cyclization. These compounds are
obtained by Sonogashira cross-coupling of 2-iodo-N,N-dimethyl-
aniline with terminal acetylenes.4(e),7,8 Though direct methylation
ofanilinesisrathersimplechemistry, a limited number of syntheses
of 2-iodo-N,N-dimethylanilines have been reported: the classical
Hoffmann’s procedure using iodomethane in the K2CO3–DMF
system4(d) or in the K2CO3–MeCN system9 and treatment of
2-iodoanilines with dimethyl sulfate10 or methyl trifluoromethane-
sulfonate.11 The efficiency of methylation of anilines depends on
the nucleophilicity of the amino group, hence ring substituents
affect the product yield. Electron-withdrawingsubstituents decrease
the yield considerably, and methylation of 2-iodoanilines with an
alkoxycarbonyl substituent using the Hoffmann reaction gives
N,N-dimethylated products in rather low yields (about 40%).8
Two examples of reductive methylation of 2-iodoaniline to
afford N,N-dimethylated derivatives have been reported: by the
Eschweiler–Clarke reaction12,13 and by treatment with formalin
and sodium borohydride as the reducing agent (modification in
dilute sulfuric acid).14 On the other hand, the use of formalin
in the presence of sodium cyanoborohydride (NaBH3CN) in
MeCN–AcOH in syntheses of aliphatic and aromatic dimethylated
amines15,16 proved to be highly efficient and selective method with
respect to the reduction of the imine intermediate in the presence
of ester, keto, ether and other functional groups.17,18 Surprisingly,
this technique was not applied previously to the preparation of
2-iodo-N,N-dimethylanilines and their derivatives from the cor-
responding 2-iodoanilines.
I
I
I
+
X
X
2a–d
X
1a–d
3a,d
a X = COOEt
b X = H
c X = COOMe
d X = CN
Scheme 1
Table 1 Reductive methylation of o-iodoanilines.
Reaction
time
Product 2 Product 3
yield (%) yield (%)
Entry
Amine
T/°C
1
2
3
4
5
6
1a
1a
1a
1b
1c
1d
7–20
7 days
7 days
3 days
2 h
2a (38)b
2a (40)b
2a (82)
2b (97)
2c (64)
2d (39)b
3a (31)b
3a (38)b
—
19–27
Up to 90a
Up to 90a
Up to 90a
Up to 90a
—
16 h
—
3d (27)b
7 days
a The experiments were carried out without external cooling of the reaction
mixture at the time when acetic acid was added. b The yields are specified
with respect to the starting amine 1a or 1d that entered the reaction.
philic cyclization, we decided to use reductive methylation of
2-iodoanilines with formalin and sodium cyanoborohydride.
2-Iodoaniline 1b, 4-amino-3-iodobenzonitrile 1d and 4-amino-
3-iodobenzoic esters 1a,c were chosen as the objects of the study
(Scheme 1, Table 1).
Methylation of 4-ethoxycarbonylaniline 1a with cooling of
the reaction mixture to the specified temperatures during the
addition of acetic acid (Table 1, entries 1, 2) resulted in the
formation of mono- and dimethylated anilines in ~1:1 ratio.
Under these conditions, conversion of the starting aniline 1a did
not exceed 86% even after 7 days. Raising the temperature up to
90°C allowed to obtain 2-iodo-N,N-dimethylaniline 2a as a single
reaction product in high yield (entry 3). The same conditions
proved to be efficient in a synthesis of dimethylated anilines 2b,c
(entries 4, 5). However, these conditions did not afford the full
conversion of substrate 1d containing a strong electron-with-
drawing nitrile group. In this case N-methyl- and N,N-dimethyl
derivatives 3d and 2d were isolated in 27% and 39% yields,
respectively (entry 6) at 92% conversion of the starting compound.
It should be emphasized that scaling up of the reaction also affected
In order to develop an efficient method for the synthesis of
2-(buta-1,3-diynyl)-N,N-dimethylanilines, substrates for electro-
© 2014 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2014, 24, 102–104
Table 2 Sonogashira coupling of iodoanilines 2a,c with diacetylenes.
Entry Iodoaniline Diacetylene Base Solvent Product Yield (%)
Table 3 Synthesis of 2-(buta-1,3-dyinyl)-N,N-dimethylanilines by cross-
coupling–N-methylation sequence.
Substituent
R
Cross-coupling
Methylation
1
2
3
4
5
6
2c
4a
4b
4a
4b
4c
4d
Et3N
Et3N
THF
THF
5a
5b
5a
5b
5c
5d
—
X
Product Yield (%) Product Yield (%)
—
DIPA DMF
DIPA DMF
DIPA DMF
DIPA DMF
43
H (1b)
H (1b)
CO2Me (1c) Ph (4b)
C8H17 (4a) 7a
90
73
52
8a
8b
5b
69–76
72–80
21
48
Ph (4b)
7b
7c
61–82
61
R
R
7
8
9
2a
4a
4b
4c
DIPA DMF
DIPA DMF
DIPA DMF
6a
6b
6c
79
NMe2
NH2
NH2
45–86
79–82
I
i
ii
R
NMe2
NMe2
X
X
X
I
1b,c
7a–c
8a,b, 5b
i
+
RC CC CH
Scheme 3 Reagents and conditions: i, 4a or 4b, Pd(PPh3)2Cl2 (0.05 equiv.),
PPh3 (0.1 equiv.), Et3N (15.0 equiv.), CuI (0.15 equiv.), THF, 40°C; ii, CH2O
(37% aqueous solution) (30.0 equiv.), NaBH3CN (4.0 equiv.), AcOH, MeCN.
4a–d
CO2Alk
CO2Alk
5a–d, 6a–c
2a,c
1,3-diynyl)-substituted anilines 7a,b by treatment with formalin
in the presence of sodium cyanoborohydride in the MeCN–AcOH
system led to compounds 8a,b in good yields. This sequence
proved to be more efficient due to higher overall yields of dimethyl
derivatives 8a,b. It should be noted that methylation of anilines
7a,b with iodomethane in the K2CO3–DMF system afforded a
mixture of N-methylated and N,N-dimethylated 2-(buta-1,3-
diynyl)anilines along with quaternized products and allowed to
isolate target products 8a,b in yields not higher than 45%.
The presence of two acceptor substituents [4-methoxycarbonyl
and 2-(buta-1,3-diynyl)] in compound 7c considerably decreases
the nucleophilicity of the amino group, which affected in prolonga-
tion of the reaction time, significantly reduced the conversion and
the yield of the product 5b. Therefore, the reverse sequence of
methylation and cross-coupling is preferable in this case.
In conclusion, reductive methylation with formalin and sodium
cyanoborohydride is an efficient alternative to the Hoffman reac-
tion for the methylation of 2-iodoanilines, including those con-
taining alkoxycarbonyl substituents at 4-position. Carrying out
the reaction without cooling the reaction mixture during the addition
of acetic acid allowed to obtain exclusively target N,N-dimethylated
aniline derivatives. The application of reductive methylation and
the Sonogashira cross-coupling using DMF as the solvent and
DIPA as the base is an efficient approach to the synthesis of
2-(buta-1,3-diynyl)-N,N-dimethylanilines – substrates for the
electrophilic cyclization. We also demonstrated that reductive
methylation in the presence of sodium cyanoborohydride in the
MeCN–AcOH system can be successfully used for the dimethyla-
tion of 2-(buta-1,3-diynyl)anilines.
2c, 5 Alk = Me
2a, 6 Alk = Et
4–6 a R = C8H17
b R = Ph
c R = (CH2)4OH
d R = (CH2)5OH
Scheme 2 Reagents and conditions: i, Pd(PPh3)2Cl2 (0.05 equiv.), PPh3
(0.1 equiv.), NEt3 (15.0 equiv.) or DIPA (4.0 equiv.), CuI (0.15 equiv.), THF
or DMF, 40°C.
the yield of the products 2a,c. When the syntheses were carried
out in less than one gram scale, the reaction gave only the
dimethylated derivatives. When the scale was raised to 5–8 g,
after three days, the reaction mixture contained all the three com-
ponents 1–3, which was apparently due to decomposition of sodium
cyanoborohydride. Therefore, an additional amount of the reagents
(50% of the initial amount) was necessary for complete conver-
sion of the starting compounds 1b,c to dimethylated products.
Then, in order to synthesize diacetylenic derivatives 5 and 6,
i.e., substrates for electrophilic cyclization, the N,N-dimethylated
products 2a,c were subjected to the Sonogashira cross-coupling7
with terminal diacetylenes 4a–d (Scheme 2, Table 2). The latter
were obtained by isomerization of internal diacetylenic hydro-
carbons and alcohols (in the case of compounds 4a,c,d),19,20 and
by retro-Favorskii reaction21 (in the case of phenyldiacetylene 4b).
The yield of cross-coupling was considerably affected by the
nature of the base and the solvent. If the reaction was carried
out in THF using triethylamine as the base, no products of the
coupling between 2c and 4a,b were observed (Table 2, entries 1, 2).
Replacement of the THF–Et3N system by a more polar one, namely,
DMF with diisopropanolamine (DIPA, 4-azaheptane-2,6-diol) as
the base, led to the complete conversion of the aniline 2c within
8 h to give the target products 5a,b (entries 3, 4). However, the
yields were moderate, probably due to the low stability of terminal
diacetylenes 4a,b under the reaction conditions. Therefore, the
excess of terminal diacetylenes was raised from 1.5 to 3 equiv. in the
case of substrate 2a. This modification allowed to increase the yield
of compounds 6a,b (entries 7, 8). A 3.5-fold excess was used for
very unstable terminal diacetylenic alcohols 4c,d providing good
yields of the cross-coupling products 5c,d and 6c (entries 5, 6, 9).
It also seemed appropriate to examine the possibility of obtaining
substrates for electrophilic cyclization by altering the sequence of
reductive methylation and cross-coupling reaction steps. Com-
mercially available 2-iodoanilines 1b,c readily underwent Pd/Cu-
catalyzed Sonogashira coupling with terminal diacetylenes using
Pd(PPh3)2Cl2 and CuI as the catalysts in the Et3N–THF system at
40°C (Scheme 3, Table 3). Methylation of the resulting 2-(buta-
This study was supported by St. Petersburg State University
(grant no. 12.38.195.2014) and grant of the President of the RF
(MK-3322.2014.3). The researches were carried out using the
equipment of the resource centres of St. Petersburg State University:
Centre of Magnetic Resonance and Center for Chemical Analysis
and Materials Research.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2014.02.013.
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Received: 20th September 2013; Com. 13/4207
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