Iron-catalyzed synthesis of glycine derivatives via carbon-nitrogen bond cleavage using diazoacetate

Article abstract of DOI:10.1039/c0cc03781h

Treatment of tertiary amines with diazoacetate in the presence of a catalytic amount of an iron salt, FeCl₃, in ethanol gave glycine derivatives. In this reaction, a carbon-nitrogen single bond of the amine was cleaved. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c0cc03781h

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Iron-catalyzed synthesis of glycine derivatives via carbon–nitrogen bond
cleavage using diazoacetatew
Yoichiro Kuninobu,* Mitsumi Nishi and Kazuhiko Takai*
Received 10th September 2010, Accepted 1st October 2010
DOI: 10.1039/c0cc03781h
Treatment of tertiary amines with diazoacetate in the presence
of a catalytic amount of an iron salt, FeCl3, in ethanol gave
glycine derivatives. In this reaction, a carbon–nitrogen single
bond of the amine was cleaved.
transition metal catalysts.11 By increasing the amount of FeCl3,
12
the yield of 3a increased to 83% yield (eqn (1)).z
The carbon–nitrogen bond (C–N bond) is strong in organic
molecules. Therefore, transformations via C–N bond cleavage
are usually difficult. However, such transformations would be
useful and powerful methods in synthetic organic chemistry
because many organic molecules contain carbon–nitrogen
bonds. There have been several reports on stoichiometric
carbon–nitrogen bond cleavage.1 However, it is still difficult
to cleave such bonds catalytically,2–4 except by using
substrates such as diazonium salts.5
ð1Þ
To investigate the scope and limitations, reactions between
several amines 1 and diazoacetate 2 were carried out (Table 1).
N,N-Dimethylanilines bearing an electron-donating group at
the para-position of the aromatic ring, 1b and 1c, gave glycines
3b and 3c in 92% and 73% yields, respectively (entries 1 and 2).
When N,N-dimethylaniline with a trifluoromethyl group,
1d, was treated with FeCl3, solvolysis of the trifluoromethyl
group of 1d occurred, 3d was not formed. By changing
the catalyst to MnBr2, the desired glycine 3d was obtained
(entry 3). The yields of the glycines 3e and 3f decreased when
N,N-dimethylanilines having a halogen atom at the para-
position of the aromatic ring were used (entries 4 and 6).
There have been several reports on transition metal-catalyzed
reactions between tertiary amines and diazoacetates.6 However,
in these reactions, the ethoxycarbonylmethyl group of the
diazoacetates was inserted into the C–H bond of the a-position
of amines (Fig. 1 (a)). We report herein iron-catalyzed reactions
between tertiary amines and diazoacetate.7,8 In our reaction,
the cleavage of a C–N single bond occurred and glycine
derivatives were formed in good yields (Fig. 1 (b)).
Table 1 Reactions between several tertiary amines 1 and ethyl
diazoacetate (2)a
Treatment of N,N-dimethylaniline (1a) with ethyl diazoacetate
(2) in the presence of 5.0 mol% of an iron salt, FeCl3,
in toluene gave glycine 3a in 25% yield.9 As a result of
investigating several solvents, ethanol was found to be the
most effective in promoting the reaction, and 3a was obtained
in 57% yield.10 In this reaction, a methyl–nitrogen bond
(not a phenyl–nitrogen bond) was cleaved selectively, and
ethyl 3-N-methyl-N-phenylaminopropanoate, which is derived
from C–H functionalization of the methyl group of 1a, was
not formed.10 It is interesting that ethanol provided a high yield
because the reaction of 2 with ethanol (insertion of a carbene
into the O–H bond of ethanol) usually occurs in the presence of
Entry
R1
R2
R3
Yieldb (%)
1c
2
4-MeOC6H4
4-MeC6H4
4-CF3C6H4
4-BrC6H4
Me
Me
Me
Me
Me
Me
Me
Me
1b
1c
1d
1e
3b
3c
3d
3e
92 (99)
73 (77)
34 (41)
52 (57)
72 (76)
49 (50)
69 (71)
77 (79)
50 (55)
3d
4c
5e
6
4-ClC6H4
Me
Me
1f
3f
7e
8c
9d,e
3-MeC6H4
2-MeC6H4
Me
Me
Me
Me
1g
1h
3g
3h
10d,e
Me
Me
1i
3i
41 (46)
11f
nC12H25
Ph
Ph
Me
Et
Me
Me
Et
Et
1j
1k
1l
3j
33 (38)
51 (55)
22 (23)
35 (38)
Fig. 1 The difference between previous works and our reaction of
12d,e
13d
3k
3k
3a
tertiary amines with a diazoacetate.
Division of Chemistry and Biochemistry, Graduate School of Natural
Science and Technology, Okayama University, Tsushima, Kita-ku,
Okayama 700-8530, Japan. E-mail: kuninobu@cc.okayama-u.ac.jp,
ktakai@cc.okayama-u.ac.jp; Fax: +81 (0)86-251-8094;
Tel: +81 (0)86-251-8095
a
b
2 (2.0 equiv.). Yield determined by 1H NMR is reported in
c
d
parentheses. 48 h. MnBr2 (20 mol%) was used as a catalyst.
e
CF3CH2OH was used as a solvent. The yield was determined after
the treatment of the reaction mixture with ethanol at 115 1C for
f
w Electronic supplementary information (ESI) available: General
experimental procedure. See DOI: 10.1039/c0cc03781h
24 h. 150 1C.
c
8860 Chem. Commun., 2010, 46, 8860–8862
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When 2,2,2-trifluoroethanol was used instead of ethanol, the
yields were improved, and 3e and 3f were generated in 72%
and 69% yields, respectively (entries 5 and 7). Although 3g
was afforded in 77% yield when an aniline derivative with a
methyl group at the meta-position, 1g, was used (entry 8), a
substituent at the ortho-position of an aromatic ring decreased
the yield of the glycine 3h (entry 9). The corresponding glycine
3i was produced in 41% yield in the case of naphthylamine 1i
(entry 10). Dodecyldimethylamine 1j also gave 3j; however, the
yield was low (entry 11). Another C–N bond, instead of the
methyl–nitrogen bond, was also cleaved (entry 12). By the
reaction of N,N-diethylaniline (1k) with ethyl diazoacetate (2)
in the presence of a catalytic amount of an iron salt, FeCl3,
ethyl (N-ethyl-N-phenylamino)acetate (3k) was formed in
51% yield (entry 12). In the case of an amine with methyl
and ethyl groups, 1l, glycines 3k and 3a were generated in 22%
and 35% yields, respectively (entry 13). This result shows that
the cleavage of an ethyl–nitrogen bond occurs more easily
than the methyl–nitrogen bond. In Table 1, the amines 1 were
recovered, and the total percentages of 3 and 1 were more than
90% except in the case of entry 11. The reaction did not
proceed using N-methylindole, N,N-dimethylacetoamide, or
N-methyl-2-pyrrolidone as tertiary amines. In the case of
N,N-dimethylaniline and N,N-dimethylanilines with an
electron-donating group, FeCl3 is more effective than MnBr2.
On the other hand, MnBr2 showed a higher catalytic
activity compared with FeCl3 when N,N-diethylaniline and
N,N-dimethylanilines bearing an electron-withdrawing group
were employed as substrates.
Another possible mechanism is that the reaction proceeds
via the formation of an ammonium salt, which is derived from
the nucleophilic addition of an amine to a diazoacetate
followed by the elimination of N2 and protonation.15 To
examine this possibility, the following experiment was carried
out. Heating ammonium salt 4 in the presence or absence of
FeCl3, glycine 3a was obtained in 47% and 63% yields,
respectively (eqn (3)). These results indicate that 3a was
formed via the formation of ammonium salt 4, and FeCl3
was not necessary in the elimination of the methyl group of 4.
ð3Þ
By the above investigations, we propose the reaction
mechanism shown in Fig. 2: (1) Coordination of diazoacetate
2 to a metal center (activation of 2 by the Lewis acid);16,17 (2)
nucleophilic substitution of the formed metal-containing
zwitterionic intermediate with amine 1 via the elimination of
N2; (3) protonation of the formed zwitterionic intermediate
to give an ammonium salt and regeneration of the metal
catalyst;18 (4) elimination of a methyl group from the nitrogen
atom (C–N bond cleavage) to give glycine derivative 3 and
trapping of one of the methyl groups by ethanol.19
A carbon–sulfur bond was also cleaved by the reaction
between thioanisol (5) and ethyl diazoacetate (2) in the
presence of a catalytic amount of MnBr2. As a result, ethyl
2-(phenylthio)acetate (6) was obtained in 51% yield (eqn (4)).
However, the desired product was not formed when FeCl3 was
used as a catalyst.20
Next, we investigated the reaction mechanism. Since an
ethoxycarbonylmethyl group was introduced on the nitrogen
atom of 3a or 3k when N,N-dimethylaniline (1a) or N,N-
diethylaniline (1k) was used (eqn (1) and Table 1, entry 12), it
is clear that the ethoxycarbonylmethyl group came from
diazoacetate 2, not from the methyl (or the methylene moiety
of the ethyl) group of aniline derivative 1a (or 1k) and the
ethoxycarbonyl moiety of 2.
In some cases, the C–N bond cleavage of N-methylamines
occurs via the formation of iminium intermediates.13 However,
iminium intermediates are usually formed under oxidative
conditions. In our case, the reaction was not performed under
oxidative conditions. Therefore, we did not consider this
pathway further.
ð4Þ
In summary, we have succeeded in iron-catalyzed cleavage
of a non-strained C–N bond by the reactions of tertiary
amines with a diazoacetate. As a result, glycine derivatives
were obtained in moderate to good yields. This reactivity is in
sharp contrast to the previous transition metal-catalyzed
reactions between tertiary amines and diazoacetates, which
produce glycine derivatives via the insertion of the ethoxy-
carbonylmethyl group of the diazoacetates into a C–H bond at
the a-position of the amines. To cleave C–N bonds, novel
To identify a byproduct, which is formed by the cleavage of the
C–N bond, the following experiment was conducted. Treatment
of 1-phenylpyrrolidine (1m) with diazoacetate 2 formed ethyl ether
3l (eqn (2)). This result shows that an alkyl chain on the nitrogen
atom of amine 1 must be trapped by ethanol. In addition, this
reaction did not proceed via the formation of an iminium
intermediate, which would cause formation of an aldehyde.13c,14
Fig. 2 Possible reaction mechanism for the formation of glycine
derivatives via C–N bond cleavage.
ð2Þ
c
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transition metal complexes or salts have previously been used
as catalysts. Iron is well known as one of the most abundant
and cheapest metals. However, there have only been a few
reports on iron-catalyzed cleavage of unactivated bonds.21
From this viewpoint, this iron-catalyzed cleavage of C–N
bond is interesting. We hope that this reaction will provide
useful insight into transformations via the cleavage of
C–N bonds.
O. G. Mancheno and C. Bolm, Chem. Soc. Rev., 2008, 37, 1108;
(c) E. B. Bauer, Curr. Org. Chem., 2008, 12, 1341.
´
8 For reviews on the use of FeCl3, see: (a) D. D. Dıaz,
P. O. Miranda, J. I. Padron and V. S. Martın, Curr. Org. Chem.,
´
´
2006, 10, 457; (b) A. A. O. Sarhan and C. Bolm, Chem. Soc. Rev.,
2009, 38, 2730.
9 This result is in sharp contrast to the result in which a carbon–
hydrogen bond at the a-carbon atom of N-methylamine is cleaved
by a rhodium catalyst. See: ref. 6d.
10 Investigation of several solvents: THF, 24%; 1,2-dichloroethane,
39%; acetonitrile, 35%.
This work was partially supported by the Ministry of
Education, Culture, Sports, Science, and Technology
of Japan.
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12 Investigation of several catalysts: FeCl3ꢀ6H2O, 76%; FeCl2, 70%;
FeCl2ꢀ4H2O, 65%; Fe(acac)3, 25%; Fe(OAc)2, 32%; Fe(OTf)2,
26%; Fe(OTf)3, 27%; Fe2(CO)9, 18%; Fe3(CO)12, 12%; MnCl2,
44%; MnBr2, 66%; RuCl3, 22%; CoCl2, 36%; CuCl, 24%; AgOTf,
18%; AlCl3, 47%; InBr3, 66%; In(OTf)3, 22%; Sc(OTf)3, 12%;
Y(OTf)3, 28%; HCl, 28%; no catalyst, 9%.
Notes and references
z Synthesis of 3a. A mixture of N,N-dimethylaniline (1a, 30.3 mg,
0.250 mmol), ethyl diazoacetate (2, 57.1 mg, 0.500 mmol), iron(III)
chloride FeCl3 (8.1 mg, 0.050 mmol), and ethanol (0.25 mL) was
heated at 115 1C for 24 h. After heating, the reaction mixture was
purified by silica gel column chromatography using hexane/ethyl
acetate (10 : 1) as the eluent to give glycine derivative 3a (40.1 mg,
83% yield).
13 Cu: (a) J. Shearer, C. X. Zhang, L. Q. Hatcher and K. D. Karlin,
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16 When 2 was heated in 1,2-dichloroethane or ethanol at 115 1C for
24 h without a catalyst, diethyl fumarate and diethyl maleate were
not formed. This result indicates that a carbene intermediate was
not formed from 2 by thermal decomposition, and 2 was activated
by a catalytic amount of FeCl3 or MnBr2.
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18 In this report, the C–N bond is weakened by the positive charge of
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bond cleavage by introducing an electron-withdrawing group on
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20 In the case of FeCl3, the reaction between 2 and ethanol occurred
and ethyl 2-ethoxyacetate was formed as the main product.
21 For an example of an iron-catalyzed C–H bond transformation,
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c
8862 Chem. Commun., 2010, 46, 8860–8862
This journal is The Royal Society of Chemistry 2010