Application of α-chloroaldoxime O-methanesulfonates to one-pot synthesis of N,N′,N″-substituted guanidines via Tiemann rearrangement

Article abstract of DOI:10.1016/j.tetlet.2009.07.147

A practical one-pot synthesis of N,N′,N″-trisubstituted guanidines via Tiemann rearrangement involving the reaction of α-chloroaldoxime O-methanesulfonates with alkyl amines is disclosed.

Full text of DOI:10.1016/j.tetlet.2009.07.147

Tetrahedron Letters 50 (2009) 5813–5815
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Application of
a
-chloroaldoxime O-methanesulfonates to one-pot synthesis
of N,N0,N00-substituted guanidines via Tiemann rearrangement
*
Yuhei Yamamoto , Hiroo Mizuno, Takayuki Tsuritani, Toshiaki Mase
Process Research, Preclinical Development, Banyu Pharmaceutical Co., Ltd, 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan
a r t i c l e i n f o
a b s t r a c t
A practical one-pot synthesis of N,N0,N00-trisubstituted guanidines via Tiemann rearrangement involving
Article history:
Received 29 July 2009
Accepted 30 July 2009
Available online 3 August 2009
the reaction of
a-chloroaldoxime O-methanesulfonates with alkyl amines is disclosed.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Guanidines
a-Chloroaldoxime O-methanesulfonates
Tiemann rearrangement
Carbodiimides
The Tiemann rearrangement, the aza analogue of the Lossen
rearrangement, was originally reported for conversion of amidox-
imes to ureas (Eq. 1).1,2 The primary product of the reaction is
the amidoxime O-benzenesulfonate, which then rearranges to give
a carbodiimide (Eq. 2).3 Although this rearrangement provides an
efficient pathway to carbodiimides, which are versatile synthetic
intermediates,4 only a few synthetic applications of this potentially
useful reaction have appeared in the literature.1,3,5
the leaving group, it seemed reasonable to expect the rearrange-
ment pathway (path b) to predominate when the substituent on
the amidine nitrogen was an alkyl group (R2=alkyl) which is unable
to cyclize. Herein we wish to report a novel one-pot synthesis of
N,N0,N00-trisubstituted guanidines via Tiemann rearrangement
involving the reaction of
a
-chloroaldoxime O-methanesulfonates
1 with alkyl amines.
ð3Þ
ð1Þ
ð2Þ
Recently, we disclosed a benzimidazole synthesis using a-chlo-
ð4Þ
roaldoxime O-methanesulfonate 1 (Eq. 3) as the key starting mate-
rial.6 The reaction proceeds via amidoxime O-methansulfonate 3
(X = OMs) which immediately cyclizes to give benzimidazole 2
(Eq. 4), path a).7 Although the amidoxime intermediate 3 could
also potentially undergo the Tiemann rearrangement (Eq. 4, path
b), no trace of carbodiimide was observed throughout the reaction.
Consistent with literature reports, this observation may be attrib-
uted to the nature of the leaving group on the amidine nitrogen.7g
The cyclization (path a) is generally preferred for amidines bearing
moderate leaving groups such as Cl,7b,7e and the rearrangement
(path b) is preferred for amidines bearing exceptionally good leav-
We initiated our investigation using N-benzylethylenediamine
as the alkyl amine to react with various -chloroaldoxime methane-
sulfonates (Table 1). The reaction should initially give the amidox-
ime O-methanesulfonate 3. If the rearrangement takes place, the
amidoxime O-methanesulfonate 3 would convert to the carbodiim-
ide which could then be intramolecularly trapped with the benzyl-
a
amine moiety to produce the cyclic guanidine.8 Four different
a-
ing groups such as N2 and I+Ph.7a,7f Independent of the nature of
þ
chloroaldoxime methanesulfonates 1a–d were employed to react
with N-benzylethylenediamine, and the results are summarized in
* Corresponding author. Tel./fax: +81 6 6300 6251.
E-mail addresses: yuhei_yamamoto@merck.com, Yamamoto_Yuuhei@takeda.
co.jp (Y. Yamamoto).
Table 1. The reaction of
a-chlorobenzaldoxime methanesulfonate
1a with N-benzylethylenediamine completed at room temperature,
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.147

5814
Y. Yamamoto et al. / Tetrahedron Letters 50 (2009) 5813–5815
Table 1
Reaction of various
amine
hibit the migration. It is interesting to note that the reaction con-
a-chloroaldoxime methanesulfonates with N-benzylethylenedi-
ditions that affect the migration can be categorized into four
types, depending on the electron density of the R1 substituent.5c
Thus, the phenyl group migrated at room temperature, but the 2-
chlorophenyl group required heat to induce the migration. The 2-
pyridyl group required strong base such as DBU to migrate, but
the 3-nitrophenyl group did not migrate even with DBU under
forcing conditions. The trend in migratory aptitudes is somewhat
analogous to that of Lossen rearrangement,11 but the reaction
mechanism in the present case is not clear at this time.
We next turned our attention to the synthesis of various
N,N0,N00-trisubstituted guanidines,12 as such compounds are found
in a number of biologically active compounds and asymmetric re-
agents.13,14 The present method enables the one-pot synthesis of
N,N0,N00-trisubstituted guanidines by sequential addition of alkyl
Entry
Substrate
Reagents
Temp (°C)
Yield (%)
3
5
1
2
3
4
5
6
7
8
1a
1b
1c
1c
1c
1d
1d
1d
None
None
None
None
rt
70
rt
70
rt
rt
<1
<5
97
<5
<1
98
<5
<5
96
87
<1
<5
89
<1
<5
<5
amines to
a-chloroaldoxime methanesulfonates. The results of
these studies are summarized in Table 2.
DBU (2.4 equiv)/DMF
None
None
The reaction conditions used for the one-pot synthesis are
basically the same as those used for the synthesis of cyclic guani-
dines (5a–c), except for the temperature of the reaction with the
70
rt
DBU (2.4 equiv)/DMF
second amine. For example, the reaction of phenyl-substituted a-
chloroaldoxime methanesulfonate 1a with amines completed at
room temperature to give the corresponding carbodiimides, but
the reaction of the intermediate carbodiimides with a second series
of amines did not proceed until the mixture was heated to 50 °C
and gave the cyclic guanidine 5a in 96% yield (entry 1). The starting
materials and the cyclic guanidine were the only observed
compounds during the reaction, and no trace of amidoxime O-meth-
anesulfonate 3a was observed. In contrast, the reaction of 2-chloro-
(entries 1–5).15 The reaction of 2-chlorophenyl-substituted
a-chlo-
roaldoxime methanesulfonate 1b gave the corresponding amidox-
ime at room temperature, and was heated to 70 °C after the
addition of second amine to give the desired guanidines in moder-
ate yield (entries 6 and 7).16 The reaction of 2-pyridyl-substituted
phenyl substituted a-chloroaldoxime methanesulfonate 1b did not
give the cyclic guanidine 5b at room temperature. Although we
were not able to isolate the compound, the reaction seemed to stall
at the amidoxime O-methansulfonate 3b.9 The desired cyclic guani-
dine 5b was obtained when the reaction mixture was heated to
a-chloroaldoxime methanesulfonate 1c with primary amines
immediately gave the corresponding amidoximes at room temper-
ature. The desired guanidine was obtained after addition of second
amine and DBU with heating (entries 8–11).17
70 °C (entry 2). When the reaction was conducted with
a-chloro-
aldoxime methanesulfonates bearing electron-withdrawing groups
such as 2-pyridyl (1c) and 3-nitrophenyl (1d), we were able to iso-
late the amidoxime intermediates 3c (entry 3) and 3d (entry 6). In
contrast to 2-chlorophenyl-substituted amidoxime 3b, both com-
pounds 3c and 3d decomposed when the reaction mixtures were
heated (entries 4 and 7). The desired cyclic guanidine 5c was ob-
tained for 2-pyridyl-substituted amidoxime 3c when DBU
(2.4 equiv) was added into the reaction mixture (entry 5),10 but only
decomposition occurred when DBU was added to the 3-nitro-
phenyl-substituted amidoxime 3d (entry 8).
The rearrangement was not limited only to aryl-substituted
a-
chloroaldoxime methanesulfonates. The reaction also proceeds
t
with the Bu-substituted
a-chloroaldoxime methanesulfonate 1e
to give the corresponding carbodiimide (Eq. 5), albeit in low
yield.18 The low yield is attributed to the low reactivity of the sub-
strate 1e caused by its steric bulk.6a
From these results, it is clear that the electron density of the R1
substituent plays a crucial role on the reaction. Electron deficient
R1 groups facilitate the first step to form amidoximes 3a–d, but in-
ð5Þ
Table 2
One-pot synthesis of various N,N0,N00-substituted guanidines
Entry
Substrate
R2
R3, R4
Reagents
Temp (°C)
Yield (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1b
1c
1c
1c
1c
iPr
Bn
iPr, H
Bn, H
None
None
None
None
None
None
None
DBU/DMF
DBU/DMF
DBU/DMF
DBU/DMF
50
50
50
50
50
70
70
35
35
35
35
91
93
95
86
91
71
79
87
88
91
87
1,2,2-Trimethylpropyl
1,2,2-Trimethylpropyl, H
Bn
Bn
Bn
Bn
nBu
Bn
iPr
nBu, H
–(CH2)4–
–(CH2)4–
–(CH2CH2OCH2CH2)–
Bn, H
–(CH2)4–
10
11
–(CH2)4–
–(CH2)4–
tBu

Y. Yamamoto et al. / Tetrahedron Letters 50 (2009) 5813–5815
5815
14. For review on guanidine in organic synthesis, see: Ishikawa, T.; Kumamoto, T.
Further elucidating the mechanism of the rearrangement and
expanding the range of substrates are ongoing in our laboratory.
Synthesis 2006, 737–752.
15. Synthesis of N,N0,N00-substituted guanidines from
a
-chlorobenzaldoxime O-
methanesulfonate (1a) (Table 2, entry 4): To 50 mL round flask were added
benzylamine (214 mg, 2 mmol), -chlorobenzaldoxime O-methanesulfonate
a
Acknowledgments
1a (467 mg, 2.0 mmol), THF (10 mL), and TMEDA (256 mg, 2.2 mmol). The
solution was stirred at room temperature for 5 h. n-Butylamine (292 mg,
4 mmol) was added to the reaction mixture, and the mixture was warmed to
50 °C. The reaction mixture was stirred at the same temperature for additional
5 h, and the reaction mixture was directly purified through SiO2 column to give
the desired guanidine as yellow oil (484 mg, 86% yield). 1H NMR (CDCl3,
400 MHz) d 7.39–7.34 (m, 4H), 7.31–7.25 (m, 3H), 6.95 (tt, J = 7.2, 1.2 Hz, 1H),
6.92 (dd, J = 8.0, 1.2 Hz, 2H), 4.39 (s, 2H), 4.21 (br s, 1H), 3.77 (br s, 1H), 3.12 (m,
2H), 1.44 (tt, J = 7.2, 7.2 Hz, 2H), 1.26 (tq, J = 7.2, 7.2 Hz, 2H), 0.87 (t, J = 7.2 Hz,
3H); 13C NMR (CDCl3, 100 MHz) d 151.3, 150.0, 139.1, 129.3, 128.7, 127.4,
127.4, 123.6, 121.6, 46.1, 41.7, 31.8, 20.0, 13.8; IR (neat, cmꢀ1) 2956, 2926,
2861, 1615, 1584, 1516, 1483, 1264, 1135, 1069, 731, 695; HRMS m/z calcd for
C18H24N3: 282.1970; Found: 282.1970.
We thank Dr. Shane W. Krska (MRL) for helpful discussion, and
Dr. Hirokazu Ohsawa (Banyu) for HRMS measurements.
References
1. Tiemann, F. Ber. Dtsch. Chem. Ges. 1891, 24, 4162–4167.
2. For review on the chemistry of amidoximes, see: Eloy, F.; Lenaers, R. Chem. Rev.
1962, 62, 155–183.
3. (a) Partridge, M. W.; Turner, H. A. J. Pharm. Pharmacol. 1953, 5, 103–110; (b)
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4. For reviews on the chemistry of carbodiimides, see: (a) Williams, A.; Ibrahim, I.
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Dietrich, W. Angew. Chem., Int. Ed. Engl. 1981, 20, 819–830; (c) Mikolajczyk, M.;
Kielbasinski, P. Tetrahedron 1981, 37, 233–284.
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Bonnier, J. M. Tetrahedron Lett. 1970, 11, 4905–4908; (d) Richter, R.; Tucker, B.;
Ulrich, H. J. Org. Chem. 1983, 48, 1694–1700; (e) Adams, G. W.; Bowie, J. H.; Hayes,
R. N.; Gross, M. L. J. Chem. Soc., Perkin Trans. 2 1992, 897–901; (f) Bakunov, S. A.;
Rukavishnikov, A. V.; Tkachev, A. V. Synthesis 2000, 1148–1159; (g) Yagupolskii,
L. M.; Shelyazhenko, S. V.; Maletina, I. I.; Sokolenko, L. V.; Chernega, A. N.;
Rusanov, E. B.; Tsymbal, I. F. J. Fluorine Chem. 2007, 128, 515–523.
16. Synthesis of N,N0,N00-substituted guanidine from
benzaldoxime O-methanesulfonate (1b) (Table 2 entry 6): To 50 mL round flask
were added benzylamine (214 mg, 2.0 mmol), -chloro(2-chlorophenyl)-
a-chloro(2-chlorophenyl)-
a
carboxaldoxime O-methanesulfonate 1b (536 mg, 2.0 mmol), THF (10 mL),
and TMEDA (256 mg, 2.2 mmol). The solution was stirred at room temperature
for 5 h. Pyrrolidine (280 mg, 4 mmol) was added to the reaction mixture, and
the mixture was warmed to 70 °C. The reaction mixture was stirred at the
same temperature for additional 5 h, and the reaction mixture was directly
purified through SiO2 column to give the desired guanidine as yellow oil
(446 mg, 71% yield). 1H NMR (CDCl3, 400 MHz) d 7.33–7.32 (m, 4H), 7.30–7.26
(m, 2H), 7.07 (td, J = 7.6, 1.6 Hz, 1H), 6.89 (dd, J = 8.0, 1.6 Hz, 1H), 6.76 (td,
J = 8.0, 1.6 Hz, 1H), 4.36 (s, 2H), 3.27–3.23 (m, 4H), 1.85–1.82 (m, 4H); 13C
NMR (CDCl3, 100 MHz) d 152.1, 139.4, 129.2, 128.6, 127.8, 127.3, 127.0, 124.3,
120.7, 47.9, 47.7, 25.5; IR (neat, cmꢀ1) 2966, 2869, 1597, 1568, 1511, 1466,
1351, 1029, 745, 697; HRMS m/z calcd for C18H21N3Cl: 314.1424; found:
314.1429.
6. (a) Yamamoto, Y.; Mizuno, H.; Tsuritani, T.; Mase, T. J. Org. Chem. 2009, 74,
1394–1396; (b) Yamamoto, Y.; Tsuritani, T.; Mase, T. Tetrahedron Lett. 2008, 49,
876–878.
7. (a) Smith, P. A.; Leon, E. J. Am. Chem. Soc. 1958, 80, 4647–4654; (b) Grenda, V. J.;
Joens, R. E.; Gal, G.; Sletzinger, M. J. Org. Chem. 1965, 30, 259–261; (c) Sauer, J.;
Mayer, K. K. Tetrahedron Lett. 1968, 9, 325–330; (d) Houghton, P. G.; Pipe, D. F.;
Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1975, 1964–1969; (e) Ichikawa, M.;
Hisano, T. Chem. Pharm. Bull. 1982, 30, 2996–3003; (f) Ramsden, C. A.; Rose, H.
L. J. Chem. Soc., Perkin Trans. 1 1995, 615–617; (g) Ramsden, C. A.; Rose, H. L. J.
Chem. Soc., Perkin Trans. 1 1997, 2319–2327. and references cited therein.
8. (a) Kim, T. H.; Lee, N.; Lee, G.-J.; Kim, J. M. Tetrahedron 2001, 57, 7137–7141; (b)
Heinelt, U.; Schultheis, D.; Jäger, S.; Lindenmaier, M.; Pollex, A.; Beckmann, H. S.
g. Tetrahedron 2004, 60, 9883–9888.
17. Synthesis of N,N0,N00-substituted guanidine from
carboxaldoxime O-methanesulfonate (1c) (Table 2, entry 8): To 50 mL round
flask were added -chloro(2-pyridyl)carboxaldoxime O-methanesulfonate 1c
a-chloro(2-pyridyl)-
a
(469 mg, 2.0 mmol), THF (10 mL), and TMEDA (256 mg, 2.2 mmol). The
mixture was cooled to 0 °C, and n-butylamine (146 mg, 2.0 mmol) was added
to the mixture. The mixture was warmed to room temperature, and was stirred
at the same temperature for 30 min. Benzylamine (428 mg, 2.0 mmol), DMF
(5 mL), and DBU (731 mg, 4.8 mmol) were added to the mixture, and the
mixture was stirred at 35 °C for 5 h. The reaction mixture was directly purified
through SiO2 column to give the desired guanidine as a white crystal (446 mg,
87% yield, mp 78 °C). 1H NMR (CDCl3, 400 MHz) d 8.09 (ddd, J = 5.2, 2.0, 0.8 Hz,
1H), 7.45 (ddd, J = 9.2, 7.2, 2.4 Hz, 1H), 7.40–7.33 (m, 4H), 7.31–7.26 (m, 1H),
6.89 (d, J = 9.2 Hz, 1H), 6.66 (ddd, J = 7.2, 5.2, 0.8 Hz, 1H), 4.56 (s, 2H), 3.23 (br s,
2H), 1.54 (tt, J = 7.6, 7.6 Hz, 2H), 1.33 (tq, J = 7.6, 7.6 Hz, 2H), 0.90 (t, J = 7.6 Hz,
3H); 13C NMR (CDCl3, 100 MHz) d 163.4, 155.4, 145.3, 139.1, 136.9, 128.7,
127.4, 127.3, 120.2, 114.4, 45.3, 40.9, 31.6, 20.1, 13.7; IR (neat, cmꢀ1) 2953,
1558, 1506, 1429, 1355, 1147, 784, 730; HRMS m/z calcd for C17H23N4:
283.1923; found: 283.1930.
9. The reaction was monitored by HPLC, and indicated the formation of
amidoxime O-methanesulfonate 3b.
10. It is reported that DBU is superior to TEA for Hofmann rearrangement: Huang,
X.; Seid, M.; Keillor, J. F. J. Org. Chem. 1997, 62, 7495–7496.
11. (a) Renflow, W. B.; Hauser, C. R. J. Am. Chem. Soc. 1937, 59, 2308–2314; (b)
Bright, R.; Hauser, C. R. J. Am. Chem. Soc. 1939, 61, 618–629; (c) Imamoto, T.;
Tsuno, Y.; Yukawa, Y. Bull. Chem. Soc. Jpn. 1971, 44, 1632–2638.
12. For recent advances in synthesis of substituted guanidines, see: (a) Linton, B.
R.; Carr, A. J.; Orner, B. P.; Hamilton, A. D. J. Org. Chem. 2000, 65, 1566–1568; (b)
Powell, D. A.; Ramsden, P. D.; Batey, R. A. J. Org. Chem. 2003, 68, 2300–2309; (c)
Ong, T.-G.; Yap, G. P. A.; Richeson, D. S. J. Am. Chem. Soc. 2003, 125, 8100–8101;
(d) Zhang, W.-X.; Hou, Z. Org. Biomol. Chem. 2008, 6, 1720–1730.
13. For review on guanidine in biologically active compounds, see: Berlinck, R. G.
S.; Burtoloso, A. C. B.; Kossuga, M. H. Nat. Prod. Rep. 2008, 25, 919–954.
18. tBu-substituted
bearing aliphatic substituent that Tiemann rearrangement proceeded. The
reaction of cyclohexyl or nBu-substituted
-chloroaldoxime methanesulfonate
a-chloroaldoxime methanesulfonate 1e was the only example
a
with benzylamine gave only the corresponding amidoxime O-methane-
sulfonate, and no rearrangement occurred under our reaction conditions.