4-Aminopyridine catalyzed direct and regioselective acylation of N-Tosylhydrazide

Article abstract of DOI:10.1021/ol9021194

An efficient and simple method for selective acylation of either one of two nitrogen atoms of tosylhydrazide was developed. The selectivity was drastically controlled by a catalytic amount of 4-amlnopyrldlne or 4-(dlmethylamlno) pyrldlne with common acyla

Full text of DOI:10.1021/ol9021194

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4970-4973
4-Aminopyridine Catalyzed Direct and
Regioselective Acylation of
N-Tosylhydrazide
Kosuke Namba,*,† Isamu Shoji,† Mugio Nishizawa,‡ and Keiji Tanino*,†
DiVision of Chemistry, Graduate School of Science, Hokkaido UniVersity, Kita-ku,
Sapporo 060-0810, Japan, and Faculty of Pharmaceutical Science, Tokushima Bunri
UniVersity, Yamashiro-cho, Tokushima 770-8514, Japan
namba@mail.sci.hokudai.ac.jp
Received September 14, 2009
ABSTRACT
An efficient and simple method for selective acylation of either one of two nitrogen atoms of tosylhydrazide was developed. The selectivity
was drastically controlled by a catalytic amount of 4-aminopyridine or 4-(dimethylamino)pyridine with common acylating agents. The nitrogen
atom masked with a tosyl group was acylated in the presence of 4-aminopyridine, whereas the primary nitrogen atom was acylated in the
absence of 4-aminopyridine.
Acyltosylhydrazides, which have functional importance as
versatile building blocks in organic synthesis, are mostly
prepared by common acylation of N-tosylhydrazide.1,2 They
are mainly obtained as N-acyl-N′-tosylhydrazide 1 and are
widely used as a synthetic synthon for constructing aza-
aromatic rings such as tetrazoles,3 indazoles,4 pyrazoles,5
benzodiazepine,6 and so on7 and are frequently used as
masked or protected functional groups that are easily
converted to aldehydes,2b,8,9 esters,10 amides,11 and acid
chloride.12 In particular, the conversion to aldehyde is well-
known as a McFadyen-Stevens reduction.13 In contrast,
there have been very few examples of N,N-acyltosylhy-
drazide 2 being employed for organic synthesis,14 although
its reactivity and properties are quite interesting. One of the
major obstacles to using N,N-acyltosylhydrazide 2 as a
building block is its difficulty of preparation. The synthesis
of related N,N-Boctosylhydrazide reported by Grehn and
Ragnarsson is the first and thus far the only useful synthesis
of N,N-diprotected hydrazine with two orthogonals.15 How-
ever, the application of their method to the synthesis of N,N-
acyltosylhydrazide 2 still requires cumbersome protection-
† Hokkaido University.
‡ Tokushima Bunri University.
(1) Brown, B. R. The Organic Chemistry of Aliphatic Nitrogen Com-
pounds; Clarendon: Oxford, 1994; p 588
.
(2) (a) Huang, Z.; Reilly, J. E.; Buckle, R. N. Synlett 2007, 1026–1030.
(b) Callman, J. P.; Decre´au, R. A.; Costanzo, S. Org. Lett. 2004, 6, 1033–
1036. (c) Dudman, C. C.; Grice, P.; Reese, C. B. Tetrahedron Lett. 1980,
(9) (a) Parasuraman, J.; Bikash, P.; Sesha, V. Synth. Commun. 2002,
32, 2569–2573. (b) Nair, M.; Shechter, H. J. Chem. Soc., Chem. Comm.
1978, 793–794.
21, 4645–4648
.
(10) (a) Attanasi, O.; Filippone, F.; Serra-Zanetti, F. Synth. Commun.
1982, 12, 1155–1162. (b) Attanasi, O.; Serra-Zanetti, F. Synthesis 1980,
314–315. (c) Dudman, C. C.; Grice, P.; Reese, C. B. Tetrahedron Lett.
1980, 21, 4645–4648.
(3) Ito, S.; Tanaka, Y.; Kakehi, A. Bull. Chem. Soc. Jpn. 1976, 49, 762–
766.
(4) Suryakiran, N.; Prabhakar, P.; Venkateswarlu, Y. Chem. Lett. 2007,
36, 1370–1371.
(11) Goelz, H.; Glatz, B.; Has, G.; Helmchen, G.; Muxfeldt, H. Angew.
Chem. 1977, 89, 742–743.
(5) Myers, M. C.; Napper, A. D.; Motlekar, N.; Shah, P. P.; Chiu, C.-
H.; Beavers, M. P.; Diamond, S. L.; Huryn, D. M.; Smith, A. B. Bioorg.
Med. Chem. Lett. 2007, 17, 4761–4766.
(12) Bellesia, F.; Pagnoni, U. M.; Pinetti, A. J. Chem. Res., Synop. 1982,
8, 222–223.
(6) Bihel, F. J.-J.; Hellal, M.; Bourguignon, J.-J. Synthesis 2007, 3791–
3796.
(13) McFadyen, J. S.; Stevens, T. S. J. Chem. Soc. 1936, 584.
(14) Ruwet, A.; Renson, M. Bull. Soc. Chim. Belg. 1966, 75, 157–168.
(15) (a) Ragnarsson, U.; Grehn, L.; Koppel, J.; Loog, O.; Tsubrik, O.;
Bredikhin, A.; Maeorg, U.; Koppel, I. J. Org. Chem. 2005, 70, 5916–5921.
(b) Grehn, L.; Ragnarsson, U. Tetrahedron 1999, 55, 4843–4852.
(7) Hameurlaine, A.; Abramov, M. A.; Dehaen, W. Tetrahedron Lett.
2002, 43, 1015–1017.
(8) Mosettig, E. Org. React. 1954, 8, 232
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10.1021/ol9021194 CCC: $40.75
Published on Web 10/01/2009
 2009 American Chemical Society

deprotection steps. We describe herein an efficient and direct
acylation of tosylhydrazide to selectively give the N-acyl-
N′-tosylhydrazide 1 or N,N-acyltosylhydrazide 2 (Figure 1).
Table 1. Acylation of Tosylhydrazide with Hexanoic Anhydride
yield (%)a
entry DMAP (equiv) base (equiv) time (min)
4
5
6
1
2
3
4
5
6
None
0.2
0.2
0.1
none
none
none
none
NEt3 (1.5)
NEt3 (1.5)
NEt3 (1.5)
pyridine (5)
90
180
25
35
180
240
85
1
Figure 1. Acyltosylhydrazide.
20 15 33
90
88
3
1
1
4
4
5
48
9
In our recent synthetic study of palau’amine, we attempted
a coupling of carboxylic acid with tosylhydrazide by the
combined action of N-(3-dimethylaminopropyl)-N′-ethylcar-
bodiimide (EDCI) and DMAP in dichloromethane. Surpris-
ingly, the nitrogen atom masked with a tosyl group partici-
pated in the condensation to give a N,N-acyltosylhydrazide
2 in acceptable yield. The primary nitrogen of 2 is regarded
as a nonbasic amine maintaining its nucleophilicity, and the
Hg(OTf)2-catalyzed direct addition of nitrogen to an alkene
was achieved by using only N,N-acyltosylhydrazide 2.16 On
the basis of this result, our effort to establish an efficient
method for the preparation of N,N-acyltosylhydrazide was
undertaken.
Although the origin of regioselectivity in the synthesis of
2 is not clear, the selectivity is sure to be controlled by a
reagent (EDCI), a catalyst (DMAP), the substrate properties,
or some combination of these factors. Therefore, to determine
the effects of reagents and catayst on selectivity, tosylhy-
drazide 3 was just treated with 1.1 equiv of hexanoic
anhydride in dichloromethane at 0 °C (Table 1). The simple
reaction was completed within 90 min, and N-acyl-N′-
tosylhydrazide 5 was obtained in 85% yield along with a
trace amount of diacylated tosylhydrazide 6 (1%), and N,N-
acyltosylhydrazide 4 was not obtained (entry 1). Presumably,
the basicity of the primary amine of tosylhydrazide is not
enough to be protonated by an in situ generated hexanoic
acid. The same reaction in the presence of 0.2 equiv of
DMAP was then conducted. Interestingly, N,N-acyltosylhy-
drazide 4 was obtained in an amount equal to DMAP (20%)
along with 5 (15%) and 6 (33%) (entry 2). The structure of
4 was unambiguously confirmed by an X-ray diffraction
study (see Supporting Information). Here, we found that
DMAP plays a significant role in this selective acylation.
As the DMAP seemed to be attenuated by a generating
hexanoic acid, 1.5 equiv of triethylamine (TEA) therefore
was employed as a base, and the reaction smoothly proceeded
at 0 °C to give 4 in 90% yield (entry 3). The amout of DMAP
could be reduced to 0.1 equiv without a significant loss of
yield (entry 4). The reaction with triethylamine in the absence
of DMAP afforded diacylated 6 as a major product, and 4
was hardly obtained (entry 5). Since monoacylated 5
possessing sulfonamide was easily converted to diacylated
6 faster than the acylation of N-tosylhydrazide 3 under the
1
74
a NMR yield using CHBr3 as an internal standard.
basic condition, the reaction using pyridine as the base was
conducted. The reaction afforded 5 in 74% yield as a major
product, and it was confirmed that the deprotonation of
sulfonamide 5 enhanced the second acylation and that
pyridine did not affect the regioselectivity as a catalyst (entry
6).
To clarify the effects of DMAP, the other catalysts were
examined (Table 2). The commercially available 4-pyrroly-
dinopyridine, which has stronger nucleophilicity, accelerated
the reaction, and the yield of 4 was slightly increased over
that of DMAP (entry 1). Interestingly, the reaction was
further accelerated by the addition of 4-aminopyridine, and
4 was obtained in 96% yield along with a trace amount of
diacylated 6 (entry 2). Under these conditions, in situ
generated 4-acylaminopyridine was suspected as being the
actual active catalyst. Then, the prepared N-(pyridin-4-
yl)hexanamide as a catalyst was applied to the same
acylation. However, only a small amount of 4 was obtained
(entry 3). The other catalysts possessing a milder nucleo-
philicity were also examined; 4-hydroxypyridine significantly
reduced the yield of 4 (entry 4), and 4-mehoxypyridine gave
almost no 4 (entry 5). The catalysts, which are not related
to DMAP, were also examined. The regioselectivity was not
affected by the addition of 1,4-diazabicyclo[2,2,2]octane
(DABCO) as an appropriate base and 1-hydroxybenzotriazole
(HOBt) as an accelerating agent of condensation (entries 4
and 5). Therefore, 4-aminopyridine was adopted as the best
catalyst for the efficient preparation of N,N-acyltosylhy-
drazide.
With the establishment of the preparation method for N,N-
acyltosylhydrazide 2, the acylations with the other acid
anhydrides were examined (Table 3). The reaction of acetic
anhydride 7 with tosylhydrazide in the presence of 4-ami-
nopyridine and triethylamine in dichloromethane at 0 °C for
30 min afforded the N,N-acetyltosylhydrazide 8 in 94%
isolated yield (Table 3, entry 1). The acylation with benzoic
anhydride 9 as an aromatic acid anhydride also gave the N,N-
benzoyltosylhydrazide 10 in quantitative yield (entry 2). In
contrast, phthalic anhydride 11, a type of cyclic anhydride,
afforded N-phthaloyl-N′-tosylhydrazide 12 in 83% NMR
(16) Namba, K.; Kaihara, Y.; Yamamoto, H.; Imagawa, H.; Tanino, K.;
Williams, R. M.; Nishizawa, M. Chem.sEur. J. 2009, 27, 6560–6563.
Org. Lett., Vol. 11, No. 21, 2009
4971

2). Although the yield of 4 was not sufficient, the regiose-
lectivity was obviously controlled by 4-aminopyridine even
in the acylation with acyl chloride. The reaction seemed to
be stopped by the simultaneous rapid acylation of 4-ami-
nopyridine with highly reactive acid chloride. Then, the
acylation using DMAP, which has no acylation site, afforded
4 in 97% yield (entry 3). Thus, in the case of acid chloride,
DMAP should be adopted in preference to 4-aminopyridine.
The DMAP-catalyzed acylation with 4-methoxybenzoyl
chloride 14 proceeded smoothly, and the desired N,N-(4-
methoxybenzoyl)tosylhydrazide 15 was obtained in quantita-
tive isolated yield (entry 4). In addition, even 4-bromoben-
zoyl chloride 16 as the aromatic acid derivative possessing
an electron-withdrawing group also gave N,N-aryloyltosyl-
hydrazide 17 in 58% yield (entry 5). The sterically bulky
pivaloyl group was also able to be directly introduced to the
nitrogen masked with a tosyl group, and N,N-pivaloyltosyl-
hydrazide 19 was obtained in 54% yield (entry 6).17 It was
therefore confirmed that the selective acylation with acid
chlorides using DMAP as a catalyst was also applicable to
various acid chlorides.
Table 2. Catalysts Related to DMAPa
a Conditions: H2NNHTs (0.27 mmol), hexanoic anhydride (0.30 mmol),
additive (0.05 mmol), TEA (0.41 mmol), CH2Cl2 (1.4 mL), 0 °C. b NMR
yield using CHBr3 as an internal standard.
Table 4. Selective Acylation with Various Acid Chloridesa
yield and was purified by recrystallization in 51% yield (entry
3). The catalyst did not affect the cyclic anhydrides. It was
confirmed that the selective acylation with acid anhydrides
using 4-aminopyridine as a catalyst was applicable to various
acid anhydrides except for a cyclic acid anhydride.
Table 3. Regioselective Acylation of Various Acid Anhydridesa
a Conditions: H2NNHTs (0.27 mmol), acid chloride (0.30 mmol), catalyst
(0.05 mmol), TEA (0.41 mmol), CH2Cl2 (1.4 mL), 0 °C-rt. b Isolated yield.
c TEA was not added.
a Conditions: H2NNHTs (0.27 mmol), acid anhydride, 4-aminopyridine
(0.05 mmol), TEA (0.41 mmol), CH2Cl2 (1.4 mL), 0 °C-rt. b Isolated yield.
c Yield after recrystallization. d NMR yield using CHBr3 as an internal
standard.
Finally, the regioselective condensation of N-tosylhy-
drazide with carboxylic acids was examined (Table 5). The
coupling of hexanoic acid 20 by the combined action of
EDCI and 4-aminopyridine in dichloromethane afforded the
desired N,N-acyltosylhydirazide 4 in 88% isolated yield
(entry 1) along with a recovery of N-tosylhydrazide 3 (10%)
Next, the other acylating condition was investigated to
extend the regioselective acylation to more valuable car-
boxylic acid derivatives (Table 4). An acylation with
hexanoyl chloride in the presence of 4-aminopyridine af-
forded 4 in 49% yield (entry 1), while 5 was obtained in
83% yield in the absence of 4-aminopyridine and TEA (entry
(17) The case of pyvaric anhydride and 4-aminopyridine hardly gave
19.
4972
Org. Lett., Vol. 11, No. 21, 2009

lective coupling were examined under these conditions. The
coupling of 3-phenylpropanoic acid 21 afforded the desired
N,N-(3-phenypropanoyl)tosylhydrazide 22 in 81% isolated
yield (entry 2) The carboxylic acids possessing such a
functional group as olefin 23, alkyne 25, and ether 27 and
29 also gave the corresponding desired N,N-acyltosylhy-
drazides, 24, 26, 28, and 30 (entries 3-6, respectively) in
acceptable yields. The condensation of cyclohexanecarboxy-
lic acid 31 afforded the desired N,N-acyltosylhydrazide 32
in 76% yield (entry 7). However, only 21% of N,N-
benzoyltosylhydrazides 10 was obtained by the coupling with
benzoic acid 33 (entry 8), and another aromatic carboxylic
acid also hardly gave N,N-aryloyltosylhydrazide. Therefore,
the N,N-aryloyltosylhydrazides should be synthesized by the
acylation with acid anhydride or acid chloride (Table 3, entry
2, and Table 4, entries 4 and 5).
Table 5. Regioselective Condensation with Various Carboxylic
Acida
In summary, a direct and regioselective acylation method
of N-tosylhydrazide for the preparation of either N,N-
acyltosylhydrazide or N-acyl-N′-tosylhydrazide was estab-
lished. The regioselectivity was drastically controlled by the
4-aminopyridine derivatives as a catalyst, and the preparation
of N,N-acyltosylhydrazide was achieved by several combina-
tions: (i) an acid anhydride and 4-aminopyridine, (ii) a
carboxylic acid, EDCI, and 4-aminopyridine, and (iii) an acid
chloride and DMAP. An investigation of other applications
of N,N-acyltosylhydrazide in addition to Hg(OTf)2-catalyzed
cyclization and the reaction mechanism that induced the
regioselectivity is currently underway in our laboratory.
Acknowledgment. We thank professor Tamotsu Inabe
(Hokkaido University) for the X-ray anyalysis of the N,N-
acyltosylhydrazide 4. This work was supported by the Global
COE Program (Project No. B01: Catalysis as the Basis for
Innovation in Materials Science). K.N. is grateful to Astellas
Co., Inc. for a Research Fund for Young Scientists.
a Conditions: H2NNHTs (0.27 mmol), carboxylic acid (0.35 mmol),
4-aminopyridine (0.11 mmol), EDCI (0.41 mmol), TEA (0.54 mmol),
CH2Cl2 (1.4 mL), rt. b Isolated yield (the remaining yields are almost all
recovery of N-tosylhydrazide.
and a trace amount of diacylated tosylhydrazide 6. In the
case of the regioselective coupling with a carboxylic acid,
4-aminopyridine was slightly better than DMAP, and 0.4
equiv of 4-aminopyridine was found to be an appropriate
amount.18 Then, various carboxylic acids for the regiose-
Supporting Information Available: Experimental details,
1H and 13C NMR spectra of each N,N-acyltosylhydrazides
and N-acyl-N′-tosylhydrazides, and data of X-ray analysis,
including CIF file. This material is available free of charge
via the Internet at http://pubs.acs.org.
(18) The condensation reactions in the absence of 4-aminopyridine gave
only a small amount of 5 and 6.
OL9021194
Org. Lett., Vol. 11, No. 21, 2009
4973