Activation and Substitution of 1-Ferrocenylalkylamines with Allenones: Application to Three-Component Synthesis of 4-(1-Ferrocenylalkyl)pyrazoles

Article abstract of DOI:10.1021/acs.orglett.7b02830

A one-pot, two-step three-component synthesis of 4-(1-ferrocenylalkyl)pyrazoles has been developed involving activation and substitution of 1-ferrocenylalkylamines with allenones under mild conditions. A range of 1-ferrocenylalkylamines reacted with allenones in the presence of dipicolinic acid at room temperature without extrusion of air and moisture, and the resulting crude products were treated with hydrazine to afford structurally diverse 4-(1-ferrocenylalkyl)pyrazoles in moderate to good yields. Moreover, the three-component reaction was successfully extended to an enantioenriched α-ferrocenylbenzylamine with complete retention of configuration.

Full text of DOI:10.1021/acs.orglett.7b02830

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Activation and Substitution of 1‑Ferrocenylalkylamines with
Allenones: Application to Three-Component Synthesis of
4‑(1-Ferrocenylalkyl)pyrazoles
Zhixiong Chen, Lu Han, and Shi-Kai Tian*
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and
Technology of China, Hefei, Anhui 230026, China
S
* Supporting Information
ABSTRACT: A one-pot, two-step three-component synthesis
of 4-(1-ferrocenylalkyl)pyrazoles has been developed involving
activation and substitution of 1-ferrocenylalkylamines with
allenones under mild conditions. A range of 1-ferrocenylalkyl-
amines reacted with allenones in the presence of dipicolinic
acid at room temperature without extrusion of air and
moisture, and the resulting crude products were treated with
hydrazine to afford structurally diverse 4-(1-ferrocenylalkyl)-
pyrazoles in moderate to good yields. Moreover, the three-component reaction was successfully extended to an enantioenriched
α-ferrocenylbenzylamine with complete retention of configuration.
Scheme 1. Plausible Mechanism for the Synthesis of
4-(1-Ferrocenylalkyl)pyrazoles
onversion of 1-ferrocenylalkylamines to the correspond-
ing ammonium salts followed by nucleophilic substitution
C
is a well-known two-step sequence for the preparation of 1-
ferrocenylalkyl-containing compounds,1 which have found wide
applications in catalysis, materials, and medicines.2 To improve
the step economy and facilitate the synthetic manipulation, a
few electrophiles3 and acids4 have been identified to activate
the amino groups of 1-ferrocenylalkylamines in the presence of
nucleophiles. Particularly noteworthy is the use of acetic
anhydride, the acetyl group of which activates the amino groups
of 1-ferrocenylalkylamines and the rest of which, the acetoxy
group, participates in nucleophilic substitution to afford esters
(Scheme 1).5 Clearly, such type of single reagent-mediated
process exhibits higher step and atom economy relative to other
substitution reactions of 1-ferrocenylalkylamines. Herein we
report a conceptually new substitution reaction of 1-ferrocenyl-
alkylamines, wherein nucleophiles are generated in situ through
activation of electrophiles by the amino groups.
In continuation of our exploration of the synthetic utilities of
C−N bond cleavage,6,7 we designed a new type of direct
substitution reaction of 1-ferrocenylalkylamines taking advant-
age of activation of allenones by the amino groups.8,9 As
depicted in Scheme 1, nucleophilic addition of 1-ferrocenyl-
alkylamine 1 to allenone 2 would generate ammonium salt I-2,
which would undergo 1,3-rearrangement, involving sequential
C−N bond cleavage and C−C bond formation, followed by
hydrolysis to afford 2-(1-ferrocenylalkyl)-1,3-diketone 3. In this
process, electrophilic allenone 2 would be activated by the
amino group to yield enamine I-4 as a carbon nucleophile. An
acid was proposed to accelerate the process by activating
allenone 2 and, furthermore, catalyze the transformation of 2-
(1-ferrocenylalkyl)-1,3-diketone 3 into 4-(1-ferrocenylalkyl)-
pyrazole 4.10 Thus, a one-pot, two-step, three-component
synthesis was expected to provide unprecedented yet
convenient access to 4-(1-ferrocenylalkyl)pyrazoles, particularly
chiral ones. It is noteworthy that some 4-(ferrocenylmethyl)-
pyrazole/metal complexes exhibit growth inhibitory activity
against human cancer cell lines,11 promising anion-sensing
properties,12 and interesting electrochemical behaviors.13 These
simple 4-(ferrocenylmethyl)pyrazoles were reported to be
Received: September 10, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02830
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
prepared in two steps by substitution of ferrocenylmethanol
with 1,3-diketones followed by condensation with hydrazine.
To test the above hypothesis, we examined a number of
readily accessible Lewis acids and Brønsted acids (50 mol %) to
catalyze the reaction between α-ferrocenylbenzylamine 1a and
allenone 2a in nitromethane at room temperature without
extrusion of air and moisture (Table 1, entries 1−14). The
more α-ferrocenylbenzylamine 1a was consumed by the acid
catalyst (Table 1, entry 25).
After the reaction of α-ferrocenylbenzylamine 1a with
allenone 2a in nitromethane proceeded at room temperature
for 12 h, the nitromethane solvent was removed under reduced
pressure and the resulting crude product was treated with
hydrazine hydrate in ethanol at room temperature for 12 h. To
our delight, the desired 4-(α-ferrocenylbenzyl)pyrazole 4a was
isolated in 75% yield (Table 2, entry 1).15 The one-pot, two-
a
Table 1. Optimization of the Reaction Conditions
Table 2. Three-Component Synthesis of
a
4-(1-Ferrocenylalkyl)pyrazoles
a
Reaction conditions: 1a (0.10 mmol), 2a (0.12 mmol), acid (0.050
b
c
mmol), solvent (2.0 mL), rt, 12 h. Isolated yield. The reaction was
run at 50 °C. 10 mol % dipicolinic acid was used. 100 mol %
d
e
dipicolinic acid was used.
reaction efficiency was dramatically affected by the acid
catalysts, and gratifyingly, the use of dipicolinic acid afforded
the desired 2-(α-ferrocenylbenzyl)-1,3-diketone 3a in the
highest yield: 70% (Table 1, entry 14).14 Replacing nitro-
methane with a few other solvents led to lower yields (Table 1,
entries 15−22). Moreover, the yield decreased dramatically
when elevating the temperature to 50 °C or decreasing the
catalyst loading to 10 mol % (Table 1, entries 23 and 24). The
requirement of a high catalyst loading (50 mol %) was
rationalized by the partial consumption of dipicolinic acid with
two amines, α-ferrocenylbenzylamine 1a, and dimethylamine
(the sole byproduct of the reaction). Nevertheless, the yield
also decreased when increasing the catalyst loading because
a
Reaction conditions: (1) 1 (0.20 mmol), 2 (0.24 mmol), acid (0.10
mmol), nitromethane (4.0 mL), rt, 12 h; (2) 85% aqueous hydrazine
(0.20 mL), ethanol (2.0 mL), rt, 12 h. Isolated yield.
b
step, three-component synthesis of 4-(α-ferrocenylbenzyl)-
pyrazole 4a was successfully extended to trialkylamines 1b−d
but not to less nucleophilic aromatic amine 1e (Table 2, entries
2−5). Secondary amine 1f and primary amine 1g could also
participate in the three-component reaction to afford 4-(α-
ferrocenylbenzyl)pyrazole 4a but in lower yields (Table 2,
entries 6 and 7). A range of 1-ferrocenylalkylamines, including
α-ferrocenylbenzylamines, reacted with allenone 2a and
B
DOI: 10.1021/acs.orglett.7b02830
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
hydrazine to afford structurally diverse 4-(1-ferrocenylalkyl)-
pyrazoles in moderate to good yields (Table 2, entries 8−16).
The desired reaction failed to occur with ferrocenylmethyl-
amine 1q due to the inferior reactivity regarding C−N bond
cleavage under the standard conditions (Table 2, entry 17).
The three-component reaction worked well with a range of
terminal allenyl aryl ketones and allenyl alkyl ketones (Table 2,
entries 18−27). While γ-methylallenone 2l participated in the
three-component reaction to afford 4-(α-ferrocenylbenzyl)-
pyrazole 4v in 54% yield, a complex mixture was observed for
the corresponding reaction with γ-phenylallenone 2m (Table 2,
entries 28 and 29).
The one-pot, two-step, three-component reaction was further
extended to enantioenriched α-ferrocenylbenzylamine (S)-1a,
and the desired 4-(α-ferrocenylbenzyl)pyrazole (R)-4n was
obtained in 65% yield with complete retention of configuration
(eq 1). The structure and the absolute configuration of product
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the National
Natural Science Foundation of China (21472178 and
21232007), the National Key Basic Research Program of
China (2014CB931800), and the Strategic Priority Research
Program of the Chinese Academy of Sciences (XDB20000000).
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benzylamine as depicted in Scheme 1.17
In summary, we have developed a one-pot, two-step, three-
component synthesis of 4-(1-ferrocenylalkyl)pyrazoles involv-
ing activation and substitution of 1-ferrocenylalkylamines with
allenones under mild conditions. A range of 1-ferrocenyl-
alkylamines reacted with allenones in the presence of
dipicolinic acid at room temperature without extrusion of air
and moisture, and the resulting crude products were treated
with hydrazine to afford structurally diverse 4-(1-ferrocenyl-
alkyl)pyrazoles in moderate to good yields. Moreover, the
three-component reaction was successfully extended to an
enantioenriched α-ferrocenylbenzylamine with complete re-
tention of configuration.
ASSOCIATED CONTENT
* Supporting Information
■
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Experimental procedures, characterization data, copies of
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crystal data of compound (R)-4n (PDF)
Crystallographic data for (R)-4n (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tiansk@ustc.edu.cn.
ORCID
Shi-Kai Tian: 0000-0002-2938-7013
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.7b02830
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Letter
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did not occur under the standard conditions. Therefore, allenone 2a is
unlikely to be converted to PhCOCH2COMe prior to the C−C bond
formation via hydrolysis of enamine intermediate I-4a (R2 = R3 = Me,
R4 = H, R5 = Ph) (Scheme 1).
(15) The desired pyrazole was not obtained when replacing
hydrazine with a monosubstituted hydrazine, such as phenylhydrazine
and p-toluenesulfonyl hydrazide.
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D
DOI: 10.1021/acs.orglett.7b02830
Org. Lett. XXXX, XXX, XXX−XXX