Chemoselective aminomethylation of bifunctional substrates: Carbonyl versus phenolic hydroxyl, carbonyl versus pyrazole and pyrrole versus phenolic hydroxyl as competing activating groups This Letter is dedicated with great admiration and affection to Professor Eugenia Comani?ǎ, teacher and mentor, in recognition of her achievements in Organic Chemistry

Article abstract of DOI:10.1016/j.tetlet.2014.01.005

Chemoselectivity in the Mannich reaction for three different types of bifunctional substrates has been investigated. 1-Hydroxy-2-naphthalenylethanone affords either phenolic Mannich bases at high pH (free amines), or ketonic Mannich bases at low pH (amine hydrochlorides), whereas the use of N,N-dimethylmethyleneiminium chloride as a preformed dimethylaminomethylation reagent gave the phenolic Mannich base. 1-Aryl-3-(1H-pyrazol-1-yl)-1-propanones undergo aminomethylation at position 4 of the pyrazole ring, and not at the methylene group α to the carbonyl function, regardless of the reaction conditions. 4-(2,5-Dimethyl-1H-pyrrol-1-yl)phenol is aminomethylated chemoselectively on the pyrrole ring under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2014.01.005

Tetrahedron Letters 55 (2014) 1229–1233
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chemoselective aminomethylation of bifunctional substrates:
carbonyl versus phenolic hydroxyl, carbonyl versus pyrazole
and pyrrole versus phenolic hydroxyl as competing activating
groups q
⇑
Gheorghe Roman
Department of Inorganic Polymers, Petru Poni Institute of Macromolecular Chemistry, 41A Aleea Gr. Ghica Voda˘, Iaßsi 700487, Romania
a r t i c l e i n f o
a b s t r a c t
Article history:
Chemoselectivity in the Mannich reaction for three different types of bifunctional substrates has been
investigated. 1-Hydroxy-2-naphthalenylethanone affords either phenolic Mannich bases at high pH (free
amines), or ketonic Mannich bases at low pH (amine hydrochlorides), whereas the use of N,N-dimethyl-
methyleneiminium chloride as a preformed dimethylaminomethylation reagent gave the phenolic Man-
nich base. 1-Aryl-3-(1H-pyrazol-1-yl)-1-propanones undergo aminomethylation at position 4 of the
Received 1 October 2013
Revised 27 November 2013
Accepted 2 January 2014
Available online 10 January 2014
pyrazole ring, and not at the methylene group
ditions. 4-(2,5-Dimethyl-1H-pyrrol-1-yl)phenol is aminomethylated chemoselectively on the pyrrole ring
under mild reaction conditions.
a to the carbonyl function, regardless of the reaction con-
This Letter is dedicated with great
admiration and affection to Professor
Eugenia Comanit¸a˘, teacher and mentor, in
recognition of her achievements in Organic
Chemistry
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Chemoselectivity
Mannich reaction
Ketones
Phenols
Pyrazoles
Pyrroles
Classical aminomethylation reactions (also known as Mannich
reactions) are three-component condensations in which the sub-
strate, a compound containing an active hydrogen atom, reacts
with formaldehyde and an amine to produce a derivative of the
substrate, usually referred to as Mannich base, in which the nitro-
gen atom of the amine is linked to the substrate through a methy-
lene group. Not only are Mannich bases important to fundamental
research, they also have a wide range of practical uses, ranging
from detergents, flocculants, chelators and anticorrosion chemicals
to radical inhibitors and crosslinking agents.2 However, the most
significant application of aminomethylation can be found in the
field of pharmaceutical chemistry, as 30–40% of the papers report-
ing Mannich reactions are published in medicinal and pharmaceu-
tical chemistry journals. Aminomethylation has played an
important role in drug discovery, as shown by the large number
of drugs whose synthesis employs the Mannich reaction as a key
step, for example, molindone (antipsychotic), dyclonine (anaes-
thetic), eprazinone (antitussive), oxyfedrine (anti-anginal agent),
amodiaquine, amopyroquine, bialamicol and clamoxyquin (anti-
malarials), pargyline (antihypertensive), morazone (analgesic)
and hexetidine (antifungal).3 Moreover, Mannich bases are precur-
sors of other interesting classes of biologically active compounds
such as amino alcohols, or can act as intermediates for the prepa-
ration of natural molecules such as alkaloids, hormones, vitamins,
flavonoids, porphyrins or terpenoids.4
A wide range of substrates have been subjected to aminomethy-
lation, and most of them belong to several classes of organic com-
pounds that possess an activating group. To mention only a few of
the most important substrates in aminomethylation and the corre-
sponding activating groups, alkyl ketones feature a carbonyl group
in their structure, phenols have at least one hydroxyl group, and
aromatic heterocycles are activated by the presence of various
heteroatoms.5 General sets of reaction conditions for each type of
substrate are available with the view to optimize the outcome of
the Mannich reaction.5 In the case of polyfunctional substrates that
q
This communication is Part 24 in the series ‘Synthesis and reactivity of Mannich
bases’; for Part 23, see Ref. 1.
⇑
Tel.: +40 232 217 454; fax: +40 232 211 299.
E-mail address: gheorghe.roman@icmpp.ro
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.005

1230
G. Roman / Tetrahedron Letters 55 (2014) 1229–1233
have different reactive sites capable of reacting with an aminome-
thylating agent, the direction of the Mannich reaction can be ratio-
nalized in terms of the relative reactivity of the reactive sites. Also,
the aminomethylation may occur at a specific reactive site accord-
ing to the particular reaction conditions that are employed. In a
classical example, hydroxyaryl methyl ketones can be aminome-
ring para to the phenolic hydroxyl to afford 1-[1-hydroxy-4-(mor-
pholin-4-ylmethyl)-2-naphthalenyl]ethanone (2a), and not at the
methylene
a
to the carbonyl function.16 The use of a two-fold ex-
cess of formaldehyde and morpholine under the same reaction
conditions raised the yield of 2a to 85%; no other by-products
could be detected in the crude reaction mixture by 1H NMR. The
same compound could be obtained, albeit in a lower yield (42%),
when one equivalent of substrate 1 was reacted with one equiva-
lent of morpholine and two equivalents of 37% aq formaldehyde
in benzene at reflux temperature for 3 h.17 The latter synthetic
methodology was subsequently used to obtain a series of phenolic
Mannich bases 2b–j from other secondary aliphatic amines. It
should be noted that diallylamine, N-methylbenzylamine and N-
ethylbenzylamine did not react with substrate 1 under these
conditions.
In order to obtain the ketonic Mannich base from 1, the sub-
strate was subjected to aminomethylation at low pH under the
same conditions (1:2:1 molar ratio of substrate 1, paraformalde-
hyde and morpholine hydrochloride, a catalytic amount of concd
HCl, 2-propanol, reflux, 4 h)12 that were successfully used for
hydroxyacetophenones (Scheme 1). As the work-up afforded only
a low yield (12%) of the desired 3-(morpholin-4-yl)-1-(1-hydro-
xy-2-naphthalenyl)-1-propanone hydrochloride (3a),18 the reac-
tion time was increased to 24 h, but the yield was improved only
marginally. In addition, 1-(1-hydroxynaphthalen-2-yl)prop-2-en-
1-one, a by-product formed from ketonic Mannich base 3a through
a deamination process due to prolonged heating, was detected by
1H NMR in the solid isolated after work-up. No trace of the pheno-
lic Mannich base 2a (as a hydrochloride salt) could be identified in
the proton NMR spectrum of crude 3a, and the TLC analysis of the
extract in ethyl acetate of the aqueous solution of crude 3a after
treatment with excess Na2CO3 [Rf 0.23 (EtOAc–hexanes, 1:1 v/v)
for the free base of compound 3a] showed no trace of compound
2a (Rf 0.44, EtOAc–hexanes, 1:1 v/v). Replacement of morpholine
hydrochloride with dimethylamine hydrochloride afforded 3b in
a yield comparable to that of Mannich base 3a. Hence, the rule
according to which alkyl hydroxyaryl ketones can be chemoselec-
thylated either at the carbon atom
a to the carbonyl group or ortho
to the phenolic hydroxyl, but chemoselective aminomethylation
can normally be achieved by using the appropriate reaction condi-
tions.6 Acetylenic ketones, which have been aminomethylated
either
a to the carbonyl group in acidic medium, or at the ethynyl
function in the presence of copper salts, represent another category
of polyfunctional substrates that can undergo the Mannich reac-
tion in a chemoselective manner.7 In addition, N-propargylanilines
have been aminomethylated either on the aromatic ring para to the
amino group or at the propargyl moiety, depending on the reaction
conditions.8 Also, hydroxyindoles generally afford phenolic Man-
nich bases, but when the position ortho to the hydroxyl function
is blocked, aminomethylation occurs at C-3 to give an indole Man-
nich base.9 To the best of our knowledge, the literature on this to-
pic appears to be limited to the types of substrates mentioned
above. In an effort to understand better, and to gain further insight
into the aminomethylation of polyfunctional substrates, the pres-
ent Letter explores the chemoselectivity of the Mannich reaction
for three distinct types of substrates, each of them featuring two
different activating functional groups in their structure.
The first bifunctional substrate examined in terms of chemose-
lectivity under the Mannich reaction conditions belongs to the al-
kyl hydroxyaryl ketones, and features a carbonyl function and a
phenolic hydroxyl as activating groups. Simple alkyl hydroxyaryl
ketones (such as the isomeric hydroxyacetophenones) have been
thoroughly investigated as substrates in aminomethylation reac-
tions, and the formation of ketonic Mannich bases derived from
hydroxyaryl methyl ketones has been shown to be favored by
the use of amine hydrochlorides in the presence of catalytic
amounts of acid,10 whereas the use of free amines normally affords
phenolic Mannich bases.11,12 However, the application of a set of
specific reaction conditions in the Mannich reaction of similar sub-
strates does not always lead to reaction products having similar
structures. For example, the aminomethylation of 2,4-dihydroxy-
acetophenone with morpholine hydrochloride at low pH produces
high yields of the 3-substituted phenolic Mannich base instead of
the expected ketonic Mannich base.13 To further complicate the
course of the Mannich reaction of this type of substrate, the prox-
imity of the acetyl and hydroxyl groups in ortho-hydroxyacetoph-
enones is known to lead to aminomethylated chromanones
obtained through a sequence comprising the Mannich reaction of
the substrate and ring-closure between the aforementioned groups
in the presence of excess paraformaldehyde.14 In contrast to
hydroxyacetophenones, the Mannich reaction of hydroxynapht-
halenylethanones appears to have been less investigated. A survey
of the literature uncovered a paper by Okuda and Matsumoto15
that reports the formation of a series of aminomethylated deriva-
tives of 1-hydroxy-2-naphthalenylethanone (1) at high pH (free
amines as amine reagents), to which they assigned the structure
of the corresponding ketonic Mannich bases. Intrigued by the
apparently abnormal behaviour of substrate 1 in the Mannich reac-
tion, we decided to replicate the conditions used by the Japanese
researchers (Scheme 1). When heated at reflux temperature in
tively aminomethylated either at the carbon atom
a to the car-
bonyl group or ortho/para to the phenolic hydroxyl, depending
on the pH of the medium, applies to 1-hydroxy-2-naphthalenyl-
ethanone (1) as well.
Dissatisfied with the low yields of ketonic Mannich base 3a, we
decided to attempt to improve them and shorten the reaction time
by employing a microwave-assisted variant of the reaction. An at-
tempt to conduct a typical experiment as described previously19
(2 mmol of substrate 1, 2 mmol of paraformaldehyde, 2 mmol of
morpholine hydrochloride in 4 mL of 1,4-dioxane at 180 °C for
500 s) using a CEM Discover reactor resulted in significant charring
of the insoluble part of the reaction mixture (presumably the
amine hydrochloride, which is also known to readily absorb micro-
waves). A second run under milder conditions (90 °C for 500 s) was
accompanied by reduced charring of the insoluble part of the reac-
tion mixture, but the work-up led only to the recovery of substrate
1. Both the extensive charring and the failure to obtain any reac-
tion products may be due to the limited solubility of morpholine
hydrochloride in 1,4-dioxane.
Preformed aminomethylation reagents have become powerful
tools in the Mannich reaction of various types of substrates.20
Iminium salts (Eschenmoser’s salt and the corresponding chloride
salt, in particular) have been mostly employed for the preparation
of ketonic Mannich bases,21 although reports on the aminomethy-
lation of phenols22 as well as indoles23 with these preformed Man-
nich reagents are also available. Even though both activating
groups present in substrate 1 could potentially direct the Mannich
reaction to either reactive site when iminium salts are employed as
aminomethylating reagents, only the hydrochloride of the phenolic
the presence of 37% formaldehyde (500
lL, 5.5 mmol), and mor-
pholine (435 L, 5 mmol) in ethanol (4 mL) for 2 h, substrate 1
l
(5 mmol) gave a yellow solid which, after one recrystallization
from ethanol, melted at 126–127 °C (Osuka and Matsumoto15 re-
ported 124–126 °C for the compound arising from the same reac-
tion). The NMR analysis of the isolated compound showed that
aminomethylation of substrate 1 had occurred on the aromatic

G. Roman / Tetrahedron Letters 55 (2014) 1229–1233
1231
Scheme 1. Chemoselective aminomethylation of 1-hydroxy-2-naphthalenylethanone (1). Reagents and conditions: (i) 37% aq formaldehyde, secondary aliphatic amine,
benzene, reflux 3 h; (ii) paraformaldehyde, secondary aliphatic amine hydrochloride, 36% HCl, 2-propanol, reflux, 4 h; (iii) N,N-dimethylmethyleneiminium chloride, anhyd
MeCN, reflux, 3 h.
Scheme 2. Chemoselective aminomethylation of 1-aryl-3-(1H-pyrazol-1-yl)-1-propanones 4. Reagents and conditions: paraformaldehyde, secondary aliphatic amine
hydrochloride, 36% HCl, 2-propanol, reflux, 4 h.
Mannich base 2k was obtained in good yield (58%) by heating
1-hydroxy-2-naphthalenylethanone 1 and N,N-dimethylmethyle-
neiminium chloride at reflux temperature in anhydrous
acetonitrile for 3 h (Scheme 1).24 Under these conditions, 1 was
chemoselectively aminomethylated para to the hydroxyl function,
thus providing an indication that the phenolic hydroxyl is a stron-
ger activating group in the Mannich reaction of substrate 1 than
the carbonyl function.
The chemoselectivity in the Mannich reaction was also investi-
gated for a bifunctional substrate that has a carbonyl function and
a pyrazole ring as activating groups. Given our previous experience
on the synthesis of 1-aryl-3-(1H-pyrazol-1-yl)-1-propanones,1,25
we decided that these compounds, in which the activating groups
are separated by two methylene groups, would serve adequately as
models for this type of substrate. It is well known that acetophe-
nones (a type of substrate among alkyl aryl ketones which has
been heavily employed in the Mannich reaction) aminomethylate
not appear to affect significantly the reactivity of these substrates
in the Mannich reaction. Although the literature contains a wealth
of information on the Mannich reaction of alkyl aryl ketones, re-
ports on aminomethylation of pyrazoles are scarce.29,30 According
to these reports, 3,5-dimethylpyrazole and its analogues substi-
tuted at N-1 can be aminomethylated at C-4 either with free
amines29 at high pH, or with amine hydrochlorides at low pH.30
As the latter reaction conditions are usually employed for the ami-
nomethylation of ketones as well, the Mannich reaction of 1-(4-
chlorophenyl)-3-(3,5-dimethyl-1H-pyrazol-1-yl)propan-1-one
(4a) with dimethylamine hydrochloride was examined under these
conditions, which lead chemoselectively to aminomethylated pyr-
azole derivative 5a.31 The limitation of the Mannich reaction with
this type of substrate under identical conditions was also exam-
ined briefly. Substrates 4b–d featuring 4-hydroxyphenyl, 2-
hydroxyphenyl and 2-thienyl moieties instead of a 4-chlorophenyl
residue afforded the corresponding 4-dimethylaminomethylated
pyrazoles 5b–d in fair to good yields (Scheme 2). The replacement
of dimethylamine hydrochloride with morpholine hydrochloride
smoothly. Furthermore, substitution of the carbon atom
a to the
carbonyl function with alkyl,26 aryl27 or aryloxy28 moieties does

1232
G. Roman / Tetrahedron Letters 55 (2014) 1229–1233
Figure 1. 1-(4-Chlorophenyl)-3-(1H-pyrazol-1-yl)-1-propanones 4e–g as examples of unreactive substrates in the Mannich reaction.
Scheme 3. Chemoselective aminomethylation of 4-(2,5-dimethyl-1H-pyrrol-1-yl)phenol (6). Reagents and conditions: 37% aq formaldehyde, secondary aliphatic amine,
EtOH, rt, 5 d.
as the amine reagent afforded consistently better yields of Man-
nich bases 5. Substitution of the 3,5-dimethyl-1H-pyrazol-1-yl
with a 3,5-diphenyl-1H-pyrazol-1-yl moiety as in substrate 4e, or
with a 1H-pyrazol-1-yl moiety as in substrate 4f (Fig. 1) rendered
the pyrazole residue unreactive towards aminomethylation under
the same conditions. While steric hindrance at the reactive site
could be deemed responsible for the lack of reactivity of the phe-
nyl-substituted pyrazole, it could however not be the reason for
the lack of reactivity of the unsubstituted pyrazole derivative.
These results suggest that the aminomethylation of the pyrazole
ring is governed by electronic effects rather than by steric factors.
Interestingly, no trace of a ketonic Mannich base was detected in
the experiments using substrates with phenyl-substituted or
unsubstituted pyrazole, even when aminomethylation did not oc-
cur on the pyrazole ring. In addition, 1-(4-chlorophenyl)-3-(4-bro-
mo-3,5-dimethyl-1H-pyrazol-1-yl)propan-1-one (4g), a substrate
having a structure similar to compounds 4a–d, but presenting
of bifunctional substrate, especially as compound 6 has already
been reported to lead to the corresponding phenolic Mannich bases
upon treatment with formaldehyde and diethylamine.33 In the ini-
tial experiment, we decided to replace diethylamine with a more
reactive secondary aliphatic amine, and to simplify and adapt the
general experimental procedure to our particular substrate. Under
very mild reaction conditions, aminomethylation with piperidine
as the amine reagent occurred at one of the free b positions of
the pyrrole ring to produce Mannich base 7a,34 and not ortho to
the phenolic hydroxyl (Scheme 3). The replacement of piperidine
with other secondary aliphatic amines led to the same type of
Mannich bases. Although the attack of the aminomethylating spe-
cies normally takes place at the more reactive
a position in pyr-
roles, examples of the Mannich reaction of 2,5-disubstituted
pyrroles at the free b positions are well known.35 The results ob-
tained for this particular type of substrate indicate that the pheno-
lic hydroxyl is a weaker activating group than the nitrogen in
pyrrole, even under the appropriate reaction conditions for the
aminomethylation of phenols, and that the Mannich reaction of 6
proceeds chemoselectively on the pyrrole ring even in the absence
of acetic acid, the catalyst normally employed in the synthesis of
aminomethylated pyrroles. For the sake of comparison, the ami-
nomethylation of 4-(1H-pyrrol-1-yl)phenol under the same reac-
tion conditions employed for 6 was briefly explored, and the
unreacted starting material was determined by TLC to be the major
component of the reaction mixture after five days. Several reaction
products were also present as minor components of the mixture,
but the investigation of the identity of these products was not pur-
sued any further owing to their insignificant contribution to the
mixture. The dissimilar reactivity of 6 and 4-(1H-pyrrol-1-yl)phe-
nol under these mild aminomethylation conditions parallels the
difference noted in the reactivity of 2,5-dimethyl-1-phenyl-1H-
pyrrole and 1-phenyl-1H-pyrrole in the Mannich reaction under
slightly more enforcing conditions.36
the methylene
a to the carbonyl function as the sole reactive site,
was completely unreactive in the Mannich reaction under the con-
ditions normally employed for 4a–d. Also, no Mannich base could
be isolated even when N,N-dimethylmethyleneiminium chloride
was used as the aminomethylating reagent with substrate 4g. On
the other hand, substrate 4a reacted easily with the same pre-
formed aminomethylating reagent in acetonitrile at reflux temper-
ature to afford Mannich base 5a in excellent yield (95%). Thus, not
only is 3,5-dimethylpyrazole highly reactive at position 4 in the
Mannich reaction, but it seems to also deactivate the carbon atom
a
to the carbonyl function in the 3-aryl-3-oxopropyl appendage in
substrates 4 towards aminomethylating species.
The third type of bifunctional substrate whose reactivity in the
Mannich reaction has been under scrutiny in this study has a phe-
nolic hydroxyl and a pyrrole ring as activating functions. An
inspection of the literature provides numerous examples of the
Mannich reaction with commonly substituted phenols, naphthols
or phenols fused with various heterocyclic ring systems, and the
usual experimental procedure involves the use of aqueous formal-
dehyde as the aldehyde component and a free amine as the amine
reagent. As mentioned in a previous review,32 the Mannich reac-
tion of pyrroles is best performed either with free amines, usually
in the presence of acetic acid, or with amine hydrochlorides. 4-
(2,5-Dimethyl-1H-pyrrol-1-yl)phenol (6) was chosen as a model
compound for the exploration of the Mannich reaction of this type
In conclusion, the influence of the activating groups on the
direction of the Mannich reaction was investigated in three types
of bifunctional substrates. In the case of 1-hydroxy-2-naphthale-
nylethanone, aminomethylation takes place either on the aromatic
ring para to the phenolic hydroxyl when free amines are used (high
pH), or at the methylene group
pH (with amine hydrochlorides as amine reagents). On the other
hand, the use of N,N-dimethylmethyleneiminium chloride,
a to the carbonyl function at low
a

G. Roman / Tetrahedron Letters 55 (2014) 1229–1233
1233
17. Gasanov, F. I.; Mamedov, V. N.; Kulibekov, M. R.; Kuliev, A. G. Azerb. Khim. Zh.
1978, (3), 39. Chem. Abstr. 1979, 90, 22666.
preformed Mannich reagent capable of aminomethylating both
phenols and ketones, gave the hydrochloride of the phenolic Man-
nich base of 1-hydroxy-2-naphthalenylethanone, which suggests
that, in this particular case, the phenolic hydroxyl is a stronger
activating group than the carbonyl function. The direct Mannich
reaction of a series of 1-aryl-3-(1H-3,5-dimethylpyrazol-1-yl)-
1-propanones proceeded in a chemoselective manner to afford
the corresponding pyrazoles aminomethylated at position 4 in fair
yields, which could be improved significantly by the use of
N,N-dimethylmethyleneiminium chloride as the aminomethylat-
ing reagent. However, this type of substrate failed to react either
18. Compound 3a: Mp 218–219 °C; 1H NMR (DMSO-d6, 400 MHz): d 3.17 (br s, 2H),
3.53 (t, J = 6.8 Hz, 4H), 3.81 (t, J = 6.8 Hz, 4H), 4.00 (br s, 2H), 7.50 (d, J = 8.8 Hz,
1H), 7.62 (t, J = 7.6 Hz, 1H), 7.75 (t, J = 7.2 Hz, 1H), 7.93 (m, 2H), 8.35 (d,
J = 8.0 Hz, 1H), 10.73 (br s, 1H), 13.57 (s, 1H); 13C NMR (DMSO-d6, 100 MHz): d
32.8, 42.7, 51.4, 63.3, 112.7, 118.7, 123.7, 124.2, 124.8, 126.5, 127.8, 130.5,
137.0, 160.9, 203.0. Anal. Calcd for C17H20ClNO3: C, 63.45; H, 6.26; N, 4.35.
Found: C, 63.74; H, 6.02; N, 4.11.
19. Lehmann, F.; Pilotti, Å.; Luthman, K. Mol. Diversity 2003, 7, 145.
20. Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044.
21. (a) Sielemann, D.; Keuper, R.; Risch, N. J. Prakt. Chem. 1999, 341, 487; (b)
Sielemann, D.; Keuper, R.; Risch, N. Eur. J. Org. Chem. 2000, 543.
22. Pochini, A.; Puglia, G.; Ungaro, R. Synthesis 1983, 906.
23. Grumbach, H.-J.; Arend, M.; Risch, N. Synthesis 1996, 883.
24. Compound 2k: Mp 210–211 °C (EtOH); 1H NMR (CD3OD, 400 MHz): d 2.77 (s,
3H), 2.94 (s, 6H), 4.77 (s, 2H), 7.63–7.70 (m, 1H), 7.82–7.89 (m, 1H), 8.14–8.20
(m, 2H), 8.52 (dd, J = 0.8 and 8.4 Hz, 1H); 13C NMR (CD3OD, 100 MHz): d 27.2,
43.2, 58.4, 113.9, 117.7, 124.3, 126.1, 126.8, 127.7, 132.6, 132.7, 136.8, 164.3,
206.2. Anal. Calcd for C15H18ClNO2: C, 64.40; H, 6.49; N, 5.01. Found: C, 64.62;
H, 6.17; N, 4.75.
on the pyrazole ring or at the methylene group
a to the carbonyl
function when the 3,5-dimethylpyrazole moiety was replaced with
pyrazole, 3,5-diphenylpyrazole or 4-bromo-3,5-dimethylpyrazole.
Finally, the aminomethylation of 4-(2,5-dimethyl-1H-pyrrol-1-
yl)phenol occurred at one of the free b positions on the pyrrole ring
under mild reaction conditions, indicating that the nitrogen atom
in the pyrrole is a stronger activating group than the phenolic hy-
droxyl in this type of bifunctional substrate.
25. Roman, G.; Comanißta˘, E.; Comanißta˘, B. Tetrahedron 2002, 58, 1617.
26. Parimoo, P.; Nobles, W. L. J. Pharm. Sci. 1970, 59, 1038.
27. Gevorgyan, G. A.; Avakyan, A. P.; Gasparyan, N. K.; Panosyan, G. A. Russ. J. Org.
Chem. 2009, 45, 1853.
28. Wright, J. B. J. Org. Chem. 1960, 25, 1867.
29. (a) Esquius, G.; Pons, J.; Yáñez, R.; Ros, J.; Solans, X.; Font-Bardıa, M. J.
´
Acknowledgments
Organomet. Chem. 2000, 605, 226; (c) Guzei, I. A.; Keter, F. K.; Spencer, L. C.;
Darkwa, J. Acta Crystallogr., Sect. C 2007, C63, o481.
30. Chavez, S. A.; Martinko, A. J.; Lau, C.; Pham, M. N.; Cheng, K.; Bevan, D. E.;
Mollnes, T. E.; Yin, H. J. Med. Chem. 2011, 54, 4659.
This work was supported by the European Union’s Seventh
Framework Programme (FP7/2007–2013) under grant agreement
No. 264115—STREAM.
31. Representative procedure for 5:
A
mixture of 1-(4-chlorophenyl)-3-(3,5-
(4a) (1050 mg, 4 mmol),
dimethyl-1H-pyrazol-1-yl)-1-propanone
paraformaldehyde (240 mg, 8 mmol), dimethylamine hydrochloride (360 mg,
4.4 mmol) and 36% aq HCl (4 drops) in 2-propanol (10 mL) was heated at reflux
temperature for 4 h. The solvent was removed under reduced pressure, and the
residue was diluted with EtOAc (25 mL) with vigorous stirring. The resulting
solid was filtered and recrystallized from EtOH to give 1-(4-chlorophenyl)-3-
(4-dimethylaminomethyl-3,5-dimethyl-1H-pyrazol-1-yl)-1-propanone
hydrochloride (5a) as colorless crystals (625 mg, 49%), mp 198–199 °C; 1H
NMR (D2O, 400 MHz): d 2.21 (s, 3H), 2.33 (s, 3H), 2.74 (s, 6H), 3.56 (t, J = 6.0 Hz,
2H), 4.12 (s, 2H), 4.49 (t, J = 6.0 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.79 (d,
J = 8.8 Hz, 2H); 13C NMR (D2O, 100 MHz): d 9.3, 10.4, 37.7, 41.6, 44.4, 49.9,
106.3, 129.0, 129.8, 134.2, 140.1, 143.6, 148.5, 200.7. Anal. Calcd for
References and notes
1. Roman, G. Acta Chim. Slov. 2013, 60, 70.
2. Tramontini, M.; Angiolini, L. Mannich Bases: Chemistry and Uses; CRC Press:
Boca Raton, FL, 1994.
3. The Merck Index; O’Neil, M. J., Smith, A., Heckelman, P. E., Budavari, S., Eds., 13th
ed.; Merck: Rahway, NJ, 2001.
4. Tramontini, M.; Angiolini, L. Tetrahedron 1990, 46, 1791.
5. Tramontini, M. Synthesis 1973, 703.
6. (a) Gautier, J.-A.; Miocque, M.; Quan, D. Q. C. R. Acad. Sci. 1964, 258, 3731; (b)
Brandes, R.; Roth, H. J. Arch. Pharm. (Weinheim) 1967, 300, 1005.
7. (a) Gautier, J.-A.; Miocque, M.; Mascrier-Demagny, L. Bull. Soc. Chim. Fr. 1967,
1560; (b) Gautier, J.-A.; Miocque, M.; Mascrier-Demagny, L.; Raynaud, G.;
Thomas, J.; Gouret, C.; Pourrias, B. Chim. Thér. 1973, 8, 14.
8. Miocque, M.; Vierfond, J. M. Ann. Pharm. Fr. 1973, 31, 721.
9. (a) Troxler, F.; Bormann, G.; Seemann, F. Helv. Chim. Acta 1968, 51, 1203; (b)
Monti, S. A.; Johnson, W. O. Tetrahedron 1970, 26, 3685.
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Chem. USSR 1972, 8, 1315; (b) Joglekar, S. J.; Samant, S. D. Synthesis 1988, 830.
11. Comanißta˘, E.; Roman, G.; Popovici, I.; Comanißta˘, B. J. Serb. Chem. Soc. 2001, 66,
9. and references cited therein.
12. (a) Vijaya Bhaskar Reddy, M.; Su, C.-R.; Chiou, W.-F.; Liu, Y.-N.; Chen, R. Y.-H.;
Bastow, K. F.; Lee, K.-H.; Wu, T.-S. Bioorg. Med. Chem. 2008, 16, 7358; (b) Vijaya
Bhaskar Reddy, M.; Chen, S.-S.; Lin, M.-L.; Chan, H.-H.; Kuo, P.-C.; Wu, T.-S.
Chem. Pharm. Bull. 2011, 59, 1549.
C17H23Cl2N3O: C, 57.31; H, 6.51; N, 11.79. Found: C, 57.56; H, 6.23; N, 11.55.
32. Roman, G. Mini-Rev. Org. Chem. 2006, 3, 167.
33. Burckhalter, J. H.; Tendick, F. H.; Jones, E. M.; Holcomb, W. F.; Rawlins, A. L. J.
Am. Chem. Soc. 1946, 68, 1894.
34. Representative procedure for 7:
A mixture of 4-(2,5-dimethyl-1H-pyrrol-1-
yl)phenol (6) (935 mg, 5 mmol), 37% formaldehyde (0.7 mL) and piperidine
(425 mg, 5 mmol) in EtOH (3 mL) was kept at room temperature for 5 d. The solid
that gradually separated was filtered, washed with cold EtOH and recrystallized
to give 4-(2,5-dimethyl-3-(piperidin-1-ylmethyl)-1H-pyrrol-1-yl)phenol (7a)
as tan crystals (695 mg, 49%), mp 208–209 °C (EtOH); 1H NMR (DMSO-d6,
400 MHz): d 1.30–1.51 (m, 6H), 1.86 (s, 3H), 1.90 (s, 3H), 2.30 (br s, 4H), 3.16 (s,
2H), 5.70 (s, 1H), 6.83 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 9.69 (br s, 1H,
exchangeable with D); 13C NMR (DMSO-d6, 100 MHz): d 10.6, 12.6, 24.2, 25.6,
53.7, 55.0, 107.7, 114.5, 115.6, 125.7, 126.5, 129.1, 129.6, 156.7. Anal. Calcd for
C18H24N2O: C, 76.02; H, 8.51; N, 9.85. Found: C, 75.71; H, 8.33; N, 9.94.
35. (a) Cerreto, F.; Villa, A.; Retico, A.; Scalzo, M. Eur. J. Med. Chem. 1992, 27, 701;
(b) Cerreto, F.; Scalzo, M.; Villa, A. Farmaco 1993, 48, 1735; (c) Biava, M.;
Fioravanti, R.; Porretta, G. C.; Mencarelli, P.; Sleiter, G. Gazz. Chim. Ital. 1995,
125, 9; (d) Biava, M.; Fioravanti, R.; Porretta, G. C.; Frachey, G.; Mencarelli, P.;
Sleiter, G.; Perazzi, M. E.; Simonetti, N.; Villa, A. Farmaco 1995, 50, 431; (e)
Biava, M.; Porretta, G. C.; Deidda, D.; Pompei, R.; Tafi, A.; Manetti, F. Bioorg.
Med. Chem. 2003, 11, 515; (f) Biava, M.; Porretta, G. C.; Giorgi, G.; Sleiter, G.
ARKIVOC 2004, (v), 325; (g) Biava, M.; Porretta, G. C.; Poce, G.; De Logu, A.;
Meleddu, R.; De Rossi, E.; Manetti, F.; Botta, M. Eur. J. Med. Chem. 2009, 44,
4734; (h) Biava, M.; Porretta, G. C.; Poce, G.; Battilocchio, C.; Alfonso, S.; De
Logu, A.; Serra, N.; Manetti, F.; Botta, M. Bioorg. Med. Chem. 2010, 18, 8076.
36. Herz, W.; Settine, R. L. J. Org. Chem. 1959, 24, 201.
13. Hagen, H. E.; Frahm, A. W.; Brandes, R.; Roth, H. J. Arch. Pharm. 1970, 303, 988.
14. (a) Werner, W. Arch. Pharm. (Weinheim) 1976, 309, 1011; (b) Caßscaval, A.
Synthesis 1983, 579; (c) Fînaru, A.; Caßscaval, A.; Prisecaru, M. Rev. Chim.
(Bucharest) 2003, 54, 837.
15. Okuda, T.; Matsumoto, U. Yakugaku Zasshi 1959, 79, 1140. Chem. Abstr. 1960,
54, 3452.
16. Compound 2a: 1H NMR (CDCl3, 400 MHz): d 2.50 (br s, 4H), 2.70 (s, 3H), 3.69 (t,
J = 4.4 Hz, 4H), 3.79 (br s, 2H), 7.49–7.61 (m, 2H), 7.63–7.72 (m, 1H), 8.23 (d,
J = 8.4 Hz, 1H), 8.48 (d, J = 8.4 Hz, 1H), 13.98 (s, 1H); 13C NMR (CDCl3,
100 MHz): d 23.7, 27.0, 54.5, 58.5, 112.6, 124.6, 124.8, 125.1, 125.6, 125.8,
126.0, 130.2, 136.6, 162.2, 204.4. Anal. Calcd for C17H19NO3: C, 71.56; H, 6.71;
N, 4.91. Found: C, 71.79; H, 6.98; N, 4.66.