Direct synthesis of diverse β-fluoroethylamines by a multicomponent protocol

Article abstract of DOI:10.1002/chem.201204621

No imines! A direct multicomponent protocol for the synthesis of highly diverse derivatives of β-fluoro(phenylsulfonyl)ethylamine has been developed (see scheme) by use of a Mannich-type reaction from their molecular subunits, α-fluoro-α-nitro(phenylsulfonyl)methane (1 a) or α-fluorobis(phenylsulfonyl)methane (1 b), formalin, and various primary and secondary amines. The products are obtained in high yields and selectivity even, in many cases, without the use of base. Copyright

Full text of DOI:10.1002/chem.201204621

COMMUNICATION
DOI: 10.1002/chem.201204621
Direct Synthesis of Diverse b-Fluoro
ACHTUNGTRNEeNUNG thylamines by a Multicomponent
Protocol
G. K. Surya Prakash,* Laxman Gurung, Parag V. Jog, Shinji Tanaka,
Tisa Elizabeth Thomas, Nimisha Ganesh, Ralf Haiges, Thomas Mathew,* and
George A. Olah[a]
In Memory of Horst Prinzbach
Multicomponent reactions (MCRs) are synthetically
highly efficient and economical as they offer high structural
diversity and incorporate molecular units of all reaction
components in a single step.[1] A well-known example of an
MCR is the Mannich reaction, in which the educts formal-
dehyde, an amine, and a ketone or aldehyde are converted
directly into the adduct bearing the molecular fragments of
which often cause problems in the Mannich reaction, are
avoided, even with sensitive substrates.[2] Therefore, it is not
surprising that direct Mannich reactions of fluorinated mole-
cules involving three components are scarce.[3i] In most Man-
nich-type reactions of fluorinated substrates, preformed
imines are used as Mannich reagents in combination with
other nucleophiles.[3a–h]
all components. It has been established as a powerful tool
Although the effectiveness of preformed electrophiles has
been demonstrated extensively,[2] a fast and selective reac-
tion with simple and basic molecular units in a Mannich-
type reaction is highly desirable. Herein, we report a new
protocol (Scheme 1) for the synthesis of fluoroethylated
[2]
À
À
for C C and C N bond forming reactions. In recent years,
Mannich-type reactions of fluorinated substrates have ac-
tively been explored[3] because of the interesting properties
imparted by the incorporation of a fluorine atom into a mol-
ecule. The presence of fluorine in organic compounds brings
forth significant changes in their biological properties. Spe-
cifically, fluorine in drug molecules has a profound impact
in their physicochemical, pharmacokinetic, and pharmaco-
logical properties.[4] For example, monofluoroacetic acid has
been found to be a powerful inhibitor for the Krebs cycle.[5]
Compounds with a monofluoromethyl moiety are of great
importance with regards to isostere-based drug design.[6]
The classical intermolecular Mannich reaction, however,
has a number of serious disadvantages.[2] Often, the harsh
reaction conditions and the long reaction times lead to un-
wanted side reactions and products. With primary amines or
ammonia as the amine component, the reaction can contin-
ue until all of the H atoms on the nitrogen are replaced.
This has been avoided by the use of preformed electrophiles
such as imines and iminium salts or nucleophiles such as
enolates, enol ethers, and enamines. Preformed electrophilic
Mannich reagents increase the concentration of the electro-
phile with significant reduction of reaction temperatures
and times. Consequently, many undesired side reactions,
Scheme 1. Preparation of b-fluoro(phenylsulfonyl)ethylamines from
a-fluoro(phenylsulfonyl)methanes, formaldehyde, and amines.
amines by the Mannich-type three-component reaction of
formalin, an amine (primary and secondary) and an activat-
ed fluoromethane, namely a-fluoro-a-nitro(phenylsulfonyl)-
methane (FNSM, 1a) or a-fluorobis(phenylsulfonyl)me-
thane (FBSM, 1b). To our knowledge, this is the first report
of a three-component protocol involving an a-fluorocarban-
ion for the preparation of diverse N-alkyl and N,N-dialkyl
fluoroethylamines from their molecular subunits. Further-
more, by introducing a proper fluoromethyl pronucleophile,
the method avoids the use of corrosive or expensive fluori-
nating reagents such diethylaminosulfur trifluoride (DAST),
morpholinosulfur trifluoride (Morpho-DAST), SF4, and HF-
amine complexes for selective fluorination. The reaction is
simple and efficient with high yields.
[a] Prof. Dr. G. K. S. Prakash, L. Gurung, Dr. P. V. Jog, Dr. S. Tanaka,
T. E. Thomas, N. Ganesh, Prof. Dr. R. Haiges, Dr. T. Mathew,
Prof. Dr. G. A. Olah
Loker Hydrocarbon Research Institute and Department of Chemistry
University of Southern California, Los Angeles, CA 90089 (USA)
Fax : (+1)213-740-6679
E-mail: gprakash@usc.edu
Application of FBSM as a monofluoromethide equivalent
was independently reported by the groups of Hu and Shiba-
ta for nucleophilic fluoroalkylation of epoxides[7a] and asym-
tmathew@usc.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204621.
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metric allylic fluorobis(phenylsulfonyl)methylation of allyl
acetates, respectively.[7b] Highly electron-withdrawing
groups, such as phenylsulfonyl, fluoro, nitro, cyano, and
3
À
acetyl, activate the sp -hybridized C H bond by significantly
enhancing its acidity, making it an efficient fluoromethyl
transfer agent.[8a] Since then, FBSM has been used by Pra-
kash et al. and others efficiently for fluoromethide transfer
in a variety of reactions.[8] Because the preparation of
FBSM by electrophilic fluorination of bisphenylsulfonylme-
thane with Selectfluor is less atom economic,[8a] we recently
discovered an efficient method for the high yield, multigram
synthesis of FBSM from cheap and readily available potassi-
um fluoride as the sole fluorinating source.[8b,c] On the other
hand, the highly electrophilic nature of iminium salts makes
them very reactive and attractive species in organic synthe-
sis. Iminium salts are the most commonly used electrophilic
Scheme 2. Formation of b-fluoro(phenylsulfonyl)ethylamines from
iminium salts and gem-amino ether precursors.
also react with FNSM. Therefore, the reaction of FNSM
with an in situ generated hemiaminal would allow us to
obtain a-fluoro-a-nitro(phenylsulfonyl)methyl derivatives
from a simple three-component Mannich-type reaction. In-
trigued by this approach, a series of reactions were carried
out. N,N-Dipropylamine, paraformaldehyde, and potassium
carbonate were stirred together to generate hemiaminal 6 in
situ, followed by the addition of FNSM to the reaction mix-
ture. The reaction was complete within 15 min of the addi-
tion of FNSM and the desired product 3c was isolated in
65% yield (Scheme 3). The yield of 3c was diminished due
Mannich reagents in the synthesis of a variety of molecules
[2,9a–j]
À
containing a C N bond.
We began our exploration by testing the reactivity of di-
methylmethylideneammonium chloride with a-fluorobis-
(phenylsulfonyl)methane (FBSM, 1b), which has a highly
À
acidic C H bond (the pKa of bis(phenylsulfonyl)methane is
12.2 in DMSO).[10] In contrast to our expectation, FBSM
showed no reactivity towards dimethylmethylideneammoni-
um chloride in the absence of a base, even after stirring for
12 h at room temperature in CH2Cl2. However, with the ad-
dition of an equivalent amount of triethylamine, the reac-
tion proceeded smoothly with 100% conversion (as shown
by TLC and 19F NMR spectroscopy) to give the desired
product,
2-fluoro-N,N-dimethyl-2,2-bis(phenylsulfonyl)-
ethanamine, 4a. Under similar reaction conditions, the imi-
nium salt dimethylmethylideneammonium chloride reacted
with FNSM (the pKa of a-nitro(phenylsulfonyl)methane is
7.1 in DMSO),[10] also giving the desired product, 2-fluoro-
N,N-dimethyl-2-nitro-2-(phenylsulfonyl)ethanamine, 3a, as
the sole product. The higher reactivity displayed by FNSM,
prompted us to continue our study with FNSM, which re-
sulted in quantitative conversion to 3a as expected.
Scheme 3. Formation of fluoroethanol 7, a competing pathway in the
synthesis of b-fluoroethylamines 3 and 4.
Due to their high electrophilicity, iminium salts are nor-
mally hygroscopic and prone to rapid hydrolysis. Particular-
ly, salts with simple anions such as ClÀ are less stable and
more sensitive to hydrolysis.[2] On the other hand, gem-
amino ethers, which are the immediate precursors of the
iminium salts,[11] have themselves been successfully utilized
as effective electrophiles in various organic reactions.[12]
Therefore, we were curious to determine the reactivity of a
gem-amino ether towards FBSM or FNSM avoiding the dif-
ficulties with iminium salts. To our delight, when compound
5 (R1 =R2 =propyl) was reacted with FNSM under similar
conditions to those described above, the reaction proceeded
smoothly to give the corresponding product, N-(b-fluoro-b-
nitroethyl)amine, 3c, in high yield (Scheme 2).
to the formation of the side product 2-fluoro-2-nitro-2-(phe-
nylsulfonyl)ethanol, 7a, isolated in 28% yield. It is clear
that 7a was formed from the direct addition of FNSM to
formaldehyde, which was confirmed by conducting a sepa-
rate reaction of FNSM with formaldehyde (formalin or par-
aformaldehyde) in dichloromethane, from which 7a was iso-
lated in 93% yield. Under similar conditions, 7b, the adduct
of FBSM and formaldehyde, was isolated in 90% yield
(Scheme 3).
N,N-Dipropylamine itself is a good base; therefore, we
decided to carry out this reaction without the addition of an
additional base. However, to increase the yield of the prod-
uct, the competing pathway, the formation of 7a, should be
suppressed (Scheme 3). To achieve this, the availability of
formaldehyde in the reaction mixture for the formation of
the aminal from the amine must be promoted to drive the
reaction of FNSM in the desired direction during its addi-
We presumed that if the methylene carbon a to both N
and O in gem-amino ether 5 is sufficiently electrophilic to
react with FNSM, then the hemiaminal 6, which can be gen-
erated from formaldehyde and N,N-dipropylamine should
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Direct Synthesis of b-Fluoroethylamines
COMMUNICATION
tion. This was achieved by using formalin (37% aqueous
solution) instead of solid polymeric paraformaldehyde.
Indeed, the use of formalin was found to increase the selec-
tivity as well as the yield of the product. The efficacy of the
reaction could be further improved by initially stirring the
amine and formalin to allow the formation of the aminal in
ample concentration before the addition of FNSM (Table 1).
FBSM in this reaction, the three-component strategy has
also been extended to FBSM.
Longer reaction times were required for the complete and
selective conversion of FBSM to the desired product. As in
the case of reactions with FNSM, reactions with primary
amines were faster and more selective than those with sec-
ondary amines. Although secondary amines did react with
FBSM and formalin (formaldehyde) in the absence of a
base, use of a base such as NaH, along with heating, pro-
moted the selective and complete conversion of FBSM to
the desired products (Table 2). A suspension of FBSM and
Table 1. Synthesis of b-fluoronitro(phenylsulfonyl)ethylamines by three-
component reaction of a-fluoro-a-nitro(phenylsulfonyl)methane, an
amine, and formalin without the addition of a base.
Table 2. Synthesis of b-fluorobis(phenylsulfonyl)ethylamines by three-
component reactions of a-fluorobis(phenylsulfonyl)methane that require
a base.
Entry
R1
R2
Product
Yield [%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
CH3
CH3CH2
CH3
CH3CH2
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
92
95
95
93
94
91
97
CH
3A
CH
3A
PhCH2
-(CH2)4-
CH3CH2
CH3
Entry
R1
R2
Product
Yield [%][a]
1
2
3
4
5
6
7
8
9
CH3
CH3
4a
4b
4c
4d
4e
4 f
4g
4h
4i
67
CH3
CH3
(CH3)2CH
H
H
H
H
H
H
H
CH
3A
CH
3A
95[b]
87
T
PhCH2
-(CH2)4-
CH3CH2
AHCTUNGRTEG(NNUN CH3)2CH
PhCH2
CH3
N
95
91[b]
89[b]
86
92[b]
94
CH3
CH3
H
H
H
E
U
95
96
65
Ph
41[b]
46[b,c]
CH
3A
93
94[b]
93[b]
p-CH3O-C6H4
Ph
p-CH3O-C6H4
[a] Yield of the isolated product. [b] Reaction was carried out at 908C.
[c] Reaction time was 3 h.
[a] Yield of the isolated product. [b] Reaction was carried out at 908C.
NaH in CH2Cl2 was stirred separately in a vial for 5 min and
subsequently added to the mixture of formalin and amine to
avoid deactivation of NaH in the aqueous medium. As for
FNSM, aromatic amines also participated in the three-com-
ponent reaction with FBSM and formalin to give the expect-
ed products, albeit in low yields (Table 2, entries 9, 10). Nei-
ther base nor heating was required for the complete conver-
sion of many primary amines to their respective products
(Table 3, entries 1–7).
Dialkylation has been reported to occur during alkylation
of primary amines. Therefore, alkylation of primary amines
is usually carried out by prior protection and then deprotec-
tion after alkylation.[14] In our reactions with primary
amines, no such dialkylation was observed. The validity of
the three-component reaction was further confirmed by
single-crystal X-ray crystallographic analysis of the product
4e (Figure 1).
Fluorinated ethylamines can be prepared by many meth-
ods,[16] such as direct alkylation of amines,[16a–c] reaction of
lithium amides with 2-fluoroethyl bromide[14] and alkylation
of suitably protected aniline by 2-fluoroethyl 4-methylbenze-
nesulfonate.[16d] Fluoride exchange with anhydrous KF on
N,N-bis(2-tosylethyl)anilines can also yield N,N-bis(2-fluo-
roethyl)anilines.[17a] Reductive amination of a-fluoroaceto-
phenone with ammonia in EtOH in the presence of titanium
isopropoxide followed by NaBH4 reduction gives 1-aryl-2-
Although the reaction was complete within 15 min of ad-
dition of FNSM in the case of N,N-dipropylamine, the re-
quired reaction time depended on the type of amine (e.g.,
primary or secondary amine) used in the reaction. In gener-
al, optimized conditions were found to be one equivalent of
FNSM for 1.7 equivalents of secondary amine, and
1.5 equivalents of formaldehyde with a reaction time of 2 h
before adding FNSM and 1 h after adding FNSM (Table 1).
Secondary amines generally took longer than primary
amines for the completion of the reaction. In terms of the
selectivity for b-fluoro(phenylsulfonyl)ethylamines 3 (or 4)
over b-fluoro(phenylsulfonyl)ethyl alcohol 7a (or 7b), reac-
tions with secondary amines were less selective than those
with primary amines. This is reflected in the slightly higher
yields of the products for reactions with primary amines. In
addition to aliphatic amines, aromatic amines also under-
went the reaction smoothly, giving the products in high
yields (Table 1, entries 14, 15).
FBSM is an attractive reagent for monofluoroalkylation
due to the susceptibility of the products to reductive desul-
fonylation to the corresponding monofluoroalkylated prod-
ucts in many cases. Reductive didesulfonylation of FBSM to
use it as a monofluoromethide equivalent has been success-
fully carried out in similar systems by using Mg and MeOH
by our group and others.[8b,k,13] Expecting similar results for
Chem. Eur. J. 2013, 19, 3579 – 3583
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3581

G. K. S. Prakash, T. Mathew et al.
Table 3. Synthesis of b-fluorobis(phenylsulfonyl)ethylamines by three-
component reaction of a-fluorobis(phenylsulfonyl)methane, amine, and
formalin without the addition of a base.
Table 4. Synthesis of b-fluoroethylamines by reductive didesulfonylation
of b-fluorobis(phenylsulfonyl)-N,N-dialkylethylamines.
Entry
R1
R2
Product
Yield [%][a]
Entry
R1
R2
Product
Yield [%][a]
1
2
3
4
5
CH
(CH2)4CH
E
H
H
H
H
8m
8n
8o
8r
35
72
55
81
76
(cyclohexyl)CH
1-adamantyl
G
N
1
2
3
4
5
6
7
8
9
CH
G
(CH2)3
H
H
H
H
H
H
CH
H
H
4j
4k
4l
4m
4n
4o
4p
4q
4r
85
78
97
88
86
94
(CH3)
CH3
8s
E
E
(cyclohexyl)CH
1-adamantyl
N
[a] Yield of the isolated product.
CH
Ph(CH2)2
(C6H5)CH
1-naphthylmethyl
3A
N
87[b]
89[c]
93[c]
68[c]
ACHTUNGTRENNUNG
ent reaction conditions, hemiaminals can be considered as
most viable because the formation of significant amounts of
the iminium salt is less likely (due to the absence of acid)
and its stability is rather low (due to the presence of water).
In conclusion, we have developed a direct Mannich-type
reaction for the facile synthesis of b-fluoro(phenylsulfon-
E
ACHTUNGTRENNUNG(CH3)
10
CH3
4s
[a] Yield of the isolated product. [b] Solvent was EtOH. [c] When the re-
action mixture was heated to 908C after the addition of FBSM, the reac-
tion was complete after 1 h.
AHCTUNGTREGyNNUN l)ethylamines by using fluorinated carbon pronucleophiles,
FNSM and FBSM. The reaction is performed under mild
conditions, is highly feasible for both primary and secondary
amines, and no base is required in many cases. More impor-
tantly, the reaction adheres to the classical Mannich reaction
conditions, bringing all three components, formaldehyde,
amine, and the activated fluoromethane, together in one pot
to form a fluorinated ethylamine in high yields. These b-flu-
oro(phenylsulfonyl)ethylamines may be candidates for fur-
ther studies on their biological effects and therapeutic activi-
ties.
Acknowledgements
Figure 1. X-ray crystal structure of the three-component reaction product
4e from FBSM, formalin, and ethyl methyl amine.[15]
Financial support from the Loker Hydrocarbon Research Institute and
the National Science Foundation for CRIF grant No. 1048807 (for X-ray
diffractometer) is gratefully acknowledged.
fluoroethylamines.[17b] Recently reported stereoselective nu-
cleophilic monofluoromethylation of (R)-(tert-butanesulfin-
Keywords: desulfonylation · fluoromethylation · formalin ·
ACHTUNGTRENNUNG
yl)imines by Hu et al.[18] and enantioselective monofluoro-
Mannich
reaction
·
multicomponent
reactions
·
methylation of in situ generated prochiral imines by Shibata
et al.[3 h] are also efficient methods. However, in both cases,
preformed imines or imines formed in situ from protected
a-amidosulfones and strong bases in equimolar or greater
amounts were always required. To our knowledge, the pres-
ent method is the only direct method that utilizes the simple
molecular units, namely, amine, formaldehyde (formalin)
and FBSM for the formation of fluorinated ethylamines and
therefore increases the scope for making the reaction more
pronucleophiles · synthetic methods
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ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
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Direct Synthesis of b-Fluoroethylamines
COMMUNICATION
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Received: December 28, 2012
Published online: February 10, 2013
Chem. Eur. J. 2013, 19, 3579 – 3583
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3583