An indium(III)-catalyzed synthesis of 4,4-dichloro-1-aryl-N-alkyl-1-yn-3- amines via an intermolecular C(sp2)-C(sp) bond formation

Article abstract of DOI:10.1002/adsc.201200680

This paper demonstrates an indium(III) triflate-catalyzed reaction of electron-deficient α,α-dichloroaldimines with terminal alkynes leading to a rapid and selective access to highly functionalized propargylic amines in good to excellent yields. The dichloromethylene moiety of the aldimine acts as an activating group to accomplish this transformation under very mild conditions.

Full text of DOI:10.1002/adsc.201200680

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DOI: 10.1002/adsc.201200680
An Indium
ACHTUNGTRENNUNG
2
À
alkyl-1-yn-3-amines via an Intermolecular C
G
Formation
Chandi C. Malakar,a Bert U. W. Maes,a and Kourosch Abbaspour Tehrania,*
a
Organic Synthesis, Faculty of Sciences, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerpen, Belgium
Fax : (+32)-32-653-233; e-mail: Kourosch.AbbaspourTehrani@ua.ac.be
Received: July 31, 2012; Published online: November 28, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200680.
Abstract: This paper demonstrates an indium
G
and mild synthesis of propargylic amines.[8] Among
the available methods, most of the procedures rely on
the addition of stoichiometric quantities of organome-
tallic reagents to imines. An efficient method using
terminal alkynes thus remains limited. To achieve this
triflate-catalyzed reaction of electron-deficient a,a-
dichloroaldimines with terminal alkynes leading to
a rapid and selective access to highly functionalized
propargylic amines in good to excellent yields. The
dichloromethylene moiety of the aldimine acts as
an activating group to accomplish this transforma-
tion under very mild conditions.
purpose, various metal salts including Cu(I), B
Ag(I), Zn(II), Zr, Fe(III), Ni(II), Au(I), Au
In(III) and Ir complexes have been employed as cata-
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
lysts in the reaction between imines or in situ generat-
ed imines and the corresponding terminal alkynes or
organometallic reagents.[9] In view of the fact that the
above-mentioned conventional methods are well ap-
plicable for the reaction of a series of imines with ter-
minal alkynes, this synthetic strategy was applied for
the transformation of a,a-dichloroaldimines to the
2
À
Keywords: A -coupling; C H activation; a-chloro
imines; indium
(III) catalysis; propargylic amines
Propargylic amines are versatile building blocks for corresponding propargylic amines using terminal alk-
a variety of fundamental organic transformations[1]
AHCTUNGTRENNUNG
and have proved to be important precursors for the preparation of b,b-dichloropropargylic amines amines
synthesis of therapeutic drug molecules and complex would allow one to further investigate the reactivity
natural products.[2] Additionally, these substructures of these highly functionalized compounds.[10d] We
have attracted substantial interest in medicinal have therefore screened the most efficient and
chemistry due to their remarkable physiological activ- common reaction conditions for the synthesis of prop-
ities.[3] Moreover, a broad range of propargylic amines argylic amines (vide infra).9a,b,k,m–o Remarkably, these
are active towards the fragmentation of nucleosomal methods only led to very low conversions for the
DNA, activation of caspase and the apoptotic cascade transformation of a,a-dichloroaldimines to the corre-
preventing collapse of mitochondrial membrane po- sponding propargylic amines. More recently, our re-
tential.[4] Propargylic amines such as rasagiline and se- search group has reported a convenient synthetic
legiline are active in preventing cell death and are ad- route towards propargylic amines by the reaction of
mired alternatives to l-DOPA for the treatment of a,a-dichloroaldimines and potassium alkynyltrifluoro-
Parkinsonꢀs disease, respectively.[5] Apart from their borates using a Lewis acid-mediated Mannich type re-
huge application in medicinal chemistry and pharma- action.[10] The fact that potassium alkynyltrifluorobo-
ceuticals[6] various propargylic amines are valuable as rate must be prepared in a separate step by metala-
herbicides and fungicides.[7]
Herein, we disclose a new, efficient and convenient tive organometallic reagent (BuLi, EtMgBr, or LDA)
(OTf)3-catalyzed reaction between a,a-dichloroaldi- anhydrously and under inert atmosphere at low tem-
mines and terminal alkynes for the synthesis of perature remains a disadvantage. Furthermore, subse-
a series of highly substituted dichloro- and trichloro- quent borylation with B(O-i-Pr)3 is an additional
propargylic amines in high to excellent yields. drawback. Therefore, we developed a new direct addi-
tion of the corresponding alkyne with a highly reac-
InACHTUNGTRENNUNG
AHCTUNGTRENNUNG
In the past few years, a great deal of research has tion reaction of alkynes to functionalized imines. Due
been devoted towards the development of an efficient to the poor electrophilicity of the azomethine carbon,
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Chandi C. Malakar et al.
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Table 1. Screening of the reaction conditions for the reaction
between 1a and 2a.[a]
a Lewis acid activator like InACHTNUTRGNEUNG(OTf)3 was used, which
À
also increases the acidity of the C(sp) H atom by for-
mation of a p-complex with the alkyne, thereby facili-
tating the formation of the active nucleophilic species.
This catalytic alkynylation is similar to the dual acti-
vation by an indiumACTHNUTRGNE(NUG III) catalyst of soft nucleophiles,
like terminal alkynes and hard electrophiles, like alde-
hydes.[11] In modern organic synthesis, the use of
indium salts as catalysts has become of increasing in-
terest due to their easy availability, low toxicity and
high endurance with regard to functional groups.[12]
Moreover it should be mentioned that indium is
a cheaper metal then, for instance, silver which is also
Entry Catalyst/
N
T/t [8C/ Yield of 3a
h]
[%]
1
2
3
4
5
6
CuBr/25
50/18
50/18
100/6
50/18
50/18
r.t./18
7[b]
Cu
Cu
U
44[b]
11[b]
2[b]
often used as a catalyst. Recently, InACTHNUTRGNE(NUG III) species have
CuCl2/25
AuCl
N
41[b]
61[c]
been used as Lewis acids in several transforma-
tions.[13]
AuClACHTNUGNRTE(NUG PPh3)/100 CH2Cl2/
As a preliminary experiment, model substrates N-
(2,2-dichloro-1-propylidene)amine (1a) and phenyl-
ACHTUNGTRENNUNGacetylene (2a) were reacted in the presence of
7
AuCl
N
r.t./18
37[c]
8
9
10
11
12
13
14
In
In
In
N
r.t./18
50/24
50/24
50/18
50/18
50/18
50/18
71[c]
69[c]
70[c,e]
43[b]
43[b]
23[b]
16[f]
5 mol% of CuBr in toluene as solvent at 608C for
18 h and 4 h, respectively, under argon according to
a recent literature procedure.[9a,b,k,m–o] Unfortunately, it
was observed that the reaction afforded a complex
mixture and the desired product 4,4-dichloro-1-
phenyl-N-propylpent-1-yn-3-amine (3a) could not be
identified.
Inspired by the negative results from preliminary
experiments, further studies were continued in order
to find suitable reaction conditions to accomplish this
transformation. Screening of the reaction conditions
revealed that the corresponding product 3a was isolat-
ed in 7% yield when the reaction was carried out
using 25 mol% of CuBr in dichloromethane as solvent
at 508C for 18 h (Table 1, entry 1). Interestingly, it
InCl3/25
ZnCl2/25
Zn
FeCl3/25
ACHTUNGRTEN(NUNG OTf)2/25
[a]
Unless otherwise indicated, all reactions were performed
using 0.5 mmol 1a and 0.5 mmol 2a in a sealed vial under
air.
Yield without acid-base work-up.
Yield after acid-base work-up.
[b]
[c]
[d]
[e]
[f]
In 9:1 ratio.
Reaction performed under argon.
Predicted from 1H NMR (without acid-base work-up),
additionally an unidentified compound was observed in
1H NMR.
was found that by replacing CuBr by CuACTHNURTGNENG(U OTf)2 as cat-
alyst, the corresponding product 3a could be isolated
in 44% yield (Table 1, entry 2) and performing the re-
action at 1008C for 6 h delivered the product 3a in
These reaction conditions were considered as opti-
11% yield (Table 1, entry 3). Moreover, CuCl2 as cata- mal and were used for further reactions. In general,
lyst was almost inactive for this transformation as the these b,b-dichloroamines could be simply purified and
reaction produces 3a only in 2% yield (Table 1, obtained in excellent yield by acid-base extraction.
entry 4). Apart from copper sources as catalyst, Purification of these propargylic amines by means of
AuCl
fective (Table 1, entries 5–14) and among the catalysts erable loss of product and resulted in a very impure
tried for this transformation In
(OTf)3 was the most product.[10d]
effective and delivered the maximum isolated yield of Using the optimized conditions, the scope of the re-
ACHTUNGTRENNUNG(PPh3), InACHTUNGTRENNUNG(III), Zn(II) and FeACHTNUGTRNE(NUGN III) were also ef- flash chromatography on silica gel resulted in consid-
AHCTUNGTRENNUNG
the product 3a (Table 1, entries 8–10). Notably, by re- action was explored using a broad range of chlorinat-
placing air by argon as reaction atmosphere no signifi- ed imines 1a–h. It was observed that a number of sub-
cant improvement in the yield of 3a has been ob- stituents on the imine, including methyl, ethyl, isopro-
served (Table 1, entry 10).
pyl, tert-butyl, allyl, benzyl and chloro groups were
In view of the yields and the reaction conditions in tolerated to achieve the corresponding products 3a–h
Table 1, a maximum yield of 69% of product 3a could in 62–85% yields (Table 2, entries 1–8). In the case of
be obtained when 0.5 mmol of 1a was reacted with N-benzylimine 1e (Table 2, entry 5), isomerization of
0.5 mmol of 2a in the presence of 25 mol% of the C=N double bond to the N-benzylidene derivative
In
for 18–24 h in a sealed vial (Table 1, entry 9, for fur- lated product was not observed.[14] On the other hand,
ther optimization see the Supporting Information). the scope of arylacetylenes has also been studied. It
ACHTUNGTRENNUNG(OTf)3 as catalyst and CH2Cl2 as solvent at 508C was not considered as an alternative as the a’-alkyny-
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An IndiumACHTUNGTRENNUNG
Table 2. InACHTUNGTRENNUNG
Entry
1
1
a
3
Yield of 3 [%]
75[b]
2
3
b
c
66;[b] 65[c]
85;[b] 83[c]
4
5
6
7
d
e
f
69;[b] 66[c]
73;[b] 72[c]
69;[b] 62[c]
66;[b] 61[c]
g
8
h
79;[b] 76[c]
[a]
All reactions were performed using 0.5 mmol 1 and 0.5 mmol 2a in a sealed vial under air.
Yield without acid-base work-up.
Yield after acid-base work-up.
[b]
[c]
revealed that a number of electron-donating substitu-
Moreover, the generality of this method has been
ents (methyl, ethyl, tert-butyl and methoxy) as well as verified by reacting 1a with cyclohexylacetylene (2i),
electron-withdrawing substituents (chloro and fluoro) 1-hexyne (2j) and methyl propargyl ether (2k)
on the aromatic ring of the arylacetylenes 2b–h were (Scheme 1). Surprisingly, the developed alkynylation
well tolerated to produce the corresponding products method is not only restricted to the use of arylacety-
3i–o in 65–88% yields (Table 3, entries 1-7).
lenes but is also applicable for alkylacetylenes and in
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Chandi C. Malakar et al.
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Table 3. InACHTUNGTRENNUNG
(OTf)3-catalyzed reaction between 1a and arylacetylenes 2b–h.[a]
Entry
1
R
3
i
Yield of 3 [%]
2-methyl; 2b
74;[b] 67[c]
2
3
4-methyl; 2c
4-ethyl; 2d
j
88;[b] 79[c]
k
78;[b] 71[c]
4
4-tert-butyl; 2e
l
70;[b] 65[c]
5
6
3-methoxy; 2f
m
n
79;[b] 71[c]
4-chloro; 2g
66[c]
7
4-fluoro-3-methyl; 2h
o
85;[b] 72[c]
[a]
All reactions were performed using 0.5 mmol 1a and 0.5 mmol 2 in a sealed vial under air.
Yield without acid-base work-up.
Yield after acid-base work-up.
[b]
[c]
all cases the corresponding final products 3p–r were
isolated in good to excellent yields.
A possible mechanism for this In
ACHTUNGTREN(NUNG III)-catalyzed al-
kynylation is proposed in Scheme 2. Most probably
the first step is the insertion of In
C(sp) H bond of the terminal acetylene to deliver an
N
À
active indium
N
companied by the release of one molecule of triflic
acid. Due to its high nucleophilic character an addi-
tion reaction of the organoindium across the C=N
double bond of the imine occurs, which leads to the
Scheme 1. InACHTUNGTRENNUNG(OTf)3-catalyzed reaction between 1a and alky-
lacetylenes 2i–k.
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An IndiumACHTUNGTRENNUNG(III)-Catalyzed Synthesis of 4,4-Dichloro-1-aryl-N-alkyl-1-yn-3-amines
nylation reaction in the presence of 2 equivalents of
triethylamine as an additive. Product 3a was isolated
in 32% yield. This lower yield can be explained by as-
suming the neutralization of triflic acid by triethyla-
mine, thus preventing the efficient regeneration of the
InACTHNUTRGNEUNG
(OTf)3 catalyst from intermediate B.[15] On the
other hand, the addition of an extra equivalent of
triflic acid to the alkynylation reaction led to a similar
yield of 3a (63%) as that obtained in the absence of
any additive (66%).
In summary, an efficient and operationally simple
InACHTNUTRGNEUNG(III)-catalyzed synthesis of 4,4-dichloro-1-aryl-N-
Scheme 2. Plausible mechanism of the InACTHNUTRGNEUNG(III)-catalyzed al-
kynylation of imines.
alkyl-1-yn-3-amines is demonstrated. The reaction
proceeds under very mild conditions, producing the
formation of the intermediate B. Finally, intermediate corresponding final products in good to excellent
B is protonated by triflic acid leading to the propar- yields in high purity. Notably, the traditional reaction
gylic amine 3a and hereby regenerating the active In- conditions for alkynylation of imines were unable to
A
accomplish this particular transformation.
proposed mechanism. An experiment with 1a and
phenylacetylene-d (2l) in the presence of 25 mol%
InACHTUNGTRENNUNG(OTf)3 as a catalyst in CH2Cl2 as solvent at 508C re-
Experimental Section
vealed that the corresponding product 3a can be iso-
lated in 66% yield. It is noteworthy to mention that
there is no incorporation of deuterium in the final
product 3a (Figure 1). Further support for the pro-
General Experimental Procedure (I) for the In
Catalyzed Synthesis of 3
ACHTUNGTRENNUNG(III)-
In an oven-dried 10-mL vial a,a-dichlorinated aldimines
acetylenes (0.5 mmol) and In(OTf)3
posed mechanism was found by performing the alky- (0.5 mmol),
ACHTUNGTRENNUNG
Figure 1. 1H NMR spectrum of product 3a from the experiment with phenylacetylene-d (2l).
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Chandi C. Malakar et al.
COMMUNICATIONS
(0.125 mmol, 70.3 mg) were added successively and the vial
was sealed under air. Then, CH2Cl2 (2 mL) was added and
the reaction mixture was stirred at 508C for 18–24 h. After-
wards, the reaction mixture was extracted with 0.5N NaOH
(4 mL). The organic phase was dried using MgSO4, and the
solvent was removed under reduced pressure. The crude re-
action mixture was then subjected to an acid-base extrac-
tion: 1N HCl (4 mL) and CH2Cl2 (2 mL) were added and
stirred for 1 h at room temperature. The aqueous phase was
isolated and washed with diethyl ether (4 mL–4 mL–2 mL)
and the combined organic phases were once more extracted
with 2N HCl (4 mL–2 mL–1 mL). Then, 3N NaOH (~7 mL)
was added to the aqueous phase until the pH was slightly
basic and the resulting solution was extracted with CH2Cl2
(10 mL–10 mL–5 mL). The CH2Cl2 fractions were com-
bined, dried using MgSO4 and concentrated under vacuum
to afford the corresponding 4,4-dichloro-1-aryl-N-alkyl-1-yn-
3-amine 3a–r as yellow oils.
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General Experimental Procedure (II) for the In
Catalyzed Synthesis of 3
ACHTUNGTRNE(NUNG III)-
In an oven-dried 10-mL vial a,a-dichlorinated aldimines
(0.5 mmol) 1a–h, acetylenes 2a–h (0.5 mmol) and In(OTf)3
AHCTUNGTRENNUNG
(0.125 mmol, 70.3 mg) were added successively and the vial
was sealed under air. CH2Cl2 (2 mL) was added and the re-
action mixture was stirred at 508C for 18–24 h. Afterwards,
the reaction mixture was diluted with 10 mL CH2Cl2 and
washed with 0.5N NaOH (10 mL). The CH2Cl2 fractions
were combined, dried using MgSO4 and concentrated under
vacuum to afford the corresponding 4,4-dichloro-1- aryl-N-
alkyl-1-yn-3-amines 3a–r as yellow oils.
Acknowledgements
We are thankful to Ing. Heidi Seykens and Ing. Norbert
Hanckꢀ for recording NMR spectra and HR-MS. We thank
Dr. Emily Mitchell for the careful editing of the text. This
work was financially supported by the University of Antwerp
(mandate CCM).
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An IndiumACHTUNGTRENNUNG(III)-Catalyzed Synthesis of 4,4-Dichloro-1-aryl-N-alkyl-1-yn-3-amines
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considered as a reason for this reduced yield because
of the earlier observed stability of 3a in the presence of
triethylamine (see ref.[10d]).
[13] For reviews on InACTHNUTRGNEUNG(III) catalysis see: a) J.-F. Zhao, H.-Y.
Tsui, P.-J. Wu, J. Lu, T.-P. Loh, J. Am. Chem. Soc. 2008,
130, 16492; b) Y. Itoh, H. Tsuji, K.-I. Yamagata, K.
Adv. Synth. Catal. 2012, 354, 3461 – 3467
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3467