Conventional tetrakis(triphenylphosphine)palladium-copper(I) iodide-catalyzed sonogashira coupling of free and BOC-Protected propargylic amines "On water"

Article abstract of DOI:10.1002/adsc.200900240

Alkynylation of aryl iodides with propargylic amines has been achieved by means of a Sonogashira coupling using "on water" methods. The use of less than 0.2mol% of tetrakis(triphenylphosphine)palladium [Pd(PPh ₃)₄] and 1.5 mol% coppe

Full text of DOI:10.1002/adsc.200900240

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DOI: 10.1002/adsc.200900240
Conventional Tetrakis(triphenylphosphine)palladium-Copper(I)
Iodide-Catalyzed Sonogashira Coupling of Free and BOC-
Protected Propargylic Amines “On Water”
Bartomeu Soberats,a Luis Martꢀnez,a Manuel Vega,a Carmen Rotger,a
and Antoni Costaa,*
a
Department de Quꢀmica, Universitat de les Illes Balears, 07122 Palma de Mallorca, Spain
Fax : (+34)-971-173266; e-mail: antoni.costa@uib.es
Received: April 8, 2009; Revised: June 3, 2009; Published online: July 16, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900240.
Abstract: Alkynylation of aryl iodides with propar-
gylic amines has been achieved by means of a Sono-
gashira coupling using “on water” methods. The use
of less than 0.2 mol% of tetrakis(triphenylphos-
A
ACHTUNGTREN(NNUG PPh3)4] and 1.5 mol% cop-
ACHTUNGTRENNUNG
pling to proceed at 958C yielding moderate to good
yields of mono-, bis-, and tris-aminoalkynylbenzene
derivatives.
Keywords: “on water” reactions; palladium-cata-
lyzed reactions; propargylic amines; Sonogashira
reaction
Figure 1. Sonogashira coupling performed under “on water”
conditions.
The Sonogashira coupling of terminal alkynes with
aryl or vinyl halides provides a powerful and widely sons as well. A number of the palladium-catalyzed al-
used tool for carbon-carbon bond formation in organ- kynylations carried out under more or less aqueous
ic synthesis.[1] The reaction has a broad scope, al- conditions which have been described so far are medi-
though it works better using electron-poor aryl io- ated by solubilizing additives or a co-solvent,[6] and/or
dides in combination with electron-rich alkynes, toler- they are performed under forced conditions such us
ating the presence of a variety of functional groups. microwave heating,[7] and/or superheated water.[8] In
In the classical and, probably, the more common for- addition, the coupling also works well in heterogene-
mulation, this coupling is performed in the presence ous aqueous media with supported Pd catalysts.[9] In
of a base, copper(I) iodide as co-catalyst and a palla- pure water, the Sonogashira coupling is effective in
(PPh3)4 in the presence of hydrophilic Pd catalysts,[10] a modifica-
dium catalyst such as [PdCl2ACHTNUGTRENNUG(PPh3)2] or PdACHTUNGTRENNUGN
organic solutions under an inert atmosphere tion which is the key for the synthesis of water-soluble
(Figure 1).[2] Recent alternatives include copper- and biomolecules.[11] In all the above experiments the dif-
ligand-free reactions,[3] new palladium catalyst sys- ferent components are mixed “in water” and much
tems,[4] as well as significant changes in the reaction emphasis is put on increasing the overall solubility of
conditions and solvents. Among these, the use of the reactants.
water as a solvent or co-solvent has attracted increas-
In spite of the problems associated with the lack of
ing attention,[5] not just for the sake of environmental solubility of organic substrates in water, recent work
sustainability, but for selectivity and activation rea- by Bhattacharya and Sengupta[12] has demonstrated
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Bartomeu Soberats et al.
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the feasibility of conducting Sonogashira couplings in
pure water without the need for soluble catalysts. In
this context, we postulated that Sonogashira couplings
in pure water could experience beneficial effects with
regard to rate and selectivity parameters when carried
out under “on water” conditions according to the def-
inition coined by Sharpless.[13]
In order to assess the utility of this protocol for Pd-
catalyzed alkynylations and, in connection with our
studies on the preparation of squaramide-based re-
ceptors,[14] we report here the direct alkynylation of
aryl iodides using relatively unreactive propargylic
amines[4] in order to prepare di- and tripodal free and
Boc-protected arylpropargylic amines. We expected
that the resulting bis- or tris-derivatives, due to their
primary amino groups being separated, could serve as
versatile non-collapsible spacer units for molecular
recognition studies.
A brief survey of different substrates identified the
hydrophobic alkynes a and b (Table 1) as effective
components for the coupling “on water”. To take ad-
vantage of the “on water” conditions the hydrophobic
tetrakis(triphenylphosphine)palladium was selected.
Copper(I) iodide was used as co-catalyst because it is
insoluble in water and readily emulsified within the
organic droplets. Using DIPEA as base,[15] the reac-
tions proceeded typically at 90–958C in an Schlenk
tube with mechanical stirring as shown in Figure 1.
Remarkably, these couplings are performed with as
little as 0.1–0.2 mol% Pd and (1–1.5)ꢂN mol% CuI/
substrate ratio in a 0.6–1 mmol scale. Under these
conditions water-insoluble reactants and catalysts
form droplets that move quickly “on water”, Figure 1.
The use of larger amounts of CuI, i.e., >3 mol% led
to the formation of a semisolid sticky paste and a
marked decrease in the product yield.
Figure 2. Evaluation of the “on water” protocol for the So-
nogashira coupling of diiodide 3 with alkyne a. (Left) Rela-
tive changes in the aromatic portion of the 1H NMR
(DMSO-d6) spectra over time. (Right) Percentage of 3 con-
verted and formed by coupling, 16 and 11. The relative
amounts of 3, 16 and 11 were determined by integration.
Initial experiments were carried out under ultrason-
ic irradiation (130 W, 20 kHz); however, we soon
learned this was not avantageous but sometimes 1,4-diiodobenzene 3 as well as in those corresponding
harmful to the reaction. In addition, although we to the mono- and bis-propargylamine derivatives, 16
never observed the competitive formation of homo- and 11, respectively. Within one hour of the addition
coupling products[16] we used simple inert gas balloon of the reactants the intermediate monocoupled iodo-
protection as a routine.
phenyl propargylamine 16 was produced in 55% yield
To test the validity of the method “on water” we along with the bis-propargylamine 11 in 25% yield.
examined the reaction of 1,4-diiodobenzene 3 with 1- After this initial fast reaction, which consumed nearly
ethynylcyclohexylamine a dissolved either in DMF, in 80% of the initial diiodobenzene, the reaction slowed
dioxane or in toluene for homogeneous coupling. and longer reaction times, 24–48 h, were required for
These reactions, performed under the same experi- complete evolution. No other significant products
mental conditions with regard to temperature, base were detected during this reaction period, thus allow-
and catalysts as were used with water, all afforded sig- ing the bis-propargylamine 11 to be isolated in good
nificantly low yields (<8%) of the coupling products yield, Table 1.
11 and 16. On the other hand, aryl bromides do not
react with propargyllic amines under identical experi- argylic amines a and b under the same experimental
mental conditions. conditions afforded moderate to good yields of mono-,
Coupling of iodobenzene derivatives 2–4 with prop-
The progress of the coupling “on water” was moni- bis-, and tris-aminoalkynylbenzene derivatives. A
1
tored by H NMR. Figure 2 shows the changes ob- somewhat incomplete reaction was observed for the
served over time in the aromatic protons of the initial Boc-protected series, but it still produced satisfactory
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Conventional Tetrakis(triphenylphosphine)palladium-Copper(I)
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Table 1. “On water” alkynylation of mono-, di- and triiodobenzenes.
Iodide
Alkyne
Product
Yield [%][a,b]
1
1
a
6
7
65
40
b
a
2
2
8
80
b
9
25
40
85
10
11
3
3
a
b
12
13
25
50
4
a
14
75
4
b
15
60c)
[a]
See Experimental Section.
[b]
[c]
Isolated yields from aryl iodides at 0.6–1 mmol scale.
1
Estimated by H NMR.
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Bartomeu Soberats et al.
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detailed experimental procedures are provided as Support-
ing Information.
results. In fact, in this case the procedure can be opti-
mized, by shortening the time of reaction, towards the
obtention of monocoupled products.
In general, it was observed that the reaction pro-
ceeds better with unprotected alkyne a with TONs
around 1000. This result was somewhat unexpected as
free unsubstituted propargylic amines are known to
be quite unreactive substrates for Sonogashira cou-
pling.[4]
Acknowledgements
This work is supported by a MEC grant ref. CTQ2008-
00841/BQU and a CAIB grant ref. PCTIB-2005GC3-08 con-
tract. B. S. thanks the DGR+D+I (Govern Balear) for a
predoctoral fellowship.
In the present case, the success of the alkynylation
of aryl iodides with 1-ethynylcyclohexylamine and
NBoc-protected propargylamine is mainly attributed
to the increase in the effective local concentration of
water-insoluble substrates and catalysts within the or-
ganic droplets compared to the concentration found
in organic solution. Although other factors, such as fa-
vourable desolvation energies and hydrogen bond in-
teractions of polar amino or amido groups with the
surrounding aqueous environment, cannot be ruled
out on this basis alone. Hence, we attributed the un-
satisfactory results observed with propargylamine
itself (3-aminopropyne), not to the already known
low reactivity of this amine,[17] but to its miscibility
with water which decreases the local concentration of
the alkyne substrate within the organic droplets with
a concomitant reduction in the rate of coupling.
In conclusion, we succeeded in applying “on water”
conditions to the synthesis of arylpropargylic amines
from the corresponding aryl iodides and propargylic
amines via Sonogashira coupling. In the examples
presented here, the use of “on water” conditions has
a number of advantages over traditional methods, in-
cluding enhanced reactivity of otherwise unreactive
propargylic amines, a minimum use of Pd catalyst and
the use of neat water as reaction medium. Overall,
these are attractive features when considering multi-
ple reactions for library generation or for large-scale
applications.
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