Highly efficient Grignard-type imine additions via C-H activation in water and under solvent-free conditions

Article abstract of DOI:10.1039/b108851n

A highly effective Cu-Ru catalyzed addition of terminal alkynes to imines via C-H activation has been achieved in water or under solvent-free conditions.

Full text of DOI:10.1039/b108851n

Highly efficient Grignard-type imine additions via C–H activation in
water and under solvent-free conditions
Chao-Jun Li* and Chunmei Wei
Department of Chemistry, Tulane University, New Orleans, Louisiana, USA. E-mail: cjli@tulane.edu;
Fax: +1-504-8655596; Tel: +1-504-8655573
Received (in Corvallis, OR, USA) 26th September 2001, Accepted 3rd December 2001
First published as an Advance Article on the web 15th January 2002
Table 1 Catalytic addition of phenylacetylene to imines in water (or
neat)
A highly effective Cu–Ru catalyzed addition of terminal
alkynes to imines via C–H activation has been achieved in
water or under solvent-free conditions.
Aniline/
conditionsa
Yield
(%)
Entry Aldehyde
1
Product
Recently, great efforts have been made on developing chemical
technologies that can intrinsically reduce or eliminate the use or
generation of hazardous substances during the design, manu-
facture, and use of chemical products and processes—Green
Chemistry.1 Metal-mediated C–C bond formations are among
the most important reactions in organic synthesis.2 However,
the standard practice for carrying out such reactions involves
the reaction of organic halides mediated by a stoichiometric
amount of metal in an anhydrous organic solvent and under an
inert atmosphere. Such a practice reveals fundamental draw-
backs as it requires a large volume of organic solvent, excess
drying agent, protection–deprotection of hydroxy groups, a
stoichiometric amount of metal, and a stoichiometric amount of
organic halide. On the other hand, an alternative reaction via
catalytic C–H activation3 in water4 by using a water-soluble
catalyst, would provide a green-approach5 for such reactions.
Recently, we described a Grignard-type reaction of alkyne to
aldehyde to generate propargyl alcohols via catalytic C–H
activation in water.6 An equally important reaction is the
corresponding addition of alkynes to imines, to generate
propargyl amines.7 For generating propargyl amine derivatives,
Miura et al. reported the addition of acetylene to nitrones
through the initial formation of a dipolar cycloaddition.8
Carreira et al. used a Zn(II)-catalyzed process in CH2Cl2 for the
addition of terminal alkynes to nitrones to form propargyl N-
hydroxyamine adducts.9 Herein, we wish to report (to the best
of our knowledge) the first direct addition of acetylene to
various imines to generate propargyl amines via C–H activation
in water or under solvent-free conditions (eqn. (1)).
PhNH2/A
PhNH2/A
91
2
90
3
4
5
PhNH2/A
PhNH2/A
PhNH2/A
89
95
93
6
7
8
9
PhNH2/A
PhNH2/A
PhNH2/A
PhNH2/A
87
86
87
64
(1)
10
11
12
PhNH2/B
85
96
82
Initially, we reacted imines, which were readily accessible by
the in situ condensation of aldehydes with anilines, with
phenylacetylene by using a Ru/In catalytic system in water.
Although this catalytic system was very effective for carbonyl
additions, it did not provide any imine addition product.6
Subsequently, we found that the desired addition product was
formed in moderate yields by using Cu catalysts in water.
Among the catalysts being tested, copper salts such as CuCl,
CuCl2, CuBr, CuI, and CuO all showed catalytic activities, with
CuSO4 CuCN, and Cu(OAc)2 being less effective. The best
yield of the addition product was obtained with CuBr as the
catalyst.10 By using RuCl3 (3 mol%) as a co-catalyst, the yield
of the desired product was dramatically increased (from 30% to
90%). However, no imine addition product was observed with
RuCl3 alone as the catalyst. As shown in Table 1, this catalytic
system could be applied to a broad range of substituted aromatic
imines and aliphatic imines (without a-hydrogen to avoid
competing aldol condensation under these conditions) to afford
the corresponding propargyl amines in high yields. In a few
cases (entries 10–14) the imines were found to be prone to
PhNH2/B
p-ClPhNH2/B
13
14
p-BrPhNH2/B
p-MePhNH2/B
88
77
a Conditions: A, in water; B, solvent free. Yields were referred to isolated
ones after column chromatography on silica gel.
268
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A typical experimental procedure follows: a mixture of the
aldehyde (2 mmol) and aniline (2.4 mmol) was heated at 60 °C
for about two hours. Then, ruthenium trichloride (3 mol%),
copper( ) bromide (30 mol%), phenylacetylene (2.4 mmol) and
I
water (flashed with nitrogen) (2 mL) were added into the
mixture under nitrogen.12 The mixture was stirred at room
temperature for 10 min and then at 40 °C overnight. The
reaction mixture was poured into water, and extracted with
diethyl ether (or methylene chloride). The organic layer was
washed with water and dried over anhydrous Mg2SO4. The
solvent was removed in vacuo. The product was isolated by
flash column chromatography on silica gel eluting with EtOAc–
hexane (1+40).
We are grateful to the NSF-EPA joint program for a
Sustainable Environment and the NSF CAREER Award
program for the support of this research.
Notes and references
1 For general references on green chemistry, see: P. T. Anastas and J. C.
Warner, Green Chemistry: Theory and Practice, Oxford University
Press, Oxford, 1998; Green Chemistry: Designing Chemistry for the
Environment, American Chemical Society Symposium Series, No. 626,
ed. P. T. Anastas and T. C. Williamson, Washington D.C. 1996.
2 For representitative monographs and reviews, see: B. J. Wakefield,
Organomagnesium Methods in Organic Chemistry, Academic Press,
1995; C. Blomberg, The Barbier Reaction and Related One-Step
Processes, Springer-Verlag, 1993; Y. H. Lai, Synthesis, 1981, 585; G.
Courtois and L. Miginiac, J. Organomet. Chem., 1974, 69, 1; H.
Normant, Adv. Org. Chem., 1960, 2, 1; S. T. Ioffe and A. N.
Nesmeyanov, The Organic Compounds of Magnesium, Beryllium,
Calcium, Strontium and Barium, North-Holland, Amsterdam, 1976.
3 For an excellent recent review, see: G. Dyker, Angew. Chem., 1999, 38,
1698; T. Naota, H. Takaya and S. I. Murahashi, Chem. Rev., 1998, 98,
2599; K. A. Horn, Chem. Rev., 1995, 95, 1317.
4 C. J. Li and T. H. Chan, Organic Reactions in Aqueous Media, John
Wiley & Sons, New York, 1997; A. Lubineau, J. Auge and Y. Queneau,
Synthesis, 1994, 741; Organic Synthesis in Water, ed. P. A. Grieco,
Blackie Academic & Professional, Glasgow, 1998.
5 B. M. Trost, Science, 1991, 254, 1471; R. A. Sheldon, Chemtech, 1994,
24, 38; P. A. Wender and B. L. Miller, in Organic Synthesis: Theory and
Applications, ed. T. Hudlicky, JAI Press, Vol. 2, 1993.
6 C. J Li and C. M. Wei, Green Chem., 2002, 4, in press.
7 R. Bloch, Chem. Rev., 1998, 98, 1407; B. A. Katherine, D. W. Mark and
B. C. David, J. Am. Chem. Soc., 2000, 122, 11084.
8 M. Miura, M. Enna, K. Okuro and M. Nomura, J. Org. Chem., 1995, 60,
4999.
9 D. E. Frantz, R. Fâssler and E. M. Carreira, J. Am. Chem. Soc., 1999,
121, 11245.
10 The use of 30 mol% of CuBr as co-catalyst was necessary for the
reaction to go to completion. The conversion was decreased when a
smaller amount of CuBr was used.
Scheme 1 Tentative mechanism for imine addition via C–H activation.
hydrolysis in water and the yields of the products were
significantly reduced. However, in these cases, we found that
the imine additions were highly effective under solvent-free
conditions. It was found that good yields of the addition
products could be achieved in a mixture of 1.0 eq. of the imine
and 1.2 eq. of phenylacetylene along with the Cu/Ru catalysts
under neat conditions. Aliphatic alkynes, such as hexyne and
trimethylsilylacetylene, were also effective for the reaction.
Their couplings with the imine generated from benzaldehyde
and aniline provided the desired product in 86% (hexyne, neat)
and 83% (trimethylsilylacetylene, neat) respectively. A tenta-
tive mechanism was proposed which involves the simultaneous
activation of the C–H bond of alkyne by a Ru(II) species11
(possibly generated in situ from reduction of Ru(III) by the
alkyne) and the imine by the copper complex. The ruthenium
intermediate generated then underwent Grignard-type addition
to the activated imine to give the desired nucleophilic addition
product and regenerated the ruthenium and copper catalysts for
further reactions (Scheme 1).
In conclusion, a highly effective Cu–Ru catalyzed addition of
acetylenes to imines via C–H activation has been achieved in
water or under solvent-free conditions. The process was simple
and generated a diverse range of acetylenic amines in excellent
yields. The scope, mechanism, stereoselectivity, and synthetic
applications of this novel reaction as well as other C–C bond
formations via C–H activations in water or under solvent-free
conditions are under investigation.
11 B. M. Trost, F. D. Toste and A. B. Pinkerton, Chem. Rev., 2001, 101,
2067.
12 The reaction also proceeded under an air atmosphere; however a
significant amount of oligomerization of alkynes was observed.
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