The effect of diethylamine on Stille alkylations with tetraalkylstannanes

Article abstract of DOI:10.1039/b103072h

The addition of diethylamine to Stille alkylation reactions using stannanes improves yields by reducing β-hydride elimination and reduction reactions, it also serves as a substitute for other additives such as Cu(I)I.

Full text of DOI:10.1039/b103072h

The effect of diethylamine on Stille alkylations with
tetraalkylstannanes†
M. Teresa Barros,a Christopher D. Maycock,*b Mariana I. Madureirab and M. Rita Venturab
a Faculdade de Cieˆncias e Tecnologia da, Universidade Nova de Lisboa, Departamento de Química
2825. Monte da Caparica, Portugal
b Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Apartado 127 2780.
Oeiras, Portugal. E-mail: maycock@itqb.unl.pt; Fax: +351 21 4469789; Tel: +351 21 4469775
Received (in Cambridge, UK) 4th April 2001, Accepted 11th July 2001
First published as an Advance Article on the web 6th August 2001
The addition of diethylamine to Stille alkylation reactions
using stannanes improves yields by reducing b-hydride
elimination and reduction reactions, it also serves as a
amido group reacted readily with allyl triphenylstannane in the
presence of Pd to form the expected product 3 in good yield
(95%). The ester 2 under a wide range of normally successful
conditions afforded a maximum of 36% of 4.
substitute for other additives such as Cu( )I.
I
Assuming that the nitrogen atom of the amide was facilitating
the aryl transfer process for 1 by intramolecular chelation,9 we
added diethylamine to the reaction mixture, containing ester 2,
to ascertain if the corresponding intermolecular process was
possible. This resulted in a 87% isolated yield of the expected
allyl compound 4. No amination10 or amidification products
were isolated. We next applied these findings to other cases.
Alkylation of the iodoenone 5 under ‘normal’ Stille condi-
tions with tetrabutylstannane gave none of the expected
butylated compound 6 but high yields of the reduced product 9
(Scheme 2). The addition of diethylamine to this reaction
The Stille reaction is a member of a large family of palladium-
catalysed cross-coupling reactions. However, its generality and
high degree of success have made it popular among synthetic
chemists. One obvious reason for such popularity is the
reaction’s versatility.1 It is frequently used in the total syntheses
of large polyfunctional molecules for the coupling of complex
subunits.2,3 However, it is sometimes found that it is not
universally applicable and that many substrates require specific
reaction conditions for cross-coupling to be successful.1–5
There are relatively few examples of the successful introduc-
tion of alkyl groups employing Stille cross-coupling reactions
described in the literature,6 and for a-iodocyclohexenones the
reported yields are only moderate. This is probably due to
failure resulting from competing b-hydride elimination when
employing stannanes with alkyl groups bearing b-hydrogens
and to the low reactivity of the system. A further problem often
encountered is the competing reduction of vinylic or aromatic
halides to the corresponding hydrocarbon. This can be a serious
problem where the halide is unreactive.
Several reports have appeared relating to the importance of
intramolecular participation by amino groups in Stille cross-
coupling reactions. For example, it has been reported that alkyl
derivatives of 1-aza-5-stannabicyclo[3.3.3]undecane were re-
active in Stille couplings with aryl and alkenyl halides,7,8
without b-hydride elimination. It was suggested that intra-
molecular tin–nitrogen coordination could be the reason.
A difficult case for Stille coupling is represented in Scheme 1
(Table 1) where the highly substituted aryl iodide 1 having an
Scheme 2 Stille coupling at a substituted a-iodoenone.
Table 2 Stille coupling of a-iodoenone 5 with Bu4Sn under several
conditionsa
Pd catalyst
Ligand
CuI Et2NH
Prod Time Yield
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd(P(o-tol)3)2Cl2
Pd(P(o-tol)3)2Cl2
AsPh3
AsPh3
AsPh3
AsPh3
PPh3
PPh3
PPh3
PPh3
P(o-tol)3
P(o-tol)3
Yes No
Yes Yes
9
6
9
6
9
9
9
9
6
9
24 h 99%
48 h 96%
24 h 98%
48 h 97%
48 h 60%
48 h 63%
48 h 54%
48 h 61%
48 h 99%
24 h 96%
No
No
No
Yes
Yes No
Yes Yes
No
No
No
No
No
Yes
Yes
No
Scheme 1 Stille coupling at a polysusbstituted aromatic compound.
Table 1 Stille coupling at polysubstituted aromatic compounds 1 and 2a
a The solvent employed was THF.
Cpd Pd cat
Ligand LiCl Et2NH
Prod. Time Yield
1
2
2
Pd(PPh3)2Cl2 PPh3
Pd(PPh3)2Cl2 PPh3
Pd(PPh3)2Cl2 PPh3
Yes No
Yes No
Yes Yes
3
4
4
2 h
1 h
1 h
95%
36%
87%
Table 3 Effect of adding diethylamine to the Stille coupling of a-iodoenone
5 with [CH3(CH2)9]4Sna
Pd catalyst
Ligand
CuI Et2NH Prod
Time
Yield
a The solvent employed was DMF.
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
a The solvent employed was THF.
AsPh3
AsPh3
Yes No
Yes Yes
9
10
24 h
48 h
99%
86%
† Electronic Supplementary Information (ESI) available: Tables—Stille
coupling of a-iodoenone 5 with Et4Sn and Me4Sn, and general procedure.
See http://www.rsc.org/suppdata/cc/b1/b103072h/
1662
Chem. Commun., 2001, 1662–1663
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b103072h

Table 4 Stille coupling of methyl 2-iodobenzoate 11 with Bu4Sn under several conditions
Pd Catalyst
Ligand
Solvent
LiCl
Et2NH
Prod
Time
Yield
Pd(P(o-tol)3)2Cl2
Pd(P(o-tol)3)2Cl2
Pd(P(o-tol)3)2Cl2
Pd(P(o-tol)3)2Cl2
Pd(P(o-tol)3)2Cl2
Pd(PPh3)2Cl2
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
PPh3
THF
THF
No
No
No
Yes
No
Yes
Yes
No
No
Yes
No
Yes
Yes
No
Yes
Yes
11
11
12
11
12 + 11a
12 + 13b
12 + 11c
12 + 11d
24 h
24 h
24 h
48 h
48 h
48 h
48 h
48 h
70%
99%
68%
96%
96%
97%
99%
98%
DMF
DMF
DMF
DMF
DMF
DMF
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
PPh3
PPh3
a 2.3+1. b 1.5+1. c 1+4. d 3.6+1.
In conclusion, the addition of diethylamine clearly prevented
b-hydride elimination/reduction in the Stille alkylation reac-
tions tested when employing alkylstannanes with b-hydrogens,
a problem frequently reported in the literature.1 Its addition
permits the use of more volatile less polar solvents in some
cases and can reduce reaction times, as is well exemplified in
the case of tetramethyltin.† In this case too the work up and
purification of the reaction products was facilitated and the need
to use cocatalytic CuI was eliminated. This method permits the
efficient introduction of alkyl side chains into the synthetically
useful a-iodoenones,12 which are particularly difficult sub-
strates for this kind of Stille cross-coupling13 reaction.
Recent reports14 highlighting the use of organozincs and
organoboranes for the alkylation of a-iodoenones and vinyl
halides have been described. Reduction and/or b-hydride
elimination not a problem in these cases. The mechanism of Pd
catalysed coupling reactions15 may change with the type of
coupling reaction depending upon the metal or non-metal
present.
Scheme 3
resulted in the formation of the butylated compound 6 in good
yield (Table 2). This was also the case for tetraethylstannane
and for tetradecylstannane. The products 7 and 10 were
obtained in good yield. Without added diethylamine, the
reduced product 9 was formed exclusively.
Having shown that diethylamine did influence the outcome of
these reactions we next proceeded to approach optimisation by
studying several variables for this reaction (Tables 2, 3). Thus,
the influence of using Pd(0) or Pd(II) as catalyst sources, the
effect of the Pd ligands (PPh3, P(o-Tol)3 and AsPh3), the
presence of CuI as cocatalyst and the additon of LiCl for the
aromatic substrates were analysed. We have concluded that
both Pd(0) and Pd(II) were equally effective, as expected. The
catalytic role of the Pd species was largely influenced by the
ligand. AsPh3 and P(o-Tol)3 were found to be the best ligands
tested while PPh3 was considerably less effective. Remarkably,
we have observed that for the Stille coupling of iodoenone 5
with tetramethyltin, CuI could effectively be replaced by
diethylamine. When this reaction was carried out in the
presence of diethylamine the workup was considerably simpli-
fied and the yields consequently higher. Analogous reactions
reported in the literature used involatile NMP as the solvent.
Studies on the electron poor aromatic substrate 11 were also
carried out. For this compound the reaction conditions as used
for the iodoenone, had to be changed and DMF became the
solvent of choice. The use of diethylamine again prevented
reduction, as seen for the reaction of 11 with tetrabutyltin. The
yield of the coupling product 12 was not improved over that of
the same reaction without added amine but starting material was
recovered when Et2NH was present, whereas several other
products were formed in its absence (Scheme 3 and Table 4).
The addition of LiCl11 alone simplified the product distribution
but did not avoid reduction and the yield of coupling product
was zero or low. When both LiCl and Et2NH were included in
the mixture the coupling product 12 was produced in low yield
and starting halide 11 was recovered as the only other
product.
We thank Fundação para a Cieˆncia e a Tecnologia for
generous financial support (PCTI/1999/QUI/36536) and for
grants (Praxis XXI) awarded to M. R. V. and M. I. M.
Notes and references
1 V. Farina, V. Krishnamurthy and W. J. Scott, The Stille Reaction, Wiley
Interscience, New York, 1998, and references therein
2 K. C. Nicolau, T. K. Chakraborty, A. D. Piscopio, N. Minowa and P.
Bertinato, J. Am. Chem. Soc., 1993, 115, 4419.
3 D. A. Evans and W. C. Black, J. Am. Chem. Soc., 1993, 115, 4497.
4 T. N. Mitchell, Metal-catalysed Cross-coupling Reactions, Organotin
Reactions in Cross Coupling, Wiley-VCH, Germany, 1998, 167–197.
5 X. Han, B. M. Stoltz and E. J. Corey, J. Am. Chem. Soc., 1999, 121,
7600.
6 F. Bellina, A. Carpita, D. Ciucci, M. De Santis and R. Rossi,
Tetrahedron, 1993, 49, 4677.
7 E. Vedejs, A. R. Haight and W. O. Moss, J. Am. Chem. Soc., 1992, 114,
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8 M. S. Jensen, C. Yang, Y. Hsiao, N. Rivera, K. M. Wells, J. Y. L. Chung,
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Chem. Soc., Chem. Commun., 1992, 1440.
10 M. H. Ali and S. L. Buchwald, J. Org. Chem., 2001, 66, 2560.
11 LiCl is known to inhibit coupling reactions in some circumstances, E.
Piers, R. W. Friesen and B. A. Keay, Tetrahedron, 1991, 47, 4555.
12 M. T. Barros, C. D. Maycock and M. R. Ventura, Chem. Eur. J., 2000,
6, 3991.
13 Stille coupling in ionic liquids has recently been reported, S. T. Handy
and X. Zhang, Org. Lett., 2001, 3, 233.
14 E. Negishi, Z. Tan, S-Y Liou and B. Liao, Tetrahedron, 2000, 56,
10197; A. Kamatani and L. E. Overman, Org. Lett., 2001, 3, 1229.
15 A. L Casado and P. Espinet, J. Am. Chem. Soc., 1998, 120, 8978.
The function of the amine is not yet clear but we suspect that
it augments the activity of the phosphine ligand in maintaining
the Pd(0) in solution. This complexation with the Pd atom of
intermediates may also reduce the ability to undergo b-hydride
elimination reactions, once it has bonded with the alkyl group
by exchanging with the tin.
Chem. Commun., 2001, 1662–1663
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