Crotylation of aldehydes by crotyltins: Discrimination between mechanisms involving transmetallation or simple lewis acid assistance through the consideration of the stereochemistry of the corresponding homoallylic alcohols

Article abstract of DOI:10.1002/ejoc.200701183

In the reaction of crotyltins with aldehydes in the presence of metal salts, the double consideration of the syn/anti ratio of the branched homoallylic alcohols and the Z/E ratio of their linear regioisomers is proposed as a way to discriminate between a reaction mechanism involving a transmetallation step and a reaction mechanism involving simple Lewis acid activation of the aldehyde. The formation of branched syn isomers along with Z-linear isomers as major compounds is considered to be indicative of a reaction occurring under Lewis acid assistance, whereas preference for the branched anti isomers together with E-linear isomers is considered to be indicative of a transmetallation step prior to crotylation. For reactions performed in the presence of CeCl₃·7H₂O/NaI, the Lewis acid assistance was shown to be the exclusive or highly prevalent pathway. Moreover, in regards to the selectivity, the regiopreference depends on the nature of the crotyltin. Whereas soluble crotyltin preferentially leads to Z-linear adducts, polymer-supported crotyltin affords the syn-branched adducts probably due to a lower 1,3-metallotropy. For reactions performed in the presence of InX ₃, simple Lewis acid assistance and transmetallation appear to be competitive processes; the first one is favoured with aromatic aldehydes especially in dichloromethane, whereas transmetallation appears to be prevalent with poorly reactive aldehydes especially with InBr₃ in acetonitrile. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701183

FULL PAPER
DOI: 10.1002/ejoc.200701183
Crotylation of Aldehydes by Crotyltins: Discrimination between Mechanisms
Involving Transmetallation or Simple Lewis Acid Assistance through the
Consideration of the Stereochemistry of the Corresponding Homoallylic
Alcohols
Valérie Fargeas,[a,b] Françoise Zammattio,*[a,b] Jean-Mathieu Chrétien,[a,b]
Marie-Jo Bertrand,[a,b] Michaël Paris,[c] and Jean-Paul Quintard*[a,b]
Dedicated to Professor Jan-Erling Bäckvall on the occasion of his 60th birthday
Keywords: Aldehydes / Allylation / Diastereoselectivity / Regioselectivity / Reaction mechanisms
In the reaction of crotyltins with aldehydes in the presence
of metal salts, the double consideration of the syn/anti ratio
of the branched homoallylic alcohols and the Z/E ratio of
their linear regioisomers is proposed as a way to discriminate
between a reaction mechanism involving a transmetallation
step and a reaction mechanism involving simple Lewis acid
activation of the aldehyde. The formation of branched syn
isomers along with Z-linear isomers as major compounds is
considered to be indicative of a reaction occurring under
Lewis acid assistance, whereas preference for the branched
anti isomers together with E-linear isomers is considered to
be indicative of a transmetallation step prior to crotylation.
For reactions performed in the presence of CeCl3·7H2O/NaI,
the Lewis acid assistance was shown to be the exclusive or
highly prevalent pathway. Moreover, in regards to the selec-
tivity, the regiopreference depends on the nature of the cro-
tyltin. Whereas soluble crotyltin preferentially leads to Z-lin-
ear adducts, polymer-supported crotyltin affords the syn-
branched adducts probably due to a lower 1,3-metallotropy.
For reactions performed in the presence of InX3, simple
Lewis acid assistance and transmetallation appear to be com-
petitive processes; the first one is favoured with aromatic al-
dehydes especially in dichloromethane, whereas transmetal-
lation appears to be prevalent with poorly reactive aldehydes
especially with InBr3 in acetonitrile.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
tions and shown to be easier when increasing the Lewis acid
character of the tin centre.[5] Alternatively, open transition
states are considered when this reaction is achieved with [γ-
substituted-allyl] triorganotins in the presence of a Lewis
acid like BF3·OEt2. In this case, an antiperiplanar transition
state is generally accepted in unhindered systems as a result
of the lower steric interactions between the R group of the
aldehyde and the γ-alkyl group of the allyltin.[6] However,
synclinal transition states can be favoured for instance in
intramolecular allylstannations of aldehydes[7] or when γ-
alkoxyallyltins containing a bulky α substituent are engaged
(Figure 1).[8]
In every case, this condensation of γ-substituted allyltins
with aldehydes is an intriguing subject with respect to its
regioselectivity (linear α adducts/branched γ adducts) and
its stereoselectivity (E/Z ratio in α adducts or syn/anti ratio
in γ adducts).
Introduction
The allylation of aldehydes by using γ-substituted al-
lyltins, which is a versatile synthetic method for the prepa-
ration of homoallylic alcohols, has been extensively investi-
gated[1] due to the usefulness of these products, which are
important building blocks for the synthesis of many natural
products and pharmaceuticals.[1,2] The mechanism of this
reaction is considered to occur through a six-membered
transition state under thermic[3] and high pressure[4] condi-
[a] Université de Nantes, Nantes Atlantique Universités, Labora-
toire de Synthèse Organique, UFR Sciences et Techniques
2 rue de la Houssinière, B. P. 92208, 44322 Nantes cedex 3,
France
Fax: +33-2-5112-5402
E-mail: francoise.zammattio@univ-nantes.fr
jean-paul.quintard@univ-nantes.fr
[b] Université de Nantes – CNRS, UMR 6513,
2 rue de la Houssinière, B. P. 92208, 44322 Nantes cedex 3,
France
It is noteworthy that the open transition states (Figure 1)
have to be considered when the Lewis acid is unable to
transmetallate the allyltin. This situation can be strongly
modified, in terms of both regioselectivity (α/γ) and stereo-
[c] Université de Nantes – CNRS, UMR 6502, Institut des Ma-
tériaux Jean Rouxel,
2 rue de la Houssinière, B. P. 32229, 44322 Nantes cedex 3,
France
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FULL PAPER
transmetallation occurring in reactions involving allyltins
anchored onto a polymeric support. Indeed, we have shown
that allylation of aldehydes with these polymer-supported
reagents in the presence of either CeCl3 or InX3 (X = Cl or
Br) is reasonably convenient and environmentally friendly,
as pollution by tin residues was measured under 5 ppm,
whereas cerium pollution appeared under 1 ppm in the final
products.[11]
However, as a result of the fact that the reaction can
proceed either by simple Lewis acid assistance of the metal
salt on the aldehyde or through a preliminary transmetalla-
tion process between allyltins and cerium or indium salts, it
was of importance to discriminate between these two
mechanisms. In fact, the real usefulness of polymer-sup-
ported allyltins might be questionable if the effective orga-
nometallic species was a soluble allylcerium or a soluble
Figure 1. Reaction of γ-substituted allyltins with aromatic alde- allylindium resulting from transmetallation. Herein, we
hydes in dichloromethane at low temperature (–78 °C) in the pres-
ence of BF3·OEt2.
would like to describe how the analysis of diastereomeric
distribution on both the branched γ adducts (ratio syn/anti)
and the linear α adducts (ratio Z/E) can be used to achieve
a primary discrimination between a transmetallation and a
simple Lewis acid assistance in the crotyltin series.
selectivity (E/Z, syn/anti), when the Lewis acids are metal
salts potentially able to transmetallate the Sn–C bond (for
instance TiCl4, SnCl4, InX3).[1,7d,9] In this last case, several
parameters including the nature of both the solvent and the
Results and Discussion
aldehyde, as well as experimental conditions (temperature,
order for the addition of the reagents, ...), may strongly af-
fect the nature of the effective allylation reagent.[1,7d,9a,10]
Accordingly, in the crotyltin series, the effective species can
be crotyltin 1 initially added or its isomer 2 formed after a
1,3-metallotropy [Scheme 1, Equation (1)], but also a new
allylmetal species (A or B) obtained after transmetallation
[Scheme 1, Equation (2)].
Our investigation of this problem was focused on the
careful analysis of the regio- and stereocontrol observed in
the addition of the soluble crotyltri-n-butyltin 1 and the
polymer-supported analogue 3 (Z/E, 30:70) to a series of
aromatic and aliphatic aldehydes under various experimen-
tal conditions. In a typical procedure, the aldehyde and the
Lewis acid were successively added to either a solution of
crotyltri-n-butyltin or to a mixture of polymer-supported
crotyltri-n-organotin in solvents such as acetonitrile or
dichloromethane, and the reaction was stirred for 1 to 48 h.
These solvents are those used in our previous work involv-
ing polymer-supported reagents, and furthermore, they are
known to have different behaviour in their ability to facili-
tate transmetallation reactions. Unless mentioned other-
wise, the reactions were conducted on the diastereomeric
mixture of crotyltins (Z/E, 30:70). Good yields were uni-
formly obtained whatever the nature of the aldehydes and
the Lewis acids used as promoters. The diastereomeric dis-
tributions were carefully analysed by gas chromatography
after complete characterisation of the corresponding
alcohols by NMR spectroscopic analysis. The obtained re-
sults are given in Tables 1 and 2.
Scheme 1. Isomerisation and transmetallation of crotyltins.
The result is the possible formation of branched and lin-
ear adducts with a stereochemistry that is directly depend-
ent on the nature of the involved mechanism: whereas (E)-
1, (Z)-1 and 2 are likely to react through open transition
states in the presence of Lewis acids, allylmetal halides A
Regio- and Stereoselective Control in Reactions Involving
Crotyltri-n-butyltin 1
In reactions involving the soluble crotyltri-n-butyltin 1
and B, owing to the higher acidity of the metal centre, are with aldehydes, the following statements or observations
likely to react through a six-membered transition state.
can be considered meaningful:
Recently, we decided to investigate more thoroughly this
(1) The reaction of crotyltri-n-butyltin with benzaldehyde
complex and intriguing subject because we needed to dis- in dichloromethane in the presence of BF3·OEt2, a Lewis
criminate between a simple Lewis acid assistance and a acid unable to give transmetallation, was considered as the
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Crotylation of Aldehydes by Crotyltins
reference for the allylation reaction mediated by simple responding linear α regioisomers were obtained with a
Lewis acid assistance. In fact, it is well known that crotyltri- strong preference for the Z configuration especially when
n-butyltin in the presence of BF3·OEt2 reacts with alde- reactions were carried out in dichloromethane.
hydes through an open transition state leading to the exclus-
(4) Interestingly, when InBr3 was used as a promoter, we
ive branched γ adducts with a high syn preference regard- observed a great influence of the solvent on the regiocontrol
less of the geometry of the tin reagent (Table 1, Entry 1).[6] of the allylation. A highly prevalent formation of the
(2) Reactions performed in the presence of CeCl3·7H2O/ branched γ adduct was observed when the allylation was
NaI in acetonitrile produced the linear α adducts as the carried out in acetonitrile with both aromatic and aliphatic
major products with a strong preference for the Z configu- aldehydes. Moreover, in regards to the diastereoselectivity,
ration as previously reported by Bartoli.[12] Otherwise, the we found that the stereopreference mainly depends on the
minor branched γ adducts were obtained as a mixture of nature of the aldehydes. Whereas aromatic aldehydes prefer-
syn/anti isomers, which was highly dependent on the nature entially led to branched syn adducts (Table 1, Entries 14
of the aldehydes (syn preference with aromatic aldehydes and 16), aliphatic aldehydes afforded the branched anti iso-
and anti preference with both cyclic and aliphatic alde- mers (Table 1, Entries 18 and 20). Interestingly, when the
hydes).
allylation was carried out in dichloromethane, the linear α
(3) In experiments using InCl3 as a promoter, the two adducts largely prevailed, whatever the nature of the alde-
regioisomers were isolated with a poor regioselectivity, hydes (Table 1, Entries 15, 17, 19 and 21), but the stereose-
whatever the nature of the aldehydes and of the solvents lectivity was shifted from a Z preference (Table 1, En-
(Table 1, Entries 6–13). However, aromatic and aliphatic al- tries 15, 17, 21) to an E preference with the cyclohexanecarb-
dehydes distinguished between themselves by exhibiting op- aldehyde (Table 1, Entry 19).
posite stereochemistry in the corresponding branched γ ad-
(5) Finally, as isomerisations of homoallylic alcohols
ducts: syn selectivity with aromatic aldehydes (Table 1, En- have been previously reported in the presence of metal salts
tries 6–9) and anti selectivity with aliphatic aldehydes or acids,[13] we also checked that the composition of the
(Table 1, Entries 10–13). On the other hand, all of the cor- isomeric mixture of homoallylic alcohols remains un-
Table 1. Crotylation of aldehydes with soluble crotyltin 1 promoted by Lewis acids.
Entry
Lewis acid
Solvent
Aldehyde[a]
Product distribution
γ adduct [%] (syn/anti)[b] α adduct [%] (Z/E)[b]
Overall yield
[%][c]
1
2
BF3·OEt2
CeCl3·7H2O
(10% NaI)
CeCl3·7H2O
(10% NaI)
CeCl3·7H2O
(10% NaI)
CeCl3·7H2O
(10% NaI)
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
InBr3
InBr3
InBr3
InBr3
InBr3
CH2Cl2
CH3CN
PhCHO
PhCHO
100 (82:18)
20 (75:25)
0
91
89
80 (99:01)
3
4
5
CH3CN
CH3CN
CH3CN
p-NO2(C6H4)CHO
c-C6H11CHO
6 (70:30)
7 (21:79)
6 (42:58)
94 (99:01)
93 (95:05)
94 (97:03)
69
73
79
n-C7H15CHO
6
7
8
9
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
PhCHO
PhCHO
60 (84:16)
63 (99:01)
57 (63:37)
57 (69:31)
59 (15:85)
54 (02:98)
59 (40:60)
69 (27:73)
94 (59:41)
22 (95:5)
95 (69:31)
43 (80:20)
80 (14:86)
21 (01:99)
75 (43:57)
5 (39:61)
40 (60:40)
37 (65:35)
43 (95:05)
43 (95:05)
41 (21:79)
46 (89:11)
41 (55:45)
31 (93:07)
6 (50:50)
78 (84:16)
5 (75:25)
57 (80:20)
20 (23:77)
79 (34:66)
25 (34:66)
95 (63:37)
79
72
82
91
63
84
93
90
79
72
43
60
96
94
72
88
p-NO2(C6H4)CHO
p-NO2(C6H4)CHO
c-C6H11CHO
c-C6H11CHO
n-C7H15CHO
n-C7H15CHO
PhCHO
10
11
12
13
14
15
16
17
18
19
20
21
PhCHO
p-NO2(C6H4)CHO
p-NO2(C6H4)CHO
c-C6H11CHO
c-C6H11CHO
n-C7H15CHO
n-C7H15CHO
InBr3
InBr3
InBr3
[a] The allylation reactions of aldehydes (1 equiv.) by crotyltri-n-butyltin (E/Z, 70:30; 1.1 equiv.) were carried out in the presence of either
CeCl3·7H2O (1 equiv.) and NaI (0.1 equiv.) or InX3 (1 equiv., X = Cl or Br). [b] The regioisomeric and stereoisomeric ratios were
1
determined by GC after assignment of the structures by H NMR spectroscopy. [c] Isolated yield of the mixture of homoallylic alcohols
after column chromatography on silica gel.
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F. Zammattio, J.-P. Quintard et al.
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changed in our experimental conditions. For this purpose,
The following statements or observations in reactions in-
mixtures of branched and linear homoallylic alcohols in volving addition of supported crotyltin 3 to aldehydes can
dichloromethane or acetonitrile solution were stirred with be considered meaningful:
metal salts (CeCl3·7H2O, 10% NaI; InCl3 or InBr3) for 24 h
at 20 °C. Fortunately, as previously observed by Zhao for
crotylations performed in protic acids,[14] no isomerisation
of γ adducts into α adducts was noticed, and the obtained
mixtures of regio- and diastereomers can be seen as a reflec-
tion of kinetic control.
(1) Reactions performed in the presence of CeCl3·7H2O/
NaI at 60 °C in acetonitrile afforded the branched γ adducts
as the major products, whatever the nature of the aldehydes.
It is noteworthy that a reversed regioselectivity was ob-
tained in comparison to the reaction carried out with solu-
ble crotyltri-n-butyltin 1 (Table 1, Entries 2–5). Moreover,
the stereocontrol in the γ adducts was strongly dependent
on the nature of the aldehydes: syn preference with benzal-
dehyde, anti preference with cyclohexanecarbaldehyde and
broadly a 1:1 mixture of the two diastereomers with octanal
(Table 2, Entries 1, 2, 3). For the minor linear α adduct, a
high Z preference was obtained, whatever the nature of the
aldehydes.
Regio- and Stereoselective Control in Reactions Involving
Polymer-Supported Crotyltin 3
Before attempting to rationalise the regio- and stereocon-
trol observed in the addition of soluble crotyltri-n-butyltin
1 to aldehydes, we wish to report the set of results obtained
in the crotylation of aldehydes with polymer-supported cro-
(2) Surprisingly, when InCl3 was used as the promoter, a
tyltin 3. For this purpose, the supported reagent 3 was pre- high preference for linear α adducts was observed for benz-
pared according to the procedure described for the synthe- aldehyde and octanal, whereas the branched γ adduct was
sis of polymer-supported allyltins[11] and treated with a the major product in the crotylation of cyclohexanecarbal-
series of aromatic and aliphatic aldehydes. In a typical pro- dehyde. In terms of stereochemistry, whereas aromatic alde-
cedure, reactions were conducted at room temperature for hydes afforded mainly branched syn-γ adducts and Z-linear
18 h by stirring the reaction mixture containing resin 3, the α adducts, octanal and cyclohexanecarbaldehyde exhibited
aldehyde and the metal salt in the appropriate solvent (in a preference for branched anti-γ adducts and a poor stereo-
suitable tubes for parallel synthesis equipment). Good GC selectivity in linear α adducts, which was shifted from a
conversions were obtained, whatever the nature of the alde- slight Z preference in dichloromethane to a slight E prefer-
hydes and experimental conditions (Table 2).
ence in acetonitrile.
Table 2. Crotylation of aldehydes with the polymer-supported crotyltin 3 promoted by InX3.
Entry
Lewis acid
Solvent
Aldehyde[a]
Product distribution
Overall conversion ra-
te[c]
[%]
γ adduct [%] (syn/anti) α adduct [%] (Z/E)
[b]
[b]
1
2
3
CeCl3·7H2O
(10% NaI)
CeCl3·7H2O
(10% NaI)
CeCl3·7H2O
(10% NaI)
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
InBr3
InBr3
InBr3
InBr3
InBr3
InBr3
CH3CN
CH3CN
CH3CN
PhCHO
85 (99:01)
15 (99:01)
70
80
75
c-C6H11CHO
n-C7H15CHO
88 (28:72)
86 (51:49)
12 (99:01)
14 (94:06)
4
5
6
7
8
9
10
11
12
13
14
15
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
PhCHO
PhCHO
c-C6H11CHO
c-C6H11CHO
n-C7H15CHO
n-C7H15CHO
PhCHO
12 (99:01)
22 (60:40)
68 (16:84)
82 (12:88)
17 (40:60)
25 (42:58)
60 (66:34)
52 (98:02)
37 (18:82)
69 (18:82)
46 (49:51)
35 (45:55)
88 (72:28)
78 (72:28)
32 (25:75)
18 (54:46)
83 (44:56)
75 (57:43)
40 (70:30)
48 (68:32)
63 (19:81)
31 (44:56)
54 (49:51)
65 (66:34)
72
80
90
98
65
95
65
93
76
71
80
75
PhCHO
c-C6H11CHO
c-C6H11CHO
n-C7H15CHO
n-C7H15CHO
[a] The allylation reactions of aldehydes (1 equiv.) by polymer-supported crotyltin 3 (E/Z, 70:30; 1.1 equiv.) were carried out in the
presence of either CeCl3·7H2O (1 equiv.) and NaI (0.1 equiv.) or InX3 (1 equiv., X = Cl or Br). [b] The regioisomeric and stereoisomeric
ratios were determined by GC after assignment of the structures by 1H NMR spectroscopy. [c] Conversion rates into homoallylic alcohols
determined by GC.
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Crotylation of Aldehydes by Crotyltins
(3) In the case of reactions carried out in the presence of
InBr3, a mixture of branched and linear adducts was ob-
tained with a poor selectivity, whatever the nature of the
aldehydes. In terms of stereochemistry, the addition of 3
to benzaldehyde gave the two regioisomers with a strong
preference for the branched syn-γ adduct and for the linear
Z-α adduct (Table 2, Entries 10 and 11), whereas the ad-
dition of 3 to cyclohexanecarbaldehyde exhibited a poor
regioselectivity with a preference for branched anti-γ ad-
ducts and a slight preference for linear E-α adduct. In the
case of octanal, the stereochemical trends appeared less
clear: the branched γ adduct was obtained with a very poor
stereoselectivity, whatever the nature of the solvent, whereas
the linear α adduct was formed with a Z preference in
dichloromethane but without stereoselectivity in acetoni-
trile.
Scheme 2. Simple Lewis acid assistance for the crotylation of alde-
hydes.
Mechanistic Considerations
However, as a result of the poor stability of allylmetal spe-
cies A, their rearrangement into the more stable crotyl spe-
cies B can occur before addition to aldehydes. Thus, when
crotyl species B are the effective crotylation reagents of al-
dehydes, the branched anti adducts are obtained through a
cyclic transition state (TSB) (Scheme 3, path D).[1]
In spite of the relative complexity of the obtained results,
a primary rationalisation of the results was attempted by
taking into account the possible isomerisation of the crotyl-
tin species through a 1,3-metallotropy process [Scheme 1,
Equation (1)] and the possible transmetallation of crotyltin
species by metal salts [Scheme 1, Equation (2)]. With this in
mind, we can reasonably expect an open transition state
when crotyltin is the effective allylation reagent by assuming
that the metal salt acts as a simple Lewis acid on the car-
bonyl functionality. In this case, the formation of homoal-
lylic alcohols can be rationalised through open transition
states involving Lewis acid assistance according to
Scheme 2. Thus, when the crotyltin species are preserved,
an antiperiplanar transition state (TS1) is usually invoked
according to Yamamoto[1,6] because of the minimisation of
steric interactions between the R group of the aldehyde and
the γ-methyl group of 1, which leads to the predominant
formation of the branched syn adduct, regardless of the ge-
ometry of the crotyltin unit. The Z geometry of the linear
adducts can also be explained through an antiperiplanar
transition state involving the less stable, but more reactive,
3-tri-n-butylstannylbut-1-ene (2), which results from the iso-
merisation of crotyltri-n-butyltin 1 in the presence of the
Lewis acid (1,3-metallotropy).[15] In this case, the approach
of 2 should occur through TS2 (Scheme 2, path B) in order
Scheme 3. Lewis acid transmetallation reaction.
Accordingly, the regiochemical outcome of the reaction
to accommodate the methyl substituent in the less-hindered will be dependent on kinetic parameters involved in these
position (as far as possible from the R group of the alde- competitive reactions and more exactly on the nature of the
hyde). In these open transition states, the tri-n-butylstannyl effective allylmetal species 1, 2, A and B. In fact, even if
group is orthogonal to the allyltin double bond in agree- organometallic species 2 and A are highly unstable relative
ment with the higher stability of the allyltins in this confor- to 1 and B, they are expected to be more reactive due to
mation: the minimisation of the molecular energy is about their lower steric requirements in the transition states where
1.7 kcalmol–1.[16]
they are involved. Thus, both the reactivity/stability of the
In contrast, when a transmetallation process is involved, organometallic species and the nature of the Lewis acid–
the primary obtained allylmetal species A can react with aldehyde complex should be taken into account to explain
the aldehyde to afford the linear E-α adduct through a six- the observed regio- and stereoselectivities. With Schemes 2
membered cyclic transition state (TSA), in which the methyl and 3 as general guidelines, the regio- and sterecontrol ob-
group of the crotyl moiety and the R group of the aldehyde served in theses crotylation reactions can be reasonably ex-
adopt a pseudoequatorial position (Scheme 3, path C). plained.
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Reactions in the Presence of Cerium Trihalides
tion occurring mainly under Lewis acid assistance accord-
ing to paths A and B (Scheme 2). With nonaromatic alde-
hydes, the involved mechanisms are less clear. Whereas the
formation of branched γ adducts with a strong preference
for the anti isomer might suggest a transmetallation reac-
tion leading to crotylindium species able to react with alde-
hydes through a cyclic transition state (TSB) (path D
Scheme 3), the high Z selectivity observed on the minor lin-
ear α adducts, especially in dichloromethane, is well ac-
counted by the acyclic antiperiplanar transition state TS2
(Path B, Scheme 2). Because of this high Z selectivity, the
whole set of experiments involving InCl3 and crotyltri-n-
butyltin can be more reasonably explained by the occur-
rence of open transition states but with a preference for
antiperiplanar ones with aromatic aldehydes and synclinal
ones with nonaromatic aldehydes.
The exclusive formation of the branched γ adduct with a
strong preference for the syn adduct in the reaction carried
out with soluble crotyltri-n-butyltin 1 in the presence of
BF3·OEt2 can be considered as a reference reaction and ra-
tionalised according to the antiperiplanar transition state
(TS1) of Yamamoto.[6]
The formation of the linear Z-homoallylic alcohols as
the major adducts when crotylation is achieved with crotyl-
tri-n-butyltin 1 in the presence of CeCl3·7H2O/NaI in aceto-
nitrile is consistent with Lewis acid assistance on the alde-
hydes. In these cases, the initial step of the sequence involves
the isomerisation of 1 (Z+E) into its unhindered isomer 2,
which then adds to aldehydes faster than 1. This in turn
leads mainly to linear Z adducts according to path B
(Scheme 2). The formation of branched γ adducts (obtained
as minor regioisomers) can also be explained by an open
Finally, the use of indium tribromide as a promoter of
the crotylation of aldehydes by soluble crotyltri-n-butyltin
exhibits quite different results in terms of regioselectivity,
which appears to be solvent dependent (preference for the
branched γ isomers in acetonitrile and for the linear α iso-
mers in dichloromethane). In regard to the stereochemical
aspects, with aromatic aldehydes, the Z preference for linear
α adducts combined with a syn selectivity for the γ adducts
is once again indicative of simple Lewis acid assistance as
a main pathway. In contrast, the double preference for the
branched anti-γ adduct and for the linear E-α adduct in
the case of the crotylation of cyclohexanecarbaldehyde is
consistent with a mechanism involving a transmetallation
step as shown in Scheme 3. For octanal, the poor observed
stereoselectivities suggest competitive processes involving
mainly transmetallation in acetonitrile and Lewis acid as-
sistance in dichloromethane. This trend in favour of an eas-
ier transmetallation in acetonitrile has been previously men-
tioned in the literature.[19] Thus, in our set of experiments,
we can reasonably assume that with less reactive aldehydes,
the transmetallation can be easier than direct reaction on
the aldehyde–Lewis acid complex. This is true for indium
tribromide promoted crotylations, but such a pathway can
also be considered (at least in part) for reactions achieved
in the presence of indium trichloride when acetonitrile is
used as the solvent.
antiperiplanar transition state according to path
A
(Scheme 2) in the case of benzaldehyde (syn preference) or
according to an open synclinal transition state when the
anti isomer is preferred (case of octanal or cyclohexanecarb-
aldehyde). This possibility is often neglected but not im-
possible due to favourable secondary orbital interac-
tions.[7b,c,d,17] The occurrence of a transmetallation reaction
can be ruled out in these reactions because of the high Z
selectivity observed on the linear adducts (vide supra). It
is worth noting that the transmetallation of crotyltins by
CeCl3·7H2O has been previously excluded on the basis of
spectroscopic analyses.[12]
When the same reactions were carried out with polymer-
supported crotyltin 3, the stereochemical trends were main-
tained (high Z selectivity for linear α adducts and syn or
anti preference for the branched γ adducts in function of
the nature of the aldehyde), but the regioselectivity of the
reaction is strongly modified with a high preference for the
branched γ adducts, as previously observed for crotylation
of aldehydes in the presence of the CeCl3·7H2O/NaI system
immobilised on alumina.[12b] In our case, this change is
probably due to lower kinetics for the 1,3-metallotropy,
which allows isomerisation of 3 into its rearranged isomer,
a result which might be seen as a matrix effect on the 1,3-
metallotropy.
In summary, the mechanism of the crotylation involving
CeCl3·7H2O/NaI as a promoter can be reasonably ex-
plained by simple Lewis acid assistance, whatever the nature
(soluble or insoluble) of the crotyltin involved in this reac-
tion. This trend appears to be similar with those encoun-
tered with other metal salts used in the presence of water,
as for instance PbI2/nBu4NBr.[18]
Reactions Involving Indium Trihalides and Polymer-
Supported Crotyltriorganotins
When reactions involving InCl3 or InBr3 were carried out
with polymer-supported crotyltin 3, the double preference
for the major linear Z-α adduct and the minor branched
syn-γ adduct observed in the case of benzaldehyde is still
consistent with a reaction occurring mainly under Lewis
acid assistance according to path A and B (Scheme 2).
For less reactive nonaromatic aldehydes, the competing
Reactions Involving Indium Trihalides and Crotyltri-
n-butyltin
For crotylations performed with soluble crotyltri-n-bu- processes envisaged for crotyltri-n-butyltin have still to be
tyltin 1 in the presence of InCl3, the situation appears quite invoked with a slower direct addition on the aldehyde–
similar with those observed in the presence of cerium salts Lewis acid complex. The result is a higher extent of both
in spite of a lower and reversed regioselectivity. The double the isomerisation by 1,3-metallotropy (with concomitant
preference for the branched syn-γ adduct and linear Z-α obtaining of linear adducts as major products in the case
adduct in the case of benzaldehyde is consistent with a reac- of benzaldehyde) and the transmetallation process, which
1686
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Eur. J. Org. Chem. 2008, 1681–1688

Crotylation of Aldehydes by Crotyltins
is probably mainly involved with cyclohexanecarbaldehyde ported allyltins should allow access to the desired targets
with both InBr3 and InCl3 when acetonitrile is used as a (sometimes with a reversed regioselectivity when compared
solvent. The case of octanal seems to be an intermediate to the reactions performed in solution), with the benefits
situation with an overlapping of several pathways and a of the allyltin reactivity but without the drawbacks of the
higher rate of transmetallation when the promoter is InBr3. organotin pollution.
When reactions were carried out in dichloromethane, the
minor formation of branched anti-γ adducts along with the
Experimental Section
major linear α adducts (with a slight preference for the Z
configuration) seems indicative of open transition states
with Lewis acid assistance on the aldehyde, but the situation
remains questionable in this case and requires further inves-
tigation. For this reason, we have attempted to elucidate the
nature of the effective organometallic species through
NMR spectroscopic studies performed with polymer-sup-
ported crotyltin 3 and InCl3 in CD2Cl2. The spectra were
taken after 2, 4 and 24 h, respectively, and no evidence of
crotylindium species could be found in solution by 1H
NMR spectroscopy. Furthermore, the 119Sn MAS-NMR
resonance for the recovered resin appeared as two signals
at –14 and –18 ppm, which are typical of (E)- and (Z)-cro-
tyltin without observable signal in the range of the triorgan-
otin chloride. These results were found to be inconsistent
with the transmetallation hypothesis for reactions carried
out with InCl3 in dichloromethane and suggest simple
Lewis acid assistance under these experimental conditions.
General: Commercially available organic and inorganic com-
pounds, as well as solvents, were purchased and used without fur-
ther purification. Crotyltri-n-butyltin 1 was prepared from tri-n-
butyltin chloride by using an already described procedure,[20] and
polymer-supported crotyltin 3 was obtained similarly in a Barbier
mode as previously achieved for other supported allyltins.[11] 1
H
and 13C NMR spectra were recorded with a Bruker Avance 300
spectrometer operating at 300 MHz for H and 75.5 MHz for 13C
1
in CDCl3 solution. Chemical shifts (δ) are expressed in ppm down-
field to tetramethylsilane (TMS) as the internal standard and coup-
ling constants (J) are expressed in Hertz. Solid-state MAS-NMR
experiments were performed at room temperature with a Bruker
Avance 500 spectrometer operating at 186.5 MHz for 119Sn by
using a 4-mm double-bearing Bruker probehead. 119Sn MAS spec-
tra were acquired with 1H TPPM decoupling during acquisition
and a MAS frequency of 10 kHz. Repetition time was set to 20 s
for quantitative purpose, as 119SnT1 were measured to be of the
order of 3 s. Spectra were referenced to Me4Sn using Ph4Sn as a
secondary reference (δ = –121.15 ppm). GC analyses were per-
formed with an HP 6890 apparatus (FID, carrier gas N2, split:
98:2) by using a methyl/phenyl silicone capillary column (Mach-
erey–Nagel, Optima δ3: 30 m, 0.25 mm, 25 µm). The flow rate was
1.3 mLmin–1 and the same programme was used for every required
analyses of homoallylic alcohols: initial temperature: 80 °C (1 min)
then 12 °Cmin–1 until 250 °C.
Conclusions
In function of the reactivity of the aldehyde, the nature
of the Lewis acid and the solvent, we can obtain: (1) a direct
addition to aldehyde, which leads to branched syn- or anti-
γ adducts through an open antiperiplanar or synclinal tran-
sition state; (2) a rearrangement of the crotyltin by 1,3-
metallotropy before addition to aldehyde, which gives linear
Z-α adducts through an open transition state; (3) a trans-
metallation of the crotyltin by the metal salts and subse-
quent reaction with aldehydes through a cyclic transition
state, either through immediate reaction of the new
branched allylmetals to afford linear E-α adducts or after
further isomerisation of these branched allylmetals into
more stable crotylmetals, whose reaction with aldehyde af-
ford mainly branched anti-γ adducts.
General Procedure for the Crotylstannation of Aldehydes in the Pres-
ence of BF3·OEt2: To a solution of aldehyde (1.7 mmol) in dry
CH2Cl2 (11 mL) was added, under an atmosphere of argon, crotyl-
tri-n-butyltin (1.1 mmol) and, dropwise at –78 °C, a solution of
BF3·Et2O (6.8 mmol). The reaction mixture was stirred at –78 °C
for 1 h and then quenched with a mixture of THF/H2O, 1:1. After
extraction with Et2O, the organic layer was washed with brine
(50 mL), dried with MgSO4 and concentrated in vacuo. The crude
product was purified by chromatography on silica gel.
General Procedure for the Crotylstannation of Aldehydes in the Pres-
ence of CeCl3·7H2O/NaI
Method A. With Crotyltri-n-butyltin 1: To
a solution of
With these possibilities in mind, the consideration of the
regioisomeric ratio together with the configuration of the
obtained homoallylic alcohols (including minor ones) can
be used to discriminate between reaction mechanisms in-
volving simple Lewis acid assistance (open transition states)
from those including a transmetallation step (cyclic transi-
tion states) when one of these pathways is exclusive or
highly prevalent.
CeCl3·7H2O (1.0 mmol) and NaI (0.1 mmol) in acetonitrile
(10 mL) was added aldehyde (1 mmol) and crotyltri-n-butyltin
(1.1 mmol). The reaction mixture was stirred 18 h at room tempera-
ture. The reaction was then quenched with HCl (0.1 , 10 mL) and
extracted with Et2O (3ϫ20 mL). The organic layer was then
washed with brine, dried with MgSO4 and concentrated in vacuo.
The crude product was used for GC analyses and purified by
chromatography on silica gel for NMR spectroscopic determi-
nation.
In terms of synthetic interest, the consideration of this
general sequence should allow to choose the appropriate
experimental conditions in order to control the formation
of the desired homoallylic alcohols with a high syn or anti
preference for branched isomers, but also with a high Z
or E preference for linear adducts. Furthermore, when the
Method B. With Polymer-Supported Crotyltin 3: To a suspension of
polymer 3 (1.0 g, 1.1 mmol) in acetonitrile were added aldehyde
(1.0 mmol), CeCl3·7H2O (1.0 mmol) and NaI (0.1 mmol). The reac-
tion mixture was stirred for 18 h at 60 °C and then quenched with
HCl (0.1 , 10 mL). The polymer was filtered and then washed
with diethyl ether (6ϫ30 mL) and then THF (6ϫ30 mL). The fil-
transmetallation can be avoided, the use of polymer-sup- trate was extracted with diethyl ether and washed with brine
Eur. J. Org. Chem. 2008, 1681–1688
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1687

F. Zammattio, J.-P. Quintard et al.
FULL PAPER
tin, B. Elissondo, A. Rahm, M. Pereyre, Tetrahedron 1989, 45,
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(50 mL), dried with MgSO4 and concentrated in vacuo. The crude
product was purified by chromatography on silica gel.
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General Procedure for the Allylstannation of Aldehydes with InX3
Method A. With Crotyltri-n-butyltin 1: To a solution of aldehyde
(1 mmol) in CH2Cl2 (or MeCN; 10 mL) was added crotyltri-n-bu-
tyltin (280 µL, 1.1 mmol) and InX3 (1 mmol). The reaction mixture
was stirred at 25 °C and monitored by TLC. After consumption of
the aldehyde, the reaction was quenched with HCl (0.1 , 10 mL)
and extracted with diethyl ether (3ϫ20 mL). The organic layer was
then washed with brine, dried with MgSO4 and concentrated in
vacuo. The crude product was purified by chromatography on silica
gel.
[6]
[7]
Method B. With Polymer-Supported Crotyltin 3: To a suspension of
polymer (1.0 g, 1.1 mmol) in CH2Cl2 (or MeCN; 10 mL) were
added aldehyde (1.0 mmol) and InX3 (1.0 mmol). The reaction
mixture was stirred for 18 h at 25 °C and then quenched with HCl
(0.1 , 10 mL). The polymer was filtered and washed with diethyl
ether (6ϫ30 mL) and then with THF (6ϫ30 mL). The filtrate was
extracted with diethyl ether and washed with brine (50 mL), dried
with MgSO4 and concentrated in vacuo.
[8]
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Products Distribution in Homoallylic Alcohols: The homoallylic
1
alcohols were firmly characterised on the basis of their H NMR
spectra in agreement with the literature[9d,13c,14,21] and their iso-
meric distribution was determined by GC analysis. GC (homoal-
lylic alcohols derived from benzaldehyde): tR = 7.03 (anti), 7.16
(syn), 7.81 (E), 7.96 (Z) min. GC (homoallylic alcohols derived
from p-nitrobenzaldehyde): tR = 12.60 (anti), 12.66 (syn), 13.06 (E),
13.24 (Z) min. GC (homoallylic alcohols derived from cyclohexane-
carbaldehyde): tR = 6.77 (anti), 6.90 (syn), 7.64 (E), 7.74 (Z) min.
GC (homoallylic alcohols derived from octanal): tR = 7.25 (anti),
7.34 (syn), 7.89 (E), 8.01 (Z) min.
[10]
[11]
[12]
Acknowledgments
We gratefully acknowledge “Nantes Métropole” for a grant (J.-M.
C.) as well as the CNRS and the MENRT for financial support.
We are indebted to Chemtura (Bergkamen) for the gift of tri-n-
butyltin hydride and tri-n-butyltin chloride.
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Received: December 13, 2007
Published Online: February 12, 2008
1688
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1681–1688