Organoborane reagents in the C-alkylation of aromatic aldimines

Article abstract of DOI:10.1002/ejoc.200700400

The reaction of an aldimine with dicyclohexylboron chloride in the presence of hydrogen peroxide gives N-[cyclohexyl(aryl)methyl]arylamines 2 in good yields via oxidized imine-borane complexes. The amines can also be obtained by a three-component reaction

Full text of DOI:10.1002/ejoc.200700400

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700400
Organoborane Reagents in the C-Alkylation of Aromatic Aldimines
María Valpuesta,*[a] Carmen Muñoz,[a] Amelia Díaz,[a] Rafael Suau,[a] and
Gregorio Torres*[a]
Dedicated to Prof. Miguel Yus Astiz on the occasion of his 60th birthday
Keywords: Boranes / Imines / Alkylation / Amines / Multicomponent reactions
The reaction of an aldimine with dicyclohexylboron chloride
a three-component reaction involving an arenecarbal-
in the presence of hydrogen peroxide gives N-[cyclohex- dehyde, an arylamine and a dialkylchloroborane reagent.
yl(aryl)methyl]arylamines 2 in good yields via oxidized im-
ine–borane complexes. The amines can also be obtained by
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
no direct addition in a Grignard-like fashion of a trialkyl-
borane reagent to imines has to date been observed except
for allylboranes.[6] Although borane reagents are typically
unreactive toward carbonyl compounds, in recent years Ka-
balka and coworkers[2] developed a number of novel reac-
tions involving these derivatives as nucleophilic alkyl do-
nors. Generally, an activated carbonyl derivative or halo- or
dihaloalkylborane is required to obtain the corresponding
alkylated alcohols in good yields. Examples include the
Grignard-like alkylation of arenecarbaldehydes or their
arylsulfonylhydrazone derivatives with organoboron rea-
gents (Scheme 1).
Introduction
Organoboranes are among the most versatile intermedi-
ates currently available to organic chemists.[1] The electron
deficiency caused by the vacant p orbital on the boron atom
and the metallic properties of boron derivatives endow
these reagents with enhanced flexibility. The Grignard-like
reactivity of organoborane compounds toward carbonyl or
imine derivatives is still being explored.[2]
1,2-Addition of alkyl groups to the C=N bond consti-
tutes a key method for the preparation of a variety of
amines. Most synthetically efficient reactions are based
either on the use of organometallic reagents[3] or on radical
additions.[4] The addition of organometallic reagents is se-
verely limited by the poor electrophilicity of the azomethine
carbon and the tendency of the substrates to undergo aza-
enolization with acidic α protons. The former problem
could be avoided by activating the C=N bond either by N-
substitution with an electron-withdrawing group or by N-
coordination to a Lewis acid. The use of less-basic organo-
metallic reagents such as organocopper or organocerium
derivatives constitutes an effective approach that prevents
enolization in aliphatic aldimines. The imine derivatives can
also act as radical acceptors and several synthetically useful
intra- and intermolecular carbon–carbon bond-forming re-
actions have been reported.[4]
The C=N bond typically reacts with organoborane deriv-
atives such as alkenyl, aryl or allyl boronates.[5] However,
Scheme 1. Known reactivity of R3B, R2BCl and RBCl2 with benz-
aldehyde derivatives.
[a] Departamento de Química Orgánica, Facultad de Ciencias,
Universidad de Málaga,
To the best of our knowledge, however, these borane de-
rivatives remain unreactive with imines. This encouraged us
to investigate the reaction of aldimines with trialkylborane
and dicyclohexylchloroborane.
Campus de Teatinos s/n, 29071 Málaga, Spain
Fax: +34-952-13-19-41
E-mail: mvalpuesta@uma.es
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
Eur. J. Org. Chem. 2007, 4467–4470
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4467

M. Valpuesta, C. Muñoz, A. Díaz, R. Suau, G. Torres
SHORT COMMUNICATION
(Table 1, Entry 7), although the amine yield was quite mod-
est (5–25%). Interestingly, we found that the cyclohex-
ylamine could be formed in good yields (80–85%) when
hydrogen peroxide was added as coreagent (Table 1, En-
try 8).
After optimization, we directly used the best reaction
conditions with aromatic N-arylimines 1a–f having different
substitution patterns in the aromatic rings (Table 2). Essen-
tially, all aldimines were successfully converted into the cor-
responding amine derivatives 2a–f.
Results and Discussion
We hereby report our initial results for this novel reaction
(Scheme 2). We chose N-(4-methoxyphenyl)aldimine 1a, de-
rived from anisaldehyde, as the model compound. We first
examined its reactivity toward various trialkylboranes and
found that no reaction occurred. Only the imine–borane
complexes were detected (by NMR spectroscopy) upon the
addition of R3B (R = Et or nBu, 1.2 equiv.) to the imine
solution (dichloromethane, n-hexane) in a nonaqueous me-
dium. No change was detected if oxygen or a base was
added to the reaction mixture.
Table 2. Synthesis of Amines 2a–f.
Entry Amine
Ar
ArЈ
Yield [%][a]
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
4-MeOC6H4
4-MeOC6H4
60
68
65
70
Scheme 2. General alkylation scheme for aldimines.
Dialkylchloroborane reagents are more electron-deficient
and coordinate more efficiently to the imine nitrogen than
do trialkylboranes. This led us to examine reactions involv-
ing dicyclohexylboron chloride (Chx2BCl) under different
conditions. Generally, the imine–borane complex precipi-
65
2,3-(MeO)2C6H3 4-MeOC6H4
66[b]
[a] Isolated yields after silica gel chromatography. [b] Isolated along
with N-[1-cyclohexyl-1-(2-hydroxy-3-methoxyphenyl)methyl]-p-
anisidine when an excess of dicyclohexylboron chloride was used
tates from nonpolar or ethereal solvents. However, its high (1.5:1).
solubility in dichloromethane makes this solvent a good
As can be seen from Table 2, the yield of cyclohexylated
choice as the reaction medium. As can be seen from
Table 1, no reaction product was obtained in the absence of
a base, whether at room temperature or under reflux, and
using various solvents (Table 1, Entries 1, 2). By contrast,
the cyclohexylated amine was formed in the presence of tri-
ethylamine under reflux conditions (Table 1, Entry 5) or in
the presence of sodium hydroxide at room temperature
product was independent of the methoxy substituent on the
aromatic rings. Imine 1f yielded a significant amount of a
demethylated product {N-[1-cyclohexyl-1-(2-hydroxy-3-
methoxyphenyl)methyl]-p-anisidine} when an excess of di-
cyclohexylboron chloride was used. However, the product
was not observed when a 1:1 mol ratio of reactants was
used.
Next, we examined the one-step reaction of anisaldehyde
and 4-methoxyaniline with an excess of dicyclohexylboron
chloride. Under these conditions, the chloroborane reagent
acts both as a Lewis acid catalyst for the imine formation
and as a chain donor to the C=N bond. As can be seen
from Table 3, the corresponding amine derivative, 2a
(Table 3, Entry 1), was obtained in a yield similar to that
for the preformed imine 1a (Table 2, Entry 1).
Table 1. Reaction of aldimine 1a with dicyclohexylboron chloride.
The electronic nature of the substituents on the benzene
rings of the aldehyde and amine had no effect on the reac-
tion efficiency. With Chx2BCl, 1H NMR spectroscopic
analysis of the crude reaction mixture revealed the almost
exclusive presence of amine derivatives (70–80% yields).
The differences in yields between compounds 2a–l (Table 3,
Entries 1–7) were due to the purification procedure used.
The reaction was found to require a longer time for com-
pletion when a borane derivative containing primary alkyl
groups was used (Table 3, Entries 8–10). The desired prod-
ucts, 2m–o, were obtained in low yields and accompanied
by unidentified byproducts. To avoid a decrease in the yield
in the purification step, we acetylated the clean crude prod-
uct of amine 2a to obtain the corresponding acetyl deriva-
tive in 80% yield.
Entry Solvent
T [°C]
Additive
Yield [%][a]
1
2
3
dichloromethane, room temp.
THF or toluene
dichloromethane, reflux
THF or toluene
dichloromethane room temp.
or THF
–
Ͻ5[b]
–
Ͻ5[b]
Ͻ5[b]
triethylamine
4
5
6
7
8
THF
reflux
triethylamine
triethylamine
NaOH (1 )
NaOH (10 )
H2O2
Ͻ5[b]
20–25
Ͻ5[b]
5–10
dichloromethane reflux
dichloromethane room temp.
dichloromethane room temp.
dichloromethane room temp.
80–85
1
[a] Determined by H NMR spectroscopy; the detection limits for
the products in the crude NMR spectra were estimated to be 5%.
[b] Although the yield is quoted as Ͻ5%, compound 2a was not
detected by NMR spectroscopy.
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Eur. J. Org. Chem. 2007, 4467–4470

Organoborane Reagents in the C-Alkylation of Aromatic Aldimines
Table 3. Three-component reactions: Synthesis of amines 2a, g–o.
at room temp. A solution of hydrogen peroxide (0.2 mL, 30%) was
then added, and the mixture was stirred for 30 min. Later, a solu-
tion of sodium hydroxide (1 , 1 mL) was added and stirred for
30 min. The crude reaction was washed with water (2ϫ10 mL) and
the organic phase dried with anhydrous MgSO4 and concentrated
under reduced pressure. The 1H NMR spectrum of the crude prod-
uct exhibited the almost exclusive presence of amine derivatives
(yields 80–85%). Purification by column chromatography (ethyl
acetate/hexane, 1:9) afforded the amines in 60–70% yield.
Entry Amine
R
Ar
ArЈ
Yield [%][a]
1
2
3
4
5
6
7
8
9
10
2a
2g
2h
2i
2j
2k
2l
2m
2n
2o
Chx
Chx
Chx
Chx
Chx
Chx
Chx
Hex
Hex
Hex
4-MeOC6H4 4-MeOC6H4
66
78
38
50
62
65
57
26
34
32
4-FC6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
One-Pot Reaction of Aldehyde, Amine and Dialkylboron Chloride:
The corresponding alkene (7.6 mmol) was added to a solution of
monochloroborane–methyl sulfide complex (1 ) in dichlorometh-
ane (3 mL) at 0 °C. The mixture was warmed to room temp. and
stirred for 3 h. A solution of aldehyde (1 mmol) and amine
(1 mmol) in dichloromethane was then added, and the mixture was
stirred at room temp. for 2 h. A solution of hydrogen peroxide
(0.2 mL, 30%) was added, and the mixture was stirred for 30 min.
Later, a solution of sodium hydroxide (1 , 1 mL) was added and
stirred for 30 min. The crude reaction was washed with water
(2ϫ10 mL), and the organic phase was dried with anhydrous
MgSO4 and concentrated under reduced pressure. The 1H NMR
spectrum of the crude product exhibited the almost exclusive pres-
ence of amine derivatives (yields 70–80%). Purification by column
chromatography (ethyl acetate/hexane, 1:9) afforded the amines in
78–32% yield.
4-MeOC6H4 4-MeC6H4
4-MeC6H4
C6H5
4-MeC6H4
C6H5
4-MeOC6H4 4-MeOC6H4
4-FC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
[a] Isolated yields after silica gel chromatography.
Although no detailed mechanistic study was undertaken,
we focused on the imine reaction with Chx2BCl; the rate of
the reaction was found to decrease in the presence of an
oxygen stream. Furthermore, the addition of radical scaven-
gers, such as cumene, failed to inhibit the alkylation reac-
tion. These results suggest that a radical reaction mecha-
nism is less likely. In an attempt to elucidate the alkylating
intermediate, we added the corresponding imine to a solu-
tion of dicyclohexyl borate. Under these conditions, no al-
kylated product was observed. In a separate experiment, we
reversed the order of the addition and we found that the
sequential addition of hydrogen peroxide and dicyclohex-
ylboron chloride to the imine solution resulted in the ex-
pected cyclohexylated derivatives. This alkylation reaction
developed smoothly with other oxidants such as Oxone,
UHP or MCPBA. In contrast, the direct treatment of the
nitrone derivative from 1a with dicyclohexylboron chloride
provided no alkylated derivatives. Although the radical
pathway could not be completely disregarded, an alterna-
tive pathway proceeding via an imine-borate intermediate
could be considered. A similar mechanism was proposed
for the boronic acid multicomponent reaction of amines
and aldehydes.[5b]
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental procedures and spectroscopic and analytical
data.
Acknowledgments
This work was supported by the Ministry of Education and Sci-
ence, Spain (grant CTQ2004-0565).
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Org. Chem. 1997, 62, 3688–3695; b) G. W. Kabalka, Z. Wu,
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S. E. Trotuan, X. Gao, Org. Lett. 2000, 2, 255–256; d) G. W.
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G. W. Kabalka, Z. Wu, Y. Ju, Tetrahedron 2002, 58, 3243–3248;
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Conclusions
We developed a one-pot alkylative amination reaction for
benzaldehyde derivatives that involves up to three compo-
nents with dialkylchloroborane as the alkylating agent. Fur-
ther studies to elucidate the mechanism of this reaction and
to expand its synthetic utility are currently being explored
by our group.
Experimental Section
Reaction of Imines with Dicyclohexylboron Chloride. General Pro-
cedure: The imine (1 mmol) was dissolved in dichloromethane
(10 mL) contained in a dry, nitrogen-flushed, 25-mL round-bot-
tomed flask. Dicyclohexylboron chloride (1  in hexane, 1 mmol)
was added by syringe, and the solution was allowed to stir for 2 h
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[5] a) R. A. Batey, D. B. MacKay, V. Santhakumar, J. Am. Chem.
Soc. 1999, 121, 5075–5076; b) N. A. Petasis in Multicomponent
Eur. J. Org. Chem. 2007, 4467–4470
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SHORT COMMUNICATION
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Received: May 2, 2007
Published Online: August 3, 2007
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Eur. J. Org. Chem. 2007, 4467–4470