An Alumino-Mannich Reaction of Organoaluminum Reagents, Silylated Amines, and Aldehydes

Article abstract of DOI:10.1002/chem.201801012

A multi-component coupling using organoaluminum reagents, silylated amines, and aldehydes results in the formation of tertiary amines. Both alkenyl- and alkylaluminum reagents undergo reaction with iminium ion substrates for which the corresponding Petasis borono-Mannich reactions are unsuccessful.

Full text of DOI:10.1002/chem.201801012

A Journal of
Accepted Article
Title: An Alumino-Mannich Reaction of Organoaluminum Reagents,
Silylated Amines, and Aldehydes
Authors: Anika Tarasewicz, Deeba Ensan, and Robert Alexander
Batey
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10.1002/chem.201801012
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COMMUNICATION
An Alumino-Mannich Reaction of Organoaluminum Reagents,
Silylated Amines, and Aldehydes
Anika Tarasewicz, Deeba Ensan, and Robert A. Batey*
intermediate 3 and, then, adding the organoaluminum reagent 1a.
Allylic amine 5a was formed in moderate yield, along with the
Abstract:
A multi-component coupling using organoaluminum
reagents, silylated amines, and aldehydes results in the formation of
tertiary amines. Both alkenyl- and alkylaluminum reagents undergo
reaction with iminium ion substrates for which the corresponding
Petasis borono-Mannich reactions are unsuccessful.
The Petasis borono-Mannich reaction1 is a practical and efficient
method for the construction of both allylic and benzylic amines,
important targets that are found in many biologically active
molecules and which are useful synthetic intermediates employed
in the total syntheses of alkaloids and other complex molecules.2
The reaction usually occurs in a two-step manner; first an
aldehyde and a secondary amine react to form an iminium ion that
in a subsequent step reacts with a boronic acid. Using
alkenylboronic acids, tertiary allylic amines can be formed in a
method that is operationally straightforward using bench stable
precursors, and which can often be conducted in a one-pot, three-
component fashion.1 However, there are some limitations in
substrate scope that have prevented its application in a general
manner, with most examples of the Petasis borono-Mannich
Scheme 1. Synthesis of (E)-alkenylaluminum reagents via hydroalumination
allylic alcohol side product 4a, formed as a result of competitive
addition into the aldehyde (Table 1, Entry 1). To ensure complete
conversion of the aldehyde and amine into 3, various additives
were evaluated to promote iminium ion formation or to form stable
iminium salts. For example, LiCl or BF3·OEt2 decreased the yield
and selectivity of the reaction. Addition of TMSOTf improved the
ratio of 5a to 4a but with a minimal effect on the yield (Table 1,
Entry 4). The Lewis acid mixture of BF3·OEt2 and TMSOTf did not
promote conversion into product.7 Modifying the number of
equivalents of TMSOTf or pyrrolidine did not improve the yield of
5a. However, heating the reaction in the presence of TMSOTf
increased the reaction yield and selectivity (Table 1, Entry 8).
reaction utilizing aldehydes (or amines) that possess
a
neighboring heteroatom.3 It is believed that this allows a
templating or tethering effect to facilitate nucleophilic addition of
the tetracoordinate borate anion to the electrophilic iminium ion in
an intramolecular manner. Moreover, the Petasis borono-
Mannich reaction is further limited to additions of alkenyl and
arylboron species.
Table 1. Additive effects in the three-component reaction of benzaldehyde,
pyrrolidine, and organoaluminum reagent 1a.a
To expand the range of aldehydes that can be used for this
reaction, we considered the use of other more reactive group XIII
based nucleophiles. Organoaluminum reagents are known to be
excellent nucleophiles for a number of organic reactions,
including additions to simple imines (forming secondary amine
products), conjugate additions, additions to sulfonyl chlorides,
and formation of Morita-Baylis-Hillman products.4 Accordingly, we
hypothesized that organoaluminum reagents could be employed
in an alumino-Mannich reaction variant that would expand the
substrate scope such that neighboring heteroatom coordination
from the aldehyde or amine components would not be required.
Herein we establish the viability of this approach for the addition
reactions of both alkenyl and alkylaluminum reagents together
with iminium ions derived from secondary amines and aldehydes.
Entry
1
Additive
None
Ratio of 4a:5a
Yield of 5a [%] [b]
1:3
1:2
2:3
1:6
-
54
39
23
58
0
2
LiCl
3
BF3·OEt2
TMSOTf
BF3·OEt2/TMSOTf
TMSOTf
TMSOTf
TMSOTf
4
The requisite (E)-alkenylaluminum reagents are readily formed
through hydroalumination5 of terminal alkynes.6 The
organoaluminum reagent (E)-hex-1-en-1-yldiisobutylaluminum 1a,
prepared by reaction of 1-hexyne with DIBAL-H (1.0 equiv, 1.0 M
in hexanes) at 55 °C for 5 h, was used as the nucleophile for the
optimization of experimental conditions (Scheme 1). The
feasibility of the approach was initially evaluated by stirring
benzaldehyde and pyrrolidine to form the iminium ion
5
6 [c]
7 [d]
8 [e]
1:5
1:9
1:8
38
48
64 [f]
[a] Reactions performed at 0.9 mmol scale under nitrogen as a 0.1 M
solution in CH2Cl2. [b] Yield determined by 1H NMR using 1,4-dioxane as an
internal standard. [c] 1.2 equiv of TMSOTf was used. [d] 1.2 equiv of
pyrrolidine was used. [e] Reaction performed at 40 °C instead of room
temperature. [f] Isolated yield of 5a.
[*]
A. Tarasewicz, D. Ensan, and Prof. R. A. Batey
Department of Chemistry
University of Toronto
80 St. George Street, Toronto, ON, M5S 3H6 (CANADA)
E-mail: rbatey@chem.utoronto.ca
The significant amount of 4a byproduct and the moderate yield of
the desired product 5a suggested that complete conversion to the
iminium ion did not occur, even in the presence of additives.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201801012
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COMMUNICATION
salt was formed using trimethylsilylated pyrrolidine 6a (Table 2).8
Based on the protocols of Schroth and co-workers, an iminium
reaction with substrates that do not contain neighbouring
heteroatoms. A survey of various solvents using a two-step, one-
pot process led to improved yields and selectivity (Table 2). The
use of dichloromethane as the solvent afforded 5a in excellent
yield, conditions that were subsequently applied for further
examples (Table 2, Entry 4). The improved yields and selectivity
for the optimized conditions utilizing the trimethylsilylamine may
occur because TMS2O is formed rather than trimethylsilanol that
is formed in the direct reaction of secondary amines.
Table 2. Solvent effect study for the reaction of silylated amine 2a, aldehyde
3a and organoaluminum 1a.[a]
The scope of the reaction was surveyed under the optimized
reaction conditions using 1a and 2a with
a variety a
trimethylsilylated amines 6 (Scheme 2). The products 5 were
generally obtained in good yields, particularly using cyclic amines.
Entry
Solvent A
-
Solvent B
CH2Cl2
CH2Cl2
Et2O
Yield [%] [b]
Scheme 2. Formation of allylic amines 5 using a trimethylsilyl protected amine
1 [c]
2
90
82
82
94
75
based alumino-Mannich reaction.a
Et2O
Et2O
3
CH2Cl2
toluene
CH2Cl2
toluene
4
5
[a] Reactions performed at 0.9 mmol scale under nitrogen as a 0.33 M
solution in CH2Cl2. [b] Isolated yield. [c] Reaction of performed iminium salt
3a with organoaluminum reagent. [d] Ether solvent removed under a
nitrogen atmosphere after first step, and dichloromethane solvent added for
the second step.
The iminium salt 3a precipitated as a white solid in the ether
solution (89% yield). Reaction of isolated 3a with
organoaluminum reagent 1a resulted in a 90% yield of the desired
product 5a (Table 2, Entry 1). Reaction of 3a with the analogous
boronic acid and boronic ester under analogous conditions did not
result in product formation (See Supporting Information for
details). Thus, organoaluminum reagents can be used as an
alternative to organoboron reagents for the Petasis Mannich
[a] Reactions performed at 0.9 mmol scale under nitrogen as a 0.33 M solution
in CH2Cl2. Isolated yields of purified products. [b] The trimethylsilyl amines were
synthesized according to literature procedures.9
Scheme 3. Aldehyde substrate scope for the alumino-Mannich reaction using 1a and 6a.a
[a] Reactions performed at 0.9 mmol scale under nitrogen as a 0.33 M solution in CH2Cl2. Isolated yields of purified products.
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The optimized conditions were also applied to a variety of
aldehydes 2 using 6a. It was found that substituted aryl aldehydes
afforded high yields of the desired products (Scheme 3).
Heteroaromatic aldehydes could also be employed, although
yields of the adducts 6 were lower. Simple alkyl aldehydes were
not successful in the formation of the allylic amine products, most
likely due to the formation of enamines rather iminium
intermediates with the silylated amines. Enal 2v and the non-
enolizable aldehyde 2w could also be employed, although in the
latter more sterically hindered case the isolated product yield was
poor.
Experimental Section
General procedure for the synthesis of allylic amines: Aldehyde (0.9
mmol) and CH2Cl2 (2.7 mL) was placed in a flamed dried reaction flask
under N2 atmosphere. TMSOTf (0.9mmol was then added and stirred for
2 min. Silylated amine 6 was then added (0.9mmol). This was left to stir at
room temperature for 4 h. Organaluminum 1 was then added and stirred
for another 4 h at room temperature. The reaction was quenched with a
solution of saturated Rochelle’s salt at 0 °C. This was brought to room
temperature and stirred for 18 hrs. The phases were separated and the
aqueous phase was extracted with CH2Cl2 (3 x 5 mL). The combined
organic phases were washed with brine (15 mL) and dried with Na2SO4.
This was concentrated under reduced pressure to provide the crude
material, which was purified by silica gel chromatography (5% MeOH in
CH2Cl2) to provide the desired product.
Variation of the organoaluminum reagent in the alumino-Mannich
reaction was also evaluated. Organoaluminums generated
through known hydroalumination of alkynes afforded the amines
7 in good yields (Scheme 4). Reaction of a Z-alkenylaluminum
reagent 1d10 gave the product amine 7c in low yield, but as a
single alkene stereoisomer (d.r. ≥ 19:1). The addition of more
equivalents of 1d or additives, such as THF or trimethylamine, did
not improve the yield. The use of alkylaluminums is also possible,
generating the product amines in moderate to good yields
(Scheme 4, 7d-7j). These results are in stark contrast to the lack
of reactivity observed for alkylboron reagents [C(sp3) based
nucleophiles] in the Petasis borono-Mannich reaction.11,12
Acknowledgements
The authors thank the University of Toronto and the Natural
Science and Engineering Research Council of Canada (NSERC)
for financial support. A.T. is grateful to the Ontario Ministry of
Education for an Ontario Graduate Scholarship. D.E. is grateful
to NSERC for a NSERC-USRA Scholarship.
Scheme 4. Organoaluminum substrate scope for the alumino-Mannich reaction
using silylated amines and aldehydes.a
Keywords: multicomponent reaction • iminium ions • alanes •
silylated amines • Mannich reaction
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was used (1.0 M in hexanes). [c] a solution of trimethylaluminum was used (2.0
M in hexanes).
In summary, a general method for the construction of tertiary
allylic and other tertiary amines using a three-component method
was investigated. The method extends the substrate scope for
tertiary amine formation, allowing the reaction of aldehydes and
amines that are unreactive in the Petasis borono-Mannich
reaction. The method can also be applied toward the addition of
alkylaluminum reagents, permitting the transfer of alkyl groups, a
process for which there has been limited success with the boron-
based counterpart. Further studies of the alumino-Mannich
addition reaction will be reported in due course.
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COMMUNICATION
COMMUNICATION
Anika Tarasewicz, Deeba Ensan, and
Robert A. Batey*
R2
R1
R2
R1
R3
R3
R5
O
R2
R3
TMSOTf, CH2Cl2
TMSOTf, CH2Cl2
N
N
N
R1
H
then
iBu
iBu
Al
R4
then
R
SiMe3
Page No. – Page No.
Al
R4
R5
R
27 examples
up to 99% yield
8 examples
up to 99% yield
An Alumino-Mannich Reaction of
Organoaluminum Reagents, Silylated
Amines, and Aldehydes
The Triple A-Team: A multi-component coupling using organoaluminum reagents,
silylated amines, and aldehydes results in the formation of tertiary amines. Both
alkenyl- and alkylaluminum reagents undergo reaction with iminium ion substrates
for which the corresponding Petasis borono-Mannich reactions are unsuccessful.
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