Direct catalytic asymmetric aminoallylation of aldehydes: Synergism of chiral and nonchiral Bronsted acids

Article abstract of DOI:10.1021/ja1110865

The development of a catalytic asymmetric method for the direct aminoallylation of aldehydes is described that gives high asymmetric inductions for a broad range of substrates including both aromatic and aliphatic aldehydes. This method allows for direct isolation of unprotected analytically pure homoallylic amines without chromatography. The unique catalyst system developed for this process involves the synergistic interaction between a chiral and a nonchiral Bronsted acid.

Full text of DOI:10.1021/ja1110865

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pubs.acs.org/JACS
Direct Catalytic Asymmetric Aminoallylation of Aldehydes:
Synergism of Chiral and Nonchiral Brønsted Acids
Hong Ren and William D. Wulff*
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
S Supporting Information
b
an entirely new class of chiral Brønsted acids that in the cases of
the boroxinate 9 exists as an ion pair consisting of a chiral
boroxinate anion derived from either the VANOL or VAPOL
ligand and a protonated iminium. In the development of these
reactions it was found that a diphenylmethyl group on the imine
nitrogen was important for high asymmetric inductions.7,9 It was
furthermore found that both the rates and inductions for the
reactioncould be increased with the proper substitution patternin
the two aryl groups in 7.8h,j Most interestingly, the boroxinate
catalyst 9 only forms when the imine substrate is added.7a,b
Boroxinate assembly can be induced by the imine either from the
ABSTRACT: The development of a catalytic asymmetric
method for the direct aminoallylation of aldehydes is
described that gives high asymmetric inductions for a broad
range of substrates including both aromatic and aliphatic
aldehydes. This method allows for direct isolation of
unprotected analytically pure homoallylic amines without
chromatography. The unique catalyst system developed for
this process involves the synergistic interaction between a
chiral and a nonchiral Brønsted acid.
ligandandcommercialB(OPh)3 or from the ligand and BH3 SMe2,
3
phenol, and H2O.7a,b,8i Characterization of this chemzymeꢀsubstrate
complex 9 (from VAPOL) by X-ray diffraction revealed the presence
of several noncovalent interactions including an H-bond of the
iminium to one of the boroxinate oxygens as well as a πꢀπ stacking
and a series of CHꢀπ interactions.7b These interactions between the
substrate and the catalyst added to the understanding of how certain
groups on the benzhydryl substituent can affect the binding and the
outcome of the aziridination reaction.
f the known catalytic asymmetric methods for the synthesis
O
of homoallylic amines1 from aldehydes, the most popular is
a two-step method that involves the formation of an imine and then
catalytic asymmetric allylation of the imine or imine derivative.2 Due
to the low reactivity of CdN bonds, activating groups or reactive
organometallic reagents are necessary. In contrast, there is only a
single report on the catalytic asymmetric synthesis of homoallylic
amines directly employing aldehydes as substrates.3 We report here
the development of a new method for the catalytic asymmetric
synthesis of homoallylic amines directly from aldehydes that is based
on a chiral polyborate catalyst generated from the vaulted biaryl
ligand VANOL. This method is scalable since it is chromatography
free and it gives rise to unprotected homoallylic amines with
excellent asymmetric inductions over a broad range of substrates
including both aromatic and aliphatic aldehydes.
We hoped to take advantage of what we learned about the
interactions of the imines 7 and the boroxinate catalyst; however,
initial results were not encouraging since the VAPOL B3 catalyst 9
gave the Cope product 12a in 2% ee and the VANOL B3 catalyst
gave 19% ee (Table 1, entries 1 and 3).11 During the course of
optimization, it was found that the rearrangement of imine 10a
prepared from a sample of benzaldehyde that had not been distilled
for 2 weeks led to a slightly higher induction with the VANOL
catalyst (27% vs 19% ee). It was speculated that a small amount of
benzaldehyde was oxidized to benzoic acid and that its presence in a
catalytic amount was responsible for the enhanced asymmetric
induction. To test this assumption, 10 mol % benzoic acid was
added to the reaction mixture. While a negligible effect was observed
for the VAPOL catalyst (entry 2), a significant increase in ee was
observed for the VANOL catalyst (entry 4).
Our approach builds on the method developed by Kobayashi4
and Rueping3 involving the aza-Cope rearrangement of imines 3
derived from 3-butenyl-1-amines of type 2. With proper control
of the nature of the substituents R2 or R3 on amine 2, they were
able to either sterically4,5 or electronically3 drive the reversible
Cope rearrangement to isomer 4.6 In the study by Rueping it was
found that two phenyl groups (R2, R3) were sufficient to drive the
equilibrium to isomer 4.
Attention was then turned to the imine 11a in which the
aryl groups are both 3,5-dimethylphenyl substituents. This
substitution pattern was found to increase the asymmetric
We recently identified the boroxinateꢀiminium complex 97 as
the active catalyst in the aziridination of imines8,9 and the
heteroatom DielsꢀAlder reactions of imines.10 This catalyst is
Received: December 9, 2010
Published: March 29, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja1110865 J. Am. Chem. Soc. 2011, 133, 5656–5659
|

Journal of the American Chemical Society
COMMUNICATION
Table 1. Effects of Ligand and Benzoic Acid on the Aza-Cope
Table 2. Direct Aminoallylation of Benzaldehydea
Reactiona
mol
MS
% yield
13ab
% ee
23ac
mol %
mol %
% yield
% ee
entry
n mol %
sieves
loading
entry imine
ligand
catalyst C6H5CO2H 12a/13ab 12a/13ac
1d
2d
3
10
10
10
10
5
4 Å
5 Å
5 Å
5 Å
5 Å
5 Å
5 Å
300
300
100
10
10e
84
82
72
82
92
15e
—
71
76
53
75
80
—
1
2
3
4
5
6
7
8
9
10a (R)-VAPOL
10a (R)-VAPOL
10a (R)-VANOL
10a (R)-VANOL
10a (R)-VANOL
10a none
20
20
20
20
10
0
0
10
0
67
67
80
78
76
NR
77
80
85
81
81
83
84
84
89
84
63
78
78
62
2
4
19
45
42
—
25
40
69
72
72
70
68
66
78d
9
4
10
5
5
100
50
6
5
10
0
7
0
300
a Unless otherwise specified, all reactions were performed on a 0.1 mmol
scale in m-xylene at 0.2 M in amine 14 with 1.1 equiv of aldehyde 1a for
18 h and went to 100% completion at 60 °C. The precatalyst was
11a (R)-VANOL
11a (R)-VANOL
11a (R)-VANOL
10
10
10
10
10
10
10
10
10
10
10
10
1
5
prepared by heating 1 equiv of ligand, 3 equiv of BH3 SMe2, 2 equiv of
3
10 11a (R)-VANOL
11 11a (R)-VANOL
12 11a (R)-VANOL
13 11a (R)-VANOL
14 11a (R)-VANOL
15 11a (R)-VANOL
16 11a (R)-VAPOL
17 11a (R)-BINOL
18 11a (R)-BINOL
10
15
20
40
60
10
5
2,4,6-trimethylphenol, and 3 equiv of H2O in toluene at 100 °C for 1 h
followed by removal of volatiles at 100 °C for 0.5 h at 0.1 mmHg.
b Isolated yield after silica gel chromatography. c Chiral HPLC. d Molec-
ular sieves added after stirring VANOL B3 catalyst and amine for 30 min
at 60 °C. e Percent completion of the reaction as determined by the 1H
NMR spectrum of the crude.
involved in two parallel steps, while, for the latter, an achiral
Brønsted acid was utilized to maintain a sufficient concentration
of iminium. In neither report was the addition of the achiral acid
observed to affect the asymmetric induction. However, in the
present case, the addition of benzoic acid led to not only a rapid
color change of the reaction mixture from beige to bright yellow
but also more importantly a significant enhancement in the
enantioselection (Table 1, entries 7 and 10), which clearly
indicates a synergistic interaction of these two Brønsted acids.
Akiyama has reported a related observation,15 which, to the best
of our knowledge, is the only other example of a nonorthogonal,
or synergistic coexistence of a chiral and an achiral strong
Brønsted acid in asymmetric catalysis where the result is an
increase in asymmetric induction.16,17
At this point, it was decided to determine whether the
conditions that have been optimized for the Cope rearrangement
of imine 11a could be translated to a direct aminoallylation of
benzaldehyde. The initial answer was no. The reaction of
benzaldehyde 1a with amine 14 in the presence of 4 Å molecular
sieves to absorb the water only went to 10% completion in 18 h
with 10 mol % catalyst (Table 2, entry 1). Remarkably, when 5 Å
sieves were employed, the reaction went to completion to give
the homoallyic imine 13a in 84% yield and 71% ee.18 The optimal
procedure gave 92% yield and 80% ee with 5 mol % catalyst19,20
and 50 mg of 5 Å molecular sieves (entry 6).
0
15e
36e
13e
ꢀ7e
10
0
19 11a (R)-3,3-Ph2BINOL 10
20 11a (R)-3,3-Ph2BINOL 10
10
a Unless otherwise specified, all reactions were performed on a 0.1 mmol
scale in toluene at 0.2 M in imine for 18 h and went to 100% completion
at 60 °C. The precatalyst was prepared by heating 1 equiv of ligand, 3
equiv of BH3 SMe2, 2 equiv of PhOH, and 3 equiv of H2O in toluene at
3
100 °C for 1 h followed by removal of volatiles at 100 °C for 0.5 h at
0.1 mmHg. b Isolated yield after silica gel chromatography. c Chiral HPLC.
d Solvent is m-xylene. e Reaction time is 44 h.
induction and the rate (10ꢁ) over that of the unsubstituted
benzhydryl group in aziridinations of imines of type 7.8h The
induction was found to increase for the aza-Cope rearrangement
from 42% ee for 10a (entry 5) to 69% ee with 11a (entry 9). The
difference between VANOL and VAPOL was significant also
with imine 11a, the former giving 69% ee and the latter 9% ee
under identical conditions (entries 9 vs 16). This is in stark
contrast to the aziridination reaction where these two ligands
were equipotent. 8g,h,j Neither the catalyst derived from BINOL
nor 3,30-diphenylBINOL proved to be effective for the Cope
rearrangement of 11a (entries 17ꢀ20).12
A survey of the effect of added benzoic acid on the induction
(entries 7ꢀ14) reveals that the optimal amount is 1 equiv relative to
the boroxinate catalyst. A number of other carboxylic acids were also
screened including substituted benzoic acids and aliphatic acids, but
none proved superior to benzoic acid (see Supporting Information
(SI)). Most of the reactions in Table 1 were performed in toluene,
but upon screening many different solvents (see SI) it was found
that m-xylene gave the highest induction (entry 15).
The scope of the asymmetric catalytic aminoallylation of aromatic
aldehydes with the VANOL boroxinate catalyst was probed with
the 12 substrates indicated in Table 3. All of the reactions in
Table 3 were performed on gram scale (4.0 mmol) to facilitate
the isolation of the homoallylic amine product. The amines 15 were
purified by dissolution into aqueous acid and then extraction of
the impurities with ethyl acetate. This simple procedure is not
scale limited and leads to the isolation of analytically pure
hydrochloride salts suitable for prolonged storage or immediate
Orthogonal interplay of chiral and nonchiral Brønsted acids
was reported by Rueping’s group13 in 2006 and Antilla’s group in
2009.14 In the former reaction, the two Brønsted acids were
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Journal of the American Chemical Society
COMMUNICATION
Table 3. Asymmetric Catalytic Aminoallylation of Aromatic
Aldehydesa
Table 4. Aminoallylation of Aliphatic and Alkenyl Aldehydesa
a Unless otherwise specified, all reactions were performed as described
in Table 2 (entry 6) on a 4.0 mmol scale and went to completion in
18ꢀ30 h. The hydrolysis step required 6ꢀ10 h for completion. The
asymmetric inductions are the average of two runs, one each with (R)- and
(S)-VANOL. The inductions were measured on the corresponding Cope
rearrangement product 13 except where indicated in the SI. The yields are
based on amine 14 and are of the salt 15 purified by dissolution in aqueous
acid and extraction of impurities with ethyl acetate.
a Unless otherwise specified, all reactions were performed as described in
Table 2 (entry 6) on a 4.0 mmol scale and went to completion in 18ꢀ30
h except the reaction of aldehyde 1f which required 55 h. The hydrolysis
step required 3ꢀ18 h for completion. The asymmetric inductions are
the average of two runs, one each with (R)- and (S)-VANOL. The
inductions were measured on the corresponding Cope rearrangement
product 13 except where indicated in the Supporting Information. The
yields are based on amine 14 and are of salt 15 purified by dissolution
into aqueous acid and extraction of impurities with ethyl acetate.
b Reaction on p-acetoxybenzaldehyde.
Scheme 1
use. Slightly higher inductions were obtained with aryl aldehydes
with electron-withdrawing substituents; nonetheless, p-meth-
oxybenzaldehyde 1f reacts to give the amine 15f in 94% yield and
85% ee. As a surrogate for p-methoxybenzaldehyde, p-acetoxy-
benzaldehyde 1d will give the homoallylic amine 15d in an
improved induction of 93% ee. The asymmetric inductions were
measured in a separate reaction in which the corresponding
imine 13 was isolated and fully characterized (see SI).
A lacuna in the only existing method for the asymmetric
catalytic amino-allylation of aldehydes is the subclass of
aliphatic aldehydes.3 Thus, we were pleased to find that the
optimized protocol developed for the aromatic aldehydes in
Table 3 could be directly applied to aliphatic aldehydes and
excellent asymmetric inductions (90ꢀ95% ee) for a variety of
unbranched and R-branched aliphatic aldehydes were ob-
served (Table 4). The only limitation encountered was with
an R,R-doubly branched aldehyde where the amine 15r was
obtained in only 72% ee.
Coniine, the hemlock alkaloid, contains a piperidine ring,
and in Scheme 1 we illustrate how the asymmetric catalytic
amino-allylation of n-butanal can be utilized in its synthesis.
The chiral center is installed in acyclic amine 15m, and the
piperidine ring is closed using a metathesis reaction. The ring-
closing metathesis reaction has been previously employed in
the synthesis of coniine; however, in all of those syntheses, the
chiral center was installed via a chiral auxiliary.21 Reductive
cleavage of the benzyl group and saturation of the double bond
gives coniine in 78% yield for the last three steps. This synthesis
was also chosen to demonstrate how the amine 14 and the
VANOL ligand can be recycled. The amino-allylation of n-
butanal was carried out on 10 mmol scale, and after the
hydrolysis of the imine 13m, the aryl ketone 16 was isolated
from the reaction in 92% yield and the VANOL could be
recovered in 86% yield. 16 could be converted back to 14 in
87% yield in one pot where an allyl Grignard was added directly
to the NꢀH imine which was generated in situ by treatment of
16 with ammonia and titanium tetrachloride.22
The spiro-boroxinate 9 is the catalyst for aziridinations and
heteroatom DielsꢀAlder reactions of imines,7 but in the present
case it is suspected that the catalyst for the aminoallylation is a
boroxinate that has incorporated a molecule of benzoic acid.
Further studies are ongoing to determine not only the structure
and function of the active catalyst for the aminoallylation but also
the synthetic applications of this practical method for the catalytic
asymmetric aminoallylation of aldehydes.
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’ ASSOCIATED CONTENT
(5) Kim, H.; Choi, D. S.; Yen, C. P.-H.; Lough, A. J.; Song, C. E.;
Chin, J. Chem. Commun. 2008, 1335–1337.
S
Supporting Information. Synthetic procedures and spec-
(6) For applications of Kobayashi's method in total synthesis, see:
(a) F€urstner, A.; Korte, A. Chem.—Asian J. 2008, 3, 310–318. (b)
Nishikawa, Y.; Kitajima, M.; Takayama, H. Org. Lett. 2008,
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Takayama, H. Tetrahedron 2009, 65, 1608–1617.
b
tral data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(7) For studies on the catalyst structure, see: (a) Hu, G.;
Huang, L.; Huang, R. H.; Wulff, W. D. J. Am. Chem. Soc. 2009,
131, 15615–15617. (b) Hu, G.; Gupta, A. K.; Huang, R. H.; Mukherjee,
M.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 14669–14675. (c) Vetticatt,
M. J.; Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13104–13107.
(8) (a) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121
5099–5100. (b) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000,
39, 4518–4521. (c) Loncaric, C.; Wulff, W. D. Org. Lett. 2001,
3, 3675–3678. (d) Patwardan, A.; Pulgam, V. R.; Zhang, Y.; Wulff,
W. D. Angew. Chem., Int. Ed. 2005, 44, 6169–6172. (e) Deng, Y.; Lee,
Y. R.; Newman, C. A.; Wulff, W. D. Eur. J. Org. Chem. 2007, 2068–
2071. (f) Lu, Z.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007,
129, 7185–7194. (g) Zhang, Y.; Desai, A.; Lu, Z.; Hu, G.; Ding, Z.; Wulff,
W. D. Chem.—Eur. J. 2008, 14, 3785–3803. (h) Zhang, Y.; Lu, Z.; Desai,
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Gupta, A. K.; Lu, Z.; Zhang, Y.; Wulff, W. D. J. Org. Chem. 2010,
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Corresponding Author
Wulff@chemistry.msu.edu
’ ACKNOWLEDGMENT
This work was supported by NSF Grant CHE-0750319.
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3
Supporting Information and in ref 8i.
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