Asymmetric Petasis Borono-Mannich Allylation Reactions Catalyzed by Chiral Biphenols

Article abstract of DOI:10.1002/anie.201611332

Chiral biphenols catalyze the asymmetric Petasis borono-Mannich allylation of aldehydes and amines through the use of a bench-stable allyldioxaborolane. The reaction proceeds via a two-step, one-pot process and requires 2–8 mole % of 3,3′-Ph₂-BINOL as the optimal catalyst. Under microwave heating the reaction affords chiral homoallylic amines in excellent yields (up to 99 %) and high enantioselectivies (er up to 99:1). The catalytic reaction is a true multicomponent condensation reaction whereas both the aldehyde and the amine can possess a wide range of structural and electronic properties. Use of crotyldioxaborolane in the reaction results in stereodivergent products with anti- and syn-diastereomers both in good diastereoselectivities and enantioselectivities from the corresponding E- and Z-borolane stereoisomers.

Full text of DOI:10.1002/anie.201611332

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Communications
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International Edition: DOI: 10.1002/anie.201611332
German Edition: DOI: 10.1002/ange.201611332
Organocatalysis
Asymmetric Petasis Borono-Mannich Allylation Reactions Catalyzed
by Chiral Biphenols
Yao Jiang and Scott E. Schaus*
Abstract: Chiral biphenols catalyze the asymmetric Petasis
borono-Mannich allylation of aldehydes and amines through
the use of a bench-stable allyldioxaborolane. The reaction
proceeds via a two-step, one-pot process and requires 2–8
mole% of 3,3’-Ph2-BINOL as the optimal catalyst. Under
microwave heating the reaction affords chiral homoallylic
amines in excellent yields (up to 99%) and high enantiose-
lectivies (er up to 99:1). The catalytic reaction is a true
multicomponent condensation reaction whereas both the
aldehyde and the amine can possess a wide range of structural
and electronic properties. Use of crotyldioxaborolane in the
reaction results in stereodivergent products with anti- and syn-
diastereomers both in good diastereoselectivities and enantio-
selectivities from the corresponding E- and Z-borolane
stereoisomers.
amines and aldehydes that possess a wide range of steric and
electronic properties; thereby maximizing the potential utility
of the method. Notable asymmetric imine allylation method-
ologies use nitrogen protecting groups that can be removed
subsequent to allylation such as acyl,[7] phosphinoyl,[8] sulfo-
nyl,[9] and silyl[10] groups. Developing a reaction that would be
highly enantioselective and yet general enough to permit the
use of amines possessing different structural and electronic
properties in the imine formation step is a significant
challenge. Progress towards this goal include two notable
examples of a three- component asymmetric imine allylation
reaction employing in situ generated imines. The condensa-
tion of aldehydes, 2-hydroxyaniline, and allyl tin reagents
catalyzed by chiral scandium complexes in excellent enantio-
selectivities was reported in 2008.[16] In addition, List and co-
workers used fluorenylmethyl carbamate, aldehydes, and allyl
silane in a chiral acid catalyzed imine allylation achieving high
enantioselectivities.[17] We sought to develop a methodology
that would utilize the multicomponent strategy of the Petasis
borono-Mannich reaction, leveraging the ability to activate
boronates for nucleophilic additions using chiral diols and
biphenols developed by us[15,18] and others.[19] We envisioned
a general method that was highly enantioselective irrespec-
tive of the imine used in the reaction.
The reaction of benzaldehyde 1a with p-anisidine 2a was
first evaluated as the aldehyde and amine component in the
Petasis reaction. Performing a screen of chiral biphenol
catalysts with the pure imine identified 3,3’-Ph2-BINOL
catalyst 4 as the optimal catalyst (see Supporting Information
for details); consistent to what was observed in the asym-
metric allylborations of acyl imines.[15] Using on 2 mole % of
the catalyst was enabled by the addition of t-BuOH as an
additive to the neat reaction, an observation we made in the
asymmetric allylboration of ketones.[18f] A one-pot procedure
was subsequently developed. A mixture of benzaldehyde 1a
and p-anisidine 2a in the presence of 3 ꢀ molecular sieves
was stirred in dichloromethane at room temperature; after
concentration, to the crude aldimine was added t-BuOH, 3,3’-
Ph2-BINOL catalyst 4 and cyclic allyldioxaborolane 3. The
reaction was then subjected to microwave irradiation con-
T
he Petasis borono-Mannich reaction is a multicomponent
condensation reaction of aldehydes, amines, and boronic acid
nucleophiles.[1] The reaction products have proven useful as
building blocks for synthesis in academic and industrial
settings.[2] A specific subset of this reaction uses allyl
boronates as nucleophiles. The corresponding chiral homo-
allylic amines are also valuable building blocks for the
synthesis of biologically and pharmacologically active mole-
cules.[3,4] Considerable efforts have been devoted to the
development of
a direct enantioselective allylation of
imines.[5–14] In addition, we introduced the use of chiral
biphenols as catalysts in the enantioselective allylboration of
acyl imines.[15] However, the reaction did not leverage the
most attractive nature of the Petasis borono-Mannich reac-
tion, the multicomponent condensation giving rise to chiral
amines that have different functionality at the aldehyde and
amine component. We sought to develop a more general
approach in performing the asymmetric allyl-Mannich reac-
tion using amines and aldehydes in the imine formation step
then performing the asymmetric allylboration reaction
[Eq. (1)]. Herein, we report a highly enantioselective Petasis
borono-Mannich reaction catalyzed by chiral biphenols in
a one-pot procedure using aldehydes, amines, and allylboro-
nates.
The challenge in performing an asymmetric allylation of
imines is identifying a set of conditions that enable the use of
[*] Y. Jiang, Prof. Dr. S. E. Schaus
Department of Chemistry, Center for Molecular Discovery
Boston University
24 Cummington Mall, Boston, MA 02215 (USA)
E-mail: seschaus@bu.edu
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201611332.
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ditions, 10 Watts achieving 508C, affording the allylation
product amine 5a in 90% isolated yield and 97:3 enantio-
meric ratio (er, Scheme 1). The observed enantioselectivity
was consistent with the reaction of allyldioxaborolane with
acyl imines.[15]
We examined the scope of the Petasis allylation reaction
using p-anisidine as the amine with the objective of identify-
ing the structural and electronic parameters of the aldehyde
component that resulted in good yields and selectivities. In
general, electron-deficient aromatic aldehydes produced
excellent yields and enantioselectivities (Scheme 1, 5b–5g).
Electron-rich aromatic aldehydes were less reactive under the
optimized conditions; however, better yields were obtained
when higher catalyst loadings (4 mole%) and conventional
heating for an extended period of time (5h–5i). Hetero-
aromatic aldehydes were also determined to be good
substrates for the reaction (5k and 5l) as was 2-naphthalde-
hyde (5j). The general reaction conditions were also effective
for aliphatic aldehydes.[20] Cyclohexane-carboxaldehyde
afforded the homoallylic product 5p in excellent yield and
enantioselectivity (93% yield, 99:1 er). Notably, ethyl glyox-
ylate could be employed as an substrate, affording the chiral
a-amino ester 5s in 70% yield and 97:3 er.[21,22] Branched
aliphatic aldehydes isovaleraldehyde and pivaldehyde, while
challenging substrates for other methods, were also excellent
substrates, affording the products 3t and 3u in great
enantioselectivities (> 97:3 er) and good yields (70 and 57%
isolated yield, respectively).
We next performed experiments to assess the use of
amines possessing different electronic and steric properties in
the multicomponent condensation reaction (Scheme 2). Cy-
clohexane carboxaldehyde was chosen as a representative
aliphatic aldehyde and aryl amines were first evaluated.
Substitution at the para-position with both electron-donating
and electron-withdrawing groups resulted in similar yields
and enantioselectivities (98:2 er, Scheme 2, 6a–6d). Substi-
tution at the meta-position led to similar results in enantio-
selectivity (6e and 6 f), and 2-bromoaniline afforded ortho-
substituted homoallyl amine 6h in excellent enantiomeric
purity (99:1 er), demonstrating tolerance for substituents at
the ortho positions. 2-Naphthylamine also proved to be an
excellent substrate in the Petasis allylation reaction (6g).
However, 2-amino pyridine afforded the desired product 6i in
lower yield, even when conventional heating reaction con-
ditions were employed, attributed to the coordinating ability
of the pyridine nitrogen. However, the product was still
isolated in 50% yield and 96:4 er.
Petasis condensation products of fluorinated and oxy-
genated anilines exhibit utility in the synthesis of anti-
bacterials and antifungals.[23] Bearing this in mind condensa-
tion products 6j and 6k were obtained with excellent yields
and selectivities (98:2 er). We then evaluated the use of
aliphatic amines in the Petasis borono-Mannich reaction.
Chiral homoallylic amine products derived from aliphatic
amine Mannich allylation reactions are challenging to achieve
in high enantioselectivities,[14] although important for natural
product and bioactive molecule synthesis.[24] Higher biphenol
catalyst concentrations enabled the use of p-methoxybenzyl-
amine and allylamine in the Petasis allylation reaction,
Scheme 1. Aldehyde substrate scope.[a] [a] Unless noted otherwise, all
reactions were run in the following conditions: aldehyde (0.4 mmol),
p-anisidine (0.8 mmol) and 3 ꢀ molecular sieves (350 mg) were mixed
in CH2Cl2 (1 mL) at room temperature for 2 h then concentrated in
vacuo by rotary evaporation and high vacuum; then allylboronate
(0.6 mmol), catalyst (0.012 mmol), t-BuOH (1.2 mmol) were added
and submitted to the microwave reactor held at 10 W for 1 h.
[b] Conventional heating at 508C for 24 h. [c] 4 mole% catalyst.
affording 6l and 6m in excellent yields and enantioselectiv-
ities (> 95:5). Products such as the diolefin 6m serve as
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precursors for ring closing metathesis, utilized as building
blocks in synthesis.[25] Furthermore, aliphatic aldehydes were
also successfully used with benzylamine (6n and 6o) further
demonstrating the scope of the asymmetric Petasis borono-
Mannich allylation reaction.
We then turned our attention to the asymmetric Petasis
crotylation reaction of imines. Crotylborations are expected
to proceed through a Zimmerman–Traxler transition state
(TS), resulting in high diastereoselectivities.[6,26] However, the
stereochemical outcome of imine crotylborations can be
complicated by factors: 1) whether a boat TS[15] or a chair TS
is involved in the reaction and 2) spontaneous E/Z isomer-
ization of the imines[27] prior to crotylboration.[26] As antici-
pated, (E)-crotylboronate 7 resulted in the formation of the
anti-diastereomer 9a in high diastereo- and enantioselectivity.
Conversely, (Z)-crotylboronate 8 afforded the syn-diastereo-
mer 10a predominantly in low er yield and dr (9:1, Scheme 3).
Scheme 3. Asymmetric crotylation. [a] 2 mole% catalyst. [b] 4 mole%
catalyst. [b] 8 mole% catalyst.
The observed enantioselectivity and diastereoselectivity
was consistent with the reaction of (E)-crotyl boronate with
acyl imines.[15] In contrast, the (Z)-crotyl boronate afforded
the anticipated syn product in the present study.[26] The
observed enantioselectivity but lower diasteroselectivity and
yield for (Z)-crotylboration can be attributed to a pseudo-
diaxial interaction between the crotyl-methyl group on the
boronate and the aryl substituent of in situ isomerized Z-
imine.[26] The benzyl amine imine was also evaluated in the
crotylation reaction. The (E)- and (Z)-crotylboronate
afforded the corresponding anti- and syn-diastereomers in
excellent diastereoselectivities and enantioselectivities
Scheme 2. Amine substrate scope.[a] [a] Unless noted otherwise, all
reactions were run in the following conditions: aldehyde (0.4 mmol),
amine (0.8 mmol) and 3 ꢀ molecular sieves (350 mg) were mixed in
CH2Cl2 (1 mL) at room temperature for 2 h then concentrated in vacuo
by rotary evaporation and high vacuum; then allylboronate (0.6 mmol),
catalyst (0.012 mmol), t-BuOH (1.2 mmol) were added and submitted
to the microwave reactor held at 10 W for 1 h. [b] Conventional heating
at 508C for 24 h. [c] 4 mole% catalyst. [d] 0.4 mmol (1 equiv) amine.
[e] 8 mole% catalyst.
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Acknowledgements
The research was supported by NIH (R01 GM078240 and P50
GM067041).
Conflict of interest
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The authors declare no conflict of interest.
Keywords: boronate · enantioselective synthesis ·
imine allylation · multicomponent reactions · organocatalysis
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Manuscript received: November 18, 2016
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Organocatalysis
Aldehydes and amines are assembled
with allylboronates in a one-pot two-step
procedure to provide chiral homoallyllic
amines. The reaction is catalyzed by
chiral biphenols to afford the products in
high enantioselectivities.
Y. Jiang, S. E. Schaus*
&&& — &&&
Asymmetric Petasis Borono-Mannich
Allylation Reactions Catalyzed by Chiral
Biphenols
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!