Redox-neutral α,β-difunctionalization of cyclic amines

Article abstract of DOI:10.1002/anie.201311165

In contrast to the continuously growing number of methods that allow for the efficient α-functionalization of amines, few strategies exist that enable the direct functionalization of amines in the β-position. A general redox-neutral strategy is outlined for amine β-functionalization and α,β-difunctionalization that utilizes enamines generated insitu. This concept is demonstrated in the context of preparing polycyclic N,O-acetals from simple 1-(aminomethyl)-β-naphthols and 2-(aminomethyl)-phenols. An unprecedented α,β-difunctionalization reaction of amines affords polycyclic N,O-acetals from simple 1-(aminomethyl)-β-naphthols or 2-(aminomethyl)-phenols. These transformations are redox-neutral and proceed in the absence of any additives.

Full text of DOI:10.1002/anie.201311165

Angewandte
Chemie
DOI: 10.1002/anie.201311165
À
C H Functionalization
Redox-Neutral a,b-Difunctionalization of Cyclic Amines**
Weijie Chen, YoungKu Kang, Richard G. Wilde, and Daniel Seidel*
Abstract: In contrast to the continuously growing number of
methods that allow for the efficient a-functionalization of
amines, few strategies exist that enable the direct functionali-
zation of amines in the b-position. A general redox-neutral
strategy is outlined for amine b-functionalization and a,b-
difunctionalization that utilizes enamines generated in situ.
This concept is demonstrated in the context of preparing
polycyclic N,O-acetals from simple 1-(aminomethyl)-b-naph-
thols and 2-(aminomethyl)-phenols.
neous a,b-difunctionalization of amines via transient enam-
ines.
Classic organic transformations, such as the Strecker and
Mannich reactions, involve the addition of a nucleophile to an
iminium ion 1 generated in situ to result in the formation of
products of type 2 (Scheme 1). We have developed a strategy
that averts the traditional reaction pathway by incorporation
of an isomerization step, allowing for amine a-functionaliza-
tion and the generation of products with the general structure
5 (Scheme 1). These redox transformations are thought to
involve the intermediacy of azomethine ylides 3 and endocy-
clic iminium ions 4. Simple carboxylic acids have been found
W
hile oxidative approaches continue to dominate the
[1]
À
vibrant field of amine a-C H bond functionalization,
redox-neutral methods continue to establish themselves as
complementary strategies and viable alternatives.[2] Increas-
ingly complex structures can be built efficiently from simple
À
to catalyze a diverse set of amine a-C H bond functionaliza-
tions, including a-cyanation,[4f] a-phosphine oxide forma-
tion,[4j] and a-arylation.[4k] Copper carboxylates have been
found to catalyze the a-alkynylation[4g] of amines. While
considering new variants of these transformations, we recog-
nized an opportunity to fundamentally alter the course of
these reactions. Specifically, we reasoned that under appro-
priate conditions, intermediates 4/4’ may provide access to
endocyclic enamines 6 by simple loss of HX. Enamines 6 are
valuable precursors that could be utilized in a wide range of b-
functionalization and a,b-difunctionalization reactions.
À
starting materials by replacing existing amine a-C H bonds
without requiring pre-functionalization or the use of external
oxidants or reductants. Whereas many redox-neutral amine a-
functionalizations involve hydride shifts or sigmatropic H-
transfer steps,[3] we have developed an alternative approach
that involves azomethine ylides as reactive intermediates
(Scheme 1).[4–6] In stark contrast to amine a-functionalization,
methods that allow the direct b-functionalization of amines
remain rare and typically require precious metal catalysts.[7–10]
Herein we disclose a new strategy that enables the simulta-
In the course of attempting to expand the scope of our
recently reported amine a-arylation method,[4k] we discovered
a unique opportunity to realize the first example of a redox-
neutral amine a,b-difunctionalization. Specifically, we were
curious to learn whether it would be possible to isomerize
compound 2a to the regioisomeric product 5a. An experi-
ment in which a solution of compound 2a was heated in
toluene under microwave irradiation at 1508C for 15 min in
the presence of benzoic acid (20 mol%) did not result in any
reaction, and starting material was recovered in essentially
quantitative yield. However, upon increasing the temperature
to 2008C, the expected isomerization was indeed observed,
giving 5a and 2a in an approximately 4:1 ratio, albeit in low
yields [Eq. (1)]. Interestingly, the main product of this
reaction was the unusual N,O-acetal 7a, which was isolated
Scheme 1. Concepts for the redox-neutral amine a-functionalization, b-
functionalization, and a,b-difunctionalization.
[*] W. Chen, Dr. Y. Kang, Dr. R. G. Wilde, Prof. Dr. D. Seidel
Department of Chemistry and Chemical Biology, Rutgers, The State
University of New Jersey
Piscataway, NJ 08854 (USA)
E-mail: seidel@rutchem.rutgers.edu
Homepage: http://seidel-group.com/
[**] Financial support from the NIH-NIGMS (R01GM101389-01) is
gratefully acknowledged. We thank Dr. Tom Emge for crystallo-
graphic analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201311165.
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as a single diastereomer in 78% yield[11] (relative configu-
ration established by X-ray crystallography).[12–15]
The formation of product 7a is consistent with the
intermediacy of an endocyclic enamine, corresponding to
proposed compound 6 (Scheme 1). Considering that the
formation of 7a from 2a requires the incorporation of one
unit of benzaldehyde (or a benzaldehyde equivalent), we
performed the reactions outlined in Equation (2). Exposure
of 2a to a small excess of benzaldehyde (1.1 equiv) yielded 7a
in 78% yield for a reaction conducted in the presence of
benzoic acid (20 mol%). Interestingly, the use of benzoic acid
as a catalyst was not required. In fact, in the absence of any
additive, 7a was obtained in an improved yield of 81%.
With the goal of establishing the course of this intriguing
transformation, we performed the experiments shown in
Scheme 2. When 2a was allowed to react with 4-chloroben-
zaldehyde, N,O-acetal 7b was isolated as the only product in
82% yield [Eq. (3)]. The complementary reaction of 2b and
benzaldehyde afforded regioisomeric N,O-acetal 7c in 75%
yield [Eq. (4)].
Scheme 3. Substrate scope for the a,b-difunctionalization/N,O-acetal
formation. Reactions were performed on a 0.5 mmol scale; substrates
containing pyrrolidine and piperidine/morpholine moieties were
heated at 200 and 2508C, respectively. Yields are combined yields of
both diastereomers (if any); the major diastereomer is shown.
Scheme 2. Experiments designed to determine the course of the
annulation reaction and proposed mechanism.[18]
Based on the outcome of these experiments, we propose
the reaction mechanism shown in Scheme 2. Upon heating,
2b reversibly fragments into pyrrolidine and ortho-quinone
methide 8. Hydrogen-bonding between the nitrogen atom and
the naphthol hydroxy group, as previously observed in X-ray
crystal structures of related compounds,[16] is expected to
facilitate this step. The released pyrrolidine is intercepted by
benzaldehyde to eventually form enamine 9 via the sequence
of events detailed in Scheme 1. The formation of N,O-acetal
7c from 8 and 9 is consistent with a diastereoselective hetero-
Diels–Alder reaction (for example, via 10), although a step-
wise pathway cannot be ruled out.
hydes. The expected products were obtained in moderate to
good yields following a reaction time of just 15 min. Good to
excellent diastereoselectivities were observed in most instan-
ces. Notably, substrates incorporating piperidine, morpholine,
thiomorpholine, and piperazine moieties readily participated
in the a,b-difunctionalization. This is despite the fact that
these heterocycles are typically challenging substrates for
À
redox-neutral amine a-C H bond functionalization.
Given that 1-(aminomethyl)-b-naphthols such as 2a can
be easily formed from the corresponding amine, b-naphthol,
and aldehyde,[17] we were curious to learn whether the amine
N-alkylation/a,b-difunctionalization could be performed as
a one-pot process simply by employing two equivalents of the
aldehyde. To also evaluate the potential scalability of such
a process, a test reaction was conducted on a 5 mmol scale
[Eq. (6)]. Gratifyingly, treatment of a 1:2.1:1 mixture of
The scope of the N,O-acetal formation was then examined
(Scheme 3). Gratifyingly, a number of 1-(aminomethyl)-b-
naphthols and 2-(aminomethyl)-phenols readily underwent
the reaction with benzaldehyde and other aromatic alde-
2
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Keywords: azomethine ylides · C H functionalization ·
enamines · heterocycles · redox neutrality
.
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Scheme 4. Product modification.
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a previous report by Maulide et al. that nicely demonstrated
the utility of N-aryl N,O-acetals in reactions with various
nucleophiles,[3r] 7e also readily engaged Grignard reagents to
form the a,b-disubstituted products 12 and 13 in excellent
yields.
In conclusion, we have developed an unprecedented
redox-neutral a,b-difunctionalization cascade reaction of
simple cyclic amines. Polycyclic N,O-acetals are now available
in just two steps from cheap commercial materials via an
annulation of transient enamines. We anticipate widespread
application of the method described herein and the emer-
gence of related processes.
Experimental Section
General procedure for the redox-neutral a,b-difunctionalization of
amines: A 10 mL microwave reaction tube was charged with a 10 ꢀ
8 mm SiC passive heating element, the 1-(aminomethyl)-b-naphthol
or 2-(aminomethyl)-phenol (0.5 mmol, 1 equiv), toluene (2 mL), and
the aldehyde (0.55 mmol, 1.1 equiv). The reaction tube was sealed
with a Teflon-lined snap cap, and heated in a microwave reactor at
2008C (200 W, 70–100 psi, for substrates containing a pyrrolidine
moiety) or 2508C (200 W, 150–200 psi, for substrates containing
piperidine/morpholine moieties) for 15 min. After cooling with
compressed air flow, the solution was transferred to a 50 mL round-
bottom flask. The solvent was then removed under reduced pressure
and the residue was purified by silica gel chromatography.
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Received: December 23, 2013
Published online: && &&, &&&&
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4
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Communications
À
C H Functionalization
W. Chen, Y. Kang, R. G. Wilde,
D. Seidel*
&&&& — &&&&
Redox-Neutral a,b-Difunctionalization of
Cyclic Amines
An unprecedented a,b-difunctionaliza-
tion reaction of amines affords polycyclic
N,O-acetals from simple 1-(amino-
phenols. These transformations are
redox-neutral and proceed in the absence
of any additives.
methyl)-b-naphthols or 2-(aminomethyl)-
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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