Intramolecular Redox-Mannich Reactions: Facile Access to the Tetrahydroprotoberberine Core

Article abstract of DOI:10.1002/chem.201501667

Cyclic amines such as pyrrolidine undergo redox-annulations with 2-formylaryl malonates. Concurrent oxidative amine α-C-H bond functionalization and reductive N-alkylation render this transformation redox-neutral. This redox-Mannich process provides regio

Full text of DOI:10.1002/chem.201501667

DOI: 10.1002/chem.201501667
Communication
&
Synthetic Methods
Intramolecular Redox-Mannich Reactions: Facile Access to the
Tetrahydroprotoberberine Core
Longle Ma and Daniel Seidel*[a]
Abstract: Cyclic amines such as pyrrolidine undergo
redox-annulations with 2-formylaryl malonates. Concur-
rent oxidative amine a-CÀH bond functionalization and re-
ductive N-alkylation render this transformation redox-neu-
tral. This redox-Mannich process provides regioisomers of
classic Reinhoudt reaction products as an entry to the tet-
rahydroprotoberberine core, enabling the synthesis of (Æ)-
thalictricavine and its epimer. An unusually mild amine-
promoted dealkoxycarbonylation was discovered in the
course of these studies.
The Reinhoudt reaction is a classic example of a redox-neutral
amine a-CÀH bond functionalization process and is thought to
occur through a 1,5-hydride shift/Mannich-type ring-closure se-
quence (e.g., 1!2, Scheme 1).[1] First reported in 1984, this
and related transformations have recently experienced a re-
newed and continuously growing interest.[2,3] This is in line
Scheme 1. Reinhoudt reaction versus redox-Mannich reaction.
with the general trend towards developing new transforma-
tions that minimize the generation of unwanted by-products
by virtue of being redox-neutral.[4] Although the majority of
methods for amine a-CÀH bond functionalization typically uti-
lize tertiary amines as starting materials,[2,5] our group has re-
cently advanced a general concept for the redox-neutral CÀH
functionalization of secondary amines.[6] This complementary
approach effectively combines a reductive N-alkylation with an
oxidative a-functionalization and involves azomethine ylides[7]
as reactive intermediates.[8] The concept has been further ex-
tended to redox-neutral b-CÀH bond functionalization via the
intermediacy of enamines.[9] Herein, we report a method that
provides access to constitutional isomers of Reinhoudt reaction
products, differing only in the position of a methylene bridge.
Products 4, obtained via intramolecular redox-Mannich reac-
tion of 3 with 1,2,3,4-tetrahydroisoquinoline (THIQ), possess
the core structure of the tetrahydroprotoberberine family of
natural products.[10]
3a[11] and pyrrolidine as the model substrates [Eq. (1)]. Accord-
ingly, 3a was exposed to three equivalents of pyrrolidine in
ethanol upon heating at reflux, conditions that were previously
developed for the formation of aminals from ortho-aminobenz-
aldehydes and pyrrolidine.[6b] Following a reaction time of
three hours during which 3a was consumed fully, a complex
mixture of unidentified polar materials was formed, and none
of the desired product 5a was observed. Instead, the unex-
pected dealkoxycarbonylated product 6 was formed in 25%
yield (see below).
We initiated our investigation of the proposed intramolecu-
lar redox-Mannich reaction by employing malonate aldehyde
Conditions that were shown previously to be applicable to
a wider range of amine redox transformations were examined
next, namely, the use of toluene as the solvent and carboxylic
acids as additives (Table 1).[6a] Exposure of 3a and pyrrolidine
(1.3 equiv) to heating at reflux in toluene in the absence of
any additives led to the consumption of 3a within 12 h
(entry 1). As before, a complex mixture of unidentified polar
materials was observed. Nevertheless, the desired product 5a
was obtained, albeit in only 5% yield. In addition, dealkoxycar-
[a] L. Ma, 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
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501667.
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Table 1. Evaluation of reaction conditions.[a]
Entry
Additive
[equiv]
T
[8C]
t
Yield
5a [%]
Yield
7 [%]
Yield
6 [%]
1
2
3
4
5
6
7
8
–
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
12 h
4 h
1 h
5
39
53
54
68
76
74
52
71
57
72
–
–
18
8
15
trace
trace
10
15
trace
trace
8
–
–
–
–
AcOH (0.2)
AcOH (1)
AcOH (5)
AcOH (10)
2-EHA (10)
2-EHA (5)
PhCO2H (10)
pivalic acid (10)
2-EHA (10)
2-EHA (10)
1.5 h
3 h
1.5 h
2 h
3 h
1 h
–
–
12
–
10
trace
9
10
11
reflux
130 [mW]
150 [mW]
45 min
10 min
Scheme 2. Scope of the intramolecular redox-Mannich reaction with pyrroli-
dine.
[a] All reactions were performed on a 0.25 mmol scale and were terminated
upon the disappearance of 3a, as was determined by TLC analysis.
bonylated product 6 was isolated in 8% yield. A dramatically
different reaction outcome was observed in the presence of
20 mol% of acetic acid (entry 2). Complete consumption of
malonate starting material occurred within four hours, and
redox-Mannich product 5a was formed in 39% yield. Further
reduction of the reaction time and increase in yield of 5a to
53% was achieved with one equivalent of acetic acid (entry 3).
In this instance, by-product 7 was isolated in 18% yield, a com-
pound formally resulting from the reaction of 5a with 6 (see
below). A further increase of the amount of acetic acid to ten
equivalents led to the isolation of 5a in 68% yield, accompa-
nied by the formation of 7 in 15% yield (entry 5). Replacement
of acetic acid for 2-ethylhexanoic acid (2-EHA) resulted in the
clean formation of 5a in 76% yield and only trace amounts of
7 (entry 6). Similar results were obtained with five instead of
ten equivalents of 2-EHA (entry 7). The use of other carboxylic
acid promoters or the application of microwave conditions did
not result in any further improvements (entries 8–11).
The optimized conditions were subsequently applied in re-
actions of various malonate-aldehydes with pyrrolidine
(Scheme 2). Starting materials with different ester groups par-
ticipated in this transformation. Ring substitution with elec-
tron-donating or -withdrawing substituents was readily tolerat-
ed. Products 5 were isolated in typically moderate to good
yields following relatively brief reaction times. Attempts to
extend the substrate scope to piperidine met with limited suc-
cess [Eq. (2)]. In order for 3a to engage in a redox-Mannich re-
action with piperidine, higher reaction temperatures were re-
Scheme 3. Intramolecular redox-Mannich reaction with THIQ and related
amines.
quired, and the best yield for product 8 was 25%. Under these
conditions, a significant amount of competing dealkoxycar-
bonylation was noted.[12]
Redox-Mannich reactions were also conducted with THIQ
and related amines, providing products that contain the tetra-
hydroprotoberberine core (Scheme 3). As expected, THIQ was
found to undergo the reaction with 3a more readily than pyr-
rolidine. The highest yield of 83% for product 9a was obtained
at 908C, using conditions otherwise identical to those utilized
in pyrrolidine-based reactions. Substituted THIQ’s and trypto-
line also underwent the title reaction. Interestingly, the related
benzazepane required higher temperatures to react with 3a,
giving 9 f in 43% yield.
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It should be noted that the reaction of 3a with THIQ was
very tolerant to deviation from the optimized conditions. In
fact, the reaction proceeded even at room temperature, albeit
slowly, using only 20 mol% of 2-EHA [Eq. (3)]. At the same cat-
alyst loading at 908C, product 9a was isolated in 79% yield
following a reaction time of three hours (not shown).[13]
An attempted redox-Mannich reaction with 3a and 1-phenyl
THIQ took an unexpected course [Eq. (4)]. Exposure of these
substrates to the standard conditions did not lead to the isola-
tion of any redox-Mannich product. Instead, product 10a was
formed in 70% yield. The formation of this lactam presumably
arises from the hydrolysis of an intermediate azomethine ylide
or iminium ion by adventitious water, followed by aminolysis
of one of the ester groups. This reactivity appears to be gener-
al for amines of this type and extends to the use of monoester
6. Employing the same reaction conditions, a tryptamine-de-
rived starting material gave rise to the formation of product
10b [Eq. (5)].
Scheme 4. Pyrrolidine b-functionalization.
addition to 5a (28% yield). Compound 7 was not observed in
this instance. Given these findings, it appears that the compet-
ing b-functionalization step occurs prior to the Mannich ring-
closure.
The unusual dealkoxycarbonylation process was also investi-
gated further (Scheme 5).[14] Remarkably, dealkoxycarbonylation
of 3a could be achieved under exceedingly mild conditions.
For example, exposure of 3a to two equivalents of piperidine
led to the isolation of dealkoxycarbonylated product 6 in 50%
yield following a reaction time of 36 h at room temperature.
The reaction remained incomplete, and no trace of 8 was ob-
served. Under otherwise identical conditions, addition of 2-
EHA (10 equiv) or use of 2-EHA (10 equiv) by itself did not lead
to any observable dealkoxycarbonylation (not shown).[15] It
should be noted that diethyl 2-phenylmalonate (12) failed to
undergo dealkoxycarbonylation to give ethyl 2-phenylacetate
(13) under a variety of conditions. In each case, even under
A number of experiments were performed to shed light on
the underlying mechanisms for by-product formation
(Scheme 4). Regarding the formation of b-functionalized prod-
uct 7, two scenarios appeared plausible. This product could be
formed either by the reaction of regular redox-Mannich prod-
uct 5a with dealkoxycarbonylated starting material 6, or b-
functionalization could take place in a prior step. To determine
which of the two pathways is operative, a mixture of 5a and 6
was exposed to reaction conditions known to facilitate the for-
mation of 7 (c.f. Table 1, entry 3). However, no 7 was isolated
in this instance. Similarly, a related experiment in which 6 was
exchanged for the more electrophilic p-chlorobenzaldehyde
failed to provide any detectable amounts of product 11. In
contrast, an experiment, in which a 1:1 mixture of malonate-al-
dehyde 3a and p-chlorobenzaldehyde were allowed to react
with pyrrolidine, resulted in the isolation of 11 in 29% yield, in
Scheme 5. Study of the dealkoxycarbonylation.
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more forcing conditions, 12 was recovered unchanged
(Scheme 5). These findings indicate, perhaps not surprisingly,
that the pendent aldehyde plays a crucial role in the dealkoxy-
carbonylation process.
Lactone 18 could then fragment into CO2 and zwitterion 19.
Subsequent hydrolysis of this species would lead to the deal-
koxycarbonylation product 6 and pyrrolidine. Azomethine ylide
16, instead of undergoing intramolecular proton transfer to
form 17, may also be protonated by external acid to form an
endocyclic iminium ion or N,O-acetal (not shown) that could
ultimately be transformed to enamine 20. This intermediate
could engage in an aldol-type reaction with 6 to give 21. Loss
of water and subsequent ring-closure provides a pathway to 7.
The redox-Mannich reaction was applied in a formal total
synthesis of (Æ)-thalictricavine[16] and the synthesis of (Æ)-epi-
thalictricavine (Scheme 7).[17] Commercially available aldehyde
22 was converted into malonate aldehyde 23 in five steps and
44% overall yield.[18] The redox-Mannich reaction of 23 with
THIQ 24 proceeded smoothly to give annulation product 25 in
87% yield. Hydrolysis of 25 with subsequent decarboxylation
provided amino acid 26 as a mixture of diastereomers that
was processed further without purification. Reduction of 26
with lithium aluminum hydride in THF gave rise to the two dia-
stereomeric alcohols 27 and 28 in 15 and 75% yield, respec-
A mechanistic rationale accounting for the formation of the
main products is presented in Scheme 6. Malonatealdehyde 3a
and pyrrolidine most likely exist in equilibrium with hemiami-
nal 14. The latter intermediate can suffer loss of water to form
zwitterion 15, which can also be considered as an ortho-qui-
noidal species (resonance structure not shown). Subsequent
1,6-proton transfer results in the formation of azomethine ylide
16. This species can participate in a second proton-transfer
step to give zwitterion 17 followed by ring-closure to provide
redox-Mannich product 5a. In analogy to our previous study
on the synthesis of benzoxazines,[6j] 2-EHA is likely involved in
one if not both proton-transfer steps and possibly in the elimi-
nation of water during the formation of 15.
Hemiaminal 14 is also likely involved in the competing deal-
koxycarbonylation, a process that could be initiated by the for-
mation of lactone 18 with concurrent elimination of ethanol.
Scheme 6. Mechanistic considerations.
Scheme 7. Synthetic applications.
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Acknowledgements
Financial support from the NIH-NIGMS (R01M101389) is grate-
fully acknowledged. We thank Dr. Tom Emge (Rutgers Universi-
ty) for crystallographic analysis.
Keywords: azomethine ylides
heterocycles · redox chemistry · synthetic methods
·
CÀH functionalization
·
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[13] Interestingly, an acid promoter was not strictly required for the reaction
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Received: April 28, 2015
Published online on July 28, 2015
Chem. Eur. J. 2015, 21, 12908 – 12913
www.chemeurj.org
12913
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