Intramolecular [3 + 2]-cycloadditions of azomethine ylides derived from secondary amines via redox-neutral C-H functionalization

Article abstract of DOI:10.1021/ol502918g

Azomethine ylides are accessed under mild conditions via benzoic acid catalyzed condensations of 1,2,3,4-tetrahydroisoquinolines or tryptolines with aldehydes bearing a pendent dipolarophile. These intermediates undergo intramolecular [3 + 2]-cycloadditio

Full text of DOI:10.1021/ol502918g

Letter
pubs.acs.org/OrgLett
Intramolecular [3 + 2]-Cycloadditions of Azomethine Ylides Derived
from Secondary Amines via Redox-Neutral C−H Functionalization
Kempegowda Mantelingu, Yingfu Lin, and Daniel Seidel*
Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United
States
S
* Supporting Information
ABSTRACT: Azomethine ylides are accessed under mild
conditions via benzoic acid catalyzed condensations of 1,2,3,4-
tetrahydroisoquinolines or tryptolines with aldehydes bearing a
pendent dipolarophile. These intermediates undergo intra-
molecular [3 + 2]-cycloadditions in a highly diastereoselective
fashion to form polycyclic amines with four new stereogenic
centers. Challenging substrates such as piperidine, morpholine, and thiomorpholine undergo the corresponding reactions at
elevated temperatures.
[3 + 2]-Cycloadditions of azomethine ylides, in particular when
performed in an intramolecular setting, are ideally suited for the
purpose of rapidly constructing highly substituted polycyclic
amines.1 Among the methods that are available to generate
nonstabilized azomethine ylides in situ, these dipolar species are
most frequently prepared via decarboxylative condensation of
aldehydes with amino acids such as proline and sarcosine.1
Examples of azomethine ylide formation from simple,
unfunctionalized cyclic amines and their subsequent dipolar
cycloadditions remain rare and require relatively high reaction
temperatures for even the most activated amines such as
1,2,3,4-tetrahydroisoquinoline (THIQ). Here we report a
method to access azomethine ylides from a range of simple
secondary amines and their application to intramolecular [3 +
2]-cycloadditions.
dramatically, possibly paving the way for the development of
asymmetric variants.
We set out to identify the mildest conditions possible under
which the reaction of aldehyde 1b with THIQ would proceed
with a synthetically useful rate (Table 1). A reaction conducted
a
Table 1. Evaluation of Reaction Conditions
PhCOOH
(mol %)
molecular
sieves
temp
[°C]
time
[h]
2b, yield
(%)
entry
Given our continuing interest in developing methods for the
redox-neutral α-C−H bond functionalization of amines,2−6 we
were inspired by seminal studies of Grigg et al., who showed
that THIQ reacts with aldehyde 1a to form polycyclic amine 2a
via nonstabilized azomethine ylide 3 (Scheme 1).7,8 Although
1
−
−
−
−
−
−
−
3 Å
3 Å
3 Å
3 Å
4 Å
3 Å
3 Å
3 Å
3 Å
reflux
reflux
100
80
24
2
63
84
72
75
82
NR
67
65
NR
91
89
92
96
68
94
2
20
20
20
20
20
−
3
2
4
3
5
60
24
24
16
24
24
2
6
50
Scheme 1. Pioneering Work by Grigg and Co-workers
7
reflux
70
8
−
−
9
60
10
11
12
13
14
15
20
20
20
20
10
50
60
60
2
50
3
rt
12
18
8
rt
rt
this transformation requires relatively high reaction temper-
atures (reflux in xylenes), product 2a was obtained as a single
diastereomer. The rate limiting step of this reaction is thought
to be the generation of the azomethine ylide 3.7 If conditions
could be identified that would allow for the generation of the
required azomethine ylide under milder conditions, the scope
and applicability of such transformations could be expanded
a
Reactions were performed with 0.5 mmol of 1b and 1.2 equiv of
THIQ. Yields are isolated yields of chromatographically purified
compounds.
Received: October 2, 2014
© XXXX American Chemical Society
A
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Letter
under reflux in toluene required 24 h to reach completion and
provided [3 + 2]-cycloaddition product 2b in 63% yield (Table
1, entry 1). This finding is in excellent agreement with the
studies of Grigg and co-workers,7 with the increase in reaction
time being fully expected based on the reduction in reaction
temperature (138 vs 111 °C). As it has been shown that
benzoic acid facilitates amine α-functionalization via inter-
mediate azomethine ylides,2d we tested this compound as an
additive. Indeed, benzoic acid used at a 20 mol % loading led to
marked rate acceleration with the reaction being completed
after 2 h (Table 1, entry 2). In addition, 2b was obtained with
an increased yield of 84%. It was found that the reaction
proceeded efficiently at temperatures down to 60 °C (Table 1,
entries 3−5). However, little product formation was observed
after 24 h in an experiment that was conducted at 50 °C (Table
1, entry 6).
Scheme 2. Substrate Scope for the [3 + 2]-Cycloaddition
with Benzylic Amines
In another set of experiments, we evaluated the effect of 3 Å
molecular sieves (3 Å MS) on the reaction rate (Table 1,
entries 7−9). Compared to the reaction without additives
(Table 1, entry 1), addition of 3 Å MS resulted in a marked
reduction of reaction time and a slight increase in yield (Table
1, entry 7). The reaction still progressed with a satisfactory rate
down to 70 °C, but stalled at 60 °C (Table 1, entries 8, 9). A
powerful cooperative effect was observed when the title
reaction was conducted at 60 °C in the presence of both
benzoic acid (20 mol %) and 3 Å MS. These conditions allowed
for the isolation of 2b in 91% yield after only 2 h (Table 1,
entry 10, compare to entry 5). The use of 4 Å MS in an
otherwise identical experiment gave very similar results (Table
1, entry 11). Remarkably, the reaction was found to proceed
efficiently even at room temperature. In fact, the highest yield
of 2b (96%) was observed in this instance (Table 1, entry 13).
A reduction in the loading of benzoic acid to 10 mol % had a
negative effect on the yield of 2b (Table 1, entry 14), whereas
an increase to 50 mol % did not offer any significant advantages
over the 20 mol % catalyst loading (Table 1, entry 15).9
Reactions of THIQ with a range of aldehydes derived from
differently substituted salicylaldehydes were evaluated under
the optimized conditions (Scheme 2). In all cases, products
were obtained in good yields at room temperature or slightly
elevated temperatures (products 2b−h). Importantly, other
benzylic amines including 6,7-dimethoxy-THIQ, tryptoline,
isoindoline, and 3-pyrroline also underwent the title reaction
under equally mild conditions. Interestingly, even sterically
demanding 1-aryl THIQ’s and a 1-aryl-tryptoline readily
participated in the reaction sequence to generate polycyclic
amines containing tetrasubstituted carbon centers (products
2q−s). Finally, the oxygen linker present in all products
discussed so far could be replaced with nitrogen or carbon
linkers (e.g., products 2t and 2u). Notably, in all cases, products
were isolated as single diastereomers.
In order to explore the regioselectivity of the dipolar
cycloaddition with nonsymmetrical amines, the reaction was
conducted with 2-substituted pyrrolidines (Scheme 4). A
reaction with 2-methylpyrrolidine resulted in the formation of
the two diastereomeric products 5a and 5b in an approximately
5:1 ratio. Interestingly, no regioisomeric product was observed
that would have resulted from the functionalization of the C−H
bond α to the methyl group in 2-methylpyrrolidine. This
preference for the functionalization of a secondary over an
electronically favorable tertiary C−H bond is presumably due
to sterical reasons. Slightly higher overall yields were observed
in the related reaction with 2-phenylpyrrolidine. Here, two
regioisomeric products 6a and 6b were obtained in 52% and
25% yield, respectively, amounting to a 2-fold preference for
the functionalization of a secondary over an electronically
favorable tertiary benzylic C−H bond.
The scope of the [3 + 2]-cycloaddition could be readily
expanded to nonbenzylic amines (Scheme 3). Not surprisingly,
higher reaction temperatures were found to be required for
these more challenging substrates. While pyrrolidine was
sufficiently reactive at reflux temperature in toluene,10 superior
results were obtained under microwave conditions. Following a
reaction time of 30 min at 160 °C, product 4a was obtained in
82% yield. Under similar conditions, piperidine, azepane,
morpholine, thiomorpholine, and indoline2i also underwent
the corresponding [3 + 2]-cycloadditions. Other aldehydes
including those with nitrogen or carbon linkers also
participated in efficient product formation.
Lastly, we wanted to establish whether a stereospecific [3 +
2]-cycloaddition could be accomplished with a chiral non-
racemic amine substrate, as this would add further value to this
type of transformation. To this end, enantioenriched (S)-3-
isopropyl-THIQ (88% ee)11 was allowed to react with aldehyde
1b (Scheme 5). In the event, product 7 was isolated as a single
B
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Letter
Scheme 3. Substrate Scope for the [3 + 2]-Cycloaddition
with Less Reactive Amines
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data, including
X-ray crystal structures of products 2g, 2q, 4a, and 5a (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: seidel@rutchem.rutgers.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the NIH−NIGMS (R01GM101389-01)
is gratefully acknowledged. K.M. acknowledges UGC, New
Delhi for a Raman Postdoctoral Fellowship. We thank Dr. Tom
Emge (Rutgers University) for crystallographic analysis.
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Scheme 5. Asymmetric Variant of the [3 + 2]-Cycloaddition
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