Formation of N-alkylpyrroles via intermolecular redox amination

Article abstract of DOI:10.1021/ja907357g

(Chemical Equation Presented) A wide variety of aldehydes, ketones, and lactols undergo redox amination when allowed to react with 3-pyrroline in the presence of a mild Bronsted acid catalyst. This reaction utilizes the inherent reducing power of 3-pyrrol

Full text of DOI:10.1021/ja907357g

Published on Web 11/03/2009
Formation of N-Alkylpyrroles via Intermolecular Redox Amination
Nirmal K. Pahadi, Miranda Paley, Ranjan Jana, Shelli R. Waetzig, and Jon A. Tunge*
Department of Chemistry, The UniVersity of Kansas, 2010 Malott Hall, 1251 Wescoe Hall DriVe, Lawrence, Kansas 66045
Received August 31, 2009; E-mail: tunge@ku.edu
Redox isomerization reactions are of particular interest because they
exhibit perfect atom economy, and they often utilize the inherent
reducing power of hydrogen that is embedded in molecules to effect
reduction of other functional groups.1-3 In doing so, redox isomer-
izations are able to circumvent the requirement for exogenous reducing
agents, which tend to be high energy reagents. The power of redox
isomerizations is arguably increased when it is used in conjunction
with C-X bond-forming reactions. The Tishchenko reaction is a classic
example of such a coupling reaction that has been proposed to proceed
via an intermediate redox isomerization.2 More recently, Seidel has
demonstrated several intriguing reactions where an intramolecular
redox reaction is used to effect a reductive amination in concert with
a second C-N bond forming reaction (eq 1).3 Herein, we report a
related, acid-catalyzed intermolecular redox amination that takes
advantage of the inherent reducing power of 3-pyrroline (eq 2).
Ultimately, redox isomerization can be used to form N-alkyl pyrroles
via reductive amination, a reaction that cannot typically occur since
pyrrole is a weak N-nucleophile. Moreover, the mild conditions, atom-
economy, and operational simplicity of the redox amination reported
herein make redox amination a viable alternative to more standard
syntheses of N-alkyl pyyroles.4
under air was problematic due to background oxidation of 3-pyr-
roline to pyrrole (entry 4). Having established that the reaction was
catalyzed by Brønsted acids, we turned our attention to the use of
milder acids. Indeed, acetic acid and benzoic acid are both
competent catalysts for the transformation and can be used
interchangeably. While reactions that were run with 1:1 pyrroline/
aldehyde did not completely consume the aldehyde within the
allotted reaction time, the yields of the reactions were still good
(entries 5, 8, and 11). Ultimately, the use of 1.5 equiv of pyrroline
allowed full conversion of starting material within a shorter time
and provided a slightly higher product yield (entry 10 vs 11).8
Next, the scope of the benzoic acid catalyzed reaction was
investigated. It was gratifying to find that both aliphatic and
aromatic aldehydes were good partners for the redox amination
(entries 1-5, Table 2). Moreover, an R,ꢀ-unsaturated aldehyde
formed the allylic pyrrole, albeit in moderate yield (entry 5). In
addition to aldehydes, aliphatic and aromatic ketones are excellent
substrates (entries 6-16). However, the ketone substrates usually
required longer reaction times than the corresponding aldehydes.
It is noteworthy that the mild acidic conditions are compatible with
a variety of functional groups including alkene, nitrile, nitro, ether,
CF3, and acetal groups. Lastly, the redox amination avoids
stoichiometric strong bases that are typically associated with the
N-alkylation of pyrroles.4 Thus, we can access products that would
be highly prone to elimination if alkylation of a basic pyrrole anion
Table 1. Bronsted Acid Catalyzed Redox Amination
Initially, we were interested in performing an intramolecular
variant of a rearrangement reaction described by Murahashi.5
However, rather than the intended product, the alkyl pyrrole 1a
was isolated in 25% yield (eq 3). Since such a reductive amination
to form aromatic amines is a potentially powerful synthetic method,
we chose to investigate the reaction further. Literature searches
reveal that Cook discovered an analogous thermal condensation of
3-pyrroline with cyclohexanone at 140 °C in xylene to produce
N-cyclohexylpyrrole in 47% yield.6,7 Unfortunately, other ketones
provided even poorer yields. Since our reaction appeared to take
place under milder conditions, we set our sights on developing a
catalytic reaction that would have broad utility.
To begin, reactions were performed to determine which species
in the original reaction mixture was responsible for catalyzing this
transformation. As can be seen from Table 1, CF3CO2H effected
the reaction alone (entry 3), and Pd(PPh3)4 was somewhat detri-
mental to the reaction (entry 2). Moreover, performing the reaction
entry
conditions
time (h)
yield (%)a
1
2
3
4
5
6
7
8
no catalyst
14
16
14
24
24
5
24
12
12
12
24
24
24
<5
25
83
<5
85b
25
85
85b
86
88
80b
<5
50
Pd(PPh3)4 (5 mol %)TFA (10 mol %)
TFA (50 mol %), N2
TFA (50 mol %), air
TFA (10 mol %), 0.2 mL tol
CH3CO2H (50 mol %)
CH3CO2H (50 mol %)
CH3CO2H (10 mol %), 0.2 mL tol
PhCO2H (10 mol %)
PhCO2H (10 mol %), 0.2 mL tol
PhCO2H (10 mol %), 0.2 mL tol
Amberlyst-15 (10 mol %)
p-TsOH
9
10
11
12
13
a Isolated yields of reaction between 3-pyrroline (0.75 mmol) and
aldehyde (0.5 mmol) in 0.5 mL of toluene unless otherwise stated. b 0.5
mmol pyrroline and aldehyde.
9
16626 J. AM. CHEM. SOC. 2009, 131, 16626–16627
10.1021/ja907357g CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Redox Amination of Lactols and Chromanolsa
Table 2. Reaction Scopea
a All reactions were run with 0.5 mmol of lactol, 0.75 mmol of
3-pyrroline, and 0.05 mmol of PhCO2H in 0.2 mL of toluene at 110 °C.
utilizes the inherent reducing power of 3-pyrroline to perform the
equivalent of a reductive amination to form alkyl pyrroles. In doing
so, the reaction avoids stoichiometric reducing agents that are
typically associated with reductive aminations. Moreover, the redox
amination protocol allows access to alkyl pyrroles that are not
available via standard reductive amination.
Acknowledgment. We the National Institute of General Medical
Sciences (1R01GM079644) and the KU Chemical Methodologies
and Library Development Center of Excellence, (P50 GM069663).
M.P. thanks the NSF-REU program (CHE-0649246) for support.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.l2;&-3q
a Reactions between 0.5 mmol of aldehyde or ketone and 0.75 mmol
of 3-pyrroline in 0.2 mL toluene with 0.05 mmol of PhCO2H at 110 °C.
References
(1) Recent reactions that proceed via redox isomerization: (a) Verboom, W.;
with a bromoalkane were attempted (entries 6-16). Finally, while
we have initially focused on the scope of aldehydes and ketones
that undergo redox amination with 3-pyrroline, the concept applies
to other pyrrolines as well. For example, 3-phenyl-3-pyrroline
readily participates in the reaction, providing the substituted pyrrole
1q in high yield (entry 17). Dehydroproline methyl ester and 2,5-
dimethyl-3-pyrroline provide high yields in the reaction with
aldehydes as well (entries 18-20); however the sterically bulky
2,5-dimethylpyrroline failed to react with ketone substrates such
as acetophenone and 4-phenyl-2-butanone.
Having demonstrated that the reaction has significant scope, it
was posited that such a reaction may allow us to engage lactols to
form ring-opened pyrrole conjugates (Table 3). Interestingly,
treatment of five- and six-membered lactols under our standard
reaction conditions produced the δ-hydroxy pyrroles in good yield
(entries 1-3). Next, we turned our attention to the redox amination
of chromanols (entries 4-6). It was particularly gratifying to
observe good yields of the pyrrolyl phenols since our previous
efforts to generate compounds of this chemotype by more standard
acyl substitution and reduction chemistry failed.9
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$52/g) and readily oxidized by air.
In conclusion, a wide variety of aldehydes, ketones, and lactols
undergo redox amination when allowed to react with 3-pyrrolines
in the presence of a mild Brønsted acid catalyst. This reaction
(9) Li, K.; Tunge, J. A. J. Org. Chem. 2008, 73, 8651–8653.
JA907357G
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