Phosphine-catalyzed intramolecular γ-umpolung addition of α-aminoalkylallenic esters: Facile synthesis of 3-carbethoxy-2-alkyl-3- pyrrolines

Article abstract of DOI:10.1039/c2cc31347b

An array of N-tosylated α-aminoalkylallenic esters was prepared and their cyclization under the influence of nucleophilic phosphine catalysts was explored. The α-aminoalkylallenic esters were prepared through aza-Baylis-Hillman reactions or novel DABCO-me

Full text of DOI:10.1039/c2cc31347b

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COMMUNICATION
Phosphine-catalyzed intramolecular c-umpolung addition of
a-aminoalkylallenic esters: facile synthesis of 3-carbethoxy-2-alkyl-3-
pyrrolineswz
Ian P. Andrews, Brian R. Blank and Ohyun Kwon*
Received 23rd February 2012, Accepted 23rd March 2012
DOI: 10.1039/c2cc31347b
An array of N-tosylated a-aminoalkylallenic esters was prepared
and their cyclization under the influence of nucleophilic phosphine
catalysts was explored. The a-aminoalkylallenic esters were prepared
through aza-Baylis–Hillman reactions or novel DABCO-mediated
decarboxylative rearrangements of allenylic carbamates. Conversion
of these substrates to 3-carbethoxy-2-alkyl-3-pyrrolines was facilitated
through Ph3P-catalyzed intramolecular c-umpolung addition.
The propensity for 2,3-butadienoates and 2-butynoates to
undergo nucleophilic attack at their g-carbon atom is well
documented in the literature; it has been employed in the
formation of carbon–carbon, carbon–oxygen, carbon–nitrogen,
and carbon–sulfur bonds.10 Of particular value to our discussion
are intramolecular examples of this reactivity; for example, in which
a hydroxyl group tethered via the g-carbon atom of an activated
alkyne can undergo 5- or 6-exo cyclization to yield a number
of different oxygen-containing heterocycles (e.g., substituted
tetrahydrofurans, dihydrobenzopyrans, and 1,3-oxazines).10b,i
Stemming from our interest in using nucleophilic phosphine
catalysts to activate allenoates and butynoates, in this study
we explored the reactivity of electron-deficient allenes bearing
a tethered nitrogen-centered nucleophile with the aim of
facilitating intramolecular g-umpolung additions to yield 2-alkyl-
substituted-3-pyrrolines (Scheme 1).11 To the best of our knowledge,
there are no previously reported examples of this type of addition
occurring via 5-endo cyclization.
Nitrogen-containing heterocycles are ubiquitous structural
elements in the realm of natural products and pharmaceutically
relevant compounds.1 Amongst these important scaffolds,
3-pyrrolines occupy a uniquely versatile position in that they
can be further transformed into their fully saturated pyrrolidines or
more highly oxidized pyrrole and pyrrolidinone counterparts.2 Of
the various approaches toward functionalized 2,5-dihydropyrroles,
Lu’s phosphine-catalyzed [3+2] annulation of allenes and imines
has emerged as one of the premiere methodologies.2b,3 Since its
first report, this annulation has undergone many developments,
including modifications,4 applications,5 and asymmetric renditions.6
Despite the great utility of this phosphine-catalyzed allene–imine
[3+2] annulation, it has its limitations—the most evident being the
necessity for imines devoid of a-protons. This prerequisite has
limited the scope of the reaction to the use of aryl-substituted
imines. Overcoming this limitation would expand the potential use
of organocatalyzed 3-pyrroline synthesis to applications requiring
non-aryl groups substituted onto the heterocycle.7 The successful
implementation of alkyl-substituted N-sulfonyl imines was reported
only recently: used in conjunction with a Me3P-catalyzed
isomerization of 3-alkynoates or when using diphenylphosphinoyl
imines along with a highly nucleophilic peptide-based chiral
phosphine.8,9 The utility of the resultant 3-pyrrolines was
demonstrated in the formal syntheses of (ꢀ)-allosecurenine
and (+)-trachelanthamidine, respectively.8,9 The development
of new methods for forming these types of heterocycles would
be a boon to the synthetic community.
To test the proposed cycloisomerization, we required a
method for synthesizing the necessary a-aminoalkylallenoates.
For this purpose, we turned to a known tertiary amine-catalyzed
rearrangement of allylic N-tosyl carbamates and tested it on the
similar, but never before utilized, allenylic N-tosyl carbamates 3.12,13
We were pleased to discover that treatment of the allenylic
carbamates with a nucleophilic catalyst facilitated the desired
rearrangement. The reaction was best facilitated by slowly
adding the allenylic carbamate to a solution of one equivalent
of DABCO (Table 1).13 Interestingly, we isolated the allenoate
1a in the highest yield (56%) when using dimethyl sulfide as
the catalyst in MeCN.14 Dimethyl sulfide failed to provide any
desired rearrangement products from any of our other tested
substrates. The DABCO-mediated reaction was tolerant of
various alkyl groups, providing the desired products in modest
yields. The best result was realized when a methyl substituent
was present, providing the desired allenoate 1b in 65%
yield (entry 2). Extending the chain decreased the efficiency
(entries 3 and 4). The reaction also proceeded smoothly when
607 Charles E. Young Drive East, Los Angeles, USA.
E-mail: ohyun@chem.ucla.edu; Tel: 310-206-9648
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
details and NMR spectra of new compounds. See DOI: 10.1039/
c2cc31347b
Scheme 1 Phosphine-catalyzed intramolecular g-umpolung addition.
Chem. Commun., 2012, 48, 5373–5375 5373
c
This journal is The Royal Society of Chemistry 2012

Table 1 Decarboxylative rearrangements of allenylic N-tosyl carbamates
prolonged reaction time (52 h, cf. 18 h). Increasing the steric
bulk of the alkyl group generally decreased the yield and
increased the reaction time. The substrate bearing a cyclopentyl
group required a reaction for 10 days at 40 1C to reach
completion, resulting in an isolated yield of only 44% for the
desired pyrroline (entry 8). We made several efforts to minimize
the reaction time and improve the yields of the alkyl-substituted
substrates. Based on reports of added Brønsted acid/base pairs
increasing reaction efficiencies for various phosphine-catalyzed
reactions, we screened several additives for their effects.
To our delight, the addition of sodium acetate and acetic acid
(0.5 equivalents each) shortened the reaction times and generally
improved the yields (entries 9 and 10).11o,16
Entry
R
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
H
methyl
ethyl
n-pentyl
i-propyl
cyclopropyl
cyclopentyl
cyclohexyl
phenyl
1a
1b
1c
1d
1e
1f
1g
1h
1i
56b
65
56
27
52
45
45
51
0
Under the optimized conditions, we converted a number of
b0-alkyl– and b0-aryl–substituted a-aminoalkylallenic esters 1
to their corresponding dihydropyrroles 2 (Table 3). The yields
for these cycloisomerizations were generally very high. The
allenoates 1a and 1j underwent cyclizations in higher yields in
the absence of any additives (entries 1 and 10). All of the other
alkyl-substituted allenoates benefited from the combination of
catalytic Ph3P and Brønsted acid/base, cyclizing in moderate
to excellent yields. The allenoates bearing short straight-chain
alkyl units, namely methyl and ethyl groups, cyclized in 99 and
97% yields, respectively (entries 2 and 3). The presence of a
longer n-pentyl group resulted in lower reaction efficiency,
with the allenoate cyclizing in 69% yield (entry 4). Branched
alkyl groups were also tolerated well, with the isopropyl-,
cyclopropyl-, cyclopentyl-, and cyclohexyl-substituted allenoates
cyclizing in 97, 95, 85, and 93% yields, respectively (entries 5–8).
Aryl-substituted a-aminoalkylallenic esters also cyclized in high
yields (entries 9–12), with the more-electronegative 4-chlorophenyl–
and 4-cyanophenyl–substituted allenoates resulting in slightly
diminished product yields of 88 and 85%, respectively
(entries 10 and 12) relative to the more-electron-rich phenyl-
and 4-methoxyphenyl–substituted allenoates, which both cyclized
in 99% yields (entries 9 and 11).
a
b
Isolated yield after column chromatography. Dimethyl sulfide was
used as the catalyst with MeCN as the solvent.
bulkier substituents, namely isopropyl and cycloalkyl groups,
were present, albeit in slightly lower yields (entries 5–8).
Notably, when an aryl substituent was present, the reaction
yielded none of the desired product (entry 9); we could,
however, synthesize those allenoates 1 featuring an aryl group
as the R unit through aza-Baylis–Hillman reactions between
ethyl 2,3-butadienoate and aryl imines.13,15
With the requisite a-aminoalkylallenic esters in hand, we
explored their reactivity under nucleophilic catalysis (Table 2).
We were pleased to find that addition of 20 mol% of Ph3P to
the allenoate 1i in CH2Cl2 at room temperature provided the
dihydropyrrole 2i in 62% yield (entry 1). Screening of various
solvents (entries 1–5) revealed that benzene was the most
efficient reaction medium in terms of the product yield and
reaction time, providing the dihydropyrrole in 93% isolated
yield after 18 h (entry 5). Use of the more-nucleophilic n-Bu3P
markedly decreased the reaction time, but led to a dramatic
loss in product yield (entry 6). Next, we extended the reaction
to b0-alkyl–substituted a-aminoalkylallenic esters in an attempt
to access 2-alkyl–substituted dihydropyrroles. In a very gratifying
initial trial, we transformed the ethyl-substituted allenic ester into
the desired 2,5-dihydropyrrole in 92% yield (entry 7). In salient
contrast to the reaction of the phenyl-substituted derivative 1i,
the b0-ethyl–substituted allenic ester 1c required a significantly
Fig. 1 displays our proposed mechanism for the cycloisomeriza-
tion. Addition of Ph3P to the a-aminoalkylallenic ester 1 leads to
the formation of the phosphonium dienolate 4. Conversion to
Table 3 Phosphine-catalyzed intramolecular g-umpolung additions
Table 2 Optimization of the phosphine-catalyzed cycloisomerization
Entry
R
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
H
Me
Et
n-Pent
i-Pr
cyclopropyl
cyclopentyl
cyclohexyl
phenyl
4-chlorophenyl
4-methoxyphenyl
4-cyanophenyl
18
19
32
48
77
72
96
96
12
4.5
22
2
2a
2b
2c
2d
2e
2f
2g
2h
2i
87a
99
97
69
97
95
85
93b
99
88a
99
85
Entry
R
Solvent Additives
Time
Product Yielda (%)
1
2
3
4
Ph CH2Cl2 none
Ph PhMe none
Ph THF
Ph MeCN none
Ph PhH
Ph PhH
Et
Cyp PhH
Et PhH
Cyp PhH
40 h
40 h
40 h
40 h
18 h
1 h
2i
2i
2i
2i
2i
2i
2c
62
89
none
0b
0
93
29
92
44
97
85
5
none
none
none
none
6c
7
PhH
52 h
9
8
9
10
10 days 1g
2c
AcOH/NaOAc 4 days 1g
10
11
12
2j
2k
2l
AcOH/NaOAc 32 h
a
b
Isolated yield after silica gel chromatography. Recovered starting
a
b
Yield in the absence of any additives. Based on recovered starting
material (69% isolated yield).
c
material. Bu3P was used.
c
5374 Chem. Commun., 2012, 48, 5373–5375
This journal is The Royal Society of Chemistry 2012

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Fig. 1 Mechanism for the intramolecular g-umpolung addition.
the sulfonamide anion 5 via proton transfer, followed by 5-endo
cyclization, yields the phosphorous ylide 6. The well-established
equilibration between 6 and 7, followed by b-elimination of the
phosphine catalyst, furnishes the final product 2.
In conclusion, we have developed a method for the high-
yield formation of 3-carbethoxy-2-alkyl-3-pyrrolines by way
of phosphine-catalyzed cycloisomerizations of a-aminoalkylallenic
esters. The necessary substrates can be prepared in moderate yields:
for aryl-substituted allenoic esters, through aza-Baylis–Hillman
reactions; for alkyl-substituted allenoic esters, through novel
decarboxylative rearrangements of allenylic carbamates catalyzed
by a tertiary amine. This paper illustrates the first example of a
5-endo cyclization occurring via intramolecular g-umpolung
addition to an activated allene.
This research was supported by the NIH (R01GM071779,
P41GM081282).
Notes and references
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Seroquels (AstraZeneca), Nexiums (AstraZeneca), and Plavixs
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by Worldwide Sales in 2009. http://cbc.arizona.edu/njardarson/
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13 See the Supporting Informationz for details regarding reaction
optimization. Cursory attempts at employing commercially available
cinchona alkaloids for the asymmetric variant of the rearrangement
failed to produce the desired products in appreciable yields.
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5373–5375 5375