Phosphonite mediated 1,3-dipolar cycloaddition: A route to polycyclic 2-pyrrolines from imines, acid chlorides and alkenes

Article abstract of DOI:10.1039/c2cc38274a

2-Pyrrolines can be generated by the PhP(2-catechyl) mediated coupling of alkene-tethered imines and acid chlorides. This reaction proceeds via phosphorus-containing 1,3-dipoles, which undergo cycloaddition with alkenes with high stereo- and regioselectivity. The modularity of this reaction can be used to assemble a range of polysubstituted pyrrolines in one pot transformations. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2cc38274a

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Phosphonite mediated 1,3-dipolar cycloaddition:
a route to polycyclic 2-pyrrolines from imines,
acid chlorides and alkenes†
Cite this: Chem. Commun., 2013,
49, 883
Received 16th November 2012,
Accepted 5th December 2012
Marie S. T. Morin, Sara Aly and Bruce A. Arndtsen*
DOI: 10.1039/c2cc38274a
www.rsc.org/chemcomm
2-Pyrrolines can be generated by the PhP(2-catechyl) mediated substituted dipole 1 can participate in alkene cycloaddition
coupling of alkene-tethered imines and acid chlorides. This reaction with high selectivity. This has allowed the design of a general
proceeds via phosphorus-containing 1,3-dipoles, which undergo approach to assemble polycyclic 2-pyrrolines directly from
cycloaddition with alkenes with high stereo- and regioselectivity. olefin-tethered imines and acid chlorides (Fig. 2).
The modularity of this reaction can be used to assemble a range of
polysubstituted pyrrolines in one pot transformations.
Our initial studies examined the reaction of the imine 2a
(Table 1). 2a is readily accessible from salicylaldehyde, and
alkene cycloaddition would provide a route to polycyclic pyrro-
2-Pyrrolines, and their fully reduced counterpart pyrrolidines, are lines2 uncomplicated by the multiple alkene cycloadditions
common structural motifs in biologically relevant products. sometimes observed with Mu¨nchnones.14 PPh3 can react with
Examples of these range from natural products,1 structures of 2a, toluoyl chloride, followed by a base to form 1/10. However no
pharmaceutical utility2 (e.g. anti-cancer agents,3 antibiotics,4 cycloaddition is observed, and this compound simply decom-
hepatitis C inhibitors5 or antitubercular agents6), amino acid poses at high temperatures (entry 1). Similar behaviour is
derivatives,7 and others. One challenge in the use of pyrrolines observed with PCy3 and P(NMe2)3 (entries 2 and 3). We have
is their synthesis. A common approach to 2-pyrrolines is via the previously noted that electron rich phosphines do not favor the
cyclization of amine-containing precursors, such as hydroamina- amide chelation necessary for cyclization of the acyclic Wittig-
tion,8 iodoamination,9 ring expansion,10 or catalytic cyclization11 type structure 10 to its 1,3-dipole form (Fig. 1),18b which could
reactions. While effective, these require the build-up of the slow down the cycloaddition to the unactivated alkene in 2a.
correctly substituted substrate for subsequent cyclization.
Consistent with this, the more electron poor phosphite P(OPh)3
A more convergent approach to 2-pyrrolines is via [4+1]12 or reacts with these same substrates to both generate 1, and
[3+2]13 cycloaddition reactions. The latter has been exploited undergo cycloaddition to form 2-pyrroline 3a in a 46% yield
with 1,3-oxazolium-5-oxides (Mu¨nchnones),14 metallated azo- (entry 4). A similar reaction occurs with P(OCH2CF3)3 (entry 5).
methine ylides,15 isocyanoesters,16 and aziridines17 in reactions The moderate yield of 3a under these conditions arises from
with alkenes or alkynes. While alkenes and alkynes are readily the poor nucleophilicity of phosphites, which reacts slowly
available, a requirement in this case is the generation of the with the in situ generated a-chloroamide 4 (Scheme 1). The
polysubstituted 1,3-dipole or dipole precursor. As an alternative, latter can be enhanced by the addition of TMSOTf to activate 4
we have recently reported a modular approach to phosphorus- towards nucleophilic attack (X = OTf, entries 6 and 7). Alter-
dipoles of the form 1 (i.e. phospha-Mu¨nchnones). 1 is generated natively, the more nucleophilic phosphonite PhP(2-catechyl)
via the equilibrium tautomerization of amide-substituted Wittig avoids the need for this additive, and with DBU base leads to
ylides (Fig. 1). By coupling the multicomponent generation of 10 the high yield and rapid formation of 3a (entry 10).
with spontaneous cyclization, 1 can be formed in one pot, with
Pyrroline 3a is formed as a single observable diastereomer
imines, acid chlorides and phosphines as the building blocks.18 and alkene regioisomer. In considering the reaction mechanism,
Considering their ease of synthesis, we became interested in
the potential utility of 1 in pyrroline synthesis. We describe the
results of these studies below. These show that the correctly
Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal,
QC H3A 0B8, Canada. E-mail: bruce.arndtsen@mcgill.ca
† Electronic supplementary information (ESI) available: Experimental procedures
Fig. 1 Multicomponent assembly of phospha-Munchnones.
and characterization data for all new compounds. See DOI: 10.1039/c2cc38274a
¨
c
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Table 2 Diversity of one pot 2-pyrroline synthesisa
Entry Imine Acid chloride Product (% yield)
Fig. 2 Phosphine mediate approach to pyrrolines.
1
Table 1 Development of PR3 mediated pyrroline synthesisa
2b
3c
Entry
PR3
Base
Additive
Time
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
PPh3
PCy3
P(NMe2)3
(PhO)3P
(CF3CH2O)3P
(PhO)3P
(CF3CH2O)3P
PhP(2-catechyl)
PhP(2-catechyl)
PhP(2-catechyl)
LiHMDSc
LiHMDSc
LiHMDSc
DBU
DBU
DBU
—
—
—
—
—
—
—
24 h
10 h
5 h
2 h
6 hd
6 hd
2 h
0
0
0
46
46
80
67
66
36
85
4
—
TMSOTf
TMSOTf
—
—
—
DBU
Et3N
Et(iPr)2N
DBU
5d
a
2a (38 mg, 0.2 mmol), TolCOCl (34 mg, 0.22 mmol), 0.5 mL CDCl3,
b
30 min; then PR3 (0.22 mmol), 1 h; base (0.36 mmol), rt. NMR yield.
c
d
Added at ꢀ78 1C. 65 1C.
6
these both likely arise from the generation of the phosphorus-
bound intermediate 5 (Scheme 1). The large steric profile of the
PR3 unit presumably favors the cis-ring fusion upon alkene
cyclization, while slow phosphine oxide loss from 5 would allow
the selective deprotonation at C4, and lead to a single pyrroline
alkene isomer.
7e
In addition to generating 3a, since this reaction relies on
imines and acid chlorides, it is straightforward to diversify
these products. As shown in Table 2, a number of N-alkyl
substituents can be employed in the reaction, including
common protecting groups (entries 2, 9, and 11). Carbon-,
sulfur- and oxygen-containing tethers can all be employed in
this chemistry (entries 1–3), as can various aromatic spacers,
including simple phenyl, naphthyl (entry 11) and even pyrrole
units (entry 5). However, amine tethered variants of 2b are not
compatible with these conditions. The alkene can be similarly
diversified, with terminal and internal olefins both affording
8f
9f
10e
11f
a
Imine (0.20 mmol), acid chloride (0.21 mmol), 0.5 mL CHCl3, 30 min;
(2-catechyl)PPh (47.5 mg, 0.22 mmol), 1 h; DBU (45.7 mg, 0.30 mmol),
b
rt, 10 min. Reduced with NaBH(OAc)3 (0.30 mmol), 1 M HCl–ether
c
d
e
f
(0.40 mmol), 18 h. 2 h. CD3CN. 60 1C, 1 h. 0.40 mmol DBU.
Scheme 1 Mechanism of formation of 3.
c
884 Chem. Commun., 2013, 49, 883--885
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5,5-Fused ring products are also accessible (entries 4, 5). The
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(entries 5–9). Overall, this provides a modular route to prepare
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and acid chlorides, where in one pot each substituent is tuned
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Pyrrolines have been demonstrated to serve as useful
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five separate bonds generated in one pot (Scheme 2). Alter-
natively, the generation of 3 with subsequent benzoquinone
oxidation allows the overall synthesis of polycyclic pyrrole 5k.
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´
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¨
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c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 883--885 885