Dual amine and palladium catalysis in diastereo- and enantioselective allene carbocyclization reactions

Article abstract of DOI:10.1021/ol303128s

A pyrrolidine and Pd catalyzed diastereoselective carbocyclization of aldehyde and ketone-linked allenes has been developed. The cooperative organo/metal-catalyzed cyclization reaction, which presumably proceeds via an enamine intermediate, is efficient and broad in scope. Also, it has been extended to a catalytic asymmetric variant using diarylprolinol-based organocatalysts to afford substituted cyclopentane and pyrrolidine reaction products in up to 82% ee.

Full text of DOI:10.1021/ol303128s

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Dual Amine and Palladium Catalysis
in Diastereo- and Enantioselective
Allene Carbocyclization Reactions
Meiling Li, Swarup Datta, David M. Barber, and Darren J. Dixon*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, U.K.
darren.dixon@chem.ox.ac.uk
Received November 13, 2012
ABSTRACT
A pyrrolidine and Pd catalyzed diastereoselective carbocyclization of aldehyde and ketone-linked allenes has been developed. The cooperative
organo/metal-catalyzed cyclization reaction, which presumably proceeds via an enamine intermediate, is efficient and broad in scope. Also, it has
been extended to a catalytic asymmetric variant using diarylprolinol-based organocatalysts to afford substituted cyclopentane and pyrrolidine
reaction products in up to 82% ee.
Combining two or more catalytically active species in
one reaction vessel can unlock new reaction pathways for
substrates and reagents not accessible by the individual
catalysts operating alone. Working either as mutually
compatible catalyst systems in separate catalytic cycles or
in cooperative harmony during bond formation, this field
of dual catalysis is emerging as a powerful tool in organic
synthesis and is mostly evident when enamine or iminium
ion catalysis meets transition metal (ion) catalysis.1,2 Pio-
π-allylpalladium complexes.4 Similary, Kirsch et al. were
able to combine gold and amino catalysis in a carbocycli-
zation of alkyne-linked aldehydes.5 At the same time,
our group developed a one-pot, pyrrolidine- and Cu(I)-
catalyzed multistep reaction cascade sequence of R,β-un-
saturated ketones and propargylated malonates to form
cyclopentene products.6 The catalyzed cascade, which we
postulated to proceed via iminium, enamine, and metal
(ion) activation modes, was also successful with pyrroli-
dine and Ag(I), Au(I), Hg(II), or Pd(0) catalyst combina-
tions. In a continuation of this research program, we
wanted to extend our work on amine and transition metal
catalyzed carbocyclizations of alkynes to include allene-
linked ketones and aldehydes. Cyclization reactions involv-
ing carbopalladation have emerged as a powerful strategy
to construct complex carbocycles.7 Among the many CꢀC
bond formations that proceed through a Pd-catalyzed acti-
vation of allenes toward nucleophilic attack, the addition
ꢀ
neering work by Cordova demonstrated that R-allylation
of aldehydes with allyl acetates was possible using a
combination of amine and Pd catalysts.3 Later, Saicic
reported a new method for the construction of five-
or six-membered rings via organocatalyzed cyclization of
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r
10.1021/ol303128s
XXXX American Chemical Society

of activated methylene compounds8ꢀ10 has been well-
studied.
Table 1. Catalyst Identification and Reaction Optimization
Scheme 1. Concept of an Amine and Pd Catalyzed Cycloi-
somerization of Aldehyde-Linked Allenes
time conv yield
amine
PdLn
solvent
(h) (%) (%)a drb
1
2
3
4
5
6
7
8
9
pyrrolidine Pd(PPh3)4 CHCl3
16 73
45 11:1
ꢀ
Pd(PPh3)4 CHCl3
CHCl3
Pd(PPh3)4 CHCl3
16 NR
16 NR
24 60
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Accordingly, through an appropriate combination of
amine and transition metal catalysts, in particular Pd
catalysts, we believed substrates of type I could be trans-
formed into cyclic products of type III via enamine and
Pd activated intermediates such as II (Scheme 1). Further-
more, through judicious choice of the catalysts employed,
achieving good diastereo- and enantioselectivity was a real
possibility. Herein we report our findings.
pyrrolidine
piperidine
ꢀ
ꢀ
5:1
ꢀ
morpholine Pd(PPh3)4 CHCl3
24 trace
24 NR
24 NR
24 22
L-proline
L-proline
DIPA
Pd(PPh3)4 CHCl3
Pd(PPh3)4 DMSO
Pd(PPh3)4 CHCl3
Pd(PPh3)4 CHCl3
ꢀ
ꢀ
10:1
ꢀ
(R)-
24 NR
PhCH(Me)
NH2
Initial proof of reactivity studies were performed on
allene-linked aldehyde 1a using 5 mol % of Pd(PPh3)4.
Pleasingly on the first attempt, treatment of 1a with both
5 mol % Pd(PPh3)4 and 30 mol % pyrrolidine in CHCl3 at
60 °C resulted in the formation of the desired cyclic
product 2a in 45% yield with 11:1 dr (Table 1, entry 1).
Two control experiments were performed which demon-
strated that, in the absence of either the pyrrolidine or Pd
catalyst, no reaction took place (Table 1, entries 2 and 3).
These results strongly support the dual activation mecha-
nism proposal for achieving reactivity. Various amines
were then investigated. Changing pyrrolidine to piperidine
led to diminished reaction conversion and diastereoselec-
tivity (Table 1, entries 1 and 4). Only a trace amount of
product was observed when 30 mol % morpholine was
used (Table 1, entry 5), presumably because of the lower
nucleophilicity of the morpholine secondary amine. Good
diastereoselectivity was obtained using diisopropylamine
as the organocatalyst, but the reaction showed very low
conversion (Table 1, entry 8). No reaction occurred using
L-proline, even if the polar solvent DMSO was used to
improve solubility (Table 1, entries 6 and 7). Changing the
Pd catalyst from Pd(PPh3)4 to Pd(OAc)2 led to an increase
in reaction yield and diastereoselectivity (Table 1, entries 1
and 10). Screening some typical reaction solvents in
the presence of 5 mol % Pd(OAc)2 and 30 mol % pyrro-
lidine demonstrated that toluene provided the best results,
in terms of both the yield (68%) and diastereoselectivity
10 pyrrolidine Pd(OAc)2 CHCl3
11 pyrrolidine Pd(OAc)2 THF
14 100
14 100
58 13:1
51 13:1
46 13:1
32 12:1
68 13:1
42 12:1
39 10:1
46 10:1
12 pyrrolidine Pd(OAc)2 1,4-dioxane 14 100
13 pyrrolidine Pd(OAc)2 CH3CN
14 pyrrolidine Pd(OAc)2 toluene
15 pyrrolidine Pd(OAc)2 DMF
16c pyrrolidine Pd(OAc)2 toluene
17d pyrrolidine Pd(OAc)2 toluene
18e pyrrolidine Pd(OAc)2 toluene
14 100
14 100
14 100
20 100
13 100
16 20
ꢀ
ꢀ
a Isolated yields of two diastereomers. b Determined by analysis of
the crude sample by 1H NMR spectroscopy. c With 50 mol % Et3N.
d With 50 mol % benzoic acid. e With 20 mol % pyrrolidine.
(13:1 dr) (Table 1, entry 14). Lowering the pyrrolidine
percentage to 20 mol % led to a significant loss in reaction
efficiency, with only 20% conversion being observed using
toluene as solvent at 60 °C for 16 h (Table 1, entry 18).
With the optimal reaction conditions identified, a range
of allene-linked aldehyde and ketone substrates 1 were
subjected to the carbocyclization reaction. Substrates hav-
ing all-carbon chains between the carbonyl and allene units
led to the desired products in good yield and diastereo-
selectivity (Scheme 2). Substrates with geminal substituents
on the chain, such as malonates 1a and 1b, diether 1d, and
ketoester 1e, all proceeded faster than those without (1h),
presumably due to a ThorpeꢀIngold effect. An aldehyde
possessing an internal allene also afforded the desired
product with good selectivity, but after a longer reaction
time (1c). Substrates possessing a nitrogen atom in the
chain also gave the desired products with good diaste-
reoselectivity although in lower yields (1f and 1g).
Notably, subjection of cyclic ketones to the optimal con-
ditions gave the desired cyclization products, but after a
longer reaction time. In the case of the five-membered
cyclic ketone 1i, cyclization gave the product 2i in 75%
yield and 14:1 dr. The six-membered cyclic ketone 1j
afforded diastereomeric products 2j and 2k in 78% yield
with 2:1 dr.
(8) (a) Besson, L.; Gore, J.; Cazes, B. Tetrahedron Lett. 1995, 36,
3853–3856. (b) Hiroi, K.; Kato, F.; Yamagata, A. Chem. Lett. 1998,
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B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Reaction Scopea
Figure 1. Organocatalysts screened in the asymmetric variant.
Table 2. Screen of Chiral Secondary Amine Organocatalysts
a Isolated yield of diastereomers. b Determined by 1H NMR spectro-
c
scopy after flash column chromatography. 2g0 also isolated in 20%
yield (see Supporting Information). d Separable isomers.
yield
(%)a of
2a
yield
(%)a of
3a
ee
time
(h)
dr of
dr of
(%)c
of 3a
We then investigated a catalytic enantioselective variant
of the carbocyclization reaction by replacing pyrrolidine
with various chiral cyclic secondary amine organocatalysts
(Figure 1). With model substrate 1a, no reaction occurred
when proline-derived catalysts 4b and 4c were employed
(Table 2, entries 2 and 3). Pleasingly, however, the product
2a was obtained using MacMillan’s catalyst11 4d with 13:1
dr and 46% ee (Table 2, entry 4), and also using chiral
pyrrolidine 4a which afforded the product 2a with 10:1 dr
and 39% ee (Table 2, entry 1). Higher levels of asym-
metric induction were achieved using the L-proline-
derived Jørgensen/Hayashi type12 catalysts 4eꢀ4j (Table 2,
entries 5ꢀ10). A range of these catalysts with variations
in the geminal aromatic rings as well as the O-protecting
group were investigated. O-TMS protected catalyst
4f possessing 3,5-bis(trifluoromethyl)phenyl groups
out-performed catalyst 4e possessing 3,5-dimethylphe-
nyl groups (67 vs 60% ee, Table 2, entry 6 vs 5). With
a series of catalysts possessing 3,5-bis(trifluoromethyl)-
phenyl groups, the enantioselectivity improved when the
steric bulk of the silyl group was increased. For example
O-TIPS protected catalyst 4g afforded the desired prod-
uct with 84% ee and 13:1 dr (Table 2, entry 7), while
4
2ab
3ab
1
2
3
4
5
6
7
8
9
10
4a
4b
4c
4d
4e
4f
36
36
36
48
20
12
20
12
12
20
24
NR
NR
36
59
65
72
70
62
58
10:1
ꢀ
85
ꢀ
10:1
ꢀ
39
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
13:1
14:1
11:1
13:1
12:1
13:1
12:1
87
80
88
89
79
75
82
13:1
14:1
11:1
13:1
12:1
13:1
12:1
46d
60
67
84
79
79
55
4g
4h
4i
4j
a Isolated yield of two diastereomers. b Determined by 1H NMR
spectroscopy after flash column chromatography. c Determined by
chiral HPLC analysis. d Opposite enantiomer obtained.
O-TMS protected catalyst 4f only gave a product with
67% ee (Table 2, entry 6).
The scope of this enantioselective carbocyclization with
the optimal catalyst 4g is presented in Scheme 3. Diethyl
malonate 1b afforded the cyclopentane product 2b in 68%
yield and 70% ee. Internal allene 1c progressed efficiently
to give cyclized product 2c with 51% ee. N-Tosyl allene 1f
cyclized smoothly to the desired product 2f in 63% ee and
16:1 dr. The N-Boc derivative 1g afforded cyclized product
2g with good enantioselectivity (79% ee) and in moderate
yield.
(11) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.;
MacMillan, D. W. C. Science 2007, 316, 582–585.
ꢀ
(12) (a) Franzen, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.;
Kjrsgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296–
18304. (b) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew.
Chem., Int. Ed. 2005, 44, 4212–4215.
The mechanism of this new carbocyclization reaction
under dual cyclic secondary amine and Pd catalysis is
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Scope of the Enantioselective Varianta
Scheme 4. Proposed Mechanism of Secondary Amine/Pd Cat-
alyzed Carbocyclization Reaction
a Isolated yield of two diastereomers. b Determined by 1H NMR spectro-
scopy after flash column chromatography. c Determined by chiral
HPLC analysis of the purified benzoate ester derivatives. d The absolute
stereochemistry of (3R,4S)-2a was determined by single crystal X-ray
analysis of a derivative (see Supporting Information).
intriguing and worthy of further comment. From the data
obtained in Table 1, it is most likely that Pd(0) (either
added from the beginning or generated in situ by reduc-
tion of Pd(II) with excess secondary amine) is key to the
observedreactivity. Accordingly, we propose the following
mechanistic pathway which is in line with those of Trost
and Yamamoto9 in related reactions using acidic pronu-
cleophiles. Initially, a rapid and reversible condensation of
4gwith1a, and a concomitantcomplexationof Pd(0), gives
iminium ion intermediate 5 (Scheme 4). The proximally
located Pd(0) species then removes the acidic R-proton9g
of the iminium ion thus forming enamine 6 bearing
the hydridopalladium(II) complexed allene. A subsequent
hydropalladation of the allene moiety generates reactive
π-allyl complex 7 which is then poised to undergo intramo-
lecular nucleophilic attack by the enamine to form iminium
ion 8. Pd(0) is released back into the catalytic cycle and
hydrolysis of the iminium ion yields the desired product 2a
and the regenerated catalyst 4g.
Alternative mechanistic scenarios can be envisaged,13
and further mechanistic studies are required, but our pro-
posed mechanism not only follows a logical set of steps
but also offers a plausible rationale for the observed
stereochemical outcome.14 Based on a reactive s-trans
intermediate 7, and with the assumption that CꢀC bond
formation is enantiodetermining, the steric shielding of the
Re face of the enamine allows for an Si-facial nucleophilic
attack of the π-allyl Pd species to give the desired (3R,4S)
stereochemistry of 2a.3b,15
In summary, a secondary amine- and Pd-catalyzed
diastereoselective carbocyclization of aldehyde and ketone-
tethered allenes has been developed. This dual catalytic
cyclization reaction is efficient and broad in scope and has
been extended to a catalytic asymmetric variant using
diarylprolinol-based organocatalysts, affording substituted
cyclopentane and pyrrolidine reaction products in up to
82% ee. Studies to probe the mechanism and origins
of enantiocontrol, as well as other reactions requiring the
cooperative action of organocatalysts and transition metal
ions, are under active investigation in our laboratories and
the results will be reported in due course.
Acknowledgment. We thank the University of Oxford
and Universities U.K. for an ORS Award (to M.L.), the
EC [IEF toS.D. (PIEF-GA-2009-255080)], the EPSRCfor
a studentship (to D.M.B.) and Leadership Fellowship
(to D.J.D.), AstraZeneca for a studentship (to D.M.B.),
Andrew Kyle, of the Department of Chemistry, University
of Oxford, for X-ray analysis, and the Oxford Chemical
Crystallography Service for the use of the instrumentation.
Supporting Information Available. Experimental pro-
cedures and characterization data for compounds 1,
2aꢀ2k, 3aꢀ3c, 3f, and 3g. This material is available free
of charge via the Internet at http://pubs.acs.org.
(13) For reviews of cycloisomerization reactions, see: (a) Aubert, C.;
Fensterbank, L.; Garcia, P.; Malacria, M.; Simonneau, A. Chem. Rev.
2011, 111, 1954–1993. (b) Watson, I. D. G.; Toste, F. D. Chem. Sci. 2012,
3, 2899–2919. For examples of enallene cycloisomerization, see: (c)
Trost, B. M.; Tour, J. M. J. Am. Chem. Soc. 1988, 110, 5231–5233. (d)
Narhi, K.; Franzen, J.; Backvall, J. E. Chem.;Eur. J. 2005, 11, 6937–
6943.
(14) For an organo-SOMO catalyzed mechanism of intramolecular
allylation of aldehydes, see: Pham, P. V.; Ashton, K.; MacMillan,
D. W. C. Chem. Sci. 2011, 2, 1470–1473.
ꢁ
(15) (a) Seebach, D.; Groselj, U.; Badine, D. M.; Schweizer, W. B.;
ꢁ
Beck, A. K. Helv. Chim. Acta 2008, 91, 1999–2034. (b) Groselj, U.;
Seebach, D.; Badine, D. M.; Schweizer, W. B.; Beck, A. K.; Krossing, I.;
Klose, P.; Hayashi, Y.; Uchimaru, T. Helv. Chim. Acta 2009, 92, 1225–
1259. (c) Schmid, M. B.; Zeitler, K.; Gschwind, R. M. J. Am. Chem. Soc.
2011, 133, 7065–7074.
€
ꢀ
€
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX