Phase-transfer and other types of catalysis with cyclopropenium ions

Article abstract of DOI:10.1002/chem.201500124

Abstract This work establishes the cyclopropenium ion as a viable platform for efficient phase-transfer catalysis of a diverse range of organic transformations. The amenability of these catalysts to large-scale synthesis and structural modification is demonstrated. Evaluation of the molecular structure of an optimal catalyst reveals some unique structural features of these systems. Finally, a discussion of electronic charge distribution underscores an important consideration for catalyst design. Aromatic ions: Tris(dialkylamino)cyclopropenium ions are shown to be effective carbocationic phase-transfer catalysts for a variety of mainstay transformations. The cyclopropenium platform is shown to be modular and accessible on scale. An X-ray structure and electron-density map revealed some unique features of this architecture (see scheme).

Full text of DOI:10.1002/chem.201500124

DOI: 10.1002/chem.201500124
Communication
&
Structure–Activity Relationships
Phase-Transfer and Other Types of Catalysis with Cyclopropenium
Ions
Jeffrey S. Bandar, Anont Tanaset, and Tristan H. Lambert*[a]
Abstract: This work establishes the cyclopropenium ion as
a viable platform for efficient phase-transfer catalysis of
a
diverse range of organic transformations. The
amenability of these catalysts to large-scale synthesis and
structural modification is demonstrated. Evaluation of the
molecular structure of an optimal catalyst reveals some
unique structural features of these systems. Finally, a
discussion of electronic charge distribution underscores
an important consideration for catalyst design.
Phase-transfer catalysis (PTC) has proven to be a highly
advantageous strategy for reaction promotion.[1] Phase-
transfer catalysts facilitate reactions of substances that are
heterogeneously distributed in immiscible phases, with catalysis
generally operating through the transfer of an anionic
species from the aqueous (or solid) phase to the organic phase.
PTC methods offer a number of important advantages, namely:
1) Decreased dependence on organic solvents; 2) excellent scal-
ability and inherent compatibility with moisture; 3) enhance-
ment of reactivity, which permits shortened reaction times and
increased yields; 4) ability to substitute costly and inconvenient
reagents [such as lithium diisopropylamide (LDA)] for simple
aqueous bases (such as KOH); and 5) amenability to enantiose-
lective variants.[2,3] For these reasons, phase-transfer catalysis
has emerged as a widely used technology throughout the do-
mains of pharmaceutical, agrochemical, and materials chemistry.
Traditionally, phase-transfer catalysts have been largely
restricted to the Group 15 onium compounds, namely, ammo-
nium and phosphonium salts (Figure 1a).[4] In particular, chiral
ammonium salts have proven to be quite effective at
promoting asymmetric PTC. On the other hand, the synthesis
of complex phase-transfer catalysts is oftentimes lengthy and/
or challenging, which presents a barrier to rapid catalyst
screening and reaction optimization. Given the substantial in-
dustrial reliance on practical PTC-based manufacturing technol-
ogies,[5] we envisioned that introduction of a versatile new
phase-transfer catalyst platform would be of high interest to
the synthetic community. Herein, we demonstrate that tris-
(dialkylamino)cyclopropenium (TDAC) salts[6] are a viable new
Figure 1. Cyclopropenium ions: A new class of phase-transfer catalysts.
PTC platform that offers excellent reactivity in a range of PTC-
based transformations.[7]
Amine-substituted cyclopropenium ions have been known
for more than 40 years,[8] but have recently attracted particular
attention for their unique structural and reactivity properties in
the context of free carbenes,[9] metal or main-group ligands,[10]
ionic liquids,[11] and polyelectrolytes.[12] Given their amenability
to scalable preparation and their inherent modularity, we envi-
sioned that TDAC ions could serve as an attractive new class of
phase-transfer catalysts. However, at the outset, it was an open
question as to whether these strained carbocations would be
compatible with the basic and nucleophilic environments
characteristic of phase-transfer reactions, given the known
propensity of these materials to undergo hydrolysis or ring-
opening reactions (Figure 1b).[6]
The synthesis of TDAC ions most conveniently utilizes penta-
chlorocyclopropane, which is accessible in large quantities
(Figure 1c).[13] As a demonstration of the ease of synthesis of
these materials, TDAC 1·Cl was prepared on a 75 g scale in
a single flask in 95% yield. TDAC ions of this type are stable,
free-flowing powders that are easily modified through
variation of the amine component or through ion exchange.
With ample quantities of 1·Cl and other TDAC salts in hand,
we first investigated the ability of these materials to function
as effective phase-transfer catalysts for enolate alkylation. With
the goal of establishing preliminary structure–activity parame-
ters, we screened a range of TDAC candidates as catalysts in
[a] J. S. Bandar, A. Tanaset, Prof. T. H. Lambert
Department of Chemistry, Columbia University
3000 Broadway New York, NY 10027 (USA)
E-mail: tl2240@columbia.edu
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500124.
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Table 1. PTC of enolate alkylation: Catalyst-optimization studies.
Table 2. PTC of enolate alkylation: Substrate scope.[a]
Entry Catalyst
Solvent
Conv. [%][a]
(a) NR2=NMe2 toluene
66
62
97
13
79
96
53
47
(b) NBu2
(c) NHex2
(d) NMorph
(a) X=Cl
(b) I
toluene
toluene
toluene
toluene
toluene
EtOAc
1
Entry
1
Product
System
A
t [h]
Yield [%][a]
44
0.5
2
3
(c) I
(d) I
iPrOAc
(e) I
(a)
(b)
(c)[b]
c-C5H9ÀOCH3 68
2
3
A
A
40
99
80
toluene
0
94
76
CH2Cl2
CH3C(O)C2H5
0.15
4
5
NBu4Cl
PPh4Cl
toluene
toluene
80
0
4
A
0.15
98
6
toluene
98
5
6
B
B
20
97
99
[a] Percent conversion after 24 h, as was recorded by 1H NMR spectro-
scopy, average of two runs. Entries 2c–e and 3c represent isolated yields
from an average of two runs. [b] 2 h reaction time.
12
1
7
8
B
95
86
the transformation depicted in Table 1. Several trends emerged
from our preliminary catalyst screen. First, comparison of tris-
symmetrical cyclopropenium salts (entries 1a–d) revealed
a positive correlation between catalyst lipophilicity and reac-
tion efficiency. The dihexylamino-substituted catalyst (entry 1c
in Table 1) was more reactive than the dimethylamino or
dibutylamino analogs (entries 1a and b), whereas the highly
polar morpholine-substituted cyclopropenium was largely
ineffective in this reaction (entry 1d in Table 1). The bis(dicyclo-
hexylamino)cyclopropenium scaffold bearing a diethylamino
head group (1) was found to be highly reactive, particularly
when iodide—rather than chloride—was used as the counter-
ion (entries 2a vs. 2b in Table 1). We believe that the iodide
counterion serves the dual function of activating the electro-
phile (BnBr!BnI) and facilitating PTC. Interestingly, the proton-
ated analogue, 2, though completely inactive in toluene
(entry 3a), promoted the reaction in CH2Cl2 with excellent effi-
ciency (entry 3b in Table 1). Having identified 1·I and 2·Cl as
optimal catalysts for this transformation, we next demonstrat-
ed their compatibility with a range of “green” solvents, includ-
ing ethyl acetate, isopropyl acetate, cyclopentyl methyl ether
(47–68% isolated yield, entries 2c–e in Table 1), and 2-buta-
none (76% isolated yield, 2 h, entry 3c). Notably, the cyclo-
propenium catalysts possess levels of efficiency comparable
or superior to those exhibited by several established phase-
transfer catalysts (entries 4–6 in Table 1).
A
1
[a] Isolated yield, average of two runs.
Thus, as shown in Table 2 (top), cyclopropenium 1·I effectively
catalyzes benzylation of a range of pro-nucleophiles, including
ketones (entries 1 and 3 in Table 2), esters (entry 2), and amides
(entry 4). In the latter substrate, we observed rapid double alky-
lation of the oxindole system at both the enolate and nitrogen
positions. We next examined addition of a glycine imine to
a range of electrophiles (Table 2, bottom). As was shown, the
glycine imine readily participates in alkylation or Michael addi-
tion with excellent efficiency (entries 5–8 in Table 2).
We have also investigated an alternative mode of catalysis
for these cyclopropenium salts with the addition of acid chlor-
ides to epoxides en route to synthetically useful halohydrin
ester adducts.[14] Thus, under catalysis by 2.5 mol% 1·Cl,
phenylacetyl chloride was observed to rapidly add to a range
of terminal epoxides with good yields and regioselectivities
(Table 3, entries 1–4). Addition of phenylacetyl chloride to
styrene oxide also proceeded in excellent yield, albeit with di-
minished regioselectivity (entry 5). More hindered epoxides
were generally less amenable to acid chloride addition (entry 6
in Table 3); however, reaction of cyclohexene oxide with phe-
nylacetyl chloride proceeded in 64% yield after 2 h (entry 7 in
Table 3). In comparisons with other PTCs, 1·Cl (entry 1) was no-
tably faster and more regioselective than either tetrabutyl-
ammonium chloride (entry 8) or an imidazolium salt (entry 9),
and equal to tetraphenylphosphonium chloride (entry 10 in
Table 3). We believe this reaction occurs through nucleophilic
We next sought to probe the scope of this alkylation
chemistry with respect to the electrophilic and nucleophilic
coupling partners. For each substrate pair, both system A (1·I,
toluene, 50% KOH) and system B (2·Cl, CH2Cl2, 50% KOH) were
evaluated for reaction time and yield. The results presented in
Table 2 reflect the optimal conditions for each transformation.
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Table 3. Cyclopropenium chloride-catalyzed addition of acid chlorides to
epoxides.
Entry Epoxide
Catalyst
t [h] Yield [%][a] A/B
1
2
3
4
5
1·Cl
1·Cl
1·Cl
1·Cl
1·Cl
4
3
2
5
3
68
6.3:1
>20:1
91[b]
74[b]
65
>20:1
>20:1
Table 4. Cyclopropenium chloride-catalyzed addition of carbon dioxide
to epoxides.
95[b]
1.9:1
6
7
1·Cl
24
2
<15
–
–
1·Cl
64
Entry
1
Epoxide
Product
t [h]
Yield [%][a]
72
8[c]
NBu4Cl
30
30
4
67
48
69
2.4:1
2.3:1
6.1:1
9[c]
48
10[c]
PPh4Cl
2
3
20
36
90
89
[a] Isolated yields. [b] Pyridine (1.0 equiv) and acid chloride (3.0 equiv)
were used; no background reaction was observed. [c] Yields determined
by 1H NMR spectroscopy.
opening of the epoxide by chloride ion, followed by acylation
of the resulting cyclopropenium alkoxide.
This epoxide-opening chemistry was subsequently expanded
to encompass carbon dioxide fixation.[15] As shown in Table 4,
a series of terminal epoxides were exposed to 2.5 mol% 1·Cl
under neat conditions with a CO2 balloon (1 atm). The adducts
were isolated in good yields within 20–48 h (entries 1–3 in
Table 4). The hindered cyclohexene oxide was somewhat less
amenable to this transformation, delivering product in only
28% yield after 5–7 days (entry 4 in Table 4).
4
5–7 d
28
[a] Isolated yields.
substantial torqueing of the diethylamino moiety can clearly
be seen in the edge view (Figure 2b). How the crystal-packing
conformation of 1 correlates to its solution-phase dynamics is
not known, but this torqueing phenomenon is undoubtedly an
unavoidable aspect of these ring systems that should be taken
into account when considering chiral variants of these
catalysts.
With the goal of establishing cyclopropenium ions as a general
class of phase-transfer catalyst, we have also demonstrated the
ability of this system to promote a wide array of mainstay PTC-
based transformations. As shown in Equations (1–4), the cyclo-
propenium catalysts were found to be effective in a range of di-
verse settings, including: Phenol alkylation, azide substitution, al-
cohol oxidation, and cyclopropanation. Importantly, in each of
these cases, no reaction was observed in the absence of catalyst:
Finally, although the Lewis structure depiction of TDAC ions
indicates a formally carbocationic ring, the cyclopropenium
core is in fact a site of relative electron richness.[17] This feature
is clearly seen in an electron-density map of tris(dimethyl-
amino)cyclopropenium ion, which showed that the areas of
maximal electron deficiency reside at the hydrogens of the pe-
ripheral methyl groups, as would be expected from a simple
consideration of relative electronegativities and the TDAC
HOMO (Figure 2c).[17e] The implication of this charge distribu-
tion is that anions can be expected to associate with the edge,
rather than the face, of the planar cyclopropenium. This ex-
pectation is supported by the unit-cell view of the X-ray struc-
ture of 1·Cl (Figure 2d), which clearly shows the chloride ions
encapsulated by the dialkylamino substituents. Assuming
these orientations translate to the solution phase, they are
Single-crystal X-ray analysis of 1·Cl revealed some interesting
structural features that may prove to be important for the
design of chiral catalysts based on this architecture (Figure 2a).
Most notably, steric crowding induces the dialkylamino
substituents to adopt a significant dihedral angle relative to
the cyclopropenium ring by 178 in the case of the dicyclo-
hexylamino groups and 378 for the diethylamino group.[16] The
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(d) Unit cell of 1·Cl.
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Financial support for this work was provided by NIGMS (R01
GM102611). T.H.L. is grateful for an Ely Lilly Grantee Award.
J.S.B. is grateful to NDSEG and NSF for graduate fellowships.
We thank Serge Ruccolo and the Parkin group for X-ray
structure determination; the National Science Foundation
(CHE-0619638) is thanked for acquisition of an X-ray
diffractometer.
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Keywords: aromaticity · aromatic ions · cyclopropenium ·
phase-transfer catalysis · structure–activity relationships
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Received: January 12, 2015
Published online on March 27, 2015
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