Phase-Transfer Catalysis via a Proton Sponge: A Bifunctional Role for Biscyclopropenimine

Article abstract of DOI:10.1021/acs.joc.5b02395

The use of a bis(diisopropylamino)cyclopropenimine-substituted bis-protonated proton sponge as a bifunctional phase-transfer catalyst is reported. Experimental studies and DFT calculations suggest it operates simultaneously as a hydrogen bond donor and a

Full text of DOI:10.1021/acs.joc.5b02395

Article
pubs.acs.org/joc
Phase-Transfer Catalysis via a Proton Sponge: A Bifunctional Role for
Biscyclopropenimine
Lee Belding, Peter Stoyanov, and Travis Dudding*
Brock University, 500 Glenridge Avenue, St. Catharines, ON L2S 3A1 Canada
S
* Supporting Information
ABSTRACT: The use of a bis(diisopropylamino)cyclopropenimine-substituted bis-protonated proton sponge as a bifunctional
phase-transfer catalyst is reported. Experimental studies and DFT calculations suggest it operates simultaneously as a hydrogen
bond donor and a phase-transfer catalyst, facilitating the movement of charged intermediates from the interface to the organic
phase via favorable partitioning of hydrophilic/hydrophobic surface areas, resulting in high catalytic activity.
INTRODUCTION
■
The interest in bis(dialkylamino)cyclopropenimine (DAC)
motifs has markedly increased in recent years, due in large
part to their emerging use in organocatalysis1 and phase-
transfer catalysis,2 in addition to applications as ionic liquids3
and nitrogen-based ligands.4 Accompanying the practical
interests in DACs has been an avid curiosity among physical
organic chemists and theoreticians alike in their strong
Brønsted−Lowry basicity, which arguably derives from an
intrinsic kinetic propensity to form stable aromatic bis-
(dialkylamino)cyclopropeniminium cations upon protonation.
Not surprisingly, this fascinating link between basicity and
aromaticity, compounded with the status of DACs as so-called
“superbases” has served as an impetus for continued study into
the underlying electronic nature and chemical reactivity of this
intriguing class of heterocycles.
Figure 1. Reported cyclopropinimine compounds by Dudding et al.
with more than one active site),8 particular emphasis has
recently been placed on bifunctional catalysts combining both
hydrogen bonding and phase-transfer motifs.9 Among this class
of PTCs, the predominant approach involves combining
positively charged quaternary ammonium cations as the
phase-transfer functionality and urea or thiourea as the
hydrogen bond donor.
As part of our continued interest in phase-transfer reactions
and hydrogen bonding, we were particularly interested to
investigate the use of protonated DACs as hydrogen bond
donors in phase-transfer catalysis. We envisioned the use of 1-
2H+ (Figure 1) as a unique, bifunctional phase-transfer catalyst.
DACs are unique phase-transfer motifs, considering that their
In this light, our recently synthesized superbases, DACN
(1)5 and Janus (2),6 further explored the nature of DACs in the
context of freebase strain and intramolecular hydrogen
bonding, within the historically relevant proton sponge scaffold.
Our group has also reported the first use of a DAC derivative
(3) as a phase-transfer catalyst (PTC) for benzylation and
fluorination reactions (Figure 1).2a From an experimental
standpoint, phase-transfer protocols are particularly advanta-
geous as they are, in general, operationally simple, amenable to
both large- and small-scale synthetic protocols, involve mild
reaction conditions, and use inexpensive reagents and solvents.
As a result, it is perhaps not surprising that the scope of phase-
transfer catalysis has continued to evolve at an accelerated pace,
resulting in a number of new catalysts and protocols offering
complementary and/or distinct modes of reactivity.7 In
building upon earlier works exploring multisite PTCs (catalysts
Received: October 15, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02395
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Table 1. Optimized Reaction Conditions with 1-2H+
positive charges are highly diffuse in nature, which stands in
contrast to the localized point charges of widely employed
quaternary ammonium (or occasionally phosphonium) cations.
With the application of 1-2H+ as a PTC, this report
demonstrates that protonated DACs can be compatible
hydrogen bond donors for phase-transfer chemistry. Thus,
DACs have a unique ability to play a bifunctional role, as both
the phase-transfer motif and hydrogen bonding donor.
The functional utility of 1-2H+ in phase-transfer catalysis was
projected to benefit from a distinct partitioning of lipophilic
and hydrophilic surface areas (Figure 1), which could be
subdivided into a (1) π-polarizable naphthyl ring that would
allow for π−π stacking interactions, (2) a pair of highly diffuse
cations that would facilitate the transport of anions into a
lipophilic organic phase, and (3) a H-bonding region for
molecular recognition. As a corollary, it was foreseen that in situ
derived freebase, 1, might serve a further role, acting as an
organic base to facilitate the deprotonation of pronucleophiles,
thus providing another mechanistic dimension to phase-transfer
catalysis.
a
bc
,
entry
solvent
temp (°C)
time
conversion (%) yield (%)
1
2
3
4
5
6
MeCN
MeCN
DCM
25
0
20 min
1 h
100
100
100
100
51
92
91
92
89
36
51
25
0
45 min
1.5 h
DCM
d
toluene
25
8 h
d
toluene
50
8 h
67
a
b
Based on 1H NMR spectroscopy. Isolated yield after column
c
chromatography. In the absence of the catalyst, no conversion was
d
observed except 6% for entry 6 based on 1H NMR. Noticeable
background reaction observed longer than 8 h.
RESULTS AND DISCUSSION
■
At the outset of this study, to explore the potential of the bis-
protonated salt of DACN (1-2H+) in PTC as a bifunctional
and/or multisite phase-transfer catalyst, we chose the well-
established alkylation of O’Donnell’s glycine imines10 given its
historical significance and the numerous mechanistic inves-
tigations using this substrate. However, it was initially uncertain
if 1-2H+ would undergo N-alkylation, as it would presumably
be in equilibrium with 1 under basic conditions, or if the
sterically encumbered environment of 1 would impede
alkylation. To investigate this possibility, 100 mg of 2 was
mixed with excess benzyl bromide in a 1:1 mixture of DCM and
50% aqueous KOH and stirred at room temperature for 8 h.
Encouragingly, there was no evidence of the alkylated catalyst,
and the catalyst could be easily recovered in near quantitative
yield. Although there was no evidence of catalyst alkylation, it
was shown that deprotonation under the reaction conditions
did indeed occur, as established by dissolution of 1-2H+ in a
50% solution of KOH in D2O at room temperature. In terms of
catalyst stability, it is notable that when a sample of 1-2H+ was
left in an aqueous 50% KOH solution at ambient temperature
there was no noticeable decomposition after 2 weeks, as
Figure 2. Alternative compounds screened for PTC activity.
sponge (7),11 and t-butyl(bisdiisopropylamino)-
cyclopropenimine (8).1a To this end, the use of 2-H+ afforded
only trace amounts of the benzylated product, while 7 resulted
in no reaction, indicating that the protonated 1,8-diamino-
naphthyl ring system was not the only structural feature of 1-
2H+ leading to PTC catalysis. Conversely, 8 catalyzed the
reaction to a small extent, providing 9% of the desired product
along with small amounts of alkylated byproduct.12 The failure
of 2-H+, 7, and 8 to impart any appreciable catalytic activity,
despite their partial structural similarity to 1-2H+, is notable, as
it provides strong evidence that 1-2H+ acts uniquely as a phase-
transfer catalyst.
In view of the dramatic differences in reactivity between
these compounds, the ability of 1-2H+ as a phase-transfer
catalyst was further explored using other electrophiles under
the conditions applied for entry 3 in Table 1 with the reaction
time extended to 1 h (Scheme 1). Along these lines,
naphthalene bromide (5b) was comparable in reactivity to
benzyl bromide, resulting in 92% isolated yield, while perhaps
more interestingly, the more sterically hindered secondary
bromide 5c afforded 6c in 91% yield, demonstrating that
substitution at the benzylic carbon was tolerated under the
reaction conditions. Alternatively, the use of less reactive benzyl
chlorides 5d and 4-methoxybenzyl chloride 5e led to lower
product yields, providing 6d and 6e in 60 and 54% yields,
respectively. In contrast, 4-methyl benzyl bromide (5f)
substrate afforded a yield comparable to that of benzyl
bromide, with 6f isolated in 92% yield. Furthermore, the use
of resonance-donating electron-withdrawing 4-chloro-substi-
tuted and strongly electron-withdrawing 4-nitro-functionalized
benzyl bromides 5g and 5h provided high product yields. Based
on these trends, it would appear that the enhanced leaving
group ability of a benzylic bromide relative to that of a chloride
effectively supersedes subtle electronic perturbations on
reactivity introduced by the inclusion of a p-substituent.
These results are consistent with a mechanistic scenario
involving halide dissociation and C−C bond formation
1
determined by H NMR.
Given this promising preliminary result, reaction conditions
were subsequently screened for the alkylation of benzophenone
imine 4 with benzyl bromide 5a (Table 1). To this end, the
polar aprotic solvent acetonitrile (MeCN) was optimal,
resulting in complete consumption of the starting material in
only 20 min at room temperature and a 92% product yield.
Comparatively, the use of slightly less polar dichloromethane
(DCM) provided a similar outcome to that of MeCN, with full
consumption of the starting material occurring in 45 min at
room temperature. Meanwhile, the use of toluene, on the other
hand, resulted in a slight background rate, extended reactions
times, and poor overall product yield.
At that stage, to investigate the hypothesis that the bis-
protonated, dicationic moiety of 1-2H+ was critical for catalysis,
three additional compounds all sharing structural similarities
with 1-2H+ were employed as potential catalysts under the
same reaction conditions (Figure 2). Namely, phase-transfer
alkylation was performed in the presence of 5 mol % of the
hydrochloride salts of Janus sponge (2-H+),6 Alder’s proton
B
DOI: 10.1021/acs.joc.5b02395
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 1. Electrophile Screen
Scheme 2. Extraction-Type PTC Reactions (See Supporting
Information for Details)
catalyst for both hydroxide-initiated interfacial and extraction-
based PTC.2a For instance, even under optimized conditions, 1-
2H+ provided only moderate rate enhancement in the benzylic
fluorination of 5b with CsF in MeCN (eq 1) with respect to the
noncatalyzed background reaction (see Supporting Informa-
tion). Furthermore, 1-2H+ had no effect on catalyzing the
bromide displacement of 5a by azide under PTC conditions
(eq 2). See Supporting Information for details.
While PTC reactions are renowned for being dynamic
processes, wherein product formation is oftentimes complicated
by “off-cycle” pre-equilibria, there is little doubt that the
alkylation of O’Donnell’s imine in this work proceeds by way of
an interfacial hydroxide-initiated mechanism.10 Granted this
fact, the more relevant question relates to the underlying source
of the high catalytic activity of 1-2H+. In part, it is thought to
derive from the tendency of the catalyst to concentrate at the
interfacial space, which is known to be an important factor in
hydroxide-initiated PTC reactions.14 Presumably, the innate
organophilicity of 1-2H+ also plays a critical role in enhancing
the transport rate of anions from the interfacial phase to the
organic layer, leading to faster reactions.15 Though conjectural,
a third aspect of 1-2H+-mediated PTC is the likelihood that the
catalyst stabilizes the benzophenone imine enolate (4−) via a
set of heteronuclear positive-charge-assisted hydrogen bonds
((+)CAHB).16 Lastly, it is reasoned that 1 undergoes a rapid
protonation/deprotonation event at the organic/aqueous
interface, given its basicity and the basicity of the aqueous
phase.15 This would in turn toggle the solubility characteristics
of the catalyst between that of a charged hydrophilic 1-2H+
dication with H-bonding residues to that of more a lipophilic 1
or 1-1H+ species, which would be prone to reside in the organic
layer. In essence, the dynamics of this system would establish a
scenario where the catalyst would be held at the interface by
rapid protonation/deprotonation processes.
a
b
c
With 1 equiv. With 1.2 equiv. Yields based on isolated product
obtained after column chromatography. No product was formed in any
d
e
reaction in the absence of catalyst 1-2H+. 5a = benzyl bromide. 5d =
benzyl chloride. 5j = allyl bromide. 5k = allyl chloride.
f
g
occurring via a transition state involving SN2 displacement or
conceivably even backside nucleophilic addition to a short-lived
benzylic cation+X− tight ion pair. Meanwhile, substrate 3-
benzyl-1-bromopropane (5i) having an aliphatic chain proved
to be a far less reactive electrophile, yielding only 10% of the
desired product 6i, though the reaction does reach completion
with longer reaction times. Lastly, allyl bromide (5j), crotyl
bromide (5l), allyl chloride (5k), and cinnamyl bromide (5m)
were all reactive, though allyl chloride gave a slightly lower
yield, while the regiochemical outcome with 5l and 5m
indicated that a SN2′ displacement of the bromide was not a
competing process.
Modeling of the hydrophobic/hydrophilic surface areas of 1-
2H+ and the corresponding hydrogen-bound complex 1-2H+·4−
supported this conjecture, as revealed by the hydrophobic/
hydrophilic surface area plots depicted in Figure 3. Apparent
from these plots was a distinct amphipathic division of
Having demonstrated that 1-2H+ was a competent catalyst
for interfacial PTC, we next applied it to nucleophilic
fluorination and sodium azide substitution reactions, which
are PTC processes generally believed to occur by extraction-
based mechanisms (Scheme 2).13 Emerging from these studies
was the instructive finding that in stark contrast to the ability of
1-2H+ to facilitate interfacial PTC, it was a markedly less
effective catalyst for extraction PTC, which is interesting given
that our recently reported cyclopropeniminium-containing
pnictogen N-centered cation 3 was an effective phase-transfer
Figure 3. Hydrophobic (orange)/hydrophilic (blue) surfaces of 1-2H+
(left) and the 1-2H+·4− complex (right) generated using Macromodel.
C
DOI: 10.1021/acs.joc.5b02395
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 4. Proposed hydroxide-initiated interfacial PTC mechanism for alkylation of imine 4 to afford 6.
hydrophobic/hydrophilic surface volumes in 1-2H+ that
suggested it would be prone to accumulate at organic/aqueous
interfaces (Figure 3a), while in 1-2H+·4−, the hydrophilic
surface density was localized at the re and si faces of the enolate
ester carbon and the oxyanion was buried within the interior of
this complex (Figure 3b). Notably, this encasing of the
oxyanion can be likened to that of the role played by
hydrophilic/hydrophobic amino acid residues in protein
folding/function.17 Yet more importantly, this discrete arrange-
ment of hydrophilic/hydrophobic surfaces and positioning of
H-bond donor sites both stabilize and protect the reactive
enolate intermediate, presumably prolonging its lifetime in the
organic phase and thereby increasing the probability of reaction
with an electrophile.
As for the PTC cycle of these alkylation reactions, it is
envisioned that a series of pre-equilibrium steps generate an
effective concentration of a reactive benzophenone imine
enolate 1-2H+·4− complex in the interphase (Figure 4). A
preliminary model derived from DFT calculations suggests that
the computed 34.9 kcal/mol binding affinity for this complex
was driven by the formation of a bifurcated ((+)CAHB) H-
bond/Coulombic interaction, akin to a salt bridge which is a
common motif found in enzymes (Figure 5).
Figure 5. (a) Computed complex 1-2H+·4‑ (left). Two-dimensional
rendering of favorable binding interaction in 1-2H+·4‑ (right). (b)
Computed benzylation transition state, TS1 (left). Two-dimensional
rendering of TS1 (right). Computations performed at the wb97xd/6-
31g(d)/def2sv (scrf = dichloromethane) level.
Migrating into the bulk of the organic phase, 1-2H+·4− then
engages in C−C bond formation via a transition state assembly
such as TS1 with an activation barrier of 10.7 kcal/mol (2.2
kcal/mol lower than that of the uncatalyzed transition state; see
Supporting Information) and elongated 2.46 Å C−C bond
forming distance, which is suggestive of an early transition state
leading to alkylated product 6 (Figure 5).
EXPERIMENTAL SECTION
■
Calculations were carried out at the Kohn−Sham hybrid DFT
wb97xd/6-31g(d)/def2sv level of theory at standard temperature and
pressure using the Gaussian 09 and GaussView v5.0.8 programs. To
account for solvent effects, the integrated equation formalism polarized
continuum solvation model (IEFPCM) was used throughout the
computations with default parameters for dichloromethane. A number
of transition state configurations were computed and were confirmed
by the presence of a single imaginary frequency, though only the
lowest energy transition states for the catalyzed and uncatalyzed
reactions are reported (see Supporting Information). The intrinsic
reaction coordinate (IRC) methodology was then implemented to
identify the corresponding minima, which were confirmed by the
presence of only real vibrational frequencies.
CONCLUSIONS
■
In closure, we have demonstrated that DACs can be used as
hydrogen bond donors in phase-transfer chemistry and have
introduced the first bifunctional DAC-based PTC, 1-2H+. The
bis-protonated salt of DACN (i.e., 1-2H+), a shelf-stable salt
easily prepared from commercially and/or readily available
reagents, was shown to be an effective catalyst for hydroxide-
initiated interfacial PTC alkylations, while it was a poor catalyst
for PTC processes occurring by extraction-based mechanisms.
Evidence was presented that suggests 1-2H+ has a tendency to
reside at the aqueous/organic interphase and the ability to
enclose reactive hydrophilic intermediates in a hydrophobic
shell, thus facilitating their transport to the organic phase.
Ongoing studies geared toward the development and
application of related PTC protocols with chiral DAC-derived
catalysts is underway in our lab and will be reported in due
course.
Materials and Methods. Materials were obtained from
commercial suppliers and were used without further purification,
unless otherwise specified. Reactions were monitored by thin layer
chromatography (TLC) using TLC silica gel 60 F254. NMR spectra
were obtained with a 300 MHz spectrometer (1H 300 MHz, 13C 75.5
MHz or 13C 150.9 MHz, 19F 292.4 MHz, 11B 96.3 MHz). The
chemical shifts are reported as δ values (ppm) relative to
tetramethylsilane.
D
DOI: 10.1021/acs.joc.5b02395
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
General Phase-Transfer Catalysis Procedure. N-
(Diphenylmethylene)glycine tert-butyl ester 4 (25 mg, 0.0846 mmol,
1 equiv), DACN 2HCl (3 mg, 0.00428 mmol, 5 mol %), and
electrophile (0.01 mmol, 1.2 equiv) was dissolved in 0.5 mL of
dichloromethane in a 10 mL vial with a stir bar, followed by the
addition of 0.5 mL of 50% aqueous potassium hydroxide. The vial was
closed, and the reaction was allowed to stir at room temperature for 1
h. The reaction was extracted with three aliquots of 2 mL of
dichloromethane; the organic layer was dried with magnesium sulfate
and concentrated in vacuo. Products were isolated using flash column
chromatography 9:1 (hexane/ethyl acetate).
tert-Butyl-2-(diphenylmethyleneamino)-3-(4-chlorophenyl)-
propanoate (6f):20 Purified compound was eluted via gravity column
chromatography, using a mixture of 97:2:1 hexanes/ethyl acetate/
triethylamine. The final product was obtained as clear oil in 91% yield
1
(0.0770 mmol, 32 mg): H NMR (300 MHz, CDCl3) δ = 1.46 (s,
9H), 3.10−3.24 (m, 2H), 4.08−4.13 (dd, J = 8.7, 4.2 Hz, 1H), 6.68−
6.70 (d, J = 7.0 Hz, 2H), 6.99−7.02 (d, J = 8.3 Hz, 2H), 7.16−7.19 (d,
J = 6.8 Hz, 2H), 7.30−7.40 (m, 6H), 7.57−7.60 (d, J = 6.8 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ = 170.6, 170.5, 139.4, 137.6, 136.2,
132.4, 132.0, 131.2, 130.7, 130.2, 130.0, 128.7, 128.4, 128.2, 81.3, 67.6,
38.9, 28.0.
tert-Butyl-2-(diphenylmethyleneamino)-3-(4-nitrophenyl)-
propanoate (6g):21 Purified compound was eluted via gravity column
chromatography, using a mixture of 97:2:1 hexanes/ethyl acetate/
triethylamine. The final product was obtained as white crystals in 93%
tert-Butyl-2-(diphenylmethyleneamino)-3-(phenyl)propanoate
(6a):18 Purified compound was eluted via gravity column chromatog-
raphy, using a mixture of 97:2:1 hexanes/ethyl acetate/triethylamine.
The final product was obtained as white crystals in 92% yield (0.0778
mmol, 30 mg): 1H NMR (300 MHz, CDCl3) δ = 1.47 (s, 9H), 3.19−
3.28 (m, J = 8.9, 4.4 Hz, 2H), 4.12−4.16 (dd, J = 9.6, 4.0 Hz, 1H),
6.62−6.64 (d, J = 7.0 Hz, 2H), 7.07−7.10 (m, 2H), 7.19−7.21 (m,
2H), 7.27−7.39 (m, 5H), 7.51−7.53 (t, J = 7.8 Hz, 1H), 7.59−7.62 (d,
J = 7.4 Hz, 2H), 7.82−7.85 (d, J = 7.4 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ = 170.8, 170.2, 139.7, 138.3, 137.6, 132.4, 130.0, 129.8,
128.7, 128.2, 128.0, 127.96, 127.69, 126.1, 81.1, 67.9, 39.6, 28.0.
tert-Butyl-2-(diphenylmethyleneamino)-3-(naphthalen-2-yl)-
propanoate (6b):18 Purified compound was eluted via gravity column
chromatography, using a mixture of 97:2:1 hexanes/ethyl acetate/
triethylamine. The final product was obtained as yellow oil in 92%
1
yield (0.0787 mmol, 34 mg): H NMR (300 MHz, CDCl3) δ = 1.46
(s, 9H), 3.30−3.33 (m, 2H), 4.17−4.21 (dd, J = 8.0, 2.3 Hz, 1H),
6.72−6.74 (d, J = 6.9 Hz, 2H), 7.25−7.36 (m, 8H), 7.57−7.60 (d, J =
6.9 Hz, 2H), 8.07−8.10 (d, J = 6.9 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ = 170.9, 170.1, 146.6, 146.5, 139.1, 136.0, 130.6, 130.4,
128.7, 128.6, 128.3, 128.1, 127.5, 123.2, 81.7, 67.0, 39.4, 28.0.
tert-Butyl-2-(diphenylmethyleneamino)-3-(4-methoxyphenyl)-
propanoate (6h):19 Purified compound was eluted via gravity column
chromatography, using a mixture of 97:2:1 hexanes/ethyl acetate/
triethylamine. The final product was obtained as clear oil in 54% yield
1
(0.0457 mmol, 19 mg): H NMR (300 MHz, CDCl3) δ = 1.47 (s, 9
1
H), 3.10−3.25 (m, 2 H), 3.77 (s, 3 H) 4.10−4.14 (t, J = 4.0 Hz, 1H),
7.02 (d, J = 6.0 Hz, 2 H), 7.38 (d, J = 4.0 Hz, 2H), 7.47−7.85 (m, 10
H); 13C NMR (75 MHz, CDCl3) δ = 170.9, 170.2, 160.1, 136.4, 132.4,
130.8, 130.1, 129.4, 128.7, 128.5, 128.2, 128.0, 127.8, 127.7, 81.0, 68.1,
55.2, 38.7, 28.0.
yield (0.0778 mmol, 34 mg): H NMR (300 MHz, CDCl3) δ = 1.48
(s, 9H), 3.35−3.42 (m, 2H), 4.24−4.29 (dd, J = 9.0, 4.4 Hz, 1H),
6.55−6.57 (d, J = 7.2 Hz, 2H), 7.16−7.24 (m, 2H), 7.29−7.35 (m,
3H), 7.41−7.44 (m, 2H), 7.51−7.60 (m, 4H), 7.67−7.70 (d, J = 7.8
Hz, 2H), 7.77−7.85 (m, 2H); 13C NMR (75 MHz, CDCl3) δ = 170.8,
170.4, 139.5, 137.7, 136.3, 135.9, 133.4, 132.4, 132.1, 130.0, 128.7,
128.4, 128.2, 128.0, 127.9, 127.6, 127.5, 127.4, 125.7, 125.2, 81.2, 67.9,
39.7, 28.0.
tert-Butyl-2-(diphenylmethyleneamino)-5-(phenyl)pentanoate
(6i):9c Purified compound was eluted via gravity column chromatog-
raphy, using a mixture of 97:2:1 hexanes/ethyl acetate/triethylamine.
The final product was obtained as clear oil in 10% yield (0.0085 mmol,
4 mg): 1H NMR (300 MHz, CDCl3) δ = 1.47 (s, 9H), 1.59−1.69 (m,
2H), 1.94−2.01 (m, 2H), 2.56−2.61 (t, J = 7.8 Hz, 2H), 3.95−3.99 (t,
J = 6.4 Hz, 1H), 7.14−7.19 (m, 5H), 7.32−7.41 (m, 4H), 7.44−7.46
(m, 3H), 7.66−7.68 (d, J = 6.8 Hz, 2H); 13C NMR (75 MHz, CDCl3)
δ = 171.5, 169.9, 142.2, 139.7, 136.7, 130.1, 128.8, 128.5, 128.4, 128.3,
128.2, 128.0, 127.8, 125.7, 80.8, 65.9, 35.6, 33.3, 28.1, 27.8.
tert-Butyl-2-(diphenylmethyleneamino)-3-(phenyl)butanoate
(6c):10 Compound was purified via gravity column chromatography,
using a mixture of 97:2:1 hexanes/ethyl acetate/triethylamine. The
final product was obtained as yellow oil 91% yield (0.0769 mmol, 31
1
mg): H NMR (300 MHz, CDCl3) δ = 1.45 (s, 9H), 3.49−3.61 (m,
1H), 3.99−4.02 (d, J = 8.2 Hz, 1H), 6.75−6.78 (d, J = 6.8 Hz, 2H),
7.14−7.25 (m, 5H), 7.30−7.40 (m, 5H), 7.50−7.53 (d, J = 7.0 Hz,
2H), 7.65−7.68 (d, J = 6.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ =
170.7, 170.4, 143.8, 143.4, 136.6, 136.4, 132.4, 130.1, 130.0, 129.97,
128.9, 128.8, 128.6, 128.3, 128.27, 128.23, 128.14, 128.14, 128.0,
127.9, 127.88, 127.82, 127.7, 126.2, 81.0, 80.8, 72.8, 71.9, 43.5, 28.0,
27.8, 18.0, 16.82.
tert-Butyl-2-(diphenylmethyleneamino)pent-4-enoate (6j):18 Pu-
rified compound was eluted via gravity column chromatography, using
a mixture of 97:2:1 hexanes/ethyl acetate/triethylamine. The final
product was obtained as clear oil in 91% yield (0.0769 mmol, 26 mg):
1H NMR (300 MHz, CDCl3) δ = 1.46 (s, 9H), 2.62−2.69 (m, 2H),
4.00−4.05 (dd, J = 7.7, 2.0 Hz, 1H), 5.01−5.12 (m, 2H), 5.69−5.79
(m, 1H), 7.17−7.21 (m, 2H), 7.31−7.46 (m, 6H), 7.64−7.67 (d, J =
6.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ = 170.8, 170.1, 139.7,
136.6, 134.7, 132.4, 130.1, 130.0, 128.8, 128.5, 128.2, 117.2, 81.0, 65.8,
38.1, 28.0.
tert-Butyl-2-(diphenylmethyleneamino)pent-4-enoate (6k =
6j):22 Purified compound was eluted via gravity column chromatog-
raphy, using a mixture of 97:2:1 hexanes/ethyl acetate/triethylamine.
The final product was obtained as clear oil in 89% yield (0.0753 mmol,
25 mg): 1H NMR (300 MHz, CDCl3) δ = 1.46 (s, 9H), 2.62−2.69 (m,
2H), 4.00−4.05 (dd, J = 7.7, 2.0 Hz, 1H), 5.01−5.12 (m, 2H), 5.69−
5.79 (m, 1H), 7.17−7.21 (m, 2H), 7.31−7.46 (m, 6H), 7.64−7.67 (d, J
= 6.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ = 170.8, 170.1, 139.7,
136.6, 134.7, 132.4, 130.1, 130.0, 128.8, 128.5, 128.2, 117.2, 81.0, 65.8,
38.1, 28.0.
tert-Butyl-2-(diphenylmethyleneamino)-3-(phenyl)propanoate
(6d = 6a):18 Purified compound was eluted via gravity column
chromatography, using a mixture of 97:2:1 hexanes/ethyl acetate/
triethylamine. The final product was obtained as white crystals in 60%
1
yield (0.0508 mmol, 19 mg): H NMR (300 MHz, CDCl3) δ = 1.47
(s, 9H), 3.19−3.28 (m, J = 8.9, 4.4 Hz, 2H), 4.12−4.16 (dd, J = 9.6,
4.0 Hz, 1H), 6.62−6.64 (d, J = 7.0 Hz, 2H), 7.07−7.10 (m, 2H),
7.19−7.21 (m, 2H), 7.27−7.39 (m, 5H), 7.51−7.53 (t, J = 7.8 Hz,
1H), 7.59−7.62 (d, J = 7.4 Hz, 2H), 7.82−7.85 (d, J = 7.4 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ = 170.8, 170.2, 139.7, 138.3, 137.6,
132.4, 130.0, 129.8, 128.7, 128.2, 128.0, 127.96, 127.69, 126.1, 81.1,
67.9, 39.6, 28.0.
tert-Butyl-2-(diphenylmethyleneamino)-3-(4-methylphenyl)-
propanoate (6e):19 Compound was purified via gravity column
chromatography, using a mixture of 97:2:1 hexanes/ethyl acetate/
triethylamine. The final product was obtained as clear oil in 92% yield
tert-Butyl-2-(diphenylmethyleneamino)hex-4-enoate (6l):18 Puri-
fied compound was eluted via gravity column chromatography, using a
mixture of 97:2:1 hexanes/ethyl acetate/triethylamine). The final
product was obtained as clear oil in 91% yield (0.0769 mmol, 27 mg):
1H NMR (300 MHz, CDCl3) δ = 1.46 (s, 9H), 1.63−1.65 (d, J = 6.1
Hz, 3H), 2.53−2.62 (m, 2H), 3.95−4.00 (dd, J = 7.6, 2.0 Hz, 1H),
5.31−5.33 (m, 2H), 7.16−7.19 (m, 2H), 7.34−7.46 (m, 6H), 7.64−
7.67 (d, J = 6.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ = 171.1,
1
(0.0778 mmol, 31 mg): H NMR (300 MHz, CDCl3) δ = 1.46 (s,
9H), 2.31 (s, 3H), 3.09−3.25 (m, 2H), 4.09−4.13 (dd, J = 9.0, 4.0 Hz,
1H), 6.60−6.71 (d, J = 7.0 Hz, 2H), 6.94−7.03 (dt, J = 8.7, 7.5 Hz,
4H), 7.27−7.39 (m, 6H), 7.58−7.61 (dd, J = 8.0, 1.4 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ = 170.9, 170.1, 139.6, 136.4, 135.5, 135.2,
130.0, 129.7, 128.7, 128.2, 128.1, 128.0, 127.9, 127.7, 81.05, 68.0, 39.1,
28.0, 21.0.
E
DOI: 10.1021/acs.joc.5b02395
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
169.8, 139.8, 136.8, 130.1, 128.8, 128.4, 128.3, 128.0, 127.95, 127.93,
127.8, 127.1, 126.1, 80.8, 66.4, 36.9, 28.0, 17.9.
K.; Maruoka, K. Angew. Chem., Int. Ed. 2014, 53, 6220−6223.
(f) Parvez, Md. M.; Haraguchi, N.; Itsuno, S. Macromolecules 2014, 47,
1922−1928. (g) Li, M.; Woods, P. A.; Smith, M. D. Chem. Sci. 2013, 4,
2907−2911.
(E)-tert-Butyl 2-((diphenylmethylene)amino)-5-phenylpent-4-
enoate (6m):23 Purified compound was eluted via gravity column
chromatography, using a mixture of 97:2:1 hexanes/ethyl acetate/
triethylamine. The final product was obtained as a viscous white oil in
(10) O’Donnell, M. J.; Eckrich, T. M. Tetrahedron Lett. 1978, 19,
4625−4628.
1
90% yield (0.0694 mmol, 24 mg): H NMR (300 MHz, CDCl3) δ =
(11) Alder, R. W.; Bowman, P. S.; Steele, W. R. S.; Winterman, D. R.
Chem. Commun. 1968, 452, 723−724.
(12) During the preparation of this paper, Lambert reported that 10
decomposed under PTC conditions. See ref 2b.
1.47 (s, 9H), 2.77−2.85 (m, 2H), 4.09−4.13 (m, 1H), 6.08−6.16 (m,
1H), 6.40−6.46 (m, 1H), 7.16−7.45 (m, 13H), 7.31−7.46 (m, 6H),
7.67−7.69 (d, J = 6.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ = 170.9,
170.3, 139.7, 137.5, 136.7, 132.4, 130.2, 128.8, 128.5, 128.4, 128.0,
127.9, 127.0, 126.5, 126.0, 81.1, 66.2, 37.3, 28.1.
(13) Hydroxide-initiated PTC alkylations of O’Donnell’s imine are
generally believed to occur by an interfacial mechanism, while SN2
−
displacements with small, charged nucleophiles (e.g., N3 and F−) are
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02395.
generally believed to occur by an extraction mechanism. See ref 7b and
references therein.
■
S
(14) Makosza, M.; Lasek, W. J. Phys. Org. Chem. 1993, 6, 412−420.
(15) Herriott, A.; Picker, D. J. Am. Chem. Soc. 1975, 97, 2345−2349.
(16) Belding, L.; Taimoory, S. M.; Dudding, T. ACS Catal. 2015, 5,
343−349.
(17) Meirovitch, H.; Scheraga, H. A. Macromolecules 1980, 13, 1406−
1414.
Coordinate and thermochemical data for all structures
and NMR spectra for all reported compounds (PDF)
(18) Kumar, S.; Sobhia, M. E.; Ramachandran, U. Tetrahedron:
Asymmetry 2005, 16, 2599−2605.
AUTHOR INFORMATION
Corresponding Author
*E-mail: tdudding@brocku.ca.
Notes
■
(19) Siva, A.; Murugan, E. Synthesis 2005, 2005, 2927−2933.
(20) Peng, W.; Wan, J.; Xie, B.; Ma, X. Org. Biomol. Chem. 2014, 12,
8336−8345.
(21) Wang, X.; Yin, L.; Yang, T.; Wang, Y. Tetrahedron: Asymmetry
2007, 18, 108−114.
The authors declare no competing financial interest.
(22) Nun, P.; Perez, V.; Calmes, M.; Martinez, J.; Lamaty, F. Chem. -
Eur. J. 2012, 18, 3773−3779.
ACKNOWLEDGMENTS
■
The authors thank Sharcnet for computing resources. Financial
support was provided in part by NSERC Discover Grant (2014-
04410). L.B. is grateful for a NSERC CGS scholarship.
(23) Lee, J. H.; Yoo, M. S.; Jung, J. H.; Jew, S. s.; Park, H. g.; Jeong,
B. S. Tetrahedron 2007, 63, 7906−7915.
REFERENCES
■
(1) (a) Bandar, J. S.; Lambert, T. H. J. Am. Chem. Soc. 2012, 134,
5552−5555. (b) Bandar, J. S.; Lambert, T. H. J. Am. Chem. Soc. 2013,
135, 11799−11802. (c) Wilde, M. M. D.; Gravel, M. Angew. Chem., Int.
Ed. 2013, 52, 12651−12654. (d) Mirabdolbaghi, R.; Dudding, T. Org.
Lett. 2015, 17, 1930−1933.
(2) (a) Mirabdolbaghi, R.; Dudding, T.; Stamatatos, T. Org. Lett.
2014, 16, 2790−2793. (b) Bandar, J. S.; Tanaset, A.; Lambert, T. A.
Chem. - Eur. J. 2015, 21, 7365−7368.
(3) (a) Curnow, O. J.; MacFarlane, D. R.; Walst, K. Chem. Commun.
2011, 47, 10248−10250. (b) Curnow, O. J.; Holmes, M. T.; Ratten, L.
C.; Walst, K. J.; Yunis, R. RSC Adv. 2012, 2, 10794−10797.
(4) (a) Bruns, H.; Patil, M.; Carreras, J.; Vazquez, A.; Thiel, W.;
Goddard, R.; Alcarazo, M. Angew. Chem., Int. Ed. 2010, 49, 3680−
́
̀
3683. (b) Kozma, A.; Gopakumar, G.; Fares, C.; Thiel, W.; Alcarazo,
M. Chem. - Eur. J. 2013, 19, 3542−3546.
(5) Belding, L.; Dudding, T. Chem. - Eur. J. 2014, 20, 1032−1037.
(6) Belding, L.; Stoyanov, P.; Dudding, T. J. Org. Chem. 2015,
DOI: 10.1021/acs.joc.5b01743.
(7) (a) Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107, 5656−
5682. (b) Denmark, S. E.; Gould, N. D.; Wolf, L. M. J. Org. Chem.
2011, 76, 4260−4336. (c) Yang, X.; Phipps, R. J.; Toste, F. D. J. Am.
Chem. Soc. 2014, 136, 5225−5228. (d) Wozniak, Ł.; Murphy, J. J.;
́
Melchiorre, P. J. Am. Chem. Soc. 2015, 137, 5678−5681.
(8) (a) Jayachandran, P.; Wang, M.-L. Synth. Commun. 1999, 29,
4101−4112. (b) Balakrishnan, T.; Jayachandran, P. J. Synth. Commun.
1995, 25, 3821. (c) Balakrishnan, T.; Jayachandran, J. P. J. Chem. Soc.,
Perkin Trans. 2 1995, 2081.
(9) (a) Bernal, P.; Fernandez, R.; Lassaletta, J. M. Chem. - Eur. J.
2010, 16, 7714−7718. (b) Johnson, K. M.; Rattley, M. S.; Sladojevich,
F.; Barber, D. M.; Nunez, M. G.; Goldys, A. M.; Dixon, D. J. Org. Lett.
̃
2012, 14, 2492−2495. (c) Novacek, J.; Waser, M. Eur. J. Org. Chem.
2013, 2013, 637−648 and references therein. (d) Wang, B.; Liu, Y.;
Sun, C.; Wei, Z.; Cao, J.; Liang, D.; Lin, Y.; Duan, H. Org. Lett. 2014,
16, 6432−6435. (e) Shirakawa, S.; Koga, K.; Tokuda, T.; Yamamoto,
F
DOI: 10.1021/acs.joc.5b02395
J. Org. Chem. XXXX, XXX, XXX−XXX