Thiophosphoramide-based cooperative catalysts for Bronsted acid promoted ionic diels-alder reactions

Article abstract of DOI:10.1002/anie.201307133

Three's a crowd: The combination of a Bronsted acid and a hydrogen-bond donor cocatalyst was found to promote various ionic [2+4] cycloadditions under mild reaction conditions (see scheme; Ts=4-toluenesulfonyl) . Thiophosphoramides are the most effective cocatalysts because of the stronger counterion activation effect resulting from three, rather than two, hydrogen bonds involved in anion binding.

Full text of DOI:10.1002/anie.201307133

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Communications
DOI: 10.1002/anie.201307133
Organocatalysis
Hot Paper
Thiophosphoramide-Based Cooperative Catalysts for Brønsted Acid
Promoted Ionic Diels–Alder Reactions**
Alina Borovika, Pui-In Tang, Seth Klapman, and Pavel Nagorny*
Over the past several decades, chemists have gathered
significant evidence that enzymes could drastically accelerate
nucleophilic addition reactions by establishing mutually
reinforcing or cooperative hydrogen bonds within a receptor.
These observations have inspired the development of various
catalytic transformations in which substrate activation is
achieved by the formation of multiple hydrogen bonds with
a synthetic hydrogen-bond donor (HBD).[1]
Our group is interested in developing organocatalytic
transformations involving unsaturated oxocarbenium ions.[4]
Among the best known transformations of this type is the
ionic [2+4] cycloaddition reaction (Gassman cycloaddition)
exemplified by the transformation depicted in Figure 2.[5,6]
The majority of such transformations rely on HBD
activation of neutral substrates by enhancing their electro-
philicity. Recent studies, however, demonstrate that various
ionic reactions proceeding through polar intermediates could
also be catalyzed by HBDs.[1b] In this case, HBD association
with the counter anion of an in situ generated ion pair results
in enhanced reactivity of the cation (Figure 1). Pioneered by
Figure 2. Proposed activation of oxocarbenium ions in ionic [2+4]
cycloadditions. CSA=camphorsulfonic acid.
One of the most popular protocols for such cycloadditions has
been developed by the Grieco group and relies on the use of
a concentrated lithium(I) perchlorate solution (4.0m in
diethyl ether) and catalytic amounts of sulfonic acids.[7a]
Remarkably, challenging cycloaddition reactions could be
achieved under these reaction conditions. Thus, by employing
the Grieco protocol, Danishefsky and co-workers accom-
plished the formation of the cycloadduct 3 (Figure 2),[8] which
is notoriously difficult to obtain by Lewis-acid activation of
the carbonyl-containing dienophiles equivalent to 1. Both the
presence of lithium(I) perchlorate and catalytic sulfonic acid
are essential for the progression of this reaction, and no
reaction occurs if one of these components is omitted. It has
been proposed that a highly ionic medium is essential for the
separation of the counterions and the generation of a more
reactive separated ion pair (4).[7] At the same time, a highly
polar medium is important for the tighter association of 4 and
diene 2, and results in a decreased transition-state volume.
Despite their synthetic utility, current ionic [2+4] cyclo-
addition protocols have significant limitations since the use of
Lewis acids in combination with low reaction temperatures or
explosive additives such as lithium(I) perchlorate are neces-
sary. Herein we describe a mild organocatalytic protocol that
is based on the cooperative catalysis of Brønsted acids and
HBD co-catalysts.[9] Driven by the hypothesis that complex-
ation to a hydrogen-bond donor could significantly enhance
the reactivity of 4 by the formation of a more separated ion
pair (5, Figure 2), we evaluated various HBDs and discovered
that catalytic quantities of the thiophosphoramide 7e (see
Table 1) significantly accelerate the rates of ionic Diels–Alder
Figure 1. Hydrogen-bond donor/anion acceptor organocatalysis.
Ts =4-toluenesulfonyl.
the Jacobsen group,[2] counterion activation has been utilized
to enhance the reactivity of various iminium ions as well as
certain reactions proceeding through stabilized oxocarbe-
nium- and carbenium-based ion pairs.[3]
[*] A. Borovika,[+] P.-I. Tang,[+] S. Klapman, Prof. Dr. P. Nagorny
Department of Chemistry, University of Michigan
Ann Arbor, MI 48109 (USA)
E-mail: nagorny@umich.edu
[+] These authors contributed equally to this work.
[**] We thank the ACS PRF (53428-DNI1 to P.N.), the University of
Michigan, and NSF GRFP (DGE 0718128 to A.B.) for the financial
support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307133.
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reactions catalyzed by the Brønsted acids. We are not aware
of the prior use of three-hydrogen-bond donors such as 7e for
anion-binding activation, and demonstrate that 7e is an
excellent activator of sulfonate anions associated with vinyl
oxocarbenium ions.
Our studies commenced with the evaluation of various
HBD cocatalysts in the p-TSA-catalyzed reaction of com-
mercially available acrolein acetal (6) and cyclopentadiene
(Table 1) in toluene at À108C. When exposed to p-TSA
cyclopentadiene, and the quantitative formation of 8 was
detected within one hour (entry 6). To test if all three NH
bonds are essential for the anion activation, 7c and 7d were
evaluated next (entries 4 and 5). Both catalysts were inferior
to 7e in promoting the formation of 8 and only minor
amounts of the product were observed in each case. A control
experiment in the absence of p-TSA was conducted (entry 7),
and formation of the product was not detected.
The geometry of 7e is optimal for forming three hydrogen
bonds with polyoxygenated tetrahedral anions formed by
group III elements (e.g. sulfonates, phosphates, perchlorates,
etc.). However, even in the situation when there is no clear
geometric preference for anion binding, 7e outperformed 7a
as the co-catalyst (Table 1, entries 8–13). While the acidity of
HCl (pKa = 1.8 in DMSO) is close to the acidity of sulfonic
acids (pKa of MsOH in DMSO is 1.6), a chloride anion could
form a tighter ion pair with an oxocarbenium than sulfonate
anions, in which the negative charge is distributed across three
oxygen atoms. Consistent with this presumption, a signifi-
cantly longer reaction time (24 h) was required to observe the
formation of the product 8, and the reaction catalyzed by 7e
proceeded to a greater extent (33%, entry 10) than the
corresponding reaction promoted by 7a (22%, entry 9).
Similar trends were observed for the HBr-catalyzed forma-
tion of 8 (entries 11–13). HBr is stronger than both hydro-
chloric and p-toluenesulfonic acids (pKa = 0.9 in DMSO), and
bromide is a weaker coordinating anion than chloride. As
expected, HBr alone promoted the reaction to a significantly
higher extent than HCl (37% conversion, 10 h, entry 11).
Similar to the HCl case, the use of 7e as a co-catalyst resulted
in an accelerated reaction (97% conversion, 10 h, entry 13).
Notably, these experiments indicate that the weaker p-
toluenesulfonic acid is a more effective catalyst than the
stronger HBr when combined with 7e in promoting the
formation of cycloadduct 8. We attribute this effect to the
higher affinity of 7e to the tetrahedral sulfate anion because
of its geometric predisposition to form three hydrogen bonds
with the sulfonate oxygen atoms. Finally, to demonstrate that
hydrogen-bond donors could accelerate reactions promoted
by triflic acid, we conducted the experiments described in
entries 14–16. Triflic acid alone promoted the formation of 8
at À358C. However, this reaction was slow and only 20% of 8
was observed after 1.5 h. The addition of thiourea co-catalyst
7a did not enhance the cycloaddition, however, 78%
conversion was observed when 7e was employed as the co-
catalyst (entry 16).
Table 1: Evaluation of HBD-based cocatalysts of the ionic [2+4] cyclo-
addition.[a]
Entry
Acid
Catalyst
t [h]
T [8C]
endo/exo
Conv. [%][b]
1
2
3
4
5
6
7
8
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
none
HCl
HCl
HCl
HBr
HBr
none
7a
7b
7c
7d
7e
7e
none
7a
7e
none
7a
7e
none
7a
7e
1
1
1
1
1
À10
À10
À10
À10
À10
À10
À10
À10
À10
À10
À10
À10
À10
À35
À35
À35
n.a.
n.a.
1.5:1
n.a.
2.5:1
3:1
n.a.
n.a.
3:1
0
0
15
2
7
98
0
1
1
24
24
24
10
10
10
1.5
1.5
1.5
0
9
22
33
37
46
97
20
0
10
11
12
13
14
15
16
2.9:1
n.a.
3:1
HBr
3:1
TfOH
TfOH
TfOH
n.a.
n.a.
3:1
78
[a] These experiments were performed on 0.5–0.7 mmol scale (0.3m
solution) using 3 equivalents of cyclopentadiene. [b] The reaction yields
were determined by 1H NMR analysis of the crude reaction mixtures
using an internal standard. p-TSA=para-toluenesulfonic acid, Tf=tri-
fluoromethanesulfonyl.
(3 mol%) without a co-catalyst or in combination with the
thiourea 7a (6 mol%), no formation of the cycloadduct 8 was
detected after one hour under the aforementioned reaction
conditions (entries 1 and 2). The NH hydrogen atoms of the
squaramide 7b are further apart than those in 7a, and
consequently 7b is better geometrically suited for binding the
oxygen atoms of the sulfate anion.[10] Indeed, when used as
a cocatalyst under identical reaction conditions, 7b promoted
the formation of 8 (entry 3), albeit in 15% conversion. In our
search for alternative HBDs, we turned our attention to the
thiophosphoramides 7c–e.[11,12] We surmised that 7e is geo-
metrically more suited for binding a sulfate anion and could
potentially form up to three hydrogen bonds with the
negatively charged oxygen atoms of sulfate (see Figure 1 for
an example of such complex).[13] Gratifyingly, when used as
a cocatalyst, 7e significantly accelerated the reaction of 6 and
With the optimal reaction conditions in hand, the scope of
the ionic [2+4] cycloadditions was explored next (Table 2). To
evaluate synthetic utility of this protocol, the scope of both
dienes (entries 1–4) and dienophiles (entries 5–7) as well as
the application of this method to the preparation of syntheti-
cally useful cis-decaline-based building blocks (entries 8–10)
has been examined. The reaction of 2-vinyl-1,3-dioxolane
with various dienes such as cyclopentadiene (entry 1), 2,3-
dimethyl-1,3-butadiene
(entry 2),
1,3-cyclohexadiene
(entry 3) and 1,4-diphenyl-1,3-butadiene (entry 4) resulted
in the formation of the cycloadducts 10 in good to excellent
yields (57–92%) upon isolation when p-TSA was used in
combination with 7e. However, neither p-TSA alone nor the
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Table 2: The scope of the organocatalytic ionic [2+4] cycloaddition.[a]
hexenone and 2-methyl-2-cyclohexenone-derived
dioxolanes were tested (Table 2, entries 8 and 9).
While the cycloadditions leading to the correspond-
ing products 10 were found to be slow in toluene, the
use of dichloromethane as the solvent and an
increased catalyst loading (5 mol% of p-TSA,
10 mol% of 7e) led to the formation of the
corresponding cycloadducts in good yields (68%
and 84% respectively).
Finally, to test whether this method is applicable
to the challenging cycloadditions the reaction of 2-
(cyclohex-1-en-1-yl)-1,3-dioxolane and 2,3-dimethyl-
1,3-butadiene was executed (Table 2, entry 10). The
Lewis acid catalyzed reactions of cyclohex-1-ene-
carbaldehyde or cyclohex-1-enecarboxylates are
notoriously difficult to execute with unactivated
dienes, while the Grieco protocol could be used to
provide the analogous cycloadduct 3 in 53% yield
(Figure 2).[8] Remarkably, 7e in combination with p-
TSA was sufficient to promote the formation of the
corresponding cycloadduct in 59% yield (Table 2,
entry 10) without resorting to the use of a highly
ionic medium [4m solution of lithium(I) perchlorate
in diethyl ether].
To confirm that 7e complexes anions and to gain
a better understanding of the observed effect, bind-
ing and computational studies have been conducted
(Figure 3). First, the association of 7e with sulfonate
anions was confirmed by combining 7e with known
methylpyridinium tosylate (11) in different propor-
tions. Thus, the addition of 11 to solution of 7e
resulted in a concentration-dependent downfield
shift of the phosphoramide NH protons in the
1H NMR spectrum, which is characteristic of hydro-
gen bonding to anion (Figure 3A).[14] The stoichi-
ometry of the resultant complex between 11 and 7e
was determined by 1H NMR titration and resulted in
the Job plot depicted in Figure 3B.[15] The stoichi-
ometry of binding is consistent with the formation of
1:1 complex between 11 and 7e. WinEQNMR[16] was
used to establish the association constant of this
complex (Ka = 7.3 ꢀ 104 mÀ1 in CDCl3). Based on the
value of Ka, we conclude that 7e strongly binds the
tosylate anion of 11 in chloroform. However, our
further attempts to compare this value with the
corresponding Ka values of 7a/TsÀ or 7e/ClÀ did not
result in conclusive results because of the more
Entry Dienophile
Diene
Product
(10)
t [h] Catalyst Yield
endo/
exo
(9)
[%][b]
none
7a
7e
18
<5
92
<5
<5
76
2.8:1
–
2.4:1
1
2
3
1
none
14 7a
–
–
–
7e
none
16 7a
<5
<5
–
–
20:1
7e
85
none
7a
<5
<5
–
–
4[c,d]
6
7e
57
8.3:1
none
0.8 7a
7
17
91
5.5:1
4.6:1
4.7:1
5[c]
7e
none
7a
7e
<5
<5
63
–
–
6
7
3
2
4.8:1
none
7a
9
<5
2:1
–
2:1
7e
81
13
<5
none
7a
–
–
–
8[c]
2
7e
68
none
24 7a
28
13
84
–
–
–
9[c,d]
7e
none
24 7a
<5
<5
59
–
–
–
10[c]
7e
[a] These experiments were performed on 0.5–0.9 mmol scale (0.3m solution in
toluene) using 5 equivalents of cyclopentadiene. [b] The yields of the isolated
products are reported for the reactions catalyzed by p-TSA/7e. The yields for the
reactions catalyzed by p-TSA or p-TSA/7a were determined by 1H NMR analysis of
the crude reaction mixtures using an internal standard. [c] These experiments were
performed on 0.3–0.7 mmol scale (0.6m solution in dichloromethane) using
5 equivalents of cyclopentadiene, 5 mol% of p-TSA and 10 mol% of 7a or 7e.
[d] The reaction was conducted at room temperature.
combination of p-TSA and 7a could promote the formation of
10 to a significant extent. Similarly, the reactions of 5,5-
dimethyl-2-vinyl-1,3-dioxane (entry 5), (E)-2-styryl-1,3-di-
oxolane (entry 6), and (E)-2-(prop-1-en-1-yl)-1,3-dioxolane
(entry 7) resulted in synthetically useful yields (63–91%)
when p-TSA/7e were employed as the catalysts, but failed to
result in significant amounts of 10 when only p-TSA or the
combination of p-TSA and 7a were used as catalysts.
The ionic [2+4] cycloadditions have found a widespread
application in the synthesis of highly functionalized decalins.
To demonstrate that our protocol is amenable to the synthesis
of these valuable building blocks, the reactions of 2-cyclo-
complex stoichiometries of the resultant supramolecular
complexes.[17]
Finally, computational studies were initiated to model the
interactions of the sulfonate and 7e (Figure 3C). Thus, DFT-
based geometry optimization of 7e and mesylate (B3LYP, 6-
31 + G*, toluene) resulted in a complex, in which the three
NH hydrogen atoms of 7e are bound to all three oxygen
atoms of the mesylate anion. This complex was found to be
more stable by 3.7 kcalmolÀ1 than the corresponding complex
of thiourea 7a (see the Supporting Information). While these
results support the proposal that 7e is the most effective
cocatalyst because of its stronger association with anions, and
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Figure 3. A) 1H NMR spectra for the titration of 7e (0.5 mm in CDCl3) with 11. The thiophosphoramide NH downfield shift is observed upon
addition of 11. B) Job plot for the titration of 11 with 7e. The maximum mole fraction equal to 0.5 is consistent to 1:1 complex between 11 and
7e with the association constant Ka of 73000mÀ1 in CDCl3 (determined by WinEQNMR). C) Complex of thiophosphoramide 7e and mesylate
anion (DFT, B3LYP, equilibrium geometry of the ground state in toluene, 6-31+G*).
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consequently results in more activated vinyl oxocarbenium
ion, a more complex mechanistic scheme is likely to be
operational.
In conclusion, the combination of a Brønsted acid as the
catalyst and a hydrogen-bond donor as the co-catalyst can be
used to catalyze a variety of ionic [2+4] cycloaddition
reactions under mild reaction conditions and does not require
the use of a highly ionic medium [e.g. 4m lithium(I)
perchlorate in ether]. Remarkably, the thiophosphoramide
7e, which has not been previously utilized for the anion
binding, was found to be superior to the standard two-
hydrogen-bond donors such as 7a or 7b. Computational and
NMR studies suggest that preference could be attributed to
the ability of 7e to form strong three-hydrogen-bond-
containing complexes with the anions. This effect was found
to be especially strong for sulfonate anions, the geometry of
which favors the formation of three hydrogen bonds with the
sulfonate oxygen atoms. Further studies of this and related
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Received: August 14, 2013
Published online: October 18, 2013
Keywords: cycloaddition · cooperative catalysis ·
.
hydrogen bonds · organocatalysis · synthetic methods
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[13] During the preparation of this manuscript, a study describing the
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[16] We thank Dr. Hynes for providing us permission to use
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