Hydrogen-Bonding Catalysis of Tetraalkylammonium Salts in an Aza-Diels–Alder Reaction

Article abstract of DOI:10.1002/asia.201600781

A piperidine-derived tetraalkylammonium salt with a non-coordinating counteranion worked as an effective hydrogen-bonding catalyst in an aza-Diels–Alder reaction of imines and a Danishefsky diene. The hydrogen-bonding interaction between the ammonium salt and an imine was observed as part of a ¹H NMR titration study.

Full text of DOI:10.1002/asia.201600781

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Hydrogen-Bonding Catalysis of Tetraalkylammonium Salts in an Aza Diels-
Alder Reaction
Authors: Yusuke Kumatabara; Shiho Kaneko; Satoshi Nakata; Seiji Shirakawa; Keiji
Maruoka
This manuscript has been accepted after peer review and the authors have elected
to post their Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by using the Digital
Object Identifier (DOI) given below. The VoR will be published online in Early View as
soon as possible and may be different to this Accepted Article as a result of editing.
Readers should obtain the VoR from the journal website shown below when it is pu-
blished to ensure accuracy of information. The authors are responsible for the content
of this Accepted Article.
To be cited as: Chem. Asian J. 10.1002/asia.201600781
Link to VoR: http://dx.doi.org/10.1002/asia.201600781
A Journal of
A sister journal of Angewandte Chemie
and Chemistry – A European Journal

Chemistry - An Asian Journal
10.1002/asia.201600781
COMMUNICATION
Hydrogen-Bonding Catalysis of Tetraalkylammonium Salts in an
Aza Diels-Alder Reaction
Yusuke Kumatabara,[a] Shiho Kaneko,[a] Satoshi Nakata,[a] Seiji Shirakawa,*[a] and Keiji Maruoka[b]
Abstract: Piperidine-derived tetraalkylammonium salt with a non-
coordinating counteranion worked as an effective hydrogen-bonding
catalyst in an aza Diels-Alder reaction of imines and a Danishefsky
diene. The hydrogen-bonding interaction between the ammonium
salt and an imine was observed as part of a 1H NMR titration study.
reaction.[9] Here we clarify the role of tetraalkylammonium salt
catalysts in an aza Diels-Alder reaction of imines 1 and
Danishefsky diene 2.
R4N+ X–
(10 mol %)
OMe
R'
H
R'
N
N
+
Tetraalkylammonium salts are important and reliable catalysts in
organocatalytic chemistry,[1] and are mainly employed in phase-
transfer catalysis and base catalysis to activate nucleophiles
through the formation of ion pairs, such as ammonium
enolates.[2] In the catalysis of tetraalkylammonium salts, Park et
al. reported the tetraalkylammonium salts-catalyzed aza Diels-
Alder reaction of imines 1 and a Danishefsky diene 2 (Scheme
1).[3] Several interesting observations were reported in that
study.[3a] First, the ammonium salt catalysts with an iodide anion
promoted the reaction more efficiently than the catalysts with
R
R
O
OSiMe3
1
2
3
Effect of counter anion
Effect of structure
Bu4N+ X–
Br
I– > Br– >> F–
N
Bu N+ Br–
high yield
>
4
Ar
OR
N
high yield
How to activate substrates??
other
halide
counteranions.
The
reaction
with
tetraalkylammonium fluorides gave almost none of the target
product 3. These results ruled out the possibility of a base
catalysis of the ammonium salts to promote the reaction.
Second, cinchona alkaloid-derived ammonium bromides proved
Scheme 1. Effect of tetraalkylammonium salt catalysts in an aza Diels-Alder
reaction, as reported by Park.[3a]
to be
bromide. The reaction with cinchona alkaloid-derived catalysts
produced the products in high yields with almost no
enantioselectivities. Although the authors suggested
a more effective catalyst than tetrabutylammonium
3
tetraalkylammonium salts worked as Lewis acid catalysts for this
reaction,[4] the theoretical and experimental evidence has never
been reported, and the role of the tetraalkylammonium salt has
remained unclear. In our recent study on a new dimension of
tetraalkylammonium
salt
catalysis,
we
proved
that
tetraalkylammonium salts
4
worked as hydrogen-bonding
catalysts[5] in a Mannich-type reaction through the hydrogen-
bonding interaction between α-hydrogens of the catalyst and
chloride on the substrate (Scheme 2).[6] The hydrogen-bonding
abilities of tetraalkylammonium salts were supported by DFT
calculations[7] and X-ray crystal structure analysis[8] by other
research groups. Based on these reports, we hypothesized that
tetraalkylammonium salts could activate imines
hydrogen-bonding interaction to promote the aza Diels-Alder
1 via a
Scheme 2. Tetraalkylammonium salt as
a hydrogen-bonding catalyst in
Mannich-type reactions, as reported by our group.[6a]
To prove our hypothesis, we initially investigated the
structure-catalytic activity relationships of tetraalkylammonium
salts in an aza Diels-Alder reaction of N-phenylbenzaldimine 1a
and Danishefsky diene 2 (Table 1). In the absence of a catalyst,
the reaction in dichloromethane proceeded very slowly at 0 °C to
give product 3a in a 4% yield after 3 h (entry 1). When
tetrabutylammonium iodide was used as a catalyst under these
conditions, the reaction was only promoted to a moderate extent
(22% yield; entry 2). Next, we examined the ammonium iodides
4a and 4b, which possess a piperidine backbone. As expected,
the reaction was efficiently accelerated by catalyst 4a (Y =
[a]
[b]
Y. Kumatabara, S. Kaneko, S. Nakata, Prof. Dr. S. Shirakawa
Department of Environmental Science, Graduate School of
Fisheries and Environmental Sciences
Nagasaki University
1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
E-mail: seijishirakawa@nagasaki-u.ac.jp
Homepage: http://seijishirakawa.wix.com/greenchemistry
Prof. Dr. K. Maruoka
Department of Chemistry, Graduate School of Science
Kyoto University
Sakyo, Kyoto 606-8502, Japan
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
For internal use, please do not delete. Submitted_Manuscript

Chemistry - An Asian Journal
10.1002/asia.201600781
COMMUNICATION
reaction.[a]
CO2Me) bearing carboxylate groups, which was an effective
hydrogen-bonding catalyst for the Mannich-type reaction in
Scheme 2,[6a] to give product 3a in a 64% yield (entry 3). The
simple piperidine derived-catalyst 4b (Y = H) was also an
effective catalyst for the aza Diels-Alder reaction, and the yield
of 3a was somewhat improved (67% yield; entry 4). Although
catalyst 4a possessed more acidic α-hydrogens that showed
superior activity to 4b in our previous work on Mannich-type
reactions,[6a] similar reactivities between 4a and 4b were
observed in the present aza Diels-Alder reaction. These different
trends might be explained by the differences in the structures of
the electrophiles, because steric repulsion was present between
the phenyl group of imine 1a and the carboxylate groups of
catalyst 4a (Figure 1a). As a result, catalysts 4a and 4b
exhibited similar reactivity for the aza Diels-Alder reaction with
imines 1. Furthermore, quinuclidine-derived ammonium iodide 5
showed higher reactivity than tetrabutylammonium iodide (57 vs.
R4N+ X–
(10 mol %)
OMe
Ph
Ph
N
N
+
CH2Cl2
0 °C, 3 h
Ph
H
Ph
O
OSiMe3
1a
2
3a
F3C
CF3
X
I
F3C
CF3
CF3
N
Y
N
Y
4
5
B
4a : X– = I–, Y = CO2Me
4b : X– = I–, Y = H
4c : X– = BArF–, Y = CO2Me
4d : X– = BArF–, Y = H
F3C
F3C
CF3
BArF–
Entry
R4N+ X–
None[c]
Bu4N+ I–
4a
Yield [%][b]
1
2
3
4
5
6
7
4
22% yields; entries
5 vs. 2). Multiple hydrogen-bonding
22
64
67
57
85
89
interactions between α-hydrogens and a counteranion were
observed in the X-ray crystal structures of cinchona alkaloid-
derived quaternary ammonium salts, as shown in Figure 1b.[10]
This multiple binding mode of α-hydrogens on quinuclidine-type
ammonium salts was similar to the mode seen in piperidine-type
ammonium salts 4 (Figure 1b and Scheme 2).[6a] Based on these
observations, we concluded that an arrangement of α-hydrogens
to appropriate positions, which were induced by the cyclic
structure, is essential in the design of effective hydrogen-
bonding catalysts based on tetraalkylammonium salts. In order
to further improve the catalytic activity of piperidine-type
catalysts 4, tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BArF–)
was employed as a non-coordinating counteranion. Finally, we
obtained product 3a in high yields using catalysts 4c and 4d,
which possessed a BArF– counteranion (85% yield with 4c; 89%
yield with 4d, entries 6 and 7).
4b
5
4c
4d
[a] Reaction conditions: 1a (0.10 mmol),
2
(0.15 mmol),
tetraalkylammonium salt (0.010 mmol, 10 mol %), CH2Cl2 (2 mL), 0 °C, 3 h.
[b] Yield of the isolated product 3a. [c] The reaction was performed without
a catalyst.
Figure 1. Hydrogen-bonding interactions on the α-hydrogens of
tetraalkylammonium salts.
To further prove the hydrogen-bonding interaction between
the α-hydrogens of 4 and imine 1, we performed a 1H NMR
titration study of 4d with imine 1a (Figure 2). As a result of the
titration of 1a, clear upfield chemical shifts of the α-hydrogens on
1
4d were observed in the H NMR measurements of CDCl3. On
the other hand, almost no chemical shift changes were observed
for the aromatic protons of the BArF– counteranion moiety. This
result
strongly
supported
the
proposition
that
tetraalkylammonium salts could activate imines 1 via hydrogen
bonding to promote an aza Diels-Alder reaction.[11]
Table 1. Effect of tetraalkylammonium salts on the aza Diels-Alder
For internal use, please do not delete. Submitted_Manuscript

Chemistry - An Asian Journal
10.1002/asia.201600781
COMMUNICATION
Table 2. Scope of the aza Diels-Alder reaction.[a]
BArF
N
4d
OMe
R'
H
R'
N
(10 mol %)
N
+
CH2Cl2
0 °C, 3 h
R
R
O
OSiMe3
1
2
3
Entry
1
Yield [%][b]
1
2
3
4
5
6
7
8
9
1b: R = Ph, R’ = 4-Cl–C6H4
1c: R = Ph, R’ = 4-MeO–C6H4
1d: R = Ph, R’ = PhCH2
80 (12[c]) [3b]
50 (6[c]) [3c]
38 (trace[c]) [3d]
70 (9[c]) [3e]
82 (9[c]) [3f]
1e: R = 3-Br–C6H4, R’ = Ph
1f: R = 4-Ph–C6H4, R’ = Ph
1g: R = 4-NO2–C6H4, R’ = Ph
1h: R = 2-furyl, R’ = Ph
64 (23[c]) [3g]
46 (10[c]) [3h]
86 (17[c]) [3i]
58 (20[c]) [3j]
Figure 2. 1H NMR titration study of tetraalkylammonium salt 4d with imine 1a.
1i: R = 2-pyridyl, R’ = Ph
1j: R = c-C6H11, R’ = Ph
With important information about the hydrogen-bonding
catalysis of tetraalkylammonium salts for an aza Diels-Alder
reaction in hand, the substrate generality of imines 1 was
examined with catalyst 4d. At first, the effect of the substituents
on the nitrogen in imines 1 (R’) was examined. Imines 1b and 1c
were derived from substituted anilines and could be applied to
this reaction to give product 3b and 3c in moderate to good
yields (80 and 50% yields respectively, entries 1 and 2).
Benzylamine derivative 1d could also be applied to this reaction,
although the yield of product 3d was only moderate (38% yield,
entry 3). Next, we examined the generality of the R group on
imines 1. Not only substituted aromatics (1e–1g) but also
heteroaromatics (1h and 1i) and alkyl (1j) group-introduced
imines could be employed for the reaction to obtain products
3e–3j in moderate to good yields (46–86% yields, entries 4–9). It
should be noted that the addition of catalyst 4d produced clear
accelerations of each reaction. Although imine 1g possessed a
[a] Reaction conditions: 1 (0.10 mmol), 2 (0.15 mmol), catalyst 4d (0.010
mmol, 10 mol %), CH2Cl2 (2 mL), 0 °C, 3 h. [b] Yield of the isolated product
3. [c] The yield in parenthesis refers to the reaction without a catalyst.
In
summary,
we
have
demonstrated
that
tetraalkylammonium salts can function as hydrogen-bonding
catalysts to activate imines 1 in an aza Diels-Alder reaction. The
structure-catalytic activity relationships of tetraalkylammonium
salt catalysts were discussed in this study based on the reported
X-ray crystal data of ammonium salts. Furthermore, 1H NMR
titration study was performed to observe the hydrogen-bonding
interaction between piperidine-derived tetraalkylammonium salt
4d and phenylbenzaldimine 1a. We are currently investigating a
further application of alkylonium salts as hydrogen-bonding
catalysts.
nitro group that could have strongly coordinated with
a
hydrogen-bonding donor, catalyst acceleration was observed,
albeit to only a moderate degree (64% yield with 4d, 23% yield
without catalyst, entry 6).
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scientific
Research(C) from JSPS, the Cooperative Research Program of
"Network Joint Research Center for Materials and Devices", and
The Naito Foundation.
Keywords: aza Diels-Alder reaction • hydrogen bonds •
hydrogen-bonding catalysis • organocatalysis •
tetraalkylammonium salts
[1]
For reviews on organocatalysis, see: a) P. I. Dalko, L. Moisan, Angew.
Chem. Int. Ed. 2001, 40, 3726; Angew. Chem. 2001, 113, 3840; b) P. I.
For internal use, please do not delete. Submitted_Manuscript

Chemistry - An Asian Journal
10.1002/asia.201600781
COMMUNICATION
Dalko, L. Moisan, Angew. Chem. Int. Ed. 2004, 43, 5138; Angew.
Chem. 2004, 116, 5248; c) D. W. C. MacMillan, Nature 2008, 455, 304;
d) Comprehensive Enantioselective Organocatalysis: Catalysts,
Reactions, and Applications (Ed.: P. I. Dalko), Wiley-VCH, Weinheim,
2013.
2004, 43, 2062; Angew. Chem. 2004, 116, 2110; c) A. G. Doyle, E. N.
Jacobsen, Chem. Rev. 2007, 107, 5713; d) T. J. Auvil, A. G. Schafer, A.
E. Mattson, Eur. J. Org. Chem. 2014, 2633.
[6]
[7]
a) S. Shirakawa, S. Liu, S. Kaneko, Y. Kumatabara, A. Fukuda, Y.
Omagari, K. Maruoka, Angew. Chem. Int. Ed. 2015, 54, 15767; Angew.
Chem. 2015, 127, 15993; see also: b) C. Thomas, A. Milet, F. Peruch,
B. Bibal, Polym. Chem. 2013, 4, 3491; c) C. Thomas, S. Brut, B. Bibal,
Tetrahedron 2014, 70, 1646.
[2]
For reviews on phase-transfer catalysis, see: a) E. V. Dehmlow, S. S.
Dehmlow, Phase Transfer Catalysis, 3rd ed., VCH, Weinheim, 1993; b)
C. M. Starks, C. L. Liotta, M. Halpern, Phase-Transfer Catalysis,
Chapman & Hall, New York, 1994; c) Handbook of Phase-Transfer
a) M. T. Reetz, Angew. Chem. Int. Ed. Engl. 1988, 27, 994; Angew.
Chem. 1988, 100, 1026; b) C. E. Cannizzaro, K. N. Houk, J. Am. Chem.
Soc. 2002, 124, 7163; c) T. Ohshima, T. Shibuguchi, Y. Fukuta, M.
Shibasaki, Tetrahedron 2004, 60, 7743; d) T. C. Cook, M. B. Andrus, D.
H. Ess, Org. Lett. 2012, 14, 5836; e) T. Kamachi, K. Yoshizawa, Org.
Lett. 2014, 16, 472; f) Q. Peng, R. S. Paton, Acc. Chem. Res. 2016, 49,
1042.
Catalysis (Eds.: Y. Sasson, R. Neumann), Blackie Academic
&
Professional, London, 1997; d) Phase-Transfer Catalysis (Ed.: M. E.
Halpern), American Chemical Society: Washington DC, 1997 (ACS
Symposium Series 659); e) M. J. O’Donnell, Aldrichimica Acta 2001, 34,
3; f) T. Ooi, K. Maruoka, Acc. Chem. Res. 2004, 37, 526; g) T. Ooi, K.
Maruoka, Angew. Chem. Int. Ed. 2007, 46, 4222; Angew. Chem. 2007,
119, 4300; h) Asymmetric Phase-Transfer Catalysis (Ed.: K. Maruoka),
Wiley-VCH, Weinheim, 2008; i) S.-s. Jew, H.-g. Park, Chem. Commun.
2009, 7090; j) S. Shirakawa, K. Maruoka, Angew. Chem. Int. Ed. 2013,
52, 4312; Angew. Chem. 2013, 125, 4408; k) S. Kaneko, Y.
Kumatabara, S. Shirakawa, Org. Biomol. Chem. 2016, 14, 5367.
a) Y. Park, E. Park, H. Jung, Y.-J. Lee, S.-s. Jew, H.-g. Park,
Tetrahedron 2011, 67, 1166; see also: b) C. Loncaric, K. Manabe, S.
Kobayashi, Chem. Commun. 2003, 574.
[8]
[9]
a) M. T. Reetz, S. Hütte, R. Goddard, J. Am. Chem. Soc. 1993, 115,
9339; b) M. T. Reetz, S. Hütte, R. Goddard, J. Phys. Org. Chem. 1995,
8, 231; c) M. T. Reetz, S. Hütte, R. Goddard, C. Robyr, Chem. Eur. J.
1996, 2, 382; d) M. T. Reetz, S. Hütte, R. Goddard, J. Prakt. Chem.
1999, 341, 297; e) R. Goddard, H. M. Herzog, M. T. Reetz, Tetrahedron
2002, 58, 7847.
[3]
[4]
For examples of hydrogen bond-promoted hetero Diels-Alder reactions,
see: a) Y. Huang, V. H. Rawal, J. Am. Chem. Soc. 2002, 124, 9662; b)
Y. Yuan, X. Li, K. Ding, Org. Lett. 2002, 4, 3309; c) Y. Huang, A. K.
Unni, A. N. Thadani, V. H. Rawal, Nature 2003, 424, 126; see also: d) Y.
Takeda, D. Hisakuni, C.-H. Lin, S. Minakata, Org. Lett. 2015, 17, 318.
Although quaternary phosphonium salts were known to work as Lewis
acid catalysts via hypervalent bonding, quaternary ammonium salts
could not form hypervalent species. Then, quaternary ammonium salts
could not work as Lewis acid catalysts. For examples of quaternary
phosphonium salts as Lewis acid catalysts, see: a) M. Terada, M.
Kouchi, Tetrahedron 2006, 62, 401; see also: b) T. Mukaiyama, S.
Matsui, K. Kashiwagi, Chem. Lett. 1989, 993; c) T. Mukaiyama, K.
Kashiwagi, S. Matsui, Chem. Lett. 1989, 1397.
[10] a) E. J. Corey, F. Xu, M. C. Noe, J. Am. Chem. Soc. 1997, 119, 12414;
b) S.-s. Jew, M.-S. Yoo, B.-S. Jeong, I. Y. Park, H.-g. Park, Org. Lett.
2002, 4, 4245; see also: c) K. Bark, E. N. Jacobsen, Angew. Chem. Int.
Ed. 2013, 52, 534; Angew. Chem. 2013, 125, 558.
[11] The 1H NMR titration study of tetraalkylammonium salt 4c with imine 1a
was also performed. For detail, see the Supporting Information.
[5]
For reviews on hydrogen-bonding catalysis, see: a) P. R. Schreiner,
Chem. Soc. Rev. 2003, 32, 289; b) P. M. Pihko, Angew. Chem. Int. Ed.
For internal use, please do not delete. Submitted_Manuscript

Chemistry - An Asian Journal
10.1002/asia.201600781
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Hydrogen-bonding catalyst
Piperidine-derived
tetraalkylammonium salt with a non-
coordinating counteranion worked as
Yusuke Kumatabara, Shiho Kaneko,
Satoshi Nakata, Seiji Shirakawa,* Keiji
Maruoka
(non-coordinating counteranion)
(six-membered ring)
BArF
an effective hydrogen-bonding
catalyst in an aza Diels-Alder
reaction of imines and a Danishefsky
diene. The hydrogen-bonding
interaction between the ammonium
salt and an imine was observed as
part of a 1H NMR titration study.
H
H
H
H
(acidic a -hydrogens)
R'
N
Page No. – Page No.
N
+
H3C CH3
R'
N
Hydrogen-Bonding Catalysis of
Tetraalkylammonium Salts in an Aza
Diels-Alder Reaction
R
H
(10 mol %)
OMe
R
O
CH2Cl2
38–89% yields
0 °C, 3 h
OSiMe3
For internal use, please do not delete. Submitted_Manuscript