Diazepane Carboxylates as Organocatalysts in the Diels–Alder Reaction of α-Substituted Enals

Article abstract of DOI:10.1002/ejoc.201801009

Ethyl diazepane carboxylate efficiently catalyzes the Diels–Alder cycloaddition of α-substituted-α,β-unsaturated aldehydes via iminium ion organocatalysis. The reaction is applicable to a range of dienes and dienophiles and generally proceeds at room temperature in the presence of 5 mol-% catalyst and 2.5 mol-% triflic acid co-catalyst. The incorporation of a stereogenic center on the diazepane backbone in combination with a menthyl carbamate produces a catalyst which affords enantioselectivities of 70–95 % ee for the cycloaddition of cyclopentadiene with a range of dienophiles. The enantioselectivity is rationalized via a transition state in which electrostatic stabilization by the carboxylate directs the diene to the more hindered face of the dienophile.

Full text of DOI:10.1002/ejoc.201801009

A Journal of
Accepted Article
Title: Diazepane Carboxylates as Organocatalysts in the Diels-Alder
Reaction of α-Substituted Enals
Authors: Nicklas Haggman, Benjamin Zank, HyunJune Jun, Dainis
Kaldre, and James L. Gleason
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801009
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10.1002/ejoc.201801009
European Journal of Organic Chemistry
COMMUNICATION
Diazepane Carboxylates as Organocatalysts in the Diels-Alder
Reaction of α-Substituted Enals
Nicklas O. Häggman, Benjamin Zank, HyunJune Jun, Dainis Kaldre and James L. Gleason*[a]
Abstract: Ethyl diazepane carboxylate efficiently catalyzes the
Diels-Alder cycloaddition of α-substituted-α,β-unsaturated aldehydes
via iminium ion organocatalysis. The reaction is applicable to a
range of dienes and dienophiles and generally proceeds at room
temperature in the presence of 5 mol% catalyst and 2.5 mol% triflic
acid co-catalyst. The incorporation of a stereogenic center on the
diazepane backbone in combination with a menthyl carbamate
produces a catalyst which affords enantioselectivities of 70-95% ee
for the cycloaddition of cyclopentadiene with a range of dienophiles.
The enantioselectivity is rationalized via a transition state in which
electrostatic stabilization by the carboxylate directs the diene to the
more hindered face of the dienophile.
α-substituted enals.[10] Both cyclic and acyclic hydrazides have
been previously developed as catalysts for the Diels-Alder
reaction of simple α-unsubstituted enals.[11] In this
Communication, we show that 1a is an outstanding catalyst for
the Diels-Alder reaction of the more challenging α-substituted
enals.[12] Moreover, we show that development of highly
enantioselective catalysts is possible and relies on weak
electrostatic interactions to induce asymmetry.
1a
N
CHO
CHO
N
H
CO2Et
10 mol%
TfOH (10 mol%)
MeCN, 24 h
Ph
Ph
Ph
The Diels-Alder cycloaddition is one of the most fundamental
reactions in organic synthesis. The ability to unite two fragments
and set up to four stereocenters in a fully atom-economical
process makes it a powerful synthetic transformation. The
prevalence of six-membered rings in natural products has
resulted in its employment in countless total syntheses.[1] Given
its high synthetic utility, the Diels-Alder reaction is among the
most well studied in the area of asymmetric catalysis.[2] Recent
work has mainly focused on organocatalytic methods, including
both iminium catalysis and chiral Brønsted acid catalysis.[3] In
the former class, seminal work by MacMillan showed that
imidazolidinones could catalyze the cycloadditions of α,β-
unsaturated aldehydes and ketone dienophiles with high
enantioselectivity.[4]
2
3
O
CHO
Ph
1a (20%)
+
H
TFA (20%)
MeCN, –20 °C, 3 h
N
Me
N
Me
4
5
6
Scheme 1. Organocatalytic Cope and Michael addition of α-substituted enals
using ethyl diazepane carboxylate (1).
We began our study by screening the effects of catalyst 1a
in the Diels-Alder addition of cyclopentadiene to α-
methylcinnamaldehyde. This dienophile is very unreactive, with
only one example its use in
a Diels-Alder, with 2,3-
dimethylbutadiene, occurring in low yield under forcing
conditions.[13] Employing 50 mol% of 1a as catalyst with an
equivalent amount of HCl as co-catalyst in CD3CN at room
temperature for 24 h resulted in only low conversion (13%) to
the cycloadduct as judged by 1H NMR (Table 1). As observed in
our Cope rearrangement chemistry, the reaction was
significantly faster with triflic acid as co-catalyst, providing >95%
A significant challenge in the organocatalytic Diels-Alder, and
in iminium ion catalysis of enals in general, are substrates
bearing α-substitution. While simple enals such as acrolein or
[5]
cinnamaldehyde are excellent substrates with most catalysts,
significant A-1,3 strain in the iminium ions formed from
secondary amines and α-substituted enals severely limits their
formation. In the context of the Diels-Alder reaction, only a single
example of chiral secondary amine catalysis of an α-substituted
enal, using the Jørgensen/Hayashi prolinol catalyst, has been
reported.[6] Examples of secondary amine catalysis are likewise
limited in other functionalizations of α-substituted enals.[7] The
most common solution to this low reactivity is the employment of
primary amine catalysts, as these relieve A-1,3 strain.[8]
In the course of developing an organocatalytic Cope
rearrangement, we identified ethyl diazepane carboxylate 1a as
a highly effective catalyst with the unusual ability to form iminium
ions from α-substituted enals, including substrates bearing
quaternary centers at the alpha position (Scheme 1).[9] We
subsequently found that 1a was also effective in catalyzing the
Michael addition of indoles and other electron rich aromatics to
Table 1. Screening of catalyst 1a in the Diels-Alder Cycloaddition of
cyclopentadiene with α-methylcinnamaldehyde.
Me
Ph
CHO
1a
CHO
+
conditions
Me
Ph
7a
8a
9a
Catalyst
Loading
Acid co-catalyst
(mol%)
Solvent
Conversion[a]
Exo/Endo
50%
50%
20%
5%
HCl (50%)
TfOH (50%)
TfOH (10%)
TfOH (2.5%)
TfOH (2.5%)
TfOH (2.5%)
TfOH (2.5%)
TfOH (2.5%)
CD3CN
CD3CN
CD3CN
CD3CN
CD3NO2
CD3OD
CDCl3
13%
>95%
81%
n.d.
16:1
17:1
13:1
14:1
n.d.
n.d.
N.A
76%
>95% (92%)[b]
5%
[a]
N. O. Häggman, B. Zank, H. Jun, D. Kaldre and Prof. Dr. J. L.
Gleason
5%
18%
Department of Chemistry, McGill University
801 Sherbrooke W., Montreal, QC, H3A 0B8 (Canada)
E-mail: jim.gleason@mcgill.ca
5%
20%
5%
toluene-d8
-
http://gleason-group.mcgill.ca
[a] Conversion measured by 1H NMR. [b] Isolated yield.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801009
European Journal of Organic Chemistry
COMMUNICATION
R2
1a (5 mol%)
TfOH (2.5 mol%)
CHO
R2
R3
CHO
+
R1
R1
conversion to the cycloadduct as a 16:1 ratio of exo to endo
isomers. The loading of the catalyst could be lowered to as little
as 5%, with 2.5% TfOH, although this resulted in moderately
attenuated conversion. Advantageously, we found that switching
solvent to d3-nitromethane re-established high conversion rates
and allowed 9a to be isolated in 92% yield. Other solvents such
as CD3OD or CDCl3 were not as effective as reactions in either
acetonitrile or nitromethane.
R3
CD3NO2, r.t.
CHO
CHO
CHO
CHO
Ph
CHO
Me
Ph
20 h, 92%
14:1 exo
Br
Ph
Me
Me
Me
9a
9b
9c
9d
9e
20 h, 84%
15:1 exo
5 h, 60%
7:1 exo
4 h, 78%
8:1 exo
4 h, 92%
19:1 exo
We compared catalyst 1a with its homologues in the
cycloaddition of 7a + 8a in CD3CN and found, as previously, that
seven-membered ring catalyst 1a was more efficient than the
five- (1b) and six-membered ring (1c) catalysts (Scheme 2). We
also assessed eight-membered ring catalyst 1d and found that it
was not as effective as 1a, in contrast to results in the Cope
rearrangement where 1d was more efficient. Known secondary
AcO
Me
Me
Me
CHO Me
CHO
CHO
CHO
OPh
Me
CHO
Me
Me
9g
9j
9f
9h
22 h, 67%
9i
168 h, 62%
3:1 endo
4 h, 71%a
2:1 exo
22 h, 91%
60 h, 92%
2:1 endo
Scheme 3. Diels-Alder scope with catalyst 1a. a) reaction conducted in EtOH,
amine catalysts such as MacMillan’s imidazolidinone 10[14] and
using HClO4 as acid co-catalyst.
Jorgensen/Hayashi catalyst 11[6,
were unreactive with 8a
15]
under our reaction conditions, highlighting the exceptional
reactivity of 1a. Finally, 1e, the N-methylated analog of 1a, also
failed to catalyze the reaction, supporting an iminium-catalyzed
reaction mechanism instead of proton catalysis.
The excellent reactivity of 1a suggested its possible use as a
scaffold for chiral catalyst development. In the Cope
rearrangement, we briefly examined C3 and C7-substituted
catalysts 12a and 13a and noted the surprising finding that the
latter afforded higher enantioselectivity even though the
stereogenic center was not next to the position of iminium ion
formation.[9] We assessed 12a and 13a and their derivatives in
the cycloaddition of cyclopentadiene with tiglic aldehyde. While
reactions in nitromethane were poorly selective, we observed
that reactions in ethanol afforded 9e in 57% and 39% ee using
12a and 13a, respectively (Table 2).[16-18] Notably, 12a was more
effective, in contrast to the results in the Cope rearrangement.
Intriguingly, we observed only small changes in ee upon
catalyst (5 mol%)
TfOH (2.5 mol%)
Me
Ph
CHO
CHO
+
CD3CN, 24 h, r.t.
Me
Ph
7a
8a
9a
N
CO2Et
N
N
N
N
H
N
H
CO2Et
CO2Et
1d
N
H
CO2Et
N
H
1b
1c
1a
<5%
6%
76%
CF3
CF3
31%
F3C
CF3
O
N
Table 2. Screening of chiral catalysts in the Diels-Alder Cycloaddition of
cyclopentadiene with α-methylcinnamaldehyde. [a]
Ph
N
N
t-Bu
N
H
CO2Et
N
H
10
Me
OTMS
11
0%
1e
catalyst (20 mol%)
HClO4 (10 mol%)
0%
0%
Me
Me
CHO
CHO
+
EtOH, 24 h, r.t.
Me
Me
Scheme 2. Comparison of organocatalysts in the Diels-Alder Cycloaddition of
cyclopentadiene with α-methylcinnamaldehyde.
7a
8e
9e
R1
R2
N
O
R2
N
N
H
N
H
R1
O
With an optimized set of conditions in hand, we examined
the scope of catalyst 1a with a range of dienophiles and dienes
(Scheme 3). In reactions with cyclopentadiene, we found that α-
12
13
Catalyst
R1
R2
ee (exo)[b]
exo/endo
bromocinnamaldehyde
was
similarly
reactive
to
α-
methylcinnamaldehyde. The reaction was complete within 20 h
and the product 9b could be isolated in 84% yield as a 15:1
exo/endo mixture. Dienophiles lacking the β-phenyl group were
significantly more reactive. The reaction with methacrolein was
complete within 5 h and the adduct 9c was isolated in 60% yield
as a 7:1 exo/endo mixture. Other dienophiles such as α-
benzylacrolein, tiglic aldehyde and α-benzyloxyacrolein were
similarly reactive, with reactions complete within 4 h and
cycloadducts 9d-f being isolated in excellent yields. Surveying
other dienes, we found that cycloadditions between
methacrolein and simple acyclic alkenes such as isoprene or
2,3-dimethylbutadiene were complete within 22 h, affording
cycloadducts 9g and 9h in 91% and 67% yield. Other less
reactive dienes such as cyclohexadiene or 1-acetoxybutadiene
required longer reaction times, but proceeded in good to
excellent yields. In contrast to reactions with cyclopentadiene,
these latter examples were slightly endo selective.
12a
13a
Ph
Ph
OEt
OEt
OEt
OEt
OBn
NHBn
Ph
57%
39%
8:1
19:1
19:1
10:1
9:1
ent-12b
ent-12c
12d
CH2OH
Np
Ph
Ph
Ph
Ph
H
-51%
-40%
62%
12e
20%
18:1
13:1
19:1
11:1
12:1
12f
-5%[c]
-43%[c]
15%
12g
tBu
12h
O-(–)-menthyl
O-(S)-2-PhEt
O-(–)-menthyl
O-(+)-menthyl
12i
H
11%
12j
Ph
Ph
71%
46%
8:1
8:1
12k
[a] All reactions proceeded to >90% conversion. [b] Product ee’s are
adjusted for the ee of the catalysts, which were typically 90-95%. [c]
Negative ee values indicate the enantiomer of 9e was the major product.
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10.1002/ejoc.201801009
European Journal of Organic Chemistry
COMMUNICATION
modification of the group adjacent to the secondary amine, with
small groups like hydroxymethyl (e.g. ent-12b) and larger groups
such as naphthyl (ent-12c) affording only minor changes in
enantioselectivity. In contrast, more significant changes were
observed upon modification of the electron withdrawing group.
While a Cbz group (12d) slightly increased the ee to 62%,
changing to a benzyl urea (12e) dropped the ee significantly.
Intriguingly, the presence of benzoyl (12f) and pivaloyl (12g)
groups inverted the sense of enantioinduction even though the
configuration of the stereogenic center remained constant.
Given the significant impact of the electron withdrawing
group on the ee of the reaction, we explored the use of chiral
carbamates. Very modest selectivity was observed for menthyl
(12h, 15% ee), and phenethyl (12i, 11% ee) carbamates.
However, we found that the combination of a menthyl carbamate
with a C3 phenyl group displayed classical matched/mismatched
behaviour. [19] Catalyst 12j bearing a (–)-menthyl group produced
the cycloadduct in 71% ee while the (+)-menthyl carbamate
(12k) resulted in 46% ee, in both cases in 8:1 exo/endo
diastereoselectivity. Moreover, reaction at –20 °C in THF with
ent-12j proceeded in only 24 h to afford a 77% isolated yield
and further improved the selectivity to 75% ee and 12:1
exo/endo (Scheme 4).
Scheme 4. Enantioselective organocatalytic Diels-Alder reaction of α-
substituted enals with cyclopentadiene. a) Reactions run in CH3CN. b)
Reaction run in EtOH.
respectively.
The diazepane carboxylate is
a
new platform for
asymmetric catalysis and we sought to understand the origins of
stereoinduction, including the significant influence of the electron
withdrawing group. We conducted a DFT study using the methyl
carbamate analogue of 12a at the M06-2X/6-311+G**//M06-
2X/6-311G* level. The most stable conformation of the iminium
ion formed with methacrolein possessed the s-trans-(Z)-iminium
geometry[21] with the phenyl group anchoring the diazepane in
an equatorial position and with the carbamate positioned
Catalyst ent-12j displayed good to excellent reactivity and
enantioselectivity for reaction of cyclopentadiene with a number
of dienophiles.[20] α-Methylcinnamaldehyde and α-bromocinnam-
aldehyde required longer reaction times (144 h) but afforded
cycloadducts 9a and 9b in good yields and 70-72% ee. More
impressively, α-benzylacrolein and α-cyclohexylmethylacrolein
both
displayed
higher
reactivity
and
outstanding
enantioselectivity, affording 9d and 9l in 92 and 95% ee,
Figure 1. DFT modelling at the M06-2X/6-311+G**//M06-2X/6-311G* level, including SMD solvation model for EtOH. a) The most stable conformations of the
iminium ion of the methyl carbamate analog of 12a with methacrolein. b,c) Favoured and disfavoured transition states for reaction the iminium ion of the
carbamate with cyclopentadiene. d,e) Favoured and disfavoured conformations of the iminium ion of pivalamide 12g. f) Favoured transition state for
cycloaddition of the iminium ion of pivalamide 12g with cyclopentadiene. All energies are relative to starting materials (cyclopentadiene, methacrolein and
protonated catalyst).
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10.1002/ejoc.201801009
European Journal of Organic Chemistry
COMMUNICATION
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significant influence of this group. A full conformational search of
potential transition states identified the lowest energy pathway
proceeding by approach of cyclopentadiene on the more
hindered face most stable iminium, proximal to the carboxyl
group (Fig 1b). This approach was favoured by 0.5 kcal/mol over
attack from the less hindered top face (Fig 1c). The transition
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the carbamates. The DFT calculations indicate that in the
iminium ion of 12g, the phenyl group again anchors the ring in
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In conclusion, we have shown that diazepane carboxylates
are exceedingly reactive catalysts in the Diels-Alder
cycloaddition of α-substituted enals, with reactions proceeding
rapidly using low catalyst loadings for achiral catalyst 1a.
Moreover, incorporation of a stereogenic center in combination
with a menthyl carbamate results in a catalyst which retains
good reactivity and affords cycloadducts in good to excellent
enantioselectivities. DFT calculations suggest that facial
selectivity of the reaction arises via an electrostatic stabilization
from the carbamate group. Overall, these results suggest that
diazepane carboxylates may be a viable platform for a variety of
organocatalytic transformations.
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The authors thank the Natural Science and Engineering
Research Council of Canada for funding of this research.
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Keywords: organocatalysis, Diels-Alder, hydrazide, electrostatic
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[16] While the reaction of 8a was slow in alcoholic solvents, tiglic aldehyde
is sufficiently reactive to permit the use of ethanol as a solvent.
[17] Other solvents such as THF and isopropanol afforded similar ee's.
[18] The absolute stereochemistry of 9e was established by reduction to the
alcohol, and comparison of the corresponding Mosher's ester with
literature values. See Supporting Information for details. The absolute
configurations of other cycloadducts were assigned by analogy.
[19] S. Masamune, W. Choy, J. S. Petersen, L. R. Sita, Angew. Chem. Int.
Ed. 1985, 24, 1-30.
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Sakakura, Chapter 00510 - 5.10 Hetero-Diels-Alder Reactions, Elsevier
[20] The less reactive diene isoprene afforded lower ee's with a-
benzylacrolein and methacrolein (49% and 55% ee, respectively)
[21] The s-trans is preferred over s-cis by 2.8 kcal/mol while the (E)-iminium
geometry is disfavoured by 4.5 kcal/mmol. An alternative conformation
where a twist along the N-N bond axis places the iminium is below the
carbonyl group is 0.9 kcal/mol less stable. See Supporting Information.
[22] Unlike the carbamate where the minor enantiomer arises from attack of
cyclopentadiene opposite to the carbonyl, the transition state leading to
the minor enantiomer with 12g results from attack of cyclopentadiene
on the minor conformer of the iminium ion (Figure 1e), syn to the
carbonyl group (see Supporting Information for structure)
Ltd., 2014; e) K. Ishihara, A. Sakakura, Chapter 00509
Intermolecular Diels-Alder Reactions, Elsevier Ltd., 2014.
- 5.09
[3]
[4]
a) P. Merino, E. Marqués-López, T. Tejero, R. Herrera, Synthesis 2009,
2010, 1-26; b) J. Franzén, (Ed.: R. Rios Torres), pp. 205-230.
a) K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J. Am. Chem. Soc.
2000, 122, 4243-4244; b) A. B. Northrup, D. W. C. MacMillan, J. Am.
Chem. Soc. 2002, 124, 2458-2460.
[5]
For examples of α-branched enals in the Diels-Alder, see Ref 2a and a)
K. Ishihara, H. Kurihara, H. Yamamoto, J. Am. Chem. Soc. 1996, 118,
3049-3050; b) E. Canales, E. J. Corey, Org. Lett. 2008, 10, 3271-3273.
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10.1002/ejoc.201801009
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
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COMMUNICATION
Nicklas O. Häggman, Benjamin Zank,
HyunJune Jun, Dainis Kaldre and James
L. Gleason*
Page No. – Page No.
Diazepane Carboxylates as
Organocatalysts in the Diels-Alder
Reaction of α-Substituted Enals
Diazepane carboxylates efficiently catalyze the Diels-Alder cycloaddition of α-
substituted enals with a range of dienes. With chiral diazepane backbones, weak
electrostatic interactions favour diene approach from the more hindered face,
leading to enantioselectivities of 70-95% with a range of dienophiles.
This article is protected by copyright. All rights reserved.