Organocatalytic Nonclassical Trienamine Activation in the Remote Alkylation of Furan Derivatives

Article abstract of DOI:10.1021/acs.orglett.5b02979

A new approach for the stereoselective remote alkylation of furan derivatives is reported. The reaction of 5-alkylfurfurals with nitroolefins as electrophilic counterparts occurs at their exocyclic ε-position and proceeds through the intermediacy of a non

Full text of DOI:10.1021/acs.orglett.5b02979

Letter
pubs.acs.org/OrgLett
Organocatalytic Nonclassical Trienamine Activation in the Remote
Alkylation of Furan Derivatives
Anna Skrzynska, Artur Przydacz, and Łukasz Albrecht*
́
̇
́
́
Institute of Organic Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Łodz, Poland
S
* Supporting Information
ABSTRACT: A new approach for the stereoselective remote alkylation of furan
derivatives is reported. The reaction of 5-alkylfurfurals with nitroolefins as
electrophilic counterparts occurs at their exocyclic ε-position and proceeds through
the intermediacy of a nonclassical catalytic trienamine intermediate. The
aminocatalyst bearing a H-bonding unit is used to control the stereochemical
reaction outcome confirming the usefulness of such catalytic systems for the remote
functionalizations of carbonyl compounds. Target products with two adjacent
stereogenic centers are obtained in excellent yields and with good to moderate
stereoselectivities.
dentification of new activation modes of organic compounds
double bonds of the triene system acting as the Diels−Alder
Iallowing for the discovery of new reactions constitutes one of diene. Importantly, the structure of the trienamine intermediate
the most significant tasks of the contemporary organic chemist.
This is particularly true in the field of asymmetric catalysis where
the chiral catalyst can be responsible not only for the
stereochemical reaction outcome but also for the activation of
a substrate through the formation of crucial synthetic
intermediates exhibiting different reactivity than the starting
material.1
directly relates to its reactivity profile. For example, when cross-
conjugated trienamine is being formed, the γ′,δ-reaction occurs
instead of the classical ε,β-functionalization (Scheme 1, to the
right).3
The ability of chiral amines to convert carbonyl compounds
into various reactive intermediates makes them a very attractive
tool in the contemporary enantioselective synthesis.4 In addition
to the two trienamine-mediated catalytic activation strategies
described above, this field of chemistry started to develop in a
new direction (Scheme 2). In 2011, the approach where the
second double bond of α,β,γ,δ-diunsaturated aldehyde is a part of
heteroaromatic framework was described (Scheme 2, to the
left).5 In such a setup, heterocyclic ortho-quinodimethanes are
generated under aminocatalytic conditions that can serve as
reactive dienes in a [4 + 2]-cycloaddition reaction proceeding
with rearomatization of the heteroaromatic framework. An
alternative strategy involves two double bonds of the furan ring as
a part of trienamine intermediate enabling remote Friedel−
Crafts alkylation to occur (Scheme 2, to the right).6
Aminocatalytic trienamine activation constitutes an excellent
example of such an activation strategy (Scheme 1, to the left).2
Herein, a catalytically employed chiral secondary amine serves a
dual purpose. First, it provides a chiral environment necessary in
the stereodifferentiating reaction. Second, aminocatalyst trans-
forms the α,β,γ,δ-diunsaturated aldehyde into the corresponding
trienamine intermediate that is nucleophilic in the ε-position. It
can undergo various [4 + 2]-cycloadditions with the last two
Scheme 1. Classical Trienamines in Asymmetric
Aminocatalysis
We envisioned that the alternative strategy for the remote
functionalization of heteroaromatic derivatives might rely on the
application of 5-alkylfurfural derivatives 1 (Scheme 3). Such
substrates in the presence of aminocatalyst should be able to
form catalytically crucial trienamine intermediate with interest-
ing synthetic applicability. However, certain challenges with
relation to such an approach had to be addressed. First, the
reactivity pattern is different from the classical trienamine
activation. 5-Alkylfurfural-derived trienamine is unable to adopt
s-cis conformation of the last two double bonds of the triene
moiety. Therefore, it cannot react via a [4 + 2]-cycloaddition
Received: October 14, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02979
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Letter
The studies were initiated with the goal of finding the optimal
conditions for the reaction (Table 1, for detailed screening
Scheme 2. Heteroaromatic Trienamines in Asymmetric
Aminocatalysis
Table 1. Enantioselective Remote Alkylation of 5-
a
Alkylfurfurals: Optimization Studies
Scheme 3. Synthetic Objectives of This Work
b
c
d
entry
solv.
cat. (prod.) t [°C] conv [%]
dr
er
nd
1
2
3
4
5
6
7
8
9
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
1,4-dioxane
CH3CN
hexane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
4a (3a)
4a (3b)
4b (3b)
4c (3b)
4d (3b)
4e (3b)
4f (3b)
4g (3b)
4g (3b)
4g (3b)
4g (3b)
4g (3b)
4g (3b)
4g (3b)
4g (3b)
4g (3b)
rt
<5
nd
rt
>95
>95
>95
>95
<5
2:1
2:1
1.5:1
1.3:1
nd
65:35
65:35
65:35
60:40
nd
rt
rt
rt
rt
rt
<5
nd
nd
rt
15
5:1
3:1
4.5:1
6:1
nd
75:25
75:25
80:20
77:23
nd
rt
33
e
10
rt
53
e
11
rt
83
12
13
rt
<5
10
10
10
10
15
5:1
5:1
5:1
5:1
82:18
82:18
82:18
82:18
f
14
70
g
15
82
h
16
95 (91)
a
Reactions performed on 0.1 mmol scale using 1 (1 equiv) and 2a (1.2
equiv) in 0.36 mL of the solvent (see Supporting Information for
b
detailed reaction conditions). Conversion as determined by 1H NMR
of a crude reaction mixture. In parentheses isolated yields are given.
c
d
Determined by 1H NMR of a crude reaction mixture. Determined by
a chiral stationary phase HPLC. Enantiomeric ratios reported for a
pathway, and simple alkylation should be preferred. Second, such
an approach involves dearomatization of the heteroaromatic
framework. Interestingly, parallel to our studies, Afonso and co-
workers demonstrated that the formation of stoichiometric 5-
alkylfurfural-derived trienamine intermediate is possible.7
However, it requires the use of organometallic catalyst in order
to facilitate its formation. Despite the interesting results
obtained, one of the main drawbacks of the approach relates to
the fact that the homocoupling reactivity pattern is observed
(trienamine intermediate reacts with its precursor, the
corresponding iminium ion). As a consequence, the amine is
used in stoichiometric amounts and serves as a reagent.
Furthermore, the reaction is not enantioselective and limited
to protected hydroxymethylfurfural.
Herein, we report our work on the development of
organocatalytic approach to the remote functionalization of 5-
alkylfurfural derivatives 1 employing catalytic amine as the
reaction promoter. The main focus of the research was on the
development of the enantioselective reaction involving electro-
philic reagent not derived from the starting furfural.
e
major diastereomer. The formation of side-products was observed.
f
Reaction was performed using 1b (0.2 mmol) and 2a (0.1 mmol) in
g
0.54 mL of CH2Cl2 for 3 days. Reaction was performed using 1b (0.2
mmol) and 2a (0.1 mmol) in 0.27 mL of CH2Cl2 for 3 days. Reaction
h
was performed using 1b (0.2 mmol) and 2a (0.1 mmol) in 0.18 mL of
CH2Cl2 for 3 days.
results, see Supporting Information). β-Nitrostyrene 2a was
selected as a model electrophile. Initial attempts involved the use
of diphenylprolinol trimethylsilyl ether 4a8 as a catalyst and
commercially available 5-methylfurfural 1a as the corresponding
trienamine precursor (Table 1, entry 1). However, under the
employed conditions no reaction was observed. We hypothe-
sized that the lack of reactivity might be related to the problems
with dearomatization of the furan moiety. Therefore, the
corresponding 5-benzylfurfural 1b was synthesized. We antici-
pated that the presence of the phenyl ring on the exocyclic
carbon atom should facilitate the dearomatization process due to
the formation of a highly conjugated π-system. To our delight,
B
DOI: 10.1021/acs.orglett.5b02979
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Letter
when 1b was employed in the trienamine-mediated reaction, the
remote alkylation was found to occur efficiently at room
temperature yielding 3b as a sole product (Table 1, entry 2).
Notably, no formation of the homocoupling product was
observed under these conditions. However, the stereochemical
reaction outcome was not satisfactory (2:1 dr, 65:35 er).
Attempts to improve the result by increasing the bulkiness of the
catalyst failed (Table 1, compare entries 2−5). At this point we
postulated that the sterically demanding substituent present in
the 2-position of aminocatalysts 4a−d prefers to position itself
away from the triene moiety adopting the anti-conformation
around the C−N bond. Consequently, control of the asymmetric
induction process taking place at the remote ε-position is almost
impossible. Therefore, an alternative approach was devised. It
utilized H-bonding catalysts9 to control stereochemical reaction
outcome. It was anticipated that a proper choice of the catalyst in
terms of distances between amine moiety and H-bonding unit
will be crucial. Initial attempts using 4e or 4f as catalysts were
unsuccessful (Table 1, entries 6,7). To our delight, a significant
improvement of the reaction stereoselectivity was observed using
4g as the catalyst (Table 1, entry 8). Further optimization studies
were focused on finding the optimal solvent for the reaction
(Table 1, entries 9−12). Interestingly, the improvement of the
enantioselectivity of the remote functionalization was observed
in the polar solvents such as 1,4-dioxane and acetonitrile (Table
1, entries 10,11). However, under these conditions the reaction
lost its chemoselectivity as the formation of side-products arising
from the homoaldol and subsequent poly homoaldol reactivity
was observed. As we were unable to separate the product 3b from
the impurities by means of flash chromatography, dichloro-
methane became a solvent of choice. Further optimization
studies (Table 1, entries 13−16) revealed that the best results
were obtained when the reaction was performed at 10 °C, 0.56 M
concentration, and using 2:1 ratio of 1b to 2a for 3 days (Table 1,
entry 16).
Scheme 4. Enantioselective Remote Alkylation of 5-
Alkylfurfurals: Scope of the Method
a
With the optimized reaction conditions in hand, the scope of
the method was studied. Initially, the scope with regard to the
nitroolefin counterpart 2 was evaluated (Scheme 4, compounds
3b−g). Gratifyingly, the reaction proceeded efficiently in all of
the cases (91−99% yield). The stereochemical reaction outcome
was found independent from the position of the substituent on
the aromatic ring in 2 (compare results for the synthesis of 3c-e).
Interestingly, the highest diastereoselectivity (>15:1) was
observed for the reaction leading to ortho-substituted derivative
3c. Furthermore, the electronic properties of the substituent had
no pronounced influence on the stereoselectivity of the
alkylation and both electron-poor and electron-rich substituents
could be present on the aromatic moiety in 2 (compare results
for the synthesis of 3e−g). Subsequently, the reaction scope of
the furfural substrate 1 was studied (Scheme 4, compounds 3h−
l). To our delight, in this case the reaction was also found to be of
general character as high yields (91−99% yield) were observed in
all cases. The enantioselectivity of the reaction was found to be
unbiased toward both the substitution pattern (compare results
for the synthesis of 3h−j) and to the electronic properties of the
substituents present on the phenyl ring in 1 (compare results for
the synthesis of 3j−l). Furthermore, control of the diaster-
eoselectivity of the process was on a similar level. However, the
introduction of the substituent in the ortho-position of this
aromatic moiety led to slight deterioration of the result. Notably,
in all of the cases major diastereomer could be separated by
means of flash chromatography.
a
Reactions performed on 0.1 mmol scale (see Supporting Information
for detailed reaction conditions). Enantiomeric ratios reported for a
major diastereomer.
The absolute configuration of the remotely alkylated furfural
3i was unambiguously assigned by the single crystal X-ray
analysis (Scheme 5, top).10 The absolute configuration of the
remaining furfurals 3b−h, 3j−l was assigned by analogy. On the
basis of the configurational assignments, the reaction mechanism
explaining the observed stereochemistry of the products was
proposed (Scheme 5, bottom). The reaction is initiated through
the condensation of aminocatalyst 4g with the corresponding 5-
alkylfurfural 1. Subsequent deprotonation from the remote ε-
position yields the key trienamine intermediate 5. It is postulated
that the reaction proceeds through the intermediacy of
thermodynamically stable Z,Z,Z-configured trienamine inter-
mediate 5. Furthermore, anti-conformation around the C−N
bond in 5 is assumed. In the next step the reaction with
electrophile 2 takes place. As the catalyst 4g is employed, H-
bonding interaction with nitroolefin 2 is essential and responsible
for the control of stereochemical reaction outcome. Therefore,
the trienamine 5 is approached from the upper-side. The
diastereoselectivity is a consequence of the shown alignment of
nitroolefin 2 with respect to 1 in which the π-stacking
C
DOI: 10.1021/acs.orglett.5b02979
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Scheme 5. Enantioselective Remote Alkylation of 5-
Alkylfurfurals: Mechanistic Considerations
ACKNOWLEDGMENTS
■
This project was realized within the Homing Plus Programme
(cofinanced from European Union, Regional Development
Fund) from the Foundation for Polish Science. A.P. acknowl-
edges Lodz University of Technology for a scholarship (Własny
Fundusz Stypendialny PŁ programme). Thanks are expressed to
Dr. Jakub Wojciechowski (Faculty of Chemistry, Lodz University
of Technology) for performing X-ray analysis.
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ASSOCIATED CONTENT
* Supporting Information
(10) See Supporting Information for details. CCDC 1431276 contains
the supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02979.
Screening details, experimental procedures, character-
ization of the products, and NMR data (PDF)
CIF information (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: lukasz.albrecht@p.lodz.pl.
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.5b02979
Org. Lett. XXXX, XXX, XXX−XXX