Intramolecular Aza-Diels–Alder Reactions of ortho-Quinone Methide Imines: Rapid, Catalytic, and Enantioselective Assembly of Benzannulated Quinolizidines

Article abstract of DOI:10.1002/anie.201800787

Aza-Diels–Alder reactions (ADARs) are powerful processes that furnish N-heterocycles in a straightforward fashion. Intramolecular variants offer the additional possibility of generating bi- and polycyclic systems with high stereoselectivity. We report her

Full text of DOI:10.1002/anie.201800787

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Accepted Article
Title: Intramolekulare Aza-Diels-Alder-Reaktionen von ortho-
Chinonmethidiminen - ein schneller, katalytischer und
enantioselektiver Aufbau benzoanellierter Chinolizidine
Authors: Christoph Schneider, Martin Kretzschmar, Fabian Hofmann,
and Daniel Moock
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800787
Angew. Chem. 10.1002/ange.201800787
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10.1002/anie.201800787
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Intramolecular Aza-Diels-Alder-Reactions of ortho-Quinone
Methide Imines – Rapid, Catalytic, and Enantioselective Assembly
of Benzannulated Quinolizidines
Martin Kretzschmar,[a] Fabian Hofmann,[a] Daniel Moock[a] and Christoph Schneider*[a]
Abstract: Aza-Diels-Alder reactions (ADAR) constitute powerful pro-
cesses that furnish N-heterocycles in a highly straightforward fashion.
Intramolecular variants offer the additional potential to generate bi-
and polycyclic systems with high stereoselectivity. We report herein a
novel Brønsted acid-catalyzed process in which ortho-quinone
methide imines tethered to the dienophile via the N-substituent react
Scheme 1. Conceptualization of the Brønsted acid catalyzed, intramolecular
ADAR of ortho-quinone methide imines.
in an intramolecular ADAR form complex quinolizidines and oxazino-
quinolines in one step. The reactions proceed under very mild condi-
tions, with very good yields and good to very good diastereo- and en-
antioselectivities. Furthermore, it is possible to expand the process to
a domino reaction which combines substrate synthesis, ortho-quinone
methide imine formation and ADAR efficiently.
The trivalency of nitrogen now opens the possibility to tether
the dienophile directly into the substrate via N-substitution of the
imine setting the stage for an intramolecular [4+2]-cycloaddition
(Scheme 1). This general strategy was first formulated by Stein-
hagen and Corey in 1999 who described a racemic ADAR of or-
tho-quinone methide imines generated under basic conditions.[8]
Since then this concept has not been followed up and there is
currently no enantioselective process available to our knowledge.
Aza-Diels-Alder-reactions (ADAR) are among the most im-
portant, straightforward, and stereoselective processes to form
six-membered N-heterocycles.[1] They can be distinguished into
two conceptionally different variants: electron-rich dienes under-
going a normal-type electron demand ADAR with imines as dieno-
philes and on the other hand electron-deficient azabutadienes un-
dergoing an inverse electron demand ADAR with electron-rich
dienophiles. A special class of strongly polarized azabutadienes
comprise ortho-quinone methide imines which easily undergo
conjugate and cycloaddition addition reactions with reconstitution
of aromaticity.[2] Due to their transient nature ortho-quinone
methide imines (also called ortho-azaxylylenes) are typically gen-
erated in situ directly from suitable precursors in the presence of
their reaction partners.
We report herein the first Brønsted acid-catalyzed, intramo-
lecular ADAR of ortho-quinone methide imines providing a rapid
synthetic access to benzannulated quinolizidines and oxazino-
quinolines with typically very good yields and good to very good
diastereo- and enantioselectivities. First experiments were carried
out with amino alcohol 1a which was obtained in a convergent
manner by reductive amination from the respective aniline (Table
1). Using chiral BINOL-based phosphoric acids only low conver-
sion was observed. However, in the presence of the more reactive
N-triflyl phosphoric amide 3a as catalyst (10 mol%), the desired
benzannulated quinolizidine 2a was obtained with moderate yield
but without any enantioselectivity (entry 1).
In recent years, we and other groups have developed numer-
ous Brønsted acid-catalyzed reactions of ortho-quinone methi-
des[3] as well as ortho-quinone methide imines[4] and applied these
processes toward the enantioselective synthesis of benzoannu-
lated O- and N-heterocycles as well.[5,6] This strategy is based
upon the acid-catalyzed dehydration of ortho-hydroxy- or ortho-
amino benzyl alcohols to form hydrogen-bonded ortho-quinone
methides and ortho-quinone methide imines, respectively. In this
sceanario the chiral phosphate anion[7] is closely bound to the qui-
none methide and therefore able to catalyze the reaction with
enol- and enamine-based nucleophiles with high enantiocontrol.
Pursuing this strategy, we have recently established formal cy-
cloadditions of enamides and β-ketoesters with ortho-quinone
methide imines providing direct access to tetrahydroacridines and
tetrahydroquinolines in good yields and enantioselectivities.[4a,b]
We then tested various N-triflyl phosphoric amides 3b-f for the
cycloaddition carrying different 3,3’-aryl substituents. N-Triflyl
phosphoric amide 3f with 9-anthracenyl groups in the 3,3’-position
of the BINOL backbone was identified as the optimal catalyst de-
livering product 2a as a single diastereomer and with an enantio-
meric ratio of 88:12 e.r. (entry 6). Performing the reaction without
the addition of 4 Å molecular sieves led to a significant accelera-
tion of the reaction and delivered quinolizidine 2a within one day
in a very good yield (entry 7). By lowering the reaction tempera-
ture to 10 °C the enantioselectivity was further improved to 90:10
e.r. (entry 8).[9]
[a]
M.Sc. M. Kretzschmar, M.Sc. F. Hofmann, M.Sc. D. Moock, Prof. Dr.
C. Schneider
Institut für Organische Chemie, Universität Leipzig
Johannisallee 29, 04103 Leipzig (Germany)
E-mail: schneider@chemie.uni-leipzig.de
Supporting information for this article can be found under:
http://dx.doi.org/ zu finden.
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10.1002/anie.201800787
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Table 1. Optimization of the phosphoric amide-catalyzed ADAR of 1a.[a]
Additive
Yield
[%][b]
e.r.[c]
Entry
Cat.
Time
1
2
3a
3b
3c
3d
3e
3f
4Å MS
4Å MS
4Å MS
4Å MS
4Å MS
4Å MS
---
10d
7d
53
50:50
27
26
63
23
68
93
70
56:44
60:40
66:34
69:31
88:12
88:12
90:10
3
7d
4
10d
10d
4d
5
6
7
3f
1d
Scheme 2. Substrate scope of the phosphoric amide-catalyzed synthesis of
benzannulated quinolizidines 2. Reaction conditions: 0.10 mmol ortho-amino
benzhydryl alcohol 1, catalyst 3f (10 mol%), CHCl3 (1 mL), rt, 1d, diastereomeric
ratio was determined via NMR and is >20:1 in all cases.; Enantiomeric ratio
determined by HPLC on a chiral stationary phase (see the Supporting Infor-
mation). [a] Reaction temperature: 10 °C, reaction time: 5d. [b] Reaction tem-
perature: 50 °C. [c] Reaction time: 7d.
8[d]
3f
---
5d
[a] Reaction conditions: 0.10 mmol ortho-aminobenzhydryl alcohol 1a, cata-
lyst 3 (10 mol%), 4 Å molecular sieves as additive (powdered, 25 mg), sol-
vent (1 mL), rt, diastereomeric ratio was determined by NMR and was >20:1
in all cases. [b] Yield of isolated product after purification by flash column
chromatography. [c] Enantiomeric ratio determined by HPLC on a chiral sta-
tionary phase (see the Supporting Information) [d] Reaction temperature:
10 °C.
The substrate scope of the reaction was investigated in reactions
of differently substituted ortho-amino alcohols 1 (Scheme 2). It
was possible to introduce different aryl groups as β-substituents
of the ortho-quinone methide imine to obtain products 2a-f in good
yields, up to 91:9 e.r. and complete diastereoselectivity. Sub-
strates containing halogen substituents generally required higher
reaction temperatures to ensure complete conversion while still
delivering products in comparable yields and enantioselectivities.
Likewise, amino alcohols with various substituents in the ortho-
quinone methide backbone were successfully transformed to fur-
nish products 2g-m in high yields and up to 91:9 e.r. Moving the
benzannulation within the dienophile backbone was also tolerated
and gave rise to product 2n with excellent yield and good enanti-
oselectivity. We assume that cycloadditions of substrates 1 pro-
ceed in a concerted and highly diastereoselective manner through
an endo-transition state.
Subsequently, we expanded the substrate scope to reactions
of amino alcohols 4 with an electronically activated enol ether as
dienophile. As expected, this modification led to a significant rate
acceleration. Substrate 4a was fully consumed within 4 hours at
room temperature whereupon oxazinoquinoline 5a was obtained
in 89% yield, 92:8 e.r. and as a mixture of two diastereomers with
a ratio of 6:1 d.r. (Scheme 3). Contrary to quinolizidines 2 the ma-
jor diastereomer of 5a contained a 2,4-trans configuration, and
the diastereoselectivity remained constant over the course of the
reaction.
Scheme 3. Expansion of the substrate scope towards amino alcohols 4 tethered
to an enol ether as dienophile. Reaction conditions: 0.10 mmol ortho-amino ben-
zhydryl alcohol 4, catalyst 3f (10 mol%), CHCl3 (1 mL), rt, 1d; [a] Reaction time:
4h, [b] Reaction time: 7d, [c] Reaction time: 1h.
Following this procedure, additional oxazinoquinolines 5b-j
were obtained in typically good yields, with up to 8:1 d.r. and with
enantiomeric ratios of 90:10 e.r. or higher (Scheme 3). Alkyl-,
alkoxy- and halogen groups were all tolerated as substituents. As
expected, substrates carrying electron-releasing substituents re-
acted particularly fast. Thus, the reaction to form cycloadduct 5h
was completed within 1 hour at room temperature and the product
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was obtained in 75% yield, 7:1 d.r. and 93:7 e.r. This result is con-
sistent with the assumption that ortho-quinone methide imine for-
mation is the rate-determining step of the reaction as we had ob-
served in similar reactions recently.[4a-b] Products 5i and 5j with
multiple substituents were also formed with enantioselectivities of
up to 95:5 e.r. and in good yields.
Scheme 5. Transformation of 5a into tetrahydroquinolines 7 and 9.
To further simplify this process, we successfully developed
a domino reaction that combines substrate synthesis and cy-
cloaddition. We were able to start with free amino alcohol 10 and
aldehyde 12 which were converted to 4a in situ by reductive ami-
nation in the presence of N-triflyl phosphoric amide 3f and
Hantzsch ester 11. Intermediate 4a now served as substrate for
the ADAR and delivered cycloadduct 5a in situ in 60% overall
yield and with good diastereo- and enantioselectivity (Scheme 6,
top).
Scheme 4. Intramolecular ADAR of substituted enol ether 4k.
Using substituted enol ethers more highly substituted cycload-
ducts were available. To showcase this scenario we subjected the
methyl-substituted enol ether 4k to the ADAR (Scheme 4). Start-
ing from a stereochemically pure Z-enol ether we obtained cy-
cloadduct 5k in 55% yield, 93:7 e.r. and moderate diastereoselec-
tivity under slightly modified reaction conditions. Interestingly, pre-
dominantly E-configured enol ether 4k delivered the same major
diastereomer 5k, however with lower enantioselectivity. Thus, the
ADAR of more polarized enol ether substrates is obviously not a
concerted reaction and delivers the 2,3-cis-diastereomer in a ste-
reoconvergent manner irrespective of the dienophile configuration.
The cycloadducts 5 contain a newly formed and highly reac-
tive N,O-acetal moiety which can be easily modified.[10] Accord-
ingly, we transformed 5a to the N-benzyl protected tetrahydro-
quinoline 6 by treatment with LiAlH4 and subsequently to tetrahy-
droquinoline 7 by hydrogenation on palladium on charcoal both in
very good yields (Scheme 5). Comparison of the specific rotation
of 7 with the literature value[11] establishes its absolute configura-
tion which was assigned to all further cycloadducts by analogy.
The relative configuration was unambiguously assigned by
1H-NMR spectroscopy.
Furthermore, we converted 5a into the 2,4-disubstituted tet-
rahydroquinoline 8 by Grignard addition of phenyl magnesium
bromide in good yield and moderate diastereoselectivity (Scheme
5). Column chromatography led to further purification and tetrahy-
droquinoline 8 was obtaind in 77% yield and 10:1 d.r. Upon
debenzylation the free tetrahydroquinoline 9 was obtained like-
wise in good yield. In doing so we were able to expand the pool
of synthetic strategies toward the stereoselective assembly of tet-
rahydroquinolines by a new, flexible and enantioselective pro-
cess.[12]
Scheme 6. Domino 3-component reaction (top) and large-scale experiment
with only 1 mol% catalyst loading (bottom).
To demonstrate the applicability of our process, a large-
scale synthesis of cycloadduct 5a was conducted. In doing so we
were able to further lower the catalyst loading to only 1 mol%
(Scheme 6, bottom). We obtained 1.1 g of oxazinoquinoline 5a in
excellent yield and 89:11 e.r. which was further optically enriched
to enantiomerically almost pure material by one recrystallization.
In conclusion, we have developed a new Brønsted acid-cata-
lyzed and enantioselective process which furnishes benzannu-
lated quinolizidines and oxazinoquinolines in a one-step process
from simple substrates. The products that contain up to 3 new
stereogenic centers were generated under mild reaction condi-
tions in good to very good yields and stereoselectivities. Further-
more, it was possible to expand the process to a domino reaction
which combined substrate synthesis, ortho-quinone methide
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10.1002/anie.201800787
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Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (SCHN
441/11-2) for the generous financial support of this work. Martin
Kretzschmar is grateful for a predoctoral fellowship from the
Deutsche Bundesstiftung Umwelt (DBU), and we thank Michael
Laue for preliminary experiments.
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Keywords: asymmetric synthesis • Brønsted acid catalysis • or-
tho-quinone methide imines • nitrogen heterocycles • organoca-
talysis
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COMMUNICATION
Martin Kretzschmar, Fabian Hofmann,
Daniel Moock und Christoph Schneider*
Page No. – Page No.
Intramolecular Aza-Diels-Alder-Reac-
tions of ortho-Quinone Methide
Imines – Rapid, Catalytic and Enanti-
oselective Assembly of Benzannu-
lated Quinolizidines
Chiral N-triflyl phosphoric amides are effective catalysts for the first
enantioselective, intramolecular aza-Diels-Alder-reaction of in situ generated ortho-
quinone methide imines. Benzannulated quinolizidines and oxazinoquinolines are
readily accessible in good yields and enantioselectivities in this one-pot process.
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