[1+1+3] Annulation of Diazoenals and Vinyl Azides: Direct Synthesis of Functionalized 1-Pyrrolines through Olefination

Article abstract of DOI:10.1002/anie.201801976

A dirhodium carboxylate catalyzed [1+1+3] annulation reaction of diazoenals and vinyl azides that gives synthetically important enal-functionalized 1-pyrroline derivatives was developed. The reaction involves a novel rhodium-catalyzed olefination of diazoenals with vinyl azides via electrophilic enal carbenoids, resulting in a new class of enal acrylates. The annulation reaction was used for the direct synthesis of valuable deuterated 1-pyrrolines. Structural diversification of the enal-functionalized 1-pyrrolines resulted in the biologically important pyrrolidine-fused oxaziridine, amino acid derivatives, and a 6-azabicyclo[3.2.1]octane motif present in polycyclic alkaloids.

Full text of DOI:10.1002/anie.201801976

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Accepted Article
Title: [1+1+3] Annulation of Diazoenals and Vinyl Azides: Direct
Synthesis of Functionalized 1-Pyrrolines via a New Olefination
Authors: Sreenivas Katukojvala and Vinaykumar Kanchupalli
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801976
Angew. Chem. 10.1002/ange.201801976
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10.1002/anie.201801976
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[1+1+3] Annulation of Diazoenals and Vinyl Azides: Direct
Synthesis of Functionalized 1-Pyrrolines via a New Olefination
Vinaykumar Kanchupalli and Sreenivas Katukojvala*
Abstract: Described herein is a dirhodium carboxylate catalyzed
[1+1+3] annulation reaction of diazoenals and vinyl azides which
gives synthetically important enal-functionalized 1-pyrroline
azides for the construction of electrophilic terminal alkenes
(Scheme 1b).[11] The new olefination involves a distinct acyclic
C-C bond fragmentation (path a), driven by the loss of N2,
leading to the formation of functionalized terminal C=C motif and
benign nitrile by-product. The olefination reaction was used in
the direct [1+1+3] annulation of diazoenals and vinyl azides to
access valuable enal-functionalized 1-pyrroline heterocycles via
in situ generation of a new class of electrophilic enal-acrylates
(Scheme 1b). The enal-functionality of 1-pyrroline was further
utilized to access diverse biologically relevant pyrrolidines.
derivatives. The reaction involves
a novel rhodium-catalyzed
olefination of diazoenals with vinyl azides via electrophilic
enalcarbenoid, resulting in the new class of enal-acrylates. The
annulation reaction was used for the direct synthesis of valuable
deuterated 1-pyrrolines. Structural diversification of the enal-
functionalized 1-pyrrolines resulted in the biologically important
pyrrolidine fused oxaziridine, amino acid derivatives, and a 6-
azabicyclo[3.2.1]octane motif present in polycyclic alkaloids.
1-Pyrroline motifs are core structures of biologically important
natural products with intriguing structural complexity (Figure 1).[1]
Moreover, 1-pyrroline derivatives are versatile precursors of
various pyrrolidine alkaloids, pharmaceuticals, and catalysts.[2]
The known approaches for the substituted 1-pyrroline include
cycloadditions,[3] Narasaka-Heck cyclization of -unsaturated
oxime esters,[4] alkyne-aminations,[5] -unsaturated iminyl
radical cyclizations,[6] and pyrrole hydrogenation.[7] However,
given the increasing demand for the biologically relevant
chemical spaces, still, there is a need for the development of
new strategies for the functionalized 1-pyrroline derivatives in
which the functional groups could be utilized to introduce further
structural diversity for drug discovery applications.[8]
Scheme 1. Methylenation of carbonyl compounds and diazo compounds
The divergent modes of reactivity of vinyl azides, due to their
distinct azide appended olefin motif, have been explored in
various annulation reactions for the construction of nitrogen
heterocycles.[12] However, their annulation reactions with diazo
compounds for the heterocycles construction remained
unexplored. The known reactions involve Rh-catalyzed
cyclopropanation and Cu-catalyzed cyclopentene synthesis by
[3+2] cycloaddition.[13,14] In continuation of our ongoing study on
the synthetic applications of a new class of diazoenals,[15] we
investigated the reactivity with vinyl azides. Control experiments
involving the slow addition of a dichloromethane solution of ester
diazoenal 1a to the excess vinyl azide 2a (2.5 equiv.) and 3
mol % Rh2(OAc)4 resulted in the [1+1+3] annulation product
Figure 1. Representative 1-pyrroline natural products
Methylenation of carbonyl compounds by Wittig reaction is a
widely used approach for the terminal olefins.[9] However, Wittig
reaction, as well as other carbonyl methylenation approaches,
involve harsh nucleophilic methylene transfer reagents that are
not compatible with the construction of electrophilic terminal
olefins.[10] Herein, we disclose an efficient rhodium-catalyzed
olefination of diacceptor diazo compounds with simple vinyl
enal-functionalized 1-pyrroline
6 in 71% yield along with
benzonitrile 5a (Table 1, entry 1). The annulation reaction
proceeded through methylenation of diazoenal with vinyl azide
resulting in the sensitive enal-acrylate 4a and subsequent [2+3]
cycloaddition with vinyl azide. It is noteworthy that, so far vinyl
azides have been utilized as either one atom, two atom or three
atom synthons in cycloadditions,[12] whereas, in the [1+1+3]
annulation, vinyl azide served as one atom as well as three atom
source leading to the synthetically important pyrroline
heterocycle.
[*]
V. Kanchupalli. and Dr. S. Katukojvala
Department of Chemistry
Indian Institute of Science Education & Research BhopaI
Madhya Pradesh 462066 (India)
E-mail: sk@iiserb.ac.in
Supporting information for this article is given via a link at the end of
the document.
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Further screening of other transition-metal catalysts
including Cu, Au, Ru and Rh complexes revealed that only
dirhodium carboxylates 3 are suitable for the [1+1+3] annulation
(Table 1, see SI for complete optimization details). Among the
dirhodium carboxylates, Rh2(oct)4, Rh2(esp)2, and Rh2(tfa)4 gave
moderate to a good yield of 6 (entries 2-4). In case of Rh2(tpa)4
rapid decomposition of diazoenal hampered the annulation
leading to low yield of pyrroline product (32%, entry 5). The
sterically hindered Rh2(S-DOSP)4 resulted in only 40% yield due
to incomplete consumption of diazoenal (entry 6). The best yield
observed with Rh2(OAc)4 indicates that the productive merger of
the methylenation and subsequent [3+2] annulation was optimal
at the room temperature in chlorinated solvents.
of annulation products, e.g., 7, 12, 13, 15, and 16 (64-81%). The
halo-substituents (F, Cl, Br) were well tolerated and gave
haloaryl-pyrrolines 17-21 in good yields (50-67%). The electron-
deficient styryl azides caused slow reactivity, resulting in
diminished yields of pyrrolines 22-27 (35-54%). The sterically
hindered o-tolyl and 1-naphthyl vinyl azides were unreactive
(e.g., 11, 0%). In contrast, 2-methoxy and 2-naphthyl vinyl
azides furnished the pyrroline 14 and 28 in good yield (55% and
65%). Thienyl vinyl azides were also suitable for the [1+1+3]
annulation which gave thienyl pyrrolines 29-31 in decent yields
(45-65%). However, aliphatic vinyl azide 2b (R= Bu) failed to
give the annulation product (32, 0%).
Table 2. Substrate scope of the [1+1+3] annulation reaction.[a]
Table 1. Optimization of the [1+1+3] annulation reaction.[a]
S.No.
Deviation from the standard conditions
Yield of 6 (%)[b]
1
2
No deviation
71
67
61
55
32
40
18
23
-
Rh2(oct)4 instead of Rh2(OAc)4
Rh2(esp)2 instead of Rh2(OAc)4
Rh2(tfa)4 instead of Rh2(OAc)4
Rh2(tpa)4 instead of Rh2(OAc)4
Rh2(S-DOSP)4 instead of Rh2(OAc)4
Reaction performed at 10 oC
3
4
5
6
7
8
Reaction performed at 40 oC
9
Cu(OTf)2 instead of Rh2(OAc)4
Cu(MeCN)4[BF4] instead of Rh2(OAc)4
IPrAuNTf2 instead of Rh2(OAc)4
[Ru(p-cymene)Cl2]2 instead of Rh2(OAc)4
[Rh(Cp*Cl2]2 instead of Rh2(OAc)4
10
11
12
13[c]
-
[a] Reaction was performed using the standard conditions of the
optimization Table 1.
-
-
The [1+1+3] annulation of diazoenal 1a/1b and deuterated 2-
azidostyrene 2a-D2, furnished the synthetically challenging
deuterated 1-pyrroline 6-D4 and 7-D4 in 67% and 78% yield
respectively (Scheme 2(I)). This new method may find
applications in the valuable deuterium labeled pyrrolidine
heterocycles and amino acid derivatives. Moreover, a large-
scale annulation of methyl ester diazoenal 1c (0.5 g, 3.25 mmol
scale) and 2-naphthyl vinyl azide 2g also proceeded smoothly to
produce 1-pyrroline 33A in 63% yield, and a trace amount of
cyclohexadiene 33B (Scheme 2(II)).[16]
-
[a] Reactions were performed with 0.18 mmol of 1a, and 0.45 mmol of 2a. For
entries 9-13 1a and 2a not reacted. [b] Yield of isolated product. [c] 10 mol %
AgOTf additive used. IPr=1,3-bis(2,6-diisopropylphenyl-imidazol-2-ylidene).
With the optimized conditions, the scope of the [1+1+3]
annulation reaction was investigated with various ester
diazoenals 1 and vinyl azides 2 (Table 2). High yield of the 1-
pyrrolines 6-8 (66-80%) obtained with the ethyl, benzyl, and
methyl ester diazoenals (1a-c). The sterically hindered t-butyl
ester diazoenal (1d) gave a moderate yield of 9 (52%). Menthyl
Detailed investigation of olefination reaction revealed that 2
mol % Rh2(esp)2 provide spontaneous methylenation (<10 min)
of the ester diazoenal 1 with vinyl azide 2 resulting in enal-
acrylate 4. Other dirhodium carboxylates Rh2(OAc)4, Rh2(oct)4,
Rh2(tfa)4, and Rh2(S-DOSP)4 gave slow methylenation (see
Table S-1, SI for details). The electronic and steric influence on
ester diazoenal (1e) produced 1-pyrroline 10 as
a 2:1
diastereomeric mixture in 72% yield. Among the vinyl azides,
neutral and electron-rich styryl azides gave good to high yields
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10.1002/anie.201801976
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olefination was investigated with various vinyl azides 2 (Scheme
2(III), see SI for full details). The efficiency of olefination
increased with the increasing electron density on the aryl ring
(5a, 5c-h, 5j-k, 5m) with the exception that sterically crowded
ortho-substitution severely hampered the methylenation
(5i/5l/5n). The electron-rich 4-methoxy vinyl azides showed the
highest efficiency for the methylenation (5c-d, 100%) whereas
the electron-deficient 4-CN and 4-CF3 vinyl azides were
inefficient for methylenation (5k, 49%; and 5m, 39%). Olefination
with aliphatic vinyl azide was less efficient (5b, 66%) than the
styryl azide (5a, 74%). Beta-methyl substituted styryl azide (2x,
see SI) was not suitable for the olefination.
catalyzed denitrogenation of diazo compound 1 (R1,2: EWG)
gives the electrophilic rhodium-carbenoid A. Nucleophilic
addition of the vinyl azide 2 to the carbenoid A establishes the
key C-C -bond leading to the acyclic zwitterion B.[21] Facile
rhodium-assisted C-C bond fragmentation of B, triggered by the
loss of N2 delivers the olefin 4 and nitrile 5. The unstable enal-
acrylate 4 (R1: CO2R1, R2: enal) reacts with another molecule of
vinyl azide 2 via a stepwise [2+2]-cycloaddition pathway leading
to the sterically crowded cyclobutane C. Rapid regioselective
ring expansion of strained cyclobutane C via migration of
quaternary carbon and loss of nitrogen gives [1+1+3] annulation
product 1-pyrroline D. A minor reaction path consisting of [4+2]-
cycloaddition of the enal-acrylate 4 and vinyl azide 2 gives
cyclohexene E which upon elimination of HN3 produces the
[1+2+3]-annulation product 33B (R1=CO2Me, R= 2-naphthyl).
Scheme 3. Plausible mechanism for the olefination and annulation
Scheme 2. See SI for details. [a] i. Standard conditions of Table 1. [b] 0.1
mmol of 1a and 0.05 mmol of 2. [c] NMR yield of the reaction mixture. [d] 0.18
mmol of 1f and 0.09 mmol of 2b or 2e. [e] 0.15 mmol 1f, 0.3 mmol 2a.
Scheme 4. Conditions: (a) MePPh3Br, KOtBu, THF, 0 oC; (b) H2, Pd/C, MeOH,
25 oC; (c) LiOH, THF-MeOH-H2O, 25 oC; (d) magnesium monoperoxyphthalate
(MMPP), MeOH, 25 oC; (e) 2-iodoxybenzoic acid (IBX), DMSO, 25 oC; (f)
NaBH(OAc)3, AcOH, DCE, 25 oC.
Methylenemalonates (MM’s) 4f are important substrates in
organic synthesis and valuable platforms to the green polymers
such as adhesives and coatings. The known approaches to
MM’s involve harsh reaction conditions and multistep
The synthetic utility of the enal-functionalized 1-pyrroline
products was demonstrated by converting to the valuable N-
heterocycles and amino acid derivatives (Scheme 4). Reductive
ring-opening of 6 by hydrogenolysis and subsequent ester
hydrolysis led to the α-disubstituted amino acid 35 in excellent
yield. On the other hand, carbonyl methylenation and selective
imine oxidation of 6 furnished the pyrrolidine based oxaziridine
36 (3:1 dr), closely related to a new family of antimalarial agent
37.[18] Controlled hydrogenation of the enal moiety in 6 led to the
intramolecular cyclization via a transient enamine (see SI).
Subsequent IBX oxidation furnished a single diastereomer of 6-
azabicyclo[3.2.1]octane 38, present in the actinobolamine,
synthesis.[17] Gratifyingly,
the mild Rh2(esp)2-catalyzed
olefination of diethyl diazomalonate 1f with vinyl azide 2b/2e
furnished the MM 4f in excellent yield (Scheme 2(IV)). This new
approach for the in situ catalytic generation of unstable MM’s
may find broad applications. The [1+1+3] annulation of 1f and 2a
at the elevated temperature provided the 1-pyrroline 34 in 39%
of unoptimized yield (Scheme 2(V)).
As shown in Scheme 3, a plausible mechanism for the
olefination and annulation reaction is proposed. The Rh(II)-
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10.1002/anie.201801976
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COMMUNICATION
peduncularine, and lyconadin alkaloids.[19] Also, thienyl 1-
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a
new rhodium-catalyzed
olefination reaction of diacceptor diazo compounds and vinyl
azides for the synthetically challenging electrophilic terminal
olefins. The olefination proceeds via C-C bond fragmentation of
the acyclic zwitterion and involve benign nitrile and nitrogen as
the by-products. The synthetic importance of the olefination was
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pyrrolines. Structural diversification of enal-functionalized 1-
pyrrolines gave biologically important pyrrolidines. Further
studies on the synthetic applications of olefination and
annulation are underway.
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Acknowledgements
We thank IISER Bhopal, Department of Science & Technology
(SERB SR/S1/OC-13/2012), and Ministry of Earth Sciences
(MoES/09-DS/02/2014 PC-IV) for generous funding. We also
thank CSIR for a graduate research fellowship to VK.
Keywords: olefination • diazoenal • carbenoid • [1+1+3]
annulation • pyrroline
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Entry for the Table of Contents
Layout 2:
COMMUNICATION
Vinaykumar Kanchupalli, Sreenivas
Katukojvala*
Page No. – Page No.
[1+1+3] Annulation of Diazoenals and
Vinyl Azides: Direct Synthesis of
Functionalized 1-Pyrrolines via a New
Olefination
A new rhodium-catalyzed olefination of diacceptor diazo compounds with vinyl azides resulted in the
electrophilic terminal olefins. The synthetic importance of the new olefination was demonstrated in a
Rh(II)-catalyzed [1+1+3] annulation of diazoenals with vinyl azides, leading to the enal-functionalized
substituted 1-pyrrolines. The methodology was applied to the synthesis of diverse pyrroline and
pyrrolidine heterocycles.
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