Phosphine-catalyzed (3+2)/(2+3) sequential annulation involving a triple nucleophilic addition reaction of γ-vinyl allenoates

Article abstract of DOI:10.1039/c9cc07346a

A phosphine-catalyzed (3+2)/(2+3) sequential annulation involving a triple nucleophilic addition reaction of γ-vinyl allenoates was successfully developed. The reaction provided efficient and more practical access to functionalized hydropyrroloimidazolone

Full text of DOI:10.1039/c9cc07346a

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Phosphine-catalyzed (3+2)/(2+3) sequential
annulation involving a triple nucleophilic addition
reaction of c-vinyl allenoates†‡
Cite this: Chem. Commun., 2019,
55, 14011
Received 18th September 2019,
Accepted 25th October 2019
Jiaxu Feng and You Huang
*
DOI: 10.1039/c9cc07346a
rsc.li/chemcomm
A phosphine-catalyzed (3+2)/(2+3) sequential annulation involving reported using
a tandem reaction involving phosphine-
a triple nucleophilic addition reaction of c-vinyl allenoates was catalyzed umpolung addition and intramolecular conjugate
successfully developed. The reaction provided efficient and more addition to form carbocycles and heterocycles.11 Later, Lu12
practical access to functionalized hydropyrroloimidazolones with and Kwon13 delivered, respectively, the efficient syntheses of
good to excellent yields under mild reaction conditions. Notably, carbocycles and heterocycles using allenoates and various
c-vinyl allenoate served as a triple-electrophilic intermediate in this dinucleophiles in a tandem reaction. Moreover, Tong14 and
protocol.
Shi15 similarly described a phosphine-catalyzed tandem annula-
tion with d-acetoxy allenoates to 1,3-bisnucleophiles, which could
Hydropyrroloimidazolones constitute a valuable class of nitrogen be converted to various heterocycles. Furthermore, the reactions
heterocycles and are widely prevalent in biologically active products of 1,1- and 1,2-bisnucleophiles with allenoates to form five- and
and pharmaceuticals (Fig. 1).1 While effective methods for their six-membered carbocyclic and heterocyclic products have also
syntheses have been reported with substituted N-heterocycles,2 been reproted.16 To the best of our knowledge, there has been
these syntheses remain a formidable challenge.
no report about reactions between allenoates and nucleophiles
Phosphine-catalyzed nucleophilic addition3 is one of the involving triple nucleophilic additions, probably because of sev-
most popular tools for the assembly of C–C and C–N bonds eral challenges that could not be ignored, such as (1) competing
in organic synthesis.4 In this field, activated allenoates have reactions at multiple reaction sites in allenoates, (2) difficulty in
been recognized as one of the most effective starting materials5 finding suitable nucleophiles, and (3) difficulty in controlling the
and the seminal work has been vastly expanded upon, leading regioselectivity. In order to overcome these issues and accomplish
to great potential for the synthesis of natural products.6 The this desired reaction, it is critical to carefully design the allenoates
formidable breakthrough in phosphine catalysis was reported and screen multifunctional nucleophiles. On the basis of our
by Trost, who discovered that the g-umpolung addition of group’s previous work in the phosphine catalysis of sequential
nucleophiles to activated allenoates and alkynoates leads to annulation,17 we designed and synthesized a new kind of g-vinyl
the formation of C–C bonds7 (Scheme 1, (a)). Subsequently, allenoate. Our group provided here the first examples of
many efforts have been devoted to the g-umpolung addition of phosphine-catalyzed (3+2)/(2+3) sequential annulation mediated
various pro-nucleophiles.8 Later on, Huang and Lu reported by a triple nucleophilic addition reaction of g-vinyl allenoates with
phosphine-catalyzed b-Michael addition9 under mild reaction urea derivatives (Scheme 1, (d)). This work featured a fine control
conditions (Scheme 1, (b)).
Phosphine-catalyzed nucleophilic addition of allenoates
using di-nucleophiles as substrates has emerged as a valuable
approach for forming functionalized carbocycles and hetero-
cycles from acyclic reactants (Scheme 1, (c)).10 In 2002, Lu
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of
Chemistry, Nankai University, Tianjin 300071, China. E-mail: hyou@nankai.edu.cn
† Dedicated to 100th anniversary of Nankai University and dedicated to the 100th
anniversary of the birth of the academician Ruyu Chen.
‡ Electronic supplementary information (ESI) available. CCDC 1938975 (3aa),
Fig. 1 Selected examples of natural products and bioactive molecules
1938970 (4aa) and 1938977 (5wa). For ESI and crystallographic data in CIF or
containing the hydropyrroloimidazolone unit.
other electronic format see DOI: 10.1039/c9cc07346a
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Scheme 1 Nucleophilic addition of the allenoate in the phosphine
catalyst.
of the regioselectivity and a wide substrate scope, which provided
a new and practical route to the construction of hydropyrrolo-
imidazolone derivatives.
Scheme 2 The scope of this reaction. The reaction was performed under
optimum conditions. Isolated yield is shown.
At the outset of our studies, we chose 1-(1-methyl-2-oxoindolin-
3-yl)-3-( p-tolyl)urea (1a) and g-vinyl allenoates (2a) as model start-
ing materials to explore the optimal conditions for this (3+2)/(2+3)
nucleophilic addition reaction. As a result of our initial screening
of conditions, the use of PPh3 in toluene at 110 1C led to the
corresponding heterocyclic product diastereomer 3aa in 23% yield
(Table 1, entry 1).
Screening of phosphine catalysts revealed that PBu3 and
( p-FC6H4)3P were ineffective in this reaction (entries 2 and 3).
Gratifyingly, when (p-MeOC6H4)3P was used, two diastereomers
were obtained in 94% total yield. Pleasingly, we were able to
completely separate the diastereomers 3aa and 4aa using silica-gel
column chromatography and achieved yields of 45% and 49%,
respectively (entry 4). Subsequent testing of the effect of temperature
confirmed that 110 1C was the best temperature (entries 5 and 6)
and in fact showed that the reaction outcome was highly affected by
the reaction temperature. Moreover, further evaluation here of
reaction conditions showed a higher yield when lowering the
catalyst loading to 20% (entry 7), but increasing the (p-MeOC6H4)3P
loading led to a similar result (entry 8). Lowering the amount of 2a
did not result in a satisfactory outcome (entry 9).
With the optimal reaction conditions in hand, we turned our
attention to validating the potential and generality of this (3+2)/
(2+3) annulation reaction. We first investigated a variety of
multifunctional nucleophiles (Scheme 2). A broad range of
substituted ureas, including those bearing electron-donating
groups (Me or MeO) and electron-withdrawing groups (F, Cl or Br)
at the para- or meta-position of the aryl ring moiety (R1), were
compatible with the reaction conditions and gave the corres-
ponding diastereoisomer products in good to excellent yields
(3aa–3ia, 4aa–4ia), respectively, showcasing the excellent func-
tional group tolerance of the reaction. The relative configurations
of the diastereoisomers 3aa and 4aa were determined by carrying
out X-ray crystal analysis and others were assigned by analogy. In
addition, urea 1j with a 3-CF3, 4-Cl substitution on the aryl group
(3-CF3, 4-Cl bis-substituted urea 1j) was found to be suitable and
afforded desired products with moderate yields. Delightedly,
5-fluorine and the 5-MeO group in the oxindole core also proved
to yield good substrates, affording the products (3ka–3la, 4ka–4la)
with good yields. Then we explored the effects of the protection of
the nitrogen atom in the oxindole core by protecting groups such
as CH2CH(OEt)2 (1m–1r), n-Pr (1s–1t) and Bn (1u). It was found
that the methyl protecting group was most effective. A gram-scale
reaction of urea 1m and allenoates 2a was tested, and resulted in
Table 1 Optimization of the reaction conditionsa
Yieldb (%)
Entry
Cat. (30 mol%)
Temp. (1C)
3
4
1
2
3
4
5
6
PPh3
PBu3
110
110
110
110
50
23
—
—
45
37
32
46
50
36
—
—
—
49
32
24
50
42
32
( p-FC6H4)3P
( p-MeOC6H4)3P
( p-MeOC6H4)3P
( p-MeOC6H4)3P
( p-MeOC6H4)3P
( p-MeOC6H4)3P
( p-MeOC6H4)3P
25
7c
8d
9c,e
110
110
110
a
Reaction conditions: 0.20 mmol 1a (1.0 equiv.), 0.60 mmol 2a
b
(3.0 equiv.), cat. (30 mol%) in toluene (2.0 mL) at 110 1C. Yield of
isolates product. Cat. (20 mol%) was added. Cat. (40 mol%) was
added. 0.40 mmol 2a (2.0 equiv.) was used.
c
d
e
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Scheme 3 Further transformations using this method.
an 83% overall yield. Meanwhile, other protecting groups were
also well tolerated, which highlighted the broad substrate scope of
this reaction. Furthermore, various g-vinyl allenoates were tested,
and produced the target compounds with good yields (3ab, 3ac,
3bb, 3bc, 4ab, 4ac, 4bb, 4bc).
In order to further underscore the synthetic utility of this
method, we also explored the reactivities of alkyne compounds.
Intriguingly, when methyl hex-5-en-2-ynoate was employed in
this annulation, the desired diastereoisomer products 3aa, 4aa,
3ma and 4ma were also obtained under the same conditions
with satisfactory yields (Scheme 3).
Scheme 5 Proposed reaction mechanism.
derived (shown in Scheme 5). This mechanism differs from the
phosphine-catalyzed reaction mechanisms of allenoates reported
before in which the key intermediates of allenoates were the
(1,n)-zwitterion or the 1,4-bis-electrophile intermediates.
To gain further insight into the mechanism of the reaction,
control experiments were performed (Scheme 4). Treatment of
1-butyl-3-(1-methyl-2-oxoindolin-3-yl)urea 1v with g-vinyl alleno-
ates under the optimal conditions did not yield the corresponding
products 3va and 4va, but the key intermediate product spiroox-
indole 5va was isolated (Scheme 4, (1)). The structure of 5va was
confirmed from NMR and HRMS spectra. Additionally, the reac-
tion of 1-benzyl-3-(1-methyl-2-oxoindolin-3-yl)urea, 1w, with 2a
was tested, and the intermediate spirooxindole 5wa was also
obtained with 20% yield (Scheme 4, (2)). The structure and relative
configuration of intermediate 5wa was confirmed using X-ray
crystallography. Next, two different pro-nucleophiles, 1x and 1y,
were synthesized and we also examined their reactivities under
optimal reaction conditions. However, when the pro-nucleophile
1x was employed as a substrate, no desired product was afforded
under optimal conditions (Scheme S1, (1), see ESI‡ for details),
which indicated that the urea nitrogen atom played a crucial role
in the annulation. Moreover, substrate 1y was also inefficient
(Scheme S1, (2), ESI‡). These outcomes indicated that the oxi-
ndole backbone was indispensable and its structurally unique
property may have triggered the formation of the important
intermediate D.
According to the currently proposed mechanism, first
nucleophilic addition to vinyl allenoates 2 by PPh3 afforded
zwitterionic intermediate A, which then acted as a base to
deprotonate the pro-nucleophile 1 leading to the construction
of the intermediates B and C. Subsequently, according to the
mechanism, nucleophilic attack of the vinyl group of inter-
mediate B by intermediate C produced intermediate D-I, which
formed an equilibrium with intermediate D-II, and then D-II
deprotonated to generate the corresponding intermediate E.
Next, according to the proposal, intramolecular Michael addition
(the second nucleophilic addition) occurred to give the intermedi-
ate F, which then underwent a proton shift and the third
nucleophilic addition (see path a in Scheme 5), finally producing
the desired (3+2)/(2+3) annulation product. Through an alterna-
tive path (path b in Scheme 5), byproduct 5 was obtained through
an H-shift and subsequent 1,2-elimination of PPh3.
In summary, we have developed a novel and efficient phosphine-
catalyzed (3+2)/(2+3) sequential annulation mediated by triple
nucleophilic addition. By using substituted urea compounds as
readily accessible precursors of triple-functional nucleophiles, a
wide range of hydropyrroloimidazolones were obtained in good to
excellent yields under mild conditions, showing the great tolerance
of the reaction to a wide variety of functional groups. This step-
economical and regionally selective method involved formation of a
C–C bond and two C–N bonds and the production of functionalized
N-hetero-bicyclic derivatives bearing three stereogenic centers. In
this sequence, g-vinyl allenoates were shown to serve as versatile
triple electrophiles and to be able to participate in three nucleophilic
additions with pro-nucleophiles. Interestingly, the (3+2)/(2+3)
sequential annulation was also compatible with the use of an
enyne, and in this case afforded hydropyrroloimidazolone with a
satisfactory outcome. This approach provides a potential method
On the basis of the detailed mechanistic understanding and
our previous works,18 a plausible reaction mechanism was
Scheme 4 Preliminary mechanism study.
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We thank the National Natural Science Foundation of China
(21672109, 21871148 and 21472097) for financial support.
Conflicts of interest
There are no conflicts to declare.
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