Annulation of allylic phosphoryl-stabilized carbanions/phosphorus ylides and vinyl azides: A practice strategy for synthesis of polyfunctionalized anilines

Article abstract of DOI:10.1039/c4cc03462g

Tandem Michael addition and Witting or Horner-Wadsworth-Emmons olefination initiated [3+3] annulation between vinyl azides and allylic phosphorus ylides or allylic phosphoryl-stabilized carbanions has been developed. This one-pot protocol furnishes highly functionalized anilines in good to excellent yields under mild, room-temperature conditions. A rational mechanism is also proposed. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc03462g

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[3+3] annulation of allylic phosphoryl-stabilized
carbanions/phosphorus ylides and vinyl azides:
a practice strategy for synthesis of
Cite this: Chem. Commun., 2014,
50, 8539
Received 8th May 2014,
Accepted 4th June 2014
polyfunctionalized anilines†
Shen Liu,‡ Wenteng Chen,‡ Jing Luo and Yongping Yu*
DOI: 10.1039/c4cc03462g
www.rsc.org/chemcomm
Tandem Michael addition and Witting or Horner–Wadsworth– the reactions of vinyl azides with allylic phosphorus ylides
Emmons olefination initiated [3+3] annulation between vinyl azides or phosphoryl-stabilized carbanions, the latter of which are
and allylic phosphorus ylides or allylic phosphoryl-stabilized carbanions frequently investigated for their C–C bond formation.9,10
has been developed. This one-pot protocol furnishes highly function- Herein, a [3+3] cascade transformation is reported under mild
alized anilines in good to excellent yields under mild, room-temperature reaction conditions, which provides a convenient method for the
conditions. A rational mechanism is also proposed.
synthesis of polyfunctionalized anilines. Additionally the exceptional
substrate scope of the reaction, which accepts heteroaryl, halo-
The aniline skeleton is an intriguing synthetic target because of its genated, nitro-containing substrates is reported.
abundance in biologically active natural products, pharmaceuticals,
Initially, the reaction of crotonate-derived phosphorus ylide
pesticides, and dyes.1,2 In industry, electrophilic nitration of arenes (1a) and (Z)-2-azido-1-(4-nitrophenyl)-3-phenylprop-2-en-1-one (2a)
followed by reduction is a key technology for aniline formation was selected as a model to optimize the reaction conditions.
though it is limited by essential position directing and a relatively Treatment of a mixture of vinyl azide 2a (1.0 equiv.) and phosphorus
narrow substrate scope.3 On the other hand, the Buchwald–Hartwig ylide 1a (1.0 equiv.) with EtONa (3.0 equiv.) in i-PrOH at room
amination reaction has been extensively utilized for generating temperature resulted in the desired aniline 3a with a conversion
anilines. These coupling reactions are commonly catalysed by metal of 15% along with unidentified complex mixtures that included
and phosphine ligands4 either using an indirect nitrogen source5 or phosphazene via a Staudinger–Meyer reaction11 (Table 1, entry 1).
by direct amination using ammonia.6 In addition to these conven-
Table 1 Optimization of the reaction conditionsa
tional modifications on benzene rings, cross coupling of malono-
nitrile and some activated moieties, such as a-methylene ketones,
ynones and nitrostyrenes, is employed for multisubstituted aniline
formation.7 Despite these advances, the control of substituents on
the aniline ring, the limited source of the starting materials and the
development of milder reaction conditions still remains a challenge.
Thus, the development of novel efficient strategies for the construc-
tion of polyfunctionalized anilines is highly desirable.
In search of alternatives to the cross-coupling of saturated
N-heterocycles, our group and others have reported the use of a
vinyl azide as a synthon for the formation of nitrogen-containing
heterocycles, such as pyrrolo[1,2-a]pyrazine,8a 4-aminopyridines,8b
pyrazoles,8c or other heterocycles.8d–g The continued interest in
electrophilic reactivity of vinyl azides motivated us to investigate
Entry
Base
Solvent
T/1C
Conversionb/%
1
2
3
4
5
6
7
8
EtONa
EtONa
EtONa
EtONa
EtONa
EtONa
EtONa
EtONa
EtONa
Et3N
i-Propanol
n-Butanol
CH3OH
THF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
15
18
52
70 (65)c
26
DMF
CH3CN
1,4-Dioxane
Toluene
DCM
DCM
DCM
58
45
47
9
87 (85)c
19
10
11
12
13
DBU
Cs2CO3
NaOH
41
DCM
DCM
Trace
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research,
College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058,
P. R. China. E-mail: yyu@zju.edu.cn; Tel: +86-571-88208452
† Electronic supplementary information (ESI) available. CCDC 1005572. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4cc03462g
75 (70)c
a
Unless otherwise specified, reactions were performed using 1a
(0.1 mmol) and 2a (0.1 mmol) in various solvents (1.0 mL) at rt in the
b
presence of the base (0.3 mmol) for 1.0 h. The conversion rate was
determined by HPLC, based on the disappearance of the starting vinyl
c
‡ Shen Liu and Wenteng Chen contributed equally to this work.
azide (2a). Isolated yield.
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When the reaction was carried out in other protic solvents, the
conversion of 3a was slightly improved to 18% (n-butanol) and 52%
(CH3OH), respectively (Table 1, entries 2 and 3). Assessment of the
reaction with additional solvents revealed that THF and DCM
worked more efficiently, giving 3a in 65% and 85% yield, respectively
(Table 1, entries 4 and 9). The use of other bases, such as Et3N, DBU
and NaOH, were less effective for this transformation (Table 1,
entries 10, 11 and 13). In fact when the reaction was carried out in
the presence of Cs2CO3, only a trace amount of the desired product
3a could be detected via LC-MS (Table 1, entry 12). As shown in
Table 1, the highest yield (85%) was obtained when the reaction was
performed in DCM at room temperature for 1.0 h using
3.0 equivalents of EtONa (Table 1, entry 9).
This facile annulation reaction encouraged us to explore
the generality of the reaction for the synthesis of a variety of
polyfunctionalized anilines. A series of substituted vinyl azides
(2a–2o) and phosphonium ylide (1a) were employed as cyclization
substrates and subjected to the previously optimized reaction
conditions (Table 2).
Scheme 1 Generality of [3+3] annulation.
phenyl group, less than 10% of this transformation occurred
under the reaction conditions (Scheme 1, eqn (1)). The poor
result was probably due to the weak nucleophilicity of the allylic
phosphonium ylide.
Various vinyl azides 2a–2o, including those with nitro or
halogen moieties, provided the corresponding multifunction-
alized anilines 3a–3o in good to excellent yields. The reaction
with vinyl azides, bearing an electron-withdrawing group at the
R1 position, resulted in the corresponding [3+3] annulation
products (Table 2, compounds 3f, 3g, 3h, 3i, 3j, and 3k) in good
yields. Likewise, the b-electron-donating group substituted vinyl
azides are capable of affording the desired anilines, albeit in lower
yields (Table 2, compounds 3b, 3c, 3d, 3e, 3l, 3m, 3n and 3o).
When varying the substitution position on the b-aryl vinyl
azides 2, the corresponding potential steric effects are tolerated
by the present method and the desired products are provided in
good yields (Table 2, compounds 3f, 3j and 3k).
To our knowledge, phosphoryl-stabilized carbanions are
generally more reactive than phosphorus ylides.12 We thus
examined the use of phosphoryl-stabilized carbanions (1b) instead
of phosphorus ylides (1a) (Scheme 1, eqn (2)) which increased the
yield of the desired product to 50% (Table 3, entry 1). The desired
product 3p was obtained in a higher isolated yield (Table 3, entry 2)
when MeONa was utilized as the base. Further increasing the
amount of base slightly improved the isolated yield (Table 3,
entry 3). As shown in Table 3, MeONa and DCM seemed to be
the best choice for the reaction of a-phenyl substituted vinyl
azide 2p with phosphoryl-substituted carbanion 1b providing
an excellent yield of 78%.
The results encouraged us to explore the expanded-scope
of this annulation. The reaction of methyl (E)-4-(dimethoxy-
phosphoryl) but-2-enoate (1b) with various a,b-substituted vinyl
azides (2) under the standard reaction conditions (given in
Table 3) gave the multisubstituted anilines (3) in good to excellent
yields (Table 4, isolated yields 470%). Both electron-rich and
-deficient aryl groups at the R2 position were tolerated in this
annulation. In contrast, when a-tributylcarbonyl-substituted
vinyl azide 2x was reacted with 1b, only a trace amount of the
corresponding aniline 3x was observed via LC-MS. Likewise, when
We then turned our attention towards the scope of substitu-
tion of viable R2 of vinyl azides 2 under the current conditions
(Scheme 1). This turned out to be rather challenging (Scheme 1).
When the R2 position of the vinyl azides 2 was substituted with a
Table 2 Scope of vinyl azides 2
Table 3 Optimization of the reaction conditionsa
Entry
2
R1
R2
Product/isolated yield
1
2
3
4
2a C6H5
4-NO2C6H5 3a (76%)
3b (68%)
3c (69%)
2b 4-MeSC6H5
2c 4-MeOC6H5
2d 3-MeC6H5
2e 4-MeC6H5
3d (73%)
3e (72%)
5
6
7
8
9
10
11
12
13
14
15
2f
2-BrC6H5
3f (83%)
Entry
Base
Equivalent
Solvent
Conversionb/%
2g 3-BrC6H5
2h 4-BrC6H5
2i
2j
2k 2-Cl-6-FC6H5
2l
2m 3-(C6H5O)C6H5
2n 4-(C6H5O)C6H5
2o 4-(4-C6H5CH2O)C6H5
3g (79%)
3h (86%)
3i (82%)
3j (78%)
3k (81%)
3l (70%)
3m (72%)
3n (71%)
3o (67%)
1
2
3
EtONa
MeONa
MeONa
3.0
3.0
5.0
DCM
DCM
DCM
56 (50)c
75 (70)c
83 (78)c
4-ClC6H5
2-FC6H5
a
3-(4-MeC6H5O)C6H5
Reactions were performed using 1b (0.1 mmol) and 2a (0.1 mmol)
in various solvents (1.0 mL) at rt in the presence of the base for 1.0 h.
b
The conversion rate was determined by HPLC, based on the dis-
c
appearance of the starting vinyl azide (2a). Isolated yield.
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Table
4
Generality of [3+3] annulation of vinyl azides with allylic
phosphoryl-stabilized carbanions
Entry
2
R1
R2
Product/isolated yield
1
1
2
3
4
5
6
7
8
9
10
11
2a
2p
2q
2r
2s
2t
2u
2v
2w
2x
2y
2z
C6H5
C6H5
4-NO2C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-MeC6H5
4-BrC6H5
C(CH3)3
OEt
3a (85%)
3p (78%)
3q (79%)
3r (80%)
3s (83%)
3t (65%)
3u (70%)
3v (76%)
3w (83%)
3x (trace)
3y (0%)
2-BrC6H5
3-BrC6H5
4-BrC6H5
2-Pyridinyl
2-Furyl
C6H5
C6H5
C6H5
C6H5
C6H5
H
3z (0%)
the a-ester substituted vinyl azide 2y was employed, no desired
aniline 3y was observed. These results suggested that the poor
electrophilicity of these vinyl azides did not enable a HWE-
olefination to form the desired anilines. While, the strong
reactivity of the aldehyde group at the a-position of vinyl azide
2z favoured an intermolecular HWE olefination over a [3+3]
annulation under the optimization reaction conditions. In
general though the tandem reaction showed broad tolerance
for various R1 groups of vinyl azides, selected substrates bearing
phenyl (2p, 2v and 2w), electron-deficient aryl (2q, 2r and 2s),
and heteroaryl (2t and 2u) at R1 groups reacted efficiently with 1b
to provide the corresponding anilines (3p–3u) in high yields at
room temperature for 1.0 h.
Scheme 2 Proposed mechanism for the annulation.
vinyl azides 2 initiates the formation of adduct III or V in the
presence of base. Adduct III exclusively undergoes 1,6-proton
shift to convert to intermediate IV, while intermediate VI is
formed from adduct V via 1, 3-proton transfer. The annulation
process is followed by an intramolecular Witting or HWE
olefination and subsequent proton transfer to afford the corre-
sponding aniline 3.
The structures of the polyfunctionalized anilines were char-
1
acterized by H NMR, 13C NMR and HRMS. The structures of
one representative compound 3c were proved by X-ray crystal
structural analysis as shown in Fig. 1 (CCDC 1005572).
The tandem reaction sequence outlined in Scheme 2 was
proposed to explain this facile transformation. Nucleophilic
attack of ylide 1a or phosphoryl-stabilized carbanion 1b with
In summary, a base-promoted [3+3] annulation between allylic
phosphoryl-stabilized carbanions or phosphorus ylides with vinyl
azides was developed under mild, room temperature conditions. This
facile reaction allows construction of polyfunctionalized anilines in
good yields. Both the substituents and positions on the anilines can
be easily controlled by choosing appropriate and accessible starting
materials. A rational mechanism was also proposed. It is anticipated
that the present annulation is potentially useful for synthesis of
biologically and medicinally important anilines.
This research was supported by the National Natural Science
Foundation of China (No. 81273356), the Natural Science
Foundation of Zhejiang Province (No. Z2110655), the Program
for Zhejiang Leading Team of S&T Innovation, and Alzheimer’s &
Aging Research Centre, USA. And we appreciate Marc Giulianotti
(Torrey Pines Institute for Molecular Studies, USA) for critical
reading of the manuscript.
Notes and references
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