Formal [4+2]-annulation of vinyl azides with N-unsaturated aldimines

Article abstract of DOI:10.1002/asia.201402421

Highly functionalized quinolines and pyridines could be synthesized by BF₃?OEt₂-mediated reactions of vinyl azides with N-aryl and N-alkenyl aldimines, respectively. The reaction mechanism could be characterized as formal [4+2]-annulation, including unprecedented enamine-type nucleophilic attack of vinyl azides to aldimines and subsequent nucleophilic cyclization onto the resulting iminodiazonium ion moieties.

Full text of DOI:10.1002/asia.201402421

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DOI: 10.1002/asia.201402421
Formal [4+2]-Annulation of Vinyl Azides with N-Unsaturated Aldimines
Xu Zhu, Yi-Feng Wang, Feng-Lian Zhang, and Shunsuke Chiba*[a]
Abstract: Highly functionalized quinolines and pyridines
could be synthesized by BF3·OEt2-mediated reactions of
vinyl azides with N-aryl and N-alkenyl aldimines, respective-
ly. The reaction mechanism could be characterized as formal
[4+2]-annulation, including unprecedented enamine-type
nucleophilic attack of vinyl azides to aldimines and subse-
quent nucleophilic cyclization onto the resulting iminodiazo-
nium ion moieties.
Design and development of new methods to assemble ni-
trogen heterocycles (azaheterocycles) is one of the most in-
tense subjects in the area of synthetic organic chemistry, as
these classes of molecules are particularly important in phar-
maceutical and materials sciences.[1,2] Among available ni-
trogen sources for construction of azaheterocycles, vinyl
azides have shown unprecedented chemical reactivity for
synthesis of azaheterocycles (Scheme 1).[3] The thermolysis
or photolysis of vinyl azides result in elimination of dinitro-
gen to generate vinyl nitrenes that undergo ring closure to
2H-azirines (Scheme 1a).[4] The 2H-azirines having adjacent
aryl or vinyl tethers are further converted into the corre-
2
À
sponding indole or pyrrole derivatives via sp C H amina-
tion. More recently, the groups of Driver and Bolm have re-
Scheme 1. Chemical reactivity of vinyl azides for synthesis of azahetero-
cycles. acac=2,4-pentanedionato.
ported that these transformation can be catalyzed by transi-
tion-metals such as RhII carboxylates, ZnI2, and Fe
(OTf)2
under much milder reaction conditions.[5–7] Vinyl azides can
function as radical acceptors, and various carbon radicals
add to the C=C bond of vinyl azides to form iminyl radicals
that can be used for azaheterocycle synthesis (Scheme 1b).
Our group has reported synthesis of azaheterocycles based
on the oxidative radical reactions of vinyl azides.[8]
Our recent interest in reaction design using vinyl azides
relies on their potential nucleophilicity as enamine equiva-
lents (Scheme 2). Indeed, we have reported amide synthesis
by BF3·OEt2-mediated nucleophilic attack of vinyl azides
onto various carbon electrophiles (E+) such as N-Ts imines
(Scheme 2a).[9,10] The reactions were initiated by nucleophil-
ic attack of vinyl azides to E+ to form iminodiazonium ion
intermediates I, which undergo substituent-1,2-migration to
form nitrilium ions II. Subsequent hydrolysis of II affords
the corresponding amides. We wondered whether, if the
electrophile is tethered with another nucleophilic part (Nu)
that can trap the resulting iminodiazonium ion intermediate,
it would be possible to construct a new cyclic structure prior
to the substituent migration (Scheme 2b). Herein, we report
a realization of this concept by BF3·OEt2-mediated reactions
of vinyl azides with N-unsaturated imines, enabling efficient
and robust synthesis of highly functionalized quinolines and
pyridines.
We began our studies using vinyl azide 1a with N-phenyl
benzaldimine (2a) in the presence of BF3·OEt2 (Scheme 3).
The reaction of 1a and N-phenyl benzaldimine 2a
(1.5 equiv) with BF3·OEt2 (1.5 equiv) in CH2Cl2 at room
temperature delivered 2,4-diphenylquinoline (3aa) in 63%
yield along with generation of N-benzyl aniline (4a) in 57%
yield. The reaction is likely initiated by nucleophilic attack
[a] X. Zhu, Dr. Y.-F. Wang, F.-L. Zhang, Prof. S. Chiba
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
Fax : (+65)6791-1961
E-mail: shunsuke@ntu.edu.sg
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201402421.
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Shunsuke Chiba et al.
increase the amounts of aldimine 2a and BF3·OEt2 to
2.2 equivalents improved the yield of 3aa to 80% (along
with formation of 4a in 78%). The reaction performed
equally well on a large scale (10 mmol of 1a).
To confirm the suitability of vinyl azide 1a for the present
[4+2]-annulation with N-phenyl benzaldimine 2a for synthe-
sis of quinoline 3aa, we next tested the reactions of analo-
gous enamide 5 and enamine 6 with 2a in the presence of
BF3·OEt2 (Scheme 4). In the case of enamide 5, the reaction
Scheme 2. Chemical reactivity of vinyl azides as nucleophile. Ts=
CH3C6H4SO2.
Scheme 4. Chemical reactivity of vinyl azides for synthesis of azahetero-
cycles.
resulted in a complex mixture that included only a small
amount of desired quinoline 3aa (15% yield) along with 4a
in 15% yield (Scheme 4a). The reaction of morpholine en-
amine 6 afforded chalcone 7 in 18% yield without formation
of quinoline 3aa (Scheme 4b). These results unambiguously
showed the special chemical reactivity of vinyl azide 1a as
an enamine-type nucleophile as well as the putative imino-
diazonium ion intermediate I (Scheme 2a) as an electrophile
for the present transformation.[13,14]
Following the established procedure, the generality of this
quinoline synthesis[15] was examined using a series of vinyl
azides 1[16] with aldimine 2a (Table 1). a-Aryl substituted
vinyl azides (1b–g) reacted smoothly with aldimine 2a to
afford the corresponding quinolines 3ba–3ga in good yields
(Table 1, entries 1–6). Notably, heteroaryl motifs such as 2-
benzofuranyl (Table 1, entry 7), 3-benzothienyl (Table 1,
entry 8), and 5-oxazolyl motifs (Table 1, entry 9) were com-
patible under the present reaction conditions, furnishing the
desired quinolines 3ha–3ja. The reaction of 3-azido-1H-
indene (1k) proceeded smoothly to give polycyclic 6-
Scheme 3. Reactions of vinyl azide 1a and N-phenyl aldimine 2a.
of vinyl azide 1a to aldimine 2a electrophilically activated
phenyl-7H-indenoACTHUGNTERNNU[G 2,1-c]quinoline 3ka in 70% yield
À
by BF3·OEt2 as the first C C bond forming process, giving
iminodiazonium ion intermediate I. Subsequent intramolec-
(Table 1, entry 10). a-Alkyl substituted vinyl azide 1l was
also capable of coupling with aldimine 2a, while the yield of
quinoline 3la was moderate (40% yield; Table 1, entry 11).
We next examined compatibility of N-aryl aldimines 2 in
this quinoline synthesis with vinyl azide 1a (Scheme 5). In-
stallation of a methoxy group as the substituent R3 did not
affect the reactions to deliver quinolines 3ab and 3ac in
À
ular cyclization to the imine moiety of I (the second C C
bond formation) forms 4-azido-tetrahydroquinoline II. Aro-
matization of II via hydrogen transfer to another molecule
of aldimine 2a[11] and elimination of HN3 delivers quinoline
3aa and N-benzyl aniline (4a). Therefore, the overall trans-
formation is characterized as formal [4+2]-annulation,[12]
and two equivalents of aldimine 2a is theoretically required
to complete the formation of quinoline 3aa. As expected, to
good yields. In the reaction of aldimine 2c having a 3-me-
3
À
thoxy group as R , the second C C bond forming process
took place exclusively at the less hindered carbon atom
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Table 1. Synthesis of quinolines 3: scope of vinyl azides 1.[a]
Entry
Vinyl azide 1
Quinoline 3, yield[b]
1
2
3
4
5
1b: R=4-Me
1c: R=4-MeO
1d: R=4-Br
1e: R=4-CO2Me
1 f: R=3-NO2
3ba 68%
3ca 69%
3da 78%
3ea 80%
3 fa 71%
6
7
8
Scheme 5. Synthesis of quinolines 3: scope of aldimines 2. The reaction
was conducted using 0.28–0.33 mmol vinyl azide 1a.
1g
3ga 79%
ethoxy carbonyl quinoline 3ai could be realized in good
yield, while that of 2-isopropyl quinoline 3aj resulted in
moderate yield.
We explored the further potential of the present strategy
using vinyl azides 1 for synthesis of pyridines.[17] In that re-
spect, N-alkenyl aldimines (2-aza-diene) 8[18] (1.5 equiv)
were utilized as annulation partners with vinyl azides
1 (Scheme 6). Treatment of a-4-tolyl vinyl azide 1b and N-
alkenyl aldimine 8a with BF3·OEt2 (1.5 equiv) proceeded
smoothly at room temperature and subsequent addition of
2,3-dicyano-5,6-dichloro-1,4-benzoquinone (DDQ, 1.5 equiv)
completed the aromatization to afford the corresponding
pyridine 9ba in 70% yield. Similarly, by varying the sub-
stituent R1 on vinyl azides 1, various aromatic motifs could
be installed for construction of the pyridine scaffold (for
9ca–9ha, 9ja).The present method allowed installation of
various aromatic moieties as substituents R3 and R4 to pro-
vide the corresponding tetrasubstituted pyridines 9ab–9ag
in good to moderate yields.
In summary, we have developed a concise and robust
method for synthesis of highly substituted quinolines and
pyridines by BF3·OEt2-mediated formal [4+2]-annulation of
vinyl azides and N-unsaturated aldimines. We anticipate that
the present annulation strategy with vinyl azides is capable
of supplying various azaheterocycles that are important in
medicinal and materials application.
1h
1i
3ha 80%
3ia 56%
9
1j
3ja 85%
10
11
1k
1l
3ka 70%
3la 40%
[a] The reaction was conducted using 0.26–0.41 mmol of vinyl azides 1.
[b] Yields of isolated product were recorded.
Experimental Section
(marked in blue). The present methods allowed introduction
of sterically hindered 2-methylphenyl group (for 3ad) as the
substituent R4, as well as electron-deficient benzene rings
(for 3af–3ah). However, the reaction with electron-rich aldi-
mine 2e having a 4-methoxybenzene ring as R4 resulted in
no formation of the desired quinoline 3ae. Synthesis of 2-
Typical Procedure: Synthesis of 2,4-diphenylquinoline (3aa, Scheme 3).
To a solution of vinyl azide 1a (1.45 g, 10.0 mmol) and N-phenyl benzal-
dimine 2a (3.99 g, 22.0 mmol) in dichloromethane (0.2m) was added
dropwise BF3·Et2O (2.7 mL, 22.0 mmol) at 08C. After the addition, the
reaction mixture was allowed to warm up to room temperature and was
stirred for another 12 h. The reaction mixture was quenched with saturat-
3
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Shunsuke Chiba et al.
Oxford, 1984; e) T. Eicher, S. Hauptmann, The Chemistry of Hetero-
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[7] Very recently, Yoon and Farney disclosed visible-light sensitization
of vinyl azides using a transition-metal photocatalyst, see: E. P.
Farney, T. P. Yoon, Angew. Chem. Int. Ed. 2014, 53, 793; Angew.
Chem. 2014, 126, 812.
[8] a) Y.-F. Wang, G. H. Lonca, S. Chiba, Angew. Chem. Int. Ed. 2014,
53, 1067; Angew. Chem. 2014, 126, 1085; b) Y.-F. Wang, K. K. Toh,
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a) C. Qin, P. Feng, Y. Ou, T. Shen, T. Wang, N. Jiao, Angew. Chem.
Int. Ed. 2013, 52, 7850; Angew. Chem. 2013, 125, 8004; b) A. Hass-
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Lett. 1969, 10, 1243.
Scheme 6. Synthesis of pyridines 9 by the reactions of vinyl azides 1 with
azadienes 8. The reaction was conducted using 0.22–0.42 mmol of vinyl
azides 1.
ed aqueous NaHCO3 and diluted with water. The aqueous layer was ex-
tracted with dichloromethane. The combined extracts were washed with
brine, dried over MgSO4, and volatile components were evaporated. Pu-
rification of the crude product by flash chromatography (silica gel; hexa-
ne:ethyl acetate=99: 1) afforded quinoline 3aa (2.28 g, 8.10 mmol) in
81% yield and aniline 4a (1.43 g, 7.80 mmol) in 78% yield.
[11] N. Shindoh, H. Tokuyama, Y. Takemoto, K. Takasu, J. Org. Chem.
2008, 73, 7451.
[12] Banert reported [4+2]-annulation of 2-azido-1,3-butadienes with
various dienophiles, see: a) K. Banert, A. Ihle, A. Kuhtz, E. Penk,
B. Saha, E.-U. Wꢂrthwein, Tetrahedron 2013, 69, 2501; b) K. Banert,
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932.
[13] The reactions of trimethylsilyl enol ether of acetophenone and sty-
rene with imine 2a under the present reaction conditions did not
form the desired quinoline 3aa at all. Akiyama reported synthesis of
aryl-substituted quinolines from N-aryl benzaldimines and silyl enol
ethers of acetophenones in a stepwise manner including CF3SO3H-
mediated attack of silyl enol ethers to imines and cyclization fol-
Acknowledgements
This work was supported by funding from Nanyang Technological Uni-
versity and Singapore Ministry of Education. Y.-F. W. is supported by
a Lee Kuan Yew postdoctoral fellowship (the LKY PDF).
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33, 922.
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332; b) V. V. Kouznetsov, Tetrahedron 2009, 65, 2721.
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141.
[16] Vinyl azides 1 were readily prepared from the corresponding al-
kenes by following the Hassner method via addition of IN3 followed
by elimination of HI with tBuOK, see: a) A. Hassner, F. W. Fowler,
Tetrahedron Lett. 1967, 8, 1545; b) F. W. Fowler, A. Hassner, L. A.
Keywords: annulation · azides · heterocycles · Lewis acids
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Levy, J. Am. Chem. Soc. 1967, 89, 2077. Detailed experimental pro-
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Received: April 22, 2014
Published online: && &&, 0000
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COMMUNICATION
Heterocycles
Xu Zhu, Yi-Feng Wang,
Feng-Lian Zhang,
Shunsuke Chiba*
&&&& — &&&&
Brought to you by the letter N: Highly
functionalized quinolines and pyridines
could be synthesized by BF3·OEt2-
mediated reactions of vinyl azides with
N-aryl and N-alkenyl aldimines,
could be characterized as formal
[4+2]-annulation, including unprece-
dented enamine-type nucleophilic
attack of vinyl azides to aldimines with
subsequent nucleophilic cyclization of
the resulting imine intermediates.
Formal [4+2]-Annulation of Vinyl
Azides with N-Unsaturated Aldimines
respectively. The reaction mechanism
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ÝÝ These are not the final page numbers!