Carbene-Catalyzed [4 + 2] Annulation of 2 H-Azirine-2-carboxaldehydes with Ketones via Azolium Aza-Dienolate Intermediate

Article abstract of DOI:10.1021/acs.orglett.8b03378

A new carbene-catalyzed [4 + 2] annulation of 2H-azirine-2-carbaldehydes with ketones was developed, thus providing the 2,3-dihydro-6H-1,3-oxazin-6-one core structures with broad scope and good to excellent yields. Notably, the azolium aza-dienolates gene

Full text of DOI:10.1021/acs.orglett.8b03378

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Carbene-Catalyzed [4 + 2] Annulation of 2H‑Azirine-2-
carboxaldehydes with Ketones via Azolium Aza-Dienolate
Intermediate
Qiupeng Peng, Bei Zhang, Yangxi Xie, and Jian Wang*
School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorous Chemistry & Chemical Biology (Ministry of
Education), Tsinghua University, Beijing 100084, China
S
* Supporting Information
ABSTRACT: A new carbene-catalyzed [4 + 2] annulation of
2H-azirine-2-carbaldehydes with ketones was developed, thus
providing the 2,3-dihydro-6H-1,3-oxazin-6-one core structures
with broad scope and good to excellent yields. Notably, the
azolium aza-dienolates generated from the addition of NHCs
to 2H-azirines are first uncovered.
ver the past decade, N-heterocyclic carbenes (NHC)-
smallest unsaturated nitrogen-containing heterocycles, have
Ocatalyzed organic reactions have attracted considerable proven to be useful building blocks12 and have attracted our
attention from the synthetic community.1 Within this context,
considerable attention recently. For example, our group has
successfully demonstrated that the Breslow intermediates could
stereoselectively attack 2H-azirines to produce chiral aziri-
dines.13 Inspired by this finding, we speculated whether we can
utilize NHC catalysts to activate 2H-azirine-2-carbaldehyde
substrates to generate aza-azolium dienolates followed by
nucleophilic addition to fluorinated ketones to yield [4 + 2]
adducts (Scheme 1b). 1,3-Oxazin-6-ones as core structures are
widely found in natural products and bioactive molecules, such
as discoipyrroles A, B, and D, spinoxazines A and B, and
Cetilistat14 (Scheme 1c). Moreover, drugs bearing fluorinated
motifs have shown unique ADMET properties.15 Therefore, this
strategy would be an important and supplementary protocol for
natural product synthesis and lead compound optimization.
We commenced our study with the model reaction of
3-phenyl-2H-azirine-2-carbaldehyde (1a) with 2,2,2-trifluoro-1-
phenylethan-1-one (2a). Under the initial conditions of catalyst
A (15 mol %), Cs2CO3 (30 mol %), and DCM as solvent, the
desired formal [4 + 2] annulation occurred and provided the
corresponding product 3a in 25% yield (Table 1, entry 1).
Catalysts B and C, bearing N-2,4,6-(Br)3C6H2 or N-C6F5
substituents, respectively, exhibited almost no reactivity
(Table 1, entries 2 and 3). The morpholine-derived triazolium
catalyst D afforded 3a in good yield (Table 1, entry 4, 70%). The
imidazole-derived catalyst F or thiazole catalyst G failed to
promote this process (Table 1, entries 5 and 6). Further
investment of solvent and bases indicated that THF and Cs2CO3
protocols exploring the Cα- or Cβ-position’s chemical reactivity
of the NHC-bound intermediates have been well investigated.2
However, the chemical reactivity of the remote position of the
NHC-bound intermediates (i.e., azolium dienolates) has gained
very little attention.3 For example, Ye and co-workers first
utilized the easily prepared α,β-unsaturated acid chlorides as
substrates to form azolium dienolate intermediates.4 Shortly
thereafter, Chi’s group reported an elegant example of using
β-methyl enals to produce vinyl enolate intermediates.5 Setting
up a leaving group at the α-position or γ-position of carbonyls
had been identified as an efficient strategy to obtain azolium
dienolates (Scheme 1a-ii).6,7 In 2013, Chi et al. disclosed
another efficient route to make azolium dienolates via the first use
of activated esters as precursors (Scheme 1a-i).8 Meanwhile, the
same group found that the cyclobutenones can be practical pre-
cursors in the preparation of azolium dienolates (Scheme 1a-iii).9
When azolium dienolates have a heteroatom at the remote
position, these intermediates will lead to the formation of new
functionalized heterocyclic molecules. The sole case is the in situ
generation of azolium oxy-dienolate intermediates reported by
Chi and co-workers recently.10
Building upon our sustainable interests in NHC organocata-
lysis,11 we herein report the unprecedented route to diversely
synthesize azolium aza-dienolate intermediates by first utilizing
2H-azirines as substrates. A novel carbene-catalyzed [4 + 2]
annulation was proposed. To complete the task, two major
challenges have to be overcome: (1) to control the competitive
reaction sites, Cγ vs [Cα, Cβ] and (2) to find suitable substrates
to prepare azolium aza-dienolates. 2H-Azirines, as one of the
Received: October 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03378
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 1. Strategies for the Generation of Azolium Dienolates
Scheme 2. Scope of 2H-Azirine-2-carbaldehyde 1
a
Table 1. Optimization of the Reaction Conditions
a
Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), cat. E (15 mol %),
4 Å MS (25 mg), Cs2CO3 (0.03 mmol), THF (1 mL), room tem-
b
c
perature. Isolated yield after flash column chromatography. At 0 °C.
d
Performed on 1 mmol scale.
have proven to be an ideal medium and organic base,
respectively (Table 1, entries 7−12). Gratifyingly, when the
morpholine-derived triazolium catalyst E replaced catalyst D
in the model reaction, a higher yield was obtained regularly
(Table 1, entry 13, 89%). Moreover, 10 mol % of catalyst E
also provided a good yield but bore a prolonged time (Table 1,
entry 14, 28 h).
With the optimized reaction conditions in hand, we examined
the scope of 2H-azirine-2-carbaldehydes. As shown in Scheme 2,
electronic effects or substituted patterns have limited influence
on reactivity (3a−e). The naphthalene ring was compatible in
the system and provided the corresponding 3f in 81%. It is
noteworthy that a set of heteroaromatic rings (e.g., furan,
thiophene, pyridine, and benzothiophene) were tolerated and
offered the desired products 3g−j in moderate yields. Then we
turned our attention to the alkyl substituents. The results
showed that they both furnished the corresponding 3k−l in
excellent yields. Additionally, when 2H-azirine-2-carbaldehyde
bears an alkenyl group, the reaction also occurred smoothly
(3m). Even with a sterically hindered group located at the
2-position of 2H-azirine-2-carbaldehyde, a good yield could still
be achieved (3n). The relative configuration of 3a was deter-
mined by X-ray crystallography, and other products were
assigned by analogy (see the Supporting Information, SI).
b
entry
cat.
solvent
base
yield (%)
1
2
3
4
5
6
7
8
A
B
C
D
F
G
D
D
D
D
D
D
E
DCM
DCM
DCM
DCM
DCM
DCM
THF
CHCl3
toluene
THF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
tBuOK
25
trace
d
nr
70
trace
d
nr
79
59
23
51
29
25
89
79
9
10
11
12
13
THF
tBuOLi
THF
THF
THF
K3PO4
Cs2CO3
Cs2CO3
c
14
E
a
Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), cat. NHC
(15 mol %), 4 Å MS (25 mg), base (0.03 mmol), solvent (1 mL),
b
20 h, room temperature. Yield was determined by 1H NMR based on
c
the use of 1,3,5-trimethoxybenzene as internal standard. Catalyst
d
E (10 mol %), Cs2CO3 (20 mol %), 28 h. No reaction.
B
DOI: 10.1021/acs.orglett.8b03378
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 3. Scope of Ketones
Scheme 4. Postulated Mechanism
Scheme 5. Mechanistic Experiments
Based on the above mechanistic studies, we postulated a
reaction pathway. The NHC catalyst reacts with 2H-azirine-2-
carbaldehyde 1l to form Breslow intermediate I.16 Intermediate
I breaks the azirine ring to generate intermediate II. Inter-
mediate II can quickly convert to intermediate III after proton
transfer. Intermediate II or III attacks 2a to form intermediate
IV followed by regenerating NHC catalyst and affording target
product 3l.
In conclusion, we have developed a new carbene-catalyzed
[4 + 2] annulation of 2H-azirine-2-carbaldehydes with ketones,
thus enabling the efficient assembly of various 2,3-dihydro-6H-
1,3-oxazin-6-one structures from simple and available starting
substrates under mild conditions. It should be noted that the
azolium aza-dienolates made from 2H-azirines catalyzed by
NHCs are first uncovered. Further exploration based on the
azolium aza-dienolate intermediates is in process in our labo-
ratory and will be reported in due course.
a
Reaction conditions: 1l (0.1 mmol), 2 (0.12 mmol), cat. E (15 mol %),
4 Å MS (25 mg), Cs2CO3 (0.03 mmol), THF (1 mL), room tem-
perature. Isolated yield.
b
Further investigation on the scope of ketones was conducted
(Scheme 3). The aromatic ketones, whether bearing halides,
methyl, or methoxy groups, afforded the desired products
in good to excellent yields (4a−g). The ketones having naphthyl
or heterocyclic motifs gave the corresponding products in
good to high yields (4h−m), as well. Likewise, the ketone
bearing an alkyl substituent performed well in the reaction (4n).
In addition, α-ketoester and difluoromethyl ketone also
successfully delivered their corresponding 4o and 4p, respec-
tively.
Our mechanistic studies mainly concentrated on identifying
the key intermediate. To capture the azolium aza-dienolate
intermediate, the reaction of 1a with EtOH catalyzed by catalyst
E was conducted and afforded the desired 3-amino-3-phenyl-
acrylate 5 in 52% (Scheme 5). This experimental result partially
proved the feasible existence of the azolium aza-dienolate
intermediate II or III (Scheme 4). To our delight, the 19F NMR
spectra exhibited a peak at −85.10 ppm (see the SI), which may
be assigned to intermediate IV despite the absence of HRMS
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03378.
■
S
Experimental procedures, product characterization, and
copies of NMR spectra (PDF)
Accession Codes
1
or H NMR. Building upon this transformation, we want to
CCDC 1873117 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
realize its asymmetric version. Unfortunately, we still have not
found an effective chiral NHC catalyst to achieve a high enantio-
selective control of this reaction (see the SI). Further investi-
gation on an asymmetric version of this process is in process in
our laboratory.
C
DOI: 10.1021/acs.orglett.8b03378
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(6) (a) Xiao, Z.; Yu, C.; Li, T.; Wang, X.-S.; Yao, C. Org. Lett. 2014, 16,
3632−3635. (b) Wang, J.; Li, Y.; Sun, J.; Wang, H.; Jin, Z.; Chi, Y. R.
ACS Catal. 2018, 8, 9859−9864.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wangjian2012@tsinghua.edu.cn.
ORCID
(7) (a) Chen, X. Y.; Xia, F.; Cheng, J. T.; Ye, S. Angew. Chem., Int. Ed.
2013, 52, 10644−10647. (b) Cheng, J. T.; Chen, X. Y.; Gao, Z. H.; Ye,
S. Eur. J. Org. Chem. 2015, 2015, 1047−1053. (c) Xiao, Y.; Wang, J.;
Xia, W.; Shu, S.; Jiao, S.; Zhou, Y.; Liu, H. Org. Lett. 2015, 17, 3850−
Jian Wang: 0000-0002-3298-6367
Notes
3853. (d) Janssen-Muller, D.; Singha, S.; Olyschlager, T.; Daniliuc, C.
̈
̈
G.; Glorius, F. Org. Lett. 2016, 18, 4444−4447. (e) Yang, W.; Hu, W.;
Dong, X.; Li, X.; Sun, J. Angew. Chem., Int. Ed. 2016, 55, 15783−15786.
(f) Chen, D.-F.; Rovis, T. Synthesis 2016, 49, 293. (g) Wang, H.; Chen,
X.; Li, Y.; Wang, J.; Wu, S.; Xue, W.; Yang, S.; Chi, Y. R. Org. Lett. 2018,
20, 333−336. (h) Poh, S. B.; Ong, J. Y.; Lu, S.; Zhao, Y. Angew. Chem.,
Int. Ed. 2018, 57, 1645−1649. (i) Yang, W.; Ma, D.; Zhou, Y.; Dong, X.;
Lin, Z.; Sun, J. Angew. Chem., Int. Ed. 2018, 57, 12097−12101.
(8) (a) Xu, J.; Jin, Z.; Chi, Y. R. Org. Lett. 2013, 15, 5028−5031.
(b) Que, Y.; Li, T.; Yu, C.; Wang, X.-S.; Yao, C. J. Org. Chem. 2015, 80,
3289−3294. (c) Xu, J.; Yuan, S.; Miao, M. Org. Lett. 2016, 18, 3822−
3825.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21871160, 21672121), the “Thousand Plan” Youth
Program of China, the Tsinghua University, the Bayer
Investigator Fellow, and the Fellowship of Tsinghua−Peking
Centre for Life Sciences (CLS) for their generous financial
support. We thank Mr. Qi Li at Tsinghua University for
assistance with analysis of X-ray crystallographic data.
(9) Li, B.-S.; Wang, Y.; Jin, Z.; Zheng, P.; Ganguly, R.; Chi, Y. R. Nat.
Commun. 2015, 6, 6207.
(10) Chen, X.; Wang, H.; Doitomi, K.; Ooi, C. Y.; Zheng, P.; Liu, W.;
Guo, H.; Yang, S.; Song, B.-A.; Hirao, H.; Chi, Y. R. Nat. Commun.
2017, 8, 15598.
REFERENCES
■
(1) For selected reviews on NHC catalysis, see: (a) Enders, D.;
Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606−5655.
(b) Marion, N.; Díez-Gonzalez, S.; Nolan, S. P. Angew. Chem., Int.
(11) (a) Wu, Z.; Li, F.; Wang, J. Angew. Chem. 2015, 127, 1649−1653.
(b) Wang, X.; Wu, Z.; Wang, J. Org. Lett. 2016, 18, 576−579.
(12) (a) Khlebnikov, A. F.; Novikov, M. S. Tetrahedron 2013, 69,
3363−3401. (b) Degennaro, L.; Trinchera, P.; Luisi, R. Chem. Rev.
2014, 114, 7881−7929. (c) Huang, C.-Y.; Doyle, A. G. Chem. Rev.
2014, 114, 8153−8198.
́
Ed. 2007, 46, 2988−3000. (c) Biju, A. T.; Kuhl, N.; Glorius, F. Acc.
Chem. Res. 2011, 44, 1182−1195. (d) Grossmann, A.; Enders, D.
Angew. Chem., Int. Ed. 2012, 51, 314−325. (e) Izquierdo, J.; Hutson, G.
E.; Cohen, D. T.; Scheidt, K. A. Angew. Chem., Int. Ed. 2012, 51, 11686−
11698. (f) Chen, X.-Y.; Ye, S. Org. Biomol. Chem. 2013, 11, 7991−7998.
(g) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature
2014, 510, 485. (h) Flanigan, D. M.; Romanov-Michailidis, F.; White,
N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307−9387. (i) Yetra, S. R.;
Patra, A.; Biju, A. T. Synthesis 2015, 47, 1357−1378. (j) Wang, M. H.;
Scheidt, K. A. Angew. Chem., Int. Ed. 2016, 55, 14912−14922.
(k) Mukherjee, S.; Biju, A. T. Chem. - Asian J. 2018, 13, 2333−2349.
(2) For selected reviews on NHC-catalyzed Cα or Cβ reaction, see:
(a) Nair, V.; Vellalath, S.; Babu, B. P. Chem. Soc. Rev. 2008, 37, 2691−
2698. (b) Nair, V.; Menon, R. S.; Biju, A. T.; Sinu, C.; Paul, R. R.; Jose,
A.; Sreekumar, V. Chem. Soc. Rev. 2011, 40, 5336−5346. (c) Douglas, J.;
Churchill, G.; Smith, A. D. Synthesis 2012, 44, 2295−2309. (d) Ryan, S.
J.; Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42, 4906−4917.
(e) Mahatthananchai, J.; Bode, J. W. Acc. Chem. Res. 2014, 47, 696−
707. (f) Menon, R. S.; Biju, A. T.; Nair, V. Chem. Soc. Rev. 2015, 44,
5040−5052. (g) Zhang, C.; Hooper, J. F.; Lupton, D. W. ACS Catal.
2017, 7, 2583−2596.
(13) Peng, Q.; Guo, D.; Bie, J.; Wang, J. Angew. Chem., Int. Ed. 2018,
57, 3767−3771.
(14) (a) Padwal, R. Curr. Opin. Investig. Drugs 2008, 9, 414−421.
(b) Hu, Y.; Potts, M. B.; Colosimo, D.; Herrera-Herrera, M. L.; Legako,
A. G.; Yousufuddin, M.; White, M. A.; MacMillan, J. B. J. Am. Chem. Soc.
2013, 135, 13387−13392. (c) Fu, P.; La, S.; MacMillan, J. B. J. Nat.
Prod. 2016, 79, 455−462. (d) Kim, M. C.; Lee, J. H.; Shin, B.; Subedi,
L.; Cha, J. W.; Park, J.-S.; Oh, D.-C.; Kim, S. Y.; Kwon, H. C. Org. Lett.
2015, 17, 5024−5027.
(15) (a) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359−4369.
(b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev.
2008, 37, 320−330.
(16) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719−3726.
(3) A recent review on azolium dienolates: (a) Chen, X. Y.; Liu, Q.;
Chauhan, P.; Enders, D. Angew. Chem., Int. Ed. 2018, 57, 3862−3873.
Recent work on remote activation: (b) Gillard, R. M.; Fernando, J. E.;
Lupton, D. W. Angew. Chem., Int. Ed. 2018, 57, 4712−4716.
(4) (a) Shen, L. T.; Shao, P. L.; Ye, S. Adv. Synth. Catal. 2011, 353,
1943−1948. (b) Jia, W.-Q.; Chen, X.-Y.; Sun, L.-H.; Ye, S. Org. Biomol.
Chem. 2014, 12, 2167−2171. (c) Que, Y.; Xie, Y.; Li, T.; Yu, C.; Tu, S.;
Yao, C. Org. Lett. 2015, 17, 6234−6237. (d) Jia, W.-Q.; Zhang, H.-M.;
Zhang, C.-L.; Gao, Z.-H.; Ye, S. Org. Chem. Front. 2016, 3, 77−81.
(e) Zhu, L.; Yu, C.; Li, T.; Wang, Y.; Lu, Y.; Wang, W.; Yao, C. Org.
Biomol. Chem. 2016, 14, 1485−1491.
(5) (a) Mo, J.; Chen, X.; Chi, Y. R. J. Am. Chem. Soc. 2012, 134, 8810−
8813. (b) Chen, X.; Yang, S.; Song, B. A.; Chi, Y. R. Angew. Chem., Int.
Ed. 2013, 52, 11134−11137. (c) Wang, M.; Huang, Z.; Xu, J.; Chi, Y. R.
J. Am. Chem. Soc. 2014, 136, 1214−1217. (d) Zhu, T.; Zheng, P.; Mou,
C.; Yang, S.; Song, B.-A.; Chi, Y. R. Nat. Commun. 2014, 5, 5027.
(e) Lin, Y.; Yang, L.; Deng, Y.; Zhong, G. Chem. Commun. 2015, 51,
8330−8333. (f) Zheng, P. C.; Cheng, J.; Su, S.; Jin, Z.; Wang, Y. H.;
Yang, S.; Jin, L. H.; Song, B. A.; Chi, Y. R. Chem. - Eur. J. 2015, 21,
9984−9987. (g) Yao, H.; Zhou, Y.; Chen, X.; Zhang, P.; Xu, J.; Liu, H. J.
Org. Chem. 2016, 81, 8888−8899. (h) Chen, X.-Y.; Liu, Q.; Chauhan,
P.; Li, S.; Peuronen, A.; Rissanen, K.; Jafari, E.; Enders, D. Angew.
Chem., Int. Ed. 2017, 56, 6241−6245.
D
DOI: 10.1021/acs.orglett.8b03378
Org. Lett. XXXX, XXX, XXX−XXX