Table 1. Optimization
Scheme 1. NHC-Catalyzed Amination Reactions
t
conversion
(%)a
ee
(%)b
entry
base
solvent
(°C)
prod.
1
Cs2CO3
K2CO3
Et3N
THF
rt
rt
rt
rt
0
NA
3
0
NA
90
90
92
95
96
2
THF
70
3
THF
3
93
4
Et3N
CH2Cl2
CH2Cl2
CH2Cl2
3
>99
5
6d
Et3N
3
>99 (65c)
>99 (89c)
Et3N
0
4
1
a Conversion into product determined by H NMR analysis of the
crude reaction mixture. b Determined by HPLC analysis. c Isolated yield.
d Reaction quenched with MeOH.
First the reaction between R-aroyloxyaldehyde 2 and
N-phenyl-N-benzoyldiazene using 10 mol % NHC pre-
catalyst 1 was investigated.13 Initial studies found that
using triethylamine as a base was more effective than
inorganic bases such as cesium or potassium carbonate,
leading to 93% conversion into cycloadduct 3 in 90% ee
after 6 h (Table 1, entries 1ꢀ3).14,15 Switching the solvent
to dichloromethane resulted in complete conversion into 3
(Table 1, entry 4), while starting the reaction at 0 °C
improved the ee to 95% without reducing the conversion
(Table 1, entry 5). However, despite high conversion into
product the isolated yield of 1,3,4-oxadiazin-6-one 3 was
only 65% due to the instability of the heterocycle to chro-
matographic purification on silica.16 This problem was
readily overcome by ring-opening product 3 in situ with
methanol, allowing R-hydrazino ester 4 to be isolated in
89% yield and 96% ee (Table 1, entry 6).
With an optimized protocol in hand, the scope of the
reaction was investigated using a series of N-aryl-N-aroyl-
diazenes (Table 2). The reaction of R-aroyloxyaldehyde 2
with electron-rich N-aryl substituted diazenes (4-MeOC6H4
and 3,4-(MeO)2C6H3) required an electron-withdrawing
N-aroyl component (4-CF3C6H4) to maintain high yields,
with R-hydrazino esters 5 and 6 isolated in 69% and 93%
yield, respectively. In contrast, electron-deficient N-aryl
substituted diazenes (4-CF3C6H4 and 4-NCC6H4) formed
R-hydrazinoesters7 and 8 inreducedyields (56% and 48%
respectively) presumably due to competitive side reactions
samarium(II) iodide mediated NꢀN bond cleavage has
also been investigated.
As we have previously demonstrated, R-aroyloxyalde-
hydes are bench stable precursors for the NHC-catalyzed
generation of both acyl azolium and azolium enolate
intermediates.8 They are readily prepared on gram scale
from the parent aldehyde and 4-nitrobenzoic acid using
Ishihara et al.’s R-oxyacylation methodology9 and can be
stored for a number of months without decomposition. We
envisaged that azolium enolate intermediates generated
through addition of an NHC to R-aroyloxyaldehydes would
undergo [4 þ 2] cycloadditions with N-aryl-N-aroyldiazenes
to form 1,3,4-oxadiazin-6-ones, which could then be ring
opened with methanol to form R-hydrazino esters.10ꢀ12
(8) (a) Ling, K. B.; Smith, A. D. Chem. Commun. 2011, 47, 373–375.
(b) Davies, A. T.; Taylor, J. E.; Douglas, J.; Collett, C. J.; Morrill, L. C.;
Fallan, C.; Slawin, A. M. Z.; Churchill, G.; Smith, A. D. J. Org. Chem.
2013, 78, 9243–9257.
(9) Uyanik, M.; Suzuki, D.; Yasui, T.; Ishihara, K. Angew. Chem.,
Int. Ed. 2011, 50, 5331–5334.
(10) For examples of R-haloaldehydes as azolium enolate precursors
in NHC-catalyzed redox [4 þ 2] cycloadditions, see: (a) He, M.; Uc,
G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088–15089. (b) He, M.;
Beahm, B. J.; Bode, J. W. Org. Lett. 2008, 10, 3817–3820. (c) Kobayashi,
S.; Kinoshita, T.; Uehara, H.; Sudo, T.; Ryu, I. Org. Lett. 2009, 11,
3934–3937. (d) Yang, L. M.; Wang, F.; Chua, P. J.; Lv, Y. B.; Zhong,
L. J.; Zhong, G. F. Org. Lett. 2012, 14, 2894–2897. (e) Jian, T.-Y.; Sun,
L.-H.; Ye, S. Chem. Commun. 2012, 48, 10907–10909.
(11) Chi et al. have shown that azolium enolates can be accessed
through NHC addition to 4-nitrophenyl esters followed by deprotona-
tion; see: (a) Hao, L.; Du, Y.; Lv, H.; Chen, X. K.; Jiang, H. S.; Shao,
Y. L.; Chi, Y. R. Org. Lett. 2012, 14, 2154–2157. (b) Hao, L.; Chuen,
C. W.; Ganguly, R.; Chi, Y. R. Synlett 2013, 24, 1197–1200. (c) Hao, L.;
Chen, S.; Xu, J.; Tiwari, B.; Fu, Z.; Li, T.; Lim, J.; Chi, Y. R. Org. Lett.
2013, 15, 4956–4959.
(14) Authentic racemic samples of all products were prepared using
(rac)-1 as the catalyst.
(15) Absolute configuration assigned by comparison of the specific
rotation of cleaved N-aryl R-amino esters with the literature. (R)-26
[R]2D0 ꢀ28.4 (c 1.48 in CHCl3) {Lit. (S)-26 [R]D20 þ26.6 (c 1.3 in CHCl3)}.
McKerrow, J. D.; Al-Rawi, J. M.; Brooks, P. Asian J. Chem. 2012, 24,
1227–1236.
(12) Azolium enolates can also be accessed from unsubstituted
aldehydes under oxidative conditions; see: (a) Zhao, X.; Ruhl, K. E.;
Rovis, T. Angew. Chem., Int. Ed. 2012, 51, 12330–12333. (b) Mo, J.;
Yang, R.; Chen, X.; Tiwari, B.; Chi, Y. R. Org. Lett. 2013, 15, 50–53.
(13) We found diazodicarboxylates to be completely unreactive
under a number of different conditions.
(16) Upon isolation, heterocycle 3 is stable for up to ca. 1 month when
stored in a freezer before undergoing ring opening.
B
Org. Lett., Vol. XX, No. XX, XXXX