Organic Letters
Letter
material in lieu of aziridines. Appel and Mayr previously
quantified the electrophilicity values of various imines in
aziridinations, and Bus- and Dpp-protected imines were
observed to be far less reactive in comparison to Ts-protected
imines.15 The difference in outcomes for Bus-imines compared
with other sulfonamide imides is striking, with steric
differences being the most likely explanation, as the tert-butyl
group of Bus imparts its large size most significantly in the
initial syn and anti Mannich adducts.16 We postulate that the
reason for absence of trans-aziridine products in the Bus-imine
series is that its precursor Mannich adduct is primarily
funneled to a 1,2-shift reaction pathway to form the enamide
product instead of the 3-exo-tet cyclization to produce the
trans-aziridine.
Table 1. Bus-Imine Annulation Studies
aziridine/enamide
cis-aziridine yield
a
entry
R
ratio
(%)
b
1
2
3
4
5
Ph
4-NO2-Ph
4-Br-Ph (25)
4-CN-Ph (26)
4-CF3-Ph (27)
4-OCF3-Ph
1:3
N/A
1:1.4
1:1.1
1.7:1
1.4:1
1:1.8
1:1
N/A
40
50
40
6
7
N/A
N/A
70
45
N/A
35
50
30
NR
We decided to explore additional substrates for a
representative sulfonamide group, namely, tosylate (Table 3,
3-NO2-Ph
8
9
2-NO2-Ph (24)
2-CN-Ph (31)
2-OMe-Ph
2-Cl-Ph (30)
3,5-bis-CF3-Ph (29)
2,4-bis-NO2-Ph (28)
Ph−CHCH
4:1
1:1
0:1
1:1.4
2.2:1
4.6:1
Table 3. Aza-Darzens Annulation Scope for Tosylate Imines
10
11
12
13
14
c
NR
a
b
Determined by 1H NMR analysis of the crude reaction mixures. N/
c
A indicates that the aziridine and enamide were inseparable. NR
indicates that no reaction occurred.
a
entry
R
trans:cis
yield (%)
b
1
2
3
4
5
6
7
8
Ph (32)
3:1
1.8:1
1:1.2
NA
2.5:1
3:1
65
b
1-Naphth (33)
2-NO2-Ph (36)
4-OMe-Ph
4-OCF3-Ph (37)
4-Br-Ph (34)
4-CF3-Ph (35)
PhCHCH (38)
65
groups to establish whether the Bus group was representative
or an outlier. Employing the same reaction conditions, we
explored the annulation behaviors of imines protected with
mesylate (Ms), besylate (Bes), nosylate (Ns), brosylate (Bs),
ansylate (Ans), and tosylate (Ts) groups (Table 2).
c
40
d
NR
b
47
b
55
b
2.4:1
1:0
50
b
40
Table 2. Aza-Darzens Annulation Protecting-Group Survey
a
b
Determined by 1H NMR analysis of the crude reaction mixures. An
inseparable mixture of trans- and cis-aziridines was isolated. Only the
major isomer was isolated and characterized. No aziridine formed,
c
d
and the starting materials were recovered.
entries 1−8). These studies revealed that electron-rich imines
such as 4-methoxyphenyl (entry 4) fail to form any aziridine
products, with only starting materials recovered. However,
when the methyl group is replaced with a trifluoromethyl
group (entry 5), the reaction proceeds to form the expected
aziridines, favoring the trans-aziridine. With respect to size and
electronic factors that impact cis/trans-aziridine ratios, we have
learned that a larger group (entry 2) will diminish the trans
selectivity slightly, with an o-nitro aryl group (entry 3)
representing the only case in which the cis-aziridine is formed
in marginal excess and cinnamyl imines (entry 8) affording the
trans-aziridine as the only products.
These intriguing imine-dependent aza-Darzens annulation
results prompted us also to evaluate acyclic sulfone nucleophile
1, which had performed poorly in comparison with 2 in
converting aldehydes to epoxides. We decided to investigate
select Bus- and Ts-protected imines as representatives of the
divergence of outcomes presented in Tables 1 and 2. The
results of employing 1 under the same reaction conditions are
detailed in Scheme 7. Most notably, the Bus-protected imines
produced only aziridine products, and no undesired enamides
were observed with annulations using cyclic nucleophile 2. For
a phenyl substituent, Bus- and Ts-protected imines (39 and
40) behaved identically, while for anisaldehyde-derived imines
a
b
c
entry
R
yield (%)
trans:cis
1
2
3
4
5
6
7
8
Bes
Ts
Ns
62
65
40
50
65
54
0
3:1
3:1
2:1
3:1
Bs
Ms
Ans
Boc
Dpp
2.6:1
3:1
imine hydrolyzed
imine hydrolyzed
0
a
Abbreviations: Bes = besylate; Ts = tosylate; Bs = brosylate; Ms =
mesylate; Ans = 4-OMe-C6H4SO2-; Boc = tert-butoxycarbonyl; Dpp =
b
diphenylphosphinyl. Inseparable mixtures of trans- and cis-aziridines
c
were isolated. Determined by 1H NMR analysis of the crude reaction
mixures.
Interestingly, and in stark contrast to the Bus-protected
imines, these six sulfonamide imines did not form enamide
products but instead only aza-Darzens aziridine products
(Table 2, entries 1−6). The yields were quite similar for these
imines, with tosyl performing best. The preferential formation
of trans-aziridines was an additional departure from what was
observed for Bus-protected imines. Perhaps unsurprisingly, Boc
and Dpp-protected imines returned hydrolyzed starting
C
Org. Lett. XXXX, XXX, XXX−XXX