Organic Letters
Letter
Ugi reaction to furnish boropeptides.15 This indicated that an
additional functionality in isocyanides and Ugi reaction could
significantly expand the chemical space of products.
a
Table 1. Reaction Optimization
Recently, Sharpless and Kelly reported that the fluorosul-
fated tyrosine could be used as building block in solid-phase
synthesis toward sulfotyrosine-containing peptides.16 In
continuation of our interests in multicomponent reaction and
drug discovery,17 we hypothesized that the sulfonyl fluoro
isocyanides might enable the combination of SuFEx click
reaction and Ugi reaction to achieve SuFExable peptides.
Herein, we describe the preparation of sulfonyl fluoro
isocyanides that were used as flexible building blocks in the
Ugi reaction for facile synthesis of sulfonyl fluoro peptides and
peptide units (Figure 1C). At the beginning, the preparation of
SuFExable isocyanides were explored. After various exploration
and optimization, four types of preparation methods toward
differential SuFExable isocyanides were established with
practicability and scalability (Figure 2; for details, see the
b
entry
solvent
yield
1
2
3
4
5
6
7
8
MeOH
DCM
THF
dioxane
MeCN
toluene
TFE
HFIP
HFIP
HFIP
HFIP
13
10
<5
−
<5
<5
45
68
82
70
85
c
9
10
d
e
11
a
Reaction conditions: 2a (0.12 mmol) and 3a (0.12 mmol) were
added to solvent (1 mL) and kept at RT for 2 h, then 1a (0.1 mmol)
and 4a (0.12 mmol) were added and kept for another 1 h. Yield
refers to isolated product. Four reagents were added simultaneously
and kept for 3 h. 4 Å MS (15 mg) was added. 1a (0.1 mmol), 2a
(0.15 mmol), 3a (0.15 mmol), and 4a (0.15 mmol) were added
simultaneously and kept for 3 h.
b
c
d
e
entries 2−6). Gratifyingly, the use of trifluoroethanol (TFE)
and hexafluoroisopropanol (HFIP) as solvent could signifi-
cantly improve the yield to 45% and 68%, respectively (Table
1, entries 7 and 8). Interestingly, by adding these four reagents
to HFIP simultaneously and keeping the reaction at room
temperature (RT) for 3 h, the yield of 5a could be further
improved (Table 1, entry 9). However, the addition of 4 Å MS
would decrease the yield (Table 1, entry 10). Besides, when
the amount of 2a, 3a and 4a was slightly elevated, 5a could be
obtained in 85% yield (Table 1, entry 11).
Figure 2. SuFExable isocyanides preparation.
With the optimized reaction condition in hand, we next
tested the scope of this SuFExable Ugi reaction. As shown in
Figure 3, various substituted benzoic acids could well engage in
this process to deliver the products, and the electron-
withdrawing substitution could give higher yields than those
electron-donating substitutions (5b−5e). The heteroaryl
carboxylic acids like nicotinic acid, furan-2-carboxylic acid,
thiophene-2-carboxylic acid, and indole-2-carboxylic acid,
could participate in this SuFExable Ugi reaction to give the
sulfonyl fluoro α-amino amides in excellent yields (5f−5i).
Besides, the unsaturated carboxylic acids, such as cinnamic acid
and 3-phenylpropiolic acid, were also tolerable (5j−5k). The
aliphatic carboxylic acids with functionalities similarl to those
of cyclopropane, bromo, alkene, and ketone were compatible
in this process (5l−5p). Besides, these functionalities could
offer ample opportunities for further functionalization. With
respect to aldehydes, a series of substituted benzaldehydes with
the substitution of fluoro, chloro, bromo, methoxy, cyano, and
nitro groups, could undergo the Ugi reaction smoothly to give
the products in good to excellent yields (5q−5u), and the
electron-deficient benzaldehydes could give higher yields than
those electron-rich benzaldehydes. The naphthyl aldehyde and
heterocyclic aldehydes including pyridine-3-aldehyde, thio-
phene-2-aldehyde, N-tosyl pyrrole-2-aldehyde, and N-Boc
indole-2-aldehyde, could well engage in this multicomponent
reaction process to deliver sulfonyl fluoro α-amino amides in
moderate to excellent yields (5v−5z). Furthermore, the
structure of 5y was confirmed by X-ray analysis. The aliphatic
available feedstock and could convert to fluorated salt A upon
a four-step transformation, and A could convert to the 2-
isocyanoethane-1-sulfonyl fluoride with another two-step
synthesis. Interestingly, the amino acids could transform to
the chiral sulfonyl fluorated amino salt B with an eight-step
synthesis, and B could transform to the chiral SuFExable
isocyanides smoothly. On the other hand, phenylalkyl amines
like benzylamine and 2-phenylethyl amine could convert to
sulfonyl fluorated formylamide C and then reached the
corresponding SuFExable aryl isocyanides through another
one-step synthesis. Meanwhile, 4-isocyanobenzenesulfonyl
fluoride could be easily prepared from the commercial 4-
nitrophenylsulfoyl chloride in a four-step synthetic route.
Notably, all these SuFExable isocyanides could be obtained in
gram scale, and the procedure is practical and reproducible.
The SuFExable isocyanide was next subjected to the Ugi
reaction. Benzoic acid 1a, benzaldehyde 2a, amine 3a, and 2-
isocyanoethane-1-sulfonyl fluoride 4a were used as model
substrates to investigate the reaction conditions. Initially, 2a
and 3a were mixed in methanol and kept for 2 h to deliver an
imine intermediate, then 1a and 4a were added and kept for 1
h (Table 1, entry 1). To our delight, a sulfonyl fluoro α-amino
amide 5a was truly formed, albeit in a low yield (13% isolated
yield). The next survey of solvents showed that dichloro-
methane (DCM), tetrahydrofuran (THF), dioxane, CH3CN,
and toluene, were inferior to decrease the yields (Table 1,
5198
Org. Lett. 2021, 23, 5197−5202