Organic Letters
Letter
new way to prepare diverse homopropargylic nitroalkanes.
Herein, we disclose a novel Cu-catalyzed method for the
propargylation of nitroalkanes. The method uses a simple Cu
catalyst, which is made in situ from inexpensive and
commercially available materials. The method is robust, is
highly functional group tolerant, and provides straightforward
access to complex secondary and tertiary homopropargylic
nitroalkanes. Furthermore, to showcase the synthetic utility, we
report conditions for the formation of 2,3,5-trisubstituted
pyrroles and 2-pyrrolines using the products of these reactions.
Our investigation began by studying the coupling between
propargyl bromide 1a (R = SiMe3) and nitroalkane 2 (Table
1). Control experiments revealed no background reaction and
the diamine backbone to the less conformationally restricted
ethylenediamine ligand 10, both an increase in the yield of
desired product 3a and less byproduct 4a were observed (entry
6).
With these results in hand, we anticipated that ligand 10
would be the optimal ligand for the general transformation.
Unfortunately, as we began to investigate its use with a variety
of other substrates, a new and unanticipated byproduct
emerged. For example, with the simpler propargyl bromide
1b (R = Me), only 39% of desired product 3b was obtained
(entry 7), and a major byproduct corresponding to β-allenyl
nitroalkane 5b was observed (entry 7). We postulated that the
formation of the competing allene product might be due to the
smaller steric nature of the substrate. This line of thinking led
us to investigate the use of larger ligands as a possible means to
gain selectivity for the desired homopropargylic product.
Indeed, when the benzyl groups of 10 were replaced with the
bulkier (R)-2-phenethyl groups (11), both suppression of the
allenic product and an increase in the level of formation of
desired homopropargylic product 3b were observed (entry 8).
Although promising, ligand 11 is fairly expensive to prepare
due to its enantioenriched nature. As it also did not provide
significant levels of enantioselectivity in the reaction,15 we
sought a more practical analogue. Fortunately, the use of
commercially available, highly inexpensive, and achiral N,N′-
diisopropylethylenediamine (12) as the ligand proved to be
similarly effective.16,17 Using this ligand, a good yield of 3b
with minimal byproduct formation was observed (entry 9). We
were further pleased to find that this reaction could be
performed at room temperature under reduced CuBr loading,
and that by adjusting the ligand:metal ratio, allene byproduct
formation could be suppressed (entry 10).
Table 1. Reaction Optimization
a
yield (%)
With these optimal conditions in hand, the substrate scope
was evaluated. Encouragingly, many combinations of nitro-
alkanes and propargyl bromides provided a product yield even
higher than that observed with the model system. As shown in
Scheme 1, a wide range of both primary (3a, 3b, and 13−20)
and secondary (21−30) nitroalkanes participated in the
reaction. Primary (3a, 3b, 13−17, and 21−28) and secondary
(18, 19, 29, and 30) propargyl bromides were well tolerated, as
well as tertiary propargyl bromides (20) (albeit with somewhat
suppressed yields). A wide range of functional groups were also
compatible with the reaction; these include aryl groups with
varying electronic properties (14, 19, 21, 22, and 24), alkyl
bromides (30), esters (3a, 3b, and 20), olefins (15 and 16),
amides (23), ketones (24 and 25), protected alcohols (13),
and amines (18 and 19). Heterocycles such as pyrimidine
(15), indole (16), and thiophene (28) could also be
incorporated without issue. In cases in which the yield was
limited, the mass balance was largely starting material, along
with traces of bis-propargylation. Attempts to increase the
catalyst loading or reaction time did not improve conversion in
these cases. One limitation we noted with respect to functional
group compatibility is with the use of nitrile groups (17),
which, while tolerated, seem to suppress the yield of the
reaction (3a vs 17). We hypothesize this is due to competitive
binding of the nitrile to the metal center.
entry
R
CuBr (mol %) ligand (mol %)
3
4
5
1
2
3
4
5
6
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
Me
Me
Me
Me
−
−
0
0
6
7
7
8
3
1
0
3
7
−
−
−
−
−
−
25
9
20
20
20
20
20
22
22
22
10
6 (25)
7 (25)
8 (25)
9 (25)
10 (25)
10 (23)
11 (23)
12 (23)
12 (30)
34
65
60
65
73
39
53
54
53
b
7
b
8
b
9
4
0
c
10
a
Determined via 1H NMR against the internal standard. 1.25 equiv of
b
1, unless otherwise noted. With 1.15 equiv of 1 and 1.05 equiv of
c
KOtBu at 70 °C for 4 h. With 1.15 equiv of 1 and 1.05 equiv of
KOtBu at rt for 4 h.
confirmed the need for a catalyst to obtain the desired reaction
(entry 1). Our previous reports have employed diketimine 6 as
the optimal ligand.13 Encouragingly, adding catalytic CuBr and
6 to the model reaction led to detectable levels of desired
product 3a. However, the yield was surprisingly low, and bis-
propargylated byproduct 4a was also detected (entry 2).
Recently, we reported the use of N,N′-dibenzylcyclohexanedi-
amine ligands in a Ni-catalyzed nitroalkane alkylation.14 We
were pleased to find that with the use of ligand 7 in this copper-
catalyzed reaction, a significant improvement in the yield of 3a
was observed (entry 3). Attempts to further improve the yield
of desired product 3a by tuning the electronic and steric
properties of the aromatic groups on the ligand proved to be
unsuccessful (entries 4 and 5).15 In contrast, with a switch of
To showcase the utility of homopropargylic nitroalkanes, the
synthesis of nitrogen-containing heterocycles was explored.
First, we were inspired by Dixon’s nitro-Mannich/Au-catalyzed
hydroamination sequence that converts primary homopropar-
gylic nitroalkanes to pyrroles.4 Although the one-pot
conditions reported by Dixon did not prove to be applicable
B
Org. Lett. XXXX, XXX, XXX−XXX
Kim, Raphael S.
