Organic Letters
Letter
Scheme 1. Background and Reaction Design of This Work
Table 1. Optimization of Mechanochemical Magnesium-
Mediated Minisci Reaction between 1a and 2a
a
entry
deviation from standard conditions
none
without Mg chip
3aa (%)
1
2
3
4
5
6
7
61
nr
15
38
without TMEDA
3.0 equiv instead of 4.0 equiv of Mg chip
1.0 equiv instead of 2.0 equiv of TMEDA
Mg foil/powder instead of Mg chip
Et3N/DMEDA/DBU instead of TMEDA
32
36/17
19/44/46
51/51
b
8
THF/1,4-dioxane as LAGs
a
b
Yield of isolated product. LAGs (20 μL, η = 0.3 [V (liquid; μL)/m
(solid reagents; mg)]) was added. MM = Mixer Mill.
Under the optimized conditions, we set out to explore the
generality of this method against a variety of unactivated alkyl
halides. As shown in Scheme 2a, primary bromoalkanes
carrying long chain and sterically hindered alkyl as well as
functionalizable alkenyl groups were compatible with this mild
protocol, generating corresponding products in synthetically
acceptable yields (3ab−3ag), despite the low stability and
nucleophilicity of primary alkyl radicals21 which made them
the challenging reactants in Minisci reactions. Comparatively,
the alkylation reactions of secondary and tertiary alkyl
bromides produced higher yields, where both cyclic and
noncyclic alkyl radicals were well tolerated. We were pleased to
find that inexpensive and widely available alkyl chlorides (2a′,
2c′, 2l′, and 2m′) could also be used in this reaction, and even
higher yields were obtained in some cases (3ac and 3la). To
the best of our knowledge, no successful examples of Minisci
C−H alkylation of alkyl chlorides have been reported thus far,
owing to the strong C−Cl bond strength.22 Thus, the current
mechanochemical process provides a cost-efficient route for
the application of alkyl chlorides in organic synthesis.
Following this, the substrate scope of pyrimidines was
evaluated (Scheme 2b). It was observed that N-pyrimidylin-
doles bearing electron-withdrawing or electron-donating
groups at the 2-, 3-, 4-, 5-, or 6-positions on the indole ring
afforded the corresponding products (3ba−3fa) in satisfactory
yields. Interestingly, the substrates that possess electron-
enriched indoles produced higher yields (compare 3ba−3ca
vs 3da−3fa). The structure of 3da (CCDC 2087972) was
unambiguously confirmed by single-crystal X-ray analysis. To
further demonstrate the regioselectivity of this mechanochem-
ical Minisci reaction, diverse 2-substituted pyrimidines
containing (hetero)arenes, aromatic amines, and alkylamines
1g−1r were tested, and the results showed that only C4
alkylation of pyrimidines occurred in all cases. Of note, the
mechanochemical conditions allowed the introduction of the
sensitive amino group (3ra), which provides synthetic handles
for further derivatization and application in drug synthesis.23
Moreover, the reaction was not restricted to substituted
pyrimidines, as pyridines were also suitable substrates. 2-
Methylpyridine 1s, pyridine 1t, and 4-methoxylpyridine 1u
furnished the desired alkylation products (3sl, 3ta, and 3up)
with 71%, 66%, and 62% yields, respectively. It should be
noted that the former two showed excellent C4 position
occurring at the indole ring.17 However, as part of our
optimization, we particularly sought to identify a mechano-
chemical strategy that would be selective for the position of
pyrimidine even in the presence of other active heterocycles.
We first examined the magnesium chip as a radical initiator
under the preferred milling conditions18 without specific inert
gas protection, which delivered the desired product 3aa in
moderate yield with excellent regioselectivity (Table 1, entry 1;
Table S1). Subsequently, the control experiments revealed that
both the magnesium and the additive N,N,N′,N′-tetramethy-
lethylenediamine (TMEDA) were essential for this trans-
formation (entries 2 and 3), while reducing their dosages led to
lower yields (entries 4 and 5). The magnesium forms were next
tested, in contrast to previous work,14 and obvious influences
on the product yields were found (entry 6). Smaller particle
size magnesium was probably inclined to the formation of
Grignard reagents rather than affording radicals. Several
nitrogen-containing bases, including triethylamine, N,N′-
dimethyl-1,2-ethanediamine (DMEDA) and 1,8-diazabicyclo
[5.4.0]undec-7-ene (DBU) were screened in a bid to improve
the yield, yet all of these failed to afford higher yields (entry 7;
Table S1). However, liquid-assisted grinding19 using either
tetrahydrofuran or 1,4-dioxane gave comparable results (entry
8). It should be noted that all the transformations precluded
the use of glovebox or Schlenk-line techniques, which is
indispensable for moisture- and/or oxygen-sensitive reagents.20
B
Org. Lett. XXXX, XXX, XXX−XXX