Angewandte
Chemie
confirmed that 5 reacts with 3a to produce 4a under the same
reaction conditions. All of these observations indicated that
3a must be consumed by an alternative pathway that is faster
than its reaction with 5. A thorough analysis of the reaction
mixture then revealed that the alkylboronic ester 6a was
could be isolated in 36% yield. Given the low mass balance of
borylated products, a second experiment using 3,5-dimethy-
liodobenzene in the presence of the less volatile electrophile,
3-phenylpropyltosylate, was undertaken. This produced the
corresponding alkylboronate in 85% yield (GC/MS) accom-
panied by smaller amounts of the aryl boronate (63%), thus
suggesting that the lower yields in the initial experiment
resulted from losses during isolation.[12]
We hypothesized that 6a was produced by an unprece-
dented copper-catalyzed cross-coupling reaction between the
alkyl halide and diboron reagent. To test this assumption, we
treated 3a with 2a in the presence of the copper catalyst
(Table 1). Gratifyingly, the desired alkylboronic ester 6a was
obtained in 84% yield at 258C in 18 hours (entry 1). To
improve the yield, different bases were tested (entries 1–6)
with LiOMe proving to be optimal giving a yield of 91%
(entry 6). Next, we optimized the ligand (entries 7–9), copper
salt (entries 10–12), and solvent (entries 13 and 14). Although
6a was successfully obtained under all reaction conditions, the
highest yield was obtained with CuI/PPh3 in DMF. In addition
to B2pin2 (2a), other diboron reagents such as bis(neopentyl
glycolato)diboron (B2neop2) function equally effectively
(entry 15). The necessity for copper in these reactions was
confirmed by the observation that without adding the catalyst
the reaction does not occur (entry 21). Moreover, the possible
involvement of palladium or nickel contamination in the
catalyst was eliminated by the observation that palladium and
nickel salts provide only a trace amount of 6a under the
optimized reaction conditions (entries 19 and 20). Finally, the
reaction is not significantly sensitive to moisture, because the
addition of 4 equivalents of water only reduces the yield to
77% (entry 22).
n-Hexyl iodide, chloride, and tosylate are also viable
substrates with optimal yields of 90%, 86%, and 76%,
respectively (Table 1, entries 16–18). However, higher tem-
peratures (608C) and the addition of (Bu4N)I are required for
reaction of the chloride and tosylate. Presumably, these
proceed via the iodide and, interestingly, for this substrate the
PPh3 ligand is not needed; however, the optimal base changes
from LiOMe to LiOtBu. Overall, the reactivity decreases in
the order: iodide > bromide > chloride ꢀ tosylate (entries 16–
18). This observation is consistent with previous copper-
catalyzed couplings of Grignard[9c] or organoboron
reagents[11] with alkyl electrophiles. This reactivity difference
can be exploited to allow the selective substitution of the
bromine atom of 6-chlorohexyl bromide at room temperature
(Scheme 2). However, on increasing the reaction temperature
to 608C, and in the presence of Bu4NI, both bromide and
chloride react efficiently.
Table 1: Borylation of n-hexyl bromide under various conditions.
Entry Catalyst
Ligand
Base
Sol.
T
Yield
(10 mol%) (13 mol%)
[8C] [%][a]
1
2
3
4
5
6
CuI
CuI
CuI
CuI
CuI
CuI
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
LiOtBu DMF
KOtBu DMF
NaOtBu DMF
25 84
25 28
25 24
25 13
25 trace
25 91
(89)[i]
LiHMDS DMF
Li2CO3
LiOMe
DMF
DMF
7
8
9
CuI
CuI
CuI
PnBu3
PtBu3
LiOMe
LiOMe
DMF
DMF
DMF
25 78
25 70
25 65
1,10-phenanthro- LiOMe
line
10
11
12
13
14
CuBr
CuCl
Cu(OTf)2
CuI
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
DMF
DMF
DMF
DMSO 25 57
THF
25 72
25 56
25 60
CuI
25 35
25 87
Scheme 2. Site-selective borylation.
15[b] CuI
DMF
(83)[i]
16[c] CuI
17[d] CuI
18[e] CuI
–
–
–
LiOtBu THF
LiOtBu THF
LiOtBu MeCN 60 76
LiOMe
LiOMe
LiOMe
LiOMe
25 90
60 86
With optimized reaction conditions identified, we exam-
ined the scope of the new borylation reaction (Scheme 3).
Many synthetically important functional groups including
ester (6b), cyano (6c), ketone (6d), ether (6 f, 6j), olefin (6g),
amide (6i, 6v), ketal (6k), and silyl ether (6t) groups are well
tolerated with yields of the desired, isolated alkylboronates
ranging from about 50% to 80%. Furthermore, arene- and
heterocycle-containing compounds (6m, 6s, 6w) are good
substrates for the borylation process. Significantly, even the
presence of a free alcohol group (6h, 6l) does not interfere
with the reaction. This feature compares favorably with early
alkylboronate syntheses starting from alkyllithium or alkyl-
magnesium reagents, in which nearly all of the alkyl groups
are only hydrocarbons.[4] More reactive electrophiles such as
19[f] Pd(OAc)2 PPh3
DMF
DMF
DMF
DMF
25 trace
25 trace
25 trace
25 77
20[g] NiI2
21
22[h] CuI
PPh3
PPh3
PPh3
–
[a] Yields as determined by GC analysis after 18 h (average of two runs).
[b] Bis(neopentyl glycolato)diboron was used in the coupling. [c] n-Hexyl
iodide was used. [d] n-Hexyl chloride was used and 1 equiv of N(Bu)4I
was added. [e] n-Hexyl tosylate was used and 1 equiv of N(Bu)4I was
added. [f] 2 mol% of Pd catalyst was added. [g] 2 mol% of anhydrous
NiI2 used. Similar negative results were obtained with NiCl2·6H2O and
NiBr2·3H2O. [h] 18 mL (1 mmol) of water was added. [i] Yield of isolated
product. DMSO=dimethylsulfoxide, HMDS=hexamethyldisilazide,
Tf =trifluoromethanesulfonyl, THF=tetrahydrofuran.
Angew. Chem. Int. Ed. 2012, 51, 528 –532
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
529