M. H. Daniels, J. Hubbs / Tetrahedron Letters 52 (2011) 3543–3546
3545
Table 3
Table 4
Reactions of nucleophiles with 12 mediated by 1a
Scope of substrate in 1-mediated allylationa
Ph
Ph
N
EWG
EWG
1, Base
R
R
MeCN, RT
N
R'
N
R'
CH2
1, PS, Nu
BF3K
N
H2C
23-27
28-32
MeCN, RT
EtO2C
EtO2C
13-20
R
Entry
1
SM
Base
P
Yieldb (%)
12
Bn2N
F3C
CN
23
24
25
26
TMSNHAc
None
28
29
30
31
58
58
56
41
Entry
1
Nu
R
Product
Yieldb (%)
13
2
3
4
N
Ph
TMS
CH2
13
H2C
Bn2N
COMe
N
DMAP
OTMS
O
O
MeOC
2
3
14
15
25
28
DMAP
Ph
OTBDMS
5
N
27
None
32
41
Ph
O
O
F3C
a
Substrate (1 mmol), 1 (1.5 mmol), base (if used, 1.1–1.5 mmol) and potassium
Me
N
Me
N
allyltrifluoroborate (2 mmol) were stirred in 5 mL MeCN for 10–20 min at room
temperature.
4
5
16
17
40
54
b
Isolated yield.
OMe
OMe
O
OTBDMS
With this knowledge in hand, we began to investigate alterna-
tive substrates, varying both the participating and non-participat-
ing substituents on the nitrogen ring (Table 4). Ultimately, we
found that while a variety of electron deficient tertiary alkyl
amines could react with nucleophiles in the presence of 1, optimi-
zation was still needed for a given substrate. For example, it was
necessary to use N-trimethylsilylacetamide to obtain an acceptable
yield (58%) of 28 from 23 (entry 1). The use of DMAP in this trans-
formation provided 28 in only 18% yield. Some substrates gave
highest yields in the absence of base (entries 2 and 5). While the
substrate scope was generally good, one notable exception was
the failure of any N-aryl amine to provide any product other than
fluorination of the phenyl ring.
OMe
Me
Me
OMe
OMe
6
18
55
OTMS
O
Me
Me Me
OMe
7
8
19
20
46
22
Me
O
S
OTMS
S
TMS
N
N
a
12 (1 mmol), 1 (1.5 mmol), PS (1.05 mmol) and Nu (2 mmol) were stirred in
5 mL MeCN for 10 min at room temperature.
b
Isolated yield.
In conclusion, we have developed a novel method for an oxida-
tive Mannich-type reaction mediated by SelectfluorÒ (1). This reac-
tion works on a variety of electron-poor tertiary alkyl amine
substrates with a diverse array of carbon nucleophiles in poor to
good yields. While substrate-specific optimization is required, this
protocol does offer a useful route to complex tertiary amines.
1, Base
CH2
Bn2N
Bn2N
MeCN, RT
CO2Me
21
CO2Me
22
BF3K
H2C
Acknowledgments
Base: PS, 52% yield
DMAP, 80% yield
Portions of this work were conducted as part of the Cooperative
Education Program with Northeastern University, Boston, MA
(M.H.D.). We thank Merck colleague Bruce Adams for assistance
with NMR analyses.
Scheme 4. Reagents and conditions: 1.5 equiv 1, 1.1 equiv PS or DMAP, 2.0 equiv
allyl-BF3K, 0.2 M in MeCN, 20 min, rt.
available glycine derivative, another round of optimization was ini-
tiated using ester 21 as the substrate. It was discovered that the
use of 1 equiv of DMAP instead of PS could provide compound
22 in 80% yield.15 As a side investigation, this substrate was used
to test the sensitivity of the reaction conditions. While the use of
a 4:1 mixture of acetonitrile and water did lead to dealkylation
of 21 (cf. Scheme 2), the 1-mediated conversion of 21 to 22 in
the presence of DMAP proceeded smoothly under air, nitrogen
and argon (80%, 77% and 84% yield, respectively). The use of an ar-
gon atmosphere with 4 Å molecular sieves to absorb ambient
water also gave a yield 80% yield. These results suggest that the
use of 1 as an oxidant in Mannich-type reactions is extremely ro-
bust, insensitive to ambient conditions and operationally simple.
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