Vanadium-catalyzed oxidative Strecker reaction: α-C-H cyanation of para-methoxyphenyl (PMP)-protected primary amines

Article abstract of DOI:10.1016/j.tetlet.2013.11.012

We describe an oxidative Strecker reaction that allows for direct cyanation of para-methoxyphenyl (PMP)-protected primary amines. A vanadium(V) complex was used as the catalyst and TBHP as the oxidant. The cyanation occurs at the α-C position bearing either an alkyl or an aromatic group. This method provides a direct access to α-aminonitrile from amines with one-carbon extension.

Full text of DOI:10.1016/j.tetlet.2013.11.012

Tetrahedron Letters 55 (2014) 232–234
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Tetrahedron Letters
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Vanadium-catalyzed oxidative Strecker reaction:
a-C–H cyanation of
para-methoxyphenyl (PMP)-protected primary amines
⇑
Chen Zhu, Ji-Bao Xia, Chuo Chen
Division of Chemistry, Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe an oxidative Strecker reaction that allows for direct cyanation of para-methoxyphenyl
Received 26 October 2013
Revised 31 October 2013
Accepted 1 November 2013
Available online 15 November 2013
(PMP)-protected primary amines. A vanadium(V) complex was used as the catalyst and TBHP as the oxi-
dant. The cyanation occurs at the
provides a direct access to -aminonitrile from amines with one-carbon extension.
Ó 2013 Elsevier Ltd. All rights reserved.
a-C position bearing either an alkyl or an aromatic group. This method
a
Keywords:
Vanadium catalyst
C–H cyanation
Oxidative Strecker reaction
Primary amine
Schiff base ligand
Cyanide, or nitrile, is a valuable one-carbon unit. It can be con-
verted into a variety of polar functional groups, for example,
amine, aldehyde, ketone, carboxylic acid, and amide. The Strecker
reaction is the most commonly used cyanation reaction, which
report here that vanadium-Schiff base complexes can catalyze oxi-
dative Strecker reaction of PMP-protected primary amines.
We recently found that vanadocene dichloride (Cp2VCl2) cata-
lyzes benzylic C–H oxidation selectively and efficiently.10 We
hypothesized that high-valent vanadium complexes could also oxi-
gives a
-aminonitriles from imines.1 Imines are normally prepared
by condensing amines and aldehydes (Fig. 1, top), but can also be
generated by oxidizing amines (Fig. 1, bottom). Recently, this oxi-
dative approach has been recognized as a powerful new way to
functionalize amines.
dize the weakly activated a-C–H group of amines and promote a
Strecker reaction. We envisioned that methods for cyanating pri-
mary amines would be most versatile because the nitrogen center
of the products could be further functionalized. We chose to use
the electron-rich para-methoxyphenyl (PMP) protecting group to
promote the oxidation and circumvent the self-condensation issue
of primary amines. After C–H cyanation, the N-PMP group can be
The oxidative Strecker reaction is a cross-dehydrogenative cou-
pling (CDC) reaction.2 It provides a more direct access to
a-amino-
nitriles than the traditional Strecker reaction. It also uses the amine
building blocks in a different way. Instead of cyanating aldehydes
at the carbonyl position after imine formation, this one-carbon
removed easily to give
a-aminonitriles that bear a primary amino
group.11
extension reaction functionalizes amines at the
a-C-position. The
focus of current research on this type of CDC reaction is the oxida-
tive functionalization of tertiary amines, in particular, N,N-dialky-
laniline and tetrahydroisoquinoline.3,4 Issues associated with
primary and secondary amines arise from the N–H oxidation
step,5,6 which often yields nitrones or N-oxides instead of imines.7
Vanadium complexes have been used widely to catalyze the oxi-
dation of olefins, thioethers, alcohols, and phenols, but not amines.8
There is only one report of vanadium-catalyzed CDC reaction, specif-
ically, oxidative Strecker reaction of tertiary amines.9 As part of a
program to expand the utility of vanadium complexes, we searched
for vanadium catalyst systems that promote the N–H oxidation. We
H
N
H
R1 Strecker
H
N
R1
N
R1
reaction
CN–
O
R2
R2
CN
R2
H
oxidative
Strecker
reaction
H
H
PG
PG
PG
CN
N
N
N
CN–
R1
R1
R1
⇑
Corresponding author. Tel.: +1 214 648 5048; fax: +1 214 648 0320.
E-mail address: Chuo.Chen@UTSouthwestern.edu (C. Chen).
Figure 1. Traditional vs. oxidative Strecker reactions.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.012

C. Zhu et al. / Tetrahedron Letters 55 (2014) 232–234
233
Table 1
Table 2
Scope of the
Development of the vanadium-catalyzed oxidative
a
-C-cyanation reactiona
a
-C-cyanation reactiona,b
OMe
OMe
5 mol % 3a
1.5 equiv TBHP
OMe
OMe
5 mol % V cat.
H
N
H
R
1.5 equiv TBHP
H
H
N
N
1.2 equiv TMSCN
N
1.2 equiv TMSCN
R
CN
CH3CN, 23 °C, 24 h
Ph
Ph
CN
solvent, 23 °C, 24 h
1
2
H
PMP
CN
H
N
PMP
CN
H
PMP
CN
Entry
Catalyst
Solvent
Yield (%)
N
N
1
2
3
4
5
6
7
8
9
VCl3 or VBr3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
DMF
0
0
<10
50
32
<10
30
<10
<10
<10
<10
61
VF4, VO2, VOSO4 or VO(acac)2
V2O5, VO(OiPr)3, VO(OSiPh3)3
3a
3b
3c
3a
3a
3a
3a
3a
3a
MeO
Me
2, 61% yield
4, 63% yield
5, 52% yield
THF
H
PMP
H
PMP
CN
H
PMP
N
N
N
10
11
12
Dioxane
Toluene
CH3CNb
CN
CN
a
Reaction conditions: 1 (0.1 mmol), TBHP (70 wt % in water, 0.15 mmol), TMSCN
F3C
F
Cl
(0.12 mmol), 1 mL solvent.
b
6, 30% yield
7, 45% yield
8, 37% yield
0.5 mL Solvent.
O
O
V
O
V
N
O
O
N
O
O
N
O
O
V
H
PMP
H
PMP
H
PMP
OMe
OMe
O2N
OMe
N
N
N
3a
3b
3c
Br
CN
CN
CN
S
9, 47% yield
10, 58% yield
11, 30% yield
We began our study by searching for an active vanadium cata-
lyst at 5 mol % loading. We used PMP-benzylamine (1) as the sub-
strate, TBHP as the oxidant, and TMSCN as the cyanide source
(Table 1). All the vanadium(III) and vanadium(IV) complexes we
examined were not able to promote this reaction (entries 1 and
2). However, various vanadium(V) complexes were found active
(entry 3), with the vanadium(V)-Schiff base complex 3a catalyzing
the oxidative cyanation of 1 to give 2 in 50% yield (entry 4). Intro-
ducing two sterically bulky and slightly electron-donating tert-bu-
tyl groups to the aromatic ring of the Schiff base ligand resulted in
a decreased reaction rate (entry 5), whereas adding an electron-
withdrawing nitro group led to a complex mixture of products (en-
try 6). Acetonitrile was proved to be the solvent of choice (entries
7–11). The yield of 2 could be improved to 61% by increasing the
reaction concentration to 0.2 M (entry 12).
The generality of this vanadium-catalyzed oxidative Strecker
reaction is shown in Table 2. A variety of PMP-protected primary
amines can be cyanated easily. For substituted benzylamines, both
electron-donating and withdrawing groups can be tolerated at the
para, meta, or ortho position (4–9). In general, electron-rich benzyl-
amines (4 and 5) are more reactive than the electron-deficient ones
(6–9). Aromatic rings other than phenyl can also be tolerated. For
example, both the PMP-protected naphthylmethylamine and thi-
ophenylmethylamine were cyanated smoothly (10 and 11). Impor-
H
PMP
H
PMP
CN
H
PMP
CN
N
N
N
CN
N
Boc
12, 41% yield
13, 64% yield
14, 70% yield
a
Reaction conditions: amine (0.2 mmol), TBHP (70 wt % in water, 0.3 mmol),
TMSCN (0.24 mmol), 1 mL CH3CN.
b
Isolated yields. PMP = para-methoxyphenyl (p-MeOPh).
Mechanistically, we believe that 3a first reacted with TBHP to
give I as the active catalyst (Fig. 3). The PMP-amine then coordi-
nated to I and formed complex II. Similar to other metal-catalyzed
amine oxidation reactions,2 a single-electron transfer (SET) from
the electron-rich nitrogen center to the vanadium complex oc-
curred to give III, a valence tautomer of II. Subsequent O–O homol-
ysis and C–H abstraction gave IV and the iminium ion, which
reacted with cyanide to give the
a-aminonitrile. Support for the
SET hypothesis followed from the observation that electron defi-
cient acetyl, tosyl, and Boc-protected benzylamines did not react
under these conditions. In addition, vanadium(III) complexes could
not promote this oxidative Strecker reaction, suggesting that a
two-electron vanadium(III/V) redox mechanism was not operative.
We also believe that amine oxidation was not mediated by
tert-butoxyl radical,12 because vanadium(IV) complexes did not
catalyze the reaction, and vanadium(V) complexes other than 3
gave only less than 10% conversion. For the same reason, we be-
lieve that the aminium ion was coordinated to vanadium (III)
when the C–H abstraction occurred. The Schiff base ligand likely
served as an electron sink to facilitate the SET. We further propose
that the silyl transfer from TMSCN to the oxide ligand of III or IV
tantly, activation of the
a-position by an aromatic group is not
necessary. This oxidative Strecker reaction can be used to function-
alizing PMP-protected aliphatic amines (12–14).
This oxidative Strecker reaction allows us to make use of amine
building blocks to prepare
a-aminonitriles that cannot be easily ac-
cessed by traditional methods. For example,
a-C-cyanation of the
PMP-protected (+)-dehydroabietylamine (15) gave 16 in 61% yield
as a 2:1 mixture of diastereomers (Fig. 2). 15 was synthesized by
copper-catalyzed N-arylation of (+)-dehydroabietylamine (see
Supplementary Material for details).

234
C. Zhu et al. / Tetrahedron Letters 55 (2014) 232–234
Me
Me
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.11.012.
Me
Me
Me
H
Me
H
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P
MP-Dehydroabietylamine (15)
d.r. 2:1
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promoted the regeneration of I and released the cyanide for the
Strecker reaction.
In summary, we have developed a vanadium-catalyzed oxida-
tive Strecker reaction of PMP-protected primary amines. This
C–H cyanation reaction allows for functionalization of amines at
the -C-position, and is complimentary to the traditional Strecker
a-
a
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further explore the utility of vanadium-catalyzed CDC reactions.
Acknowledgements
Financial Support was provided by NIH (NIGMS R01-
GM079554) and the Welch Foundation (I-1596). C.C. is a South-
western Medical Foundation Scholar in Biomedical Research.
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Supplementary data
Supplementary data (experimental procedures and character-
ization data of the reaction products) associated with this article