Preparation of Aldehydes by Oxidation of Benzylic Amines with Selectfluor (F-TEDA-BF4)

Article abstract of DOI:10.1055/s-0035-1561642

Aldehydes are obtained by mild oxidation of benzylic amines with Selectfluor. The results are compared favorably with the Polonovski-like process using hypervalent iodine.

Full text of DOI:10.1055/s-0035-1561642

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–C
letter
A
A. Hauser, R. Bohlmann
Letter
Synlett
Preparation of Aldehydes by Oxidation of Benzylic Amines with
Selectfluor™ (F-TEDA-BF4)
Anett Hausera
Rolf Bohlmann*b
Cl
O
N+
NR1R2
20–80%
H
+
a Leibniz-Institut für Molekulare Pharmakologie,
Robert-Roessle-Str. 10, 13125 Berlin, Germany
b Bayer Pharma AG, Müllerstr. 178, 13353 Berlin,
Germany
N+
F
MeCN
20 min, r.t.
R3
–
R3
2BF4
various
benzylic amines
substituted
benzaldehydes
Selectfluor(TM)
rolf.bohlmann@bayer.com
R1 = H, aliphatic, R2 = aliphatic
R3 = H, Hal, MeO, NO2
fast reaction
mild conditions
Received: 05.02.2016
Accepted after revision: 15.04.2016
Published online: 18.05.2016
the best of our knowledge the observed reaction with 1 has
not been reported before. There are several reports and re-
views3 on fluorination reactions employing 1, but despite
early reports of the slow oxidation of benzylic alcohols with
1 they were not extended to the oxidation of amines.4 Con-
sequently, the newly observed reaction of 1 was investigat-
ed in detail comparing also the conditions and yields with
those of the more frequently applied oxidation strategy us-
ing hypervalent iodine.2
DOI: 10.1055/s-0035-1561642; Art ID: st-2016-b0082-l
Abstract Aldehydes are obtained by mild oxidation of benzylic amines
with Selectfluor™. The results are compared favorably with the Polon-
ovski-like process using hypervalent iodine.
Key words Selectfluor™, amines, oxidation, aromatic aldehydes
A key transformation occurring during many metabolic
pathways is the oxidation of amines to aldehydes or ke-
tones.1 It is an important source for the incorporation of
carbon- and nitrogen-containing building blocks by biogen-
esis. Specialized amine oxidases perform this vital function
for instance in the liver. In addition, it plays a vital part in
the metabolism of drugs. The toolbox of organic chemistry
includes numerous processes for this oxidation. However,
they often require either heavy metals or multiple steps.
Therefore, two recent papers report mild oxidations of
amines into aldehydes by hypervalent iodine in chloro-
form.2
H
F-TEDA (1)
NR2R3
N+R2R3
F
R1
R1
– HF
2
3
CHO
+ H2O
N+R2R3
R1
R1
4
5
Scheme 1 Proposed mechanism of the reaction
Cl
Regarding the reaction mechanism, the first step of the
new transformation might be the nucleophilic attack of 2 at
the fluorine atom in 1, analogous to the SN2 reaction on car-
bon.5 Elimination of hydrofluoric acid would intermediately
give an imine 4 which in turn could be hydrolyzed to the
isolated aldehyde 5.
N+
N+
–
BF4
F
1
To find the most practical conditions different equiva-
lents of 1 were reacted with 2f along with 2d and 2e (Table
1, entry 4–6) at different temperatures in acetonitrile as
well as in chloroform, and the conversion of 2f was deter-
mined via UPLC at distinct time points (Table S1). Forma-
tion of product 5b was observed in each experiment even
though to different extent, hence, for best results and con-
venience the reaction conditions were chosen as follows:
Figure 1 Selectfluor™ (1, F-TEDA-BF4)
We were investigating the reaction of benzylic amines 2
with Selectfluor™ (1, Figure 1, F-TEDA-BF4) for the prepara-
tion of fluorinated derivatives as part of the late-stage deri-
vatization strategy. Analysis of our reaction mixtures indi-
cated the formation of aldehydes 5 instead (Scheme 1). To
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–C

B
A. Hauser, R. Bohlmann
Letter
Synlett
Table 1 (continued)
1.3 equivalents of 1 in acetonitrile at 25 °C for 20 minutes.
Subsequently, a complete set of differently substituted ter-
tiary amines each with three differently substituted benzyl
moieties was investigated under these conditions (Table 1,
entries 1–9). In addition to that, the reactivities of (1) a sec-
ondary along with a tertiary amine (Table 1, entries 10, 11)
and (2) a steric unrestricted together with a constraint
amine (Table 1, entries 12, 13) were compared to illustrate
the scope of the reaction. Therefore, the reported substrates
2a–m were either purchased commercially or derived from
the corresponding benzylic bromides 6 by amination with
amines 7 (Scheme 2).6 The subsequent reaction of 1 with
these 2a–m resulted in the formation of the corresponding
aldehydes 5a–f in all cases, though showing varying conver-
sions from poor to excellent (see Table S2, Figures S2 and
S3). These results indicate that the chemical environment
of the amines has a larger impact on the product formation
than the aromatic substituents. In case of the diisopropyl-
amine derivatives good to excellent yields were observed,
surpassing the reported results obtained when using hy-
pervalent iodine in chloroform over two hours at 60 °C.2a
Due to different volatility of the products, not all purified
fractions could be fully dried under high vacuum resulting
partially in decreased purity (see Table S1).
Entry
Substrate
Product 5
Yield Yield
(%)
(%)a
I
I
N
N
b
5
5b
45
–
2e
6
5b
92
75
2f
2g
2h
CHO
N
b
7
8
49
20
–
MeO
MeO
MeO
5c
5c
N
b
–
N
9
5c
72
21
93
69
50
82
MeO
Br
2i
2j
CHO
N
H
10
11
Br
5d
5d
HNR2R3 (7)
NR2R3
Br
R1
R1
73–100%
N
6
2
Br
Br
Scheme 2 Synthesis of benzylic amines 2 from bromides 6
2k
2l
Br
CHO
CHO
N
12
13
90
30
42
42
Table 1 Synthesis of Benzylic Aldehydes 5 from Amines 2 with 1
5e
5f
CHO
1 (1.3 equiv)
NR2R3
R1
N
20 min, r.t.
R1
O2N
O2N
2
5
2m
a Yields obtained by Desjardins et al.2a
b Reactions were not performed by Desjardins et al.2a
Entry
1
Substrate
Product 5
Yield Yield
(%)
(%)a
PhCHO
5a
b
N
83
–
To test the applicability of our developed protocol for
more complex substrates the commercially available com-
pound imatinib (8) in which various different amine func-
tionalities are present was reacted with 1 under similar
conditions as described before (Scheme 3). We were de-
lighted to observe the distinct conversion of the benzylic
amine into the corresponding aldehyde 9 (Figure S1) which
is known to be an in vivo metabolite of imatinib.7 By this
model transformation the generality of our novel developed
synthesis strategy was demonstrated.8
Bn
2a
b
2
3
4
5a
5a
25
90
88
–
N
Bn
2b
N
95
55
Bn
2c
I
I
CHO
N
5b
2d
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–C

C
A. Hauser, R. Bohlmann
Letter
Synlett
O
O
N
H
NH
N
NH
H
1 (1.8 equiv), MeCN
O
N
N
N
N
150 min, r.t.
13%
N
N
H
N
N
imatinib
8
9
Scheme 3 Reaction of imatinib (8) with 1
In conclusion, we report the discovery of a rapid, mild,
convenient method for the straightforward preparation of
benzylic aldehydes from amines by the use of Selectfluor™
(1).9,10 The efficacy, selectivity, and easy handling of 1 far
outweigh its higher risk and slightly higher price than hy-
pervalent iodine. The reaction can be carried out without
metals or detours via protecting group manipulations. This
transformation should be kept in mind while reacting ben-
zylic amines with 1. Apart from being a side reaction during
the fluorination protocol, this strategy provided smooth ac-
cess to different metabolic intermediates of diverse drugs.
In future experiments, this approach together with a larger
scope of substrates and the influence of different solvents
shall be investigated more in detail.
of the smaller reaction scope they cover. See: (a) Ling, Z.; Yun,
L.; Liu, L.; Wu, B.; Fu, X. Chem. Commun. 2013, 49, 4214.
(b) Gong, J. L.; Qi, X.; Wei, D.; Feng, J.-B.; Wu, X.-F. Org. Biomol.
Chem. 2014, 12, 7486.
(9) Experimental Procedure
To a suspension of 1-(chloromethyl)-4-fluoro-1,4-diazoniabicy-
clo[2.2.2]octane ditetrafluoroborate (1, 0.975 mmol) in MeCN
(3 mL) the amine (2, 0.75 mmol) dissolved in MeCN (3 mL) was
added dropwise at r.t. The reaction was stirred at r.t. for another
20 min. The solvent was evaporated, and the obtained residue
was purified via flash column chromatography using silica gel
as stationary phase.
(10) Benzaldehyde (5a)
1H NMR (400 MHz, CDCl3): δ = 10.05 (s, 1 H), 7.89–7.95 (m, 2 H),
7.63–7.69 (m, 1 H), 7.54–7.60 (m, 2 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 192.4, 136.5, 134.5, 129.8, 129.0 ppm. IR: ν = 3070
(m), 2837 (m), 2678 (w), 1559 (w), 1686 (vs) cm–1
.
3-Iodobenzaldehyde (5b)
1H NMR (400 MHz, CDCl3): δ = 9.95 (s, 1 H), 8.23 (t, J = 1.5 Hz, 1
H), 7.98 (dt, J = 7.6, 1.6 Hz, 1 H), 7.87 (dt, J = 7.8, 1.3 Hz, 1 H),
7.31 (t, J = 7.8 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
190.7, 143.2, 138.5, 138.1, 130.8, 128.9, 94.7 ppm. IR: ν = 3377
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561642.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(w), 3057 (w), 2825 (m), 2727 (m), 1699 (vs) cm–1
.
4-Methoxybenzaldehyde (5c)
References and Notes
1H NMR (400 MHz, CDCl3): δ = 9.92 (s, 1 H), 7.87 (d, J = 8.8 Hz, 2
H), 7.01–7.06 (m, 2 H), 3.92 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 190.8, 164.7, 132.0, 130.1, 114.4, 55.6 ppm.
4-Bromobenzaldehyde (5d)
(1) Chajkowski-Scarry, S.; Rimoldi, J. M. Future Med. Chem. 2014, 6,
697.
(2) (a) Desjardins, S.; Jacquemot, G.; Canesi, S. Synlett 2012, 23,
1497. (b) Iinuma, M.; Moriyama, K.; Togo, H. Synlett 2012, 23,
2663.
(3) (a) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.;
Wong, C.-H. Angew. Chem. Int. Ed. 2005, 44, 192. (b) Banks, R. E.;
Mohialdin-Khaffaf, S. N.; Lal, G. S.; Sharif, I.; Syvret, R. G. J. Chem.
Soc., Chem. Commun. 1992, 595. (c) Stavber, S. Molecules 2011,
16, 6432.
(4) Banks, R. E. Synlett 1994, 831.
(5) Antelo, J. M.; Crugeiras, J.; Leis, J. R.; Ríos, A. J. Chem. Soc., Perkin
Trans. 2 2000, 2071.
(6) Sakakura, A.; Ohkubo, T.; Yamashita, R.; Akakura, M.; Ishihara,
K. Org. Lett. 2011, 13, 892.
(7) Genovino, J.; Lütz, S.; Sames, D.; Touré, B. J. Am. Chem. Soc. 2013,
135, 12346.
1H NMR (300 MHz, CDCl3): δ = 10.00 (s, 1 H), 7.77 (dd, J = 6.4,
2.1 Hz, 2 H), 7.71 (dd, J = 6.8, 1.8 Hz, 2 H) ppm. 13C NMR (75
MHz, CDCl3): δ = 191.0, 135.1, 132.4, 131.0, 129.8 ppm. IR: ν =
3350 (w), 3086 (m), 2860 (s), 1699 (vs), 1585 (vs), 1383 (vs),
835 (vs), 814 (s) cm–1
.
3-Bromobenzaldehyde (5d)
1H NMR (400 MHz, CDCl3): δ = 9.99 (s, 1 H), 8.04 (t, J = 1.8 Hz, 1
H), 7.83 (dt, J = 7.7, 1.2 Hz, 1 H), 7.78 (ddd, J = 7.9, 2.0, 1.0 Hz, 1
H), 7.45 (t, J = 7.8 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
190.7, 138.1, 137.3, 132.4, 130.7, 128.4, 123.4 ppm. IR: ν = 1695
(s), 1556 (s), 1252 (m), 754 (vs) cm–1
4-Nitrobenzaldehyde (5f)
.
1H NMR (400 MHz, CDCl3): δ = 10.18 (s, 1 H), 8.41 (d, J = 8.6 Hz,
2 H), 8.10 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ
= 190.3, 151.2, 140.1, 130.5, 124.3 ppm. IR: ν = 3107 (w), 2850
(m), 1709 (vs), 1605 (m), 1539 (s), 1381 (m), 1346 (vs), 1327 (s),
(8) Since our work for this manuscript was finished, two novel
approaches for the oxidative deamination of benzylic amines
have been published which should be mentioned here despite
1288 (m), 1105 (m), 1007 (w), 851 (s), 818 (s), 741 (s) cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–C