Amine Functionalization through Sequential Quinone-Catalyzed Oxidation/Nucleophilic Addition

Article abstract of DOI:10.1002/ejoc.201600786

A simple and efficient method for the synthesis of α-branched amines through formal oxidative C–H functionalization is reported. A commercially available quinone organocatalyst is employed to promote the aerobic oxidation of primary amines to the corresponding N-protected imines, which are then trapped in situ with an appropriate nucleophile to give access to versatile functionalized amines in good to excellent yields (70–90 %).

Full text of DOI:10.1002/ejoc.201600786

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DOI: 10.1002/ejoc.201600786
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Organocatalysis
Amine Functionalization through Sequential Quinone-Catalyzed
Oxidation/Nucleophilic Addition
Martin A. Leon,[a][‡] Xinyun Liu,[a][‡] Johnny H. Phan,[b] and Michael D. Clift*[a]
Abstract: A simple and efficient method for the synthesis of α- amines to the corresponding N-protected imines, which are
branched amines through formal oxidative C–H functionaliza- then trapped in situ with an appropriate nucleophile to give
tion is reported. A commercially available quinone organocata- access to versatile functionalized amines in good to excellent
lyst is employed to promote the aerobic oxidation of primary yields (70–90 %).
Introduction
The importance of amines in many disciplines of chemistry has
fueled the development of a variety of methods to enable their
synthesis, including amine alkylation,[1] reductive amination,[2]
and imine addition.[3] More recently, hydroamination[4,5] and
C–H amination[6] methods have been reported. These powerful
methods for the synthesis of amine are conceptually related
in that they deliver the target amine by means of C–N bond
construction. In comparison, there are only few methods that
enable the direct α-functionalization of amine-containing mol-
ecules.
MacMillan,[7] Stephenson,[8] and others[9] have utilized pho-
toredox catalysis to enable a variety of amine C–H α-functionali-
zations, but these reactions are currently limited to applications
involving tertiary amine substrates (Scheme 1 a).[10] Krische has
demonstrated that transfer hydrogenation can be used to func-
tionalize secondary amines (Scheme 1 b).[11] Stoichiometric
methods that enable the functionalization of secondary[12] and
tertiary[13,14] amines have also been reported. Dehydrogenative
cross-coupling has also been heavily utilized to enable the func-
tionalization of such substrates.[15,16] On the other hand, the
α-functionalization of primary amines has been underexplored
(Scheme 1 c).[17] To address this gap, we have developed a new
protocol that enables the formal α-functionalization of primary
amines through sequential quinone-catalyzed amine oxidation/
nucleophilic addition.
Scheme 1. Established amine α-functionalizations and the underexplored α-
functionalization of primary amines. FG = functional group; EWG = electron-
withdrawing group.
to promote the stoichiometric oxidation of an amine to the
corresponding ketone in an abiotic environment.[19] Later stud-
ies by Klinman and Mure further demonstrated that appropriate
In biology, quinone cofactors are commonly employed by
copper amine oxidases to enable the conversion of primary
amines to the corresponding aldehyde derivatives.[18] Corey and
Achiwa were the first to show that quinones could be used
[a] Department of Chemistry, The University of Kansas,
2010 Malott Hall, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA
E-mail: mclift@ku.edu
www.cliftgroup.ku.edu
[b] Eli Lilly and Company,
893 S. Delaware Street, DC-1920, Indianapolis, IN 46285, USA
[‡] These authors contributed equally to this work.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600786.
Scheme 2. Key precedents and present application to formal amine α-func-
tionalization. PG = protecting group.
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cofactor analogs could be utilized to enable the oxidation of imine product. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
benzylic amines to provide dimeric imines (Scheme 2 a).[20] The (DDQ, 13) provided imine 4a in only 28 % yield. Finally, 2,6-
potential synthetic utility of cofactor mimics of this type has disubstituted quinones were studied and commercially avail-
recently been recognized and this has led to the development able quinone 2 was identified as a suitable catalyst, providing
of new organocatalytic protocols for amine oxidation by Stahl the desired oxidation product in initially 80 % yield. Increasing
(Scheme 2 b)[21] and others.[22–24]
the reaction concentration while employing quinone 2 as the
catalyst provided imine 4a in a satisfactory yield of 97 %. Impor-
tant trends can be inferred from analysis of these data. Quin-
ones that are prone to 1,4-addition (5 and 6)[26] or addition/
elimination processes (10, 14, and 15) are ineffective catalysts.
Additionally, very sterically encumbered (7 and 11) and elec-
tron-rich quinones (8 and 12) that likely fail to undergo amine
condensation are generally ineffective. DDQ (13) also provides
poor conversion, perhaps owing to its inability to undergo
oxidative turnover under these conditions. Taken together,
these studies have led us to conclude that to promote amine
oxidation, a quinone catalyst must 1) be sterically encumbered
or electronically constituted in such a way as to prevent conju-
gate addition of the amine, 2) be sterically accessible to allow
condensation of an amine substrate, and 3) provide a reduced
catalyst that is sufficiently electron rich to undergo catalytic
turnover by autoxidation.[20b] Quinone 2 meets all of these cri-
teria and, therefore, serves as an efficient catalyst for amine
oxidation.
With the optimized conditions for amine oxidation in hand,
sequential oxidation/nucleophilic addition reactions were ex-
amined. These studies began by exploring the efficiency of in
situ addition reactions by using the lithiated ketene imine de-
rived from acetonitrile[27] as the nucleophilic reaction partner
in combination with a variety of imines generated through
quinone-promoted amine oxidation to deliver a series of ꢀ-
amino nitriles (17, Table 2). A wide range of benzylic amines
Results and Discussion
We sought to explore the possibility of using sequential quin-
one-catalyzed amine oxidation/nucleophilic addition to enable
the formal oxidative functionalization of amine substrates
(Scheme 2 c). In such a process, we envisioned that quinone-
catalyzed amine oxidation would deliver an N-protected imine
intermediate (not shown) that could be trapped in situ by an
appropriate nucleophilic reaction partner (Nuc–M) to deliver
the desired amine product. Herein, we report the development
of this method and its application to the efficient synthesis of
α-branched amines.
Using Wendlandt and Stahl's protocol as a starting point,[21a]
we set out to identify a commercially available alternative to
quinone 1[25] that would enable catalytic amine oxidation
(Table 1). It was found that 1,4-benzoquinone (5) and methyl
1,4-benzoquinone (6) provided very poor conversion to the de-
sired N-para-methoxyphenyl (PMP) imine (4a, 0 and 44 % yield,
respectively). When examining 2,5-substitution patterns on the
quinone catalyst, we found that none of the commercial quin-
ones were superior to quinone 1, which facilitated amine oxid-
ation in near quantitative yield. Tetrasubstituted quinones gave
universally poor conversion. Duroquinone (11) and tetra-
hydroxy-1,4-benzo-quinone (12) failed to provide the desired
Table 1. Optimization of the amine oxidation protocol.[a]
Table 2. Amine scope by using a ketene imine nucleophile.
[a] Yields determined by 1H NMR spectroscopy by using an internal standard.
[a] Isolated yields. [b] With 20 mol-% of catalyst 2. [c] With 10 mol-% of
catalyst 2.
[b] Reaction run at 0.625
M
concentration.
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was well tolerated under these conditions. When benzylamine this is the first example of allylic amines being utilized in quin-
was employed, the corresponding nitrile was obtained in 88 % one-catalyzed oxidations.
yield (entry 1). Substitution at the ortho-position of the amine
substrate resulted in a reduced reaction efficiency (entry 2,
82 % yield) compared to meta- and para-substitution (entries 4
and 6, 85 and 90 % yield, respectively). Electron-donating and
electron-withdrawing substituents were compatible (entries 3,
5 and 7–9, 70–89 % yield) and showed no apparent trends with
respect to the reaction efficiency. Heteroarylamines were also
competent substrates, providing the corresponding nitriles in
good yields when 10 mol-% of the catalyst was employed (en-
Scheme 3. Application to allylic amine substrates.
tries 11–13, 70–89 % yield). A limitation of the present method
This new protocol for formal amine functionalization also re-
mained efficient when employed on a gram-scale and the re-
sulting products represent useful synthetic building blocks
(Scheme 4).[30] When 4-methylbenzylamine was used as a sub-
strate under the optimized conditions for ketene imine addition
on a gram-scale, nitrile 17f was isolated in a slightly diminished
yield of 73 %. Nitrile 17f was readily converted to ꢀ-amino acid
21 in 69 % yield by using methanolic potassium hydroxide; ꢀ-
amino acids of this type are commonly employed in the synthe-
sis of ꢀ-lactams and peptidomimetics.[31] Reduction of 17f with
a borane-tetrahydrofuran complex delivered the corresponding
diamine 22 in 86 % yield. Finally, 17f was treated with potas-
sium hydroxide in tert-butanol to afford amino amide 23 in
83 % yield.
for amine functionalization is that aliphatic amines, α-branched
amines, and secondary amines failed to undergo the requisite
oxidation under the current reaction conditions.
Next, the scope of the nucleophilic reaction partner was ex-
amined (Table 3). By using aryllithium reagents,[28] a variety of
medicinally relevant benzhydrylamine derivatives[29] were gen-
erated from benzylamine in good yields (entries 1–9, 70–84 %
yield). N-PMP benzhydrylamine can be synthesized in good
yield by using this protocol (entry 1, 77 % yield). Substitution
of a methyl substituent at the ortho-position of the nucleophile
(entry 2, 78 % yield) resulted in a slightly diminished reaction
efficiency compared to meta- and para-substitution (entries 4
and 5, 81 % and 84 %, respectively); however, steric effects
seemed to have very little impact when employing isomeric
1- and 2-naphthyl nucleophiles (entries 8 and 9, 81 and 82 %,
respectively). Aryl nucleophiles with electron-donating and
electron-withdrawing substituents were also competent reac-
tion partners (entries 3, 6, and 7, 70–80 % yield). α-Branched
amines bearing an α-Csp3 substituent also underwent formal
oxidative alkylation (entries 10–12, 71–89 % yield) and allylation
(entry 12, 84 %) reactions.
Table 3. Nucleophile scope by using benzylamine.
Scheme 4. Gram-scale reaction and product utility.
Conclusions
In conclusion, we have developed a simple and efficient
method for the preparation of α-branched amines through a
sequential quinone-promoted amine oxidation/nucleophilic ad-
dition process. This new protocol provides access to versatile
[a] Isolated yields. [b] Organolithium nucleophile used. [c] Nuc–M added at
0 °C. [d] Organomagnesium bromide nucleophile used.
Allylic amines were also suitable substrates (Scheme 3). By amine products in good to excellent yields (70–90 %). Amine
using 20 mol-% of the catalyst, both di- and tri-substituted pri- substrates are currently limited to benzylic and allylic amines;
mary allylic amines were well tolerated in reactions by using future work will include the development of new quinone cata-
allylmagnesium bromide as the nucleophilic reaction partner lysts that will enable the oxidative functionalization of aliphatic
(82 and 78 % yield, respectively). To the best of our knowledge, amines.
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to –78 °C and then tert-butyllithium (3.0 mmol, 1.7
M
solution in
Experimental Section
pentane) was added dropwise under vigorous stirring. The reaction
mixture was allowed to stir at –78 °C for 1 h. Then, the solution was
warmed to room temperature and the product of amine oxidation
(see Procedure A: General Oxidation) was added dropwise by us-
ing cannula (followed by rinsing with THF, 2 × 1.0 mL). The resulting
solution was allowed to stir overnight and then quenched by slow
addition of saturated aq. NH4Cl (2.0 mL) followed by saturated aq.
NaHCO3 (4.0 mL). The mixture was transferred to a separatory fun-
nel by the aid of Et2O, shaken vigorously, and the organic phase
was collected. The aqueous phase was further extracted with Et2O
(3 × 5.0 mL) and the combined organic extracts were dried
(Na2SO4), filtered, and concentrated under reduced pressure. Flash
chromatography on silica gel provided the desired arylamines
(18b–18j).[28]
General Experimental Information: All reactions were carried out
in flame-dried glassware with magnetic stirring unless otherwise
stated. Toluene, THF, acetonitrile, and DCM were purified by passage
through a bed of activated alumina.[32] Diisoproplyamine was dis-
tilled from calcium hydride[33] under nitrogen immediately prior to
use. Commercially available aryl bromides were distilled prior to
use. Purification of reaction products was carried out by flash chro-
matography using Fisher Chemical silica gel (230–400 Mesh, Grade
60). Analytical thin layer chromatography (TLC) was performed on
EMD millipore TLC silica gel 60 – F 254: 25 glass plates. Visualization
was accomplished with UV light and/or phosphomolybdic acid
staining followed by heating. Melting point data were recorded us-
ing a Digimelt SRS. Film, NaCl pellet, or KBr pellet infrared spectra
1
were recorded using a Shimadzu FTIR-8400S. H NMR spectra were
Procedure D: General Nucleophilic Addition for the Synthesis of
α-Substituted Benzylamines by Using Commercially Available
Aryllithium (or Grignard) Reagents as Nucleophiles (18a,
18k–18m, and 20a–20b): The vial containing the product of amine
oxidation (see Procedure A: General Oxidation) was purged with
nitrogen and cooled to 0 °C. The organolithium reagent or the Gri-
gnard reagent (1.5 mmol) was added dropwise under N2 atmos-
phere and vigorous stirring. Then, the mixture was warmed to room
temperature and allowed to stir overnight and then quenched by
slow addition of saturated aq. NH4Cl (2.0 mL) followed by saturated
aq. NaHCO3 (4.0 mL). The mixture was transferred to a separatory
funnel by the aid of Et2O, shaken vigorously, and the organic phase
was collected. The aqueous phase was further extracted with Et2O
(3 × 5.0 mL) and the combined organic extracts were dried
(Na2SO4), filtered, and concentrated under reduced pressure. Flash
chromatography on silica gel (10 % ethyl acetate in hexanes with
1 % triethylamine) provided the desired amines (18a, 18k–18m,
20a–20b).
recorded on a Bruker Advance 400 (400 MHz) or a Bruker 500
(500 MHz) spectrometer and are reported in ppm using the solvent
as a reference (residual CHCl3 at δ = 7.26 ppm). Data are reported
as (app = apparent, obs = obscured, s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, b = broad; integration; coupling
constant(s) in Hz). Proton-decoupled 13C NMR spectra were re-
corded on a Bruker 500 (125 MHz) spectrometer and are reported
in ppm using the solvent as a reference (CDCl3 at δ = 77.16 ppm).
Mass spectra data were obtained on a Micromass Ltd. LCT Premier
quadrupole and time-of-flight tandem mass analyzer.
Sequential Amine Oxidation/Nucleophilic Addition; General
Procedures
Procedure A: General Amine Oxidation (17, 18, and 20): To a
solution of 2,6-di-tert-butyl-1,4-benzoquinone (5.5 mg, 0.025 mmol,
unless otherwise noted) and p-anisidine (123.1 mg, 1.0 mmol) in
toluene (800 μL, 0.625
M with respect to the amine substrate) was
added the amine (0.50 mmol), followed by purging the reaction vial
with a balloon of O2. The reaction mixture was allowed to stir under
O2 at 80 °C for 24 h.
3-[(4-Methoxyphenyl)amino]-3-phenylpropanenitrile (17a): The
reaction was carried out according to the general oxidation proce-
dure (A) by using benzylamine (55 μL, 0.50 mmol) followed by the
general addition procedure (B) to provide after purification on silica
gel (20 % ethyl acetate in hexanes) nitrile 17a (98.2 mg, 88 %) as a
brown oil, which was spectroscopically identical to previous re-
ports.[34]
Procedure B: General Nucleophilic Addition for the Synthesis of
ꢀ-Amino Nitriles (17a–17m): To a flame dried round-bottomed
flask under N2 was added THF (12.5 mL) and diisopropylamine
(410 μL, 2.92 mmol); the solution was cooled to 0 °C. Then, n-butyl-
lithium (2.62 mmol, 1.6
M solution in hexanes) was added dropwise.
The solution was warmed to room temperature and stirred for
30 min. Then, the solution was cooled to –78 °C and acetonitrile
(130.5 μL, 2.5 mmol) was added dropwise. After the addition, the
reaction was warmed to room temperature and stirred for 15 min.
Then, the solution was cooled again to –78 °C and the product of
amine oxidation (see Procedure A: General Amine Oxidation) was
added by using a cannula (followed by rinsing with toluene, 3 ×
0.20 mL). At –78 °C, the reaction was monitored by TLC until the
imine was consumed (typically between 30 min and 1 h) and then
quenched by the addition of saturated aq. NH4Cl (1.5 mL). The mix-
ture was transferred to a separatory funnel by the aid of EtOAc;
saturated aq. NaHCO3 (3.0 mL) was added, the mixture was shaken
vigorously, and the organic layer was collected. The aqueous layer
was further extracted by using EtOAc (3 × 15 mL) and the combined
organic layers were dried (Na2SO4), filtered, and concentrated under
reduced pressure. Flash chromatography on silica gel provided the
desired nitriles (17a–17m).[27]
3-[(4-Methoxyphenyl)amino]-3-(o-tolyl)propanenitrile
(17b):
The reaction was carried out according to the general oxidation
procedure (A) by using 2-methylbenzylamine (62 μL, 0.50 mmol)
while employing a 20 mol-% loading of 2,6-di-tert-butyl-1,4-benzo-
quinone (22 mg, 0.10 mmol) followed by the general addition pro-
cedure (B) to provide after purification on silica gel (20 % ethyl
acetate in hexanes) nitrile 17b (103.8 mg, 82 %) as a brown oil. IR
(film): ν = 3379, 2993, 2833, 2248, 1228 cm–1 1H NMR (400 MHz,
.
˜
CDCl3): δ = 7.48–7.41 (m, 1 H), 7.27–7.18 (m, 3 H), 6.78–6.70 (m, 2
H), 6.54 (d, J = 8.4 Hz, 2 H), 4.90 (t, J = 6.2 Hz, 1 H), 3.91 (br. s, 1 H),
3.72 (s, 3 H), 2.94–2.77 (m, 2 H), 2.43 (s, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 153.0, 139.9, 138.0, 135.3, 131.2, 128.3, 127.0,
125.0, 117.4, 115.3, 115.0, 55.8, 51.5, 24.7, 19.3 ppm. HMRS (ESI):
calcd. for C17H19N2O [M + H]+ 267.1497; found 267.1488.
3-(2-Methoxyphenyl)-3-[(4-methoxyphenyl)amino]propane-
nitrile (17c): The reaction was carried out according to the general
oxidation procedure (A) by using 2-methoxybenzylamine (65 μL,
0.5 mmol) followed by the general addition procedure (B) to pro-
vide after purification on silica gel (20 % ethyl acetate in hexanes)
nitrile 17c (102.8 mg, 73 %) as a brown solid, m.p. 84 °C. IR (NaCl):
Procedure C. General Nucleophilic Addition for the Synthesis of
α-Substituted Benzylamines by Using Organolithium Nucleo-
philes Prepared in Situ (18b–18j): To a flame dried 25 mL round-
bottomed flask under N2 were added the corresponding aryl-
bromide (1.5 mmol) and dry THF (5.0 mL). The solution was cooled
ν = 3373, 2933, 2835, 1240 cm–1 1H NMR (400 MHz, CDCl3): δ =
.
˜
7.31 (dd, J = 7.5, 1.7 Hz, 1 H), 7.30–7.27 (m, 1 H), 6.94 (dd, J = 7.5,
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