Oxidant-free conversion of cyclic amines to lactams and H2 using water as the oxygen atom source

Article abstract of DOI:10.1021/ja500026m

Direct conversion of cyclic amines to lactams utilizing water as the only reagent is catalyzed by pincer complex 2. In contrast to previously known methods of amine-to-amide conversion, this reaction occurs in the absence of oxidants and is accompanied by liberation of H₂, with water serving as a source of oxygen atom. Formation of a cyclic hemiaminal intermediate plays a key role in enabling such reactivity. This represents an unprecedented, conceptually new type of amide formation reaction directly from amines and water under oxidant-free conditions.

Full text of DOI:10.1021/ja500026m

Communication
pubs.acs.org/JACS
Oxidant-Free Conversion of Cyclic Amines to Lactams and H2 Using
Water As the Oxygen Atom Source
Julia R. Khusnutdinova, Yehoshoa Ben-David, and David Milstein*
Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel
S
* Supporting Information
This has raised the intriguing possibility of developing a reaction
of amines with water to form amides, with concurrent liberation
of hydrogen gas (eq 2). Developing a dehydrogenative amine-to-
ABSTRACT: Direct conversion of cyclic amines to
lactams utilizing water as the only reagent is catalyzed by
pincer complex 2. In contrast to previously known
methods of amine-to-amide conversion, this reaction
occurs in the absence of oxidants and is accompanied by
liberation of H2, with water serving as a source of oxygen
atom. Formation of a cyclic hemiaminal intermediate plays
a key role in enabling such reactivity. This represents an
unprecedented, conceptually new type of amide formation
reaction directly from amines and water under oxidant-free
conditions.
amide conversion can ultimately provide a more atom-
economical method for amide synthesis that does not require
the use of a stochiometric oxidant, with water serving as a source
of oxygen in the amide group.
Reported herein is the dehydrogenation of cyclic amines in
water to produce γ- and δ-lactams catalyzed by an acridine-based
Ru pincer complex (AcrPNP)RuH(CO)Cl (2)11−13 in the
presence of a catalytic amount of a base (Scheme 2). This
he synthesis of amides and lactams is one of the most
Timportant transformations in organic synthesis, as they are
widely used as precursors for synthesis of polymers, biologically
active compounds, and pharmaceuticals. Common methods for
the preparation of amides include coupling of amines with
carboxylic acid derivatives, nitrile hydrolysis, rearrangement of
ketoximes,1 or catalytic dehydrogenative coupling of amines with
alcohols.2,3 The direct conversion of amines to amides via
oxygenation of an α-methylene group remains relatively rare.
Such oxygenation reactions typically require the use of a
stoichiometric oxidant such as iodosobenzene,4 tBuOOH,5
RuO2/NaIO4,6 O2,7 or other oxidants8 (eq 1).
Scheme 2. Lactam Formation from Cyclic Amines Catalyzed
by 2
transformation is accompanied by liberation of H2, while water
serves as a source of the oxygen atom in the amide group. Since
complex 2 also catalyzes the amination of 1,4-butanediol with
NH3 to pyrrolidine, this also opens up the possibility for the
direct synthesis of lactams from diols and NH3.
We have reported that complex 2 catalyzes the deamination of
aliphatic amines by water to produce alcohols and NH3 in a
water−dioxane mixture at 100−135 °C (eq 3).14 This trans-
formation was proposed to occur via a reversible dehydrogen-
ation/hydrogenation sequence (“borrowing hydrogen”)15 and
likely involves the formation of a hemiaminal as a key
intermediate (Scheme 3).14 The major side reaction was the
formation of carboxylate salts by further alcohol dehydrogen-
ation, which could be suppressed under a H2 atmosphere.14
Our group has recently developed the direct dehydrogenation
of alcohols in water to selectively produce carboxylic acid salts in
the presence of a stochiometric amount of base, catalyzed by a
bipyridyl-based pincer Ru complex 1 (Scheme 1).9 In this
reaction, water serves as the oxygen atom source, while the
reaction is accompanied by liberation of H2.9,10
In effect, water can be viewed as an oxidant in this system with
this very unusual role for H2O enabled by the production of H2.9
Scheme 1. Conversion of Alcohols to Carboxylate Salts Using
a Stoichiometric Base and 1 as a Catalyst
[Ru]
RNH2 + H2O ⎯⎯⎯→ ROH + NH3
(3)
The loss of NH3 from a hemiaminal intermediate was the
predominant reaction for aliphatic amines in water under these
Received: January 2, 2014
Published: February 12, 2014
© 2014 American Chemical Society
2998
dx.doi.org/10.1021/ja500026m | J. Am. Chem. Soc. 2014, 136, 2998−3001

Journal of the American Chemical Society
Communication
a
Scheme 3. Proposed Mechanisms for Deamination
Table 1. Cyclic Amine-to-Lactam Conversion Catalyzed by 2
conditions. However, if the deamination pathway could be
prevented, further dehydrogenation of the hemiaminal inter-
mediate could potentially lead to amides (Scheme 3).
Accordingly, when n-butylamine was heated in a water−
dioxane mixture under 5 atm of NH3 in the presence of 2 for 65 h
at 150 °C, the formation of n-butanamide and N-butyl
butanamide was detected; however, the combined yields of
amides did not exceed 5%, while the formation of 1-butanol (8%)
and butyrate ammonium salt (7%) was also observed under these
conditions. Therefore, the entropically driven loss of NH3 could
not be completely prevented even under NH3 pressure for
primary aliphatic amines.
We then employed cyclic amines which could entropically
stabilize cyclic hemiaminal intermediates against deamination.
Heating a pyrrolidine solution in a degassed water−dioxane
mixture (1:1 v/v) under N2 in a closed system at 150 °C in the
presence of 1 mol % 2 produced 2-pyrrolidone in 24% yield
(Table 1, entry 1) after 48 h, also generating H2 gas that was
detected by TCD-GC. A control experiment showed no
conversion in the absence of 2 under the same conditions
upon prolonged heating of pyrrolidine in water/dioxane at 150
°C.
Notably, the analogous reaction of pyrrolidine in the presence
of complex 1 (1 mol %) which was previously used for alcohol-to-
carboxylate conversion (Scheme 1)9,16 produced <1% of lactam
after heating at 150 °C for 48 h in the absence or in the presence
of a catalytic amount of NaOH (1.5 mol %) and pyrrolidine
remained mostly unreacted.17 The unselective formation of 2-
pyrrolidone in 19% yield was observed only in the presence of a
stoichiometric amount of NaOH.
We have shown earlier that the more selective alcohol
dehydrogenation to esters could be achieved when acridine-
based pincer complex 2 was employed in combination with a
catalytic amount of NaOH, while, in the absence of a base,
formation of a mixture of esters and acetals was observed.13
When the pyrrolidine solution was heated in water/dioxane in
the presence of 1 mol % of 2 in combination with 1.5 mol % of
NaOH, formation of pyrrolidone in 59% yield was observed
(Table 1, entry 2). The beneficial effect of the base could be due
to stabilization of a hemiaminal intermediate against the
elimination of amine or the formation of a Ru(0) catalyst via
deprotonation of 2.13 Hydrogen gas formation was detected by
GC analysis of the gas phase above the reaction mixture, and the
average yield of H2 is 79 4% based on pyrrolidine conversion
determined by volumetric measurements. Further increasing the
amount of a base to 6 mol % did not improve the lactam yield and
led to slightly lower selectivity (entry 3). The yield and selectivity
could further be increased in the presence of higher catalyst
loadings (5 mol % 2 and 5 mol % NaOH) to give 2-pyrrolidone in
83% yield with ∼90% selectivity (entry 4). The yields of the
reaction were unaffected in the presence of a drop of mercury
metal, a common test that checks for the formation of catalytic
metal particles under these conditions. Lactam formation was
also observed in a biphasic toluene−water or in pyridine−water
a
Substrate (1 mmol), 2 (0.01 mmol, 1 mol %), water (1.5 mL), and
dioxane (1.5 mL) were heated in a 50 mL thick wall pressure tube at
150 °C (silicon oil bath temperature), if not indicated otherwise. %
NMR yields and conversions and isolated yields (in square brackets)
b
c
are reported as averages of two runs. No base added. NaOH 1.5 mol
%. NaOH 6.0 mol %. Cat. [2] 5 mol % and NaOH 5 mol %,
dioxane/water 2:1 v/v. Cat. [2] 1 mol % and NaOH 1.5 mol %,
lutidine/water 1:1 v/v.
d
e
f
solutions, albeit with lower yields and selectivities.17 The reaction
in lutidine−water (1:1 v/v) solution using 1 mol % of 2 and 1.5
mol % of NaOH affords 2-pyrrolidone in 73% yield with 83%
selectivity (entry 5).
The major side products formed during the reaction with
pyrrolidine were identified as 4-(1-pyrrolidinyl)butanoic acid
(S1) and a trace amount of succinic acid (S2). In particular, S1
formed in 9−10% and 4−5% yield after heating for 48 h at 150 °C
in the presence of 1 mol % 2 (entry 2, Table 1) and 5 mol % 2
(entry 4), respectively, while succinic acid was present only in
trace amounts (<3% in entry 2).18 Since 2 equiv of pyrrolidine
are consumed during the formation of 1 equiv of 4-(1-
pyrrolidinyl)butanoic acid, this may account for the mass balance
of pyrrolidine conversion.19 The possible mechanisms for the
formation of S1 an S2 are discussed in the Supporting
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Journal of the American Chemical Society
Communication
Information (SI) in more detail (Scheme S1) and likely involve
4-aminobutyric acid as an intermediate formed either via a base-
catalyzed 2-pyrrolidone hydrolysis or via further oxidation of 4-
amino-1-butanal II (n = 1, Scheme 4) resulting from the ring
opening of I (n = 1, Scheme 4).9,14,17
The initial dehydrogenation step to produce imine (Scheme 4)
is reversible as evident from an H/D exchange experiment. Thus,
heating pyrrolidine in the presence of 2 (1 mol %) and NaOH
(1.5 mol %) in a D2O−dioxane mixture at 135 °C leads to 58%
and 48% deuterium incorporation in α- and β-CH2 groups,
respectively (Scheme 5). Notably, the formation of 2-
Scheme 4. Proposed Pathway of Lactam Formation Catalyzed
by 2
Scheme 5. Deuterium Incorporation in Pyrrolidine CH2
Groups in the Presence D2O Catalyzed by 2
pyrrolidone under these conditions, at 135 °C, is only minimal
(<5%), suggesting that the initial dehydrogenation step occurs
before the rate-limiting step of the reaction and requires a lower
temperature than the lactam formation. A control experiment in
the absence of 2 and in the presence of 1.5 mol % NaOH shows
only 3% deuterium incorporation in the α- and β-CH2 groups of
pyrrolidine under analogous conditions. The incorporation of
deuterium in the β-position might be due to increased acidity of
the β-CH2 groups in the imine;16 however, an alternative
mechanism involving formation of 2-pyrroline cannot be
completely excluded.22
As a factor that helps drive the reaction forward, we found that
the formation of 2-pyrrolidone is irreversible under the reaction
conditions. The attempted hydrogenation of 2-pyrrolidone in
the presence of 2 (1 mol %) and NaOH (1.5 mol %) in water−
dioxane (1:1 v/v) under 10 atm of H2 does not yield pyrrolidine
after heating at 150 °C for 60 h, and the starting material remains
mainly unreacted.
Overall, the formation of amides via dehydrogenation of cyclic
amines in water suggests that the stability of the hemiaminal
intermediate plays an important role in determining the
reactivity of amines with water catalyzed by 2. Although
deamination of primary aliphatic amines catalyzed by 2 was
also proposed to occur via hemiaminal intermediates, the
entropically driven loss of NH3 leads to the predominant
formation of alcohols and carboxylates. Similarly, heating an
acyclic secondary amine, di-n-hexylamine, in water−dioxane at
150 °C for 48 h in the presence of 2/NaOH leads to the
formation of 1-hexanol (∼20%) and hexanoate salt (∼9%)
resulting from secondary amine splitting9,14,23 while no amides
were present among the products in detectable amounts. At the
same time, entropic stabilization of a cyclic hemiaminal
intermediate I (Scheme 4) toward the loss of an amine group
likely enables its further dehydrogenation leading to the lactam
formation.
Chart 1. Byproducts of the Reactions with Pyrrolidine in
Water−Dioxane Catalyzed by 2/NaOH
The substituted pyrrolidines 2-methylpyrrolidine and 2-
methoxymethylpyrrolidine react in a similar way and afford the
corresponding lactams in 43.5% and 64.5% yields respectively,
using 1 mol % of catalyst 2 (Table 1, entries 6 and 8). The lactam
product of the reaction with 2-methoxymethylpyrrolidine could
be obtained in up to 85% yield when 5 mol % of 2 was used (entry
9), while the reaction with 2-methylpyrrolidine was less selective
at higher catalyst loadings (entry 7).20 The products were
isolated and characterized by NMR, IR, and HR-MS. By contrast,
3-dimethylaminopyrrolidine undergoes deamination to generate
Me2NH and pyrrole under these conditions (entry 10).21
Indoline undergoes dehydrogenation to form indole in 69% yield
(entry 11), while no amide product was detected by GC-MS and
NMR.
The six-membered cyclic secondary amines (entries 12−16)
reacted in a similar way to produce the corresponding lactams in
54−75% yield using 5 mol % of 2 and NaOH. During
dehydrogenation of 1,2,3,4-tetrahydroquinoline, no quinoline
was detected among the reaction products. The major byproduct
in the reaction with piperidine is most likely a 5-(1-piperidinyl)-
pentanoic acid (S3) that was formed in 10−15% yields and was
characterized by ESI-MS and NMR.17 The yields of the lactams
are generally lower for six-membered cyclic amines compared to
five-membered substrates likey due to the lower stability of the
hemiaminal intermediate or steric factors.
Based on previous mechanistic studies,3,11−13 the following
pathway is proposed for the lactam formation from cyclic amines
(Scheme 4). In the proposed mechanism complex 2 catalyzes the
initial dehydrogenation of the cyclic amine to form a cyclic imine
intermediate, which undergoes a nucleophilic attack by water to
afford a hemiaminal intermediate I, and then further
dehydrogenation of the latter species catalyzed by complex 2
yields the corresponding lactam (Scheme 4).
To confirm that the O-atom in the amide group originates
from water, the reaction with pyrrolidine was performed in a
dioxane−H218O (≥98 atom % 18O) mixture. Heating pyrrolidine
in dioxane−H218O in the presence of 2 (1 mol %) and NaOH (1
mol %) at 150 °C for 72 h gave 2-pyrrolidone that was shown by
HR-MS to be ≥98% 18O-labeled.
Combined with the ability of complex 2 to catalyze the
amination of alcohols with ammonia,12 the reactivity observed
herein opens up the possibility of one-step formation of lactams
directly from diols and NH3 in water. Accordingly, we found that
a one-step reaction of 1,4-butanediol under 6 atm of NH3 in the
presence of 5 mol % of 2 and 5 mol % of NaOH in water−
dioxane generates a mixture of pyrrolidine (58%) and
pyrrolidone (31%) after heating at 150 °C for 72 h.17,24 The
reaction was more selective at a lower concentration of NH3:
when an aqueous ammonia solution (24−27 w/w%) was used, 2-
pyrrolidone and pyrrolidine were obtained in 49% and 23%
yields, respectively (Scheme 6).17
The formation of pyrrolidine in Scheme 6 likely occurs via
initial amination of 1,4-butanediol to give 4-amino-1-butanol
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Journal of the American Chemical Society
Communication
Feng, J.-B.; Neumann, H.; Pews-Davtyan, A.; Langer, P.; Beller, M.
Green Chem. 2013, 15, 1956. (c) Wu, X.-F.; Bheeter, C. B.; Neumann,
H.; Dixneuf, P. H.; Beller, M. Chem. Commun. 2012, 48, 12237.
(6) Tanaka, K.; Yoshifuji, S.; Nitta, Y. Chem. Pharm. Bull. 1988, 36,
3125.
Scheme 6. Synthesis of Pyrrolidine and 2-Pyrrolidone by
Amination of 1,4-Butanediol with NH3 in Water−Dioxane
(7) (a) Wang, Y.; Kobayashi, H.; Yamaguchi, K.; Mizuno, N. Chem.
Commun. 2012, 48, 2642. (b) Xu, W.; Jiang, Y.; Fu, H. Synlett 2012, 23,
801. (c) Klobukowski, E. R.; Mueller, M. L.; Angelici, R. J.; Woo, L. K.
ACS Catalysis 2011, 1, 703.
(8) Nishinaga, A.; Shimizu, T.; Matsuura, T. J. Chem. Soc., Chem.
Commun. 1979, 970.
(9) Balaraman, E.; Khaskin, E.; Leitus, G.; Milstein, D. Nat. Chem.
2013, 5, 122.
(10) Rodríguez-Lugo, R. E.; Trincado, M.; Vogt, M.; Tewes, F.;
followed by the cyclization of the latter,12,14,25 while the
formation of 2-pyrrolidone may occur via two possible pathways:
(i) a dehydrogenative reaction of pyrrolidine with water (Scheme
2) or (ii) dehydrogenative intramolecular amide formation
directly from 4-amino-1-butanol.3 While both pathways could be
involved in the observed lactam formation via the same
intermediate I (n = 1, Scheme 4), our experiments suggest that
direct reaction of pyrrolidine with water (path i) likely
contributes to the overall yield of lactam under these conditions
(see SI for more detail).
In summary, we reported for the first time the formation of
lactams via dehydrogenation of cyclic amines in water with H2
liberation. The reaction is homogeneously catalyzed by complex
2 in the presence of a catalytic base, with water serving as a source
of the oxygen atom of the formed amide. Although the currently
obtained yields are in part modest, such reactivity is unique and it
represents a fundamentally new type of amide formation reaction
directly from amines and water under oxidant-free conditions.
The lactam formation likely occurs via a cyclic hemiaminal
intermediate which is entropically stabilized against the loss of
amine, thus enabling its further dehydrogenation to an amide.
Overall, combined with the ability of 2 to catalyze the amination
of primary alcohols with NH3, this opens up new possibilities for
novel atom-economical approaches to the synthesis of lactams
that avoid the use of stoichiometric oxidants.
Santiso-Quinones, G.; Grutzmacher, H. Nat. Chem. 2013, 5, 342.
̈
(11) Gunanathan, C.; Gnanaprakasam, B.; Iron, M. A.; Shimon, L. J.
W.; Milstein, D. J. Am. Chem. Soc. 2010, 132, 14763.
(12) Gunanathan, C.; Milstein, D. Angew. Chem., Int. Ed. 2008, 47,
8661.
(13) Gunanathan, C.; Shimon, L. J. W.; Milstein, D. J. Am. Chem. Soc.
2009, 131, 3146.
(14) Khusnutdinova, J. R.; Ben-David, Y.; Milstein, D. Angew. Chem.,
Int. Ed. 2013, 52, 6269.
(15) Gunanathan, C.; Milstein, D. Science 2013, 341, DOI: 10.1126/
science.1229712.
(16) Khaskin, E.; Milstein, D. ACS Catalysis 2013, 3, 448.
(17) See SI for more detail.
(18) The lack of catalytic activity of 1 could be due to the catalyst
deactivation by carboxylic acids S1 and S2 in the absence of a large
amount of strong base.
(19) For example, the sum of pyrrolidine, pyrrolidone, and S1 accounts
for 98−100% of the mass balance in entries 2 and 4. However, a greater
fraction (up to 20%) of unidentified insoluble products was observed in
the presence of excess of NaOH (entry 3) where the yield of S1 was 4−
5%.
(20) The major product of reaction with 2-methylpyrrolidine is most
likely 4-(2-methylpyrrolidin-1-yl)pentanoic acid, which was detected by
ESI-MS in the reaction mixtures (m/z 186.1, M*H+).
(21) This reaction might involve tertiary amine splitting similar to that
in ref 23, resulting in the formation of Me2NH and pyrrolidin-3-one or
3-hydroxypyrrolidine. Dehydration of the latter would produce
pyrroline, which could undergo dehydrogenation to the aromatic
pyrrole system. However, other mechanisms cannot be excluded.
(22) N-Methylpyrrolidine undergoes unselective reaction to produce
N-methyl-2-pyrrolidone in 22% yield at 69% conversion after heating for
48 h at 160 °C in the presence of 1 mol % of 2 and 1.5 mol % of NaOH,
which could also indicate an alternative pathway involving enamine or
iminium intermediates (see: Sundararaju, B.; Achard, M.; Sharma, G. V.;
Bruneau, C. J. Am. Chem. Soc. 2011, 133, 10340. Leete, E. Planta Med.
1990, 56, 339 ). However, the reaction with N-methylpiperazine (entry
15) generates secondary amide exclusively, suggesting that the imine
formation (Scheme 4) is likely a predominant path towards lactams.
ASSOCIATED CONTENT
* Supporting Information
Experimental details of catalytic reactions and characterization
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
david.milstein@weizmann.ac.il
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the European Research Council
under the FP7 framework (ERC No. 246837) and by the Israel
Science Foundation. We thank Feinberg Graduate School for a
Dean of Faculty Fellowship to J.K. D.M. is the holder of the Israel
Matz Professorial Chair of Organic Chemistry.
(23) Bahn, S.; Imm, S.; Neubert, L.; Zhang, M.; Neumann, H.; Beller,
̈
M. Chem.Eur. J. 2011, 17, 4705.
(24) The reaction of 1,5-pentanediol in dioxane/water under 6 atm of
NH3 affords a mixture of piperidine (63%) and 2-piperidone (30%).
(25) (a) Yamaguchi, R.; Kawagoe, S.; Asai, C.; Fujita, K.-i. Org. Lett.
2007, 10, 181. (b) Fujita, K.-i.; Fujii, T.; Yamaguchi, R. Org. Lett. 2004, 6,
3525. (c) Hamid, M. H. S. A.; Allen, C. L.; Lamb, G. W.; Maxwell, A. C.;
Maytum, H. C.; Watson, A. J. A.; Williams, J. M. J. J. Am. Chem. Soc.
2009, 131, 1766.
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dx.doi.org/10.1021/ja500026m | J. Am. Chem. Soc. 2014, 136, 2998−3001