Palladium-catalyzed insertion of an allene into an aminal: Aminomethylamination of allenes by C-N bond activation

Article abstract of DOI:10.1002/anie.201403774

A new and atom-economic palladium-catalyzed aminomethylamination of allenes with aminals by C-N bond activation is described. This direct and operationally simple method provides a fundamentally novel approach for the synthesis of 1,3-diamines. Mechanistic studies suggest that a unique cationic π-allylpalladium complex containing an aminomethyl moiety is generated as a key intermediate through the carbopalladation of the allene with a cyclometalated palladium-alkyl species.

Full text of DOI:10.1002/anie.201403774

Angewandte
Chemie
DOI: 10.1002/anie.201403774
À
C N Activation
Palladium-Catalyzed Insertion of an Allene into an Aminal:
À
Aminomethylamination of Allenes by C N Bond Activation**
Jianhua Hu, Yinjun Xie, and Hanmin Huang*
Abstract: A new and atom-economic palladium-catalyzed
À
aminomethylamination of allenes with aminals by C N bond
activation is described. This direct and operationally simple
method provides a fundamentally novel approach for the
synthesis of 1,3-diamines. Mechanistic studies suggest that
a unique cationic p-allylpalladium complex containing an
aminomethyl moiety is generated as a key intermediate through
the carbopalladation of the allene with a cyclometalated
palladium–alkyl species.
T
he 1,3-diamines are important structural motifs in many
Scheme 1. Palladium-catalyzed difunctionalization of allenes.
natural products and pharmaceuticals.[1] As a result, much
effort has been devoted to the development of effective
methods to access these compounds.[2] However, unlike their
1,2-diamine counterparts, few methods for the direct synthesis
of 1,3-diamines have been described.[3] An unusual and direct
synthetic method to produce this class of compounds could be
the use of these strategies for the synthesis of 1,3-diamines has
remained unexplored, which is presumably due to the lack of
efficient methods to simultaneously generate both a nitrogen
nucleophile and a carbon nucleophile (containing an amine
moiety) in the same reaction step.
=
À
the insertion of a C C bond into an aminal by C N bond
activation under transition-metal catalysis, which is poten-
tially an atom- and step-economical process. This alkene
aminomethylamination could be an alternative to the classic
Mannich reaction/reduction sequence, which generally uti-
lizes stoichiometric amounts of a reductant (Scheme 1).[4] To
realize the proposed alkene difunctionalization reaction with
palladium catalysis, the inherent b-hydride elimination of the
resulting Pd–alkyl species must be suppressed to enable the
second bond construction.[5] Over the past decades, elegant
strategies, such as the formation of p-allyl or p-benzyl
complexes,[6a–k] and the oxidation of the PdII–alkyl intermedi-
ates to a PdIV species, have been developed to circumvent this
issue.[6l–q] The formation of a p-allylpalladium species by the
carbometalation of allenes, a useful strategy for suppressing
the b-hydride elimination of metal–alkyl species, has been
extensively used and successfully applied in the synthesis of
various compounds.[7] However, to the best of our knowledge,
In seeking to address this limitation, we recently found
that aminals could serve as useful electrophiles for an
oxidative addition with a Pd0 species to form a unique
electrophilic cationic Pd–alkyl species I (a carbon nucleo-
phile) while simultaneously releasing one molecule of a nitro-
gen nucleophile.[8a] The cationic Pd–alkyl species, which
contains an aminomethyl group, was highly reactive towards
the formation of allylic amines or aminoacetals with
alkenes,[8] which suggested that a palladium-catalyzed amino-
methylamination process between aminals and allenes might
be possible. It was expected that the desired p-allylpalladium
species II with an aminomethyl group would be facilely
generated by the carbopalladation of allene 1 with the active
Pd–alkyl species I. Subsequent allylic amination with the
amine nucleophile should give the desired 1,3-diamine
products. Herein, we describe the successful implementation
of the first palladium-catalyzed insertion of an allene into an
À
aminal by C N bond activation for the construction of 1,3-
diamines with high atom economy (Scheme 1). These studies
[*] J. Hu,[+] Prof. Dr. H. Huang
College of Chemical Engineering, Zhejiang University of Technology
Hangzhou 310024 (China)
E-mail: hmhuang@licp.cas.cn
represent the first example of the insertion of an allene into
II
À
a C N bond that is catalyzed by an isolated Pd complex.
In accord with our hypothesis, we used propa-1,2-dien-
ylbenzene (1a) and N,N,N’,N’-tetrabenzylmethanediamine
(2a) for screening the reaction conditions. When these
substrates were treated with [Pd(Xantphos)(CH3CN)2](OTf)2
(5 mol%), which has been shown to be highly effective for the
generation of Pd–alkyl complex I, in toluene at 1108C for
twelve hours, 1,3-diamine 3aa was obtained in 70% yield
(Table 1, entry 1). The structure of 3aa was confirmed by
single-crystal X-ray analysis (see the Supporting Informa-
tion).[9] In addition, the undesired allylic amine 4aa was
isolated in 22% yield, which might result from the off-cycle
Y. Xie,[+] Prof. Dr. H. Huang
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences
Lanzhou 730000 (China)
[+] These authors contributed equally to this work.
[**] This research was supported by the Chinese Academy of Sciences
and the National Natural Science Foundation of China (21222203,
21172226, and 21133011).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403774.
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Table 1: Optimization of the reaction conditions.[a]
Table 2: Substrate scope of the aminomethylamination.[a]
Entry Palladium precursor
Solvent T [8C]
Yield [%]
3aa 4aa
1
2
3
4
5
6
7
8
[Pd(Xantphos)(CH3CN)2](OTf)2 toluene
110
110
110
110
110
110
110
110
80
70
56
55
43
42
62
48
70
66
74
38
43
22
21
26
14
29
15
15
19
20
15
25
11
[Pd(Xantphos)(CH3CN)2](OTf)2 benzene
[Pd(Xantphos)(CH3CN)2](OTf)2 CH2Cl2
[Pd(Xantphos)(CH3CN)2](OTf)2 THF
[Pd(Xantphos)(CH3CN)2](OTf)2 CH3CN
[Pd(Xantphos)(CH3CN)2](OTf)2 DMF
[Pd(Xantphos)(CH3CN)2](OTf)2 iPrOH
[Pd(Xantphos)(CH3CN)2](OTf)2 toluene
[Pd(Xantphos)(CH3CN)2](OTf)2 toluene
[Pd(Xantphos)(CH3CN)2](OTf)2 toluene
[Pd(Xantphos)(CH3CN)2](PF6)2 toluene
[Pd(Xantphos)(CH3CN)2](SbF6)2 toluene
[Pd(Xantphos)(CH3CN)2](OTs)2 toluene
9
10
11
12
13
14
15
16
17
18
19
20
120
120
120
120 trace trace
120 trace 12
[Pd(Xantphos)Cl2]
toluene
toluene
toluene
toluene
toluene
toluene
toluene
[Pd(BINAP)(CH3CN)2](OTf)2
[Pd(DPPF)(CH3CN)2](OTf)2
[Pd(DPPB)(CH3CN)2](OTf)2
[Pd(DPPPen)(CH3CN)2](OTf)2
Pd(OAc)2
120 trace trace
120 trace trace
120 trace trace
120 trace trace
120 trace trace
[Pd(Xantphos)(CH2NBn2)]OTf
120
77 trace
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.4 mmol), palladium
precursor (0.02 mmol, 5 mol%), solvent (1.5 mL), 12 h. Yields of
isolated products are given. BINAP=2,2’-bis(diphenylphosphino)-1,1’-
binaphthyl, DPPB=1,4-bis(diphenylphosphino)butane, DPPF=1,1’-
bis(diphenylphosphino)ferrocene, DPPPen=1,5-bis(diphenylphosphi-
no)pentane, OTs=para-toluenesulfonate, Xantphos=4,5-bis(diphenyl-
phosphino)-9,9-dimethylxanthene.
[a] Reaction conditions: 1 (0.5 mmol), 2 (0.4 mmol), [Pd(Xantphos)-
(CH2NBn2)](OTf) (0.02 mmol, 5 mol%), toluene (1.5 mL), 1208C, 12 h.
Yields of isolated products are given. [b] Z/E=70:30, determined by
1H NMR spectroscopy. [c] The reaction was conducted at 1008C with
[Pd(Xantphos)(CH3CN)2](OTf)2 (5 mol%).
hydroamination of the allene. Among the solvents tested,
toluene was the best in terms of both reactivity and selectivity,
even though the reaction was also compatible with common
organic solvents (entries 1–7). During further optimization of
this reaction, it was found that raising the temperature to
1208C improved the yield without diminishing the selectivity.
Variations of the counterion of the palladium complex
indicated that the counterion was a key factor. The desired
reaction hardly occurred when OTsÀ or ClÀ served as the
counterion. Several other palladium catalysts with different
phosphine ligands, such as BINAP, DPPF, DPPB, and
DPPPen, were examined, but most of them furnished poor
results. Interestingly, the use of the unique cationic cyclo-
metalated complex [Pd(Xantphos)(CH2NBn2)]OTf (I) in
place of [Pd(Xantphos)(CH3CN)2](OTf)2 in toluene com-
pletely suppressed the formation of side product 4aa and
furnished 3aa in 77% yield. In the absence of the Pd catalyst
and under otherwise identical conditions, the desired product
was not formed.
good yields (44–80%). The steric hindrance of the substitu-
ents on the aryl ring of the allene did not have a strong
influence on the reactivity. For example, the aryl-substituted
allenes 1d and 1e, which bear ortho substituents on the aryl
ring, reacted smoothly and gave the desired products in good
yields (3da and 3ea). Typical functional groups, such as alkyl,
alkoxy, fluoro, chloro, and bromo moieties, were also
tolerated under the reaction conditions, providing ample
opportunities for further elaboration of the products by
transition-metal-catalyzed coupling reactions or other trans-
formations. Aside from aryl-substituted allenes, the naphthyl-
substituted allene 1m was also compatible with this new
reaction, generating the corresponding 1,3-diamine 3ma in
58% yield. The reaction of gem-diphenyl-substituted allene
1n with aminal 2a afforded the desired product 3na in 44%
yield; the 1,3-diphenyl-substituted allene, however, failed to
give the desired product, but afforded the aminomethyl
product 4 in 66% yield. Unfortunately, an alkyl-substituted
allene (1o) was less reactive (3oa). The substrate scope was
further extended to a wide variety of aminals with different
substituents. Several aminals that are derived from simple
alkyl amines were also compatible with this process and
After establishing these optimized reaction conditions, we
examined the scope of this aminomethylamination with
respect to variation of the allene (Table 2). A series of
either electron-donating or -withdrawing substituents on the
aryl ring of the aromatic allene were well tolerated, and the
corresponding 1,3-diamines were obtained in moderate to
2
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afford the desired products in moderate to good yields (3ab–
3ad). Moreover, aminals that are based on cyclic amines
could also be used as coupling partners, giving the corre-
sponding products in good yields (3ae–3af).
We further evaluated the utility of this reaction by
performing a large-scale experiment (Scheme 2). The reac-
unsymmetric allyl ligand with an aminomethyl moiety
(CH2NBn2)is coordinated to the Pd center in an h3 mode,
and that the Ph group is oriented anti to the attached
CH2NBn2 group. This solid-state structure correlated well
with the 1H and 31P NMR data; in the 31P NMR spectrum, two
doublets could be seen, which is consistent with the unsym-
metric nature of the structure shown in Scheme 2. Further-
more, the magnitude of the J(PH) coupling constant (5.6 Hz)
for CHPh at 5.46 ppm suggested that the CH2NBn2 group and
the phenyl group were arranged in a trans fashion.[13]
Having confirmed that the cyclometalated palladium
complex I could be facilely converted into complex II, we
proceeded to conduct a set of experiments to elucidate the
catalytic cycle of the present reaction (Scheme 3). Complex I,
together with the desired product 3aa, was obtained in high
yield when p-allylpalladium complex II was treated with one
equivalent of aminal 2a in toluene at 1208C for one hour
[Scheme 3, Eq. (2)].[14] Moreover, when the isolated p-allyl-
palladium complex II replaced cyclometalated Pd complex I
as the catalyst, the reaction proceeded well under the
standard conditions, thus indicating the plausible intermedi-
acy of complex II in the catalytic cycle [Scheme 3, Eq. (3)].
Taking the results described above into consideration, we
propose the following catalytic cycle for the novel palladium-
catalyzed aminomethylamination of allenes (Figure 1). Ini-
tially, the terminal double bond of allene 1a coordinates to
the palladium center to form intermediate III. Subsequently,
Scheme 2. Synthetic utility of the 1,3-diamines. a) [Pd(Xantphos)-
(CH2NBn2)]OTf (2.5 mol%), toluene, 1208C, 12 h, 76%. b) Na/NH3,
THF, À788C, 1.5 h, 74%. c) CAN (4.2 equiv), MeOH/H2O (4:1), RT,
12 h, 58%. d) [Pd(PPh3)4] (5 mol%), tBuONa, K2CO3, toluene, 1008C,
5 h; then Pd/C, H2 (50 atm), EtOAc, RT, 20 h, 65% over two steps.
e) [Pd(PPh3)4] (5 mol%), tBuONa, K2CO3, toluene, 1008C, 5 h; then
(Boc)2O, DMAP, THF, RT, 12 h, 73% over two steps. f) [{RuCl2(ben-
zene)}2] (5 mol%), TBHP (2.5 equiv), benzene, RT, 2 h, 64%. Boc=
tert-butyloxycarbonyl, CAN=cerium ammonium nitrate, DMAP=4-
dimethylaminopyridine, TBHP=tert-butyl hydroperoxide.
=
migratory insertion of the more electron-deficient C C bond
À
of the allene into the C Pd bond of complex I takes place.
À
The selective C C bond formation proceeds at the
sp-hybridized carbon atom of the allene to give p-allylpalla-
dium complex II, which contains an aminomethyl moiety that
is located trans to the phenyl group because of steric
hindrance. Nucleophilic addition of a nitrogen nucleophile
to the p-allylpalladium species at the less substituted carbon
atom affords the desired 1,3-diamine and regenerates the
cationic Pd–alkyl complex I for the next catalytic cycle.
tion proceeded smoothly on a gram scale even at a lower
catalyst loading (2.5 mol%). The double bond of 3aa could be
selectively reduced by Na/NH3 to give product 5.[10] Further-
more, the two benzyl groups of 3la were rapidly removed to
give 6 by treatment with CAN in MeOH/H2O at room
temperature; 6 could then be successfully trans-
formed into tetrahydroquinoline 7, which contains
À
an aminomethyl group, through sequential C N
coupling and hydrogenation. Furthermore, 1,2-dihy-
À
droquinoline 8, which resulted from the C N
coupling reaction, could be isolated and selectively
oxidized by [{RuCl2(benzene)}2]/TBHP to give the
corresponding 2-quinolinone derivative 9 in good
yield.[11] Both 7 and 9 are valuable precursors for the
synthesis of some bioactive compounds.[12]
Several experiments were conducted to gain
insight into the possible mechanism of this process.
As shown in Scheme 3, treatment of the cyclometa-
lated PdII complex I with allene 1a (1.5 equiv) in
=
CH3CN at 1208C resulted in rapid C C double bond
insertion to afford the expected p-allylpalladium
species II in an 85% yield [Scheme 3, Eq. (1)]. The
p-allylpalladium complex was fully characterized by
1H, 13C, and 31P NMR spectroscopy as well as high-
resolution mass spectrometry (see the Supporting
Information). Furthermore, an X-ray crystal struc-
ture of II was obtained,[9] which revealed that an Scheme 3. Preliminary mechanistic studies.
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Figure 1. Plausible reaction mechanism. Ligand omitted for clarity.
In summary, we have developed the first direct insertion
À
of an allene into an aminal C N bond to provide 1,3-diamines
À
through a palladium-catalyzed C N bond activation. A
unique cyclometalated PdII complex has been identified as
an efficient catalyst for this reaction. This new transformation
may be used for the coupling of a broad range of substrates
and thus represents a concise, operationally simple, and useful
method for the preparation of 1,3-diamines that are of
interest in synthetic organic chemistry. Mechanistic studies
suggest that the reaction proceeds via a p-allylpalladium
complex, which has promise as a valuable intermediate in
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Experimental Section
N,N,N’,N’-Tetrabenzylmethanediamine 2a (162.4 mg, 0.4 mmol),
propa-1,2-dienylbenzene 1a (58 mg, 0.5 mmol), [Pd(Xantphos)-
(CH2NBn2)](OTf) (20.8 mg, 0.02 mmol), and toluene (1.5 mL) were
added to a 25 mL flame-dried Young-type tube. The mixture was
degassed by a freeze–thaw method and stirred at 1208C for 12 h. The
solvent was removed under reduced pressure, and the residue was
purified by flash column chromatography on silica gel with diethyl
ether/petroleum ether (1:200–1:50) as the eluent, affording the
desired product 3aa as a white solid.
Received: March 27, 2014
Revised: May 6, 2014
Published online: && &&, &&&&
À
Keywords: allenes · aminals · C N activation · diamines ·
.
palladium
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diamino- and 2-amino-8-carbamoxyl-4-hydroxy-alkanoic acid/
amide, see: b) V. Rastti, H. Rꢂeger, J. K. Maibaum, R. Mah, M.
Grꢂtter, N. C. Cohen, U.S. Patent 5719141, 1998; for the
production and use of similar amine compounds, see: c) N.
Suzuki, K. Kato, S. Takekawa, J. Terauchi, S. Endo, U.S. Patent
6329389 B1, 2001.
[13] T. Bai, L. Xue, P. Xue, J. Zhu, H. H. Sung, S. Ma, I. D. Wiliams, Z.
Lin, G. Jia, Organometallics 2008, 27, 2614.
[14] The isolated cyclometalated PdII complex I has been charac-
terized by NMR spectroscopy. The p-allylpalladium complex II
could be trapped by some other free amines; see the Supporting
Information for details.
[11] H. Kato, T. Ishigame, N. Oshima, N. Hoshiya, K. Shimawaki, M.
Arisawa, S. Shuto, Adv. Synth. Catal. 2011, 353, 2676.
[12] a) V. Vecchietti, G. D. Clarke, R. Colle, G. Giardina, G. Petrone,
M. Sbacchi, J. Med. Chem. 1991, 34, 2624; for the synthesis of 2,9-
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
À
C N Activation
J. Hu, Y. Xie, H. Huang*
&&&& — &&&&
Palladium-Catalyzed Insertion of an
Allene into an Aminal:
Aminomethylamination of Allenes by
Break to link: The direct insertion of an
for the atom-economic synthesis of
a broad range of 1,3-diamines. The
À
allene into the C N bond of an aminal in
À
À
C N Bond Activation
the presence of a palladium catalyst is
described. This new method is concise
and operationally simple and can be used
reaction involves cleavage of the C N
bond, formation of a p-allylpalladium
intermediate, and nucleophilic addition.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!