Asymmetric N-H Insertion of secondary and primary anilines under the catalysis of palladium and chiral guanidine derivatives

Article abstract of DOI:10.1002/anie.201308501

Efficient enantioselective N-H insertion reactions of secondary and primary anilines were catalyzed by palladium(0) in combination with chiral guanidine derivatives. A broad range of substituted anilines were tolerated, and the corresponding products were obtained in high yield (up to 99 %) with good enantioselectivity (up to 94 % ee) under mild reaction conditions. The N-H insertion mechanism was examined by the study of kinetic isotope effects, control experiments, HRMS, and spectroscopic analysis. Hidden talents: Chiral guanidine derivatives were developed as useful ligands for the enantioselective insertion of carbenoids into the N-H bonds of secondary and primary anilines in combination with palladium(0), which was not previously known to promote asymmetric N-H insertion (see scheme; dba=dibenzylideneacetone). The N-H insertion mechanism was examined by kinetic isotope studies, control experiments, HRMS, and spectroscopic analysis. Copyright

Full text of DOI:10.1002/anie.201308501

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Angewandte
Communications
DOI: 10.1002/anie.201308501
Asymmetric Catalysis
À
Asymmetric N H Insertion of Secondary and Primary Anilines under
the Catalysis of Palladium and Chiral Guanidine Derivatives**
Yin Zhu, Xiaohua Liu,* Shunxi Dong, Yuhang Zhou, Wei Li, Lili Lin, and Xiaoming Feng*
À
Abstract: Efficient enantioselective N H inser-
tion reactions of secondary and primary anilines
were catalyzed by palladium(0) in combination
with chiral guanidine derivatives. A broad range
of substituted anilines were tolerated, and the
corresponding products were obtained in high
yield (up to 99%) with good enantioselectivity
(up to 94% ee) under mild reaction conditions.
À
The N H insertion mechanism was examined by
the study of kinetic isotope effects, control
experiments, HRMS, and spectroscopic analysis.
T
he enantioselective insertion of metal car-
À
Scheme 1. Possible mechanisms of the asymmetric N H insertion reaction.
[1]
À
benes into N H bonds provides an attractive
route for the synthesis of chiral a-amino acids.[2]
process (Scheme 1).[13] Only when the stereodetermining 1,2-
H shift occurs in a concerted manner or in a metal-associated-
ylide pathway[4b,5–7] (path A) or is assisted by a chiral proton-
transfer shuttle[9] (path B) can high enantioselectivity be
achieved. Alternatively, the intermediacy of a free ylide from
which the chiral catalyst has dissociated would result in low
enantioselectivity (path C).[1c,5b] As compared with the reac-
À
Remarkable progress on asymmetric N H insertion reactions
of primary amines with a-diazoesters[3] has been made.[4]
Copper(I) and dirhodium(II) complexes are the most widely
used catalysts for this type of reaction. A pioneering study of
McKervey and co-workers demonstrated the ability of chiral
rhodium(II) carboxylates to catalyze asymmetric intramolec-
ular N H insertion reactions. Copper complexes of well-
[4a]
À
defined chiral ligands, such as spiro bisoxazolines,[5] bipyr-
idines,[6] and binol derivatives,[7] were later developed to
achieve high enantioselectivity (Scheme 1, path A). Recently,
intriguing strategies involving the cooperative catalysis of
dirhodium(II) carboxylates with cinchona alkaloids[8a] or
chiral spiro phosphoric acids[9] were also exploited
(Scheme 1, path B). A further, earlier example of a sil-
ver(I)-mediated reaction proceeded with moderate enantio-
selectivity.[4b] Although palladium has been applied increas-
ingly in carbenoid chemistry,[10] its use in catalytic asymmetric
tion of primary amines, the N H insertion of secondary
À
amines, such as N-alkyl anilines, would generate a more stable
ylide intermediate bearing alkyl/aryl substituents at the
nitrogen atom. It is reasonable to hypothesize that the
relatively high stability of ammonium ylides might facilitate
the degeneration of the catalyst-associated ylide to a free
ylide and thus lead to poor enantioselectivity.[5b] On the other
hand, the more nucleophilic nitrogen atom is inclined to
coordinate strongly with the metal center, which may lead to
À
the inactivation of the catalyst. Less asymmetric N H
À
X H insertion reactions (X = heteroatom) has rarely been
insertion of secondary amines[14] with a-diazoesters has yet
been developed with satisfactory enantioselectivity.[4a,b,5a,7]
The highest enantioselectivity observed for the asymmetric
reported.[1f,11,12]
À
The general consensus on the N H insertion mechanism is
that the electron-deficient metal carbene inserts into the N H
bond according to a stepwise ylide-generation/proton-shift
À
À
N H insertion of N-methylaniline was the formation of the
product with 70% ee.[7] Thus, the development of a new and
À
efficient catalytic system for the asymmetric N H insertion of
secondary amines is of interest and is challenging.
[*] Y. Zhu, Prof. Dr. X. H. Liu, Dr. S. X. Dong, Y. H. Zhou, W. Li,
Dr. L. L. Lin, Prof. Dr. X. M. Feng
Chiral guanidine derivatives have been developed as
useful organocatalysts in recent years.[15] Our research group
has dedicated itself to the design of bifunctional chiral
guanidine–amide organocatalysts and has thereby discovered
several efficient reactions.[16] Guanidine has abundant coor-
dination modes with various metals;[17] however, neutral
guanidine derivatives have been overlooked as ligands and
have received a disproportionately low amount of atten-
tion.[18] In 2005, Anders and co-workers reported a unique
example of an asymmetric Henry reaction promoted by
a chiral guanidine–zinc(II) complex; however, the product
Key Laboratory of Green Chemistry and Technology
Ministry of Education, College of Chemistry, Sichuan University
Chengdu 610064 (China)
E-mail: liuxh@scu.edu.cn
xmfeng@scu.edu.cn
[**] We thank the National Natural Science Foundation of China
(21222206, 21332003, and 21321061), the National Basic Research
Program of China (973 Program: 2010CB833300), and the Ministry
of Education (NCET-11-0345) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308501.
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was formed with only 2% ee.[19a,b] Herein, we report our
compared with 4a (Table 1, entries 5–7). Intriguingly,
preliminary results on the combination of chiral guanidine
a decrease in the amount of guanidine 4a to 2 mol% led to
slightly higher enantioselectivity without loss of yield
(90% ee and 86% yield; Table 1, entry 8). The requirement
of an excess amount of palladium might be partly attributable
to deactivation by the precipitation of Pd0. Further lowering
of the amount of the guanidine derivative to 1 mol% led to
the formation of the insertion product in maintained yield but
with a somewhat lower ee value (87% ee; Table 1, entry 9).
Various substituted secondary anilines were tested in the
derivatives with Pd0 as catalysts for asymmetric N H
À
insertion reactions of both secondary and primary amines.
Good yields and enantioselectivities were observed for the
synthesis of various substituted anilines.
À
The insertion of ethyl 2-diazopropanoate (2a) into the N
H bond of N-methylaniline (1a) in dichloromethane at 308C
was chosen as the model reaction. We initiated our inves-
tigation with a screening of several metal catalysts in the
presence of chiral guanidine 4a derived from (S)-tetrahy-
droisoquinoline-3-carboxylic acid (Table 1, entries 1–4). With
CuCl, product 3a was obtained with acceptable enantiose-
lectivity (71% ee) in up to 99% yield (Table 1, entry 1).
Whereas Rh2(OAc)4 gave comparable enantioselectivity to
À
asymmetric N H insertion reaction under the optimized
conditions (Table 1, entry 8). The influence of the electronic
properties of the N-methylaniline on the enantioselectivity of
the reaction was evaluated by varying the substitution of the
aryl group. Generally, the use of substrates with electron-
withdrawing groups gave slightly higher enantioselectivities
than the use of those with electron-donating groups (Table 2,
entries 1–6 and 12 versus entries 7–11). The position of the
substituent on the aryl group had no clear influence on the
enantioselectivity of the reaction. Moreover, N-methylnaph-
thalen-1-amine, N-ethylaniline, N-allylaniline, and N-benzyl-
aniline were well tolerated in terms of enantioselectivity when
the l-proline-derived guanidine 4c was used (Table 2,
Table 1: Effect of various reaction parameters.[a]
Entry
Metal precursor
4
x
Yield [%][b]
ee [%][c]
[a]
1[d]
2
CuCl
4a
4a
4a
4a
4b
4c
4d
4a
4a
10
10
10
10
10
10
10
2
99
60
99
86
75
74
75
86
86
71
70
0
88
72
86
88
À
Table 2: Scope of the N H insertion of secondary anilines.
Rh2(OAc)4
Fe(ClO4)2·6H2O
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
3[d]
4
5
6
7
8
Entry
R1
R2
R3
R4
Yield [%][b]
ee [%][c]
90 (S)[e]
87
1
2
3
4
5
6
7
8
2-FC6H4
3-FC6H4
4-FC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
3-MeC6H4
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
4-CF3OC6H4
1-naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
allyl
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Et
Et
Et
Et
Me
tBu
Bn
Et
77 (3b)
77 (3c)
80 (3d)
82 (3e)
75 (3 f)
80 (3g)
70 (3h)
75 (3i)
65 (3j)
82 (3k)
91 (3l)
93 (3m)
59 (3n)
60 (3o)
24 (3p)
66 (3q)
50 (3r)
55 (3s)
20 (3t)
75 (3u)
79 (3v)
85 (3w)
85 (3a)
88
91
91
93
92
92
90
87
92
90
87
93
88
92
94
85
92
90
90
90
81
93
90
9
1
[a] Unless otherwise noted, reactions were carried out with the metal
precursor (5 mol%), 4 (x mol%), 1a (0.10 mmol), and 2a (0.20 mmol,
2.0 equiv) in CH2Cl2 (1.0 mL) at 308C for 5 h. [b] Yield of the isolated
product as based on aniline 1a. [c] The ee value was determined by HPLC
analysis on a chiral stationary phase. [d] The amount of the metal
precursor was 10 mol%. [e] The absolute configuration of 3a was
determined by comparison of the optical rotation with that given in
Ref. [20], as shown in the Supporting Information. dba=dibenzyli-
deneacetone.
9[d]
10
11[e]
12
13[d]
14[d]
15[d,f]
16[d,g]
17[d]
18[d]
19[d]
20[f]
21[d]
22[d]
23[h]
nPr
Me
Me
Me
Me
Ph
CuCl, but a lower yield, Fe(ClO4)2·6H2O showed excellent
reactivity, but the product was obtained as a racemate
(Table 1, entries 2 and 3). A remarkable improvement in
enantioselectivity was observed when [Pd2(dba)3] was used as
the metal precursor (86% yield, 88% ee; Table 1, entry 4).
Although l-ramipril-derived guanidine 4d was superior to l-
pipecolic acid derived 4b and l-proline-derived 4c, no
improvement in enantioselectivity or yield was observed as
[a] Unless otherwise noted, reactions were carried out with [Pd2(dba)3]
(5 mol%), 4a (2 mol%), 1 (0.10 mmol), and 2 (0.20 mmol, 2.0 equiv) in
CH2Cl2 (1.0 mL) at 308C for 5 h. [b,c] See Table 1. [d] Guanidine 4c was
used. [e] The reaction was carried out at 158C. [f] The reaction was
carried out in CH2Cl2 (2.0 mL). [g] The reaction was carried out at 358C.
[h] The reaction was carried out with [Pd2(dba)3] (5 mol%), 4a (2 mol%),
1a (7.0 mmol), and 2a (14.0 mmol, 2.0 equiv) in CH2Cl2 (70 mL) at 308C
for 12 h. Bn=benzyl.
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entries 13–17). The lower yields might be due to an adverse
effect of steric hindrance on nucleophilic addition to the
electron-deficient carbene intermediate. Next, the substitu-
ents on the a-diazoester were investigated (Table 2,
entries 18–22). The length of the a-alkyl group had a remark-
able effect on the yield. When ethyl a-diazobutyrate was used,
A competition experiment between aniline and N-methyl-
aniline under identical reaction conditions indicated a much
higher reactivity of aniline (Scheme 2a). We speculated that
the steric hindrance of the secondary amine was disadvanta-
geous for nucleophilic addition to carbene species; thus, the
yield was lower than that observed for the primary amine
À
the N H insertion product was obtained in 55% yield with
90% ee (Table 2, entry 18). A low yield was observed for the
corresponding reaction with ethyl 2-diazopentanoate,
although the enantioselectivity was maintained (90% ee,
20% yield; Table 2, entry 19). The ester group could be
changed from an ethyl to a methyl group without deterio-
ration of the enantioselectivity (Table 2, entry 20). The
reaction of tert-butyl-substituted 2-diazopropanoate pro-
ceeded well in 79% yield with 81% ee (Table 2, entry 21).
Furthermore, benzyl 2-diazopropanoate was transformed into
the corresponding product with excellent results (93% ee,
85% yield; Table 2, entry 22). Unfortunately, in attempts at
À
the N H insertion of a-aryl- and other a-alkyl-substituted
diazoesters, the aniline substrate was not consumed under the
present conditions. A gram-scale synthesis was performed
under the optimized reaction conditions, and the desired
product 3a was obtained without loss of yield or enantiose-
lectivity (Table 2, entry 23; 85% yield, 90% ee).
À
Subsequently, we examined the asymmetric N H inser-
tion reactions of several primary anilines with the catalytic
system of [Pd2(dba)3] and guanidine 4a. Most of the
substituted anilines in Table 3 could be smoothly converted
into the corresponding products in good yields (83–98%) with
high ee values (87–92%; Table 3, entries 1–6). In the case of 2-
Scheme 2. Control experiments.
(Table 2 versus Table 3). No kinetic isotope effect (kH/kD =
1.0) was detected in the guanidine–palladium(0)-catalyzed
[a]
À
Table 3: Scope of the N H insertion of primary anilines.
À
N H insertion reaction of a-diazoester 2a with either N-
methylaniline (1a)[23] or aniline (5a; Scheme 2b), in contrast
À
to the N H insertion of anilines with a chiral copper(I)
catalyst.[5b,6] This result implied that a proton transfer was not
involved in the rate-limiting step in the current system.
Decomposition of the a-diazoester and nucleophilic addition
of the amine to the metal carbene might account for the
reaction process. Hence, high enantioselectivity was gained
through simultaneous intramolecular 1,2-proton transfer[14c,24]
and dissociation of the chiral catalyst. Otherwise, a stabilized
free ammonium ylide and oxygen-associated intermediate
Entry
R
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
Ph
98 (6a)
97 (6b)
83 (6c)
85 (6d)
88 (6e)
96 (6 f)
99 (6g)
90 (S)[d]
92
92
90
87
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
2-BrC6H4
88
82
À
would cause formation of the N H insertion product with
lower enantioselectivity.
[a] Reactions were carried out with [Pd2(dba)3] (5 mol%), 4a (2 mol%), 5
(0.10 mmol), and 2a (0.20 mmol, 2.0 equiv) in CH2Cl2 (2.0 mL) at 358C
for 5 h. [b,c] See Table 1. [d] The absolute configuration of 6a was
determined by comparison of the optical rotation with that given in
Refs. [5a,21].
À
The detailed mechanism of the N H insertion catalyzed
by the combination of a guanidine derivative and palladium is
not yet clear, but some observations may offer insight.
Considering the strong Brønsted basicity of guanidine,[15b,f,25]
we suspected that it could coordinate with Pd[19c] instead of
acting as a chiral proton-transfer shuttle.[9] The action of
palladium was probed by ESI HRMS analysis. MS peaks
observed at m/z 206.9566, 441.0638, and 655.2812 corre-
sponded to [Pd0 + (2aÀN2) + H+]+, [Pd0 + (2aÀN2) + dba +
H+]+ and [Pd0 + 4a + H+]+, respectively, and confirmed the
generation of palladium–carbene species and the coordina-
tion of the guanidine with Pd0. Next, the catalytically active
oxidation state of palladium in the system was investigated
bromoaniline, an excellent yield was observed with slightly
lower enantioselectivity (99% yield, 82% ee; Table 3,
entry 7). Interestingly, the correlation of the log(er) values
(er is the ratio of enantiomers) of the products with the
Hammett substituent constants[22] of the corresponding para-
substituted aniline followed a linear relationship, but an
opposite trend between secondary and primary amines was
observed (see the Supporting Information for details).
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through additional control experiments. In the presence of
guanidine 4a, palladium(II) compounds, such as PdCl2,
Pd(OAc)2, [PdCl2(CH3CN)2], and [Pd2Cl2(allyl)2], promoted
the reaction of 1a with 2a either in poor yield or with low
enantioselectivity. Taking these results together, we identified
the Pd0 complex as the active species.
desired. The catalytic system is based on the unique proper-
ties of the chiral guanidine ligand and palladium–carbene
chemistry, and provides new opportunities for novel trans-
formations. Further study of the reaction mechanism and
extensive exploration of the use of the catalyst system for
other asymmetric reactions are under way.
Fluorescence and UV/Vis absorption spectroscopy
experiments were also used to analyze the catalytic species.
Complete fluorescence quenching was observed upon the Experimental Section
General procedure: A mixture of [Pd2(dba)3] (4.6 mg, 0.005 mmol,
5 mol%) and guanidine 4a (1.1 mg, 0.002 mmol, 2 mol%) was
weighed into test tube under an inert atmosphere. CH2Cl2
addition of [Pd2(dba)3] to the solution of 4a (Figure 1a). CuCl
and Rh2(OAc)4 lowered the fluorescence intensity to a certain
a
(1.0 mL) was then added, followed by N-methylaniline (1a; 10.8 mL,
10.7 mg, 0.1 mmol) and then a-diazoester 2a (24.0 mL, 25.6 mg,
0.2 mmol). The resulting mixture was stirred for 5 h at 308C, and the
product 3a was purified by flash chromatography (Rf = 0.5, petroleum
ether/Et2O 4:1).
Received: September 30, 2013
Revised: December 4, 2013
Published online: January 8, 2014
À
Keywords: a-diazoesters · guanidine derivatives · N
H insertion · palladium · secondary amines
.
À
[1] For representative reviews of the catalyzed N H insertion of
diazo compounds, see: a) M. P. Doyle, M. A. McKervey, T. Ye,
Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds, Wiley, New York, 1998, chap. 3 and 8; b) T. Ye,
M. A. McKervey, Chem. Rev. 1994, 94, 1091 – 1160; c) C. J.
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Res. 2012, 45, 1365 – 1377; f) D. Gillingham, N. Fei, Chem. Soc.
Rev. 2013, 42, 4918 – 4931; for the first example of asymmetric
À
vinylogous N H insertion, see: g) X. F. Xu, P. Y. Zavalij, M. P.
Doyle, Angew. Chem. 2012, 124, 9967 – 9971; Angew. Chem. Int.
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[2] For selected reviews, see: a) R. M. Williams, in Synthesis of
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Figure 1. a) Fluorescence spectra of 4a at 4ꢀ10À3 m with or without
a metal precursor (4ꢀ10À3 m) in CH2Cl2; b) UV spectra of 4a at
2ꢀ10À3 m with or without a metal precursor (2ꢀ10À3 m) in CH2Cl2.
À
[4] For early enantioselective N H reactions of primary amines,
see: a) C. F. Garcꢁa, M. A. McKervey, T. Ye, Chem. Commun.
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degree. Furthermore, the maximum UV absorption wave-
length of the mixture of 4a and [Pd2(dba)3] was shifted toward
a longer wavelength (from 226 nm for 4a to 230 nm), and the
addition of CuCl or Rh2(OAc)4 to 4a uniformly led to
a redshift (Figure 1b). These observations indicated that
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In summary, we have developed a new kind of chiral
À
complex catalyst for the highly enantioselective N H inser-
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À
dium(0) could also be active in the asymmetric N H
À
the N H insertion of anilines under the catalysis of cinchona
insertion. Moreover, a chiral guanidine derivative was for
the first time successfully developed as a fascinating ligand,
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