Asymmetric intermolecular N-H insertion reaction of phenyldiazoacetates with anilines catalyzed by achiral dirhodium(II) carboxylates and cinchona alkaloids

Article abstract of DOI:10.3987/COM-10-11930

Asymmetric N-H insertion of phenyldiazoacetates with anilines catalyzed cooperatively by achiral dirhodium(II) carboxylates and cinchona alkaloids is described. A new catalytic system of dirhodium(II) tetrakis(triphenylacetate), Rh₂(TPA)_4<

Full text of DOI:10.3987/COM-10-11930

HETEROCYCLES, Vol. 81, No. 5, 2010
1149
HETEROCYCLES, Vol. 81, No. 5, 2010, pp. 1149 - 1155. © The Japan Institute of Heterocyclic Chemistry
Received, 24th February, 2010, Accepted, 9th March, 2010, Published online, 11th March, 2010
DOI: 10.3987/COM-10-11930
ASYMMETRIC INTERMOLECULAR N–H INSERTION REACTION OF
PHENYLDIAZOACETATES WITH ANILINES CATALYZED BY
ACHIRAL DIRHODIUM(II) CARBOXYLATES AND CINCHONA
ALKALOIDS
Hiroaki Saito,*a Taketo Uchiyama,a Muneharu Miyake,a Masahiro Anada,b
Shunichi Hashimoto,b Tohru Takabatake,a and Shinichi Miyairia
a
School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi,
Chiba, 274-8555, Japan
b
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812,
Japan
e-mail: saito.hiroaki@nihon-u.ac.jp
Abstract – Asymmetric N–H insertion of phenyldiazoacetates with anilines
catalyzed cooperatively by achiral dirhodium(II) carboxylates and cinchona
alkaloids is described.
A
new catalytic system of dirhodium(II)
tetrakis(triphenylacetate), Rh2(TPA)4, and dihydrocinchonine provides
phenylglycine derivatives in up to 71% ee.
The transition metal-catalyzed N–H insertion reaction of -diazocarbonyl compounds, which features
C–N bond formation with simultaneous creation of a stereogenic center, offers a potentially powerful
strategy for the synthesis of nitrogen-containing compounds.1 Consequently, much effort has been
directed towards the development of an enantioselective version of this catalytic process.2 While
exceptionally high levels of enantiocontrol in C–H insertions of -diazocarbonyl compounds have
already been achieved by the device of well-defined dirhodium(II) carboxylates and carboxamidates as
chiral catalysts,3 it was not until recently that a highly enantioselective N–H insertion process was
developed.4–6 In 2007, Zhou and co-workers demonstrated the first successful examples of intermolecular
N–H insertion of -alkyl--diazoacetates with anilines (up to 98% ee) using a chiral copper(I)–spiro
bis(oxazoline) catalyst.7 Thereafter, Fu and Lee reported enantioselective N–H insertion reactions of
tert-butyl aryldiazoacetates with benzyl or tert-butyl carbamates catalyzed by a planer-chiral
copper(I)-bipyridine complex with up to 95% ee.8

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HETEROCYCLES, Vol. 81, No. 5, 2010
In recent years, we have achieved high levels of enantiocontrol in C–H9 and Si–H10 insertion reactions by
developing dirhodium(II) carboxylate catalysts, which incorporate N-phthaloyl- or
N-benzene-fused-phthaloyl-(S)-amino acids as bridging ligands. As a logical extension of our studies, we
addressed the issue of enantiocontrol in Rh(II)-catalyzed N–H insertion reactions.
At the outset of this work, we explored the N–H insertion reaction of methyl phenyldiazoacetate (1a) with
aniline (2a) in dichloromethane using 0.5 mol% of Rh2(S-PTPA)4 (3a). The reaction proceeded smoothly
completion at room temperature within 1 h, giving phenylglycine derivative (4a) in 90% yield (Table 1,
Entry 1). The enantioselectivity of this reaction was determined to be 14% ee by HPLC analysis (Daicel
Chiralpak AD-H). The preferred absolute stereochemistry of 4a [[]22D +10.3° (c 2.16, THF) for 14% ee]
was established as S by comparing the sign of the optical rotation with the literature value [lit.,11 []26
D
+68.3° (c 0.32, THF) for > 98% ee of (S)-4a]. A survey of solvents revealed that dichloromethane was the
optimal solvent for this transformation.12 We next screened other chiral dirhodium(II) carboxylates,
Rh2(S-PTA)4 (3b), Rh2(S-PTV)4 (3c), and Rh2(S-PTTL)4 (3d), derived from N-phthaloyl-(S)-alanine,
-valine, and -tert-leucine, respectively. Although the reactions with 3b-d afforded 4a in high yields at
similar reaction rates as those observed with 3a, these catalysts led to much lower enantioselectivities
than Rh2(S-PTPA)4 (Entries 2–4).
Table 1.

1a
Enantioselective N H Insertion Reaction of Methyl Phenyldiazoacetate ( ) with Aniline
a)
2a
(
) Catalyzed by Chiral Rh(II) Carboxylates
N2
NHPh
Rh(II) catalyst (0.5 mol %)
CH2Cl2, 23 °C
O
N
+
PhNH2
Ph
CO2Me
R
Ph
CO2Me
(S)
2a
(1.2 equiv)
1a
H
4a
O
O
O
-Amino ester
4a
Rh Rh
c)
d)
b)
Time (h)
Entry Rh(II) catalyst
Ee (%) Confign
Yield (%)
Rh (S-PTPA) (
)
3a
)
1
90
83
86
89
14
7
S
S
R
S
1
3a
R = Bn: Rh2(S-PTPA)4 (
)
2
4
Rh (S-PTA) (
R = Me: Rh2(S-PTA)4 (3b)
R = iPr: Rh2(S-PTV)4 (3c)
3b
2
3
4
1
2
4
Rh2(S-PTV)4 (3c)
Rh (S-PTTL) (
1
1.5
1
t
3d
R = Bu: Rh2(S-PTTL)4 (
)
)
3d
1
2
4
a) The following procedure is representative (Entry 1): Rh (S-PTPA) ( ) (1.4 mg,
3a
2
4
0.001 mmol, 0.5 mol %) was added in one portion to a solution of
phenyldiazoacetate ( ) (35 mg, 0.20 mmol) and aniline ( ) (22 mg, 0.24 mmol,
1a 2a
1.2 equiv) in CH2Cl2 (2 mL) at 23 °C. After 1 h of stirring, the mixture was
concentrated and chromatographed on silica gel to af ford (43.2 mg, 90%) as a
4a
colorless needle. b) Isolated yield. c) Determined by HPLC (Daicel Chiralpak AD-
H). d) Determined by comparison of the sign of optical rotation with the literature
value.
In order to further improve the enantioselectivity, our efforts were centered on a double asymmetric
induction with the use of a chiral additive.13,14 To this end, we explored the N–H insertion reaction of 1a
with 2a in the presence of 1 mol % of 3a as a catalyst and 0.1 mol % of cinchonine (5a) as a chiral
additive. To our delight, the reaction proceeded at room temperature smoothly to provide (R)-4a in 86%

HETEROCYCLES, Vol. 81, No. 5, 2010
1151
Table 2.

2a
Enantioselective N H Insertion Reaction of Phenyldiazoacetates with Aniline ( ) Catalyzed by Rh(II)
Carboxylates and Cinchona Alkaloidsa)
Rh(II) catalyst (1 mol %)
N2
NHPh
cinchona alkaloid (0.1 mol %)
+
PhNH2
Ph
CO2R
Ph
*
CO2R
CH2Cl2, 23 °C
2a (1.2 equiv)
1
4
-Amino esters
Phenyldiazoacetates
R
c)
d)
b)
Time (h)
Rh(II) catalyst
Cinchona alkaloid
Entry
Ee (%) Conf ign
Yield (%)
1a CH3
1a CH3
Rh2(S-PTPA)4 (3a) cinchonine (5a)
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
86
87
84
88
86
88
94
83
84
91
83
99
88
93
72
31
37
55
53
<1
2
R
S
1
2
2
1
Rh (S-PTPA) ( ) cinchonidine (
)
3a
5b
2
4
CH3
1a
Rh (TPA) (
)
3e
cinchonine ( )
5a
R
3
12
12
10
10
9
2
4
1a CH3
1a CH3
Rh2(TPA)4 (3e)
Rh (TPA) (
cinchonidine (5b)
S
e)
S
4
)
quinine ( )
3e
4
5c
quinidine ( )
5
2
CH3
1a
Rh (TPA) (
)
3e
5d
dihydrocinchonine (5e)
6
2
4
1a CH3
1a CH3
Rh2(TPA)4 (3e)
Rh (TPA) (
59
58
36
24
36
62g)
63h)
67
59
R
7
8f)
)
3e
dihydrocinchonine (
dihydrocinchonine (
)
)
5e
22
1
R
2
4
CH3
1a
Rh (OAc) ( )
3f
5e
R
9
2
4
1a CH3
1a CH3
Rh2(oct)4 (3g)
Rh (piv) (
dihydrocinchonine (5e)
R
10
11
12
13
14
15
1
)
dihydrocinchonine (
)
)
3h
5e
5e
0.5
10
30
36
120
R
2
4
e)
e)
e)
e)
CH2CH3
1b
Rh (TPA) ( )
3e
dihydrocinchonine (
2
4
1c CH2C(CH3)3
1d CH2CH(CH3)2
Rh2(TPA)4 (3e)
Rh (TPA) (
dihydrocinchonine (5e)
)
dihydrocinchonine (
)
)
3e
5e
5e
2
4
CH(CH3)2
1e
Rh (TPA) ( )
3e
dihydrocinchonine (
2
4
a) The f ollowing procedure is representative (Entry 14): A solution of
(44 mg, 0.20 mmol) and (22 mg, 0.24 mmol,
2a
1d
1.2 equiv) in CH Cl (1 mL) was added dropwise to a solution of Rh (TPA) ( ) (2.8 mg, 0.002 mmol, 1 mol %) and
3e
2
2
dihydrocinchonin2e (5e) (0.06 mg, 0.0002 mmol, 0.1 mol %) in CH2Cl2 (1 mL)4at 23 °C. After 36 h of stirring, the mixture
was concentrated and chromatographed on silica gel to afford (53.3 mg, 93%) as a colorless needle. b) Isolated yield. c)
4d
Determined by HPLC (Daicel Chiralpak AD-H) unless otherwise stated. d) Determined by comparison of the sign of optical
rotation with the literature value. e) Not determined. f) The reaction was carried out using 1 mol % of 5e. g) Determined by
HPLC (Daicel Chiralcel OJ-H). h) Determined by HPLC (Daicel Chiralpak AS-H).
X
6'
X
R
R
6'
OH
OH
O
O
N
N
Rh Rh
H
N
N
H
5a
R = CH2=CH, X = H: cinchonine (
R = CH2=CH, X = MeO: quinine (5c)
R = Et, X = H: dihydrocinchonine (5e)
5b
)
3e
)
X = H: cinchonidine (
X = MeO: quinidine (5d)
R = Ph3C: Rh2(TPA)4 (
)
R = Me: Rh2(OAc)4 (3f)
3g
R = C7H15: Rh2(oct)4 (
)
t
3h
)
R = Bu: Rh2(piv)4 (
yield with 31% ee (Table 2, Entry 1). On the other hand, the use of cinchonidine (5b), a
pseudo-enantiomer of 5a, gave (S)-4a in 87% yield with 37% ee (Entry 2). Although the mechanistic
profile is not clear at this time, these results suggest that the chirality of cinchona alkaloids rather than
that of a dirhodium(II) catalyst dictates the stereochemical course of this process. Thus, we were intrigued
by the possibility of the combined use of achiral dirhodium(II) carboxylate catalysts and cinchona
alkaoids.15 We were gratified to find that switching the Rh(II) catalyst to Rh2(TPA)4 (3e), a dirhodium(II)
carboxylate complex incorporating bulky triphenylacetates as bridging ligands, gave even higher
enantioselectivities than those found with Rh2(S-PTPA)4 (55% ee and 53% ee, Entries 3 and 4). A survey

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HETEROCYCLES, Vol. 81, No. 5, 2010
of chiral additives revealed that dihydrocinchonine (5e) was the optimal additive for this transformation,
giving (R)-4a in 94% yield with 59% ee (Entry 7). Quinine (5c) and quinidine (5d), 6'-methoxy
substituted cinchona alkaloids, were not effective (Entries 5 and 6).16 Interestingly, increasing the amount
of 5e to 1 mol % had no beneficial effect on enantioselectivity, but the reaction required a significantly
longer time to reach completion (Entry 8).17 Using 5e as a chiral additive, we then evaluated the
performance of other dirhodium(II) carboxylate catalysts, Rh2(OAc)4 (3f), Rh2(oct)4 (3g), and Rh2(piv)4
(3h). The reactions with the use of these catalysts (3f-h) proceeded to completion much faster than the
catalysis with Rh2(TPA)4 (3e), although a considerable drop in enantioselectivity was observed (Entries
9–11). To further enhance the enantioselectivity, we examined the effect of an alkoxy group in the ester
moiety on the enantioselectivity. Higher enantioselectivities were obtained by increasing the steric bulk of
the ester alkyl group of phenyldiazoacetates (1b-d) with a significant reduction in the reaction rate
(62–67% ee, Entries 12–14); however, with the more sterically demanding isopropyl ester (1e), further
enhancement of enantioselectivity could not be attained (59% ee, Entry 15).18 Eventually, we assessed the
isobutyl ester (1d) as the ester of choice from the standpoint of enantioselectivity.
With optimized conditions in hand, we then investigated the scope of the reaction with respect to the
aniline component (Table 3). High yields and good enantioselectivities were consistently observed with
electron-withdrawing substituents such as chlorine and bromine at the para, meta, or ortho position on

Table 3. Enantioselective N H Insertion Reaction of Isobutyl Phenyldiazoacetate (1d)
with Anilines Catalyzed by Rh2(TPA)4 (3e) and Dihydrocinchonine (5e)
3e
Rh2(TPA)4 ( ) (1 mol %)
dihydrocinchonine (5e)
NHAr
N2
(0.1 mol %)
+
ArNH2
Ph
CO2
Ph
CO2
*
CH2Cl2, 23 °C
2
(1.2 equiv)
1d
4
-Amino esters
Aniline
R
b)
a)
Time (h)
Entry
Ee (%)
Yield (%)
4f
94
63
1
2
2
30
20
20
8
2b 4-CF3C6H4
2c 4-FC6H4
4g
4h
4i
92
93
91
93
92
90
98
91
91
93
91
68
70
3
4-ClC6H4
2d
71
4
2e 4-BrC6H4
2f 4-IC6H4
4j
69
5
10
3
4k
4l
67
6
3-ClC6H4
2g
56
7
2h 3-BrC6H4
2i 2-ClC6H4
4m
4n
4o
4p
4q
55c)
56c)
64
8
1
1
9
2-BrC6H4
2j
10
11
12
13
36
72
12
2k 4-MeC6H4
2l 3-MeC6H4
61
56
2-MeC6H4
2m
2n 4-MeOC6H4
No reaction
a) Isolated yield. b) Determined by HPLC (Daicel Chiralcel OD-H) unless otherwise stated.
c) Determined by HPLC (Daicel Chiralcel OJ-H).

HETEROCYCLES, Vol. 81, No. 5, 2010
1153
the benzene ring (Entries 1–9). It is notable that the enantioselectivity of 71% ee obtained with
p-bromoaniline (2e) is the highest reported to date for dirhodium(II) complex-catalyzed N–H insertions
(Entry 4).4,5 The reaction with anilines 2k-m bearing a methyl group at the para, meta, or ortho position
also afforded the corresponding phenylglycine derivatives (4o-q) in high yields and good
enantioselectivities (56–64% ee, Entries 10–12). However, no reaction occurred when p-anisidine (2n)
bearing an electron-donating methoxy group was used (Entry 13).
In summary, we have demonstrated that a new catalytic system of Rh2(TPA)4 and dihydrocinchonine is
effective for enantiocontrol in intermolecular N–H insertion reaction of phenyldiazoacetates with anilines.
Mechanistic and stereochemical studies on the present N–H insertion reaction are currently in progress.
ACKNOWLEDGEMENTS
This research was supported in part by a grant from the "Academic Frontier" Project for Private
Universities and a matching fund subsidy from MEXT (Ministry of Education, Culture, Sports, Science
and Technology) 2007–2010. We thank Dr. Koichi Metori (Analytical Center, School of Pharmacy,
Nihon University) for performing the mass measurement.
REFERENCES AND NOTES
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46, 9148.
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Chem. Rev., 1998, 98, 911; (b) G. A. Sulikowski, K. L. Cha, and M. M. Sulikowski, Tetrahedron:
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M. A. McKervey, and T. Ye, Chem. Commun., 1996, 1465.
5. Moody and co-workers reported that intermolecular N–H insertion reactions of methyl

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HETEROCYCLES, Vol. 81, No. 5, 2010
phenyldiazoacetate and dimethyl phenyldiazophosphonate with benzyl carbamates catalyzed by
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J. Moody, and A. G, Pepper, ARKIVOC, 2002, 8, 16.
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derivatives in up to 48% ee, see: S. Bachmann, D. Fielenbach, and K. A. Jørgensen, Org. Biomol.
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toluene, 84% yield, 7% ee (R); CHCl3, 78% yield, 11% ee (S); chlorobenzene, 69% yield, 10% ee
(S); 1,2-dichloroethane, 78% yield, 13% ee (S); THF, 87% yield, 2% ee (R).
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HETEROCYCLES, Vol. 81, No. 5, 2010
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Lett., 2007, 9, 4359; (d) W. Hu, X. Xu, J. Zhou, W.-J. Liu, H. Huang, J. Hu, L. Yang, and L.-Z.
Gong, J. Am. Chem. Soc., 2008, 130, 7782; (e) X. Zhang, H. Huang, X. Guo, X. Guan, L. Yang, and
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16. The product yields and enantioselectivities obtained with other chiral additives are as follows:
(–)-sparteine, 1.5 h, 82% yield, 5% ee (S); brucine, 22 h, 65% yield, 7% (R).
17. The reaction of 1a with 2a under identical conditions in the absence of Rh2(TPA)4 did not work even
after 24 h.
18. The N–H insertion reaction of tert-butyl phenyldiazoacetate with aniline under the same conditions
did not go to completion even after 1 week, and the corresponding phenylglycine derivative was
obtained in 58% yield with 57% ee.