Rhodium-catalyzed, three-component reaction of diazo compounds with amines and azodicarboxylates

Article abstract of DOI:10.1002/adsc.200404306

A novel, three-component C-N bond forming reaction is described. Reaction of diazo compounds with both azodicarboxylates and arylamines in the presence of dirhodium acetate catalyst gives good yields of the corresponding aminal with high selectivity and, in most cases, N-H insertion side products were suppressed. This is the first example of a C-N bond formation from the addition of ammonium ylides to azodicarboxylates.

Full text of DOI:10.1002/adsc.200404306

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Rhodium-Catalyzed, Three-Component Reaction of Diazo
Compounds with Amines and Azodicarboxylates
Haoxi Huang, Yuanhua Wang, Zhiyong Chen, Wenhao Hu*
Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan Province and Union Laboratory of Asymmetric
Synthesis, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, Peopleꢀs Republic of
China, and Graduate School of Chinese Academy of Sciences, Beijing, Peopleꢀs Republic of China
Fax: þ86-28-8522-9250, e-mail:huwh@cioc.ac.cn
Received: October 6, 2004; Accepted: January 10, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
ꢀ
Abstract: A novel, three-component C N bond
forming reaction is described. Reaction of diazo
compounds with both azodicarboxylates and aryl-
amines in the presence of dirhodium acetate catalyst
gives good yields of the corresponding aminal with
from a single synthetic step, the multi-component reac-
tion also provides chances to explore new pathways. In
this particular case, unsymmetrical aminals were formed
by a novel three-component reaction comprising dirho-
dium acetate-catalyzed diazo decomposition of ethyl di-
azoacetate in the presence of an arylamine and an azodi-
carboxylate 3 (Scheme 1). We began exploration of the
reaction by surveying the ability of different arylamines
to react with ethyl diazoacetate and DEAD (diethyl
azodicarboxylate). The three-components reaction pro-
ꢀ
high selectivity and, in most cases, N H insertion
side products were suppressed. This is the first exam-
ple of a C N bond formation from the addition of
ꢀ
ammonium ylides to azodicarboxylates.
ꢀ
ꢀ
Keywords: ammonium ylides; C N bond formation;
diazo compounds; dirhodium acetate; multi-compo-
nent reaction
ceeded smoothly to give aminal 4. N H insertion afford-
ing 5 was found to be a side reaction competing with the
desired process. As shown in Table 1, the reaction gave
ꢀ
almost entirely the C N bond three-component prod-
ucts 4 in good isolated yields.
In general, the yield of 4 and the ratio of 4/5 were not
affected by the substituent on the arylamines. In most
It is well known that metal-carbene complexes (or car- cases (Table 1, entries a–d), good isolated yields of 4
[11]
ꢀ
benoids) react with heteroatoms to form onium ylides. were obtained, and N H insertion
side products 5
The chemisty of onium ylides is an area of continuing in- were suppressed (4/5 >99/1). But a significant amount
terest. For example, carbonyl, phosphorus, sulfur, oxoni- of side product 5e was formed when 2,4-dinitroaniline
ꢀ
um and ammonium ylides, have been widely studied and was used (Table 1, entry e). The structure of the C N
utilized in organic synthesis.[1–4] In the study of ammoni- bond product 4b was confirmed as an aminal by single
um ylides derived from metal carbenoids, [2,3]-sigma- crystal X-ray analysis[10] (Figure 1).
tropic[5] and [1,2]-Stevens[6] rearrangements have been
We further examined the scope of this process with
shown to be powerful strategies for the synthesis of ni- different substitutions on the nitrogen atoms of azo
trogen heterocycles. In addition to rearrangement reac- compounds 3 (Table 2). EDA 1a and aniline 2b were em-
ꢀ
tions, we have recently unveiled a novel C C bond for-
mation by nucleophilic addition of ammonium ylides
to imines and arylaldehydes, whereby the ammonium
ylides were in situ generated from phenyl diazoacetate
and arylamines.[7]
ꢀ
Based on the mechanistic interpretation of the C C
bond formation, we anticipated that this novel strategy
would be similarly applicable to other electrophiles
and diazo compounds. Herein, we present the first ex-
ample of a C N bond formation reaction[8] of ammoni-
ꢀ
um ylides with azodicarboxylates serving as electro-
philes.
In addition to constructing complex chemical struc-
tures through selective multiple-bond formation[9] Scheme 1.
Adv. Synth. Catal. 2005, 347, 531–534
DOI: 10.1002/adsc.200404306
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Haoxi Huang et al.
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Table 1. Three-component reaction of EDA (1a) with aryl-
amine (2) and DEAD (3a) catalyzed by dirhodium acetate.[a]
Entry
Ar
Yield [%][b]of
Product 4a–e
Ratio
of 4:5[c]
a
b
c
d
e
p-OCH3C6H4 (2a)
C6H5 (2b)
p-ClC6H4 (2c)
p-NO2C6H4 (2d)
2,4-NO2C6H4 (2e)
61 (4a)
75 (4b)
72 (4c)
68 (4d)
60 (4e)
>99: 1
>99: 1
>99: 1
>99: 1
85: 15
[a]
Reaction conditions: to a refluxing CH2Cl2 mixture of aryl-
amine (2, 1.1 equivs.), DEAD (3a, 1.1 equivs.) and
Rh2(OAc)4 (0.01 equivs.) was added ethyl diazoacetate
(1a, 1.0 equiv.) via a syringe pump over 1 h.
Isolated yield of 4 after column chromatography purifica-
tion.
Figure 1. X-Ray structure of aminal 4b.
[b]
[c]
1
Determined by H NMR of crude product.
Table 2. Effect of the nitrogen substitution of the electro-
phile on the three-component reaction.[a]
Scheme 2.
Entry
R
Yield [%][b] Ratio of 4:5b[c]
of Product
4b, 4f–g
a
b
c
d
e
CO2Et (3a)
CO2CH(CH3)2 (3b) 70 (4f)
CO2Bu-t (3c)
C(CH3)2CN (3d)
Ph (3e)
75 (4b)
>99: 1
>99: 1
>99: 1
59 (4g)
–
–
0: 100
0: 100
[a]
Reaction conditions: same as Table 1.
Same as in Table 1.
Same as in Table 1.
[b]
[c]
Scheme 3.
ophilic addition of the ammonium ylide to the azodicar-
ployed to generate ammonium ylides, and 1 mol % boxylate, since a more electron-deficient azo compound
Rh2(OAc)4 was used as the catalyst.
As shown in Table 2, the reaction proceeded well with
3 is a better electrophile.
The reaction was further expanded to other a-diazo
azodicarboxylates (Table 2, entries a–c), but not with compounds. Reaction of 2-diazo-1-phenylethanone 1b,
2,2’-azobiisobutylnitrile (AIBN) (Table 2, entry d) and aniline 2b and DEAD 3a in the presence of 1%
ꢀ
ꢀ
azobenzene (Table 2, entry e). The yields of C N bond Rh2(OAc)4 successfully afforded the desired C N
forming products gradually decreased when the more bond formation product 4h in 90% yield after column
sterically hindered ester groups were attached to azodi- chromatographic purification (Scheme 2).
carboxylates 3, while still maintaining a high ratio of 4/
Interestingly, with methyl phenyldiazoacetate 1c, a fa-
ꢀ
5b (Table 2, entries a–c). These results revealed that vorable diazo compound for the three-component C C
electron-withdrawing groups in 3 were critical for the bond formation,[7] the reaction did not give the desired
ꢀ
success of the reaction. This is consistent with a pro- C N bond product but the a-imino ester product 6a in-
posed reaction pathway in which 4 is formed via a nucle- stead (Scheme 3).
532
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Adv. Synth. Catal. 2005, 347, 531–534

Reaction of Diazo Compounds with Amines and Azodicarboxylates
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compounds as well as electronic features of the aryl-
amines. Detailed investigations of this transformation
will be reported in a separate publication.
In conclusion, we have unraveled a novel, three-com-
ponent reaction for the preparation of aminals in good
ꢀ
isolated yields whereby N H insertion side products
were suppressed. The aminal products may be used in
the synthesis of densely functional a-hydrazino acid
frameworks which represent an important class of com-
pounds used for chemical modification of peptide back-
bones.[12]
Scheme 4.
Experimental Section
General Methods
Melting points are uncorrected. NMR spectra were recorded
on a Bruker 300 MHz spectrometer. Mass spectra (EI) were re-
corded on a VG7070E spectrometer. Elemental analyses were
performed on a Carlo Erba-1106 instrument. Dichlorome-
thane was distilled over calcium hydride. Toluene was distilled
over sodium benzophenone ketyl.
Scheme 5.
Ethyl [N,N’-Bis(ethoxycarbonyl)hydrazino]-
phenylaminoacetate (4b)
To 10 mL of a CH2Cl2 solution of Rh2(OAc)4 (3.6 mg,
0.0081 mmol), aniline 2b (82.8 mg, 0.89 mmol) and DEAD 3a
(154.8 mg, 0.89 mmol) was added ethyl diazoacetate 1a
(92.2 mg, 0.81 mmol) in 5 mL of CH2Cl2 under an argon atmos-
phere via a syringe pump over 1 h under reflux. After comple-
tion of the addition, the reaction mixture was cooled to room
temperature. The solvent was removed and a portion of the
crude mixture was subjected to 1H NMR analysis for determi-
nation of the product ratio. The crude product was purified by
flash chromatography on silica gel by using 10% EtOAc-light
petroleum ether as eluent to give 4b as a solid, yield: 75%.
Rf ¼0.35 (30% EtOAc/light petroleum); mp 97.8–98.98C; 1H
NMR (300 MHz, CDCl3): d¼7.21 (m, 2H), 6.81 (m, 1H),
6.74 (m, 2H), 6.21 (br, 2H), 5.03 (s, 1H), 4.33 (m, 4H), 4.14 (q,
J¼7.1 Hz, 2H), 1.34 (t, J¼7.1 Hz, 3H), 1.25 (m, 6H); 13C
Scheme 6.
¼
NMR (75 MHz, CDCl3): d¼167.8, 155.7 (two C O carbons),
A similar reaction was observed with methyl diazo-
malonate. The reaction with aniline and DEAD gener-
ated the a-imino ester 6b in 72% yield (Scheme 4).
However, the electronic features of the aniline 2 dra-
matically affected the reaction pathway. Treatment of
diazomalonate 1d and DEAD 3a with more electronic
deficient aniline, 4-nitroaniline 2d, gave the desired
143.7, 129.6, 119.5, 113.9, 67.1, 63.2, 62.7, 62.4, 14.6, 14.4, 14.2;
EI-MS (70 eV): m/z (rel. intensity)¼353 [Mþ, 4], 280 [(Mꢀ
COOEt)þ, 7], 178 [C10H12NO2þ, 84], 104 [C7H6Nþ, 100], 77
[C6H5þ, 89]; anal. calcd. for C16H23N3O6: C 54.38, H 6.56, N
11.89; found: C 54.34, H 6.57, N 11.88.
A single crystal 4b was grown in hexane and ethyl acetate
solution. Products 4a–4h, 6a, 6b and 7 were obtained by the
same procedure.
ꢀ
C N bond product 7 in 50% yield (Scheme 5).
Further investigations indicated that a-imino esters 6
were formed from a hydrazine elimination of the three-
component products. Treatment of the three-compo-
nent product 7 in refluxing toluene for 24 hours com-
pletely converted it to a-imino ester 6c and hydrazine
8 (Scheme 6). This transformation was likely dependent
on the stability of the aminal as well as the resulting
Dimethyl 2-(4-Nitrophenylimino)-malonate (6c)
A toluene solution (8.0 mL) of 7 (40 mg. 0.09 mmol) was re-
fluxed for 24 h. The reaction mixture was cooled to room tem-
perature. The solvent was removed, and a portion of the crude
mixture was subjected to 1H NMR analysis for determination
imines. The stability was affected by the nature of diazo of the conversion. The crude product was purified by flash
Adv. Synth. Catal. 2005, 347, 531–534
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Haoxi Huang et al.
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chromatography on silica gel by using 15% EtOAc-light petro-
leum ether as eluent to give 6c; yield: 23.4 mg (0.088 mmol,
98%). Rf ¼0.53 (30% EtOAc/light petroleum); 1H NMR
(300 MHz, CDCl3): d¼8.24 (m, 2H), 7.04 (m, 2H), 4.01 (s,
3H), 3.70 (s, 3H); 13C NMR (75 MHz, CDCl3): d¼161.3,
160.8, 153.4, 152.9, 146.1, 125.0, 119.5, 54.1, 53.2; EI-MS
(70 eV): m/z (rel. intensity)¼266 [(Mþ1)þ, 267]; anal. calcd.
for C11H10N2O6: C 49.63, H 3.79, N 10.52; found: C 50.01, H
3.95, N 10.40.
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[7] Y. H. Wang, Y. X. Zhu, Z. Y. Chen, A. Mi, W. H. Hu,
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ꢀ
[8] For C N bond formation, see: a) T. D. Quach, R. A. Ba-
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Acknowledgements
[9] For multiple-bond formation, see: a) P. Wipf, C. R. J. Ste-
phenson, K. Okumura, J. Am. Chem. Soc. 2003, 125,
14694; b) I. Ugi, Pure Appl. Chem. 2001, 73, 187; c) A.
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We are grateful for financial support from the Chinese Academy
of Sciences and National Science Foundation of China (Grant
No. 20202011). We thank Prof. Kaibei Yu of Chengdu Institute
of Organic Chemistry for the X-ray measurements.
References and Notes
[10] a) Crystal data for 4b: C16H23N3O6, MW¼353.37, Mono-
clinic, space group Cc, a¼9.514(1) ꢂ, b¼21.178(3) ꢂ,
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3
¼
¼
c¼9.742(1) ꢂ, b¼109.4418, V
1851.1(4) ꢂ , Z
4,
1calcd. ¼1.268 Mg/m3, F(000)¼752, l
0.71073 ꢂ, T¼
¼
292(2) K, m (Mo-Ka)¼0.098 mm–1. Data for the struc-
ture were collected on a Siemens P-4X four-circle dif-
fractometer. Intensity measurements were performed
on a crystal (dimensions 0.56ꢁ0.28ꢁ0.28 mm) in the
range 3.84<2q<55.988. Of the 2548 measured reflec-
tions, 2379 were independent (Rint ¼0.0088). The struc-
ture was solved by direct methods (SHELXS-97) and re-
fined by full-matrix least squares on F2. The final refine-
ments converged at R1 ¼0.0407 for I>2s(I), wR2 ¼
0.0874 for all data. The final difference Fourier synthesis
gave a min/max residual electron density of –0.253/þ
0.203 e ꢂ–3; b) CCDC-238733 contains the supplementa-
ry crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/re-
trieving.html [or from the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB21EZ,
UK; fax (þ44) 1223-336-033; or deposit@ ccdc.cam.
ac.uk].
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534
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Adv. Synth. Catal. 2005, 347, 531–534