Pyridine group assisted addition of diazo-compounds to imines in the 3-CC reaction of 2-aminopyridines, aldehydes, and diazo-compounds

Article abstract of DOI:10.1021/ol400148r

A novel three-component coupling (3-CC) reaction of 2-aminoazines, aromatic aldehydes, and diazo-compounds producing polyfunctional β-amino-α- diazo-compounds has been developed. The reaction features an unprecedented heterocycle-assisted addition of a di

Full text of DOI:10.1021/ol400148r

ORGANIC
LETTERS
2013
Vol. 15, No. 4
956–959
Pyridine Group Assisted Addition of
Diazo-Compounds to Imines in the 3‑CC
Reaction of 2‑Aminopyridines, Aldehydes,
and Diazo-Compounds
Anton V. Gulevich, Victoria Helan, Donald J. Wink, and Vladimir Gevorgyan*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607, United States
vlad@uic.edu
Received January 18, 2013
ABSTRACT
A novel three-component coupling (3-CC) reaction of 2-aminoazines, aromatic aldehydes, and diazo-compounds producing polyfunctional
β-amino-R-diazo-compounds has been developed. The reaction features an unprecedented heterocycle-assisted addition of a diazo-compound to
an imine. The obtained diazoesters were efficiently converted into valuable heterocycles as well as β-amino acid derivatives.
Nucleophilic addition of diazo-compounds to activated
imines bearing strong electron-withdrawing groups at
the nitrogen atom represents an important method of
CÀC bond formation, employed in the synthesis of
β-amino acid derivatives, as well as other valuable products
(Scheme 1, eq 1).1,2 Thus, Wang and co-workers reported
a base-promoted reaction of N-SO2R imines with diazo-
esters producing β-amino-R-diazocarbonyl compounds.3
Terada, Maruoka, and others reported Brønsted acid
catalyzed addition of diazo-compounds to N-COAr and
N-Boc imines (eq 1).4 However, these efficient methods
are limited to activated imines only.
(1) For selected recent reviews on reactivity of diazo-compounds, see:
(a) Zhao, X.; Zhang, Y.; Wang, J. Chem. Commun. 2012, 48, 10162.
(b) Zhang, Y.; Wang, J. Eur. J. Org. Chem. 2011, 1015. (d) Davies,
H. M. L.; Manning, J. R. Nature 2008, 451, 417. (e) Timmons, D. J.;
Doyle, M. P. J. Organomet. Chem. 2001, 617À618, 98.
Herein we report an efficient Lewis acid catalyzed addi-
tion of diazoesters to pyridine-containing imines 1 produc-
ing β-amino-R-diazocarbonyl compounds 2 (eq 2).5 More-
over, we also developed a 3-CC reaction of 2-aminoazines,
aldehydes, and diazo-compounds to form 2. The obtained
β-amino-R-diazoesters represent useful synthetic scaffolds,
which can be efficiently converted into diversely substi-
tuted heterocycles, such as imidazo[1,2-a]pyridine and
pyrido[1,2-a]pyrimidine-4-one, as well as into N-pyridyl
substituted β-amino acids.
(2) For a recent review on reactions of diazo-compounds as nucleo-
philes, see: Zhang, Y.; Wang, J. Chem. Commun. 2009, 5350.
(3) For base-promoted addition of diazo-compounds to activated
imines, see: (a) Jiang, N.; Qu, Z.; Wang, J. Org. Lett. 2001, 3, 2989.
(b) Jiang, N.; Wang, J. Tetrahedron Lett. 2002, 43, 1285. (c) Zhao, Y.;
Jiang, N.; Wang, J. Tetrahedron Lett. 2003, 44, 8339. (d) Chen, S.; Zhao,
Y.; Wang, J. Synthesis 2006, 1705. For a diastereoselective reaction, see:
(e) Zhao, Y.; Ma, Z.; Zhang, X.; Zou, Y.; Jin, X.; Wang, J. Angew.
Chem., Int. Ed. 2004, 43, 5977.
(4) For enantioselective acid-catalyzed addition of diazo-compounds
to activated imines, see: (a) Uraguchi, D.; Sorimachi, K.; Terada, M.
J. Am. Chem. Soc. 2005, 127, 9360. (b) Hashimoto, T.; Maruoka, K.
J. Am. Chem. Soc. 2007, 129, 10054. (c) Maruoka, K.; Hashimoto, T.
Synthesis 2008, 3703. (d) Hashimoto, T.; Kimura, H.; Nakatsu, H.;
Maruoka, K. J. Org. Chem. 2011, 76, 6030. (e) Hashimoto, T.; Kimura,
H.; Kawamata, Y.; Maruoka, K. Nat. Chem. 2011, 3, 642. (f) Zhang, H.;
Wen, X.; Gan, L.; Peng, Y. Org. Lett. 2012, 14, 2126. For heterogeneous
catalysis of this reaction, see: (g) Kantam, M. L.; Balasubrahmanyam,
V.; Kumar, K. B. S.; Venkanna, G. T.; Figueras, F. Adv. Synth. Catal.
2007, 349, 1887.
In continuation of our studies6 toward a multicomponent
synthesis of heterocycles,7 we explored a three-component
(5) A single example of a low efficiency (24% yield) Ag-mediated
addition of ethyl diazoacetate to a nonactivated imine was reported:
Wenkert, E.; McPherson, C. A. J. Am. Chem. Soc. 1972, 94, 8084.
(6) (a) Chernyak, N.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49,
2743. (b) Chernyak, D.; Chernyak, N.; Gevorgyan, V. Adv. Synth. Catal.
2010, 352, 961.
r
10.1021/ol400148r
Published on Web 02/01/2013
2013 American Chemical Society

Accordingly, optimization studies toward a more effi-
cient formation of 2 were performed. It was found that
strong acids such as TfOH (entry 2), as well as Tf2NH
(entry 3), can catalyze this reaction to produce 2a, together
with a byproduct enamine 3a. Employment of weaker
acids, such as CF3CO2H (entry 4), did not give any
product, whereas the use of a phenylphosphinic acid
catalyst produced the product 2a selectively, though in
moderate yield only (entry 5). We found that the reaction
of tert-Bu and c-Hex-diazoacetates afforded products 2b
and 2c, respectively, in slightly better yields. However,
formation of significant amounts of enamine 3 was ob-
served (entries 6, 7). To our delight, the amount of enamine
byproduct 3 was significantly decreased when lanthanide
triflates were used (entries 8À11). After this two-component
coupling (2-CC) reaction was optimized, we focused on
the development of a more synthetically attractive 3-CC
reaction. We found that this transformation can indeed
be performed in a three-component fashion starting from
an aldehyde, a 2-aminopyridine, and a c-Hex diazoace-
tate which forms the product 2c in high yield (entry 12).
With optimized conditions in hand, we explored the
scope of this novel 3-CC reaction. Thus, aromatic alde-
hydes bearing electron-donating and -neutral groups
(Table 2, entries 1À7) at the o-, m-, and p-positions reacted
smoothly. Benzaldehydes having electron-withdrawing
groups, such as fluoro (entry 8), bromo (entries 9, 10),
NO2 (entry 12), and CF3 (entry 13), produced the corre-
sponding diazo esters in slightly lower yields (entries
8À13). In addition, an aldehyde bearing an unprotected
hydroxy group (entry 11), as well as a heteroaromatic
aldehyde, such as 2-thiophenecarboxaldehyde (entry 14),
were tolerated under these reaction conditions. Substituted
2-aminopyridines were also competent partners for this
3-CC reaction (entries 15À18). However, the reaction of
2-aminopyridine, having an electron-withdrawing group,
afforded the product in a diminished yield (entry 18). The
reaction could also be performed with other 2-amino-
azines, namely 2-aminopyrimidine (entry 19), and 2-amino-
pyrazine (entry 20), as well as with 2-aminothiazole (entry 21),
producing the corresponding products in reasonable
yields. In addition to diazoesters, diethyl (diazomethyl)-
phosphonate can also be employed to form the corresponding
Scheme 1. Pyridine-Directed Addition of Diazo-Compounds to
Imines
coupling reaction of a 2-aminopyridine, an aldehyde, and
a diazoester. It was found that the reaction of the imine of
2-aminopyridine 1a with ethyl diazoacetate in the pres-
ence of Py•TfOH (10 mol %) produced diazo-compound
2a8 along with some amounts of enamine 3a, a product of
the 1,2-aryl shift (Table 1, entry 1).9 We considered this
outcome to be quite interesting, as it represents the first
efficient5 addition of diazo-compounds to an imine that
does not possess a strong electron-withdrawing group at
the N-atom.
Table 1. Optimization of the New 3-CC Reaction Conditionsa
entry
catalyst
R
t
2
3
1b
Py•TfOH
TfOH
Et
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
56%
45%
55%
À
15%
15%
15%
À
(7) For selected reviews on multicomponent coupling reactions, see:
ꢀ
2b
Et
(a) Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH:
2005. (b) Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Angew. Chem., Int. Ed.
3b
4b
Tf2NH
Et
€
2011, 50, 6234. (c) Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012,
CF3CO2H
PhP(OH)2
Py•TfOH
Py•TfOH
Sc(OTf)3
La(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Et
112, 3083. (d) Synthesis of Heterocycles via Multicomponent Reactions I,
II; Orru, R. V. A., Ruijter, E., Eds.; Topics in Heterocyclic Chemistry;
Springer, Vol. 23, 2010.
(8) The X-ray analysis of the product 2j confirmed the presence of the
diazo-group in the obtained products (see Supporting Information for
details). CCDC-916523 contains the supplementary crystallographic
data for this compound. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(9) Notably, the likely aza-Darzens aziridination reaction of imine
was not observed. For Py•TfOH-catalyzed aziridination of imines with
diazocompounds, see: (a) Bew, S. P.; Carrington, R.; Hughes, D. L.;
Liddle, J.; Pesce, P. Adv. Synth. Catal. 2009, 351, 2579. For Ln(OTf)3-
catalyzed aziridination of imines with diazocompounds, see: (b)
Nagayama, S.; Kobayashi, S. Chem. Lett. 1998, 685. (c) Xie, W.; Fang,
J.; Li, J.; Wang, P. G. Tetrahedron 1999, 55, 12929.
5b,c
6b
Et
50%
59%
63%
42%
63%
52%
75%
74%
2%
t-Bu
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
14%
13%
14%
10%
1%
7b
8b
9b
10b
11b
12d
10 °C
10 °C
3%
4%
a NMR yields after 24 h. b 2-CC reaction of imine 1a with diazo-
compounds. c Toluene was used as a solvent. d 3-CC reaction from
2-aminopyridine, p-tolualdehyde, and c-Hex diazoacetate.
Org. Lett., Vol. 15, No. 4, 2013
957

Table 2. Scope of the New 3-CC Reactiona
a
˚
Unless otherwise noted: aldehyde (1 equiv), 2-aminoazine (1.1 equiv), diazo-compound (1.2 equiv), Y(OTf)3 (10%), and MS 4 A (125 mg/mmol) in
CH2Cl2 (0.3 M). b Preformed imine was used. c See ref 10.
β-amino-R-diazo-compounds 2v,w efficiently (entries 22
and 23). In general, the reaction shows high functional
group tolerance with respect to all three components.
Scheme 2. Proposed Mechanism of New 3-CC Reaction
Notably, aryl amines without a nitrogen atom at the
R-position of the ring, such as aniline as well as 3- and
4-aminopyridines, do not produce detectable amounts of
the corresponding diazo-products (entry 24).10
We rationalize these observations in the following way
(Scheme 2). First, the formed Y(III)-activated imine A
undergoes a nucleophilic attack by the diazo-compound to
produce zwitterion B/C. It is likely that the nitrogen atom
of the pyridine ring serves as an intramolecular proton
shuttle. Thus, deprotonation in B/C by the pyridine
N-atom leads to diazo-intermediate D, producing diazo-
compound 2 upon release of a Y(III)-catalyst and tauto-
merization process. Therefore, the overall process can be
considered as a pyridine group assisted addition of diazo-
compounds to imines. This mechanism is in good agreement
(10) For 3-CC reaction attempts employing aniline as well as 3- and
4-aminopyridines, see Supporting Information.
958
Org. Lett., Vol. 15, No. 4, 2013

with the fact that aniline, as well as 3- and 4-aminopyridines,
which do not possess a properly situated N-atom, do not
undergo this addition reaction (Table 2, entry 24).10
The obtained azine-containing β-amino-R-diazo-com-
pounds 2 represent a versatile scaffold for various types of
transformations. Thus, exploring the carbene reactivity of
the obtained molecules, we found that diazoester 2c (R =
CO2c-Hex) could undergo a selective 1,2-hydride shift11 in
the presence of AgBF4 (5 mol %) to produce enamine 4.12
Interestingly, the corresponding R-diazoethylposphonate
2v (R = PO(OEt)2), under these reaction conditions,
underwent an exclusive 1,2-aryl shift to form the enamine
product 5.3c
Scheme 4. Proposed Mechanism for Formation of 8
Thus, in the presence of La(OTf)3, it underwent lactamiza-
tion into pyrido[1,2-a]pyrimidine-4-one 7. On the other
hand, NIS-mediated cyclization converted 4 into imidazo-
[1,2-a]pyridine 8 (Scheme 3). Presumably, the cyclization
of 4 into 8 proceeds via intramolecular attack of the
pyridine nitrogen at the double bond of the enamine acti-
vated by an electrophilic agent, followed by a subsequent
elimination and a tautomerization process (Scheme 4).
In conclusion, we have developed a novel three-component
coupling reaction of 2-aminoazines, aromatic aldehydes, and
diazo compounds producing β-amino-R-diazoesters. This
reaction features an unprecedented heterocycle-assisted addi-
tion of a diazocompound to an imine. The obtained β-amino-
R-diazoesters represent an important polyfunctional syn-
thetic scaffold suitable for useful transformations. Thus, the
obtained diazo-compounds could be efficiently converted
into valuable heterocyclic molecules such as imidazo[1,2-a]-
pyridines and pyrido[1,2-a]pyrimidine-4-ones, as well as
β-(2-pyridyl)-amino acid derivatives.
Scheme 3. Synthetic Applications of Diazo-Compounds 2
In addition, hydrogenation of the diazo-group of 2c
efficiently converted it to β-amino acid derivative 6. The
synthetic usefulness of the diazo-compounds 2 was further
demonstrated in an efficient one-pot synthesis of N-fused
heterocyclesvia cyclization oftheinsituformedenamine4.
Acknowledgment. We thank the National Institutes of
Health (GM-64444 and 1P50 GM-086145) for financial
support of this work. We thank Prof. V. H. Rawal and Prof.
S. Kozmin (University of Chicago) for fruitful discussions.
(11) For 1,2-migrations in β-amino-R-diazoesters, see: (a) Jiang, N.;
Wang, J. Synlett 2002, 149. (b) Jiang, N.; Ma, Z.; Qu, Z.; Xing, X.; Xie,
L.; Wang, J. J. Org. Chem. 2003, 68, 893. (c) Shi, W.; Jiang, N.; Zhang,
S.; Wu, W.; Du, D.; Wang, J. Org. Lett. 2003, 5, 2243. (d) Shi, W.; Xiao,
F.; Wang, J. J. Org. Chem. 2005, 70, 4318. (e) Xu, F.; Zhang, S.; Wu, X.;
Liu, Y.; Shi, W.; Wang, J. Org. Lett. 2006, 8, 3207. (f) Xiao, F.; Wang, J.
J. Org. Chem. 2006, 71, 5789. See also refs 3a, 3c, 3d.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) See Supporting Information for full optimization results.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
959