A new reactivity mode for the diazo group: Diastereoselective 1,3-aminoalkylation reaction of β-amino-α-diazoesters to give triazolines

Article abstract of DOI:10.1002/anie.201404352

A novel mode of reactivity for the diazo group, the 1,3-addition of a nucleophile and an electrophile to the diazo group, has been realized in the intramolecular aminoalkylation of β-amino-α-diazoesters to form tetrasubstituted 1,2,3-triazolines. The reaction exhibited a broad scope, good functional group tolerance, and excellent diastereoselectivity. In addition, a new Au-catalyzed intramolecular transannulation reaction of the obtained propargyl triazolines to give pyrroles has been discovered.

Full text of DOI:10.1002/anie.201404352

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Chemie
DOI: 10.1002/anie.201404352
Reactivity of Diazo Compounds
A New Reactivity Mode for the Diazo Group: Diastereoselective 1,3-
Aminoalkylation Reaction of b-Amino-a-Diazoesters To Give
Triazolines**
Alexey Kuznetsov, Anton V. Gulevich, Donald J. Wink, and Vladimir Gevorgyan*
Abstract: A novel mode of reactivity for the diazo group, the
1,3-addition of a nucleophile and an electrophile to the diazo
group, has been realized in the intramolecular aminoalkylation
of b-amino-a-diazoesters to form tetrasubstituted 1,2,3-triazo-
lines. The reaction exhibited a broad scope, good functional
group tolerance, and excellent diastereoselectivity. In addition,
a new Au-catalyzed intramolecular transannulation reaction of
the obtained propargyl triazolines to give pyrroles has been
discovered.
D
iazo compounds are important building blocks that have
been extensively studied over the years.[1,2] They are widely
used in organic chemistry due to the high energy and diverse
reactivity of the diazo group. Primarily, diazo compounds are
utilized in denitrogenative generation of metal carbene
species.[3] On the other hand, reactions with preservation of
the diazo group are also known. Thus, [3+2] cycloaddition
reactions of diazo compounds are commonly used for the
synthesis of N-heterocycles.[4] There are also scattered reports
on the reaction of nucleophiles and electrophiles with the
diazo group in a 1,1-fashion in which both, nucleophile and
electrophile, are added to the terminal nitrogen atom of the
diazo group. Reactions of this type are limited to the addition
of nucleophiles (RLi or hydride ion), followed by protona-
tion, to produce hydrazones [Scheme 1, Eq. (1)].[5,6] Herein
we disclose a novel reactivity mode of diazo compounds:
a 1,3-addition of a nucleophile and an electrophile at the
nitrogen and carbon atom of the diazo group [Eq. (2)],
respectively. This reactivity mode was applied in the highly
diastereoselective aminoalkylation reaction of the b-amino-a-
diazoesters 1 with alkyl halides furnishing 1,2,3-triazolines 2
[Eq. (3)].
Scheme 1. Reaction of diazo compounds with nucleophiles and elec-
trophiles: 1,1- and 1,3-addition.
Scheme 2. Diastereoselective aminoalkylation of b-pyridylamino-a-
diazoester 1aa.
Recently, we have developed a method for the synthesis of
b-pyridylamino-a-diazoesters through a three-component
coupling reaction of 2-aminoazines, aldehydes, and diazo
compounds [Scheme 2, reaction (a)].[7] Upon investigation of
the synthetic utility of the obtained products, we found an
unexpected reactivity of the diazo group. Thus, an alkylation
reaction of N-pyridyl diazo compound 1aa with benzyl
bromide in the presence of NaH produced 1,2,3-triazoline
2a, the product of C-alkylation of the diazo group, instead of
the expected N-alkylation product 1’ [Scheme 2, reaction
(b)].[8] This reaction proceeds exclusively in a trans manner
with respect to the aryl substituent at the b-position of the
diazoester.[9]
Not only is the observed aminoalkylation reaction con-
ceptually interesting, because it represents the first example
of an intramolecular 1,3-addition of a nucleophile and an
electrophile to the diazo group, but it also holds synthetic
promise as a modular approach toward valuable 1,2,3-triazo-
line molecules.[10] Accordingly, we turned our attention to the
investigation of the scope of this new transformation
(Table 1). Gratifyingly, we found that this aminoalkylation
[*] A. Kuznetsov, Dr. A. V. Gulevich, Prof. Dr. D. J. Wink,
Prof. Dr. V. Gevorgyan
Department of Chemistry, University of Illinois at Chicago
845 West Taylor Street, Room 4500 SES, Chicago (USA)
E-mail: vlad@uic.edu
Homepage: http://www.chem.uic.edu/vggroup
[**] The support of the NIH (GM-64444) is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404352.
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Table 1: The scope of the aminoalkylation reaction of b-amino-a-diazoesters 1.[a]
Entry
1
Product
Yield [%]
71
Entry
13
Product
Yield [%]
86
Entry
28
Product
Yield [%]
71[e]
2
3
81
49
14
69
29
30
79[e]
15
16
17
78
71
75
56[e]
47
4
5
6
7
58
31
32
33
34
66[f]
85
49[g]
67
18
19
69
59
36[b]
20
21
64
58
65
59
22
23
62
76
8
61[c]
35
36
37
70
67
54
87
9
24
25
70
59
64[d]
10
83
91
11
12
26
27
41
45
38
39
62
[h]
89
–
[a] Yields of isolated products, d.r. >99:1 in all cases unless otherwise noted. [b] d.r. 97:3. [c] Yield determined by NMR spectroscopy. [d] BnOTf was
used. [e] MeI was used. [f] nBuI was used. [g] iPrI was used. [h] Trace of product, the starting diazo compound was recovered. Py=2-pyridyl, p-Tol=4-
CH3C6H4, o-Tol=2-CH3C6H4, Cbz=carboxybenzyl, Boc=tert-butoxycarbonyl.
2
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reaction is quite general with respect to the substituent at the
Nb atom of the diazoester 1.
Noteworthy, the b-amino-a-diazoesters 1 are easily avail-
able through the previously reported methods proceeding by
a base-[11] or acid-mediated[12] addition of diazoacetates to
imines. Furthermore, b-pyridylamino-a-diazoesters can be
obtained through a three-component coupling reaction pre-
viously developed in our group (Scheme 1).[7] Accordingly,
the newly discovered aminoalkylation reaction provides
a direct access to triazolines starting from commercially
available aldehydes, amines, diazo compounds, and alkyl
halides. To this end, we demonstrated the feasibility of this
approach by an efficient gram-scale synthesis of 1,2,3-triazo-
line 2aa through a formal four-component coupling reaction
of 2-aminopyridine, an aldehyde, a diazo compound, and
benzyl bromide (Scheme 4).
Thus, upon reaction of 1 with benzyl bromide, triazolines
bearing pyrimidyl (2ab), acetyl (2ac), pivaloyl (2ad), carb-
oxybenzyl (2ae), and tert-butoxycarbonyl (2af) groups at the
N atom were formed in high yields and diastereoselectivities
(Table 1, entries 1–5). In the case of b-N-benzoyl diazoester,
the product 2ag was formed in a low yield and diastereose-
lectivity (entry 6), whereas b-N-tosyl amino and b-N-diphe-
nylphosphonyl diazoesters produced the corresponding
enamines 1ah’ and 1ai’ as major products (entries 7 and 8).
Next, we examined the scope of alkylating agents in this
transformation. It was found that benzyl triflate is also
a competitive reaction partner; however the product 2aj was
obtained in a slightly lower yield than in the case of reaction
with benzyl bromide (Table 1, entry 9). Benzyl bromides
having electron-donating (entries 10–12) or electron-with-
drawing groups (entries 13 and 14), as well as allyl bromide
(entries 15–17), also underwent the aminoalkylation reaction
with different diazo compounds producing the desired
products in high yields. This reaction also works with internal
(entries 18–24) and terminal (entry 25) propargyl bromides as
well as with methyl bromoacetate (entry 26) and bromoace-
tonitrile (entry 27) as the alkylating agent. Notably, simple
aliphatic alkylating agents, such as methyl iodide (entries 28–
30), n-butyl iodide, and n-butyl bromide (entry 31), efficiently
participated in the aminoalkylation reaction. Notably, secon-
dary alkyl halides (entries 31–33) produced the corresponding
triazolines in good yields. The reaction showed good toler-
ance with respect to the electronic properties of the aryl
substituent and N-pyridyl group of b-amino-a-diazoesters
(entries 35–38, 20 and 21). However, it was found that this
aminoalkylation reaction was not efficient with the diazome-
thylenephosphonate derivative (entry 39).
Scheme 4. Four-component synthesis of triazoline 2aa from 2-amino-
pyridine, aldehyde, ethyl diazoacetate and benzyl bromide. p-Tol=4-
CH3C6H4, Py=2-pyridyl.
In continuation of our studies on the synthesis of hetero-
cycles through transition-metal-catalyzed cycloisomerization
reactions of alkynes[13] and transannulation reactions of
triazoles,[14] a potential heterocyclization reaction of prop-
argyl triazolines 2as–av was investigated [Scheme 5, Eq. (1)].
We screened different transition-metal catalysts and found
that under the Au-catalyzed conditions, propargyl triazolines
2as–av undergo a denitrogenative cycloisomerization reac-
tion with formation of tetrasubstituted pyrroles 5 [Scheme 5,
Eq. (1)]. It is believed that triazoline 2 produces enamine E
through a metal-catalyzed denitrogenative rearrangement of
the open triazoline form D.[15] A subsequent aminoauration of
the triple bond of E results in the formation of a vinyl–gold
intermediate F,[16] which gives pyrrole 3 upon protodemeta-
lation and aromatization.[17] The proposed mechanism was
supported by the observation of trace amounts of intermedi-
ate E in the reaction mixtures. Moreover, by treatment of
triazoline 2aw with AgBF4, we were able to isolate enamine 4
in good yield. Under the standard Au-catalyzed reaction
conditions, 4 was efficiently transformed into pyrrole 3c
[Scheme 5, Eq. (2)].
The proposed mechanism for the aminoalkylation reac-
tion of b-amino-a-diazoesters implies initial deprotonation of
the amino group of 1 with sodium hydride to produce anion
A, which undergoes cyclization to form enolate B/C
(Scheme 3). The subsequent nucleophilic attack of the
enolate at the electrophile approaches from the less sterically
hindered side and leads to the formation of the corresponding
1,2,3-triazoline 2 in a highly diastereoselective fashion.
The reaction works with N-pyridyl and N-acyl triazolines
possessing ethyl- and phenyl-substituted propargyl moieties
and produced pyrroles 3a–d in good yields. The substrates
possessing Br and CF3 substituents at the aryl ring also
produced the corresponding pyrroles 3e,f in moderate yields.
This cycloisomerization process represents the first example
of a denitrogenative transannulation reaction of 1,2,3-triazo-
lines with alkynes, which is complementary to the denitroge-
native transannulation of 1,2,3-triazoles.[14,18]
Scheme 3. The proposed mechanism for the aminoalkylation reaction
of b-amino-a-diazoesters.
In conclusion, we have developed a highly diastereose-
lective intramolecular aminoalkylation reaction of b-amino-
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a-diazoesters leading to the tetrasubstituted 1,2,3-triazolines.
The reaction features a novel 1,3-addition of a nucleophile
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Received: April 16, 2014
Revised: May 14, 2014
Published online: && &&, &&&&
Keywords: aminoalkylation · diastereoselectivity ·
.
diazo compounds · heterocycles · triazolines
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Communications
Reactivity of Diazo Compounds
Tetrasubstituted 1,2,3-triazolines were
synthesized from b-amino-a-diazoesters.
This aminoalkylation proceeds through
the unusual 1,3-addition of a nucleophile
and an electrophile to the diazo group.
The reactions exhibit a broad scope and
good functional group tolerance as well
as excellent diastereoselectivity.
A. Kuznetsov, A. V. Gulevich, D. J. Wink,
V. Gevorgyan*
&&&& — &&&&
A New Reactivity Mode for the Diazo
Group: Diastereoselective 1,3-
Aminoalkylation Reaction of b-Amino-a-
Diazoesters To Give Triazolines
6
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