A versatile synthetic platform based on strained propargyl amines

Article abstract of DOI:10.1002/anie.200906066

"Chemical Equation Presented" Divergent reactivity: Various ethynylaziridines behave as strained propargyl amines and can be directly converted into unprotected α-amino allenes by a highly diastereoselective S_N2′ hydride delivery (see scheme). Additional reaction routes involve chemo- and regioselective transformation into either bicyclic aziridine/ enol ethers or highly strained azirine alkynes.

Full text of DOI:10.1002/anie.200906066

Angewandte
Chemie
DOI: 10.1002/anie.200906066
Propargyl Amines
AVersatile Synthetic Platform Based on Strained Propargyl Amines**
Zhi He and Andrei K. Yudin*
Gabriel prepared ethylene imine in 1888.[1a] Despite the
Table 1: N H terminal ethynylaziridines from aziridine aldehyde
À
dimers.[a]
À
overall instability of this compound and other N H aziridines,
particularly under acidic conditions, their nitrogen center
possesses some notable features. In 2006, we capitalized on
the fact that aziridines are quite nucleophilic (pKaH = 8.0) but
do not easily form iminium ions when exposed to aldehydes.
This allowed us to create a series of bench-stable unprotected
amino aldehydes.[1] The present paper describes the develop-
ment of a versatile platform for synthetic elaboration of
strained propargyl amines. We show that unprotected amino
Starting material
R1
R2
R3
Product
Yield[b]
1a
1b
1c
Ph
H
H
H
H
H
H
2a
2b
2c
95%
70%
84%
p-MeOC6H4
p-FC6H4
À
aldehydes are one step away from unprotected N H ethyny-
laziridines. Despite apparent simplicity and considerable
synthetic potential of these molecules, they have eluded
synthesis until now.[2]
1d
H
H
2d
76%
1e
1 f
Ph
H
Me
H
H
Ph
2e
2 f
74%
80%
Partial dissociation of aziridine aldehyde dimers previ-
ously enabled attack at the aldehyde carbon atom by soft
nucleophiles such as organoindium reagents.[3] When sub-
jected to the Corey–Fuchs procedure, the aziridine aldehyde
dimer 1a participated in the Wittig-type transformation,
which afforded the corresponding dibromoolefin. However,
the second step of this process, namely the nBuLi-promoted
conversion of the dibromoolefin into the ethynyl end point,
was plagued by rapid formation of intractable tars due to ring-
opening. Fortunately, a one-step homologation with the
Bestmann–Ohira reagent[4] in anhydrous methanol in the
presence of K2CO3 did not trigger decomposition. The desired
ethynylaziridine 2a was furnished as a bench-stable solid in
1g
H
H
2g
90%
1h
H
H
2h
72%
[a] Reactions were carried out using 1.0 equiv of aziridine aldehyde
dimer, 2.2 equiv of the Bestmann–Ohira reagent, and 4.0 equiv of K2CO3
in methanol at 258C. [b] Yield of isolated product.
the molecular structure[5] of these molecules as a way of
probing their electronic properties. An X-ray structure of
2c[12] confirms the presence of a stabilizing aziridine–alkyne
interaction. The average length of the C3(aziridine)–C2(acetylene)
À
95% yield. Several N H ethynylaziridines having different
bond is 1.444 ꢀ, which is significantly shorter than a typical
3
À
substitution patterns were prepared using this method
(Table 1). The reaction works well not only with alkyl-
substituted aziridine aldehydes (1g–h), but also with electron-
neutral (1a), electron-rich (1b), and electron-deficient (1c)
aryl substrates. The thiophenyl-substituted aziridine aldehyde
dimer (1d) also showed excellent reactivity. The hindered
starting materials (1e–f) worked equally well in this process.
Interestingly, despite a possibility for decomposition
through intermolecular attack of the nucleophilic aziridine
nitrogen atom on the alkyne carbon atom (causing SN2’
C(sp ) C(sp) single bond (1.472 ꢀ). Strained rings such as
cyclopropanes, epoxides, and aziridines are known to partake
in strong hyperconjugative interactions with sp2- or sp-
carbon-containing functional groups.[6] These interactions
have been manifested not only in the ground-state stabiliza-
tion, but also in lowering the activation barrier of chemical
transformations.[7]
Armed with an insight into the structural features of
ethynylaziridines, we opted to exploit one-step transforma-
tions involving both amine and alkyne functional groups.
First, we envisioned a possibility for direct preparation of
unprotected a-amino allenes, versatile intermediates in aza-
À
scission), the unprotected N H ethynylaziridines were found
to be stable up to at least 1008C. We were curious to examine
cycle synthesis,[8] by an SN2’ scission of N H ethynylazir-
À
idines.[9] Of the hydride transfer reagents tested (DIBAL, 9-
BBN, [{(Ph3P)CuH}6], and Cp2Zr(H)Cl),[10] 9-BBN showed
optimal reactivity, giving the a-amino allene 3g exclusively in
[*] Z. He, Prof. Dr. A. K. Yudin
Davenport Research Laboratories, Department of Chemistry
University of Toronto
80 St. George St., Toronto, ON, M5S3H6 (Canada)
Fax: (+1)416-946-7676
À
high yield from the N H ethynylaziridine 2g (Table 2,
entry 7) in just over one hour without any alkyne hydro-
boration by-products. We evaluated the generality of the
reaction by treating ethynylaziridines with 9-BBN (Table 2).
To gain insight into the stereochemistry of this allene
construction, the internal phenyl ethynylaziridine 4a was first
obtained from 2a through a Sonogashira coupling with phenyl
iodide (Scheme 1). The NH group did not interfere in this
E-mail: ayudin@chem.utoronto.ca
[**] The authors would like to thank the Natural Science and Engineer-
ing Research Council (NSERC) and the Canadian Institutes of
Health Research (CIHR) for financial support. Dr. A. Lough is
thanked for the X-ray crystal structure analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906066.
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À
Table 2: Synthesis of a-amino allenes from N H terminal ethynylazir-
that significant pre-coordination of boron to the aziridine
nitrogen atom contributes to the high diastereo- and regio-
control of this allene synthesis.
idines.[a]
A variety of substituted aryl ethynylaziridines, prepared
by Sonogashira coupling, showed similar reactivity towards 9-
BBN reduction, producing the corresponding anti-configured
a-amino allenes with good to excellent diastereoselectivities
(Table 3, entries 1–4). Notably, vinyl-substituted ethynylazir-
idines can also afford the corresponding anti-configured
conjugated vinyl allenes with high yields and exclusive
diastereoselectivities (Table 3, entries 5–7). Interestingly, the
vinyl groups remained intact during the reduction.
Entry
1
Ethynylaziridine
Allene
Yield[b]
84%
2
3
70%
76%
À
Table 3: Synthesis of internal a-amino allenes from N H aryl or vinyl
ethynylaziridines.[a]
4
5
6
7
75%
88%
77%
77%
Entry
1
Halide
Allene product
Yield[b]
74%
d.r.[c]
>99:1
2
3
4
81%
75%
84%
90:10
97:3
8
55%
[a] Reactions were carried out using 1.0 equiv of ethynylaziridine and
1.0 equiv of 9-BBN in THFat 258C. [b] Yield of isolated product. 9-BBN=
9-borabicyclo[3,3,l] nonane.
87:13
process. Treating phenyl ethynylaziridine 4a under the
hydride reduction conditions resulted in the corresponding
internal a-amino allene 5a (Scheme 1) as the predominant
diastereomer (d.r. 92:8). It was subsequently converted into
the dihydropyrrole 6 upon treatment with AuCl with com-
plete transfer of chirality.[8c] The crystal structure of the
tosylated derivative 7,[12] revealing the anti configuration of
the internal allene 5a, indicates that the 9-BBN mediated
allene formation is consistent with the syn hydride transfer
from the boron to the distal alkyne carbon atom. It is likely
5
6
7
83%
79%
82%
>99:1
>99:1
>99:1
[a] The allene preparation reactions were carried out using 1.0 equiv of
ethynylaziridine and 1.0 equiv of 9-BBN in THF at 258C. [b] Yield of
isolated 5. [c] Determined by 1H NMR analysis of the crude reaction
mixture. 9-BBN=9-borabicyclo[3,3,l] nonane.
Encouraged by the above results, we have additionally
investigated the extent of regiocontrol possible by way of
À
nitrogen-mediated nucleophilic attack at the C C triple bond.
Interestingly, the ethynylaziridines 2a and 2 f readily fur-
nished fused bicycles 8 and 9,[11] respectively, upon reaction
with acetone in DMSO in the presence of a LiOH/CsF base
combination (Scheme 2). In contrast to the boron reagents, no
SN2’ attack forming cyclic allene species 10 was initiated in
this case. The unique feature of aziridine nitrogen atom also
Scheme 1. Preparation of an internal a-amino allene for elucidation of
the relative stereochemistry.
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distinguished by their chemo- and regioselective transforma-
tions into bicyclic aziridine/enol ethers and highly strained
azirine alkynes. The ongoing renaissance in alkyne chemis-
try[14] should render these readily accessible chiral building
blocks synthetically useful. On the basis of the dissected
reactivity patterns, we anticipate that a myriad possibilities
await these and related molecules.
Experimental Section
À
General procedure for the synthesis of a-amino allene 3 or 5: N H
ethynylaziridine 2 or 4 (0.4 mmol) in 3 mL of anhydrous THF was
added to a flame dried flask equipped with a magnetic stirring bar and
a rubber septum. 0.5m 9-BBN in THF solution (0.4 mmol) was then
added at 08C. The reaction mixture was then warmed to room
temperature and stirred under N2 at room temperature for 1 h until
the reaction was complete as indicated by TLC analysis. The reaction
was cooled to 08C again, and then 0.6 mL of 10% NaOH and 0.2 mL
of 30% H2O2 were added. The mixture was vigorously stirred for 2 h
at room temperature. An additional 5 mL of 10% NaOH solution was
added to the reaction mixture, which was then extracted with diethyl
ether (5 mL ꢁ 3). The combined ether layers were dried with
anhydrous Na2SO4 and concentrated under reduced pressure. The
resulting residue was purified using flash column chromatography on
silica gel, eluting with 2%–5% methanol (containing 2m ammonia) in
dichloromethane.
À
Scheme 2. Annulation of N H ethynylaziridines with acetone.
prevents formation of the energetically uphill iminium ion 11,
enabling ring closure to afford the cyclic enol ether product.
The reactions considered thus far involved both aziridine
and alkyne units. To our delight, we have also collected
evidence for regio- and chemoselective oxidation of the
À
aziridine moiety in N H ethynylaziridine without touching
the alkyne unit. Under the conditions normally prescribed for
the Swern oxidation, compounds 2a and 2g afforded the
corresponding bench-stable 2H-azirines 12 and 13, respec-
Received: October 28, 2009
Published online: January 29, 2010
=
tively, with the C N bond on the oposite side of the ring
Keywords: aldehydes · allenes · chemoselectivity ·
propargyl amines · stereoselectivity
relative to the acetylene group (Scheme 3). Interestingly, in
.
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Scheme 3. Chemoselective and regioselective azirine synthesis from
À
N H ethynylaziridines.
the presence of either aryl or alkyl groups, the regioselectivity
remains high. This chemoselective transformation is intrigu-
ing, as is the stability of 12 and 13. The structure of azirine
alkyne 12 was confirmed by X-ray crystallographic analysis.[12]
À
In summary, N H ethynylaziridines have been prepared
from amphoteric aziridine aldehydes. Given recent interest in
structural characterization of the unusual interactions involv-
ing unprotected amines and acetylenes,[13] molecules of this
sort are noteworthy from the theoretical viewpoint. They also
À
open up a plethora of synthetic opportunities. N H terminal
ethynylaziridines, together with their corresponding aryl- or
vinyl-substituted internal analogues, can be directly converted
into unprotected a-amino allenes by a highly diastereoselec-
[3] R. Hili, A. K. Yudin, Angew. Chem. 2008, 120, 4256 – 4259;
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À
tive syn hydride delivery. N H ethynylaziridines are also
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Communications
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