Direct Synthesis of Unprotected 2-Azidoamines from Alkenes via an Iron-Catalyzed Difunctionalization Reaction.

TLDR: Applications of the methodology in the concise synthesis of RO 20-1724 as well as in the formal total syntheses of both (±)-hamacanthin B and (±-quinagolide further demonstrate the broad synthetic potential of this highly functional-group-tolerant reaction.

Abstract: Unprotected, primary 2-azidoamines are versatile precursors to vicinal diamines, which are among the most common motifs in biologically active compounds. Herein, we report their operationally simpl...

Figures

Table 1. Selected optimization resultsa

Figure 1: Selected examples outside the reaction scope or difficulties of isolation.

Figure 2: 1H-NMR spectra of 2-azido-3-(p-tolyl)propan-1-amine after: purification B as HCl salt (above, blue), purification A via column chromatography (middle, green) and 0.5 mmol scale after column chromatography (below, red). The protons of the free amino group are interchangeable which causes its different chemical shifts in chloroform.

Full text

doi.org/10.26434/chemrxiv.12063411.v1
Direct Synthesis of Unprotected 2-Azidoamines from Alkenes via an
Iron-Catalyzed Difunctionalization Reaction
Szabolcs Makai, Eric Falk, Bill Morandi
Submitted date: 02/04/2020 • Posted date: 03/04/2020
Licence: CC BY-NC-ND 4.0
Citation information: Makai, Szabolcs; Falk, Eric; Morandi, Bill (2020): Direct Synthesis of Unprotected
2-Azidoamines from Alkenes via an Iron-Catalyzed Difunctionalization Reaction. ChemRxiv. Preprint.
https://doi.org/10.26434/chemrxiv.12063411.v1
Unprotected, primary 2-azidoamines are versatile precursors to vicinal diamines, which are among the most
common motifs in biologically active compounds. Herein, we report their operationally simple synthesis
through an iron-catalyzed difunctionalization of alkenes. A wide array of alkene substrates are tolerated,
including complex drug-like molecules and a tripeptide. Facile derivatizations of the azidoamine group
demonstrate the versatility of this masked diamine motif in chemoselective, orthogonal transformations.
Applications of the methodology in the concise synthesis of RO 20-1724 and in a formal total synthesis of
(±)-hamacanthin B further demonstrate the broad synthetic potential of this highly functional group tolerant
reaction.
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1
Direct Synthesis of Unprotected 2-Azidoamines from Alkenes via an
Iron-Catalyzed Difunctionalization Reaction
Szabolcs Makai, Eric Falk, Bill Morandi*
ETH Zürich, Vladimir-Prelog-Weg 3, HCI, 8093, Zürich, Switzerland
Supporting Information Placeholder
ABSTRACT: Unprotected, primary 2-azidoamines are versatile precursors to vicinal diamines, which are among the most common
motifs in biologically active compounds. Herein, we report their operationally simple synthesis through an iron-catalyzed difunction-
alization of alkenes. A wide array of alkene substrates are tolerated, including complex drug-like molecules and a tripeptide. Facile
derivatizations of the azidoamine group demonstrate the versatility of this masked diamine motif in chemoselective, orthogonal trans-
formations. Applications of the methodology in the concise synthesis of RO 20-1724 and in a formal total synthesis of (±)-hamacan-
thin B further demonstrate the broad synthetic potential of this highly functional group tolerant reaction.
Vicinal diamines are privileged structural motifs encountered across the molecular sciences, particularly in natural products, medic-
inal chemistry and catalysis.
1
Therefore, the rapid access to this ubiquitous functionality starting from simple hydrocarbon feedstocks,
such as alkenes, can dramatically facilitate the synthesis and discovery of functional molecules. Several approaches have been ex-
plored to install two vicinal amino groups through the catalytic diamination of alkenes.
2
However, these reactions are still consider-
ably limited when compared to well established methods for the synthesis of other important 1,2-difunctionalized alkanes, such as
diols.
3
Besides the scope being often limited to activated alkenes, a more significant limitation is the lack of methods to access a
diamine precursor which can be orthogonally transformed into synthetically relevant unsymmetrical diamine products (Scheme 1).
Scheme 1. Importance of unsymmetrical vicinal diamines
The azido group has recently emerged as a convenient amino group surrogate in formal catalytic diamination reactions (Scheme 2).
4
Most notably, Lin
5
and Xu
6
have described elegant electrochemical and iron-catalyzed processes, respectively, for the direct synthesis
of diazides starting from a wide variety of alkenes (Scheme 2a). Whereas these reactions are powerful tools to access symmetrical
vicinal diamines in two steps, they are less suitable in cases where two chemically distinct amino groups need to be orthogonally
synthesized (e. g. through amide coupling), a scenario which is common in target-oriented synthesis.
7
Indeed, diazides suffer from
poor regioselectivity upon monoreduction, making the direct synthesis of 2-azidoamines from alkenes highly challenging.
8

2
Scheme 2. Synthesis of azido-containing, masked vicinal diamines from alkenes
Table 1. Selected optimization results
a
Entry
Deviation from standard conditions
Yield of 2
b
1
None
68
2
Under inert atmosphere
65
3
Fe(OAc)
2
65
4
Fe(OAc)
2
trace metals basis (>99.99%)
66
5
No metal
<5
6
AcONH
3
OTf as reagent
43
7
1.5 eq PivONH
3
OTf
43
8
Covalent azide source
c
<5
9
MeCN as solvent
64
10
HFIP as solvent
<5
a
See SI for detailed information.
b
H-NMR yields in % using trichloroethylene as an internal standard.
c
Such as trimethylsilyl azide, to-
syl azide or diphenylphosphoryl azide.
Alternatively, some progress has been made to install both an azido group and a protected amino group. However, these reactions are
synthetically limited because they either introduce a nearly unprotectable form of the amino group (e.g. N(SO
2
Ph)
2
, Scheme 2b)
10
or
they rely on a suitably positioned directing group (Guan/Bi/Fu´s work, Scheme 2c).
11
Thus, a simple, catalytic aminoazidation reaction exhibiting a broad substrate scope and allowing for the installation of, ideally, an
unprotected amino group, would certainly allow for the step-economical and orthogonal synthesis of nearly any 1,2-diamine deriva-
tive, thereby accelerating the synthesis and discovery of bioactive molecules (Scheme 2d).
12–15
Herein, we report an iron-catalyzed difunctionalization reaction of unactivated alkenes to directly access unprotected, primary 2-
azidoamines. This process tolerates a broad substrate scope including unactivated mono-, di- and trisubstituted alkenes bearing un-
protected polar functional groups commonly found in drug-like molecules.
Based on our recent research interest to access amino alcohols and 2-chloroamines under iron catalysis,
16
we set out to develop
conditions for the aminoazidation of alkenes using a traditionally more challenging substrate, 1-dodecene (Table 1, for further details
see SI). Evaluation of different azide salts in combination with different transition metal catalysts and hydroxylamine derivatives led
us to identify suitable reaction conditions for the aminoazidation of 1-dodecene. Especially iron(II) acetate and triflate efficiently

3
catalyzed the desired reaction in good yields using this usually unreactive substrate (Entries 1, 3, 4). The possible catalytic effect of
impurities from the iron source was ruled out by a control experiment with a trace metals-based source which
Scheme 3. Scope of the aminoazidation reaction
Yields are of isolated products; dr determined by
1
H-NMR.
a
(E)-alkene used.
b
Purified via column chromatography.
c
Purified via ammonium
salt precipitation.
d
Starting from an ester bearing a terminal alkene.
e
See SI for detailed experimental information.

4
Scheme 4. Derivatization of azidoamine 2r
Conditions: i) Phenyl acetylene (1.2 eq), sodium ascorbate (0.4 eq), CuSO
4
•5 H
2
O (20%), tBuOH/H
2
O, r.t., 62%; ii) PPh
3
(1.2 eq), THF/H
2
O,
50 °C, then TsOH•H
2
O (2.2 eq), Et
2
O, r.t., 75%; iii) PMe
3
(1.1 eq), CO
2
, MeCN, r.t., 67%; iv) N-Boc-Leu (1.2 eq), DIPEA (2.4 eq), HBTU
(1.3 eq), THF, r.t., 70%; v) PMe
3
(3.4 eq), THF/H
2
O, r.t., 79%; vi) benzaldehyde (1.2 eq), acetic acid (2.0 eq), NaBH(OAc)
3
(1.4 eq), DCE,
r.t., 31%.
delivered the same outcome, confirming that the iron species plays a key role.
17
Covalent azide sources failed to afford any product
while ionic azides were most suitable (Entry 8). Interestingly, this reaction can be performed open to air in technical grade methanol,
a critical issue in the possible rapid adoption of this new reaction by synthetic practitioners.
With the optimized conditions in hand, we then investigated the scope of the aminoazidation reaction (Scheme 3). Looking into aryl
substituted alkenes, electron-poor (2b–e, 2g–h), as well as electron-rich (2k) systems were efficiently transformed into their corre-
sponding azidoamines. Aryl substituted internal alkenes indene and trans-β-methyl styrene afforded syn-addition products 2l and 2m
in excellent diastereoselectivity (dr > 19:1).
With regards to unactivated alkenes, mono-, 1,1-di- and trisubstituted alkenes performed well (2n–q). This is especially important,
since the products bearing a tertiary azide offer the possibility to be transformed into an α-tertiary amine functionality, a common
motif in natural products with only limited accessibility.
18
Aside from various carbon scaffolds, several functional groups were found to be tolerated under the reaction conditions, such as aryl
(pseudo)halides (2b, 2e), multiple aryl substituents (2b–l), nitriles (2c, 2s), protected amines (2k, 2t, 2ah), free alcohols (2u, 2v, 2y)
and phosphonates (2w, 2x). Remarkably, even alkynes in close proximity remained untouched (2y). Acid labile functionalities were
also tolerated, e.g. free, tertiary alcohols (2v), silyl ethers (2z) and N-Boc protecting groups (2k, Boc = tert-butyloxycarbonyl). Fur-
thermore, heterocycles (indole in 2k, oxetane in 2aa) further expanded the wide scope of this transformation. Synthetically relevant
carboxylic acid derivatives, such as amides (2ab–ae), formamides (2f) and esters (2af), performed well under the reaction conditions.
Interestingly, esters with a shorter alkenyl chain cyclized in the process to afford lactams 2ab and 2ac in a single step.
This excellent functional group tolerance encouraged us to tackle even more challenging substrates. An artemether derived substrate
(2ag) was converted in moderate yield to the desired product, leaving the highly oxidized cage structure and the sensitive peroxo

Frequently asked questions

Q1. What have the authors contributed in "Direct synthesis of unprotected 2-azidoamines from alkenes via an iron-catalyzed difunctionalization reaction" ?

Herein, the authors report their operationally simple synthesis through an iron-catalyzed difunctionalization of alkenes. Applications of the methodology in the concise synthesis of RO 20-1724 and in a formal total synthesis of ( ± ) -hamacanthin B further demonstrate the broad synthetic potential of this highly functional group tolerant reaction. 

Q2. What was used for the purification of primary amines?

For purification via flash column chromatography, silica gel (Sigma Aldrich, 40 – 60 m), solvents of technical grade and an air pressure of 0.3 – 0.5 bar was applied. 

Q3. How many mmol of NaN3 was added to the reaction mixture?

NaN3 (34 mg, 0.52 mmol, 1.05 eq) and PivONH3OTf (334 mg, 1.25 mmol, 2.5 eq) were added subsequently to the reaction mixture and the reaction was stirred for 16 h at room temperature. 

Q4. How many mmol of hex-5-enyl artemether was?

found 541.2695.44Rf: 0.23 (Hex:EtOAc 3:1)Fmoc-allyl-L-glycine-Phe-OtBu 1ah-SM-Fmoc (0.808 g, 1.498 mmol, 1.0 equiv.) was dissolved in DMF (8.5 mL). 

Q5. How many mL of piperidine was added to the reaction mixture?

) was added under stirring and the reaction mixture was stirred at room temperature for 3 hours before DCM (20 mL) and water (80 mL) were added. 

Q6. How was the reaction mixture dissolved in DCM?

At 0 °C, PPh3 (164 mg, 0.625 mmol, 1.2 eq) was added and the reaction mixture was allowed to warm to r.t. and stirred at 50 °C overnight. 

Q7. how much amine 3e is a viscous yellow oil?

Drying over Na2SO4 and purification via column chromatography (DCM:MeOH 100:0 to 96:4, NEt3-deactivated SiO2) yielded a 1:1 mixture of both diastereomers of amine 3e (61.8 mg, 0.164 mmol, 79%) as a viscous yellow oil. 

Q8. How many mL of n-BuLi was added to the reaction mixture?

After stirring at room temperature for 12 hours, the reaction mixture was quenched by the addition of saturated aqueous NH4Cl (50 mL). 

Q9. What is the spectral composition of the 81H-NMR?

81H-NMR (400 MHz, CDCl3): H = 7.76 (s, 1H), 1.49 (s, 9H), 1.30 (s, 9H).13C-NMR (101 MHz, CDCl3): C = 178.0, 155.8, 83.2, 38.3, 28.2, 27.1.O-Pivaloyl hydroxylamine triflic acid (SI-1)tert-Butyl pivaloyloxy carbamate SI-1SM (45 g, 0.21 mol, 1.0 eq.) was dissolved in Et2O (400 mL).