Achieving regio- and stereo-control in the fluorination of aziridines under acidic conditions

Article abstract of DOI:10.1039/c6cc07855a

We developed an efficient fluorination protocol that converts easily accessible aziridines into β-fluoroamines, which are important motifs in biologically active molecules. In contrast with traditional fluorination approaches, DMPU-HF has shown both highe

Full text of DOI:10.1039/c6cc07855a

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O. E. Otome, B. Xu, C. F. Tormena, N. Robertson, U. R. Couto, M. S. Mashuta and Z. Li, Chem. Commun.,
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Achieving Regio- and Stereo-Control in the Fluorination of
Aziridines under Acidic Conditions
Okoromoba E. Otome,a Zhou Li,a Nicole Robertson,a Mark M. Mashuta,a Uenifer R. Couto,b Cláudio
F. Tormena,b Bo Xu,c,* and Gerald B. Hammonda,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
We developed an efficient fluorination protocol that converts stereo-control (Scheme 1b).1 This may be one reason why,
easily accessible aziridines into β-fluoroamines, which are compared to the well-defined base-mediated aziridine
important motifs in biologically active molecules. In contrast with opening, the acid mediated ring-opening of aziridines is under-
traditional fluorination approaches, DMPU-HF has shown both utilized in synthesis. Additionally, because the absolute
higher reactivity and regioselectivity and good functional group stereochemistry is not easy to establish unequivocally, studies
tolerance; thus, a wide scope of β-fluoroamines can now be on the absolute stereochemistry of the products derived from
accessed conveniently. The stereochemical behavior of ring the acid-catalyzed ring-opening of epoxides or aziridines are
opening depends on the substitution pattern of the aziridine sketchy at best.1, 5-8
standard SN2 pathway
substrates.
basic condition
(a)
Regioselectivity:
attack of least substituted carbon
Stereoselectivity:
inversion of stereo configuration
Nu-
Nu
R1
X
The ring-opening of small ring heterocycles (epoxides and
aziridines) by a nucleophile is an important method for the
preparation of vicinal di-functionalized compounds.1 Although
this reaction appears in any beginners’ course in organic
chemistry, the factors that control the selectivity of the ring
opening, especially under acidic conditions, are ambiguous.2-4
Although the mechanism for most acid-mediated nucleophilic
substitutions approximates that of an SN1 pathway, in
*
R
X
R
H+
*
R
acidic condition
H-Nu
R1
* chiral center
β
α
X
Regioselectivity?
Stereoselectivity?
δ+
R
H
R1
X = N, O
H-Nu
X
R1
A
aziridines, for example, a free carbocation (
hardly expected to form because the nearby amino group will
strongly coordinate to -carbocation; therefore, the
A in Scheme 1) is
Stereoselectivity
Stereoselectivity
(b)
ring opening
hydrofluorination
R
N
a
β
R1
R1
F
F
R1
R
NH
R1
R
NH
*
*
nucleophilic displacement will not follow the SN1 pathway of
traditional acid catalyzed nucleophilic substitutions. Thus, the
acid-mediated ring opening of epoxides or aziridines probably
*
*
+
+
*
+
2
HF
β
α
NH
R1
* chiral center
NH
β
α
F
F
R
R
traverses
a path somewhere between a SN2 and SN1
regioselectivity
+
mechanisms, leading to products with lack of regio- and
other byproducts
Scheme 1. Synthetic routes toward β-fluoroamines.
Nowhere is the lack of selectivity more consequential than
in the ring opening fluorination of aziridines by hydrogen
fluoride given that β-fluoroamines (Scheme 1b) are important
building blocks and motifs in medicinal chemistry;9 therefore,
efficient synthetic approaches toward β-fluoroamines are
highly sought after. Among these methods, the nucleophilic
ring-opening of aziridines (Scheme 1b) by HF is ideal because
of the low cost of reagents, mild reaction conditions, and
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general accessibility of substrates,10, 11 but the production of less hindered side leaving the hydroxyl group untouched; X-ray
regioisomers and stereoisomers makes this approach crystallography confirmed the stereo configuration of 2k 30
.
12-15
problematic (Scheme 1b).6,
Early work by Wade16 and
Table 1. Development of reaction conditions.a
Laurent17 demonstrated the use of anhydrous hydrogen
fluoride as well as HF-amine reagents18-22 to open the aziridine
ring (Scheme 1b). However, in addition to the inconvenience
related to use of hazardous anhydrous HF, aziridine ring-
opening suffers from low yields, production of isomeric
mixtures, and side products. Furthermore, bicyclic aziridines
Variation on standard Conversion
Entry
Yield
(%)b
93 (87d)
N/A
69
Ratio of 2a:3ac
conditions
None
(%)
> 99
0
1
2
3
4
5
6
7
8
>30:1
N/A
usually give rise to the formation of
a mixture of
In THF
diastereomers. Coutts and co-workers also reported the ring-
opening of N-tosylaziridines employing pyridine-HF-KF
system.23 However, their yields were not improved
significantly, and the scope of reactive substrates was limited.
Recently, Doyle and co-workers reported opening aziridines
with hydrogen fluoride generated in situ from acyl fluoride,
but their method only worked with symmetrical cis-2,3-
disubsituted aziridines, which also needed expensive
hexafluoroisopropanol as reaction medium.24, 25
Add 10 mol% of Sc(OTf)3
15 equiv of HF
9 h
97
>30:1
>30:1
>30:1
>30:1
7:1
99
86
54
> 99e
43
55 oC
88
70% HF-Pyridine
3HF·NEt3
85
78
0
N/A
N/A
a
Standard reaction conditions: 1 (0.2 mmol), HF (7.5 equiv, 1.5 mmol) in 0.5 mL
of dichloroethane (DCE) at room temperature in a sealed polypropylene vial over
for 18 h. b Determined by 19F NMR using benzotrifluoride as an internal standard.
c Determined by 19F NMR. d Isolated yield. e Reaction time was shortened to 12 h.
Recently, we developed a new HF-based reagent
—DMPU-
HF (DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidi-
none, now commercially available26), and demonstrated that it
was an efficient nucleophilic fluorination reagent in the gold-
catalyzed hydrofluorination of alkynes27 and fluoro-Prins
cyclization reactions.28 We chose the hydrofluorination of 2-
methyl N-tosylaziridine 1a as our model reaction (Table 1). We
found that, by treating 1a with 65% HF-DMPU in DCE under
room temperature, 1a was regioselectively converted into the
desired 2-fluoropropyl-N-tosylamine 2a in high yield and with
the tosyl protecting group intact (Table 1, entry 1). The
reaction did not take place in tetrahydrofuran (entry 2), and
the addition of scandium triflate significantly reduced the yield
(entry 3). No substantial changes were observed when the
amount of DMPU-HF was doubled (Table 1, entry 4).
Shortened reaction times caused an incomplete conversion,
but the material balance remained good (Table 1, entry 5).
Elevating the reaction temperature did not reduce the yield
(Table 1, entry 6). In comparison, Olah’s reagent (70% HF in
pyridine) provided an incomplete conversion within the same
time frame, and the material balance and regioselectivity were
not as good (Table 1, entry 7). Another common HF-based
reagent, triethylamine trihydrofluoride, gave no reaction at all
(Table 1, entry 8).
The effectiveness of this method was confirmed in the ring
opening of various N-tosyl aziridines (Scheme 2).
Hydrofluorination of the mono alkyl-, aryl-, and benzyl-
substituted N-tosylaziridines 1a-1g occurred at the most
substituted carbon and delivered primary alkyl amines 2a-2g in
good yields (Scheme 2). 2-Ethyl-3-methyl-1-tosylaziridine 1h
yielded an inseparable mixture of regioisomers and
diastereomers under these conditions (Table 1, 2h). gem-
Disubstituted aziridine 1i decomposed significantly under
these conditions, without providing isolable amount of
product 2i. Bicyclic aziridine 1j was converted into trans-β-
fluoroamines 2j in good yield and diastereoselectivity.29 The
reaction of β-hydroxyl bicyclic aziridine 1k took place at the
Scheme 2. Scope of N-tosylaziridines. Only major regioisomers are presented. Numbers
are isolated yields. Numbers in parenthesis are regioisomeric ratio determined by 19F
NMR. Reaction conditions: aziridine 1 (0.5 mmol), 65% HF-DMPU (98 µL, 3.6 mmol HF),
DCE (1 mL), room temperature for 18 h.
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Trisubstituted aziridines 1l and 1m were fluorinated also at
COMMUNICATION
the more substituted carbon in moderate-to-good efficiency
(Table 1, 2l and 2m). Bicyclosubstituted aziridine 1n yielded
the trans-substituted product 2n with the same
regioselectivity.
Next, we tested aziridines with various N-protecting groups
(Scheme 3). Aziridines protected by Cbz (1o), Fmoc (1p) and
benzoyl (1q) groups were well tolerated under the reaction
conditions, affording the corresponding β-fluoroamines 2o, 2p
and 2q in excellent yields and regioselectivity under the
standard reaction conditions (Scheme 3). It should be noted
that in reaction of 1q, the re-cyclized Heine product31 that was
the major side product in Laurent’s report17, was not observed
at all under our reaction conditions. The benzyl-protected
aziridine 1r was only partially converted into 2r, even after an
extended reaction time. We think that even though the more
basic NBn in 1r can be easily protonated, the protonated NBn
is not a good leaving group, so 1r is less reactive.
Scheme 4. Regioselectivity in ring-opening of aziridine by DMPU-HF.
For example, alkyl aziridine (R)-1a furnished the
configurational inversion product (S)-2a (Scheme 5a). This
result can be rationalized by a quasi-SN2 concerted pathway
(see TS-2 in Scheme 4). In contrast, phenyl-substituted (S)-1c
gave a completely racemized product (Scheme 5b). This result
could be rationalized by a quasi-SN1 step-wise pathway due to
fact that the corresponding carbocation intermediate
B can be
strongly stabilized by the phenyl group. More surprisingly, (S)-
1d, under standard conditions, yielded (S)-2d with almost
perfect retention of stereoconfiguration (Scheme 5c). The
stereochemistry of both starting material and product was
confirmed by X-ray crystallography (Scheme 5c). Neighboring
group participation by the phenyl group in (S)-1d could help
forming a highly delocalized phenonium ion-like transition
structure, hence preventing racemization from taking place
Scheme 3. Scope of N-protective groups. Only major regioisomers are presented.
Reaction conditions: aziridine 1 (0.5 mmol), 65% HF-DMPU (98 µL, 3.6 mmol HF), DCE
[a]
(1 mL), room temperature for 18 h, all yields are isolated yields.
parenthesis are regioisomeric ratio determined by 19F NMR.
Numbers in
An idealized SN2 pathway would foster the
α
-attack (less
(
TS-3, Scheme 5). Fluoride was delivered internally from the
hindered position) product (Scheme 4a). In our case,
fluorination at the more substituted internal carbon renders a
carbocation-like intermediate, which follows an SN1-type
regioselectivity accompanied with inversion of stereochemical
configuration, even though a free carbocation does not
actually form (TS-2, Scheme 4b). Our proposed mechanism can
also explain the poor results obtained with pyridine-HF and
Et3N-HF (Table 1). In the case of Et3N-HF, the acidity of the
system was low due to the high basicity of Et3N and only an
SN2 like pathway was allowed, but, due to the poor
nucleophilicity of HF, no conversion took place (Table 1, entry
7). On the other hand, pyridine-HF has a higher acidity than
Et3N-HF but it is less acidic than DMPU-HF, therefore
nucleophilic substitution with pyridine-HF will exhibit a higher
tendency towards a classic SN2 attack (Scheme 4a) with
diminished regioselectivity (Table 1, entry 8). Of course, steric
factors may also influence the regioselectivity of the reaction
but because HF is a small nucleophile, the influence of steric
factors is negligible.
same enantiomeric face of nitrogen assisted by an N-H
hydrogen bond, which resulted in retention of
stereoconfiguration (a quasi-SNi mechanism). This pathway
was supported by DFT analysis and further rationalized by the
fact that HF itself is a very strong hydrogen-bond donor
(underscored by the relative acidity of DMPU-HF).31-34 These
results indicated that the stereochemical outcome depended
on the relative stability of the carbocation-like intermediate
(e.g.
B in Scheme 5). With only alkyl groups attached, there is
no real carbocation-like intermediate, so the reaction
mechanism is close to an SN2 concerted pathway with
inversion of stereoconfiguration (Scheme 5a). With a strong
carbocation stabilizing group (phenyl), a semi-free carbocation
intermediate is formed, so the mechanism is close to a step-
wise SN1 mechanism (Scheme 5b). And the reaction of (S)-1d
lies between the two extremes (Scheme 5c).
In sum, DMPU-HF is a very effective reagent for the ring-
opening hydrofluorination of aziridines, giving products with
both high regioselectivity and high stereoselectivity. The scope
We also studied the stereochemical outcome of aziridine
opening by DMPU-HF and observed a substrate-dependent
stereochemical behavior. Reaction of bicyclic aziridines yielded
stereoconfigurational inversion products (see Scheme 5a and
also Scheme 2).
of the β-fluoroamines produced in this fashion includes cyclic
and acyclic structures with diverse sets of functional groups.
Acknowledgements
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