C-F bond substitution via aziridinium ion intermediates

Article abstract of DOI:10.1039/c5cc04723d

Aliphatic 1,2-aminofluorides undergo extremely fast substitution reactions under the influence of lanthanum tris(hexamethyldisilazide). The substitution proceeds via an in situ generated aziridinium ion intermediate, which subsequently undergoes ring opening by addition of a nucleophile, yielding various β-substituted amines.

Full text of DOI:10.1039/c5cc04723d

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C-F bond substitution via aziridinium ion intermediates
Received 00th January 20xx,
Accepted 00th January 20xx
A. M. Träff, M. Janjetovic and G. Hilmersson*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Aliphatic C-F bonds in β-position to a nitrogen undergo extremely fast present a simple and fast approach to use the C-F bond as a
substitution reactions under the influence of lanthanum precursor for aziridinium ion formation.
tris(hexamethyldisilazide). The substitution proceeds via an in situ
generated aziridinium ion intermediate, which subsequently ring opens by
additon of a nucleophile, yielding various β-substituted amines.
Me
N
Me
N
R
Me
La[N(SiMe3)2]3
Nuc
R
F
N
R
Nuc
Nuc= R'R''NH,H2O,
R'OH, R'SH, TMS-X,
R'MgY
The prospect of utilizing stable aliphatic organofluorides as a novel
modular functionality in synthetic chemistry is an engaging task,
exploitable thanks to the numerous fluorinating protocols available
nowadays.1 However, aliphatic organofluorides are traditionally
considered impractical for chemical transformation, and the
challenge of selective activation and transformation under mild
conditions can be ascribed to the overall chemical inertness of the
C-F bond. Compounds with the possibility of utilizing intramolecular
assistance, as shown by Paquin et al., Gouverneur et al. and Hu et
al., may overcome the activation energy and contribute to the C-F
bond cleavage.2 In line with this aspect, β-amino fluorides have
received little attention and literature reports are scarce.3 Chong et
al. recently reported on a Lewis acid promoted β-haloamine
substitution, with one example of fluoride displacement affording
only 24% yield, noticeably showing fluoride as a poor leaving
group.4 Concerning the development of new C-F bond cleavage
methodology, our group has focused on designing selective
substitution of unactivated alkyl fluorides using trivalent
lanthanides. Recently we communicated that various lanthanide
(III) salts mediates mild and selective substitution of aliphatic
fluorides into aliphatic iodides5 and tertiary amines6. In these
transformations, we have proposed that a strong lanthanide-
fluoride interaction is central in the C-F bond cleavage. Having
established these results, we hypothesized that intramolecular
amine substitution of β-amino fluorides, with the proper choice of
lanthanide (III) reagent, would generate aziridinium ions.
Subsequent ring-opening of such reactive intermediates, with
various nucleophiles, would give access to a plethora of different β-
substituted amines, and it would expand the use of aziridinium ions
as key intermediates in organic synthesis (Scheme 1).7 Herein we
Scheme 1: Schematic picture of in situ aziridinium formation, generated from β-amino
fluorides, and the scope of β-subsituted amines formed.
When adding N-benzyl-N-methyl-2-fluoroethylamine (1a) to
a
mixture of dibutylamine and lanthanum tris(hexamethyldisilazide)
(La[N(SiMe3)2]3) an increase in reaction rate was observed,
affording the product in matter of seconds. Close observation of the
1H NMR spectra revealed an instantaneous formation of an
aziridinium ion as a reactive intermediate (Figure 1).11
Figure 1:
A
1H NMR overview of the β-amino fluoride C-F bond substitution
mediated by La[N(SiMe3)2]3. A= N-benzyl-N-methyl-2-fluoroethylamine (1a). B=
Aziridinium ion intermediate formed by mixing 1a with La[N(SiMe3)2]3 (1:1). C=
N1-benzyl-N2,N2-dibutyl-N1-methylethane-1,2-diamine (2a).
A higher shift change of approximately 0.9 ppm for the Ph-CH2-N-
and 0.8 ppm for the -N-CH3 protons were observed, simultaneously
with a lower shift of 1.1 ppm for the –CH2-F protons, clearly
indicating that the C-F bond has been cleaved and that a charged
intermediate species has been formed (Figure 1B). We believe that
the formation of a strong La-F bond is the driving force of the
instantaneous ring closure. Furthermore, when adding 1 equivalent
of dibutylamine, the aziridinium ion subsequently underwent an
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extremely fast nucleophilic ring opening and the β-substituted
amine product (2a) was obtained after work-up (Figure 1C). It is
well known that β-substituted amines with a good leaving group
readily undergo transformation into the corresponding aziridines8
or aziridinium ions.7,9 However, since aliphatic fluorides are
generally not considered a good leaving group, a fluorophilic
reagent is needed to activate the C-F bond towards cleavage. To
explore this, a range of different Lewis acids (La[N(SiMe3)2]3, SmF3,
YbF3, AlCl3, MgCl2, SmCl3, KBr, SmBr3, AlI3, LiI, KI, YbI3, La(OTf)3,
Sm(OTf)3, and Yb(OTf)3) were subjected to the reaction between 1a
and benzylmethylamine in dichloromethane (CH2Cl2) (see
supporting information, SI). In the presence of La[N(SiMe3)2]3 the
strong C-F bond was cleaved within the matter of seconds. Most of
the other Lewis acids did not promote the reaction at all, and the
few that did could not compare with La[N(SiMe3)2]3 in terms of yield
and reactivity. The efficacy of these transformations relies on the
nature of the neighbouring group and its distance from the fluorine.
In general the presence of a hydroxyl, carboxyl, sulfydryl, primary or
secondary amine or a carbanionic carbon in the β-position could act
as a neighbouring group to assist in intramolecular substitution.2,3,4
Different heteroatoms were incorporated to a β-substituted alkyl
fluoride to investigate the effect of the neighbouring group (Table
1). Since carbon cannot assist in the substitution of fluoride this
substrate was included as a reference (entry 4).
Table 2: The effect of varying the distance between the neighbouring group and the
fluorine in the C-F substitution reaction.a
Entry
n
t1/2 (s) b
~4
1
2
3
4
5
1 (1a)
2 (1b)
3 (1c)
4 (1d)
5 (1e)
~30
<<1
~1
240
a
La[N(SiMe3)2]3 (0.044 mmol), CH2Cl2 (0.25 mL), Bu2NH (0.044 mmol), (1.0 M in
CH2Cl2, 0.040 mmol). n-Dodecane (0.040 mmol) was added to the reaction as
internal standard. b Analysed by GC-FID.
The reactivity decreased according to the following order of ring
size 5>6>3>4>>7.3 For β-amino fluoride 1a a t1/2 of 4 s was observed
(entry 1). A t1/2 of approximately 30 s was observed for the
substrate with the nitrogen in γ-position (1b, entry 2). For 1c and
1d, the 5- and 6-exo-tet ring formation were extremely fast, with
t1/2 <<1 s and t1/2 ∼1 s respectively (entry 3-4). Even with the
nitrogen in ζ-position (1e), 7-exo-tet ring formation was observed,
Table 1: The effect of different heteroatoms as neighbouring group participants in the
C-F substitution reaction.a
albeit at
a lower rate (entry 5). Neither of the charged
intermediates of the 5-, 6-, or 7-membered rings (entry 3, 4 and 5)
showed any reactivity towards the nucleophilic amine even with
prolonged reaction time (24 h). Such charged quaternary amines
are known to be very stable, and therefore require harsh conditions
to undergo ring opening.10 The release of the large strain of the 3-
membered ring is suggested to be the driving force for fast
nucleophilic opening of the aziridinium ion. Despite the synthetic
versatility, ring opening of aziridinium ions are not as common than
other less reactive three-membered congeners such as aziridines
and epoxides.8,9 However, in our case, activated aziridinium ions are
produced in situ which makes it possible to add different
nucleophiles directly to the reaction mixture (Table 3). Not only
secondary amines, such as dibutylamine and benzylmethylamine,
underwent nucleophilic ring-opening of the aziridinium ion, but
even morpholine provided the corresponding diamine. The reaction
reached full conversion within 1 min, and 2b was isolated in 93%
yield. Even a heteroaromatic secondary amine, such as imidazole,
gave clean ring-opening and 2c was obtained in 81% yield. The
nucleophilic amide phthalimide was incorporated, generating 2m in
78% isolated yield. Thiol and alcohol as nucleophiles gave the
corresponding thioether (2d) and ether (2e) in high to excellent
yields within 5 min. In a similar fashion 2-hydroxypyridine, which
potentially can react in both its tautomeric forms, only yielded the
ether product (2h). With water as nucleophile either the β-hydroxy
amine (2f) or the tridentate ether ligand (2g) was obtained in high
to moderate yields, with the ratio being dependent on the amount
of water and reaction time.
Entry
X
t (min)
yield (%)b
93 (2a)
87 (4)
1
2
3
4
NMe (1a)c
1
1
S (3)
O (5a)d
CH2 (7)d
60
60
89 (6)
93 (8)
a
La[N(SiMe3)2]3 (0.176 mmol), CH2Cl2 (1.0 mL), Bu2NH (0.176 mmol), substrate
b
c
(1.0 M in CH2Cl2, 0.160 mmol). Isolated yields are reported. 95% conversion
within 10 s measured by GC-FID. d Bu2NH (0.48 mmol)
Replacing the carbon (7) for nitrogen (1a) or sulphur (3) gave a >60
fold increase in reaction rate, clearly showing a neighbouring group
effect (entry 1-2, 4). Exchanging for oxygen (5a) did not give any
observable effect (entry 3). It was also investigated if an amide
group in the β-position could assist in the C-F bond cleavage, but
only degradation of the substrate was observed under present
conditions. As stated, the distance between the functional group
and the fluorine will also influence the rate of the reaction. To
obtain such an effect, a relative rate study of the ring formation of
each charged intermediate were estimated based on the respective
half-life-times (t1/2) (Table 2).
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Table 3: Scope of different nucleohphiles.a
slower and full conversion into product (2n) was reached only after
several hours.
Table 4: Scope of different β-amino fluorides.
Substrate
conditions
product
1bb
2n (90%, 180 min)
2b (93%, 1 min)
2c (81%, 60 min)
Nuc: morpholine (1.05 equiv.)
Nuc: imidazole (1.5 equiv.)
1fa
2o (75%, 5 min)
2d (96%, 5 min)
2e (72%, 5 min)b
Nuc: BnOH (3.0 equiv.)
2f (70%, 60 min)
Nuc: BnSH (1.1 equiv.)
Nuc: H2O (1.1 equiv.)
1ga
2p (81%, 5 min)
2q (89%, 5 min)
2g (61%, 1 min)
2h (69%, 60 min)
Nuc: 2-hydroxypyridine (1.5 equiv.)
Nuc: H2O (100 equiv.)
1hb,c
2i (87%, 60 min)b
Nuc: MeMgCl
(1.1 equiv.)
2j (89%, 5 min)
2k (78%, 1 min)
Nuc: TMS-Cl
(3.0 equiv.)
Nuc: TMS-CN
(1.1 equiv.)
1ib
2r (90%, 5 min)
2l (71%, 5 min)b
2m (78%, 120 min)
1jd
2s (51%, 180 min)
Nuc: TMS-ethynyl (3.0 equiv.)
Nuc: phthalimide (1.5 equiv.)
a
La[N(SiMe3)2]3 (0.176 mmol), CH2Cl2 (1.0 mL), substrate (1.0 M in CH2Cl2, 0.16
a
La[N(SiMe3)2]3 (0.20 mmol), CH2Cl2 (1.25 mL), 1a (1.0 M in CH2Cl2, 0.20 mmol).
b
mmol), nucleophile (0.176 mmol). Isolated yields are reported. La[N(SiMe3)2]3
(0.20 mmol), CH2Cl2 (1.25 mL), substrate (1.0 in CH2Cl2, 0.20 mmol),
nucleophile (0.22 mmol). Isolated yields are reported. Bu2NH (0.60 mmol).
Isolated yields are reported. b Run in Et2O (1.25 mL)
M
c
d
With this methodology it was even possible to achieve C-C bond
La[N(SiMe3)2]3 (0.40 mmol), CH2Cl2 (1.25 mL), substrate (1.0 M in CH2Cl2, 0.20
mmol), morpholine (0.42 mmol).
formation
utilizing
Grignard
reagent
(MeMgCl,
2i),
ethynyltrimethylsilane (2l), or TMS-CN (2j), all isolated in high
yields. Noteworthy, in the case of 2l the TMS group is not cleaved. A
halogen exchange was accomplished by utilizing TMS-Cl as
nucleophile, and the corresponding β-chloro amine (2k) was
obtained within 1 min in high yield. The β-chloro amine (2k) was in
turn subjected to the same conditions as 1a (Table 1, entry 1), and
only 10% conversion into product 2a was observed within 1 min.
Thus, the β-chloro amine is much less reactive then the
corresponding β-fluoro amine (1a). The scope of the reaction was
further elaborated by its application on other β-amino alkyl
fluorides (Table 4). As presented in the literature, the azetidinium
ion is less reactive towards nucleophiles then the corresponding
aziridinium ion.11 The nucleophilic ring opening of 1b was a bit
Assistance from neighbouring groups allowed secondary alkyl
fluorides (1f-g) to easily be cleaved within
5 minutes. The
corresponding diamines were isolated in high yield (2o-p). Non-
symmetric aziridinium ions are generated from secondary alkyl
fluorides, and different isomeric products can be obtained in the
nucleophilic ring opening. In the examples displayed herein, 2p was
obtained in high regioselectivity (see SI for NMR). Thus, the
substitution predominantly occurs on the unsubstituted carbon of
the corresponding aziridinium ion intermediate.7,9,11 Furthermore,
even vicinal fluorides (1j yielding 2s) were substituted with the
assistance of a neighbouring group. Of the two possible charged
intermediates, the aziridinium ion was the major one, while the
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Chem. Soc., 2015, 137, 2468; S. Bloom, M. McCann and T.
Lectka, Org. Lett., 2014, 16, 6338; Z. Li, Z. Wang, L. Zhu, X.
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azetidinium ion was minor one. Allylbenzylamine (1h) and N-
[(trimethylsilyl)methyl]benzylamine (1i), which both are capable of
rearrangement,12 yielded the corresponding diamines (2q and 2r
respectively) within
5 min, indicating an extremely fast and
M. Wang and F. D. Toste, J. Am. Chem. Soc., 2014, 136
,
selective activation and substitution of the β-alkyl fluoride.
Compound 1k, with a trifluoromethyl group in the α-position, was
unreactive, resulting from a shorter and stronger C-F bond as more
fluorines are added to the carbon.13 No substitution of the
secondary fluoride took place in 5b, due to lack of neighbouring
group assistance from the oxygen.
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It is well established that the formation and ring opening of an
aziridinium ion proceeds via an SN2 pathway.4,7,9 Accordingly,
double inversion of anti-1l afforded anti-2t, while syn-1l did not
react at all (Scheme 2).
3
4
5
6
7
M. E. Tanner and S. Miao, Tetrahedron Lett., 1994, 35. 4073;
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V. V. Speybroeck, N. D. Kimpe and H.-J. Ha, Chem. Soc. Rev.,
2012, 41, 643.
Scheme 2: Investigating the stereochemical outcome of the substitution. La[N(SiMe3)2]3
(0.080 mmol), CD2Cl2 (0.5 mL), substrate (1.0 M in CD2Cl2, 0.080 mmol) BnMeNH (0.080
mmol). Analysed by 1H-NMR.
8
For recent selected examples see: M. Nonn, L. Kiss, M.
Haukka, S. Fustero and F. Fülöp, Org. Lett., 2015, 17, 1074; D.
Yang, L. Wang, F. Han, D. Li, D. Zhao and R. Wang, Angew.
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and J. Cossy, Chem. Soc. Rev., 2010, 39, 89; M. D’hooghe, S.
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The results communicated herein shows that the seemingly inactive
C-F bond should under these conditions be considered a very
reactive functional group. Thus, a combination of a chelating group
(N or S) in close proximity to fluorine enables selective and fast ring
formation by instantaneous C-F bond cleavage mediated by
La[N(SiMe3)2]3. Subsequent ring opening of these 3-membered
intermediates by various nucleophiles generated novel β-
substituted amines. Overall, our findings present a distinct and mild
methodology for C-F bond activation of several β-amino fluorides.
Not only does this approach of activation illustrate the convenience
of utilizing aziridinium ions as reactive intermediates, but it also
enables the usage of fluorine as a novel and interesting modular
functionality. In the laboratory we are currently exploring the usage
of β-amino fluorides in complex structures as well as developing
methodology for catalytic lanthanide mediated C/F substitution.
9
10 G. Cerichelli and L. Luchetti, Tetrahedron, 1993, 49, 10733;
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Notes and references
‡ Footnotes relating to the main text should appear here. These might include
comments relevant to but not central to the matter under discussion, limited
experimental and spectral data, and crystallographic data.
1
For a recent review see: P. A. Champagne, J. Desroches, J.-D.
Hamel, M. Vandamme and J.-P. Paquin, Chem. Rev., 2015,
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