Synthesis of 5-trichloromethyl-Δ4-1,2,4-oxadiazolines and their rearrangement into formamidine derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.04.012

A series of 5-trichloro-Δ⁴-1,2,4-oxadiazolines have been synthesised by 1,3-dipolar cycloaddition of nitrones to trichloroacetonitrile. These oxadiazolines rearrange into formamidine derivatives, via ring opening and a 1,2-aryl shift from carbo

Full text of DOI:10.1016/j.tetlet.2008.04.012

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3596–3599
Synthesis of 5-trichloromethyl-D4-1,2,4-oxadiazolines and
their rearrangement into formamidine derivatives
Gabriele Wagner *, Tim Garland
Chemical Sciences, FHMS, University of Surrey, Guildford, Surrey, GU2 7XH, United Kingdom
Received 12 January 2008; revised 14 March 2008; accepted 2 April 2008
Available online 7 April 2008
Abstract
A series of 5-trichloro-D4-1,2,4-oxadiazolines have been synthesised by 1,3-dipolar cycloaddition of nitrones to trichloroacetonitrile.
These oxadiazolines rearrange into formamidine derivatives, via ring opening and a 1,2-aryl shift from carbon to the adjacent amino
nitrogen. Both cycloaddition and rearrangement are facilitated when electron deficient nitriles and electron rich nitrones are used.
Ó 2008 Published by Elsevier Ltd.
Keywords: 1,2,4-Oxadiazolines; Amidines; Ring opening; Rearrangement
D4-1,2,4-Oxadiazolines are a comparatively rare class of
heterocycles, and to date, only a small number of deriva-
tives have been described in the literature. The first
reported D4-1,2,4-oxadiazolines were made by the cyclo-
addition of nitrones to organic cyanates,1 or by the reac-
tion of nitrosobenzene with D2-oxazolin-5-ones2 or nitrile
ylides.3 The latter method usually produces mixtures of
the D3- and D4-1,2,4-oxadiazolines, among other products.
The most general synthetic method involves the cycloaddi-
tion of nitrones to electron deficient nitriles.4 Aliphatic and
aromatic nitriles can be activated by coordination to a
suitable transition metal, for example, platinum(IV),5 plat-
inum(II)6 and palladium(II)7 centres. This technique also
allows for chemoselective activation of nitriles in the pres-
ence of a more reactive C@C bond.8 Moreover, a stereo-
selective synthesis in the coordination sphere of a chiral
Pt(II) complex has been developed, leading to enantiomeri-
cally enriched D4-1,2,4-oxadiazolines.9
mentioned,10 but not much effort seems to have been made
to analyse the products formed. D4-1,2,4-Oxadiazolines
bearing a carboxylate at C3 on the ring undergo ring open-
ing and decarboxylation to form N-acyl-formamidines,2 as
shown in Scheme 1. Similarly, a ring-opening H-migration
reaction of D4-1,2,4-oxadiazolines has been reported.11
Comparatively little is known about the reactivity and
general properties of D4-1,2,4-oxadiazolines. The poor sta-
bility of this type of compounds has occasionally been
Scheme 1. Rearrangements of D4-1,2,4-oxadiazolines reported in the
literature: (a) ring opening and decarboxylation;2 (b) ring opening and
H-migration.11
*
Corresponding author. Tel.: +44 0 1483 686831; fax: +44 0 1483
686851.
E-mail address: G.Wagner@surrey.ac.uk (G. Wagner).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.04.012

G. Wagner, T. Garland / Tetrahedron Letters 49 (2008) 3596–3599
3597
Formation of a related tautomeric rearrangement product
has been observed in the coordination sphere of a platinum
complex under an atmosphere of hydrogen.12 In this case,
the hydrogen attached to the amine nitrogen N2 and the
electron lone pair of the imino N4 was blocked by coordi-
nation to the metal.
These intriguing observations prompted us to undertake
the present study on the reaction of electron rich nitrones
with trichloroacetonitrile (see Scheme 2 and Table 1) in
the course of which we discovered a new type of rearrange-
ment of D4-1,2,4-oxadiazolines where ring opening is
accompanied by a highly selective 1,2 aryl shift from the
oxadiazoline C3 to the adjacent amine nitrogen N2, rather
than the imino nitrogen N4. In the course of the reaction,
no competing H migration was observed.
obtained exclusively, except for the 2,6-dimethoxy- and
2,4,6-trimethoxy-derivatives (2e and 2j) where a small
amount of the E-configured nitrone could be detected in
the NMR.
All the synthesised nitrones underwent facile cyclo-
addition with trichloroacetonitrile 1a to provide 5-tri-
chloromethyl-D4-1,2,4-oxadiazolines.15 The reaction of a
chloroform solution of the most reactive nitrone 2j (0.17
M) with a tenfold excess of 1a at 60 °C was complete within
approximately 1 h, but reactions with less activated nitro-
nes required 3–5 h under the same conditions. In the case
of nitrones 2e and 2j, the E-isomer reacted slightly faster
than the Z-isomer but, as expected, D4-1,2,4-oxadiazolines
3e and 3j, respectively, were obtained. The reaction of nit-
rone 2j with the less electron deficient dimethylmalononit-
rile 1b was slow and required 4 days to complete. These
trends are in good agreement with published kinetic data
of similar reactions,4b,c and show that the cycloaddition
is of ‘normal electron demand’.16 All the spectroscopic data
of oxadiazolines 3 agreed well with those reported previ-
ously for 5-trichloromethyl-oxadiazolines,4b,c including
the characteristic broad NMe and N–CH–N signals in
the 1H and 13C NMR, which are due to nitrogen inversion
taking place in the NMR dynamic range at room tempera-
ture. The chemical shift of the CCl3 carbon (85 ppm) is
similar to that in trichloroacetic anhydride (87.9 ppm)
but significantly higher than in trichloroacetonitrile
(70.1 ppm). Under GC–MS conditions, all the oxadiazo-
lines underwent retro-cycloaddition, as previously
observed for similar compounds.4b,c,10
Nitrones 2a–j were synthesised by the condensation of
the corresponding aldehydes with N-methyl-hydroxyl-
amine under the standard conditions.13 As expected for
acyclic aldonitrones,14 the Z-configured products were
Under prolonged reaction times the oxadiazolines rear-
ranged into new products.17 This reaction is facilitated
when the substituent at C5 of the oxadiazoline is electron
deficient and the migrating aryl group is electron rich,
hence D4-1,2,4-oxadiazolines that form easily are also fast
to rearrange. The elemental analysis and spectroscopic
data revealed the new product to be an isomer of the parent
oxadiazoline for which structures 4 to 7 are possible (see
Scheme 3). The 13C NMR signal of the CCl3 moiety
Scheme 2. Synthesis of the D4-1,2,4-oxadiazolines studied in this work and
their thermal rearrangement into formamidine derivatives.
Table 1
Reaction conditions for the cycloaddition and rearrangement reactions
Nitrone
Ar
D4-1,2,4-Oxadiazoline
Formamidine
No.
No.
Conditions
Yield
No.
Conditions
Yield
2a
2b
2c
2d
2e
2f
2g
2h
2i
2-Methoxyphenyl
3a
3b
3c
3d
3e
3f
60 °C, 5 h
60 °C, 4 h
60 °C, 3 h
60 °C, 4 h
60 °C, 3 h
60 °C, 4 h
60 °C, 3 h
60 °C, 4 h
60 °C, 3 h
60 °C, 1 h
60 °C, 4 d
(a)
(a)
(a)
(a)
(a)
(a)
(a)
(a)
(a)
(a)
(a)
4a
4b
4c
4d
4e
4f
60 °C, 8 d
60 °C, 8 d
60 °C, 3 d
60 °C, 8 d
60 °C, 8 d
60 °C, 4 d
60 °C, 8 d
60 °C, 8 d
60 °C, 2 d
60 °C, 12 h
60 °C, 70 d
(b)
(b)
2,3-Dimethoxyphenyl
2,4-Dimethoxyphenyl
2,5-Dimethoxyphenyl
2,6-Dimethoxyphenyl
3,4-Dimethoxyphenyl
2,3,4-Trimethoxyphenyl
3,4,5-Trimethoxyphenyl
2,4,5-Trimethoxyphenyl
2,4,6-Trimethoxyphenyl
2,4,6-Trimethoxyphenyl
80%
(b)
78%
44%
(b)
3g
3h
3i
4g
4h
4i
(b)
79%
82%
66%
2j
3j
3k
4j
4k
2j
(a): NMR yields are nearly quantitative.
(b): NMR yields 15–25%, the rearrangement is accompanied by side reactions.

3598
G. Wagner, T. Garland / Tetrahedron Letters 49 (2008) 3596–3599
Scheme 4. General EI mass fragmentation pattern of formamidines 4.
Scheme 3. Proposed mechanism for the rearrangement of D4-1,2,4-
oxadiazolines into formamidine derivatives. Pathway (a) leads to the
observed product, the alternative pathway (b) and the formation of
products 6 and 7 were not observed.
amino substituted cyanate ion, which is usually the base
peak in the spectrum, further decomposes via loss of a
methyl radical from the amino nitrogen (ꢀ15 mass units,
typically 2–5%), or under elimination of methylcyanate
(ꢀ57 mass units, typically 30–35%). Only structure 4 is
compatible with this type of fragmentation (see Scheme 4).
appeared at 96 ppm in the typical range for trichloroacetyl
groups, similar to trichloroacetamide (93.0 ppm) or tri-
1
chloroacetyl chloride (94.1 ppm). H and 13C NMR data
1
revealed the presence of an N–Me, an N–Ar, a C@O and
an imino CH moiety. The latter appeared at a 13C chemical
shift of 163–166 ppm and was evident as a CH group in
the DEPT spectrum. This correlated with a proton singlet
In the H NMR, a strong NOE between the NMe and
the aryl OMe or H in the ortho position was observed, in
support of structure 4. Accordingly, the HMBC spectrum
displayed a strong cross peak for a long range correlation
between the NMe protons and the ipso-carbon of the aryl
substituent, suggesting that these two groups are bound
to the same nitrogen. Additionally, DFT calculations
1
at d 8.3–8.7 in the H, 13C-HSQC, as one would expect
1
for a N@CH group. The H, 13C-HSQC also showed that
all the protons correlated to a carbon, excluding the possi-
ble presence of an NH group. The IR spectrum suggests the
presence of a C@O and a C@N group, and confirmed the
absence of an NH group. On the basis of these observa-
tions, structures 6 and 7 can be ruled out although their
formation through an acid mediated process or rearrange-
ment via H migration would have been plausible. The
remaining two structures, 4 and 5, can form via rearrange-
ment of D4-1,2,4-oxadiazolines as shown in Scheme 3. Both
pathways involve an electrocyclic reaction with ring open-
ing and aryl migration, but the direction of the electron
flow is different. Consequently, pathway (a) involves aryl
migration onto the amino nitrogen, whereas the alternative
pathway (b) requires 1,2 aryl shift onto the imino N. The
latter product is analogous to those described previously
in the case of H-migration.2,11
*
(B3LYP/6-31G ) have been undertaken for the derivatives
where Ar = Ph. These predicted that isomer 4 was
39.6 kcal/mol more stable than 5.
The proposed reaction mechanism involves formation of
a Z-configured product. Unfortunately, the stereochemis-
try cannot be determined from NOE measurements due
to the lack of protons in the trichloroacetyl group. Com-
pound 4k, bearing a dimethylcyanomethyl moiety in the
place of the CCl3 group also did not display any NOE sig-
nals, which may be due to the compound adopting a pre-
ferred conformation where the dimethylcyanomethyl
group points away from the NMeAr moiety, as depicted
in Scheme 2. Attempts to determine the stereochemistry
3
from the JCH coupling constant between the formamidine
proton and the carbonyl carbon of the trichloroacetyl
group were not fully conclusive due to the non-availability
On the basis of our NMR and mass spectrometry data,
the product obtained in the experiment can be clearly iden-
tified as structure 4 whereas 5 can be ruled out. The typical
MS fragmentation pattern is characterised by the loss of a
CCl3 radical from the molecular radical ion. The remaining
3
of the E-isomer for comparison. For compound 4j, JCH
was determined to be 6.3 Hz, which is in between the values
for Z- or E-substituted propenoic acids (3Jtrans = 10 Hz,
3
3Jcis = 5 Hz),18 and also significantly lower than the JCH

G. Wagner, T. Garland / Tetrahedron Letters 49 (2008) 3596–3599
3599
value of 12 Hz observed in purine derivatives.19 However,
our DFT calculations suggest that the H–C–N–C moiety
in 4 is not fully planar, and the Karplus dependence of
3JCH on the dihedral angle predicts that any deviation from
planarity should lower the coupling constant. In light of
this a value of 6.3 Hz is acceptable for trans- but not a
cis-coupling, thereby supporting the Z-configuration of 4.
In conclusion, a new method is reported for the synthe-
sis of N-acyl-formamidines from easily accessible starting
materials such as nitrones and nitriles, by means of a 1,3-
dipolar cycloaddition followed by a new type of rearrange-
ment consisting of ring opening and a concomitant 1,2-aryl
shift from the oxadiazoline carbon to the adjacent amino
nitrogen.
Danks, T. N.; Wagner, G. Dalton Trans. 2004, 166; (c) Coley, H. M.;
Sarju, J.; Wagner, G. J. Med. Chem. 2008, 51, 135.
7. Wagner, G. Inorg. Chim. Acta 2004, 357, 1320.
8. Desai, B.; Danks, T. N.; Wagner, G. J. Chem. Soc., Dalton Trans.
2003, 2544.
9. Wagner, G.; Haukka, M. J. Chem. Soc., Dalton Trans. 2001, 2690.
10. Sang, H.; Janzen, E. G.; Poyer, J. L. J. Chem. Soc., Perkin Trans. 2
1996, 1183.
11. Plate, R.; Hermkens, P. H. H.; Smits, J. M. M.; Nivard, R. J. F.;
Ottenheijm, H. C. J. J. Org. Chem. 1987, 52, 1047.
12. Charmier, M. A. J.; Haukka, M.; Pombeiro, A. J. L. Dalton Trans.
2004, 2741.
13. Tyrrell, E.; Allen, J.; Jones, K.; Beauchet, R. Synthesis 2005, 2393.
14. Bjorgo, J.; Boyd, D. R.; Neill, D. C.; Jennings, W. B. J. Chem. Soc.,
Perkin Trans. 1 1977, 254.
15. General procedure for the synthesis of 3-(2,4,6-trimethoxyphenyl)-2-
methyl-5-trichloromethyl-D4-1,2,4-oxadiazoline (3j): A 10-fold excess of
trichloroacetonitrile (100 ll, 144.4 mg, 1 mmol) was added to a
solution of nitrone 2j (0.1 mmol) in CDCl3 (0.5 ml). The reaction
mixture was stirred at 60 °C and the progress of the reaction was
monitored by 1H NMR at regular time intervals. The cycloaddition
was completed within 1 h. The crude product was used for the
subsequent reactions without further purification. GC-TOF MS:
225 [MꢀCCl3CN (nitrone)]+ (11%), 209 [nitroneꢀO]+ (6%), 208
[nitroneꢀOH]+ (8%), 194 [nitroneꢀOMe]+ (38%), 179 [nit-
Acknowledgements
The authors are grateful to the EPSRC for the provision
of a studentship and the Proof of Concept Fund of the
University of Surrey for supporting this work.
roneꢀNMeOH]+ (100%). IR (neat film, selected bands), cmꢀ1
:
Supplementary data
3004, 2962 and 2941 m m(C–H), 2842 m m(C–H of OMe), 1670 s m
(C@N), 1610 m m (C@C). 1H NMR (500 MHz, CDCl3), d (ppm):
2.95 (s, br s, 3H, NMe) 3.78 (s, 3H, OMe), 3.79 (s, 6H, 2 ꢁ OMe), 6.10
(s, 2H, aryl-H), 6.36 (s, br s, 1H, N–CH–N). 13C NMR (125.8 MHz,
CDCl3), d (ppm): 48.4 (CH3, NMe), 55.5 (CH3, OMe), 56.0 (CH3,
2 ꢁ OMe), 85.8 (Cq, CCl3), 87.6 (CH, N–CH–N), 91.1 (aryl CH),
106.5, 159.1 and 162.3 (aryl Cq), 160.1 (Cq, C@N).
Synthetic procedures and spectroscopic data of nitrones
2, oxadiazolines 3 and formamidines 4 are available. Sup-
plementary data associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2008.04.012.
16. (a) Wagner, G. Chem. Eur. J. 2003, 9, 1503; (b) Wagner, G.; Danks,
T. N.; Desai, B. Tetrahedron 2008, 64, 477.
References and notes
17. General procedure for the synthesis of N-(2,4,6-trimethoxyphenyl)-N-
methyl-N 0 -(trichloroacetyl)-formamidine (4j): The crude D4-1,2,4-
oxadiazoline 3j (0.1 mmol) in CDCl3 (0.5 ml) or, alternatively, a
solution of nitrone 2j (0.1 mmol) and trichloroacetonitrile (10 ll,
14.44 mg, 0.1 mmol) in CDCl3 (0.5 ml) was heated to 60 °C and the
reaction was periodically monitored by 1H NMR spectroscopy. The
cycloaddition to the D4-1,2,4-oxadiazoline and the subsequent rear-
rangement into the formamidine derivative was complete after 12 h.
The product was purified by chromatography (SiO2/CH2Cl2) and
obtained as a colourless solid. Yield 82%. Elemental Anal. Calcd for
C13H15Cl3N2O4: C, 42.24; H, 4.09;N, 7.58. Found: C, 42.38; H, 3.87;
N, 7.58. GC-TOF MS: 368, 370, 372 [M]+ (1%, 1%, 0.3%), 337, 339,
341 [MꢀOMe] + (3%, 3%, 0.8%), 251 [MꢀCCl3]+ (100%), 236
[MꢀCCl3–Me] + (4%), 194 [MꢀCCl3–MeNCO] + (31%). Mp 124–
126 °C.
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