Radical and Nitrenoid Reactivity of 3-Halo-3-phenyldiazirines

Article abstract of DOI:10.1021/acs.orglett.6b01753

3-Halo-3-phenyl-3H-diazirines (halogen = Br or Cl) undergo a dissociative single-electron transfer from alkyllithiums (RLi) in THF-based solvent mixtures. The resulting 3-phenyldiazirinyl radical, observed by EPR spectroscopy, is eventually transformed to benzonitrile. In Et₂O, 2 equiv of RLi add to both nitrogens of halodiazirine N=N bond, affording N,N′-dialkylbenzamidines. The nitrenoid reactivity of some N-alkyl-1H-diazirine intermediates is manifested by their insertion into the α-C-H bond of THF or Et₂O.

Full text of DOI:10.1021/acs.orglett.6b01753

Letter
pubs.acs.org/OrgLett
Radical and Nitrenoid Reactivity of 3‑Halo-3-phenyldiazirines
Rafael Navratil,† Jan Tarabek,‡ Igor Linhart,† and Tomas Martinu*,†
́
́
́
́
̌
̊
†Department of Organic Chemistry, University of Chemistry and Technology, Technicka
‡Institute of Organic Chemistry and Biochemistry CAS, v.v.i., Flemingovo nam
estí 542/2, 166 10 Prague, Czech Republic
́
5, 166 28 Prague, Czech Republic
́
̌
S
* Supporting Information
ABSTRACT: 3-Halo-3-phenyl-3H-diazirines (halogen = Br or
Cl) undergo a dissociative single-electron transfer from
alkyllithiums (RLi) in THF-based solvent mixtures. The
resulting 3-phenyldiazirinyl radical, observed by EPR spec-
troscopy, is eventually transformed to benzonitrile. In Et2O, 2
equiv of RLi add to both nitrogens of halodiazirine NN bond, affording N,N′-dialkylbenzamidines. The nitrenoid reactivity of
some N-alkyl-1H-diazirine intermediates is manifested by their insertion into the α-C−H bond of THF or Et2O.
Scheme 1. Attempted H/D Exchange with Diazirine 3
he chemistry of 3H-diazirines is dominated by denitroge-
1
T
nation of their CN2 cycles affording carbenes, but other
reactive intermediates, e.g. diazirinyl radicals,2−5 diazirinyl
anions,5−7 or imidoylnitrenes,3b,8,9,10a,11 have also been
observed or implicated in reactions of diazirines under specific
conditions. Here, we report the solvent-dependent radical and
nitrenoid reactions of 3-halo-3-phenyldiazirines (1) with
alkyllithiums that have resulted from our search for the 3-
1
product yields have been determined by H NMR spectrosco-
py.
−
phenyldiazirinyl anion Phc-CN2 (2) in solution. Our
After these initial observations we turned our attention to the
lithium−halogen exchange reactions of bromodiazirine 1a (the
potentially more suitable iododiazirines are not synthetically
available). The reaction of 1a with 3 equiv of t-BuLi in 5:1:1
THF−Et2O−pentane at −115 °C followed by quenching with
MeOH afforded tert-butyl ketimine 6 as the only product in
93% yield (Scheme 2). The formation of 6 can be explained by
observations shed new light on the reactivity of halodiazirines
with electron donors and nucleophiles, with high relevance to
the diazirine halogen exchange reactions.1,12
Ab initio calculations have indicated that the nonaromatic
−
4π-electron cycle of 3-unsubstituted diazirinyl anion Hc-CN2
is stabilized by the inductive effect of two nitrogen atoms and
by cyclic conjugation.13 In accordance with theory, several
diazirinyl anions (including 2) have been generated in the gas
phase by deprotonation of the corresponding diazirines;6
however, these species have remained elusive in solution.
Anion 2 was considered as an intermediate in superoxide-
initiated radical dehalogenation of 3-bromo-3-phenyldiazirine
(1a),5 and 3-alkoxydiazirinyl anions were suggested as
intermediates in anionic fragmentation of 3-halodiazirine-3-
carboxylic esters.7 To the best of our knowledge, no attempt at
deprotonation of a diazirine ring in solution has been reported
despite its relatively favorable predicted acidity (pKa ≈ 34−39
for the 3,3-unsubstituted diazirine in DMSO).13 Other
reactions can, however, be expected to occur when diazirines
are exposed to the usual strong bases. We have indeed observed
that, instead of the diazirine ring lithiation (followed by
attempted deuteration), t-BuLi adds to the NN bond14 of 3-
phenyldiazirine (3) even at −115 °C to form tert-butyldiaziri-
dine 4 in quantitative yield after quenching with MeOH-d4 and
aqueous workup (Scheme 1). Similarly, LDA/iPr2ND does not
accomplish the CN2 ring H/D exchange with 3, but it reduces
the NN bond, affording diaziridine 5 in 64% yield.15 NOTE:
All reactions reported here have been carried out by the
addition of a diazirine to a solution of organolithium, and the
Scheme 2. Reaction of Diazirine 1a with t-BuLi
one-electron reduction of 1a to nitrogen-centered radical 7 with
the first equivalent of tert-BuLi, dimerization of 7 to bis-1H-
diazirine 8, and its denitrogenation to benzonitrile (9) which
reacts with the second equivalent of the lithium reagent; a
mixture of 6 and 9 is indeed obtained if only 1 equiv of t-BuLi
is used. The irreversible reduction of 1a to 9 had been
previously described using electrochemistry on platinum14 and
reactions with trialkylstannyl or trialkylsilyl radicals,2 superoxide
ion, or lithium naphtalenide.5 We have also found a good
Received: June 16, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01753
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Organic Letters
Letter
agreement between the yield of 6 and the volume of gas,
assumed to be N2, evolved in the reaction of 1a with 5 equiv of
t-BuLi at −60 °C (75% of 6 and 70% of N2 by ideal gas law; the
reaction temperature was increased to facilitate the liberation of
gas).
In an effort to minimize the undesired single-electron
transfer (SET) from the organolithium to the halodiazirine,
we chose to replace t-BuLi with MeLi. The reactions of
bromodiazirine 1a or chlorodiazirine 1b with MeLi, however,
afforded nitrile 9 at −115 °C again, and mixtures of 9 and
methyl ketimine 10 at −78 °C (Scheme 3). Unlike 6, imine 10
Figure 2. Spin density (iso value = 2.4 × 10−3 e/Å3) of radical 7
calculated at the B3LYP/EPR-III//B3LYP/6-311+G(d,p)/CPCM-
(THF) level. Blue surfaces: positive values (α spins). Red surfaces:
negative values (β spins).
Scheme 3. Reaction of Diazirines 1 with MeLi
Scheme 4. Dehalogenation of Diazirine 1a to 3
is prone to hydrolysis and it is accompanied by varying
amounts of acetophenone. Since 1a always reacts faster than 1b
(typically 100% vs 70% conversion in 20 min at −115 °C in 2:1
THF−Et2O), it is likely that the irreversible SET from MeLi is
concerted with the dissociation of the halide ion, the bromide
being a better leaving group than the chloride ion. We have
eventually confirmed the intermediacy of the diazirinyl radical
7, expected to be involved in the formation of 9, by EPR
spectroscopy at room temperature. The spectrum of the
nitrogen-centered radical 7, corresponding to literature data2a
and our DFT calculations, was obtained upon mixing 1a with
MeLi in a flow cell EPR cavity (Figures 1 and 2).
reaction with MeOH-d4 suggests the intermediacy of an anionic
species, potentially the lithiated diazirine 2-Li or the hyper-
valent bromine ate complex 11-Li (Figure 3). The latter
Figure 3. Possible intermediates in dehalogenation of diazirine 1a.
possibility is consistent with no observed favorable effect of the
electron-withdrawing CF3 or NO2 groups in the para position
of the substrate’s phenyl ring on the yield of the dehalogenated
product. The formation of the anionic intermediate appears to
be kinetically preferred to the SET process leading to nitrile 9,
as the 3:9 ratio tends to be higher at lower conversions (1:1 vs
1:2.8 at 40% vs 75% conversion). The intermediate is unstable
at −78 °C; brief warming of the reaction mixture to this
temperature followed by recooling to −115 °C and quenching
with MeOH resulted in quantitative conversion of 1a to the
mixture of 9 and 10 with no 3 observed (cf. Scheme 3). The
lability of the ate complex 11-Li can be explained by its
dissociation back to 1a and MeLi, or by its loss of an electron
resulting in the formation of radical 7 via a bromine-centered
radical 11′ eliminating MeBr (such a process has been
described for iodine ate complexes16). Alternatively, if the
intermediate corresponds to 2-Li, radical 7 could be formed
directly by the loss of an electron.
While MeLi or t-BuLi brought about the reduction of
bromodiazirine 1a to nitrile 9 in THF−Et2O−(pentane)
mixtures above −115 °C, the reaction of 1a with n-BuLi
under similar conditions afforded only traces of 9, the major
product being N,N′-di-n-butylbenzamidine (12). Moreover, we
identified minor amounts (up to 10%) of N,N′-dimethyl-
benzamidine (13) in the reaction products of MeLi with
chlorodiazirine 1b. In further experiments using Et2O in the
absence of THF, the reaction of 1a with n-BuLi afforded 12 in
78% yield, and 1a or 1b with MeLi gave 13 in 53% or 70%
yields, respectively (Table 1); all reactions proceeded with
virtually no reduction to 9. Under similar conditions, t-BuLi
Figure 1. EPR spectrum of 3-phenyldiazirinyl radical (7), centered at g
= 2.0039, a(14N) = 0.749 mT; generated from THF solutions of
diazirine 1a (8.5 × 10−2 M) and MeLi (5.1 × 10−1 M) at room
temperature.
At very low temperatures (down to −120 °C), the reactions
of 1a with MeLi also yielded small amounts of dehalogenated
diazirine 3; no such reaction was observed with 1b. The lack of
reaction progress with time much beyond the conversion
reached immediately after all of 1a had been syringe-pumped to
the reaction mixture indicates that the reaction may actually
occur in hotspots created during the addition process. The
overall yield of 3 was maximized to 20% (at 75% conversion)
when a low total concentration of 1a (ca. 5 × 10−3 M) and a
sufficient concentration of MeLi (ca. 5 × 10−1 M) were used,
the reagent thus being in a 100-fold excess relative to 1a
(Scheme 4). No improvement in the yield of 3 resulted from
the use of common additives such as LiCl, LiBr, or HMPA.
Complete deuteration of 3 on the CN2 ring after quenching the
B
DOI: 10.1021/acs.orglett.6b01753
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Letter
Table 1. Formation of N,N′-Disubstituted Amidines
R, R′
n-Bu (12)
reagent
n-BuLi
equiv
solvent
t (°C)
yield (%)
2
Et2O/hexane 3:1
Et2O
0
78
a
b
Me (13)
MeLi
20 (5)
−110 (−78)
−110
−78
53 (70)
20 [15]
65
t-Bu (14) [t-Bu,H (15)]
iPr (16)
t-BuLi
5
3
Et2O/pentane 3:1
THF
iPrMgCl·LiCl
a
b
Using chlorodiazirine 1b. No reaction at −110 °C.
and 1a afforded N,N′-di-tert-butyl- and N-tert-butylamidines 14
and 15 in 20% and 15% yields, respectively, with traces of imine
6. Our results are in agreement with the previously known
addition of PhLi to 1b in Et2O affording N,N′-diphenyl-
benzamidine in a high yield.9 We note in passing that N,N′-
diisopropylamidine 16 can be prepared in 65% yield from 1a
and the Turbo Grignard reagent iPrMgCl·LiCl in THF, instead
of the much less readily available iPrLi.
From the above-mentioned observations, the following
mechanistic scheme can be drawn: (i) Alkyllithium transfers
one electron to a halodiazirine in an irreversible dissociative
SET generating a diazirinyl radical, eventually affording a nitrile.
This pathway appears to be promoted by solvents based on
THF. With 1a and MeLi, SET may be preceded by the
formation of an anionic intermediate, stable only at very low
temperatures and affording the dehalogenated diazirine 3 upon
protonation. (ii) Competing with SET is the nucleophilic
addition of organolithium to the halodiazirine NN bond.
Upon a loss of the halide ion, the resulting N1-substituted 1H-
diazirine undergoes the addition of the second equivalent of
organolithium to position N2.
sigmatropic rearrangement10 should be reconsidered; examples
of such a rearrangement have been reported.18
Remarkably, in a reaction of 1a with 3:1 MeLi/ZnCl2 (the
resulting Me3ZnLi was tested for the improvement of the yield
of 3 in the dehalogenation of 1a), we observed a formal
insertion of the putative 1H-diazirine intermediate 17 into the
α-C−H bond of THF. N-Methyl-N′-(2-oxolanyl)amidine 18
was obtained along with dimethylamidine 13 in 40% and 42%
yields, respectively (Scheme 6). We had previously reported a
Scheme 6. Formation of C−H Insertion Product 18
similar diazirine−nitrogen insertion into the α-C−H bond of
Et2O in a reaction of a 3-bromo-3H-diazirine-3-carboxylic ester
with phenylmagnesium bromide, affording dihydrooxazole 21
via 1H-diazirine 19 (Figure 4).11 The mechanism of these
Apart from phenyl- and alkyllithiums in Et2O, trisubstituted
phosphines in CH2Cl2 have also been reported to add to both
nitrogen atoms of halodiazirines 1, affording various N,N′-
bis(phosphine)benzamidinium salts.10 It is important to note
that this reactivity differs substantially from the “signature”
reaction of halodiazirines−the halogen exchange by the
fluoride, alkoxide, or cyanide ions or by primary and secondary
amines.1,12 According to the generally accepted “double SN2′”
mechanism, the 1H-diazirine intermediate undergoes a second
nucleophilic attack at C3, releasing the first equivalent of a
nucleophile from N1 (path a in Scheme 5). The amidine-
Figure 4. 1H-Diazirine 19 and its follow-up products in Et2O (ref 11).
insertions is unclear at present, and we remain focused on its
elucidation. A question also arises whether the intermediacy
and subsequent hydrolysis of the corresponding O-ethyl
hemiaminal may explain the observed formation of mono-
substituted amidine 15 (cf the previously reported 20 → 22).
In the above-mentioned nucleophilic addition and C−H
insertion reactions, the putative 1H-diazirine intermediates
exhibit nitrenoid reactivity. In the literature, 1H-diazirines are
often postulated to isomerize to imidoylnitrenes,3b,8,9,10a,19 but
no such ring opening has been observed experimentally20 or
described computationally. In fact, calculations supported by
observation in a cryogenic matrix show that the CN2 ring of 3-
methyl-1H-diazirine (23) is distorted, with a N−C−N angle of
ca. 78° resembling the ground-state singlet acetimidoylnitrene
in which the nitrene center is stabilized by nonbonding
electrons of the imidoyl nitrogen (Figure 5).21 No other
structures with a smaller or larger N−C−N angle were found
computationally on the singlet potential energy surface. The
same effect has been generally accepted for the ground-state
singlet acetylnitrene/3-methyloxazirene (24a) and benzoyl-
nitrene/3-phenyloxazirene (24b) hybrids22 with the larger O−
C−N angle of ca. 86°, most likely due to the less efficient
stabilization of the nitrene center by the more electronegative
Scheme 5. Reactions of 3H- and 1H-Diazirines with
Nucleophiles
forming and the halogen exchange pathways have not been
known to occur simultaneously, with the exception of the
reaction of 1a with tetrabutylammonium cyanide, affording 3-
phenyldiazirine-3-carbonitrile17 and traces of N,N′-dicyano-
benzamidine.11 In light of the above-mentioned facts, it will be
necessary to analyze the effect of various nucleophiles, solvents,
and other conditions on the reactivity of 1H-diazirines. The
suggestion that the second step of the diazirine halogen
exchange may not involve an SN2′-like process but a [1,3]-
C
DOI: 10.1021/acs.orglett.6b01753
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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duality.
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1060.
oxygen atom. The lack of recognition of the 1H-diazirine/
imidoylnitrene duality has led to a conclusion that, based on
computational results, singlet imidoylnitrenes are not inter-
mediates in amidine-forming double nucleophilic additions of
phosphines to bromodiazirine 1a.10b The properties of 1H-
diazirine nitrenoids should therefore be studied in detail to
determine the effect of intramolecular stabilization on their
reactivity.
̌
́
(11) Kolar
́
o
̌
va,
́
P.; Cmolík, V.; Linhart, I.; Alvarez Martínez, I.;
Martinu, T. Tetrahedron Lett. 2013, 54, 6764.
̊
(12) Creary, X. Acc. Chem. Res. 1992, 25, 31.
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56, 4062.
(14) Chemistry of Diazirines; Liu, M. T. H., Ed.; CRC Press, Inc.:
Boca Raton, FL, 1987; Vols. I and II.
The following conclusions can be drawn from this work: (i)
3-Halo-3-phenyl-3H-diazirines may be considered as mecha-
nistic probes for distinguishing between SET and the direct
nucleophilic reactivity of organolithiums under various
conditions, affording benzonitrile in the former and N,N′-
disubstituted amidines in the latter case. (ii) The bis-
electrophilic nature of the NN bond in halodiazirines may
be more extensively exploited in the synthesis of N,N′-
disubstituted amidines. (iii) The 1H-diazirine/imidoyl-nitrene
duality should be considered in future work, with special regard
to the reactivity with nucleophiles under various conditions
both reactions at positions N2 and C3 are possible.
(15) LDA is known to reduce the NN bond of azobenzenes, but to
the best of our knowledge no LDA reduction of diazirines has been
̀
reported: Nguyen, T. T. T.; Boussoniere, A.; Banaszak, E.; Castanet,
A.-S.; Nguyen, K. P. P.; Mortier, J. J. Org. Chem. 2014, 79, 2775. In
spite of its extreme structural simplicity, diaziridine 5 has not been
described in the literature thus far.
(16) Hoffmann, R. W.; Bronstrup, M.; Muller, M. Org. Lett. 2003, 5,
̈
̈
313.
(17) Moss, R. A.; Kmiecik- Ławrynowicz, G.; Cox, D. P. Synth.
Commun. 1984, 14, 21.
(18) Martinu, T.; Dailey, W. P. J. Org. Chem. 2006, 71, 5012.
(19) Beg
134, 5339.
́ ́
ue, D.; Qiao, G. G.; Wentrup, C. J. Am. Chem. Soc. 2012,
(20) A 1-phosphoranyl-3-thioxophosphoranyl-1H-diazirine may be a
possible exception: Dubau-Assibat, N.; Baceiredo, A.; Bertrand, G. J.
Am. Chem. Soc. 1996, 118, 5216.
(21) Nunes, C. M.; Araujo-Andrade, C.; Fausto, R.; Reva, I. J. Org.
Chem. 2014, 79, 3641.
(22) (a) Liu, J.; Mandel, S.; Hadad, C. M.; Platz, M. S. J. Org. Chem.
2004, 69, 8583. (b) Sherman, M. P.; Jenks, W. S. J. Org. Chem. 2014,
79, 8977. (c) Pritchina, E. A.; Gritsan, N. P.; Maltsev, A.; Bally, T.;
Autrey, T.; Liu, Y.; Wang, Y.; Toscano, J. P. Phys. Chem. Chem. Phys.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01753.
Experimental procedures and spectroscopic data for
compounds 4, 5, 12−16, and 18; summary of DFT
calculations and detailed description of EPR experiment
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: martinut@vscht.cz.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Institutional research concept (RVO61388963) by IOCB (J.
■
Tarab
́
ek) is gratefully acknowledged. Dr. Hana Dvora
̌
k
́
ova
́
(UCT) is acknowledged for measuring high temperature NMR
spectra, and Ms. Kveta Bartova (UCT), for technical assistance.
̌
́
́
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D
DOI: 10.1021/acs.orglett.6b01753
Org. Lett. XXXX, XXX, XXX−XXX