Preparation of 2-azaallyl anions and imines from N-chloroamines and their cycloaddition and allylation

Article abstract of DOI:10.1016/j.tetlet.2010.11.142

Exposure of N-chloroamines to KO^tBu or LDA, in the presence of PMDETA or HMPA, provides 2-azaallyl anions capable of π4s + π2s cycloaddition reactions with a range of olefins. Good yields were achieved with stabilised systems, however, they were more modest when accessing semi-stabilised 2-azaallyl anions. By modifying the reaction conditions, one-pot dehydrochlorination/allylation can also be achieved with a range of N-chloroamines.

Full text of DOI:10.1016/j.tetlet.2010.11.142

Tetrahedron Letters 52 (2011) 671–674
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation of 2-azaallyl anions and imines from N-chloroamines
and their cycloaddition and allylation
⇑
Shveta Pandiancherri, David W. Lupton
School of Chemistry, Monash University, Clayton 3800, Victoria, Australia
a r t i c l e i n f o
a b s t r a c t
Exposure of N-chloroamines to KOtBu or LDA, in the presence of PMDETA or HMPA, provides 2-azaallyl
Article history:
Received 10 September 2010
Revised 17 November 2010
Accepted 26 November 2010
Available online 2 December 2010
anions capable of
p4s + p2s cycloaddition reactions with a range of olefins. Good yields were achieved
with stabilised systems, however, they were more modest when accessing semi-stabilised 2-azaallyl
anions. By modifying the reaction conditions, one-pot dehydrochlorination/allylation can also be
achieved with a range of N-chloroamines.
Ó 2010 Published by Elsevier Ltd.
Keywords:
2-Azaallyl anion
N-Chloroamine
Halogen–metal exchange
Allylation
In the seminal work of Kauffmann and Köppelmann, the
4s + 2s cycloaddition of 2-azaallyl anions and olefins was dis-
anions. To this end we envisaged halogen–metal exchange of
N-haloamines as a potentially useful method.
p
p
covered.1 In these studies 2-azaallyl anions 1, bearing two or more
aryl substituents, were formed by deprotonation of the corre-
sponding imine, however, with one or no aryl groups this reaction
failed.1b Addressing this limitation Kanemasa and Tsuge developed
silicon-based transmetalation approaches,2 while Pearson
exploited imino stannanes to access semi-stabilised (one aryl)
and non-stabilised (no aryl) 2-azaallyl anions.3 While the latter ap-
proach has proved highly useful, shortcomings remain. As stated
by Pearson, methods for the generation of ‘nonstabilized 2-azaallyl
anions with a longer lifetime and preferably featuring tin-free tech-
niques are required.’3a Inspired by these challenges we commenced
studies aimed at developing new methods for the preparation of
2-azaallyl anions. Herein we report a novel tin-free approach to
stabilised and semi-stabilised 2-azaallyl anions exploiting N-chlo-
roamines, that is, 2, as starting materials. In addition, the use of
N-chloroamines in a one-pot dehydrohalogenation/allylation is re-
ported (Scheme 1).
N-Chloroamines (i.e., 2) are useful aminating agents that under-
go substitution reactions with organometallics,6,7 heteroaromat-
ics8 and enolates.9 While the halogen–metal exchange of these
reagents has not been developed, this process has been observed
as a side reaction.6,10,11a To explore the use of N-chloroamines in
2-azaallyl anion formation, N-methyl benzylamine N-chloride
(2a) was prepared and its
p4s + p2s cycloaddition with styrene
investigated. Using LDA in the absence of a donor failed to deliver
pyrrolidine 4a, however, reductive dechlorination of 2a demon-
strated the viability of halogen–metal exchange (Table 1, entry
1). To favour b-hydride elimination HMPA/TMEDA was trialed as
a pseudo tridentate donor in the presence of LDA. Under these con-
ditions, isomeric cycloadducts 4a and 4a0 formed in a combined
yield of 32% and with 1.3:1 regioselectivity (Table 1, entry 2).3c
Changing the donor to N,N,N0,N0-pentamethyldiethylenetriamine
(PMDETA) failed to increase the yield, however, the reaction now
occurred with complete regioselectivity (Table 1, entry 3).
Our strategy builds upon the observation that 2-azaallyl anions
(i.e., 1) can be formed from metalated dibenzylamides, which un-
dergo b-hydride elimination and deprotonation, when exposed to
appropriate ligands.4,5 While this sequence provides 2-azaallyl an-
ions, it requires multiple operations and as such has not been
exploited in reaction development.5a We postulated that improved
procedures for metalation should allow better access to 2-azaallyl
H
M
N
R1
R2
R3
R1
N
R2
LDA or KOtBu,
PMDETA or HMPA,
THF, -78 oC
π4s + π2s
R3
H
Cl
N
1
R1
R2
MgX
R1
R3
N
R2
R3
2
R1
N
R2
Allylation
⇑
Corresponding author. Tel.: +61 3 9902 0327; fax: +61 3 9905 4597.
E-mail address: david.lupton@monash.edu (D.W. Lupton).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.11.142

672
S. Pandiancherri, D. W. Lupton / Tetrahedron Letters 52 (2011) 671–674
Table 1
Unfortunately, systematic modification of temperature, solvent,
donor, order-of-addition and stoichiometry failed to improve upon
this result. In each case the starting material was consumed and
broad signals in the 1H NMR corresponding to decomposition prod-
ucts were observed.
Selected optimisation of 2-azaallyl anion/cycloadditiona
2.5 equiv. base ,
H
N
H
N
2.5 equiv. donor,
-78 oC, THF, 2 h
M
N
Cl
N
Ph
R
R
Ph
Ph
Ph
Ph
R
Ph
R
2a, R=H
2b, R=Ph
1a
1b
4a
4b
4a'
Ph
Attempts to access stabilised 2-azaallyl anions proved more
successful. With N-chloroamine 2b, pyrrolidine 4b was formed in
50% isolated yield using the previously developed conditions (Ta-
ble 1, entry 6). After screening a number of bases and ligands we
found KOtBu and HMPA improved the yield of cycloadduct 4b to
82% (Table 1, entry 7). Although metalation of the N-chloroamine
2b under these conditions is plausible,11a it is more likely that
dehydrochlorination,11b followed by deprotonation provides the
2-azaallyl anion 1b (M@K). Further support for this explanation
can be derived from the use of one equivalent of KOtBu, in this case
providing the imine as the sole product (Table 1, entry 8). If halo-
gen–metal exchange and b-hydride elimination were occurring
then one equivalent of KH would be generated in this reaction
allowing 2-azaallyl anion 1b (M@K) to form.
Entry
R
Base
Donor
—
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
H
LDA
THF
THF
THF
THF
THF
THF
THF
THF
—
H
H
H
H
Ph
Ph
Ph
LDA
LDA
HMPA/TMEDA
PMDETA
PMDETA
PMDETA
PMDETA
HMPA
32 (1.3:1)c
26 (>95:5)c
BuLi
NaH
LDA
—
—
50
82
KOtBu
KOtBud
e
HMPA
—
a
b
c
For details of conditions, see the Supplementary data.
Isolated yield following flash column chromatography.
Ratio of 4a:4a0 determined from 1H NMR analysis.
1 equiv KOtBu.
d
e
Imine formation.
In effect, two distinct methods have been developed for the
assembly of 2-azaallyl anions from N-chloroamines. The first
Table 2
Scope of the cycloaddition of 2-azaallyl anions 1a–fa
Entry
N-Chloride
Olefin
Product
Yieldb (%)
82
Cl
Ph
H
N
Ph
Ph
N
Ph
Ph
Ph
4b
Ph
Ph
1
2b
Cl
N
Ph
H
N
Ph
Ph
Ph
CH3
2
3
62 (dr 5:1)d
2b
4f
CH3
H
Cl
N
Ph
Ph
Ph
N
Ph
Ph
Ph
Ph
Ph
85
2b
4g
Ph
Ph
Cl
N
H
N
Ph
Ph
C6H4p-OMe
PMB
2c
4c
4
83
H
N
Ph
C6H4p-OMe
4c'
Ph
Cl
N
Ph
H
N
Ph
Ph
Ph
5c
20
—
Ph
2d
4d
Ph
Cl
N
Ph
Ph
6a,c
—
Ph
2e
Cl
H
N
Ph
N
Ph
H3C
7c
26
2a
Ph
H
4a
Ph
Cl
N
N
Ph
Ph
Ph
Ph
8c
33
2f
4b
a
b
c
See Ref. 13 and Supplementary data for conditions.
Isolated yield following flash column chromatography.
Conducted as in Table 1, entry 3.
d
Diastereomeric ratio determined by 1H NMR analysis.

S. Pandiancherri, D. W. Lupton / Tetrahedron Letters 52 (2011) 671–674
673
Table 3
exploits halogen–metal exchange and constitutes a rare example of
Allyation of imines derived from N-chloroamines 2a-ha
a tin-free preparation of semi-stabilised 2-azaallyl anions;12 while
the second likely involves dehydrochlorination/deprotonation and
is suited to stabilised 2-azaallyl anion formation.
Entry
1c
N-Chloride
Product
Yieldb (%)
89
Cl
H
Application of the conditions described above (Table 1, entries 3
and 7) to alternative N-chloroamines allowed the scope of the two
procedures to be examined.13 Reaction of other olefins with the
stabilised 2-azaallyl anion 1b (M@K) provided the expected pyrrol-
idines in good isolated yields (Table 2, entries 1–3) and with stere-
oselectivity as previously described (Table 2, entry 2).3,14 The effect
of electronics was subsequently investigated, with N-chloroamine
2c providing a 2:1 mixture of 4c and 4c0, in a combined yield of
83% (Table 2, entry 4). Reaction with cinnamyl N-chloride 2d was
selective for isomer 4d, however, the yield was a modest 20% (Ta-
ble 2, entry 5). The related allyl system decomposed under the
N
N
Ph
H3C
H3C
5a
Ph
H
2a
Cl
N
Ph
N
2c
3c
85
71
5h
2h
Ph
Cl
N
H
N
Ph
5g
2g
Ph
Cl
H
Ph
N
4c
5c
86
66
Ph
N
Ph
reaction conditions (Table 2, entry 6). The p4s + p2s cycloaddition
5b
5c
2b
of semi-stabilised 2-azaallyl anions derived from N-chloride 2f sur-
prisingly gave pyrrolidine 4b as the only isolable product. Its for-
mation either occurs via cycloaddition followed by excision of an
allylic anion or by 2-azaallyl anion formation, followed by dispro-
portionation and cycloaddition. Although the latter may be more
conceivable, attempts to demonstrate disproportionation with la-
belled substrates have failed to date.
Ph
Cl
H
N
Ph
N
PMB
PMB
Ph
2c
Cl
H
6c
7c
64
68
N
Ph
N
Imine formation from N-chloroamines has been extensively
investigated from a mechanistic perspective,11 although the appli-
cation of this reaction has largely been neglected. An exception
being the recent work of Davis10,15 who found that cyclic pyrroli-
dine-derived N-chloroamines could be converted into the corre-
sponding imine using DBU, isolated, then reacted with
nucleophiles. Surprisingly, although imine formation was facile
with our acyclic substrates using KOtBu, DBU failed to deliver these
products. The conversion of amines into the corresponding imine is
2f
5f
Ph
H
Cl
N
Ph
N
Ph
Ph
5d
2d
Ph
Cl
N
H
Ph
N
H3C
H3C
8c
27
2i
5i
Ph
a useful transformation,16 since it enables functionalisation of
a-to
Cl
H
N
N
Ph
the nitrogen, thus we decided to examine the utility of our reaction
conditions with a range of N-chloroamines poorly suited to
2-azaallyl anion formation. For this study we surveyed one-
pot dehydrochlorination/allylation of N-chloroamines 2a–h using
allylmagnesium reagents (Table 3).17 Using N-chloroamines 2a,
2h and 2g, derived from primary and secondary amines, the allyla-
tion with allylmagnesium bromide proceeded in good to excellent
yields to provide the expected homoallylic amines (Table 3, entries
1–3). The allylation of dibenzyl amine 2b gave the expected prod-
uct in excellent yield (Table 3, entry 4). With all reactions 2.5 equiv
of KOtBu gave optimal results. The N-chloroamine 2c, derived from
PMB benzylamine and 2f from tetralone, allowed the stereoelec-
tronic requirements to be investigated. In both cases single prod-
ucts were obtained, in good yield, with addition occurring at the
carbon distal to the electron-releasing group, (Table 2, entry 5)
and at the least hindered carbon (Table 2, entry 6). Addition to
the benzylic over the cinnamic carbon was demonstrated with
N-chloroamine 2d (Table 2, entry 7), providing dienes useful for
tetrahydropyridine preparation.18
Next, the reactions of N-chloroamines 2i and 2j were investi-
gated. In both cases, allylation proceeded with selectivity for the
cinnamic carbon (Table 2, entries 8 and 9). The modest yields for
these reactions arise as a result of conjugate addition providing
aldehyde 7 (Scheme 2).
Finally, the reaction of the crotyl Grignard reagent with N-chlo-
roamines 2b and 2h was investigated, providing the branched
products in good yields (Table 3, entries 10 and 11). The reaction
proceeded with reasonable diastereoselectivity in the former case
(Table 3, entry 10) and 92:8 selectivity in the latter (Table 3, entry
11), favouring the anti-product.
9c
33
2j
5j
Ph
CH3
Cl
N
H
Ph
Ph
Ph
Ph
N
10d
11d
65 (dr 7:3)e
2b
6b
CH3
Ph
Cl
N
H
N
57 (dr 92:8)e
2h
Ph
6h
a
b
c
See Ref. 17 and Supplementary data for detailed conditions.
Isolated yield following flash column chromatography.
N-Chloroamine was reacted with KOtBu (2.5 equiv) followed by HMPA
(2.5 equiv) and allylmagnesium bromide (2 equiv).
d
Following imine formation as described previously the solution was treated
with crotylmagnesium bromide (2 equiv).
Diastereomeric ratio determined by 1H NMR analysis.
e
H
R
O
N
KOtBu, HMPA,
3Å sieves, THF,
-50 oC, 30 min.
Ph
Ph
BrMg
Cl
N
R
5i or j
R
R
N
Ph
R
R
3i or j
2i R=H
2j R=-(CH2)5
Ph
7, 33% from 2i
23% from 2j
Scheme 2.
stabilised 2-azaallyl anions, competent in cycloaddition reactions,
semi-stabilised systems were more difficult to access in high
yields. Thus, while tin-free methods have been successfully
Two sets of conditions for the formation of 2-azaallyl anions
from the corresponding N-chloroamines have been developed.
While this reaction proceeded with excellent yield to provide

674
S. Pandiancherri, D. W. Lupton / Tetrahedron Letters 52 (2011) 671–674
11. The dehydrochlorination of related compounds, and competing halogen–metal
exchange, has been studied using alkoxide bases and found to be controlled by
a combination of electronic and steric factors: (a) Cho, B. R.; Yoon, J. C.; Bartsch,
R. A. J. Org. Chem. 1985, 50, 4943; For studies on the kinetics of imine formation,
see: (b) Bartsch, R. A.; Cho, B. R. J. Am. Chem. Soc. 1979, 101, 3587.
12. Although 2-azaallyl anion formation by deprotonation for intermolecular
cycloaddition fails, intramolecular cycloaddition has been achieved: Pearson,
W. H.; Walters, M. A.; Oswell, K. D. J. Am. Chem. Soc. 1986, 108, 2769.
developed, further work is required to improve this process. In
addition to 2-azaallyl anion formation and cycloaddition, one-pot
allylation of N-chloroamines in good to excellent yields is reported.
The halogen–metal exchange of N-chloroamines is under-
developed in reaction discovery. The application of this process
in other transformations is subject to ongoing studies.
13. General Procedure for cycloaddition reactions: Table 1, entry 7, N-chloroamine
(1 mmol) was added to a flame-dried and N2-purged round-bottomed flask and
dissolved in 15 ml of dry THF. Alkene (1.2 mmol) and HMPA (2.5 mmol) were
added and the reaction mixture cooled to ꢀ78 °C and treated with KOtBu
(2.5 mmol). At this time the solution was deep red/pink in colour. After 3 h the
mixture was warmed to rt and immediately worked-up by quenching with
H2O (5 mL) and extracting with Et2O (3 ꢁ 15 mL). The organic phase was
washed with H2O, saturated NaHCO3 and brine, dried over MgSO4 and
concentrated in vacuo to give the crude product, which was then purified via
column chromatography (silica gel, ratios between 1:9 and 1:4 EtOAc/hexane).
Table 1, entry 3, a flame-dried and N2-purged round-bottomed flask was
charged with dry THF and diisopropylamine (2.5 mmol). The reaction was
cooled to ꢀ78 °C and n-BuLi (2.5 mmol) was added dropwise. This was allowed
to stir for 30 min after which time the solution of LDA was treated with
Acknowledgements
We acknowledge useful discussions with Assoc. Professor Philip
C. Andrews. We are also grateful for the financial support of the
Australian Research Council through the Discovery program
(DP0881137) and Monash University through the Early Career
Researcher program.
Supplementary data
PMDETA (2.5 mmol) and alkene (1.5 mmol) was added.
A solution of N-
Supplementary data associated with (procedures for the prepa-
ration of all new materials as well as copies of 1H and 13C NMR
spectra of the compounds) this article can be found, in the online
version, at doi:10.1016/j.tetlet.2010.11.142.
chloroamine (1 mmol) in dry THF was added dropwise to the LDA solution
which was stirred for 2 h at ꢀ78 °C and then allowed to slowly warm to rt in
the Dewar. The reaction was quenched with H2O (5 mL) and extracted with
Et2O (3 ꢁ 15 mL). The organic phase was washed with H2O, saturated NaHCO3
and brine, dried over MgSO4 and concentrated in vacuo to give the crude
product, which was then purified via flash column chromatography (silica gel,
ratios between 1:9 and 1:4 EtOAc/hexane).
References and notes
14. Jerzykiewicz, L. B.; Lis, T.; Bran, J.; Dziewonska-Baran, D. Acta Crystallogr., Sect. C
1998, 868.
15. Chapman, T. M.; Davies, I. G.; Gu, B.; Block, T. M.; Scoped, D. I. C.; Hay, P. A.;
Courtney, S. M.; McNeill, L. A.; Schofield, C. J.; Davis, B. D. J. Am. Chem. Soc. 2005,
127, 506.
1. (a) Kauffmann, T.; Berg, H.; Koppelmann, E. Angew. Chem., Int. Ed. Engl. 1970, 9,
380; (b) Kauffmann, T. Angew. Chem., Int. Ed. Engl. 1974, 13, 627.
2. Tsuge, O.; Kanemasa, S.; Hatada, A.; Matsuda, K. Bull. Chem. Soc. Jpn. 1986, 59,
2537.
3. For reviews and early reports, see: (a) Pearson, W. H.; Stoy, P. Synlett 2003, 903;
(b) Pearson, W. H.; Walters, M. A.; Rosen, M. K.; Harter, W. G. Arkivoc 2002, viii,
91; (c) Pearson, W. H.; Szura, D. P.; Postich, M. J. J. Am. Chem. Soc. 1992, 114,
1329.
4. For work on the coordination chemistry of 2-azaallyl anions, see: (a) Veya, P.;
Floriani, C.; Chiesi-Villa, A.; Guastini, C. J. Chem. Soc., Chem. Commun. 1991, 991;
(b) Young, R. N. J. Organomet. Chem. 1988, 338, 139.
5. (a) Andrews, P. C.; Armstrong, D. R.; Baker, D. R.; Mulvey, R. E.; Clegg, W.;
Horsburgh, L.; O’Neil, P. A.; Reed, D. Organometallics 1995, 14, 427; (b) Andrews,
P. C.; Armstrong, D. R.; Clegg, W.; Dunbar, L.; Mulvey, R. E. Chem. Commun.
1997, 319.
16. For imine formation by chemical oxidative methods, see: (a) Zhu, B.; Angelici,
R. J. Chem. Commun. 2007, 2157; (b) Kamal, A.; Reddy, Devaiah. V.; Reddy, K. L.;
Shankaraiah, N. Adv. Synth. Catal. 2006, 348, 249; (c) Maeda, Y.; Nishimura, T.;
Uemura, S. Bull. Chem. Soc. Jpn. 2003, 76, 2399; For electrochemical methods,
see: (d) Largeron, M.; Chiaroni, A.; Fleury, M.-B. Chem. Eur. J. 2008, 14, 996.
17. General procedure for the allylation reaction: A flame-dried and N2-purged flask
was charged with activated 3 Å molecular sieves and THF (15 mL). The N-
chloroamine (1 mmol) was added to the flask, cooled to ꢀ50 °C and treated
with KOtBu (0.2806 g, 2.5 mmol) followed by HMPA (0.44 ml, 2.5 mmol). The
resulting deep red solution was allowed to stir for 1 min then allylmagnesium
bromide was introduced dropwise (2 mL of a 1 M solution in Et2O, 2 mmol).
The reaction was stirred for 30 min at this temperature then allowed to warm
to rt and stirred for a further 3 h. At this point the mixture was quenched
slowly with H2O (2 ml) and the mixture concentrated in vacuo. The
concentrate was diluted with EtOAc (20 mL) washed with H2O (5 mL) and
the resulting aqueous layer extracted with EtOAc (10 mL). The combined
organic fractions were washed with brine, dried (MgSO4) and concentrated to
provide oil, which was purified via column chromatography (silica gel, ratios
between 1:9 and 1:4 EtOAc/hexane).
6. Coleman, G. H. J. Am. Chem. Soc. 1933, 55, 3001.
7. For examples of the aminations of organometallics using N-chloroamines, see:
(a) Sinha, P.; Knochel, P. Synlett 2006, 3304; (b) Barker, T. J.; Jarvo, E. R. J. Am.
Chem. Soc. 2009, 131, 15598.
8. Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc. 2010, 132, 6900.
9. For intramolecular enolate amination with N-chloromamines, see: (a) Bew, S.
P.; Hughes, D. L.; Palmer, N. J.; Savic, V.; Soapi, K. M.; Wilson, M. A. Chem.
Commun. 2006, 4338; (b) Makosza, M.; Bobryk, K.; Krajewski, D. Heterocycles
2008, 76, 1511.
18. Kumareswaran, R.; Balasubramanian, T.; Hassner, A. Tetrahedron Lett. 2000, 41,
8157.
10. Chapman, T. M.; Courtney, S.; Hay, P.; Davis, B. G. Chem. Eur. J. 2003, 9, 3397.