Reaction of imines with N-iodosuccinimide (NIS): Unexpected formation of stable 1 : 1 complexes

Article abstract of DOI:10.1039/b615183c

Imines react with N-iodosuccinimide (NIS) to afford unexpected 1 : 1 complexes and the structure of one of these was determined by single-crystal X-ray diffraction; the reaction seems to be very general for substituted cyclic imines with solid stable comp

Full text of DOI:10.1039/b615183c

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Reaction of imines with N-iodosuccinimide (NIS): unexpected
formation of stable 1 : 1 complexes{
Isabel Castellote,a Mar´ıa Moro´n,a Carolina Burgos,*a Julio Alvarez-Builla,a Avelino Martin,b
Pilar Go´mez-Salb and Juan J. Vaquero*a
Received (in Cambridge, UK) 18th October 2006, Accepted 15th December 2006
First published as an Advance Article on the web 16th January 2007
DOI: 10.1039/b615183c
It was shown that the iminic bond in 1a seems to be critical for
Imines react with N-iodosuccinimide (NIS) to afford unex-
pected 1 : 1 complexes and the structure of one of these was
determined by single-crystal X-ray diffraction; the reaction
seems to be very general for substituted cyclic imines with solid
stable complexes obtained in high yields; this is the first
reported example of a halogen bonding interaction involving
the CLN bond and NIS.
the formation of the unexpected reaction product with NIS, since
1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine either does not
react, or affords the 6-iodo derivative in the presence of NIS. For
this reason, we decided to test the reaction with other imines in the
hope that we could obtain an appropriate crystal for X-ray
diffraction analysis. Fortunately, this aim was achieved in the
reaction of 6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinoline (1h)
with NIS, which allowed us to establish structure 2a for the
reaction product between 1a and NIS. We report here further
details on the scope of this unprecedented reaction (Scheme 2).
First, substitution at the C-1 position of 3,4-dihydropyrrolo[1,2-
a]pyrazine was explored with alkyl (methyl and n-propyl), aryl and
heteroaryl substituents3 (Table 1, entries 2–7). Other related
bicyclic and tricyclic imines such as 1-substituted 3,4-dihydroiso-
quinolines (entries 8 and 9) and 2-substituted 3,4-dihydropyra-
zino[1,2-a]indoles (entries 10–12) were also employed as iminic
substrates.4 The results are summarised in Table 1 and show the
reaction to be very general for all aryl (Table 1, entries 4–6, 8, 10
and 12) and heteroaryl (entries 7 and 13) substituted substrates,
with complexes being formed in yields of up to 64% and reactions
completed within 1 h. The behaviour of alkyl substituted substrates
depends of the heterocyclic imine and the nature of the alkyl
group. For example, the reaction of 1-methyl-6,7-dimethoxy-3,4-
dihydroisoquinoline 1i (entry 9) and 2-methyl-3,4-dihydropyra-
zino[1,2-a]indole (1k) (entry 11) afforded the addition compounds
2i and 2k in excellent yields (86 and 89%, respectively). However,
the methyl derivative 1b gave a complex mixture of products and
the n-propyl derivative 1c was extensively iodinated on the
n-propyl substituent.
As part of a project focussed on the preparation of a small library
of derivatives of 1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine 1a we
needed to prepare either the 6-bromo or 6-iodo derivatives as
appropriate substrates for the Stille and/or Suzuki reactions.1 The
reaction with NBS afforded the expected halogenated product 3
(Scheme 1) but under the same conditions, the reaction of 1a with
NIS gave a yellow solid compound, the structure of which
incorporates the iodo atom and the full heterocyclic and
succinimide moieties—as evidenced by NMR spectroscopy and
elemental analysis. Further structural analysis allowed us to rule
out the co-halogenation compound2 and we therefore tried to
confirm the structure of this apparently simple compound by
X-ray analysis. However, all our initial attempts to obtain suitable
crystals failed.
Further examples with monocyclic imines,5 such as 2-substituted
pyrrolines (entries 14–16), also showed similar behaviour to that
found for 3,4-dihydropyrrolo[1,2-a]pyrazines, with 2-methylpyrro-
line 1o also forming complex mixtures (entry 15) and 2-aryl-
substituted derivatives leading to the expected compounds in good
yields (entries 14 and 16). However, all of these complexes are less
stable than those obtained from bicyclic imines. It is also worth
Scheme 1
aDepartamento de Qu´ımica Orga´nica, Universidad de Alcala´, 28871-
Alcala´ de Henares, Madrid, Spain. E-mail: juanjose.vaquero@uah.es;
Fax: +34-91-8854686; Tel: +34-91-8854761
bDepartamento de Qu´ımica Inorga´nica, Universidad de Alcala´, 28871-
Alcala´ de Henares, Madrid, Spain
{ Electronic supplementary information (ESI) available: Experimental
procedures and full characterization data for stable complexes 2, unknown
imines 1 and intermediates. See DOI: 10.1039/b615183c
Scheme 2
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Table 1 Complexes 2 from imines 1 and NIS
Complex (2)
yield (%)
Entry
Imine (1)
1
2
3
4
5
6
7
1a: C6H5
1b: CH3
64
a
—
—
b
1c: CH2CH2CH3
1d: 2,4-Me2C6H3
1e: 2,4-(MeO)2C6H3
1f: 3,5-(CF3)2C6H3
1g:
82
69
67
70
Fig. 1 X-Ray crystal structure of complex 2h. Thermal ellipsoids at 50%
level are shown.
and anhydrous conditions are necessary to ensure acceptable
yields. Under non-anhydrous conditions the corresponding ketone
was isolated as the main reaction product. The attempted reaction
of representative aldimines did not afford the expected addition
products and the starting materials were recovered unaltered.
Moreover, unsubstituted cyclic imines were also unreactive
towards NIS under analogous conditions to those used with the
imines selected for this study.
8
9
1h: R = C6H5
1i: R = Me
92
86
Crystals obtained from 1h and NIS allowed us to establish the
structure of complexes 2 shown in Table 1. The X-ray crystal
structure9 of complex 2h is shown in Fig. 1 and its solid structure is
based on a non-covalent interaction between the iminic nitrogen
and the iodine atom of the NIS. Only a few examples of this
uncommon halogen bonding interaction10 involving oxygen11 and
nitrogen atoms as donor atoms (Lewis base) and diiodo-
perfluorocarbons12 and 1,4-diiodotetrafluorobenzene13 as accep-
tors have being reported previously. In this case the iodine atom of
the NIS reagent seems to be a Lewis acid hard enough to be
involved in the formation of these unexpected and unprecedented
complexes.
10
11
12
13
1j: C6H5
1k: CH3
1l: 2,4-(MeO)2C6H3
1m:
81
89
80
77
14
15
16
17
1n: C6H5
1o: CH3
1p: 4-MeOC6H4
1q:
81
a
—
80
73c,d
The co-crystal 2h shows bond lengths between the iodine and
˚
the iminic and succinic nitrogens being 2.486(2) and 2.120(2) A,
respectively,14 and these three atoms have an almost linear
disposition [173.0(1)u for the angle N(2)–I(19)–N(20)]. Contrary
to previously reported data for melting points of other complexes
involving halogen bonding interactions,12,13 this complex (and all
shown in Table 1) exhibits a lower melting point (112–114 uC)
than those reported for the single components of the complex
(200–202 uC for NIS and 121–125 uC for 1h). Also, 2h and the
remainder of the complexes show a pale yellow colour, indicating a
degree of change-transfer to the iminic chromophore.15
18
19
a
1r: X = N; R1 = CHMe2;
81e
R2 = 2-pyridyl
1s: X = CH; R1 = CHMe2;
a
—
R2 = Ph
b
Complex mixture.
Iodination on the n-propyl substituent.
d e
Reaction difficult to reproduce. Unstable. Unstable in solution.
c
In general, IR and NMR spectra for these complexes show
significant modifications when compared with those of the starting
materials. As an example, in the 1H NMR spectra of the imine 1h,
the aromatic protons for the phenyl substituent appear at
d 7.60 ppm (ortho hydrogens) and d 7.42 ppm (meta and para
hydrogens) while in the complex 2h these aromatic signals collapse
in a non-resolvable multiplet at d 7.49 ppm. Furthermore, H5 and
H8 aromatic protons in 1h appear as a broad singlet centered at
d 6.76 ppm while the spectrum of 2h show two well-differentiated
singlets at d 6.49 ppm and d 6.72 ppm for the same hydrogens.
noting the successful reaction with the 1-aza-2-methoxycyclohep-
tene (entry 17), although the formation of this complex it is not
easy to reproduce.6
The study was completed by testing different acyclic ketimines
and aldimines.7 The results show that only one of the ketimines
tested (Table 1, entry 18) was reacted with NIS to afford the
corresponding product, with a yield similar to those observed with
cyclic imines.8 In this case the reaction is quite sensitive to water
1
Some changes are also observed in the aliphatic region of the H
1282 | Chem. Commun., 2007, 1281–1283
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5 Imines 1o,q are commercially available and 1n,p were prepared
according to the literature procedure: N. de Kimpe, K. A. Tehrani,
C. Stevens and P. de Cooman, Tetrahedron, 1997, 53, 3693–3706.
6 In different experiments using commercially available imine 1q and NIS
the corresponding complex 2q was not formed or was formed in low
yields under the same conditions that had previously afforded this
complex in 73% yield (Table 1, entry 17).
NMR spectra of the imine 1h and NIS separately and in complex
2h. For example, the signal assigned to the CH2 in 3-position of 1h
is shifted 0.2 ppm downfield (3.79 ppm in 1h and 3.98 in 2h) and
the signal of the methylenic hydrogens of the succinimide moiety in
the complex also appears shifted 0.4 ppm when compared with the
signal of these protons in NIS (d 2.68 ppm and d 3.01 ppm,
respectively).
7 I. Moretti and G. Torre, Synthesis, 1970, 141.
8 General procedure for compounds 2: A solution of N-iodosuccinimide
(1 mmol) in dry CH2Cl2 (4 mL) was added dropwise under an argon
atmosphere to a stirred solution of the corresponding imine 1 (1 mmol)
for compounds 1e,h–s or imine salt for compounds 1a–d,f.g, in dry
CH2Cl2 (4 mL) at room temperature. The reaction mixture was stirred
for 1 h at this temperature, concentrated in vacuo and the residue
triturated with Et2O. Compounds 2 are yellow solids and were isolated
by filtration.
In the IR spectrum of 2h, all relevant bands for NIS and 1h are
present along with some typical modifications12 affecting both
aliphatic and aromatic C–H stretching bands which are shifted to
higher frequencies in the complex (selected bands at 3059, 2930
and 2830 cm21 for 2h and 3058, 2925 and 2828 cm21 for 1h).
In summary, a variety of substituted cyclic imines and some
ketimines react with NIS to afford, in high yields, stable 1 : 1
complexes in which the iodine atom is linearly bonded to both
iminic and succinic nitrogens. Ongoing work is aimed at
demonstrating that such complexes based on a halogen bonding
between the iminic nitrogen and the iodine of NIS could behave as
better iodination reagents than NIS itself.
9 Crystal data for 2h: C21H21IN2O4, M = 492.3, monoclinic, P21/c, a =
˚
8.9590(2), b = 12.0504(4), c = 19.2674(11) A, b = 96.661(4)u, Z = 4, V =
3
2066.1(1) A , T = 293 K, m(Mo-Ka) = 1.579 mm21. Of 46 207 total
˚
reflections (5 ¡ h ¡ 25u), 3594 were independent (Rint = 0.02). A multi-
scan absorption correction was performed. Direct methods were used to
solve the structure. All non-hydrogen atoms were refined anisotropi-
cally. Hydrogen atoms were found in the difference Fourier map and
refined isotropically. Largest minimum and maximum in the final
difference Fourier synthesis: 20.465 and 0.31 e A23. R1 = 0.020 (for
˚
Financial support from the Spanish Ministerio de Educacio´n y
Ciencia (project CTQ2005/011060), Comunidad de Madrid
(CAM) and Universidad de Alcala´ (UAH) (project CAM/UAH-
2005/044) and grant (M-M.) from CAM-UAH is gratefully
acknowledged.
3260 reflections with F . 4s(F)) and wR2 = 0.024 (all data). The values
of R1 and wR2 are defined as R1 = g||Fo| 2 |Fc||/[g|Fo|]; wR2 =
{[gw(Fo 2 Fc2)2]/[gw(Fo ) ]}1/2. CCDC 207325. For crystallographic
data in CIF or other electronic format see DOI: 10.1039/b615183c.
10 P. Metrangolo and G. Resnati, Chem. Eur. J., 2001, 7, 2511–2519, and
references therein.
2
2 2
11 P. Auffinger, F. A. Hays, E. Westhof and P. S. Ho, Proc. Natl. Acad.
Sci. USA, 2004, 101, 16789–16794.
Notes and references
12 For some examples, see: P. L. Wash, S. Ma, U. Obst and J. Rebek, Jr.,
J. Am. Chem. Soc., 1999, 121, 7973–7974; F. Fontana, A. Forni,
P. Metrangolo, W. Panzeri, T. Pilati and G. Resnati, Supramol. Chem.,
2002, 14, 47–55; D. D. Burton, F. Fontana, P. Metrangolo, T. Pilati and
G. Resnati, Tetrahedron Lett., 2003, 44, 645–648; M. Amati, F. Lelj,
R. Liantonio, P. Metrangolo, S. Luzzati, T. Pilati and G. Resnati,
J. Fluorine Chem., 2004, 125, 629–640; P. Metrangolo, C. Pra¨sang,
G. Resnati, R. Liantonio, A. C. Whitwood and D. W. Bruce, Chem.
Commun., 2006, 3290–3292.
1 I. Castellote, PhD Thesis, University of Alcala´, 2001; I. Castellote,
J. J. Vaquero, J. Ferna´ndez Gadea and J. Alvarez-Builla, J. Org. Chem.,
2004, 69, 8668–8675.
2 J. Rodriguez and J. P. Dulce`re, Synthesis, 1993, 1177–1205.
3 Preparation of substrates 1d–g is detailed in the ESI{ and ref. 1. The
following imines were prepared according to literature procedures; 1a
and 1c: A. M. Likhosherstov, V. P. Peresada, V. G. Vinokurov and
A. P. Skoldinov, Zh. Org. Khim., 1983, 22, 2610–2614;1b: I. Jirkovsky
and R. Baudy, Synthesis, 1981, 481–483.
13 J. L. Syssa-Magale´, K. Boubekeur, P. Palvadeau, A. Meerschaut and
B. Scho¨llhorn, J. Mol. Struct., 2004, 691, 79–84.
˚
14 The N–I bond length in NIS is 2.059 A, see: K. Padmanabhan, I. C. Paul
4 Substrates 1h and 1i are commercially available. 1k: M. P. Mat´ıa,
J. Ezquerra, F. Sanchez-Ferrando, J. L. Garc´ıa-Nav´ıo, J. J. Vaquero
and J. Alvarez-Builla, Tetrahedron, 1991, 47, 7329–7342. Compounds 1j
and 1l,m are unknown and are described in the ESI{.
and D. Y. Curtin, Acta Crystallogr., Sect. C, 1990, 46, 88–92.
15 D. J. Price, T. Richardson and D. W. Bruce, J. Chem. Soc., Chem.
Commun., 1995, 1911–1912.
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