CH2I2–Et3Al reagent in the cyclopropanation of 2-alkenyl amines

Article abstract of DOI:10.1016/j.tetlet.2016.07.043

An aluminum carbenoid is the efficient cyclopropanation reagent for the transformation of 2-alkenyl amines into cyclopropyl amines. The addition of iodine facilitates the cyclopropanation of poorly reactive 2-alkenyl amines.

Full text of DOI:10.1016/j.tetlet.2016.07.043

Accepted Manuscript
CH2I2 - Et3Al reagent in the cyclopropanation of 2-alkenyl amines
Ilfir R. Ramazanov, Alsu V. Yaroslavova, Usein M. Dzhemilev
PII:
S0040-4039(16)30889-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.043
TETL 47905
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Tetrahedron Letters
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22 June 2016
12 July 2016
Please cite this article as: Ramazanov, I.R., Yaroslavova, A.V., Dzhemilev, U.M., CH2I2 - Et3Al reagent in the
cyclopropanation of 2-alkenyl amines, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.07.043
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Tetrahedron Letters
CH2I2 - Et3Al reagent in the cyclopropanation of 2-alkenyl amines
Ilfir R. Ramazanov, Alsu V. Yaroslavova, Usein M. Dzhemilev
Institute of Petrochemistry and Catalysis of Russian Academy of Sciences, 141 Prospekt Oktyabrya, Ufa 450075, Russian Federation
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An aluminum carbenoid is the efficient cyclopropanation reagent for the transformation of 2-
alkenyl amines into cyclopropyl amines. The addition of iodine facilitates the cyclopropanation
of poorly reactive 2-alkenyl amines.
2016 Elsevier Ltd. All rights reserved.
Available online
Keywords:
cyclopropanation
2-alkenyl amines
aluminum carbenoid
diiodomethane
triethylaluminum
Introduction
were examined in the reaction. We proposed that the double bond
in N-alkyl substituted alkenyl amines has a higher nucleophilicity
Recently, we reported that aluminum carbenoids are efficient
reagents for the transformation of enamines into
cyclopropylamines.1 On the other hand it is known that the
Simmons-Smith reagent (ICH2ZnI),2,3 Furukawa reagent
(EtZnCH2I),4,5 and Denmark reagent (Zn(CH2Cl)2)6 are
ineffective for the cyclopropanation of enamines and 2-alkenyl
amines.7–10 For example, the reaction of N,N-dibenzylcyclohex-2-
en-1-amine using the Furukawa and Denmark reagents gave the
cyclopropanation product in 11% and 33% yield,
respectively.10,11 The best yield of 92% has been obtained with
the Shi reagent (CF3CO2ZnCH2I), however, the yield was
dramatically decreased when the reaction time was more than one
hour.10,11 Apparently, the introduction of an electron-withdrawing
group at the zinc atom increases the Lewis acidity of the zinc
carbenoid and promotes the formation of stronger adducts with 2-
alkenyl amines that prevents the N-alkylation side-reaction. Thus,
we suggested that the Lewis acidity of the metal carbenoid plays
an important role and proposed an effective cyclopropanation
agent (CH2I2–Et3Al) for enamines.1 While the R3Al–CH2I2
reagent was previously used for the cyclopropanation of
unactivated olefins, allylic alcohols,12,13 silyl vinyl esters1,12 and
allenes,14 there is no information regarding the use of this reagent
for the cyclopropanation of substituted alkenyl amines. The three
main pathways for the reaction of 2-alkenyl amines with
aluminum carbenoids include the formation of a donor-acceptor
complex, N-alkylation of the amine, and cyclopropanation of the
carbon-carbon double bond. Thus, the chemoselectivity of
cyclopropanation depends on the nucleophilicity of the double
bond and the nitrogen atom in the 2-alkenyl amine. This
consideration led to the careful choice of 2-alkenyl amines that
compared to N-aryl substituted alkenyl amines or allyl substituted
heterocycles. It is obvious that the nucleophilicity of the nitrogen
atom varies analogously in these compounds. It was also of
interest to study the effect of the introduction of electron-
donating and electron-withdrawing substituents at the double
bond. 2-Alkenyl amines with bulky alkyl substituents were used
to study the influence of steric factors.
Results and discussion
We found that the N-alkyl substituted 2-alkenyl amines 1a-f
and 3a reacted with 2-3 equivalents of Et3Al and CH2I2 at room
temperature in dichloromethane to give homocyclopropyl amines
2a-f and 4a in 68-85% yield (Table 1). The presence of bulky
alkyl substituents at the nitrogen atom in compounds 1b, 1e and
3a does not hinder the cyclopropanation reaction (Table 1,
Entries 2, 5, 7). The introduction of a methyl substituent at the
double bond increased the reactivity of compound 1d by ~1.5
times relative to compound 1c under the same reaction conditions
(Table 1, Entries 3, 4). We found that a second aminomethyl
substituent at the double bond strongly reduced the reactivity of
the double bond. Thus, reaction of (E)-1,4-di(piperidin-1-yl)but-
2-ene 6 for one day using 5 equivalents of Et3Al and CH2I2 was
less than 5% (Scheme 1). The cyclopropanation reaction is
therefore accelerated by the introduction of electron-donating
substituents at the double bond, and slows down with the
introduction of electron-withdrawing substituents.
 Corresponding author. Tel./fax: +7 347 284-27-50; e-mail: ilfir.ramazanov@gmail.com

2
Tetrahedron
2-alkenyl amines, the use of I2 can significantly reduce the
Table 1. Cyclopropanation of 2-alkenyl amines
reaction time.
Entry Substrate R’
R”
R’”
Yield
(%)
71
1
Et
tert-Oct
Et
H
H
H
H
Me
H
1a
1b
1c
1d
1e
1f
2
3
4
5
6
7
77
Scheme 1. Iodine-promoted cyclopropanation of 2-alkenyl amines
with Et3Al–CH2I2.
-(CH2)5-
-(CH2)5-
82
85
75
81
68
c-Hex
H
To estimate the relative reactivity of the distal and proximal
double bond in 2,-dienyl amines, we examined the reactions of
(S)-1-((4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl)piperidine
8, (E)-1-(3,7-dimethylocta-2,6-dien-1-yl)piperidine 9 and (E)-1-
(octa-2,7-dien-1-yl)piperidine 10 with Et3Al and CH2I2. Using 1
equivalent of Et3Al and CH2I2, the amines gave a mixture of the
two monocyclopropanation products along with the
dicyclopropyl compounds 11-15. Thus, the relative reactivity of
the distal and proximal double bond was similar to the studied
unsaturated amines. When using 3 equivalents Et3Al and CH2I2,
all three 2,-dienyl amines gave only double cyclopropanation
products 11-15 in good yield (Scheme 2). In the case of (S)-1-((4-
-(CH2)2O(CH2)2-
H
3a
The character of the nitrogen atom substituent was found to
have significant role. The conversion of N,N-
diallylbenzylamine did not exceed 50% after 24 hours using 5
equivalents of Et3Al and CH2I2. The reaction proceeded in a non-
a
selective manner to give a mixture of
mono- 5 and
dicyclopropanation 4b products in a 3:1 ratio (Scheme 1). At the
same time, the reaction of 4-allyl morpholine with 3 equivalents
of Et3Al and CH2I2 afforded the cyclopropanation 2f product in
high yield (Table 1, entry 6). Alkenyl amines with electron-
withdrawing substituents at the nitrogen atom, such as N-
allylaniline, N,N-diallylaniline, N,N-diallylnaphthalen-1-amine,
N-allylimidazole, and N,N-diallylacetamide, showed no
reactivity.
(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl)piperidine
8,
a
doubled set of the carbon signals in a ~1: 1 ratio was observed in
the 13C NMR spectrum which indicated the formation of two
diastereomers 11 and 12.
The electronic effects of the substitutents can be estimated
using the pKa values of the corresponding ammonium ion which
decreases in the series: Et2NH (10.84) > c-HexNH2 (10.64) >
morpholine (9.85) > benzylamine (9.34) > imidazole (6.99) >
aniline (4.87) > 1-naphthaleneamine (3.92) > acetamide (-0.51).15
Electron-withdrawing substituents at the nitrogen atom reduce
the electron density on the carbon atoms of the double bond via
an electron-withdrawing inductive effect that reduces the
reactivity of the 2-alkenyl amine. Indeed, allyl derivatives of
acetamide, 1-naphthaleneamine, aniline and imidazole were
unreactive, and N,N-diallylbenzylamine showed lower reactivity
compared with compounds 1a-g. However, we noted that after 2
days, the conversion of N,N-diallylbenzylamine exceeded 80%,
and only the double cyclopropanation product 4b was observed
after 3 days. Since aluminum carbenoids are relatively unstable
compounds and decompose to form Et2AlI,16–18 it can be assumed
that IAl(Et)CH2I or I2AlCH2I are formed in the reaction mixture
due to ligand exchange. The presence of electron-withdrawing
substituents at the aluminum atom increase the electropositive
character of the metal atom and may accelerate the
cyclopropanation reaction. The calculated activation energies
((B3LYP/6-31G(d,p)) for the cyclopropanation of N-allyl-N-
benzylprop-2-en-1-amine 3b using aluminum carbenoids
decreases in the series: Me2AlCH2I (25.0) > IAl(Me)CH2I (24.1)
> I2AlCH2I (23.6). To check this assumption, the reaction of N-
allyl-N-benzylprop-2-en-1-amine 3b with 5 equivalents of Et3Al–
CH2I2 and 1 equivalent of I2 was carried out. Indeed, the yield of
double cyclopropanation product 4b was 89% after 18 hours
(Scheme 1). Moreover, compound 7 was obtained in 74% yield
in the presence of I2 from the previously inactive (E)-1,4-
di(piperidin-1-yl)but-2-ene 6. Thus, in the case of poorly reactive
Scheme 2. The cyclopropanation of 2,-dienyl amines.
Selective cyclopropanation of the distal double carbon-carbon
bond has been achieved in the cases of ammonium 16, 17 and
acetamide 18 derivatives of 2,-dienyl amines (Scheme 3). The
hindered rotation of the acetamide group in compound 21 led to
significant signal splitting of the carbon atoms at the nitrogen
atom of up to 4.2 ppm.

at the Institute of Petrochemistry and Catalysis of the Russian
Academy of Sciences.
Supplementary Material
Supplementary data associated with this article can be found
in the online version at doi:
References and notes
(1)
(2)
(3)
(4)
(5)
Kadikova, R. N.; Ramazanov, I. R.; Zosim, T. P.; Yaroslavova, A.
V.; Dzhemilev, U. M. Tetrahedron 2015, 71, 3290–3295.
Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323–
5324.
Simmons, H. E.; Seyferth, D. Org. Reactions; V. 20.; Wiley: N.Y.,
1973.
Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron Lett. 1966,
7, 3353–3354.
Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968, 24,
53–58.
Scheme 3. Cyclopropanation of ammonium and acetamide
derivatives of 2,-dienyl amines.
We compared the relative reactivity of the aluminum carbenoid
(Et2AlCH2I) and Shi reagent (CF3CO2ZnCH2I) towards N,N-
dibenzylcyclohex-2-en-1-amine (Scheme 4). While reaction with
the Shi reagent gave the cyclopropanation product 22 in 92%
yield after 1 h,11 the use of the aluminum carbenoid resulted in
the formation the same compound in 87% yield after 6 h.
However, in the latter case, we did not observe the formation of
the N-alkylation side-product even after 24 h.
(6)
(7)
Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991, 56, 6974–6981.
Blanchard, E. P.; Simmons, H. E.; Taylor, J. S. J. Org. Chem. 1965,
30, 4321–4322.
Kuehne, M. E.; King, J. C. J. Org. Chem. 1973, 38, 304–311.
Friedrich, E. C.; Lewis, E. J. J. Org. Chem. 1990, 55, 2491–2494.
Csatayová, K.; Davies, S. G.; Lee, J. A.; Ling, K. B.; Roberts, P.
M.; Russell, A. J.; Thomson, J. E. Tetrahedron 2010, 66, 8420–
8440.
Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A. J.; Thomson,
J. E. Chem. Commun. (Camb). 2007, 4029–4031.
Maruoka, К.; Fukutani, Y.; Yamamoto, H. J. Org. Chem. 1985, 50,
4412–4414.
Charette, A. B.; Beauchemin, A. J. Organomet. Chem. 2001, 617-
618, 702–708.
Ramazanov, I. R.; Yaroslavova, A. V.; Dzhemilev, U. M.; Nefedov,
O. M. Tetrahedron Lett. 2010, 51, 6268–6269.
Handbook of biochemistry and molecular biology: proteins;
Fasman, G. D., Ed.; 3rd ed.; CRC Press, 1976.
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
Hoberg, H. J. Lieb. Ann. 1962, 656, 1–14.
Hoberg, H. J. Lieb. Ann. Chem. 1967, 709, 123–134.
Hoberg, H. J. Lieb. Ann. Chem. 1967, 703, 1–16.
Synthesis of 1-(cyclopropylmethyl)piperidine (2c): To a solution of
1-allylpiperidine (0.25 g, 2 mmol) and Et3Al (0.6 mL, 4 mmol)
(caution: organoaluminums are pyrophoric and can ignite on
contact with air, water or any oxidant) in CH2Cl2 (5 mL),
diiodomethane (0.32 mL, 4 mmol) was added at 0 °C under an
argon atmosphere. The mixture was stirred at room temperature for
6 h. Then, a solution of EtMgBr (10 mL, 3M in Et2O) was added to
the reaction mixture while cooling the flask in an ice bath. The
mixture was stirred at room temperature for 1 hour and quenched
with a 25% aqueous solution of NaOH (5 mL). The precipitate was
filtered through filter paper. The aqueous layer was extracted with
diethyl ether (3×5 mL). The combined organic layers were washed
with brine (10 mL) and dried over anhydrous CaCl2. The solvent
was removed under reduced pressure and the residue distilled to
give 0.23 g (82%) of 2c as a colorless oil. Bp 71-75 ºC (10 Torr).
1H NMR δ: 0.05-0.15 (m, 2Н, C(2,3)Ha), 0.45-0.55 (m, 2Н,
С(2,3)Нb), 0.85-0.95 (m, 1Н, С(1)H), 1.45-1.46 (m, 2H, C(7)H2),
1.55-1.65 (m, 4H, C(6,8)H2), 2.23 (d, J = 6.8 Hz, 2Н, С(4)Н2), 2.47
(brs, 4H, C(5,9)H2). 13C NMR δ: 3.97 (2С, C(2,3)), 8.39 (C(1)),
24.47 (C(7)), 25.95 (2C, C(6,8)), 54.64 (2С, C(5,9)), 64.63 (C(4)).
Mass m/z (%): 129 (9) [М]+, 114 (21), 100 (100), 86 (42). Anal.
calcd for C9H17N, %: C, 77.63; H, 12.31; N, 10.06. Found, %: C,
77.70; H, 12.30; N, 9.91.
Scheme 4. Cyclopropanation of N,N-dibenzylcyclohex-2-en-1-
amine using Et2AlCH2I and CF3CO2ZnCH2I.
Conclusion
Thus, the known Yamamoto reagent (R3Al–CH2I2),
representing an equimolar mixture of a trialkylaluminum with
diiodomethane, exhibits reactivity towards 2-alkenyl amines to
afford the corresponding cyclopropyl amines in high yield. This
provides a useful extension to existing approaches for the
cyclopropanation of alkenyl amines. 2-Alkenyl amines with
electron-withdrawing substituents at the nitrogen atom, such as
N-allylaniline,
N,N-diallylaniline,
N,N-diallylnaphthalen-1-
amine, N-allylimidazole, and N,N-diallylacetamide, showed no
reactivity in the reaction. The reaction of poorly reactive
substrates can be accelerated by the addition of iodine.
Acknowledgments
This work was supported by Department of Chemistry and
Material Sciences of the Russian Academy of Sciences (program
No. 1-OKhNM), the Russian Foundation for Basic Research
(grant no. 16-03-00935) and by Grant of the RF President (Sci.
Sh.–6651.2016.3) which are gratefully acknowledged. We also
acknowledge the Center for collective use of equipment «Agidel»

4
Tetrahedron
Graphical Abstract
CH2I2 - Et3Al reagent in the
Leave this area blank for abstract info.
cyclopropanation of 2-alkenyl amines
Ilfir R. Ramazanov, Alsu V. Yaroslavova, Usein M. Dzhemilev

Highlights
The Et3Al-CH2I2 reagent is an efficient cyclopropanation reagent for 2-alkenyl amines.
The addition of iodine facilitates the cyclopropanation of 2-alkenyl amines.
The reaction does not result in the formation of the N-alkylation by-product.