The von Braun Reaction Applied to Azetidines

Article abstract of DOI:10.1002/ejoc.201701443

The von Braun reaction (the reaction of cyanogen bromide with tertiary amines) was applied to a series of functionalized N-alkyl-substituted azetidines. This reaction mainly led to the cleavage of the strained four-membered ring to produce 3-bromo N-alkyl cyanamides in good yields with variable regioselectivity. The resulting cyanamide products were then employed as original building blocks for the synthesis of nitrogen heterocycles.

Full text of DOI:10.1002/ejoc.201701443

A Journal of
Accepted Article
Title: The von Braun Reaction Applied to Azetidines
Authors: Karen Wright, Bruno Drouillat, Laurence Menguy, Jérôme
Marrot, and François Couty
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10.1002/ejoc.201701443
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The von Braun Reaction Applied to Azetidines
Karen Wright, Bruno Drouillat, Laurence Menguy, Jérôme Marrot and François Couty* [a]
Abstract: The von Braun reaction, that is the reaction of cyanogen
bromide with tertiary amines, was applied to
a series of
functionalized N-alkyl azetidines. This reaction mainly leads to the
cleavage of the strained four-membered ring, producing 3-bromo N-
alkyl cyanamides in good yield and variable regioselectivity, which
can be used as original building blocks for the synthesis of nitrogen
heterocycles.
Introduction
Azetidines, due to their inherent ring-strain and growing
availability by various synthetic methods,1 have emerged as
valuable substrates for the discovery of new reactions involving
either ring-expansions2 or ring-cleavages,3 that have boosted
their utility for the synthesis of nitrogen-containing compounds.
Among numerous variations of such reactions, N-alkyl
azetidines have been reported to react with chloroformates,
leading to intermediate N-acyl azetidinium ions that are opened
Scheme 1. Reaction of azetidines with chloroformates, triphosgene, and
cyanogen bromide (von Braun reaction).
Results and Discussion
regioselectively by
a
chloride anion.4 In the same vein,
In order to examine in detail the scope of the von Braun reaction
applied to azetidines, a set of different substrates was selected.
It includes unsubstituted N-benzhydryl azetidine 5, chosen to
examine possible competition between ring and N-benzhydryl
cleavages, and a series of differently substituted azetidines,
(mono-, di- and trisubstituted, depicted in the different frames of
Figure 1) in order to examine issues of regio- and
stereoselectivity of the ring cleavage.
azetidines react with triphosgene, leading to dealkylation or ring
cleavage, and the produced compounds can be converted into
cyclic ureas upon reaction with amines.5 (Scheme 1). The former
reaction (tertiary amines reacting with chloroformates) now
belongs to the toolbox of synthetic chemists facing the problem
of a regioselective N-dealkylation reaction, and has supplanted
the venerable von Braun reaction,6 (tertiary amines reacting with
cyanogen bromide) mainly used for this purpose at the dawn of
the 20th century. Despite its precedence, the von Braun reaction
has been applied only once to an azetidine in the course of a
more comprehensive study looking at cyclic amines reacting
with cyanogen bromide. Thus, Hageman et al7 reported the
cleavage of N-butyl azetidine 1, leading to 3-bromo cyanamide 2,
and its subsequent reaction with diamine 3, leading to bis-
guanidine 4 (Scheme 1). As stated by the authors in this seminal
article, “although this reaction proceeds in good yield, the
limiting factor in its usefulness is the lack of suitable methods for
the synthesis of azetidines in good yield”. Since this situation is
no longer valid, azetidines being available with different
substitution patterns, even in homochiral form, we decided to
revisit this reaction and its applications, with careful examination
of the issues of its regio- and stereoselectivity, as well as the
synthetic applications of the produced bromo cyanamides. This
is the purpose of this article.
[a]
Institut Lavoisier de Versailles, UMR 8180
Université de Versailles St-Quentin-en-Yvelines, Université Paris
Saclay.
45 av. des Etats-Unis, 78035 Versailles Cedex, France
E-mail: couty@chimie.uvsq.fr; http://www.ilv.uvsq.fr
Fax: +33 (0)1 39 25 44 52
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
Figure 1. Structures of azetidines 5-22 used in this study
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In this series, azetidines 7-9, 15 and 18-22 were used as
homochiral substrates and other chiral compounds were used as
racemic mixtures. All of them were either commercially available
(5) or synthesized readily in a few steps.1f,2c,8
was more complicated, since mixtures of epimers and
regioisomers 36 and 37 were obtained in both cases, together
with small amounts of epimerized starting azetidine. By running
the reactions at lower temperature (0°C for 18, and -18°C for 19),
it was however possible to minimize epimerization, and we were
able to produce each regioisomer with high diastereoisomeric
excess. An X-ray structure of compound (S,S)-37,9 resulting
from ring opening at C-2 in 19, allowed the determination of the
structures of the produced products and gave insights into the
mechanism of the reaction (vide supra). (Scheme 4).
First the reaction of 5 with BrCN under standardized conditions
(0.2 M solution of the azetidine in CHCl3 at rt, 1.5 eq. of 3 M
BrCN solution in dichloromethane) was examined. This led
mostly to the cleavage of the azetidine ring after 1h at rt, leading
to 3-bromo cyanamide 24 in excellent isolated yield, with a 12%
ratio of N-cyano azetidine 23. It is worthy to note that this
preferential ring-cleavage contrasts with the reaction with
triphosgene, which mostly leads to N-benzhydryl cleavage.5
However, by encumbering the 3-position of the azetidine ring
(14) with a benzyloxy substituent, cleavage of the N-benzhydryl
group became the major event (Scheme 2).
Scheme 3. Switching from a N-methyl to a N-benzyl group lowers reactivity.
Scheme 2. Reaction of N-benzhydryl azetidine with cyanogen bromide.
Among all the azetidines we tested in this reaction, 5 and 14 are
the only substrates that showed competing N-alkyl cleavage,
thus highlighting the positive effect of ring strain to promote ring-
cleavage. Other tested compounds displayed contrasting
reactivities, depending essentially on the nucleophilic character
of the azetidine, which itself depends on the substitution pattern
and on the nature of the N-substituent. Let us examine the
different cases considering this last parameter. The smallest N-
substituent is a methyl group present in ephedrine-derived
azetidines 20 and 22. These compounds reacted at rt with BrCN,
but required protracted reaction time compared to 5, yielding 27
and 28 with total regioselectivity as single diastereoisomers. The
structure of 27 was determined by X-Ray crystallography,
demonstrating the SN2 process operating during ring cleavage.9
Switching to a N-Bn group in 21 considerably lowered the
reactivity and gave only a modest yield of similar ring opened
product 29 after 7 days of heating at 80°C, demonstrating the
critical parameter of steric crowding around the amine (Scheme
3).
The reactivity of other azetidines fitted with a N-Bn group varied
upon the substitution pattern of the four-membered ring. Alpha-
monosubstituted 6,11,12 and alpha-disubstituted 16 reacted
rapidly at rt, leading to ring-opened products with varying levels
of regioselectivity. In all cases, except for 6, the regioisomer
resulting from opening by the bromide anion at the unsubstituted
position was privileged. With azetidine 10, with a hydroxymethyl
group, further reaction led to the unstable 2-iminooxazolidine 35.
With the ,-disubstituted azetidines 18 and 19, the outcome
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10.1002/ejoc.201701443
European Journal of Organic Chemistry
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unsubstituted carbon, in line with the general rules governing
SN2 reactions. This rule does not however apply to a nitrile
substituent, for which the observed regioselectivity is poor,
probably due to its small size. Reactivity is highly affected by the
nature of the N-substituent and is dramatically lowered in the
order Me > Bn > phenylethyl > aryl, which follows the
nucleophilic character and/or the steric crowding of the tertiary
amine. The epimerization observed in some cases can be
explained by the reversible formation of an intermediate N-ylide
B, produced by deprotonation of the intermediate ammonium
salt A, A’ by the unreacted azetidine acting as a base (Scheme
6). To the best of our knowledge, this possible side-reaction in
the von Braun reaction is shown here for the first time and
highlights the importance of the rates of the two elementary
steps for the overall stereospecificity of the process, which
depends on the substrate used .10
Scheme 4. Reaction of N-benzyl azetidines in the von Braun reaction.
Altogether, this set of results demonstrate that N-Bn azetidines
react with fair regioselectivity and reasonable rates when mono-
or disubstituted at the 2 position, but the introduction of another
substituent at C-3 is detrimental to attain good regioselectivity.
When a N-phenylethyl group is present, instead of a N-Bn group,
then steric crowding is enhanced, and reactivity is dramatically
lowered. Thus, azetidines 7-9 reacted sluggishly and required
several days of reaction at 80°C to reach completion.
Regioselectivity was poor, and epimerization was also detected
in the produced compound 40. An interesting substrate was the
azetidine 15 devoid of substituents at C-2. This compound
reacted readily at rt to give a diastereoisomeric mixture of
opened products 44 in a 70:30 ratio. This could be improved to
75:25 by running the reaction at -25°C for 24h (Scheme 5).
Finally, N-Ph azetidines 13 and 17 did not react with BrCN, even
upon reflux, probably due to the decreased nucleophilic
character of the N-aryl amine.
Scheme 6. Possible mechanism via a N-ylide, explaining the epimerization
detected with some substrates (shown with 18).
Having demonstrated the potential of the von Braun reaction
applied to azetidines, we briefly focused on the use of the
produced 3-bromo N-cyanamides as original building blocks for
the synthesis of nitrogen heterocycles.11 Indeed, the cyanamide
moiety offers various opportunities to act as an electrophile or as
a partner in cycloadditions and radical reactions.12 The presence
of an extra electrophilic carbon, in the bromoalkane group,
renders these compounds particularly relevant. Thus, reaction of
24 with 4-methylbenzylamine in refluxing ethanol gave a good
yield of cyclic guanidine 45, isolated as its hydrobromide salt.
Such cyclic guanidines have found increasing interest recently,
particularly in the field of nucleophilic catalysis.13 Alternatively,
the substitution of the bromide by an azido group in 24, followed
by [3+2] intramolecular cycloaddition14 gave a fair yield of
tetrazole 46 over two steps (Scheme 7).
Scheme 5. Reaction of N-phenylethyl azetidines in the von Braun reaction.
All these results allow us to delineate general trends in this
reaction. Regarding regioselectivity, it is clear that a good level
of regioselectivity is attained if the azetidine ring is alpha mono-
or disubstituted, with the bromide anion reacting on the
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and the residue was purified by flash chromatography or by thin layer
chromatography over silica gel.
N-benzhydryl-(3-bromo-propyl)-cyanamide 24
From N-benzhydryl azetidine 5, 12% of azetidine carbonitrile 23 and 1,1-
diphenylbromomethane were detected in the crude reaction mixture.
Compound 24 was purified as
a colourless oil (87%); Rf= 0.55
1
(PE/EtOAc : 80/20); H NMR (300 MHz, CDCl3): δ = 7.48-7.30 (m, 10H,
Ar), 5.32 (s, 1H, NCHPh2), 3.56 (t, 2H, J=6.0 Hz, CH2Br), 3.30 (t, 2H,
J=6.0 Hz, CH2N), 2.29 (appt. quint., 2H, J=6.0 Hz, CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 137.2 (Cq), 129.0, 128.7, 128.3 (CHAr), 116.1 (CN),
69.2 (NCH), 49.3, 30.4, 29.8 (CH2) ppm. IR: νmax = 3325(b), 2969, 2835,
1610, 1511, 1244, 1171, 1031, 817, 792, 510 cm-1. HRMS (TOF MSES
positive mode) m/z calcd for C17H17BrN2Na [M+Na]+ : 351.0473; found :
351.0460.
Scheme 7. Two example of the use of 3-bromo N-cyanamides for the
synthesis of nitrogen heterocycles.
3-benzyloxy-azetidine-1-carbonitrile
benzyloxy-3-bromo-propyl)-cyanamide 26
25
and
N-benzhydryl-(2-
Conclusions
In conclusion, we have studied in detail the von Braun reaction
applied to azetidines, and have shown that excellent levels of
regio- and stereoselectivity can be reached in the ring-opening
process, which is the favored pathway in most cases, even with
a N-benzydryl group. Considering the recent progress made in
the preparation of azetidines, allowing the easy preparation of a
vast array of diversely substituted compounds even in non-
racemic forms,1 coupled with the synthetic relevance of the 3-
bromo N-cyanamide as original building blocks to create
nitrogen containing heterocycles, we feel that this revival of the
von Braun reaction when applied to azetidines should be of
interest for the synthetic community.
From azetidine 14, compounds 25 (43%) and 26 (18%) were isolated.
25 Colourless oil (43%); Rf= 0.34 (PE/EtOAc : 75/25); 1H NMR (300 MHz,
CDCl3): δ = 7.41-7.30 (m, 5H, Ar), 4.45 (bs, 2H, OCH2Ph), 4.42-4.34 (m,
1H, CHOBn), 4.24-4.19 (m, 2H, CHHNCHH), 4.10-4.05 (m, 2H,
CHHNCHH) ppm. 13C NMR (75 MHz, CDCl3): δ = 136.5 (Cq), 128.5,
128.2, 127.9 (CHAr), 117.3 (CN), 71.5 (OCH2Ph), 68.7 (CHOBn), 62.3
(CH2NCH2) ppm. IR: νmax = 3060, 3040, 2955, 2875, 2207, 1457, 1258,
1121, 745, 700 cm-1. HRMS (TOF MSES positive mode) m/z calcd for
C11H13N2O [MH]+ : 189.1028; not found.
26 Colourless oil (18%); Rf= 0.58 (PE/EtOAc : 75/25); 1H NMR (300 MHz,
CDCl3): δ = 7.42-7.28 (m, 15H, Ar), 5.38 (s, 1H, NCHPh2), ~4.73 (appt. d,
A part of AB syst., 1H, J=12.0 Hz, OCH2Ph), ~4.61 (appt. d, B part of AB
syst., 1H, J=12.0 Hz, OCH2Ph), 4.02-3.95 (m, 1H, CHOBn), 3.55-3.47 (m,
AB part of ABX syst., 2H, CH2Br), ~3.44 (appt. dd, AB part of ABX syst.,
1H, NCH2), ~3.30 (appt. dd, AB part of ABX syst., 1H, NCH2) ppm. 13C
NMR (75 MHz, CDCl3): δ = 137.8, 137.6, 137.1 (Cq), 128.8, 128.7, 128.5,
128.4, 128.3, 128.1, 128.0 (CHAr), 116.4 (CN), 76.2 (CHOBn), 72.3
(OCH2Ph), 69.2 (CH(Ph)2), 53.5 (NCH2), 31.0 (BrCH2) ppm. IR: νmax =
3062, 3032, 2945, 2867, 2205, 1493, 1453, 1064, 734, 694 cm-1. HRMS
(TOF MSES positive mode) m/z calcd for C24H24N2OBr [MH]+ : 435.1072;
found : 435.1064.
Experimental Section
General information: 1H and 13C NMR spectra were recorded at 200 or
300 and 75 MHz, respectively; chemical shifts (δ) are reported in ppm
and coupling constants (J) reported in Hertz and rounded up to 0.1 Hz.
Splitting patterns are abbreviated as follows: singlet (s), doublet (d),
triplet (t), quartet (q), septuplet (sep), multiplet (m), broad (br), or a
combination of these. Solvents were used as internal standard when
assigning NMR spectra (δ H : CDCl3 7.26 ppm ; δ C: CDCl3 77.0 ppm).
Assignments for signals from 1H and 13C in the NMR spectra were
validated by two-dimensional correlated spectroscopy (2D COSY) and
Heteronuclear Multiple Bond Correlation (HMBC). IR data were collected
with an ATR-FT-IR spectrometer. All reactions were carried out under
argon. Column chromatography was performed on silica gel (230–400
mesh) with use of various mixtures of CH2Cl2, EtOAc, petroleum ether
(35-60°C fraction) (PE) and methanol. TLC was performed on Merck
Kieselgel 60 F254 plates. Melting points are uncorrected. Isomeric ratios
were determined by NMR analysis of crude reaction mixtures before
purification.
(1S,2S,3R)-N-methyl-(3-bromo-3-cyano-1-methyl-2-phenyl-propyl)-
cyanamide 27
White solid (90%); Mp= 92°C; Rf= 0.23 (PE/EtOAc : 75/25); 1H NMR
(300 MHz, CDCl3): δ = 7.46-7.43 (m, 3H, Ar), 7.40-7.36 (m, 2H, Ar), 5.05
(d, 1H, J=3.9 Hz, CHBrCN), 3.55-3.45 (m, 1H, NCHCH3), ~3.23 (appt. dd,
1H, J=10.8 Hz, J=3.9 Hz, CHPh), 3.07 (s, 3H, NCH3), 1.19 (d, 3H, J=6.3
Hz, CHCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 133.6 (Cq), 129.3,
129.0 (CHAr), 115.9, (CHCNBr), 115.6 (NCN), 59.0 (NCH), 52.1 (CHPh),
39.0 (NCH3), 32.0 (CHBrCN), 15.4 (CH3) ppm. IR: νmax = 3026, 3000,
2979, 2959, 2923, 2196, 1497, 1449, 1378, 1251, 770, 703, 600 cm-1.
HRMS (TOF MSES positive mode) m/z calcd for C13H14N3BrNa [MNa]+ :
20
314.0269; found : 314.0269. [] 578 : - 19 (c 1.0, CH2Cl2).
General procedure for the Von Braun reaction with azetidines
(1S,2S,3S)-N-methyl-(3-bromo-3-cyano-1-methyl-2-phenyl-propyl)-
cyanamide 28
To a solution of the required azetidine in chloroform (concentration: 0.2
M) was added dropwise a 3 M solution of BrCN in CH2Cl2 (1.5 equiv.).
The reaction was monitored by TLC. When no reaction was detected
immediately after the addition, it was heated at 80°C. In the case of
protracted reaction time, an additional 1 equiv. of BrCN was added each
24h. After completion, solvent was evaporated under reduced pressure,
White solid (75%); Mp= 92°C; Rf= 0.71 (PE/EtOAc : 75/25); 1H NMR
(300 MHz, CDCl3): δ = 7.43-7.40 (m, 3H, Ar), 7.35-7.32 (m, 2H, Ar), 5.01
(d, 1H, J=5.1 Hz, CHBrCN), 3.51-3.45 (m, 1H, NCHCH3), ~3.23 (appt. dd,
1H, J=11.1 Hz, J=4.8 Hz, CHPh), 3.06 (s, 3H, NCH3), 1.15 (d, 3H, J=6.3
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10.1002/ejoc.201701443
European Journal of Organic Chemistry
FULL PAPER
Hz, CHCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 135.1 (Cq), 129.1,
128.8 (CHAr), 116.1, (CHCNBr), 115.4 (NCN), 60.7 (NCH), 53.8 (CHPh),
39.3 (NCH3), 29.4 (CHBrCN), 16.1 (CH3) ppm. IR: νmax = 3070, 3026,
2987, 2971, 2943, 2196, 1490, 1453, 1374, 782, 702 cm-1. HRMS (TOF
MSES positive mode) m/z calcd for C13H15N3Br [MH]+ : 292.0449; found :
N-benzyl-(1-acetoxymethyl-3-bromo-propyl)-cyanamide 34
Yellow oil (75%); Rf= 0.29 (PE/EtOAc : 75/25); 1H NMR (300 MHz,
CDCl3): δ = 7.40-7.36 (m, 5H, Ar), 4.38-4.24 (m, 3H, NCH2Ph, CHHOAc),
4.08-4.02 (m, 1H, CHHOAc), 3.54-3.34 (m, 3H, CHN, CH2Br), 2.34-2.23
(m, 1H, CHHCH2Br), 2.10-1.98 (m, 4H, CHHCH2Br, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 170.4 (CO), 134.4 (CqAr), 129.0, 128.9 (CHAr),
115.1 (NCN), 63.7 (CH2O), 56.5 (CHN), 56.4 (NCH2Ph), 32.6
(CH2CH2Br), 28.9 (CH2Br), 20.6 (CH3) ppm. IR: νmax = 3031, 2948, 2211,
1740, 1496, 1456, 1349, 1316, 1218, 1153, 1114, 1067, 1008, 868, 763,
706 cm-1. HRMS (TOF MSES positive mode) m/z calcd. for
C14H18N2O2Br [MH]+ : 325.0552; found : 325.0555.
20
292.0443. [] : - 47 (c 0.5, CH2Cl2).
578
(1S,2S,3R)-N-benzyl-(3-bromo-3-cyano-1-methyl-2-phenyl-propyl)-
cyanamide 29
Pale yellow viscous oil (29%); Rf= 0.18 (PE/EtOAc : 85/15); 1H NMR
(300 MHz, CDCl3): δ = 7.49-7.34 (m, 10H, Ar), 5.04 (d, 1H, J=3.9 Hz,
CHBrCN), 4.36 (s, 2H, NCH2Ph), 3.67-3.57 (m, 1H, NCHCH3), 3.28 (dd,
1H, J=10.5 Hz, J=3.6 Hz, CHPh), 1.11 (d, 3H, J=6.3 Hz, CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 134.1, 133.6 (Cq), 129.4, 129.3, 128.9 (CHAr),
115.9 (CHCNBr), 114.7 (NCN), 57.5 (NCH), 56.9 (NCH2Ph), 52.4 (CHPh),
32.1 (CHBrCN), 16.4 (CH3) ppm. IR: νmax = 3061, 3030, 2971, 2935,
2872, 1499, 1456, 1381, 1140, 730, 702 cm-1. HRMS (TOF MSES
(1S,2R)-N-benzyl-(3-bromo-1-cyano-2-phenyl-propyl)-cyanamide
(S,R)-36 and (2S,3R)-N-(benzyl)-(3-bromo-3-cyano-2-phenyl-propyl)-
cyanamide (S,R)-37
Reaction of azetidine 18 with BrCN at 0°C for 8 days gave compound
(S,R)-36 as a single epimer (clear needles, 43%) and compound (S,R)-37
as a single epimer (white crystals, 15%).
positive mode) m/z calcd for C19H19N3Br [MH]+ : 368.0762; found :
20
578
368.0756. []
: +6 (c 2.9, CH2Cl2).
(S,R)-36 Mp= 116°C; Rf =0.25 (PE/EtOAc : 50/50); 1H RMN (300 MHz,
CDCl3) :  (ppm) = 7.52-7.43 (m, 8H, Ar), 7.35-7.30 (m, 2H, Ar), ~4.44 (d,
A part of AB syst., 1H, J=13.2 Hz, NCH2Ph), 4.42 (d, 1H, J=10.2 Hz,
CHCN), ~4.35 (d, B part of AB syst., 1H, J=13.2 Hz, NCH2Ph), 3.80 (dd,
A part of ABX syst., 1H, J=11.1 Hz, CH2Br), 3.72 (dd, B part of ABX syst.,
1H, J=10.8 Hz, CH2Br), 3.66-3.59 (m, 1H, CHPh) ppm. 13C NMR (75
MHz, CDCl3): δ = 134.7, 132.0 (Cq), 129.6, 129.3, 129.1, 128.2 (CHAr),
114.3 (CHCN), 113.2 (NCN), 56.8 (NCH2Ph), 54.0 (NCHCN), 47.6
(CHPh), 33.4 (BrCH2) ppm. IR: νmax = 3066, 3033, 2969, 2890, 2208,
1495, 1457, 1124, 1078, 751, 702 cm-1. HRMS (TOF MSES positive
mode) m/z calcd for C18H17N3Br [MH]+ : 354.0606; found : 354.0613.
N-benzyl-(3-bromo-1-cyano-propyl)-cyanamide 30
Yellow oil (43%); Rf= 0.55 (PE/EtOAc : 75/25); 1H NMR (300 MHz,
CDCl3): δ = 7.45-7.37 (m, 5H, Ar), 4.45 (d, J=13.6 Hz, 1H, NCHHPh),
4.31 (d, J=13.7 Hz, 1H, NCHHPh), 4.15-4.10 (m, 1H, CHCN), 3.55-3.42
(m, 2H, CH2Br), 2.59-2.36 (m, 2H, CH2) ppm. 13C NMR (75 MHz, CDCl3):
δ = 132.0 (CqAr), 129.5, 129.3, 129.0 (CHAr), 115.2 (CHCN), 113.0 (NCN),
56.4 (NCH2Ph), 48.8 (CHCN), 33.8 (CH2), 26.7 (CH2Br) ppm. IR: νmax =
3031, 2949, 2212, 1496, 1462, 1348, 1316, 1255, 1218, 1164, 1153,
1115, 1068, 1029, 953, 925, 852, 763, 734, 707, 601 cm-1. HRMS (TOF
MSES positive mode) m/z calcd for C12H13N3Br [MH]+ : 278.0293; not
found.
20
[α] : + 3 (c 1.3, CH2Cl2).
578
(S,R)-37 Mp= 85°C; Rf =0.17 (PE/EtOAc : 50/50); 1H RMN (300 MHz,
CDCl3) :  (ppm) = 7.48-7.40 (m, 6H, Ar), 7.35-7.30 (m, 2H, Ar), 7.27-
7.24 (m, 2H, Ar), 4.63 (pd, 1H, J=4.2 Hz, CHBrCN), ~4.18 (d, A part of
AB syst., 1H, J=14.1 Hz, NCH2Ph),~4.05 (d, B part of AB syst., 1H,
J=14.4 Hz, NCH2Ph), 3.77-3.65 (m, A part of ABX syst., 1H, CH2N), 3.55-
3.44 (m, B part of ABX syst., 1H, CH2N and 1H, CHPh) ppm. 13C NMR
(75 MHz, CDCl3): δ = 134.5, 133.8 (Cq), 129.4, 129.3, 129.1, 129.0,
128.6, 128.4 (CHAr), 116.7 (NCN), 115.5 (CHCNBr), 56.9 (NCH2Ph), 51.3
(NCH2), 48.0 (CHPh), 29.8 (BrCHCN) ppm. IR: νmax = 3065, 3032, 2969,
2889, 2207, 1495, 1456, 1124, 1078, 751, 703 cm-1. HRMS (TOF MSES
positive mode) m/z calcd for C18H17N3Br [MH]+ : 354.0606; found :
N-benzyl-(3-bromo-3-cyano-propyl)-cyanamide 31
Colourless oil (49%); Rf= 0.32 (PE/EtOAc : 75/25); 1H NMR (300 MHz,
CDCl3): δ = 7.46-7.34 (m, 5H, Ar), 4.40 (t, J=7.4 Hz, 1H, CHBrCN), 4.23
(s, 2H, NCH2Ph), 3.22 (t, J=6.5 Hz, 2H, NCH2CH2), 2.48-2.30 (m, 2H,
NCH2CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 133.8 (CqAr), 129.1,
129.0, 128.5 (CHAr), 116.5, 116.3 (CHCNBr, NCN), 56.7 (NCH2Ph), 47.2
(NCH2CH2), 34.0 (NCH2CH2), 23.4 (CHBrCN) ppm. IR: νmax = 3031,
2949, 2212, 1496, 1456, 1349, 1316, 1255, 1218, 1164, 1153, 1115,
1068, 1008, 953, 925, 868, 763, 734, 707 cm-1. HRMS (TOF MSES
positive mode) m/z calcd for C12H13N3Br [MH]+ : 278.0293; found :
278.0287.
20
354.0606. [] : - 16 (c 1.3, CH2Cl2).
578
(1R,2R)-N-(benzyl)-(3-bromo-1-cyano-2-phenyl-propyl)-cyanamide
(R,R)-36 and (2S,3S)-N-benzyl-(3-bromo-3-cyano-2-phenyl-propyl)-
cyanamide (S,S)-37
N-benzyl-(1-benzyloxymethyl-3-bromo-propyl)-cyanamide 32 and N-
benzyl-(3-benzyloxymethyl-3-bromo-propyl)-cyanamide 33
Reaction of azetidine 19 with BrCN at -18°C for 12 days gave compound
(R,R)-36 (white solid, 17%) and compound (S,S)-37 (white crystals, 62%).
(R,R)-36 Mp= 116°C; Rf =0.30 (PE/EtOAc : 50/50); 1H RMN (300 MHz,
CDCl3) :  (ppm) = 7.44-7.31 (m, 6H, Ar), 7.18-7.14 (m, 2H, Ar), 7.06-
7.02 (m, 2H, Ar), ~4.23 (d, A part of AB syst., 1H, J=13.8 Hz, NCH2Ph),
~4.17 (d, B part of AB syst., 1H, J=14.7 Hz, NCH2Ph), 4.13 (d, 1H,
J=10.5 Hz, CHCN), 3.86-3.75 (m, AB part of ABX syst., 2H, CH2Br),
3.67-3.62 (m, 1H, CHPh) ppm. 13C NMR (75 MHz, CDCl3): δ = 134.5,
131.6 (Cq), 129.4, 129.1, 129.0, 128.9, 128.0 (CHAr), 114.7 (CHCN),
113.3 (NCN), 56.5 (NCH2Ph), 53.6 (NCHCN), 47.7 (CHPh), 33.5 (BrCH2)
ppm. IR : νmax = 3066, 3033, 2969, 2890, 2207, 1495, 1456, 1239, 1124,
Compounds 32/33 were obtained as an inseparable mixture of
regioisomers; yellow oil (99%); Rf= 0.41 (PE/EtOAc : 60/40); 1H NMR
(300 MHz, CDCl3): δ = 7.42-7.33 (m, 10H, Ar), 4.61-4.51 (m, 2H,
OCH2Ph), 4.40-4.20 (m, 2H, CHCH2O), 3.64-3.32 (m, 5H, CHN, NCH2Ph,
CH2Br), 2.27-2.18 (m, 1H, CHHCH2Br), 2.08-1.96 (m, 1H, CHHCH2Br)
ppm. Major regioisomer: 13C NMR (75 MHz, CDCl3): δ = 137.5, 134.8
(CqAr), 128.9, 128.8, 128.6, 127.8, 127.6 (CHAr), 115.6 (NCN), 73.4
(OCH2Ph), 70.8 (CHCH2O), 57.8 (CHN), 56.8 (NCH2Ph), 32.6
(CH2CH2Br), 29.3 (CH2Br) ppm. IR: νmax = 3030, 2863, 2206, 1496,
1454, 1362, 1252, 1111, 1076, 953, 734, 697 cm-1. HRMS (TOF MSES
positive mode) m/z calcd for C19H22N2OBr [MH]+ : 373.0915; found :
373.0918.
1078, 751, 703 cm-1. HRMS (TOF MSES positive mode) m/z calcd for
20
578
C18H17N3Br [MH]+ : 354.0606; found : 354.0614. [α]
: + 35 (c 1.3,
CH2Cl2).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701443
European Journal of Organic Chemistry
FULL PAPER
(S,S)-37 Mp= 97°C; Rf =0.15 (PE/EtOAc : 50/50); 1H RMN (300 MHz,
CDCl3) :  (ppm) = 7.48-7.39 (m, 6H, Ar), 7.35-7.30 (m, 2H, Ar), 7.28-
7.25 (m, 2H, Ar), 4.65 (d, 1H, J=6.6 Hz, CHBrCN), ~4.16 (d, A part of AB
syst., 1H, J=14.1 Hz, NCH2Ph),~4.10 (d, B part of AB syst., 1H, J=14.4
Hz, NCH2Ph), ~3.63 (dd, A part of ABX syst., 1H, J=12.3 Hz, CH2N),
3.52 (m, 1H, CHPh), ~3.41 (dd, B part of ABX syst., 1H, J=12.3 Hz,
CH2N) ppm. 13C NMR (75 MHz, CDCl3): δ = 134.5, 133.6 (Cq), 129.2,
129.1, 129.0, 128.9, 128.5, 128.3 (CHAr), 116.6 (NCN), 115.4 (CHCNBr),
56.7 (NCH2Ph), 52.4 (NCH2), 48.4 (CHPh), 29.3 (BrCHCN) ppm. IR:
νmax = 3066, 3033, 2969, 2890, 2207, 1495, 1456, 1124, 1078, 751, 703
cm-1. HRMS (TOF MSES positive mode) m/z calcd for C18H16N3BrNa
[MNa]+ : 378.0405; found : 378.0413. [α] 52708 : - 69 (c 1.3, CH2Cl2). X-Ray
data: see supplementary material.
2.62-2.38 (m, 2H, CH2CH2Br), 1.79 (d, 3H, J=6.9 Hz, CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 137.9 (Cq), 129.6, 127.4, 127.0 (CHAr), 115.6
(CHCN), 111.9 (NCN), 60.9 (NCHPh), 48.3 (NCHCN), 34.2 (CHCH2),
26.6 (BrCH2), 21.3 CH3 ppm. IR: νmax = 3065, 3026, 2978, 2935, 2876,
2213, 1495, 1456, 1235, 1097, 766, 695 cm-1. HRMS (TOF MSES
positive mode) m/z calcd for C13H14N3BrNa [MNa]+: 314.0269; not
20
detected. [] : +42 (c 1.0, CH2Cl2).
578
40 Clear oil (39%, 95:5 mixture of epimers) Rf= 0.17 (PE/EtOAc 80/20);
1H NMR (300 MHz, CDCl3): δ = 7.47-7.36 (m, 5H, Ar), 4.42-4.38 (m, 1H,
CHCNBr), 4.15 (q, 1H, J=7.1 Hz, NCHCH3), 3.21-3.06 (m, 2H, NCH2),
2.47-2.27 (m, 2H, NCH2CH2), 1.71 (d, 3H, J=6.9 Hz, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 139.8 (Cq), 129.3, 128.8, 126.5 (CHAr), 116.5
(CHCNBr), 115.3 (NCN), 60.8, (NCH), 47.2, 34.1 (CH2), 23.7, (BrCHCN),
20.9 (CH3) ppm.
2-(benzyl-cyano-amino)-4-bromo-2-methyl-butyric acid tert-butyl
ester 38
[2(1’R),2S]-2-[cyano-(1’-phenyl-ethyl)-amino]-4-bromo-butyric acid
tert-butyl ester 42 and [(2R and 2S) 4(1’R)]-4-[cyano-(1’-phenyl-
ethyl)-amino]-2-bromo-butyric acid tert-butyl ester 43
Clear oil (75%); Rf= 0.28 (PE/EtOAc : 90/10); 1H NMR (300 MHz,
CDCl3): δ = 7.46-7.30 (m, 5H, Ar), 4.20 (d, A part of AB syst., 1H, J=13.8
Hz, NCH2Ph),~4.13 (d, A part of AB syst., 1H, J=14.1 Hz, NCH2Ph),
3.49-3.32 (m, 2H, CH2Br), 2.63-2.46 (m, 2H, CH2CH2Br), 1.58 (s, 3H,
CH3), 1.55 (s, 9H, C(CH3)3) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.1
(COO), 134.6 (Cq), 129.0, 128.8, 128.7 (CHAr), 115.2 (NCN), 83.7
(COOC(CH3)3), 65.8 (NCqCOO), 52.4 (NCH2Ph), 39.6 (BrCH2CH2), 28.0
(C(CH3)3), 25.3 (BrCH2), 21.4 (CH3) ppm. IR: νmax = 3015, 2979, 2931,
2212, 1724, 1497, 1457, 1391, 1370, 1144, 1116, 754, 695, 663 cm-1.
HRMS (TOF MSES positive mode) m/z calcd for C17H23N2O2BrNa
[MNa]+ : 389.0841; found : 389.0850.
From azetidine 8, compounds 42 (23%) and 43 (inseparable mixture of
epimers, 79:21 ratio, 26%) were obtained.
42 Yellow oil (23%); Rf= 0.51 (PE/EtOAc : 90/10); 1H NMR (300 MHz,
CDCl3): δ = 7.42-7.28 (m, 5H, Ar), 4.26-4.19 (q, 1H, J=6.0 Hz,
NCHCH3Ph), 3.49-3.42 (m, 2H, CH2Br), 3.29-3.21 (m, 1H, NCHCN),
2.44-2.23 (m, 2H, CH2CH2Br), 1.71 (d, 3H, J=6.0 Hz, CH3), 1.50 (s, 9H,
C(CH3)3) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.7 (COO), 139.6 (Cq),
129.0, 128.7, 126.9 (CHAr), 113.7 (NCN), 83.2 (COOC), 60.3 (NCHPh),
59.1 (NCHCOO), 33.2 (CHCH2), 28.5 (BrCH2), 27.9 (C(CH3)3), 21.4
(CH3) ppm. IR: νmax = 3042, 3022, 2977, 2936, 2211, 1729, 1457, 1394,
(1S, 1’R) N-(1’-phenyl-ethyl)-(3-bromo-1-cyano-propyl)-cyanamide 39
and
(1’R,
3R)
N-(1’-phenyl-ethyl)-(3-bromo-3-cyano-propyl)-
1368, 1248, 1153, 767, 703 cm-1. HRMS (TOF MSES positive mode) m/z
20
578
cyanamide 40
calcd for C17H24O2N2Br [MH]+ : 367.1021; found : 367.1032. []
(c 1.2, CH2Cl2).
: - 2
43 Inseparable mixture of epimers (79:21 ratio); yellow oil (26%); Rf=
0.46 (PE/EtOAc 90/10); 1H NMR (300 MHz, CDCl3): δ = 7.40-7.29 (m, 5H,
Ar), 4.23-4.18 (m, 1H, CHCOOBr), 4.10 (q, 1H, J=6.0 Hz, NCHCH3),
3.13-2.91 (m, 2H, NCH2), 2.38-2.25 (m, A part of ABX syst., 1H,
NCH2CH2), 2.23-2.08 (m, B part of ABX syst., 1H, NCH2CH2), 1.65 (d, 3H,
J=6.0 Hz, CH3), 1.44 (s, 9H, C(CH3)3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 167.7 (COO), 140.2 M, 140.0 m (Cq), 128.9, 128.4, 126.9, 126.4,
126.2 (CHAr), 115.6 m, 115.6 M, 115.30 (NCN), 82.8 (COOC), 60.2 M,
59.7 m (NCH), 47.7 M, 47.6 m (NCH2), 44.0 (BrCHCOO), 32.3 m, 32.2 M
(CHCH2), 27.5 (C(CH3)3), 20.9 M, 20.8 m (CH3) ppm. IR: νmax = 3042,
3022, 2980, 2936, 2207, 1729, 1457, 1394, 1368, 1280, 1147, 767, 703
cm-1. HRMS (TOF MSES positive mode) m/z calcd for C17H23O2N2BrNa
[MNa]+ : 389.0840; found : 389.0838.
From azetidine 7, compounds 39 (39%) and (1’R, 3R)-40 (36%) were
obtained.
39 White solid (39%); Mp= 63-65°C; Rf= 0.28 (PE/EtOAc : 80/20); 1H
NMR (300 MHz, CDCl3): δ = 7.52-7.42 (m, 5H, Ar), 4.38 (q, 1H, J=6.9 Hz,
NCHCH3Ph), 4.19-4.14 (m, 1H, NCHCN), 3.59-3.47 (m, 2H, CH2Br),
2.59-2.34 (m, 2H, CH2CH2Br), 1.79 (d, 3H, J=7.5 Hz, CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 138.2 (Cq), 129.6, 129.5, 126.9 (CHAr), 115.5
(CHCN), 112.1 (NCN), 62.1 (NCHPh), 48.9 (NCHCN), 34.5 (CHCH2),
27.2 (BrCH2), 20.6 CH3 ppm. IR : νmax = 3061, 3030, 2978, 2935, 2209,
1495, 1456, 1239, 1117, 766, 702 cm-1. HRMS (TOF MSES positive
mode) m/z calcd for C13H14N3BrNa [MNa]+ : 314.0269; not detected.
20
578
[]
: - 60 (c 1.0, CH2Cl2).
(1’R, 3R)-40 Clear oil (36%); Rf= 0.17 (PE/EtOAc : 80/20); 1H NMR (300
MHz, CDCl3): δ = 7.47-7.36 (m, 5H, Ar), 4.43-4.38 (m, 1H, CHCNBr),
4.15 (q, 1H, J=7.1 Hz, NCHCH3), 3.22-3.07 (m, 2H, NCH2), 2.42-2.35 (m,
2H, NCH2CH2), 1.71 (d, 3H, J=6.9 Hz, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 139.8 (Cq), 129.3, 128.9, 126.5 (CHAr), 116.5 (CHCNBr),
115.3 (NCN), 60.6, (NCH), 47.2, 34.1 (CH2), 23.6 (BrCHCN), 20.9 (CH3)
ppm. IR : νmax = 3061, 3026, 2974, 2923, 2872, 2205, 1495, 1452, 1377,
(2R and 2S) N-[(1’R)-phenyl-ethyl)]-(2-benzyloxy-3-bromo-propyl)-
cyanamide 44
From azetidine 15, compounds 44 were obtained as an inseparable
mixture of epimers (70:30); white solid (98%); Rf= 0.67 (PE/EtOAc
1
1124, 766, 695 cm-1. HRMS (TOF MSES positive mode) m/z calcd for
75/25); H RMN (300 MHz, CDCl3) :  (ppm) = 7.41-7.28 (m, 10HM and
20
578
C13H14N3BrNa [MNa]+ : 314.0269; found : 314.0274. []
: - 50 (c 1.0,
10Hm, Ar), ~4.68 (appt. d, A part of AB syst., 1Hm, J=11.1 Hz, OCH2Ph),
~4.67 (appt. d, A part of AB syst., 1HM, J=11.4 Hz, OCH2Ph), ~4.58
(appt. d, B part of AB syst., 1Hm, J=12.6 Hz, OCH2Ph), ~4.54 (appt. d, B
CH2Cl2).
(1R, 1’R) N-(1’-phenyl-ethyl)-(3-bromo-1-cyano-propyl)-cyanamide 41 part of AB syst., 1HM, J=11.7 Hz, OCH2Ph), 4.19 (q, 1Hm, J=7.2Hz,
and 40.
NCHCH3), 4.10 (q, 1HM, J=6.9Hz, NCHCH3), 3.89-3.82 (m, 1Hm, CHOPh),
3.82-3.75 (m, 1HM, CHOPh), ~3.50 (dd, AB part of ABX syst., 1HM,
J=11.1Hz, BrCH2), ~3.44 (dd, AB part of ABX syst., 1HM, J=11.1Hz,
BrCH2), ~3.36 (appt. d, AB part of ABX syst., 2Hm, BrCH2), ~3.25 (dd, AB
part of ABX syst., 1Hm, J=14.1Hz, NCH2), ~3.18 (dd, AB part of ABX
syst., 1HM, J=14.7Hz, NCH2), ~3.12 (dd, AB part of ABX syst., 1HM,
J=14.7Hz, NCH2), ~3.01 (dd, AB part of ABX syst., 1Hm, J=14.1Hz,
From azetidine 9, compound 41 (32%) and 40 (39%, 95:5 mixture of
epimers) were obtained.
41 Clear oil (32%); Rf= 0.39 (PE/EtOAc : 80/20); 1H NMR (300 MHz,
CDCl3): δ = 7.50-7.37 (m, 5H, Ar), 4.45-4.39 (q, 1H, J=6.6 Hz,
NCHCH3Ph), 3.98-3.93 (m, 1H, NCHCN), 3.53-3.40 (m, 2H, CH2Br),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701443
European Journal of Organic Chemistry
FULL PAPER
NCH2), 1.63 (d, 3Hm, J=6.9Hz, CHCH3), 1.62 (d, 3HM, J=6.9Hz, CHCH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 140.5, 140.1, 137.1, 137.0 (Cq),
128.9, 128.5, 128.4, 128.1, 128.0, 127.9, 126.4 (CHAr), 116.4, 116.2 (CN),
76.3, 75.5 (CHOPh), 72.4, 72.1 (OCH2Ph), 60.7, 59.9 (CHCH3), 52.9,
52.0 (NCH2), 31.1, 31.0 (BrCH2), 21.1, 21.0 (CHCH3) ppm. IR: νmax =
3069, 3031, 2977, 2933, 2869, 2211, 1495, 1457, 1090, 1068, 742, 700
cm-1. HRMS (TOF MSES positive mode) m/z calcd for C19H22N2OBr
[MH]+ : 373.0915; found : 373.0917.
cyano azetidines, see: F. Couty, G. Evano, B. Drouillat, O. David Eur. J.
Org. Chem, 2013, 2045-2056. g) T. M. Bott, F. G. West, Heterocycles,
2012, 84, 223-264. For other recent leading references on the
synthesis of azetidines, see: h) P. Sulmon, N. De Kimpe, N. Schamp, B.
Tinant, J-P. Declerck, Tetrahedron, 1988, 44, 3653-3670. i) N. De
Kimpe, D. De Smaele, Tetrahedron, 1995, 51, 5465-5478. j) S.
Stancović, S. Catac, M. D’hooghe, H. Goossens, K. A. Tehrani, P.
Bogaert, M. Waroquier, V. Van Speybroeck, N. De Kimpe, J. Org.
Chem. 2011, 76, 2157-2167. k) F. Colpaert, S. Mangelinckx, S. De
Brabandere, N. De Kimpe, J. Org. Chem. 2011, 76, 2204-2213. l) L.
Kiss, S. Mangelinckx, F. Fülöp, N. De Kimpe, Org. Lett. 2007, 9, 4399-
4402. For previous synthesis of 2-cyano azetidines, see: m) P. Sulmon,
N. De Kimpe, N. Schamp, N. J. Chem. Soc. Chem. Commun. 1985,
715-716, and references cited therein.
1-Benzhydryl-3-(4-methyl-benzyl)-tetrahydro-pyrimidin-2-
ylideneamine hydrobromide 45
A
solution of 3-bromo cyanamide 24 (1 mmol) and of 4-
methylbenzylamine (1 mmol) was heated at 80° in abs. EtOH (4 mL) for 5
days. The solution was concentrated under reduced pressure, and the
residue was triturated with small portions of diethyl ether until
crystallization to give 45 as a white solid (235 mg, 72%); Mp= 228°C;
Rf= 0.25 (EtOAc/MeOH/40% aq. NH3 : 94/5/1); 1H NMR (300 MHz,
CD3OD): δ = 7.51-7.20 (m, 14H, Ar), 6.63 (s, 1H, NHPh2), 4.88 (bs, 2H,
+NH2), 4.72 (s, 2H, NCH2Ar), 3.41 (appt. t, 2H, J=6.0 Hz, CH2N), 3.30 (t,
2H, J=6.0 Hz, CH2N), 3.41 (appt. t, 2H, J=6.0 Hz, CH2), 3.20 (appt. t, 2H,
J=6.0 Hz, CH2), 2.37 (s, 3H, CH3), 1.91 (appt. quint., 2H, J=6.0 Hz, CH2)
ppm. 13C NMR (75 MHz, CD3OD): δ = 156.0 (Cguanidine), 139.2, 138.3
(CqAr), 133.0, 130.8, 130.1, 129.9, 129.7, 129.4, 128.2 (CHAr), 66.8 (CH),
54.9, 47.7, 44.4, 22.4 (CH2), 21.2 (CH3) ppm. IR: νmax = 3346, 3269,
3124, 2918, 2202, 1643, 1590, 1574, 1545, 1451, 1328, 1180, 1075,
1030, 789, 722, 694 cm-1. HRMS (TOF MSES positive mode) m/z calcd
for C25H28N3 [MH]+ : 370.2283; found : 370.2273.
[2]
[3]
For reviews on this topic, see: a) F. Couty, F. Durrat, G. Evano, Targets
in heterocyclic systems-Chemistry and Properties. O. A. Attanasi and D.
Spinelli Eds. Italian Society of Chemistry, Rome, vol 9, 2005, 186. b) F.
Couty, O. R. P. David Top. Heterocycl. Chem. 2016, 41, 1-48. See
also: c) B. Drouillat, I. V. Dorogan, M. Kletskii, O. N. Burov, F. Couty, J.
Org. Chem. 2016, 81, 6777-6785.
For a seminal work on azetidinium ion opening, see: a) J. Heliński, Z.
Skrzypczyński, J. Michalski Tetrahedron Lett. 1995, 36, 9201-9204. b)
A. Bakalarz, J. Heliński, B. Krawiecka, J. Michalski, M. J. Potrzebowski,
Tetrahedron 1999, 55, 12211-12226. c) A. Bakalarz-Jeziorna, J.
Heliński, B. Krawiecka, J. Chem. Soc., Perkin Trans. 1 2001, 1086-
1090. d) A. Jeziorna, J. Heliński, B. Krawiecka, Tetrahedron Lett. 2003,
44, 3239-3243. e) B. Krawiecka, A. Jeziorna, Tetrahedron Lett. 2005,
46, 4381-4384. For opening with amines: f) J. M. Concellόn, P. L.
Bernad, J. A. Pérez-Andrés, Tetrahedron Lett. 2000, 41, 1231-1234. g)
F. Couty, F. Durrat, G.Evano, Synlett, 2005, 1666-1670. h) S. Bernstein,
M. Heller, J. Org. Chem. 1971, 36, 1386-1389. i) J. Szmuszkovicz, M. P.
Kane, J. Org. Chem. 1981, 46, 3728-3730. j) H. Oike, M. Washizuka, Y.
Tezuka, Macromol. Chem. Phys. 2000, 201, 1673-1678. k) S. Kenis, M.
D’hooghe, G. Verniest, T. A. Thi, D. C. P. The, T. V. Nguyen, N. De
Kimpe, J. Org. Chem. 2012, 77, 5982-5992. For opening with
oxygenated nucleophiles: l) V. R. Gaertner, Tetrahedron Lett. 1967, 4,
343-347. m) V. R. Gaertner, J. Org. Chem. 1968, 33, 523-530. n) N. J.
Leonard, D. A. Durand, J. Org. Chem. 1968, 33, 1322-1333. o) R. H.
Higgins, W. J. Faircloth, R. G. Baughman, Q. L. Eaton J. Org. Chem.
1994, 59, 2172-2178. p) P. O’Brien, D. W. Phillips, T.D. Towers,
Tetrahedron Lett. 2002, 43, 7333-7335. q) A. Sudo, Y. Iitaka, T. Endo
Journal of Polymer Science: Part A: Polymer Chemistry 2002, 40,
1912-1917. r) F. Couty, O. David, F. Durrat, G. Evano, S. Lakdhar, J.
Marrot, M. Vargas-Sanchez, Eur. J. Org. Chem. 2006, 3479-3490. For
opening with hydride ions and carbon nucleophiles, see: s) F. Couty, O.
David, F. Durrat, Tetrahedron Lett. 2007, 48, 1027-1031. t) F. Couty, O.
David, B. Drouillat Tetrahedron Lett. 2007, 48, 9180-9184. u) B.
Drouillat, K. Wright, O. David, F. Couty, Eur. J. Org. Chem. 2012, 30,
6005-6012.
4-benzhydryl-4,5,6,7-tetrahydro-tetrazolo[1,5-]pyrimidine 46
The bromide 24 (66 mg, 0.2 mmol) was dissolved in DMF (1 mL), and
sodium azide (13 mg, 0.2 mmol) was added. The solution was then
heated in a sealed tube at 140 °C for 48h. The solution was allowed to
cool, concentrated under reduced pressure, and the residue obtained
was purified by column chromatography to give 46 as a white solid (33
mg, 57%); Mp= 152-154°C; Rf= 0.22 (PE/EtOAc 75/25); 1H NMR (300
MHz, CDCl3): δ = 7.35-7.24 (m, 10H, Ar), 6.79 (s, 1H, CHPh), 4.23 (t,
J=6.1 Hz, 2H, CH2N), 3.17 (t, J=5.5 Hz, 2H, CH2N), 2.22-2.14 (m, 2H,
CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 154.8 (CqN), 137.8 (CqAr),
128.5, 128.4, 127.8 (CHAr), 65.0 (CHPh), 42.8 (CH2N), 40.8 (CH2N), 20.9
(CH2) ppm. IR: νmax = 3140, 3060, 2961, 2866, 1612, 1488, 1448, 1331,
1302, 1104, 1078, 1041, 975, 925, 786, 744, 733, 712, 699, 642, 619
cm-1. HRMS (TOF MSES positive mode) m/z calcd. for C17H18N5 [MH]+ :
292.1562; found : 292.1564.
Acknowledgements
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The University of Versailles St-Quentin-en-Yvelines, University
Paris-Saclay and the CNRS are acknowledged for funding.
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Keywords: azetidines, von Braun reaction • guanidines
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X-Ray structures of 27 and (S,S)-37 were deposited at the Cambridge
database and were allocated numbers: 1576396 and 1576395
respectively.
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10.1002/ejoc.201701443
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10.1002/ejoc.201701443
European Journal of Organic Chemistry
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Entry for the Table of Contents (Please choose one layout)
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Azetidines, von Braun reaction.
Karen Wright, Bruno Drouillat, Laurence
Menguy, Jérôme Marrot and François
Couty *
Page No. – Page No.
The von Braun Reaction Applied to
Azetidines
The regio- and stereoselectivity of ring cleavage of N-alkyl azetidines induced by reaction with cyanogen bromide
(the von Braun reaction) was studied in depth. The produced 3-bromo N-alkyl cyanamides were used as original
building blocks for the synthesis of nitrogen heterocycles.
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