RuO4-mediated oxidation of N-benzylated tertiary amines. Four- And three-membered azacycloalkanes as substrates

Article abstract of DOI:10.24820/ark.5550190.p010.698

Similarly to N-benzylpiperidine and -pyrrolidine, N-benzylazetidine underwent RuO4-catalyzed oxidation by attack at both types of N-methylene C-H bonds: Endocyclic and exocyclic (benzylic). If the reaction is performed in the presence of cyanide, α-aminon

Full text of DOI:10.24820/ark.5550190.p010.698

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RuO4-mediated oxidation of N-benzylated tertiary amines. Four- and
three-membered azacycloalkanes as substrates
Cristina A. Florea,* Anca Hîrtopeanu, Cristina Stavarache, and Horia Petride
Romanian Academy, “Costin D. Nenitzescu” Center of Organic Chemistry, Spl. Independenţei 202-B, RO-060023
Bucharest, Romania
E-mail: antonetaflorea@yahoo.com
Received 07-26-2018
Accepted 10-08-2018
Published on line 10-27-2018
Abstract
Similarly to N-benzylpiperidine and -pyrrolidine, N-benzylazetidine underwent RuO4-catalyzed oxidation by
attack at both types of N-methylene C-H bonds: endocyclic and exocyclic (benzylic). If the reaction is
performed in the presence of cyanide, α-aminonitriles were obtained instead of amides. The regioselectivity
(endocyclic/exocyclic) decreased constantly with the decrease of the azacycle size, from about 2 (for N-
benzylpiperidine) to about 0.6 (for N-benzylazetidine). The highest regioselectivity was found for N-
benzylaziridine, for which only products of benzylic functionalization resulted. Iminium ions, complexed to
ruthenium species, were proposed as reactive intermediates during the oxidation of N-benzylated
azacycloalkanes.
Keywords: Oxidation, azacycloalkanes, ruthenium tetroxide, iminium ions, α-aminonitriles
DOI: https://doi.org/10.24820/ark.5550190.p010.698
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Introduction
The powerful oxidant ruthenium tetroxide (RuO4)1 is widely used to functionalize C-H bonds in various organic
compounds, such as hydrocarbons,2,3 halides,4 ethers,5 alcohols,6 amines,7-12 or amides.13 Rarely, the oxidative
attack takes place at a heteroatom, like in the transformation of sulfide into sulfone.14 Since RuO4 has
electrophilic character, the more electron-rich C-H bonds are attacked first. This explains why the C-H bonds in
α-position to a heteroatom are oxidized preferentially in alcohols, ethers or amines.1 In most cases these
reactions result in products that are biologically active intermediates useful in the synthesis of amino acids,
fragrances and drugs.4,7,11,12,14
Regarding the oxidation of amines, primary or secondary ones (R2CH-NH-R) are transformed by RuO4 into
imines (R2C=N-R), by a formal 1,2-dehydrogenation process.15,16 In addition, a less common 1,1-
dehydrogenation reaction transforms tertiary amines (R-CH2-NR2) to amides (R-CO-NR2), with iminium ions as
intermediates.7-11
Our previous research on oxidation of tertiary amines focused on the oxidative behaviour of medium-size
azacycloalkanes, namely 1-benzylpiperidine (1a) and 1-benzylpyrrolidine (1b).8 In this paper the studies are
completed with the oxidation of small-ring analogues, 1-benzylazetidine (1c) and -aziridine (1d) (Scheme 1).
Results and Discussion
A general overview of the oxidation reactions of 1-benzylazacycloalkanes is presented in Scheme 1. Influence
of the ring size on the reactivity and regioselectivity, in the RuO4-mediated oxidation, revealed interesting
aspects of the reaction mechanism.
Scheme 1. Oxidative routes for 1a-d
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Previously studied8 substrates 1a-b are tertiary amines with two types of N-CH2 groups: endocyclic and
exocyclic (benzylic). Both types of methylene C-H bonds are attacked to yield the corresponding iminium ions
as intermediates (Scheme 1): endocyclic (2a-b) and exocyclic (3a-b). At the same time, small amounts of N-
oxides (4a-b) were present in the reaction mixtures, indicating that an N-oxidative attack (Scheme 1) was
possible only to a minor extent.
Scheme 2. Oxidation products of 1a-d.
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The cations gave the final oxidation products after capture by nucleophiles, namely water under normal
conditions (Scheme 2; part A). Along this pathway, the expected lactams 5a-b resulted from 2a-b, respectively,
in essentially two steps. These steps are similar to those shown explicitly for the transformation of 3a-b into
6a-b: (i) formation of hemiaminals 7a-b and (ii) oxidation of these alcohols to yield benzamides 6a-b,
respectively. Alternatively, the hemiaminals can split into benzaldehyde (BzH) and the corresponding
unsubstituted azacycloalkanes 8a-b. Since iminium ions 2a-b carry β-N protons, stabilization to enamines 9a-b
through deprotonation can occur. Further oxidation of the C=C double bond in 9a-b was the source of
dioxygenated derivatives 10a-b and 11a-b.
When the oxidation was performed in the presence of NaCN, the initial iminium ions were trapped as the
corresponding cyano derivatives 12a-b and 13a-b (Scheme 2, part B).
In this work, identically to the case of 1a-b,8 the oxidation of 1c-d was performed in two ways: in the
absence of cyanide (conditions A) or in its presence (conditions B). The respective results are presented in
Table 1, together with those previously obtained for 1a-b.8 For simplicity, the desired entry (x) of Table 1 will
be cited as T-x. Since free benzoic acid is always derived from benzaldehyde (BzH),8-10,15,16 the amount quoted
in Table 1 for BzH actually refers to the sum BzH+benzoic acid.
Values of endocyclic/exocyclic ratio (Selectivity) are shown in the last column of Table 1. Values smaller
than 1 indicate that the exocyclic attack is favored. Analogously, the endocyclic attack will be favored when
the Selectivity is greater than 1. A value of 1 for Selectivity means no regioselectivity. Selectivity was calculated
with equations (1)-(3), where the amount of a particular compound is symbolized by its number in brackets:
endocyclic = (5) + (10) + (11) + (12) [plus (unk) for T-2]
exocyclic = (BzH) + (6) + (13)
Selectivity = endocyclic/(2 * exocyclic)
(1)
(2)
(3)
Since there are two identical endocyclic CH2 groups, but only one exocyclic (benzylic), a statistical
correction (the factor 2) is needed in equation (3).
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Table 1. Oxidation of azacycloalkanes 1a-d
Entry
no.
0
Substrate
(recovd., %)a
1
Reaction products (molar, %)a,b
Selectivityc
2
3
A) Oxidations without NaCN d
4a (4), 5a (33.5),f 10a (1), 11a (42), BzH
(16), 6a (2)
1
2
1a (0)e
1b (0)e
2.1
1.0
4b (6.5), 5b (40.5),g 10b (1.5), 11b
(13.5), unk (5.5),h BzH (27), 6b (4)
5c (0.4), BzH (43.1), 6c (40)
BzH (51.3), 6d (3.2),i 15 (2.7), 16 (0.5),
17 (1.3)
3
4
1c (7)
1d (10)
0.002
0
B) Oxidations in the presence of NaCN d
4a (1.9), 5a (0.2), 11a (0.2), 12a (38.2),
BzH (0.2), 13a (7.9)
5
6
1a (52)e
1b (6)e
2.4
1.2
4b (4.7), 5b (<0.5), 11b (<0.5), 12b
(60.6), BzH (1.9), 6b (0.5), 13b (24)
4c (0.1), 12c (6.5), BzH (0.3), 13c (5.4)
BzH (0.2), 15 (1.7), 23 (0.4)
7
8
1c (82)
1d (92)
0.6
-
a Molar amounts calculated against the initially added substrate, taken as 100; see also
Experimental. b Formulae in Schemes 1-3. c Regioselectivity (endocyclic/exocyclic) was calculated
with eqs. (1)-(3). d Reaction conditions (for 1 mmol of substrate): A - RuO2.xH2O (10-15 mg), co-
oxidant NaIO4 (4 mmol), CCl4 (for 1a-b) or CHCl3 (for 1c-d) (10 mL), water (10 mL), room
temperature, 3-5 h; B - as in A, but NaCN (4 mmol) in water (10 mL) was also added. e Data from
ref. 8. f Including 1% of 1-benzyl-2,6-piperidinedione. g Including 1% of 1-benzyl-2,5-
pyrrolidinedione. h Unknown benzylic compound. i Including variable amounts of oxazoline 14
(see text).
Oxidation of azetidine 1c
In the absence of cyanide (conditions A), azetidine 1c gave mainly benzaldehyde and benzamide 6c (T-3).
Azetidinone 5c was formed too, albeit in a very small amount (T-3). No doubly oxygenated compounds such as
10c17 or 11c18 were present, in contrast to the results obtained for piperidine 1a (T-1) or pyrrolidine 1b (T-2).
In the presence of cyanide (conditions B), comparable amounts of cyano derivatives 12c and 13c resulted
from 1c (T-7), indicating that both iminium ions 2c and 3c (Scheme 1) were generated. The presence of the N-
oxide 4c, although in a relatively small amount, indicated that the third oxidative route (by N-attack, Scheme
1) was also active. Therefore, the oxidation of azetidine 1c follows the same scheme as that previously
discussed for 1a-b.
Judging from the substrate recovery (7% in T-3, 82% in T-7), it appears that the oxidation occurred with
more difficulty under conditions B. This appears to be true also for 1a and 1d (see below), but not for 1b.
Some of this effect could be due to the involvement of cyanide in another reaction, namely the oxidation
towards cyanogen.19 This reaction subtracts both cyanide and periodate (co-oxidant) from the desired amine
oxidation.
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Interesting aspects come from the values of Selectivity. On one hand, the decrease of the size of the
azacycle (1a → 1b → 1c) led to decreasing Selectivity values. Thus, the endocyclic route is relatively prefered
by piperidine 1a (Selectivity ~ 2 in T-1 and T-5), no selectivity is shown by pyrrolidine 1b (Selectivity ~ 1 in T-2
and T-6), and the exocyclic route becomes favored in the case of azetidine 1c (Selectivity ~ 0 in T-3, but 0.6 in
T-7). Practically, the absence of one CH2 unit in the heterocycle resulted in a two-fold reduction of Selectivity,
at least under conditions B.
On the other hand, for the same substrate, Selectivity has higher values under conditions B than under
conditions A. In the case of 1a-b, there is only a tendency, but in the case of azetidine 1c the difference is quite
clear: still being less favored than the exocyclic route, the endocyclic route seems to recover some order of
magnitude on passing from conditions A (Selectivity = 0.002) to conditions B (Selectivity = 0.6). No explanation
can be given for this yet. For instance, at first sight, one could invoke a possible change in the active oxidant, in
connection with the known relationship1,20 between pH and the most stable oxidant structure: RuVIIIO4 under
conditions A (pH ~ 5), but possibly the less aggressive agent [RuVIIO4]- under conditions B (pH ~ 9). This could
explain the aforementioned variation of substrate recovery, but not that of Selectivity. In fact, a softer oxidant
(like perruthenate) should be more selective than a stronger one (like ruthenium tetroxide), which is just
opposite to the experimental evidence.
2-Cyanoazetidines like 12c are versatile intermediates for a wide variety of catalysts,21 biological amines,22
or nitrogen heterocycles.23 Even if it is out of the scope of this paper, the RuO4-oxidation of 1c under cyanide-
trapping conditions (T-7) might be viewed, after further optimization, as a new way to synthesize 2-
cyanoazetidines and may be added to the already known methods.24,25
Oxidation of aziridine 1d
Aziridine 1d behaved differently (Scheme 3) than 1a-c. Under conditions A (T-4), BzH was by far the main
reaction product, but some benzamide 6d was detected too. Sometimes, 6d was accompanied by variable
amounts of its isomer, the oxazoline 14, thermally formed during work-up.26 The reaction mixture contained
also the piperazine 15 (a “dimer” of 1d), piperazinedione 16 and the acyclic diformamide 17 (Scheme 3). It is
worth mentioning that BzH, 16 and 17 are, all three, main products of the RuO4-oxidation of 15.10 At the same
time, it is known that 15 undergoes oxidation more easily than 1d.27 Taking into account also that the value of
2.6 for the ratio (17)/(16) is almost the same as that found in the RuO4-oxidation of 15,10 it appears logical that
6d+14 came from 3d and 16+17 from 15. At the same time, since both routes produce benzaldehyde, the
value of 51.3% in T-4 is the sum of two contributions: from 3d (BzHfrom 3d) and from 15 (BzHfrom 15). No
aziridinone 5d28 was detected, but, at first sight, this does not exclude its transient formation and subsequent
fast oxidation towards formamide 18 and CO2 (Scheme 3). This is suggested by the known29 behaviour of
aziridine 19 (lower part of Scheme 3), for which the intermediacy of the non isolable aziridinone 20 was
proven: both 19 and 20 (synthesized independently) gave the same products, 21 and CO2. In our case,
formamide 18 was not detected in the oxidation mixture of 1d (T-4). Therefore, the existence of 5d, even
transiently, can be ruled out, as indicated in Scheme 3.
Several previous works,27,30,31 performed with 1d and oxidants acting according to known mechanisms
(bona fide oxidants) certified that dimer 15 can result from 1d either by oxidation or heterolytically (HETERO).
In the latter case, the aziridinium ion 22, generated transiently from 1d, undergoes an SN2-type ring opening
by reaction with 1d itself,32,33 followed by ring closure to 15.
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Scheme 3 Reaction products of 1d.
Control experiments were performed with 1d under conditions similar to those of T-4, but without
oxidants. Working in the two-layer system of CHCl3/buffered water (pH 5), 1 mmole of 1d gave 50 μmoles of
15, corresponding to a relative amount of 5%. This value is quite close to that found in T-4
[(15)+(16)+(17)+(BzHfrom 15) = 4.5+(BzHfrom 15)]. Therefore, the dotted arrow marked by “ox ?” connecting 1d
and 15 in Scheme 3 can be safely cancelled out.
Thus, the exclusive oxidation products of 1d in T-4 are BzHfrom 3d and 6d. Since only the benzylic position of
1d has been attacked, the corresponding value of Selectivity is zero.
Under cyanide-trapping conditions (T-8), aziridine 1d did not give the nitriles 12c and 13c (Scheme 2).
Instead, piperazine 15 and the open chain nitrile 23 (Scheme 3) have been detected in the reaction mixture.
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Control experiments with 1d at pH 9 and without oxidants showed the formation of 15 and 23 in 1.5% and
0.3% molar amounts, respectively, values close to those found in T-8. Therefore, piperazine 15 and nitrile 23
resulted both by a HETERO mechanism, as discussed before for T-4. Summing up, it appears that RuO4 was
practically not active towards 1d in the presence of cyanide, in contrast to the aforementioned cases of 1 a-c.
Therefore, the behaviour of aziridine 1d is a consequence of the competition between the RuO4-mediated
oxidation and the heterolytic steps, just as in other oxidative media.27,30,31 In the case of RuO4-oxidation, only
the exocyclic (benzylic) route was active under conditions A, as in the case of azetidine 1c. However, unlike 1c,
the oxidation of 1d is largely or totally suppressed under conditions B and the reaction follows only the
HETERO route.
Mechanistic considerations
Two very similar mechanisms have been proposed so far1,7,11,12 for the oxidation by RuO4 of tertiary amines
like 1a-d. Based on these we propose the multi-step mechanism of Scheme 4.8-10 The first step consists in the
formation of the ion pair consisting of ruthenate (RuVI) anion 24 and iminium ion 25. In the corresponding
transition state (TS), the electronic lone pair on nitrogen is used to create a new C=N double bond (Electron
Transfer process), concomitantly to hydrogen abstraction (HAB) and generation of a RuVI species. The
existence of both ET and HAB processes in the rate-determining step was already proven.4,7 Prior to ET+HAB,
the substrate could give also a complex with a low-valent ruthenium species7 (not displayed in Scheme 4).
Cation 25 is then trapped by nucleophiles, in our case water or cyanide, to form the corresponding
derivative 26. The reaction stops at this stage if Y=CN, but in the case of a hemiaminal (26, Y=OH), the reaction
continues with two new oxidation steps, giving the final product, amide 27. The hemiaminal is a transient,
non-isolable intermediate: it undergoes oxidation presumably faster than the initial amine, because the
involved C-H bond is now in α-position to two electron-rich heteroatoms (O and N). The catalytic cycle is
completed by oxidizing back all RuVI species to RuVIII, at the expense of the co-oxidant (for instance NaIO4).
The substrate reactivity and the corresponding endocyclic/exocyclic Selectivity should be governed by the
activation energies required on passing from the reactants to the respective transition states TS. The
governing factors could be of (i) electronic (ET+HAB) and (ii) steric nature, as presented below.
A high electron-donating ability of the nitrogen atom is known to reduce the energy of the adjacent C-H
bond. Since the donating ability decreases with the increase of the s-character of the nitrogen lone pair,32 it
emerges that, within the homologous series 1a-d, the highest C-H bond energy will belong to aziridine 1d.
However, the energies of both endocyclic and exocyclic α-C-H bonds are influenced in the same way and,
consequently, the regioselectivity of a particular substrate might remain unchanged.
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Scheme 4. Mechanism of the RuO4-oxidation of tertiary amines
At the same time, on going from 1a to 1d, that is towards azacycles with increasing geometrical
constraints,34 the accommodation of the new C=N bond in TS should be easier in the exocyclic position relative
to that in the more energetically demanding endocyclic position. An approximation of this effect might be
revealed by the differences in heats of formation (∆∆Hf) calculated for endocyclic-25 and exocyclic-25. We
remember that the system 24+25 could be a good approximation for TS, if TS is structurally more similar to
the products than to the reactants. By a proper choice of ruthenium catalyst and reaction conditions, this
hypothesis was already experimentally proven.7 Working with the PM6 method (free MNDO-version), the
computed ∆∆Hf’s were: -1.4 (2a-3a), +1.5 (2b-3b), +13.4 (2c-3c), and +24.5 kcal/mol (2d-3d). These differences
parallel closely the experimental endocyclic/exocyclic selectivities (Table 1, column 3).
For the steric factor (ii), RuO4 is supposed to approach less easily the endocyclic position of the amine than
the exocyclic one. This derives from the more rigid azacycle structure compared to the freely rotating benzylic
group around the PhCH2-N bond. The energetic difference between the endocyclic and exocyclic attack seems
to increase in the order 1a<1b<1c<1d. Since the endocyclic and the exocyclic transition states are both more
polar than the reactants, solvation could influence the relative stability. More sophisticated theoretical
calculations are needed for better accuracy.
Summing up, all these considerations suggest that Selectivity (endocyclic/exocyclic) should decrease going
from 1a to 1d, in accord with the experimental findings.
Conclusions
1-Benzylazetidine (1c) showed the same RuO4-oxidation pattern as that followed by the analogous 1-
benzylpiperidine (1a) and 1-benzylpyrrolidine (1b) derivatives: both endocyclic and exocyclic (benzylic) C-H
bonds in α to the nitrogen atom are attacked. If the reaction is conducted in the presence of cyanide, α-
aminonitriles were obtained instead of amides. The statistically corrected endocyclic/exocyclic regioselectivity
diminishes constantly with the decrease of the azacycle size, from 2.4 for 1a to 0.6 for 1c. The oxidation of 1-
benzylaziridine (1d) occurred only in the absence of cyanide and took place exclusively at the benzylic position.
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The proposed reaction mechanism was discussed and used to explain the variation of selectivity. The key step
is the formation of an ion pair: an iminium ion and a ruthenate anion.
Experimental Section
General. NMR spectra were acquired mainly on a Varian ICON 300 apparatus, operating at 300 MHz (1H) and
75 MHz (13C). In particular cases, a Bruker Avance DRX 400 spectrometer, operating at 400 MHz (1H) and 100
MHz (13C), was employed. Mass spectra were obtained with a GC 6890 Agilent Technologies gas-
chromatograph coupled with a MS 5975 B quadrupole mass spectrometer, using the standard 70 eV ionization
energy.
Hydrated RuO2, oxazoline 14, aminonitrile 18, NaIO4, and the organic solvents were used as purchased from
commercial sources, except for CHCl3, which was stored over anhydrous Na2CO3 and filtered prior to use.
All information on the synthesis and characterization of piperidine 1a, pyrrolidine 1b, and their reaction
products of type 4, 5, 6, 10, 11, 12, and 13 was already reported.8 Azetidine 1c35,36 and some of its identified
oxidation products (4c,36 5c,37 6c,38 12c24) are all known compounds and were synthesized according to the
indicated procedures. The same is true for aziridine 1d27 and the corresponding reaction products (6d,39 14,26
15,10,27,30,40 16,10 1741).
Oxidations by RuO4/NaIO4 (with or without NaCN)
To a heterogeneous mixture of CHCl3 (5 mL) and aqueous solution of NaIO4 (0.4 M; 10 mL, 4 mmol) was added
solid RuO2∙xH2O (10-15 mg), followed by the substrate (1 mmol of 1c or 1d), previously dissolved in CHCl3 (5
mL) (reaction conditions A). In the case of the cyanide-trapping experiments (reaction conditions B), to the
NaCN solution [196 mg (4 mmol) in water (10 mL)] was added RuO2, the substrate (1 mmol in 10 mL of CHCl3),
and the co-oxidant NaIO4 solution (10 mL, as before), in this order. The heterogeneous reaction mixture was
magnetically stirred at room temperature for 3-5 h and then worked-up as described in a previous paper.19
Identification of the various reaction products was made by comparison of the NMR and GC-MS spectra
before and after the addition of small samples of the pure compounds into the analyzed samples.
The amounts quoted in Table 1 were calculated from the NMR and GC-MS data obtained in the presence of
1.4-dimethoxybenzene, added as internal standard.19
2-(1-Azetidinyl)-2-phenylacetonitrile (13c). Aqueous NaHSO3 solution (39%, 0.4 mL, 2 mmol) was added under
stirring to benzaldehyde (0.2 mL, 2 mmol). To the formed white solid a suspension of azetidine hydrochloride
(187 mg, 2 mmol) in cold, aqueous NaOH solution (80 mg, 2 mmol; 1.5 mL of water) was added and the
reaction mixture was stirred at room temperature for one hour. A solution of NaCN (98 mg, 2 mmol; 1 mL of
water) was added and the stirring was maintained for another hour. The mixture was extracted with CHCl3,
the organic extract was dried over Na2SO4, and the solvent was evaporated. The residue was cromatographed
on a silica gel column eluted first with benzene (30 mL). The fraction eluted with PhH/EtOAc (9/1, v/v)
afforded 110 mg of oily 13c.
Yield: 32%. Anal. calcd. for C11H12N2: C, 76.72; H, 7.01; N, 16.27%. Found: C, 76.42; H, 6.87; N, 16.45%. 1H-NMR
3
3
(300 MHz, CDCl3) δ (ppm) 2.13 (2H, quintet, J 7.1 Hz, N-CH2-CH2), 3.31+3.39 (2+2H, symmetrical q+q , J 7.0
Hz, CH2-N-CH2), 4.69 (1H, s, CH), 7.30-7.55 (5H, m, arom.). 13C-NMR (75 MHz, CDCl3) δ (ppm) 17.3 (N-CH2-CH2),
51.9 (CH2-N-CH2), 61.3 (CH), 116.2 (CN), 127.6 (o), 128.9 (m), 129.0 (p), 133.1 (i). EI-MS [70 eV, m/z (relative
abundance, %)]: 172 (M+, 43.5), 171 (78), 117 (15), 116 (100), 95 (7), 91 (7), 90 (6), 89 (20).
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Spectral data of selected compounds
1
The H and 13C NMR chemical shifts of the following compounds are referenced to internal (CH3)4Si (δH = 0)
and CDCl3 (δC = 77.16 ppm).42 Aromatic ortho, meta, and para hydrogens or carbons are labeled o, m, and p,
respectively; ipso carbons are abbreviated as i. All NMR data were in accordance with those cited in literature,
but with complete assignments. In addition, the corresponding MS data are presented, except for 4c
(unstable), 16 and 17 (experimental limitations).
3
1-Benzylazetidine (1c).35,36 1H-NMR (300 MHz, CDCl3) δ (ppm) 2.07 (2H, quintet, J 7.1 Hz, N-CH2-CH2), 3.20
(4H, t, 3J 7.1 Hz, CH2-N-CH2), 3.55 (2H, s, Ph-CH2), 7.20-7.32 (5H, m, arom.). 13C-NMR (75 MHz, CDCl3) δ (ppm)
17.6 (N-CH2-CH2), 55.1 (CH2-N-CH2), 63.9 (Ph-CH2), 126.8 (p), 128.2 (o), 128.4 (m), 138.4 (i). EI-MS [70 eV, m/z
(relative abundance, %)]: 147 (M+; 22), 146 (47), 92 (9.5), 91 (100), 70 (5.5), 65 (11).
1-Benzylaziridine (1d).27 1H-NMR (300 MHz, CDCl3) δ (ppm) 1.23-1.29 + 1.78-1.83 (2+2H, m+m, CH2-CH2), 3.37
(2H, s, Ph-CH2), 7.20-7.40 (5H, m, arom.). 13C-NMR (75 MHz, CDCl3) δ (ppm) 27.6 (CH2-CH2), 65.3 (Ph-CH2),
127.1 (p), 128.0 (o), 128.4 (m), 139.3 (i). EI-MS [70 eV, m/z (relative abundance, %)]: 133 (M+; 13), 132 (45),
105 (6.0), 104 (8), 92 (8), 91 (100), 89 (7), 77 (10), 65 (22), 63 (7), 51 (10), 42 (57).
1-Benzylazetidine-1-oxide (4c).36 1H-NMR (400 MHz, CDCl3) δ (ppm) 1.90-1.94 + 2.33-2.40 (1+1H, m+m, N+-
CH2-CH2), 4.25-4.29 (4H, m, CH2-N+-CH2), 4.41 (2H, s, Ph-CH2), 7.33-7.44 (3H, m, m+p), 7.54 (2H, d, J 6.4 Hz, o).
13C-NMR (100 MHz, CDCl3) δ (ppm) 12.1 (N+-CH2-CH2), 68.9 (CH2-N+-CH2), 70.2 (Ph-CH2), 128.4 (p), 129.3 (m),
130.1 (i), 131.9 (o).
1-Benzyl-2-azetidinone (5c).37 1H-NMR (300 MHz, CDCl3) δ (ppm) 2.94 (2H, t, J 4.0 Hz, N-CH2-CH2), 3.12 (2H, t, J
4.0 Hz, N-CH2-CH2), 4.36 (2H, s, Ph-CH2), 7.25-7.35 (5H, m, arom.). 13C-NMR (75 MHz, CDCl3) δ (ppm) 36.6 (N-
CH2-CH2), 38.3 (N-CH2-CH2), 46.0 (Ph-CH2), 127.5 (p), 128.0 (o), 128.5 (m), 135.5 (i), 167.5 (CO). EI-MS [70 eV,
m/z (relative abundance, %)]: 161 (M+; 41.5), 133 (28.5), 132 (11), 105 (55), 104 (15), 92 (8.5), 91 (100), 77
(24).
1
1-Benzoylazetidine (6c).38 (the underlined signals show the C-H correspondence). H-NMR (300 MHz, CDCl3) δ
(ppm) 2.32 (2H, quintet, J 7.4 Hz, N-CH2-CH2), 4.22 + 4.28 (2+2H, t+t, J 7.4 Hz, CH2-N-CH2 ), 7.32-7.48 (3H, m,
m+p), 7.62 (2H, dd, 3J 7.8 Hz, 4J 1.5, o). 13C-NMR (75 MHz, CDCl3) δ (ppm) 15.9 (N-CH2-CH2), 48.7 + 53.2 (CH2-N-
CH2 ), 127.6 (o), 128.1 (m), 130.7 (p), 133.1 (i), 170.1 (CO). EI-MS [70 eV, m/z (relative abundance, %)]: 161 (M+,
25), 160 (7), 106 (8.5), 105 (100), 77 (43.5).
1-Benzoylaziridine (6d).39 1H-NMR (300 MHz, CDCl3) δ (ppm) 2.39 (4H, s, CH2-CH2), 7.55-7.65 (3H, m, m+p),
8.07 (2H, d, J 7.6 Hz, 2H, o). 13C-NMR (75 MHz, CDCl3) δ (ppm) 26.1 (CH2-CH2), 128.0 (o), 129.3 (m), 132.9 (p),
134.2 (i), 179.3 (CO). EI-MS [70 eV, m/z (relative abundance, %)]: 147 (M+, 7), 105 (100), 77 (72), 51 (19).
1-Benzylazetidine-2-carbonitrile (12c).24 1H-NMR (300 MHz, CDCl3) δ (ppm) 2.35-2.45 (2H, m, N-CH2-CH2),
3.12+3.35 (1+1H, q+q, J 7.2 Hz, N-CH2-CH2), 3.64+3.72 [1+1H, d+d (ABq), JAB 13.2 Hz, Ph-CH2], 3.90 (1H, t, J 7.2
Hz, CH-CN), 7.15-7.18 (5H, m, arom.). 13C-NMR (75 MHz, CDCl3) δ (ppm) 22.9 (N-CH2-CH2), 51.7 (CH-CN), 52.4
(N-CH2-CH2), 60.8 (Ph-CH2), 118.8 (CN), 127.5 (o), 128.6 (p), 128.8 (m), 136.1 (i). EI-MS [70 eV, m/z (relative
abundance, %)]: 172 (M+, 22), 171 (20), 120 (9), 95 (8), 92 (15), 91 (100), 81 (6), 65 (13).
2-Phenyloxazoline (14).43 1H-NMR (300 MHz, CDCl3) δ (ppm) 4.05 (2H, t, J 9.2 Hz, N-CH2), 4.41 (2H, t, J 9.2 Hz,
O-CH2), 7.35-7.50 (3H, m, m+p), 7.94 (2H, d, J 7.8 Hz, o) 13C-NMR (75 MHz, CDCl3) δ (ppm) 54.9 (N-CH2), 67.5
(O-CH2), 127.7 (i), 128.1+128.2 (o+m), 131.2 (p), 164.4 (C=N). EI-MS [70 eV, m/z (relative abundance, %)]: 148
(10), 147 (M+, 85), 118 (15), 117 (100), 105 (12), 91 (13), 77 (25), 51 (13).
1,4-Dibenzylpiperazine (15).10 1H-NMR (300 MHz, CDCl3) δ (ppm) 2.48 (8H, s, CH2-CH2), 3.51 (4H, s, 4H, Ph-
CH2), 7.21-7.30 (10H, m, arom.). 13C-NMR (75 MHz CDCl3) δ (ppm) 53.1 (CH2-CH2), 63.1 (Ph-CH2), 127.0 (p),
128.2 (o), 129.2 (m), 138.2 (i). EI-MS [70 eV, m/z (relative abundance, %)]: 266 (M+, 25), 175 (42), 146 (11), 132
(12), 120 (28), 119 (7.5), 92 (8), 91 (100), 65 (9).
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1,4-Dibenzyl-2,3-piperazinedione (16).16 1H-NMR (300 MHz, CDCl3) δ (ppm) 3.34 (4H, s, CH2-CH2), 4.67 (4H, s,
Ph-CH2), 7.20-7.33 (10H, m, arom.). 13C-NMR (75 MHz, CDCl3) δ (ppm) 43.6 (CH2-CH2), 50.7 (Ph-CH2), 128.2 (p),
128.6 (o), 129.0 (m), 135.6 (i), 157.6 (CO).
Bis-(N-Benzylformamido)ethylene (17).41 Mixture of 3 isomers: A (48%; asymmetric E,Z), B (45%; symmetric
E,E), and C (7%; symmetric Z,Z). No specific assignements could be made for the aromatic m+p protons and
carbons (see below under isomers A+B+C). The following integrals are intended for the considered isomer.
1
Isomer A: [the N atoms are labelled as (E)-N1 and (Z)-N2]. H-NMR (400 MHz, CDCl3) δ (ppm) 3.19 (2H, t, J 6.4
Hz, N2-CH2), 3.29 (2H, t, J 6.4 Hz, N1-CH2), 4.31 (2H, s, Ph-CH2-N1), 4.48 (2H, s, Ph-CH2-N2), 7.15 (2H, d, J 6.4 Hz,
(o of Ph-CH2-N1), 7.20 (2H, d, J 6.4 Hz, o of Ph-CH2-N2), 8.01 (1H, s, N2-CHO), 8.30 (1H, s, N1-CHO). 13C-NMR
(100 MHz, CDCl3) δ (ppm) 40.9 (N1-CH2), 43.6 (N2-CH2), 45.3 (Ph-CH2-N2), 52.2 (Ph-CH2-N1), 127.6 (o of Ph-CH2-
N1), 128.3 (o of Ph-CH2-N2), 135.4 (i of Ph-CH2-N2), 136.1 (i of Ph-CH2-N1), 162.7 (N2-CHO), 163.0 (N1-CHO).
Isomer B: 1H-NMR (400 MHz, CDCl3) δ (ppm) 3.38 (4H, s, CH2-CH2), 4.46 (4H, s, Ph-CH2), 7.21 (4H, d, J 6.8 Hz, o),
8.26 (2H, s, CHO). 13C-NMR (100 MHz, CDCl3) δ (ppm) 37.7 (CH2-CH2), 50.8 (Ph-CH2), 127.6 (o), 128.8 (m), 135.7
(i), 163.3 (CHO).
Isomer C: 1H-NMR (400 MHz, CDCl3) δ (ppm) 3.17 (4H, s, CH2-CH2), 4.49 (4H, s, Ph-CH2), 7.21 (4H, d, J 6.8 Hz, o),
7.91 (2H, s, CHO). 13C-NMR (100 MHz, CDCl3) δ (ppm) 45.3 (CH2-CH2), 46.0 (Ph-CH2), 128.4 (o), 135.9 (i), 162.6
(sh, CHO).
1
Isomers A+B+C: H-NMR (400 MHz, CDCl3) δ (ppm) 7.25-7.40 (10H, m, m+p). 13C-NMR (100 MHz, CDCl3) δ
(ppm) 127.7+128.0+128.2+128.7+128.9+129.0 (m+p).
3-(Benzylamino)propanenitrile (18).44 1H-NMR (300 MHz, CDCl3) δ (ppm) 2.45 (2H, t, J 6.5 Hz, CH2-CN), 2.87
(2H, t, J 6.5 Hz, N-CH2-CH2), 3.80 (2H, s, Ph-CH2), 7.20-7.40 (5H, m, arom.). 13C-NMR (75 MHz, CDCl3) δ (ppm)
18.7 (CH2-CN), 44.3 (N-CH2-CH2), 53.1 (Ph-CH2), 118.7 (CN), 127.1 (p), 128.0 (m), 128.4 (o), 139.5 (i). EI-MS [70
eV, m/z (relative abundance, %)]: 160 (M+, 5), 120 (40), 92 (10), 91 (100); 65(15).
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