Studies on the formal [3 + 2] cycloaddition of aziridines with alkenes for the synthesis of 1-azaspiroalkanes

Article abstract of DOI:10.1021/jo502333j

The Lewis acid-mediated [3 + 2] cycloaddition of N-sulfonyl- and N-sulfamoylaziridines with alkenes provides a rapid and efficient access to 1-azaspiro[4.n]alkanes. Experimental studies have been combined with DFT calculations to explore the mechanism of the reaction. They demonstrate that the nature of the electron-withdrawing nitrogen protecting group has a very limited influence on the course of the reaction and, particularly, on the initial formation of the 1,3-zwitterionic species through C-N bond cleavage, which has been found to be the rate-determining step. Compared to N-sulfonylaziridines, N-sulfamoylaziridines have proved to be more synthetically useful synthons that afford crystalline polycyclic structures in good yields. A short sequence of catalytic C(sp³)-H amination-cyclization-[3 + 2] cycloaddition has then been successfully designed to afford the homologue 1-azaspiro[5.n]alkanes, thereby illustrating the higher versatility of sulfamates in these cycloadditions.

Full text of DOI:10.1021/jo502333j

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Article
Studies on the formal [3+2] cycloaddition of aziridines
with alkenes for the synthesis of 1-azaspiroalkanes.
Elodie Martinand-Lurin, Raymond Grüber, Pascal Retailleau, Paul Fleurat-Lessard, and Philippe Dauban
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502333j • Publication Date (Web): 18 Dec 2014
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Studies on the formal [3+2] cycloaddition of aziridines
with alkenes for the synthesis of 1-azaspiroalkanes.
Elodie Martinand-Lurin,† Raymond Gruber,‡ Pascal Retailleau,† Paul Fleurat-Lessard,‡,* and Philippe
Dauban†,*
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† Centre de Recherche de Gif-sur-Yvette, Institut de Chimie des Substances Naturelles, UPR 2301
CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
‡ Laboratoire de Chimie, Ecole Normale Supérieure de Lyon, UMR 5182 CNRS, 46 Allée d’Italie,
69364 Lyon Cedex 7, France
RECEIVED DATE
philippe.dauban@cnrs.fr, Paul.Fleurat-Lessard@ens-lyon.fr
Graphical Abstract
Ph
Ph
O
N
S
N
BF3.OEt2
O
Tces
Cl3C
O
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Abstract
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The Lewis acid-mediated [3+2] cycloaddition of N-(sulfonyl)- and N-(sulfamoyl)-aziridines with
alkenes provides a rapid and efficient access to 1-azaspiro[4.n]alkanes. Experimental studies have been
combined with DFT calculations to explore the mechanism of the reaction. They demonstrate that the
nature of the electron-withdrawing nitrogen protecting group has a very limited influence on the course
of the reaction, and, particularly, on the initial formation of the 1,3-zwiterionic species through C-N
bond cleavage, which has been found to be the rate-determining step. Compared to N-
(sulfonyl)aziridines, N-(sulfamoyl)aziridines have proved to be more synthetically useful synthons that
afford crystalline polycyclic structures in good yields. A short sequence of catalytic C(sp3)-H
amination-cyclization-[3+2] cycloaddition has then been successfully designed to afford the homolog
1-azaspiro[5.n]alkanes, thereby illustrating the higher versatility of sulfamates in these cycloadditions.
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Introduction
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Growing attention is paid to the development of methodologies for the synthesis of spirocyclic
compounds.1 These 3D-scaffolds offer new opportunities in organic chemistry as they allow the
exploration of a chemical space orthogonal to that provided by sp2-based molecular structures.2 This is
particularly relevant in medicinal chemistry where the introduction of such motif could influence either
the pharmacodynamic or the pharmacokinetic properties of a drug candidate.3 Among the frameworks
accessible to the chemists, azaspirocycles hold a paramount importance since the insertion of a
protonable nitrogen could generally improve the solubility of bioactive molecules. Accordingly, the
occurrence of these nitrogenous motifs in medicinal chemistry has increased in the past decade with
several derivatives being reported for their antimitotic or antibacterial activities.4 One of the leading
members, MI-888 (Figure 1), belongs to the family of spirooxindoles which is a potent orally active
anticancer agent acting through inhibition of MDM2-p53 interaction.5 It is worth mentioning that
azaspirocycles can be also found in several natural products, as for example in the immunosuppressive
alkaloid FR901483.6
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Figure 1. Azaspirocyclic compounds
OH
OMe
Cl
O
F
NH
NH
HO
N
NHMe
HO
Cl
O
HO
P
O
N
H
O
MI-888
FR901483
Various strategies have been reported over the years for the synthesis of azaspirocyclic scaffolds.1,7
These range from classical alkylation methods to ring-closing metathesis, and include ring
rearrangements, metal-catalyzed additions to alkenes, and cycloaddition reactions. Among these
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transformations, cycloadditions provide an elegant solution as several bonds can be formed efficiently
and selectively in a single pot. Different types of cycloadditions have thus been applied to the
preparation of spiro compounds.8-10 Not surprisingly, the [3+2] cycloaddition with alkenes stands as the
method of choice for the formation of azaspiro[4.n]alkanes. When the nitrogen-containing cycles are
formed through 1,3-dipolar cycloadditions, the reactions generally rely on the use of azomethine ylides.
These common 1,3-dipoles can be generated in situ according to various conditions.11 One of these
involve the thermal ring-opening of N-alkyl or N-arylaziridines that occurs through stereospecific C-C
bond cleavage (Scheme 1a).12 Interestingly, recent studies have shown that a different zwiterrionic
species can be formed from aziridines following C-N bond cleavage, and also engaged in [3+2]
cycloadditions with alkenes, alkynes, carbonyl compounds, nitriles and CO2 (Scheme 1b).13
Scheme 1. Aziridines and formation of dipolar intermediates
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1a. Formation of a1,3-dipole via C-C bond cleavage
R1
N
R1
N
R1
N
heat
R1: alkyl, aryl
R2: EWG
R2
R2
R2
1b. Formation of a1,3-zwiterionic species via C-N bond cleavage
R1
N
Lewis
acid
R1: EWG
R2: aryl, CH2[Si],...
R2
N
NR1
R2
R1
R2
The formation of azomethine ylides through conrotary C-C bond breaking proceeds from simple
aliphatic N-(alkyl)- or N-(aryl)aziridines. Inversely, C-N bond cleavage is observed starting from
aziridines bearing an electron-withdrawing group on the nitrogen and with substituents on one of the
carbon atoms likely to stabilize a transient positive charge.14 This step is typically mediated by the
introduction of a Lewis acid that activates the aziridine towards the ring-opening, and its use in formal
cycloadditions with alkenes was first reported almost simultaneously by two groups at the end the
90’s.15,16 Whereas Bergmeier and coworkers have reported the formation of bicyclic pyrrolidines via
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intramolecular [3+2] cycloaddition from well-designed substituted aziridines,15 the group of Mann has
investigated the intermolecular version of the reaction.16 In both cases, BF3·OEt2 was found efficient to
perform the overall transformation but, since then, it has been demonstrated that several other Lewis
acids can trigger the formal [3+2] cycloaddition from N-(tosyl)-2-arylaziridines with alkenes and
alkynes.17 It is worth mentioning that the scope of the reaction has also been extended, in terms of
dipolarophiles, to nitriles and carbonyl compounds,18 while azetidines have been found to be suitable
precursors of the homolog 1,4-zwiterionic species under these conditions.18a,19
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Interestingly, a survey of these studies reveals that almost all the Lewis-acid mediated cycloadditions
with alkenes have been carried out only starting from N-(tosyl)aziridines.20 While the reported yields
are generally good, it appeared to us that the presence of a tosyl substituent could be detrimental to the
possible application of these methodologies in synthesis and medicinal chemistry. It is indeed well
acknowledged that this protecting group can raise intractable problems when it comes to remove it.21
On the other hand, it has been demonstrated that the rate of the aziridine ring-opening depends on the
nature of the arenesulfonyl substituent.22 These observations, therefore, convinced us to study the
influence of the “N-(SO2R)” protecting group on the formal [3+2] cycloaddition with alkenes.23
Fundamentally, this screening has been useful to better understand the course of the reaction that has
been investigated for the first time by DFT calculations. The results of both our experimental and
theoretical studies are thus presented in this article that documents the first use of N-
(sulfamoyl)aziridines in [3+2] cycloaddition in the context of the preparation of 1-azaspiro[5.n]alkanes
(Scheme 2).
Scheme 2. Background for the study
2a. Previous studies
2b. This work
n
n
Ts
O
OR
R
O S
N
N
R
Lewis acid
Lewis acid
Ar
N
N
Ar
Ts
Ar
SO3R
Ar
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Results and Discussion
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Experimental studies: synthesis of azaspirocycles. The recent developments in metal-catalyzed
alkene aziridination make the synthesis of aziridines efficient and straightforward.24 Significant results,
in particular, have been reported with the use of iodine(III) oxidants for the generation of nitrenes from
sulfonamides and sulfamates, in the presence of readily available copper25 and rhodium26 complexes.
This methodology, that has been widely applied either in total synthesis or medicinal chemistry,27 was
appropriate to prepare the starting N-(sulfonyl)- and N-(sulfamoyl)aziridines 1, respectively with
copper25c and rhodium26b catalysts (Scheme 3). As already pointed out in previous studies,24 the
catalytic nitrene additions proceed more efficiently with sulfamoyl-derived nitrenes, leading to the
corresponding aziridines with higher yields (88-89% for 1e,f vs. 57-77% for 1a-d) in the presence of
lower amounts of reagents (nitrene precursors, iodine oxidant, catalyst).
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Scheme 3. Preparation of aziridines 1
3a. Preparation of N-(sulfonyl)aziridines
10 mol%
O
O
N
Cu(MeCN)4PF6
S
H
+
p-RC6H4SO2NH2
Ph
R
Ph
PhIO (1.6 equiv)
MeCN, MS 4Å
-20 °C, 48 h
1 equiv.
1.5 equiv.
1a: R = Me - 73%
1b: R = H - 72%
1c: R = NO2 - 77%
1d: R = MeO - 57%
3b. Preparation of N-(sulfamoyl)aziridines
R
2 mol%
Rh2(NHCOCF3)4
O
R
O
N
CCl3
O
S
H
+
Ph
Cl3C
OSO2NH2
PhI(OAc)2 (1.3 equiv)
MgO (2.3 equiv), C6H6
0 °C to rt, 6 h
Ph
1 equiv.
1.1 equiv.
1e: R = H - 89%
1f: R = Ph - 88% (dr: 60:40)
The aziridines were then engaged in the formal [3+2] cycloaddition with methylenecyclopentane to
investigate the influence of the N-protecting group on the reactivity (Table 1). After an extensive
screening, the following experimental conditions, i.e. use of BF3·OEt2 as the Lewis acid at -78 °C in
CH2Cl2,28 were applied and led us to isolate the 1-azaspirocycles starting either from N-(sulfonyl)- or N-
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(sulfamoyl)-aziridines 1. Contrary to the hypothesis, no improvement in the yield was made by the
modification of the N-(sulfonyl) substituent (entries 1-4). But interestingly, whereas N-(carbamoyl)-
aziridines do not react under these conditions,17c the reaction tolerates the presence of an N-(sulfamoyl)
group. The cycloadducts 2eb and 2f, which gave crystals suitable for X-ray analysis (see supporting
information), have been obtained with yields comparable to those of compounds 2a-d (entries 5 and 6).
It should be mentioned that the chiral N-(sulfamoyl)aziridine 1f was prepared with the aim to develop a
diastereoselective process but this did not prove successful as 2f was isolated as a 1:1 mixture of
isomers.29
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Table 1. [3+2] cycloaddition with N-(SO2R)-aziridines 1a
BF3•OEt2
(1.5 equiv)
Ph
O
O
N
S
H
R
+
N
DCM, -78 °C, 2 h
Ph
SO2R
1
1.5 equiv.
2
Entry Substrate
Product
Yieldb
Ph
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
66
N
2a
Ts
Ph
65
47
49
56
62
N
2b
SO2Ph
Ph
N
2c
SO2Ph-p-NO2
Ph
N
2d
SO2Ph-p-OMe
Ph
N
2eb
Tces
Ph
N
2f
SO3CH(Ph)CCl3
a
Reactions conditions: aziridine 1 (0.3 mmol), BF3·OEt2 (1.5
equiv), methylenecyclopentane (1.5 equiv), DCM (3 mL), -78 °C,
2h. b Isolated yields
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The good reactivity of N-(sulfamoyl)aziridines convinced us of the relevance of these substrates for
further studies. As shown in Scheme 3, these are more readily accessible from alkenes. They also
generally give rise to the formation of crystalline products. In addition, the higher reactivity of
sulfamate-derived nitrenes offers more synthetic opportunities in terms of molecular diversity (vide
infra). Thus, though the moderate yields for the cycloaddition reactions could partly offset these
benefits, we decided to explore the reactivity of various N-(Tces)aziridines (Tces:
trichloroethoxysulfonyl) for the preparation of a collection of 1-azaspirocycles. We first investigated
the reaction of 1e with methylenecycloalkanes and found that the yield varies with the size of the
carbocycle (Scheme 4a). Particularly, the crystalline 1-azaspiro[4,5]decane 2ec was isolated with a
yield of 68% yield, that is comparable to that reported for the N-(tosyl) analogue.16b
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Scheme 4. [3+2] Cycloadditions with N-(Tces)aziridines
4a. Reaction of N-(Tces)aziridine 1e with methylenecycloalkanes
n
BF3•OEt2
(1.5 equiv)
Ph
n
H
+
NTces
1e
N
DCM, -78 °C, 2 h
Ph
Tces
n = 0; 2ea - 49%
n = 1; 2eb - 56%
n = 2; 2ec - 68%
1.5 equiv.
4b. Reaction of other N-(Tces)aziridines
H
H
Ph
NTces
Ph
N
1g
Tces 2g - 70%
NTces
th2-Naph
(1.5 equiv)
BF3•OEt2
(1.5 equiv)
DCM, -78 °C, 2 h
N
1h
2h - 62%
2i - 69%
Tces
NTces
H
H
1i
N
Tces
The other N-(Tces)aziridines 1g-i also proved to afford the expected cycloadducts 2g-i with yields in
the 62-70% range (Scheme 4b). Not surprisingly, the trans-aziridine 1g, prepared stereospecifically
from trans-2-methylstyrene in 98% yield, was converted to a 1:1 mixture of isomers. By contrast, the
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cis-aziridine 1i derived from dihydronaphthalene (67% yield) led preferentially to the cis-cycloadduct
2i (d.r. > 9:1) as indicated by the vicinal coupling constant of 3.3 Hz for the protons at the ring
junction.
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We then turned our attention to fused bicyclic (sulfamoyl)aziridines that are readily accessible
through application of intramolecular catalytic aziridination of alkenes.30 These are useful synthetic
intermediates that can be selectively converted to polysubstituted amines following sequential additions
of nucleophiles. Use of the copper-catalyzed intramolecular aziridination, thus, led to the stereospecific
formation of the trans-aziridine 1j isolated in 69% yield. The latter subsequently reacts with
methylenecycloalkanes though with limited efficiency as the corresponding cycloadducts have been
obtained with yields ranging from 28% to 38% (Scheme 5). However, it is worth pointing out that the
reaction takes place with good levels of stereoselectivity as the trans configuration of the aziridine was
partially transferred to the products isolated with d.r.s of up to 4:1. This is a result rarely observed for
this type of [3+2] cycloaddition with alkenes.13
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Scheme 5. [3+2] Cycloadditions with bicyclic aziridine 1j
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Based on the good results recorded from N-(sulfamoyl)aziridines, we decided to capitalize on the
higher reactivity of sulfamoylnitrenes to extend the scope of the cycloadditions and study the case of N-
(sulfamoyl)azetidines. Mann and coworkers had previously investigated the ability of N-(tosyl)-2-
phenylazetidine to behave as a 1,4-zwiterionic species in the presence of BF3·OEt2.19 However, the
preparation of the starting material remains poorly practical. Inspired by the recent studies on rhodium-
catalyzed C-H amination with sulfamates,31 we thus designed a two step synthesis of phenylazetidines
that relies on a key step of intermolecular benzylic C-H amination of 1-bromo-3-phenylpropane
derivatives. This method is likely to give access to a wide range of N-(Tces)azetidines as illustrated by
the p-MeO analog 4b (Scheme 6). Then, we were pleased to observe that the formal [4+2]
cycloaddition with methylenecyclopentane cleanly proceeds to afford the 1-azaspiro[4,5]decanes in
good yields.32 Once again, the structures of the cycloadducts were secured by X-ray analysis.
Scheme 6. [4+2] Cycloadditions with azetidines 3
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1. 2 mol% Rh2(esp)2,
1 equiv. TcesNH2,
Tces
N
2 equiv. PhI(OCOt-Bu)2
Br
R
2. Et3N, MeCN, rt
R
R = H; 3a - 21%
R = MeO; 3b - 48%
NTces
1.5 equiv.
BF3•OEt2
(1.5 equiv)
R
DCM, -78 °C, 2 h
R = H; 4a - 84%
R = MeO; 4b - 54%
Finally, the relevance of N-(Tces)-aziridines for the formation of azaspirocycles was confirmed by
the application of mild conditions for the removal of the sulfamoyl protecting group.26b Thus, cleavage
of the latter was performed with the zinc-copper couple under acidic conditions to afford the free NH-
spiro products which can be subsequently converted to amides (Scheme 7).
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Scheme 7. Removal of the Tces protecting group.
4
5
6
7
n
n
Ph
Ph
1. Zn/Cu, AcOH, MeOH
2. AcCl, or BzCl
N
N
Tces
R
8
9
5a: n = 0, R = Ac - 50%
5b: n = 2, R = Bz - 59%
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Mechanistic considerations: computational studies of the [3+2] cycloaddition. In order to better
understand the lack of stereoselectivity and the low influence of the protecting group, we have
performed the theoretical study of the [3+2] cycloaddition of methylenecyclobutane with N-(tosyl)- and
N-(Tces)aziridines 1a and 1e. We first paid attention to the reaction of methylenecyclobutane with the
N-(tosyl)aziridine 1a. The first step of the overall process, i.e. the formation of the 1,3-zwiterionic
species, requires the complexation of one BF3 molecule to stabilize this ionic intermediate.
Fundamentally, it should be kept in mind that the aziridine 1a has two complexation sites for BF3: the
nitrogen atom and one of oxygen atom of the sulfonyl group. Our calculations have revealed that BF3
preferential binds to the nitrogen atom: the N-BF3 complex IIbis-s is more stable than the O-BF3
complex by 3.2 kcal/mol (see also calculations on model systems in the Supporting Information).
Consequently, the first step of the reaction leads to the formation of the N-BF3 complex II-s where the
Et2O molecule is still close to the aziridine with a small gain in energy of 0.1 kcal/mol (Scheme 8).
This result arises from the bond strength in the BF3·OEt2 adduct, that is equal to 21.9 kcal/mol.
Conversely, in the absence of the interaction with Et2O, formation of the N-BF3 complex IIbis-s is
disfavored as it requires an energy barrier of 4.7 kcal/mol due to the poor stabilization of ether by
dichloromethane.
Formation of the zwiterionic species could not be observed when stretching the C-N bond starting
from IIbis-s. Nevertheless, the calculations have shown that the charged intermediate IVbis-s can be
formed from this complex following stabilization by another equivalent of BF3 complexed on one of
the oxygen of the SO2 group to give III-bis-s. Complexing a second BF3 on IIbis-s, however, is
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unfavorable by 14.3 kcal/mol because the O-BF3 bond formation does not compensate the Et2O-BF3
breaking. This value is much higher than the complexation energy of BF3 on II-s because of the
attractive effect of the first BF3 molecule bound to the neighboring nitrogen atom. In parallel, starting
from II-s, the expected intermediate III-s is also generated with a stabilization provided by the
neighboring Et2O molecule. Thus, the difference energy between the two transition states of aziridine
opening II-s-TS and IIIbis-s-TS is 15.4 kcal/mol in favor of the opening assisted by the Et2O molecule.
Ultimately, the activation barrier for the formation of the 1,3-zwiterionic species is only 9.5 kcal/mol,
which is reachable at the experimental temperature.33
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Scheme 8. Aziridine opening catalyzed by BF3.Et2O.
The second step of the reaction is the cycloaddition between the zwiterionic intermediate and the
alkene, that can proceed through a concerted pathway with the simultaneous formation of the C-C and
C-N bonds, or in a stepwise manner. As the alkene reacts as the nucleophile, its HOMO will intereact
with the LUMO of the 1,3-zwiterionic species. A close examination of the frontier orbitals of the
intermediate III-s reveals that the LUMO is almost exclusively developed on the carbon atom while the
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HOMO of the alkene is polarized towards the outer carbon atom (Scheme 9); such a dissymetry in the
frontier orbital rules out the involvement of a concerted pathway and is in line with the cycloaddition
occurring in a stepwise manner with the C-C bond being created first with the alkene outer atom.
Scheme 9. Frontier orbitals for the 1,3-zwiterionic species III-s and the methylenecyclobutane.
(Atoms Color code: H in white, C in gray, O in red, N in blue, S in yellow, B in pink, F in pale blue)
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Alkene HOMO
III-s HOMO
III-s LUMO
Scheme 10. Cycloaddition of methylenecyclobutane with III-s. Structural figure of IV-s was
created with CYLView.34
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The E+ZPE for the cycloaddition of methylenecyclobutane is shown in Scheme 10. The C-C bond
formation IV-s → V-s, in which the Et2O molecule is replaced by the alkene, proceeds with a barrier of
9.0 kcal/mol. The 5-member ring closure V-s → VI-s then takes place barrierless. The overall energetic
gain during the cycloaddition is about 42.5 kcal/mol. This huge gain is due to the creation of the new
C-C and C-N bonds, as well as to the strain release arising from the disappearance of the exocyclic
double bond. The cycloaddition, therefore, is the driving force of the reaction, the limiting step being
the formation of the 1,3-zwiterionic species.
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In terms of stereochemistry, the involvement of a 1,3-zwiterionic species with a planar carbocation
center inevitably induces the loss of the stereochemical information from 2-(aryl)aziridines. However,
application of the reaction conditions to 2,3-substituted aziridines leads to diastereomeric transition
states as the stereochemistry of the bridging carbon is not lost. Because the C-C bond formation is the
rate limiting step, and the ring closing step takes place barrierless, one can expect that the geometry of
the starting material can be partly transferred to the products in this case. This should particularly apply
to aziridines with significant conformational restriction likely to lead to diastereomeric transition states
with sufficient difference in energy. This hypothesis is in line with the diastereoselectivity observed
starting from bicyclic fused aziridines 1i and 1j.
It should be pointed out that, during the screening of the reaction conditions, formation of the
cycloaddition products was not observed experimentally when using other fluoro catalysts like AlF3,
InF3, ScF3 and GaF3. This result might be surprising at first sight because AlF3 is known to be a better
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Lewis acid than BF3. The main difference comes from the fact that the fluoro salts such as AlF3 are
solid and do not possess an ether moiety which, therefore, is absent in solution. As we did before for
BF3, we have computed the 1,3-zwiterionic species formation step with one and two AlF3 molecules.
As for BF3, the intermediate is not stable with one equivalent complexed on the aziridine nitrogen. Two
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AlF3 molecules are needed to observe the formation of the charged intermediate. The aziridine opening
then occurs with a barrier of 4.8 kcal/mol, less than the one observed with two equivalents of BF3.
Given the poor solubility of AlF3 in dichloromethane,36 such a scenario is unlikely thereby explaining
the lack of reactivity in the presence of AlF3. Nevertheless, these theoretical results corroborate the
proposed mechanism depicted in scheme 8.
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We then turned our attention to the reaction starting from the N-(Tces)aziridine 1e to better
understand the weak influence of the nitrogen protecting group on the course of the cycloaddition. As
the rate-determining step of the reaction is the dipole formation, we have focused only on this step. The
energetic profiles for the dipole formation for the N-(Tces) and N-(Ts) derivatives are shown in Scheme
11. For the N-(Tces)aziridine 1e, the complexation of one BF3 is less favorable than for the N-(Ts)
substrate 1a by 2.7 kcal/mol. This is due to the fact that the nitrogen atom in 1e is less nucleophilic than
in 1a because of the inductive attractor effects of chlorine atoms. Nonetheless, as Tces is more
attractive than the sulfonyl group, the C-N bond is easier to break in II-Tces than in II-s: the barrier for
C-N breaking is 2.7 kcal/mol lower for the Tces derivative. As a consequence, the two transition state
II-Tces-TS and II-s are nearly degenerate as the two effects, complexation and bond breaking costs,
compensate each other. Finally, the attractive effect of the Tces group can be detected in the stability of
the intermediate III-Tces: it is 4.0 kcal/mol more stable than III-s. The formation of III-Tces is thus
exothermic by 2.4 kcal/mol, in contrast to the slightly endothermic reaction leading to III-s.
Scheme 11. Comparition between the formation of 1,3-dipole III-s and III-Tces.
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In conclusion, the use of N-(sulfamoyl)aziridines in [3+2] cycloaddition with alkenes affords a rapid
access to 1-azaspiro[4.n]alkanes in good yields. The scope of the reaction has been extended to
azetidines with equal efficiency. These studies have demonstrated that the nitrogen protecting group
has a low influence on the efficiency of the cycloaddition, an experimental result that has been
rationalized by theoretical calculations. However, use of sulfamates gives access to a wider diversity of
spiro compounds as the starting aziridines and azetidines are readily accessible by application of,
respectively, efficient catalytic alkene aziridination or benzylic C(sp3)-H amination. In addition, DFT
calculations have allowed to draw a mechanism of the formal [3+2] cycloaddition for the first time, for
which the formation of the 1,3-zwiterionic species appears to be the limiting step. Application of this
strategy to the production of building blocks for further derivatization is in progress.
Experimental Section
General procedure A for aziridination (RSO2NH2)
To a solution of tetrakis(acetonitrile)copper (I) hexafluorophosphate (0.1 equiv) and alkene (1 equiv)
held under argon in acetonitrile (c = 0.4 M) in the presence of activated 4Å molecular sieves was added
the sulfonamide (1.4 equiv) at room temperature. Iodosylbenzene (1.4 equiv) was then added
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portionwise at 0 °C. The suspension was allowed to warm up slowly to room temperature over 20 h.
The reaction mixture was diluted with CH2Cl2 and filtered through celite®. The filter cake was washed
throroughly with CH2Cl2 and the filtrate was concentrated under reduced pressure. The crude product
was purified by flash chromatography on silica gel.
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General procedure B for aziridination (TcesNH2)
To a solution of TcesNH2 (1.1 equiv) in C6H6 were added sequentially the olefin (1.0 equiv,
c = 0.5 mM), MgO (2.3 equiv), and Rh2(tfacam)4 (0.01 equiv). The resulting purple mixture was cooled
to 0 °C and PhI(OAc)2 (1.3 equiv) was added. The suspension quickly turned orange after the addition
of PhI(OAc)2 and was allowed to warm up slowly to 25 °C over 2 h. After 6 h of stirring at 25 °C,
during which time the solution color faded to pale yellow, the reaction was diluted with CH2Cl2 and
filtered through celite®. The filter cake was washed thoroughly with CH2Cl2 and the combined filtrates
were concentrated under reduced pressure. The isolated material was purified by chromatography on
silica gel to afford the desired aziridine.
General procedure C for cycloaddition
To a solution of aziridine (0.3 mmol) in CH2Cl2 (c = 0.2 M) cooled at -78 °C under argon was added
the alkene (1.5 equiv). BF3·OEt2 (1.5 equiv) was then added dropwise. After 2 h at -78 °C, the reaction
mixture was quenched with water. The aqueous layer was extracted with CH2Cl2 (x3). The combined
organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product
was purified by flash chromatography on silica gel.
Computational Details
Quantum mechanics calculations were performed with the Gaussian09 software package.37 Energy and
forces were computed by density functional theory with the ωB97X-D38 exchange-correlation
functional and the /6-31+G(d,p) basis set. The zero point energy (ZPE) contributions are taken into
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account after a frequency calculations at the same level. A polarizable continuum model39 (PCM) of
solvent was used as implemented in Gaussian09 to describe the medium (dichloromethane). Transition
states were localized using the string theory40 as implemented in Opt’n Path.41 All structures were
optimized and frequency calculations were performed to ensure the absence of any imaginary
frequencies on local minima, and the presence of only one imaginary frequency on transition states.
Reactants and products were re-localized starting from the transition states (IRC calculations followed
by optimizations) to ensure that no TS were forgotten.
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Iodosylbenzene. To iodosobenzene diacetate (74 mmol) was added a 3 M solution of NaOH (402
mmol). After completion of the addition, the mixture was stirred for 1 h, diluted with 150 ml of water
and stirred for 2 additional hours. The solid was collected on a Büchner funnel, washed twice with 100
mL of water, twice with 100 mL of CH2Cl2 and dried under high vacuum for 48 h (the solid was
crushed two or three times) to afford the desired product as a yellow solid (91%); iodosylbenzene was
stored under an atmosphere of argon in the freezer (-20 °C). Anal Calcd for C6H5IO: C, 32.75; H, 2.29;
O, 7.27. Found C, 32.61; H, 2.33; O, 7.24; mp 209-210 °C (decomposition).
Rh (tfacam) 26b A 25 mL recovery flask was charged with Rh2(OAc)4 (0.32 mmol) and 18.5 mL of
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C6H5Cl, and to this suspension was added CF3CONH2 (14 equiv). The reaction flask was equipped with
a short-path distillation head fitted with a 25 mL receiving bulb. The apparatus was placed in a bath
preheated to 155 °C. At this temperature, solvent distilled at a rate of ~1 mL/h for 36 h. Approximately
every 8 h, an appropriate amount of C6H5Cl was added in order to restore the solvent volume of the
reaction to ~18 mL. The solution color slowly changed to a deep green and a white crystalline
precipitate (CF3CONH2) slowly formed in the receiving flask. After 36 h, additional CF3CONH2 (14
equiv) was added to this reaction mixture and heating at 155 °C was continued. Within 48 h, a dark
blue-green solid slowly collected on the sides of the reaction vessel. Following this time, the reaction
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was cooled to 25 °C and the mixture was filtered. The blue-green solid was washed thoroughly with
CH2Cl2, and the filtrate discarded. To ensure quantitative recovery of the desired product, acetone was
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used to dissolve the powder. The purple filtrate was concentrated under reduced pressure and the
isolated material was dried by heating at 50 °C in vacuo (1 mm Hg) for 1 h. For all applications, the
Rh2(tfacam)4 complex was used without further purification. Purification of this material by
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chromatography on silica gel (CH2Cl2/EtOAc 3/1) is possible and affords a blue-green solid, (83%). Rf
= 0.4 (petroleum ether/EtOAc 7/3); 19F NMR (282 MHz, (CD CO): -75.1 ppm; IR (Neat): ν = 3399,
)
3 2
1649, 1455, 1429, 1263, 1190, 1140 cm-1; HRMS (ESI-; MeCN/MeOH): m/z calculated for
C9H5N4O6Rh2F12 698.8130, found 698.8128.
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2,2,2-Trichloro-1-phenylethyl sulfamate. Formic acid (1.5 equiv) was slowly added to chlorosulfonyl
isocyanate (1.5 equiv) at 0 °C under an argon atmosphere. The solution was stirred overnight at room
temperature and the resulting white solid was cooled down at 0 °C and dissolved in dry DMA (c = 2 M
for isocyanate). Then, the appropriate alcohol42 in DMA (c = 2.5 M) was added to the solution. The
reaction mixture was stirred for 4 hours before being quenched with brine and EtOAc. The resulting
solution was then poured to an EtOAc/H2O mixture. The aqueous layer was extracted with EtOAc (x3).
Organic layers were combined, washed with water twice, dried over MgSO4 and concentrated.
Purification on a column of silica gel with a gradient of ethyl acetate in petroleum ether (from 80/20 to
70/30) as eluent gave the desired product (435 mg, 71%) as a white solid. Rf = 0.5 (petroleum
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1
ether/ethyl acetate 70/320); mp 141-142 °C; H NMR (300 MHz, DMSO, 25 °C): δ = 7.97 (br s, 2H),
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7.68-7.55 (m, 2H), 7.50-7.37 (m, 3H), 5.96 (s, 1H); C NMR (75 MHz, DMSO, 25 °C): δ = 132.9,
129.7, 129.6, 127.8, 98.8, 86.3; IR (Neat): ν = 3389, 3285, 2966, 1556, 1498, 1456, 1379, 1368, 1326,
1273, 1193, 1177, 1031 cm-1; HRMS (ESI-; MeCN/CH2Cl2): m/z calculated for
C8H7Cl3NO3S 301.9212, found 301.9201.
2-Phenyl-1-tosylaziridine (1a). Prepared according to the general procedure A. Purification on a
column of silica gel with ethyl acetate in petroleum ether (90/10) as eluent gave the desired product
(359 mg, 73%) as a white solid. Rf = 0.2 (petroleum ether/ethyl acetate 80/20); mp 90-91 °C; 1H NMR
(500 MHz, CDCl3, 25 °C): δ = 7.87 (d, 2H, J = 8.2 Hz), 7.33 (d, 2H, J = 8.2 Hz), 7.30-7.27 (m, 3H),
7.22 (dd, 2H, J = 7.5, 2.0 Hz), 3.78 (dd, 1H, J = 7.2, 4.4 Hz), 2.98 (d, 1H, J = 7.2 Hz), 2.44 (s, 3H),
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2.39 (d, 1H, J = 4.4 Hz); C NMR (75 MHz, CDCl3, 25 °C): δ = 144.7, 135.1, 135.0, 129.8, 128.6,
128.4, 128.0, 126.6, 41.1, 36.0, 21.7; IR (Neat): ν = 3011, 1595, 1495, 1458, 1385, 1320, 1307, 1291,
1232, 1193, 1155, 1134, 1117, 1093, 1082, 1029, 1018 cm-1; HRMS (ESI+; MeCN/CH2Cl2): m/z
calculated for C15H16NO2S 274.0902, found 274.0909.
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2-Phenyl-1-(phenylsulfonyl)aziridine (1b). Prepared according to the general procedure A.
Purification on a column of silica gel with a gradient of ethyl acetate in petroleum ether (from 90/10 to
80/20) as eluent gave the desired product (375 mg, 72%) as a colorless solid. Rf = 0.2 (petroleum
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ether/ethyl acetate 90/10); mp 76-77 °C; H NMR (300 MHz, CDCl3, 25 °C): δ = 8.04-7.95 (m, 2H),
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7.67-7.59 (m, 1H), 7.58-7.50 (m, 2H), 7.33-7.27 (m, 3H), 7.25-7.17 (m, 2H), 3.81 (dd, 1H, J = 7.2, 4.5
Hz), 3.02 (d, 1H, J = 7.2 Hz), 2.42 (d, 1H, J = 4.5 Hz); 13C NMR (75 MHz, CDCl3, 25 °C): δ = 138.1,
135.0, 133.8, 129.2, 128.7, 128.5, 128.0, 126.6, 41.2, 36.1; IR (Neat): ν = 3094, 3068, 3011, 1584,
1497, 1480, 1459, 1449, 1380, 1320, 1291, 1229, 1194, 1183, 1169, 1155, 1132, 1119, 1093, 1081,
1027, 1000 cm-1; HRMS (ESI+; MeCN/CH2Cl2): m/z calculated for C14H14NO2S 260.0745, found
260.0741.
1-((4-Nitrophenyl)sulfonyl)-2-phenylaziridine (1c). Prepared according to the general procedure A.
Purification on a column of silica gel with a gradient of ethyl acetate in petroleum ether (from 90/10 to
80/20) as eluent gave the desired product (203 mg, 77%) as a yellow solid. Rf = 0.4 (petroleum
ether/ethyl acetate 80/20); mp 137-138 °C; 1H NMR (300 MHz, CDCl3, 25 °C): δ = 8.41-8.35 (m, 2H),
8.23-8.16 (m, 2H), 7.35-7.29 (m, 3H), 7.24-7.18 (m, 2H), 3.90 (dd, 1H, J = 7.3, 4.6 Hz), 3.12 (d, 1H,
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J = 7.3 Hz), 2.51 (d, 1H, J = 4.6 Hz); C NMR (75 MHz, CDCl3, 25 °C): δ = 150.8, 144.0, 134.2,
129.3, 128.9, 126.5, 124.5, 42.0, 36.7; IR (Neat): ν = 3111, 2987, 2920, 1607, 1526, 1461, 1403, 1348,
1307, 1292, 1235, 1192, 1157, 1122, 1092 cm-1; HRMS (ESI-; MeCN/CH2Cl2): m/z calculated for
C14H12ClN2O4S 339.0206, found 339.0203.
1-((4-Methoxyphenyl)sulfonyl)-2-phenylaziridine (1d). Prepared according to the general procedure
A. Purification on a column of silica gel with ethyl acetate in petroleum ether (80/20) as eluent gave the
desired product (329 mg, 57%) as a yellow solid. Rf = 0.2 (petroleum ether/ethyl acetate 90/10); mp 83-
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84 °C; H NMR (300 MHz, CDCl3, 25 °C): δ = 7.96-7.87 (m, 2H), 7.33-7.26 (m, 3H), 7.24-7.18 (m,
2H), 7.03-6.96 (m, 2H), 3.87 (s, 3H), 3.75 (dd, 1H, J = 7.2, 4.5 Hz), 2.97 (d, 1H, J = 7.2 Hz), 2.38 (d,
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1H, J = 4.5 Hz); C NMR (75 MHz, CDCl3, 25 °C): δ = 163.8, 135.2, 130.2, 129.4, 128.6, 128.4,
126.6, 114.4, 55.7, 41.1, 36.0; IR (Neat): ν = 3009, 1593, 1576, 1498, 1458, 1442, 1415, 1387, 1322,
1310, 1300, 1260, 1232, 1193, 1183, 1150, 1115, 1093, 1018 cm-1; HRMS (ESI+; MeCN/CH2Cl2): m/z
calculated for C15H16NO3S 290.0851, found 290.0847.
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2,2,2-Trichloroethyl 2-phenylaziridine-1-sulfonate (1e). Prepared according to the general procedure
B. Purification on a column of silica gel with a gradient of ethyl acetate in petroleum ether (from 95/5
to 80/20) as eluent gave the desired product (1.09 g, 89%) as a white solid. Rf = 0.7 (petroleum
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ether/ethyl acetate 80/20); mp 56-57 °C; H NMR (300 MHz, CDCl3, 25 °C): δ = 7.43-7.27 (m, 5H),
4.88 (d, 1H, J = 10.8 Hz), 4.81 (d, 1H, J = 10.8 Hz), 3.87 (dd, 1H, J = 7.2, 4.7 Hz), 3.09 (d, 1H,
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J = 7.2 Hz), 2.63 (d, 1H, J = 4.7 Hz); C NMR (75 MHz, CDCl3, 25 °C): δ = 133.9, 129.0, 128.9,
126.6, 92.9, 79.8, 42.8, 37.6; IR (Neat): ν = 3018, 2971, 1606, 1499, 1461, 1446, 1365, 1317, 1293,
1270, 1233, 1196, 1180, 1144, 1114, 1095, 1043, 1008 cm-1; HRMS (ESI+; MeCN/CH2Cl2): m/z
calculated for C10H11Cl3NO3S 329.9525, found 329.9523.
2,2,2-Trichloro-1-phenylethyl 2-phenylaziridine-1-sulfonate (1f). Prepared according to the general
procedure B. Purification on a column of silica gel with a gradient of ethyl acetate in petroleum ether
(from 98/2 to 95/5) as eluent gave the desired product (356 mg, 88%) as a 6:4 mixture of unseparable
diastereomers (white solid). Rf = 0.4 (petroleum ether/ethyl acetate 90/10); 1H NMR (300 MHz, CDCl3,
25 °C): δ = 7.67 (dd, 1H, J = 7.8, 2.0 Hz), 7.53 (dd, J = 7.4, 1.6 Hz, 1H), 7.49-7.33 (m, 2H), 7.33-7.11
(m, 4H), 7.06-6.89 (m, 2H), 6.06 (s, 0.4H), 6.05 (s, 0.6H), 3.70 (dd, 1H, J = 7.2, 4.6 Hz), 2.92 (d, 0.4H,
J = 7.2 Hz), 2.86 (d, 0.6H, J = 7.2 Hz), 2.29 (d, 0.4H, J = 4.6 Hz), 2.03 (d, 0.6H, J = 4.6 Hz); 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 134.0, 133.8, 132.1, 131.4, 130.4, 130.3, 129.8, 129.6, 128.70, 128.67,
128.6, 128.5, 128.1, 127.9, 126.3, 126.2, 98.0, 97.7, 90.63, 90.55, 42.9, 42.7, 37.9, 37.8; IR (Neat):
ν = 2973, 1499, 1463, 1456, 1368, 1346, 1322, 1232, 1198, 1172, 1140, 1115, 1085, 1031 cm-1; HRMS
(ESI+; MeCN/CH2Cl2): m/z calculated for C18H18Cl3N2O3S 447.0104, found 447.0103.
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2,2,2-Trichloroethyl 2-methyl-3-phenylaziridine-1-sulfonate (1g). Prepared according to the general
procedure B. Purification on a column of silica gel with ethyl acetate in petroleum ether (90/10) as
eluent gave the desired product (506 mg, 95%) as a white solid. Rf = 0.5 (petroleum ether/ethyl acetate
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90/10); mp 72-73 °C; H NMR (500 MHz, CDCl3, 25 °C): δ = 7.40-7.32 (m, 3H), 7.30-7.26 (m, 2H),
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4.80 (d, 1H, J = 10.7 Hz), 4.77 (d, 1H, J = 10.7 Hz), 3.79 (d, 1H, J = 4.4 Hz), 3.08-3.01 (qd, 1H,
J = 6.0, 4.4 Hz), 1.78 (d, 3H, J = 6.0 Hz); 13C NMR (75 MHz, CDCl3, 25 °C): δ = 134.3, 128.9, 128.8,
126.6, 93.0, 79.6, 50.9, 48.6, 13.7; IR (Neat): ν = 2948, 1500, 1461, 1436, 1417, 1378, 1366, 1343,
1291, 1244, 1206, 1174, 1130, 1089, 1077, 1065, 1042, 1012 cm-1; HRMS (ESI-; MeCN/CH2Cl2): m/z
calculated for C11H12Cl4NO3S 377.9292, found 377.9293.
2,2,2-Trichloroethyl 2-(naphthalen-2-yl)aziridine-1-sulfonate (1h). Prepared according to the
general procedure B. Purification on a column of silica gel with a gradient of ethyl acetate in petroleum
ether (from 95/5 to 80/20) as eluent gave the desired product (696 mg, 49%) as a white solid. Rf = 0.6
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(petroleum ether/ethyl acetate 80/20); mp 103-104 °C; H NMR (500 MHz, CDCl3, 25 °C): δ = 7.88-
7.80 (m, 4H), 7.56-7.50 (m, 2H), 7.34 (dd, 1H, J = 8.6, 1.7 Hz), 4.90 (d, 1H, J = 11.0 Hz), 4.84 (d, 1H,
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J = 11.0 Hz), 4.04 (dd, 1H, J = 7.3, 4.8 Hz), 3.16 (d, 1H, J = 7.3 Hz), 2.74 (d, 1H, J = 4.8 Hz); C
NMR (125 MHz, CDCl3, 25 °C): δ = 133.5, 133.1, 131.3, 128.9, 128.0, 127.9, 126.9, 126.8, 126.7,
123.4, 93.0, 79.8, 43.2, 37.6; IR (Neat): ν = 3066, 2957, 1600, 1510, 1473, 1455, 1397, 1363, 1334,
1271, 1228, 1209, 1179, 1162, 1138, 1128, 1090, 1046, 1002 cm-1; HRMS (ESI+; MeCN/CH2Cl2): m/z
calculated for C14H13Cl3NO3S 379.9682, found 379.9675.
2,2,2-Trichloroethyl 1a,2,3,7b-tetrahydro-1H-naphtho[1,2-b]azirine-1-sulfonate (1i). Prepared
according to the general procedure B. Purification on a column of silica gel with a gradient of ethyl
acetate in petroleum ether (from 95/5 to 80/20) as eluent gave the desired product (275 mg, 39%) as a
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white solid. Rf = 0.4 (petroleum ether/ethyl acetate 90/10); mp 93-94 °C; H NMR (500 MHz, CDCl3,
25 °C): δ = 7.42 (d, 1H, J = 7.4 Hz), 7.29 (td, 1H, J = 7.4, 1.3 Hz), 7.23 (t, 1H, J = 7.4 Hz), 7.12 (d, 1H,
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J = 7.4 Hz), 4.77 (d, 1H, J = 11.0 Hz), 4.72 (d, 1H, J = 11.0 Hz), 3.90 (d, 1H, J = 7.1 Hz), 3.68 (br d,
1H, J = 6.9 Hz), 2.81 (ddd, 1H, J = 15.4, 13.2, 6.7 Hz), 2.65 (dd, 1H, J = 15.4, 5.7 Hz), 2.45 (ddt, 1H,
J = 14.5, 6.9, 2.2 Hz), 1.82-1.73 (m, 1H); 13C NMR (125 MHz, CDCl3, 25 °C): δ = 136.4, 130.0, 129.1,
129.0, 128.8, 126.7, 93.1, 79.6, 44.1, 43.8, 24.7, 20.1; IR (Neat): ν = 3025, 2953, 1493, 1461, 1439,
1382, 1360, 1275, 1263, 1233, 1197, 1174, 1086, 1061, 1038, 1004 cm-1; HRMS (ESI-;
MeCN/CH2Cl2): m/z calculated for C12H12Cl4NO3S 389.9292, found 389.9285.
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7-Phenyl-3-oxa-2-thia-1-azabicyclo[4.1.0]heptane 2,2-dioxide (1j). Prepared according to the
literature.29 Purification on a column of silica gel with a gradient of ethyl acetate in petroleum ether
(from 90/10 to 70/20) as eluent gave the desired product (1.14 g, 68%) as a colorless solid. Rf = 0.3
(petroleum ether/ethyl acetate 60/40); mp 84-85 °C; 1H NMR (500 MHz, CDCl3, 25 °C): δ = 7.41-7.27
(m, 5H), 4.88 (dt, J = 11.7, 6.8 Hz, 1H), 4.54 (dt, J = 11.7, 6.8 Hz, 1H), 3.87 (d, J = 4.3 Hz, 1H), 3.30-
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3.21 (m, 1H), 2.58-2.32 (m, 2H); C NMR (75 MHz, CDCl3, 25 °C): δ = 134.2, 128.9, 126.4, 68.9,
50.5, 47.9, 18.9; IR (Neat): ν = 3040, 1497, 1474, 1453, 1413, 1373, 1358, 1290, 1244, 1180, 1127,
1055, 1027 cm-1; HRMS (ESI+; MeCN/CH2Cl2): m/z calculated for C10H12NO3S 226.0538, found
226.0535.
3-Phenyl-1-tosyl-1-azaspiro[4.4]nonane (2a). Prepared according to the general procedure C.
Purification on a column of silica gel with ethyl acetate in petroleum ether (95/5) as eluent gave the
desired product (70 mg, 66%) as a white solid. Rf = 0.2 (petroleum ether/ethyl acetate 95/5); mp 100-
101 °C; 1H NMR (500 MHz, CDCl3, 25 °C): δ = 7.74 (d, J = 8.3 Hz, 2H), 7.34-7.27 (m, 4H), 7.25-7.20
(m, 1H), 7.17 (d, 2H, J = 7.8 Hz), 3.92 (dd, 1H, J = 9.1, 7.1 Hz), 3.44-3.33 (m, 1H), 3.20 (dd, 1H,
J = 10.6, 9.1 Hz), 2.72-2.63 (m, 1H), 2.42 (s, 3H), 2.40-2.33 (m, 1H), 2.24 (dd, J = 12.1, 6.1, 1H), 1.92-
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1.82 (m, 3H), 1.78-1.72 (m, 1H), 1.58-1.45 (m, 3H); C NMR (75 MHz, CDCl3, 25 °C): δ = 142.8,
139.9, 138.5, 129.5, 128.6, 127.11, 127.07, 127.0, 74.8, 55.3, 48.8, 41.1, 38.5, 37.0, 23.6, 23.0, 21.5; IR
(Neat): ν = 2982, 2953, 2919, 2878, 2866, 1593, 1491, 1478, 1453, 1396, 1340, 1322, 1302, 1290,
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1266, 1244, 1207, 1180, 1154, 1137, 1121, 1107, 1091, 1081, 1065, 1036 cm-1; HRMS (ESI+;
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MeCN/CH2Cl2): m/z calculated for C21H26NO2S 356.1684, found 356.1672.
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3-Phenyl-1-(phenylsulfonyl)-1-azaspiro[4.4]nonane (2b). Prepared according to the general
procedure C. Purification on a column of silica gel with ethyl acetate in petroleum ether (95/5) as
eluent gave the desired product (66 mg, 65%) as a yellow solid. Rf = 0.4 (petroleum ether/ethyl acetate
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90/10); mp 83-84 °C; H NMR (500 MHz, CDCl3, 25 °C): δ = 7.87 (d, 2H, J = 7.9 Hz), 7.58-7.52 (m,
1H), 7.52-7.46 (m, 2H), 7.33-7.27 (m, 2H), 7.25-7.20 (m, 1H), 7.18 (d, 2H, J = 7.6 Hz), 3.94 (dd, 1H,
J = 9.0, 7.5 Hz), 3.46-3.34 (m, 1H), 3.21 (dd, 1H, J = 10.7, 9.0 Hz), 2.71-2.63 (m, 1H), 2.42-2.33 (m,
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1H), 2.25 (dd, 1H, J = 12.1, 6.0 Hz), 1.93-1.82 (m, 3H), 1.80-1.72 (m, 1H), 1.54-1.45 (m, 3H); C
NMR (75 MHz, CDCl3, 25 °C): δ = 141.5, 139.9, 132.2, 129.0, 128.7, 127.18, 127.15, 127.1, 75.0,
55.4, 48.8, 41.2, 38.6, 37.1, 23.7, 23.1; IR (Neat): ν = 3025, 2988, 2952, 2861, 1602, 1494, 1478, 1449,
1347, 1322, 1306, 1231, 1206, 1153, 1093, 1070, 1025, 1005 cm-1; HRMS (ESI+; MeCN/CH2Cl2): m/z
for C20H24NO2S 342.1528, found 342.1529.
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1-((4-Nitrophenyl)sulfonyl)-3-phenyl-1-azaspiro[4.4]nonane (2c). Prepared according to the general
procedure C. Purification on a column of silica gel with ethyl acetate in petroleum ether (95/5) as
eluent gave the desired product (55 mg, 47%) as an off-white solid. Rf = 0.4 (petroleum ether/ethyl
acetate 90/10); mp 146-147 °C; 1H NMR (500 MHz, CDCl3, 25 °C): δ = 8.35 (d, 2H, J = 8.8 Hz), 8.04
(d, 2H, J = 8.8 Hz), 7.34-7.28 (m, 2H), 7.26-7.21 (m, 1H), 7.17 (d, 2H, J = 7.6 Hz), 4.01 (dd, 1H,
J = 9.1, 7.6 Hz), 3.48-3.38 (m, 1H), 3.21 (dd, 1H, J = 10.7, 9.1 Hz), 2.64-2.56 (m, 1H), 2.38-2.31 (m,
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1H), 2.28 (dd, 1H, J = 12.8, 5.9 Hz), 1.95-1.84 (m, 3H), 1.84-1.77 (m, 1H), 1.62-1.44 (m, 3H); C
NMR (75 MHz, CDCl3, 25 °C): δ = 149.8, 147.0, 139.2, 128.8, 128.2, 127.4, 127.1, 124.4, 75.6, 55.7,
48.5, 41.2, 38.8, 37.0, 23.6, 23.0; IR (Neat): ν = 3114, 2954, 2877, 1605, 1526, 1497, 1476, 1455,
1400, 1371, 1345, 1302, 1249, 1209, 1156, 1137, 1106, 1093, 1080, 1067, 1004 cm-1; HRMS (ESI-;
MeCN/CH2Cl2): m/z calculated for C20H21N2O4S 385.1222, found 385.1235.
1-((4-Methoxyphenyl)sulfonyl)-3-phenyl-1-azaspiro[4.4]nonane (2d). Prepared according to the
general procedure C starting from 0.2 mmol of aziridine. Purification on a column of silica gel with
ethyl acetate in petroleum ether (95/5) as eluent gave the desired product (37 mg, 49%) as an off-white
solid. Rf = 0.3 (petroleum ether/ethyl acetate 90/10); mp 85-86 °C; 1H NMR (500 MHz, CDCl3, 25 °C):
δ = 7.79 (d, 2H, J = 8.8 Hz), 7.29 (t, 2H, J = 7.5 Hz), 7.22 (t, 1H, J = 7.5 Hz), 7.18 (td, 2H, J = 7.5, 1.3
Hz), 6.96 (d, 2H, J = 8.8 Hz), 3.89 (dd, 1H, J = 9.1, 7.4 Hz), 3.86 (s, 3H), 3.43-3.33 (m, 1H), 3.18 (dd,
1H, J = 10.4, 9.1 Hz), 2.72-2.64 (m, 1H), 2.40-2.33 (m, 1H), 2.24 (dd, 1H, J = 12.2, 6.0 Hz), 1.92-1.81
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(m, 3H), 1.78-1.72 (m, 1H), 1.59-1.47 (m, 3H); C NMR (75 MHz, CDCl3, 25 °C): δ = 162.5, 140.0,
133.3, 129.2, 128.7, 127.2, 127.1, 114.1, 74.8, 55.7, 55.4, 48.9, 41.2, 38.5, 37.1, 23.7, 23.1; IR (Neat):
ν = 2952, 2874, 2836, 1595, 1579, 1497, 1478, 1457, 1441, 1411, 1332, 1305, 1253, 1184, 1147, 1138,
1114, 1094, 1064, 1028 cm-1; HRMS (ESI+; MeCN/CH2Cl2): m/z calculated for C21H26NO3S 372.1633,
found 372.1640.
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2,2,2-Trichloroethyl 3-phenyl-1-azaspiro[3.4]octane-1-sulfonate (2ea). Prepared according to the
general procedure C. Purification on a column of silica gel with a gradient of ethyl acetate in petroleum
ether (from 100/0 to 98/2) as eluent gave the desired product (58 mg, 49%) as a colorless solid. Rf = 0.3
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(petroleum ether/ethyl acetate 98/2); mp 81-82 °C; H NMR (500 MHz, CDCl3, 25 °C): δ = 7.37-7.31
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(m, 2H), 7.29-7.23 (m, 3H), 4.66 (s, 2H), 3.97 (dd, 1H, J = 10.0, 7.2 Hz), 3.50 (t, 1H, J = 10.0 Hz),
3.43-3.32 (m, 1H), 3.19 (q, 1H, J = 10.5 Hz), 2.86 (q, 1H, J = 10.5 Hz), 2.66 (dd, 1H, J = 12.2, 5.6 Hz),
2.22 (t, 1H, J = 12.2 Hz), 2.09-2.00 (m, 2H), 1.87-1.77 (m, 1H), 1.66 (sext, 1H, J = 9.7 Hz); 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 139.1, 128.8, 127.3, 127.1, 93.8, 77.6, 67.3, 56.6, 46.9, 40.5, 35.6, 34.1,
14.0; IR (Neat): ν = 2944, 2883, 1603, 1496, 1479, 1446, 1431, 1360, 1289, 1278, 1256, 1211, 1180,
1159, 1138, 1116, 1083, 1047, 1029 cm-1; HRMS (ESI-; MeCN/CH2Cl2): m/z calculated for
C15H18Cl4NO3S 431.9762, found 431.9763.
2,2,2-Trichloroethyl 3-phenyl-1-azaspiro[4.4]nonane-1-sulfonate (2eb). Prepared according to the
general procedure C. Purification on a column of silica gel with a gradient of ethyl acetate in petroleum
ether (from 100/0 to 98/2) as eluent gave the desired product (69 mg, 56%) as a white solid. Rf = 0.3
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(petroleum ether/ethyl acetate 98/2); mp 103-104 °C; H NMR (300 MHz, CDCl3, 25 °C): δ = 7.39-
7.31 (m, 2H), 7.31-7.21 (m, 3H), 4.67 (d, 1H, J = 11.0 Hz), 4.63 (d, 1H, J = 11.0 Hz), 4.06-3.98 (m,
1H), 3.57-3.37 (m, 2H), 2.67-2.54 (m, 1H), 2.38-2.22 (m, 2H), 2.04 (td, 1H, J = 12.1, 1.3 Hz), 1.90-
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1.69 (m, 4H), 1.64-1.51 (m, 2H); C NMR (75 MHz, CDCl3, 25 °C): δ = 139.3, 128.9, 127.4, 127.2,
94.0, 77.7, 75.5, 56.3, 48.8, 41.3, 37.5, 37.2, 23.7, 23.5; IR (Neat): ν = 3032, 2958, 2920, 2884, 2851,
1603, 1497, 1476, 1456, 1433, 1364, 1323, 1312, 1281, 1252, 1214, 1195, 1170, 1140, 1118, 1077,
1067, 1033, 1010 cm-1; HRMS (ESI-; MeCN/CH2Cl2): m/z calculated for C16H20Cl4NO3S 445.9918,
found 445.9908.
2,2,2-Trichloroethyl 3-phenyl-1-azaspiro[4.5]decane-1-sulfonate (2ec). Prepared according to the
general procedure C. Purification on a column of silica gel with a gradient of ethyl acetate in petroleum
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ether (from 100/0 to 98/2) as eluent gave the desired product (87 mg, 68%) as a colorless solid. Rf = 0.8
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(petroleum ether/ethyl acetate 95/5); mp 84-95 °C; H NMR (500 MHz, CDCl3, 25 °C): δ = 7.38-7.31
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6.9 Hz), 3.50 (dd, 1H, J = 10.9, 9.4 Hz), 3.47-3.38 (m, 1H), 2.65 (dd, 1H, J = 12.6, 6.3 Hz), 2.38 (td,
1H, J = 12.6, 3.6 Hz), 2.17 (td, 1H, J = 13.4, 3.9 Hz), 1.91-1.76 (m, 5H), 1.64 (d, 1H, J = 10.7 Hz),
1.43-1.20 (m, 3H); 13C NMR (75 MHz, CDCl3, 25 °C): δ = 139.4, 128.9, 127.4, 127.2, 94.0, 77.7, 70.7,
55.9, 43.7, 41.0, 37.4, 34.6, 24.9, 24.3; IR (Neat): ν = 2931, 2861, 1603, 1496, 1476, 1454, 1371, 1346,
1306, 1281, 1259, 1222, 1177, 1159, 1142, 1082, 1061, 1035, 1014 cm-1; HRMS (ESI+;
MeCN/CH2Cl2): m/z calculated for C17H23Cl3NO3S 426.0464, found 426.0460.
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2,2,2-Trichloro-1-phenylethyl 3-phenyl-1-azaspiro[4.4]nonane-1-sulfonate (2f). Prepared according
to the general procedure C. Purification on a column of silica gel with ethyl acetate in petroleum ether
(95/5) as eluent gave the desired product (91 mg, 62%) as a 1:1 mixture of unseparable diasteromers
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(white solid). Rf = 0.6 (petroleum ether/ethyl acetate 90/10); H NMR (300 MHz, CDCl3, 25 °C):
δ = 7.70-7.62 (m, 2H), 7.52-7.40 (m, 3H), 7.35-7.19 (m, 3H), 7.11-7.04 (m, 1H), 7.00-6.93 (m, 1H),
5.89 (s, 0.5H), 5.88 (s, 0.5H), 3.75 (ddd, 0.5H, J = 9.2, 7.4, 1.5 Hz), 3.64 (ddd, 0.5H, J = 9.2, 7.4, 1.5
Hz), 3.28 (dd, 0.5H, J = 11.0, 9.4 Hz), 3.24-3.06 (m, 1H), 2.91 (dd, 0.5H, J = 11.0, 9.2 Hz), 2.76-2.54
(m, 1H), 2.35-2.13 (m, 2H), 1.94-1.64 (m, 4.5H), 1.64-1.41 (m, 2.5H); 13C NMR (75 MHz, CDCl3, 25
°C): δ = 139.2, 139.1, 132.9, 132.8, 130.3, 130.1, 130.0, 128.8, 128.7, 128.2, 128.1, 127.3, 127.1, 98.9,
98.8, 88.8, 75.5, 75.2, 55.9, 55.8, 48.9, 48.5, 41.14, 41.09, 37.8, 37.4, 37.2, 37.0, 23.7, 23.50, 23.49,
23.4; IR (Neat): ν = 2953, 2874, 1498, 1476, 1455, 1381, 1346, 1325, 1169, 1116, 1074, 1027 cm-1;
HRMS (ESI+; MeCN/CH2Cl2): m/z calculated for C22H25Cl3NO3S 488.0621, found 488.0619.
2,2,2-Trichloroethyl
2-methyl-3-phenyl-1-azaspiro[4.4]nonane-1-sulfonate
(2g).
Prepared
according to the general procedure C. Purification on a column of silica gel with a gradient of ethyl
acetate in petroleum ether (from 100/0 to 98/2) as eluent gave the desired product (90 mg, 70%) as a
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The Journal of Organic Chemistry
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6:4 mixture of unseparable diasteromers (yellow oil). Rf = 0.3 (petroleum ether/ethyl acetate 98/2); H
NMR (300 MHz, CDCl3, 25 °C): δ = 7.39-7.22 (m, 3.8H), 7.21-7.14 (m, 1.2H), 4.67 (s, 0.8H), 4.66 (s,
1.2H), 4.33 (quint, 0.6H, J = 6.9 Hz), 4.05 (dq, 0.4H, J = 8.1, 6.2 Hz), 3.65 (ddd, 0.6H, J = 13.5, 7.4,
5.6 Hz), 3.01 (ddd, 0.4H, J = 11.2, 8.1, 6.6 Hz), 2.75-2.64 (m, 0.4H), 2.64-2.51 (m, 0.6H), 2.47-2.07
(m, 3H), 1.94-1.48 (m, 6H), 1.43 (d, 1.2H, J = 6.2 Hz), 0.96 (d, 1.8H, J = 6.6 Hz); 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 140.5, 137.6, 128.9, 128.6, 128.1, 127.7, 127.3, 127.2, 94.1, 77.4, 77.3, 76.1, 74.6,
66.1, 61.9, 50.7, 48.2, 44.7, 42.1, 39.4, 38.9, 36.3, 36.0, 23.7, 23.3, 21.3, 16.2; IR (Neat): ν = 2960,
2876, 1603, 1498, 1452, 1363, 1327, 1250, 1181, 1111, 1074, 1046, 1000 cm-1; HRMS (ESI-;
MeCN/CH2Cl2): m/z calculated for C17H22Cl4NO3S 460.0075, found 460.0054.
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2,2,2-Trichloroethyl 3-(naphthalen-2-yl)-1-azaspiro[4.4]nonane-1-sulfonate (2h). Prepared
according to the general procedure C. Purification on a column of silica gel with a gradient of ethyl
acetate in petroleum ether (from 100/0 to 98/2) as eluent gave the desired product (87 mg, 62%) as a
1
white solid. Rf = 0.6 (petroleum ether/ethyl acetate 90/10); mp 103-104 °C; H NMR (300 MHz,
CDCl3, 25 °C): δ = 7.87-7.79 (m, 3H), 7.69 (s, 1H), 7.54-7.44 (m, 2H), 7.37 (dd, 1H, J = 8.6, 1.8 Hz),
4.69 (d, 1H, J = 11.0 Hz), 4.66 (d, 1H, J = 11.0 Hz), 4.18-4.03 (m, 1H), 3.72-3.54 (m, 2H), 2.72-2.56
(m, 1H), 2.47-2.25 (m, 2H), 2.22-2.09 (m, 1H), 1.99-1.46 (m, 6H); 13C NMR (75 MHz, CDCl3, 25 °C):
δ = 136.6, 133.5, 132.6, 128.6, 127.75, 127.70, 126.5, 126.0, 125.7, 125.3, 94.0, 77.7, 75.6, 56.2, 48.7,
41.4, 37.5, 37.2, 23.7, 23.5; IR (Neat): ν = 3058, 2976, 2953, 2873, 1601, 1511, 1475, 1454, 1381,
1359, 1324, 1312, 1257, 1250, 1211, 1186, 1167, 1140, 1121, 1092, 1072, 1046, 1012, 1000 cm-1;
HRMS (ESI+; MeCN/CH2Cl2): m/z calculated for C20H23Cl3NO3S 462.0464, found 462.0457.
2,2,2-Trichloroethyl 3a,4,5,9b-tetrahydrospiro[benzo[e]indole-1,1'-cyclopentane]-3(2H)-sulfonate
(2i). Prepared according to the general procedure C. Purification on a column of silica gel with a
gradient of ethyl acetate in petroleum ether (from 100/0 to 98/2) as eluent gave mainly (>90/10) the cis
1
product (91 mg, 69%) as a white solid. Rf = 0.7 (petroleum ether/ethyl acetate 90/10); H NMR of
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