Formal substitution of bromocyclopropanes with nitrogen nucleophiles

Article abstract of DOI:10.1021/jo4011798

A highly chemo- and diastereoselective protocol toward amino-substituted donor-acceptor cyclopropanes via the formal nucleophilic displacement in bromocyclopropanes is described. A wide range of N-nucleophiles, including carboxamides, sulfonamides, azoles, and anilines, can be efficiently employed in this transformation, providing expeditious access to stereochemically defined and densely functionalized cyclopropylamine derivatives.

Full text of DOI:10.1021/jo4011798

Article
pubs.acs.org/joc
Formal Substitution of Bromocyclopropanes with Nitrogen
Nucleophiles
Joseph E. Banning, Jacob Gentillon, Pavel G. Ryabchuk, Anthony R. Prosser,† Andrew Rogers,‡
Andrew Edwards, Andrew Holtzen, Ivan A. Babkov, Marina Rubina, and Michael Rubin*
Department of Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045-75832
S
* Supporting Information
ABSTRACT: A highly chemo- and diastereoselective protocol toward
amino-substituted donor−acceptor cyclopropanes via the formal
nucleophilic displacement in bromocyclopropanes is described. A wide
range of N-nucleophiles, including carboxamides, sulfonamides, azoles,
and anilines, can be efficiently employed in this transformation,
providing expeditious access to stereochemically defined and densely functionalized cyclopropylamine derivatives.
Scheme 1
INTRODUCTION
■
β-Aminocyclopropanecarboxylic acid derivatives (β-ACCs)1 are
important members of a versatile and synthetically challenging
family of donor−acceptor cyclopropanes (DAC).2 β-ACCs
have been recognized for their ability to produce surprisingly
stable secondary structures even in short peptides,3−5 and
served as useful tools for conformational analysis.4a,6 They have
also been used as key elements in natural products,7
organocatalysts,8 and prospective drug candidates,6,9 including
potent antiviral,10 antitumor,11 and antihypertensive agents.12
In contrast to a plethora of natural and synthetic analogues of
α-aminocyclopropanecarboxylic acid (α-ACC), which have
been extensively exploited in medicinal, chemical, and
agricultural research,13 synthesis of many β-ACC analogues
faces a number of difficulties and limitations. The problem
associated with stability of the three-membered ring in
heteroatom-substituted “push−pull” cyclopropanes,14 narrows
the access to these structural motifs and limits their further use
in the assembly of complex architectures.15 As a result,
substituted aminocyclopropane carboxylic acids possessing an
additional stabilizing carboxylic group in the three-membered
unit have been commonly used as more available β-ACC
surrogates.3−15
[2 + 1]-cyclopropanation of acrylates with α-nitrodiazo
compounds (route B),19 and more rarely, diazo transfer onto
enamines (route C).20 Approaches that allow direct and
efficient installation of an amine function in a pre-existing
three-membered ring remain scarce;21 most earlier attempts on
the addition of N-nucleophiles to cyclopropenes resulted in
cleavage of the small ring.22 Prior to our studies, a few examples
of formal nucleophilic substitution of halocyclopropanes with
N-based nucleophiles have been reported (route D), which
proceeded readily only with unsubstituted cyclopropyl halides,
or in the presence of vicinal electron-withdrawing
groups.21d,23,24
Recently, we reported a method for direct addition of oxygen
and sulfur-based nucleophiles to cyclopropenes generated in
situ via 1,2-dehydrobromination of bromocyclopropanes.25,26
To access β-ACC derivatives through this methodology, we
tested a series of different amines as N-pronucleophiles;
however, our initial attempts to induce addition of ammonia,
as well as primary and secondary amines, were unsuccessful.
Moreover, we discovered that amino alcohols and amino thiols
can be employed as O- and S-nucleophiles, respectively, in
highly chemo- and diastereoselective reactions with bromocy-
clopropanes 1a,b and 4a (Schemes 2 and 3).26b
We have recently communicated a convergent synthesis of
racemic trans-β-ACC diamides16 and N-cyclopropylheteroar-
yls17 via a formal nucleophilic substitution of bromocyclopro-
panes. Herein, we wish to report a full account of this
methodology that has evolved into a general approach to a
broad spectrum of N-cyclopropyl derivatives including
carboxamides, heterocycles, sulfonamides, and anilines. Factors
affecting the reactivity of the nucleophilic components and
modes for controlling the stereoselectivity of the addition are
discussed.
RESULTS AND DISCUSSION
■
Carboxamides as N-Based Nucleophiles. The β-ACC
core is usually assembled via the following routes (A−C,
Scheme 1): Michael-initiated ring closure reactions (route A),18
Received: May 29, 2013
© XXXX American Chemical Society
A
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Scheme 2
Scheme 3
Such high chemoselectivity was attributed to selective
deprotonation of the more acidic alcohol or thiol functions in
the presence of a relatively weak base, which rendered these
moieties more nucleophilic as compared to less acidic 1° or 2°
amines.27 As we have demonstrated previously,26 success in the
formal substitution reaction is strongly dependent on a fine
balance between basicity and nucleophilicity of the reactive
species, which creates certain limitations. Thus, soft nucleo-
philes with decreased basicity, like phenolates and thiolates, can
produce a buffer with the base, inhibiting the dehydrohaloge-
nation reaction. On the other hand, generation of a nucleophilic
species via deprotonation of less acidic pronucleophiles, such as
amines, is suppressed, which explains the observed lack of
reactivity.
Since the inertness of N-nucleophiles was apparently related
to their insufficient acidity, the following solutions to
circumvent this problem were put forth: (a) use of stronger
bases or (b) installation of electron-withdrawing activating
groups to enhance N−H deprotonation or employment of
other acidic amine surrogates. The first idea was previously
evaluated by Taylor,23d who attempted synthesis of amino acid
derivative 9 via dehydrobromination of bromocyclopropane 7
in the presence of K[N(SiMe3)2], followed by trapping of
intermediate cyclopropene 8 with ammonia (Scheme 4). This
approach proved inefficient, leading to the formation of
methoxycyclopropane 10 in low yields as the only isolable
product. The methoxide nucleophile in this case was generated
in the reaction mixture via a base-assisted hydrolysis of the
methyl ester function.23d
Scheme 4
We have previously demonstrated that conversion of
bromocyclopropylcarboxylic acid precursors into carboxamides
helped alleviate problems associated with intolerance of
sensitive ester functionalities toward strong bases at higher
temperatures, often required for generation of cyclopropenes
via 1,2-elimination.26b,28 Nonetheless, our initial attempts to
react cyclopropylcarboxamide 1c with various alkali dialkyla-
mides, generated from 1° or 2°, amines proved unsuccessful
(Scheme 5). In all cases the consumption of the starting
material was very sluggish and, when forced by heating,
substrates decomposed, providing no isolable products. We
believe that such outcome can be rationalized as follows.
Intermediate 11c possessing an acidic C(sp2)−H bond reacts
with basic amide species as an acid rather than electrophile.29
As a result, deprotonation leads to the formation of anionic
species 12 as a resting state, in which the double bond has
reduced electrophilicity, rendering the subsequent reaction with
a nucleophile impossible. Thus, the reaction poses two
contradicting requirements: a weaker base must be employed
B
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Scheme 5
Table 1. Steric Effect in the Formal Substitution of
Bromocyclopropane 1a with Secondary Amides
a
b
c
no.
R1
R2
NuH
product
yield,
%
dr
1
2
3
4
5
6
7
8
Me
n-Pr
n-Pr
i-Pr
n-Bu
tBu
Me
14aa
14bd
14bc
14 cd
14de
14ed
14fa
16aaa
16abd
16abc
16acd
16ade
16aed
16afa
16afd
88
51
28
31
11:1
25:1
25:1
17:1
n-Bu
i-Pr
d
d
n-Bu
tBu
e
nr
nr
75
72
to avoid inhibition of the electrophilic species, while a stronger
base is needed for N-nucleophile activation. To overcome this
problem, we turned to an alternative method for activating the
reaction by employing more acidic N-pronucleophiles bearing
electron-withdrawing substituents. First, we probed the reaction
in the presence of N-methylacetamide (NMA, 14aa).
n-Bu
Me
Ph
>25:1
>25:1
Ph
n-Bu
14fd
a
b
Reactions performed in 0.5 mmol scale. Isolated yields of
diastereomeric mixtures unless specified otherwise. Diastereomeric
ratio (trans:cis) determined by GC or H NMR analyses of crude
reaction mixtures. NMR yields determined by analyses of crude
reaction mixtures. Bromocyclopropane 1a was consumed completely.
No reaction.
c
1
Gratifyingly, nucleophilic attack by NMA at the double bond
of the generated in situ cyclopropene (5a)28,30 afforded trans-
cyclopropylamine derivative 15aaa in good yield and high
diastereoselectivity, which was controlled by sterics (Scheme
6). Encouraged by these results, we tested the reactivity of
NMA toward unstable conjugated cyclopropene 11a,31
generated via 1,2-elimination of bromocyclopropane 1a
(Scheme 6) under conditions previously employed for
reactions with O-nucleophiles.26 To our delight, trapping of
11a with NMA proceeded efficiently affording a high yield of
trans-diamide 16aaa, with diastereoselectivity controlled by
thermodynamically driven epimerization of the α-CH center.26a
Next, we investigated the formal nucleophilic substitution
reaction with carboxamides 14ba−14ed possessing substituents
with variable steric demands. It was found that increased steric
hindrance at the N- or C-termini of the pronucleophile had a
profound adverse effect on the reaction course. Thus, amides
bearing secondary alkyl substituents significantly decreased the
reaction’s efficacy (entries 3, 4), while substrates with tertiary
alkyl groups at either terminus did not undergo the addition at
all (entries 5, 6). We reasoned that the effective nucleophilicity
of the sterically hindered amide species (which in this process
correlates with N−H acidity) can be enhanced by tuning their
electronic properties. To test this idea, we substituted an alkyl
group at the C-terminus of the pronucleophile with a more
electron-deficient phenyl ring. Along with our expectations, the
reaction between bromocyclopropane 1a and benzamides 14fa
and 14fd afforded the corresponding diamides 16afa and 16afd
with high yields and excellent diastereoselectivities (Table 1,
entries 7, 8). To further unveil the important role of electronic
factors, we tested 1a against a series of differently substituted
d
e
N-butylbenzamides 14gd−md (Table 2). Remarkably, intro-
duction of an electron-donating p-MeO group resulted in no
reaction (Table 2, entry 2); however, incorporation of electron-
withdrawing groups in the ortho (entry 3) or para (entries 4−
7) positions of the aromatic ring in the benzamide
pronucleophile allowed for improved reactivity. The best
results were achieved with p-CF3- (16ald, entry 7) and 3,5-
bis(CF3)2-substituted aryl groups (16amd, entry 8). It should
be mentioned that no diamide product 17 was obtained in the
reaction with primary amide p-CF3C6H4CONH2 (20) despite
complete consumption of the bromocyclopropane 1a. We
failed to detect any cyclopropane-containing products in this
reaction; instead, a complete conversion of starting material
into aldehyde 21 was observed in GC/MS analysis of the crude
reaction mixture. We propose the following rationale to
account for the distinct reactivity of primary carboxamides
(Scheme 7). Addition of primary amide pronucleophile 20 to
cyclopropene 11a produces secondary diamide 17, the high N−
H acidity of which is additionally enhanced by the adjacent
electron-deficient aromatic ring. As a result, it undergoes facile
base-assisted deprotonation under our typical reaction con-
ditions to give an activated DAC species 18 with relatively high
electron density on the nitrogen atom. Subsequent facile
cleavage of the small ring gives rise to linear acylimine 19,
which after hydrolysis affords aldehyde 21 and regenerates
primary amide 20. In contrast, adducts of secondary amide
Scheme 6
C
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Another benefit of the presence of fluorine is the possibility to
Table 2. Electronic Effect in the Formal Substitution of
Bromocyclopropane 1a with Secondary Benzamides
use 19F NMR to assess stereoselectivity in the product mixtures,
1
since H NMR was inapplicable due to severe line broadening
resulting from slow conformational rotation. Accordingly, CF3-
substituted benzamides were chosen for more detailed
investigation of the scope and limitations of this reaction. It
was found that p-CF3-substituted benzamides possessing
primary N-alkyl groups undergo efficient nucleophilic addition
to give n-octyl- (16ale), benzyl- (16alf), and 2-phenethyl
benzamides (16alg) in high yields and perfect diastereoselec-
tivities (Table 3, entries 1−3). At the same time, nucleophilic
addition of a more sterically hindered N-cyclohexyl 4-
(trifluoromethyl)benzamide (14lh) proceeded sluggishly, re-
sulting in marginal yield of the corresponding diamide 16alh
(Table 3, entry 4). In contrast, amides 14mc and 14mg−mi
derived from 3,5-bis(trifluoromethyl)benzoic acid reacted with
bromocyclopropane 1a much more readily. Improved product
yields were obtained not only for the less sterically hindered
derivative 16amg (Table 3, entry 8) but also for more
challenging bulky products 16amh, 16amc, and 16ami (entries
5−7), bearing secondary N-alkyl substituents. However, very
bulky N-tert-butylamide 14me did not provide any product in
the reaction with 1a (entry 9).
The scope of the cyclopropylcarboxamides 1 was also
investigated. Bromocyclopropylcarboxamide derivatives of
piperidine (1d), morpholine (1e), and cyclohexylamine (1f)
afforded diamides 16dmg, 16dmf, 16emg, and 16fmh in good
to high yields (Table 3, entries 10−13). Weinreb amide 1g was
also tested in this reaction; however, the corresponding product
16gmf was obtained in 31% yield only, presumably due to a
decreased stability of the intermediate cyclopropene species
(Table 3, entry 14). Derivatives of 4-nitro- (14kf, 14kj) and 4-
cyanobenzoic (14jf, 14jk) acids were also successfully
employed for activation of benzylamine and hetarylmethyl-
amines (Table 3, entries 15−18).
a
b
c
no.
X−C6H4−
Ph
NuH
product
yield,
%
dr
1
2
3
4
5
6
7
8
14fd
14gd
14hd
14id
14jd
14kd
14ld
14md
16afd
16agd
16ahd
16aid
16ajd
16akd
16ald
72
d
>25:1
p-MeOC6H4
o-ClC6H4
nr
e
80
81
80
80
85
87
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
p-ClC6H4
p-CNC6H4
p-NO2C6H4
p-CF3C6H4
3,5-(CF3)2C6H3
f
f
16amd
a
Typical reaction conditions: bromocyclopopane 1a (0.5 mmol),
amide 14 (1.0 mmol), powdered KOH (1.75 mmol), 18-crown-6
b
(0.05 mmol), THF (5 mL)stirred at 85 °C for 12 h. Isolated yields
c
of trans-diamide. Diastereomeric ratio (trans:cis) determined by GC
or 1H NMR analysis of crude reaction mixtures. The notation >25:1 is
d
e
used when no minor diastereomer was detected. No reaction. NMR
yields determined by analysis of a crude reaction mixture.
f
Diastereomeric ratio (trans:cis) determined by 19F NMR analysis of
crude reaction mixtures.
pronucleophiles 16 do not possess acidic N−H bond and
therefore are stable toward ring-opening.
The described methodology can potentially serve as a
convenient route for convergent synthesis of a large number of
conformationally constrained trans-cyclopropyl amino acid
derivatives (Scheme 8). A variety of fragments can be
introduced with the possibility for a three-dimensional
diversification. The readily available acyl chloride 22 can be
converted into an array of amides 1 by varying primary or
secondary amines 23. At the same time, a variety of
pronucleophiles 14 can be obtained from primary amines 25
and different carboxylic acids 24. As shown above, amides 14
derived from linear aliphatic and electron-deficient benzoic
acids 19 provide the highest yields in this transformation
(Tables 1 and 2). Installation of the CF3 groups in the
benzamide derivatives 14ld and 14md improved solubility in
organic solvents and significantly facilitated isolation and
purification of the corresponding products 16ald and 16amd.
Similarly to the previously reported formal nucleophilic
substitution reaction with alkoxides and phenoxides,26 the trans
stereoselectivity in the described transformation was a result of
a base-assisted epimerization of the α-carbon. However,
t
additional treatment of the reaction mixture with BuOK was
not required in this case,26 as the thermodynamically more
favored trans-diastereomer was produced exclusively under the
standard reaction conditions. Trans configuration of diamide
16emg was unambiguously assigned by X-ray crystallography
32
.
Sulfonamides as N-Based Nucleophiles. Sulfonamides
are broadly employed as N−H acidic surrogates of amines in
various C−N bond forming processes, such as classical
nucleophilic displacement reactions33 (including Mitsunobu
Scheme 7
D
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Scheme 8
Table 3. Convergent Approach to Conformationally Constrained trans-Cyclopropyl Amino Acid Derivatives via Formal
Substitution of Bromocyclopropanes with Nucleophilic Carboxamides
a
R3, R4 (1)
tBu, H (1a)
tBu, H (1a)
tBu, H (1a)
tBu, H (1a)
tBu, H (1a)
tBu, H (1a)
tBu, H (1a)
tBu, H (1a)
R1
R2
14
16
yield, %
1
p-CF3C6H4
n-Oct
14le
16ale
85
80
82
45
83
61
59
94
2
p-CF3C6H4
PhCH2
Ph(CH2)2
c-Hex
14lf
16alf
3
p-CF3C6H4
14lg
16alg
4
p-CF3C6H4
14lh
16alh
16amh
16amc
16ami
16amg
16ame
16dmg
16emg
16fmh
16dmf
16gmf
16akf
16akj
5
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
4-NO2−C6H4
4-NO2−C6H4
4-CN−C6H4
c-Hex
14mh
14mc
14 mi
14 mg
14me
14mg
14mg
14mh
14mf
14mf
14kf
6
i-Pr
7
c-Pr
8
Ph(CH2)2
tBu
9
tBu, H (1a)
10
11
12
13
14
15
16
17
18
−(CH2)5− (1d)
−(CH2)2O(CH2)− (1e)
c-Hex, H (1f)
−(CH2)5− (1d)
Me, OMe (1g)
tBu, H (1a)
tBu, H (1a)
tBu, H (1a)
tBu, H (1a)
Ph(CH2)2
Ph(CH2)2
c-Hex
76
76
66
68
31
63
52
47
81
PhCH2
PhCH2
PhCH2
b
ThCH2
14kj
PhCH2
14jf
16ajf
c
4-CN−C6H4
FuCH2
14jk
16ajk
a
b
c
Isolated yields. In all cases diastereomeric ratio (trans:cis) > 25:1 was obtained. Th = 2-thienyl. Fu = 2-furyl.
coupling),33,34 conjugate addition,35 and transition metal
catalyzed coupling involving both C−Hal36 and C−H bond
activation.37 Having met success with reaction of carboxamides,
we focused on extending this methodology to the synthesis of
β-ACC sulfonamide derivatives via a formal substitution of
bromocyclopropanes with nucleophilic sulfonamide species.
Initial attempts to employ sulfonamide nucleophile 26ad under
the reaction conditions previously optimized for addition of
carboxamides resulted in recovery of bromocyclopropane 1a
(Scheme 9). We rationalized the lack of reactivity by increased
acidity of sulfonamides as compared to other nucleophiles, that
could decrease the effective concentration of the base in the
reaction mixture. This phenomenon was previously observed in
the reactions of relatively acidic pronucleophiles (such as
phenols and thiols), when overall basicity of the medium was
too low to achieve the base-assisted epimerization into
thermodynamically more stable trans products, calling for a
requisite additional treatment of crude product mixtures with a
stronger base. However, in the reaction with sulfonamides, the
basicity appears to be insufficient even for the initial
dehydrobromination step.
Accordingly, we increased the base load to 7.0 equiv in the
reaction of tosylamide 26ad and 1a to obtain the desired
product 27aad in excellent yield and high diastereoselectivity
(Scheme 9, Table 4, entry 1). Trans configuration of
sulfonamide 27aad was unambiguously assigned by X-ray
crystallography.32 Encouraged by the promising reactivity of
tosylamide 26ad, we set out to explore the efficacy of this
reaction as a function of electronic factors. Interestingly, in
contrast to carboxamides, which required activating electron-
withdrawing groups, sulfonamides bearing electron-donating p-
anisyl (26ed, Table 4, entry 2) and p-tolyl groups (26af, 26ad,
and 26ak, entries 3−5), as well as electron-neutral phenyl
(26fd) and β-naphthyl substituents (26gd) added smoothly,
affording the corresponding cyclopropylamine sulfonates in
high yield (Table 4, entries 6−8). Furthermore, mesylamides
26he, 26hf, and 26hh also reacted efficiently providing the
corresponding products 27ahe, 27ahf, and 27ahh in good to
excellent yield (Table 4, entries 9−11). Sulfonamides bearing
relatively weak inductively electron-withdrawing groups, such as
p-FC6H4 (26id, 26ik), p-ClC6H4 (26jd, 26jf), and p-BrC6H4
Scheme 9
E
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Table 4. Convergent Approach to Conformationally Constrained trans-Cyclopropyl Amino Acid Derivatives via the Formal
Substitution of Bromocyclopropanes with Nucleophilic Sulfonamides
a
b
R1, R2
1
R3, R4
26
27
yield,
%
dr
1
tBu, H
tBu, H
tBu, H
1a
1a
1a
1f
4-MeC6H4, n-Bu
4-MeOC6H4, n-Bu
4-MeC6H4, Bn
4-MeC6H4, n-Bu
4-MeC6H4, Furfuryl
Ph, n-Bu
26ad
26ed
26af
26ad
26ak
26fd
26gd
26gd
26he
26hf
26hh
26id
26id
26id
26ik
26jd
26jf
27aad
27aed
27aaf
27fad
27aak
27afd
27agd
27fgd
27ahe
27ahf
27ahh
27aid
27fid
90
95
75
89
84
73
78
94
90
83
67
96
97
71
93
94
72
91
16:1
11:1
11:1
15:1
25:1
10:1
10:1
25:1
9:1
2
3
4
c-Hex, H
tBu, H
tBu, H
5
1a
1a
1a
1f
6
7
tBu, H
β-C10H8, n-Bu
β-C10H8, n-Bu
Me, n-Hex
8
c-Hex, H
tBu, H
tBu, H
tBu, H
tBu, H
9
1a
1a
1a
1a
1f
10
11
12
13
14
15
16
17
18
Me, Bn
15:1
11:1
19:1
10:1
11:1
25:1
11:1
25:1
11:1
Me, c-Hex
4-FC6H4, n-Bu
4-FC6H4, n-Bu
4-FC6H4, n-Bu
4-FC6H4, Furfuryl
4-ClC6H4, n-Bu
4-ClC6H4, Bn
c-Hex, H
−(CH2)2O(CH2)−
tBu, H
tBu, H
tBu, H
1e
1a
1a
1a
1a
27eid
27aik
27ajd
27ajf
tBu, H
4-BrC6H4, n-Bu
26kd
27akd
a
b
1
Isolated yields. Diastereomeric ratio (trans:cis) determined by GC or H NMR analysis of crude reaction mixtures.
(26kd), also proved efficient in this reaction (Table 4, entries
12−18). At the same time, highly acidic 4-nitro- (26bd), 2-
nitro- (26cd), and 2,4-dinitrobenzenesulfonates (26dd) of n-
butylamine failed to react with 1a (Scheme 9). When the
amount of base was increased to 15 equiv, dehydrobromination
took place to give the cyclopropene intermediate; however, the
nucleophilicity of nosylates was still insufficient to produce
observable quantities of adducts. Reaction with TsNH2 did not
yield cyclopropylamine sulfonate, but led to complete cleavage
of the small cycle to afford aldehyde 21, apparently, via the
same mechanistic pathway realized in the case of carboxamides
(Scheme 7).
unsubstituted cyclopropenewhich undergoes rapid concur-
rent polymerization. Indeed, we have previously shown that
analogous transformation proceeding via a stable, isolable
cyclopropene 29h28,29 produced N-pyrrolyl cyclopropane 31ha
in good yield (Table 5, entry 1).25 Nucleophilic attack of
Table 5. Convergent Approach to Conformationally
Constrained cis-Cyclopropyl Amino Acid Derivatives via the
Formal Substitution of Bromocyclopropanes with
Nucleophilic Azoles: Mode A, Directed Addition of
Nucleophiles
Azoles as N-Based Nucleophiles. Efficient overlap of the
cyclopropane’s Walsh orbitals with the π-system of the adjacent
aromatic substituent endows cyclopropyl(het)arenes with
unique conformational features. It has been demonstrated
that arylcyclopropanes can efficiently mimic active conforma-
tions of the bis-aryl38 or benzylaryl moieties,39 producing
remarkable pharmacological effects. Successful employment of
cyclopropyl(het)arenes as bioisosteres is evidenced by a
growing number of aryl- and hetarylcyclopropanes with
impressive biological profiles, including antimalarial,40 anti-
cancer,41 anti-HIV,42 antidepressant,43 immunemodulatory,39
antibiotic,44 and analgesic45 activity. Assembly of hetarylcyclo-
propanes possessing a cyclopropyl−NHetAr bond is a challenging
task and thus far has been achieved only via Cu-catalyzed
coupling of azoles to cyclopropylboronic acids46 and cyclo-
propylbismuth reagents,47 and the reaction of magnesium
cyclopropylidene with N-lithioarylamines.48 The N−H bond
acidity of azoles (whose pKa fall in the same range as values for
carboxamides and sulfonamides) makes them good candidates
for the title reaction. The lack of success in previous attempts
on N-alkylation of azoles via the formal nucleophilic
substitution of bromocyclopropane by other groups21c,49 can
be attributed to the unstable, electron-rich intermediate
a
b
R1, R2 (28)
30
31
yield,
%
dr
1
2
3
4
5
6
−(CH2)4− (28h)
pyrrole
(30a)
31ha
85
54
45
61
41
67
14:1
−(CH2)2NMe(CH2)2−
(28i)
pyrrole
(30a)
31ia
9:1
−(CH2)2NMe(CH2)2−
(28i)
indole (30b) 31ib
10:1
19:1
11:1
3:1
−(CH2)2O(CH2)2−
(28e)
pyrrole
(30a)
31ea
−(CH2)2O(CH2)2−
indole (30b) 31eb
(28e)
tBu, H (28a)
pyrrole
(30a)
31aa
a
b
Isolated yields. Diastereomeric ratio (cis:trans) determined by GC
1
or H NMR analyses of crude reaction mixtures.
F
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pyrrole (30a) in this case was efficiently directed by the
carboxamide function affording predominantly cis diaster-
eomer. Likewise, trans products were obtained selectively,
albeit in slightly lower yields, in the reactions of pyrrole (30a)
or indole (30b) with tertiary cyclopropylamidesderivatives of
N-methylpiperazine (28i) and morpholine (28e) (Table 5,
entries 2−5). In contrast, cyclopropyl bromide 28a bearing a
secondary carboxamide moiety provided adduct 31aa with poor
diastereoselectivity (entry 6). This result was rather surprising
as we previously demonstrated that the secondary carboxamide
function served as superior directing group in reactions with O-
based nucleophiles.26
Table 6. Convergent Approach to Conformationally
Constrained trans-Cyclopropyl Amino Acid Derivatives via
the Formal Substitution of Bromocyclopropanes with
Nucleophilic Azoles: Mode B, Nucleophilic Addition
Followed by Thermodynamically Driven Base-Assisted
Epimerization
We have shown earlier that conjugation of the strained CC
bond with an electron-withdrawing functionality can enhance
the affinity of the cyclopropene intermediate toward soft
nucleophiles, such as phenoxides and thiolates.26 However, the
corresponding rather acidic pronucleophiles reduce the overall
basicity of the media leading, to inefficient epimerization at the
α-carbon and, consequently, lower diastereoselectivities. Along
these lines, 1,2-dehydrobromination of bromocyclopropane 1a
in the presence of pyrrole (30a) (mode B) afforded the
corresponding cyclopropyl pyrrole 32aa in high yield but poor
diastereomeric ratio (dr), which was addressed by our standard
postreaction treatment of a crude mixture with a stronger
base26 (Table 6, entry 1) to give a 98:2 trans selectivity with
perfect material balance (Table 6, entry 1). Likewise, reaction
of 1a with 2-cyanopyrrole (30c), followed by base-assisted
epimerization, afforded the corresponding trans adduct 32ac in
high yield and excellent diastereoselectivity (Table 6, entry 2).
Indoles reacted uneventfully, in spite of their susceptibility to
Friedel−Crafts alkylation, dimerization, and polymerization.50
As expected, skatole (30d), possessing a substituent at the
vulnerable C3 position, provided the best yield in the series
(entry 3−7). When imidazole 30g was used as a nucleophilic
component, we stumbled upon the isolation issue. Although the
corresponding adduct 32ag was produced in reasonable yield
(50% as judged by 1H NMR analysis of crude reaction
mixture), chromatographic purification of the product proved
inefficient due to its partial decomposition on silica gel (27%
isolated yield, entry 8). In contrast, reactions in the presence of
its fused analogues benzimidazoles 30h, 30i, and 30j proceeded
cleanly to afford the corresponding trans products in high yields
and excellent diastereoselectivities (entries 8−10). Similarly,
pyrazole (30k) was engaged in a very efficient transformation
with cyclopropyl bromides 1a and 1j, providing good yields of
N-cyclopropylpyrazoles 32ak and 32jk, respectively (entries 12
and 13). The trans configuration of the carboxamide and azole
substituents was unambiguously confirmed by X-ray analysis of
32jk.32 It should be mentioned that the scope of this reaction is
generally limited to poorly acidic azoles with pKa ∼ 16−23.
Nonetheless, a more acidic N-heterocycle benzotriazole (30l,
pKa 11.9) was also reactive, producing two regioisomers, 32al
and 33al resulting from two tautomeric forms51,52 (Scheme
10). Attempts on addition of tetrazoles 30m and 30n (pKa ∼
8.2) were unsuccessful (Scheme 10), which was expected for
such poor aza-Michael donors.53
a
R1, R2
crude
b
yield, % (dr
after upgrade)
b
(1)
heterocycle (30)
32
dr
1
2
3
4
5
6
7
8
9
tBu, H pyrrole (30a)
(1a)
tBu, H 2-cyanopyrrole (30c)
(1a)
tBu, H indole (30b)
(1a)
32aa
72:28
85:15
73:27
75:25
75:25
75:25
58:42
87:13
87:13
93:7
66 (98:2)
82 (95:5)
66 (97:3)
48 (97:3)
73 (99:1)
61 (97:3)
48 (97:3)
32ac
32ab
32jb
32ad
32ae
32af
32ag
32ah
32ai
32aj
Bn, H indole (30b)
(1j)
tBu, H 3-methyl-1H-indole
(30d)
(1a)
tBu, H 5-methoxy-1H-indole
(30e)
tBu, H 5-bromo-1H-indole
(30f)
(1a)
(1a)
c
tBu, H imidazole (30g)
(1a)
50 (100:0)
tBu, H 1H-benzo[d]imidazole
66 (100:1)
84 (95:5)
72 (97:3)
(30h)
(1a)
10 tBu, H 2-methyl-1H-benzo[d]
imidazole (30i)
11 tBu, H 5,6-dimethyl-1H-
(1a)
95:5
benzo[d]imidazole
(30j)
(1a)
12 tBu, H pyrazole (30k)
(1a)
32ak
32jk
86:14
85 (99:1)
73 (97:3)
13 Bn, H pyrazole (30k)
(1j)
88:12
a
b
Isolated yields, unless specified otherwise. Diastereomeric ratio
(trans:cis) determined by GC or H NMR analyses of crude reaction
1
c
mixtures. NMR yield.
Scheme 10
Anilines as N-Based Nucleophiles. The higher N−H
acidity of anilines as compared to alkylamines makes them
attractive N-based nucleophiles for the formal substitution
reaction. However, our initial test using anilines as nucleophiles
proved unsuccessful: reaction of N-methylaniline (35a) with 1a
produced aldehyde 21 as the only isolable compound.
Formation of the latter can be envisioned via a formal addition
G
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of water to cyclopropene 11a, followed by a base-assisted
cleavage of the intermediate cyclopropanol 34; yet product 21
was never observed in our reactions in the absence of the
secondary aniline, suggesting an alternative mechanism. We
believe the reaction begins with a base-assisted conjugate
addition of aniline species 35a across the CC bond of
cyclopropene 11a. The resulting donor−acceptor cyclopropane
36aa undergoes ring-opening to give the iminium intermediate
37aa, which upon base-assisted hydrolysis produces aldehyde
21 (Scheme 11). It should be emphasized that, mechanistically,
Table 7. Conformationally Constrained trans-Cyclopropyl
Amino Acid Derivatives via the Formal Substitution of
Bromocyclopropanes with Nucleophilic Anilines
a
b
R1, R2 (1)
tBu, H (1a)
R3, R4 (35)
36
yield,
%
dr
1
2
3
4
5
4-NO2C6H4, Me 36ab
(35b)
99
99
65
75
50
>25:1
>25:1
>25:1
>25:1
>25:1
tBu, H (1a)
tBu, H (1a)
4-NCC6H4, Bn
(35c)
36ac
36ad
36ee
36af
Scheme 11
4-CF3C6H4, Bn
(35d)
−(CH2)2O(CH2)2− 4-NO2C6H4, Bn
(1e)
(35e)
tBu, H (1a)
3-NO2C6H4, Bn
(35f)
6
7
tBu, H (1a)
tBu, H (1a)
Ph, Ph (35g)
36ag
36ah
96
59
>25:1
>25:1
10H-
phenothiazine
(35h)
a
b
Isolated yields. Diastereomeric ratio (trans:cis) determined by GC
1
or H NMR analysis of crude reaction mixtures.
dehydrobromination followed by addition of a nucleophilic
N-moiety across the strained CC bond of a cyclopropene
intermediate. Strong influence of steric and electronic factors
on the efficiency of the formal substitution reaction has been
demonstrated. A range of N-based pronucleophiles, including
secondary carboxamides and sulfonamides, azoles, and anilines,
have been successfully employed in the featured transformation.
The trans selectivity of the addition is controlled by a
thermodynamically driven base assisted epimerization, while
cis selectivity is governed by a directed effect of the functional
group. This methodology addresses some of the long-standing
challenges in synthesis of DAC and β-ACC derivatives through
the synergism of strain release-powered thermodynamics and
chelation-enforced selectivity. The diastereoconvergent ap-
proach allows for efficient installation of N-substituents in the
last step, making the described method very attractive for the
diversity oriented synthesis.
this ring-opening process is related to the small cycle cleavage
observed in the attempted additions of primary carboxamides
and sulfonamides discussed above (Scheme 7). The propensity
of the donor−acceptor cyclopropane toward ring-opening
depends on the extent of polarization of the C−C bond
between the electron-donating (EDG) and electron-with-
drawing groups (EWG). Polarization is commonly achieved
through installation of strong EWGs, typically two ester
functions, additionally activated by a Lewis acid (“pull”
strategy).2 In our case polarization is realized through
installation of an EDG with increased electron density, such
as anionic N-moiety or a neutral N-group bearing an electron-
donating substituents (“push” strategy).54
Accordingly, the aptitude toward small ring cleavage was
significantly reduced in cyclopropylanilines possessing electron-
deficient nitrogen. Thus, reaction of p-nitroaniline 35b with 1a
in the presence of tBuOK and 18-crown-6 proceeded smoothly
providing a single diastereomer of cyclopropylaniline 36ab in
nearly quantitative yield (Table 7). Several other electron-
deficient N-benzyl protected anilines, possessing cyano- (35c),
trifluoromethyl- (35d), and nitro- (35e) groups in para
positions, reacted in a similar manner, affording the
corresponding aminocyclopropanes 36ac, 36ad, and 36ee in
good to excellent yields. m-Nitroaniline 35f possessing a less
electron-deficient nitrogen atom provided the corresponding
adduct 36af in lower yield (entry 5). Regardless of the yield, the
diastereoselectivity of addition was perfect in all these examples
(Table 7). It should be also mentioned that diphenylamine
(35g) and 10H-phenothiazine (35h) did not require electron-
withdrawing substituents to furnish trans-diastereomers of the
corresponding cyclopropylamine derivatives 36ag and 36ah
(Table 7, entries 6 and 7).
EXPERIMENTAL SECTION
■
General Information. NMR spectra were recorded on a 400 MHz
instrument, equipped with a quadruple-band gradient probe (H/C/P/
F QNP) or a 500 MHz instrument with a dual carbon/proton
cryoprobe (CPDUL). 13C NMR spectra were registered with broad-
band decoupling. The (+) and (−) designations represent positive and
negative intensities of signals in 13C DEPT-135 experiments. GC/MS
analyses were performed using a 30 m × 0.25 mm × 0.25 μm capillary
column (polydimethylsiloxane, 5% Ph). Helium (99.96%), additionally
purified by passing consecutively through an oxygen/moisture/
hydrocarbon trap and an oxygen/moisture trap, was used as a carrier
gas. High resolution mass spectra were obtained using electrospray
ionization and time-of-flight detection techniques. Glassware em-
ployed in moisture-free syntheses was flame-dried in vacuum prior to
use. Water was purified by dual stage deionization, followed by dual
stage reverse osmosis. Anhydrous THF was obtained by passing
degassed commercially available HPLC-grade inhibitor-free solvent
consecutively through two columns filled with activated alumina.
Anhydrous triethylamine was obtained by distillation of ACS-grade
commercially available materials over calcium hydride in a nitrogen
atmosphere. All other commercially available reagents were used as
received. Bromocyclopropanes 1a−g,16 1j17 4a,30 28a,25 28e,28 28h,25
and 28i28 were prepared according to the previously published
procedures. Preparative procedures and characterization data for
CONCLUSIONS
■
An efficient diastereoselective synthesis of β-aminocyclopro-
pylcarboxylic acid derivatives via the formal nucleophilic
substitution of bromocyclopropanes with N-based nucleophiles
has been developed. This transformation proceeds via
H
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carboxamide adducts 15aaa25 (16aaa, 16abd, 16abc, 16acd, 16afa,
16afd, 16agd, 16ahd, 16aid, 16ajd, 16akd, 16ald, 16amd, 16ale,
16alf, 16alg, 16alh, 16amh, 16amc, 16ami, 16amg, 16dmg, 16emg,
16fmh, 16dmf, 16gmf)16 and azole adducts 31ha25 (32aa, 32ac, 32ab,
32jb, 32ad, 32ae, 32ag, 32ah, 32ai, 32aj, 32ak, 32jk, 32al, 32al)17 are
described in the Supporting Information files of the corresponding
preliminary communications. Synthesis, physical properties, and
spectral data of all new compounds obtained in the frame of these
studies are described below. Accurate assignment of the product
286.0872, calculated for C14H17NO2SNa (M + Na) 286.0878 (2.1
ppm).
4-Fluoro-N-(furan-2-ylmethyl)benzenesulfonamide (26ik). Com-
pound was prepared by adding furfural amine (1.3 g, 13 mmol) to a
stirred solution of 4-fluorobenzenesulfonyl chloride (1.0 g, 5.3 mmol)
in dry CH2Cl2 (25 mL). The mixture was stirred for 2 h and then
worked up as described above in the protocol for preparation of
compound 26gd. Yield: 1.01 g (4.3 mmol, 81%), colorless solid, mp
1
92−93 °C. H NMR (400 MHz, CDCl3): δ 7.84 (dd, J = 8.9, 5.0 Hz,
3
configuration by 1H NMR based on the analysis of JHH coupling
2H), 7.23 (dd, J = 1.8, 0.9 Hz, 1H), 7.16 (t, J = 8.6 Hz, 2H), 6.23 (dd,
J = 3.2, 1.9 Hz, 1H), 6.11−6.09 (m, 1H), 4.98 (s, 1H), 4.23 (d, J = 6.0
Hz, 2H). 13C NMR (101 MHz, Chloroform-d): δ 169.3, 165.3 (d, J =
255.3 Hz), 133.5, 130.2 (d, J = 9.1 Hz, 2C), 116.5 (d, J = 22.5 Hz, 2C),
67.1, 67.0, 46.2, 42.6, 38.6, 30.2, 21.4, 20.1, 15.0, 13.7. 19F NMR (376
MHz, chloroform-d): δ −104.67 to −104.78 (m). Ir (salt plate): 3331,
3087, 2962, 2872, 1645, 1585, 1547, 1475, 1454, 1392, 1294, 1225,
1205, 1167, 1094. HRMS: found 255.0363, calculated for
C11H10FNO3S (M+) 255.0365, (0.7 ppm).
constants of the cyclopropyl proton signals was impeded by severe
broadening of the corresponding resonance lines. Careful optimization
of the sample temperature provided acceptable resolution for
measuring the coupling constants in 16aba in DMSO-d6. Trans
configurations of products 16emg, 27aad, and 32jk were unambig-
uously assigned by X-ray crystallography. Cis configuration of
compound 31aa was assigned based on 1D NOE experiments.
These data were used to assign the structures of all other products by
analogy.
Adducts Resulting from Nucleophilic Attack by Carbox-
amides. N-Benzyl-N-((1R*,2R*)-2-(tert-butylcarbamoyl)-
cyclopropyl)-4-nitrobenzamide (16akf). Typical Procedure I. An
oven-dried 10 mL Wheaton vial was charged with 2-bromo-N-(tert-
butyl)cyclopropanecarboxamide 1a (110 mg, 0.5 mmol, 1.0 equiv), 18-
crown-6 (13.2 mg, 0.05 mmol, 10 mol %), KOH (98 mg, 1.75 mmol,
3.5 equiv), N-benzyl-4-nitrobenzamide (14kf)55 (256 mg, 1.0 mmol,
2.0 equiv), and anhydrous THF (5 mL). The mixture was stirred at 85
°C for 12 h, then the reaction mixture was filtered into a 100 mL
round-bottom flask, and both the reaction vessel and filter were rinsed
consecutively with DCM (15 mL) and EtOAc (15 mL), which were
combined with filtrate. The product was isolated by column
chromatography in 24:1 DCM:MeOH as a white solid (Rf 0.17, mp
Preparation of Starting Materials. 4-Nitro-N-(thiophen-2-
ylmethyl)benzamide (14kj). To a stirred solution of 4-nitrobenzoyl
chloride (930 mg, 5.0 mmol) in dry CH2Cl2 (50.0 mL) was added a
solution of 2-thiophenemethylamine (850 mg, 7.5 mmol) and
triethylamine (510 mg, 5.0 mmol) in dry CH2Cl2 (8 mL). The
mixture was stirred for 2 h at room temperature and then quenched
with 10% aqueous HCl (20 mL). The organic phase was separated,
washed consecutively with 10% NaOH and brine, then dried with
MgSO4, and concentrated to provide the title compound as yellowish
solid (mp 147−149 °C) pure enough to use at the following step
1
without additional purification. Yield: 1.06 g (4.05 mmol, 81%). H
NMR (400.13 MHz, CDCl3): δ 8.29 (d, J = 8.8 Hz, 2H), 7.96 (d, J =
8.8 Hz, 2H), 7.35−7.24 (m, 1H), 7.08 (dd, J = 3.3, 1.2 Hz, 1H), 7.00
(dd, J = 5.1, 3.5 Hz, 1H), 6.69 (s, 1H), 4.85 (dd, J = 5.7, 0.8 Hz, 2H).
13C NMR (100.67 MHz, CDCl3): δ 165.2, 149.7, 139.8, 139.7, 128.3
(+, 2C), 127.1 (+), 126.7 (+), 125.8 (+), 123.9 (+, 2C), 39.1 (−).
FTIR (NaCl, cm−1): 3311, 3097, 3068, 1643, 1596, 1547, 1487, 1425,
1346, 1296, 1251, 1224, 1012, 870, 709 cm−1. HRMS (TOF ES):
found 269.0569, calculated for C12H10N2O3SLi (M + Li) 269.0572
(1.1 ppm).
1
146−150 °C). Yield: 124.0 mg (0.32 mmol, 63%). H NMR (500.13
MHz, CD3OD): δ ppm 8.37−8.23 (m, 2H), 7.75−7.64 (m, 2H), 7.39
(d, J = 5.6 Hz, 4H), 7.32 (d, J = 4.3 Hz, 1H), 7.19 (s, 1H), 4.90 (d, J =
14.6 Hz, 1H), 4.67 (d, J = 14.6 Hz, 1H), 3.01−2.86 (m, 1H), 1.33 (d, J
= 4.1 Hz, 2H), 1.10 (s, 10H). 13C NMR (125.76 MHz, CD3OD): δ
ppm 171.3, 169.7, 148.4, 143.0, 137.0, 128. Six (+, 2C), 128.4 (+)
127.9 (+), 127.7 (+), 127.4 (+), 123.6 (+), 50.5, 49.7 (−), 38.0 (+),
27.5 (+, 3C), 26.9 (+), 15.4 (−). FTIR (NaCl, cm−1): 3336, 2968,
2931, 1643, 1523, 1454, 1396, 1348, 1267, 1155, 846, 702. HRMS
(TOF ES): found 394.1763, calculated for C22H24N3O4 (M − H)
394.1767 (1.0 ppm).
4-Cyano-N-(furan-2-ylmethyl)benzamide (14jk). Compound was
prepared by adding furfurylamine (850 mg, 8.8 mmol) to a stirred
solution of 4-cyanobenzoyl chloride (580 mg, 3.5 mmol) in dry DCM
(15 mL). The mixture was stirred for 2 h at room temperature and
then worked up as described above for the synthesis of 14kj. Yield:
N-Benzyl-N-((1R*,2R*)-2-(tert-butylcarbamoyl)cyclopropyl)-4-cy-
anobenzamide (16ajf). This compound was synthesized according to
typical procedure
I employing 2-bromo-N-(tert-butyl)-
1
975 mg (4.3 mmol, 49%), colorless solid, mp 150−151 °C. H NMR
cyclopropanecarboxamide (1a) (110 mg, 0.5 mmol), N-benzyl-4-
cyanobenzamide (14jf)56 (236 mg, 1.0 mmol), 18-crown-6 (13.2 mg,
0.05 mmol), and KOH (56 mg, 1.75 mmol). The product was isolated
by column chromatography (eluting with a ternary mixture hexanes/
acetone/DCM 3:1:1) as a tan solid (Rf 0.37, mp 79−82 °C). Yield:
(500.13 MHz, CDCl3): δ 7.91 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz,
2H), 7.40 (s, 1H), 6.64 (br, 1H), 6.37 (dd, J = 3.2, 1.9 Hz, 1H), 6.33
(d, J = 3.4 Hz, 1H), 4.66 (d, J = 5.6 Hz, 2H). 13C NMR (125.76 MHz,
CDCl3): δ 165.5, 150.5, 142.6 (+), 138.1, 132.5 (+, 2C), 127.8 (+,
2C), 118.0, 115.3, 110.6 (+), 108.1 (+), 37.21 (−). FTIR (NaCl,
cm−1): 3292, 3089, 2995, 2972, 1639, 1608, 1546, 1499, 1418, 1350,
1301, 1143, 1072, 1023, 883, 729 cm−1. HRMS (TOF ES): found
249.0637, calculated for C13H10N2O2Li (M + Li) 249.0640 (1.2 ppm).
N-Butylnaphthalene-2-sulfonamide (26gd). Compound was
prepared by adding N-butylamine (804 mg, 11 mmol) to a stirred
solution of 2-naphthylenesulfonyl chloride (1.00 g, 4.41 mmol) in dry
CH2Cl2 (40 mL). The mixture was stirred for 2 h followed by quench
with 10% aqueous HCl. The organic phase was washed consecutively
with 10% NaOH and brine, dried with MgSO4, and concentrated to
provide the title compound as white crystalline solid, mp 54−58 °C.
1
177.0 mg (0.24 mmol, 47%). H NMR (400.13 MHz, CD3OD): δ
ppm 7.85−7.79 (m, 2H), 7.66−7.59 (m, 2H), 7.39 (d, J = 4.5 Hz, 3H),
7.32 (q, J = 4.2 Hz, 1H), 7.26 (s, 1H), 4.88 (d, J = 14.6 Hz, 1H), 4.67
(d, J = 14.6 Hz, 1H), 2.91 (ddd, J = 7.4, 4.2, 4.2 Hz, 1H), 1.62 (m, J =
8.5 Hz, 1H), 1.37−1.30 (m, 1H), 1.18 (s, 9H), 1.02 (m, 1H). 13C
NMR (125.76 MHz, CD3OD): δ ppm 171.5, 169.7, 141.2, 137.0,
132.3 (+), 128.5 (+), 128.5 (+), 127.7 (+), 127.5 (+), 127.4 (+),
117.8, 113.3, 50.5, 49.7 (−), 37.9 (+), 27.5 (+, 3C), 26.7 (+), 15.4 (−).
FTIR (NaCl, cm−1): 3339, 2966, 2929, 2230, 1643, 1544, 1497, 1396,
1336, 1267, 1153, 849, 734. HRMS (TOF ES): found 374.1867,
calculated for C23H24N3O2 (M − H) 374.1869 (0.5 ppm).
N-((1R*,2R*)-2-(tert-Butylcarbamoyl)cyclopropyl)-4-nitro-N-(thi-
ophen-2-ylmethyl)benzamide (16akj). This compound was synthe-
sized according to typical procedure I employing 2-bromo-N-(tert-
butyl)cyclopropanecarboxamide (1a) (110 mg, 0.50 mmol), 4-nitro-N-
(thiophen-2-ylmethyl)benzamide (14kj) (262 mg, 1.00 mmol), 18-
crown-6 (13.2 mg, 0.05 mmol), and KOH (56 mg, 1.75 mmol). The
product was isolated by column chromatography eluting with a
DCM:MeOH mixture (24:1) as a yellow solid (Rf 0.27, mp 150−152
°C). Yield: 104 mg (0.26 mmol, 52%). 1H NMR (500.13 MHz,
1
Yield: 1.06 g (4.01 mmol, 91%). H NMR (400.13 MHz, CDCl3): δ
8.47 (s, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.94 (d, J = 7.7 Hz, 1H), 7.88
(d, J = 8.6 Hz, 1H), 7.70−7.60 (m, 2H), 4.71 (s, 1H) 3.00 (q, J = 6.9
Hz, 2H), 1.47 (p, J = 7.1 Hz, 2H), 1.30 (h, J = 14.3, 7.3 Hz, 2H), 0.85
(t, J = 7.3 Hz, 3H). 13C NMR (100.67 MHz, CDCl3): δ 136.7, 134.8,
132.2, 129.5 (+), 129.2 (+), 128.8 (+), 128.5 (+), 127.9 (+), 127.6
(+), 122.4 (+), 43.0 (−), 31.6 (−), 19.7 (−), 13.5 (+). FTIR (NaCl,
cm−1): 3273, 3053, 2958, 2931, 1587, 1502, 1464, 1427, 1348, 1317,
1244, 1130, 1078, 953, 825, 744, 642 cm−1. HRMS (TOF ES): found
I
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The Journal of Organic Chemistry
Article
CD3OD): δ ppm 8.31 (dd, J = 8.9, 2.2 Hz, 2H), 7.66 (dd, J = 9.0, 2.3
Hz, 2H), 7.39 (d, J = 4.8 Hz, 1H), 7.21 (s, 1H), 7.13 (s, 1H), 7.01 (dd,
J = 5.2, 3.3 Hz, 1H), 5.08 (d, J = 15.0 Hz, 1H), 4.86−4.79 (d, J = 15.0,
1H), 3.04−2.97 (m, 1H), 1.68−1.53 (m, 1H), 1.34 (s, 1H), 1.12 (s,
9H). 13C NMR (125.76 MHz, CD3OD): δ ppm 171.0, 169.7, 148.5,
142.8, 139.3, 127.8 (+, 2C), 126.8 (+), 126.5 (+), 125.5 (+), 123.6 (+,
2C), 50.4, 44.7 (−), 37.8 (+), 27.5 (+, 3C), 27.0 (+), 15.3 (−). FTIR
(NaCl, cm−1): 3348, 2968, 2930, 1637, 1524, 1439, 1418, 1346, 1261,
856, 717. HRMS (TOF ES): found 401.1411, calculated for
C22H24N3O4 (M+) 401.1409 (0.5 ppm).
9.8, 6.0 Hz, 1H), 3.00 (ddd, J = 13.6, 9.8, 5.7 Hz, 1H), 2.43 (s, 3H),
2.13 (ddd, J = 7.4, 4.6, 2.8 Hz, 1H), 1.99 (ddd, J = 9.1, 6.3, 2.8 Hz,
1H), 1.43−1.58 (m, 2H), 1.41 (s, 9H), 1.22−1.33 (m, 3H), 1.16 (dt, J
= 9.2, 4.7 Hz, 1H), 0.89 (t, J = 7.3 Hz, 3H). 13C NMR (125.76 MHz,
CDCl3): δ ppm 169.5, 143.7, 134.3, 129.6 (+, 2C), 127.6 (+, 2C),
51.5, 51.1 (−), 37.4 (+), 30.3 (−), 28.9 (+, 3C), 25.8 (+), 21.5 (+),
20.1 (−), 13.7 (+), 13.1 (−). FT IR (KBr, cm−1): 3334, 2962, 2931,
1647, 1545, 1456, 1205, 1045, 816. HRMS (TOF ES): found
366.1980, calculated for C19H30N2O3S (M+) 366.1977 (0.8 ppm).
( 1 R * , 2 R * ) - N - ( t e r t - B u t y l ) - 2 - ( N - b u t y l - 4 -
methoxyphenylsulfonamido)cyclopropanecarboxamide (27aed).
The reaction was performed according to typical procedure II,
employing bromocyclopropane 1a (35 mg, 0.16 mmol, 1.2 equiv), 18-
crown-6 (3.5 mg, 0.013 mmol, 10 mol %), KOH (52 mg, 0.93 mmol,
7.0 equiv), and N-butyl-p-methoxybenzenesulfonamide (26ed)58 (32
mg, 0.133 mmol, 1.0 equiv). Column chromatography on silica gel
afforded the title compound as a white solid (diastereomeric mixture
11:1), mp 97−100 °C, Rf 0.18 (eluent hexane/EtOAc 3:1). Yield: 51
mg (0.126 mmol, 95%). 1H NMR (400.13 MHz, CDCl3): δ ppm 7.72
(m, 2H), 6.97 (m, J = 8.8 Hz, 2H), 5.85 (s, 1H), 3.87 (s, 3H), 3.19
(ddd, J = 13.6, 9.6, 6.1 Hz, 1H), 3.00 (ddd, J = 13.9, 9.6, 5.6 Hz, 1H),
2.13 (ddd, J = 7.4, 4.5, 2.8 Hz, 1H), 1.98 (ddd, J = 9.1, 6.2, 2.9 Hz,
1H), 1.43−1.58 (m, 2H), 1.41 (s, 9H), 1.23−1.32 (m, 3H), 1.17 (dt, J
= 9.0, 4.7 Hz, 1H), 0.89 (t, J = 7.3 Hz, 3H). 13C NMR (100.67 MHz,
CDCl3): δ ppm 169.6, 163.0, 129.6 (+, 2C), 128.7, 114.1 (+, 2C), 55.5
(+), 51.4, 51.0 (−), 37.3 (+), 30.1 (−), 28.8 (+, 3C), 25.6 (+), 20.0
(−), 13.6 (+), 13.2 (−). FT IR (KBr, cm−1): 3325, 2962, 2934, 2872,
1653, 1541, 1443, 1259, 1092, 835. HRMS (TOF ES): found
405.1834, calculated for C19H30N2O4SNa (M + Na) 405.1824 (2.5
ppm).
(1R*,2R*)-2-(N-Benzyl-4-methylphenylsulfonamido)-N-(tert-
butyl)cyclopropanecarboxamide (27aaf). The reaction was per-
formed according to typical procedure II, employing bromocyclopro-
pane 1a (35 mg, 0.16 mmol, 1.2 equiv), 18-crown-6 (3.5 mg, 0.013
mmol, 10 mol %), KOH (52 mg, 0.93 mmol, 7.0 equiv), and N-benzyl-
4-methylbenzenesulfonamide (26af)59 (35 mg, 0.133 mmol, 1.0
equiv). Column chromatography on silica gel afforded the title
compound as a yellow oil (diastereomeric mixture 11:1), Rf 0.65
(eluent hexane/EtOAc 3:1). Yield: 40 mg (0.10 mmol, 75%). 1H
NMR (500.13 MHz, CDCl3): δ ppm 7.71 (d, J = 8.2 Hz, 2H), 7.33 (d,
J = 8.2 Hz, 2H), 7.34−7.36 (m, 5H), 5.16 (s, 1H), 4.42 (d, J = 13.9
Hz, 1H), 4.04 (d, J = 13.6 Hz, 1H), 2.45 (s, 3H), 2.09 (ddd, J = 7.4,
4.6, 2.8 Hz, 1H), 1.32−1.37 (m, 1H), 1.30 (s, 9H), 1.08−1.19 (m,
2H). 13C NMR (125.76 MHz, CDCl3): δ ppm 169.5, 143.9, 136.7,
133.8, 129.8 (+, 2C), 129.1 (+, 2C), 128.5 (+, 2C), 127.8 (+), 127.7
(+, 2C), 55.4 (−), 51.3, 38.0 (+), 28.8 (+, 3C), 25.1 (+), 21.5 (+),
13.5 (−). FT IR (KBr, cm−1): 3334, 2966, 1651, 1599, 1537, 1456,
1256, 1028, 849. HRMS (TOF ES): found 423.1717, calculated for
C22H28N2O3SNa (M + Na) 423.1718 (0.2 ppm).
N-((1R*,2R*)-2-(tert-Butylcarbamoyl)cyclopropyl)-4-cyano-N-
(furan-2-ylmethyl)benzamide (16ajk). This compound was synthe-
sized according to typical procedure I employing 2-bromo-N-(tert-
butyl)cyclopropanecarboxamide (1a) (110 mg, 0.5 mmol), 4-cyano-N-
(furan-2-ylmethyl)benzamide (14jk) (226 mg, 1.0 mmol), 18-crown-6
(13.2 mg, 0.05 mmol), and KOH (56 mg, 1.75 mmol). The product
was isolated by column chromatography on silica gel eluting with
ternary mixture hexane/DCM/acetone 3:1:1 as a yellow solid, mp
1
126−130 °C, Rf 0.17. Yield: 149 mg (0.41 mmol, 81%). H NMR
(500.13 MHz, CD3OD): δ ppm 7.82 (s, 2H), 7.62 (d, J = 8.3 Hz, 2H),
7.52 (s, 1H), 7.21 (s, 1H), 6.42 (s, 2H), 4.87 (d, J = 12.8 Hz, 1H), 4.66
(d, J = 14.2 Hz, 1H), 2.99 (s, 1H), 1.60 (s, 1H), 1.22 (s, 9H), 1.11 (s,
2H). 13C NMR (125.76 MHz, CD3OD): δ ppm 171.4, 169.7, 150.3,
142.5, 141.0 (+), 132.3 (+, 2C), 127.6 (+), 117.8, 113.3, 110.2 (+),
108.5 (+), 50.5, 42.7 (−), 37.9 (+), 27.6 (+, 3S), 26.8 (+), 15.5 (−).
FTIR (NaCl, cm−1): 3325, 2966, 2925, 2331, 1645, 1524, 1456, 1396,
1346, 1261, 1178, 862, 700. HRMS (TOF ES): found 365.1740,
calculated for C21H23N3O3 (M+) 365.1739 (0.3 ppm).
Adducts Resulting from Nucleophilic Attack by Sulfona-
m i d e s . ( 1 R * , 2 R * ) - N - ( t e r t - B u t y l ) - 2 - ( N - b u t y l - 4 -
fluorophenylsulfonamido)cyclopropanecarboxamide (27aid). Typ-
ical Procedure II. An oven-dried 10 mL Wheaton vial was charged
with bromocyclopropane 1a (44 mg, 0.20 mmol, 1.5 equiv), 18-crown-
6 (3.5 mg, 13 μmol, 10 mol %), KOH (52 mg, 0.93 mmol, 7.0 equiv),
N-butyl-4-fluorobenzenesulfonamide (26id)36b (31 mg, 0.13 mmol,
1.0 equiv), and anhydrous THF (8 mL). The mixture was stirred at 85
°C for 12 h and then filtered through a sintered funnel into a 100 mL
round-bottom flask. Both the reaction vessel and the filter were rinsed
consecutively with EtOAc (15 mL), which was combined with filtrate.
silica gel (2.0 g) was added to a filtrate, and then the solvent was
removed by rotary evaporation. The residue absorbed onto silica gel
was loaded on the top of the column packed with silica gel, which was
eluted with hexane/EtOAc 3:1 to afford two fractions. The major
fraction (Rf = 0.30) contained the title product as a colorless solid, mp
112−113 °C. Yield: 47 mg (96%, 0.127 mmol). A second fraction (Rf
1
= 0.07) contained minute amounts of (1R*,2S*)-isomer. H NMR
(400.13 MHz, CDCl3): δ ppm 7.76−7.83 (m, 2H), 7.19 (t, J = 8.5 Hz,
2H), 5.87 (s, 1H), 3.19 (ddd, J = 13.6, 9.6, 6.1 Hz, 1H), 3.02 (ddd, J =
13.6, 9.6, 5.6 Hz, 1H), 2.15 (ddd, J = 7.3, 4.3, 2.9 Hz, 1H), 1.99 (ddd, J
= 9.2, 6.3, 2.8 Hz, 1H), 1.47−1.57 (m, 2H), 1.39 (s, 9H), 1.23−1.32
(m, 3H), 1.19 (dt, J = 9.3, 4.9 Hz, 1H), 0.89 (t, J = 7.3 Hz, 3H). 13C
NMR (100.67 MHz, CDCl3): δ ppm 169.4, 165.2 (d, J = 255.4 Hz),
133.3 (d, J = 2.9 Hz), 130.3 (+, d, J = 9.5 Hz, 2C), 116.4 (+, d, J = 22.7
Hz, 2C), 51.5, 51.1 (−), 37.3 (+), 30.1 (−), 28.8 (+, 3C), 25.7 (+),
20.0 (−), 13.7 (+), 13.4 (−). 19F NMR (376.31 MHz, CDCl3): δ ppm
−104.81 (tt, J = 8.1, 5.7 Hz, 1 F). FT IR (KBr, cm−1): 3325, 2964,
2934, 2874, 1651, 1593, 1493, 1456, 1229, 839. HRMS (TOF ES):
found 393.1621, calculated for C18H27N2O3SFNa (M + Na) 393.1624
(0.8 ppm).
(1R*,2R*)-2-(N-Butyl-4-methylphenylsulfonamido)-N-cyclohexyl-
cyclopropanecarboxamide (27fad). The reaction was performed
according to typical procedure II, employing bromocyclopropane 1f
(39 mg, 0.16 mmol, 1.2 equiv), 18-crown-6 (3.5 mg, 0.013 mmol, 10
mol %), KOH (52 mg, 0.93 mmol, 7.0 equiv), and N-butyl-4-
methylbenzenesulfonamide (26ad)57 (30 mg, 0.133 mmol, 1.0 equiv).
Column chromatography on silica gel afforded the title compound as a
white solid (diastereomeric mixture 15:1), mp 118−120 °C, Rf 0.24
1
(eluent hexane/EtOAc 3:1). Yield: 46 mg (0.118 mmol, 89%). H
NMR (400.13 MHz, CDCl3): δ ppm 7.66 (d, J = 8.1 Hz, 2H), 7.30 (d,
J = 8.3 Hz, 2H), 5.89 (d, J = 8.1 Hz, 1H), 3.74−3.86 (m, 1H), 3.20
(ddd, J = 13.9, 9.9, 6.1 Hz, 1H), 3.01 (ddd, J = 13.9, 9.9, 5.6 Hz, 1H),
2.43 (s, 3H), 2.17 (ddd, J = 7.2, 4.0, 2.9 Hz, 1H), 1.95−2.06 (m, 2H),
1.91 (d, J = 12.4 Hz, 1H), 1.68−1.81 (m, 2H), 1.60−1.66 (m, 1H),
1.51−1.57 (m, 1H), 1.31−1.49 (m, 4H), 1.16−1.30 (m, 6H), 0.89 (t, J
= 7.3 Hz, 3H). 13C NMR (100.67 MHz, CDCl3): δ ppm 169.3, 143.7,
134.2, 129.7 (+, 2C), 127.6 (+, 2C), 51.1 (−), 48.5 (+), 37.5 (+), 33.4
(−), 33.0 (−), 30.2 (−), 25.5 (−), 25.2 (+), 24.9 (−, 2C), 21.5 (+),
20.0 (−), 13.7 (+), 13.4 (−). FT IR (KBr, cm−1): 3296, 2932, 2854,
1639, 1599, 1548, 1450, 1346, 1165, 1090, 816. HRMS (TOF ES):
(1R*,2R*)-N-(tert-Butyl)-2-(N-butyl-4-methylphenylsulfonamido)-
cyclopropanecarboxamide (27aad). The reaction was performed
according to typical procedure II, employing bromocyclopropane 1a
(176 mg, 0.8 mmol, 1.2 equiv), 18-crown-6 (18 mg, 0.067 mmol, 10
mol %), KOH (263 mg, 4.7 mmol, 7.0 equiv), and N-butyl-4-
methylbenzenesulfonamide (26ad)57 (151.4 mg, 0.67 mmol, 1.0
equiv). Column chromatography on silica gel afforded the title
compound as a white solid (diastereomeric mixture 16:1), mp 115−
117 °C Rf 0.26 (eluent hexane/EtOAc 3:1). Yield: 216 mg (0.60
mmol, 90%). 1H NMR (500.13 MHz, CDCl3): δ ppm 7.67 (m, J = 8.5
Hz, 2H), 7.30 (m, J = 8.2 Hz, 2H), 5.83 (s, 1H), 3.20 (ddd, J = 13.9,
J
dx.doi.org/10.1021/jo4011798 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
found 392.2143, calculated for C21H32N2O3S (M+) 392.2134 (2.3
ppm).
Column chromatography on silica gel afforded the title compound as a
white solid (diastereomeric mixture 11:1), mp 110−113 °C, Rf = 0.41
1
(1R*,2R*)-N-(tert-Butyl)-2-(N-(furan-2-ylmethyl)-4-
methylphenylsulfonamido)cyclopropanecarboxamide (27aak).
The reaction was performed according to typical procedure II,
employing bromocyclopropane 1a (35 mg, 0.16 mmol, 1.2 equiv), 18-
crown-6 (3.5 mg, 0.013 mmol, 10 mol %), KOH (52 mg, 0.93 mmol,
7.0 equiv), and 4-methyl-N-(furan-2-ylmethyl)benzenesulfonamide
(26ak)60 (33 mg, 0.133 mmol, 1.0 equiv). Column chromatography
on silica gel afforded the title compound as a white solid
(diastereomeric mixture 25:1), mp 108−110 °C, Rf 0.20 (eluent
hexane/EtOAc 3:1). Yield: 43 mg (0.112 mmol, 84%). 1H NMR
(400.13 MHz, CDCl3): δ ppm 7.64 (d, J = 8.3 Hz, 2H), 7.26−7.30 (m,
3H), 6.28 (dd, J = 3.2, 1.9 Hz, 1H), 6.20 (d, J = 3.3 Hz, 1H), 5.62 (s,
1H), 4.46 (d, J = 14.9 Hz, 1H), 4.19 (d, J = 15.2 Hz, 1H), 2.42 (s, 3H),
2.17 (ddd, J = 7.3, 4.6, 2.8 Hz, 1H), 1.68 (ddd, J = 9.1, 6.3, 2.8 Hz,
1H), 1.37 (s, 9H), 1.25−1.30 (m, 1H), 1.16 (ddd, J = 9.3, 4.8 Hz, 1H).
13C NMR (100.67 MHz, CDCl3): δ ppm 169.5, 149.3, 143.8, 142.4
(eluent hexane/EtOAc 2:1). Yield: 53 mg (0.125 mmol, 94%). H
NMR (400.13 MHz, CDCl3): δ ppm 8.33−8.40 (m, 1H), 7.90−8.00
(m, 3H), 7.78 (dd, J = 8.7, 1.9 Hz, 1H), 7.60−7.70 (m, 2H), 5.93 (d, J
= 8.1 Hz, 1H), 3.77−3.89 (m, 1H), 3.27 (ddd, J = 13.7, 9.8, 6.1 Hz,
1H), 3.12 (ddd, J = 13.8, 9.7, 5.6 Hz, 1H), 2.33 (ddd, J = 7.3, 4.5, 2.8
Hz, 1H), 2.06 (tt, J = 6.1, 3.0 Hz, 2H), 1.89−1.97 (m, 1H), 1.70−1.84
(m, 2H), 1.53−1.68 (m, 2H), 1.36−1.51 (m, 4H), 1.18−1.34 (m, 6H),
0.89 (t, J = 7.3 Hz, 3H). 13C NMR (100.67 MHz, CDCl3): δ ppm
169.3, 134.8, 134.4, 132.1, 129.3 (+), 129.2 (+), 128.8 (+, 2C), 127.9
(+), 127.6 (+), 122.8 (+), 51.0 (−), 48.5 (+), 37.4 (+), 33.4 (−), 33.0
(−), 30.2 (−), 25.5 (−), 25.3 (+), 24.8 (−, 2C), 20.0 (−), 13.7 (+),
13.5 (−). FT IR (KBr, cm−1): 3321, 2932, 1637, 1541, 1535, 1450,
1269, 1116, 1020, 858. HRMS (TOF ES): found 428.2139, calculated
for C24H32N2O3S (M+) 428.2134 (1.2 ppm).
(1R*,2R*)-N-(tert-Butyl)-2-(N-hexylmethylsulfonamido)-
cyclopropanecarboxamide (27ahe). The reaction was performed
according to typical procedure II, employing bromocyclopropane 1a
(44 mg, 0.2 mmol, 1.5 equiv), 18-crown-6 (3.5 mg, 0.013 mmol, 10
mol %), KOH (52 mg, 0.93 mmol, 7.0 equiv), and N-
hexylmethanesulfonamide (26he)62 (39 mg, 0.133 mmol, 1.0 equiv).
Column chromatography on silica gel (eluent hexane/EtOAc 1:1)
afforded two fractions. The major fraction contained a title compound
as a white solid mp 62−64 °C, Rf 0.52. Yield: 36.3 mg (0.114 mmol,
86%). 1H NMR (400.13 MHz, CDCl3): δ ppm 5.74 (br s, 1H), 3.15−
3.31 (m, 2H), 2.88 (s, 3H), 2.58 (ddd, J = 7.3, 4.4, 2.9 Hz, 1H), 1.90
(ddd, J = 9.2, 6.3, 2.9 Hz, 1H), 1.57−1.74 (m, 2H), 1.37−1.41 (m,
1H), 1.35−1.38 (m, 9H), 1.26−1.33 (m, 6H), 1.21 (dt, J = 9.4, 4.8 Hz,
1H), 0.87−0.94 (m, 3H). 13C NMR (100.67 MHz, CDCl3): δ ppm
169.5, 51.4, 51.0 (−), 36.7 (+), 36.4 (+), 31.4 (−), 28.8 (+), 28.0 (+,
3C), 26.5 (−), 25.8 (+), 22.5 (−), 14.0 (+), 13.6 (−). FT IR (KBr,
cm−1): 3331, 2960, 2932, 2858, 1647, 1591, 1541, 1500, 1458, 1155,
883. HRMS (TOF ES): found 341.1871, calculated for
C15H30N2O3SNa (M + Na) 341.1875 (1.2 ppm). The minor fraction
(Rf 0.31) contained minute amounts (3.7 mg) of (1R*,2S*)-
diastereomer.
(+), 133.7, 129.6 (+), 127.8 (+), 110.5 (+), 110.0 (+), 51.4, 47.1 (−),
37.0 (+), 28.9 (+), 25.6 (+), 21.5, 13.7 (−). FT IR (KBr, cm−1): 3384,
2968, 2929, 2872, 1666, 1599, 1504, 1456, 1350, 1227, 885, 656.
HRMS (TOF ES): found 413.1515, calculated for C20H26N2NaO4S
(M + Na) 413.1511 (1.2 ppm).
(1R*,2R*)-N-(tert-Butyl)-2-(N-butylphenylsulfonamido)-
cyclopropanecarboxamide (27afd). The reaction was performed
according to typical procedure II, employing bromocyclopropane 1a
(35 mg, 0.16 mmol, 1.2 equiv), 18-crown-6 (3.5 mg, 0.013 mmol, 10
mol %), KOH (52 mg, 0.93 mmol, 7.0 equiv), and N-
butylbenzenesulfonamide (26fd)61 (28 mg, 0.133 mmol, 1.0 equiv).
Column chromatography on silica gel afforded the title compound as a
white solid (diastereomeric mixture 10:1), mp 65−68 °C. Rf = 0.25
1
(eluent hexane/EtOAc 3:1). Yield: 34.2 mg (0.097 mmol, 73%). H
NMR (400.13 MHz, CDCl3): δ ppm 7.79 (d, J = 7.3 Hz, 2 H), 7.60 (t,
J = 7.5 Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 5.85 (s, 1H), 3.21 (ddd, J =
13.7, 9.7, 5.9 Hz, 1H), 2.98−3.08 (m, 1H), 2.15 (ddd, J = 7.3, 4.5, 2.8
Hz, 1H), 1.99 (ddd, J = 9.2, 6.3, 3.0 Hz, 1H), 1.43−1.57 (m, 2H), 1.40
(s, 9H), 1.22−1.36 (m, 3H), 1.18 (dt, J = 9.2, 4.7 Hz, 1H), 0.88 (t, J =
7.5 Hz, 3H). 13C NMR (100.67 MHz, CDCl3): δ ppm 169.5, 137.1,
132.8 (+), 129.0 (+, 2C), 127.5 (+, 2C), 51.5, 51.1 (−), 37.3 (+), 30.1
(−), 28.8 (+, 3C), 25.7 (+), 20.0 (−), 13.7 (+), 13.2 (−). FT IR (KBr,
cm−1): 3303, 2962, 2932, 2872, 1651, 1539, 1447, 1248, 1045, 887.
HRMS (TOF ES): found 353.1907, calculated for C18H29N2O3S (M +
H) 353.1899 (2.3 ppm).
(1R*,2R*)-2-(N-Benzylmethylsulfonamido)-N-(tert-butyl)-
cyclopropanecarboxamide (27ahf). The reaction was performed
according to typical procedure II, employing bromocyclopropane 1a
(46 mg, 0.21 mmol, 1.5 equiv), 18-crown-6 (3.5 mg, 0.013 mmol, 10
mol %), KOH (52 mg, 0.93 mmol, 7.0 equiv), and N-
benzylmethanesulfonamide (26hf)63 (26 mg, 0.14 mmol, 1.0 equiv).
Column chromatography on silica gel afforded the title compound as a
white solid (diastereomeric mixture 15:1), mp 136−137 °C, Rf 0.28
(1R*,2R*)-N-(tert-Butyl)-2-(N-butylnaphthalene-2-sulfonamido)-
cyclopropanecarboxamide (27agd). The reaction was performed
according to typical procedure II, employing bromocyclopropane 1a
(35 mg, 0.16 mmol, 1.2 equiv), 18-crown-6 (3.5 mg, 0.013 mmol, 10
mol %), KOH (52 mg, 0.93 mmol, 7.0 equiv), and N-
butylnaphthalenesulfonamide (26gd) (34 mg, 0.133 mmol, 1.0
equiv). Column chromatography on silica gel afforded the title
compound as a white solid (diastereomeric mixture 10:1), mp 97−99
°C, Rf 0.38 (eluent hexane/EtOAc 3:1). Yield: 44 mg (0.103 mmol,
1
(eluent hexane/EtOAc 3:2). Yield: 37.8 mg (0.117 mmol, 83%). H
NMR (400.13 MHz, CDCl3): δ ppm 7.31−7.42 (m, 5H), 5.36 (br s,
1H), 4.60 (d, J = 14.1 Hz, 1H), 4.21 (d, J = 14.1 Hz, 1H), 2.74 (s, 3H),
2.55 (ddd, J = 7.4, 4.5, 2.8 Hz, 1H), 1.54 (ddd, J = 9.2, 6.3, 2.8 Hz,
1H), 1.33−1.38 (m, 1H), 1.31 (s, 9H), 1.20−1.27 (m, 1H). 13C NMR
(100.67 MHz, CDCl3): δ ppm 169.3, 135.5, 129.3 (+, 2C), 128.7 (+,
2C), 128.2 (+), 54.8 (−), 51.4, 36.9 (+), 36.5 (+), 28.7 (+, 3C), 25.8
(+), 14.0 (−). FT IR (KBr, cm−1):, 2964, 2929, 2972, 1651, 1537,
1456, 1258, 1049, 841. HRMS (TOF ES): found 325.1588, calculated
for C16H25N2O3S (M + H) 325.1586 (0.6 ppm).
(1R*,2R*)-N-(tert-Butyl)-2-(N-cyclohexylmethylsulfonamido)-
cyclopropanecarboxamide (27ahh). The reaction was performed
according to typical procedure II, employing bromocyclopropane 1a
(35 mg, 0.16 mmol, 1.2 equiv), 18-crown-6 (3.5 mg, 0.013 mmol, 10
mol %), KOH (52 mg, 0.93 mmol, 7.0 equiv), and N-cyclo-
hexylmethanesulfonamide (26hh)64 (34 mg, 0.133 mmol, 1.0 equiv).
Column chromatography on silica gel afforded the title compound as a
yellow oil (diastereomeric mixture 9:1), Rf 0.28 (eluent hexane/EtOAc
2:1). Yield: 28 mg (0.089 mmol, 67%). 1H NMR (400.13 MHz,
CDCl3): δ ppm 5.83 (br s, 1H), 3.67 (tt, J = 12.1, 3.3 Hz, 1H), 2.87 (s,
3H), 2.49 (ddd, J = 7.4, 4.5, 3.0 Hz, 1H), 1.92 (ddd, J = 9.2, 6.3, 2.9
Hz, 1H), 1.75−1.87 (m, 4H), 1.49−1.74 (m, 3H), 1.36−1.41 (m, 1H),
1.35 (s, 9H), 1.24−1.32 (m, 3H), 1.00−1.15 (m, 1H). 13C NMR
(100.67 MHz, CDCl3): δ ppm 169.8, 60.2 (+), 51.4, 37.9 (+), 32.8
(+), 32.7 (−), 31.1 (−), 28.8 (+, 3C), 26.2 (−), 26.1 (−), 25.4 (−),
1
78%). H NMR (400.13 MHz, CDCl3): δ ppm 8.36 (s, 1H), 7.90−
7.99 (m, 3H), 7.78 (dd, J = 8.6, 1.8 Hz, 1H), 7.59−7.69 (m, 2H), 5.81
(s, 1H), 3.26 (ddd, J = 13.7, 9.8, 6.1 Hz, 1H), 3.09 (ddd, J = 13.7, 9.7,
5.7 Hz, 1H), 2.27 (ddd, J = 7.4, 4.5, 2.8 Hz, 1H), 2.01 (ddd, J = 9.1,
6.3, 2.8 Hz, 1H), 1.45−1.58 (m, 2H), 1.43 (s, 9H), 1.25−1.37 (m,
3H), 1.18−1.24 (m, 1H), 0.88 (t, J = 7.3 Hz, 3H). 13C NMR (100.67
MHz, CDCl3): δ ppm 169.5, 134.8, 134.4, 132.1, 129.2 (+, 2 C), 128.8
(+, 2 C), 127.9 (+), 127.6 (+), 122.8 (+), 51.5, 51.1 (−), 37.3 (+),
30.3 (−), 28.9 (+, 3 C), 25.9 (+), 20.0 (−), 13.7 (+), 13.2 (−). FT IR
(KBr, cm−1): 3377, 2961, 2930, 2870, 1649, 1589, 1541, 1456, 1259,
1132, 1020, 860. HRMS (TOF ES): found 403.2043, calculated for
C22H31N2O3S (M + H) 403.2055 (3.0 ppm).
(1R*,2R*)-2-(N-Butylnaphthalene-2-sulfonamido)-N-cyclohexyl-
cyclopropanecarboxamide (27fgd). The reaction was performed
according to typical procedure II, employing bromocyclopropane 1f
(39 mg, 0.16 mmol, 1.2 equiv), 18-crown-6 (3.5 mg, 0.013 mmol, 10
mol %), KOH (52 mg, 0.93 mmol, 7.0 equiv), and N-
butylnaphthylsulfonamide (26gd) (35 mg, 0.133 mmol, 1.0 equiv).
K
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25.3 (+), 14.0 (−). FT IR (KBr, cm−1): 3373, 2964, 2934, 2856, 1651,
1547, 1454, 1256, 1084, 893. HRMS (TOF ES): found 339.1721,
calculated for C15H28N2O3SNa (M + Na) 339.1718 (0.9 ppm).
(1R*,2R*)-2-(N-Butyl-4-fluorophenylsulfonamido)-N-cyclohexyl-
cyclopropanecarboxamide (27fid). The reaction was performed
according to typical procedure II, employing bromocyclopropane 1f
(39 mg, 0.16 mmol, 1.2 equiv), 18-crown-6 (3.5 mg, 0.013 mmol, 10
mol %), KOH (52 mg, 0.93 mmol, 7.0 equiv), and N-butyl-4-
fluorobenzenesulfonamide (26id)36b (31 mg, 0.133 mmol, 1.0 equiv).
Column chromatography on silica gel afforded the title compound as a
white solid (diastereomeric mixture 10:1), mp 91−93 °C, Rf 0.29
(1R*,2R*)-N-(tert-Butyl)-2-(N-butyl-4-chlorophenylsulfonamido)-
cyclopropanecarboxamide (27ajd). The reaction was performed
according to typical procedure II, employing bromocyclopropane 1a
(35 mg, 0.16 mmol, 1.2 equiv), 18-crown-6 (3.5 mg, 0.013 mmol, 10
mol %), KOH (52 mg, 0.93 mmol, 7.0 equiv), and N-butyl-4-
chlorobenzenesulfonamide (26jd)65 (33 mg, 0.133 mmol, 1.0 equiv).
Column chromatography on silica gel afforded the title compound as a
white solid (diastereomeric mixture 11:1), mp 109−112 °C. Major: Rf
0.47 (major), 0.17 (minor), eluent hexane/EtOAc 3:1. Yield: 48 mg
(0.126 mmol, 95%). 1H NMR (400.13 MHz, CDCl3): δ ppm 7.73 (d,
J = 8.6 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 5.82 (s, 1H), 3.21 (ddd, J =
6.1, 9.6, 13.6 Hz, 1H), 3.04 (ddd, J = 5.6, 9.5, 13.7 Hz, 1H), 2.16 (ddd,
J = 2.8, 4.5, 7.4 Hz, 1H), 2.00 (ddd, J = 2.8, 6.3, 9.2 Hz, 1H), 1.46−
1.63 (m, 2H), 1.42 (s, 9H), 1.25−1.37 (m, 3H), 1.21 (ddd, J = 4.8, 9.4
Hz, 1H), 0.91 (t, J = 7.3 Hz, 3H). 13C NMR (100.67 MHz, CDCl3): δ
ppm 169.3, 139.7, 136.2, 129.5 (+, 2C), 129.1 (+, 2C), 128.6 (+, 2C),
128.0 (+, 2C), 55.4 (−), 51.4, 37.9 (+), 28.8 (+), 25.2 (+), 13.7. FT IR
(KBr, cm−1): 3386, 3087, 2962, 2871, 1645, 1547, 1475, 1352, 1259,
829, 739. HRMS (TOF ES): found 387.1506, calculated for
C24H32N2O3S (M + H) 387.1509 (0.8 ppm).
1
(eluent hexane/EtOAc 3:1). Yield: 51.3 mg (0.129 mmol, 97%). H
NMR (400.13 MHz, CDCl3): δ ppm 7.75−7.84 (m, 2H), 7.20 (t, J =
8.6 Hz, 2H), 5.90 (d, J = 8.1 Hz, 1H), 3.73−3.86 (m, 1H), 3.19 (ddd, J
= 13.7, 9.8, 5.8 Hz, 1H), 3.04 (ddd, J = 13.9, 9.9, 5.6 Hz, 1H), 2.21
(ddd, J = 7.3, 4.5, 2.8 Hz, 1H), 1.86−2.07 (m, 3H), 1.75 (td, J = 8.0,
3.8 Hz, 2H), 1.63 (dt, J = 12.8, 3.6 Hz, 1H), 1.49−1.57 (m, 1H),
1.34−1.48 (m, 4H), 1.16−1.32 (m, 6H), 0.89 (t, J = 7.3 Hz, 3H). 13C
NMR (100.67 MHz, CDCl3): δ 169.3, 165.2 (d, J = 255.4 Hz), 133.4
(d, J = 2.9 Hz), 130.3 (+, d, J = 8.8 Hz, 2C), 116.4 (+, d, J = 22.7 Hz,
2C), 51.1 (−), 48.6 (+), 37.4 (+), 33.5 (−), 33.0 (−), 30.2 (−), 25.5
(−), 25.3 (+), 24.89 (−), 24.88 (−), 20.1 (−), 13.7 (+), 13.6 (−). 19F
NMR (376.46 MHz, CDCl3): δ ppm −104.8 (tt, J = 8.6, 4.7 Hz, 1F).
FT IR (KBr, cm−1): 3302, 2932, 2855, 1639, 1593, 1545, 1492, 1450,
1350, 1292, 1116, 1043, 872. HRMS (TOF ES): found 419.1799,
calculated for C20H29N2O3SFNa (M + Na) 419.1781 (4.3 ppm).
N-Butyl-4-fluoro-N-((1R*,2R*)-2-(morpholine-4-carbonyl)-
cyclopropyl)benzenesulfonamide (27eid). The reaction was per-
formed according to typical procedure II, employing (2-
bromocyclopropyl)(morpholino)methanone (1e) (37 mg, 0.16
mmol, 1.2 equiv), 18-crown-6 (3.5 mg, 0.013 mmol, 10 mol %),
KOH (52 mg, 0.93 mmol, 7.0 equiv), and N-butyl-4-fluorobenzene-
sulfonamide (26id)36b (31 mg, 0.133 mmol, 1.0 equiv). Column
chromatography on silica gel afforded the title compound as a colorless
oil (11:1 mixture of diastereomers), Rf = 0.25 (eluent EtOAc:hexane
2:1). Yield: 36 mg (0.11 mmol, 71%). 1H NMR (400.13 MHz,
CDCl3): δ 7.82 (ddd, J = 8.7, 5.0, 1.4 Hz, 2H), 7.23 (t, J = 8.5 Hz,
2H), 3.89 (m, 1H), 3.85−3.64 (m, 7H), 3.55 (ddd, J = 12.6, 7.1, 2.9
Hz, 1H), 3.21−3.02 (m, 2H), 2.51−2.41 (m, 2H), 1.64−1.49 (m, 1H),
1.50−1.19 (m, 5H), 0.95−0.84 (m, 3H). 13C NMR (100.67 MHz,
CDCl3): δ 169.3, 165.3 (d, J = 255.3 Hz), 133.5, 130.2 (d, J = 9.1 Hz,
2C), 116.5 (d, J = 22.5 Hz, 2C), 67.1, 67.0, 46.2, 42.6, 38.6, 30.2, 21.4,
20.1, 15.0, 13.7. 19F NMR (376.46 MHz, CDCl3): δ −104.67 to
−104.78 (m). FT IR (NaCl, cm−1): 3331, 3087, 2962, 2872, 1645,
1585, 1547, 1475, 1454, 1392, 1294, 1225, 1205, 1167, 1094. HRMS
(TOF ES): found 383.1441, calculated for C18H24FN2O4S (M − H)+
383.1435 (1.6 ppm).
(1R*,2R*)-N-(tert-Butyl)-2-(4-fluoro-N-(furan-2-ylmethyl)-
phenylsulfonamido)cyclopropanecarboxamide (27aik). The reac-
tion was performed according to typical procedure II, employing
bromocyclopropane 1a (35 mg, 0.16 mmol, 1.2 equiv), 18-crown-6
(3.5 mg, 0.013 mmol, 10 mol %), KOH (52 mg, 0.93 mmol, 7.0
equiv), and 4-fluoro-N-(furan-2-ylmethyl)benzenesulfonamide (26ik)
(34 mg, 0.133 mmol, 1.0 equiv). Column chromatography on silica gel
afforded the title compound as a white solid (diastereomeric mixture
25:1), mp 121−124 °C, Rf 0.17 (eluent hexane/EtOAc 3:1). Yield: 49
mg (0.123 mmol, 93%). 1H NMR (400.13 MHz, CDCl3): δ ppm 7.74
(dd, J = 5.1, 8.8 Hz, 2H), 7.25 (dd, J = 0.9, 1.9 Hz, 1H), 7.14 (dd, J =
8.6 Hz, 2H), 6.27 (dd, J = 1.9, 3.2 Hz, 1H), 6.21 (d, J = 3.0 Hz, 1H),
5.66 (s, 1H), 4.52 (d, J = 15.4 Hz, 1H), 4.20 (d, J = 15.4 Hz, 1H), 2.25
(ddd, J = 2.8, 4.5, 7.4 Hz, 1H), 1.74−1.78 (m, 1H), 1.38 (s, 9H),
1.31−1.35 (m, 1H), 1.20 (ddd, J = 4.8, 9.4 Hz, 1H). 13C NMR (100.67
MHz, CDCl3): δ ppm 169.3, 165.2 (d, J = 259.40 Hz, 1C), 148.9,
142.5 (+), 133.0 (d, J = 2.93 Hz, 1C), 130.5 (+, d, J = 8.78 Hz, 1C),
116.2 (+, d, J = 22.69 Hz, 1C), 110.5 (+), 110.2 (+), 51.5, 47.0 (−),
36.9 (+), 28.9 (+), 25.9 (+), 13.9 (−). 19F NMR (376 MHz, CDCl3):
δ ppm −104.73 (tt, J = 8.0, 5.7 Hz, 1F). FT IR (KBr, cm−1): 3387,
3021, 2969, 2867, 1645, 1593, 1493, 1337, 1155, 885, 734. HRMS
(TOF ES): found 401.1535, calculated for C19H23FLiN2O4S (M + Li)
401.1523 (3.0 ppm).
(1R*,2R*)-2-(N-Benzyl-4-chlorophenylsulfonamido)-N-(tert-
butyl)cyclopropanecarboxamide (27ajf). The reaction was per-
formed according to typical procedure II, employing bromocyclopro-
pane 1a (35 mg, 0.16 mmol, 1.2 equiv), 18-crown-6 (3.5 mg, 0.013
mmol, 10 mol %), KOH (52 mg, 0.93 mmol, 7.0 equiv), and N-benzyl-
4-chlorobenzenesulfonamide (26jf)66 (38 mg, 0.133 mmol, 1.0 equiv).
Column chromatography on silica gel afforded the title compound as a
white solid (diastereomeric mixture 25:1), mp 88−92 °C, Rf = 0.17
1
(eluent hexane/EtOAc 3:1). Yield: 41 mg (0.096 mmol, 72%). H
NMR (400.13 MHz, CDCl3): δ ppm 7.75 (d, J = 8.6 Hz, 2H), 7.52 (d,
J = 8.8 Hz, 2H), 7.30−7.37 (m, J = 2.5 Hz, 5H), 5.16 (s, 1H), 4.48 (d,
J = 13.9 Hz, 1H), 4.05 (d, J = 13.9 Hz, 1H), 2.13 (ddd, J = 2.8, 4.7, 7.5
Hz, 1H), 1.36−1.40 (m, 1H), 1.32 (s, 9H), 1.14−1.24 (m, 2H). 13C
NMR (100.67 MHz, CDCl3): δ ppm 169.4, 139.5, 135.7, 129.4 (+),
129.0 (+), 51.6, 51.2 (−), 37.3 (+), 30.2 (−), 28.9 (+), 25.7 (+), 20.1
(−), 13.7 (+), 13.4 (−). FT IR (KBr, cm−1): 3332, 3031, 2966, 2867,
1645, 1546, 1496, 1336, 827, 739. HRMS (TOF ES): found 421.1341,
calculated for C24H32N2O3S (M + H) 421.1353 (2.8 ppm).
(1R*,2R*)-2-(4-Bromo-N-butylphenylsulfonamido)-N-(tert-butyl)-
cyclopropanecarboxamide (27akd). The reaction was performed
according to typical procedure II, employing bromocyclopropane 1a
(35 mg, 0.16 mmol, 1.2 equiv), 18-crown-6 (3.5 mg, 0.013 mmol, 10
mol %), KOH (52 mg, 0.93 mmol, 7.0 equiv), and N-butyl-4-
bromobenzenesulfonamide (26kd)65 (39 mg, 0.13 mmol, 1.0 equiv).
Column chromatography on silica gel (eluent hexane/EtOAc 3:1)
afforded two fractions. The major fraction (Rf 0.44) contained the title
compound as a white solid, mp 101−103 °C. Yield: 47.8 mg (0.11
mmol, 85%). Minor fraction (Rf 0.16) contained minute amounts (4.5
1
mg) of (1R*,2S*)-diastereomer. H NMR (400.13 MHz, CDCl3): δ
ppm 7.65 (s, 4 H), 5.82 (s, 1 H), 3.19 (ddd, J = 13.7, 9.8, 6.1 Hz, 1 H),
3.03 (ddd, J = 13.6, 9.6, 5.6 Hz, 1 H), 2.15 (ddd, J = 7.5, 4.5, 2.9 Hz, 1
H), 1.98 (ddd, J = 9.2, 6.3, 2.8 Hz, 1 H), 1.44−1.57 (m, 2 H), 1.40 (s,
9 H), 1.23−1.34 (m, 3 H), 1.15−1.23 (m, 1 H), 0.89 (t, J = 7.3 Hz, 3
H). 13C NMR (100.61 MHz, CDCl3): δ ppm 169.3, 136.1, 132.4 (+,
2C), 129.1 (+, 2C), 128.0, 51.5, 51.2 (−), 37.3 (+), 30.2 (−), 28.9 (+,
3C), 25.7 (+), 20.0 (−), 13.7 (+), 13.3 (−). FT IR (KBr, cm−1): 3325,
2962, 2931, 2871, 1654, 1535, 1388, 1259, 1087, 821, 570. HRMS
(TOF ES): found 453.0827, calculated for C18H27N2O3SBrNa (M +
Na) 453.0823 (0.9 ppm).
Adducts Resulting from Nucleophilic Attack by Azoles.
(1R*,2R*)-2-(5-Bromo-1H-indol-1-yl)-N-(tert-butyl)-
cyclopropanecarboxamide (32af). To a 10 mL Wheaton vial
equipped with a magnetic stir bar, under N2, were added THF (5
mL), powdered KOH (56 mg, 1.0 mmol), 5-bromo-1H-indole (30f)
(147 mg, 0.75 mmol), 18-crown-6 (6.0 mg, 0.025 mmol), and 2-
bromo-N-(tert-butyl)cyclopropanecarboxamide (1a) (55 mg, 0.25
mmol). This solution was stirred at 55 °C for 12 h, and then filtered
through a fritted funnel. The filtrate was concentrated to yield a crude
mixture of diastereomeric products with dr 42:58. This mixture was
subjection to the epimerization procedure, involving treatment with
L
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tBuOK (84 mg, 0.75 mmol, 3.0 equiv) in dry THF (5 mL) at 80 °C for
according to typical procedure III, employing (2-bromo-1-
methylcyclopropyl)(4-methylpiperazin-1-yl)methanone (28i) (78
mg, 0.30 mmol), pyrrole (30a) (40 mg, 0.60 mmol), potassium tert-
butoxide (101 mg, 0.90 mmol), and 18-crown-6 (8 mg, 0.03 mmol)
affording after purification the title compound as yellow oil, Rf = 0.23
18 h. After this treatment the diastereomeric ratio was improved to
97:3. The product was purified by flash column chromatography on
silica gel eluting with hexane/EtOAc 6:1 to afford the title compound
as amber oil, Rf 0.39. Yield: 40 mg (0.12 mmol, 48%). 1H NMR
(400.13 MHz, CDCl3): δ ppm 7.74 (dd, J = 1.7, 0.8 Hz, 1H), 7.34−
7.32 (m, 2H), 7.09 (d, J = 3.3 Hz, 1H), 6.39 (dd, J = 3.2, 0.7 Hz, 1H),
5.68 (s, 1H), 3.84−3.73 (m, 1H), 1.79−1.68 (m, 2H), 1.56−1.48 (m,
1H), 1.45 (s, 9H). 13C NMR (100.61 MHz, CDCl3): δ ppm 169.3,
135.8, 130.3, 128.2 (+), 124.8 (+), 123.6 (+), 113.3, 111.3 (+), 101.2
(+), 51.8, 34.3 (+), 29.0 (+, 3C), 24.4 (+), 13.9 (−). FT IR (KBr,
cm−1): 3325, 2966, 2934, 2874, 1647, 1549, 1508, 1462, 1225, 795.
HRMS (TOF ES): found 357.0570, calculated for C16H19BrN2ONa
(M + Na) 357.0578 (2.2 ppm).
1
(CH2Cl2/MeOH 20:1). Yield: 39 mg (0.16 mmol, 52%, dr 10:1). H
NMR (400.13 MHz, CDCl3): δ ppm 6.58 (t, J = 2.1 Hz, 2H), 6.08 (t, J
= 2.2 Hz, 2H), 3.73 (br s, 1H), 3.51−3.46 (dd, J = 7.8, 5.3 Hz, 1H),
3.40 (br s, 1H), 3.27 (br s, 2H), 2.33 (br s, 1H), 2.23 (br s, 2H), 2.15
(s, 1H), 2.01 (br s, 1H), 1.90 (dd, J = 6.9, 5.4 Hz, 1H), 1.39 (s, 3H),
1.14 (dd, J = 8.6, 6.9 Hz, 1H). 13C NMR (125.76 MHz, CDCl3): δ
ppm 168.8, 119.2 (+, 2C), 108.6 (+, 2C), 54.0 (−, 2C), 45.6 (+), 44.5
(+), 41.8 (−, 2C), 28.8, 21.6 (+), 16.9 (−). FT IR (KBr, cm−1): 2935,
2856, 1630, 1492, 1437, 1227, 827. HRMS (TOF ES): found
247.1690, calculated for C14H21N3O (M+) 247.1685 (2.0 ppm).
((1R*,2S*)-2-(1H-Indol-1-yl)-1-methylcyclopropyl)(4-methylpiper-
azin-1-yl)methanone (31ib). This compound was synthesized
according to typical procedure III, employing (2-bromo-1-
methylcyclopropyl)(4-methylpiperazin-1-yl)methanone (28i) (78
mg, 0.30 mmol), indole (30b) (70 mg, 0.60 mmol), potassium tert-
butoxide (101 mg, 0.90 mmol), and 18-crown-6 (10 mg, 0.03 mmol)
affording after purification the title compound as yellow oil, Rf 0.23
(CH2Cl2:MeOH 20:1). Yield: 46 mg (0.15 mmol, 52%, dr >25:1). 1H
NMR (500.13 MHz, CDCl3): δ ppm 7.61 (d, J = 7.9 Hz, 1H), 7.49 (d,
J = 8.3 Hz, 1H), 7.23 (dd, J = 8.0, 7.7 Hz, 1H), 7.13 (dd, J = 8.1, 7.9
Hz, 1H), 6.96 (d, J = 3.4 Hz, 1H), 6.43 (d, J = 3.3 Hz, 1H), 3.84 (dd, J
= 8.7, 5.4 Hz, 1H), 3.70 (br, 1H), 3.16 (br, 3H), 2.50−2.26 (m, 1H),
2.25−2.16 (dd, 7.3, 5.4, Hz, 1H), 1.95 (s, 3H), 1.85 (br, 3H), 1.51 (s,
3H), 1.30 (dd, J = 10.5, 5.1 Hz, 1H). 13C NMR (125.76 MHz,
CDCl3): δ 168.7, 137.4, 129.2, 123.9 (+), 121.7 (+), 121.2 (+), 119.9
(+), 108.8 (+), 101.5 (+), 54.0 (−), 45.5 (+), 41.9 (−), 41.0 (+), 28.8,
21.4 (+), 16.4 (−). FT IR (KBr, cm−1): 3325, 2966, 2934, 2874, 1647,
1549, 1508, 1462, 1225, 795. HRMS (TOF ES): found 297.1840,
calculated for C18H23N3O (M+) 297.1841 (0.3 ppm).
((1R*,2S*)-2-(1H-Indol-1-yl)-1-methylcyclopropyl)(morpholino)-
methanone (31eb). Typical Procedure III. An oven-dried 10 mL
Wheaton vial equipped with a magnetic stir bar was loaded under N2
with potassium tert-butoxide (168 mg, 1.5 mmol), 18-crown-6 (13 mg,
0.05 mmol), (2-bromo-1-methylcyclopropyl)(morpholino)methanone
(28e) (124 mg, 0.50 mmol), indole (30b) (117 mg, 1.00 mmol), and
THF (5 mL). The mixture was stirred at 80 °C for 12 h, then filtered
through a fritted funnel, and concentrated. Preparative column
chromatography on silica gel afforded the title compound as an
amber oil, Rf 0.46 (CH2Cl2:MeOH 20:1). Yield: 58 mg (0.25 mmol,
1
50%, dr >25:1). H NMR (400.13 MHz, CDCl3): δ ppm 7.63 (d, J =
7.7 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.23 (dd, J = 8.2, 7.0 Hz, 1H),
7.14 (dd, J = 8.0, 7.0 Hz, 1H), 6.95 (d, J = 3.4 Hz, 1H), 6.45 (d, J = 3.3
Hz, 1H), 3.84 (dd, J = 8.8, 5.4 Hz, 1H), 3.79−3.69 (br s, 1H), 3.61−
3.44 (br s, 2H), 3.19 (br s, 2H), 2.97 (m, 3H), 2.22 (dd, J = 6.9, 5.4
Hz, 1H), 1.49 (s, 3H), 1.29 (dd, J = 8.7, 6.8 Hz, 1H). 13C NMR
(100.61 MHz, CDCl3): δ ppm 168.8, 137.2, 129.1, 123.8 (+), 121.8
(+), 121.4 (+), 120.0 (+), 108.6 (+), 101.5 (+), 46.1 (−), 42.4(−),
41.0 (+), 28.8, 21.0 (+), 16.1 (−). FT IR (KBr, cm−1): 2962, 2921,
2856, 1635, 1512, 1464, 1223, 847. HRMS (TOF ES): found
284.1530, calculated for C17H20N2O2 (M+) 284.1525 (1.8 ppm).
((1R*,2S*)-N-(tert-Butyl)-1-methyl-2-(1H-pyrrol-1-yl)-
cyclopropanecarboxamide (31aa). This compound was synthesized
according to typical procedure III, employing 2-bromo-N-(tert-butyl)-
1-methylcyclopropanecarboxamide (28a) (214 mg, 0.91 mmol),
pyrrole (30a) (112 mg, 1.82 mmol), potassium tert-butoxide (307
mg, 2.74 mmol), and 18-crown-6 (24 mg, 0.09 mmol) to afford after
purification the title compound as a light brown solid, mp 80 °C, Rf
0.34 (hexane/EtOAc 1:1), 133 mg (0.61 mmol, 67%, dr 3:1). 1H
NMR (400.13 MHz, chloroform-d): δ 6.70 (t, J = 2.1 Hz, 2H), 6.14 (t,
J = 2.1 Hz, 2H), 4.78 (s, 1H), 3.45 (dd, J = 7.9, 5.0 Hz, 1H), 1.86 (dd,
J = 6.0, 5.3 Hz, 1H), 1.41 (s, 3H), 1.23 (dd, J = 7.8, 6.4 Hz, 1H), 1.12
(s, 9H). 13C NMR (125.76 MHz, CDCl3): δ 169.4, 121.4 (+, 2C),
109.0 (+, 2C), 50.9, 42.6 (+), 28.3 (+, 3C), 20.8 (+), 19.3 (−). FT IR
(NaCl, cm−1): 3393, 2966, 2929, 1653, 1526, 1495, 1456, 1392, 1364,
1258, 1238, 1221, 725. HRMS (TOF ES): found 220.1577, calculated
for C13H20N2O (M+) 220.1576 (0.5 ppm).
((1R*,2S*)-2-(1H-Pyrrol-1-yl)-1-methylcyclopropyl)(morpholino)-
methanone (31ea). This compound was synthesized according to
typical procedure III, employing (2-bromo-1-methylcyclopropyl)-
(morpholino)methanone (28e) (124 mg, 0.50 mmol), pyrrole (30a)
(60 mg, 1.00 mmol), potassium tert-butoxide (168 mg, 1.50 mmol),
and 18-crown-6 (13 mg, 0.05 mmol) to afford after purification the
title compound as yellow oil, Rf 0.34 (hexane/EtOAc 1:1), 72 mg
(0.31 mmol, 61%, dr >25:1). 1H NMR (400.13 MHz, CDCl3): δ ppm
6.59 (t, J = 2.1 Hz, 2H), 6.11 (t, J = 2.1 Hz, 2H), 3.81 (br s, 1H), 3.58
(br s, 1H), 3.49 (dd, J = 8.6, 5.4 Hz, 1H), 3.36 (br s, 1H), 3.46 (br s,
1H), 3.27 (br s, 2H), 3.15 (br s, 1H), 2.59 (br s, 1H), 1.93 (dd, J = 6.9,
5.5 Hz, 1H), 1.39 (s, 3H), 1.15 (dd, J = 8.6, 7.0 Hz, 1H). 13C NMR
(100.61 MHz, CDCl3): δ ppm 168.9, 119.1 (+), 108.7 (+), 66.1 (−,
2C), 46.0 (−), 44.5 (+), 42.4 (−), 28.7, 21.3 (+), 16.7 (−). FT IR
(KBr, cm−1): 2962, 2925, 2901, 2856, 1634, 1494, 1464, 1230, 851.
HRMS (TOF ES): found 235.1448, calculated for C13H19N2O2 (M+)
235.1447 (0.4 ppm).
Adducts Resulting from Nucleophilic Attack by Anilines.
(1R*,2R*)-N-(tert-Butyl)-2-(methyl(4-nitrophenyl)amino)-
cyclopropanecarboxamide (36ab), Typical Procedure IV. A 10 mL
Wheaton vial equipped with a magnetic stir bar, under dry nitrogen
atmosphere, was charged with THF (5 mL), powdered KOH (112 mg,
2.00 mmol), N-methyl-4-nitroaniline (35b) (228 mg, 1.50 mmol), 18-
crown-6 (13 mg, 0.050 mmol), and 2-bromo-N-(tert-butyl)-
cyclopropanecarboxamide (1a) (110 mg, 0.50 mmol). This solution
was stirred at 55 °C for 12 h, then filtered through a fritted funnel, and
concentrated in vacuum. Purification by flash chromatography on silica
gel (eluent hexane:EtOAc 3:1) afforded the title compound as yellow
1
solid (Rf 0.18), yield 142 mg (0.49 mmol, 98%). H NMR (400.13
MHz, CDCl3): δ ppm 8.07 (d, J = 9.4 Hz, 2H), 6.76 (d, J = 9.4 Hz,
2H), 5.86 (s, 1H), 3.09 (s, 3H), 3.06 (ddd, J = 7.6, 4.8, 3.1 Hz, 1H),
1.56 (m, 2H), 1.44 (s, 9H), 1.22 (ddd, J = 4.4, 4.9, 9.4 Hz, 1H). 13C
NMR (CDCl3, 100.61 MHz): δ 169.5, 154.6, 138.1, 125.6 (+, 2C),
111.8 (+, 2C), 51.7, 40.6 (+), 38.0 (+), 29.0 (+, 3C), 27.1 (+), 16.3
(−). FT IR (NaCl, cm−1): 3325, 2966, 2930, 2874, 1643, 1547, 1493,
1396, 1315, 1113, 831, 754. HRMS (TOF ES): found 290.1504,
calculated for C15H20N3O3 (M − H) 290.1505 (0.3 ppm).
(1R*,2R*)-2-(Benzyl(4-cyanophenyl)amino)-N-(tert-butyl)-
cyclopropanecarboxamide (36ac). This compound was synthesized
according to the typical procedure employing 2-bromo-N-(tert-
butyl)cyclopropanecarboxamide (1a) (22 mg, 0.10 mmol), KOH
(22 mg, 0.40 mmol), 18-crown-6 (2.6, 0.01 mmol), THF (1 mL), N-
benzyl-4-cyanoaniline (35c)67 (62 mg, 0.3 mmol). Column
chromatography on silica gel eluting with hexane/EtOAc (3:1)
afforded the title compound as pale yellow oil, Rf 0.28. Yield: 32 mg
(0.092 mmol, 92%). 1H NMR (400.13 MHz, CDCl3): δ ppm 7.43 (d,
J = 9.0 Hz, 2H), 7.35 (m, 3H), 7.11 (d, J = 6.9 Hz, 2H), 6.83 (d, J =
9.0 Hz, 2H), 5.69 (s, 1H) 4.71 (d, J = 17.2 Hz, 1H) 4.62 (d, J = 17.2
Hz, 1H), 3.15 (ddd, J = 6.7, 4.8, 3.2 Hz, 1H), 1.55 (m, 2H), 1.41 (s,
9H), 1.20 (ddd, J = 8.7, 4.3, 3.4 Hz, 1H). 13C NMR (CDCl3, 100.61
MHz): δ ppm 169.6, 152.2, 137.9, 133.3 (+, 2C), 128.9 (+, 2C), 127.4
(+), 126.0 (+, 2C), 113.7 (+, 2C), 99.7, 55.2 (−), 51.6, 40.3 (+), 29.0
(+, 3C), 26.9 (+), 16.0 (−). FT IR (NaCl, cm−1): ν = 3338, 2964,
((1R*,2R*)-2-(1H-Pyrrol-1-yl)-1-methylcyclopropyl)(4-methylpi-
perazin-1-yl)methanone (31ia). This compound was synthesized
M
dx.doi.org/10.1021/jo4011798 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
2927, 2871, 2216, 1644, 1605, 1546, 1435, 1383, 821, 737. HRMS
(TOF ES): found 347.1993, calculated for C22H25N3O (M + H)
347.1998 (1.4 ppm).
0.27 (hexane/EtOAc 6:1). Yield: 74 mg (0.24 mmol, 96%). H NMR
(400.13 MHz, CDCl3): δ ppm 7.36−7.29 (m, 4H), 7.08−6.99 (m,
6H), 5.50 (s, 1H), 3.20 (ddd, J = 7.5, 4.8, 2.9 Hz, 1H), 1.04 (ddd, J =
8.6, 4.8 Hz, 1H), 1.43−1.39 (m, 9H), 1.53 (ddd, J = 7.2, 5.4 Hz, 1H),
1.50−1.46 (m, 1H). 13C NMR (100.61 MHz, CDCl3): δ 170.1, 147.3,
129.2 (+, 4C), 122.3 (+, 2C), 121.4 (+, 4C), 51.5, 40.6 (+), 29.0 (+,
3C), 27.6 (+), 16.5 (−). FT IR (NaCl, cm−1): 3325, 3057, 3044, 2966,
2930, 1647, 1591, 1500, 1456, 1394, 1364, 1313, 1248, 1224, 748.
HRMS (TOF ES): found 308.1880, calculated for C20H24N2O (M+)
308.1889 (2.9 ppm).
(1R*,2R*)-2-(Benzyl(4-(trifluoromethyl)phenyl)amino)-N-(tert-
butyl)cyclopropanecarboxamide (36ad). This compound was
synthesized according to the typical procedure employing 2-bromo-
N-(tert-butyl)cyclopropanecarboxamide (1a) (22 mg, 0.1 mmol),
KOH (22 mg, 0.40 mmol), 18-crown-6 (2.6 mg, 0.01 mmol), THF (1
mL), and N-benzyl-4-trifluoroaniline (35d)67 (75 mg, 0.30 mmol).
Column chromatography on silica gel eluting with hexane/EtOAc
(3:1) afforded the title compound as white solid, mp 125−128 °C, Rf
0.45. Yield: 25 mg (0.064 mmol, 65%). 1H NMR (400.13 MHz,
CDCl3): δ ppm 7.46 (m, 2H), 7.33 (m, 2H), 7.29 (m, 1H), 7.16 (m,
2H), 6.89 (d, J = 8.6 Hz, 2H), 5.54 (s, 1H), 4.72 (d, J = 17.1 Hz, 1H),
4.61 (d, J = 17.0 Hz, 1H), 3.14 (ddd, J = 7.7, 4.7, 3.1 Hz, 1H), 1.53 (m,
2H), 1.42 (s, 9H), 1.20 (m, 1H). 13C NMR (CDCl3, 100.61 MHz): δ
(1R*,2R*)-N-(tert-Butyl)-2-(10H-phenothiazin-10-yl)-
cyclopropanecarboxamide (36ah). This compound was prepared
according to the typical procedure employing 2-bromo-N-(tert-
butyl)cyclopropanecarboxamide (1a) (55 mg, 0.25 mmol), powdered
KOH (56 mg, 1.0 mmol), 18-crown-6 (6.6 mg, 0.025 mmol), THF (5
mL), and 10H-phenothiazine (35h) (149 mg, 0.75 mmo l). Crude
reaction mixture (dr 3.5:1) was concentrated in vacuum and treated
with potassium tert-butoxide (112 mg, 1.00 mmol) in anhydrous THF
(5 mL) at 80 °C for 12 h to improve the dr to 49:1. Purification by
flash chromatography on silica gel (eluent hexane:EtOAc 8:1) afforded
the title compound as white solid, mp 187−188 °C, Rf 0.52. Yield: 50
3
169.8, 151.6, 138.6, 130.9, 128.8 (+, 2C), 127.2 (+), 126.3 (+, q, J =
3.9 Hz, 2C), 126.2 (2C), 124.9 (q, 1J = 270.3 Hz), 119.6 (q, 2J = 32.5
Hz), 113.4 (+, 2C), 55.7 (−), 51.6, 40.4 (+), 29.0 (+, 3C), 27.1 (+),
16.0 (−). FT IR (NaCl, cm−1): 3315, 2964, 2929, 1730, 1643, 1556,
1454, 1393, 1325, 1226, 1111, 823, 725 cm. HRMS (TOF ES): found
391.2001, calculated for C22H26N2OF3 (M + H) 391.1997 (1.0 ppm).
((1R*,2R*)-2-(Benzyl(4-nitrophenyl)amino)cyclopropyl)-
(morpholino)methanone (36ee). This compound was synthesized
according to the typical procedure employing (2-bromocyclopropyl)-
(morpholino)methanone (1e) (23 mg, 0.10 mmol), KOH (22 mg,
0.40 mmol), 18-crown-6 (2.6, 0.01 mmol), THF (1 mL), and N-
benzyl-4-nitroaniline (35e)68 (68 mg, 0.30 mmol). Column
chromatography on silica gel eluting with hexane/EtOAc (1:1)
afforded the title compound as pale yellow oil, Rf 0.13. Yield: 27 mg
(0.071 mmol, 71%). 1H NMR (400.13 MHz, CDCl3): δ ppm 8.12 (d,
J = 9.3 Hz, 2H), 7.36 (m, 2H), 7.31 (d, J = 7.2 Hz, 1H), 7.13 (d, J =
7.5 Hz, 2H), 6.84 (d, J = 9.3 Hz, 2H), 4.81 (d, J = 17.3, 1H) 4.69 (d, J
= 17.3, 1H), 3.78−3.63 (m, 6H), 3.53 (m, 2H), 3.37 (ddd, J = 2.9, 4.8,
7.6 Hz, 1H), 2.01 (ddd, J = 2.9, 5.8, 9.1 Hz, 1H), 1.65 (ddd, J = 5.39,
5.39, 7.20 1H), 1.35 (td, J = 5.0, 9.6 Hz, 1H). 13C NMR (100.61 MHz,
CDCl3): δ ppm 169.0, 154.1, 138.9, 137.6, 129.0 (+, 2C), 127.6 (+),
125.8 (+, 2C), 125.7 (+, 2C), 112.7 (+, 2C), 66.9 (−), 66.8 (−), 55.6
(−), 46.1 (−), 42.6 (−), 41.3 (+), 22.2 (+), 17.3 (−). HRMS (TOF
ES): found 382.1784, calculated for C21H24N3O4 (M + H) 382.1767
(4.4 ppm).
1
mg (0.148 mmol, 59%). H NMR (400.13 MHz, CDCl3): δ ppm
7.24−7.12 (m, 4H), 6.98 (t, J = 8.0 Hz, 2H), 5.57 (s, 1H), 3.29 (ddd, J
= 7.2, 4.7, 2.9 Hz, 1H), 1.83 (ddd, J = 6.7, 5.8, 4.9 Hz, 1H), 1.57 (ddd,
J = 5.8, 2.9 Hz, 1H), 1.20 (ddd, J = 9.3, 4.8 Hz, 1H). 13C NMR
(100.61 MHz, CDCl3): δ ppm 169.8, 127.2, 127.1, 122.9, 51.6, 35.4,
29.0, 28.5, 18.1. FT IR (NaCl, cm−1): 3358, 2992, 2961, 1649, 1542,
1461, 1374, 1367, 1250, 1129, 825, 750. HRMS (TOF ES): found
339.1528, calculated for C20H23N2OS (M + H) 339.1531 (0.9 ppm).
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR spectral charts for new compounds, X-ray
crystallography information, and CIF files. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mrubin@ku.edu.
■
Present Addresses
(1R*,2R*)-2-(Benzyl(3-nitrophenyl)amino)-N-(tert-butyl)-
cyclopropanecarboxamide (36af). This compound was synthesized
according to the typical procedure employing 2-bromo-N-(tert-
butyl)cyclopropanecarboxamide (1a) (22 mg, 0.10 mmol), KOH
(22 mg, 0.40 mmol), 18-crown-6 (2.6 mg, 0.01 mmol), THF (1 mL),
and N-benzyl-3-nitroaniline (35e)69 (68 mg, 0.30 mmol). Column
chromatography on silica gel eluting with hexane/EtOAc (3:1)
afforded the title compound as yellow oil, Rf 0.26. Yield: 18 mg
(0.049 mmol, 50%). 1H NMR (400.13 MHz, CDCl3): δ ppm 7.79 (t, J
= 2.4 Hz, 1H), 7.61 (dd, J = 7.9, 2.0 Hz, 1H), 7.33 (m, 3H), 7.29 (m,
1H), 7.16 (d, J = 7.4 Hz, 2H), 7.03 (dd, J = 8.4, 2.5 Hz, 1H), 5.65 (s,
1H), 4.75 (d, J = 17.0 Hz, 1H), 4.62 (d, J = 17.1 Hz, 1H), 3.12 (m,
1H), 1.59 (m, 2H), 1.45 (s, 9H), 1.20 (m, 1H). 13C NMR (CDCl3,
100.61 MHz): δ 169.3, 149.9, 138.0, 129.6 (+, 2C), 128.9 (+, 2C),
127.3 (+), 126.2 (+, 2C), 119.6 (+), 112.5 (+), 108.1 (+), 55.7 (−),
51.8, 40.4 (+), 29.0 (+, 3C), 27.4 (+), 15.7 (−). FT IR (KBr, cm−1):
3336, 2964, 2929, 2869, 1642, 1605, 1549, 1447, 1381, 821, 736.
HRMS (TOF ES): found 347.1993, calculated for C22H25N3O (M+)
347.1998 (1.4 ppm).
†Emory University, Department of Chemistry.
‡UC Berkeley, Department of Chemistry.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank USDA (Award 2911-10006-30362) and International
Collaboration Program, funded by Perm Krai Governor and
Department of Education (Russia), for financial support. We
are grateful for NSF Graduate Fellowship (A.P.R.), SMART
Fellowship (J.E.B.), US Navy Undergraduate Fellowship
(I.A.B.), NSF REU Award (A.R.), KU UGRA program
(A.H.), and to Department of Chemistry, University of Kansas
for 2012 K. Barbara Schowen Undergraduate Mentor Award
(M. Rubin). We also thank NSF-MRI for Award CHE-
0923449, used for purchasing an X-ray diffractometer.
( 1 R * , 2 R * ) - N - ( t e r t - B u t y l ) - 2 - ( d i p h e n y l a m i n o ) -
cyclopropanecarboxamide (36ag). This compound was synthesized
according to the typical procedure employing 2-bromo-N-(tert-
butyl)cyclopropanecarboxamide (1a) (55 mg, 0.25 mmol), powedered
KOH (56 mg, 1.0 mmol), 18-crown-6 (6.6 mg, 0.025 mmol), THF (5
mL), and diphenyl amine (35g) (126 mg, 0.75 mmol). Crude mixture
(dr 1.1:1) was concentrated in vacuum and treated with potassium
tert-butoxide (112 mg, 1.0 mmol) in anhydrous THF (5 mL) at 80 °C
for 12 h, to improve the dr to 25:1. Flash column chromatography on
silica gel afforded the title compound as white solid, mp 111.3 °C, Rf
REFERENCES
■
(1) See, for example: (a) Lang, M.; De Pol, S.; Baldauf, C.; Hofmann,
H.-J.; Reiser, O.; Beck-Sickinger, A. G. J. Med. Chem. 2006, 49, 616.
(b) Suarez del Villar, I.; Gradillas, A.; Gomez-Ovalles, A.; Martinez-
Murillo, R.; Martinez, A.; Perez-Castells, J. Chem. Lett. 2008, 37, 1222.
(c) Hikichi, H.; Nishino, M.; Fukushima, M.; Satow, A.; Maehara, S.;
Kawamoto, H.; Ohta, H. Eur. J. Pharmacol. 2010, 639, 99.
(2) For review, see: (a) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005,
61, 321. For recent contributions, see: (b) Campbell, M. J.; Johnson,
N
dx.doi.org/10.1021/jo4011798 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
J. S. Synthesis 2010, 2841. (c) Chagarovskiy, A. O.; Budynina, E. M.;
Ivanova, O. A.; Grishin, Y. K.; Trushkov, I. V.; Verteletskii, P. V.
Tetrahedron 2009, 65, 5385. (d) Pohlhaus, P. D.; Sanders, S. D.;
Parsons, A. T.; Li, W.; Johnson, J. S. J. Am. Chem. Soc. 2008, 130, 8642.
(3) See, for example: (a) Koglin, N.; Zorn, C.; Beumer, R.; Carbele,
C.; Bubert, C.; Sewald, N.; Reiser, O.; Beck-Sickinger, A. G. Angew.
Chem., Int. Ed. 2003, 42, 202. (b) Urman, S.; Gaus, K.; Yang, Y.;
Strijowski, U.; Sewald, N.; De Pol, S.; Reiser, O. Angew. Chem., Int. Ed.
2007, 46, 3976.
(4) See, for example: (a) De Pol, S.; Zorn, C.; Klein, C. D.; Zerbe,
O.; Reiser, O. Angew. Chem., Int. Ed. 2004, 43, 511. (b) Schmid, M. B.;
Fleischmann, M.; D’Elia, V.; Reiser, O.; Gronwald, W.; Gschwind, R.
M. ChemBioChem 2009, 10, 440.
(5) Beumer, R.; Bubert, C.; Carbele, C.; Vielhauer, O.; Pietzsch, M.;
Reiser, O. J. Org. Chem. 2000, 65, 8960 and references cited therein..
(6) See, for example: (a) Benfield, A. P.; Teresk, M. G.; Plake, H. R.;
DeLorbe, J. E.; Millspaugh, L. E.; Martin, S. F. Angew. Chem., Int. Ed.
2006, 45, 6830. (b) DeLorbe, J. E.; Clements, J. H.; Teresk, M. G.;
Benfield, A. P.; Plake, H. R.; Millspaugh, L. E.; Martin, S. F. J. Am.
Chem. Soc. 2009, 131, 16758.
(7) For reviews, see: (a) Chemistry and Biochemistry of the Amino
Acids; Barrett, G. C., Ed.; Chapman and Hall: New York, 1985.
(b) Hoekstra, W. J. Curr. Med. Chem. 1999, 6, 905. (c) Cardillo, G.;
Tomasini, C. Chem. Soc. Rev. 1996, 25, 117.
(8) D’Elia, V.; Zwicknagl, H.; Reiser, O. J. Org. Chem. 2008, 73, 3262.
(9) (a) Ott, G. R.; Chen, X.; Duan, J.; Voss, M. E. WO 2002074738.
(b) Duan, J.; Ott, G.; Chen, L.; Lu, Z.; Maduskuie, T. P., Jr.; Voss, M.
E.; Xue, C.-B. WO 2001070673. (c) Behling, J. R.; Boys, M. L.; Cain-
Janicki, K. J.; Colson, P.-J.; Doubleday, W. W.; Duran, J. E.; Farid, P.
N.; Knable, C. M.; Muellner, F. W.; Nugent, S. T.; Topgi, R. S. WO
9802410.
(10) (a) Chai, H.; Zhao, Y.; Zhao, C.; Gong, P. Bioorg. Med. Chem.
2006, 14, 911. (b) Zhao, C.; Zhao, Y.; Chai, H.; Gong, P. Bioorg. Med.
Chem. 2006, 14, 2552.
(11) (a) Li, Q.; Woods, K. W.; Claiborne, A.; Gwaltney, S. L., II;
Barr, K. J.; Liu, G.; Gehrke, L.; Credo, R. B.; Hui, Y. H.; Lee, J.;
Warner, R. B.; Kovar, P.; Nukkala, M. A.; Zielinski, N. A.; Tahir, S. K.;
Fitzgerald, M.; Kim, K. H.; Marsh, K.; Frost, D.; Ng, S. C.; Rosenberg,
S.; Sham, H. Bioorg. Med. Chem. Lett. 2002, 12, 465. (b) Swann, E.;
Barraja, P.; Oberlander, A. M.; Gardipee, W. T.; Hudnott, A. R.; Beall,
H. D.; Moody, C. J. J. Med. Chem. 2001, 44, 3311.
(12) (a) Carosati, E.; Cruciani, G.; Chiarini, A.; Budriesi, R.; Ioan, P.;
Spisani, R.; Spinelli, D.; Cosimelli, B.; Fusi, F.; Frosini, M.; Matucci,
R.; Gasparrini, F.; Ciogli, A.; Stephens, P. J.; Devlin, F. J. J. Med. Chem.
2006, 49, 5206. (b) Carosati, E.; Budriesi, R.; Ioan, P.; Ugenti, M. P.;
Frosini, M.; Fusi, F.; Corda, G.; Cosimelli, B.; Spinelli, D.; Chiarini, A.;
Cruciani, G. J. Med. Chem. 2008, 51, 5552.
For development of stereoselective protocols, see: (b) Sladojevich, F.;
Trabocchi, A.; Guarna, A. Org. Biomol. Chem. 2008, 6, 332. (c) Denton,
J. R.; Davies, H. M. L. Org. Lett. 2009, 11, 787. (d) Bonge, H. T.;
Pintea, B.; Hansen, T. Org. Biomol. Chem. 2008, 6, 3670.
(e) Chanthamath, S.; Nguyen, D. T.; Shibatomi, K.; Iwasa, S. Org.
Lett. 2013, 15, 772.
(21) For ring-retentive nucleophilic addition of amines to cyclo-
propenes, see: (a) Gritsenko, E. I.; Khaliullin, R. R.; Plemenkov, V. V.;
Faizullin, E. M. Zh. Obshch. Khim. 1988, 58, 2733. (b) Franck-
Neumann, M.; Miesch, M.; Kempf, H. Tetrahedron 1988, 44, 2933.
For nucleophilic displacement of halogen in cyclopropyl halides with
nitrogen-based nucleophiles, see: (c) Kang, S. Y.; Lee, S.-H.; Seo, H. J.;
Jung, M. E.; Ahn, K.; Kim, J.; Lee, J. Bioorg. Med. Chem. Lett. 2008, 18,
2385. (d) Basle, E.; Jean, M.; Gouault, N.; Renault, J.; Uriac, P.
Tetrahedron Lett. 2007, 48, 8138. (e) Liang, G.-B.; Qian, X.; Feng, D.;
Biftu, T.; Eiermann, G.; He, H.; Leiting, B.; Lyons, K.; Petrov, A.;
Sinha-Roy, R.; Zhang, B.; Wu, J.; Zhang, X.; Thornberry, N. A.; Weber,
A. E. Bioorg. Med. Chem. Lett. 2007, 17, 1903.
(22) (a) Yang, Y.; Fordyce, E. A. F.; Chen, F. Y.; Lam, H. W. Angew.
Chem., Int. Ed. 2008, 47, 7350. (b) Ma, S. Pur. Appl. Chem. 2008, 80,
695. (c) Chen, J.; Maz, S. J. Org. Chem. 2009, 74, 5595. (d) Ma, S.;
Zhang, J.; Lu, L.; Jin, X.; Cai, Y.; Hou, H. Chem. Commun. 2005, 909.
(e) Ma, S.; Zhang, J.; Cai, Y.; Lu, L. J. Am. Chem. Soc. 2003, 125,
13954. (f) Nakamura, I.; Bajracharya, G. B.; Yamamoto, Y. J. Org.
Chem. 2003, 68, 2297.
(23) (a) Jonczyk, A.; Kocmierowski, T.; Zdrojewski, T. New J. Chem.
2003, 27, 295. (b) Ishihara, T.; Kudaka, T.; Ando, T. Tetrahedron Lett.
1984, 25, 4765. (c) Parham, W. E.; McKown, W. D.; Nelson, V.;
Kajigaeshi, S.; Ishikawa, N. J. Org. Chem. 1973, 38, 1361. (d) Taylor, E.
C.; Hu, B. Synth. Commun. 1996, 26, 1041.
(24) Tran, T. P.; Ellsworth, E. L.; Stier, M. A.; Domagala, J. M.;
Showalter, H. D. H.; Gracheck, S. J.; Shapiro, M. A.; Joannides, T. E.;
Singh, R. Bioorg. Med. Chem. Lett. 2004, 14, 4405.
(25) Alnasleh, B. K.; Sherrill, W. M.; Rubina, M.; Banning, J.; Rubin,
M. J. Am. Chem. Soc. 2009, 131, 6906.
(26) (a) Banning, J. E.; Prosser, A. R.; Rubin, M. Org. Lett. 2010, 12,
1488. (b) Banning, J. E.; Prosser, A. R.; Alnasleh, B. K.; Smarker, J.;
Rubina, M.; Rubin, M. J. Org. Chem. 2011, 76, 3968.
(27) For similar chemoselectivity in addition of aminoalcohols to
cyclopropenes, see: Sharvin, K. N.; Gvozdev, V. D.; Nefedov, O. M.
Russ. Chem. Bull. 2008, 57, 2117.
(28) Sherrill, W. M.; Kim, R.; Rubin, M. Synthesis 2009, 1477.
(29) Sherrill, W. M.; Kim, R.; Rubin, M. Tetrahedron 2010, 4947.
(30) (a) Sherrill, W. M.; Kim, R.; Rubin, M. Tetrahedron 2008, 64,
8610. (b) Rubin, M.; Gevorgyan, V. Synthesis 2004, 796.
(31) Cyclopropene 11a decomposes rapidly unless intercepted with a
nucleophile. Although never observed directly, this intermediate was
proved in the reaction of 1a with phenoxides.
(32) See Supporting Information for details.
(33) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373.
(34) See, for example: (a) Mitsunobu, O. Synthesis 1981, 1.
(b) Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.;
Harris, G. D., Jr.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709.
(13) For leading reviews, see: (a) Salaun, J.; Baird, M. S. Curr. Med.
̈
Chem. 1995, 2, 511. (b) Salaun, J. Top. Curr. Chem. 2000, 207, 1.
̈
(14) For recent reviews, see: (a) Mel’nikov, M. Ya.; Budynina, E. M.;
Ivanova, O. A.; Trushkov, I. V. Mendeleev Commun. 2011, 21, 293.
(b) Tang, P.; Quin, Y. Synthesis 2012, 2969. (c) Wang, Z. Synlett 2012,
2311.
(15) (a) Bubert, C.; Cabrele, C.; Reiser, O. Synlett 1997, 827.
(b) Voigt, J.; Noltemeyer, M.; Reiser, O. Synlett 1997, 202. (c) Melby,
T.; Hughes, R. A.; Hansen, T. Synlett 2007, 2277.
(16) Prosser, A. R.; Banning, J. E.; Rubina, M.; Rubin, M. Org. Lett.
2010, 12, 3968.
̂
(c) Tsunoda, T.; Yamamoto, H.; Goda, K.; Ito, S. Tetrahedron Lett.
1996, 37, 2457. (d) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.
(e) Guisado, C.; Waterhouse, J. E.; Prince, W. S.; Jorgensen, M. R.;
Miller, A. D. Org. Biomol. Chem. 2005, 3, 1049.
(17) Ryabchuk, P.; Rubina, M.; Xu, J.; Rubin, M. Org. Lett. 2012, 14,
1752.
(35) See, for example: (a) Witek, J.; Weinreb, S. M. Org. Lett. 2011,
13, 1258. (b) Kumar, P.; Li, P.; Korbukh, I.; Wang, T. L.; Yennawar,
H.; Weinreb, S. M. J. Org. Chem. 2011, 76, 2094. (c) Kim, J. N.;
Chung, Y. M.; Im, Y. J. Tetrahedron Lett. 2002, 43, 6209. (d) Kim, J.
N.; Lee, H. J.; Lee, K. Y.; Kim, H. S. Tetrahedron Lett. 2001, 42, 3737.
(36) (a) Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346,
1599. (b) Hicks, J. D.; Hyde, A. M.; Martinez Cuezva, A.; Buchwald, S.
L. J. Am. Chem. Soc. 2009, 131, 16720. (c) Kubo, T.; Katoh, C.;
Yamada, K.; Okano, K.; Tokuyama, H.; Fukuyama, T. Tetrahedron
2008, 64, 11230.
(18) See for example: (a) Inokuma, T.; Sakamoto, S.; Takemoto, Y.
Synlett 2009, 1627. (b) Fan, R.; Ye, Y.; Li, W.; Wang, L. Adv. Synth.
Catal. 2008, 350, 2488. (c) Zhang, J.; Hu, Z.; Dong, L.; Xuan, Y.; Lou,
C.-L.; Yan, M. Tetrahedron: Asymmetry 2009, 20, 355. (d) Lv, J.;
Zhang, J.; Lin, Z.; Wang, Y. Chem.Eur. J. 2009, 15, 972.
(19) See for example Zhu, S.; Perman, J. A.; Zhang, X. P. Angew.
Chem., Int. Ed. 2008, 47, 8460.
(20) For discussion, see: (a) Miller, J. A.; Hennessy, E. J.; Marshall,
W. J.; Scialdone, M. A.; Nguyen, S. T. J. Org. Chem. 2003, 68, 7884.
O
dx.doi.org/10.1021/jo4011798 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(37) (a) Xiao, B.; Gong, T.-J.; Xu, J.; Liu, Z.-J.; Liu, L. J. Am. Chem.
Soc. 2011, 133, 1466. For review, see: (b) Lyons, T. W.; Sanford, M.
S. Chem. Rev. 2010, 110, 1147.
(38) (a) Qiao, J. X.; Cheney, D. L.; Alexander, R. S.; Smallwood, A.
M.; King, S. R.; He, K.; Rendina, A. R.; Luettgen, J. M.; Knabb, R. M.;
Wexler, R. R.; Lam, P. Y. S. Bioorg. Med. Chem. Lett. 2008, 18, 4118.
(b) Qiao, J. X.; King, S. R.; He, K.; Wong, P. C.; Rendina, A. R.;
Luettgen, J. M.; Xin, B.; Knabb, R. M.; Wexler, R. R.; Lam, P. Y. S.
Bioorg. Med. Chem. Lett. 2009, 19, 462.
(39) Cee, V. J.; Frohn, M.; Lanman, B. A.; Golden, J.; Muller, K.;
Neira, S.; Pickrell, A.; Arnett, H.; Buys, J.; Gore, A.; Fiorino, M.;
Horner, M.; Itano, A.; Lee, M. R.; McElvain, M.; Middleton, S.;
Schrag, M.; Rivenzon-Segal, D.; Vargas, H. M.; Xu, H.; Xu, Y.; Zhang,
(53) (a) Boncel, S.; Mączka, M.; Walczak, K. Z. Tetrahedron 2010,
66, 8450. (b) Boncel, S.; Saletra, K.; Hefczyc, B.; Walczak, K. Z.
Beilstein J. Org. Chem. 2011, 7, 173.
(54) Similar push-effect was recently described in the ring-opening of
cyclopropanol derivatives. See: Delaye, P. O.; Didier, D.; Marek, I.
Angew. Chem., Int. Ed. 2013, 52, 5333.
(55) Katritzky, A. R.; Cai, C.; Singh, S. K. J. Org. Chem. 2006, 71,
3375.
(56) Maki, T.; Ishihara, K.; Yamamoto, H. Org. Lett. 2005, 7, 5043.
(57) Watson, A. J. A.; Maxwell, A. C.; Williams, J. M. J. J. Org. Chem.
2011, 76, 2328.
(58) Barange, D. K.; Tu, Y.-C.; Kavala, V.; Kuo, C.-W.; Yao, C.-F.
Adv. Synth. Catal. 2011, 353, 41.
(59) Johnson, D. C.; Widlanski, T. S. Tetrahedron Lett. 2004, 46,
X.; Siu, J.; Wong, M.; Burli, R. W. ACS Med. Chem. Lett. 2011, 2, 107.
̈
8483.
(40) (a) Skerlj, R. T.; Bastos, C. M.; Booker, M. L.; Kramer, M. L.;
Barker, R. H.; Celatka, C. A., Jr.; O’Shea, T. J.; Munoz, B.; Sidhu, A. B.;
Cortese, J. F.; Wittlin, S.; Papastogiannidis, P.; Angulo-Barturen, I.;
Jimenez-Diaz, M. B.; Sybertz, E. ACS Med. Chem. Lett. 2011, 2, 708.
(b) Rueda, L.; Castellote, I.; Castro-Pichel, J.; Chaparro, M. J.; de la
Rosa, J. C.; Garcia-Perez, A.; Gordo, M.; Jimenez-Diaz, M. B.; Kessler,
A.; Macdonald, S. J. F.; Martinez, M. S.; Sanz, L. M.; Gamo, F. J.;
Fernandez, E. ACS Med. Chem. Lett. 2011, 2, 840.
(60) Kamal, A.; Reddy, J. S.; Bharathi, E. V.; Dastagiri, D. Tetrahedron
Lett. 2008, 49, 348.
(61) Garcia Ruano, J. L.; Parra, A.; Marzo, L.; Yuste, F.; Mastranzo,
V. M. Tetrahedron 2011, 67, 2905.
(62) Fan, R.; Pu, D.; Wen, F.; Wu, J. J. Org. Chem. 2007, 72, 8994.
(63) Shi, F.; Tse, M. K.; Zhou, S.; Pohl, M.-M.; Radnik, J.; Huebner,
S.; Jaehnisch, K.; Brueckner, A.; Beller, M. J. Am. Chem. Soc. 2009, 131,
1775.
(64) Jacob, P.; Richter, W.; Ugi, I. Lieb. Ann. Chem 1991, 519.
(65) Chen, J.; Dang, L.; Li, Q.; Ye, Y.; Fu, S.; Zeng, W. Synlett 2012,
595.
(66) Hamid, M. H. S. A.; Allen, C. L.; Maxwell, A. C.; Maytum, H.
C.; Watson, A. J. A.; Williams, J. M. J. J. Am. Chem. Soc. 2009, 131,
1766.
(67) Xie, J.; Xinhai, Z.; Huang, M.; Meng, F.; Chen, W.; Wan, Y. Eur.
J. Org. Chem. 2010, 3219.
(68) Likhar, P. R.; Arundhathi, R.; Kantam, M. L.; Prathima, P. S.
Eur. J. Org. Chem. 2009, 5383.
(69) Yang, M.; Liu, F. J. Org. Chem. 2007, 72, 8969.
(41) (a) Benelkebir, H.; Hodgkinson, C.; Duriez, P. J.; Hayden, A. L.;
Bulleid, R. A.; Crabb, S. J.; Packham, G.; Ganesan, A. Bioorg. Med.
Chem. Lett. 2011, 19, 3709. (b) Noolvi, M. N.; Patel, H. M.; Singh, N.;
Gadad, A. K.; Cameotra, S. S.; Badiger, A. Eur. J. Med. Chem. 2011, 46,
4411.
(42) (a) Antunes, A. M. M.; Novais, D. A.; da Silva, J. L. F.; Santos, P.
P.; Oliveira, M. C.; Beland, F. A.; Marques, M. M. Org. Biomol. Chem.
2011, 9, 7822. (b) McCauley, J. A.; McIntyre, C. J.; Rudd, M. T.;
Nguyen, K. T.; Romano, J. J.; Butcher, J. W.; Gilbert, K. F.; Bush, K. J.;
Holloway, M. K.; Swestock, J.; Wan, B.-L.; Carroll, S. S.; DiMuzio, J.
M.; Graham, D. J.; Ludmerer, S. W.; Mao, S.-S.; Stahlhut, M. W.;
Fandozzi, C. M.; Trainor, N.; Olsen, D. B.; Vacca, J. P.; Liverton, N. J.
J. Med. Chem. 2010, 53, 2443.
(43) Chen, G.; Cho, S. J.; Huang, X.-P.; Jensen, N. H.; Svennebring,
A.; Sassano, M. F.; Roth, B. L.; Kozikowski, A. P. ACS Med. Chem. Lett.
2011, 2, 929.
(44) (a) Pavlovic,
2010, 18, 8566. (b) Pavlovic,
́
D.; Fajdetic,
́
A.; Mutak, S. Bioorg. Med. Chem.
́
D.; Mutak, S. ACS Med. Chem. Lett.
2011, 2, 331. (c) Tripathi, R. P.; Pandey, J.; Kukshal, V.; Ajay, A.;
Mishra, M.; Dube, D.; Chopra, D.; Dwivedi, R.; Chaturvedi, V.;
Ramachandran, R. Med. Chem. Commun. 2011, 2, 378. (d) Wetzstein,
H.-G.; Hallenbach, W. J. Antimicrob. Chemother. 2011, 66, 2801.
(45) (a) Marrazzo, A.; Cobos, E. J.; Parenti, C.; Arico,
G.; Ronsisvalle, S.; Pasquinucci, L.; Prezzavento, O.; Colabufo, N. A.;
Contino, M.; Gonzalez, L. G.; Scoto, G. M.; Ronsisvalle, G. J. Med.
̀
G.; Marrazzo,
́
Chem. 2011, 54, 3669. (b) Butcher, K. J.; Denton, S. M.; Field, S. E.;
Gillmore, A. T.; Harbottle, G. W.; Howard, R. M.; Laity, D. A.; Ngono,
C. J.; Pibworth, B. A. Org. Process Res. Dev. 2011, 15, 1192.
(46) (a) Benard, S.; Neuville, L.; Zhu, J. J. Org. Chem. 2008, 73, 6441.
(b) Tsuritani, T.; Strotman, N. A.; Yamamoto, Y.; Kawasaki, M.;
Yasuda, N.; Mase, T. Org. Lett. 2008, 10, 1653.
(47) Gagnon, A.; St-Onge, M.; Little, K.; Duplessis, M.; Barabe, F. J.
Am. Chem. Soc. 2007, 129, 44.
(48) Satoh, T.; Miura, M.; Sakai, K.; Yokoyama, Y. Tetrahedron 2006,
62, 4253.
(49) Reported yields did not exceed 13%. See: (a) Lambertucci, C.;
Antonini, I.; Buccioni, M.; Ben, Dal; Kachare, D.; Volpini, D. D.; Klotz,
R.; Cristalli, K.-N.; Bioorg., G. Med. Chem. 2009, 17, 2812. (b) Kaur,
N.; Monga, V.; Jain, R. Tetrahedron Lett. 2004, 45, 6883.
(50) Houlihan, W. J. Indoles; Wiley: New York, NY, 1972; Vol. 1, p
71.
(51) Shaw, G.; Wamhoff, H.; Butler, R. N. In Comprehensive
Heterocyclic Chemistry; Katritzky, A. L., Rees, C. W., Potts, K. T., Eds.;
Pergamon: Oxford, 1984; Vol. 5, Chapter 4.11.
(52) For aza-Michael addition of triazoles, see: (a) Gandelman, M.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 2393. (b) Luo, G.;
Zhang, S.; Duan, W.; Wang, W. Synthesis 2009, 1564.
P
dx.doi.org/10.1021/jo4011798 | J. Org. Chem. XXXX, XXX, XXX−XXX