Cyclopropylamines from N,N-dialkylcarboxamides and grignard reagents in the presence of titanium tetraisopropoxide or methyltitanium triisopropoxide

Article abstract of DOI:10.1002/chem.201001550

Thirty-three different N,N-dialkyl- and N-alkyl-N-phosphorylalkyl- substituted carboxamides 9-17 were treated with unsubstituted as well as with 2-alkyl-, 2,2-dialkyl-, and 3-alkenyl-substituted ethylmagnesium bromides 6 in the presence of stoichiometric amounts of titanium tetraisopropoxide or methyltitanium triisopropoxide to furnish substituted cyclopropylamines 20-25 in 20-98 % yield, depending on the substituents with no (1:1) to excellent (>25:1) diastereoselectivities. Generally higher yields (up to 98 %) of the cyclopropylamines 20-28 without loss of the diastereoselectivity were obtained with methyltitanium triisopropoxide as the titanium mediator. Under these conditions, even dioxolane-protected ketones and halogen-substituted and chiral as well as achiral alkyloxyalkyl-substituted carboxamides could be converted to the correspondingly substituted cyclopropylamines with unsubstituted as well as phenyl- and a variety of alkyl-substituted ethylmagnesium bromides in addition to numerous heteroatom-containing (e.g., halogen-, trityloxy-, tetrahydropyranyloxy-substituted) Grignard reagents (62 examples altogether). The transformation of N,N-diformylalkylamines 54 with ethylmagnesium bromide in the presence of methyltitanium triisopropoxide to N,N-dicyclopropyl-N- alkylamines 55 can be brought about in up to 82 % yield (6 examples). An asymmetric variant of the titanium-mediated cyclopropanation of N,N-dialkylcarboxamides has been developed by applying chiral titanium mediators generated from stoichiometric amounts of titanium tetraisopropoxide and chiral diamino or diol ligands, respectively. The most efficient chiral mediators turned out to be titanium bistaddolates that provided the corresponding cyclopropylamines with enantiomeric excesses (ee) of up to 84 %. Evaluation of several silyl-based additives revealed that the reaction can also efficiently be carried out with substoichiometric amounts (down to 25 Mol %) of the titanium reagent, as long as 2-aryl- or 2-ethenyl-substituted ethylmagnesium halides are used and a concomitant slight decrease in yields is accepted. The newly developed methodology was successfully applied for the preparation of analogues with cyclopropylamine moieties of known drugs and natural products such as the nicotine metabolite (S)-Cotinine as well as the insecticides Dinotefuran and Imidacloprid. Ti is it: Cyclopropylamines have been obtained in low to excellent yield through the reaction of different N,N-dialkyl- and N-alkyl-N- phosphorylalkyl-substituted carboxamides with Grignard reagents in the presence of stoichiometric amounts of titanium tetraisopropoxide or methyltitanium triisopropoxide (see scheme). Copyright

Full text of DOI:10.1002/chem.201001550

DOI: 10.1002/chem.201001550
Cyclopropylamines from N,N-Dialkylcarboxamides and Grignard Reagents
in the Presence of Titanium Tetraisopropoxide or Methyltitanium
Triisopropoxide**
Armin de Meijere,*[a] Vladimir Chaplinski,[a] Harald Winsel,[a] Markus Kordes,[a]
Bjçrn Stecker,[a] Vesta Gazizova,[a] Andrei I. Savchenko,[a] Roland Boese,[b] and
Farina Schill (nꢀe Brackmann)[a]
Dedicated to Professor Ryoji Noyori on the occasion of his birthday
Abstract: Thirty-three different N,N-di-
alkyl- and N-alkyl-N-phosphorylalkyl-
substituted carboxamides 9–17 were
treated with unsubstituted as well as
with 2-alkyl-, 2,2-dialkyl-, and 3-alken-
yl-substituted ethylmagnesium bro-
mides 6 in the presence of stoichiomet-
ric amounts of titanium tetraisopropox-
ide or methyltitanium triisopropoxide
to furnish substituted cyclopropyl-
amines 20–25 in 20–98% yield, depend-
ing on the substituents with no (1:1) to
excellent (>25:1) diastereoselectivities.
Generally higher yields (up to 98%) of
the cyclopropylamines 20–28 without
loss of the diastereoselectivity were ob-
tained with methyltitanium triisoprop-
oxide as the titanium mediator. Under
these conditions, even dioxolane-pro-
tected ketones and halogen-substituted
and chiral as well as achiral alkyloxy-
alkyl-substituted carboxamides could
be converted to the correspondingly
substituted cyclopropylamines with un-
substituted as well as phenyl- and a va-
riety of alkyl-substituted ethylmagnesi-
um bromides in addition to numerous
heteroatom-containing (e.g., halogen-,
trityloxy-, tetrahydropyranyloxy-substi-
tuted) Grignard reagents (62 examples
altogether). The transformation of
N,N-diformylalkylamines 54 with ethyl-
magnesium bromide in the presence of
methyltitanium triisopropoxide to N,N-
dicyclopropyl-N-alkylamines 55 can be
brought about in up to 82% yield (6
examples). An asymmetric variant of
the titanium-mediated cyclopropana-
tion of N,N-dialkylcarboxamides has
been developed by applying chiral tita-
nium mediators generated from stoi-
chiometric amounts of titanium tetra-
isopropoxide and chiral diamino or
diol ligands, respectively. The most effi-
cient chiral mediators turned out to be
titanium bistaddolates that provided
the corresponding cyclopropylamines
with enantiomeric excesses (ee) of up
to 84%. Evaluation of several silyl-
based additives revealed that the reac-
tion can also efficiently be carried out
with substoichiometric amounts (down
to 25 mol%) of the titanium reagent,
as long as 2-aryl- or 2-ethenyl-substitut-
ed ethylmagnesium halides are used
and a concomitant slight decrease in
yields is accepted. The newly devel-
oped methodology was successfully ap-
plied for the preparation of analogues
with cyclopropylamine moieties of
known drugs and natural products such
as the nicotine metabolite (S)-Cotinine
as well as the insecticides Dinotefuran
and Imidacloprid.
Keywords: amines
· enantioselec-
tivity · organometallics · small ring
systems · titanium
[a] Prof. Dr. A. de Meijere, Dr. V. Chaplinski, Dr. H. Winsel,
Dr. M. Kordes, Dr. B. Stecker, Dr. V. Gazizova, Dr. A. I. Savchenko,
Dr. F. Schill (nꢀe Brackmann)
[+] Crystal-structure analyses.
[**] Cyclopropyl Building Blocks for Organic Synthesis, Part 156; Part
155: A. Lygin, M. Limbach, A. Janssen, V. S. Korotkov, C. Funke, A.
de Meijere, Eur. J. Org. Chem. 2010, 3665–3671.
Institut fꢁr Organische und Biomolekulare Chemie
der Georg-August-Universitꢂt
Tammannstrasse 2, 37077 Gçttingen (Germany)
Fax : (+49)551-399475
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001550. It contains general
remarks, experimental details, compound characterization data, X-ray
crystal-structure analysis data, and details of the compound number-
ing.
E-mail: Armin.deMeijere@chemie.uni-goettingen.de
[b] Prof. Dr. R. Boese+
Institut fꢁr Anorganische Chemie, Universitꢂt Essen
Universitꢂtsstrasse 3–5, 45117 Essen (Germany)
Fax : (+49)201-183-2535
13862
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 13862 – 13875

FULL PAPER
Introduction
The aminocyclopropyl moiety is a key constituent in a varie-
ty of natural and non-natural compounds that exhibit impor-
tant biological activities. For example, 1-aminocyclopropane-
carboxylic acid (ACC, 1) is present in every plant on this
Scheme 1. Preparation of cyclopropylamines 20–28 from carboxamides
9–17 in the presence of TiACHTNUGTRNEUNG(OiPr)4. For details, see Tables 1 and 2.
Results and Discussion
Reductive cyclopropanation of N,N-dialkylcarboxamides in
the presence of titanium tetraisopropoxide: On the basis of
our own observations and stereochemical investigations by
Casey et al.,[15] the title reaction can best be described as
proceeding by means of an oxatitanacyclopentane 18,
formed by insertion of the amide carbonyl group into a tita-
nacyclopropane 7, which can also be described as the titani-
um-alkene complex 8, formed in situ from two molecules of
the alkylmagnesium halide 6 and a titanium tetraalkoxide
such as the most commonly used titanium tetraisopropoxide.
This occurs with retention of configuration at the carbon
planet as the immediate precursor to the plant hormone eth-
ylene, which plays a pivotal role in the induction of flower-
ing, fruit ripening, leaf wilting, and several other plant phys-
iological processes.[1] The Streptomyces sp. UCK 14 metabo-
lite Belactosin A (2) and its derivatives, which contain the
unusual 2-trans-(2-aminocyclopropyl)alanine residue, exhibit
remarkable proteasome inhibitory activities.[2] The simple
trans-2-phenylcyclopropylamine (3) is in use as an antide-
pressant (generic name Tranylcypramine).[3] The diazepi-
none derivative Nevirapine (4) is an anti-HIV drug candi-
date,[4] and the N-cyclopropylquinolone derivative Cipro-
floxacin (5) is an important commercial antiinfectant.[5]
Until about 20 years ago, synthetic accesses to cyclopro-
pylamines and the installation of a cyclopropyl residue on
nitrogen heterocycles was rather limited.[6–8] Vilsmeier et al.
pioneered and developed new accesses, in particular to in-
teresting bicyclic cyclopropylamines from easily available 3-
chloro-2-dialkylaminocycloalk-1-enes.[7] This was preceded
and followed by other developments, mostly for specific
target cyclopropylamines.[6,8] The advent of the titanium-cat-
alyzed conversion of carboxylic acid esters to cyclopropanols
(the Kulinkovich reaction)[9] has spurred our forays into the
chemistry of organotitanium reagents and culminated in the
discovery in 1996 of the novel and straightforward access to
N,N-disubstituted cyclopropylamines from N,N-dialkylcar-
boxamides and alkylmagnesium halides in the presence of
titanium tetraisopropoxide or, even better, methyltitanium
triisopropoxide (Scheme 1).[10] The succeeding years have
witnessed a host of modifications and applications of this ex-
tremely useful transformation.[11–14] To this end, we wish to
disclose our hitherto unpublished results and experimental
details in this area, which have been collected over the last
decade up to the present date.
À
center, which is involved in the C C bond formation. Due
to the oxophilicity of titanium and the poor nucleofugic
characteristics of the dialkylamino group, this intermediate
evolves into the 1,6-zwitterion 19 with a titanium oxide
anion and an iminium cation terminus. Subsequent ring clo-
sure, with inversion of configuration at the carbon bound to
titanium, leads to the N,N-dialkylcyclopropylamines 20–28
(Scheme 1).
The reaction generally proceeds in good yields (up to
92%) with N,N-dialkylcarboxamides of sterically noncon-
gested carboxylic acids (Table 1). Thus, the reactions of for-
mamides, acetamides, and propion- and n-butyramides with
ethylmagnesium bromide (6a) in the presence of stoichio-
metric amounts of titanium tetraisopropoxide readily furnish
the corresponding 1-alkyl-N,N-cyclopropylamines in 20–
76% yield (Table 1, entries 1–10). Likewise, applications of
2-alkyl- or 2-alkenyl-substituted Grignard reagents, respec-
tively, provide the corresponding 2-substituted as well as
1,2-disubstituted cyclopropylamines in 35–63% yield (en-
tries 11–18), and the 2,2-dialkyl-substituted isobutylmagnesi-
um bromide gave rise to the corresponding 1,2,2-trisubstitut-
ed cyclopropylamine (entry 19). Even 1-phosphorylethyl-
substituted cyclopropylamines could be synthesized in mod-
erate yields (39–47%) by reaction of the correspondingly
substituted carboxamides with either unsubstituted or 2-
alkyl-substituted ethylmagnesium bromides (entries 20–22),
Chem. Eur. J. 2010, 16, 13862 – 13875
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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13863

A. de Meijere, R. Boese et al.
Table 1. Cyclopropylamines 20–25 from carboxamides 9–14 and unsubstituted as well as substituted EtMgBr 6
in the presence of Ti(OiPr)4 (see Scheme 1).
most highly congested tertiary
amine known to date, the N,N-
di-tert-butylcyclopropylamine
(24aa), can be prepared by this
method. As an X-ray crystal-
structure analysis of cyclopro-
pyldiisopropylamine (25aa) re-
vealed, the steric crowding in
this tertiary amine does not
lead to quite as much flattening
of the central nitrogen (sum of
C-N-C angles 340.08)[16] as in
triisopropylamine (sum of C-N-
C angles 350.48).[17]
The reactions usually proceed
with moderate stereoselectivies
(up to 2.5:1–3:1), thereby re-
flecting reduced steric interac-
tions between the upcoming di-
alkylamino group and the sub-
stituent R1 (R2) in the transition
structure between the inter-
mediate 19 and the products
20–28. In certain cases (e.g.,
Table 1, entry 18), however, a
rather high level of diastereo-
control does occur, and this is
ACHTUNGTRENNUNG
Entry
6
R1
R2 Amide R3
R4
Product Yield [%] (d.r.)[a]
2
1
2
3
4
5
6
7
8
a
a
a
a
a
a
a
a
a
a
b
b
c
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
9a
9b
9c
9d
10a
10b
11a
12a
13a
14a
9b
9c
9d
9a
9a
10b
9b
9a
H
Bn2
Bn2
Bn2
Bn2
Me2
Me2
À
20aa
20ab
20ac
20ad
21aa
21ab
22aa
23aa
24aa
25aa
20bb
20bc
20 cd
20ba
20ca
21cb
20 db
20ea
20 fb
21ae
21be
21de
20ga
20ha
69
60
63
52
73
56
74
74
Me
Et
nPr
H
Me
H
H
H
H
Me
Et
nPr
H
À
(CH2)5
À
E
À
U
9
H
H
E
20
76
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
E
Me
Me
nBu
Me
nBu
nBu
Et
CH2=CH
Me2
H
Me
Et
Bn2
Bn2
Bn2
Bn2
Bn2
Me2
Bn2
Bn2
Bn2
50[b]
38[b]
35[b]
63 (1:1)
52 (1:2.3)
37[b]
47[b]
42 (>25:1)
51
b
c
c
H
Me
Me
H
Me
G
d
e
f
a
b
d
g
h
À
[c]
9b
10e
10e
10e
9a
E
47
N
E
39 (8.5:1)
42 (10:1)
63–92[d]
34[d]
A
ACHTUNGTRENNUNG
À
À
À
G
H
H
Bn2
Bn2
À
(CH2)4
E
9a
[a] d.r.=diastereomeric ratio. [b] Only one diastereomer was isolated, presumably with an E configuration.
[c] 2,2-Dimethylcyclopropyl derivative. [d] Only the exo isomer was isolated.
and employment of cyclic Grignard reagents furnished bicy-
clic, that is, ring-annelated cyclopropylamines in low to very
good yields of 34–92% (entries 23 and 24).
Likewise, with N-substituted lactams 29 and 31 as the
amide starting materials, spirocyclopropanated nitrogen het-
erocycles 30 and 32 can be prepared (Scheme 2).
apparently due to stabilizing polar interactions between the
partially negatively charged allyl moiety and the cationic
iminium terminus in the transition structure derived from
19. Unlike the transformation of carboxylic acid esters to cy-
clopropanols, in which a tetraalkoxytitanium species is con-
stantly being regenerated, the transformation of N,N-di-
alkylcarboxamides 9–17 to cyclopropylamines 20–28 is non-
catalytic in titanium, since the oxotitanium side product
most probably is oligomeric and thus can no longer partici-
pate in the reaction.
Reductive cyclopropanation of N,N-dialkylcarboxamides in
the presence of methyltitanium triisopropoxide: Methyltita-
nium triisopropoxide has been found to be a superior titani-
um reagent for the reductive cyclopropanation of N,N-dia-
lkylcarboxamides.[10b,18] Its advantage over titanium tetraiso-
propoxide derives from the possibility that it more rapidly
reacts with the Grignard reagent to give the alkylmethyltita-
nium diisopropoxide 33, which, by b-hydride transfer from
the alkyl to the methyl group, selectively cleaves off meth-
ane to furnish the key reactive intermediate 7. In compari-
son, the more sterically congested titanium tetraisopropox-
ide has to undergo two consecutive exchanges of isopropox-
ide with alkyl ligands from the Grignard reagent to provide
the dialkyltitanium diisopropoxide as a precursor to the tita-
nacyclopropane 7 or the titanium-alkene complex 8, respec-
tively. Thus, the use of methyltitanium triisopropoxide has
the additional advantage that only one equivalent of a—po-
tentially precious—alkylmagnesium halide 6 is consumed to
produce the immediate precursor 7 to the cyclopropylamine
Scheme 2. Preparation of spirocyclopropane-annelated nitrogen heterocy-
cles from N-substituted lactams.
It can be concluded that the nature of the substituents on
the amide nitrogen does not impose severe limitations on
the reactivity, as long as they tolerate the moderately Lewis
acidic reaction media; however, a significant drop in yields
is observed with a drastic increase in the steric bulk of the
substituents in the substrates and reagents. Thus, on going
from N,N-diisopropylformamide (14a) to N,N-di-tert-butyl-
formamide (13a), the yield of the resulting corresponding
N,N-dialkylcyclopropylamine drops from 76% for 25aa to
20% for 24aa (Table 1, entries 10 and 9). Yet the sterically
13864
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Chem. Eur. J. 2010, 16, 13862 – 13875

Cyclopropylamines
FULL PAPER
20–28, and with the use of more than one equivalent of 6,
the achievable yields of the desired products are improved
(Scheme 3).
39a, albeit only in very low to moderate yields (2–53%).
This might be a consequence of the steric congestion by the
trityl group or a facile elimination of the trityloxy group
from the Grignard reagent (Scheme 4; Table 3, entries 1–6).
Likewise, use of tetrahydropyranyloxyalkylmagnesium hal-
ides gave the corresponding cyclopropylamines 40a–43a
(entries 7–10); however, the yields remained low to moder-
ate (14–48%) and could not be improved significantly by
application of a benzyloxy- or a tert-butyloxyalkyl Grignard
reagent (entries 11 and 12). In contrast, a protected ketone
functionality could be brought in with excellent yield (92%)
by using the dioxolane-containing butylmagnesium bromide
46 to furnish cyclopropylamine 47a (Scheme 4).
In analogy to the reductive cyclopropanation of e-capro-
lactam 29 mediated by titanium tetraisopropoxide (see
Scheme 2), the spirocyclopropanated azacycloheptane 30
can also be prepared using methyltitanium triisopropoxide,
and in an even higher yield (47 versus 33%). An intramo-
lecular reductive cyclopropanation of the amide carbonyl
group in 6-bromo-N,N-dimethylhexaneamide (48) by the al-
kylmagnesium bromide terminus generated in situ furnished
the fused bicyclic cyclopropylamine 49, albeit in a rather
low yield of 28%. Cyclobutylmagnesium bromide with N,N-
dimethyl- (9b) and N,N-dibenzylformamide (9a) provided
Scheme 3. Preparation of cyclopropylamines 20–28 from carboxamides
9–17 in the presence of MeTiACTHNUTRGNE(UNG OiPr)3. For details, see Table 2.
In analogy to the reductive cyclopropanation of N,N-di-
alkylcarboxamides 9–17 with ethylmagnesium bromide in
the presence of stoichiometric amounts of titanium tetraiso-
propoxide, a large variety of N,N-dialkylcarboxamides and
-formamides in the presence of stoichiometric amounts of
methyltitanium triisopropoxide have been converted to the
corresponding 1-substituted cyclopropylamines 20–28 in
moderate to excellent yields (up to 96%) depending on the
steric congestion evoked by the amide substituent R3
(Scheme 3; Table 2, entries 1–16). Among the latter were
even amides with benzyloxyalkyl and chloroalkyl (entries 11
and 12) as well as dioxolane moieties (entries 13 and 14),
which furnished the correspondingly 1-substituted cyclopro-
pylamines in 38–85% yield. Likewise, several 2-substituted
ethylmagnesium bromides were successfully employed,
thereby providing 2-alkyl- (entries 17–19 and 21–24), 2-al-
kenyl- (entries 20, 25, 28, 29, 32, 37, and 43), and 2-aryl-sub-
stituted (entries 26 and 27) cyclopropylamines. Phosphonate
and phosphine oxide moieties are tolerated in the carbox-
amide and remain unaffected by the organotitanium species.
Accordingly, interesting and potentially useful isosters of g-
aminocarboxylic acids as well as cyclopropyl analogues of 3-
aminoalkylphosphines were prepared in 21–86% yield (en-
tries 30–39). Carboxamides 9v and 9w derived from (S)-
lactic acid were succesfully transformed with several
Grignard reagents to the corresponding cyclopropylamines
in 56–63% yield (entries 40–43); however, when 2-substitut-
ed Grignard reagents were used, mixtures of all four possi-
ble diastereomers were obtained, thus indicating that virtu-
ally no stereocontrol was exerted by the stereogenic center
in the starting material (entries 42 and 43).
the corresponding bicycloACTHNURTGNEU[GN 2.1.0]pent-5-ylamines 50 and 51 in
yields of 72 and 87%, respectively (Scheme 5). The exo con-
figuration of the dimethylamino derivative 51 was unequivo-
cally proved by an X-ray crystal-structure analysis of the hy-
drooxalate 50·ACTHNUTRGNEUNG(COOH)2 formed upon treatment of an ethe-
real solution of 51 with oxalic acid dihydrate.[16]
Titanium-mediated twofold reductive cyclopropanations of
bisamides: In bisamides with two carboxamide functionali-
ties, both carbonyl groups can be transformed to cyclopropyl
moieties, even if they are attached to the same nitrogen
atom, especially as in diformylamines 53. Thus, several N-
alkyl-N,N-dicyclopropylamines 54 are readily available in
good yields (53–82%) by treactment of N-alkyldiformyl-
amines 53 with ethylmagnesium bromide (6a) in the pres-
ence of methyltitanium triisopropoxide (Scheme 6; Table 4,
entries 1–3, 5, and 6). N-Allyldiformylamine (53d) failed to
give the corresponding N-allyl-N,N-dicyclopropylamine 54d
(entry 4), which may be due to a rapid ligand exchange of
the allyl groups with ethylene in the titanacyclopropane in-
termediate of type 7.[11g] In contrast to previous observa-
tions, according to which the conversion of a tert-butyl ester
moiety to a cyclopropanol occurs much more slowly than
that of an N,N-dibenzylformamide to a cyclopropylamine,[19]
tert-butyl N,N-diformylglycinate 53g, under the conditions
employed in this context, furnished 1-(N,N-dicyclopropyl-
aminomethyl)cyclopropanol (55) as the only isolable prod-
uct in 28% yield (entry 7). The overall efficiency of this
access to the peculiar tertiary amines 54 is potentiated by
the straightforward preparation of diformylamines 53, since
the inexpensive formamide 52, upon treatment with sodium
methoxide in methanol, quantitatively yields sodium difor-
mylamide with liberation of ammonia,[20,21] which undergoes
To determine whether oxygen functionalities can be incor-
porated into the side chain on C-2 of the cyclopropylamine,
oxygen-functionalized Grignard reagents were employed in
the titanium-mediated cyclopropanation reaction. Indeed,
protected alcohol functionalities could be brought in by ap-
plication of trityloxyalkyl-substituted alkylmagnesium hal-
ides to afford the corresponding cyclopropylamines 34a–
Chem. Eur. J. 2010, 16, 13862 – 13875
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13865

A. de Meijere, R. Boese et al.
Table 2. Cyclopropylamines 20–28 from carboxamides 9–17 and unsubstituted as well as substituted EtMgBr 6
in the presence of MeTi(OiPr)3 (see Scheme 3).
Twofold cyclopropanation of
the bis(N,N-dimethyl)dicarbox-
amide 56 derived from (R,R)-
tartaric acid afforded the bis(di-
methylaminocyclopropylethane
derivative 58 in almost quanti-
tative yield. Yet an attempted
analogous transformation of the
bis(N,N-dibenzyl)dicarboxamide
57 failed completely (Scheme 7),
which must be attributed to the
steric demand of the four
benzyl groups suppressing for-
mation of the required inter-
mediate titanaoxacyclopentane
derivative analogous to 18 (see
Scheme 1).
ACHTUNGTRENNUNG
Entry
6
R1
R2 Amide R3
R4
Product Yield [%] (E/Z ratio)
2
l
2
3
4
5
6
7
8
a
a
a
a
a
a
a
a
a
a
a
a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
9a
9b
9c
9d
9 f
9g
9h
11i
9j
9k
9 L
9m
H
Me
Et
nPr
iPr
tBu
iBu
Ph
Ph
Bn
BnOACTHNUTGRNEUNG(CH2)2
Cl
Bn2
Bn2
Bn2
Bn2
Bn2
Bn2
Bn2
À
20aa
20ab
20ac
20ad
20af
20ag
20ah
20ai
96
77
70
62
44
25
56
73
63
47
38
49
À
(CH2)5
9
(CH2)2
Bn2
Bn2
Bn2
Bn2
20aj
20ak
20al
10
11
12
(CH2)2
20am
13
a
H
H
9n
Bn2
20an
20ao
53
14
a
H
H
9o
Bn2
85[a]
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
a
a
c
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
14a
15a
10b
9d
9l
10a
9a
9a
9a
9a
9a
H
H
Me
nPr
BnO
H
H
H
H
H
iPr2
Et2
25aa
26aa
21cb
20cd
20bl
21ea
20ba
20ia
20ca
20ja
20ea
20ka
22ka
27ea
20ep
20aq
21bq
21eq
21kq
28ar
21as
21bs
21es
21ks
20at
86
Enantioselective cyclopropana-
tion of N,N-dialkylcarboxa-
mides in the presence of chiral-
ly modified titanium reagents:
2-Substituted ethylmagnesium
halides 6 generally provide mix-
tures of diastereomeric 2-substi-
tuted cyclopropylamines with-
out or with moderate at best
diastereoselectivities of about
1:2 (see Table 2) in favor of the
thermodynamically more stable
E isomer. The only exception
was found upon application of
3-butenylmagnesium bromide
(6e) (homoallylmagnesium bro-
mide) on N,N-dibenzylform-
amide (9a) to yield N,N-diben-
zyl-2-ethenylcyclopropylamine
(20ea) with an E/Z ratio of
7.0:1 (Table 2, entry 25). Since
2-substituted ethylmagnesium
83
nBu
nBu
Me
CH2=CH
Me
nPr
nBu
CH2cPr
CH2=CH
Ph
Ph
CH2=CH
CH2=CH
H
Me
CH2 =CH-
Ph
H
H
Me2
Bn2
Bn2
Me2
Bn2
Bn2
Bn2
Bn2
Bn2
Bn2
À
51[b]
c
47 (10:1)
33 (1:3)
52 (10:1)
89 (1.2:1)
85 (2.1:1)
87 (2.1:1)
85 (2.2:1)
54[c] or 98 (7.0:1)
98 (2.3:1)
92 (1.5:1)
44 (7:1)
84[c]
b
e
b
i
c
j
ACHTUGNTERN(NUNG CH2)2
À
À
e
k
k
e
e
a
b
e
k
a
a
b
e
k
a
H
H
H
H
9a
À
11a
16a
9p
ACHTUGNTERN(NUNG CH2)5
À
PhMe
Bn2
Bn2
Me2
Me2
Me2
Ph2
À
CH2NBn2
9q
Ph2P(O)
Ph2P(O)
Ph2P(O)
Ph2P(O)
A
83
10q
10q
10q
17r
10s
10s
10s
10s
9t
N
80 (1:3.5)
83 (1:3)
67 (1:1.6)
21
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Ph2P
(MeO)2P(O)
(MeO)2P(O)
(MeO)2P(O)
(MeO)2P(O)
(BnO)2P(O)(CH2)2
ACHTUGNTERN(NUNG CH2)2
T
G
79
Me
CH2=CH
Ph
H
R
E
81 [1:6]
86 (1:1.6)
82 (1:1.4)
62
À
N
ACHTUNGTRENNUNG
T
ACHTUNGTRENNUNG
A
E
Bn2
Bn2
40
41
42
43
a
a
d
e
H
H
Et
H
H
H
H
9u
9v
9u
9u
20au
20av
20du
20eu
63
halides
6
in this reaction
(Scheme 2) provide chiral cy-
clopropylamines, it was of inter-
est to test whether or not a rea-
sonable level of enantioselectiv-
ity could in principle be ach-
ieved by using chiral titanium
alkoxide mediators instead of
the established methyltitanium
Bn2
Bn2
Bn2
56
58[d]
61[e]
À
CH2=CH
[a] Several previously published reviews[14] erroneously list an additional CH2 group in compounds 9o and
20ao, respectively. [b] Only one diastereomer was isolated, presumably with an E configuration. [c] Two dia- triisopropoxide. Such an asym-
stereomers were obtained, the ratio of which was not determined. [d] Four diastereomers were obtained, ratio
1:1.6:1.6:3.1. [e] Four diastereomers were obtained, ratio 1:1.3:2.1:3.2.
metric variant of a titanium-
mediated cyclopropanation had
already been described by
Corey et al. for the Kulinko-
vich-type conversion of ethyl acetate with 2-phenylmagnesi-
um bromide to (Z)-2-phenyl-1-methylcyclopropanol with an
enantiomeric excess (ee) of up to 78% by employing a stoi-
facile alkylation with various alkyl sulfates[20] and bromides
(Scheme 6).[21]
13866
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Chem. Eur. J. 2010, 16, 13862 – 13875

Cyclopropylamines
FULL PAPER
Scheme 4. Oxygen functionalities are introduced into 2-substituted cyclo-
propylamines with the help of oxygen-functionalized Grignard reagents.
For details, see Table 3.
Scheme 5. Accesses to spiroannelated and fused bicyclic cyclopropyl-
amines.
Table 3. Introducing oxygen functionalities into 2-substituted cyclopro-
pylamines with the help of of oxygen-functionalized Grignard reagents
(see Equation (1) in Scheme 4).
Entry
Amide
R4
R5
n
Product
Yield [%] (E/Z ratio)
2
1
2
3
4
5
6
7
8
10a
9a
10a
9a
10a
9a
10a
9a
10a
9a
10a
9a
Me2
Bn2
Me2
Bn2
Me2
Bn2
Me2
Bn2
Me2
Bn
Ph3C
Ph3C
Ph3C
Ph3C
Ph3C
Ph3C
THP
THP
THP
THP
Bn
3
3
4
4
5
5
4
4
5
5
4
5
34a
35a
36a
37a
38a
39a
40a
41a
42a
43a
44a
45a
18[a]
2[a]
23 (1.2:1)
36 (4.4:1)
53 (1.8:1)
34 (2.7:1)
48 (2.5:1)[b]
34 (2.1:1)[b]
51 (1.2:1)[b]
14 (1.6:1)[b]
54 (1.1:1)
59 (2:1)
Scheme 6. Synthesis of dicyclopropylamines. For details, see Table 4.
9
clohexane (DACH) 60 and (1R,2R)-N,N’-bis(trifluorometha-
nesulfonyl)-1,2-diaminodiphenylethane (DADPE) 61, or the
diol (S)-1,1’-bi-2-naphthol (BINOL) 62 did only furnish es-
sentially racemic products (Table 5, entries 1–3) with con-
comitant loss of yield (52–65% vs. 87% for the variant with
achiral methyltitanium triiso-
10
11
12
Me2
Bn2
tBu
[a] Only one diastereomer was isolated, presumably the
[b] Two diastereomeric pairs were obtained.
E isomer.
propoxide). In contrast, applica-
tion of tetraphenyldioxolanedi-
Table 4. Synthesis of dicyclopropylamines (see Scheme 6).
Entry
RX
R
N-Alkyl-N,N-
Yield
[%]
N,N-Dicyclo-
propylamine
Yield
[%]
methanol (TADDOL) 63 led to
2-butyl-N,N-dibenzylcyclopro-
pylamine (20ca) in 59% yield
with moderate enantiomeric ex-
cesses of 41% for the Z and
35% for the E isomer (entry 4).
Further improvement of the
enantiomeric excesses to 66%
diformylamine
1
2
3
4
5
6
7
N
Me
Et
nBu
All
53a
53b
53c
53d
53e
53 f
53g
70
71
74
52
97
52
99
54a
54b
54c
54d
54e
54 f
55
67
82
53
0
57
53
28
Bn
4-MeOC6H4CH2
tBuO2CCH2
chiometric amount of a chiral titanium tetraalkoxide[22] pre-
pared from an appropriately substituted chiral tetraphenyl-
dioxolanedimethanol (TADDOL) ligand and a titanium tet-
raalkoxide.[23] Encouraged by this success, the development
of similar conditions for the enantioselective cyclopropana-
tion of N,N-dialkylcarboxamides was envisaged.
As a model system, the transformaton of N,N-dibenzylfor-
mamide (9a) with n-hexylmagnesium (6c) bromide was
chosen (Scheme 8 and Table 2, entry 23). After initial opti-
mization experiments, it was found that chiral titanium li-
gands generated from one equivalent of titanium tetraiso-
propoxide and one equivalent of either diamines, such as
(1R,2R)-N,N’-bis(trifluoromethanesulfonyl)-1,2-diaminocy-
Scheme 7. Titanium-mediated cyclopropanation of (R,R)-tartaric acid de-
rivatives.
for the Z and 42% for the E isomer could be achieved,
when the chiral titanium mediator was generated from two
instead of one equivalent of TADDOL 63 (entry 5).
Chem. Eur. J. 2010, 16, 13862 – 13875
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13867

A. de Meijere, R. Boese et al.
for the Z and 55% for the E isomer (Table 6, entry 2). Simi-
lar improvements were observed when one phenyl or one
mesityl substituent (entries 4 and 5) was introduced on the
dioxolane ring, whereas a spiroanellated five-membered ring
(entry 3) did not increase the enantiomeric excesses. The
highest enantioselectivities were obtained by application of
a tert-butyl-substituted dioxolane derivative (entry 6) that
gave rise to 84% enantiomeric excess for the Z isomer and
77% for the E isomer, but decreased the yield to 47%. Sim-
ilar enantioselectivities (80% for the Z and 75% for the E
isomer) were observed, when the aryl substituents on the
diol moiety were changed from phenyl to the sterically more
demanding 1-naphthyl groups, however, the yield went
down even more to 38% (entry 7), whereas 3,5-dimethyl-
phenyl- or 3,5-trifluoromethylphenyl substituents significant-
ly decreased the enantioselectivities (entries 8 and 9). Since
application of di-tert-butyl tartrate (entry 10) or 1,4-dime-
thoxy-1,1,4,4-tetraphenylbutane-2,3-diol (entry 11), respec-
tively, only led to moderate enantiomeric excessses for both
isomers, it can be concluded that close proximity of the
chiral information and the titanium center is generally less
important than steric bulk of the dioxolane substituents.
Similar results were observed for the reductive cyclopro-
panation of N,N-dibenzylformamide (9a) with 3-butenyl-
magnesium bromide (6e) (Scheme 9) in the presence of
Scheme 8. Enantioselective reductive cyclopropanation of carboxamide
9a with 6c. For details, see Table 5.
Table 5. Enantioselective reductive cyclopropanation of carboxamide 9a
with 6c (see Scheme 8).
Entry “Ti”
Ligand Yield
20ca [%]
Z/E ee Z iso-
ee E iso-
mer [%][a] mer [%][a]
1
2
3
4
5
Ti
Ti(OiPr)2L 61
Ti(OiPr)2L 62
Ti(OiPr)2L 63
TiL2 63
G
52
50
65
59
57
1:3.2
1:2.3
1:1.7
1:2.0 41
1:5.0 66
2
1
2
1
2
5
35
42
[a] Enantiomeric excesses were determined after reductive debenzylation
of 20ca, thereby trapping the cyclopropylamine as a hydrotrifluoroace-
tate, and separation by analytical chiral-phase gas chromatography.
These results induced an attempt to optimize the enantio-
selectivity by systematic modification of the TADDOL
ligand (Table 6). Switching from the two methyl substituents
R1 and R2 on the dioxolane ring to the more bulky ethyl
groups improved the enantiomeric excess slightly to 70%
Scheme 9. Enantioselective reductive cyclopropanation of carboxamide
9a with 6e in the presence of chirally modified TiACTHNUTRGNEUNG
(L*2)2. For details, see
Table 7.
Table 6. Enantioselective reductive cyclopropanation of carboxamide 9a
with 6c in the presence of chirally modified Ti(L2)2 (see Scheme 8).
enantiomerically pure titanium bisACTHNUTRGNEUNG(TADDOL)ates. Thus,
application of tetraphenyldioxolanedimethanol as the ligand
furnished the corresponding cyclopropylamine with an enan-
tiomeric excess of 24% for the E isomer (Table 7, entry 1;
the ee value of the Z isomer was not determined) and
switching to the sterically more congested tert-butyl deriva-
tive significantly improved the enantiomeric excess to 62%
(entry 2; the ee value of the Z isomer was not determined,
but by comparison with the ee values for (E)-20ca and (Z)-
20ca it is estimated to be 67%). It is noteworthy that, in
Entry R1
R2 Ar
Yield
20ca [%]
Z/E ee Z iso-
ee E iso-
mer [%][a] mer [%][a]
1
Me Me Ph
57
61
64
55
55
47
38
40
1:5.0 66
42
55
50
62
65
77
75
49
11
59
50
2
Et
Et Ph
1:3.5 70
1:2.8 65
1:3.0 73
1:2.7 71
1:3.0 84
1:3.1 80
1:2.5 60
1:2.5 25
1:2.9 70
1:2.5 55
À
G
À
3
4
Ph
H
H
H
Ph
Ph
Ph
5
6
Mes
tBu
Table 7. Enantioselective reductive cyclopropanation of carboxamide 9a
(L*2)2 (see Scheme 9).
ACHTUNGTRENNUNG
7
8
Me Me 1-naphthyl
Me Me 3,5-Me2Ph
with 6e in the presence of chirally modified Ti
Entry R1 R2
Ar Yield Z/E ee Z
20ae [%]
isomer [%][a] isomer [%][b]
Me Me Ph 43
tBu Ph 45
ee E
9
Me Me 3,5-(CF3)2Ph 73
[b]
10
11
43
45
[c]
1
2
1:7.0
1:7.0
–
–
24
62
H
[a] Enantiomeric excesses were determined by comparison of the mea-
sured [a]2D0 values with the maximum [a]2D0 values extrapolated from the
values for samples, for which the enantiomeric excesses were determined
by chiral-phase gas chromatography (see footnote in Table 5). [b] Di-tert-
butyl tartrate was used as the ligand L. [c] 1,4-Dimethoxy-1,1,4,4-tetra-
phenylbutane-2,3-diol was used as the ligand L.
[a] Enantiomeric excesses of the
Z isomer were not determined.
[b] Enantiomeric excesses of the E isomer were determined by 19F-decou-
pled 1H NMR spectroscopy of the (+)-Mosher ester obtained after hy-
droboration–oxidation of 20ae and subsequent esterification with Mosh-
erꢄs acid chloride.
13868
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Chem. Eur. J. 2010, 16, 13862 – 13875

Cyclopropylamines
FULL PAPER
contrast to the corresponding cyclopropanations with n-hex-
ylmagnesium bromide (6e) (see Scheme 8, Table 6), the dia-
stereoselectivity in comparison with the achiral titanium re-
agent was not affected (1:7.0 for the chiral as well as the
achiral reagent), and the chemical yield decreased only
slightly (45–47% vs. 54% for the achiral reagent, see
Table 2, entry 25).
Although the first asymmetric synthesis of 2-substituted
cyclopropylamines by applying chirally modified titanium
reagents could thus be achieved with acceptable enantiose-
lectivities and in moderate yields, this success was hampered
by the fact that equimolar amounts of the titanium mediator
had to be used, probably due to the formation of an oligo-
meric, unreactive dialkoxytitanium oxide, which principally
required two equivalents of the chiral ligand to form the
active Ti(L2)2 species. Thus, the development of a catalytic
variant of the titanium-mediated reductive cyclopropanation
of N,N-dialkylcarboxamides in the presence of substoichio-
metric amounts of a chiral ligand is highly desirable.
It could be shown that the twofold alkylation of N,N-di-
alkylformamides with Grignard reagents that lack b-hydro-
gen atoms can be carried out with a catalytic amount of tita-
nium reagent (3 mol%), if the intermediately formed titani-
um species is trapped with one equivalent of trimethylsilyl
chloride.[24,25] Similarly, the cyclopropanation of N,N-diben-
zylformamide (9a) with 2-phenylethylmagnesium bromide
6k in the presence of 20 mol% of titanium tetraisopropox-
ide and one equivalent of trimethylsilyl chloride furnished
N,N-dibenzyl-2-phenylcyclopropylamine (20ka) in 67%
yield (Z/E=1:2.0), and the reaction of 9a with 3-butenyl-
magnesium bromide (6e) in the presence of 25 mol% of ti-
tanium tetraisopropoxide and one equivalent of trimethyl-
silyl chloride provided N,N-dibenzyl-2-ethenylcyclopropyl-
amine (20ea) in 68–73% yield (Z/E=1:7.0) with concomi-
tant formation of the bisalkylation product 64 in 10–12%
yield (Scheme 10).
turned out to be the bisalkylation products 64 in 38, 32, and
35% yield, respectively (Scheme 10).
However, since the titanium-tetraisopropoxide-catalyzed
cyclopropanation of N,N-dibenzylformamide (9a) with 3-bu-
tenylmagnesium bromide (6e) in the presence of trimethyl-
silyl chloride had furnished a satisfying yield of 20ea (68–
73%), a systematic evaluation was undertaken, in which the
amount of titanium catalyst and the silyl additive was
varied. It could be shown that further reduction of the
amount of titanium tetraisopropoxide continuously de-
creased the quantity of cyclopropylamine 20ea formed, with
a lowest yield of 30% in the presence of 3 mol% titanium
tetraisopropoxide (Table 8, entries 2–6). An increase in the
amount of added trimethylsilyl chloride to two equivalents
even led to a decrease of the yield to just 20% (entry 7).
Additionally, several other alkylsilyl reagents were exam-
ined and found to either have virtually no effect on the
yield (1,2-bis(chlorodimethysilyl)ethane, dichlorodimethylsi-
lane, entries 8–10) or cause a significant decrease (tert-butyl-
dimethylsilyl chloride, entry 11).
Table 8. Reductive cyclopropanation of carboxamide 9a with 6e in the
presence of a substoichiometric amount of Ti
silyl derivatives.
ACHTUNGTNER(NUGN OiPr)4 and stoichiometric
Entry
Ti(OiPr)4 [mol%]
Si Additive ([equiv])
Yield 20ea [%]
1
2
3
4
5
6
7
8
100
3
none
94
30
40
47
63
73
25
33
78
71
34
Me3SiCl (1)
Me3SiCl (1)
Me3SiCl (1)
Me3SiCl (1)
Me3SiCl (1)
Me3SiCl (2)
(Me2SiClCH2)2 (1)
(Me2SiClCH2)2 (1)
Me2SiCl2 (1)
Me2tBuSiCl (1)
10
15
20
25
3
3
9
10
11
25
25
25
As indicated by these results, the application of 25 mol%
of titanium tetraisopropoxide and one equivalent of relative-
ly inexpensive trimethylsilyl chloride as the silyl additive ap-
peared to be the best conditions for a titanium-catalyzed
variant of the reductive cyclopropanation of N,N-dialkylcar-
boxamides. Employing these conditions to the cyclopropana-
tion of N,N-dibenzylformamide (9a) with 3-butenylmagnesi-
um bromide (6e) in the presence of the chiral titanium bis-
AHCTUNGTREG(NNNU TADDOL)ates provided enantiomerically enriched N,N-di-
Scheme 10. Reductive cyclopropanation of carboxamide 9a with 2-substi-
benzyl-2-ethenylcyclopropylamine (20ea) in yields of 7–8%
for the Z and 51–59% for the E isomer, the latter with an
enantiomeric excess of up to 56%. In analogy to the nonca-
talyzed variant (see Scheme 9 and Table 7), the bis-
tuted EtMgBr in the presence of a substoichiometric amount of Ti
and stoichiometric Me3SiCl.
ACHTUNGERTN(NUNG OiPr)4
Encouraged by these results, similar reaction conditions
were applied to an analogous cyclopropanation with b-hy-
drogen-containing alkylmagnesium halides. The reactions of
n-hexyl-, n-butyl-, and ethylmagnesium bromide with 9a
under such conditions did indeed furnish the corresponding
cyclopropylamines 20, but in disappointingly low yields of
only 14, 15, and 20%, respectively. The major products
ACHTUNGTREN(NUGN TADDOL)ates with the tert-butyl substituent gave (E)-
20ea with a higher, albeit only slightly, enantiomeric excess
(56 vs. 46%) than the (TADDOL)ate with two methyl sub-
stituents (Scheme 11; the ee value of the Z isomer was not
determined).
Although the enantioselectivities in this new asymmetric
synthesis of 2-substituted cyclopropylamines remain moder-
Chem. Eur. J. 2010, 16, 13862 – 13875
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13869

A. de Meijere, R. Boese et al.
The importance of nicotinic acetylcholine receptor
(nAChR) ligands arise from their significant therapeutic po-
tential for the treatment of central nervous system (CNS)
disorders such as Alzheimerꢄs and Parkinsonꢄs disease as
well as Touretteꢄs syndrome.[27,28] 3-Pyridyl ether derivatives
such as 3-(pyrrolidin-2-ylmethoxy)pyridine, which corre-
sponds to 69 (Scheme 12) without the spirocyclopropane
moiety, have been found to exhibit subnanomolar affinities
towards nAChRs.[29] Due to its influence on the basicity on
the adjacent nitrogen, a spirocyclopropanated analogue such
as 69 might have a modified activity. Therefore, N-methyl-5-
oxoprolinol 67, obtained by esterification with concomitant
N-methylation of 5-oxoproline[30] and subsequent reduction
of the ester moiety,[31] was transformed with 3-hydroxypyri-
dine in a Mitsunobu reaction to yield the pyridyl ether with
a g-lactam substructure 68.[29] As expected, the methyltitani-
um-triisopropoxide-mediated cyclopropanation of 68 with
ethylmagnesium bromide (6a) gave the desired spirocyclo-
propane derivative 69 in an unoptimized moderate yield of
only 28% (Equation (2) in Scheme 12).
An interesting modification of the commercial insecticide
Dinotefuran [N’’-nitro-N-methyl-N’-(tetrahydrofuran-3-yl-
methyl)guanidine] was conceived with the introduction of a
cyclopropane ring instead of the originally present methyl-
ene group in the tetrahydrofuran ring. The preparation of 74
was achieved by starting with tetrahydrofuran-3-carboxylic
acid (70) and its conversion to N,N-dibenzyltetrahydrofuran-
3-carboxamide (71) through the acid chloride. Subsequent
methyltitanium-triisopropoxide-mediated cyclopropanation
of 71 succeeded in 75% yield to provide the corresponding
N,N-dibenzylcyclopropylamine derivative 72, which was de-
benzylated by hydrogenation over palladium on charcoal.
Final condensation of the thus obtained cyclopropylamine
73 with methyl N’-nitro-N-methylimidothiocarbamate[32]
gave the cyclopropylamine analogue 74 of Dinotefuran
(Scheme 13).
Scheme 11. Preparation of enantiomerically enriched cyclopropylamine
20ea. [a] Enantiomeric excesses for the Z isomer were not determined.
ate, it constitutes the first enantioselective reductive cyclo-
propanation of carboxamides with substoichiometric quanti-
ties of the titanium mediator and sets the stage for potential
further improvement of the enantioselectivities towards syn-
thetically useful levels.
Application of the titanium-mediated cyclopropanation of
N,N-dialkylcarboxamides in the synthesis of analogues of
natural products and bioactive compounds: Having devel-
oped a reliable method with reproducible results for the
transformation of N,N-dialkylcarboxamides into cyclopro-
pylamines, a variety of applications towards drug develop-
ment and natural product synthesis were considered. Thus,
the titanium-mediated cyclopropanation does not only allow
the transformation of known N,N-dialkylcarboxamide- and
lactam-based biologically active compounds into potentially
even more active cyclopropylamine analogues, but also the
preparation of cyclopropylamine analogues of known bio-
logically active compounds with methylene groups adjacent
to a nitrogen atom.
Among the variety of drugs that have an N,N-dialkylcar-
boxamide moiety, (S)-Cotinine 65, a metabolite of nicotine
with antidepressive activity, was chosen.[26] The lactam 65
was treated with ethylmagnesium bromide (6a) in the pres-
ence of methyltitanium triisopropoxide, and indeed, the spi-
rocyclopropane derivative 66 could be isolated in 77% yield
(Equation (1) in Scheme 12). Thus, Cotinine can be regard-
ed as a prime example for the one-step modification of a
biologically active substance without influencing the stereo-
chemical features.
Scheme 13. Synthesis of a spirocyclopropanated Dinotefuran analogue.
Imidacloprid is one of the most effective and widest used
insecticides worldwide. In analogy to the derivatization of
the insecticide Dinotefuran, Imidacloprid, which corre-
sponds to 79 without the cyclopropane moiety (Scheme 14;
R1 =NO2, X=NH, R2 =6-chloropyridin-3-yl) can be modi-
fied by attaching a spirocyclopropane moiety to either one
of the two methylene groups in the imidazolidine ring. To-
Scheme 12. Reductive cyclopropanation of the carbonyl groups in g-lac-
tams.
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Chem. Eur. J. 2010, 16, 13862 – 13875

Cyclopropylamines
FULL PAPER
mmol of carboxamide) was cooled to À788C. A solution of Ti
ACHTUNGTRENNUNG(OiPr)4
(1.00 equiv) in anhydrous THF (0.5 mL per mmol of carboxamide) was
added within 1 min. The mixture was stirred for 2 min before a solution
of the respective N,N-dialkylcarboxamide 9--17 (1.00 equiv) in anhydrous
THF (0.5 mL per mmol of carboxamide) was added within 1 min, which
led to a yellow mixture. This mixture was stirred at À788C for 5 min, the
cooling bath was removed, and the mixture was allowed to warm to
208C, upon which the mixture turned brown-black, and then it was
stirred for the indicated time at 208C or first warmed to reflux, then
stirred under reflux for the indicated time and recooled to 208C.
Workup, variant A: All volatile components (product, THF, Et2O,
iPrOH) were distilled off from the reaction mixture under reduced pres-
sure (100 Torr) and condensed into a cold trap (À788C). The residue was
either purified by column chromatography to give the corresponding cy-
clopropylamine, or it was transformed into the corresponding cyclopro-
pylamine hydrochloride by acidification to pH 1 with HCl sol. (5–6m in
anhydrous Et2O), filtered, and subsequently recrystallized from the indi-
cated solvent.
Scheme 14. Spirocyclopropanated analogues of Imidacloprid.
wards that goal, bromoacetyl bromide (75) was treated with
N,N-dibenzylamine to give N,N-dibenzylaminoacetic acid
N’,N’-dibenzylamide (9p). Methyltitanium-triisopropoxide-
mediated cyclopropanation of the latter with ethylmagnesi-
um bromide (6a) provided the corresponding cyclopropyl-
amine derivative 76 in a moderate yield of 47%, and cata-
lytic hydrogenation over palladium on charcoal gave 1-(ami-
nocyclopropyl)methylamine, which was best isolated as its
bis(hydrochloride) 77. However, further transformation into
the two different spirocyclopropane derivatives 78 of Imida-
cloprid according to published procedures[33] was hampered
by the fact that a successful, fourfold debenzylation of 78
only succeeded on a scale of up to 1.5 g and required
33 mol% of a highly active palladium catalyst.
Workup, variant B: The reaction mixture was hydrolyzed by addition of
sat. NH4Cl sol. (7.5 mL per 1.00 mmol of carboxamide) and H2O (2.5 mL
per 1.00 mmol of carboxamide), and the resulting mixture was stirred for
1–3 h until its color had changed from brown-black to white-yellow. The
mixture was filtered, and the precipitate was washed with Et2O (2ꢅ
1.5 mL per 1.00 mmol of carboxamide). The filtrate was made basic
(pH>11) by addition of 15% aq. NaOH sol. and extracted with Et2O
(3ꢅ2.5 mL per 1.00 mmol carboxamide). The combined organic extracts
were washed with brine, dried (MgSO4 or K2CO3), and concentrated
under reduced pressure. The residue was either purified by column chro-
matography to give the corresponding cyclopropylamine, or it was acidi-
fied pH 1 with HCl sol. (5–6m in anhydrous Et2O), filtered, and the thus
formed corresponding cyclopropylamine hydrochloride subsequently re-
crystallized from the indicated solvent.
Workup, variant C: The reaction mixture was hydrolyzed by addition of
H2O (10 mL per 10.0 mmol of carboxamide, stirred until a colorless pre-
cipitate had formed (1–3 h), filtered through a pad of Celite, and the
filter cake was washed with the indicated solvent. The filtrate was ex-
tracted with the indicated solvent (3 times). The combined organic ex-
tracts were dried (MgSO4, Na2SO4, or K2CO3) and the solvents concen-
trated under reduced pressure. The residue was purified by column chro-
matography.
Conclusion
The utility and broad scope of the titanium-mediated reduc-
tive cyclopropanation of N,N-dialkylcarboxamides has been
demonstrated on numerous examples. Wide ranges of
amides and Grignard reagents can be employed to give a va-
riety of diversely substituted cyclopropylamines, which have
great synthetic and even medicinal potential. Initially, the
reagents and substrates were mixed at À788C, and the mix-
ture was then warmed to ambient temperature and stirred
for some time. However, this original version is inferior to
the newer protocols according to which the Grignard re-
agent is added to the mixture of the respective N,N-dialkyl-
carboxamide and the titanium tetraisopropoxide or—pref-
erably—methyltitanium triisopropoxide at ambient tempera-
ture. The reliability, efficiency, and unproblematic scalability
of these protocols have made them a benchmark method for
the synthesis of this class of compounds. An asymmetric ver-
sion of this useful transformation has also been developed
for the first time, thereby providing moderate levels of
enantiocontrol and setting the stage for further exploratory
research in this area of asymmetric synthesis.
Representative example: N,N-dibenzyl-N-(1-ethylcyclopropyl)amine hy-
drochloride (20ac·HCl): According to GP 1, ethylmagnesium bromide
(6a) (50.0 mmol in Et2O/THF), TiACTHNUTRGNENUG(OiPr)4 (5.94 mL, 20.0 mmol), and
N,N-dibenzylpropionamide (9c) (5.04 g, 19.9 mmol) in THF (200 mL)
were allowed to react and stirred under reflux for 10 h. Workup accord-
ing to variant B, transformation into the hydrochloride, and recrystalliza-
tion from CH2Cl2/hexane (1:5) yielded 3.81 g (63%) of 20ac·HCl as a col-
1
orless solid. M.p. 1718C; H NMR (250 MHz, CDCl3): d=11.2 (brs, 1H),
7.65–7.77 (m, 4H), 7.05–7.33 (m, 6H), 4.07–4.29 (m, 4H), 1.98 (q, J=
7.4 Hz, 2H), 1.16–1.22 (m, 2H), 0.56 (t, J=7.4 Hz, 3H), 0.25–0.35 ppm
(m, 2H); 13C NMR (62.9 MHz, CDCl3): d=131.93 (CH), 129.58 (CH),
129.21 (C), 128.69 (CH), 56.88 (CH2), 44.04 (C), 19.05 (CH2), 8.78 (CH2),
8.43 ppm (CH3); MS (ESI): m/z (%): 266 (100) [M+H+], 533 (42)
[2M+H+]; elemental analysis calcd (%) for C19H24ClN (301.85): C 75.60,
H 8.01; found: C 75.62, H 7.93.
General procedure for the synthesis of cyclopropylamines by using titani-
um tetraisopropoxide with inverse addition of the reactants (GP 2): A
vigorously stirred solution of the respective N,N-dialkylcarboxamide 9–17
(1.00 equiv) and TiACTHNUTRGNEUNG(OiPr)4 (1.10 equiv) in anhydrous THF (6 mL per
1.00 mmol of carboxamide) was treated with the respective alkylmagnesi-
um bromide (2.50 equiv, sol. in Et2O) within 20 s (the color of the mix-
ture changed to brown-black and the temperature rose to around 458C).
The reaction mixture was stirred at 208C for 10 h and then worked-up as
described in GP 1, variants A–C.
Experimental Section
Representative example: N-cyclopropylpiperidine (22aa): According to
General procedure for the synthesis of cyclopropylamines by using titani-
um tetraisopropoxide (GP 1): A suspension of the respective alkylmagne-
sium bromide 6 (2.50 equiv, sol. in Et2O) in anhydrous THF (5 mL per
GP 2, ethylmagnesium bromide (6a) (13 mmol in Et2O/THF), TiACHTUNGTRENNUNG(OiPr)4
(1.6 mL, 5.5 mmol), and N-formylpiperidine (11a) (0.57 g, 5.0 mmol) in
THF (40 mL) were allowed to react for 10 h. Workup according to var-
Chem. Eur. J. 2010, 16, 13862 – 13875
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13871

A. de Meijere, R. Boese et al.
iant B and purification of the residue by column chromatography (50 g
silica, pentane/Et2O 20:1, Rf =0.31) yielded 0.47 g (74%) of 22aa as a
colorless liquid. 1H NMR (250 MHz, CDCl3): d=2.41–2.56 (m, 4H),
1.31–1.52 (m, 7H), 0.30–0.40ppm (m, 4H); 13C NMR (62.9 MHz, CDCl3):
d=54.72 (CH2), 39.20 (CH), 25.85 (CH2), 24.51 (CH2), 5.74 ppm (CH2).
For further characterization, the cyclopropylamine 22aa was transformed
into the corresponding solid hydrochloride 22aa·HCl by treatment with
sat. HCl sol. in Et2O and the hydrochloride purified by recrystallization.
M.p. 215–2168C (dec.); elemental analysis calcd (%) for C8H16ClN
(161.67): C 59.43, H 9.98; found C 59.34, H 9.93.
K2CO3) and the solvents evaporated under reduced pressure. The residue
was purified by column chromatography on silica gel.
Representative example: N,N-dimethyl-2-[3-(trityloxy)propyl]cyclopropyl-
amine (38a): According to GP 4, ClTiACHTNUTRGNEUNG(OiPr)3 (2.50 mL, 5.00 mmol,
2.00m in THF) and MeLi (3.21 mL, 5.00 mmol, 1.56m in Et2O) were al-
lowed to react. The mixture was then treated with N,N-dimethylforma-
mide (10a) (365 mg, 5.00 mmol) and 3-trityloxypentylmagnesium bro-
mide (21.7 mL, 4.99 mmol, 0.23m in THF) in anhydrous THF (20 mL),
and was stirred at R.T. for 2 d. Workup according to variant E and purifi-
cation by column chromatography (60 g silica, Et2O) yielded 1.02 g
(53%) of 38a as a colorless oil, a separable mixture of two diastereomers
(E/Z=1.8:1). (Z)-38a: Rf =0.77. 1H NMR (250 MHz, CDCl3): d=7.19–
7.49 (m, 15H), 3.10 (t, 3J=6.6 Hz, 2H), 2.29 (s, 6H), 1.69–1.87 (m, 1H),
1.50–1.55 (m, 1H), 1.21–1.37 (m, 1H), 0.62–0.72 (m, 1H), 0.51–0.59 (m,
1H), À0.05–0.03 ppm (m, 1H); 13C NMR (62.9 MHz, CDCl3): d=144.52
(C), 128.69 (CH), 127.64 (CH), 126.74 (CH), 86.31 (C), 63.73 (CH2),
45.80 (CH3), 44.69 (CH), 30.58 (CH2), 23.57 (CH2), 18.66 (CH),
11.49 ppm (CH2); IR (film): n˜ =3059, 2937, 2813, 2768, 1490, 1448, 1073,
745, 705, 633 cmÀ1; MS (DCI, NH3): m/z (%): 386 (100) [M++H], 243
(44) [Ph3C+], 142 (16) [M+ÀCPh3]; elemental analysis calcd (%) for
C27H31NO (385.55): C 84.11, H 8.10; found C 84.43, H 8.00. (E)-38a: Rf =
0.38. 1H NMR (250 MHz, CDCl3): d=7.18–7.45 (m, 15H), 3.06 (t, 3J=
7.0 Hz, 2H), 2.28 (s, 6H), 1.74 (ddt, 3J=7.0, 7.5, 6.5 Hz, 2H), 1.38 (ddt,
2J=14.0 Hz, 3J=7.5, 6.5 Hz, 1H), 1.21–1.26 (m, 1H), 1.16 (ddt, 2J=14.0,
3J=7.5, 6.5 Hz, 1H), 0.69–0.74 (m, 1H), 0.49–0.56 (m, 1H), 0.21–
0.27 ppm (m, 1H); 13C NMR (62.9 MHz, CDCl3): d=144.43 (C), 128.63
(CH), 127.67 (CH), 126.79 (CH), 86.27 (C), 63.34 (CH2), 47.00 (CH),
44.98 (CH3), 29.80 (CH2), 29.31 (CH2), 20.40 (CH), 13.77 ppm (CH2); IR
General procedure for the synthesis of cyclopropylamines by using meth-
yltitanium triisopropoxide (GP 3): A vigorously stirred solution of the re-
spective N,N-dialkylcarboxamide 9–17 (1.00 equiv) and MeTiACTHNUTRGNEUNG(OiPr)3
(1.20 equiv) in anhydrous THF (3 mL per 1.00 mmol of carboxamide)
was treated with the respective alkylmagnesium bromide (2.00 equiv, sol.
in Et2O) within 20 s (the color of the mixture changed to brown-black
and the temperature rose to around 458C), and the resulting mixture was
stirred at 208C for the indicated time.
Workup, variant D: The reaction mixture was diluted with Et2O (3 mL
per 1.00 mmol of carboxamide) and the reaction then quenched by addi-
tion of H2O (1 mL per 10.0 mmol of carboxamide). The resulting mixture
was stirred until a colorless precipitate had formed (1–3 h), filtered
through a pad of Celite, and the filter cake was washed with Et2O
(3 times). The filtrate was dried (Na2SO4 or K2CO3) and the solvents
evaporated under reduced pressure. The residue was purified by column
chromatography on silica gel. In specifically indicated cases, CH2Cl2 in-
stead of Et2O was used as the solvent for the workup without dilution of
the reaction mixture before quenching.
(film): n˜ =3058, 2934, 2812, 2768, 1490, 1448, 1072, 745, 706, 633 cmÀ1
;
MS (DCI, NH3): m/z (%): 386 (100) [M++H], 243 (32) [Ph3C+]; elemen-
tal analysis calcd (%) for C27H31NO (385.55): C 84.11, H 8.10; found C
84.04, H 8.20.
Representative example: N,N-dibenzyl-N-(2-phenylcyclopropyl)amine
(20ka): According to GP 3, N,N-dibenzylformamide (9a) (2.25 g,
9.99 mmol), MeTiACHTUNGTRENNUNG(OiPr)3 (2.88 g, 12.0 mmol), and 2-phenylethylmagnesi-
um bromide (6k) (23.6 mL, 20.1 mmol, 0.85m in THF) in anhydrous
THF (30 mL) were stirred for 16 h. Workup according to variant D and
purification by column chromatography (70 g silica, CH2Cl2) yielded
3.06 g (98%) of 20ka as a colorless oil, a separable mixture of two diaste-
reomers (E/Z=2.3:1). (Z)-20ka: Rf =0.74. 1H NMR (250 MHz, CDCl3):
d=7.09–7.45 (m, 15H), 3.62 (d, 2J=13.4 Hz, 2H), 3.35 (d, 2J=13.4 Hz,
2H), 2.19 (ddd, 3J=4.8, 7.0, 7.0 Hz, 1H), 2.10 (ddd, 3J=4.9, 7.0, 8.8 Hz,
1H), 1.04 (ddd, 2J=5.6 Hz, 3J=7.0 Hz, 8.8 Hz, 1H), 0.89 ppm (ddd, 2J=
5.6 Hz, 3J=4.8, 4.9 Hz, 1H); 13C NMR (62.9 MHz, CDCl3): d=138.33
(C), 138.22 (C), 129.49 (CH), 128.41 (CH), 127.83 (CH), 127.48 (CH),
126.68 (CH), 125.44 (CH), 57.30 (CH2), 43.66 (CH), 23.75 (CH),
13.52 ppm (CH2). (E)-20ka: Rf =0.56. 1H NMR (250 MHz, CDCl3): d=
General procedure for the twofold reductive cyclopropanation of N-
alkyl-N,N-diformylamines with ethylmagnesium bromide in the presence
of methyltitanium triisopropoxide (GP 5): Ethylmagnesium bromide (6a)
(4.00 equiv) was added dropwise to a solution of the respective diformyl-
amine 53 (1.00 equiv) and MeTiACTHNUTRGNE(NUG OiPr)3 (2.40 equiv) in the indicated
amount of anhydrous THF, and the mixture was stirred at 208C for 16 h.
The reaction mixture was hydrolyzed by addition of H2O (5 mL), stirred
until a colorless precipitate had formed (1–3 h), filtered through Celite,
and the precipitate was washed with Et2O. The filtrate was extracted with
Et2O (3 times). The combined organic extracts were dried (K2CO3) and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel.
2
7.24–7.47 (m, 13H), 6.70–6.87 (m, 2H), 3.79 (d, J=13.5 Hz, 2H), 3.67 (d,
In the cases of volatile products, concentrated aqueous HCl was added to
the reaction mixture after hydrolysis, the mixture was filtered, and all
liquid components were distilled off in vacuo. Et2O (10 mL) and K2CO3
were added to the residue to liberate the amine, and the mixture was
submitted to bulb-to-bulb distillation. The pure amine was obtained from
this mixture of product and Et2O by preparative-scale gas chromatogra-
phy.
2J=13.5 Hz, 2H), 2.04 (ddd, 3J=3.2, 4.5, 7.5 Hz, 1H), 1.82 (ddd, 3J=3.2,
6.0, 9.2 Hz, 1H), 1.05 (ddd, 2J=4.3 Hz, 3J=4.5, 9.2 Hz, 1H), 0.97 ppm
3
(ddd, 2J=4.3 Hz, J=6.0, 7.5 Hz, 1H); 13C NMR (62.9 MHz, CDCl3): d=
142.05 (C), 138.65 (C), 129.36 (CH), 128.06 (CH), 127.96 (CH), 126.85
(CH), 125.72 (CH), 125.32 (CH), 58.42 (CH2), 47.57 (CH), 26.39 (CH),
17.57 ppm (CH2).
General procedure for the synthesis of cyclopropylamines with reagent
Representative example: N,N-dicyclopropylethylamine (54b): According
to GP 5, ethyl-N,N-diformylamine (53b)[20] (1.01 g, 10.0 mmol) and MeTi-
AHCTUNGTERG(NNNU OiPr)3 (5.76 g, 24.0 mmol) were treated with ethylmagnesium bromide
mixing at À788C using methyltitanium triisopropoxide generated in situ
(GP 4): A solution of ClTiACTHNUTRGNE(UNG OiPr)3 (1.00 equiv) in the indicated amount of
anhydrous THF (2 mL per 1.00 mmol of ClTiACTHNUTRGNEN(UG OiPr)3) was cooled to 08C
(6a) (22.3 mL, 40.1 mmol, 1.80m in Et2O) in anhydrous THF (50 mL).
Purification by preparative-scale gas chromatography (SE 30, column
2 mꢅ0.5 cm, 958C, RT =6.10 min) gave 54b (82%, yield determined by
gas chromatography of the mixture with Et2O) as a colorless liquid.
1H NMR (250 MHz, CDCl3): d=2.77 (q, J=7.2 Hz, 2H), 1.81–1.89 (m,
2H), 1.12 (t, J=7.2 Hz, 3H), 0.35–0.48 ppm (m, 8H); 13C NMR
(62.9 MHz, CDCl3): d=50.81 (CH2), 36.07 (CH), 11.42 (CH3), 5.51 ppm
(CH2); IR (film): n˜ =3092, 3011, 2968, 2931, 2874, 1446, 1362, 1217, 1024,
937, 822 cmÀ1; MS (EI, 70 eV), m/z (%): 125 (39) [M+], 110 (100) [M+
ÀCH3], 96 (28) [M+ÀC2H5], 84 (18) [M+ÀC3H5], 82 (25) [NC5H8+], 69
(27) [M+ÀC3H5ÀCH3], 68 (40) [NC4H6+], 56 (57), 41 (94) [C3H5+];
HRMS (EI): calcd for C8H15N: 125.1204 (correct HRMS); elemental
analysis calcd (%) for C8H15N (125.21): C 76.74, H 12.07, N 11.19; found
C 76.75, H 12.16, N 11.09.
and treated dropwise with MeLi (1.00 equiv, approximately 2.0m sol. in
Et2O). The cooling bath was removed; the reaction mixture was stirred
for 1 h and then cooled to À788C. The respective alkylmagnesium bro-
mide (1.00 equiv) was added. The resulting mixture was warmed to the
indicated temperature, treated with a solution of the respective N,N-di-
alkylcarboxamide 9–17 (1.00 equiv) in anhydrous THF (3–5 mL per
1.00 mmol), and stirred for the indicated time.
Workup, variant E: The reaction mixture was hydrolyzed by addition of
H2O (20 mL per 5.00 mmol of carboxamide) and sat. aq. (NH4)2CO3 sol.
(10 mL per 5.00 mmol of carboxamide), stirred until a colorless precipi-
tate had formed (1–3 h), filtered through a pad of Celite, and the filter
cake was washed with Et2O. The filtrate was extracted with Et2O (3
times). The combined organic extracts were dried (Na2SO4, MgSO4, or
13872
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 13862 – 13875

Cyclopropylamines
FULL PAPER
General procedure for the synthesis of chiral titanium bis
(GP 6): A solution of the respective ligand (2.00 equiv) in anhydrous
benzene (2 mL per 1 mmol of ligand) was treated with Ti(OiPr)4
(1.00 equiv). The reaction mixture was warmed to 40–458C and stirred at
this temperature for 5 h. All volatile components were distilled off into a
cold trap (liquid N2), and the residue was dried under reduced pressure.
G
enantiomeric excess of the minor isomer could be determined. (E)-20ae:
Rf =0.20 (Et2O/pentane 1:100), [a]2D0 =+4.218 (c=1.4, CHCl3; 62% ee).
The enantiomeric excess was determined by analysis of the 1H NMR
spectrum of the (+)-Mosher ester of the 2-hydroxyethyl derivative ob-
tained by hydroboration–oxidation of (E)-20ae.
Catalytic enantioselective synthesis of N,N-dibenzyl-2-(ethenylcyclopro-
pyl)amine (20ae) in the presence of trimethylsilyl chloride: According to
The titanium bisACHTUNGTRENNUNG(TADDOL)ates thus obtained can be stored for several
weeks under an inert atmosphere.
GP 6, but using only 50 mol% of Ti
(4R,5R)-2-tert-butyl-4,5-bis(diphenylmethanol)-1,3-dioxolane
2.51 mmol), the corresponding titanium bis(TADDOL)ate was generated
ACHTUNGTRENNUNG
General procedure for the enantioselective synthesis of cyclopropyla-
AHCTUNGTRENNUNG
mines (GP 7):
A solution of the respective chiral titanium bis-
and then converted according to GP 8 with N,N-dibenzylformamide (9a)
(1.13 g, 5.02 mmol), trimethylsilyl chloride (610 mL, 5.00 mmol) and 3-bu-
tenylmagnesium bromide (6e). Workup and purification by column chro-
matography (100 g silica, Et2O/pentane 100:1) gave 758 mg (58%) of
20ae as a separable mixture of two diastereomers (E/Z=7.0:1). The
spectroscopic data correspond to the ones listed above. The enantiomeric
excess was determined by analysis of the 1H NMR spectrum of the (+)-
Mosher ester of the 2-hydroxyethyl derivative obtained by hydrobora-
tion–oxidation of 20ae. (Z)-20ae: Because of the high diastereoselectiv-
ity, neither optical rotation nor the enantiomeric excess of the minor
isomer could be determined. (E)-20ae: [a]2D0 =+3.808 (c=0.8, CHCl3;
56% ee).
ACHTUNGTRENNUNG(TADDOL)ate (1.10 equiv, generated according to GP 6 or used as com-
mercially available) in anhydrous THF (2.5–3 mL per 1.00 mmol of car-
boxamide) was treated with N,N-dibenzylformamide (1.50–2.50 mmol,
1.00 equiv). The respective alkylmagnesium bromide (2.20 equiv, sol. in
Et2O) was added dropwise. The reaction mixture was stirred for 15 h,
then diluted with Et2O (10 mL) and H2O (1 mL) and stirred for an addi-
tional 1 h. The mixture was filtered, and the precipitate was washed with
Et2O (3ꢅ20 mL). The combined organic phases were washed with brine
(20 mL), dried (MgSO4), and the solvents concentrated under reduced
pressure. The residue was treated with pentane (5 mL), and the thus pre-
cipitating ligand was re-isolated by filtration. The filtrate was again con-
centrated under reduced pressure. The residue was purified by column
chromatography on silica gel.
General procedure for the synthesis of cyclopropylamines in the presence
of trialkylsilyl derivatives (GP 8): A solution of N,N-dibenzylformamide
(1.00 equiv) in anhydrous THF (1 mL per 1.00 mmol of carboxamide)
Acknowledgments
was treated with the desired amount of TiACTHNUTRGNENUG(OiPr)4 (3–100 mol%). The tri-
alkylsilyl derivative (1.00 or 2.00 equiv) was added, and the resulting mix-
ture was cooled to 08C. The respective alkylmagnesium bromide
(2.20 equiv, sol. in Et2O) was added dropwise, and the reaction mixture
was stirred for 16 h while warming up to 208C. The mixture was diluted
with Et2O (5 mL), hydrolyzed by addition of H2O (1 mL), and stirred for
1–2 h (a colorless precipitate formed). The reaction mixture was filtered,
and the precipitate was washed with Et2O (3ꢅ20 mL). The combined or-
ganic phases were washed with brine (5 mL), dried (MgSO4), and the sol-
vents evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel.
This work was supported by the Land Niedersachsen, BayerCropScience
AG, and the Fonds der Chemischen Industrie. B.S. is grateful for stipends
from the Otto-Vahlbruch-Stiftung, the Karl-Ziegler-Stiftung, as well as a
graduate student fellowship of the Land Niedersachsen. M.K. is indebted
to the Fonds der Chemischen Industrie for a graduate student fellowship.
V.C. is grateful to the Gottlieb-Daimler- und Karl-Benz-Stiftung for a
graduate student fellowship. We are grateful to Dr. Matthias Noltemeyer,
Gçttingen, for an X-ray crystal-structure analysis of compound 21bq.
The authors acknowledge the contribution of one control experiment
(compound 20ga) by Dr. Sergei V. Sviridov and the initial help by Dr.
Oleg V. Larionov and Dr. Vadim S. Korotkov in assembling this manu-
script.
Representative examples for GP 6–8
Enantioselective synthesis of N,N-dibenzyl-(2-butylcyclopropyl)amine
(20ca) by using a stoichiometric amount of titanium reagent: According
to GP 6, the corresponding titanium bis
from (4R,5R)-2-tert-butyl-4,5-bis(diphenylmethanol)-1,3-dioxolane
(2.17 g, 4.40 mmol) and Ti(OiPr)4 (645 mL, 2.20 mmol) and then convert-
ACHTUNGERTN(NUNG TADDOL)ate was generated
[1] S. F. Yang, N. E. Hoffman, Ann. Rev. Plant Physiol. 1984, 35, 155–
189; H. Kende, Ann. Rev. Plant Physiol. 1993, 44, 283–307.
[2] a) T. Mizukami, A. Asai, Y. Yamashita, R. Katahira, A. Hasegawa,
K. Ochiai, S. Akinaga, US Patent 5663298, 1997; [Chem. Abstr.
1997, 126, 79]; b) A. Asai, A. Hasegawa, K. Ochiai, Y. Yamashita, T.
Mizukami, J. Antibiot. 2000, 53, 81–83; c) H. Yamaguchi, A. Asai,
T. Mizukami, Y. Yamashita, S. Akinaga, S.-i. Ikeda, Y. Kanda, EP
Patent 1166781A1, 2000; [Chem. Abstr. 2000, 133, 751]; d) A. Asai,
T. Tsujita, S. V. Sharma, Y. Yamashita, S. Akinaga, M. Funakoshi,
H. Kobayashi, T. Mizukami, M.-s. Asahi-machi, Biochem. Pharma-
col. 2004, 67, 227–234; e) M. Groll, O. V. Larionov, A. de Meijere,
R. Huber, Proc. Natl. Acad. Sci. USA 2006, 103, 4576–4579.
[3] a) T. Fujita, J. Med. Chem. 1973, 16, 923–927; b) V. St. Georgiev,
R. A. Mack, D. J. Walter, L. A. Radov, J. E. Baer, Helv. Chim. Acta
1987, 70, 1526–1529; c) D. Caille, O. E. Bergis, C. Fankhauser, A.
Gardes, R. Adam, T. Charieras, A. Grosset, V. Rovei, F.-X. Jarreau,
J. Pharmacol. Exp. Ther. 1996, 277, 265–277.
[4] a) K. D. Hargrave, J. R. Proudfoot, K. G. Grozinger, E. Cullen, S. R.
Kapadia, U. R. Patel, V. U. Fuchs, S. C. Mauldin, J. Vitous, M. L.
Behnke, J. M. Klunder, K. Pal, J. W. Skiles, D. W. McNeil, J. M.
Rose, G. C. Chow, M. T. Skoog, J. C. WU, G. Schmidt, W. W. Engel,
W. G. Eberlein, T. D. Saboe, S. J. Campbell, A. S. Rosenthal, J.
Adams, J. Med. Chem. 1991, 34, 2231–2241; b) T. A. Kelly, U. R.
Patel, J. Org. Chem. 1995, 60, 1875–1877.
AHCTUNGTRENNUNG
ed according to GP 7 with N,N-dibenzylformamide (9a) (450 mg,
2.00 mmol) and n-hexylmagnesium bromide (6c). Workup and purifica-
tion by column chromatography (100 g silica, Et2O/pentane) gave 275 mg
(47%) of 20ca as a separable mixture of two diastereomers (E/Z=3.0:1).
The spectroscopic data correspond to the ones listed above. The enantio-
meric excesses were determined by gas chromatography of the hydrotri-
fluoroacetates of (Z/E)-2-butylcyclopropylamine on a capillary column
with the chiral-phase Lipodex E (2,6-di-O-pentyl-3-O-butyryl-g-cyclodex-
trin at 1008C. (Z)-20ca: Rf =0.30 (Et2O/pentane 1:100), [a]2D0 =À19.18
(c=1.2, CHCl3; 84% ee). (E)-20ca: Rf =0.12 (Et2O/pentane 1:100),
[a]2D0 =À17.78 (c=1.8, CHCl3; 77% ee).
Enantioselective synthesis of N,N-dibenzyl-2-(ethenylcyclopropyl)amine
(20ae) using a stoichiometric amount of titanium reagent: According to
GP 6, the corresponding titanium bis
(4R,5R)-2-tert-butyl-4,5-bis(diphenylmethanol)-1,3-dioxolane
3.30 mmol) and Ti(OiPr)4 (484 mL, 1.65 mmol) and then converted ac-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
cording to GP 7 with N,N-dibenzylformamide (9a) (338 mg, 1.50 mmol)
and 3-butenylmagnesium bromide (6e). Workup and purification by
column chromatography (100 g silica, Et2O/pentane) gave 166 mg (43%)
of 20ae as a separable mixture of two diastereomers (E/Z=7.0:1). The
spectroscopic data correspond to the ones described above. The enantio-
1
meric excess was determined by analysis of the H NMR spectrum of the
(+)-Mosher ester of the 2-hydroxyethyl derivative obtained by hydrobo-
ration-oxidation of 20ae. (Z)-20ae: [a]2D0: Rf =0.38 (Et2O/pentane 1:100).
Because of the high diastereoselectivity, neither optical rotation nor the
[5] P. Remuzon, D. Bouzard, P. Di Cesare, M. Essiz, J. P. Jacquet, J. R.
Kiechel, B. Ledoussal, R. E. Kessler, J. Fung-Tomc, J. Med. Chem.
1991, 34, 29–37.
Chem. Eur. J. 2010, 16, 13862 – 13875
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13873

A. de Meijere, R. Boese et al.
[6] For some recent synthetic applications of cyclopropylamines, see:
a) M. Winn, B. W. Horrom, R. R. Rasmussen, E. B. Chappell, N. P.
Plotnikoff, J. Med. Chem. 1975, 18, 437–438; b) P. Beak, S. Wu,
E. K. Yum, Y. M. Jun, J. Org. Chem. 1994, 59, 276–277; c) R. K.
Thaper, Y. Kumar, S. M. Dileep Kumar, S. Misra, J. M. Khanna,
Org. Process Res. Dev. 1999, 3, 476–479; d) P. J. Campos, A. Solde-
villa, D. Sampedro, M. A. Rodriguez, Org. Lett. 2001, 3, 4087–4089;
e) C. Tanguy, P. Bertus, J. Szymoniak, O. V. Larionov, A. de Meijere,
Synlett 2006, 2339–2341; f) C. Tanguy, P. Bertus, J. Szymoniak, O. V.
Larionov, A. de Meijere, Synlett 2006, 3164–3166.
[7] a) E. Vilsmaier, R. Adam, P. Altmeier, J. Fath, H.-J. Scherer, G.
Maas, O. Wagner, Tetrahedron 1989, 45, 6683–6696; b) E. Vilsmaier,
C. Tetzlaff, V. Butz, G. Maas, Tetrahedron 1991, 47, 8133–8144; c) V.
Butz, E. Vilsmaier, Tetrahedron 1993, 49, 6031–6044; d) J. Seibel, E.
Vilsmaier, K. Frçhlich, G. Maas, R. Wagemann, Tetrahedron 1994,
50, 715–730; e) R. Wagemann, E. Vilsmaier, G. Maas, Tetrahedron
1995, 51, 8815–8828; f) E. Vilsmaier, M. Grosse, W.-R. Schlag, G.
Milch, U. Bergstrꢂsser, A. R. v. Onciul, J. Prakt. Chem. 1996, 338,
479–484; g) E. Vilsmaier, G. Milch, U. Bergstrꢂßer, Tetrahedron
1998, 54, 6403–6414; h) E. Vilsmaier, J. Prakt. Chem. 2000, 342,
218–229, and references therein.
[8] For some interesting approaches to cyclopropylamines in the last 30
years, see: a) J. J. Tufariello, J. H. Chang, A. C. Bayer, J. Am. Chem.
Soc. 1979, 101, 3315–3324; b) J. Kang, K. S. Kim, J. Chem. Soc.
Chem. Commun. 1987, 897–898; c) M. L. Gillaspy, B. A. Lefker,
W. A. Hada, D. J. Hoover, Tetrahedron Lett. 1995, 36, 7399–7402;
d) Y. Yoshida, K. Umeza, Y. Hamada, N. Atsumi, F. Tabuchi, Synlett
2003, 2139–2142; e) D. Diez, P. Garcia, P. Fernandez, I. S. Marcos,
N. M. Garrido, P. Basabe, H. B. Broughton, Synlett 2005, 158–160;
f) T. Satoh, M. Miura, K. Sakai, Y. Yokoyama, Tetrahedron 2006, 62,
4253–4261; g) C. C. Tsai, I. L. Hsieh, T. T. Cheng, P.-K. Tsai, K.-W.
Lin, T.-H. Yan, Org. Lett. 2006, 8, 2261–2263; h) G. Bꢀgis, T. D.
Sheppard, D. E. Cladingboel, W. B. Motherwell, D. A. Tocher, Syn-
thesis 2006, 3186–3188; i) A. Gagnon, M. St-Onge, K. Little, M. Du-
plessis, F. Barabꢀ, J. Am. Chem. Soc. 2007, 129, 44–45; j) G.-B.
Liang, X. Qian, D. Feng, T. Biftu, G. Eiermann, H. He, B. Leiting,
K. Lyons, A. Petrov, R. Sinha-Roy, B. Zhang, J. Wu, X. Zhang,
N. A. Thornberry, A. E. Weber, Bioorg. Med. Chem. Lett. 2007, 17,
1903–1907; k) T. P. Tran, E. L. Ellsworth, M. A. Stier, J. M. Doma-
gala, H. D. H. Showalter, S. J. Gracheck, M. A. Shapiro, T. E. Joan-
nides, R. Singh, Bioorg. Med. Chem. Lett. 2004, 14, 4405–4409.
[9] a) O. G. Kulinkovich, S. V. Sviridov, D. A. Vasilevski, T. S. Prityt-
skaya, Zh. Org. Khim. 1989, 25, 2244–2245; O. G. Kulinkovich, S. V.
Sviridov, D. A. Vasilevski, T. S. Pritytskaya, J. Org. Chem. USSR
1989, 25, 2027–2028; b) O. G. Kulinkovich, S. V. Sviridov, D. A. Va-
silevski, A. I. Savchenko, T. S. Pritytskaya, Zh. Org. Khim. 1991, 27,
294–298; O. G. Kulinkovich, S. V. Sviridov, D. A. Vasilevski, A. I.
Savchenko, T. S. Pritytskaya, J. Org. Chem. USSR 1991, 27, 250–
253; c) O. G. Kulinkovich, D. A. Vasilevski, S. V. Sviridov, Synthesis
1991, 234.
Voigt, H. Winsel, A. de Meijere, Synlett 2002, 1362–1364; i) G.-D.
Tebben, K. Rauch, C. Stratmann, C. M. Williams, A. de Meijere,
Org. Lett. 2003, 5, 483–485; j) S. Wiedemann, D. Frank, H. Winsel,
A. de Meijere, Org. Lett. 2003, 5, 753–755; k) M. Gensini, A. de
Meijere, Chem. Eur. J. 2004, 10, 785–790; l) A. de Meijere, H.
Winsel, B. Stecker, Org. Synth. 2004, 81, 14–25; m) S. Wiedemann,
K. Rauch, A. Savchenko, I. Marek, A. de Meijere, Eur. J. Org.
Chem. 2004, 631–635; n) F. Brackmann, A. de Meijere, Synthesis
2005, 2008–2014; o) A. de Meijere, A. V. Lygin, Experiments in
Green and Sustainable Chemistry (Eds.: H. W. Roesky, D. Kenne-
pohl), Wiley-VCH, Weinheim, 2009, pp. 173–177.
[12] For publications of other groups in this area, see review: A. Wolan,
Y. Six, Tetrahedron 2010, 66, 15–61, and references therein.
[13] For related titanium-mediated syntheses of primary cyclopropyl-
amines from nitriles and imides in the presence of Grignard re-
agents, see: a) P. Bertus, J. Szymoniak, Chem. Commun. 2001, 1792–
1793; b) P. Bertus, J. Szymoniak, Org. Lett. 2007, 9, 659–662; c) P.
Bertus, C. Menant, C. Tanguy, J. Szymoniak, Org. Lett. 2008, 10,
777–780; d) see also: P. Bertus, J. Szymoniak, Synlett 2007, 1346–
1356, and references therein.
[14] For reviews, see: a) O. G. Kulinkovich, A. de Meijere, Chem. Rev.
2000, 100, 2789–2834; b) A. de Meijere, S. I. Kozhushkov, A. I. Sav-
chenko in Titanium and Zirconium in Organic Synthesis (Ed.: I.
Marek), Wiley-VCH, Weinheim 2002, pp. 390–434; c) A. de Mei-
jere, S. I. Kozhushkov, A. I. Savchenko, J. Organomet. Chem. 2004,
689, 2033–2055.
[15] C. P. Casey, N. A. Strotman, J. Am. Chem. Soc. 2004, 126, 1699–
1704.
[16] CCDC-783413 (25aa), and 791878 (51) contain the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[17] R. Boese, D. Blꢂser, M. Y. Antipin, V. Chaplinski, A. de Meijere,
Chem. Commun. 1998, 781–782.
[18] For a systematic evaluation of different titanium reagents in the re-
ductive cyclopropanation of carboxylic acid esters, see: J. C. Lee,
M. J. Sung, J. K. Cha, Tetrahedron Lett. 2001, 42, 2059–2061.
[19] a) V. Chaplinski, Dissertation, Universitꢂt Gçttingen (Germany),
1996, pp. 36–38; b) S. Wiedemann, I. Marek, A. de Meijere, Synlett
2002, 0879–0882.
[20] E. Allenstein, V. Beyl, Chem. Ber. 1967, 100, 3551–3563.
[21] H. Yinglin, H. Hongwen, Synthesis 1990, 122–124.
[22] E. J. Corey, S. Achyutha Rao, M. C. Noe, J. Am. Chem. Soc. 1994,
116, 9345–9346.
[23] D. Seebach, A. K. Beck, A. Heckel, Angew. Chem. 2001, 113, 96–
142; Angew. Chem. Int. Ed. 2001, 40, 92–138.
[24] a) U. Welz-Biermann, Dissertation, Universitꢂt Gçttingen (Gçttin-
gen), 1999; b) O. Tomashenko, V. Sokolov, A. Tomashevskiy, H. A.
Buchholz, U. Welz-Biermann, V. Chaplinski, A. de Meijere, Eur. J.
Org. Chem. 2008, 5107–5111.
[10] a) V. Chaplinski, A. de Meijere, Angew. Chem. 1996, 108, 491–492;
Angew. Chem. Int. Ed. Engl. 1996, 35, 413–414; b) V. Chaplinski, H.
Winsel, M. Kordes, A. de Meijere, Synlett 1997, 111–114.
[25] To suppress the reaction of the Grignard reagent with trimethylsilyl
chloride, the reaction was started at 0 instead of 208C and the mix-
ture then slowly warmed to 208C overnight.
[11] For more results from the authorsꢄ own laboratory, see: a) C. M.
Williams, V. Chaplinski, P. R. Schreiner, A. de Meijere, Tetrahedron
Lett. 1998, 39, 7695–7698; b) A. de Meijere, V. Chaplinski, H.
Winsel, M. A. Kusnetsov, P. Rademacher, R. Boese, T. Haumann,
M. Trætteberg, P. von R. Schleyer, T. Zywietz, H. Jiao, P. Merstetter,
F. Gerson, Angew. Chem. 1999, 111, 2582–2585; Angew. Chem. Int.
Ed. 1999, 38, 2430–2433; c) H. Winsel, V. Gazizova, O. Kulinkovich,
V. Pavlov, A. de Meijere, Synlett 1999, 1999–2003; d) V. Pavlov, V.
Gazizova, G. Shamov, V. Moskva, H. Winsel, A. de Meijere, M.
Baird, O. Kulinkovich, Phosphorus Sulfur Silicon Relat. Elem. 1999,
147, 311; e) M. Kordes, H. Winsel, A. de Meijere, Eur. J. Org. Chem.
2000, 3235–3245; f) M. Gensini, S. I. Kozhushkov, D. S. Yufit,
J. A. K. Howard, M. Es-Sayed, A. de Meijere, Eur. J. Org. Chem.
2002, 2499–2507; g) A. de Meijere, C. M. Williams, A. Kourdioukov,
S. V. Sviridov, V. Chaplinski, M. Kordes, A. I. Savchenko, C. Strat-
mann, M. Noltemeyer, Chem. Eur. J. 2002, 8, 3789–3801; h) T.
[26] H. McKennis, Jr, L. B. Turnbull, E. R. Bowman, E. Wada, J. Am.
Chem. Soc. 1959, 81, 3951–3954.
[27] R. Gray, A. S. Rajan, K. A. Radcliffe, M. Yakehiro, J. A. Dani,
Nature 1996, 383, 713–716.
[28] H. Gohlke, D. Gundisch, S. Schwarz, G. Seitz, M. C. Tilotta, T.
Wegge, J. Med. Chem. 2002, 45, 1064–1072.
[29] M. A. Abreo, N.-H. Lin, D. S. Garvey, D. E. Gunn, A.-M. Hettinger,
J. T. Wasicak, P. A. Pavlik, Y. C. Martin, D. L. Donnelly-Roberts,
D. J. Anderson, J. P. Sullivan, M. Williams, S. P. Arneric, M. W. Hol-
laday, J. Med. Chem. 1996, 39, 817–825.
[30] P. Cauliez, B. Rigo, D. Fasseur, D. Couturier, J. Heterocycl. Chem.
1991, 28, 1143–1146.
[31] P. D. Williams, D. S. Perlow, L. S. Payne, M. K. Holloway, P. K. S.
Siegl, T. W. Schorn, R. J. Lynch, J. J. Doyle, J. F. Strouse, G. P.
Vlasuk, K. Hoogsteen, J. P. Springer, B. L. Bush, T. A. Halgren,
13874
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Chem. Eur. J. 2010, 16, 13862 – 13875

Cyclopropylamines
FULL PAPER
A. D. Richards, J. Kay, D. F. Veber, J. Med. Chem. 1991, 34, 887–
900.
[32] G. J. Durant, J. C. Emmett, C. R. Ganellin, P. D. Miles, M. E. Par-
sons, H. D. Prain, G. R. White, J. Med. Chem. 1977, 20, 901–906.
[33] F. Brackmann, D. S. Yufit, J. A. K. Howard, M. Es-Sayed, A. de
Meijere, Eur. J. Org. Chem. 2005, 600–609.
Received: June 3, 2010
Published online: October 13, 2010
Chem. Eur. J. 2010, 16, 13862 – 13875
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13875