Synthesis of trans-2-Substituted Cyclopropylamines from α-Chloroaldehydes

Article abstract of DOI:10.1021/acs.orglett.9b03172

Cyclopropylamines are prevalent in pharmaceuticals and agrochemicals. Herein, we report the synthesis of trans-2-substituted cyclopropylamines in high diastereoselectivity from readily available α-chloroaldehydes. The reaction proceeds via trapping of an electrophilic zinc homoenolate with an amine followed by ring closure to generate the cyclopropylamine. We have also observed that cyclopropylamine cis/trans-isomerization occurs in the presence of zinc halide salts and that this process can be turned off by the addition of a polar aprotic cosolvent.

Full text of DOI:10.1021/acs.orglett.9b03172

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of trans-2-Substituted Cyclopropylamines from
α‑Chloroaldehydes
Michael S. West, L. Reginald Mills, Tyler R. McDonald, Jessica B. Lee,† Deeba Ensan,‡
and Sophie A. L. Rousseaux*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S
3H6, Canada
S
* Supporting Information
ABSTRACT: Cyclopropylamines are prevalent in pharma-
ceuticals and agrochemicals. Herein, we report the synthesis of
trans-2-substituted cyclopropylamines in high diastereoselec-
tivity from readily available α-chloroaldehydes. The reaction
proceeds via trapping of an electrophilic zinc homoenolate
with an amine followed by ring closure to generate the
cyclopropylamine. We have also observed that cyclopropyl-
amine cis/trans-isomerization occurs in the presence of zinc
halide salts and that this process can be turned off by the
addition of a polar aprotic cosolvent.
he cyclopropylamine motif is present in a wide range of
homoenolate with an amine (Scheme 1b, gray box). We
Tbiologically active pharmaceutical compounds, natural previously reported a preliminary result in which cyclopropyl-
products, and agrochemicals (Scheme 1a).1−3 Cyclopropyl-
amine 2a was prepared in 78% yield and 4.7:1 d.r. from α-
chloroaldehyde 1a.14 Herein we describe the synthesis of trans-
amines have also been used as synthetic intermediates, as they
readily participate in ring-opening reactions.4 Several methods2
2-substituted-cyclopropylamines from readily accessible α-
chloroaldehydes in up to >20:1 d.r.17 We have found that
for the synthesis of trans-cyclopropylamines have been
cyclopropylamines undergo reversible ring opening in the
presence of certain zinc salts, leading to low diastereoselectiv-
ity, and that this process can be inhibited by the addition of
DMF and other Lewis basic cosolvents to the reaction mixture.
We initiated our investigation by treating α-chloroaldehyde
1a with CH2(ZnI)2 at 0 °C for 1 h, followed by addition of
morpholine and subsequent heating of the reaction mixture at
90 °C for 18 h. Under these conditions, cyclopropylamine 2a
was obtained in 77% yield and 4.4:1 d.r. (Table 1, entry 1).
Addition of i-PrOH to quench any remaining CH2(ZnI)2 prior
to the addition of the amine led to a quantitative yield of the
desired product in 4.4:1 d.r. (entry 2). Screening a range of
conditions, including the addition of polar aprotic cosolvents,
revealed that the presence of DMF improved the d.r. to >20:1
while maintaining excellent product yield (entry 3). While a
mixed solvent system of DMF/THF (3:2 ratio) proved
optimal, DMA, DMSO, and DMI also had a beneficial impact
on the diastereoselectivity of the reaction (see Supporting
Information). Raising the reaction temperature to 110 °C
resulted in a decrease of the d.r. to 10:1 (entry 4). The order of
addition of CH2(ZnI)2 followed by the amine is very
important, as the inverse order (i.e., amine followed by
CH2(ZnI)2) resulted in no detectable amount of 2a (entry 5)
with both secondary and primary amines.
developed including the Kulinkovich−de Meijere and
Kulinkovich−Szymoniak reactions,5,6 the Curtius rearrange-
ment of cyclopropyl acyl azides,7 metal-catalyzed cyclo-
propanations using carbenoids,8 and the metal-catalyzed
desymmetrization of cyclopropenes.9 However, achieving
high levels of diastereoselectivity often remains a challenge
for the synthesis of trans-2-substituted cyclopropylamines.
Matsubara and co-workers have reported that bis-
(iodozincio)methane, a readily available one-carbon dianionic
building block,10 can efficiently generate substituted amino-
cyclopropanols from α-ketoimines (Scheme 1b, top
arrow).11,12 This protocol works with high yield and selectivity
for 1,2-disubstituted derivatives (when R = Ar), but is not
viable when R = H. In contrast, Walsh and co-workers have
shown that α-chloroaldehydes are competent substrates for
generating trans-cyclopropanols, where the C1 substituent is H
(Scheme 1b, middle arrow).13 This procedure works in high
yield and high diastereoselectivity and proceeds through a zinc
homoenolate intermediate. However, a related transformation
to access trans-2-substituted cyclopropylamines using this
dianionic building block strategy remains elusive.
Our group recently reported that cyclopropanols react with
amines in the presence of Zn(II) to yield cyclopropylamines,
via trapping of a zinc homoenolate intermediate.14,15 Inspired
by the contributions of Matsubara and Walsh, we wondered if
trans-cyclopropylamines could be accessed from α-chloroalde-
hydes16 and CH2(ZnI)2 by trapping the intermediate zinc
Received: September 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03172
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2a displays the scope of cyclopropylamines that can
be prepared in high d.r. using this method. Cyclic secondary
amines afford cyclopropylamines in moderate to good yields
and excellent d.r. as shown by products 2a−d, 2f, and 2l.
Amines such as diallylamine and benzylamines, which can later
be deprotected to reveal the free amine,14 gave 2e, 2g, and 2h
in moderate to good yields. Functional groups such as nitriles,
Scheme 1. Biologically Active trans-Cyclopropylamines and
the Use of 1,1-Dianions in Their Synthesis
Scheme 2. Reaction Scope for the Synthesis of trans-
a
Cyclopropylamines from α-Chloroaldehydes
Table 1. Effect of Co-Solvent and Temperature on Product
a
Diastereomeric Ratio
entry
cosolvent
temp (°C)
yield
d.r.
b
1
−
−
DMF
DMF
−
90
90
85
110
85
(77%)
(99%)
78%
85%
n.r.
4.4:1
4.4:1
>20:1
10:1
−
2
3
4
c
c
d
5
a
Reactions were performed using α-chloroaldehyde 1a (0.4 mmol, 2.0
equiv), a solution of CH2(ZnI)2 in THF (0.8 mmol, 4.0 equiv,
typically 0.22−0.25 M), i-PrOH (1.6 mmol, 8.0 equiv), and
morpholine (0.2 mmol, 1.0 equiv). Yield in parentheses determined
by GC-MS with dodecane as internal standard, otherwise yields are
b
1
for isolated material; d.r. determined by GC-MS or H NMR. No i-
c
PrOH. The volume of DMF added was 1.5× the volume of THF.
Morpholine (0.2 mmol, 1.0 equiv) added to α-chloroaldehyde 1a
d
(0.4 mmol, 2.0 equiv) at 0 °C followed by addition of a solution of
CH2(ZnI)2 in THF (0.8 mmol, 4.0 equiv) and heating at 85 °C for 18
h.
a
Reactions were performed on 0.10−0.20 mmol scale. Yields are
isolated and the average of two runs.
B
DOI: 10.1021/acs.orglett.9b03172
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
protected ketals, terminal alkynes, and heterocycles are
compatible as demonstrated by the synthesis of cyclopropyl-
amines 2c, 2f, 2i, and 2j. Product 2k contains a biologically
active piperazine derivative frequently used in active
pharmaceutical ingredients such as antihistamines.18 Primary
amines were not competent in the reaction due to the
diminished stability of the resulting products.19 This trans-
formation can also be performed on 1 mmol scale; 2a was
prepared in 83% yield and >20:1 d.r. at this scale.
found that the nature of the zinc salt was important, and that
simply stirring trans-2a (>20:1 d.r.) with ZnCl2 in THF at 85
°C led to efficient product epimerization to 6.3:1 d.r. (Table 2,
Table 2. Effect of Zinc(II) Salt and Solvent on
a
Epimerization of trans-Cyclopropylamine Product
The scope of α-chloroaldehyde starting materials is
demonstrated in Scheme 2b. trans-2-Arylcyclopropylamines
2m and 2n were isolated in moderate to good yield and
excellent diastereoselectivity. Aliphatic aldehydes afforded
cyclopropylamines 2o−2t in good yields. Ethers and a silyl
ether were also tolerated as shown by the efficient synthesis of
2r−2t. When the reaction was carried out using enantioen-
riched α-chloroaldehyde 1a (88% ee), product 2a was
recovered in moderate enantiomeric excess (34% ee). The
mechanism for loss of stereochemical information in this
reaction is still under investigation.
Intrigued by the significant improvement in the diaster-
eoselectivity upon addition of DMF to the reaction mixture, we
examined the stability of the product to the reaction conditions
in the absence of DMF. To probe this, an equivalent of
independently isolated cyclopropylamine 2b (>20:1 d.r.) was
added to a standard reaction for the synthesis of cyclopropyl-
amine 2a from α-chloroaldehyde 1a (Scheme 3). At the end of
entry
ZnX2
ZnCl2
ZnCl2
ZnCl2
ZnCl2·TMEDA
ZnCl2·2DMF
solvent
THF
DMF/THF
MeCN/THF
THF
yield
d.r.
1
2
3
4
5
87%
77%
54%
94%
90%
6.3:1
>20:1
7.1:1
>20:1
14:1
THF
a
Reactions were performed using trans-cyclopropylamine 2a (0.1
mmol, 1.0 equiv) and ZnCl2 (0.2 mmol, 2.0 equiv) in THF (0.1 M) at
85 °C for 18 h. Yield and d.r. determined by 1H NMR with
dibromomethane as internal standard. The volume of DMF and
MeCN added was 1.5× the volume of THF used.
entry 1). As previously observed, this epimerization does not
occur when DMF is added to the reaction mixture, as
demonstrated by the recovery of trans-2a in 77% yield and
>20:1 d.r. (entry 2). We wondered if a change in overall
solvent polarity upon the addition of DMF was key for
preventing product epimerization. To test this hypothesis, we
replaced DMF with acetonitrile, a solvent of similar dielectric
constant. Upon heating this mixture, trans-2a was recovered in
7.1:1 d.r., suggesting that the observed effect is not due to
solvent polarity (entry 3). Reactions using coordinatively
saturated zinc(II) sources, such as ZnCl2·TMEDA and ZnCl2·
2DMF, revealed that DMF may be playing an important role as
a ligand for zinc to modulate its ability to ring-open
cyclopropylamines. Using ZnCl2·TMEDA and ZnCl2·2DMF,
trans-2a was isolated in >90% yield and >20:1 d.r. or 14:1 d.r.,
respectively, even when the reaction was performed in the
absence of DMF as a cosolvent (entries 4−5).
Scheme 3. Probing Product Stability Under the Reaction
Conditions in the Absence of DMF
In summary, we have developed a highly diastereoselective
synthesis of trans-2-substituted-cyclopropylamines from readily
accessible α-chloroaldehydes. The reaction proceeds through a
zinc homoenolate intermediate that is trapped by an amine and
subsequently undergoes ring closure to generate the cyclo-
propylamine. In the absence of a strongly coordinating
cosolvent, ring closure is a reversible process and the
cyclopropylamine product is isolated as the thermodynamic
mixture of trans- and cis-diastereomers (≈5:1 d.r.). This
protocol is compatible with a range of functional groups, and a
variety of pharmaceutically relevant cyclopropylamines have
been prepared. Further work exploring the reactivity of these
homoenolate intermediates is ongoing in our laboratory.
the reaction, 2a was obtained in 5.9:1 d.r. as expected, and 2b
was recovered in moderate 5.5:1 d.r. This suggests that, under
these conditions, the trans-cyclopropylamine product is able to
epimerize to an approximately 5:1 mixture of trans- and cis-
diastereomers, presumably via trapped homoenolate inter-
mediate I (Scheme 1b). In the presence of DMF, the reaction
appears to be under kinetic control; the >20:1 d.r. (Table 1,
entry 3) is maintained and is consistent with the d.r. of our
related transformation of cyclopropanols to cyclopropylamines,
which we have shown is under kinetic control.14
To further understand the effect of DMF on the product d.r.,
as well as the parameters that control the reversibility/
epimerization in this process, we investigated the impact of
various zinc(II) salts and solvents on product formation. We
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03172.
Synthetic procedures, characterization data, and NMR
spectra (PDF)
C
DOI: 10.1021/acs.orglett.9b03172
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Savchenko, A. I.; Stratmann, C.; Noltemeyer, M. Mono- and
Disubstituted N,N-Dialkylcyclopropylamines from Dialkylformamides
via Ligand-Exchanged Titanium − Alkene Complexes. Chem. - Eur. J.
2002, 8, 3789−3801. (c) de Meijere, A.; Kozhushkov, S. I.;
Savchenko, A. I. Titanium-Mediated Syntheses of Cyclopropylamines.
J. Organomet. Chem. 2004, 689, 2033−2055. (d) Wiedemann, S.;
Rauch, K.; Savchenko, A.; Marek, I.; de Meijere, A. Convenient Route
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sophie.rousseaux@utoronto.ca.
ORCID
Sophie A. L. Rousseaux: 0000-0002-6505-5593
Present Addresses
†Paraza Pharma, Inc., 275 Boulevard Armand-Frappier, Laval,
QC, H7 V 4A7, Canada.
‡Ontario Institute for Cancer Research, 661 University Avenue
Suite 510, Toronto, ON, M5G 0A3, Canada.
́
Schill (nee Brackmann), F. Cyclopropylamines from N,N-Dialkylcar-
boxamides and Grignard Reagents in the Presence of Titanium
Tetraisopropoxide or Methyltitanium Triisopropoxide. Chem. - Eur. J.
2010, 16, 13862−13875.
Notes
The authors declare no competing financial interest.
(6) Kulinkovich−Szymoniak synthesis of cyclopropylamines:
(a) Bertus, P.; Szymoniak, J. New and Easy Route to Primary
Cyclopropylamines from Nitriles. Chem. Commun. 2001, 1792−1793.
(b) Bertus, P.; Szymoniak, J. A Direct Synthesis of 1-Aryl- and 1-
Alkenylcyclopropylamines from Aryl and Alkenyl Nitriles. J. Org.
Chem. 2003, 68, 7133−7136. (c) Bertus, P.; Szymoniak, J. Titanium-
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ACKNOWLEDGMENTS
■
We thank NSERC (Discovery Grants, Engage Grants, and
Canada Research Chair programs), the Canada Foundation for
Innovation (project number 35261), the Ontario Research
Fund and the University of Toronto for generous financial
support of this work. The authors also wish to acknowledge the
Canada Foundation for Innovation (Project number 19119)
and the Ontario Research Fund for funding the Centre for
Spectroscopic Investigation of Complex Organic Molecules
and Polymers. L.R.M. and T.R.M. thank NSERC for graduate
scholarships (PGS D, CGS-M). Dr. Jason D. Burch (Inception
Sciences) is thanked for insightful discussions.
̂
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