Dichotomy of reductive addition of amines to cyclopropyl ketones vs pyrrolidine synthesis

Article abstract of DOI:10.1021/acs.orglett.6b02945

An interesting catalytic dichotomy was discovered: switching between simple ligand-free catalysts leads to fundamentally different outcomes of reductive reaction between amines and α-carbonylcyclopropanes. Whereas a rhodium catalyst leads to the tradition

Full text of DOI:10.1021/acs.orglett.6b02945

Letter
pubs.acs.org/OrgLett
Dichotomy of Reductive Addition of Amines to Cyclopropyl Ketones
vs Pyrrolidine Synthesis
Oleg I. Afanasyev,‡ Alexey A. Tsygankov,‡ Dmitry L. Usanov,‡,† and Denis Chusov*,‡,§
‡A.N.Nesmeyanov Institute of Organoelement Compounds of the Russian Academy of Sciences, Vavilova St 28, Moscow 119991,
Russian Federation
§Department of Organic Chemistry, RUDN University, 6 Miklukho-Maklaya Street, Moscow 117198, Russia
S
* Supporting Information
ABSTRACT: An interesting catalytic dichotomy was discovered: switching
between simple ligand-free catalysts leads to fundamentally different outcomes of
reductive reaction between amines and α-carbonylcyclopropanes. Whereas a
rhodium catalyst leads to the traditional reductive amination product, ruthenium
catalysis enables a novel reaction of pyrrolidine synthesis via ring expansion. The
protocols do not require an external hydrogen source and employ carbon monoxide
as a deoxygenative agent. The developed methodologies are perfectly compatible
with a number of synthetically important functionalities such as ester, carboxyl, bromo, and Cbz moieties.
he past decade can be called the golden age of donor−
to the expected reductive amination adduct 2 (36%),
comparable amounts of pyrrolidine 1 were also formed
(20%). This feature could provide the grounds for the
development of an interesting and synthetically valuable
methodology of pyrrolidine synthesis, and therefore, we
initiated efforts to shift the ratio of the products in the model
reaction toward the desired product 1. Solvent screening
(Table 1, entries 1−8) demonstrated that highest pyrrolidine
content could be achieved in tetrahydrofuran, diethyl ether, and
2-propanol (Table 1, entries 1, 6, and 8), yet the product yields
remained low. We hypothesized that pyrrolidine formation
could be the result of the rearrangement of initially formed
traditional adduct 2 and tested if elevated temperature could
favor product 1. Surprisingly, increasing the temperature
resulted in higher yields of cyclopropane 2 (Table 1, entries
1, 9−12); bringing the temperature from 110 to 130 °C
changed the pyrrolidine−cyclopropane ratio from 1:1.8 to
1:4.4. On the contrary, when we decreased the temperature to
100 °C, pyrrolidine 1 became the main product with 6-fold
higher yield over the cyclopropane. No pyrrolidine was
detected when pure 2 was subjected to the reaction conditions
in dioxane, THF, or water, which indicated that the two
products were formed via independent pathways. While
keeping the reaction temperature at 130 °C in line with the
observed trend, we found dioxane to be the best media for
selective preparation of the traditional product: 92% yield of
compound 2 could be detected, which was accompanied by
only trace amounts of the pyrrolidine counterpart (Table 1,
entry 13). At this point, however, it became obvious that the
Rh-based catalytic system had no potential for optimization
into a preparative tool for pyrrolidine synthesis from cyclo-
propyl ketones.
1
Tacceptor (D−A) cyclopropane chemistry.
Despite the
fact that D−A cyclopropanes have been known since the
1980s,2 the unique synthetic potential of these compounds has
become fully appreciated only during recent years.3 D−A
cyclopropropanes can undergo various notable transformations,
such as [2 + 2], [3 + 2], [3 + 3], [4 + 2], and [4 + 3]
cycloadditions, annulations, and ring openings that lead to
pyrroles, furans, amines, silylenolates, lactones, etc. The natural
limitation of some of D−A cyclopropane chemistry is that both
an electron-donating and an electron-withdrawing group have
to be present in the cyclopropyl ring in order to provide a
synergistic activation effect. In contrast, we have been excited
about opportunities to expand the types of transformations
which usually require a special substitution pattern of the
cyclopropyl ring onto less specialized cyclopropane substrates.4
Recently, we have demonstrated the unique potential of
carbon monoxide as a reducing agent on the examples of
efficient atom-economical transformations, such as reductive
amination of aldehydes5a,c,6 and ketones5d as well as reductive
Knoevenagel condensation.5b The developed methodologies
are notable for favorable environmental profiles, synthetically
useful functional group compatibility, and access to sterically
challenged molecules; synthetic superiority over conventional
highly selective reagents (e.g., sodium cyanoborohydride) was
vividly demonstrated.6 The net effect of the reported protocols
corresponds to reductive formation of a single C−C or C−N
bond, which represents highly useful yet synthetically simple
transformations. On the contrary, herein we report a novel
methodology which likewise takes advantage of the reductive
potential of carbon monoxide6 but at the same time represents
conceptually more advanced chemistry compared to the
previously described contributions to the field.5−9
In a Rh-catalyzed reaction between methyl cyclopropyl
Received: September 29, 2016
ketone and p-anisidine, we were excited to find that, in addition
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02945
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
With these results in hand, we explored the substrate scope
of pyrrolidine synthesis (Figure 1). A number of adducts of
Table 1. Catalyst and Solvent Optimization for the
Preparation of Pyrrolidines vs Cyclopropylamines
a
entry
catalyst
temp (°C)
solvent
THF
1 (%)
2 (%)
1
2
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
RuCl3
110
110
110
110
110
110
110
110
100
120
130
140
130
160
160
160
160
160
160
160
160
160
160
160
20
2
36
0
solvent free
MeCN
MeOH
water
d
3
3
0
4
3
0
5
12
28
0
8
6
Et2O
56
65
44
4
7
dioxane
iPrOH
THF
8
16
24
16
18
18
trace
89
75
40
80
76
72
59
48
76
92
91
9
10
11
12
13
THF
72
80
80
92
6
THF
THF
dioxane
b
c
14
THF
b
15
RuCl3
solvent free
MeCN
MeOH
Et2O
18
4
b
16
RuCl3
b
17
RuCl3
10
21
25
15
16
16
8
b
18
RuCl3
b
19
RuCl3
toluene
dioxane
tBuOH
EtOH
b
20
RuCl3
b
21
RuCl3
b
22
RuCl3
b
23
RuCl3
water
d
24
RuCl3
water
trace
a
100 mol % of methyl cyclopropyl ketone, 100 mol % of p-anisidine, 1
mol % of Rh2(OAc)4, 4 h, or 1 mol % of RuCl3, 5 h. Yields were
b
1
determined by H NMR with internal standard. 4 mol % of RuCl3
c
were used over 5 h. Obtained with a particularly rigorous exclusion of
d
water. 24 h.
We switched our attention to identification of an alternative
catalyst which would favor formation of product 1. After
screening a number of metal complexes (such as PtO2,
Pd(PPh3)4, Pd(OAc)2, Re2(CO)10, Ir4(CO)12, [(COD)IrCl]2,
CpIrI2, RhCl3, Rh6(CO)16, RuCl3, see the Supporting
Information), we were delighted to find ruthenium trichloride
as a basis for an orthogonal catalytic system. In contrast to
rhodium acetate, ruthenium-mediated reaction demonstrated
an inverted selectivity profile (Table 1, entry 14).
Figure 1. Investigation of the substrate scope for the preparation of
pyrrolidines and cyclopropylamines from cyclopropyl ketones. Yields
1
were determined by H NMR with internal standard. Isolated yields
are shown in parentheses. For pyrrolidine synthesis: 1.0 mmol of
amine, 1.5 mmol of ketone (for each amino group), 1 mol % of RuCl3
(to each amino group), water, 30 bar CO, 160 °C, 22 h. For
cyclopropylamine synthesis: 1.0 mmol of amine, 1.5 mmol of ketone, 2
mol % of Rh2(OAc)4, dioxane, 30 bar CO, 130 °C, 24 h. (a) THF was
used as solvent. (b) 2 mol % of RuCl3. (c) 4 mol % of RuCl3. (d) 110
°C. (e) dr 2.5:1. (f) dr 1.4:1. (g) 110 °C, 48 h. (h) 160 °C, 48 h.
Solvent screening (Table 1, entries 14−23) showed that
among organic solvents the best results could be achieved in
THF with very rigorous exclusion of water (Table 1, entry 14).
However, an even higher yield of 1 was obtained in pure water
(entry 23). The effect of the water content on the reaction
outcome is therefore very peculiar: both anhydrous THF and
water represent better solvents for pyrrolidine synthesis than
wet THF (see the Supporting Information). The possibility of
using aqueous media is interesting in the context of green
chemistry in addition to the advantageous sustainability profile
already provided by the use of CO as an atom-economical
reductant.5 Another important advantage of Ru-based method-
ology of pyrrolidine synthesis is associated with the fact that the
average cost of ruthenium is over 10-fold lower than the cost of
rhodium.10
methyl cyclopropyl ketone with different amines were obtained
with good to excellent yields (1a−g,i,l). No substantial
influence of electronic properties of the aniline substituents
was observed: p-methoxy-, p-methyl-, p-bromo-, p-ethoxycar-
bonyl-, and m-hydroxycarbonyl-substituted derivatives were
obtained in similar yields (83−96%). In addition to aliphatic
ketones, the reaction worked equally well for aromatic
counterparts (1h), among which D−A cyclopropanes have
been successfully employed (1j,k). The protocol exclusively
furnished 2,5-disubstituted pyrrolidines when 1,2-disubstituted
cyclopropanes were used as starting materials, and no other
isomeric pyrrolidines were detected. The methodology could
be successfully applied to diamines (1i), which in the broader
B
DOI: 10.1021/acs.orglett.6b02945
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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context can be useful for the synthesis of bidentate ligands. The
reaction was scaled up to 2 mmol without any erosion of the
yield (see the Supporting Information).
Likewise, a useful preparative profile was observed for the
Rh-catalyzed protocol. Various products 2a−g were successfully
isolated in good yields (Figure 1).
Investigation of the mechanistic details of the described
processes is beyond the scope of this paper. However, schemes
of possible mechanisms are provided in the Supporting
Information.
In summary, we have developed highly efficient orthogonal
methodologies for a novel one-step preparation of pyrrolidines
or traditional preparation of cyclopropyl-substituted amines via
reductive amination; the direction of the process can be altered
by simply changing the catalyst from ruthenium trichloride to
rhodium acetate. The reactions do not require an external
hydrogen source or any ligands and employ the unique
properties of carbon monoxide as a deoxygenative agent, which
renders our methodologies more atom-economical in compar-
ison to the existing synthetic alternatives.
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.6b02945.
Detailed experimental procedures and full spectroscopic
data for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: chusov@ineos.ac.ru, denis.chusov@gmail.com.
Present Address
†(D.L.U.) Harvard University, Department of Chemistry and
Chemical Biology, 12 Oxford Street, Cambridge, MA 02138.
Notes
The authors declare no competing financial interest.
(8) For other applications of carbon monoxide as a reducing agent,
see: (a) Li, H.-Q.; Liu, X.; Zhang, Q.; Li, S.-S.; Liu, Y.-M.; He, H.-Y.;
Cao, Y. Chem. Commun. 2015, 51, 11217−11220. (b) Park, J. W.;
Chung, Y. K. ACS Catal. 2015, 5, 4846−4850.
ACKNOWLEDGMENTS
■
The work was financially supported by the Russian Science
Foundation (Grant No. 16-13-10393). We gratefully acknowl-
edge Dr. Rinat Salikov for the cyclopropyl starting materials.
(9) For synthesis of pyrrolidines, see: (a) Bhat, C.; Tilve, S. G. RSC
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(10) For example, rhodium(II) acetate dimer and ruthenium(III)
trichloride hydrate (1 g, >99.98% trace metal basis) can be purchased
from Sigma-Aldrich for $1050 and $59, respectively.
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DOI: 10.1021/acs.orglett.6b02945
Org. Lett. XXXX, XXX, XXX−XXX