A One-Pot Synthesis of N-Aryl-2-Oxazolidinones and Cyclic Urethanes by the Lewis Base Catalyzed Fixation of Carbon Dioxide into Anilines and Bromoalkanes

Article abstract of DOI:10.1002/chem.201602338

The multicomponent assembly of pharmaceutically relevant N-aryl-oxazolidinones through the direct insertion of carbon dioxide into readily available anilines and dibromoalkanes is described. The addition of catalytic amounts of an organosuperbase such as Barton's base enables this transformation to proceed with high yields and exquisite substrate functional-group tolerance under ambient CO₂pressure and mild temperature. This report also provides the first proof-of-principle for the single-operation synthesis of elusive seven-membered ring cyclic urethanes.

Full text of DOI:10.1002/chem.201602338

DOI: 10.1002/chem.201602338
Communication
&
Metal-Free Catalysis
A One-Pot Synthesis of N-Aryl-2-Oxazolidinones and Cyclic
Urethanes by the Lewis Base Catalyzed Fixation of Carbon
Dioxide into Anilines and Bromoalkanes
Teemu Niemi,[a] Jesus E. Perea-Buceta,*[a] Israel Fernꢀndez,*[b] Otto-Matti Hiltunen,[a]
Vili Salo,[a] Sari Rautiainen,[a] Minna T. Rꢁisꢁnen,[a] and Timo Repo*[a]
also withdraw traditional toxic phosgene derivatives, is magni-
fied by their synthetic origin, the relatively high production
costs of their multistep syntheses and a global emergence of
antimicrobial resistance.[7–9]
Abstract: The multicomponent assembly of pharmaceuti-
cally relevant N-aryl-oxazolidinones through the direct in-
sertion of carbon dioxide into readily available anilines
and dibromoalkanes is described. The addition of catalytic
amounts of an organosuperbase such as Barton’s base en-
ables this transformation to proceed with high yields and
exquisite substrate functional-group tolerance under am-
bient CO2 pressure and mild temperature. This report also
provides the first proof-of-principle for the single-opera-
tion synthesis of elusive seven-membered ring cyclic ure-
thanes.
A number of the existing methods to directly prepare NAOs
from CO2 use suitably prefunctionalized substrates such as
propargyl amines[10] or strained N-aziridines (Scheme 1a).[11] In
this manner, NAOs are afforded as a narrow set of structurally
predefined products, or as the result of a multistep sequence
that includes a late-stage N-arylation reaction of an intermedi-
ate 2-oxazolidinone and the respective purification steps.[12] Al-
ternatively, two reports this year have disclosed the construc-
tion of NAOs by fixating simultaneously CO2 into anilines and
epoxides.[13] A contribution by Kleij and co-workers describes
the partnership of a Al-based Lewis acid with a source of bro-
mide to effectively catalyze the conversion of epoxy amines
into NAOs at room temperature, yet using 10 bar of CO2.[13c]
However, the selectivity of this method relies on a precise
tuning of the reaction conditions and a careful predesign of
substrates.
The development of efficient methods to valorize CO2 as an
abundant and nontoxic chemical feedstock[1] entails a promis-
ing carbon-neutral approach while society shifts from fossil
fuels towards sustainable energy sources.[2] Albeit this task is
not trivial due to the stability and inertness of hyperoxidized
CO2 molecules,[3] the intrinsic value of the potential products is
key to stimulate further research.[4] In this sense, the urethane
motif features scintillating properties. For instance, converting
a primary amine into an urethane is a common strategy in
pharmaceutical development to improve the bioactivity of
drug candidates.[5]
In parallel, a report by Gao and co-workers illustrates the
challenge to avoid prefunctionalizing the substrate by con-
ducting intermolecularly this reaction with poorly nucleophilic
anilines.[13a,b] In this case, high conversion rates are only ach-
ieved by resorting to a large excess of the epoxide, as well as
high reaction temperatures and CO2 pressures that are inimical
to desirable levels of selectivity and substrate functional-group
tolerance. As part of our research in CO2 utilization,[14] herein
we disclose the unprecedented construction of NAOs by the
one-pot organocatalytic fixation of CO2 into dibromoalkanes
and anilines upon ambient pressure and mild temperature
(Scheme 1b).
Specifically, N-aryl-oxazolidinones (NAOs) excel amongst ure-
thane-containing pharmaceuticals as a result of their unmatch-
ed efficiency against a broad spectrum of gram-positive strains
that are resistant to other powerful antibiotics.[6] Nowadays,
the significance of developing efficient processes using CO2 as
a C-1 synthon to assemble the urethane core of NAOs, and
Selecting aniline (1a) and 1,2-dibromoethane (2) as the sim-
plest possible model system, we began our investigation by
evaluating the conditions from our previous work[14a] to con-
vert 1,2-haloamines into the corresponding 2-oxazolidinones
(Cs2CO3, EtOH, 35 bar CO2, 508C, 16 h). While the desired N-
phenyl-oxazolidinone (3a) was obtained in just 9% yield
(Table 1, entry 1), decreasing the pressure to 1 bar led the yield
up to 15% (entry 2). This suggests that the main carbamate
species at high pressures are barely able to cyclize and yield
3a. Inspection of different reaction solvents (entries 3–6) re-
vealed the superiority of polar aprotic solvents that markedly
enhanced the reaction conversions (entries 5, 6).
[a] T. Niemi, Dr. J. E. Perea-Buceta, O.-M. Hiltunen, V. Salo, S. Rautiainen,
Dr. M. T. Rꢀisꢀnen, Prof. T. Repo
Department of Chemistry
P.O. Box 55, 00014 University of Helsinki (Finland)
E-mail: timo.repo@helsinki.fi
jesus.pereabuceta@helsinki.fi
[b] Dr. I. Fernꢁndez
Departamento de Quꢂmica Orgꢁnica I, Facultad de Ciencias Quꢂmicas
Universidad Complutense de Madrid
Ciudad Universitaria, 28040 Madrid (Spain)
E-mail: israel@quim.ucm.es
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201602338.
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At this point, our interest concerning Lewis bases
in the catalytic activation of small molecules,[15] and
their rising prevalence in recent research to utilize
CO2,[16,17] led us to explore their potential catalytic
role in the reaction (Table 1, entries 8–12). Originally,
strong nitrogen bases such as TMG (entry 9), a hin-
dered phosphazene (entry 11), or the proton sponge
BTMGN (entry 12), failed to effect any negligible
change. Gratifyingly, a nearly two-fold increase of
yield ensued the addition of 10 mol% of a guanidine
base such as 2-tBuTMG (entry 10, 72%). However,
limited catalytic amplification was found by using
larger amounts of this base. Additionally, the amidine
base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) provid-
ed a slightly inferior result (entry 8, 70%).
We were pleased to find quantitative conversion
after raising the reaction time from 16 to 20 h and
the temperature up to 608C (Table 1, entry 14). Inter-
estingly, the protic guanidine base TBD, that often is
deemed as the base of choice in many studies to fa-
cilitate the insertion of CO2 into OꢀH and NꢀH bond-
s,[17a–d] showed inferior catalytic activity upon these
optimized conditions (entry 13, 75%).
Scheme 1. Different synthetic methodologies to construct NAOs by CO2 fixation.
We then turned our attention to the substrate
scope of the reaction, initially focusing on the aniline
component since its nucleophilicity was a key factor in previ-
ous precedents (Scheme 2).[13] To our delight, the high yield
obtained of 3a (92% yield) was the general trend observed for
several anilines with either electron-donating (Me, tBu, OMe)
or -withdrawing (Cl) substituents (3b–j, 72–92%), with the no-
table exception of NO2 that diminished enough the nucleophi-
licity to prevent any conversion (3d). Notably, we also found
that the reaction tolerates rather well the presence of a coordi-
nating heteroatom (3w, 64%), or severe steric hindrance near
the reaction site (3x, 75%). We then sought to investigate the
conversion of anilines bearing pharmaceutically important
groups that are barely compatible with the drastic conditions
used in many of the previous reports.[13]
Table 1. Screening of reaction conditions for the direct insertion of CO2
into aniline and 1,2-dibromoethane.[a]
Entry
Solvent
Cat. [mol%]
t [h]
Yield [%][b]
1[c]
2
3
4
5
6
7[d]
8
EtOH
EtOH
THF
PhMe
DMF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
–
–
–
–
–
–
–
16
16
16
16
16
16
16
16
16
16
16
16
20
20
9
15
3
In practice, the reaction accommodated well the presence of
groups (Br, I, B(pin)) that may provide a versatile synthetic
handle for further transformations on the aniline ring (3k–m,
55-83%). Furthermore, the presence of one or two, F or CF3
groups, in different locations of the aniline ring did not com-
promise the reaction yields (3n–u, 57–74%). We also success-
fully extended our protocol to 3-fluoro-4-morpholinoaniline
(3y, 78%), a motif present in the last generation antibiotic
Linezolid. On the other hand, a perfluorinated aniline proved
to be remarkably less reactive under the optimized conditions
(3v, 25%).
Using CO2 as synthon is not only underdeveloped for the
construction of six-membered cyclic urethanes, but to the best
of our knowledge, also unprecedented for seven-membered
ones, despite their interesting biological profiles.[18] Thus, we
set out to investigate the synthetic utility of our method
toward the construction of these cyclic products (Scheme 3). In
practice, we were pleased to find a similar pattern of reactivity
for the formation of several six-membered rings with diverse
0
48
49
4
70
41
72
36
44
75
99
DBU (10)
TMG (10)
2-tBuTMG (10)
P1-tBu(pyr)3 (10)
BTMGN (10)
TBD (10)
2-tBuTMG (10)
9
10
11
12
13[e]
14[e]
[a] 1a (1.0 equiv), 2 (2.0 equiv), Cs2CO3 (2.0 equiv), 508C, CO2 (1 bar), sol-
vent (0.2m), 16 h. [b] Yields determined by GCMS analysis using hexade-
cane as a standard. [c] Reaction with 35 bar of CO2. [d] Reaction without
CO2. [e] Reaction at 608C. For full details, see the Supporting Information.
Additionally, a control experiment demonstrated that only
traces of 3a are formed in MeCN without CO2 pressure
(Table 1, entry 7).
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Scheme 2. 2-tBuTMG-catalyzed syntheses of NAOs by the multicomponent fixation of CO2. Yields refer to the isolated product (for full details, see the Sup-
porting Information).
optimized conditions. Analogously to the formation of five-
membered rings, our protocol also was fit-for-purpose to con-
vert aniline substrates with troublesome features such as the
presence of a coordinating heteroatom (5i, 63%), or severe
steric hindrance near the newly formed urethane functionality
(5j, 75%). Furthermore, the reaction also proceeded rather
well with fluorine-based groups of pharmaceutical interest
(5 f–h, 64–85% and 5k, 78%).
We suggest that this CO2 fixation method also holds prom-
ise for the generation of scarce seven-membered urethanes. To
that end, we gathered a valuable proof-of-principle by isolat-
ing in a relatively respectable yield the products of the reac-
tion between 1,4-dibromobutane and several anilines (6a–f,
22–35%). Conversely, our conditions were not effective
enough to render the corresponding cyclized products using
larger chain dibromoalkyl electrophiles such as 1,5-dibromo-
pentane or 1,12-dibromododecane. Instead, the large ring
strain (eight-membered ring formation) or entropic contribu-
tion (15-membered ring formation) prevents the final cycliza-
tion from occurring, as was corroborated by the isolation of
the corresponding acyclic linear urethanes with a distal bro-
mide substituent in moderate yields (7a–b, 34–58%).
DFT calculations at the PCM(MeCN)-M06-2X/6-311+G(d)//
M06-2X/6-31+G(d) level[19] were carried out to gain more in-
sight into the reaction mechanism of the above described
Scheme 3. 2-tBuTMG-catalyzed syntheses of six- and seven-membered cyclic
NAOs formation. To this end, the formation of the parent NAO
urethanes by the multicomponent fixation of CO2. Yields refer to the isolated
3a from aniline and 1,2-dibromoethane (2) in the presence of
CO2 and catalytic amounts of 2-tBuTMG was explored. As seen
in Figure 1, which shows the computed reaction profile gather-
ing the corresponding relative free energies (DG, at 298 K), the
process begins with the slightly exergonic formation of inter-
mediate INT2 (DGR =ꢀ0.8 kcalmolꢀ1).
product (for full details, see the Supporting Information). [a] Reaction carried
out with 20 mol% of 2-tBuTMG. [b] Reaction conducted for 36 h.
electronic properties in moderate to good yield (5a–e, 50–
82%), using 1,3-dibromopropane as an electrophile upon our
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Figure 1. Computed reaction profile for the reaction of aniline and 1,2-dibromoethane (2) in the presence of CO2 and catalytic amounts of 2-tBuTMG. Relative
free energies and bond distances are given in kcalmolꢀ1 and ꢃ, respectively. All data have been computed at the PCM(MeCN)-M06-2X/6-311+G(d)//M06-2X/
6-31+G(d) level.
This zwitterionic species, which strongly resembles that iso-
lated in the reaction of CO2 with 1,5,7-triazabicyclo[4.4.0]dec-5-
ene (TBD),[20] derives from the easy nucleophilic attack of 2-
tBuTMG to CO2 via TS1 (activation barrier of only 6.0 kcalmolꢀ1
from the separate reactants). INT2 is then transformed into
INT3 by reaction with 1,2-dibromoethane through TS2 in
a strongly exergonic transformation (DGR =ꢀ12.8 kcalmolꢀ1).
This saddle point is associated with the formation of the new
CꢀO bond and release of bromide following a typical SN2 reac-
ing access to a wide range of NAOs in a single step from
highly cost-effective commercial substrates; 2) it takes place
upon ambient pressure and mild temperature, yet only re-
quires a relatively low loading of an Lewis base as organocata-
lyst;[16] 3) it presents high substrate functional-group tolerance
amenable for drug-development programs; 4) it is also
a proof-of-principle for the single-step syntheses of six-mem-
bered, and elusive seven-membered cyclic urethanes. In addi-
tion, with the help of DFT calculations it is suggested that the
process involves the formation of an initial zwitterion by reac-
tion of CO2 and the organocatalyst followed by successive SN2
reactions and final cyclization reaction. Work is ongoing in our
laboratories to further expand the substrate scope of this mul-
ticomponent process to more challenging electrophiles part-
ners such as secondary and tertiary bromides or alkenes, which
would reinforce even more the pharmaceutical applicability of
our methodology.
¼
tion (DG =23.9 kcalmolꢀ1). From INT3, a new SN2 reaction in-
volving deprotonated aniline as a nucleophile (readily formed
in the presence of Cs2CO3) leads to the formation of the new
CꢀN bond of INT4 with concomitant release of the second
bromide again in a highly exergonic process (DGR =ꢀ38.7 kcal
molꢀ1) with an activation barrier of 19.6 kcalmolꢀ1 via TS3.[21]
A
final intramolecular cyclization reaction affords the protonated
NAO 3a (which would produce the observed 3a by reaction
with base) regenerating the catalyst 2-tBuTMG. This last step
proceeds with an activation barrier of 26.5 kcalmolꢀ1, which in-
dicates that the final cyclization reaction constitutes the rate-
limiting step of the entire transformation. Indeed, the comput-
ed activation barrier for the analogous cyclization reaction in-
volving the corresponding INT4 derived from 1,5-dibromopen-
tane was 49.1 kcalmolꢀ1, which suggests that the formation of
the eight-membered ring derivative is unfeasible, as experi-
mentally observed (see above).[22]
Acknowledgements
The work was supported by the Magnus Ehrnrooth foundation
and the Spanish MINECO-FEDER (grant CTQ2013-44303-P).
Keywords: 2-oxazolidinones · antibiotics · carbon dioxide ·
density functional calculations · guanidine superbases
In summary, we have described an unprecedented construc-
tion of NAOs by the one-pot fixation of CO2 into dibromoal-
kanes and anilines. This constitutes a significant advance in the
area because 1) it is a robust multicomponent reaction provid-
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¼
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Received: May 17, 2016
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COMMUNICATION
Come together: Carbon dioxide can be
simultaneously fixated into anilines and
primary dibromoalkanes under metal-
free ambient mild conditions to afford
a broad range of N-aryl-oxazolidinones
or six and seven-membered cyclic ure-
thanes in good yields.
&
Metal-Free Catalysis
T. Niemi, J. E. Perea-Buceta,*
I. Fernꢁndez,* O.-M. Hiltunen, V. Salo,
S. Rautiainen, M. T. Rꢀisꢀnen, T. Repo*
&& – &&
A One-Pot Synthesis of N-Aryl-2-
Oxazolidinones and Cyclic Urethanes
by the Lewis Base Catalyzed Fixation
of Carbon Dioxide into Anilines and
Bromoalkanes
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