Urea activation of α-nitrodiazoesters: An organocatalytic approach to N-H insertion reactions

Article abstract of DOI:10.1021/ja3031054

The combination of a urea catalyst and an α-nitro-α-diazo ester gives rise to a reactive species able to undergo insertion into the N-H bonds of anilines. This new strategy to achieve N-H insertion reactivity is in contrast to typical metal-catalyzed cond

Full text of DOI:10.1021/ja3031054

Communication
pubs.acs.org/JACS
Urea Activation of α-Nitrodiazoesters: An Organocatalytic Approach
to N−H Insertion Reactions
Sonia S. So and Anita E. Mattson*
The Ohio State University, Department of Chemistry, 100 West 18th Avenue, Columbus, Ohio 43210, United States
S
* Supporting Information
donor (HBD)-activated α-nitro diazo compounds (1) in the
presence of a urea catalyst (2).
ABSTRACT: The combination of a urea catalyst and an
α-nitro-α-diazo ester gives rise to a reactive species able to
undergo insertion into the N−H bonds of anilines. This
new strategy to achieve N−H insertion reactivity is in
contrast to typical metal-catalyzed conditions for the
generation of carbenoids from α-diazocarbonyl com-
pounds. This report includes the extension of the insertion
reaction to a three-component coupling for the con-
struction of α-amino-α-aryl esters in high yield.
The ability of ureas to recognize nitro groups through
hydrogen bonding interactions has led to a successful platform
for the development of new HBD-catalyzed processes.4
Conventionally, urea and thiourea catalysis involving nitro
groups is centered on the activation of electrophiles, such as
nitroalkenes, for nucleophilic attack.5 We wished to break away
from this traditional reactivity pattern and uncover new
opportunities for urea catalysis. We reasoned that we could
exploit the urea-nitro group recognition to facilitate the loss of
nitrogen gas from 1 to generate a reactive intermediate capable
of producing useful products (3) as the result of an N−H
insertion reaction. The reactivity of HBD-activated diazo
compounds in the presence of amines could then be harnessed
in the development of new directions in organic catalysis, such
as the development of multicomponent coupling reactions to
yield valuable synthetic building blocks (4). While we were
motivated by the promise of HBD-catalyzed N−H insertion
methodologies, the project was initiated with a significant
amount of uncertainty as to whether a urea could aid in the
decomposition of a diazo compound. The assessment of this
approach began with studies of the urea-catalyzed insertion of
α-diazo-α-nitro ester 56 into the N−H bond of aniline (6,
Table 1).
etal-catalyzed insertion chemistry of α-diazocarbonyl
M
compounds has evolved into a remarkable synthetic tool
enabling the efficient construction of useful building blocks.1
The insertion into N−H bonds is a particularly attractive subset
of metal carbenoid chemistry giving rise to valuable amines with
direct applications in bioactive target synthesis (Scheme 1, eq
Scheme 1
N−H Insertion Development. Early on into our inves-
tigations we were surprised to collect a modest yield of α-
amino-α-aryl ester 7a formed from 5 and 6 after 48 h at 80 °C
in toluene with 20 mol % of difluoroboronate urea 2a; no
products containing a nitro group, as in 3, were isolated. We
hypothesized that the N−H insertion product 3 was unstable to
the reaction conditions and converted into 7a by loss of NO2
followed by further reaction with a second equivalent of aniline.
This unexpected HBD-catalyzed multicomponent coupling
excited us, and driven by the synthetic utility of an
organocatalytic single-flask process to access α-amino-α-aryl
esters, we set out to further develop the process. After
optimization of the reaction concentration, a high yield (83%)
of 7a was isolated with 20 mol % of 2a after 24 h in toluene at
40 °C (entry 1). A brief survey of ureas and thioureas was next
carried out to find the best catalyst for this reaction system.
Boronate pinacol ester urea 2b and traditional urea 2d both
afforded modest yields of desired product 7a (61% and 58%
respectively, entries 2 and 4). Conventional thiourea 2c, one of
the most active dual HBD catalysts in the literature, performed
1).2 This methodology includes the recently developed benefit
of excellent control over the newly formed nitrogen-bearing
stereocenter under appropriate conditions.3 We were inspired
by the power of N−H insertion methodology of metal
carbenoids and set out to investigate an organocatalytic
approach for the insertion of diazo compounds into N−H
bonds. In addition to the potential for an organocatalytic
method to offer less expensive and more ecological alternatives
to metal carbenoid processes, we were also excited to advance
N−H insertion chemistry as a new direction in noncovalent
organic catalysis. This communication describes our success
with the discovery of a multicomponent coupling process
resulting from N−H insertion reactions of hydrogen bond
Received: March 30, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja3031054 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 1. Urea Catalyzed N−H Insertion Development
time
(h)
yield
b
kobs (× 10−5
,
c
entry
1
2
(%)
s−1
)
20 mol %
24
24
24
24
83
61
27
58
9.19
0.77
1.10
1.38
catalyst structure
study
2a
2
3
4
20 mol %
2b
20 mol %
2c
20 mol %
Figure 1. Difluoroboronate urea 2a cocrystallized with nitrobenzene.
The ORTEP plot is drawn with 50% probability ellipsoids for the non-
hydrogen atoms. The hydrogen atoms are drawn with an artificial
radius.
2d
5
6
10 mol %
48
48
94
77
catalyst loading
study
2a
7.5 mol %
2a
evidence of the superior nature of difluoroboronate urea 2a in
the N−H insertion reaction (Table 1). Urea 2a offers observed
rates nearly 10 times faster than those of 2b, 2c, and 2d. In
addition to offering enhanced rates of 7a formation, it is
important to point out that catalysis of the N−H insertion
reaction with urea 2a also prevents undesired side reactions
observed with catalysts 2b−2d.
7
8
5 mol % 2a
72
72
85
73
2.5 mol %
2a
9
0 mol % 2a
24
8
a
Reactions performed using 10 equiv of aniline at a concentration of 1
M. See Supporting Information for detailed experimental procedures.
Isolated yield. An average of kobs, determined at multiple catalyst
b
c
HBD-Catalyzed Three-Component Coupling. Encouraged
by our success with the HBD-catalyzed additions of 2 equiv of
aniline to α-nitro-α-diazo ester 5, we set out to extend the
utility of the method by developing it into a three-component
coupling reaction (Table 2). More specifically, the reaction of 5,
an amine for N−H insertion (6), and a different nucleophile
would allow access to a wide range of α-amino esters (7). The
treatment of 5 with 4-fluoroaniline and diethylaniline afforded
product 7b in excellent yield (94%, entry 1). A near-
quantitative yield of 7c was isolated after the multicomponent
coupling of 5 with p-toluidine in the presence of 2,6-
diisopropylaniline (99%, entry 2). p-Anisidine was also well
tolerated in the process yielding 95% of 7d after 48 h in toluene
(entry 3). The selective insertion into the N−H bond of 4-
fluoroaniline in the presence of aniline proceeded well giving
rise to 72% of 7e after 72 h in toluene (entry 4). An
improvement in yield for the selective N−H insertion reaction
was observed with multicomponent coupling of 4-fluoroaniline
and 2,6-dimethylaniline to generate 7f (91%, entry 5). It is
reasoned that the steric bulk of the substituents in the 2 and 6
positions slows N−H insertion into 2,6-dimethylaniline leading
to higher yields of insertion into 4-fluoroaniline. In addition to
aniline derivatives, indoles were also found to operate well as
nucleophiles in the coupling reaction. For example, the urea-
catalyzed insertion of 5 into p-anisidine followed by reaction
with N-methylindole provided a high yield of 7g after 48 h in
toluene at room temperature (83%, entry 6). The N−H
insertion reaction is limited to anilines at this time; initial
attempts to insert into tert-butyl carbamate and tosylamide were
unsuccessful. Investigations are ongoing to expand the reaction
scope with respect to other amines.
loadings; see Supporting Information.
most poorly in this process, likely a result of catalyst
decomposition at elevated temperatures (27%, entry 3).7
Notably, no evidence of the decomposition of difluoroboronate
urea 2a was observed. Excellent yields of product were obtained
even at low loadings of optimal catalyst 2a by simply extending
the reaction times. For instance, a 10 mol % loading of 2a for
48 h gave rise to 94% of 7a (entry 5). Even reducing the
catalyst loading to just 5 mol % afforded an 85% yield of
product after 72 h (entry 7). In the absence of an HBD catalyst
just an 8% yield of 7a was isolated (entry 9).
The enhanced activity of 2a over conventional urea 2d is
proposed to arise from internal coordination of the urea
functionality to the strategically placed boron resulting in
polarization of the urea carbonyl and enhanced urea acidity.8−10
Cocrystallization of 2a with nitrobenzene indicates increased
polarization of the urea based upon the carbonyl bond length
(1.274 Å for 2a vs 1.211 Å for ureas lacking internal
coordination to boron9) and shows urea recognition of the
nitro group through hydrogen bonding (Figure 1). The
improved activity of difluoroboronate urea 2a over pinacol
ester boronate urea 2b demonstrates the importance of the
tunable nature of internal Lewis acid assisted ureas based on
ligand modification. In this case, the more electron-withdrawing
fluorine ligands give rise to a more active catalyst. A comparison
of the relative rates of these catalysts afforded additional
A plausible reaction pathway for this urea-catalyzed N−H
insertion begins with coordination of boronate urea 2a to
nitrodiazoester 5, giving rise to complex I (Scheme 2). The
entropically favorable loss of nitrogen gas generates HBD-
stabilized carbene complex II, and a subsequent N−H insertion
reaction with aniline (6) ensues to yield intermediate III.11 The
B
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Journal of the American Chemical Society
Communication
a
evidence of potential organocarbene intermediate II accessed
from α-nitro-α-diazo ester 5 in the presence of 2a. In general, it
is less common to generate carbenes and carbenoids from α-
nitro-α-diazo carbonyls than α-aryl/carbonyl-α-diazo carbonyls
as there are only a few literature reports in this area.12 The
publication from O’Bannon and Dailey in 1989 exploring the
cyclopropanation chemistry of rhodium carbenoids derived
from 5 was particularly interesting, as it outlined a proposed
decomposition pathway of nitrocarbene 8 (Scheme 3).12c This
Table 2. HBD-Catalyzed Three-Component Coupling
Scheme 3. Evidence for HBD-Generated Carbene: Reactions
of in Situ Generated Acyl Nitroso Compound 9
is important because the study of decomposition products is
the predominant strategy to probe mechanisms proposed to
proceed through nitrocarbenes: the direct observation of a
nitrocarbene remains an unsolved challenge.12a−c In the
absence of a suitable alkene for cyclopropanation, it is proposed
that nitrocarbene 8 undergoes rearrangement to acyl nitroso
compound 9, a species that is unstable and cannot be isolated.
Due to its instability, evidence for 9 was collected through two
different reactions: (1) a Diels−Alder reaction of 9 with 9,10-
dimethylanthracene to yield adduct 10 (eq 1) and (2) a
reaction of 9 with enophile 2,3-dimethyl-2-butene to yield ene
product 11 (eq 2). Based upon these experiments done by
O’Bannon and Dailey, we reasoned we could remove aniline
from our reaction system and effect either the Diels−Alder
reaction or the ene reaction to offer support for a catalytic cycle
proceeding through an HBD-generated carbene. Despite the
number of decomposition pathways acyl nitroso species can
participate in, we were pleased to find when 5 was combined
with 2a in the presence of 9,10-dimethylanthracene an 18%
yield of 10 was isolated. The treatment of 5 and 2a with 2,3-
dimethyl-2-butene in toluene at 40 °C gave rise to the expected
ene product 11 in 31% yield. These experiments suggest that in
the absence of a suitable reaction partner the combination of 5
and 2a lead to an acyl nitroso intermediate (9), conceivably
originating from nitrocarbene complex II.
a
See Supporting Information for detailed experimental procedures.
Isolated yield.
b
Scheme 2. Plausible Catalytic Cycle
−
extrusion of NO2 from III generates iminium ion IV and
More direct evidence for the participation of a carbene-like
intermediate in the N−H insertion reaction under development
in this report was obtained from the isolation of product 13 in
19% yield when the reaction was conducted in 0.25 M toluene,
conditions where it is unlikely the carbene will find an N−H
insertion reaction pathway prior to rearrangement (Scheme 4).
The product (13) is proposed to arise from the addition of p-
anisidine to the acyl nitroso species 9.13 It is reasoned that
carbene intermediate II undergoes rearrangement to 9 in the
reintroduces the urea catalyst back into the cycle. Iminium ion
IV goes on to react with a nucelophile, such as a second
equivalent of aniline, present in the reaction system affording
the observed product 7. Alternate reaction pathways, such as
those involving stepwise N−H insertions, have not been
explicitly ruled out at this time.
HBD-generated carbenes are a new direction in the field of
organic catalysis and we were interested to collect some
C
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Journal of the American Chemical Society
Communication
(3) For recent examples of enantioselective N−H insertion reactions
of carbenoids, see: (a) Bachmann, S.; Fielenbach, D.; Jorgensen, K. A.
Org. Biomol. Chem. 2004, 2, 3044. (b) Lee, E. C.; Fu, G. C. J. Am.
Chem. Soc. 2007, 129, 12066. (c) Liu, B.; Zhu, S. F.; Zhang, W.; Chen,
C.; Zhou, Q. L. J. Am. Chem. Soc. 2007, 129, 5834. (d) Hou, Z.; Wang,
J.; He, P.; Wang, J.; Qin, B.; Liu, X.; Lin, L.; Feng, X. Angew. Chem., Int.
Ed. 2010, 49, 4763. (e) Xu, B.; Zhu, S. F.; Xie, X. L.; She, J. J.; Zhou,
Q. L. Angew. Chem., Int. Ed. 2011, 50, 11483.
Scheme 4. Evidence for HBD-Generated Carbene:
Rearrangement to Acyl Nitroso Species 9 under Dilute
Reaction Conditions
(4) For reviews on urea and thiourea catalysis, please see:
(a) Berkessel, A.; Groger, H. Asymmetric Organocatalysis; Wiley-
VHC: Weinheim, 2005. (b) Takemoto, Y. Chem. Pharm. Bull. 2010,
58, 593. (c) Connon, S. J.; Kavanagh, S. A.; Piccinini, A. Org. Biomol.
Chem. 2008, 6, 1339. (d) Zhang, Z. G.; Schreiner, P. R. Chem. Soc. Rev.
2009, 38, 1187. (e) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299.
(5) For examples of nitroalkene activation with ureas and thioureas,
see: (a) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X. N.; Takemoto, Y.
J. Am. Chem. Soc. 2005, 127, 119. (b) Herrera, R. P.; Sgarzani, V.;
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(c) Kimmel, K. L.; Weaver, J. D.; Ellman, J. A. Chem. Sci. 2012, 3, 121.
(6) For the preparation of 5, see: Chiara, J. L.; Suarez, J. R. Adv.
Synth. Catal. 2011, 353, 575.
(7) For examples of thiourea decomposition at elevated temper-
atures, see: (a) Ishihara, K.; Niwa, M.; Kosugi, Y. Org. Lett. 2008, 10,
2187. (b) Kirsten, M.; Rehbein, J.; Hiersemann, M.; Strassner, T. J.
Org. Chem. 2007, 72, 4001.
(8) (a) So, S. S; Burkett, J. A.; Mattson, A. E. Org. Lett. 2011, 13, 716.
(b) So, S. S.; Auvil, T. J.; Garza, V. J. Org. Lett. 2012, 14, 444.
(9) For pioneering reports of internal Lewis acid assisted ureas in the
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B. D. J. Org. Chem. 1997, 62, 4492.
absence of an opportunity for rapid participation in an N−H
insertion reaction, such as dilute reaction conditions. These
results point to the potential involvement of an HBD-generated
carbene species (II) in the reaction pathway.
In summary, ureas operate as catalysts for the three-
component coupling of nitrodiazoesters, amines, and nucleo-
philes. This report includes evidence for the first organo-
catalytic activation of diazo compounds for participation in N−
H insertion reactions; the reaction pathway may proceed
through an HBD-stabilized carbene. Results of ongoing studies
in our laboratory exploring the full potential of HBD-activation
of diazo compounds, including the development of enantiose-
lective organocatalytic N−H insertion reactions, as new
synthetic tools will be reported as soon as possible.
(10) For early work demonstrating that diaryl ureas with
trifluoromethyl substituents have enhanced activity, please see:
(a) Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217. (b) Wittkopp,
A.; Schreiner, P. R. Chem.Eur. J. 2003, 9, 407.
ASSOCIATED CONTENT
* Supporting Information
■
(11) On the rare occasion α-amino α-nitro esters are reported, they
are typically prepared at low temperature and contain electron-
withdrawing groups on the amine: Ji, B.-C.; Liu, Y.-L.; Zhao, X.-L.;
Guo, Y.-L.; Wang, H.-Y.; Zhou, J. Org. Biomol. Chem. 2012, 10, 1158.
(12) For examples of carbene generation from α-nitro-α-diazo
carbonyl compounds, see: (a) Shollkopf, U.; Tonne, P. Leibigs Ann.
Chem. 1971, 753, 135. (b) O’Bannon, P. E.; Dailey, W. P. Tetrahedron
Lett. 1988, 29, 5719. (c) O’Bannon, P. E.; Dailey, W. P. J. Org. Chem.
1989, 54, 3096. (d) Charette, A. B.; Wurz, R. P.; Ollevier, T. Helv.
Chim. Acta 2002, 85, 4468. (e) Wurz, R. P.; Charette, A. B. J. Org.
Chem. 2004, 69, 1262. (f) Zhu, S.; Perman, J. A.; Zhange, X. P. Angew.
Chem., Int. Ed. 2008, 47, 8460. (g) Lindsay, V. N.; Lin, W.; Charette,
A. B. J. Am. Chem. Soc. 2009, 131, 16383. (h) Vanier, S. F.; Larouche,
G.; Wurz, R. P.; Charette, A. B. Org. Lett. 2010, 12, 672.
S
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
mattson@chemistry.ohio-state.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support for this work has been provided by the OSU
Department of Chemistry. We acknowledge the Ohio Bio-
Products Innovations Center (OBIC) for seminal support of
the OSU mass spectrometry facility. Dr. Judith Gallucci (OSU)
is thanked for expert crystallographic analysis.
(13) For reactions of acyl nitroso compounds with nucleophilic
amines, see: Atkinson, R. N.; Storey, B. M.; King, S. B. Tetrahedron
Lett. 1996, 37, 9287.
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dx.doi.org/10.1021/ja3031054 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX