Urea-catalyzed construction of oxazinanes

Article abstract of DOI:10.1039/c3ob41517a

Highly functionalized oxazinanes are efficiently prepared through urea-catalyzed formal [3 + 3] cycloaddition reactions of nitrones and nitrocyclopropane carboxylates. The reaction system is general with respect to both the nitrocyclopropane carboxylates and nitrones enabling the preparation of a large family of oxazinanes, typically in high yield. This method affords access to enantioenriched oxazinane products through chirality transfer from enantioenriched nitrocyclopropane carboxylates.

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ARTICLE TYPE
Urea Catalyzed Construction of Oxazinanes
Andrea M. Hardman, Sonia S. So, Anita E. Mattson*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
Highly functionalized oxazinanes are efficiently prepared
through urea-catalyzed formal [3+3] cycloaddition reactions
of nitrones and nitrocyclopropane carboxylates. The reaction
system is general with respect to both the nitrocyclopropane
35
The development of cycloaddition methodology of
nitrocyclopropane carboxylates (4) presents the opportunity for
compelling investigations for at least two reasons: (1) the
incorporation of the nitro group, an easily manipulated
functionality for bioactive target synthesis, into the product and
10 carboxylates and nitrones enabling the preparation of a large
family of oxazinanes, typically in high yield. This method 40 (2) the rapid buildup of molecular complexity via the direct
affords access to enantioenriched oxazinane products through
chirality transfer from enantioenriched nitrocyclopropane
carboxylates.
installation of several stereocenters, including an additional
stereocenter when compared to similar reactions of 1,1-
diestercyclopropanes. Intrigued by the promise of developing a
new process to access highly-functionalized building blocks in a
15
Formal cycloaddition reactions of donor acceptor cyclopropanes 45 single step, we became curious to identify conditions in which
have emerged as useful methods to access biologically important
heterocycles.1 More specifically, the activation of 1,1-
diestercyclopropanes (1) under Lewis acidic conditions is a
nitrocyclopropane 4 would react in a formal [3+3] cycloaddition
reaction with
a nitrone to generate highly functionalized
oxazinane 5.
20 powerful strategy to effect formal [3+2] cycloaddition reactions
The starting point for our studies on formal cycloaddition
with partners such as imines and aldehydes to give rise to 50 chemistry of nitrocyclopropane carboxylates was inspired by the
pyrrolidines (2, X = N) and tetrahydrofurans (2, X = O, Scheme
1).2 Similarly, formal [3+3] cycloadditions of 1 with nitrones are
efficiently catalyzed in the presence of Lewis acids to yield
25 oxazinanes (3).3 It is surprising that reactions of
recent discovery in our laboratory that ureas7 are able to catalyze
ring-opening reactions of nitrocyclopropane carboxylates (4) in
the presence of strong nitrogen nucleophiles (Scheme 2).6 While
the urea-catalyzed conversion of 4a to 7 did provide encouraging
nitrocyclopropane carboxylates (4), another interesting family of 55 evidence to pursue our investigations, we were also aware this
activated cyclopropanes, remain significantly less studied than
1,1-diestercyclopropanes.4
Only few reports exist on
nucleophilic ring-opening reactions of nitrocyclopropane
30 carboxylates5,6 and to the best of our knowledge there are no
methodology was limited to strong nucleophiles. At the
beginning of our studies we were uncertain if ureas would be
effective catalysts to activate nitrocyclopropane carboxylates for
reactions with less nucleophilic species, such as nitrones, imines
a
previous publications exploring formal cycloaddition reactions of 60 and aldehydes, envisioned for participation in cycloaddition-type
species like 4.
chemistry. Our work in this area was initiated with testing the
reaction of 4a and 8a to give rise to 5a (Scheme 2).
Scheme 1. Select reactions of activated cyclopropanes.
Useful Reactions of 1,1-Diestercyclopropanes
Scheme 2. Urea activation of nitrocyclopropane carboxylates.
R4
O
R1
O
CO2R
O
O
Lewis
Acid
Lewis
Acid
RO2C
R2
N
R
O
OMe
RO
OR
R3
X
R
R
R1
NH
Ph NH2
NO2
X
N
H
N
H
RO2C CO2R
O
R4
Urea
Catalyst
Ph
R1
N
2
1
3
R2
H
Ph
MeO2C
O
O
7: 87%
O
Ph
N
O
O
R3
H
N
N
Ph
O
Ph
N
This Work: Formal [3+3] of Nitrocyclopropane Carboxylates
CO2Me
4a
Ph
H
8a
R4
O
R1
Ph
6
O
O
N
N
urea
Ph
Installation of additional
stereocenter
O2N CO2Me
RO
O
5a
R3
MeO2C NO2
R4
O
R1
N
4
5
Direct introduction of
nitrogen functionality
R3
H
65
Gratifyingly, optimization of the reaction conditions enabled
the identification of a protocol affording access to 5a in high
yield as a 2:1 mixture of diastereomers from 4a and 8a in the
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presence of 15 mol % urea catalyst 9a (Table 1).8 The success of 30 the nitro group.
the reaction was dependent on solvent and reaction temperature.
Early testing with dichloromethane provided 5a in low yield
(35%, entry 1). Select higher boiling solvents, like toluene and
chloroform, provided improvements in yield (91% and 79%,
entries 2 and 3). The best set of reaction conditions were
identified as toluene at 80 °C with a urea loading of 15 mol %
giving rise to 91% of 5a after 24 h (entry 5). Notably,
difluoroboronate urea 9a is a highly active dual HBD catalyst for
5
10 the activation of nitrocyclopropane carboxylates, potentially a
result of enhanced urea polarization due to internal coordination
of the urea carbonyl to the strategically placed boron.6,9,10,11 The
difluoroboronate substituent is key as the related boronate urea
pinacol ester (9c) afforded low yields of 5a (27%). Conventional
15 urea 9b gave rise to good yields of product while conventional
thiourea 9d yielded just 9% of the desired oxazinane 5a.
Thiourea decomposition at elevated temperatures is proposed to
be the reason for the poor performance of catalyst 9d.12
O
N
H3CO
Ph
O
Ph
Ph
Ph
O
O
O
N
N
Ph
Ph
H
H
H
H
N
O
O
O
H3CO
5a'
5a"
Figure 1. ORTEP representations of oxazinanes 5a' and 5a''. Drawn with
50% probability displacement ellipsoids.
Table 1. Urea-catalyzed formal [3+3] cyloaddition optimization.
The identification of the two diastereomers isolated in
combination with the observed chirality transfer, led us to a
plausible stepwise reaction pathway for the transformation
35 (Scheme 3).13 After initial activation of the nitrocyclopropane
carboxylate with the urea catalyst, the nitrone undergoes
nucleophilic addition with inversion of configuration giving rise
to species I and II. Evidence for inversion of configuration was
collected by establishing the absolute configuration of the major
40 enantiomer of the oxazinane 5k.8 The stereochemical outcome of
the reaction may result from the cyclization of I and II through
chair-like transition states.
Ph
O
Ph
N
O
Ph
catalyst
Ph
MeO2C
O
N
+
N
Ph
solvent
24 h
O
Ph
H
O2N CO2Me
4a: 89% ee
8a
5a: 91% ee; 2:1 dr
entrya
mol % 9a
20 mol %
20 mol %
20 mol %
20 mol %
15 mol %
10 mol %
solvent
temp. (oC) 5a yieldb
1
2
3
4
5
6
dichloromethane
toluene
35
100
50
35
91
79
36
91
74
chloroform
acetonitrile
toluene
50
80
toluene
80
Scheme 3. Plausible stepwise reaction pathway.
Select urea catalysts explored and yields under the optimized conditions
in entry 5:
R'
O
N
H
O
O
N
Ph
O
Ph
CF3
CF3
CF3
N
F
F
F
F
R
Ph
O
H
Ph
B
B
N
Ph
NO2
H
O
O
O
N
Ph
H
H
R
O
O
MeO
N
H
N
H
N
H
N
H
CF3
F3C
N
H
N
H
CF3
I
5a'
O
O
MeO
8a
9a: 91% (2:1 dr)
9b: 75% (2:1 dr)
Ph
O
CF3
CF3
CF3
O
O
Ph
N
Ph
O
Ph
Bpin
O
N
OMe
S
CO2Me
H
Ph
OMe
N
N
O
Ph
H
H
O
O
H
N
N
H
N
H
CF3
F3C
N
H
N
H
CF3
NO2
Ph
II
5a"
H
N
(1R, 2S)-4a: 89% ee
91% ee
2:1 dr
9c: 27% (2:1 dr)
9d: 9% (2:1 dr)
aReactions performed using 1.5 equivalents of nitrone at a concentration
of 0.5 M. Control experiments for entry 5 result in a 13% yield of 5a in
the absence of the catalyst. See Supporting Information for detailed
experimental procedures. bPercent isolated yield as a 2:1 mixture of
diastereomers.
R'
R
45
A variety of substituted phenyl rings on the nitrocyclopropane
were found to be well tolerated in the transformation giving rise
to high yields of the corresponding oxazinane products (Table 2).
Nitrocyclopropane carboxylates derived from p-chlorostyrene
and p-bromostyrene afforded good yields of 5b and 5c (67% and
20
Chirality transfer was observed from an enantioenriched
nitrocyclopropane carboxylate. Specifically, the subjection of
enantioenriched 4a to the optimized reaction conditions gave rise
to 5a as a 2:1 mixture of enantioenriched (91% ee) diastereomers.
25 The assignment of the relative stereochemistry of 5a' and 5a''
was achieved through x-ray crystallographic analysis of crystals
collected from a racemic mixture (Figure 1).8 The major
diastereomer 5a' was found to have the two aromatic rings and
the nitro group cis while 5a'' was epimeric at the carbon bearing
50 73%, respectively, entries 2 and 3). A near quantitative yield of
oxazinane 5d was isolated when naphthalene-derived
a
nitrocyclopropane was incorporated into the process (entry 4).
Steric hindrance resulting from substitution in the ortho position
of the phenyl did not prevent the bond-forming event, although in
55 select cases lower yields were observed. For example, the
nitrocyclopropanes derived from o-methylstyrene gave rise to a
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modest yield of 5e (41%, entry 5). Even 2,4,6-trimethylphenyl 10 25% yield (entry 8). The methodology is currently limited from
substituted nitrocyclopropane 4f participated in the cycloaddition
reaction giving rise to 5f in 47% yield (entry 6). A good yield of
oxazinane 5g was observed when the more nucleophilic nitrone
derived from p-anisaldehyde was employed in the reaction (76%,
entry 7). Alkenyl substitutents on the nitrocyclopropane did not
prevent the reaction; however, lower yields were isolated. For
example, formal [3+3] cycloaddition of 4g and 8a afforded 5h in
the incorporation of electron-rich nitrocyclopropane carboxylates
because these substrates are unstable and difficult to isolate as
they easily rearrange to the isoxazoline N-oxide.5e,14
5
Table 3. Substrate scope of nitrones.
R2
R1
O
Ph
N
O
R2
15 mol % 9a
Ph
MeO2C
O
O
N
+
N
toluene
80 °C, 24 h
R1
H
O2N CO2Me
Table 2. Substrate scope of nitrocyclopropane carboxylates.
8
(±)-5
(±)-4a
entrya
Ph
O
R
N
O
Ph
R
O
O
15 mol % 9a
N
8
5
yield (%)b
+
N
Ph
toluene
80 °C, 24 h
MeO2C
Ph
H
O2N CO2Me
O
Ph
H
Ph
O
Ph
N
N
(±)-5
(±)-4
8a
1
4-Me-Ph
99
91
87
O2N CO2Me
entrya
1
(±)-4
5
O
yield (%)b
Me
5i (3:1 dr)
Ph
Ph
Ph
8b
N
O
Ph
H
Ph
O
Ph
O
N
N
N
91
67
73
99
MeO2C
O2N CO2Me
O
4-OMe-Ph
2
3
4a
5a
O
O2N CO2Me
Ph
4-Cl-Ph
MeO
N
5j (4:1 dr)
8c
O
O
Cl
Ph
2
3
4
N
O
Ph
H
MeO2C
O2N CO2Me
Ph
O
Ph
N
N
4b
5b
O
Ph
Ph
4-Br-Ph
4-Cl-Ph
N
O2N CO2Me
O
O
Cl
Br
5k
N
8d
MeO2C
O2N CO2Me
Ph
O
Ph
4c
5c
O
N
Ph
2-Nap
O
Ph
N
N
4
5
6
93
56
47
Ph
O
O
Ph
O2N CO2Me
N
Ph
H
MeO2C
O2N CO2Me
8e
5l
4d
5d
4-Me-Ph
Ph
O
Ph
Me
N
Ph
O
2-Me-Ph
O
4-Me-Ph
N
N
O
O
5c
41
47
76
25
O2N CO2Me
Ph
Ph
H
N
EtO2C
O2N CO2Et
8f
5m (3:1 dr)
4e
Me
5e
Ph
O
Ph
O
Ph
H
N
N
Ph
O
IMes
N
O
O
O
O
6c
O2N CO2Me
Me
Ph
N
CO Et
2
O
O
O2N CO2Et
Me
5n
8g
4f
Me
5f
aReactions performed using 1.5 equiv of nitrone at a concentration of 0.5
Ph
O
IMes
o
N
M in toluene at 80 C for 24 h. See Supporting Information for detailed
experimental procedures. bIsolated yield as a 2:1 mixture of diastereomers
O
O
7c,d
Me
4-OMePh
N
CO Et
2
O2N CO2Et
Me
unless otherwise noted.
4f
5g (3:1 dr)
15
Ph
Ph
O
N
The reaction of a variety of nitrones (8) with 4a led to the
formation of variously substituted oxazinanes 5i-n, typically in
good yield (Table 3). The nitrone derived from p-tolualdehyde,
afforded a quantitative yield of oxazinane 5i with 15 mol % of
O
8
N
CO2Me
O2N CO2Me
O
4g
5h
20 catalyst 9a (entry 1). Oxazinane 5j was isolated in excellent yield
from the nitrone containing an electron-donating methoxy
substituent (entry 2). An electron-withdrawing substituent on the
nitrone derived from p-chlorobenzaldehyde was also well
tolerated in the formal cycloaddition reaction, affording 87% of
aReactions performed using 1.5 equiv of nitrone at a concentration of 0.5
o
M in toluene at 80 C for 24 h. See Supporting Information for detailed
experimental procedures. bIsolated yield as a 2:1 mixture of diastereomers
unless otherwise noted. cThe ethyl ester derivative of the
nitrocyclopropanes was used. dThe nitrone derived from p-anisaldehyde
was used.
25 oxazinane 5k (entry 3).
The nitrone 8e derived from
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‡ Support for this work has been provided by the OSU Department of
Chemistry and the American Chemical Society Petroleum Research
45 Foundation (Award No. 52183-DNI1). Dr. Judith Gallucci is thanked for
expert crystallographic analysis.
cinnamaldehyde also performed well affording 93% of oxazinane
5l (entry 4). The N-p-tolyl substituted as well as a piperonal
derived nitrones were tolerated in the reaction giving rise to
oxazinanes 5m and 5n in 56% and 47% yields, respectively
(entries 5 and 6). In its present state, the reaction precludes use
of nitrones derived from aliphatic aldehydes and N-alkyl
substituents. In our attempts to incorporate nitrones from both
acetaldehyde and isobutyraldehyde into the cycloaddition
reaction we observed only decomposition of nitrone and
1
For reviews on the reactivity of activated cyclopropanes, please see:
5
(a) Carson C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051. (b)
Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117. (c) Yu, M.;
50 Pagenkopf, B. L. Tetrahedron 2005, 61, 321. (d) Reissig, H. U.; Zimmer,
R. Chem. Rev. 2003, 103, 1151. (e) Burrit, A.; Coron, J. M.; Steel, P. J.
Trends Org. Chem. 1993, 4, 517. (f) Wong, H. N. C.; Hon, M. Y.; Tse, C.
W.; Yip, Y. C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165. (g)
Danishefsky, S. Acc. Chem. Res. 1979, 12, 66.
10 nitrocyclopropane: no cycloaddition adducts were observed.
The highly functionalized oxazinane products present
opportunities as building blocks in the synthesis of more complex
nitrogen-containing target molecules. Decarboxylation of a 2:1
mixture of 5a was achieved in good yield in the presence of
15 lithium hydroxide to give rise to 10a as a 5:1 diastereomers.8
Chirality transfer from 5a was observed enabling the preparation
of 10a' and 10a'' as an enantioenriched (95% ee) mixture of
diastereomers.8 Subjecting 5a (2:1 dr) to mild reduction
conditions selectively reduced the nitro group providing
20 hydroxylamine 11a in excellent yield as a 3:1 mixture of
diastereomers. Treating 10a' with similar conditions selectively
reduced the nitro group to the corresponding amine in 97% yield
(Scheme 4).
55 2 For recent examples of Lewis acid-catalyzed reactions of
diestercyclopropanes for the formation of pyrrolidines and
tetrahydrofurans, see: (a) Jackson, S. K.; Karadeolian, A.; Driega, A. B.;
Kerr, M. A. J. Am. Chem. Soc. 2008, 130, 4196. (b) Perreault, C.;
Goudreau, S.; Zimmer, L.; Charette, A. B. Org. Lett. 2005, 7, 2313. (c)
60 Pohlhaus, P. D.; Johnson, J. S. J. Am Chem. Soc. 2005, 127, 16014. (d)
Magolan, J.; Kerr, M. A. Org. Lett. 2006, 8, 4561.
3
For examples of formal cycloaddition reactions of nitrones and 1,1-
diestercyclopropanes, see: (a) Young, I. S.; Kerr, M. A. Angew. Chem.
Int. Ed. 2003, 42, 3023. (b) Young, I. S.; Williams, J. L.; Kerr, M. A.
65 Org. Lett. 2005, 7, 953. (c) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am.
Chem. Soc, 2005, 127, 5764. (d) Kang, Y.-B.; Sun, X.-L.; Yong, T.;
Angew. Chem. Int. Ed. 2007, 46, 3918.
4
For a review on nitrocyclopropanes please see: Averina, E. B.;
Yashin, N. V.; Kuznetsova, T. S.; Zefirov, N. S. Russian Chem. Rev.
70 2009, 78, 887.
5
For reports of ring-opening reactions of nitrocyclopropanes please
see: (a) Vettiger, T.; Seebach, D. Liebigs Ann. Chem. 1990, 195. (b)
Seebach, D.; Haener, R.; Vettiger, T. Helv. Chim. Acta 1987, 70, 1507.
(c) Wurz, R. P.; Charette, A. Org. Lett. 2005, 7, 2313. (d) Budynina, E.
75 M.; Ivanova, O. A.; Averina, E. B.; Kuznetsova, T. S.; Sefirov, N. S.
Tetrahedron Lett. 2006, 47, 647. (e) Lifchits, O.; Charette, A. B. Org.
Lett. 2008, 10, 2809. (f) Lifchits, O.; Alberico, D.; Zakharian, I.; Charette,
A. B. J. Org. Chem. 2008, 73, 6838.
Scheme 4. Transformations of oxazinane 5a.
Ph
Ph
O
O
Ph
Ph
Ph
Ph
Ph
Ph
O
O
Ph
Ph
LiOH:H2O
N
N
N
N
Dioxanes:H2O
Ph
Ph
60% yield
CO2Me
CO2Me
O2N
O2N
NO2
NO2
5a'
2:1 dr
5a"
10a' 5:1 dr 10a"
Zn; HCl
iPrOH
6
So, S.S.; Auvil, T. J.; Garza, V. J.; Mattson, A. E. Org. Lett. 2012,
97% yield
Zn; AcOH
iPrOH
94% yield
80 14, 444.
7
For recent reviews on urea catalysis, see: (a) Takemoto, Y. Chem.
Ph
Ph
Ph
O
O
O
Ph
Ph
Ph
Ph
Ph
N
Pharm. Bull. 2010, 58, 593. (b) Zhang, Z. G.; Schreiner, P. R. Chem.
Soc. Rev. 2009, 38, 1187. (c) Connon, S. J. Synlett 2009, 354. (d)
Berkessel, A., Groger, H. Asymmetric Organocatalysis; 1st ed.; Wiley-
85 VCH, 2005.
N
N
single
diastereomer
Ph
CO2Me
CO2Me
HN
HN
NH2
OH
OH
8
See Supporting Information for additional details about the
11a'
3:1 dr
11a"
12a'
optimization of the reaction conditions, urea catalyst structure, x-ray
crystal data, chirality transfer, and mechanistic studies.
9
(a) So, S. S.; Mattson, A. E. J. Am. Chem. Soc. 2012, 134, 8798. (b)
90 So, S. S.; Burkett, J. A.; Mattson, A. E. Org. Lett. 2011, 13, 716. (c)
Nickerson, D. M.; Angeles, V. V.; Auvil, T. J.; So, S. S.; Mattson, A. E.
Chem. Comm., 2013, 49, 4289.
10 For pioneering work using boronate ureas in anion recognition,
please see: (a) Hughes, M. P.; Shang, M. Y.; Smith, B. D. J. Org. Chem.
95 1996, 61, 4510. (b) Hughes, M. P.; Smith, B. D. J. Org. Chem. 1997, 62,
4492.
11 For additional recent, interesting examples of alternate strategies to
access hydrogen bond donors with enhanced activity see: (a) Robak, M.
T.; Trincado, M.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 15110. (b)
100 Ganesh, M.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 16464.
12. For examples of thiourea decomposition at elevated temperatures, 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.
25 Conclusions
In summary, ureas operate as catalysts for the preparation of
highly substituted oxazinanes produced from the reaction of
nitrones with nitrocyclopropane carboxylates. This is the first
report of nitrocyclopropane carboxylates participating in formal
30 [3+3] cycloaddition reactions. The oxazinane products can be
isolated in high enantiomeric access via chirality transfer of an
enantioenriched nitrocyclopropane.
nitrocyclopropane carboxylates fits into
research program in our laboratory focused on interesting
35 reactivity patterns accessed via hydrogen bond donor catalysis.
The urea-activation of
larger on-going
a
105 13. For mechanistic speculation on related reactions of nitrones and 1,1-
diestercyclopropanes see: (a) Wanapu, D.; Van Gorp, K. A.; Mosey, N. J.;
Kerr, M. A.; Woo, T. K. Can. J. Chem. 2005, 83, 1752. (b) Karadeolian,
A. Kerr, M. A. J. Org. Chem. 2007, 72, 10251.
14. For rearrangements of nitrocyclopropanes to isoxazoline N-oxides
110 see: Bianchi, L.; Dell’Erba, C.; Gasparrini, F.; Novi, M.; Petrillo, G.;
Sancassan, F.; Tavani, C. ARKIVOC 2002, xi, 142.
Notes and references
a The Ohio State University, 100 W. 18th Ave., Columbus, OH USA. Fax:
1-614-292-1685; Tel: 1-614-247-7931; E-mail: mattson@chemistry.ohio-
state.edu
40 † Electronic Supplementary Information (ESI) available: detailed
experimental procedures and characterization data are included in the
supporting information. See DOI: 10.1039/b000000x/
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