New C-C coupling reaction of cyclic nitronates with carbon nucleophiles. Umpolung of the conventional reactivity of nitronates

Article abstract of DOI:10.1021/jo048944k

Cyclic six-membered nitronates 1 are involved in diastereoselective C-C coupling reactions with various nucleophiles in the presence of either catalytic or stoichiometric amounts of TBDMSOTf to give the previously unknown N-siloxytetrahydrooxazines. The i

Full text of DOI:10.1021/jo048944k

SCHEME 1. Reactivity of Nitronates
New C-C Coupling Reaction of Cyclic
Nitronates with Carbon Nucleophiles.
Umpolung of the Conventional Reactivity
of Nitronates
Vladimir O. Smirnov,† Sema L. Ioffe,*,†
Alexander A. Tishkov,† Yulia A. Khomutova,†
Ivan D. Nesterov,‡ Michael Yu. Antipin,‡
William A. Smit,† and Vladimir A. Tartakovsky†
N. D. Zelinsky Institute of Organic Chemistry,
Russian Academy of Sciences, Leninsky Prospect 47, 119991
Moscow, Russian Federation, and A. N. Nesmeyanov
Institute of Organoelement Compounds,
Russian Academy of Sciences, Vavilov Street 28,
119991 Moscow, Russian Federation
iof@ioc.ac.ru
Received June 22, 2004
scope of the application of this protocol for the selective
organic transformations.
Abstract: Cyclic six-membered nitronates 1 are involved
in diastereoselective C-C coupling reactions with various
nucleophiles in the presence of either catalytic or stoichio-
metric amounts of TBDMSOTf to give the previously un-
known N-siloxytetrahydrooxazines. The intermediacy of
N,N-bis(oxy)iminium cations was proven by NMR data.
We suggest that the activation of nitronates 1 by
means of silylation instead of protonation should improve
the possibilities of this strategy. In the course of our
systematic study of silylation of ANC, we have encoun-
tered a number of extraordinary processes, which proceed
under very mild conditions and could be accounted for
with an intermediacy of silylated cations 2 (M ) A )
SiR3).5 However, it is still an open issue whether cationic
intermediates of this type can be generated as kinetically
stable species and can be involved in the intermolecular
C-C bond-forming reactions with carbon nucleophiles.6
The investigation of this problem is the subject of the
present paper.
In line with the above-mentioned facts, silyl (M ) SiR3)
and alkyl (M ) alkyl) nitronates 1 are considered possible
precursors of target cations 2. However, the protolytic
lability of silyl nitronates and the thermal instability of
acyclic alkyl nitronates1 can hamper the systematic study
of cations 2. This circumstance prompted us to choose
the generally more-stable and readily available six-
Nitronate functionality is normally associated with
R-C-nucleophilic1,2 or 1,3-dipolar reactivity1 (Scheme 1,
eqs 1 and 2), in which both reactivities constitute the
basis of the numerous synthetic transformations of
aliphatic nitro compounds (ANC).1,2 However, as it is
reflected in the canonical form B, the electronic structure
of nitronates 1 can also provoke an R-C-electrophilic
activity of these species if appropriate reaction partners
are employed (eq 3).
Due to the feebly marked electrophilic reactivity of
nitronates 1, reactions similar to eq 3 are very rare, and
all cases of C-C coupling of nitronates found in the
literature imply the activation of the nitronate function-
ality with strong acids in harsh conditions (Scheme 2,
e.g., M ) H; A-X ) a mixture of H-OTf and H-O2CCF3,
20-70 °C).3,4
(3) Prakash, S.; Schleyer, P. V. R. Stable Carbocation Chemistry;
John Wiley & Sons: New York, 1997; pp 525-539 and references
therein.
(4) N,N-Bis(hydroxy)iminium cations are widely discussed as in-
termediates of the Nef reaction: Kornblum, N.; Brown, R. A. J. Am.
Chem. Soc. 1965, 87, 1742.
Although iminium cations 2, tentatively proposed as
intermediates of these processes, should possess a high
reactivity, the incompatibility of strong Brønsted acids
with the majority of nucleophilic reagents narrows the
(5) For the suggested generation of 2 by silylation of silylnitronates,
see: (a) ref 2d. For the suggested generation of 2 by interaction of N,N-
bissiloxyenamines with certain electrophiles, see: (b) Dilman, A. D.;
Lyapkalo, I. M.; Ioffe, S. L.; Strelenko, Yu. A.; Tartakovsky, V. A. J.
Org. Chem. 2000, 65, 8826. (c) Dilman, A. D.; Ioffe, S. L.; Mayr, H. J.
Org. Chem. 2001, 66, 3196. (d) Ustinov, A. V.; Dilman, A. D.; Ioffe, S.
L.; Strelenko, Yu. A.; Smit, W. A.; Tartakovsky, V. A. Mendeleev
Commun. 2003, 74.
(6) (a) It is likely that the bistrimethylsilyl derivative of methazonic
acid, obtained 40 years ago by silylation of nitromethane, is formed as
a result of the analogue’s C-C coupling between cation [CH2d
N(OSiMe3)2]+ and silyl nitronate CH2dN(O)OSiMe3: Klebe, J. F. J.
Am. Chem. Soc. 1964, 86, 3399. For intramolecular trapping of N,N-
bis(siloxy)iminium cations, see: (b) Tishkov, A. A.; Kozintsev, A. V.;
Lyapkalo, I. M.; Ioffe, S. L.; Kachala, V. V.; Strelenko, Yu. A.;
Tartakovsky, V. A. Tetrahedron Lett. 1999, 5075. (c) Smirnov, V. O.;
Tishkov, A. A.; Kozintsev, A. V.; Lyapkalo, I. M.; Ioffe, S. L.; Kachala,
V. V.; Strelenko, Yu. A.; Tartakovsky, V. A. Russ. Chem. Bull. 2000,
49, 874.
* Author to whom correspondence should be addressed. FAX: +7
(095) 135-5328.
† N. D. Zelinsky Institute of Organic Chemistry.
‡ A. N. Nesmeyanov Institute of Organoelement Compounds.
(1) (a) Ono, N. The Nitro Group in Organic Synthesis; John Wiley
& Sons-VCH: New York, 2001; pp 249-301. (b) Torssell, K. B. G.
Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis; VCH:
New York, 1988.
(2) For employment of silyl nitronates in classical reactions of ANC.
For modification of the Henry reaction, see: (a) Seebach, D.; Beck, A.
K.; Lehr, F.; Webler, T.; Colwin, E. W. Angew. Chem., Int. Ed. Engl.
1981, 20 and references therein. For modification of the Mannich
reaction, see: (b) Kalinin, A. V.; Apasov, E. T.; Ioffe, S. L.; Kozjukov,
V. P.; Kozjukov, V. P. Bull. Acad. Sci. Div. Chem. Sci. 1985, 34, 2442
(Russian translation, 1985, 2635). For modification of the Michael
reaction, see: (c) Marti, R. E.; Heinzer, J.; Seebach, D. Liebigs Ann.
1995, 1193. (d) Tartakovsky, V. A.; Ioffe, S. L.; Dilman, A. D.; Tishkov,
A. A. Russ. Chem. Bull. 2001, 50, 1936.
10.1021/jo048944k CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/04/2004
J. Org. Chem. 2004, 69, 8485-8488
8485

SCHEME 2. Strategy for Nucleophilic Addition to Nitronates
TABLE 1. C-C Coupling of Nitronates 1 with Silyl
could expect then species 2 to react smoothly with the
silyl-capped nucleophiles.10
Ketene Acetal 3
yield
An efficient C-C coupling of nitronates 1a-j with the
model ketene acetal 3 was indeed achieved in the
presence of a catalytic amount of TBDMSOTf under very
mild conditions (eq 4 and Table 1).11 As a result, a
representative set of functionalized N-siloxytetrahydro-
[4H]-oxazines (4a-j) have been prepared in excellent
yields.
entry
1
R1
R2
R3
R4 oxazine 4 (%)
ratioa
1
2
3
4
5
6
7
1a H Ph
1b H Me
1c H Ph
1d H An
1e H An
1f H OBz
Me Me 4a
Me Me 4b
OMe Me 4c
91
88
91
93
H
OEt 4d
4e:4e′
OEt
H
88 1.5:1
Me Me 4f:4f ′:4f′′
88 19:1:2b
1g H OCO-C6H4- Me Me 4g:4g′: 4g′′ 92 20:1.5:1c
NO2-p
8
9
10
1h Me H
1i Me H
1j Me Ph
H
H
4h
95
90
92
Me Me 4i
Me Me 4j
a Determined by integration of the 1H NMR spectra of the crude
product. b The column chromatography allowed us to isolate pure
4f (77%) and a mixture of its invertomer 4f′′ and diastereomer
4f ′ (2:1; 11%). 4f transforms slowly into 4f′′ during storage in
CDCl3 solution at rt (see Supporting Information). c The column
chromatography allowed us to isolate pure 4g (82%) and a mixture
of its invertomer 4g′′ and diastereomer 4g′ (2:3; 10%). 4g trans-
forms slowly into 4g′′ during storage in CDCl3 solution at rt (see
Supporting Information).
membered cyclic nitronates 1a-j (Table 1) as the objects
of silylation for this preliminary study.7
The presence of a substituent (R1 ) Me) at C-3
significantly retards the reaction, and an increase in the
reaction time and amount of catalyst is needed to achieve
the complete conversion (see Table 1, entries 8-10).
The formation of compounds 4 proceeds mostly with a
high diastereoselectivity. In fact, products 4a-d,h-j
were isolated as individual diastereomers in almost
quantitative yields.12 For adducts 4f,g, minor diastereo-
isomers 4f ′,g′ were also obtained in e6% yields (entries
6 and 7). Practically no diastereoselectivity was observed
for the formation of a mixture of 4e and 4e′ (entry 5).
To evaluate the scope and limitations of this new C-C
coupling reaction, the reactivity of model nitronate 1a
toward some other nucleophiles was investigated (Scheme
4).
Thus, nitronate 1a reacts with silyl enol ether 5 to give
the expected ketone 6. The same diastereomer of product
6 was also obtained upon the interaction of 1a with
enamine 7 followed by the hydrolysis of salt 8 that formed
initially.
In contrast to enamine 7, its silylated analogue 9
underwent an exclusive N-C coupling with 1a to give
enamine 10 in good yield.13 At the same time, N-
siloxyenamine 11 turned out to be unreactive toward 1a.
Methallylstannane 12 reacts with 1a to give the
corresponding oxazine 13.
The generation of iminium cations 2 from nitronates
1 and TBDMSOTf has been studied by NMR with the
example of 1a (Scheme 3).
The addition of an equimolecular amount of TBDM-
SOTf to a solution of 1a in CDCl3 in an NMR tube leads
to the generation of cation 2a (with significant downfield
1
shifts of both H and 13C NMR signals of the CH-3 and
CH-4 fragments8). The characteristic 29Si signal of 2a (δ
) 50.1 ppm) was also observed in the 29Si NMR spectrum.
The presence of a large 3JH,H value for the CH-4 proton
in cation 2a and its precursor 1a shows that both species
exist predominantly in a half-chair conformation with the
pseudoequatorial arrangement of the Ph group.
1
The study of the correlation of H NMR spectra with
temperature has shown an exchange between 1a, 2a, and
TBDMSOTf to be slow at -50 °C and rapid at -20 °C
(see Supporting Information, page S26). The reversibility
of the observed changes indicated that 2a is stable up to
0 °C for at least 15 min.9
The introduction of two electronegative oxygen atoms
to the nitrogen center of the iminium moiety should bring
about a noticeable increase in its electrophilicity, and one
(7) Compounds 1a-j were prepared from nitromethane or nitro-
ethane using the modified procedures of the following: (a) Denmark,
S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137. (b) Kanemasa, S.;
Yoshimiya, T.; Wada, E. Tetrahedron Lett. 1998, 8869.
(8) Similar changes in NMR spectra upon the silylation of nitrones
have been attributed to the generation of N-siloxy-N-alkyliminium
cations: Chalaye-Mauger, H.; Denis, J.-N.; Averbuch-Pouchot, M.-T.;
Vallee, Y. Tetrahedron 2000, 56, 791.
(9) The NMR investigation of the N,N-bis(oxy)iminium cations
formed upon the interaction of TBDMSOTf with other nitronates will
be published in due course.
(10) The electrophilicity parameter (E) for N,N-dialkyliminium
cations is ca. -5: Mayr, H.; Ofial, A. R. Tetrahedron Lett. 1997, 3503.
It might be expected that the E parameter for cations 2 is higher.
(11) For catalytic activation of electrophilic reagents with silicon
Lewis acids, see: Dilman, A. D.; Ioffe, S. L. Chem. Rev. 2003, 103,
733.
(12) The 1H NMR data of crude reaction mixtures did not reveal
the presence of the diastereomers, except those shown in Table 2.
8486 J. Org. Chem., Vol. 69, No. 24, 2004

SCHEME 3. Interaction of Nitronate 1a with TBDMSOTf (δ in parts per million relative to TMS)
SCHEME 4. Interaction of Nitronate 1a with Various Nucleophiles Promoted by TBDMSOTf
TABLE 2. Stereochemical Outcome of Reaction in Eq
Reactions 1a + 7 and 1a + 12 require no less than a
(5)
stoichiometric amount of TBDMSOTf. All adducts shown
R1 relative to OSi relative to
in Scheme 4 were obtained as individual diastereomers.12
R2 (position
of R1)a
R1 (position
of OSi)
entry
1
R2 (position)a product
The configurations of nitronates 1 and the target
products were determined by means of NMR (analysis
of the 3JH,H coupling constants14 and NOE experiments)
and X-ray analysis (see Table 2).15 For nitronates 1a-j
and cations 2a-j, a half-chair conformation was as-
sumed. The X-ray analysis revealed that tetrahydroox-
azines 4c,d,f,g′′,j and 10 exist in a chair conformation
in a solid state.15,16
1
2
3
4
5
1a Ph (eq)
1b Me (eq)
1c Ph (eq)
1d An (ax)
1e An (eq)
4a
4b
4c
4d
4e
4e′
4f
4f ′
4f′′
4g
trans (eq)
trans (eq)
trans (eq)
cis (ax)
trans (eq)b
trans (eq)b
trans (eq)c
trans (ax)c
trans (eq)b
trans (eq)b
cis (eq)c
cis (eq)
trans (eq)
6
1f OBz (ax)
cis (eq)c
trans (eq)
cis (ax)d
cis (eq)d
trans (eq)b
trans (eq)d
cis (eq)d
It should be mentioned that X-ray data secured an
unambiguous determination of the configuration of the
7
1g OCO-C6H4-
NO2-p (ax)
4g′
4g′′
4h
4i
trans (eq)
cis (ax)c
trans (eq)b
trans (eq)c
trans (eq)b
trans (eq)b
trans (eq)c
trans (eq)b
trans (eq)b
cis (ax)c
8
9
10
11
12
13
14
1h
1i
H
H
(13) The N-attack of carbenium cations on enamines can be char-
acterized by a rate higher than that of the C-attack (for the discussion,
see ref 10 and references therein). Normally, N-vinylammonium cations
are thermodynamically less stable than the isomeric iminium ions (i.e.,
the products resulted from C-attack). Therefore, N-alkylated enamine
9 could be formed as a kinetic product, which cannot rearrange to the
iminium cation like 8 due to the fast irreversible loss of the silyl group.
(14) (a) Hesse, M.; Meier, H.; Zeeh, B. Spektroskopische Methoden
in der organischen Chemie; Thieme, G., Ed.; Verlag: Berlin, 1995; p
108. (b) Lambert, J. B.; Takeuchi, Y. Cyclic Organonitrogen Stereody-
namics; VCH: New York, 1992; Chapters 7.1.1 and 7.2.1 and references
therein.
(15) CCDC 230273 (4d), CCDC 230274 (4c), CCDC 230275 (4f),
CCDC 230276 (10), CCDC 230277 (4g′′), and CCDC 230278 (4j) contain
the supplementary crystallographic data for this paper. These data
can be obtained online (http://www.ccdc.cam.ac.uk/cgi-bin/catreq.cgi)
free of charge.
1j Ph (eq)
1a Ph (eq)
1a Ph (eq)
1a Ph (eq)
1a Ph (eq)
4j
trans (eq)c
trans (eq)
trans (eq)
trans (eq)c
trans (eq)
6
8
10
13
trans (eq)b
a Established by NMR. b Established by comparison with NMR
data for 4c. c Established by X-ray data. d Stereochemical assign-
ments for 4f′′ and 4g were based on the similarity of their NMR
spectra with those of 4g′′ and 4f, respectively.
endocyclic nitrogen atom in these adducts.17 NMR and
X-ray data show that all of the studied compounds adopt
(16) For conformational analysis of some N-oxides, 5,6-dihydro-[4H]-
oxazines, and tetrahydro-[4H]-oxazines, see ref 14b and the follow-
ing: Tishkov, A. A.; Lesiv, A. V.; Khomutova, Yu. A.; Strelenko, Yu.
A.; Nesterov, I. D.; Antipin, M. Yu.; Ioffe, S. L.; Denmark, S. E. J. Org.
Chem. 2003, 68, 9477.
(17) For data on the hindered inversion of the nitrogen atom in the
systems bearing the O-N-O fragment, see: Rudchenko, V. F. Chem.
Rev. 1993, 93, 725.
J. Org. Chem, Vol. 69, No. 24, 2004 8487

SCHEME 5. Stereoselectivity of the C-C Coupling
Reaction of Cations 2 with Nucleophiles
reaction of 1d + 3, is likely a product of the ring inversion
(IR) of the initially formed unstable 4d′.
The slow transformation of products 4f and 4g into 4f′′
and 4g′′, respectively, is most likely a result of a sequence
of the IN and IR stereodynamic processes (cf. refs 14b and
17).
The formation of diastereomers 4e′-g′, along with 4e-
g, in reactions of 1e-g with ketene acetal 3 can be
observed due to the competitive attack of 3 on both
conformers C and D of cations 2e-g.20
In conclusion, the described stereoselective C-C coup-
ling reaction of the cyclic six-membered alkyl nitronates
with nucleophiles creates an opportunity for the prepara-
tion of various tetrahydro-[4H]-N-siloxyoxazines, bearing
the functionalized substituents at C-3.21 The search for
applications of this new class of compounds in organic
synthesis, as well as further studies of the masked
electrophilic reactivity of various nitronates, will soon be
the subject of our research.
Experimental Section
General Procedure for Addition of 3 to Cyclic Nitro-
nates 1a-j. To a stirred solution of nitronate 1 (1 mmol) and
ketene acetal 3 (0.24 mL, 205 mg, 1.09 mmol) in CH2Cl2 (5 mL)
at -78 °C was added TBDMSOTf [0.023 mL, 0.1 mmol, if R1 )
H (1a-g) or 0.046 mL, 0.2 mmol, if R1 ) Me (1h-j)]. The
reaction mixture was stirred for 1 h at -78 °C (R1 ) H) or for
18 h at -78 °C (R1 ) Me) (TLC monitoring) and was quenched
at -78 °C by the successive addition of hexane (5 mL) and a
saturated aqueous solution of NaHCO3 (5 mL). The temperature
was allowed to reach 20 °C; the organic layer was separated,
and the aqueous layer was back-extracted with hexane (2 × 5
mL). Combined organic layers were washed successively with a
saturated aqueous solution of NaHCO3 (10 mL) and brine (10
mL), dried over Na2SO4, and evaporated in vacuo. The residue
was subjected to column chromatography (silica gel, EtOAc/
hexane, 1:20 f 1:3) to give 4 (88-95%).
the same conformations in a solution and in a crystal
state.
The stereochemical course of the reaction 1a-j + Nu
(eq 5) is described in Table 2 and Scheme 5. The general
feature of this reaction is the formation of cis-function-
alized tetrahydrooxazines (e-R2 and a-Nu) from nitro-
nates with e-R2 and trans-functionalized tetrahydroox-
azines (a-R2 and a-Nu) from nitronates with a-R2.
Similar procedures were used for the preparation of com-
pounds 6, 8, 10, and 13 (for details, see the Supporting
Information).
Acknowledgment. This work was performed with
the financial support of the Russian Basic Research
Foundation (Grants 02-03-33350, 03-03-32777, 03-03-
04001, and 03-03-06149) Deutsche Forschungsgemein-
schaft MA 673/19 and Federal Program “Integration”
(Project B0062). We thank Drs. I. M. Lyapkalo and A.
D. Dilman for helpful discussions.
Nitronates 1 should exist as a mixture of conformers
A and B with a low barrier of interconversion.18 It seems
reasonable to suggest that the same factors could deter-
mine the relative stability of nitronates 1 and silylated
cations 2 derived thereof. The next suggestion is that only
a major conformation of cation 2 reacts, in general, with
nucleophiles.
The attack of a nucleophile on an oxazinium ion should
proceed from the side opposite to the C-6 atom of the
oxazine ring (bold arrows in Scheme 5).19 Commonly, the
most-stable conformer of a target product is generated
initially. However, tetrahydrooxazine 4d, obtained in the
Supporting Information Available: Full experimental
procedures, analytical data for all compounds, CIF files for
4c,d,f,g′′,j and 10, and NMR data for cationic intermediate
2a and for some initial and target products. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO048944K
(20) Alternatively, the generation of 4e′-g′, along with 4e-g, could
be explained as a result of the competition between syn and anti
approaches of 3 relative to C-6 of the cationic intermediate 2 (cf. ref
19).
(21) The prepared tetrahydrooxazine derivatives 4a-j, 6, 8, 10, and
13 could be considered structural analogues to the well-known N-
trialkylsiloxyisoxazolidines. (For preparation of natural and biologically
active compounds from N-trialkylsiloxyisoxazolidines, see ref 1b.)
(18) For the discussion of IR and IN processes in oxazine derivatives,
see ref 14b.
(19) For the discussion of stereochemistry of the reduction of 5,6-
[4H]-dihydrooxazines, see: Zimmer, R.; Arnold, Th.; Homann, K.;
Reissig, H.-U. Synthesis 1994, 1050.
8488 J. Org. Chem., Vol. 69, No. 24, 2004