C-C coupling of acyclic nitronates with silyl ketene acetals under silyl triflate catalysis: Reactivity umpolung of aliphatic nitro compounds

Article abstract of DOI:10.1002/ejoc.201200239

TBSOTf-promoted C-C coupling of alkyl and trialkylsilyl nitronates with silyl ketene acetals yields functionalized nitroso acetals. This conversion may serve as a new simple procedure to reverse the conventional reactivity of aliphatic nitro compounds. Preliminary results on the hydrogenation of nitroso acetals into amino acids derivatives, as well as TFA-catalyzed transformations of nitroso acetals, are examined to prove the possible utility of this umpolung procedure. A very simple approach for umpolung of the conventional reactivity of nitroalkanes through their activation by silylation offers a convenient and efficient strategy for their C-C coupling with π-nucleophiles. Both primary (8 examples) and secondary (4 examples) nitroalkanes may be involved in coupling with silyl ketene acetals (4 examples) to provide a concise route to substituted β-amino acids.

Full text of DOI:10.1002/ejoc.201200239

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FULL PAPER
DOI: 10.1002/ejoc.201200239
C–C Coupling of Acyclic Nitronates with Silyl Ketene Acetals under Silyl
Triflate Catalysis: Reactivity Umpolung of Aliphatic Nitro Compounds
Vladimir O. Smirnov,*[a] Yulia A. Khomutova,[a] Vladimir A. Tartakovsky,[a] and
Sema L. Ioffe*[a]
Dedicated to Professor Dr. Dieter Seebach on the occasion of his 75th birthday
Keywords: Umpolung / C–C coupling / Nitro compounds / Hydrogenation / Amino acids
TBSOTf-promoted C–C coupling of alkyl and trialkylsilyl ni-
tronates with silyl ketene acetals yields functionalized nitroso
tro compounds. Preliminary results on the hydrogenation of
nitroso acetals into amino acids derivatives, as well as TFA-
acetals. This conversion may serve as a new simple pro- catalyzed transformations of nitroso acetals, are examined to
cedure to reverse the conventional reactivity of aliphatic ni-
prove the possible utility of this umpolung procedure.
When treated with bases, AN 1 reversibly form ambident
anions A, which smoothly interact successively with various
π-electrophiles E and a proton to yield corresponding ad-
ducts 3. This is the classic reactivity of AN that becomes
apparent in Henry, Michael, and Mannich reactions.[1] On
the other hand, aci-forms 2, which exist in equilibrium with
AN 1, can react with Brønsted acids reversibly to give reso-
nance stabilized cations B.[3b,6] The latter can be formally
regarded as bis-protonated anions A. The C–C bond-form-
ing reactions of cations B with π-nucleophiles NuH afford
corresponding nitroso compounds 4 or oxime isomers 4Ј. If
the nitro functionality is desirable again, it could be created
by final oxidation of 4 or 4Ј to RRЈC(NO2)Nu nitro com-
pounds.
Introduction
Reactivity umpolung of organic compounds is com-
monly understood as an interchange of their usual alternat-
ing donor and acceptor reactivity patterns. Such inversion
of conventional reactivity of functional groups obviously
extends the application of the corresponding type of or-
ganic compounds in targeted organic synthesis. In this re-
gard, reversal of polarity of readily available aliphatic nitro
compounds (AN), which are widely employed as α-nucleo-
philes, appears to be of high interest for expanding organic
synthesis methodology.[1] In this paper, we report on a new
efficient way to solve this challenging task. To make the
idea of our design most clear, a brief survey of state-of-the-
art methods for umpolung precedes the Results and Dis-
cussion section.
In contrast to the well-studied reactivity of highly nucleo-
philic anions A,[7] there are only a few reports on the C–C
Prof. D. Seebach, in his classic review on reactivity rever- bond-forming reactions of cations B. Until recently, the
sal,[2] discussed conversion of AN into the respective carb- only example was the C–C coupling of primary AN 1 with
onyl compounds (known for more than a century as the Nef benzene and its electron-rich derivatives (Nu = Ar).[8] This
reaction)[3] as the key step in the umpolung procedure.[4] was discovered and developed independently by French and
However, this approach has the serious disadvantage of los- Japanese groups about 20 years ago, and the reaction runs
ing a nitrogen atom in the substrate, whose presence in the under highly acidic conditions to yield the oximes 4Ј. Cat-
final structure is often highly preferable. At the same time, ions B were found to be weak electrophiles[8a] requiring ad-
change of polarity of the α-carbon atom of AN 1 might be ditional protonation to be involved in the C–C coupling,
achieved with retention of the nitrogen atom according to which brings about the necessity of using strong acids. De-
a fairly simple and effective approach based on the peculiar- spite some improvements in this approach,[9] any of its vari-
ity of the AN structure (Scheme 1).
ants requires strongly acidic conditions, which significantly
restricts the set of suitable nucleophiles for C–C cou-
pling.[10,11]
To avoid this inevitable restriction, we now propose sub-
stantial modification (Scheme 2) of the above approach by
replacing both OH protons in cations B (Scheme 1) with
alkyl and/or trialkylsilyl moieties (cations C, Scheme 2).
[a] N.D. Zelinsky Institute of Organic Chemistry,
Leninsky prosp. 47, 119991 Moscow, Russian Federation
Fax: +7-499-1355328
E-mail: iof@ioc.ac.ru
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200239.
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V. O. Smirnov, Yu. A. Khomutova, V. A. Tartakovsky, S. L. Ioffe
FULL PAPER
Scheme 1. Reactivity umpolung of AN.[5]
This allows one to transfer resulting intermediates C from
protic to aprotic solvents to facilitate their reactivity
change. Such modification of the reactive intermediate can
be easily effected via available nitronates 5, which can be
easily obtained from AN 1. The reversible silylation of 5
with the appropriate silyl Lewis acid SiX is expected to af-
ford cations C, which will couple with π-nucleophile Nu–E
to yield target nitroso acetals 6.[12]
Scheme 3. C–C coupling of cyclic nitronates with π-nucleophiles
9.[12]
coupling between acyclic nitronates 5 and silyl ketene acet-
als 9 (X = O, E = SiAlk3, R = OAlk), which proved to
be most effective in the C–C coupling reactions with cyclic
nitronates 7 and 8[12] and, therefore, can be considered as
π-nucleophiles of choice.[13]
Scheme 2. Our approach to reactivity umpolung of AN 1.[5a,12]
The expected efficiency of such a modification is sup-
ported by successful C–C coupling of six-membered cyclic
nitronates 7 (n = 2) with a rather diverse collection of π-
nucleophiles 9,[12a] and also the successful C–C coupling of
five-membered cyclic nitronates 8 (n = 1) with silyl ketene
acetal 9a (X = O, E = TBS, R = OMe)[12c] (Scheme 3).
Results and Discussion
C–C Coupling of Nitronates 5 with Silyl Ketene Acetals 9
Silyl nitronates 5a–d and 5i (Scheme 4, Table 1) were pre-
These transformations were shown truly to proceed through pared by standard silylation procedures from the appropri-
bis(oxy)iminium cation intermediates 7-TBS+ and 8-TBS+, ate AN 1a–d or 1f.[14] Alkyl nitronates 5e–h and 5j–m
respectively. It was also proved that acyclic silyl and alkyl (Scheme 4, Table 1) were generated from isolated potassium
nitronates generate similar cations under close condi- salts of the corresponding AN 1b–i by treatment with
tions.[12b]
Et3O+BF4– in CH2Cl2 according to a known method[15] and
Thus, we have all the prerequisites for the proposed reac- used in situ because of their thermal instability. Readily
tivity umpolung of AN 1 via corresponding nitronates 5 available silyl ketene acetal 9a was exploited as a model π-
(Scheme 2) to be successful. In continuation of our previous nucleophile. The main results for the C–C coupling of ni-
studies, the present work systematically explores the C–C tronates 5 with 9a (Scheme 4) are summarized in Table 1.
2
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Reactivity Umpolung of Aliphatic Nitro Compounds
Table 1. Addition of silyl ketene acetal 9a to silyl and alkyl nitronates 5a–m.
Entry
AN 1,
Nitronate 5
R
RЈ
RЈЈ
TBSOTf
[equiv.]
T
[°C]
Time
[h]
Product 6
Yield of 6
[%][a]
1
2
3
4
5
6
7
8
1a, 5a
1b, 5b
1c, 5c
1d, 5d
1b, 5e
1c, 5f
1d, 5g
1e, 5h
1f, 5i
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Et
PhCH2
TBS
TBS
TBS
TBS
Et
Et
Et
0.20
0.20
0.10
0.10
0.10
0.10
0.10
0.10
0.20
0.20
0.20
0.20
0.20
0.20
–94
–94
–94
–94
–78
–78
–78
–78
–78
–30
–78
–78
–78
–78
0.75
1.0
2.0
1.0
1.5
18
15
18
18
18
1.0
18
2.0
1.0
6a
6b
6c
6d
6e
6f
6g
6h
–
–
6j
6k
6l
6m
88
82
90
92
70
78
87
56
MeO2CCH2CH2
Et
PhCH2
MeO2CCH2CH2
MeCOCH2CH2
Me
Et
[b]
9
TBS
TBS
Et
Et
Et
–
–
[c]
10
11
12
13
14
1f, 5i
Me
Me
PhCH2
1f, 5j
70
18
51
72
1g, 5k
1h, 5l
1i, 5m
–(CH2)4–
–(CH2)5–
Et
[a] Isolated yield. [b] No target product, initial nitronate 5i was recovered in nearly quantitative yield after workup. [c] No target product,
complex mixture of intractable products was obtained.
As can be seen from Table 1, both silyl and alkyl ni-
tronates derived from primary AN 1a–e (Table 1, Entries 1–
8) smoothly react with silyl ketene acetal 9a to afford de-
sired nitroso acetals 6a–h in good to excellent yields. With
silyl nitronates, the yields obtained are typically higher than
those for the corresponding alkyl nitronates. The situation,
however, is drastically changed with a switch to nitronates
5i–m derived from secondary AN 1f–i. In particular, silyl
nitronate 5i derived from 2-nitropropane is completely un-
reactive toward ketene acetal 9a (Table 1, Entries 9 and 10
and footnotes), although ethyl analogue 5j affords corre-
sponding adduct 6j in a good yield (Table 1, Entry 11).
Ethyl nitronates 5k–m derived from other typical secondary
AN 1f–i react with 9a in a similar fashion to give corre-
sponding adducts 6k–m in low to good yields (Table 1, En-
tries 11–14).
A priori, the absence of C–C coupling between silyl ni-
Scheme 4. C–C coupling of silyl and alkyl nitronates 5a–m with
tronate 5i derived from secondary AN 1f and π-nucleophile
ketene acetal 9a.
9a can be due to thermodynamic as well as kinetic factors.
Thermodynamic causes could consist of an insufficient
equilibrium concentration of ionic intermediate 5i-
TBS+·OTf– or the thermodynamically unfavorable reaction
of 5 with 9 as a whole in the case of silyl nitronates derived
from secondary AN 1. The first reason can be ruled out, as
treatment of nitronate 5i with 1.5–2 equiv. of TBSOTf in
the temperature range from –60 to –10 °C results in com-
plete formation of corresponding cation 5i-TBS+·TfO–.[16]
The second reason seems to be very unlikely, because ethyl
nitronates derived from secondary AN (Table 1, entries 11–
14), as well as cyclic nitronates with a substituent at the C-
3 atom, react with 9a smoothly.[12a,12b] The nature of the
oxygen substituent of nitronate 5 also has a negligible (if
any) influence on the thermodynamics of 5+9 coupling, as
both ethyl and silyl nitronates derived from primary AN 1
react with 9a in a similar fashion (cf. Table 1, Entries 2 and
5). Therefore, there is no reason to expect drastic changes
in the thermodynamics of the reaction 5+9 for the respec-
tive silyl derivatives of secondary AN 1. Apparently, the
lack of reactivity of cation 5i-TBS+ toward 9a is due to
This umpolung procedure was found to be applicable to
a wide range of AN 1a–i. Importantly, mild conditions dur-
ing the reaction mixture workup are crucial for preparation
of pure nitroso acetals 6 in good yields. Quenching with
saturated aqueous sodium hydrogen carbonate solution,
which was used earlier in the processes run with nitronates
7,[12a] results in decreased yields of nitroso acetals 6 and
their contamination with difficult-to-remove impurities.
This can be avoided by addition of methanol and triethyl-
amine to the reaction mixture prior to aqueous workup, as
it was done previously with nitronates 8.[12c] Certain pre-
cautions should be also taken in the purification of nitroso
acetals 6. Whereas adducts 6a–d can be isolated by using
conventional column chromatography, purification of ad-
ducts 6e–m requires chromatography on triethylamine-
treated silica gel. We attribute this dissimilarity to the fact
that nitroso acetals 6 are very sensitive to Brønsted acids
(for more detail, see section “Transformations of Nitroso
Acetals 6”).
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V. O. Smirnov, Yu. A. Khomutova, V. A. Tartakovsky, S. L. Ioffe
FULL PAPER
Table 2. C–C coupling of AN 1 with silyl ketene acetal 9a.
Entry
AN 1
R
Base
T
[°C]
Time
[h]
Product 6
Yield of 6
[%][a]
1
2
3
4
5
6
1b
1c
1c
1d
1j
Et
PhCH2
PhCH2
DBU
DBU
Et3N
DBU
DBU
Et3N
–94
–94
–25
–94
–94
–25
1.0
0.75
18.0
0.75
1.0
6b
6c
–
6d
6n
6o
65
93
0[b]
87
82
88
MeO2C(CH2)2
H
4-MeO-C6H4
1k
18
[a] Isolated yield. [b] No product of C–C coupling was detected by TLC.
kinetic factors, most likely due to steric hindrance arising compared to the initially used procedure for the synthesis
from the presence of two bulky TBSO substituents in the of nitroso acetals 6 (Scheme 4). In particular, it allows the
reactive species.[17]
employment of AN 1 that produce non-isolable silyl ni-
Thus, the successful C–C coupling between nitronates 5 tronates 5 (for example, nitromethane;[18] Table 2, Entry 5,
derived from secondary AN 1 and π-nucleophiles 9 requires adduct 6n) in the C–C coupling with π-nucleophiles. An-
the use of alkyl derivatives only, whereas in the case of pri- other plus is the ability to vary the number of reacting
mary AN 1, the more stable and readily available silyl ni- –CH2NO2 centers in the C–C coupling reactions of polyni-
tronates are preferred.
tro compounds. This can be demonstrated with 1,4-dini-
It is noteworthy that with primary AN 1, the method can trobutane (1l). Depending on the ratio of reactants, the
be performed in a one-pot fashion, combining the genera- 1l+9a one-step procedure may lead to monoadduct 6p
tion of appropriate silyl nitronate 5 and its C–C coupling (86%) or to bis-coupling product 6q (58%) with minor for-
with π-nucleophile 9. Specifically, consecutive treatment of mation of an easily removable admixture of 6p (20%,
primary AN 1 with 1 equiv. of DBU taken as a base and Scheme 6).
1.1 equiv. of TBSOTf in the presence of silyl ketene acetal
The scope and limitations of the above C–C coupling
9a furnishes the corresponding adducts 6 in good to excel- reaction with regard to the nature of silyl ketene acetals 9
lent yields (Scheme 5, Table 2). The yields obtained here were studied briefly by using model nitronate 5a
compare well with those for the corresponding products 6 (Scheme 7).
obtained from isolated silyl nitronates 5 (cf. Tables 1 and
Substituted silyl ketene acetal 9b reacted with 5a to af-
2). If the parent AN 1 has no protons in the β-position, ford target nitroso acetal 12 diastereoselectively in high
triethylamine may be used instead of DBU (cf. Table 2, En- yield [Scheme 7, Eq. (1)]. In this case, however, the reaction
tries 3 and 6).
required a rather long time and an increased amount of
Along with convenience and simplicity, the procedure il- TBSOTf to go to completion. Cyclic silyl ketene acetal 9c
lustrated in Scheme 5 offers some additional advantages reacted with nitronate 5a under the same conditions that
were used for unsubstituted π-nucleophile 9a to afford ad-
duct 13 in excellent overall yield but with low diastereo-
selectivity [1.3:1dr; Scheme 7, Eq. (2)]. With ambident silyl
ketene acetal 9d, the addition preferably occurred at the less
sterically hindered terminal nucleophilic center to give ad-
duct (E)-14 along with the formation of an insignificant
amount of alternative adduct 15 as a single isomer of unas-
signed configuration. The total yield of 14+15 adducts was
fairly high [Scheme 7, Eq. (3)].
As shown in our preliminary experiments, the range of
π-nucleophiles active toward nitronates 5 under conditions
of electrophilic catalysis is not confined to silyl ketene acet-
als. However, the use of less-reactive nucleophiles requires
Scheme 5. One-pot procedure for C–C coupling of primary AN 1
much more effort to optimize the synthesis procedure; the
with π-nucleophile 9a.
Scheme 6. Selectivity in coupling of 1,4-dinitrobutane (1l) with silyl ketene acetal 9a.
4
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Reactivity Umpolung of Aliphatic Nitro Compounds
Scheme 7. C–C coupling of nitronate 5a with silyl ketene acetals 9b–d.
results of these studies will be reported in our next publica- well-known chemistry of acetals, studies of the chemistry of
tions.
nitroso acetals is rather fragmented (the main reviews on
The structures of nitroso acetals 6a–q and 12–15 were nitroso acetals are given in ref.[19]). Here we report some
unequivocally confirmed by NMR spectroscopy (1H, 13C, reactions of nitroso acetals 6 that may be helpful to under-
and 29Si nuclei), and elemental analysis was used to assess stand their properties somewhat better. However, this study
product purity. Due to the well-known slow nitrogen inver- is made in an illustrative manner only.
sion in nitroso acetals,[19] the nitrogen atom of the N(OEt)-
(OTBS) moiety forms a stereocenter in adducts 6e–h and
6j–m; in addition, the TBSO groups of the N(OTBS)2
moiety are diastereotopic in adducts 6a–d, 6o–q, and 12–
15, which is clearly observable in their NMR spectra.
The acid sensitivity of nitroso acetals is well known.[19a]
In full keeping with this, even very dilute TFA solutions in
MeOH or EtOH cause the conversion of 6d, 6g, 6j, and 6l
into products 16–18, whose formation is likely to occur via
nitrenium cation intermediates D (Scheme 8). If one of the
R and RЈ radicals in these cations is a proton, they are
stabilized through the elimination of the latter (possibly
Transformations of Nitroso Acetals 6
From the aforesaid, it is evident that AN 1 are conve- through initial 1,2-C,N hydride shift) to form oximes 16a
nient precursors for nitroso acetals 6. In contrast to the and 16b (Scheme 8, pathway 1). If nitroso acetals 6 are de-
Scheme 8. Acid-catalyzed transformations of nitroso acetals 6.
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V. O. Smirnov, Yu. A. Khomutova, V. A. Tartakovsky, S. L. Ioffe
FULL PAPER
rived from secondary AN 1, that is R = RЈ ϶ H, cations D
are stabilized by alternative pathways, that is, either through
addition of the solvent (EtOH) followed by deprotonation
(products 17a and 17b; Scheme 8, pathway 2), or by 1,2-
C,N shift of radical R with generation of cations E followed
by elimination of the flexible proton from the carbon atom
attached to the CO2Me moiety (product 18; Scheme 8,
pathway 3). Noticeably, nitroso acetals 6d and 6j containing
the N(OEt)(OTBS) moiety underwent exclusive elimination
of the more sterically hindered TBSO group to form 16b
and 18, respectively.
Among the reactions of nitroso acetals 6, the selective
reduction of the O–N–O fragment into the amino function,
commonly effected by hydrogenation over Raney nickel,
seems to be of the highest synthetic value.[19,20] In this con-
text, the reduction of adducts 6 can be considered as a final
step in the convenient synthetic route to unnatural β-amino
acids utilizing available AN 1 as precursors (Scheme 9).
Scheme 10. Hydrogenation of nitrosoacetals 6d-d1 and 6g-d1 on Ni/
Ra.
mechanism of hydrogenation depend on the nature of the
oxygen substituents in the nitroso acetal moiety.[21] Specifi-
cally, successful hydrogenation of more sterically hindered
N(OTBS)2 group requires the presence of KF or KHF2,
which provides essentially complete retention of the deute-
rium label and an excellent yield of target amino derivative
19 (Table 3, Entries 2 and 3). At the same time, the N(OEt)-
(OTBS) moiety is smoothly hydrogenated without any addi-
tives, yet with an 80% loss of the deuterium label (Table 3,
Entry 4). In the presence of KHF2, hydrogenation also pro-
ceeds with a considerable (although lesser) loss of the deute-
rium label and affords product 19 in good yield, whereas
the use of KF, on the contrary, results in almost complete
retention of the deuterium label but a low yield of 19
(Table 3, Entries 5 and 6). A partial loss of deuterium in the
hydrogenation of 6g-d1 (Table 3, Entries 4 and 6) implies a
complicated mechanism for this reaction. The above hydro-
genation is likely to follow two (or more) competitive path-
ways with one involving C–D bond cleavage and another
retaining it unchanged. Such a result is of particular interest
and warrants further investigation, as the hydrogenation of
the nitroso acetal moiety is commonly considered to pro-
ceed while keeping the adjacent carbon stereocenter in-
tact.[19b,20]
Scheme 9. A new strategy for the synthesis of unnatural β-amino
acids from AN 1.
If R ϶ RЈ, the 1+9 coupling results in adducts 6 with
an asymmetric center at the carbon atom attached to the
nitroso acetal nitrogen atom. When using primary AN 1
(RЈ = H), this asymmetric center may be lost in the course
of the reduction of the corresponding nitroso acetals 6 due
to the ease of formation of oxime derivatives 16 (Scheme 8),
whose reduction would ultimately lead to the same product
as the direct reduction of 6. To probe the behavior of the
asymmetric center during the reduction of the nitroso acetal
Conclusions
The conversion of AN 1 into the corresponding silyl or
fragment, we performed Raney nickel catalyzed hydrogena- alkyl nitronates 5 followed by their C–C coupling with silyl
tion of deuterium-labeled nitroso acetals 6d-d1 and 6g-d1 ketene acetals 9 (π-nucleophiles) under conditions of elec-
(Scheme 10, Table 3).
trophilic catalysis with TBSOTf to yield functionalized ni-
The data of Scheme 10 and Table 3 present experimental troso acetals 6 was realized and proposed as a new general
evidence that the stereoselective hydrogenation of nitroso strategy for reactivity umpolung of AN 1. Tentative in-
acetals 6 is realizable. Of note, hydrogenation product 19 terpretation of the results on the catalytic hydrogenation of
can be formed with complete retention of the deuterium nitroso acetals 6 and their interaction with dilute alcohol
label. Surprisingly, deuterium retention and, probably, the solutions of TFA are suggested. Nitroso acetals 6 were
Table 3. Hydrogenation of labeled adducts 6d-d1 and 6g-d1.
Entry
Adduct
Additive
(2.5 equiv.)
Yield of 19
Isotopic purity of 19[a] Deuterium retention in 19
(% isotopic purity)[a]
[%][b]
[%]
[%]
1
2
3
4
5
6
6d-d1, RЈЈ = TBS (88)
6d-d1, RЈЈ = TBS (88)
6d-d1, RЈЈ = TBS (88)
6g-d1, RЈЈ = Et (84)
6g-d1, RЈЈ = Et (84)
6g-d1, RЈЈ = Et (84)
none
KF
KHF2
none
KF
n.r.[c]
83
95
85
35
–
–
87
84
15
81
44
99
95
18
96
52
KHF2
81
[a] Determined by NMR spectroscopy. [b] Hydrogenation of nonlabeled compounds 6d and 6g under tested conditions leads to nonlabeled
aminoester 19 in essentially the same yields. [c] No reaction product was determined by TLC.
6
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Reactivity Umpolung of Aliphatic Nitro Compounds
acetal 9a (1.1 equiv.) in CH2Cl2 (2.5–3.3 mL/mmol of 1) at 0 °C
was added DBU (1.0 equiv.), and the reaction mixture was stirred
for an additional 10 min. Then, the reaction mixture was cooled
to –94 °C, and TBSOTf (1.10 equiv.) was added with stirring. The
reaction mixture was stirred at –94 °C for 45–80 min. (In prepara-
tion of adduct 6s from AN 1m, a twofold amount of other reagents
was used; for details, see Scheme 5, Table 2 and the respective text
in the Supporting Information), quenched at –94 °C by the success-
ive addition of Et3N (0.25 equiv.) and methanol (0.15 equiv.). Fur-
ther operations are the same as in Procedure A.
shown to be convenient precursors of unnatural β-amino
acids. Alcoholysis of nitroso acetals 6 bearing the N(OEt)-
(OTBS) moiety with C1–C2 alcohols under acid catalysis
proceeds with selective N–OTBS bond cleavage.
Experimental Section
General Remarks: 1D and 2D NMR spectra were recorded at room
temperature in CDCl3, unless otherwise stated. The chemical shifts
(1H, 13C, and 29Si) are given in ppm (δ scale) relative to the solvent
residual signals.[22] All 1D and 2D NMR experiments were per-
formed by using standard techniques and Bruker NMR software.
The ratios of the stereoisomers were derived from the relative inte-
gral intensities of the characteristic signals in the 1H NMR spectra.
Elemental analyses were performed by the Analytical Laboratory
of the N. D. Zelinsky Institute of Organic Chemistry. Melting
points were determined with a Kofler apparatus. Reactions with
TBSOTf were performed under an atmosphere of dry Ar. CH2Cl2
was distilled prior to use from CaH2. Triethylamine was distilled
from KOH under an atmosphere of Ar. Ethyl acetate and hexane
for column chromatography and extractions were distilled without
additional agents. Merck silica gel 60 (0.040–0.063 mm) was used
for column chromatography. For the successful isolation of some
products, silica gel was deactivated with triethylamine.[23] Alumi-
num TLC plates with silica gel QF 254 (Merck) were used for ana-
lytical thin-layer chromatography; the eluents used for analytical
TLC are specified in parentheses after the Rf values. Visualization
for analytical TLC: UV (254 nm) and treatment with 4-MeOC6H4-
CHO (AnCHO), phosphomolybdic acid (PMA), or ninhydrin
(NHN) solutions followed by heating. “Brine” refers to saturated
aqueous solution of sodium chloride.
Procedure C
C–C Coupling of AN 1 (via Silyl Nitronates 5) with Silyl Ketene
Acetal 9a: To a stirred solution of AN 1 (1.0 equiv.), triethylamine
(1.5 equiv.), and silyl ketene acetal 9a (1.1 equiv.) in CH2Cl2
(3.0 mL/mmol of 1) at –50 °C was added TBSOTf (1.20 equiv.), and
the reaction mixture was kept at –25 °C (freezer) for 18 h, cooled to
–50 °C, and methanol (1.5 equiv.) was added with stirring. Further
operations are the same as in Procedure A.
Procedure D
C–C Coupling of Alkyl Nitronates 5 with Silyl Ketene Acetal 9a: To
a stirred solution of Et3O+BF4– (1.0 equiv.) in CH2Cl2 (2 mL/mmol
of 1) was added the potassium salt of AN 1 (1.03 equiv.) at –78 °C,
and the resulting slurry was stirred at –78 °C for 45–150 min (see
the Supporting Information for details; for the K salt of AN 1e,
the reverse order of addition was applied.) Then, silyl ketene acetal
9a (1.1 equiv.) and TBSOTf (0.1–0.2 equiv.) were added success-
ively at –78 °C with stirring. The resulting mixture was kept at
–78 °C for 1–18 h, quenched at –94 °C by the successive addition
of Et3N (0.4 equiv.) and methanol (0.3 equiv.). Further operations
are the same as in Procedure A, except silica gel deactivated with
triethylamine was used for column chromatography.
Conventional procedures were applied for the synthesis and isola-
tion of silyl nitronates 5a–d and 5i[14] and silyl ketene acetals 9a,[24]
9b,[25] 9c,[26] and 9d.[27] For isolation of potassium nitronates, a
known procedure[15] was applied with a minor modification: solu-
tion of KOtBu in THF was used instead of methanolic NaOH.
Labeled adducts 6d and 6g were obtained from methyl γ,γ-di-
deutero-γ-nitropentanoate by the same procedure as for respective
nonlabeled compounds.
Procedure E
TFA-Catalyzed Transformations of Nitroso Acetals 6d, 6g, 6j, and
6l (Scheme 8): To a stirred solution of nitroso acetal 6 (0.60 mmol)
in the indicated alcohol (EtOH or MeOH, 2.9 mL) was added a
freshly prepared solution (0.10 mL) of TFA (23 μL, 34 mg,
0.30 mmol) in the same alcohol (10.0 mL) at room temperature to
achieve a 0.20 m solution of adduct in 0.0010 m alcoholic solution
of TFA. The resulting reaction mixture was stirred for 16 h (for 6i
and 6m) or 3 d (for 6d and 6g). Then, Et3N (4.0 μL, 2.9 mg,
29 μmol, 9.6 equiv. to TFA) was added with stirring. The reaction
mixture was concentrated, and the residue was purified by short-
path distillation or column chromatography to afford target prod-
ucts 16–18.
General Procedures
Procedure A
C–C Coupling of Isolated Silyl Nitronates 5a–d with Silyl Ketene
Acetals 9: To a stirred solution of silyl nitronate 5a–d (1.0 equiv.)
and silyl ketene acetal 9 (1.10 equiv.) in CH2Cl2 (2.0–3.0 mL/mmol
of 5) at –94 °C was added TBSOTf (0.1–1.0 equiv.), and the reac-
tion mixture was stirred at –94 °C for the indicated time. The mix-
ture was then quenched at –94 °C by the successive addition of
Et3N (2 equiv. per equiv. of TBSOTf) and methanol (1.5 equiv. per
equiv. of TBSOTf). After additional stirring at –94 °C for 5 min,
hexane (4 mL per mmol of nitronate 5) and water (2 mL per mmol
of nitronate 5) were added, and the reaction mixture was warmed
to room temperature. The aqueous layer was separated and washed
with hexane (2ϫ5 mL per mmol of nitronate 5), and the combined
organic layers were washed with brine (one-third of the combined
organic layers volume) and dried with anhydrous sodium sulfate.
After evaporation of the solvents, the crude products were purified
by gradient column chromatography (ethyl acetate/hexane, from
1:30 to 1:5 by volume).
Procedure F
Hydrogenation of Nitroso Acetals 6d-d1 and 6g-d1 (Scheme 10,
Table 3): Adduct 6d or 6g (0.4 mmol) was hydrogenated over Raney
nickel in MeOH (≈200 mg, 2.0 mL) under an atmosphere of hydro-
gen (25 bar) at room temperature with stirring in the presence of
Boc2O (0.15 mL, 0.15 g, 0.7 mmol) and, in some cases, with indi-
cated promoter (Table 3). After 18 h, the catalyst was filtered off,
washed twice with methanol (≈4 mL), and the combined filtrates
were concentrated. The residue was treated with ethyl acetate
(5 mL), the inorganic precipitate was filtered off, and the filtrate
was evaporated. Crude products were purified by gradient column
chromatography (ethyl acetate/hexane, from 1:3 to 1:1 by volume).
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures for the synthesis of nitroso
acetals 6, 12–15, and 17; compounds 16, 18, and 19; and their char-
acterization, including NMR spectra.
Procedure B
C–C Coupling of AN 1 (via Silyl Nitronates 5) with Silyl Ketene
Acetal 9a: To a stirred solution of AN 1 (1.0 equiv.) and silyl ketene
Eur. J. Org. Chem. 0000, 0–0
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Job/Unit: O20239
/KAP1
Date: 09-05-12 10:40:12
Pages: 9
V. O. Smirnov, Yu. A. Khomutova, V. A. Tartakovsky, S. L. Ioffe
FULL PAPER
ported by the fact that, as yet, the C–C coupling with π-nucleo-
philes was realized successfully with cations B derived only
from primary AN.
Acknowledgments
This work was performed with the financial support of the Russian
Foundation for Basic Research (Grants 12-03-00278-a, 05-03-
08175, and 03-03-04001), Deutsche Forschungsgemeinschaft
(MA 673/19), and the Federal program “Scientific and Educational
Personnel of Innovative Russia” (Project 02.740.11.0258).
[11] Only fragmentary literature data can be interpreted as exam-
ples of interaction of various nitronates with nucleophiles. For
reactions of nitronates with organometallic compounds, see: a)
S. L. Ioffe, O. P. Shitov, I. E. Chlenov, A. A. Medvedeva, V. A.
Tartakovsky, S. S. Novikov, Russ. Chem. Bull. Div. Chem. Sci.
1967, 2522–2526 (in Russian); S. L. Ioffe, O. P. Shitov, I. E.
Chlenov, A. A. Medvedeva, V. A. Tartakovsky, S. S. Novikov,
Russ. Chem. Bull. Div. Chem. Sci. 1967, 2399–2402 (in English)
b) T. Fujisawa, Yo. Kurita, T. Sato, Chem. Lett. 1983, 1537–
1540; c) E. W. Colvin, A. D. Robertson, D. Seebach, A. K.
Beck, J. Chem. Soc., Chem. Commun. 1981, 952–953; d) W. M.
David, S. M. Kerwin, J. Am. Chem. Soc. 1997, 119, 1464–1465;
with isonitriles: e) P. Dumestre, L. El Kaim, A. Gregoire,
Chem. Commun. 1999, 775–776; f) P. Dumestre, L. El Kaim,
Tetrahedron Lett. 1999, 40, 7985–7986.
[1] For synthesis and reactivity of AN, see: N. Ono, The Nitro
Group in Organic Synthesis, Wiley-VCH, New York, 2001.
[2] D. Seebach, Angew. Chem. 1979, 91, 259; Angew. Chem. Int.
Ed. Engl. 1979, 18, 239–258.
[3] a) For a recent review on the Nef reaction, see: R. Ballini, M.
Petrini, Tetrahedron 2004, 60, 1017–1047; b) for the mechanism
of the Nef reaction, see: N. Kornblum, R. A. Brown, J. Am.
Chem. Soc. 1965, 87, 1742–1747.
[4] It is noteworthy that the Nef reaction as a tool for reactivity
inversion initially was considered with acyl synthon umpolung
through alkylation of AN followed by the Nef reaction. This
consideration reveals AN as equivalents of the acyl anion syn-
thon; see, for example, the review: H. W. Pinnick, Org. React.
1990, 38, 655–792. To the best of our knowledge, the Nef reac-
tion as a route for umpolung of AN themselves was considered
for the first time in the paper: J. E. McMurry, J. Melton, J. Org.
Chem. 1973, 38, 4367–4373.
[5] a) S. L. Ioffe in Nitrile Oxides, Nitrones, and Nitronates in Or-
ganic Synthesis (Ed.: H. Feuer), John Wiley & Sons, Inc., Ho-
boken, 2007, p. 626; b) M. Takamoto, H. Kurouchi, Yu. Otani,
T. Ohwada, Synthesis 2009, 4129–4136.
[12] a) V. O. Smirnov, S. L. Ioffe, A. A. Tishkov, Yu. A. Khomu-
tova, I. D. Nesterov, M. Yu. Antipin, W. A. Smit, V. A. Tar-
takovsky, J. Org. Chem. 2004, 69, 8485–8488; b) Yu. A. Kho-
mutova, V. O. Smirnov, H. Mayr, S. L. Ioffe, J. Org. Chem.
2007, 72, 9134–9140; c) V. O. Smirnov, A. S. Sidorenkov, Yu. A.
Khomutova, S. L. Ioffe, V. A. Tartakovsky, Eur. J. Org. Chem.
2009, 3066–3074.
[13] For the general reactivity scale, see: H. Mayr, B. Kemp, A. R.
Ofial, Acc. Chem. Res. 2003, 36, 66–77.
[14] For the silylation of AN, see ref.[5a] (pp. 469–484) and literature
therein.
[15] N. Kornblum, R. A. Brown, J. Am. Chem. Soc. 1964, 86, 2681–
2687.
[6] Unlike the tautomerization between keto and enol forms, tau-
tomerization between nitro and aci forms is not acid catalyzed
in dilute aqueous acids. Moreover, it is even somewhat in-
hibited under acidic conditions due to the lowered activity of
water, which acts as a base in tautomerization via the nitronate
anion, see J. T. Edward, P. H. Tremaine, Can. J. Chem. 1971,
49, 3493–3501. It should be noted, however, that previously
reported examples of protic acid-assisted AN umpolung ac-
cording to Scheme 1(see ref.[5b,8,9]) were realized in non-basic
solvents (such as dichloromethane or trifluoroacetic acid) or
without solvent at all, and under these conditions acid catalysis
for 1 to 2 tautomerization is plausible. Furthermore, aci-nitro
forms may be generated from isolated nitronate salts by the
action of acid, as kinetic protonation of anion A takes place at
the oxygen atom.
[7] For the estimation of the nucleophilicity of anions A see: T.
Bug, T. Lemek, H. Mayr, J. Org. Chem. 2004, 69, 7565–7576.
[8] a) T. Ohwada, N. Yamagata, K. Shudo, J. Am. Chem. Soc.
1991, 113, 1364–1373; b) C. Berrier, R. Brahmi, H. Carreyre,
J.-M. Coustard, J.-C. Jacquesy, Tetrahedron Lett. 1989, 30,
5763–5766; c) J.-M. Coustard, J.-C. Jacquesy, B. Violeau, Tetra-
hedron Lett. 1991, 32, 3075–3078; d) J.-M. Coustard, J.-C. Jac-
quesy, B. Violeau, Tetrahedron Lett. 1992, 33, 8085–8086.
[9] Among the most recent improvements of the originally pro-
posed procedure (see ref.[8]) are the modified procedure for tre-
ating B with arenes (see ref.[5b]), as well as an alternative
method to activate cations B on the basis of the replacement
of both their O–H protons by more electronegative polyp-
hosphoric acid residues {[MeCH=N(OPPA)2]+}, see A. V. Ak-
senov, N. A. Aksenov, O. N. Nadein, I. V. Aksenova, Synlett
2010, 2628–2630.
[16] Yu. A. Khomutova, A. A. Mikhaylov, S. L. Ioffe, unpublished
data.
[17] The replacement of the C-3 proton by the Me group in six-
membered cyclic nitronates 7 also resulted in a sharp decrease
in the rate of C–C coupling with π-nucleophiles (see ref.[12b]).
In the near future, we plan to thoroughly investigate the C–C
coupling mechanism of acyclic nitronates 5 with π-nucleophiles
by using experimental and computational methods.
[18] J. F. Klebe, J. Am. Chem. Soc. 1964, 86, 3399–3400.
[19] For reviews on nitroso acetals, see: a) V. F. Rudchenko, Chem.
Rev. 1993, 93, 725–739; b) S. E. Denmark, A. Thorarensen,
Chem. Rev. 1996, 96, 137–166.
[20] The reduction of bicyclic nitroso acetals into amines is dis-
cussed in: a) S. E. Denmark, A. Thorarensen, J. Org. Chem.
1994, 59, 5672–5680; b) S. E. Denmark, V. Guagnano, J. Vaug-
eois, Can. J. Chem. 2001, 79, 1606–1616.
[21] It should be emphasized that although retention of the deute-
rium label in the reductive process points on the retained con-
figuration of a stereocenter at the carbon atom attached to the
nitroso acetal nitrogen atom, its loss does not mean the loss of
configuration of this stereocenter.
[22] H. E. Gottlieb, V. Kotlyar, A. Nudelman, J. Org. Chem. 1997,
62, 7512–7515.
[23] J. A. Marshall, C. A. Sehon, Organic Syntheses, Wiley, New
York, 2004, Collect. Vol. 10, 599; J. A. Marshall, C. A. Sehon,
Org. Synth. 1999, 76, 263.
[24] Y. Kita, J. Segawa, J. Haruta, H. Yasuda, Y. Tamura, J. Chem.
Soc. Perkin Trans. 1 1982, 1099–1104.
[25] H. Emde, D. Domsch, H. Feger, U. Frick, A. Goetz, H. H.
Hergott, K. Hofmann, W. Kober, K. Kraegeloh, T. Oesterle,
W. Steppan, W. West, G. Simchen, Synthesis 1982, 1–26.
[26] C. H. Heathcock, S. K. Davidsen, K. T. Hug, L. A. Flippin, J.
Org. Chem. 1986, 51, 3027–3037.
[27] R. V. Hoffman, H. O. Kim, J. Org. Chem. 1991, 56, 1014–1019.
Received: February 28, 2012
[10] It cannot be excluded that the active species in the above-dis-
cussed C–C coupling reactions is the N-hydroxynitrilium ion
[R–CϵNOH]+ formed after dehydration of cations B rather
than cations B themselves. Anyhow, that was the conclusion of
French researchers (see ref.[8c,8d]). This is additionally sup-
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20239
/KAP1
Date: 09-05-12 10:40:12
Pages: 9
Reactivity Umpolung of Aliphatic Nitro Compounds
Nitroalkanes as α-Electrophiles
V. O. Smirnov,* Yu. A. Khomutova,
V. A. Tartakovsky, S. L. Ioffe* .......... 1–9
C–C Coupling of Acyclic Nitronates with
Silyl Ketene Acetals under Silyl Triflate Ca-
talysis: Reactivity Umpolung of Aliphatic
Nitro Compounds
A very simple approach for umpolung of
the conventional reactivity of nitroalkanes
through their activation by silylation offers
a convenient and efficient strategy for their
C–C coupling with π-nucleophiles. Both
primary (8 examples) and secondary (4 ex-
amples) nitroalkanes may be involved in
coupling with silyl ketene acetals (4 ex-
amples) to provide a concise route to sub-
stituted β-amino acids.
Keywords: Umpolung / C–C coupling /
Nitro compounds
Amino acids
/
Hydrogenation
/
Eur. J. Org. Chem. 0000, 0–0
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