Br?nsted acid mediated N-O bond cleavage for α-amination of ketones through the aromatic nitroso aldol reaction

Article abstract of DOI:10.1039/c5cc10102f

A Br?nsted acid mediated N-O bond cleavage for α-amination of ketones has been developed through the nitroso aldol reaction of less-reactive aromatic nitroso compounds and silyl enol ethers having a disilane (-SiMe₂TMS) backbone. This transform

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DOI: 10.1039/C5CC10102F
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Brønsted acid mediated N–O bond cleavage for -amination of
ketones through aromatic nitroso aldol reaction
Isai Ramakrishna,a Harekrishna Sahoo,a and Mahiuddin Baidya*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A Brønsted acid mediated N–O bond clevage for -amination of
ketones has been developed through nitroso aldol reaction of less-
reactive aromatic nitroso compounds and silyl enol ethers having
disilane (-SiMe2TMS) backbone. This transformation is
operationally simple and scalable, offering structurally diverse -
amino ketones in high yields (up to 98%) with complete
regioselectivity. It represents a mechanistically unique and rare
example of metal-free N–O bond clevage process.
The -amino ketone functionality is a common motif in many
classes of bioactive compounds and complex natural products,
which has inspired considerable efforts towards the
development of efficient synthetic strategies for this high
value synthon.1-3 A conceptually simple and direct way is the
electrophilic
-amination of ketones using nitroso
compounds.4,5 Among the various nitroso compounds,
nitrosobenze is one of the oldest candidates prepared by
Baeyer at the end of nineteenth century.6 It is bench-stable
and many derivatives thereof are also readily prepared.
However, the progress of their use in organic synthesis is
limited with respect to the choice of nucleophiles, particularly
when the nitroso-aldol reaction is considered. This has been
rationalized based on the weak reactivity of aromatic nitroso
compounds. Consequently, successes have primarily been
achieved with more reactive reaction partners such as metal-
enolates and enamines both in racemic and asymmetric
fashion (Scheme 1A).7,8 Additionally, nitroso compounds are
prototypes of ambient electrophiles and thus, under judicious
reaction conditions both the C–N and C–O bonds can be
selectively fabricated from a single source. While more
examples are known for O-selective nitroso aldol reaction with
aromatic nitroso compounds, only a handful of reports are
available for their N-selective nitroso aldol reaction.9,10 This is
Scheme 1 -Amination of ketones through nitroso aldol reaction.
likely because N-selective aromatic nitroso aldol product is
sensitive to water elimination leading to product
decomposition. Thus, the reaction is largely restricted for the
fully substituted enolates.8b,9 For other cases, either special
precaution was adapted during isolation process or the acidity
of the -hydrogen was altered via in situ reduction of carbonyl
group to alcohol.8,11 Furthermore, additional steps were
enforced to cleave the N–O bond. Very often metal catalyzed
reduction and toxic Mo(CO)6 mediated N–O bond cleavage
routes are considered for this purpose, which are unsuitable
for the late-stage derivatization of functionalized molecules
(Scheme 1A).4 Therefore, the development of N-selective aldol
reaction of aromatic nitroso compounds with concomitant N–
O bond cleavage without affecting the ketone functionality
under mild conditions is highly desirable.
In an effect to achieve a solution to the preceding
problems, we sought to develop a mechanistically distinct
pathway for general N-selective aromatic nitroso aldol
reaction followed by highly functional group compatible N–O
bond cleavage in one-pot manner. Early reports of Sasaki have
revealed that reaction of TMS-silyl enol ethers with
nitrosobenzene proceeds with N-selectivity.12 However, the
a.Department of Chemistry, Indian Institute of Technology Madras,
Chennai 600 036, Tamil Nadu, India. E-mail: mbaidya@iitm.ac.in
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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scope of this reaction is very limited and N–O bond cleavage have selected phenylboronic acid for further reaction
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DOI: 10.1039/C5CC10102F
en route to -amino ketones was not addressed. Based on our optimization. Interestingly, the reaction yield was improved up
previous experiences–transition metal catalyzed N-selective to 94% when loading of phenylboronic acid was reduced from
Mukaiyama nitroso aldol reactions of in situ generated 5 equivalent to 3 equivalent; however, further lowering the
nitrosocarbonyl compounds (Scheme 1B)13–we have reasoned catalyst loading is not fruitful giving diminished yield of the
that ketones derived silyl enol ethers having disilane backbone desired product (entries 7-9).
might react with less reactive aromatic nitroso compounds
(Scheme 1C). The Si–Si bond not only increases the reactivity
Table 1 Screening of Brønsted acids and optimization of the reaction conditions.a
of enol ether by hyperconjugation,10g it will also favor the N-
selectivity by blocking the oxygen center of the nitroso
compound through coordination (Scheme 1, below). Further,
the product (II) thus obtained is also expected to be more
stable due the protection of bulky pentamethyldisilanyl group
and hence, it is unbiased from decomposition. Now, the
presence of a Brønsted acid (BAOH) would selectively trigger
the N–O bond cleavage as depicted in Scheme 1, III. This is
likely because basicity of aromatic amines is high enough to
interact with weak Brønsted acid, which stimulates oxophilic
silicon for the rearrangement. Consideration of higher Si–O
(110 kcal mol-1) bond energy compared to Si–Si (52 kcal mol-1)
and N–O (55 kcal mol-1) bond energies also supports this
conjecture.14 Therefore, both the installation of C–N bond and
the cleavage of N–O bond can be accomplished in one-pot
manner under metal free conditions. However, a decisive
choice of Brønsted acids is necessary to nullify the
protodesilylation pitfall (Scheme 1, IV).

Entry
1
2c
3c
4
5
6
7
8d
9d,e
BAOH
PhCO2H
CH3CO2H
Yield [%]b
81
< 5
trace
58
CF3CH2OH
4-tert-Butylcatechol
PhB(OH)2
90
42
94
62
H3PO4
PhB(OH)2 (3 equiv.)
PhB(OH)2 (1.5 equiv.)
PhB(OH)2 (1 equiv.), MeOH
46
a Reaction conditions: 1a (0.15 mmol), 2a (0.18 mmol), CH3CN (3 ml), BAOH (0.75
mmol). Yield of isolated product. c TLC showed the presence of intermediate 3
and its decomposition was not observed with the course of the reaction.
Incomplete conversion. Reaction time was 36 h and 100 equiv. of MeOH was
b
d
e
used. BAOH: Brønsted acid.
Herein, we describe a Brønsted acid mediated N–O bond
cleavage for
-amination of ketones through perfect N-
Crystal structure of 4:
selective nitroso aldol reaction of aromatic nitroso compounds
and ketones derived silyl enol ethers having disilane backbone.
Further, the products are also converted to fully substituted
heterocycles, for which limited methods are available.
Table 2 Scope of the -amination reaction.a
To prove the viability of this approach, we have intently
investigated the reaction of readily available disilane backbone
containing silyl enol ether 1a with nitroso compound 2a in
acetonitrile and the influence of Brønsted acids (BAOH)
covering a broad range of pKa values in one-pot fashion (Table
1). After the consumption of silyl enol ether (TLC monitored),
the Brønsted acid, benzoic acid (pKa = 4.20, 5 equiv.), was
introduced into the reaction flask at room temperature and we
were thrilled to discover the direct formation of
ketone in 81% isolated yield (Table 1, entry 1). It is worth
noting that O-selective nitroso aldol product was undetected
for this reaction. The compound was recrystallized and the X-
-amino
4
4
ray analysis unambiguously demonstrated that the aldol
reaction proceeded not only with N-selectivity but
concomitant N–O bond cleavage also took place selectively.15
Changing the Brønsted acids to acetic acid (pKa = 4.76) and
2,2,2-trifluoroethanol (pKa = 12.5) resulted in only trace
amount of the product (entries 2,3). Presence of substituted
catechol (pKa = 9.96) delivered only moderate yield (entry 4).
When phenylboronic acid (pKa = 8.83) was employed, the
reaction was very clean and the desired product was isolated
with very high yield (90%, entry 5). Use of stronger acid such as
phosphoric acid (pKa = 2.12) reduced the yield significantly
(entry 6). Considering relatively benign toxicology profile of
boronic acids and their importance in organic synthesis,16 we
a
Reaction conditions: 1 (0.15 mmol), 2 (0.18 mmol), CH3CN (3 ml), PhB(OH)2
(0.45 mmol). Yield of the isolated products are given. b Reaction time was 24 h.
Under the optimised conditions, the scope of this metal-
-amination of ketones has been explored. The reaction
free
proceeded smoothly with various silyl enol ethers delivering
the desired products (
16) in very high yields (Table 2).17 The
functional group compatibility of this reaction is remarkable;
halogens ( ), double bond ( ), triple bond ( ), ketone (10)
5
-
5
,6
8
9
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and ester substitutions were undisturbed. The silyl enol ether 2a. The presence of electron withdrawing groupVireewdAurticcelesOntlhinee
DOI: 10.1039/C5CC10102F
derived from heterocyclic and cyclic ketones are also suitable basicity of the aldol product and this disparity in pKa values is
for this reaction, generating compound 12 and 13 in 86% and possibly the reason of this failure.
55% isolated yields respectively. The double
-amination
Table 3 Silica gel promoted N–O bond cleavage for -amination of ketones through
nitroso aldol reaction.a
reaction furnished synthetically important 1,5-diamine 14 in
92% yield. The reaction is not restricted only for the electron-
withdrawing substituted nitroso compound (2a); commercially
available parent nitrosobenze (2b) also gave the desired
products (15-16) in excellent yields (92-96%).
In order to probe the reaction mechanism, we have
executed the reaction of TBS- and TMS-Si(Me)2-substituted
silyl enol ethers with 2a (Scheme 2). The reaction was N-
selective for both the silyl enol ethers and the nitroso aldol
products
3 and 17 were isolated as silicon protected in 98%
and 95% yields, respectively. When the product 17 was
exposed to phenylboronic acid under standard conditions, N–
O bond cleavage was not observed even after prolonging the
reaction time. In sharp contrast, N–O bond cleavage took place
efficiently with product
3
under the identical conditions and
the -amino ketone

4 was isolated in 95% yield, which is
comparable to the result obtained for the reaction with
boronic acid. These findings suggest that disilane backbone is
very important for this strategy.
a
Reaction conditions: 1 (0.15 mmol), 2 (0.18 mmol), CH3CN (3 ml), Silica gel
(Merck 100-200 mesh, 30 g, 30 cm column length). Yield of the isolated products
were given. b Reaction time was 36 h.
To highlight the synthetic utility of the present protocol,
we have executed the reaction of silyl enol ethers 1a and 1c
with nitroso compound 2 in gram sale (Scheme 3). Gratifyingly,
both the amination products were obtained in comparable
yields (92 and 91% respectively).
Scheme 2 Control experiments with TBS- and TMS-Si(Me)2-substituted silyl enol
ethers.
While monitoring the progress of the reaction of silyl enol
ether 1a with nitrosobenzene 2b by TLC, we have noticed that
a new spot was generated in the TLC plate and the Rf–value of
this new spot is also identical with the final cleavage product
15. From this observation, we envisaged that silica gel could
also promote this reaction and in that scenario, N–O bond
might cleave during the purification by silica gel column
chromatography. Accordingly, after the completion of the first
aldol step, the crude reaction mixture was loaded directly onto
the silica gel column. To our delight, the N–O bond cleavage
Scheme 3 Scale up of the -amination reaction.
took place cleanly delivering the
yield (Table 3). This novel reaction is quite general and a broad
spectrum of highly functionalized -amino ketones including
substituted heterocycles (15 34) were synthesized in very high
-amino ketone 15 in 90%

-
44 (X-ray)
to excellent yields (up to 96%, Table 3). The reaction also
worked well for p-bromo and p-methyl substituted nitroso
compounds producing the
-amino ketones 35-41 in high
yields (65-80%). However, the aldol step needed longer time
for the latter case. For more electron enriched nitroso
compound such as 2e (R = OMe), the aldol reaction did not
proceed. Overall, silica gel promoted N–O bond cleavage
protocol augurs well as an alternative potent strategy towards Scheme 4 Application towards the synthesis of fully substituted imidazoles and
indoles.
-amino ketone synthesis. However, it is not effective for
electron-withdrawing substituted nitroso compounds such as
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18948; (b) C. Xu, L. Zhang and S. Luo, Angew. CVhieewmA.rtiIcnlet.OEnldin.e,
Given the significance of the heterocycles in medicinal
chemistry and as synthetic intermediates, we have also
successfully converted the -amino ketone products to highly
substituted heterocycles.18 Treatment of NH4SCN under acidic
conditions followed by base promoted alkylation delivered
fully substituted imidazoles 45-46 in high yields (Scheme 4a).
Compound 44 was crystalized and X-ray analysis results were
used to determine the regioselectivity. Furthermore,
substituted indoles 47-48 were also synthesized in
2014, 53, 4149; (c) B. Maji, M. Baidya and H. Yamamoto,
DOI: 10.1039/C5CC10102F
Chem. Sci., 2014,
5, 3941; (d) S. Murru, C. S. Lott, F. R.
Fronczek and R. S. Srivastava, Org. Lett., 2015, 17, 2122. (e)
D. J. Fisher, G. L. Burnett, R. Velasco and J. Read de Alaniz, J.
Am. Chem. Soc., 2015, 137, 11614; (f) D. Sandovol, A. V.
Samonshin and J. Read de Alaniz, Org. Lett., 2015, 17, 4514.
6
7
A. Baeyer, Chem. Ber., 1874,
Reaction with metal enolates: (a) N. Momiyama and H.
Yamamoto, Org. Lett., 2002, , 5360; (b) K. Shen, X. Liu, G.
Wang, L. Lin and X. Feng, Angew. Chem. Int. Ed., 2011, 50
7, 1638.
4
,
straightforward manner using [3+2] cycloaddition reaction
with benzynes in good yields (Scheme 4b).
4684; (c) A. Yanagisawa, T. Fujinami, Y. Oyokawa, T. Sugita
and K. Yoshida, Org. Lett., 2012, 14, 2434.
8
9
Reaction with enamines: (a) N. Momiyama and H.
Yamamoto, J. Am. Chem. Soc., 2005, 127, 1080; (b) H.-M.
Guo, L. Cheng, L.-F. Cun, L.-Z. Gong, A.-Q. Mi and Y.-Z. Jiang,
Chem. Commun., 2006, 429; (c) C. Palomo, S. Vera, I. Velilla,
A. Mielgo and E. Gomez-Bengoga, Angew. Chem. Int. Ed.,
2007, 46, 8054.
For N-selective aromatic nitroso aldol reactions: (a) J. L.
Cantarero, M. B. Cid, T. B. Poulsen, M. Bella, J. L. G. Ruano
and K. A. Jørgensen, J. Org. Chem., 2007, 72, 7062; (b) See
also ref. 8.
In conclusion, we have developed
a novel one-pot
synthesis of -amino ketones by integrating nitroso aldol

reaction of aromatic nitroso compounds with silyl enol ethers
having disilane backbone and a Brønsted acid mediated
unprecedented N–O bond cleavage strategy. This protocol is
operationally simple, scalable, perfect N-selective, and displays
a broad substrates scope with high yields (up to 98%).
Computational studies to unfold the mechanistic details and
investigations towards
a catalytic variant of this novel
10 For O-selective aromatic nitroso aldol reactions: (a) N.
Momiyama and H. Yamamoto, Angew. Chem. Int. Ed., 2002,
41, 2986; (b) N. Momiyama and H. Yamamoto, J. Am. Chem.
Soc., 2003, 125, 6038; (c) S. P. Brown, M. P. Brochu, C. J. Sinz
and D. W. C. MacMillan, J. Am. Chem. Soc., 2003, 125, 10808;
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Maruoka, J. Am. Chem. Soc., 2006, 128, 6046; (f) D. Font, A.
Bastero, S. Sayalero, C. Jimeno and M. A. Pericas, Org. Lett.,
transformation are currently ongoing.
We gratefully acknowledge IITM for financial support (seed
grant). I.R. and H.K. thank IITM for HTRA.
Notes and references
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