Free-radical addition to ketimines generated in situ. New one-pot synthesis of quaternary α-aminoamides promoted by a H2O 2/TiCl4-Zn/HCONH2 system

Article abstract of DOI:10.1021/ol1015916

A free radical multicomponent reaction mediated by an acidic TiCl ₄-Zn/H₂O₂ system allows the assembly of an amine, a ketone, and formamide in one pot, affording instant access to quaternary α-amino acid derivatives.

Full text of DOI:10.1021/ol1015916

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3898-3901
Free-Radical Addition to Ketimines
Generated In Situ. New One-Pot
Synthesis of Quaternary r-Aminoamides
Promoted by a H2O2/TiCl4-Zn/HCONH2
System
Nadia Pastori, Cosimina Greco, Angelo Clerici, Carlo Punta,* and
Ombretta Porta*,†
Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”, Politecnico
di Milano-Sezione Chimica, Via Mancinelli 7, 20131 Milano, Italy
carlo.punta@polimi.it
Received July 9, 2010
ABSTRACT
A free radical multicomponent reaction mediated by an acidic TiCl4-Zn/H2O2 system allows the assembly of an amine, a ketone, and formamide
in one pot, affording instant access to quaternary r-amino acid derivatives.
The use of free radical reactions in organic synthesis has
continued to increase in the past years, providing multiple
Scheme 1
.
Synthesis of Quaternary R-Aminoamides Mediated
advantages over classical ionic chemistry, which often
requires expensive reagents and hazardous operating condi-
tions.1 In particular, nucleophilic radical addition to the
carbon atom of imine derivatives has attracted much attention
in the past decade as a versatile route to the synthesis of a
wide range of polyfunctional molecules,2 and many proce-
dures based on this convenient approach3 have been devel-
oped.
by a TiCl4/Zn/H2O2 System
Herein we present a new one-pot multicomponent free-
radical synthesis of quaternary R-aminoamides promoted by
an acidic TiCl4/Zn/H2O2 system (Scheme 1).
on aldimines.4 Among the few examples reported, in all cases
the preformation of the ketimines is required. The reason of
Until now studies involving the reductive radical addition
to ketimines are scant in comparison with those conducted
(2) For reviews in the field, see: (a) Friestad, G. K. Tetrahedron 2001,
57, 5461–5496. (b) Miyabe, H.; Ueda, M.; Naito, T. Synlett 2004, 7, 1140–
1157. (c) Friestad, G. K. Eur. J. Org. Chem. 2005, 3157–3172. (d) Yamada,
K.; Tomioka, K. Chem. ReV. 2008, 108, 2874–2886. (e) Akindele, T.;
Yamada, K.; Tomioka, K. Acc. Chem. Res. 2009, 42, 345–355. Gambarotti,
C.; Punta, C. In Tomorrow’s Chemistry Today; Pignataro, B., Ed.; Wiley-
VCH: Weinheim, 2008.
† Deceased May 3, 2008.
(1) For reviews in the field, see: (a) In Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: New York, 2001; Vols. 1 and
2. (b) Sibi, M. P.; Manyam, S.; Zimmerman, J. Chem. ReV. 2003, 103,
3263–3296. (c) Rowlands, G. J. Tetrahedron 2009, 65, 8603–8655. (d)
Rowlands, G. J. Tetrahedron 2010, 66, 1593–1636.
10.1021/ol1015916  2010 American Chemical Society
Published on Web 08/09/2010

to ca. 8 mL of a 15% aqueous acidic solution), which could
negatively affect the formation and the stability of the
ketimine.
Table 1. Radical Addition of Formamide to Ketimines
Generated in Situ from PMP-NH2 1a and Cyclohexanone 2aa
To verify this hypothesis and improve progressively the
efficiency of the protocol, we added Zn metal (powder) to a
lower amount of TiCl3 solution (entry 2) and then completely
replaced TiCl3 with stoichiometric amounts of an anhydrous
TiCl4 solution in CH2Cl2. In doing so we succeeded in
increasing the yield up to 74% (entry 3), whereas in the
absence of Zn metal no reaction occurred (entry 4).
In a generic procedure, a homogeneous solution of
formamide (10 mL) containing 1a-c (2 mmol), 2a-v (12
mmol), and TiCl4 (2.5 mL of a 1 M CH2Cl2 solution, 2.5
mmol) was stirred at 0 °C under N2 atmosphere. After 30
min, Zn powder (300 mg, ca. 5 mmol) was suspended in
the reaction medium, and an aqueous 35 wt % H2O2 solution
(ca. 0.5 mL, 5 mmol), diluted in 4.5 mL of formamide, was
added dropwise over 3 h. Analogous results were observed
by reducing the amount of TiCl4 (1.5 mmol) in favor of the
cheaper Zn metal (8 mmol), after addition of a 37% HCl
aqueous solution (Table 1, entries 6-9). The reaction
proceeds like a titration, with periodic changes of color from
orange to violet, until a pale orange is barely maintained
also upon further addition of Zn. On the basis of these
observations we suggest the possible mechanism depicted
in Scheme 2.
While the changes of color prove the periodic variation
of the oxidation state of titanium ion in solution, the lack of
conversion in the desired products in the absence of titanium
salts (Table 1, entry 5) makes it obvious that zerovalent Zn
metal has the sole role to continuously convert Ti(IV)
(orange) to Ti(III) (violet) (paths i and iii). Instead, titanium
species play a multiple key role. Ti(III) acts both as radical
initiator, generating the hydroxyl radical (path ii), which is
in turn responsible for the hydrogen abstraction from
formamide (path iV), and as radical terminator, causing the
reduction of the aminium radical intermediate (path Vii). In
both cases, Ti(III) is reoxidized to Ti(IV), thus prolonging
the redox cycle and justifying the color oscillation. At the
same time, Ti(IV), as a Lewis acid, increases the electro-
Zn,
HCl 37%, 3a yield,
b
entry TiCl3, mmol TiCl4, mmol mmol
mL
%
1
2
3
4
5
6
7
8
9
8
2
23
47
74
5
5
2.5
2.5
5
5
5
8
8
1.5
1.5
1.5
1.5
33
72
71
60
1
1
2
a 2 mmol of 1a was reacted with 12 mmol of 2a in 10 mL of formamide.
Yield determined by H NMR with 2-methyl-benzylalcohol added as an
internal standard to the crude reaction mixture.
b
1
this lack in the literature can be ascribed to the lower
reactivity (due to the poor electrophilicity of the CdN bond)
combined with the lower stability of ketimines (anhydrous
conditions are usually required because they easily undergo
hydrolysis). However, free-radical addition to ketone-derived
imino compounds is particularly intriguing as it could provide
an unique route to the synthesis of tert-alkyl-amino-deriva-
tives not conventionally prepared via ionic chemistry.
We have recently reported that a novel system, based on
TiCl3 and hydroperoxides (t-BuOOH or H2O2), promotes
one-pot bond-forming transformations via the radical addition
of ethers,5 formamide,6 and alcohols7 to aldimines, generated
in situ under aqueous conditions.8 As a part of our ongoing
interest in this field, we wanted to verify whether the free-
radical addition to aldimines, promoted by our system in
formamide6 as a pivotal subtrate, could be also applied to
ketimines generated in situ for the one-pot synthesis of R,R-
disubstituted-R-aminoamides. This procedure would repre-
sent a convenient route to quaternary R-amino acids, which
are considered important building blocks in the design of
bioactive peptides with enhanced properties, as they are able
to introduce conformational constraints and consequent
structure stabilization.9
(3) For some leading references, see: (a) Ueda, M.; Miyabe, H.; Sugino,
H.; Naito, T. Org. Biol. Chem 2005, 3, 1124–1128. (b) Yamada, K.;
Yamamoto, Y.; Maekawa, M.; Akindele, T.; Umeki, H.; Tomioka, K. Org.
Lett. 2006, 8, 87–89. (c) Akindele, T.; Yamamoto, Y.; Maekawa, M.; Umeki,
H.; Yamada, K.; Tomioka, K. Org. Lett. 2006, 8, 5729–5732. (d) Yamada,
K.; Nakano, M.; Maekawa, Akindele, T.; Tomioka, K. Org. Lett. 2008, 10,
3805–3808.
(4) (a) Torrente, S.; Alonso, R. Org. Lett. 2001, 3, 1985–1987. (b)
Miyabe, H.; Yamaoka, Y.; Takemoto, Y. J. Org. Chem. 2005, 70, 3324–
3327. (c) Miyabe, H.; Yamaoka, Y.; Takemoto, Y. J. Org. Chem. 2006,
71, 2099–2106. (d) Friestad, G. K.; Ji, A. Org. Lett. 2008, 10, 2311–2313.
(5) Clerici, A.; Cannella, R.; Pastori, N.; Panzeri, W.; Porta, O.
Tetrahedron 2006, 62, 5986–5994.
Initial experiments, devoted to the optimization of the
protocol, were conducted under different operating conditions
by reacting p-methoxyaniline (PMP-NH2) 1a in the presence
of cyclohexanone 2a. Disappointingly, preliminary attempts
to extend the free radical addition to ketimines by using our
classic TiCl3/H2O2 system and HCONH2 gave poor results,
affording only 23% of the desired product 3a (Table 1, entry
1). We ascribed this behavior to the high amount of water
present in the reaction medium (8 mmol of TiCl3 corresponds
(6) Cannella, R.; Clerici, A.; Panzeri, W.; Punta, C.; Porta, O. J. Am.
Chem. Soc. 2006, 128, 5358–5359.
(7) (a) Clerici, A.; Ghilardi, A.; Pastori, N.; Punta, C.; Porta, O. Org.
Lett. 2008, 10, 5063–5066. (b) Spaccini, R.; Ghilardi, A.; Pastori, N.; Clerici,
A.; Punta, C.; Porta, O. Tetrahedron 2010, 66, 2044–2052.
(8) A review: Pastori, N.; Gambarotti, C.; Punta, C. Mini-ReV. Org.
Chem. 2009, 6, 184–195.
(9) For reviews in the field, see: (a) Gro¨ger, H. Chem. ReV. 2003, 103,
2795–2827. (b) Cativiela, C.; D´ıaz-de-Villegas, M. Tetrahedron: Asymmetry
2007, 18, 569–623. (c) Cativiela, C.; Ordo´n˜ez, M. Tetrahedron: Asymmetry
2009, 20, 1–63.
Org. Lett., Vol. 12, No. 17, 2010
3899

Scheme 2
.
Reaction Mechanism
Table 2. Radical Addition of Formamide to Ketimines
Generated in Situ from Aryl Amines 1a and Cyclic Ketones
2a-na
1a/TiCl4/Zn/H2O2/HCONH2
2a-n
3-n
(1)
0 °C, N2
entry
2
3 yield, %b (yield, %)c
1
2
3
2a: cyclohexanone
3a: 70 (74)
3b: 33 (36)
3c: 68 (73)
3d: 72 (78)
3e: 45 (51)
3f: 36 (40)
3g: 25 (28)
3h:
3i: 51 (55)
3j: 84 (90)
3k: 60 (65)
3l: 24 (30)
3m: 70 (75)
3n: 40 (51)
2b: 2-methyl-cyclohexanone
2c: 3-methyl-cyclohexanone
2d: 4-methyl-cyclohexanone
2e: 4-tert-butyl-cyclohexanone
2f: 3,3,5-trimethyl-cyclohexanone
2g: 2-methoxy-cyclohexanone
2h: 2,2,6-trimethyl-cyclohexanone
2i: 4-phenyl-cyclohexanone
2j: cyclopentanone
4
5d
6
7
8d
9
10
11
12
2k: cyclobutanone
2l: cycloheptanone
13e 2m: cyclohexanone
philicity of the CdN carbon atom (path Vi), thus promoting
both the formation of the ketimine (path V) and its activation
toward the carbamoyl radical addition.
14f 2n: cyclohexanone
a The molar ratio of 1/2/TiCl4/Zn was 2:12:2.5:5. b Yield of isolated
products is based on the starting amine; yields based on converted amines
were always g90%. c Yield determined by 1H NMR with 2-methyl-
benzylalcohol added as an internal standard to the crude reaction mixture.
d 10 mL of acetic acid was added to the reaction mixture. e 1b was used
instead of 1a. f 1c was used instead of 1a.
This is a further example of highly selective radical
reaction due to dominant polar effects: it occurs when
charged species are involved. The nucleophilic carbamoyl
radical is much more reactive and selective with protonated
or coordinated than with the simple imines.10,2e It is probably
because of the same ketimine stabilization, due to the Ti(IV)
coordinating effect, that the ketone is not free to directly
afford the classical addition product with formamide under
our acidic conditions.11
With the optimized conditions in hand, we set out to
examine the scope of the reaction. Both cyclic (Table 2) and
acyclic (Table 3) ketones resulted suitable for this new
procedure, thus confirming its general applicability. In
particular, the synthesis of rigidified cyclic amino acid
precursors is intriguing as they play an important role in drug
design and development.12
PMP-NH2 1a was chosen as a representative primary
arylamine, since the protective PMP group can be further
removed according to the methodologies reported in the
literature.13 However we also proved that the reaction might
be extended to other substituted anilines, by reacting p-
toluidine 1b and N-methyl-aniline 1c both with cyclohex-
anone (Table 2, entries 13 and 14) and acetone (Table 3,
entries 7 and 8). In analogy with what is observed for
aldimines,5-7 steric hindrance around the CdN bond nega-
tively affects the reaction. As for ketimines deriving from
Table 3. Radical Addition of Formamide to Ketimines
Generated in Situ from PMP-NH2 1a and Acyclic Ketones
2o-va
1a/TiCl4/Zn/H2O2/HCONH2
2o-v
3o-v
(2)
0 °C, N2
entry
2
3 yield, %b (yield, %)c
1d
2
3
4
5
2o: acetone
3o: 72 (76)
3p: 54 (60)
3q: 33 (37)
3r: 25 (30)
3s: 26 (32)
3t: 14 (18)
3u: 72 (77)
3v: 58 (62)
2p: butan-2-one
2q: pentan-2-one
2r: hexan-2-one
2s: 1-methoxy-propan-2-one
2t: 4-phenyl-butan-2-one
2u: acetone
6
7d,e
8d,f
2v: acetone
a The molar ratio of 1/2/TiCl4/Zn was 2:24:2.5:5. b See footnote b of
Table 2. c See footnote c of Table 2. d 5 mL of acetone (68 mmol) was
added. e 1b was used instead of 1a. f 1c was used instead of 1a.
cyclic ketones, the best results were achieved in the presence
of strained rings (Table 2, entries 1, 3, 4, 10, and 11), while
cycloheptanone afforded the desired product in poor yields
(entry 12). Because of similar steric effects, relatively lower
yields were observed with cyclic ketones bearing an alkyl
or aryl substituent in the R position to the carbonyl (Table
2, entries 2 and 7), while no product was observed with 2,2,6-
trimethyl-cyclohexanone (entry 8). Moreover, the steric effect
was also confirmed by difference NOE experiments carried
out to detect the isomer distribution for compounds 3b, 3c,
3d, 3e, 3f, 3g, and 3i (see Supporting Information for details).
(10) Punta, C.; Minisci, F. Trends Heterocycl. Chem. 2008, 13, 1–68
.
(11) (a) Pirrung, M. C.; Wang, J. J. Org. Chem. 2009, 74, 2958–2963.
(b) Maison, W.; Schlemminger, I.; Westerhoff, O.; Martens, J. Bioorg. Med.
Chem. 2000, 8, 1343–1360.
(12) Park, K. H.; Kurth, M. J. Tetrahedron 2002, 58, 8629–8659, and
references therein.
(13) (a) Hasegawa, M.; Tanijama, D.; Tomioka, K. Tetrahedron 2000,
56, 10153–10158. (b) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg,
P. J. L. M.; Alsters, P. L.; van Delft, F. L.; Rutjes, F. P. J. T. Tetrahedron
Lett. 2006, 47, 8109–8113. (c) Verkade, J. M. M.; van Hemert, L. J. C.;
Quaedflieg, P. J. L. M.; Schoemaker, H. E.; Schu¨rmann, M.; van Delft,
F. L.; Rutjes, F. P. J. T. AdV. Synth. Catal. 2007, 349, 1332–1336.
3900
Org. Lett., Vol. 12, No. 17, 2010

In all of these cases, the geometry of the major isomers
resulted in a chair conformation with the alkyl substituent
in equatorial position and the amino group in the axial
position, the carbamoyl addition occurring in the less
hindered equatorial position.14 For the same reasons, the
reactivity of imines deriving from acyclic ketones was also
variable: whereas in the presence of acetone the correspond-
ing products were achieved in good yields (Table 3, entries
1, 7, and 8), the efficiency of the reaction progressively
decreased by increasing the length of the ketone side chains
and with the introduction of ramifications (entries 2-6).
In conclusion, the protocol shown herein describes the first
application of a Ti(IV)/Zn mediated free-radical addition
leading to the selective carbamoylation of ketimino acceptors.
This reaction leads to a novel synthesis of quaternary
R-amino acid precursors and may be conducted under
nonanhydrous conditions, requiring neither the preformation
of the ketimine nor the protection of the amino group. Owing
to its versatility, this protocol offers an expeditious access
to a wider range of tert-alkyl-amino-derivatives, and future
studies will be devoted to the extension to other families of
nucleophilic radicals (i.e., alcohols and ethers).
Acknowledgment. We thank MURST for continual
support of our free-radical chemistry (PRIN 2006 and
2008). We thank Prof. Francesco Minisci (Politecnico di
Milano) for chemical discussions. We are grateful to Prof.
Ombretta Porta, coauthor of this manuscript, for the time
shared with us.
Supporting Information Available: General experimental
procedures and chracterization and spectral data for products
3a-v. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Avenoza, A.; Campos, J. C.; Cativela, C.; Peregrina, J. M.;
Rodr´ıguez, M. A. Tetrahedron 1999, 55, 1399–1406.
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