Polymer-supported α-aminonitriles: Alkylation reactions and carbonyl compound cleavage

Article abstract of DOI:10.1055/s-0030-1259032

A polystyrene-supported α-aminonitrile has been prepared and its successive mono- and dialkylations achieved. Complementary procedures allow cleavage of the alkylated moities in either carbonyl or acetal form. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259032

LETTER
2913
Polymer-Supported a-Aminonitriles: Alkylation Reactions and Carbonyl
Compound Cleavage
P
olymer-Supporte
i
d Amin
r
onitrilesginie Beaufort-Droal,a,b Elisabeth Pereira,a,b Fabrice Vergne,c David J. Aitken*a,d
a
b
c
d
Clermont Université, Université Blaise Pascal, Laboratoire SEESIB, BP 10448, 63000 Clermont-Ferrand, France
CNRS, UMR 6504, SEESIB, 24 Avenue des Landais, 63177 Aubière Cedex, France
Sanofi-Aventis, 13 Quai Jules Guesde, BP 14, 94403 Vitry-sur-Seine Cedex, France
Université Paris-Sud, ICMMO, CNRS–UMR 8182, Bât. 420, 15 Rue Georges Clemenceau, 91405 Orsay Cedex, France
Fax +33(1)69156278; E-mail: David.Aitken@u-psud.fr
Received 23 September 2010
gant solid-supported synthesis of saframycin A ana-
logues, Myers15 used a Lewis acid catalysed aminonitrile
translocation strategy for the cyclo-release step. To our
knowledge, only one successful alkylation of solid-sup-
ported aminonitriles has been described: polystyrene-
bound Reissert compounds (i.e., N-acyl aminonitriles)
were alkylated using strong base (LDA) and allylic elec-
trophiles, and a 1,3-dipolar cycloaddition followed by
Reissert hydrolysis provided substituted isoxazolinoiso-
quinolines.16,17 Efforts to perform a polymer-bound ver-
sion of the alkylation of Husson’s CNRS synthon were
reportedly unsuccessful.18 In this letter, we present the
first examples of solid-phase aminonitrile deprotonation–
alkylation procedures and compare them with solution-
phase reactions.
Benzylaminomethyl polystyrene 119 was treated with an
excess of chloroacetonitrile to give supported aminoni-
trile 2 (Scheme 1).20 Combustion analysis of 2 showed
that the nitrogen content had doubled, while HR-MAS
NMR spectroscopic data indicated the presence of a
CH2CN function. An NF-31 test21 was negative, which in-
dicated no residual secondary amine functions.
Abstract: A polystyrene-supported a-aminonitrile has been pre-
pared and its successive mono- and dialkylations achieved. Com-
plementary procedures allow cleavage of the alkylated moities in
either carbonyl or acetal form.
Key words: aminonitriles, alkylations, solid-phase synthesis,
cleavage, carbanions
a-Aminonitriles, first described by Strecker 160 years
ago,1 are today recognised as versatile synthetic interme-
diates displaying a wide array of synthetically useful
chemical reactivities.2 One of their important features is
their ability to undergo deprotonation at the a-carbon cen-
tre followed by reaction of the anion with carbon electro-
philes, permitting elaboration of the carbon skeleton prior
to transformation of the aminonitrile function into an ami-
no acid, diamine, or other functional group array. This
chemistry provides an attractive route to structural diver-
sity which has been exploited synthetically by a number
of research groups,3,4 and we have used this approach for
the construction of a wide range of highly functionalised
cyclopropanes.5 One of the key reactions of aminonitriles
was established in pioneering contributions by Hauser,6
Büchi,7 and Stork,8 who demonstrated that a retro-
Strecker reaction performed on an alkylated or dialkylated
aminonitrile leads to the corresponding carbonyl com-
pound. As such, deprotonated a-aminonitriles are formal-
ly acyl anion equivalents.
ClCH2CN
N
Ph
N
H
Ph
Et3N, DMF
90 °C, 4 d
CN
1
2
Scheme 1 Preparation of the supported aminonitrile
Solid-phase technology is a powerful technique for the
rapid preparation of a diversity of small organic mole-
cules.9 Many of the commonly used polymer supports will
tolerate the presence of carbanions, and a variety of solid-
phase enolates have been generated from carbonyl com-
pounds for alkylation or other carbon–carbon bond-form-
ing reactions.10–12 Curiously, however, very little work
has been described concerning aminonitrile chemistry on
the solid phase. Polymer-supported aminonitriles have
served as intermediates for the preparation of a library of
2-pyrazinones,13 while a solid-phase Strecker reaction has
been used as a route to selected aminoacids.14 In an ele-
The first series of experiments was conducted to deter-
mine the optimal conditions for monoalkylation. A known
excess of LDA was added slowly to a cooled suspension
of resin 2 in THF and a deep orange-pink coloration ap-
peared. A known excess of benzyl bromide 4a was then
added, which returned the resin coloration to pale yellow.
The mixture was finally quenched with aqueous NH4Cl.
To evaluate the extent of alkylation, the resins 5a obtained
from the above procedures were treated overnight with
oxalic acid in a THF–water mixture to perform a retro-
Strecker reaction;22 direct analysis of the liquid-phase ex-
tracts by GC-MS indicated the content of phenylacetalde-
hyde 6a and diphenylacetone 7a (Table 1).
SYNLETT 2010, No. 19, pp 2913–2917
x
x
.x
x
.2
0
1
0
Several interesting points emerged from this optimisation
study. With only 2 equivalents of LDA, deprotonation
Advanced online publication: 10.11.2010
DOI: 10.1055/s-0030-1259032; Art ID: D25810ST
© Georg Thieme Verlag Stuttgart · New York

2914
V. Beaufort-Droal et al.
LETTER
Table 1 Monobenzylation of Resin 2 in Different Conditions
oxalic acid
O
a) LDA (HMPA),
THF–H2O (1:1)
N
Ph
N
Ph
THF, –70 °C
Ph
CHO
Ph
Ph
+
reflux, 18 h
b) PhCH2Br
4a
6a
7a
PhCH2
CN
CN
c) aq. NH4Cl
then wash
2
5a
Entry
LDA (equiv)a
HMPA (equiv)a
PhCH2Br (equiv)a
Content 6a (%)b
Content 7a (%)b
c
c
1
2
3
4
5
6
7
8
2
2
–
8
5
5
–
–
c
c
–
–
c
5
–
15
15
25
25
60
60
95
65
–
–
c
5
20
–
–
15
15
25
25
–
4
60
–
72
23
43
c
–
100
5
a Expressed relative to resin loading (0.57 mmol g–1).
b Expressed as the percentage content of the crude cleaved material; determined by GC-MS (see ref. 24 for details).
c Not detected.
was inefficient; however 5 equivalents of the base gave a this product is degraded by the oxalic acid cleavage con-
smooth monoalkylation, and these conditions were re- ditions, so an alternative cleavage protocol was sought.
tained as standard for the next series of experiments. The
use of larger amounts of base and electrophile did not pro-
duce significant changes. It was noteworthy that the for-
mation of ketone 7a was very low, which indicated that
Efforts to induce mild hydrolytic cleavage of phenylace-
taldehyde from resin 5a using AgNO3 in aqueous THF3c,25
were hampered by the appearance of a dark coating (pre-
sumably AgCN) on the resin. The mild generation of car-
the one-pot double alkylation reaction was minimal, even
bonyl functions from aminonitriles using copper(II)
in the presence of a large excess of reagents. This obser-
sulfate pentahydrate in aqueous methanol was first pro-
vation contrasts with solution-state behaviour. In the pres-
posed by Büchi,7 and has been used successfully by vari-
ence of 2 equivalents of LDA and 2.5 equivalents of
ous groups.3k,8,26 Initial tests on resin 5a indicated that
exposure to a solution of CuSO4·5H2O in aqueous metha-
nol liberated a mixture of 6a and its dimethyl acetal 8a.
Use of a CuSO4·5H2O solution in dry methanol gave only
the acetal 8a, and it was found that pre-swelling of the res-
in in a few drops of DMF improved product recovery sig-
nificantly. This procedure was therefore adopted for the
benzyl bromide, aminonitrile 3 gave a dialkylated product
which was not sufficiently stable to be purified, and was
therefore hydrolysed with oxalic acid to give ketone 7a in
77% overall yield (Scheme 2). HMPA did not have a ben-
eficial effect on the benzylation of supported aminonitrile
2.
A series of deprotonation–monoalkylation reactions was cleavage of alkylated resins 5a–d (Table 2).27 Acetals 8a,
next performed under the standard conditions using dif- 8b, and 8d were thus obtained smoothly; the latter com-
ferent electrophiles 4 (Table 2).23 The resulting alkylated pound is notably a succinaldehyde protected by two dif-
resins 5a–d were treated with oxalic acid to liberate the ferent acetal groups. The geranyl derivative 8c, however,
desired aldehyde 6.24 Iodooctane (4b) and geranyl bro- appeared to have been degraded by this procedure.
mide (4c) produced results comparable to that for benzyl
bromide (4a), although the effects of the presence of
HMPA during the deprotonation step were variable. No
trace of a succinaldehyde dioxolane monoacetal (6d) was
detected when 2-(2-bromoethyl)-1,3-dioxolane (4d) was
used as the electrophile. A control reaction confirmed that
Although Büchi alluded to acetal formation in a footnote,7
aminonitrile methanolysis has not been previously de-
scribed. We therefore checked that this procedure also
works in solution state reactions the analogous nonsup-
ported aminonitriles 9 (Table 3). As had been observed
for resin 5c, the geranyl derivative 9c underwent degrada-
tion; otherwise the procedure appeared to constitute a di-
a) LDA (2 equiv),
oxalic acid
THF–H2O (1:1)
NBn2
O
HMPA (8 equiv)
NBn2
Ph
Ph
THF, –70 °C
Ph
Ph
CN
reflux, 1 h
77%
CN
b) PhCH2Br 4a (2.5 equiv)
c) aq NH4Cl
7a
3
Scheme 2 One-pot double alkylation of aminonitrile 3
Synlett 2010, No. 19, 2913–2917 © Thieme Stuttgart · New York

LETTER
Polymer-Supported Aminonitriles
2915
Table 2 Monoalkylation of Resin 2 with Different Electrophiles23
RCHO
OMe
6
C
A or B
N
Ph
N
Ph
R
CN
CN
2
D
5
R
OMe
8
A: a) LDA (5 equiv), THF, –70 °C, 2 h; b) electrophile 4 (15 equiv), 6 h;
c) aq. NH4Cl then wash
B: as for A, with HMPA (20 equiv) added to LDA
C: oxalic acid, THF–H2O (1:1), reflux, 18 h
D: pre-swell in DMF, then CuSO4⋅5H2O in dry MeOH, reflux, 18 h
Entry
Electrophile 4
6 (A then C) purity (%)a
6 (B then C) purity (%)a
8 (A then D) purity (%)a
a
b
c
95
71
65
32
55
54
Ph
Br
I
Br
b
56
71
–
d
Br
O
O
b
b
–
–
55
a Determined by GC-MS (see ref. 24 or 27 for details).
b Complex mixture obtained.
rect, one-pot transformation of aminonitriles 9 into acetals bromide 4a and iodooctane 4b but only if HMPA was
8.
present. In contrast, the absence of HMPA was actually
beneficial for the procedure in the case of geranyl bromide
4c. It is noteworthy that the intermediate dialkylated res-
ins 10a–c are stable versions of a,a-dialkylaminonitriles.
Such compounds are often labile and readily undergo
retro-Strecker processes to liberate ketones (e.g., vide
supra, Scheme 2).
We then turned our attention to the dialkylation of poly-
mer-bound aminonitriles. Monobenzylated resin 5a was
subjected to a second alkylation protocol,23 using the stan-
dard reagent proportions (5 equiv LDA, optional presence
of 20 equiv HMPA, 15 equiv electrophile) for each of the
three electrophiles 4a–c. The resulting resins 10a–c were
washed and stocked; subsequent treatment with oxalic In summary, this study delineates the successful deproto-
acid24 allowed cleavage of the expected ketones 7 nation–alkylation reactivity of polymer-bound aminoni-
(Table 4). The second alkylation worked well for benzyl triles. Treatment with an excess of LDA and an
Table 3 One-Pot Methanolysis of Aminonitriles
CuSO4⋅5H2O (1 equiv)
NBn2
OMe
OMe
dry MeOH
CN
R
R
reflux, 90 min
8
9
Entry
Aminonitrile 9a
Product acetal 8
Yield of 8 (%)
a
NBn2
OMe
60
Ph
Ph
CN
OMe
b
c
NBn2
OMe
OMe
58
CN
NBn2
OMe
b
–
CN
OMe
d
NBn2
CN
OMe
OMe
O
O
O
O
57
a Prepared by alkylation (LDA/electrophile 4) of N,N-dibenzylamino-acetonitrile (3) according to a standard procedure (ref. 5e).
b Extensive degradation.
Synlett 2010, No. 19, 2913–2917 © Thieme Stuttgart · New York

2916
V. Beaufort-Droal et al.
LETTER
Table 4 Second Alkylation of Resin 5a with Different Electrophilesa
Rabbe, G.; Fleischhauer, J. Eur. J. Org. Chem. 2005, 1984.
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O
N
Ph
CN
N
Ph
C
A or B
PhCH2
R
PhCH2
PhCH2
CN
R
7
5a
10
Entry Electrophile 4
Procedure A,
Procedure B,
7 purity (%)b
7 purity (%)b
c
a
–
68
73
Ph
Br
c
b
c
–
I
Br
42
24
a Reaction conditions: A: a) LDA (5 equiv), THF, –70 °C, 2 h; b) RX
(4; 15 equiv), 6 h; c) aq NH4Cl then wash. B: as for A, with HMPA
(20 equiv) added to LDA. C: oxalic acid, THF–H2O (1:1), reflux, 18 h.
b Determined by GC-MS (see ref. 24 for details).
c Complex mixture obtained.
(c) McMath, A. R.; Guillaume, D.; Aitken, D. J.; Husson,
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D. J.; Guillaume, D.; Husson, H.-P. Tetrahedron 1993, 49,
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Chem. 1992, 57, 6071. (i) Guillaume, D.; Aitken, D. J.;
Husson, H.-P. Synlett 1991, 747. (j) Aitken, D. J.; Royer, J.;
Husson, H.-P. J. Org. Chem. 1990, 55, 2814. (k) Aitken,
D. J.; Royer, J.; Husson, H.-P. Tetrahedron Lett. 1988, 29,
3315.
electrophile induces specific monoalkylation, in contrast
with the solution-state behaviour of aminonitriles in
which an excess of reagents induces significant double
alkylation. Sequential dialkylation of aminonitrile resins
is thus facilitated, and these dialkylated materials have
stability advantages over their small molecule equiva-
lents. Two complementary cleavage protocols are avail-
able, with the choice depending on the sensitivity of the
grafted functionality. The presence of HMPA cosolvent,
sometimes a requirement for efficient solution state reac-
tions, does not seem to be so important on the solid sup-
port (at least for monoalkylation), which is advantageous
from an environmental point of view. These observations
suggest a potential use for solid-supported aminonitrile
chemistry, with possible advantages over the solution-
state equivalent.
(6) Hauser, C. R.; Taylor, H. M.; Ledford, T. G. J. Am. Chem.
Soc. 1960, 82, 1786.
(7) Büchi, G.; Liang, P. H.; Wüest, H. Tetrahedron Lett. 1978,
2763.
(8) Stork, G.; Ozorio, A. A.; Leong, A. Y. W. Tetrahedron Lett.
1978, 5175.
(9) (a) Dolle, R. E.; Le Bourdonnec, B.; Goodman, A. J.;
Morales, G. A.; Thomas, C. J.; Zhang, W. J. Comb. Chem.
2009, 11, 739; and previous surveys in this annual series.
(b) Combinatorial Chemistry and Technologies, 2nd ed.;
Miertius, S.; Fassina, G., Eds.; CRC Press: Boca Raton,
2005. (c) Handbook of Combinatorial Chemistry; Nicolaou,
K. C.; Hanko, R.; Hartwig, W., Eds.; Wiley: Weinheim,
2002. (d) Dörwald, F. Z. Organic Synthesis on Solid Phase.
Supports, Linkers, Reactions, 2nd ed.; Wiley: Weinheim,
2002. (e) Solid-Phase Organic Synthesis; Czarnik, A. W.,
Ed.; Wiley: New York, 2001. (f) Seneci, P. Solid Phase and
Combinatorial Technologies; Wiley: New York, 2000.
(g) Combinatorial Chemistry. Synthesis, Analysis,
Screening; Jung, G., Ed.; Wiley: Weinheim, 1999.
(10) Some recent examples: (a) Lazny, R.; Nodzewska, A.;
Sienkiewicz, M. Lett. Org. Chem. 2010, 7, 21. (b) Green,
R.; Merritt, A. T.; Bull, S. D. Chem. Commun. 2008, 508.
(c) McGhee, A. M.; Kizirian, J.-C.; Procter, D. J. Org.
Biomol. Chem. 2007, 5, 1021. (d) Sheng, S.-R.; Wang,
Q.-Y.; Huang, Y.-X.; Xin, Q.; Liu, X.-L. Synth. Commun.
2006, 36, 429. (e) Liu, Y.; Mills, A. D.; Kurth, M. J.
Tetrahedron Lett. 2006, 47, 1985. (f) Lazny, R.;
Acknowledgment
We are very grateful to Pfizer Global Research & Development for
generous support of this work in the form of a CIFRE grant (to
V.B.-D.), provision of analytical equipment, and other funding for
consumables.
References and Notes
(1) Strecker, A. Justus Liebigs Ann. Chem. 1850, 75, 27.
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Chem. Rev. 1989, 58, 148.
(3) A selection of recent leading references from different
groups: (a) Perry, M. A.; Morin, M. D.; Slafer, B. W.;
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2010, 132, 9591. (b) Louafi, F.; Hurvois, J.-P.; Chibani, A.;
Roisnel, T. J. Org. Chem. 2010, 75, 5721. (c) Enders, D.;
Bonten, M. H.; Raabe, G. Angew. Chem. Int. Ed. 2007, 46,
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Synlett 2010, No. 19, 2913–2917 © Thieme Stuttgart · New York

LETTER
Polymer-Supported Aminonitriles
2917
(11) For an excellent review of this area up until 2000, see:
Kruger, J. In Handbook of Combinatorial Chemistry, Vol. 1;
Nicolaou, K. C.; Hanko, R.; Hartwig, W., Eds.; Wiley:
Weinheim, 2002, 492–530.
(12) In a larger context, see: (a) Lorsbach, B. A.; Kurth, M. J.
Chem. Rev. 1999, 99, 1549. (b) Sammelson, R. E.; Kurth,
M. J. Chem. Rev. 2001, 101, 137.
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2005, 7, 90.
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(17) In related work, polyaminonitriles were prepared by
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subsequent hydrolysis provided aromatic poly etherketones;
see: Yang, J.; Tyberg, C. S.; Gibson, H. W. Macromolecules
1999, 32, 8259.
from 1.6 M BuLi in hexane (5 equiv) and DIPA (5 equiv)]
and optionally HMPA (20 equiv) in THF (4 mL) at –70 °C
was added dropwise by cannula to a carefully stirred
suspension of supported aminonitrile 2 or 5a (0.3 mmol) pre-
swollen in anhyd THF (4 mL) and cooled to –70 °C. After
2 h, electrophile 4 (15 equiv) was added dropwise, and the
mixture was stirred at –70 °C for a further 6 h. Saturated
NH4Cl solution (10 mL) was then added, and the mixture
was allowed to warm to r.t. The resin was recovered by
filtration and washed successively with H2O (50 mL), a
mixture of THF–H2O (1:1, 50 mL), CH2Cl2 (50 mL), and
MeOH (50 mL). The resin was finally dried under reduced
pressure over P2O5 overnight.
(24) Oxalic Acid Hydrolysis
Aminonitrile resin 5 or 10 (0.3 mmol) was swollen in THF
(15 mL) at r.t., then a solution of 30% aq oxalic acid (15 mL)
was added. The mixture was heated at reflux overnight, then
cooled to r.t., then a mixture of ice–H2O was added. The
resin was removed by filtration and washed with H2O
and CHCl3. Liquid phases (filtrate and washings) were
separated, and the aqueous phase was extracted once with
CHCl3. Combined organic extracts were dried over MgSO4
and evaporated under reduced pressure to give the carbonyl
compound 6 or 7. Product purity and identity (comparison
with reference samples) was assessed by GC-MS.
(25) (a) Enders, D.; Milovanović, M. Z. Naturforsch., B: J. Chem.
Sci. 2007, 62, 117. (b) Roux, M.-C.; Patel, S.; Mérienne, C.;
Morgant, G.; Wartski, L. Bull Soc. Chim. Fr. 1997, 134,
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(27) Copper Sulfate Methanolysis Procedure
(18) Blommaert, A.; James, P.; Valleix, F.; Husson, H.-P.; Royer,
J. Heterocycles 2001, 55, 2273.
(19) Resin 1 was prepared according to the procedure described
in the supporting information of the following paper:
Schunk, S.; Enders, D. J. Org. Chem. 2002, 67, 8034.
(20) Preparation of Resin 2
Under argon, chloroacetonitrile (0.052 mL, 0.82 mmol) and
Et3N (0.115 mL, 0.82 mmol) were added to amine resin 1
(0.097 g, 0.062 mmol) pre-swollen in anhyd DMF (1 mL).
The mixture was heated at 90 °C for 4 d. The resin was
recovered by filtration then washed successively with DMF
(20 mL), a mixture of DMF–H2O (1:1, 20 mL), CH2Cl2 (20
mL), MeOH (20 mL), CH2Cl2 (20 mL), and MeOH (20 mL).
The resin was finally dried over P2O5 under reduced
pressure. HR-MAS 1H NMR (300 MHz, CDCl3): d = 3.4–3.6
(H2), 3.9–4.1 (H4 and H3). HR-MAS 13C NMR (75 MHz,
CDCl3): d = 41 (C2), 58 (C3 and C4), 115 (C1). Combustion
analysis N: 1.58% (1.13 mmol g–1).
(21) Madder, A.; Farcy, N.; Hosten, N. G. C.; De Muynck, H.;
De Clercq, P. J.; Barry, J.; Davis, A. P. Eur. J. Org. Chem.
1999, 2787.
(22) (a) Mander, L. N.; Turner, J. V. J. Org. Chem. 1973, 38,
2915. (b) Jacobson, R. M.; Clader, J. W. Tetrahedron Lett.
1980, 21, 1205. (c) Takaghashi, K.; Matauzaki, M.; Ogura,
K.; Iida, H. J. Org. Chem. 1983, 48, 1909. (d) Dauben, W.
G.; Saugler, R. K.; Fleishhauer, I. J. Org. Chem. 1985, 50,
3767.
Aminonitrile resin 5 (0.2 mmol) was swollen in a few drops
of DMF at r.t., then a solution of CuSO4·5H2O (2 equiv) in
anhyd MeOH (4 mL) was added. The mixture was heated at
reflux overnight, then cooled to r.t. The resin was removed
by filtration and washed with pentane and CH2Cl2.
Combined filtrate and washings were dried over MgSO4, and
evaporated under reduced pressure to give the dimethyl
acetal 8. The reaction product was analyzed by GC-MS.
Product purity and identity (comparison with reference
samples) was assessed by GC-MS.
(23) General Alkylation
Under an atmosphere of argon, a solution of LDA [prepared
Synlett 2010, No. 19, 2913–2917 © Thieme Stuttgart · New York