A New and Practical Procedure for the Bruylants Reaction. Zinc-Mediated Synthesis of Tertiary Homoallylamines and β-Aminoesters

Article abstract of DOI:10.1055/s-2003-41471

N,N-Disubstituted α-aminonitriles undergo Bruylants reaction under Barbier and Reformatsky conditions with activated halides, in the presence of zinc and 10 mol% HOAc. The high yields and the simple operational conditions make this reaction an appealing, approach to N,N-disubstituted homoallylamines and β-aminoesters.

Full text of DOI:10.1055/s-2003-41471

1778
LETTER
A New and Practical Procedure for the Bruylants Reaction. Zinc-Mediated
Synthesis of Tertiary Homoallylamines and b-Aminoesters
A
Newand
P
rac
u
tical Proced
c
ure for the
a
Bn
ernardi,* Bianca F. Bonini, Elena Capitò, Gabriella Dessole, Mariafrancesca Fochi, Mauro Comes-Franchini,
Alfredo Ricci*
Dipartimento di Chimica Organica ‘A. Mangini’, Facoltà di Chimica Industriale, Università di Bologna, V. Risorgimento 4, 40136 Bologna,
Italy
Fax +39(51)2093654; E-mail: nacca@ms.fci.unibo.it
Received 23 June 2003
reagents. Herein we report a general, concise and very
Abstract: N,N-Disubstituted a-aminonitriles undergo Bruylants re-
simple procedure based on an unprecedented combination
between the Bruylants and the Barbier or Reformatsky-
type reactions, aimed at the straightforward transforma-
action under Barbier and Reformatsky conditions with activated ha-
lides, in the presence of zinc and 10 mol% HOAc. The high yields
and the simple operational conditions make this reaction an appeal-
ing approach to N,N-disubstituted homoallylamines and b-ami- tion of a-aminonitriles into N,N-disubstituted homoallylic
noesters.
amines and b-aminoesters.
Key words: a-aminonitriles, Bruylants reaction, tertiary amines,
zinc, metathesis
The a-aminonitriles 1a–i were synthesized in very good
yields following Suginome’s procedure3 (Scheme 1) us-
ing simple aldehydes and different bis(dialkylami-
no)cyanoboranes8 as starting materials (Table 1).
a-Aminonitriles are very popular bifunctional compounds
useful not only as synthetic intermediates for a-aminoac-
R'
R'
R''
ids, but also as versatile synthons in organic chemistry.1
The Strecker reaction which involves treatment of alde-
hydes with ammonia and hydrogen cyanide (or equiva-
lents) provides one of the most popular and widely used
routes to a-aminonitriles and has been applied on an in-
dustrial scale towards the synthesis of racemic a-aminoac-
ids via hydrolysis of the intermediate a-aminonitriles.
Moreover an emerging field of importance deals2 with di-
rect and viable methods for the synthesis of homochiral a-
aminonitriles via catalytic asymmetric Strecker-type reac-
tions. Besides these well established methodologies, very
recently a Strecker-type aminative cyanation of aldehydes
and ketones using bis(dialkylamino)cyanoboranes has
been reported3 disclosing a general and highly flexible
new entry to these synthetically useful building blocks
(Scheme 1). Regarding the further synthetic elaborations,
whereas the hydrolysis and the reduction of the cyano
group in N,N-disubstituted a-aminonitriles are well docu-
mented,1a the reaction sequence involving the addition of
an organometallic reagent to the nitrile group, with forma-
tion of the intermediate imine, is more problematic. As a
matter of fact only in particular circumstances4 the addi-
tion reaction prevails over the replacement of the cyano
THF
rt, 6-24 h
N
O
N
CN
R''
R''
B
N
+
R
CN
R
H
82-97%
R'
1a-i
Scheme 1
Besides dialkyl substituted aminonitriles, we successfully
extended this synthesis to derivatives bearing a reactive
framework at nitrogen, e.g. a double bond, and removable
groups, such as the benzyl and the p-methoxybenzyl
(PMB) groups (entries 7–9).
Though several variants in the use of the Bruylants reac-
tion have been proposed so far, the use of preformed orga-
nometallic species and the frequent presence of
stoichiometric amounts of additives such as AgBF4 or
AgOTf6b,d are common features of these reactions. In our
approach to a revisited version of the Bruylants reaction,
inspired by our recent findings in the indium-mediated ad-
dition of reactive halides to unsaturated N-containing
molecules,9 we envisaged the possibility of using a Barbi-
er–type protocol to generate in situ the organometallic
species.
group by a C-nucleophile. The latter pathway, known as Barbier-type allylation reaction of phenyl-(1-pyrrolidi-
Bruylants reaction, is an old widely used procedure5 for nyl)acetonitrile (1a) mediated by metals was extensively
the preparation of a-substituted tertiary amine moieties.6 examined. Using indium this reaction proved to be ineffi-
In the course of our ongoing research program aimed at cient and not reproducible. However, when mediated by
the synthesis of new core units for HIV protease inhibi- zinc and in THF as the solvent, the same reaction was usu-
tors,7 we became interested in the synthesis of a-aminoni- ally complete in less than 2 h to give the tertiary homoal-
triles and in their reactivity towards organometallic lylamine 2a in good yield. A standard procedure using 2
equivalents of activated halide with respect to the starting
a-aminonitrile followed by 2 equivalents of powdered
SYNLETT 2003, No. 12, pp 1778–1782
2
9
.0
9
.2
0
0
3
zinc soon emerged as the best reaction conditions. The ad-
dition of a small amount of HOAc (10 mol%) was found
to be crucial for the reaction to proceed (Scheme 2). At the
Advanced online publication: 19.09.2003
DOI: 10.1055/s-2003-41471; Art ID: G14603ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
A New and Practical Procedure for the Bruylants Reaction
1779
ditions with aminonitriles 1a–i, led to the expected
tertiary b-aminoesters 3a–i (Scheme 2).10 Moreover, in
this case the products were obtained in good yields and
purity irrespectively of the steric hindrance of the sub-
stituents at nitrogen (Table 1).
1)
2) Zn, 2eq
3) AcOH, 0.1 eq
THF, rt
2eq
Br
R''
R
R'
R''
R
R'
N
N
CN
2a-i
1a-i
1) BrCH2COOEt, 2eq
2) Zn, 2eq
3) AcOH, 0.1 eq
THF, rt
R''
R'
The experimental procedure described here is straightfor-
ward and does not require the handling of reactive orga-
nometallic reagents or the use of stoichiometric amounts
of metal salts to promote the formation of the intermediate
iminium ion.6b,d Moreover, the scarce basicity of the orga-
nometallic species involved should prevent the deproto-
nation of the a-aminonitrile or of the intermediate
iminium ion,6b which are often side reactions in Bruylants
transformations.
N
O
R
OEt
3a-i
Scheme 2
present state of the research, no other metals have been
tested.
All the a-aminonitriles 1b–i synthesised so far were then
treated under the optimised conditions, furnishing the cor-
responding homoallylamines 2b–i in good yields and pu-
rity in most cases, after basic work up (aq Na2CO3) and
chromatography on silica gel or neutral alumina, to sepa-
rate oligomeric by-products, formed in small amounts
during the reaction (Table 1).10 While both aliphatic and
aromatic groups are well tolerated in a position to the cy-
ano group (entries 1–3), the successful outcome of the al-
lylation rather relies upon the substituents at nitrogen,
since we observed a lowering in the yields when the steric
hindrance becomes too severe, as in the case of the N,N-
dibenzyl derivative 1g (entry 7), or in the case of the mor-
pholino derivative 1f (entry 6). It is worthy to note that in
these cases we could obtain an improvement in the yields
by heating the reaction mixture to reflux for a few minutes
immediately after the addition of HOAc.
The possibility of obtaining tertiary homoallylamines
bearing a double bond at nitrogen can be chemically ex-
ploited to synthesise, via ring closing metathesis (RCM),
simple nitrogen containing heterocycles, such as the tet-
rahydropyridines 6a,b,15 employing Grubbs’ catalyst 5
(Scheme 3).16 Since the Bruylants reaction and the RCM
tolerate well both benzyl and PMB protecting groups, the
latter removable without affecting the double bond,17 this
sequence could represent in principle a simple and rapid
access to unprotected 2-substituted piperidines and
1,2,3,6-tetrahydropyridines, structures widely found in bi-
ologically active natural products and pharmaceuticals.18
4 mol% 5
Toluene, 85°C
4h30'
R
Ph
N
N
Cy
Cy
We assume that the reaction proceeds through the forma-
tion of a highly reactive iminium ion (Figure 1),11 as it is
evidenced by the isolation of the corresponding homoal-
lylic alcohol when the reaction was performed in wet
THF. The role of HOAc is not clear at the moment, al-
though we believe that it might be necessary for the acti-
vation of the metal surface thus facilitating the subsequent
formation of the organozinc species.12 However, we can-
not exclude an involvement of the acid in the formation of
the iminium ion, since it is known that Brønsted acids
can promote the displacement of the cyano group in N,N-
disubstituted a-aminonitriles.1b
6a: R = Bn, 96%
6b: R = PMB, 93%
2h: R = Bn
2i: R = PMB
PCy3
Cl
Cl
Ru
Ph
PCy3
5
Scheme 3
Moreover, we thought that this new and simple protocol
for the Bruylants reaction could be a useful tool in alka-
loid chemistry for the introduction of reactive side chains
in nitrogen containing heterocycles. To this purpose, we
performed, on the N-benzyl-2-cyano-piperidine 7,19 both
the Barbier and the ‘Reformatsky-type’ reactions obtain-
ing the substituted piperidines 8 and 9, respectively, albeit
in modest yields (Scheme 4). In this particular case, how-
ever, the Reformatsky reaction is much more efficient, in
terms of the yield of 9, when carried out with a pre-formed
organozinc species.14 Moreover, even though also direct
addition of organozinc reagents to the iminium ion pre-
cursor of 719 might afford compounds 8 and 9, a limit of
this more straightforward route could lie in the possible
incompatibility of the organometallic species with the
conditions of the modified Polonovski–Potier reaction.
R'
R''
N
R
H
Figure 1 Postulated reaction intermediate
Inspired by the work of Mosset,13 who also reported a ‘Re-
formatsky-type’ addition to iminium ions generated from
enamines, we turned our attention to a different activated
halide, namely ethyl bromoacetate.14 And indeed, the ‘Re-
formatsky-type’ reaction, performed under the same con-
Synlett 2003, No. 12, 1778–1782 © Thieme Stuttgart · New York

1780
L. Bernardi et al.
LETTER
Table 1 Cyanoboranes, a-Aminonitriles and Products Obtained by the Bruylants Reaction under Barbier and Reformatsky Conditions
Entry
1
Bis(dialkylamino)cyano
boranes
a-Aminonitriles 1 (isolated
yield%)
Homoallylamines 2 (isolated b-Aminoesters 3 (isolated
yield%)
yield%)
N
N
N
O
O
N
N
B
Ph
Ph
CN
Ph
O
CN
2a (65)
1a (88)
3a (75)
2
N
N
N
N
N
B
Cy
CN
Cy
OEt
Cy
CN
1b (86)
2b (82)
3b (45)
3
4
5
N
N
N
O
O
N
N
B
Ph
Ph
CN
Ph
OEt
CN
2c (75)
1c (90)
3c (50)
NEt2
Et2N
B
N
N
N
CN
Cy
OEt
OEt
Cy
CN
Cy
1d (86)
2d (92)
3d (75)
N
N
N
N
O
N
B
CN
Cy
CN
Cy
Cy
1e (93)
O
2e (77)
3e (87)
6
O
O
O
N
N
N
O
O
N
O
N
B
CN
Cy
Cy
CN
Ph
Cy
OEt
OEt
2f (Traces, 66a)
1f (90)
3f (80)
7
8
Ph
Ph
N
Ph
Ph
Ph
Ph
Ph
N
N
N
Ph
Ph
N
N
B
B
Cy
CN
Cy
Cy
CN
Ph
N
2g (15, 38a)
3g (87)
1g (94)
Ph
Ph
Ph
N
N
N
O
Cy
CN
Cy
Cy
OEt
Ph
CN
3h (70)
1h (97)
2h (67)
9
O
O
O
N
N
N
N
B
O
CN
Cy
Cy
CN
2i (72)
3i (84)
1i (82)
a Heating the reaction mixture to reflux for 2 min after the addition of HOAc.
Synlett 2003, No. 12, 1778–1782 © Thieme Stuttgart · New York

LETTER
A New and Practical Procedure for the Bruylants Reaction
1781
(7) Bernardi, L.; Bonini, B. F.; Dessole, G.; Fochi, M.; Comes-
Franchini, M.; Gavioli, S.; Ricci, A.; Varchi, G. J. Org.
Chem. 2003, 68, 1418.
N
N
(8) The cyanoboranes were obtained, according to ref.3, using a
one pot procedure starting from the corresponding N-
silylamines, BCl3 and TMSCN, and were directly used after
evaporation of the solvent, without purification.
45%
37%
8
9
Ph
Ph
N
CN
O
7
Ph
(9) Bernardi, L.; Cerè, V.; Femoni, C.; Pollicino, S.; Ricci, A. J.
Org. Chem. 2003, 68, 3348.
OEt
(10) Zinc-Mediated Bruylants Reaction – General procedure:
To a stirred solution of the a-aminonitrile 1 (0.5 mmol) in
dry THF (1 mL) were sequentially added allyl bromide or
ethyl bromoacetate (1 mmol), zinc dust (1 mmol), and HOAc
(0.05 mmol in 0.05 mL of dry THF). A slightly exothermic
reaction occurred. The mixture was stirred at r.t. for 2 h,
quenched with sat. Na2CO3 and then extracted three times
with Et2O. The organic extracts were dried (MgSO4),
filtered, evaporated and the crude product purified by
chromatography on silica gel or neutral Al2O3 (hexane/
EtOAc mixtures). Selected data for representative examples:
1-(1-Phenyl-3-butenyl)-pyrrolidine (2a). Colourless oil.
1H NMR (300 MHz, CDCl3): d = 7.22–7.05 (m, 5 H), 5.53–
5.39 (m, 1 H), 4.90–4.72 (m, 2 H), 3.06 (dd. J = 4.2, 9.3 Hz,
1 H), 2.65–2.55 (m, 1 H), 2.52–2.40 (m, 3 H), 2.38–2.20 (m,
2 H), 1.79–1.60 (m, 4 H). 13C NMR (70 MHz, CDCl3): d =
142.5, 135.4, 128.2, 128.0, 126.9, 116.4, 70.9, 52.7, 40.5,
23.2. HRMS: exact mass calcd for C14H19N [M + Na]+
224.1415. Found: 224.1399. N-Allyl-N-benzyl-1-
Scheme 4
In summary, we developed a new procedure for the
Bruylants reaction, simply consisting in mixing an a-ami-
nonitrile, an activated halide and zinc powder in THF, in
the presence of 10 mol% HOAc. The method presented
here therefore avoids the use of preformed organometallic
species and does not need stoichiometric metal salts to
promote the loss of the cyano group. The resulting tertiary
homoallylamines and b-aminoesters are generally formed
in good yields and can be used for further synthetic trans-
formations.
Further studies will be aimed at clarifying the mechanism
of the reaction, with particular attention at the role played
by HOAc. Moreover, the scope of the reaction will be
expanded to other activated halides.
cyclohexyl-3-buten-1-amine (2h). Colourless oil. 1H NMR
(300 MHz, CDCl3): d = 7.30–7.08 (m, 5 H), 5.96–5.60 (m, 2
H), 5.17–4.80 (m, 4 H), 3.79 (d, J = 14.4 Hz, 1 H), 3.54 (d,
J = 14.1 Hz, 1 H), 3.22 (ddt, Jt = 1.7 Hz, Jd = 4.9 Hz,
Jd = 14.2 Hz, 1 H), 3.08 (dd, J = 7.5 Hz, J = 14.4 Hz, 1 H),
2.42–2.22 (m, 2 H), 2.18–2.03 (m, 1 H), 2.00–1.90 (m, 1 H),
1.70–1.50 (m, 4 H), 1.45–1.30 (m, 3 H), 1.22–0.71 (m, 3 H).
13C NMR (70 MHz, CDCl3): d = 141.0, 139.0, 138.0, 128.7,
128.0, 126.5, 116.1, 115.1, 62.9, 54.4, 53.6, 40.7, 32.1, 31.1,
31.0, 26.7, 26.6. HRMS: exact mass calcd for C20H29N [M +
H]+ 284.2378. Found: 284.2388. Ethyl 3-Phenyl-(1-
pyrrolidinyl)propanoate (3h). Colourless oil. 1H NMR
(300 MHz, CDCl3): d = 7.34–7.05 (m, 5 H), 3.88 (q, J = 7.2
Hz, 2 H), 3.63 (dd. J = 5.7, 9.0 Hz, 1 H), 2.90 (dd. J = 5.7,
14.7 Hz, 1 H), 2.63 (dd. J = 9.0, 14.7 Hz, 1 H), 0.99 (t,
J = 7.2 Hz, 3 H). 13C NMR (70 MHz, CDCl3): d = 171.5,
141.5, 128.1, 128.0, 127.4, 66.4, 60.2, 52.1, 41.6, 23.2, 13.9.
IR (thin layer): n = 1728 cm–1. HRMS: exact mass calcd for
C15H21NO2 [M + H]+ 248.1651. Found: 248.1667. Ethyl 3-
[Allyl(benzyl)amino]-3-cyclohexylpropanoate (3h).
Colourless oil. 1H NMR (300 MHz, CDCl3): d = 7.40–7.18
(m, 5 H), 5.89–5.86 (m, 1 H), 5.21–5.02 (m, 2 H), 4.14 (q,
J = 7.2 Hz, 2 H), 3.75 (d, J = 14.1 Hz, 1 H), 3.43 (d, J = 14.1
Hz, 1 H), 3.18 (m, 1 H), 3.01–2.86 (m, 2 H), 2.58 (dd, J = 5.1
Hz, J = 15.0 Hz, 1 H), 2.26 (dd, J = 7.2 Hz, J = 15.0 Hz, 1
H), 2.18–2.14 (m, 1 H), 1.80–1.58 (m, 4 H), 1.40–1.05 (m, 3
H), 1.25 (t, J = 7.2 Hz, 3 H), 0.98–0.80 (m, 2 H). 13C NMR
(70 MHz, CDCl3): d = 173.8, 140.3, 137.3, 128.8, 128.0,
126.6, 116.6, 61.0, 60.3, 54.1, 53.1, 41.1, 33.3, 31.0, 30.3,
26.5, 26.4, 26.3, 14.2. IR (thin layer): n = 1734 cm–1. HRMS:
exact mass calcd for C21H31NO2 [M + Na]+ 352.2252.
Found: 352.2237.
Acknowledgement
The financial support by the University of Bologna (Funds for Sel-
ected Research Topics, A. A. 1999–2001), by the National Project
‘Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni’
2002–2003, and by the ex-60% MURST-Funding 2002 is gratefully
acknowledged.
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Synlett 2003, No. 12, 1778–1782 © Thieme Stuttgart · New York

1782
L. Bernardi et al.
LETTER
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5 (4 mol%). The solution was stirred at 85 °C for 4 h 30 min,
then pentane was added, followed by celite and charcoal.
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concentrated. Chromatography on silica gel (hexane/EtOAc)
afforded tetrahydropyridines 6.
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Synlett 2003, No. 12, 1778–1782 © Thieme Stuttgart · New York