Alkylation of aryl N-(2-pyridylsulfonyl)aldimines with organozinc halides: Conciliation of reactivity and chemoselectivity

Article abstract of DOI:10.1002/anie.200703239

(Chemical Equation Presented) The best of both worlds: With a coordinating 2-pyridylsulfonyl group as the N-activating group, aromatic aldimines show unprecedented high reactivity towards the direct addition of alkyl zinc bromide reagents in the presence of catalytic amounts of Cu(OTf)₂. The reaction combines high reactivity with wide functional-group compatibility to provide ready access to functionalized benzylamines and derivatives (see example). Tf=trifluoromethanesulfonyl.

Full text of DOI:10.1002/anie.200703239

Angewandte
Chemie
DOI: 10.1002/anie.200703239
Addition Reactions
Alkylation of Aryl N-(2-Pyridylsulfonyl)aldimines with Organozinc
Halides: Conciliation of Reactivity and Chemoselectivity**
Jorge Esquivias, Ramón Gómez Arrayµs,* and Juan Carlos Carretero*
[13]
The direct addition of organometallic reagents to imines is a
very convergent route to a-branched primary and secondary
amines.[1] Consequently, a number of synthetically useful
addition reactions for the formation of carbon–carbon bonds
have been developed with organolithium,[2] Grignard,[3]
dialkyl zinc,[4] alkenyl zirconium,[5] aryl tin,[6] aryl titanium,[7]
and aryl boron[8] reagents as nucleophiles, including some
very efficient catalytic enantioselective procedures.[9] Despite
this great progress, limitations in the scope of this reaction
remain, especially with regard to functional-group compati-
bility. Highly reactive organometallic species, such as organo-
lithium or Grignard reagents, have typically been used for the
alkylation of imines, as the reactions occur under mild
conditions with such reagents. However, drawbacks associ-
ated with these organometallic reagents are the competitive
formation of reduction products and difficulties in the
reconciliation of reactivity and chemoselectivity when func-
tional groups are present in either the nucleophile or the
imine substrate. The use of softer boron, tin, or silicon
reagents has been limited mainly to arylation reactions[6–8] and
resonance-stabilized allyl metal species,[10] which are more
reactive than ordinary alkyl organometallic reagents. Orga-
nozinc reagents show an optimal compromise in terms of
reactivity and wide functional-group tolerance, but only a
limited number of simple dialkyl zinc reagents (typically
dimethylzinc or diethylzinc) have been used for the alkylation
of imines.[4] Owing to their straightforward preparation[11] and
commercial availability, alkyl zinc halides offer a unique
opportunity to satisfy the need for a general method for the
alkylation of imines that combines high reactivity and wide
functional-group tolerance. Although an increasing number
of methodologies benefit from the unique reactivity/selectiv-
ity profile of RZnX reagents,[12] alkyl zinc halides have been
scarcely used as nucleophiles in 1,2-addition reactions to
imines,
probably as a result of the poor electrophilicity of
the imine group.
In recent years, we[14] and others[3f,15] have demonstrated
that N-(heteroarylsulfonyl) imines show better reactivity and/
or selectivity than other N-sulfonyl imines, such as N-
tosylimines, in some addition and cycloaddition reactions.
Furthermore, the N-(heteroarylsulfonyl) group facilitates the
often problematic deprotection of the amine functionality.
Herein, we report a novel procedure for the alkylation of
aromatic N-sulfonyl imines with alkyl zinc bromides. Key
features of this method, which relies on the presence of a
heteroarylsulfonyl coordinating group on the imine nitrogen
atom, are high reactivity and broad functional-group compat-
ibility, as well as straightforward deprotection to generate the
free amine.
To find a suitable sulfonyl substituent, we treated a
representative set of imines, 1a–g, with N-hexylzinc bromide
(2equiv) in CH 2Cl2 at room temperature (Table 1). Sub-
Table 1: Influence of the N-sulfonyl group on the reactivity of the imine.
Entry
Ar
1
t
Product
Yield [%][a]
[b]
1
2
3
4
5
6
7
p-tolyl
1a
1b
1c
1d
1e
1 f
1g
12 h
12 h
12 h
12 h
15 min
5 m in
12 h
–
–
–
–
–
80
97
–
[b]
p-NO2C6H4
o-NO2C6H4
2-thienyl
8-quinolyl
2-pyridyl
3-pyridyl
–
[b]
–
[b]
–
2e
2 f
[b]
–
[a] After chromatographic purification. [b] Only the products of imine
hydrolysis were recovered after aqueous workup. Tf=trifluoromethane-
sulfonyl.
[*] J. Esquivias, Dr. R. Gómez Arrayµs, Prof. Dr. J. C. Carretero
Departamento de Química Orgµnica
Facultad de Ciencias
strates 1a with a tosyl group, 1b with a p-nosyl group, 1c with
an o-nosyl group, and 1d with a 2-thienylsulfonyl group did
not undergo the desired reaction in the presence of Cu(OTf)2
(10 mol%; Table 1, entries 1–4).[16] Only products of imine
hydrolysis were recovered following an aqueous workup. In
contrast, the (8-quinolylsulfonyl)imine 1e[14d] and (2-pyridyl-
sulfonyl)imine 1 f[14a,b] underwent smooth addition reactions
Universidad Autónoma de Madrid (UAM)
Cantoblanco 28049 Madrid (Spain)
Fax: (+34)91-497-3966
E-mail: ramon.gomez@uam.es
juancarlos.carretero@uam.es
[**] This research was supported by the Ministerio de Educación y
Ciencia (MEC, project CTQ2006-01121) and UAM–Consejería de
Educación de la Comunidad Autónoma de Madrid (CAM, project
CCG06-UAM/PPQ-0557). J.E. thanks the MEC for a predoctoral
fellowship. We thank Prof. J. L. Mascareæas and Dr. F. López for
helpful discussions.
[17]
under the catalysis of Cu(OTf)2 (10 mol%) to afford the
corresponding adducts 2e and 2 f in 80 and 97% yield,
respectively, in 15 min or less (Table 1, entries 5 and 6). Imine
1 f underwent addition with N-hexylzinc bromide even in the
absence of a copper salt, although the reaction became much
slower (8 h at room temperature), and the yield of 2 f
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
Angew. Chem. Int. Ed. 2007, 46, 9257 –9260
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9257
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Communications
Table 3: Scope of the direct addition of alkyl zinc bromides to imines.
decreased to 64% as a result of partial hydrolysis of the imine.
Interestingly, the (3-pyridylsulfonyl)imine 1g, an isomer of 1 f,
proved to be unreactive under the optimized reaction
conditions (Table 1, entry 7), which suggests that a chelating
interaction of the heteroaryl moiety with the metal center
may be responsible for the dramatic increase in reactivity
observed with imines 1e and 1 f.
Next, the influence of catalyst loading was investigated for
the addition of the secondary alkyl zinc reagent 2-pentylzinc
bromide to 1 f (Table 2). The addition was equally effective
with 5 mol% (Table 2, entry 1) and 1 mol% (entry 2) of
Entry R1
Imine R2
Product Yield [%][a]
1
2
Ph
Ph
1f
1f
2f
3f
93
92
3
4
Ph
Ph
1f
1f
13f
14f
88
81
[b]
5
6
7
Ph
Ph
Ph
1f
1f
1f
tBu
–
15f
16f
–
Table 2: Effect of the catalyst loading and scaling up on the reaction.
90
84
8
Ph
1f
17f
92
9
10
11
Ph
Ph
Ph
1f
1f
1f
18f
19f
20f
95
88
90
Entry
Quantity of
1 f [mmol]
x
t [min]
Yield [%][a]
1
2
3
4
0.2
2
4
5
1
0.1
0
5–10
15
75
92
90
77
66
12
Ph
1f
21f
90
0.2
270
13
Ph
1f
22f
82
[a] After chromatographic purification.
14
15
16
4-MeOC6H4
4-MeOC6H4
4-FC6H4
4f
4f
5f
23f
24f
25f
80
83
88
Cu(OTf)2: In both cases the product 3 f was formed in over
90% yield in less than 15 min.[18] As a further demonstration
of the potential of this method, the addition of 2-pentylzinc
bromide to imine 1 f on a gram scale (4 mmol) in the presence
of 0.1 mol% of Cu(OTf)2 (molar ratio S/C = 1000) led to 3 f in
77% yield after 75 min at room temperature (Table 2,
entry 3). In the absence of a copper catalyst, the reaction
afforded 3 f in 66% yield after 4.5 h (Table 2, entry 4).
The scope of this Cu-catalyzed reaction was examined
with a variety of aryl and heteroaryl N-(2-pyridylsulfonyl)ald-
imines (Table 3). Aliphatic imines were not investigated, as to
date we have not succeeded in developing a general method
for the isolation of this more labile type of imine.[19] For
practical reasons, this study was undertaken with 5 mol% of
Cu(OTf)2, although we confirmed later that the catalyst is
equally effective in a loading of 1 mol% (Table 3, entry 27). A
wide variety of alkyl zinc bromide reagents of different
substitution patterns and degrees of functionalization partici-
pated in the addition reaction to provide the corresponding
protected amines in less than 10 min in yields typically in the
range of 80–90%. Primary and secondary alkyl zinc bromide
reagents with a broad variety of functional groups, including
alkene, ether, acetal, chloride, ester, and nitrile groups, were
used successfully in this procedure. Even an unprotected
indole substituent with an acidic NH group proved to be
compatible (Table 3, entry 13). Only the very bulky reagent
tert-butylzinc bromide was unreactive under these conditions
(Table 3, entry 5).
17
4-FC6H4
5f
26f
85
18
2-BrC6H4
6f
27f
87
19
20
21
22
23
24
3-MeC6H4
2-naphthyl
2-naphthyl
2-furyl
2-furyl
2-thienyl
7f
8f
8f
9f
9f
28f
29f
30f
31f
32f
33f
84
91
89
92
90
80
10f
25
11f
12f
34f
68[c]
26
35f
77
27
28
12f
12f
36f
37f
83[d]
85
[a] After chromatographic purification. [b] The product was not observed
after 16 h at room temperature. [c] Reaction time: 3 h. [d] Cu(OTf)2:
1 mol%.
proved to be suitable (Table 3, entries 22–25). The more
challenging substrate 12 f, with a potentially competitive
ketone group, underwent imine alkylation with complete
chemoselectivity (Table 3, entries 26–28).
In a competition experiment that highlights the excep-
tional reactivity of the N-(2-pyridylsulfonyl)imines, an equi-
molar mixture of benzaldehyde and imine 1 f was treated with
With respect to the imine substrate, aryl moieties with
donor or acceptor substituents at the ortho, meta, or para
position are tolerated well (Table 3, entries 14–21). Hetero-
aromatic 2-furyl, 2-thienyl, and 2-pyrryl imine derivatives also
9258
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 9257 –9260
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Angewandte
Chemie
4-chlorobutylzinc bromide (2.0 equiv) under the optimized
reaction conditions. After a reaction time of 5 min, the
sulfonamide adduct 18 f was obtained as the only product. No
trace of the product of addition to the aldehyde was detected
by NMR spectroscopy, and benzaldehyde was recovered
(Scheme 1).
À
Figure 1. X-ray crystal structure of complex 42. (The PF6 anion and
the hydrogen atoms have been omitted).
Scheme 1. Chemoselectivity competition experiment between (2-pyri-
dylsulfonyl)imine 1 f and benzaldehyde. Py=pyridyl.
The 2-pyridylsulfonyl group was removed by the simple
treatment of the sulfonamide adducts with an excess of Mg in
MeOH at room temperature for 2h. [27] The corresponding
primary amines were obtained in 90–94% yield (Scheme 3).
In connection with our studies on the conjugate addition
of Et2Zn to a,b-unsaturated N-(2-pyridylsulfonyl)ket-
imines,[14a] we examined the addition of alkyl zinc bromides
to 38, the (2-pyridylsulfonyl)imine of chalcone (Scheme 2).
Scheme 2. Conjugate addition of alkyl zinc bromides to the N-(2-
pyridylsulfonyl)imine of chalcone.
Only conjugate addition was observed,[20] and the correspond-
ing enamides 39–41 were obtained in high yields (88–97%)
and with very good Z stereoselectivity.[21] In contrast, chal-
cone itself and its N-tosylimine were recovered unaltered
after treatment under the same conditions, even after
prolonged reaction times.
The exceptional reactivity of 2-pyridylsulfonylimines
prompted us to study the mode of their coordination to
copper. Initial attempts to isolate a copper complex of
aldimine 1 f failed as a result of its high propensity to undergo
Scheme 3. Deprotection of the sulfonamide adducts and cyclization
reactions.
This smooth deprotection reaction is compatible with sensi-
tive functional groups, such as ketals, halides, and esters. The
free chloroamine 44 was converted into the piperidine
derivative 45 in 78% yield by subsequent treatment with
K2CO3. The deprotection of the sulfonamide esters 19 f and
36 f led to the d-lactams 46 and 47, respectively, in excellent
yields (> 90%) through the spontaneous cyclization of the
corresponding free amines under the reaction conditions.
In conclusion, readily available alkyl zinc bromide
reagents are excellent nucleophilic species for the alkylation
of aromatic N-(2-pyridylsulfonyl)aldimines with unprece-
dented functional-group compatibility. Functionalized free
amines can be accessed in very good yields upon facile
deprotection under mild conditions. We attribute the excep-
tional reactivity of these imines to their N,N-bidentate
character with respect to metal coordination, evidence for
which was obtained from an X-ray crystallographic study of a
CuI complex.
hydrolysis. However, the treatment of the more stable
[22]
ketimine 38 with 1 equivalent of [Cu(CH3CN)4]PF6
in
CH2Cl2 at room temperature produced an instantaneous color
change from colorless to deep red, accompanied by nearly
quantitative formation of complex 42, which was isolated as
an air-stable red solid. X-ray diffraction analysis of suitable
crystals[23] revealed a distorted trigonal-pyramidal N,N,N,N-
tetracoordinated copper complex[24] in which the CuI atom
coordinates to two molecules of 38 through the imino and
pyridyl nitrogen atoms (Figure 1). The observation that the
bonds between CuI and the imine nitrogen atoms (2.34 Š) are
much longer than those between CuI and the pyridine
nitrogen atoms (1.93 Š) reflects the higher affinity of the
metal center to the more basic pyridine nitrogen atoms. The
bidentate N,N chelation of N-(2-pyridylsulfonyl)imines
through a favorable five-membered chelate ring[25] with the
electrophilic copper salt provides a reasonable explanation
for the much higher reactivity of 2-pyridylsulfonylimines over
that of nonchelating N-sulfonyl imines.[26]
Received: July 19, 2007
Revised: September 5, 2007
Published online: October 30, 2007
Keywords: alkylation · copper · N,N ligands · sulfonyl imines ·
.
zinc
Angew. Chem. Int. Ed. 2007, 46, 9257 –9260
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
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[17] CuI salts, such as [Cu(CH3CN)4]PF6 or CuTC, were also effective
catalysts in a concentration of 10 mol% for the reaction of 1 f:
Compound 2 f was formed in 93 or 94% yield within 15 min.
[18] In this model reaction, a similar high reactivity was observed in
the presence of Cu(OTf)2 (5 mol%) and a phosphine ligand
(5 mol%), such as 2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl
(binap). Unfortunately, however, the racemic product 3 f was
obtained when (R)-binap was used as the ligand.
[19] Although aliphatic N-(2-pyridylsulfonyl)imines appear to be
formed quantitatively in 2–3 h upon the direct condensation of
an aldehyde with 2-pyridylsulfonamide in the presence of
Ti(OEt)4 (1 equiv) in CH2Cl2 at room temperature (TLC
monitoring), all attempts to isolate the pure aldimine resulted
in the recovery of the hydrolysis products.
[20] For examples of the Michael-type addition of organometallic
reagents to a,b-unsaturated imines, see: a) K. Tomioka, Y.
Shioya, Y. Nagaoka, K. Yamada, J. Org. Chem. 2001, 66, 7051;
b) J. P. McMahon, J. A. Ellman, Org. Lett. 2005, 7, 5393; c) T.
Soeta, M. Kuriyama, K. Tomioka, J. Org. Chem. 2005, 70, 297;
d) F. Palacios, J. Vicario, Org. Lett. 2006, 8, 5405; ref. [13a].
[21] The Z configuration was assigned to the major N-sulfonyl
enamide by analogy with the corresponding product of the
addition of Et2Zn (see ref. [13a]). The configuration of the latter
product was in turn established by NMR spectroscopy.
[22] [Cu(CH3CN)4]PF6 was chosen as the stoichiometric copper
source as a result of its much higher solubility in CH2Cl2 relative
to that of Cu(OTf)2.
[23] See the Supporting Information for experimental details and
crystallographic data. CCDC-654016 contains the supplemen-
tary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif..
[24] For an N,N,N,N-tetracoordinated CuII complex of bis(2-pyri-
dyl)sulfonamido ligands, see: A. Nanthakumar, J. Miura, S.
Diltz, C.-K. Lee, G. Aguirre, F. Ortega, J. W. Ziller, P. J. Walsh,
Inorg. Chem. 1999, 38, 3010.
[25] This N,N coordination the imine to copper contrasts with the
N,O-type metal complexes of (2-pyridylsulfonyl)aldimines pro-
posed by Toru and co-workers on the basis of theoretical
calculations, whereby the pyridyl nitrogen atom and one of the
sulfonyl oxygen atoms were proposed to form a five-membered
chelate ring with the metal center; see refs. [3f,14a].
[26] This mode of coordination could also facilitate pseudointramo-
lecular delivery of the organocopper nucleophile following the
Zn/Cu transmetalation; see, for example: P. Knochel, R. D.
Singer, Chem. Rev. 1993, 93, 2117.
[12] For
a review on the reactivity and utility of organozinc
compounds, see: The Chemistry of Organozinc Compounds: R-
Zn (Eds.: Z. Rappoport, I. Marek), Wiley, Chichester, 2006; for
very recent examples, see: a) A. Whitehead, J. P. McParland,
P. R. Hanson, Org. Lett. 2006, 8, 5025; b) F. Denes, S. Cutri, A.
Perez-Luna, F. Chemla, Chem. Eur. J. 2006, 12, 6506; c) H. Ren,
[27] C. S. Pak, D. S. Lim, Synth. Commun. 2001, 31, 2209.
9260 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 9257 –9260
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