Imines in Stille-Type Cross-Coupling Reactions: A Multicomponent Synthesis of α-Substituted Amides

Article abstract of DOI:10.1002/anie.200352123

An alternative to nucleophilic chemistry for the construction of α-substituted amides and amine derivatives from imines is provided by the Stille-type coupling of imines with organotin reagents and acid chlorides (see scheme). This Pd-catalyzed reaction is suitable for components with a range of functional groups and has been extended into a four-component-coupling reaction with carbon monoxide. dba = dibenzylideneacetone, RT = room temperature.

Full text of DOI:10.1002/anie.200352123

Communications
Imines in Stille Reactions
Imines in Stille-Type Cross-Coupling Reactions:
A Multicomponent Synthesis of a-Substituted
Amides**
Jason L. Davis, Rajiv Dhawan, and Bruce A. Arndtsen*
Palladium-catalyzed cross-coupling processes such as the
Stille reaction have emerged as some of the more important
[
1–3]
methods for the construction of carbon–carbon bonds.
A
useful feature of the Stille coupling is its use of nonpolar
organostannanes,rather than nucleophilic agents,in reactions
with organic halides. Organotin reagents are generally air-
and moisture-stable,and they can be prepared with a diverse
range of transferrable substituents,many of which are less
readily formed,or unavailable,within nucleophilic reagents
[*] J. L. Davis, R. Dhawan, Prof. B. A. Arndtsen
Department of Chemistry, McGill University
801 Sherbrooke Street West
Montreal, Quebec H3A 2K6 (Canada)
Fax: (1)514-398-3797
E-mail: bruce.arndtsen@mcgill.ca
[**] This work was supported by NSERC (Canada) and FQRNT
(Quebec). R.D. thanks NSERC for a graduate scholarship.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200352123
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Angewandte
Chemie
(
e.g. Grignard,organozinc,and organolithium reagents). In
addition,the lower reactivity of organotin reagents makes
them easily handled and compatible with most functional
groups,allowing their use on substrates without prior func-
[
1]
tional-group protection.
While Stille couplings with organotin reagents have been
performed extensively with electrophilic compounds RX
(
organic halides and triflates,and related s-bonded sub-
[
1]
strates), one traditional limitation of this process is its
inability to mediate similar reactions with a second important
1
class of electrophiles: multiply bonded substrates R C=X
the H NMR spectrum reveals reduction of the imine C=N
bond upon addition to palladium (d = 5.06 ppm (s,C HTol)),
2
[
4]
such as imines. Carbon–carbon bond formation with imines
is typically performed with nucleophilic agents and provides a
1
3
and C NMR data indicates that amide chelation has
occurred to form
182.3 ppm (COPh)).
[
5]
useful method to construct a-substituted amines. However,
these reactions lack many of the features detailed above in the
complementary Stille cross-coupling reactions. This limitation
is of relevance,since a-substituted amines and amides are
among the more common units in biologically relevant
molecules,including a-amino acids,peptides,peptidomimet-
a
five-membered metallacycle (d =
Mass spectrometric data is consis-
[
13,14]
tent with the dimeric structure of 1’,likely formed through
bridging chloro ligands to generate a pseudo-square-planar
16-electron palladium complex.
The oxidative addition chemistry in Equation (1b) sug-
gested that this process might also be employed with imines in
palladium-catalyzed carbon–carbon bond-forming reactions,
provided the palladium–carbon-bonded intermediate 1 can
be intercepted with transmetalation. This does turn out to be
the case. The reaction of a solution of Tol(H)C=NEt,
[
6]
ics,and b-lactam antibiotics. We report below the develop-
ment of a method to utilize multiply bonded substrates such
as imines in cross-coupling reactions. This provides a palla-
dium-catalyzed alternative to nucleophilic chemistry for the
preparation of a-substituted amides,protected amines,and a-
amino acid derivatives by a Stille-type coupling of imines with
PhCOCl,and
Bu
3Sn(CH=CH2)
with
2.5 mol%
[
7]
organotin reagents.
[Pd (dba )]·CHCl results in the rapid disappearance of
2
3
3
Analysis of a generalized mechanism for palladium-
catalyzed cross-coupling reactions (Scheme 1) reveals why
starting materials at ambient temperature. Workup of the
reaction solution reveals that the clean coupling of the three
reactants has occurred to form the vinyl-substituted amide 2a
in 82% yield (Table 1,entry 1).
This palladium-catalyzed three-component coupling
occurs under mild conditions and with high selectivity,
considering that acid chlorides themselves are known to
[
1]
undergo cross-coupling reactions. In examining the plau-
sible mechanism (Scheme 2),we can attribute this selectivity
to the equilibrium reaction of imine and acid chloride strongly
favoring N-acyl iminium salt/a-chloroamide (3) formation,
0
[12]
Scheme 1. General mechanism of Stille couplings.
which undergoes selective addition to Pd . This is facilitated
by the ability of 3 to chelate to give 1,allowing catalysis to
proceed in the absence of the ligands often required to aid in
imines and related substrates (aldehydes,ketones) have
remained inappropriate as cross-coupling partners: imines
have no demonstrated propensity to add directly to palladium
to generate a PdÀC bond. This is likely due to the lack of
[
1]
oxidative addition. Indeed,the addition of ligands signifi-
[
15]
cantly inhibits this coupling, consistent with reports that
suggest that an empty coordination site can facilitate trans-
[
16]
stabilization of either the nitrogen anion or palladium cation
shown in Equation (1a). This analysis suggests,however,that
the addition of substrates that could neutralize the nitrogen
anionic charge might provide a route to activate imines
metalation from tin. As such,reaction with the organotin
reagent can occur directly with the three-coordinate complex
[
17]
1 to form 4, which yields products by reductive elimination.
Overall,these multiple mechanistic steps create what is to our
knowledge a unique method to utilize palladium-catalyzed
cross-coupling chemistry to convert imines into a-substituted
amides.
[
8]
towards this transformation. Indeed,we have recently
observed that imines can undergo a catalyzed coupling with
carbon monoxide and acid chlorides to generate 1,3-oxazo-
[
9]
lium-5-oxides (Münchnones), a process that was postulated
Further investigation of this catalytic reaction shows it to
have a good degree of generality. Thus both aryl and alkyl
acid chlorides (Table 1,entry 2) can be employed to generate
vinyl-substituted amides. Alternatively,acid chlorides can be
replaced with chloroformates. This is somewhat surprising,
since the iminium salt of a chloroformate does not oxidatively
[
10]
to proceed by formation of palladium-chelated amides.
This indicates that the addition of acid chlorides to imines
can convert the latter into a substrate capable of oxidative
[
11,12]
addition.
control experiments [Eq. (1b)],where the mixing of
Tol(H)C=NBn
(Tol = 4-CH C H ),PhCOCl,and
Pd (dba )]·CHCl (dba = dibenzylideneacetone) leads to
This is clearly demonstrated in stoichiometric
0
add to Pd to form a stable product. This provides a catalytic
3
6
4
[
method to convert imines directly into N-protected, a-
2
3
3
the quantitative formation of chelated product 1’. Notably,
substituted amine building blocks. As anticipated,the cata-
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Communications
[
a]
Table 1: Palladium-catalyzed synthesis of amides.
Entry Imine
Acid
Product (yield)
chloride
1
2
PhCOCl
MeCOCl
Scheme 2. Postulated mechanism for the palladium-catalyzed three-
component coupling.
(entry 6). Similarly,imines containing standard Stille coupling
groups such as aryl bromides and electron-rich aryl iodides
undergo preferential coupling as the iminium salt (entries 7
and 8). This selectivity can be attributed to the stabilizing
effect of amide chelation in the product arising from oxidative
addition of the iminium salt,which leads to the favored
generation of 1 for transmetalation and coupling.
In addition to imines of aromatic aldehydes, a,b-unsatu-
rated imines react with benzoyl chloride and tributylvinyltin
to form a-substituted amides (2m,entry 10). Interestingly,
replacement of the acid chloride with benzylchloroformate
results in the generation of the Michael addition product 2m’
as well as 2m (ca. 1:1 ratio). Based on the mechanism of this
reaction,this would appear to result from the rearrangement
of a chelated amide intermediate 5 to the p-allylic structure 6,
which can reductively eliminate at the remote carbon
(Scheme 3). The addition of a weakly coordinating bromide
3
BnOCOCl
4
5
BnOCOCl
BnOCOCl
6
7
8
BnOCOCl
PhCOCl
BnOCOCl
9
BnOCOCl
1
1
0
1
PhCOCl
Scheme 3. Palladium-catalyzed vinylation of a,b-unsaturated imines.
+
À
source (Bu N Br ),which can presumably accelerate an
4
[
b]
BnOCOCl
associative rearrangement mechanism relative to transmeta-
[
20]
lation, results in the favored formation of the 1,4-addition
a] Reaction conditions: 0.75 mmol imine, 0.75 mmol acid chloride, product 2m’ (entry 11). This provides a useful catalyst-based
.75 mmol tributylvinyltin, 2.5 mol% [Pd (dba )]·CHCl for 16 h in 20 mL method to control the regioselectivity of the addition to
[
0
2
3
3
CH CN/CH Cl (1:1). [b] In the presence of 0.75 mmol Bu NBr.
3
2
2
4
unsaturated imine substrates as opposed to nucleophilic
approaches,which typically rely upon variation of the actual
[
21]
lytic reaction shows tolerance to various functional groups
e.g. ethers,thioethers,and esters; entries 3–5,8,9),although
enolizable C-alkyl imines are not compatible with these
vinyl-transfer substrate.
(
The use of organotin reagents also provides a route to
incorporate substrates into the a-position beyond those
accessible from nucleophilic sources. This is illustrated in
Equation (2),where the palladium-catalyzed reaction of
[
18]
coupling conditions.
substrates capable of undergoing other palladium-catalyzed
reactions. Imines with terminal alkene substituents,which can
undergo Heck couplings with acid chlorides, react exclu-
sively at the imine carbon to form a-substituted carbamates
This process is also amenable to
[
22]
benzoyltributyltin with imine and chloroformate leads to
transfer of the benzoyl unit to the imine carbon and formation
of 7. Even more simplified,the intermediacy of PdÀC-bonded
[
19]
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Angew. Chem. Int. Ed. 2004, 43, 590 –594

Angewandte
Chemie
solution (25 mL). The white precipitate was filtered off and extracted
water/ethyl acetate,and the organic layers were dried over MgSO 4.
Product 2 was isolated by column chromatography (silica gel 60,
hexanes/ethyl acetate).
Received: June 11,2003 [Z52123]
complexes suggests the possibility of incorporating insertion
substrates into the overall catalytic process. Thus,the
catalytic coupling of Tol(H)C=NBn,BnOCOCl,and phenyl-
Keywords: amides · imines · multicomponent reactions ·
palladium · Stille reaction
[
1]
.
tributyltin under one atmosphere of carbon monoxide yields
[
10]
the same product 7 in 51% yield. Examination of the crude
mixture revealed that the only starting materials present were
free imine and phenyltributyltin. The addition of excess
chloroformate (4 equiv) can thus be used to drive conversion
[1] a) J. K. Stille, Angew. Chem. 1986, 98,504 – 520; Angew. Chem.
Int. Ed. Engl. 1986, 25,508 – 523; b) V. Farina,V. Krishnamurthy,
W. J. Scott, Org. React. 1997, 50,1 – 652; c) T. N. Mitchell in
Metal-Catalyzed Cross-Coupling Reactions (Eds.: F. Diederich,
P. J. Stang),Wiley-VCH,New York, 1998,chap. 4.
[
23]
of the imine into 7 in 93% yield. This represents a rare
example of a selective four-component cross-coupling reac-
tion,in this case from imine,chloroformate,phenyltin,and
carbon monoxide,and allows the construction of a-amido
ketones. The latter are useful components for the synthesis of
[
2] For product-diversity applications: B. A. Lorsbach,M. J. Kurth,
Chem. Rev. 1999, 99,1549 – 1581.
[
3] For examples in natural product synthesis: a) K. C. Nicolaou,N.
Winssinger,J. Pastor,F. Murphy, Angew. Chem. 1998, 110,2677 –
2680; Angew. Chem. Int. Ed. 1998, 37,2534 – 2537; b) L. Alcaraz,
G. Macdonald,J. Ragot,N. J. Lewis,R. J. K. Taylor, Tetrahedron
[
24]
[25]
heterocycles and as enzyme inhibitors.
In conclusion,this study describes a convenient and
general one-pot synthesis of a-substituted amides and N-
protected amines by a palladium-catalyzed three-component-
coupling of imines,acid chlorides or chloroformates,and
organotin reagents. Mechanistically,this process provides an
oxidative addition/reductive elimination-based alternative to
nucleophilic approaches to CÀC bond formation with imines,
1999, 55,3707 – 3716.
[
4] Certain reactive tin species (allyl,allenyl,cyano,etc.) undergo
addition to multiply bonded substrates by alternative mecha-
nisms.: a) Y. Yamamoto,N. Asao, Chem. Rev. 1993, 93,2207;
b) H. Yamamoto in Comprehensive Organic Synthesis, Vol. 2
(Ed.: B. M. Trost),Pergamon,Oxford,
1991,chap. 1; c) J. A.
Marshall, Chem. Rev. 1996, 96,31; d) H. Ishitani,S. Komiyama,
Y. Hasegawa,S. Kobayashi, J. Am. Chem. Soc. 2000, 122,762 –
in which the imines are activated towards addition to
palladium by RCOCl. Considering the utility of imine-
reduction products,as well as the generality and mild features
of tin couplings,this chemistry could prove useful in the
preparation of a range of a-substituted amine derivatives.
One illustration of this is in Equation (3),where the
766.
[
[
5] S. Kobayashi,H. Ishitani, Chem. Rev. 1999, 99,1069 – 1094.
6] a) Chemistry and Biochemistry of the Amino Acids (Ed.: G. C.
Barrett),Chapman and Hall,London,
1985; b) A. E. Taggi,
A. M. Hafez,T. Leckta, Acc. Chem. Res. 2003, 36,10 – 19,and
references therein.
[
[
7] The palladium-catalyzed a-arylation of ketones to form amino
acids has been reported recently: a) J. F. Hartwig,S. Lee,N. A.
Beare, J. Am. Chem. Soc. 2001, 123,8410 – 8411; b) S. L.
Buchwald,J. L. Rutherford,M. P. Rainka, J. Am. Chem. Soc.
2002, 124,15168 – 15169.
8] For the oxidative addition of protonated imines: C. R. Baar,L. P.
palladium-catalyzed reaction of Tol(H)C=NBn,BnOCOCl,
Carbray,M. C. Jennings,R. J. Puddephatt,
Organometallics
and tributylvinyltin followed by ozonolysis of the vinylic
2001, 20,408 – 417.
[
26]
[9] a) R. Dhawan,R. Dghaym,B. A. Arndtsen, J. Am. Chem. Soc.
003, 125,1474 – 1475; b) R. D. Dghaym,R. Dhawan,B. A.
group under Marshall conditions provides a simple two-
step route to diprotected a-arylglycine derivatives from air-
stable reagents and a commercially available catalyst. Studies
directed towards the extension of this process to other general
classes of cross-coupling reactions,as well as the incorpora-
tion of asymmetry into the reaction products,are currently
underway.
2
Arndtsen, Angew. Chem. 2001, 113,3328 – 3330; Angew. Chem.
Int. Ed. 2001, 40,3228 – 3230.
[
[
10] Palladium-catalyzed amidocarbonylations are postulated to
proceed by a similar process. For a review: M. Beller,M.
Eckert, Angew. Chem. 2000, 112,1026; Angew. Chem. Int. Ed.
2000, 39,1010.
11] Structurally,this can be considered to arise from stabilization of
the nitrogen anion by acylation and the palladium cation by
chloride coordination.
Experimental Section
[12] For a review of the oxidative addition chemistry of iminium
salts: K. Severin,R. Bergs,W. Beck, Angew. Chem. 1998, 110,
1722 – 1743; Angew. Chem. Int. Ed. 1998, 37,1634 – 1654.
[13] R. D. Dghaym,K. J. Yaccato,B. A. Arndtsen, Organometallics
1998, 17,46 – 48.
All reactions were carried out under an N2 atmosphere using a
Vacuum Atmospheres 553-2 drybox or by standard Schlenk techni-
ques.
Synthesis of 2: Imine (0.75 mmol) and acid chloride or chloro-
formate (0.75 mmol) were dissolved in CH CN (10 mL) and stirred
[14] For characterization of compounds 1, 2,and 7 see the Supporting
Information.
3
for 1 h. To this solution was added [Pd (dba) ]·CHCl (20 mg,
2
3
3
0
.019 mmol). Tributylvinyltin (238 mg,0.75 mmol) in CH 2Cl2
[15] The addition of 2,2’-bipyridyl resulted in no appreciable coupling
under similar conditions.
(10 mL) was added,and the resulting solution was stirred at ambient
temperature for 16 h. The solvent was removed in vacuo,the residue
was dissolved in ethyl acetate (50 mL) and added to a saturated KF
[16] a) J. Louie,J. F. Hartwig, J. Am. Chem. Soc. 1995, 117,11598 –
11599; b) C. Gennari,S. Ceccarelli,U. Piarulli, J. Org. Chem.
Angew. Chem. Int. Ed. 2004, 43, 590 –594
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
593

Communications
2000, 65,6254 – 6256; c) A. L. Casado,P. Espinet,A. M. Gallego,
J. Am. Chem. Soc. 2000, 122,11771 – 11782.
17] The three-coordinate complexes 1 and 4 are likely solvent-
stabilized in acetonitrile solution.
[
[
[
18] These imines rapidly generate enamides with acid chlorides.
19] I. P. Beletskaya,A. V. Cheprakov, Chem. Rev. 2000, 100,3009 –
3066.
[
20] Isomerization on square-planar complexes can be facilitated by
ligating species: R. H. Crabtree, The Organometallic Chemistry
of the Transition Metals,3rd ed.,Wiley,New York, 2001.
[
21] a) L. N. Pridgen,M. K. Mokhallalati,M.-J. Wu, J. Org. Chem.
1992, 57,1237 – 1241; b) K. Tomioka,Y. Shioya,Y. Nagaoka,K.
Tamada, J. Org. Chem. 2001, 66,7051 – 7054.
[
[
22] G. Reginato,A. Faggi, J. Org. Chem. 1989, 54,2966 – 2968.
23] Interestingly,phenyltributyltin does not undergo direct coupling
to generate a-phenyl-substituted amides. We are currently
investigating this selectivity.
[
[
[
24] a) J. A. Murry,D. E. Frantz,A. Soheili,R. Tillyer,E. J.
Grabowski,P. J. Reider, J. Am. Chem. Soc. 2001, 123,9696 –
9
697; b) R. R. Gupta,M. Kumar,V. Gupta in
Chemistry,Springer,Berlin, 1998,chap. 2.
25] a) A. Lee,L. Huang,J. Ellman, J. Am. Chem. Soc. 1999, 121,
907 – 9914; b) T. A. Rano,T. Timkey,E. P. Peterson,J.
Heterocyclic
9
Rotonda,D. W. Nicholson,J. W. Becker,K. T. Chapman,N. A.
Thornberry, Chem. Biol. 1997, 4,149 – 155.
26] J. A. Marshall,A. W. Garofalo, J. Org. Chem. 1993, 58,3675.
5
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