Indium- and zinc-mediated Barbier-type allylations of an N,N-(dimethylsulfamoyl)-protected aldimine and subsequent deprotection

Article abstract of DOI:10.1016/j.tetlet.2007.07.167

Barbier-type Zn and In-mediated allylations of an N,N-(dimethylsulfamoyl)-protected aldimine with different allyl bromides were investigated for the preparation of N-homoallylic sulfamides. The desired N,N-(dimethylsulfamoyl)-protected products were obtai

Full text of DOI:10.1016/j.tetlet.2007.07.167

Tetrahedron Letters 48 (2007) 6958–6961
Indium- and zinc-mediated Barbier-type allylations
of an N,N-(dimethylsulfamoyl)-protected aldimine
and subsequent deprotection
Sara Kallstrom,a Tiina Saloranta,a Adriaan J. Minnaardb,* and Reko Leinoa,*
¨
¨
a
˚
˚
Laboratory of Organic Chemistry, Abo Akademi University, FI-20500 Abo, Finland
bDepartment of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
Received 26 May 2007; revised 18 July 2007; accepted 25 July 2007
Available online 28 July 2007
Abstract—Barbier-type Zn and In-mediated allylations of an N,N-(dimethylsulfamoyl)-protected aldimine with different allyl bro-
mides were investigated for the preparation of N-homoallylic sulfamides. The desired N,N-(dimethylsulfamoyl)-protected products
were obtained in moderate to high yields in THF as the optimal solvent. Their further derivatization was demonstrated by a facile
preparation of a functionalized dehydropiperidine by an allylation/olefin metathesis reaction sequence. A high yielding deprotection
of the N,N-dimethylsulfamoyl group was likewise demonstrated.
Ó 2007 Elsevier Ltd. All rights reserved.
R2
H
R2
Methods for generating new carbon–carbon bonds con-
stitute the essence of organic synthesis and provide the
means for the preparation of more complex molecules
from simpler ones.1 Among these methods, the addition
of allyl metal derivatives to imines is particularly useful
for the preparation of other nitrogen-containing com-
pounds.2 The homoallylic amines obtained are impor-
tant intermediates in the synthesis of a range of
pharmaceutically active substrates and other biologi-
cally active compounds.3
N
O
HN
R1
metal
+
+
X
X
R1
solvent
A
B
OH
metal
solvent
R1
R2
R1
R2
Imines are less electrophilic and thus less reactive to-
wards nucleophiles than the corresponding carbonyl
compounds.2c,4 This problem may, however, be circum-
vented by the use of more electrophilic imines or by
enhancing the strength of the nucleophile by selecting
a suitable metal.
Scheme 1.
under Barbier-type conditions was first reported in
1988.9 Compared to other metals, indium offers a num-
ber of advantages, including its low toxicity, tolerance
towards air and moisture and, due to its low ionization
potential, a high reactivity in the absence of external
activators and proton sources.10 Zinc was first employed
in Barbier-type allylations by Wolinsky and co-workers
in 1977,11 and has likewise proved to be a highly useful
mediator for the allylation of various substrates. In con-
trast to In-mediated allylations, which commonly are
carried out in water/THF mixtures without additives,
the use of Zn generally requires the application of satu-
rated aqueous NH4Cl as a proton source together with
the organic solvent.
Several metals have been employed as mediators for the
allylations of both imines (A) and aldehydes or ketones
(B) (Scheme 1).5,6 Among these, indium7 and zinc8 are
widely represented. The use of In metal as a mediator
in the addition of allyl bromides to carbonyl compounds
*
Corresponding authors. Tel.: +31 50 3634258; fax: +31 50 3634296
(A.J.M.); tel.: +358 2 2154132; fax: +358 2 2154866 (R.L.); e-mail
addresses: a.j.minnaard@rug.nl; reko.leino@abo.fi
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.167

S. Ka¨llstro¨m et al. / Tetrahedron Letters 48 (2007) 6958–6961
6959
Table 1. Metal-mediated allylation of N,N-(dimethylsulfamoyl)-benz-
aldimine 1 in different solventsa
In a recent study, Lu and Chan investigated the In
and Zn-mediated allylations of various sulfonimines in
aqueous media.6c The corresponding homoallylic
sulfonamides were generally obtained in high yields.
Allylations with crotyl and cinnamyl halides gave high
regioselectivities and in some cases moderate diastereo-
selectivities. Reactions with Zn required the use of satu-
rated aqueous NH4Cl solution in combination with
THF. In a separate study, Lin and co-workers recently
reported high diastereoselectivities in the Zn-mediated
allylation of chiral N-tert-butylsulfinyl imines in THF
in the presence of additives.12 Analogously, chiral ald-
imines derived from phenylglycinol have been subjected
to In-mediated allylations in methanol to provide both
aliphatic and aromatic homoallylic amines in good
yields and diastereoselectivities.13 Barbier-type In or
Zn-mediated allylations of unactivated aldimines in
alcoholic solvents14 and trifluoromethyl aldimines in
DMF and THF15 have likewise been investigated
earlier.
O
O
N
N
S
S
N
HN
allyl bromide (3 equiv.)
metal (3 equiv.)
O
O
solvent, r.t.
1
2
Entry
Metal
Solvent
Conversionb
(%)
Yieldd
(%)
1
2
3
4
5
6
In
In
In
Zn
Zn
Zn
THF
THF/H2O 1:1
H2O
THF
THF/NH4Claq 1:1
NH4Claq
100
89c
19c
100
74c
84c
90
81
13
81
50
54
a Allylations were performed at rt on a 0.10–0.30 mmol scale with
3 equiv of metal and allyl bromide, respectively.
b Conversions were determined by 1H NMR.
c Lower conversions are due to formation of 1-phenyl-3-buten-1-ol as a
result of hydrolysis of 1 in the aqueous solvent and subsequent
allylation.
With the exception of the sulfinyl and phosphanoyl
groups, the activating and protecting groups applied
have in common that their removal after the allylation
is not trivial. Hydrogenolysis is not possible in the pres-
ence of the olefin and removal of sulfonyl groups
requires either harsh conditions, for the tosyl group,
or environmentally unfriendly reagents like thiophenol
in DMF for the nosyl group. Here, we report the results
of our initial investigation on the Zn- and In-medi-
ated Barbier-type allylation of the N,N-(dimethylsulfa-
d Isolated yield.
aldimine decreasing the yield of the amine product 2
(Table 1, entries 5 and 6). Similar results were obtained
for the In-mediated allylation of 1 in aqueous media
(Table 1, entries 2 and 3). Nevertheless, a comparison
of the reactions performed with In and Zn in aqueous
media alone (Table 1, entries 3 and 6) demonstrates
the substrate and metal surface activation in the Zn
mediated reaction by NH4Cl.18 This, supposedly, leads
to the more efficient formation of the allylating reagent
as well as the product 2.
moyl)-protected aldimine
1 (Fig. 1) under both
anhydrous and aqueous conditions. The N,N-dim-
ethylsulfamoyl group was recently introduced as an
inexpensive, low-molecular weight protecting/activating
group for the rhodium-catalyzed asymmetric arylation
of aldimines.16 We anticipated that it would also serve
as a suitable activating group for allylations being simul-
taneously readily subjected to cleavage under mild con-
ditions for the preparation of the corresponding
homoallylic amines.
Next, the In or Zn-mediated allylation of 1 was contin-
ued by investigating different allylating agents. The
results are presented in Table 2. In order to avoid
substrate hydrolysis, the reactions were carried out in
anhydrous THF. Excellent conversions and isolated
yields were observed in all reactions with allyl, methallyl,
crotyl and prenyl bromides in the presence of either Zn
or In. Conversions lower than 100% were obtained with
the bulkier prenyl bromide reagent only (Table 2, entries
4 and 8). Here, moderate yields of 2d were obtained
(In = 63%, Zn = 46%), most likely due to the steric con-
straints induced by the bulkier allylating agent.
The allylation of 1 was first studied in different solvents
(THF, water, NH4Claq, and mixtures thereof) by in situ
formation of the allyl metal species from In or Zn
powder and allyl bromide at room temperature.17 The
results are presented in Table 1. The In- and Zn-medi-
ated allylations in anhydrous THF gave full conversions
and high yields independent of the metal employed
(Table 1, entries 1 and 4). The use of aqueous NH4Cl
as a solvent or in combination with THF in the Zn-med-
iated reaction resulted in undesired hydrolysis of the
Recently, it has been demonstrated that the N,N-dim-
ethylsulfamoyl group is readily removed from diarylam-
ines in two hours by microwave-assisted transamination
under mild conditions.16 Deprotection of the N-homoal-
lylic sulfamide 2a was thus investigated in a similar fash-
ion (Scheme 2).19 In the case of 2a, the deprotection
took place cleanly in refluxing 1,3-diaminopropane by
conventional heating with an oil bath. The reaction
was complete in 2 h and the homoallylic amine 3 was
obtained in 92% yield.
O
N
S
N
O
H
1
As an example of the use of the allylation products in
the synthesis of nitrogen-containing heterocycles, com-
Figure 1. The N,N-(dimethylsulfamoyl)-protected aldimine substrate
1.

6960
S. Ka¨llstro¨m et al. / Tetrahedron Letters 48 (2007) 6958–6961
Table 2. Metal-mediated allylation of N,N-(dimethylsulfamoyl)-benz-
aldimine 1 with different allylating agentsa
O
O
N
N
S
S
crotyl bromide
(3 eq.)
HN
N
O
O
N
O
R1
O
In (3 eq.)
O
N
S
S
THF, r.t.
N
HN
allylating agent (3 equiv.)
metal (3 equiv.)
O
2c
1
R2
THF, r.t.
R3
KOH (3 eq.)
allyl bromide (3 eq.)
DMF, r.t.
1
2a, R1 = R2 = R3 = H
2b, R1 = R2 = H, R3 = Me
2c, R1 = Me, R2 = R3 = H
2d, R1 = R2 = Me, R3 = H
O
Grubbs´ 2nd
gen.cat.
(5 mol%)
O
N
N
S
S
N
N
O
Entry Metal/allylating
agent
R1, R2, R3 Conversionb Yieldc
O
(%)
(%)
CH2Cl2, r.t.
1
2
In/allyl bromide
In/methallyl
H, H, H
H, H, Me
100
100
90
87
5 (91% yield)
Scheme 3.
bromide
In/crotyl bromide
In/prenyl bromide Me, Me, H
Zn/allyl bromide
Zn/methallyl
bromide
Zn/crotyl bromide Me, H, H
Zn/prenyl bromide Me, Me, H
4
3
4
5
6
Me, H, H
100
75
100
100
89d
63
81
72
H, H, H
H, H, Me
drous THF, providing the corresponding N-homoallylic
sulfamoylamides in very good yields. The reaction pro-
ceeds fairly well in aqueous media but is accompanied
by the concomitant hydrolysis of the imine substrate.
The N,N-dimethylsulfamoyl protecting group can be
efficiently cleaved from the product amides by transam-
ination. Finally, the N-homoallylic sulfamides can be
further utilized for the preparation of heterocyclic build-
ing blocks. Allylation followed by ring-closing olefin
metathesis provides access to functionalized dehydropi-
peridines in excellent yield, demonstrating the potential
of the protocol.
7
8
100
89
68d
46
a Allylations were performed at rt on a 0.10–0.30 mmol scale with
3 equiv of metal and allylating agent, respectively.
b Conversions were determined by 1H NMR.
c Isolated yield.
d The crotylated products were determined to be racemic mixtures of
the syn/anti diastereoisomers (entries 3 and 7) by 1H NMR of the
crude product.
O
N
S
O
HN
NH2
1,3-diaminopropane
reflux, ~2 h
Acknowledgements
Financial support from the Academy of Finland (SK,
Project Number 203283), the Swedish Academy of Engi-
neering Sciences in Finland (Svenska Tekniska Vetens-
kapsakademien i Finland) and the Graduate School of
Organic Chemistry and Chemical Biology (TS) is grate-
fully acknowledged. We thank Mrs. T. D. Tiemersma-
Wegman and Mr. Markku Reunanen for technical
support.
2a
3 (92% yield)
Scheme 2.
pound 2c was converted into the corresponding diallylic
sulfamide 4 in excellent yield (Scheme 3).20 Exposure of
a degassed CH2Cl2 solution of 4 to Grubbs’ 2nd gener-
ation Ru-catalyst (NHC)(PCy3)Cl2Ru@CHR at room
temperature provided, after purification, the functional-
ized dehydropiperidine 5 in 91% yield.21 This reaction
generates a double bond in the six-membered ring for
further derivatization and shows the compatibility of
the sulfamoyl group with ruthenium-catalyzed metathe-
sis reactions.21,22 Similar preparation of dehydropiperi-
dines has been previously described by Couty and
co-workers.23 Further research on the synthesis of anal-
ogous piperidine building blocks and removal of the sul-
famoyl group in these systems is currently in progress.
Supplementary data
Complete experimental and analytical details, spectral
1
data and copies of H NMR and 13C NMR spectra of
selected compounds are available as Supporting data.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2007.
07.167.
In summary, we have shown that the Zn- and In-medi-
ated Barbier-type allylations of an N,N-(dimethylsulfa-
moyl)-protected aldimine with different allylating
agents takes place in a highly efficient manner in anhy-
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19. Deprotection procedure: 0.20 mmol of 2a in 2 mL of 1,3-
diaminopropane was heated to 140 °C and refluxed for
2 h. After cooling to rt, the mixture was diluted with
CH2Cl2 and washed with water. Subsequent extraction of
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(65 lL, 0.75 mmol) were added and the resulting mixture
was stirred for 1 h at rt. Quenching with H2O and
extraction with ether was followed by drying over anhy-
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which was used in the subsequent step without further
purification. Next, a Schlenk tube flushed with argon was
charged with a solution of 4 (30.0 mg, 0.10 mmol) in
anhydrous CH2Cl2 (0.7 mL) and degassed using three
evacuation/argon-fill cycles. In a separate tube, a degassed
solution of Grubbs’ 2nd generation catalyst in anhydrous
CH2Cl2 (0.3 mL) was prepared. The solution of 4 was
cooled on an ice bath and treated dropwise with the
catalyst solution over a period of 5 min. The reaction
mixture was removed from the ice bath, allowed to warm
to room temperature and stirred overnight. After 12 h, the
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