Cross-coupling of grignard reagents with sulfonyl-activated sp3 carbon-nitrogen bonds

Article abstract of DOI:10.1002/adsc.201100285

Sulfonyl-activated sp³ carbon-nitrogen bonds have been found to be cleaved by Grignard reagents in the presence of 5 mol% of copper(I) iodide (CuI). Significantly, a broad range of sulfonyl-activated benzylic, allylic, and propargylic amines smoothly undergo the cross-coupling reaction with Grignard reagents to afford structurally diverse coupling products in good to excellent yields and with high chemo-, regio-, and stereoselectivity. Moreover, an S _N2 mechanism has been demonstrated to be involved in the cross-coupling reaction that allows the asymmetric synthesis of chiral hydrocarbons from optically active α-branched amine derivatives. Copyright

Full text of DOI:10.1002/adsc.201100285

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DOI: 10.1002/adsc.201100285
Cross-Coupling of Grignard Reagents with Sulfonyl-Activated sp3
Carbon-Nitrogen Bonds
Man-Bo Li,a Xiang-Ling Tang,a and Shi-Kai Tiana,*
a
Joint Laboratory of Green Synthetic Chemistry, Department of Chemistry, University of Science and Technology of
China, Hefei, Anhui 230026, Peopleꢀs Republic of China
Fax : (+86)-0551-3601-592; e-mail: tiansk@ustc.edu.cn
Received: April 15, 2011; Published online: August 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100285.
Abstract: Sulfonyl-activated sp3 carbon-nitrogen
bonds have been found to be cleaved by Grignard
reagents in the presence of 5 mol% of copper(I)
iodide (CuI). Significantly, a broad range of sulfon-
Whereas alkylamines are readily accessible, they do
not serve as useful sp3 carbon electrophiles in chemi-
cal synthesis due to the extremely poor leaving ability
of their amino groups. In this regard, it is necessary to
activate alkylamines to enhance their electrophilicity
by modifying the amino groups. A few early studies
show that Grignard reagents are able to couple with
some quaternary ammonium salts derived from terti-
ary allylic amines[8] or (3-indolyl)methylamines[9]
through sp3 carbon-nitrogen bond cleavage. To the
best of our knowledge, Grignard reagents have not
been reported to couple with the non-ionic deriva-
tives of primary and secondary alkylamines, which
can significantly expand the scope of sp3 carbon elec-
trophiles for carbon-carbon bond-forming reactions.
Since Grignard reagents are very reactive, it is a
formidable challenge to avoid side reaction pathways
in their cross-coupling with the non-ionic derivatives
of primary and secondary alkylamines. In the course
of exploring carbon-nitrogen bond cleavage for selec-
tive organic synthesis,[10] we found that Grignard re-
ACHTUNGTRENNUNGyl-activated benzylic, allylic, and propargylic amines
smoothly undergo the cross-coupling reaction with
Grignard reagents to afford structurally diverse
coupling products in good to excellent yields and
with high chemo-, regio-, and stereoselectivity.
Moreover, an SN2 mechanism has been demonstrat-
ed to be involved in the cross-coupling reaction that
allows the asymmetric synthesis of chiral hydrocar-
bons from optically active a-branched amine deriv-
atives.
Keywords: alkylamines; cross-coupling; Grignard
reagents; sulfonamides; sulfonimides
Owing to their ready availability and high reactivity, agents were able to cleave the sp3 carbon-nitrogen
Grignard reagents are employed as carbon nucleo- bonds of sulfonyl-activated benzylic, allylic, and prop-
philes in a number of carbon-carbon bond-forming re- argylic amines in the presence of a catalytic amount
actions.[1] In recent years, the cross-coupling of of copper(I) iodide. Moreover, high levels of chemo-,
Grignard reagents with sp3 carbon electrophiles has regio-, and stereoselectivity were obtained from the
emerged as a synthetically useful approach for the copper-catalyzed cross-coupling reaction of Grignard
construction of sp3 carbon-carbon bonds,[2] and certain reagents with alkylamine derivatives.
alkyl halides,[3] alkyl sulfonates,[3h,l,o,4] alkyl esters,[5]
The high reactivity of Grignard reagents prompted
alkyl phosphorothioates,[6] and alkyl ethers[7] have us to employ sulfonyl groups to activate alkylamines
been identified as suitable sp3 carbon electrophiles because many other electron-withdrawing groups,
under appropriate reaction conditions. Significantly, such as acyl groups, alkoxycarbonyl groups, and phos-
different reactivities and selectivities have been re- phoryl groups, are less compatible with Grignard re-
vealed with these sp3 carbon electrophiles. In this con- agents. The model reaction of double p-toluenesulfon-
text, it is very interesting and rewarding to explore yl-activated p-methoxybenzylamine (sulfonimide 1a)
other types of sp3 carbon electrophiles to couple with with phenylmagnesium bromide in tetrahydrofuran
Grignard reagents involving the cleavage of sp3 was found to be very sluggish at room temperature
carbon-heteroatom bonds other than sp3 carbon-halo- (Table 1, entry 1). Gratifyingly, diarylmethane 3a was
gen bonds and sp3 carbon-oxygen bonds.
obtained in 68% yield, together with sulfonamide 2a
1980
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Adv. Synth. Catal. 2011, 353, 1980 – 1984

Cross-Coupling of Grignard Reagents with Sulfonyl-Activated sp3 Carbon-Nitrogen Bonds
Table 1. Optimization of reaction conditions.[a]
Table 2. Cross-coupling of Grignard reagents with sulfonim-
AHCTUNGTRENNUNG
ides.[a]
[a]
Reaction conditions: sulfonimide (0.50 mmol), PhMgBr
(0.60 mmol), catalyst (if any, 5 mol%), THF (1.0 mL).
Isolated yield.
Biphenyl was obtained as the major product in 65%
[b]
[c]
yield.
as a by-product in 7% yield, after the reaction mix-
ture had been heated at 708C for 2 h (Table 1,
entry 2).[11] Prolonging the reaction time did not lead
to a significant increase in the yield owing to more se-
rious side reactions (Table 1, entry 3). To improve the
chemoselectivity for the cleavage of the carbon-nitro-
gen bond rather than the nitrogen-sulfur bond in sul-
fonimide 1a, a broad range of readily accessible metal
salts was examined as catalysts in the reaction and the
yield for diarylmethane 3a was enhanced up to 93%
[a]
Reaction conditions: sulfonimide 1 (0.50 mmol), Grignard
reagent (0.60 mmol), CuI (5 mol%), THF (1.0 mL),
708C, 2 h (for entries 14–23, 1 h).
Isolated yield.
98:2 E/Z.
98:2 E/Z.
5:95 E/Z.
5:95 E/Z.
[b]
[c]
[d]
[e]
[f]
when using 5 mol% of CuI (Table 1, entry 14). It is ly underwent cross-coupling reactions with various
noteworthy that the major reaction pathway was com- Grignard reagents in the presence of 5 mol% of CuI
pletely switched by the presence of PdACTHNUTRGNE(NUG OAc)2 and at 708C to afford products 3 in good to excellent
FeCl3, with which the reaction afforded biphenyl and yields and with extremely high regioselectivity. The
sulfonamide 2a as the major products, respectively R1 group in the sulfonimide could be an aryl group, a
(Table 1, entries 8 and 10). Moreover, replacing the p- heteroaryl group, an alkenyl group, or an alkynyl
toluenesulfonyl group on the amine nitrogen with a group,[12] and the R2 group in the Grignard reagent
methanesulfonyl group or a trifluoromethanesulfonyl could be an aryl group or an alkyl group with differ-
group resulted in the cleavage of the nitrogen-sulfur ent electronic properties and steric demands. More-
bond rather than the desired sp3 carbon-nitrogen over, the cross-coupling reaction tolerated functional
bond (Table 1, entries 15 and 16).
groups such as halides, alkenes, alkynes, benzyl ethers,
As demonstrated by the results summarized in and allyl ethers (Table 2, entries 8–10 and 14–25). It is
Table 2, a broad range of double p-toluenesulfonyl-ac- noteworthy that the geometric configuration of the
tivated primary alkylamines (sulfonimides 1) smooth- carbon-carbon double bond in a sulfonimide was com-
Adv. Synth. Catal. 2011, 353, 1980 – 1984
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1981

Man-Bo Li et al.
COMMUNICATIONS
Table 4. Cross-coupling of Grignard reagents with p-toluene-
sulfonyl-activated a-branched amines.[a]
pletely preserved in the cross-coupling reaction
(Table 2, entries 16–21). Significantly, no rearrange-
ment was observed for the carbon-carbon multiple
bonds in the reaction with double p-toluenesulfonyl-
activated allylic or propargylic amines (Table 2, en-
tries 16–22, 24, and 25).
The copper-catalyzed cross-coupling reaction was
found to occur smoothly between a Grignard reagent
and a single p-toluenesulfonyl-activated secondary al-
lylic or propargylic amine (sulfonamide 4, Table 3). In
contrast, a single sulfonyl-activated benzylic carbon-
nitrogen bond could not be cleaved by a Grignard re-
agent under the same reaction conditions. For exam-
ple, we did not obtain compound 3a at all through the
cleavage of the benzylic sp3 carbon-nitrogen bond in
the reaction of sulfonamide 4a with 4-methoxyphenyl-
magnesium bromide (Table 3, entry 1). Instead, the al-
lylic sp3 carbon-nitrogen bond of sulfonamide 4a was
readily cleaved to afford compound 3o in 63% yield.
Further investigation revealed that p-toluenesulfon-
yl-activated a-branched amines could also serve as
suitable sp3 carbon electrophiles to couple with
Grignard reagents in the presence of 5 mol% of CuI
(Table 4). To prepare chiral hydrocarbons and gain in-
sights into the reaction mechanism, we examined opti-
cally active a-branched amine derivatives in the
cross-coupling reaction. While enantioenriched sulfo-
nimides were subjected to epimerization under the re-
action conditions, no loss of optical purity was detect-
ed for sulfonamides during the reaction. The reaction
of sulfonimide 5e in 99% ee with 4-methoxyphenyl-
[a]
Reaction conditions: amine derivative (0.50 mmol),
Grignard reagent (0.60 mmol), CuI (5 mol%), THF
(1.0 mL), 708C, 2 h.
Isolated yield.
Allylmagnesium chloride was used.
PMPMgBr was used.
PhMgBr was used.
[b]
[c]
[d]
[e]
Table 3. Cross-coupling of Grignard reagents with sulfon-
ACHTUNGTRENNUNG
amides.[a]
magnesium bromide in the presence of 5 mol% of
CuI afforded product 6f in only 44% ee (Table 4,
entry 6). In contrast, the employment of sulfonamide
5f in 95% ee resulted in the formation of product 6g
as a single regioisomer without loss of optical purity
(Table 4, entry 7). Significantly, configurational inver-
sion was observed for the chiral centers of both sulfo-
nimide 5e and sulfonamide 5f. These results allow us
to conclude that an SN2 mechanism is involved in the
copper-catalyzed cross-coupling reaction of Grignard
reagents with sulfonimides or sulfonamides.
In summary, we have developed an unprecedented
cross-coupling reaction of Grignard reagents with sul-
fonyl-activated sp3 carbon-nitrogen bonds. In the pres-
ence of 5 mol% of CuI, a broad range of sulfonyl-acti-
vated benzylic, allylic, and propargylic amines
smoothly undergo cross-coupling reaction with
Grignard reagents to afford structurally diverse cou-
pling products in good to excellent yields and with
high chemo-, regio-, and stereoselectivity. Moreover,
an SN2 mechanism has been demonstrated to be in-
volved in the cross-coupling reaction that allows the
asymmetric synthesis of chiral hydrocarbons from op-
[a]
Reaction conditions: sulfonamide
Grignard reagent (0.60 mmol), CuI (5 mol%), THF
(1.0 mL), 708C, 2 h.
Isolated yield.
PMPMgBr was used.
Me3CMgCl was used.
2-MeC6H4MgCl was used.
4
(0.50 mmol),
[b]
[c]
[d]
[e]
1982
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Adv. Synth. Catal. 2011, 353, 1980 – 1984

Cross-Coupling of Grignard Reagents with Sulfonyl-Activated sp3 Carbon-Nitrogen Bonds
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Experimental Section
General Procedure for the Cross-Coupling of
Grignard Reagents with Sulfonyl-Activated
Alkylamines (Table 2, Table 3, and Table 4)
A mixture of a sulfonyl-activated alkylamine (0.50 mmol),
copper(I) iodide (4.76 mg, 5 mol%), and the corresponding
Grignard reagent (0.60 mmol) in tetrahydrofuran (1.0 mL)
was heated under nitrogen at 708C for 1 h or 2 h. The mix-
ture was cooled to room temperature, ice water (5.0 mL)
was added, and the mixture extracted with ethyl acetate (2ꢂ
20 mL). The combined organic extracts were dried over an-
hydrous magnesium sulfate, and concentrated. The residue
was purified by preparative thin layer chromatography, de-
veloping with petroleum ether, to afford the desired prod-
uct.
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We are grateful for the financial support from the National
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