Stereoretentive Pd-catalysed Stille cross-coupling reactions of secondary alkyl azastannatranes and aryl halides

Article abstract of DOI:10.1038/nchem.1652

The development of transition metal-catalysed cross-coupling reactions has greatly influenced the manner in which the synthesis of complex organic molecules is approached. A wide variety of methods are now available for the formation of C(sp²)-C(sp²) bonds, and more recent work has focused on the use of C(sp³) electrophiles and nucleophiles. The use of secondary and tertiary alkyl nucleophiles in cross-coupling reactions remains a challenge because of the propensity of these alkyl groups to isomerize under the reaction conditions. Here, we report the development of a general Pd-catalysed process for the stereoretentive cross-coupling of secondary alkyl azastannatrane nucleophiles with aryl chlorides, bromides, iodides and triflates. Coupling partners with a wide range of electronic characteristics are well tolerated. The reaction occurs with minimal isomerization of the secondary alkyltin nucleophile, and with retention of absolute configuration. This process constitutes the first general method to use secondary alkyltin reagents in cross-coupling reactions.

Full text of DOI:10.1038/nchem.1652

ARTICLES
PUBLISHED ONLINE: 19 MAY 2013 | DOI: 10.1038/NCHEM.1652
Stereoretentive Pd-catalysed Stille cross-coupling
reactions of secondary alkyl azastannatranes
and aryl halides
Ling Li1,2, Chao-Yuan Wang1,2, Rongcai Huang1,2 and Mark R. Biscoe1,2
*
The development of transition metal-catalysed cross-coupling reactions has greatly influenced the manner in which the
synthesis of complex organic molecules is approached. A wide variety of methods are now available for the formation of
C(sp2)–C(sp2) bonds, and more recent work has focused on the use of C(sp3) electrophiles and nucleophiles. The use of
secondary and tertiary alkyl nucleophiles in cross-coupling reactions remains a challenge because of the propensity of these
alkyl groups to isomerize under the reaction conditions. Here, we report the development of a general Pd-catalysed process
for the stereoretentive cross-coupling of secondary alkyl azastannatrane nucleophiles with aryl chlorides, bromides, iodides
and triflates. Coupling partners with a wide range of electronic characteristics are well tolerated. The reaction occurs with
minimal isomerization of the secondary alkyltin nucleophile, and with retention of absolute configuration. This process
constitutes the first general method to use secondary alkyltin reagents in cross-coupling reactions.
he development of transition metal-catalysed carbon–carbon as the covalency of the carbon–metal bond increases. Additionally,
bond-forming reactions has greatly influenced the manner rapid reductive elimination is still required to circumvent the com-
T
in which we approach the synthesis of complex organic mol- peting b-hydride elimination pathway.
ecules. Although previous studies have largely focused on the gen- Secondary alkyltin and alkylboron nucleophiles may be activated
eration of C(sp2)–C(sp2) bonds, more recently, the use of C(sp3) towards transmetallation and reductive elimination by the inclusion
nucleophiles and electrophiles in metal-catalysed cross-coupling of an sp2-hybridized carbon atom in the a-position to the secondary
reactions has been investigated1. The use of secondary and tertiary alkyl centre20–23. The use of secondary alkyltin24–30 and secondary
main-group organometallic nucleophiles in Pd-catalysed cross- alkylboron31–37 nucleophiles containing C(sp3) a-carbons requires
coupling reactions is particularly challenging because of the propen- remote activation via a coordinating group on the nucleophile in
sity of the alkyl group to isomerize via b-hydride elimination/ order to accelerate transmetallation38 and/or retard the formation
reinsertion sequences (Fig. 1a)2–4. Such side reactions result in the of isomerized products via competitive b-hydride elimination path-
formation of inseparable isomeric products alongside reduced aryl ways. These limitations have prevented the development of a general
products3. The use of electronically or sterically activated electro- method to make use of configurationally stable, optically active
philes can curb the background isomerization reactions by acceler- nucleophiles directly in cross-coupling reactions. Recently devel-
ating reductive elimination in Pd-catalysed reactions5–9. However, oped methods for the Pd-catalysed cross-coupling of activated opti-
the overall utility of a synthetic method decreases dramatically cally active alkylboron and alkyltin nucleophiles with aryl
when it is mainly limited to activated substrates.
electrophiles are shown in Fig. 1c. Because optically active organotin
A major focus of the research in our laboratory is the development and organoboron reagents are stable, storable and can undergo
of new methods for carbon–carbon bond formation via metal-cata- stereospecific transmetallation/reductive elimination, the develop-
lysed cross-coupling reactions using alkyl nucleophiles10–13
.
ment of a general method by which to efficiently employ unacti-
Recently, we reported general Ni-catalysed processes for the cross- vated secondary alkyltin or secondary alkylboron nucleophiles in
coupling of secondary alkylzinc and tertiary alkylmagnesium nucleo- a cross-coupling reaction would potentially alter the paradigm by
philes with aryl electrophiles10–12. These methods largely circumvent which asymmetric synthesis is approached.
the b-hydride elimination/reinsertion sequences that have limited
previous Pd-catalysed systems. To expand the versatility of the Results and discussion
cross-coupling reactions that use secondary alkyl nucleophiles, we Development of
a cross-coupling reaction using racemic
sought to extend the processes to the use of isolable, configurationally secondary alkyl azastannatranes. The use of unactivated
stable, optically active organometallic nucleophiles. The development alkylstannane reagents in cross-coupling reactions is also
of such transformations is impeded by the inverse relationship that complicated by the need for four substituents on the tin centre.
exists between the nucleophilicity and configurational stability of This problem is overcome in traditional Stille cross-coupling
carbon–metal bonds in main-group organometallic nucleophiles reactions by exploiting the enhanced migratory aptitude of C(sp2)
(Fig. 1b)14. Although increased covalency tends to coincide with and C(sp) substituents relative to C(sp3) substituents on tin1,39,40
.
enhanced configurational stability of the carbon–metal bond, it also Alkyl ligands can therefore be used as inert ‘dummy ligands’ in
tends to coincide with reduced nucleophilicity15–19. This trend, in cases where the transfer of aryl, alkenyl or alkynyl substituents is
addition to the inherent bulk of a secondary nucleophile, results in desired. However, in cases where tetraalklylstannanes are used as
the prohibitively slow transmetallation of a secondary nucleophile a nucleophile, only one alkyl group is typically transmetallated. As
1Department of Chemistry, The City College of New York (CCNY), 160 Convent Avenue, New York, New York 10031, USA, 2The Graduate Center of The
City University of New York (CUNY), 365 Fifth Avenue, New York, New York 10016, USA. e-mail: mbiscoe@ccny.cuny.edu
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1652
ARTICLES
a
Ar
LPdIIAr
L-Pd0
R2
ArX
R1
R1
R2
1
3b
Reductive
elimination
Oxidative
addition
b
M =
M =
B > Sn > Zn > Mg > Li
Configurational stability
M
Reinsertion
LPdII(H)Ar
R1
R2
LPdIIAr
β-hydride
elimination
LPdII(X)Ar
B < Sn < Zn < Mg < Li
Nucleophilicity
R2
R1
R2
3a
R1
2
Secondary alkyltin and alkylboron reagents are
configurationally stable and isolable
Dissociation
M
R2
LPdII(H)Ar
Trans-
metallation
R2
R1
MX
R1
c
Hall (2011)
Hoppe (2006)
Pd(OAc)2 (10 mol%)
XPhos (20 mol%)
K2CO3 (3 equiv.)
NiPr2
NiPr2
O
O
BF3K
B(dan)
O
Ar
Ar-Br
O
O
SnBu3
CH3
Pd(PPh3)4 (4 mol%)
DMF, 60–75 ºC
O
Ar
MeO
MeO
B(dan)
Toluene/H2O (10:1), 80 ºC
Ar-Br/I
Ph
Ph
CH3
Falck (2011)
Crudden (2009)
BPin
Ph
Ph
O
Pd2(dba)3 (8 mol%)
PPh3 (1 equiv.)
Ar
Pd(dppe)Cl2 (10 mol%)
THF, 45 ºC
O
O
O
Ar-I
CH3
CH3
tBu
Ar-I
Ag2O (1.5 equiv.)
THF, 70 ºC
Ph
SnBu3
Ph
Ar
Ohmura and Suginome (2010)
tBu
Molander (2012)
OBn
(7.5 mol%)
Pd NH2
Pd(dba)2 (5 mol%)
XPhos (10 mol%)
K2CO3 (3 equiv.)
OBn
Ad2(nBu)P
Cl
Ar-Cl
HN
O
HN
O
Ph
BF3K
Ph
Ar
CsOH•H2O (5 equiv.)
Ar-Br
BPin
H2O (2 equiv.)
Toluene, 80 ºC
Ar
CPME/H2O (1:1), 105 ºC
This work
Pd(dba)2 (5 mol%)
5 (10 mol%)
CuCl (2 equiv.)
KF (2 equiv.)
Molander (2010)
BF3K
N
Pd(OAc)2 (10 mol%)
XPhos (20 mol%)
K2CO3 (3 equiv.)
O
O
Ar
Ar
Sn
Ar–Br
Ar-Br/Cl
R2N
CH3
CH3CN, 60 °C
R2N
CH3
Ph
CH3
CPME/H2O (6.7:1), 95 ºC
Ph
CH3
Figure 1 | Cross-coupling reactions using configurationally stable, optically active secondary alkyl nucleophiles. a, Proposed catalytic cycle for the Pd-
catalysed cross-coupling of secondary nucleophiles and aryl electrophiles. It is necessary for reductive elimination to occur in the absence of the competing
b-hydride elimination pathway to avoid the formation of isomeric by-products. b, Inverse relationship between configurational stability and nucleophilicity in
secondary alkyl organometallic nucleophiles. c, Recent advances in Pd-catalysed cross-coupling reactions between isolable, optically active organometallic
nucleophiles and aryl halides. The groups of Hoppe29, Crudden22, Ohmura and Suginome32, Molander31,37, Hall35 and Falck28 have demonstrated the use of
isolable, optically active organometallic nucleophiles in cross-coupling reactions. However, nucleophiles in these examples require activation via the presence
of a C(sp2) a-carbon, heteroatomic a-carbon and/or a strongly coordinating b-carbonyl group. DMF, dimethylformamide; THF, tetrahydrofuran;
CPME, cyclopentyl methyl ether; dba, dibenzylideneacetone; XPhos, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.
a result, three equivalents of a potentially precious alkyl unit are azastannatrane nucleophiles and aryl electrophiles. This reaction
effectively wasted. Vedejs and colleagues demonstrated an elegant displays little dependence on the electronic characteristics of
solution to this problem, achieving selective alkyl transfer from an either coupling partner, and occurs with minimal concurrent
alkyl-azastannatrane reagent (4)41.
isomerization of the secondary alkyltin nucleophile. Aryl chlorides,
bromides, iodides and triflates are all viable electrophiles in
this process. Furthermore, optically active secondary alkyl
azastannatranes undergo cross-coupling reactions with complete
retention of absolute configuration using this method. This
process constitutes the first general method to use secondary
alkyltin reagents in cross-coupling reactions, and the first cross-
coupling reaction that is conducive to the broad use of isolable
OMe
P
CF3
CF3
MeO
iPr
N
R
Sn
iPr
2
4
JackiePhos (5)
iPr
Internal coordination of the nitrogen atom in the azastannatrane and optically active nucleophiles.
backbone was proposed to selectively labilize the apical alkyl substi-
Using the Pd-catalysed coupling of bromobenzene and s-butyl
tuent towards transmetallation. Although this original work was azastannatrane (6) as a model system, ligand effects were investi-
limited to the use of primary alkyl azastannatranes42,43, we felt gated. Low conversions and a preponderance of rearrangement
that an analogous approach might be used to achieve selective product resulted from the use of most ligands. JackiePhos (5), a
alkyl transfer from secondary alkyl azastannatranes, which might bulky electron-deficient biarylphosphine, emerged as the most
then be expanded to the use of optically active secondary azastanna- promising ligand for this transformation. This commercially
tranes. Here, we report the development of a general Pd-catalysed available ligand was developed by the Buchwald group to
process for the cross-coupling of unactivated secondary alkyl facilitate the rate-limiting transmetallation of secondary amides in
2
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Table 1 | Pd-catalysed cross-coupling reactions using s-butyl azastannatrane (6) and aryl/heteroaryl electrophiles.
H3C
Pd(dba)2 (5 mol%)
5 (6–10 mol%)
CuCl (2 equiv.)
KF (2 equiv.)
H3C
X
CH3
Sn
N
CH3
R
CH3CN, 60 ºC
R
X = Br, Cl
6 (1.1–1.5 equiv.)
7
(1.0 equiv.)
Entry
X
Product
Yield* (%)
s-Bu:n-Bu§
Entry
X
Product
Yield* (%)
s-Bu:n-Bu§
.50:1
sBu
sBu
sBu
sBu
1
Br
86
.50:1
9
Cl
79
EtO2C
NC
7j
7b
7c
7d
sBu
O
2
3
Br
Br
77
62
.50:1
10
11
Br
Br
82
67
.50:1
.50:1
O
Me
MeO
7k
H
N
37:1
O
sBu
Me2N
O
7l
sBu
O
4
Br
67
.50:1
12
13
Br
Br
45
66
26:1
49:1
sBu
H
S
7e
7m
sBu
Me
5
6
Br
Br
77
74
.50:1
N
sBu
sBu
Me
7n
7f
sBu
Me
29:1
14
15
Br
Br
86
56
.50:1
.50:1
Me
N
Me
7o
7g
7h
7i
F3CO
sBu
MeO
N
sBu
7
8
Br
Cl
73
94
.50:1
.50:1
7p
sBu
O2N
Reaction conditions: aryl halide (1 mmol), 6 (1.1–1.5 mmol), CuCl (2 mmol), KF (2 mmol), Pd(dba)2 (0.05 mmol), 5 (0.06–0.10 mmol), CH3CN (3 ml).
*Average isolated yield of two runs.
§Ratio of retention product (s-Bu) to isomerization product (n-Bu) determined by gas chromatography.
Pd-catalysed amidation reactions of aryl halides44. The efficacy of 5 Scope of Pd-catalysed cross-coupling reactions using racemic
as a supporting ligand in the cross-coupling of secondary alkyl alkyl azastannatranes. To evaluate the substrate scope
azastannatranes may similarly result from the propensity of 5 to accommodated in this reaction, we used 6 in cross-coupling
facilitate transmetallation of the secondary alkyl group while reactions with a series of aryl and heteroaryl electrophiles (Table 1;
still promoting rapid reductive elimination. Systematic reaction Supplementary Information). In general, cross-coupling products
optimizations revealed that the cross-coupling reaction proceeded were obtained with ratios of retention to isomerization greater than
most efficiently at 60 8C in acetonitrile and in the presence of 50:1. A nominal dependence on the electronic properties of the aryl
CuCl and KF45.
bromide electrophile was observed. Electron-rich, electron-neutral
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1652
ARTICLES
successful cross-coupling reactions. The presence of an ortho-
substituent was also well-tolerated. Importantly, heteroaromatic
electrophiles could be broadly used without significant isomerization
of the secondary alkyl nucleophile. Electron-deficient aryl chloride
electrophiles also underwent efficient cross-coupling reactions under
these conditions. All these reactions were performed on the
benchtop, without the need for an inert-atmosphere glovebox.
Inductively coupled plasma mass spectrometry analysis of a sample
prepared using this cross-coupling procedure showed the presence
of only 30 mg g21 trace tin.
R1
R2
R1
R2
THF or DMA
N
N
M
Sn Cl
Sn
(M = Li, MgX, ZnX)
• Up to 98% yield
• Air-stable
• Moisture-stable
4b
Figure 2 | Preparation of alkyl azastannatrane derivatives. Stable and easily
handled alkyl azastannatrane reagents can be prepared by reaction of a
variety of organometallic nucleophiles with the azastannatrane chloride.
THF, tetrahydrofuran; DMA, dimethylacetamide.
To demonstrate the general application of secondary azastannatrane
nucleophiles in Pd-catalysed reactions, we used a variety of secondary
azastannatranes. These substrates were readily generated from 4b using
and electron-deficient aryl bromides all reacted to give high yields of a modified version of the procedure developed by Vedejs (Fig. 2). The
product. Aryl bromides bearing electrophilic functional groups such judicious choice of solvent allowed secondary lithium, magnesium
as aldehydes, ketones, esters, amides and nitriles underwent halide and zinc halide nucleophiles to be used as precursors to the
Table 2 | Pd-catalysed cross-coupling reactions using secondary alkyl azastannatrane (8) and aryl/heteroaryl electrophiles.
R1
Pd(dba)2 (5 mol%)
X
5 (6–10 mol%)
CuCl (2 equiv.)
KF (2 equiv.)
R1
R2
R2
Sn
N
R
R
CH3CN, 60 ºC
X = Br, I, or OTf
(1.0 equiv.)
8 (1.1–2.0 equiv.)
9
Entry
X
Product
Yield* (%)
Ret:Iso§
Entry
X
Product
Yield* (%)
Ret:lso§
Me
Me
1
Br
71
85
79
26:1
7
8
9
OTf
88
.50:1
Me
Me
N
S
9h
9b
Me
O
2
3
Br
Br
.50:1
.50:1
I
63
84
.50:1
.50:1
O
Me
N
O
Me
H
9i
9c
Me
O
Me
Br
Me
OEt
N
9d
Me
9j
Et
H2N
N
Me
Me
4
Br
95
42:1
10
Br
Br
26
63
.50:1
.50:1
Pent
S
Me
N
9k
9e
Me
Boc
5
6
Br
Br
87
76
.50:1
.50:1
11
N
NC
O2N
9l
9f
NMe
EtO2C
9g
Reaction conditions: aryl halide (0.5 mmol), 6 (0.55–1.0 mmol), CuCl (1 mmol), KF (1 mmol), Pd(dba)2 (0.025 mmol), 5 (0.03–0.05 mmol), CH3CN (3 mL).
*Average isolated yield of two runs.
§Ratio of retention product to isomerization product determined by gas chromatography.
4
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1652
ARTICLES
secondary azastannatrane reagents. All alkyl azastannatranes were air-
and moisture-stable and were prepared in excellent yield. We success-
fully employed secondary alkyl groups bearing ethers, amines, esters
and amides (Table 2). Secondary benzylic nucleophiles and bis-a-
substituted nucleophiles underwent efficient cross-coupling reactions.
During these studies, we also demonstrated that the use of aryl triflates
and aryl iodides can be tolerated in these reactions. Therefore, this
cross-coupling reaction appears to be highly general with respect to
the nucleophile and electrophile employed.
Pd(dba)2 (5 mol%)
5 (10 mol%)
CuCl (2 equiv.)
KF (2 equiv.)
N
Ar
Sn
CH3
Ar–Br
CH3CN, 60 °C
CH3
12, 94% e.e.
13b Ar =
65% (91% e.e.)
N
13c Ar =
65% (92% e.e.)
Stereospecificity of cross-coupling reactions using optically active
alkylstannatranes. In the field of drug discovery, it is particularly
important that non-racemic molecules can be readily and reliably
generated for evaluation as potential therapeutic agents. With this in
mind, we evaluated the ability of non-racemic alkyl azastannatrane
derivatives to undergo a stereospecific cross-coupling reaction without
erosion of the original enantiomeric excess (e.e.). Using the
N
CH3
Figure 4 | Pd-catalysed cross-coupling reactions using unactivated,
optically active secondary alkyl azastannatrane 12. Cross-coupling can be
achieved without significant loss of enantiopurity, even without the
potentially stabilizing effect of an a-heteroatom.
asymmetric lithiation procedure described by Beak and colleagues46,47
,
we prepared and isolated optically active 2-stannylpyrrolidine an optically active secondary alkylstannatrane not containing an
derivative 10 with 93% e.e. (Fig. 3a). The enantiomers of racemic 10 a-heteroatom or a carbonyl coordinating group (12) via preparatory
have also been successfully separated using preparatory chiral chiral HPLC. Because heterocyclic electrophiles are generally difficult
high-performance liquid chromatography (HPLC). Under ambient to cross-couple, we specifically choose 2-bromopyridine and
conditions, 10 appears to exhibit configurational stability indefinitely. 6-bromo-2-methylquinoline as the electrophilic components in
When enantiopure 10 was used in a cross-coupling reaction with these reactions. When enantioenriched 12 was used in the cross-coup-
4-bromo benzonitrile, only nominal erosion of enantiomeric excess ling reactions, minimal erosion of enantiomeric excess was observed
was observed in cross-coupling product 9l (Fig. 3b). To determine the (Fig. 4). This suggests that our process is indeed general and does
absolute stereochemistry of the product, we obtained an X-ray crystal not require the use of an activated secondary alkyl nucleophile.
structure of a derivative of 9l containing a heavy atom (11) (Fig. 3c).
In conclusion, we have developed the first general stereoretentive
Because it has been well-established that Beak’s (–)-sparteine- method to use secondary alkylstannane nucleophiles in cross-coup-
mediated asymmetric lithiation of pyrrolidine selectively abstracts the ling reactions. Using an azastannatrane backbone, secondary alkyl
pro-S hydrogen of prochiral C-1, the X-ray structure confirms that groups underwent transmetallation to palladium with excellent fide-
transmetallation occurs with complete retention of stereochemistry.
lity, independent of the electronic properties of the alkyl nucleo-
It has been shown that the presence of a-heteroatoms and carbonyl phile. Only nominal isomerization of the secondary alkyl
coordinating groups can activate alkyltin and alkylboron reagents nucleophile was observed using this method. Aryl chloride, bro-
towards stereospecific cross-coupling reactions23–35,37. Therefore, it is mides, iodides and triflates could be efficiently used as the electro-
conceivable that the successful transfer of stereochemical information philic component of these cross-coupling reactions. Furthermore,
in 10 arises as a result of similar activation. To demonstrate that our retention of configuration was observed when an optically active
stereospecific cross-coupling method can be used in a general secondary alkyl azastannatrane was used. The benchtop stability
manner for unactivated secondary alkyl nucleophiles, we prepared of optically active alkyl azastannatrane reagents, coupled with the
ease by which stereochemical information may be transferred via
a
1. s-BuLi,
(–)-sparteine, –78 ºC
2. 4b, –40 ºC
Pd-catalysed cross-coupling reactions, should enable our process
to be broadly applied in organic syntheses, particularly in the prep-
aration of libraries of optically active drug candidates. Use of this
N
N
Boc
Sn
N
Boc
method in such applications will be facilitated by the development
of new methods for the generation of optically active alkyl azastan-
natranes. We are currently exploring the use of asymmetric catalysis
for the production of enantioenriched alkyl azastannatranes.
10, 93% e.e.
(99% e.e. via preparatory HPLC of racemate)
b
c
Pd(dba)2 (5 mol%)
5 (10 mol%)
NC
Methods
N
General procedure for cross-coupling reactions using secondary alkyl
azastannatranes. Pd(dba)2 (29 mg, 0.05 mmol), JackiePhos (80 mg, 0.10 mmol),
CuCl (200 mg, 2 mmol) and KF (116 mg, 2 mmol) were weighed out on the benchtop
then transferred to an oven-dried Schlenk tube with stir bar. With stirring, the Schlenk
tube was evacuated (50 mtorr) and backfilled with argon. This process was repeated
three times. Azastannatrane (1.5 mmol) and aryl halide/triflate (1 mmol) were then
added to the Schlenk tube via microsyringe, followed by degassed CH3CN (3 ml). If the
aryl halide/triflate or tin reagent were a solid, it was weighed on the benchtop alongside
the other solids. The Schlenk tube was sealed with a Teflon stopper and heated to 60 8C
for 18 h (unoptimized reaction time). The reaction mixture was cooled to room
temperature and diluted with ether. The organic layer was washed sequentially with
saturated aqueous KF and brine, and then dried over Na2SO4. The dried organic layer
was filtered, concentrated, and purified by column chromatography on silica gel.
10
Boc
CuCl (2 equiv.)
KF (2 equiv.)
CH3CN, 60 °C
CN
99% e.e.
Br
9l, 96% e.e.
(Retention of configuration)
N
CN
O
Br
11
11
X-ray crystallography data. CCDC 928782 contains the crystallographic data for
compound 11. These data can be obtained free of charge from the Cambridge
Cyrstallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Figure 3 | Investigation of the stereorentention of transmetallation.
a, Preparation of enantioenriched 10. b, Transfer of stereochemistry in cross-
coupling reaction using 10. c, X-ray crystal structure of 11 (thermal ellipsoids
at 50% probability).
Received 24 January 2013; accepted 11 April 2013;
published online 19 May 2013
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1652
ARTICLES
30. Lange, H., Fro¨hlich, R. & Hoppe, D. Cu(I)-catalyzed stereospecific coupling
reactions of enantioenriched a-stannylated benzyl carbamates and their
application. Tetrahedron 64, 9123–9135 (2008).
31. Sandrock, D. L., Jean-Gerard, L., Chen, C-Y., Dreher, S. D. & Molander, G. A.
Stereospecific cross-coupling of secondary alkyl b-trifluoroboraroamides. J. Am.
Chem. Soc. 132, 17108–17110 (2010).
32. Ohmura, T., Awano, T. & Suginome, M. Stereospecific Suzuki–Miyaura coupling
of chiral a-(acylamino)benzylboronic esters with inversion of configuration.
J. Am. Chem. Soc. 132, 13191–13193 (2010).
33. Daini, M. & Suginome, M. Palladium-catalyzed, stereoselective, cyclizative
alkenylboration of carbon–carbon double bonds through activation of a boron–
chlorine bond. J. Am. Chem. Soc. 133, 4758–4761 (2011).
34. Awano, T., Ohmura, T. & Suginome, M. Inversion or retention? Effects of acidic
additives on the stereochemical course in enantiospecific Suzuki–Miyaura
coupling of a-(acetylamino)benzylboronic esters. J. Am. Chem. Soc. 133,
20738–20741 (2011).
35. Lee, J. C. H., McDonald, R. & Hall, D. G. Enantioselective preparation and
chemoselective cross-coupling of 1,1-diboron compounds. Nature Chem. 3,
894–899 (2011).
36. Partridge, B. M., Chausset-Boissarie, L., Burns, M., Pulis, A. P. & Aggarwal, V. K.
Enantioselective synthesis and cross-coupling of tertiary propargylic boronic
esters using lithiation–borylation of propargylalic carbamates. Angew. Chem. Int.
Ed. 51, 11795–11799 (2012).
37. Molander, G. A. & Wisniewski, S. R. Stereospecific cross-coupling of secondary
organotrifluoroborates: potassium 1-(benzyloxy)alkyltrifluoroborates. J. Am.
Chem. Soc. 134, 16856–16868 (2012).
38. Itami, K., Kamei, T. & Yoshida, J. Unusually accelerated silylmethyl transfer
from tin in Stille coupling: implication of coordination-driven transmetalation
J. Am. Chem. Soc. 123, 8773–8779 (2001).
39. Littke, A. F. & Fu, G. C. The first general method for Stille cross-coupling of aryl
chlorides. Angew. Chem. Int. Ed. 38, 2411–2413 (1999).
40. Labadie, J. W. & Stille, J. K. Mechanisms of the palladium-catalyzed couplings
of acid chlorides with organotin reagents. J. Am. Chem. Soc. 105,
6129–6137 (1983).
41. Vedejs, E., Haight, A. R. & Moss, W. O. Internal coordination at tin promotes
selective alkyl transfer in the Stille coupling reaction. J. Am. Chem. Soc. 114,
6556–6558 (1992).
42. Jensen, M. S. et al. Anti-methicillin-resistant Staphylococcus aureus (MRSA)
carbapenem via stannatrane-mediated Stille coupling. Org. Lett. 2,
1081–1084 (2000).
43. Sebehar, H. L., Yoshida, K. & Hegedus, L. S. Effect of adjacent chiral tertiary and
quaternary centers on the metal-catalyzed allylic substitution reaction. J. Org.
Chem. 67, 3788–3795 (2002).
44. Hicks, J. D., Hyde, A. M., Cuezva, A. M. & Buchwald, S. L. Pd-catalyzed
N-arylation of secondary acyclic amides: catalyst development, scope, and
computational study. J. Am. Chem. Soc. 131, 16720–16734 (2009).
45. Mee, S. P. H., Lee, V. & Baldwin, J. E. Stille coupling made easier—the synergistic
effect of copper(I) salts and the fluoride ion. Angew. Chem. Int. Ed. 43,
1132–1136 (2004).
46. Beak, P., Kerrick, S. T., Wu, S. & Chu, J. Complex induced proximity effects:
enantioselective syntheses based on asymmetric deprotonations of N-boc-
pyrrolidines. J. Am. Chem. Soc. 116, 3231–3239 (1994).
References
1. De Meijere, A. & Diederich, F. (eds) Metal-Catalysed Cross-Coupling Reactions
(Wiley-VCH, 2004).
2. Netherton, M. R. & Fu, G. C. in Topics in Organometallic Chemistry: Palladium
in Organic Synthesis (ed. Tsuji, J.) 85–108 (Springer, 2005).
3. Rudolph, A. & Lautens, M. Secondary alkyl halides in transition metal-catalyzed
cross-coupling reactions. Angew. Chem. Int. Ed. 48, 2656–2670 (2009).
4. Chemler, S. R., Trauner, D. & Danishefsky, S. J. The b-alkyl Suzuki–Miyaura
cross-coupling reaction: development, mechanistic study, and applications in
natural product synthesis. Angew. Chem. Int. Ed. 40, 4544–4568 (2001).
5. Luo, X. et al. Superior effect of a p-acceptor ligand (phosphine-electron-
deficient olefin ligand) in the Negishi coupling involving alkylzinc reagents. Org.
Lett. 9, 4571–4574 (2007).
6. Dreher, S. D., Dormer, P. G., Sandrock, D. L. & Molander, G. A. Efficient cross-
coupling of secondary alkyltrifluoroborates with aryl chlorides—reaction discovery
using parallel microscale experimentation. J. Am. Chem. Soc. 130, 9257–9259 (2008).
7. Han, C. & Buchwald, S. L. Negishi coupling of secondary alkylzinc halides with
aryl bromides and chlorides. J. Am. Chem. Soc. 131, 7532–7533 (2009).
8. Nakao, Y., Takeda, M., Matsumoto, T. & Hiyama, T. Cross-coupling reactions
through the intramolecular activation of alkyl(triorgano)silanes. Angew. Chem.
Int. Ed. 45, 4447–4450 (2010).
9. Calimsiz, S. & Organ, M. G. Negishi cross-coupling of secondary alkylzinc
halides with aryl/heteroaryl halides using Pd–PEPPSI–IPent. Chem. Commun.
47, 5181–5183 (2011).
10. Joshi-Pangu, A., Ganesh, M. & Biscoe, M. R. Nickel-catalyzed Negishi cross-
coupling reactions of secondary alkylzinc halides and aryl iodides. Org. Lett. 13,
1218–1221 (2011).
11. Joshi-Pangu, A., Wang, C-Y. & Biscoe, M. R. Nickel-catalyzed Kumada cross-
coupling reactions of tertiary alkylmagnesium halides and aryl
bromides/triflates. J. Am Chem. Soc. 133, 8478–8481 (2011).
12. Joshi-Pangu, A. & Biscoe, M. R. The use of tertiary alkyl nucleophiles in metal-
catalyzed cross-coupling reactions. Synlett 23, 1103–1107 (2012).
13. Joshi-Pangu, A. et al. Palladium-catalyzed borylation of primary alkyl bromides.
J. Org. Chem. 77, 6629–6633 (2012).
14. Boudier, A., Bromm, L. O., Lotz, M. & Knochel, P. New applications of
polyfunctional organometallic compounds in organic synthesis. Angew. Chem.
Int. Ed. 39, 4414–4435 (2000).
15. Hoffman, R. W., Ho¨lzer, B., Knopff, O. & Harms, K. Asymmetric synthesis of a
chiral secondary Grignard reagent. Angew. Chem. Int. Ed. 39, 3072–3074 (2000).
16. Ho¨lzer, B. & Hoffman, R. W. Kumada–Corriu coupling of Grignard reagents,
probed with a chiral Grignard reagent. Chem. Commun. 732–733 (2003).
17. Boudier, A., Darcel, C., Flachsman, F., Micouin, L., Oestreich, M. & Knochel, P.
Stereoselective preparation and reactions of configurationally defined dialkylzinc
compounds. Chem. Eur. J. 6, 2748–2761 (2000).
18. Campos, K. R., Klapars, A., Waldman, J. H., Dormer, P. G. & Chen, C-Y.
Enantioselective, palladium-catalyzed a-arylation of N-boc-pyrrolidine. J. Am.
Chem. Soc. 128, 3538–3539 (2006).
19. Thaler, T. et al. Highly diastereoselective Csp3–Csp2 Negishi cross-coupling with
1,2-, 1,3- and 1,4-substituted cycloalkylzinc compound. Nature Chem. 2,
125–130 (2010).
20. Denmark, S. E. & Werner, N. S. On the stereochemical course of palladium-
catalyzed cross-coupling of allylic silanolate salts with aromatic bromides. J. Am.
Chem. Soc. 132, 3612–3620 (2010).
21. Ridgway, B. H. & Woerpel, K. A. Transmetalation of alkylboranes to palladium
in the Suzuki coupling reaction proceeds with retention of stereochemistry.
J. Org. Chem. 63, 458–460 (1998).
47. Beak, P., Basu, A., Gallagher, D. J., Park, Y. S. & Thayumanavan, S.
Regioselective, diastereoselective, and enantioselective lithiation–substitution
sequences: reaction pathways and synthetic applications. Acc. Chem. Res. 29,
552–560 (1996).
22. Imao, D., Glasspoole, B. W., Laberge, V. S. & Crudden, C. M. Cross coupling
reactions of chiral secondary organoboronic esters with retention of
configuration. J. Am. Chem. Soc. 131, 5024–5025 (2009).
23. Kells, K. W. & Chong, J. M. Stille coupling of stereochemically defined
a-sulfonamidoorganostannanes. J. Am. Chem. Soc. 126, 15666–15667 (2004).
24. Ye, J., Bhatt, R. K. & Falck, J. R. Stereospecifc palladium/copper cocatalyzed
cross-coupling of a-alkoxy- and a-aminostannanes with acyl chlorides. J. Am.
Chem. Soc. 116, 1–5 (1994).
25. Falck, J. R., Bhatt, R. K. & Ye, J. Tin–copper transmetalation: cross-coupling of
a-heteroatom-substituted alkyltributylstannanes with organohalides. J. Am.
Chem. Soc. 117, 5973–5982 (1995).
26. Mohapatra, S., Bandyopadhyay, A., Barma, D. K., Capdevila, J. H. & Falck, J. R.
Chiral a, b-dialkoxy- and a-alkoxy-b-aminostannanes: preparation and copper-
mediated cross-coupling. Org. Lett. 5, 4759–4762 (2003).
Acknowledgements
The authors acknowledge the National Institutes of Health (5SC2GM096932), the City
College of New York (CCNY), the Alfred P. Sloan Foundation and PSC-CUNY for financial
support. The authors also acknowledge the National Science Foundation for an
instrumentation grant (CHE-0840498). The donors of the American Chemical Society
Petroleum Research Fund (50307-DNI1) are thanked for partial support of this research.
The authors thank Chunhua Hu for assistance with the X-ray analysis and acknowledge the
Molecular Design Institute of NYU for purchase of the single-crystal diffractometer.
The authors thank J. Norton for donation of a sample of (–)-sparteine.
Author contributions
L.L. and C-Y.W. performed the experiments and isolated all products. R.H. performed
initial exploratory reactions. M.R.B. directed the project and wrote the manuscript.
27. Falck, J. R., Patel, P. K. & Bandyopadhyay, A. Stereospecific cross-coupling of
a-(thiocarbamoyl)organostannanes with alkenyl, aryl, and heteroaryl iodides.
J. Am. Chem. Soc. 129, 790–793 (2007).
Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Correspondence and requests for materials should be addressed
to M.R.B.
28. Goli, M., He, A. & Falck, J. R. Pd-catalyzed cross-coupling of alpha-(acyloxy)-tri-
n-butylstannanes with alkenyl, aryl, and heteroaryl electrophiles. Org. Lett. 13,
344–346 (2011).
29. Kalkofen, R. & Hoppe, D. First example of an enantiospecific sp3–sp2 Stille
coupling of a chiral allylstannane with aryl halides. Synlett 2006,
1959–1961 (2006).
Competing financial interests
The authors declare no competing financial interests.
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