Generation of quaternary centers by reductive cross-coupling: Shifting of regioselectivity in a subset of allylic alcohol-based coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2010.11.059

Regioselective titanium alkoxide-mediated reductive cross-coupling reactions of allylic alcohols with vinylsilanes and imines have previously been demonstrated to proceed with allylic transposition by formal metallo-[3,3]-rearrangement [thought to proceed

Full text of DOI:10.1016/j.tetlet.2010.11.059

Tetrahedron Letters 52 (2011) 2144–2147
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Generation of quaternary centers by reductive cross-coupling: shifting
of regioselectivity in a subset of allylic alcohol-based coupling reactions
Dexi Yang a, Justin K. Belardi b, Glenn C. Micalizio a,
⇑
a Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, United States
b Department of Chemistry, Yale University, New Haven, CT 06520, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 18 November 2010
Regioselective titanium alkoxide-mediated reductive cross-coupling reactions of allylic alcohols with
vinylsilanes and imines have previously been demonstrated to proceed with allylic transposition by for-
mal metallo-[3,3]-rearrangement [thought to proceed by a sequence of: (1) directed carbometalation,
and (2) syn-elimination]. While many examples have been described that support this reaction path, a
collection of substrates have recently been identified that react by way of an alternative pathway, deliv-
ering a concise convergent route to coupled products bearing a quaternary center.
I hope that you enjoy this special issue of
Tetrahedron Letters in honour of your
contributions and service. Happy 90th
birthday, Harry!
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Stereoselective synthesis
Reductive cross-coupling
Allylic alcohol
Titanium alkoxide
Quaternary center
Reductive cross-coupling is emerging as a powerful strategy for
bimolecular C–C bond formation.1 Within this broad class of chem-
ical reactions, metallacycle-mediated union of allylic alcohols with
alkynes, vinylsilanes, and imines, defines a suite of transformations
that provide convergent stereoselective access to a variety of struc-
tural motifs not readily achieved by other convergent methods in
organic/organometallic chemistry.2 As depicted in Figure 1A, inter-
molecular C–C bond formation is accomplished in concert with the
stereoselective generation of isolated (Z)-trisubstituted alkenes,
stereodefined 1,4-dienes, and complex homoallylic amines through
processes that afford C–C bond formation at the sp2 carbon located
distal to the allylic alcohol. Overall, these coupling reactions pro-
ceed with allylic transposition, deliver products containing stereo-
defined di- or trisubstituted alkenes, and can be performed in an
enantioselective manner with transfer of stereochemical informa-
tion from the allylic alcohol starting material to the functionalized
product.3 Herein, we describe recent observations in a subset of
these coupling reactions where subtle changes in substrate struc-
ture result in a change in the regiochemical course of carbometala-
tion. In short, these observations have culminated in the
identification of reductive cross-coupling reactions of utility for
A. Previously reported: Reductive cross-coupling of allylic alcohols
with vinylsilanes, alkynes and imines:
OH
R1
Ti(Oi-Pr)4, RMgX
TMS
+
R1
TMS
reductive cross-coupling*
R2
R2
Z:E ≥ 20:1
R2
R4
R3
OH R2
as above*
+
R1
R4
R1
R3
E:Z up to ≥ 20:1
R4
R4
H
HN
OH R2
as above*
N
R1
+
R3
R1
96% ee
* = in some cases ClTi(Oi-Pr)3 is used in place of Ti(Oi-Pr)4.
R3
R2
dr ≥ 20:1; E:Z ≥ 20:1
≥ 95% ee
B. Described here: Reductive cross-coupling for the generation of
quaternary centers:
R4
R3
R4
H
OH
X
OH
Ti(Oi-Pr)4
RMgX
X
R1
+
*
R1
*
*
R3
R2 Me
R2
site of C–C bond formation
⇑
Corresponding author.
E-mail address: micalizio@scripps.edu (G.C. Micalizio).
Figure 1. Reductive cross-coupling reactions of allylic alcohols.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.059

D. Yang et al. / Tetrahedron Letters 52 (2011) 2144–2147
A. Reductive cross-coupling by directed carbometalation–syn-elimination:
2145
SiMe2Cl
R3
R4
X
R3
R1
OH
OH
OH
R4
previously
described
present
(Oi-Pr)n
OH R2
R3
Ti(Oi-Pr)4, RMgX
X
R1
R1
Ti
observations
O
R3
R2 Me
R2
R2
R1
R1
then add allylic
alkoxide
R2
H
2
when R1 = aryl or alkenyl
OH
1
R2
R1
A shift in regioselection with benzylic alcohols:
O
(i-PrO)n
syn-elimination
(protic quench)
directed
Ti
H
R4
TMS
X
R4
R1
X
carbometalation
H
Me Me
ClTi(Oi-Pr)3
R3
4
OH
13
c-C5H9MgCl, Et2O
R3
R2
+
(1)
+
TMS
3
then 1N HCl
87%
Me
TMS
B. Hoveyda's carbomagnesiation:
(13:14 = 1:1)
11
15
12
12
Cp2ZrCl2 (5 mol%)
EtMgCl (3-4 eq)
OR2
7
OR2
8
Me
OH
OH
OR2
14
+
R1
R1
R1
rt
OH
OH
as above
49%
then O2, 0 °C
5; R2 = H
Me
Me
(2)
F
F
F
F
TMS
+
+
6; R2 = alkyl
Me Me
Me
proposed to occur via:
F
F
16
OR2
OR2
Cp
EtMgCl
R2 = H; dr (7:8) from 1:1 to 95:5
OH
OH
as above
48%
R1
MgCl
R1
Zr
R2 = alkyl; dr (7:8) from 1:2 to 1:99
(3) F3C
F3C
TMS
TMS
12
12
H
Cp
Me Me
Me
10
Me
9
CF3
17
CF3
18
OH
Figure 2. Reductive cross-coupling of allylic alcohols/ethers: regioselection.
OH
as above
48%
+
(4)
Me Me
20
Me
MeO
MeO
MeO
the generation of quaternary carbon centers (Fig. 1B). Due to the
relative scarcity of intermolecular reactions suitable for the estab-
lishment of quaternary centers, and the well-accepted difficulties
associated with their synthesis,4 these initial findings are of consid-
erable interest, pointing to a new bimolecular class of reactions
capable of forging these highly congested C–C bonds.
19
Access to 1,4-diols containing a quaternary carbon:
i) ClTi(Oi-Pr)3
c-C5H9MgCl, Et2O
OH
OH
then 1N HCl
(5)
MeO
OH
+
SiMe2Cl
ii) t-BuOOH, CsOH•H2O
TBAF, DMF
Me Me
Me
Our study of metallacycle-mediated reductive cross-coupling
reactions of substituted allylic alcohols with alkynes,2a vinylsil-
anes,2b and imines2c–f has defined a collection of novel stereoselec-
tive synthetic methods. Initial observations in this area pointed to
a general and reproducible pattern of reactivity, where C–C bond
formation occurs with allylic transposition. These observations
were consistent with the proposition of a reaction pathway com-
posed of: (1) directed carbometalation, and (2) syn-elimination
(Fig. 2A). While regioselective reactions of this ilk had previously
been described, they were uniformly of limited synthetic utility,
as bimolecular C–C bond formation was demonstrated to result
in mixtures of alkene isomers.5 Our studies, focused on the use
of a titanium alkoxide as the central metal component and an
allylic alkoxide as the reactive allylic system, led to highly stereo-
selective coupling reactions that likely derive from a distinct and
highly organized boat-like transition state for regioselective
directed carbometalation (2 ? 3), and a conserved mechanistic
pathway for syn-elimination (3 ? 4). Our early investigations have
led to the identification of stereoselective reactions for the prepa-
ration of products bearing either an (E)-disubstituted, or (Z)-trisub-
stituted alkene, whereby C–C bond formation occurs distal to the
allylic alcohol.
49%
MeO
21
MeO
22
23
Me OH
Me OH
as above
59%
+
22
OH
(6)
Me
Me
Me Me
Me
24
25
Regioselection appears sensitive to substrate substitution
Me
i) ClTi(Oi-Pr)3
Et
c-C5H9MgCl, Et2O
Me
Me
Me OH
then 1N HCl
+
22
(7)
OH
OH
27
Me
ii) t-BuOOH, CsOH•H2O
TBAF, DMF
Me OH
Et
73%
26
Et Me
28
not observed
Figure 3. Access to quaternary centers by allylic alcohol–vinylsilane reductive
cross-coupling
pattern of the products from this process were similar to those
anticipated from Claisen rearrangement, but possessed a stereo-
chemistry not easily attained with this classic sigmatropic rear-
rangement.2b In subsequent studies of this transformation, we
observed an unprecedented shift in regioselection, and accompa-
nying mechanistic course of this subset of metallacycle-mediated
cross-coupling reaction.
As depicted in Eq. 1 of Figure 3, reductive cross-coupling of
allylic alcohol 11 with vinyltrimethylsilane proceeds in 87% yield,
but delivers a mixture of regioisomeric products 13 and 14. While
this cross-coupling reaction did not proceed in a regioselective
manner, the differences in polarity associated with these two
products made purification of product 13 trivial. As illustrated in
Interestingly, related studies in Zr-catalyzed carbomagnesiation
by Hoveyda, define coupling processes that proceed by a unique
regioselective path, where C–C bond formation occurs
a- to the
allylic alcohol, and delivers saturated products (7 and 8) by way
of metallacycle 9 (Fig. 2B).6 While being described over 15 years
ago, this regio- and stereoselective intermolecular carbomagnesia-
tion has, to our knowledge, not been demonstrated to be useful for
the establishment of quaternary centers.7
Initial study of allylic alcohol–vinylsilane reductive cross-
coupling resulted in the elucidation of a useful reaction for the
preparation of (Z)-trisubstituted olefins. In fact, the substitution

2146
D. Yang et al. / Tetrahedron Letters 52 (2011) 2144–2147
Eqs. 2–4, related substrates 15, 17, and 19 could also be converted
to products containing a quaternary center (16, 18, 20) in ca. 50%
yield. Aiming to define a synthetically more useful coupling reac-
tion, 1,4-diols could be prepared from a related reaction of allylic
alcohol 21 with chlorodimethylvinyl silane 22. Here, reductive
cross-coupling was followed by oxidation of the C–Si bond to deli-
ver diol 23 in 49% yield (over two-steps).
R4
H
R4
H
N
N
R4
R3
R3
R3
R4
R3
R2 HN
OH
OH HN
previously
present
*
R1
R1
*
*
described
observations
R2 Me
R1
R2
when R1 = H, aryl, vinyl, or alkyl;
R2 = Me, Et, Cl, Br, I
Coupling reactions that proceed by allylic transposition:
While these observations marked a dramatic shift in regioselec-
tion for reductive cross-coupling reactions of benzylic alcohols,
similar results were obtained for the coupling of the 1,4-diene-
3-ol substrate 24 with 22. After the two-step process of cross-
coupling and oxidation, the 1,4-diol 25 was isolated in 59% yield.
Next, we aimed to realize a version of this coupling reaction
that would be suitable for generating a stereodefined quaternary
center. As depicted in Eq. 7 of Figure 3, these efforts targeted the
coupling of substrate 26 with 22. While the only difference in sub-
strate structure of 26 with respect to substrate 24 was the substi-
tution of a Me- group for an Et-substituent, this coupling reaction
of 26 with 22 delivered diene 27 in 73% yield; no evidence was
found for the production of 28. Overall, this result indicated that
the regioselection associated with coupling reactions of benzylic-
and allylic- alcohols is quite sensitive to subtle perturbation of sub-
strate structure.
In the related coupling reactions of allylic alcohols with imines,
a similar change in regioselection was not observed. As shown in
Eq. 8 of Figure 4, coupling of the benzylic alcohol 11 with imine
29 proceeds in 87% yield, and delivers the homoallylic amine prod-
uct 30. Unlike the coupling reaction of 11 with a vinylsilane, no
evidence could be found for the formation of a product containing
a quaternary center. Similarly, the coupling of allylic alcohol 26
with 29 also delivered homoallylic amine products (Eq. 9).
Interestingly, in this subset of reductive cross-coupling, if the
starting material is a primary allylic alcohol, substantial quantities
of isomeric products result. For example, coupling of 32a with 29
resulted in a 2:1 mixture of products 33a and 34a in 90% combined
yield (Eq. 10). While the product containing a quaternary center
was the minor product of this transformation, a subtle change in
the structure of 32a resulted in a significant perturbation of the
reaction course. As depicted in Eq. 11, coupling of 32b with imine
29 resulted in the preferential formation of the 1,3-aminoalcohol
product 34b over the homoallylic amine 33b (selectivity = 4:1).2f
The stereochemistry of the major product formed was addressed
as illustrated in Eq. 12. Here, coupling of 32b with imine 35 was
followed by formation of the rigid bicyclic heterocycle 37. Subse-
quent NOE analysis indicated that the major product of this cou-
pling reaction is as depicted in 36.
Bn
Ti(Oi-Pr)4
Me HN
30
Bn
H
OH
N
c-C5H9MgCl, Et2O
+
(8)
Ph
then NaHCO3 (sat)
87%
Me
11
29
Bn
Et HN
Ti(Oi-Pr)4
Me OH
c-C5H9MgCl, Et2O
+
(9)
29
Me
Me
then NaHCO3 (sat)
73%
Et
Me
26
31*
* = isolated as a 1:0.7 mixture of alkene isomers
Coupling reactions that proceed with unique regioselection:
Combined influence of TMSCH2- and a 1° allylic alcohol
Ti(Oi-Pr)4
Bn
OH
Bn
OH HN
c-C5H9MgCl, Et2O
R
HN
+
+
29
then NaHCO3 (sat)
R
Me
R
allylic alcohol:
yield:
90%
ratio (33:34):
(10)
(11)
32a; R = Me
2:1
1:4
33a; R = Me
33b; R = CH2TMS
34a; R = Me
32b; R = CH2TMS 94%
34b; R = CH2TMS
Concerning stereochemistry of the 1,3-amino alcohol products:
MeO
MeO
H
OMe
Ti(Oi-Pr)4
OH
(
)
2
MeO
c-C5H9MgCl, Et2O
HO HN
+
(12)
TMS
32b
N
then NaHCO3 (sat)
58%
Me
H
Ph
TMS
35
36
dr = 4:1
Me
O
N
37
TMS
Ph
nOe
O
N
H
H
HCl
H
H
THF
94%
nOe
stereochemistry of major product
Me
TMS
37
Regioselection is influenced by substitution at the allylic position:
Ti(Oi-Pr)4
TMS
Bn
Bn
H
OH
HN
N
c-C5H9MgCl, Et2O
+
(13)
Me
TMS
38
Ph
then NaHCO3 (sat)
70%
Me
29
39
While the reaction of 32b with imines is selective for the forma-
tion of products containing a quaternary center, simple substitu-
tion of this starting material results in a shift of regioselection
back to the preferential formation of homoallylic amine products.
As depicted in Eq. 13, coupling of the secondary allylic alcohol 38
with imine 29 results in the formation of 39 in 70% yield, as a single
olefin isomer. Here, no evidence was found for the production of a
1,3-aminoalcohol-containing product.2f
These studies have identified structural features that lead to
a change in the regiochemical course of Ti(Oi-Pr)4-mediated
reductive cross-coupling reactions between allylic alcohols and
vinylsilanes or imines. The factors that influence each of these
cross-coupling reactions are distinct. With vinylsilane-based cou-
pling reactions, additional unsaturation (in the form of a benzylic
alcohol or a 1,4-diene-3-ol system) shifts the regiochemical course
of coupling. In these cases, substantial quantities of products con-
taining a quaternary carbon are formed. With imine–allylic alcohol
coupling, such additional unsaturation does not affect the regio-
chemical course of reductive cross-coupling. However, a different
structural feature shifts regioselection in these reactions. Specifi-
no evidence found for the
production of a regio- or
stereoisomeric product
Figure 4. Access to quaternary centers by allylic alcohol–imine reductive cross-
coupling.
cally, coupling of primary allylic alcohols with imines results in a
substantial quantity of product containing a 1,3-aminoalcohol
and accompanying quaternary center. This tendency is further en-
hanced with a substrate that contains a TMSCH2-substituent (32b),
indicating a potential role of electronic factors in changing the
regiochemical course of this coupling reaction. A mechanistic
rationale in support of these subtle changes in regioselection as a
function of substrate structure remains to be defined.
Acknowledgments
We gratefully acknowledge financial support of this work by
the National Institutes of Health (GM80266 and GM80266-S1).

D. Yang et al. / Tetrahedron Letters 52 (2011) 2144–2147
2147
alcohol–imine coupling, see: (c) Takahashi, M.; McLaughlin, M.; Micalizio, G. C.
Angew. Chem., Int. Ed. 2009, 48, 3648; (d) Tarselli, M. A.; Micalizio, G. C. Org. Lett.
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11, 5402; (f) Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2009, 131, 17548; For
related coupling reactions, see: (g) Lysenko, I. L.; Kim, K.; Lee, H. G.; Cha, J. K. J.
Am. Chem. Soc. 2008, 130, 15997; (h) Lysenko, I. L.; Lee, H. G.; Cha, J. K. Org. Lett.
2009, 11, 3132.
Supplementary data
Supplementary data (experimental procedures, compound
characterization, copies of spectral data) associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2010.11.059.
3. Chen, M. Z.; McLaughlin, M.; Takahashi, M.; Tarselli, M. A.; Yang, D.; Umemura,
S.; Micalizio, G. C. J. Org. Chem., accepted for publication, doi:10.1021/
jo101535d.
4. For recent reviews, see: (a) Denissova, I.; Barriault, L. Tetrahedron 2003, 59,
10105; (b) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 36,
5969.
5. (a) Suzuki, N.; Kondakov, D. Y.; Takahashi, T. J. Am. Chem. Soc. 1993, 115, 8485;
(b) Suzuki, N.; Kondakov, D. Y.; Kageyama, M.; Kotora, M.; Hara, R.; Takahashi, T.
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Fujii, T.; Furukawa, I. Chem. Lett. 1995, 315; (d) Barluenga, J.; Rodríguez, F.;
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7. For examples, where a related mode of reactivity in intramolecular settings was
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