Regio- and stereoselective cross-coupling of substituted olefins and imines. A convergent stereoselective synthesis of saturated 1,5-aminoalcohols and substituted piperidines

Article abstract of DOI:10.1021/ja071974v

A mild and efficient alkoxide-directed C-C bond-forming reaction is described that provides a regio- and stereoselective route to 1,5-aminoalcohols based on cross-coupling of substituted olefins and imines. Single and double diastereoselection is explored

Full text of DOI:10.1021/ja071974v

Published on Web 05/26/2007
Regio- and Stereoselective Cross-Coupling of Substituted Olefins and Imines.
A Convergent Stereoselective Synthesis of Saturated 1,5-Aminoalcohols and
Substituted Piperidines
Masayuki Takahashi and Glenn C. Micalizio*
Department of Chemistry, Yale UniVersity, New HaVen, Connecticut 06520-8107
Received March 20, 2007; E-mail: glenn.micalizio@yale.edu
The development of reactions that facilitate the syntheses of
nitrogen-containing small molecules continues to be an intense area
of research in organic chemistry. Whereas many powerful methods
exist for the preparation of such targets, recent accomplishments
in reductive coupling chemistry have provided new strategies of
untapped potential for the convergent synthesis of secondary
carbinolamines. To date, methods have been described for bi-
molecular alkyne-imine coupling that provide a convenient route
to substituted allylic amines.1 The corresponding cross-coupling
reaction between internal olefins and imines represents a signifi-
cantly more complex and potentially more powerful bond construc-
tion.2 In addition to overcoming the lower reactivity of substituted
olefins in bimolecular carbometalation reactions, a synthetically
useful cross-coupling process must address the additional complex-
ity that results from the need to simultaneously control site
selectivity and diastereoselection in the carbon-carbon bond-
forming event (2+3 f 4-7, Figure 1). The development of a
synthetic method to accomplish the cross-coupling of internal olefins
and imines in a regio- and stereoselective manner would represent
a significant advance and provide a fundamentally new strategy
for the synthesis of stereodefined secondary carbinolamines.
Here we describe a method for cross-coupling of aromatic imines
with terminal, 1,1-disubstituted, (E)- and (Z)-disubstituted olefins.
Additionally, we describe the use of this coupling reaction in single
and double asymmetric synthesis, as well as define a novel route
for convergent stereoselective synthesis of substituted piperidines.
Previously, we have described titanium alkoxide-mediated reac-
tions for alkyne-alkyne,3 alkyne-alkene,4 and alkyne-imine5
cross-coupling. These methods have provided a means to overcome
the sluggish reactivity of highly substituted π-systems in reductive
coupling chemistry and defined a means to control regioselection
in bimolecular carbometalation that is independent of the differential
steric environment around an unsymmetrically substituted alkyne
or alkene. As depicted in Figure 2, the present study explores
alkoxide-directed, titanium-mediated, reductive cross-coupling be-
tween homoallylic alkoxides 8 and imines 9 as a method for the
synthesis of acyclic aminoalcohols (i.e., 10 or 12) and substituted
heterocycles (i.e., 11 or 13). In contrast to established reductive
cross-coupling reactions between alkynes and heterosubstituted
π-systems (alkyne-aldehyde, alkyne-imine), this alkene-imine
cross-coupling process is significantly more complex as the carbon-
carbon bond formation proceeds with the simultaneous generation
of two stereogenic sp3 carbon centers.
Figure 1. Bimolecular coupling of imines and substituted olefins via
formation of azametallacyclopentanes.
Figure 2. Cross-coupling of substituted olefins and iminessa potential
pathway for the synthesis of aminoalcohols and substituted heterocycles.
(Oi-Pr)4, c-C5H9MgCl, Et2O, -70 to -40 °C), followed by
protonation of the presumed bicyclic azametallacyclopentane,
resulted in formation of the 1,5-aminoalcohol 16 in 76% yield (rr
g 95:5). The success of this coupling reaction not only defines a
convergent route to aminoalcohols but also provides a convenient
means to access substituted piperidines. Treatment of 1,5-amino-
alcohol 16 with PPh3 and CCl4 (reflux) resulted in the formation
of the substituted piperidine 17 in 85% yield.6
More highly substituted olefins were well tolerated in this cross-
coupling reaction. As illustrated in entry 2, coupling of the (E)-
disubstituted homoallylic alcohol 18 with imine 15 provided the
4,5-anti-1,5-aminoalcohol 19 in 73% yield (dr g 95:5; rr g 95:5)
and, on cyclization, the 2,3-trans-disubstituted piperidine 20 in 81%
yield. Coupling of the related (Z)-disubstituted homoallylic alcohol
21 with imine 15 provided the 4,5-anti-1,5-aminoalcohol 22 in 63%
yield (dr g 95:5; rr g 95:5) and, on cyclization, the 2,3-trans-
disubstituted piperidine 23 in 77% yield (entry 3).
As depicted in Figure 3, the stereoconvergence observed in these
coupling reactions can be rationalized by assuming preferential
reaction by way of transition-state structures that avoid 1,2-steric
interactions in a developing cis-fused bicyclo[3.3.0] ring system
(B and C).7,8
The homoallylic alcohol 24, bearing a 1,1-disubstituted olefin,
was also an effective coupling partner with imine 15 providing the
1,3-syn-1,5-aminoalcohol product 25 in 67% yield (dr ) 4:1; rr g
95:5)9 and, on cyclization, the corresponding 2,4-trans-disubstituted
To examine the potential of this proposed reaction pathway for
regio- and diastereoselective C-C bond formation, a study was
initiated to explore the reactivity of azametallacyclopropanes
(generated in situ from aromatic imines) with homoallylic alkoxides
of general structure 8. As depicted in entry 1 of Table 1,
deprotonation of homoallylic alcohol 14 (n-BuLi, Et2O) and addition
to a preformed azametallacyclopropane derived from imine 15 (Ti-
9
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C O M M U N I C A T I O N S
Table 1.
Table 2.
a Reaction conditions for cross-coupling: imine (1 equiv), Ti(Oi-Pr)4
(1.5 equiv), c-C5H9MgCl (3.0 equiv), Et2O (-60 to -30 °C), then add
alkoxide (1.5 equiv, -30 to 0 °C or rt). b Reaction conditions for
cyclization: For 30: 2-NsCl, Et3N, DMAP, CH2Cl2, rt. For 32: MsCl, Et3N,
CH2Cl2, rt. R ) CH(Ph)CH2OMe.
Table 3.
a Reaction conditions for cross-coupling: imine (1 equiv), Ti(Oi-Pr)4
(1.5 equiv), c-C5H9MgCl (3.0 equiv), Et2O (-70 to -40 °C), then add
alkoxide (1.5 equiv, -40 to -20 °C, 0 °C, or rt; see Supporting Information
for details). b Reaction conditions for cyclization: PPh3, imidazole, CCl4,
reflux.
Figure 3. A model for stereoselection in imine-alkene cross-coupling.7,8
a Reaction conditions for cross-coupling: imine (1 equiv), Ti(Oi-Pr)4
(1.5 equiv), c-C5H9MgCl (3.0 equiv), Et2O (-60 to -30 °C), then add
alkoxide (1.5 equiv, -30 to 0 °C (entries 1, 2a, 3, and 4) or rt (entry 2b)).
b Reaction conditions for cyclization: (1) H2 (1 atm), Pd(OH)2, AcOH/
MeOH (1:10 v/v), rt; (2) 2-NsCl, Et3N, DMAP, CH2Cl2, 0 °C to rt; (3)
PPh3, DIAD, THF, rt. Ar ) 2-nitrophenyl. c Major diastereomer shown.
d Cyclization of 36 to 37 was performed with the enantiomer of 36 (for
data on ent-37, see Supporting Information).
piperidine 26 in 76% yield. The stereoselectivity in this case is
consistent with preferential progression through a transition-state
geometry that has the phenyl substituent occupying a position
outside the developing cis-fused bicyclo[3.3.0] ring system (F in
Figure 3).7,8
Next, coupling reactions of achiral homoallylic alcohols with
chiral imines were examined. As depicted in Table 2, coupling of
homoallylic alcohols with chiral imine 28 proceeded in a generally
efficient manner (61-83%).10 Highest selectivities were observed
in coupling reactions of the terminal- (14) and (Z)-disubstituted
(27) olefins and provided products with dr g 20:1 (entries 1 and
2). Cyclization of these 1,5-aminoalcohols (29 and 31) provides
the corresponding substituted piperidines 30 and 32 with good
efficiency (77 and 87% yield). Coupling of the (E)-disubstituted
olefin 18 with chiral imine 28 also led to aminoalcohol 31, yet this
product was obtained with levels of stereoselection (25:4:1) lower
than that observed with the isomeric olefin 27.
Cross-coupling reactions were also examined to determine the
extent to which stereochemical matching and/or mismatching might
occur in double diastereodifferentiating cases.11 As illustrated in
Table 3, coupling of the (Z)-homoallylic alcohol 33 with chiral
imine ent-28 furnished the 1,4-anti-1,5-syn-1,5-aminoalcohol 34 in
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C O M M U N I C A T I O N S
stereoreinforcing relationship with the (Z)-olefin, whereas (S,E)-
homoallylic alcohol + 28 is also a matched double asymmetric
reaction but there is a non-stereoreinforcing relationship with the
(E)-olefin.
Overall, we report a titanium alkoxide-mediated reaction for
regio- and stereoselective cross-coupling of substituted olefins and
imines. The reported process provides convenient access to
substituted 1,5-aminoalcohols and piperidines. Our studies focusing
on simple diastereoselection have shown that this reaction is
stereoconvergent with respect to olefin stereochemistrysboth (E)-
and (Z)-disubstituted homoallylic alcohols provide anti-products
in coupling reactions with achiral imines. We have studied this
reaction in both single and double asymmetric modes, have defined
matched and mismatched double asymmetric relationships, and have
shown a reversal of stereochemical matching/mismatching as a
function of the olefin geometry of the chiral homoallylic alcohol.
Research focused on further understanding the nature of stereo-
selection in this cross-coupling reaction, as well as application to
the synthesis of complex heterocycles, is underway.
Figure 4. A model for stereoselection in the double asymmetric cross-
coupling reactions of disubstituted olefins with chiral imines.
Acknowledgment. We gratefully acknowledge financial support
of this work by the American Cancer Society (RSG-06-117-01),
the American Chemical Society (PRF-45334-G1), the Arnold and
Mabel Beckman Foundation, Boehringer Ingelheim, Eli Lilly &
Co., the National Institutes of Health, NIGMS (GM80266), and
Yale University.
76% yield (dr g 50:1), cyclization of which provided the 2,3-trans-
2,6-trans-tetrasubstituted piperidine 35 (entry 1a). Coupling of the
same homoallylic alcohol (33) with 28 proceeded with low
conversion (30%) and provided a mixture of diastereomeric products
(dr ) 4:1:1; entry 2a). Although the efficiency of this coupling
reaction can be increased on warming (entry 2b), the dr is affected.
The disparate reactivity and selectivity observed defines a clearly
matched (entry 1) and mismatched (entry 2) double asymmetric
relationship in these coupling reactions.
Supporting Information Available: Experimental procedures and
tabulated spectroscopic data for new compounds (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
The (E)-disubstituted homoallylic alcohol 38 displayed inverse
double asymmetric behavior as compared to (Z)-disubstituted
homoallylic alcohol 33. As illustrated in entries 3 and 4, coupling
of 38 with 28 represents a matched double asymmetric process (88%
yield, dr ) 35:4:1), whereas coupling of 38 with ent-28 represents
a mismatched double asymmetric reaction (dr ) 19:12:4:1).
A preliminary empirical model to explain these double asym-
metric reactions is proposed in Figure 4. The model is based on
(1) diastereoselective coordination of the pendent methyl ether to
the titanium center,10 (2) intramolecular delivery of the olefin to
the azametallacyclopropane,3-5 (3) minimization of 1,2-interactions
in the developing five-membered ring, and (4) positioning of the
alkyl group (R) outside of the developing cis-fused ring system.
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(34) or 1,4-syn-1,5-anti (36) aminoalcohols via transition-state
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4) may suffer from the requirement of placing the alkyl substituent
(R) on the inside of the developing cis-fused ring system (I and J,
Figure 4).
These double asymmetric cross-coupling reactions proceed with
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the stereochemical relationship of the secondary alcohol, imine,
and olefin. Interestingly, matched double asymmetric reactions can
provide stereoselective access to either the 1,4-anti-1,5-syn-1,5-
aminoalcohol or 1,4-syn-1,5-anti-1,5-aminoalcohol products and the
corresponding tetrasubstituted piperidines 35 and 37. The variability
in the diastereomeric ratio of products observed in each of these
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