Complex allylation by the direct cross-coupling of imines with unactivated allylic alcohols

Full text of DOI:10.1002/anie.200900236

Communications
DOI: 10.1002/anie.200900236
Synthetic Methods
Complex Allylation by the Direct Cross-Coupling of Imines with
Unactivated Allylic Alcohols**
Masayuki Takahashi, Martin McLaughlin, and Glenn C. Micalizio*
ꢀ
Since the birth of the field, convergent C C bond-forming
reactions have defined the backbone of organic synthesis.[1]
While significant advances in reaction development have
recently been made in the area of catalysis,[2] contributions
ꢀ
that describe novel bimolecular C C bond construction
remain central to the evolution of organic synthesis. Such
contributions provide new paradigms for molecular assembly,
greatly facilitating the manner in which complex molecules
are made. Herein, we describe a convergent coupling reaction
between allylic alcohols and imines that delivers complex
homoallylic amines with high levels of regio- and stereose-
lectivity by a pathway that proceeds without the intermediacy
of allylic organometallic reagents (Scheme 1, top).
Over the last thirty years, allylation has emerged as a
ꢀ
particularly powerful bimolecular C C bond-forming process,
ꢀ
Scheme 1. Allylation for convergent C C bond formation. Top: Com-
plex allylation without allylic organometallic reagents. Bottom: Allyla-
tion with allylic organometallic reagents.
with current examples demonstrating the ability to achieve
enantio- and diastereoselective allyl, crotyl, and prenyl trans-
fer.[3] While powerful, the typical dependence on allylic
organometallic reagents often restricts the utility of these
processes, limiting them to the addition of these simple
hydrocarbon fragments.[4] The synthesis and application of
more functionalized allylic organometallic reagents for con-
vergent coupling is complicated and typically unwieldy owing
to: 1) Functional group tolerance in the preparation of the
allylic organometallic reagent, 2) challenges associated with
the control of site selectivity in the metalation step, 3) diffi-
stereodefined alkene and the tetrahedral stereochemistry at
the allylic and homoallylic positions (Scheme 1, bottom). In
cases where the allylic metal reagent is generated in a
catalytic fashion, functional group tolerance is often
enhanced, but complexities still remain because of competing
isomerization (of the allylic metal species) as well as the
previously mentioned issues with regio- and stereoselection in
ꢀ
culties in controlling site-selective C C bond formation
the C C bond-forming event.[5] As such, the potential impact
of the bond constructions made possible with allylic organ-
ometallic reagents (independent of whether such processes
are rendered catalytic in the metal) remains limited.
ꢀ
(resulting from the competition between a vs. g attack and
the known propensity for allylic isomerization of the inter-
mediate organometallic reagent), and 4) problems associated
with attaining selectivity in both the establishment of a
Recent contributions from our laboratory have focused on
ꢀ
harnessing the power of metallacycle-mediated C C bond
[*] M. Takahashi,[+] M. McLaughlin,[+] Prof. G. C. Micalizio
Department of Chemistry
formation for new convergent coupling reactions in organic
chemistry.[6] These accomplishments have derived from the
development of general strategies to control the reactivity of
metal–p complexes. In particular, association of neighboring
alkoxides with the metal center has played a central role in
The Scripps Research Institute, Scripps Florida
130 Scripps Way 3A2, Jupiter, FL 33458 (USA)
and
Department of Chemistry, Yale University
225 Prospect Street, New Haven, CT 06520-8107 (USA)
E-mail: micalizio@scripps.edu
these processes; these functional groups often complicate
other C C bond-forming reactions. One powerful mode of
[7]
ꢀ
[+] These authors contributed equally to this manuscript.
control is reaction by formal metallo-[3,3] rearrangement.[8]
Here, we describe a new stereoselective convergent coupling
reaction by formal metallo-[3,3] rearrangement that
addresses long-standing problems in allyl-transfer chemistry
and defines a pathway for complex allylation of imines that:
1) Proceeds by the direct coupling of allylic alcohols, thereby
eliminating the need for preformed allylic organometallic
reagents, 2) occurs with diverse functional group tolerance,
3) progresses in a highly regioselective manner with net
allylic transposition, 4) delivers homoallylic amines with high
[**] We gratefully acknowledge financial support of this work by the
American Cancer Society (RSG-06-117-01), the Arnold and Mabel
Beckman Foundation, Boehringer Ingelheim, Eli Lilly & Co., and the
National Institutes of Health-NIGMS (GM80266). The authors also
thank the W. M. Keck Foundation Biotechnology and Resource
Laboratory at Yale University for high-resolution mass spectrometry
and Filip Kolundzic for an early demonstration of this imine/allylic
alcohol reductive cross-coupling reaction.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200900236.
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Table 1: Stereoselective synthesis of homoallylic amines.
anti selectivity, and 5) establishes a stereodefined di- or
ꢀ
trisubstituted alkene in concert with C C bond formation
(Scheme 1, top).
Our generic design for an allylic alcohol–imine cross-
coupling process is outlined in Scheme 2. Treatment of an
imine (A) with a low-valent metal reagent (B) was anticipated
Entry
Allylic alcohol
Yield Z/E
d.r.
Product
[%][a]
1
2
70
83
–
–
–
–
3
4
80
–
–
–
87 ꢁ20:1
5
6
10; R1 =Me; R2 =H 81
12; R1 =H; R2 =Me 68
–
–
ꢁ20:1
ꢁ20:1
Scheme 2. Reaction design.
7
8
92 1.6:1 ꢁ20:1[b]
57 ꢂ1:20 ꢁ20:1
to result in the formation of an intermediate azametallacy-
clopropane (C). Addition of an allylic alkoxide (D) to this
preformed complex was expected to result in rapid and
reversible ligand exchange to deliver E. Rearrangement by
ꢀ
way of F results in the formation of a C C bond, two
stereogenic centers, and one geometrically defined substi-
tuted alkene and delivers homoallylic metalated amine G.
From G, simple hydrolysis provides the complex homoallylic
amine product H. Alternatively, depending on the metal
employed, we envisioned a potential pathway for capturing
the precious metal intermediate G by net reduction and
epimetalation with imine A. Defining this portion of the
reaction would render the process catalytic in the metal
component, but was thought to be necessary only if: 1) The
reaction requires a complex ligand for control of selectivity
(enantio-, diastereo-, or regioselectivity), or 2) the metal
employed is rare, expensive, or toxic.
The metal reagent (B) selected for this process was a
readily available titanium alkoxide, and the control of the
coupling reaction was anticipated to follow from the geo-
metrical constraints imposed by reaction through a formal
metallo-[3,3] rearrangement. As such, the primary goal of our
studies was to investigate the possibility of this stereoselective
new bond construction without concern for turning over the
nontoxic and readily available titanium alkoxide reagent.
As illustrated in Table 1, coupling of allyl alcohol 2 with
imine 1 delivers the simple homoallylic amine 3 in 70% yield
(entry 1).[9] With more substituted allylic alcohols (4 and 6),
coupling provides homoallylic amines bearing proximal tri-
and tetrasubstituted alkenes (Table 1, entries 2 and 3); in one
9
54 ꢁ20:1 ꢁ20:1
[a] Reaction conditions: See the Supporting Information for details.
[b] Each alkene isomer (Z and E) was identified as the anti diastereomer
(d.r.ꢁ20:1). Bn=benzyl.
case a useful reaction for the prenylation of aromatic imines is
defined (4!5).[10] Interestingly, coupling of allylic alcohol 8
with imine 1 proceeds with both high regio- and stereoselec-
tivity delivering homoallylic amine 9 in 87% yield as a single
geometrical isomer (Z/E ꢁ 20:1; Table 1, entry 4).
When terminally substituted allylic alcohols are
ꢀ
employed, this C C bond-forming process proceeds in a
highly anti-selective manner. For example, coupling of either
allylic alcohol 10 or 12 with 1 provides the stereodefined
product 11 in 81 and 68% yield, respectively (d.r. ꢁ 20:1 in
both cases; Table 1, entries 5 and 6). With secondary allylic
alcohols having geometrically defined alkenes, the control of
stereochemistry is more complex, as the challenge of estab-
lishing allylic and homoallylic stereochemistry is coupled to
the construction of a stereodefined alkene. Nevertheless,
reaction of allylic alcohol 13 with 1 provides 14 in 92% yield
(anti/syn ꢁ 20:1; Table 1, entry 7). While this coupling reac-
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Table 3: Stereoselective synthesis of highly functionalized homoallylic amines.
tion does not deliver the stereodefined alkene with
high levels of selectivity (Z/E = 1.6:1), coupling of the
isomeric allylic alcohol 15 with 1 delivers 16 with
much higher levels of selectivity, favoring the anti
product with a proximal disubstituted E alkene
(d.r. ꢁ 20:1; E/Z ꢁ 20:1; Table 1, entry 8). Finally,
coupling of the E-trisubstituted allylic alcohol 17
with 1 provides homoallylic amine 18 in 54% yield, in
this case delivering the anti product with a central Z-
trisubstituted alkene.
While this convergent coupling reaction affords
complex homoallylic amines that are otherwise
difficult to prepare, it is also compatible with vinyl
halides—a feature that further defines a rather
unique stereoselective bond construction for complex
molecule synthesis (Table 2). It was found that 2-
haloallylic alcohols (19–21) are suitable substrates for
coupling with 1 (Table 2, entries 1–3). In addition,
more complex bond constructions are possible in
which high anti selectivity is coupled to the formation
of geometrically defined vinyl halides (d.r. ꢁ 20:1; E/
Z ꢁ 20:1; Table 2, entries 4 and 5). Finally, allylic
alcohols bearing carbocyclic vinyl halides are also
viable partners in this coupling reaction. Coupling of
imine 29 with 30 provides the functionalized cyclo-
hexene 31 in 53% yield (d.r. ꢁ 20:1; Table 2, entry 6).
This stereoselective convergent coupling reaction
is compatible with a variety of aromatic imines and
Entry
1
Imine
Allylic alcohol
Yield
[%][a]
Product
53
52
2
3
55
67
4
Table 2: Stereoselective synthesis of 3-halohomoallylic amines.
5
6
41; R1, R2 =Me
43[c]; R1 =H,
4
4
79
69
42; R1, R2 =Me
44; R1 =H,
R2 =CH2TMS
R2 =CH2TMS
Entry Imine
Allylic alcohol Yield E/Z
d.r.
Product
[%][a]
7
8
4
83
72
1
2
3
19; X=Cl
20; X=Br
21; X=I
59
61
60
–
–
–
–
–
–
22; X=Cl
23; X=Br
24; X=I
1
[a] Reaction conditions: See the Supporting Information for details. [b] No evidence
was found for the production of stereoisomeric products. [c] Compound 43 was
used as a mixture of alkene isomers (E/Z=4:1). TBS=tert-butyldimethylsilyl,
TBDPS=tert-butyldiphenylsilyl, TMS=trimethylsilyl.
4
5
6
1
1
53 ꢁ20:1 ꢁ20:1
56 ꢁ20:1 ꢁ20:1
substituted allylic alcohols. Table 3 highlights the use of this
reaction for the synthesis of homoallylic amines bearing
heteroaryls (33 and 38; entries 1 and 3), tetrasubstituted vinyl
halides (36; entry 2), aromatic halides (40, 42, and 44;
entries 4–6), additional alkenes (42 and 44; entries 5 and 6),
as well as a trifluoromethyl-substituted aryl (40; entry 4). This
reaction can also be extended to ketimines, in this case
providing the tertiary carbinolamine 46 in 83% yield (Table 3,
entry 7).
53
–
ꢁ20:1
[a] Reaction conditions: See the Supporting Information for details.
[b] No evidence was found for the production of stereoisomeric
products. PMB=p-methoxybenzyl.
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[4] Notable exceptions include bifunctionalized allylmetal reagents
Finally, the absolute stereochemistry of this reaction can
be controlled in a substrate-directed manner. Coupling of the
stereodefined allylic alcohol 47 with imine 1 provides the
chiral stereodefined product 48 in 72% yield, as a single
isomer (Table 3, entry 8).[11]
The regiochemical course of this coupling reaction is
consistent with an empirical model based on a formal metallo-
[3,3] rearrangement via a mixed titanate ester intermediate
(Figure 1). The stereochemical control observed is consistent
with reaction through a conformation where the sC-M orbital is
and complex crotylsilanes. For recent discussions, see: a) E. M.
Flamme, W. R. Roush, J. Am. Chem. Soc. 2002, 124, 13644, and
references therein; b) C. E. Masse, J. S. Panek, Chem. Rev. 1995,
95, 1293.
[5] For a review of catalytic enantioselective addition of allylic
organometallic reagents to aldehydes and ketones, see: a) S. E.
Denmark, J. Fu, Chem. Rev. 2003, 103, 2763. For a review of
catalytically generated allylic metal reagents that serve as
electrophiles, see: b) Z. Lu, S. Ma, Angew. Chem. 2008, 120,
264; Angew. Chem. Int. Ed. 2008, 47, 258.
[6] For the cross-coupling of two internal alkynes, see: a) J. Ryan,
G. C. Micalizio, J. Am. Chem. Soc. 2006, 128, 2764. For the cross-
coupling of internal alkynes with substituted alkenes, see:
b) H. A. Reichard, G. C. Micalizio, Angew. Chem. 2007, 119,
1462; Angew. Chem. Int. Ed. 2007, 46, 1440. For the cross-
coupling of allenes with internal alkynes, see: c) H. L. Shimp,
G. C. Micalizio, Chem. Commun. 2007, 4531; d) H. L. Shimp, A.
Hare, M. McLaughlin, G. C. Micalizio, Tetrahedron 2008, 64,
6831. For cross-coupling of internal alkynes with aromatic
imines, see: e) M. McLaughlin, M. Takahashi, G. C. Micalizio,
Angew. Chem. 2007, 119, 3986; Angew. Chem. Int. Ed. 2007, 46,
3912. For cross-coupling of internal alkenes with aromatic
imines, see: f) M. Takahashi, G. C. Micalizio, J. Am. Chem.
Soc. 2007, 129, 7514.
aligned with the pC C orbital, while allylic strain (A-1,2/A-1,3)
=
and developing nonbonding 1,2-interactions (A and B;
Figure 1) are minimized.[12]
[7] For a discussion of the burden of protecting groups in the
synthesis of complex molecules, see: P. S. Baran, T. J. Maimone,
J. M. Richter, Nature 2007, 446, 404.
Figure 1. Empirical model for regio- and stereoselection. In conforma-
tions A and B the sC-M orbital is aligned with the pC C orbital.
=
ꢀ
[8] For other examples of bimolecular C C bond formation by
formal metallo-[3,3] rearrangement, see: a) allylic alcohol–
internal alkyne: J. K. Belardi, G. C. Micalizio, J. Am. Chem.
Soc. 2008, 130, 16870 – 16872; b) allenic alcohol–aromatic imine:
F. Kolundzic, G. C. Micalizio, J. Am. Chem. Soc. 2007, 129,
15112; c) allenic alcohol–internal alkyne: M. McLaughlin, H. L.
Shimp, R. Navarro, Synlett 2008, 735; and d) allenic alcohol–
internal alkyne: see Ref. [6d].
In conclusion, we have described a new reaction design to
accomplish complex convergent coupling by formal allyl
transfer that proceeds without the requirement of allylic
organometallic reagents. This process, while not yet rendered
catalytic in the metal (Ti or Mg), defines a unique and
powerful convergent bond construction. Owing to the low
cost of the metal-containing reagents, benign nature of the by-
products (TiO2 and magnesium (II) salts), and substrate-
controlled stereoselection, this type of process in its current
form should be of great utility in organic chemistry.
[9] For recent examples of imine allylation using preformed allylic
silanes, see: a) J. D. Huber, N. R. Perl, J. L. Leighton, Angew.
Chem. 2008, 120, 3079 – 3081; Angew. Chem. Int. Ed. 2008, 47,
3037; b) R. Berger, P. M. A. Rabbat, J. L. Leighton, J. Am.
Chem. Soc. 2003, 125, 9596; c) J. V. Schaus, N. Jain, J. S. Panek,
Tetrahedron 2000, 56, 10263. For recent examples using pre-
formed allylic stannanes, see: d) T. Gastner, H. Ishitani, R.
Akiyama, S. Kobayashi, Angew. Chem. 2001, 113, 1949; Angew.
Chem. Int. Ed. 2001, 40, 1896; e) D. J. Hallett, E. J. Thomas,
Tetrahedron: Asymmetry 1995, 6, 2575; f) G. E. Keck, E. J.
Enholm, J. Org. Chem. 1985, 50, 146. For recent examples
employing preformed allylic boron reagents, see: g) T. R. Wu,
J. M. Chong, J. Am. Chem. Soc. 2006, 128, 9646; h) S. Li, R. A.
Batey, Chem. Commun. 2004, 1382; i) S. Lou, P. M. Moquist,
S. E. Schaus, J. Am. Chem. Soc. 2007, 129, 15398; j) S. Itsuno, K.
Watanabe, K. Ito, A. A. El-Shehawy, A. A. Sarhan, Angew.
Chem. 1997, 109, 105; Angew. Chem. Int. Ed. Engl. 1997, 36, 109.
For recent examples using in situ generated allylic boron
reagents, see: k) N. Selander, A. Kipke, S. Sebelius, K. J.
Szabꢀ, J. Am. Chem. Soc. 2007, 129, 13723; l) M. Shimizu, M.
Kimura, T. Watanabe, Y. Tamaru, Org. Lett. 2005, 7, 637. For
examples using allylic palladium reagents generated in situ, see:
m) R. A. Fernandes, A. Stimac, Y. Yamamoto, J. Am. Chem. Soc.
2003, 125, 14133; n) C. Hopkins, H. C. Malinakova, Org. Lett.
2006, 8, 5971. For recent examples employing allylic zinc
reagents, see: o) P. Wipf, C. Kendall, Org. Lett. 2001, 3, 2773;
p) P. Wipf, J. G. Pierce, Org. Lett. 2005, 7, 3537. For a recent
example using allylic titanium reagents generated in situ, see:
q) Y. Gao, F. Sato, J. Org. Chem. 1995, 60, 8136. For reviews on
the synthesis of homoallylic amines via allylic metal reagents,
see: r) P. V. Ramachandran, T. E. Burghardt, Pure Appl. Chem.
Received: January 14, 2009
Published online: April 9, 2009
Keywords: allylic compounds · homoallylic amines ·
.
metallacycles · stereoselective synthesis · titanium
[1] For a discussion of strategy in the synthesis of complex
molecules, along with detailed case studies, see: a) E. J. Corey,
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[2] For a recent review of advances in catalysis, see: Catalysis from
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[10] Prenylation of imines has represented a significant challenge in
organic chemistry. For a route to products like 5 based on the
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Ogasawara, K. Yasue, H. Yamamoto, J. Chem. Soc. Chem.
Commun. 1996, 367.
[11] The relative stereochemistry of 48 is proposed based on the
model depicted in Figure 1 and is supported by observations
made in related titanium-mediated reductive cross-coupling
[12] The empirical model described is based on the minimization of
A-1,2 strain in a formal metallo-[3,3] rearrangement process,
and does not account for the geometry at titanium. The proposed
empirical model does not exclude a mechanism that follows from
directed carbometalation and syn elimination. For a review of
allylic strain as a principle for stereochemical control, see: R. W.
Hoffmann, Chem. Rev. 1989, 89, 1841.
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