Preparation of stereodefined homoallylic amines from the reductive cross-coupling of allylic alcohols with imines

Article abstract of DOI:10.1021/jo101535d

Regio-, diastereo-, and enantioselective coupling reactions between imines and allylic alcohols have been developed. These coupling reactions deliver complex homoallylic amine products through a convergent C-C bond forming process that does not proceed through intermediate allylic organometallic reagents. In general, convergent coupling, by exposure of an allylic alkoxide to a preformed Ti-imine complex, occurs with allylic transposition in a predictable and stereocontrolled manner. While simple diastereoselection in these reactions is high, delivering anti-products with ≥20:1 selectivity, the organometallic transformation described is compatible with a diverse range of functionality and substrates (including aliphatic and aromatic imines, allylic silanes, trisubstituted alkenes, vinyl- and aryl halides, trifluoromethyl groups, thioethers, and aromatic heterocycles). Alkene geometry of the products is a complex function of the allylic alcohol structure and is consistent with a mechanistic proposal based on syn-carbometalation followed by syn-elimination by way of a boat-like transition state geometry. Single asymmetric coupling reactions provide a means to translate the stereochemical information of the allylic alcohol to the homoallylic amine or to control diastereoselection in the coupling reactions of achiral allylic alcohols with chiral imines. Double asymmetric coupling reactions are also described that afford a unique means to control stereoselection in these complex convergent coupling processes. Finally, empirical models are proposed that are consistent with the observed stereochemical course of these coupling reactions en route to chiral homoallylic amines possessing di- or trisubstituted alkenes and anti- or syn- relative stereochemistry at the allylic and homoallylic positions.

Full text of DOI:10.1021/jo101535d

pubs.acs.org/joc
Preparation of Stereodefined Homoallylic Amines from the Reductive
Cross-Coupling of Allylic Alcohols with Imines
Ming Z. Chen,† Martin McLaughlin,‡ Masayuki Takahashi,‡ Michael A. Tarselli,‡
Dexi Yang,‡ Shuhei Umemura,‡ and Glenn C. Micalizio*,‡
Department of Chemistry, The Scripps Research Institute, and Kellogg School of Science and Technology at The
Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States. †Kellogg School of Science and
Technology at The Scripps Research Institute. ‡Department of Chemistry, The Scripps Research Institute.
micalizio@scripps.edu
Received August 10, 2010
Regio-, diastereo-, and enantioselective coupling reactions between imines and allylic alcohols have been
developed. These coupling reactions deliver complex homoallylic amine products through a convergent
C-C bond forming process that does not proceed through intermediate allylic organometallic reagents.
In general, convergent coupling, by exposure of an allylic alkoxide to a preformed Ti-imine complex,
occurs with allylic transposition in a predictable and stereocontrolled manner. While simple diastereo-
selection in these reactions is high, delivering anti-products with g20:1 selectivity, the organometallic
transformation described is compatible with a diverse range of functionality and substrates (including
aliphatic and aromatic imines, allylic silanes, trisubstituted alkenes, vinyl- and aryl halides,
trifluoromethyl groups, thioethers, and aromatic heterocycles). Alkene geometry of the products
is a complex function of the allylic alcohol structure and is consistent with a mechanistic proposal
based on syn-carbometalation followed by syn-elimination by way of a boat-like transition state
geometry. Single asymmetric coupling reactions provide a means to translate the stereochemical
information of the allylic alcohol to the homoallylic amine or to control diastereoselection in the
coupling reactions of achiral allylic alcohols with chiral imines. Double asymmetric coupling
reactions are also described that afford a unique means to control stereoselection in these complex
convergent coupling processes. Finally, empirical models are proposed that are consistent with the
observed stereochemical course of these coupling reactions en route to chiral homoallylic amines
possessing di- or trisubstituted alkenes and anti- or syn- relative stereochemistry at the allylic and
homoallylic positions.
Introduction
Despite their central role in the construction of natural
products and synthetic small molecules of biological signifi-
cance, the broad classes of reactions suitable for complex
Methods that accomplish bimolecular (convergent) C-C
bond formation define the backbone of organic synthesis.1
8048 J. Org. Chem. 2010, 75, 8048–8059
Published on Web 11/11/2010
DOI: 10.1021/jo101535d
r
2010 American Chemical Society

Chen et al.
JOCArticle
FIGURE 1. State-of-the-art methods for allyl transfer via the intermediacy of allylic organometallic reagents.
convergent C-C bond formation remain rather limited and
include reactions based on (1) nucleophilic substitution, (2)
nucleophilic addition to polarized π-bonds, (3) cycloaddi-
tion, (4) metal-catalyzed “cross-coupling”, and (5) crossed
olefin metathesis. Arguably, carbonyl addition chemistry is
among the most powerful subclass of convergent coupling,
offering opportunities for fragment union through the gen-
eration of a diverse range of stereodefined architecture
(including di- and trisubstituted alkenes, β-hydroxy carbonyls,
allylic- and homoallylic alcohols).2
Carbonyl allylation is a subset of carbonyl addition chem-
istry that, over the last thirty years, has emerged as a particu-
larly attractive method for acyclic stereocontrol, offering highly
stereoselective pathways to homoallylic alcohols and amines.3
The vast majority of established methods for carbonyl allyla-
tion, while powerful, depend on the use of allylic organome-
tallic reagents. Despite the discovery of catalytic methods for
the in situ generation of such reagents, the dependence on
accessing an allylic organometallic species has generally limited
the utility of such processes to the addition of simple unsatu-
rated hydrocarbon fragments.4,5 While the synthesis and ap-
plication of more functionalized allylic organometallic reagents
for complex fragment union is possible, as illustrated in Figure 1
such processes are often complicated by (1) functional group
tolerance in the preparation of the allylic organometallic re-
agent (A f B1/B2), (2) challenges associated with the control of
site-selectivity in the metalation step (A f B1/B2), (3) difficul-
ties in controlling the regioselectivity of C-C bond formation
[due to (a) the propensity for allylic isomerization of the in-
termediate allylorganometallic (B1 h B2), and (b) competition
between R- vs γ- attack], and (4) problems associated with
stereoselection [both tetrahedral stereochemistry and olefin
geometry (i.e., C vs E, or D vs F)]. In cases where the allylic
metal reagent is generated in a catalytic fashion, functional
group tolerance is often enhanced, but complexities still remain
due to competing isomerization of the allylic metal species, and
the aforementioned issues with regio- and stereoselection in the
C-C bond forming event.5 As such, the impact that carbonyl
allylation has in complex convergent bond construction, in-
dependent of whether such processes are rendered catalytic in
the metal, remains fundamentally limited.
An orthogonal strategy for allyl transfer can be envisioned
to proceed in an umpolung sense,6 with bond formation
occurring between a carbonyl-derived anion and an allylic
electrophile (Figure 2A). In the simplest of analyses, such a
transformation has related challenges to the use of allylic
organometallic reagents, where issues of regioselection de-
rive instead from a competition between SN2 and SN20
modes of addition, leading to the isomeric products of formal
allyl transfer (3 and 4). While the regiochemical course of trans-
formations in this class have the potential to be influenced by the
character of the groups flanking the allyl-unit (R3 and R4), and
the nature of the metal counterion associated with 1, major
barriers associated with the control of relative and absolute
stereochemistry combine to further complicate this subset of
potential coupling processes.7
(1) For a discussion of strategy in complex molecule synthesis, along with
detailed case studies, see: (a) Corey, E. J.; Cheng, X.-M. The Logic of
Chemical Synthesis; John Wiley & Sons, Inc.: New York, 1989. (b) Nicolaou,
K. C.; Sorensen, E. J. Classics in Total Synthesis; Wiley VCH: New York,
1996.
(2) For reviews, see: (a) Otera, J., Ed. Modern Carbonyl Chemistry; Wiley-
VCH: Weinheim, 2000; p 613. (b) Takeda, T., Ed. Modern Carbonyl
Olefination: Methods and Application; Wiley-VCH: Weinheim, 2004; p 365.
(3) For a current review of allylation chemistry, see: (a) Denmark, S. E.;
Almstead, N. G. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH:
New York, 2000; p 299. For a current review on the application of the
allylation reaction to the synthesis of natural products, see: (b) Chemler,
S. R.; Roush, W. R., in Modern Carbonyl Chemistry; Otera, J., Ed., Wiley-
VCH: New York, 2000; p 403. (c) Zanoni, G.; Pontiroli, A.; Marchetti, A.;
Vidari, G. Eur. J. Org. Chem. 2007, 3599.
As depicted in Figure 2B, a related reaction with a
heteroatom-substituted metallacyclopropane 5 was rea-
soned to proceed through a mechanistically distinct process,
where bimolecular C-C bond formation would result from
carbometalation of 2 (via a formal metal-centered [2 þ 2 þ 1]
(4) Notable exceptions include bifunctionalized allylmetal reagents
and complex crotylsilanes. For recent discussions, see: (a) Flamme, E. M.;
Roush, W. R. J. Am. Chem. Soc. 2002, 124, 13644 and references therein. (b)
Masse, C. E.; Panek, J. S. Chem. Rev. 1995, 95, 1293.
(5) For a review of catalytic enantioselective addition of allylic organo-
metallic reagents to aldehydes and ketones, see: (a) Denmark, S. E.; Fu, J.
Chem. Rev. 2003, 103, 2763. For a review of catalytically generated allylic
metal reagents that serve as electrophiles, see: (b) Lu, Z.; Ma, S. Angew.
Chem., Int. Ed. 2008, 47, 258.
(6) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239.
(7) For recent reviews that describe allylic substitution chemistry, see:
€
ꢀ
ꢀ
(a) Alexakis, A.; Backvall, J. E.; Krause, N.; Pamies, O.; Dieguez, M. Chem.
Rev. 2008, 108, 2796. (b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103,
2921.
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of a broadly useful convergent coupling reaction remain
ill-defined.9
Here, we present a full account of the scope and limitations
of a mild and general titanium alkoxide-mediated coupling
reaction between allylic alcohols and imines as a route to
stereochemically defined and highly functionalized homo-
allylic amines (Figure 3A).10 The scope of these reactions
now encompasses (1) the coupling of aromatic and aliphatic
imines, (2) enantioselective allyltransfer through the use of
chiral allylic alcohols, (3) double asymmetric coupling as a
strategy to override inherent trends in selectivity of single
asymmetric reactions, (4) the use of coupling partners bear-
ing a diverse range of functionality (including di- and
trisubstituted alkenes, thioethers, allylic silanes, aromatic
heterocycles, and aliphatic, vinyl- and aromatic halides), and
(5) stereodivergent coupling reactions to afford a range of
substituted homoallylic amines (Figure 3B).
Background Associated with Ti-alkoxides in Azametalla-
cyclopropane-mediated C-C Bond Formation. The discovery
that Ti(IV) alkoxides can be employed in a simple experi-
mental procedure for the generation of metallacyclopro-
panes represented perhaps an underappreciated advance in
the chemistry of Group 4 metallacycles.11 While reaction
development in this broad area of chemistry was initiated
with cyclopentadienyl-based Zr- and Ti- reagents,12,13 the
observation that related reactivity was accessible from in-
expensive and robust Ti-alkoxides, marked what could be
referred to as a historic advance in the area. Early attention
remained focused on the Kulinkovich reaction as a means to
prepare functionalized cyclopropanes from the reaction of
Grignard reagents with esters.14 Later, this general mode of
reactivity was expanded to encompass intermolecular variations
FIGURE 2. Umpolung-based strategy for carbonyl allylation.
process) in preference to simple nucleophilic addition (via SN2
or SN20 reaction pathways). The resulting isomeric metallacy-
clopropanes 6 and 7 would differ with respect to stability and
reactivity, affording a pathway to 3 by elimination of 6. Control
of this process could derive from one of two basic mechanistic
considerations. If the carbometalation process (5 þ 2 f 6 or 7)
is reversible, the elimination reaction (6 f 3) may represent a
means to funnel the mixture of metallacycles (6 þ 7) to the
desired product 3, through a process that would have the
potential to offer stereochemical control via selective elimina-
tion through the lowest energy transition state. Alternatively,
if the carbometalation process were to proceed under kinetic
control, then the stereochemical information derived from the
carbometalation (en route to metallacyclopentane 6) would
translate directly to the relative stereochemistry of the product,
assuming that the elimination reaction would proceed in a
mechanistically predictable fashion (syn- or anti-). While
glimpses of this mode of reactivity with Cp2Zr-imine com-
plexes were reported twenty years ago,8 the complex issues
associated with selectivity that are critical to the development
(10) (a) Takahashi, M.; McLaughlin, M.; Micalizio, G. C. Angew. Chem.,
Int. Ed. 2009, 48, 3648. Concurrent with our studies, Professor Cha recently
reported a related process: (b) Lysenko, I. L.; Lee, H. G.; Cha, J. K. Org. Lett.
2009, 11, 3132.
(11) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevsky, D. A.; Prityckaja,
T. S. Zh. Org. Khim. 1989, 25, 2245. For chemistry related to Ti-aryloxides,
see: (b) Chamberlain, L. R.; Durfee, L. D.; Fanwick, P. E.; Kobriger, L.;
Latersky, S. L.; McMullen, A. K.; Rothwell, I. P.; Folting, K.; Huffman,
J. C.; Streib, W. E.; Wang, R. J. Am. Chem. Soc. 1987, 109, 390.
(c) Chamberlain, L. R.; Durfee, L. D.; Fanwick, P. E.; Kobriger, L. M.;
Latesky, S. L.; McMullen, A. K.; Steffey, B. D.; Rothwell, I. P.; Folting, K.;
Huffman, J. C. J. Am. Chem. Soc. 1987, 109, 6068. (d) Thorn, M. G.; Hill,
J. E.; Waratuke, S. A.; Johnson, E. S.; Fanwick, P. E.; Rothwell, I. P. J. Am.
Chem. Soc. 1997, 119, 8630.
(12) For reviews, see: (a) Marek, I., Ed. Titanium and Zirconium in
Organic Synthesis; Wiley-VCH: Weinheim, 2002; p 512. (b) Buchwald, S. L.;
Nielsen, R. B. Chem. Rev. 1988, 88, 1047. (c) Negishi, E. J. Chem. Soc.,
Dalton Trans. 2005, 827.
(13) For early examples, see: (a) McDermott, J. X.; Whitesides, G. M.
J. Am. Chem. Soc. 1974, 96, 947. (b) McDermott, J. X.; Wilson, M. E.;
Whitesides, G. M. J. Am. Chem. Soc. 1976, 98, 6529. (c) Grubbs, R. H.;
Miyashita, A. J. Chem. Soc., Chem. Commun. 1977, 864. (d) Erker, G.;
Kropp, K. J. Am. Chem. Soc. 1979, 101, 3659. (e) Cohen, S. A.; Auburn,
P. R.; Bercaw, J. E. J. Am. Chem. Soc. 1983, 105, 1136. (f) Nugent, W. A.;
Calabrese, J. C. J. Am. Chem. Soc. 1984, 106, 6422. (g) Cohen, S. A.; Bercaw,
J. E. Organometallics 1985, 4, 1006. (h) Negishi, E.; Holmes, S. J.; Tour,
J. M.; Miller, J. A. J. Am. Chem. Soc. 1985, 107, 2568. (i) Negishi, E.;
Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett. 1986, 27, 2829.
(j) Buchwald, S. L.; Lum, R. T.; Dewan, J. C. J. Am. Chem. Soc. 1986,
108, 7441. (k) Buchwald, S. L.; Watson, B. T.; Huffman, J. C. J. Am. Chem.
Soc. 1986, 108, 7411. (n) Buchwald, S. L.; Watson, B. T.; Huffman, J. C. J.
Am. Chem. Soc. 1987, 109, 2544. (l) Buchwald, S. L.; Watson, B. T.; Lum,
R. T.; Nugent, W. A. J. Am. Chem. Soc. 1987, 109, 7137. (m) Fagan, P. J.;
Nugent, W. A. J. Am. Chem. Soc. 1988, 110, 2310. (n) RajanBabu, T. V.;
Nugent, W. A.; Taber, D. F.; Fagan, P. J. J. Am. Chem. Soc. 1988, 110, 7128.
(o) Hoveyda, A. H.; Xu, Z. J. Am. Chem. Soc. 1991, 113, 5079. (p) Hoveyda,
A. H.; Morken, J. P.; Houri, A. F.; Xu, Z. J. Am. Chem. Soc. 1992, 114, 6692.
(14) For a recent review, see: Kulinkovich, O. Eur. J. Org. Chem. 2004,
4517.
(8) For the coupling of alkynes with allylic ethers, see: (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. Tetrahedron 1995, 51, 4519. (c) Takai, K.; Yamada, M.;
Odaka, H.; Utimoto, K.; Fujii, T.; Furukawa, I. Chem. Lett. 1995, 315.
ꢀ
guez, F.; Alvarez-Rodrigo, L.; Zapico, J. M.;
(d) Barluenga, J.; Rodrı
´
Fananas, F. J. Chem.;Eur. J. 2004, 10, 109.
~
ꢀ
(9) For related chemistry of azametallacyclopropanes, see: (a) Buchwald,
S. L.; Watson, B. T.; Woods Wannamaker, M.; Dewan, J. C. J. Am. Chem.
Soc. 1989, 111, 4486. (b) Coles, N.; Whitby, R. J.; Blagg, J. Synlett 1990, 271.
(c) Grossman, R. B.; Davis, W. M.; Buchwald, S. L. J. Am. Chem. Soc. 1991,
113, 2321. (d) Gao, Y.; Yoshida, Y.; Sato, F. Synlett 1997, 1353.
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FIGURE 3. Homoallylic amines by Ti-alkoxide-mediated reductive cross-coupling.
of this reaction that proceeded by transfer of Ti from a pre-
formed metallacyclopropane to a synthetically valuable terminal
alkene.15 Concurrent with these studies, the basic reactivity
patterns of (RO)2Ti-alkyne and (RO)2Ti-imine complexes,
reflecting the related chemistry of Cp2Ti- and Cp2Zr- com-
plexes, were beginning to emerge.16
These early studies served to demonstrate that metallacyclo-
propanes/propenes, formed by the in situ reduction of Ti(IV)
alkoxides, were competent organometallic intermediates for
metal-centered [2 þ 2 þ 1] chemistry. However, barriers
associated with the control of regioselectivity, stereoselectivity,
and generally low levels of reactivity in these bimolecular C-C
bond forming processes have broadly restricted this, and
related areas of reaction development to a relatively modest
collection of convergent coupling processes between a limited
set of unsaturated substrates.17
Only recently have reaction strategies emerged that offer
FIGURE 4. General strategy for Ti-alkoxide-mediated coupling of
allylic alcohols with imines.
general and highly selective means for the control of inter-
molecular metal-centered [2 þ 2 þ 1] chemistry.17 The early
observations of Rothwell and Kulinkovich validated that
C-C bond formation with Ti-alkoxide-based metallacyclo-
propanes was viable. Given the well established propensity
for Ti(IV) alkoxides to undergo rapid and reversible ligand
exchange,18 and their ability to generate reactive metallacy-
clopropanes, we have been actively pursuing the develop-
ment of alkoxide-directed metal-centered [2 þ 2 þ 1]
chemistry based on these relatively benign, readily available,
inexpensive, and easily handled metal alkoxides. The allylic
alcohol-imine coupling reaction described here is a unique
bimolecular bond construction that has surfaced from our
studies in this area.
complex 9, followed by exposure to an allylic alkoxide 10
would lead to the transient mixed titanate ester 11 by rapid
and reversible ligand exchange. Subsequent carbometalation,
by way of 12, would deliver a strained bicyclic azametallacyclo-
pentane (13), which has the potential to undergo a syn-elimina-
tion similar to that postulated in the Tebbe olefination.19
If such a sequence were possible, we anticipated that car-
bometalation would proceed through a boat-like transition
state geometry, as in 12, based on mechanistic assumptions
that include (1) alignment of the σTi-C bond with πCdC bond
and (2) association of the allylic alkoxide of 10 with Ti to
render the carbometalation event intramolecular.20 Further
assuming that the carbometalation (12 f 13) would be
essentially irreversible,21 we anticipated that all aspects of
Results and Discussion
Our pursuit began with the proposal of a general pathway
for Ti-alkoxide-mediated reductive cross-coupling of imines
with allylic alcohols (Figure 4).10a Formation of a Ti-imine
(19) Related processes for the stereoselective coupling of internal alkynes
or vinylsilanes with allylic alcohols, see: (a) Kolundzic, F.; Micalizio, G. C.
J. Am. Chem. Soc. 2007, 129, 15112. (b) Belardi, J. K.; Micalizio, G. C. J. Am.
Chem. Soc. 2008, 130, 16870.
(15) Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118, 4198.
(16) For reviews, see: (a) Olan, A.; Six, Y. Tetrahedron 2010, 66, 15.
(b) Wolan, A.; Six, Y. Tetrahedron 2010, 66, 3097. (c) Sato, F.; Urabe, H.;
Okamoto, S. Chem. Rev. 2000, 100, 2835. (d) Kulinkovich, O. G.; de Meijere,
A. Chem. Rev. 2000, 100, 2789.
(17) (a) For a recent discussion on a subset of such limitations (with
respect to alkynes), see: Reichard, H. A.; McLaughlin, M.; Chen, M. Z.;
Micalizio, G. C. Eur. J. Org. Chem. 2010, 391. For a review of metallacycle-
mediated cross-coupling with substituted and electronically unactivated
alkenes, see: (b) Reichard, H. A.; Micalizio, G. C. Chem. Sci. 2010,
10.1039/C0SC00394H.
(20) As a result of the low reactivity of substituted alkenes in intermolec-
ular carbometalation chemistry, we reasoned that pre-association of the
allylic alkoxide with the Ti-imine complex would be required for productive
C-C bond formation. For a discussion of directed reactions in organic
chemistry, see: Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307.
(21) For a recent study that explores the potential of reversibility in
related Ti-promoted coupling reactions of homoallylic alcohols with imines,
see: Takahashi, M.; Micalizio, G. C. Chem. Commun. 2010, 46, 3336.
(22) An empirical model based on related boat-like transition states is
consistent with the stereochemical results of Ti-alkoxide-promoted vinylsi-
lane-allylic alcohol (ref 19b), and alkyne-allylic alcohol (ref 19a) coupling
reactions.
(18) Woodard, S. S.; Finn, M. G.; Sharpless, K. B. J. Am. Chem. Soc.
1991, 113, 106.
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We initiated study of the proposed bond construction with
the attempted coupling of an aromatic imine with simple
allylic alcohols. As illustrated in eq 1 of Figure 5, coupling of
imine 14 with allyl alcohol (15) delivers homoallylic amine 16
in 70% yield. While we were delighted to observe success in
this initial coupling reaction, our enthusiasm was dampened
by the host of other methods available for simple allylation
of imines.24 We therefore decided to move on to explore
more challenging and unprecedented bond constructions
with this novel Ti-mediated coupling reaction.
Imine prenylation remains a challenging problem in reaction
methodology, as allylic organometallic reagents typically deliver
homoallylic amine products derived from inverse prenylation.25
Interestingly, as depicted in eq 2 of Figure 5, Ti-alkoxide-
mediated coupling of imine 14 with the tertiary allylic alcohol
17 proceeds with exquisite levels of regioselection to deliver the
product of prenylation 18 in 83% yield. In this process, no
evidence could be found for the production of isomeric homo-
allylic amine products (rs g 20:1). This impressive level of
regioselection can be extended to the production of homoallylic
amines bearing a tetrasubstituted alkene. As depicted in eq 3,
coupling of imine 14 with allylic alcohol 19 delivers 20 in 80%
yield, again with high regioselection (g20:1).
While initial reports documenting the conversion of im-
ines to azatitanacyclopropanes with Ti(Oi-Pr)4 were limited
to a small subset of aromatic imines, subtle perturbation of
the established reaction conditions defined a pathway to
employ aliphatic imines in this reductive cross-coupling
reaction.26 Simply replacing the Grignard reagent typically
employed to access the initial “low-valent” Ti-species with
n-BuLi provides a set of conditions suitable to extend this
mode of reactivity to aliphatic imines. While we are uncertain
of the mechanistic underpinnings that allow for success in
these transformations, imine prenylation of branched (21)
and unbranched (23) imines proceed in g80% yield and
deliver products as single regioisomers (eqs 4 and 5).
Next, we shifted our attention to the examination of
relative stereochemistry in the coupling of achiral imines
with achiral allylic alcohols bearing an internal alkene. Cou-
pling of imine 14 with the (E)-allylic alcohol 25 delivers
homoallylic amine 26 in 87% yield (Figure 6A, eq 6). Here,
the regioselective allyl transfer reaction is coupled to very
high levels of diastereoselection that favor the formation of
the anti- product (ds g20:1). In the related example depicted
in eq 7, coupling of imine 14 to the isomeric (Z)-allylic
alcohol 27 also furnishes homoallylic amine 26 with very
high levels of stereoselection, albeit with slightly diminished
yield (68%). This stereoconvergence, whereby each alkene
isomer 25 and 27 furnishes the same anti-product 26, is
consistent with an empirical model that is based on the
minimization of nonbonded steric interactions in the boat-
like transition state geometries A and B (Figure 6B). The
isomeric transition states C and D suffer from the build-up of
significant nonbonded steric interactions as a result of the
eclipsing of Me- and Ph- substituents about the developing
C-C bond.
FIGURE 5. Allyl and prenyl transfer chemistry.
stereochemistry associated with product (3) would derive
from stereochemical control through minimization of non-
bonded stericinteractionsinthe boat-liketransition state12.22
Interestingly, complexities with this process emerge from
a cursory inspection of this proposal, as the Ti-imine com-
plex 9 is chiral, and the addition to substituted allylic alcohols
(10) could be complicated by significant double asymmetric
relationships.23
(23) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 1.
(24) For recent examples of imine allylation using preformed allylic
silanes, see: (a) Huber, J. D.; Perl, N. R.; Leighton, J. L. Angew. Chem.,
Int. Ed. 2008, 47, 3037. (b) Berger, R.; Rabbat, P. M. A.; Leighton, J. L.
J. Am. Chem. Soc. 2003, 125, 9596. (c) Schaus, J. V.; Jain, N.; Panek, J. S.
Tetrahedron 2000, 56, 10263. For recent examples using preformed allylic
stannanes, see: (d) Gastner, T.; Ishitani, H.; Akiyama, R.; Kobayashi, S.
Angew. Chem., Int. Ed. 2001, 40, 1896. (e) Hallett, D. J.; Thomas, E. J.
Tetrahedron: Asymmetry 1995, 6, 2575. (f) Keck, G. E.; Enholm, E. J. J. Org.
Chem. 1985, 50, 146. For recent examples employing preformed allylic boron
reagents, see: (g) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2006, 128, 9646.
(h) Li, S.; Batey, R. A. Chem. Commun. 2004, 1382. (i) Lou, S.; Moquist,
P. M.; Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398. (j) Itsuno, S.;
Watanabe, K.; Ito, K.; El-Shehawy, A. A.; Sarhan, A. A. Angew. Chem., Int.
Ed. Engl. 1997, 36, 109. For recent examples using in situ generated allylic
ꢀ
boron reagents, see: (k) Selander, N.; Kipke, A.; Sebelius, S.; Szabo, K. J.
J. Am. Chem. Soc. 2007, 13723. (l) Shimizu, M.; Kimura, M.; Watanabe, T.;
Tamaru, Y. Org. Lett. 2005, 7, 637. For examples using in situ generated allyl
palladium reagents, see: (m) Fernandes, R. A.; Stimac, A.; Yamamoto, Y.
J. Am. Chem. Soc. 2003, 125, 14133. (n) Hopkins, C.; Malinakova, H. C.
Org. Lett. 2006, 8, 5971–5974. For recent examples employing allylic zinc
reagents, see: (o) Wipf, P.; Kendall, C. Org. Lett. 2001, 3, 2773. (p) Wipf, P.;
Pierce, J. G. Org. Lett. 2005, 7, 3537. For a recent example using in situ
generated allylic titanium reagents, see: (q) Gao, Y.; Sato, F. J. Org. Chem.
1995, 60, 8136. For reviews on the synthesis of homoallylic amines via allylic
metal reagents, see: (r) Ramachandran, P. V.; Burghardt, T. E. Pure Appl.
Moving on, we explored the potential of this allylic
alcohol-imine coupling process for the establishment of
(25) For a rare example of imine prenylation, see: Yanagisawa, A.;
Ogasawara, K.; Yasue, K.; Yamamoto, H. J. Chem. Soc., Chem. Commun.
1996, 367.
ꢀ
Chem. 2006, 78, 1397. (s) Kouznetsov, V. V.; Mendez, L. Y. V. Synthesis
2008, 491. (t) Yamamoto, T.; Asao, N. Chem. Rev. 1993, 93, 2207.
(26) Tarselli, M. A.; Micalizio, G. C. Org. Lett. 2009, 11, 4596.
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FIGURE 6. Simple diastereoselection.
homoallylic amines bearing stereodefined alkenes.27 As de-
picted in eq 8 of Figure 7A, coupling of imine 14 with allylic
alcohol 28 provides the stereodefined homoallylic amine 29
in 87% yield. Here, the highly regioselective coupling process
proceeds with exquisite levels of selectivity for the formation
of a (Z)-trisubstituted alkene (Z:E g 20:1). Unfortunately,
union of 14 with 30 did not proceed in a similarly selective
manner (eq 9). While this coupling reaction delivers homo-
allylic amines in 92% yield, with very high levels of regio- and
anti-selectivity, the homoallylic amine products are formed
as a 1.6:1 mixture of alkene isomers, favoring the (Z)-isomer
31. Interestingly, the related coupling reaction of 14 with the
isomeric allylic alcohol 32 does proceed in a highly selective
manner, and delivers homoallylic amine 33 in 57% yield
(eq 10). Here, highly regioselective C-C bond formation occurs
in concert with the establishment of an anti-homoallylic
amine possessing an (E)-disubstituted alkene (anti:syn g 20:1;
E:Z g 20:1).
(27) Few reactions are broadly useful for the formation of homoallylic
amines that establish both an allylic stereocenter and a stereodefined alkene.
Examples include: (a) Kazmaier, U.; Zumpe, F. L. Eur. J. Org. Chem. 2001,
4067. (b) Kojima, K.; Kimura, M.; Tamaru, Y. Chem. Commun. 2005, 4717.
(c) Kojima, K.; Kimura, M.; Ueda, S.; Tamaru, Y. Tetrahedron 2006, 62,
7512. (d) Garigipati, R. S.; Cordova, R.; Parvez, M.; Weinreb, S. M.
Tetrahedron 1986, 42, 2979. (e) Bartlett, P. A.; Barstow, J. F. J. Org. Chem.
1982, 47, 3933. See also refs 24b and 24e.
FIGURE 7. Allylic alcohol-imine coupling reactions that establish
stereodefined di- and trisubstituted alkenes.
In a similarly impressive example, coupling of imine 14 with
the trisubstituted allylic alcohol 34 provides the stereodefined
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homoallylic amine 35 in 54% yield (eq 11). Here, regioselective
coupling again occurs to deliver a homoallylic amine possessing
an anti-stereochemical relationship, yet this time it does so
while establishing a (Z)-trisbustituted alkene with high levels of
stereocontrol (g20:1).
The reactions depicted in Figure 7A are quite complex and
deserve further comment. All allylic alcohols employed in
these reactions were racemic, and formation of the Ti-imine
complex of 14 occurs without stereochemical bias. As a
result, all of these coupling reactions are complicated by the
potential of diastereomeric combinations of metallacyclopro-
pane and allylic alcohol [i.e., (R)-imine complex þ (R)-28 vs
(R)-imine complex þ (S)-28]. Nevertheless, the results of these
experiments are consistent with an empirical model that is
based on: 1) in situ interconversion of azatitanacyclopropane
enantiomers,28 2) kinetically controlled carbometalation,21 and
3) syn-elimination through a boat-like transition state geometry.
As depicted in Figure 7B, coupling reactions of (Z)-allylic
alcohols are reasoned to be (E)-selective via reaction by way
of a transition state geometry E, where minimization of A-1,3
strain29 results in an equatorial disposition of the allylic sub-
stituent (R). If this stereoselective carbometalation is followed
by syn-elimination, then the equatorial disposition of this group
results in the formation of the (E)-alkene of 33. The high anti-
selectivity observed in the formation of 33 is consistent with the
minimization of eclipsing nonbonded steric interactions about
the developing C-C bond.
Alternatively, in the (Z)-selective coupling reaction of 34,
stereoselection is consistent with transition state F (Figure 7B).
Here, minimization of A-1,2 interactions in a boat-like transi-
tion state geometry is reasoned to result in a pseudoaxial
disposition of the allylic substituent. As discussed previously,
stereoselective carbometalation followed by syn-elimination
would then furnish the (Z)-anti-homoallylic amine 35.
The lack of stereoselection observed in the coupling reac-
tion of the (E)-disubstituted allylic alcohol 30, likely results
from the ability of the boat-like transition state geometry to
accommodate pseudoaxial or pseudoequatorial orientations
of the allylic substituent without suffering destabilization
from significant A-1,2 or A-1,3 strain.
Enantioselective Coupling. The high anti-selectivities ob-
served in the reactions of allylic alcohols 30, 32, and 34 point
to the ability of these coupling reactions to accomplish
kinetic resolution. In each case, one enantiomer of the allylic
alcohol (32 or 34) preferentially reacts with one enantiomer
of the Ti-imine complex to afford the anti- products.30 If
this were incorrect, then one would anticipate the appear-
ance of syn-homoallylic amine products. Their absence in
these coupling reactions led us to conclude that coupling
reactions of optically active allylic alcohols with racemic
Ti-imine complexes would define a means to render this
convergent coupling process enantioselective.
FIGURE 8. Enantioselective allylic alcohol-imine coupling.
stereochemical information from the allylic alcohol starting
material to the homoallylic amine products.31 While these
observations are consistent with reasoning derived from
analysis of the reactions depicted in Figure 7A, we realized
that a central feature of the enantioselective reactions de-
picted in eqs 12-14 was the translation of stereochemical
information from the allylic alcohol to the azametallacyclo-
propane through the minimization of eclipsing interactions
about the developing C-C bond (see the positioning of the
highlighted Me- and Ph substituents in E and F of Figure 7B).
We wondered whether this control feature is necessary for
(31) Note that the %ee of homoallylic amine products (eqs 12-14) reflect
the %ee of the allylic alcohol starting materials. While we were also successful
at accomplishing asymmetric coupling between a chiral allylic alcohol
possessing a trisubstituted alkene [(R)-34] and imine 14, we were unable to
establish the ee of the homoallylic amine product by HPLC or derivatization
(this coupling reaction proceeded in 77% yield). Given the likely mechanistic
course of this coupling reaction, and our inability to identify a minor isomer,
the transfer of stereochemical information in this process is reasoned to be as
high as that depicted in eq 12. This expectation is in accord with a the highly
diastereoselective coupling of imine 14 with the chiral allylic alcohol 60 which
occurred with superb levels of diastereoselectivity.10a
As depicted in Figure 8, eqs 12-14, we were delighted to
find that coupling reactions of (R)-32 with aromatic and
aliphatic imines proceed in a manner to effectively translate
(28) For a recent evaluation of the rate of interconversion of zirconaazir-
idine enantiomers, see: Cummings, S. A.; Tunge, J. A.; Norton, J. R. J. Am.
Chem. Soc. 2008, 130, 4669.
(29) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
(30) In these experiments, 2 equiv of the imine were employed. While it is
likely that the chiral Ti-imine complex rapidly undergoes inversion, these
experiments cannot provide support that the current process defines a
dynamic kinetic resolution.
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FIGURE 9. One-pot annulation for the synthesis of stereodefined
exoalkylidene γ-lactams.
the enantioselective version of this convergent coupling
reaction. As such, we examined the coupling of the enan-
tioenriched allylic alcohol (R)-28 (80% ee); a substrate that
lacks terminal substitution of the alkene. While this coupling
reaction did proceeded in an enantioselective fashion, sig-
nificant erosion of optical purity was observed for homo-
allylic amine product 29 (46% ee).
These studies (focused on stereochemistry) provided sup-
port that the present Ti-mediated allylic alcohol-imine
coupling can proceed in a highly controlled manner. Along-
side these efforts, we have broadly explored functional group
compatibility associated with this reductive cross-coupling
reaction. Due to the wealth of reactivity available with vinyl-
and aromatic halides, we initiated studies to explore the
compatibility of the allylic alcohol-imine coupling reaction
with substrates harboring this functionality. As depicted in
Figure 9A, allylic alcohols that contain vinyl chlorides,
bromides and iodides are all compatible with the coupling
process.10a,32 Recently, the orthogonality of this Ti-mediated
coupling process with vinyl halides was employed to define a
simple one-pot process for the stereoselective synthesis of
exoalkylidene γ-lactams (Figure 9B).32
This allylic alcohol-imine reductive cross-coupling reac-
tion is also compatible with allylic silanes. As illustrated in
Figure 10, orthogonality of this formal allyltransfer process
to the chemistry of allylsilanes10a,33 was demonstrated in a
reaction sequence of utility for the formation of stereode-
fined heterocycles. This complex example, also revealing the
compatibility of indoles and acetals in the Ti-mediated
coupling process, delivers the stereodefined polycyclic het-
erocycle 43 (dr g20:1), in just two steps from allylic alcohol
40 and imine 41.
FIGURE 10. Convergent synthesis of complex heterocycles via Ti-
mediated coupling of allylic alcohols with imines.
offering control over regioselection, relative stereochemistry
(allylic and homoallylic positions), and olefin geometry. As
depicted in Figure 11, coupling reactions have proven useful
for the stereoselective synthesis of anti-homoallylic amines pos-
sessing (E)-disubstituted (eq 16), and “(Z)”-trisubstituted ole-
fins (eq 17). While a related coupling reaction did produce an
anti-homoallylic amine bearing a (Z)-disubstituted alkene
(eq 18) (anti:syn g 20:1), this process did not proceed with
very high levels of stereochemical control (Z:E=1.6:1). In
addition to these observations concerning relative stereo-
chemical control, we have been successful in defining a highly
enantioselective cross-coupling reaction (eq 19). Unfortu-
nately, asymmetric coupling of a simple 1,1-disubstituted
olefin with an achiral imine does not proceed with good
translation of optical purity (eq 20). In an effort to over-
come the limitations in stereochemical control observed
from these studies(i.e., eqs18and20), wedirectedourattention
to the study of double asymmetric reductive cross-coupling
reactions.
While it was straightforward to prepare enantiodefined
allylic alcohols suitable for these studies, the selection of an
appropriate chiral imine was more complicated. As illus-
trated in Figure 12, chiral substituents could be introduced
by modification of R3, R4, or both.We selected to pursue
installation of a chiral auxiliary at R3 as a general means to
control formation of the chiral azametallacyclopropane
reaction partner. This choice was made based on previous
success in Zr- and Ti-mediated coupling reactions of imine
44 with TMS-acetylene (Figure 13). First reported in the Zr-
promoted reaction by Taguchi, imine 44 could be converted to
the chiral allylic amine 45 with very high levels of stereoselection
(ds = 95:5; obtained after heating the preformed azametallacy-
clopropane to 70 °C prior to addition of the alkyne).34 Later, in
2003, Sato demonstrated that this bond construction can be pro-
moted at low temperature with a Ti-alkoxide reagent, providing
45 with similarly high levels of stereoselection (dr > 97:3).35
Double Asymmetric Coupling Processes. Overall, the Ti-
mediated allylic alcohol-imine coupling process has been
demonstrated to be a powerful convergent coupling reaction,
being compatible with a range of functional groups and
(32) Umemura, S.; McLaughlin, M.; Micalizio, G. C. Org. Lett. 2009, 11,
5402.
(33) Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2009, 131, 17548.
During the course of these studies with allylsilanes, we observed that a simple
allylsilane related to 73, but bearing a primarly allylic alcohol, undergoes
reductive cross-coupling with aromatic imines in a uniquely regioselective
manner. Here, C-C bond formation occurs primarily at the internal carbon
of the alkene, generating a 1,3-aminoalcohol product. Studies aimed at
understanding this shift in site-selectivity are ongoing.
(34) Ito, H.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 1992, 33, 4469.
(35) Fukuhara, K.; Okamoto, S.; Sato, F. Org. Lett. 2003, 5, 2145.
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FIGURE 11. Summary of stereochemical observations.
bond construction. As depicted in eq 29 (Figure 14), reaction
of ent-44 with 47 delivers the syn-homoallylic amine 57, albeit
with only modest levels of stereoselection (57:58 = 2.3:1).
The sum of the experiments depicted in Figure 14 defines a
substantial double asymmetric relationship in these Ti-
mediated allylic alcohol-imine reductive cross-coupling re-
actions. The stereochemical pairing in eqs 24-28 clearly
represent matched double asymmetric reactions, while that
depicted in eq 29 represents a mismatched double asym-
metric relationship.
FIGURE 12. Potential double asymmetric coupling reactions.
An empirical model for these complex coupling reactions
is depicted in Figure 15. As has been previously proposed,
chirality transfer from the phenylglycine auxiliary to the azame-
tallacyclopropane likely results from two factors: (1) coordina-
tion of the pendant methyl ether to Ti, and (2) minimization of
nonbonded steric interactions inside the resulting cis-fused
bicyclo[3.1.0] system (Figure 15A). As depicted in Figure 15B,
assuming that ligand exchange (Ti-O bond formation) is
required prior to carbometalation, the matched and mis-
matched transition state geometries may resemble A and B.
If these models were correct, then they would seem to imply
that the alkyl substituent (R) is best accommodated in a
position oriented toward the developing C-C bond. While
it is not yet possible to conclude that this is a preferred
orientation of the allylic substituent, we searched for an
alternative explanation, as we could not find a compelling
argument to support this proposition.
FIGURE 13. Use of a phenylglycine auxiliary in azametallacyclo-
propane-based coupling reactions.
If instead, the carbometalation could proceed prior to
ligand exchange, with association occurring by a different
Lewis acid-Lewis base interaction, then one could imagine
reaction through a conformation consistent with the “inside
alkoxy effect.”36 As depicted in Figure 15C, the matched
double asymmetric pairing could then occur through a ge-
ometry similar to C, where the allylic substituent (R) is
preferentially disposed awayfrom thedevelopingσTi-C bond.
In a similar fashion, the mismatched pair could react through
As depicted in Figure 14, the double asymmetric reductive
cross-coupling between imine 44 and a range of chiral
(E)-allylic alcohols proved to be quite effective in preparing
(Z)-anti-homoallylic amine products (eqs 24-27). This reac-
tion is also compatible with chiral imines derived from aliphatic
aldehydes. As illustrated in eq 28, reductive cross-coupling of
imine 55 with allylic alcohol 53 proceeds in 60% yield, and
delivers the stereodefined homoallylic amine 56 with very high
levels of stereocontrol (Z:E g 95:5; anti/syn g 95:5).
Interestingly, changing the absolute stereochemistry of the
imine coupling partner results in a unique stereoselective
€
(36) Houk, K. N.; Moses, S. R.; Wu, Y.-D.; Rondan, N. G.; Jager, V.;
Schohe, R.; Fronczek, F. R. J. Am. Chem. Soc. 1984, 106, 3880.
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FIGURE 15. Empirical model for double asymmetric allylic
alcohol-imine reductive cross-coupling.
FIGURE 16. Stereoselective coupling for the synthesis of chiral
(Z)-trisubstituted homoallylic amines.
a related geometry (D). Here, while the allylic moiety (R) is
positioned antito the developingσTi-C bond, thisrelationship
requires that the transition state suffer from the build up of
significant nonbonded steric interactions about the develop-
ing C-C bond. We propose these models to provide a tool
FIGURE 14. Double asymmetric reductive cross-coupling.
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to aid in the selection of appropriate reaction partners for this
complex convergent coupling process and recognize that
future computational studies may aid in both refining their
structure and assessing their validity.
precipitate became white in color. The mixture was diluted with
saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc
(3 ꢀ 20 mL). The organic extracts were combined, dried over
MgSO4 then concentrated in vacuo. The crude product was
purified by flash column chromatography on silica gel (10%
EtOAc/hexanes) to afford homoallylic amine 16 as a colorless
Finally, in an effort to overcome the low levels of stereo-
induction in the asymmetric coupling of chiral 1,1-disubsti-
tuted olefins with achiral imines, we pursued a modified
version of this process to deliver (Z)-homoallylic amines with
high levels of stereocontrol. As illustrated in Figure 16, eq 30,
coupling of the chiral imine ent-44 with the racemic allylic
alcohol (()-28 proceeded in a highly stereoselective fashion
and delivered 59 in 89% yield. With (()-28 as the limiting
reagent, success in this process indicates the ability of each
enantiomer to react with the chiral complex of ent-44 in a
stereoconvergent manner.
1
oil (112 mg, 70%). H NMR (500 MHz, CDCl3) δ 7.37-7.21
(m, 10H), 5.75-5.66 (m, 1H), 5.09-5.02 (m, 2H), 3.71-3.66 (m,
2H), 3.52 (d, J = 13.3 Hz, 1H), 2.46-2.36 (m, 2H), 1.75 (br, 1H);
13C NMR (125 MHz, CDCl3) δ 144.1, 140.9, 135.7, 128.6, 128.5,
128.3, 127.5, 127.3, 127.0, 117.7, 61.9, 51.7, 43.3; IR (thin film,
NaCl) νmax 3063, 3026, 2835, 1639, 1603, 1585, 1493, 1453, 1356,
1326, 1307, 1198, 1117, 1070, 1028, 995, 916, 824, 759, 700 cm-1
;
HRMS (EI, H) m/z calc’d for C17H20N [M þ H]þ 238.1590,
found 238.1590.
General Procedure for the Reductive Cross-Coupling of Ali-
phatic Imines with Allylic Alcohols. Synthesis of (()-N-Benzyl-
2-methylundec-2-en-5-amine (24). To 6.0 mL of Et2O at -78 °C
was added successively Ti(Oi-Pr)4 (300 μL, 288 mg, 1.0 mmol)
and n-BuLi (2.4 M in hexanes, 2.0 mmol). The resulting orange
solution was stirred for 10 min, and then imine 23 (203 mg,
1.0 mmol) in THF (1.0 mL) was added in one portion via a
syringe. The bright orange solution was allowed to warm to room
temperature over 1 h, during which it became deep red-brown.
In a separate flask at -30 °C the lithium alkoxide of alcohol 17
(52 μL, 43.1 mg, 0.5 mmol) was generated in THF (0.5 mL) with
an equimolar amount of n-BuLi, and allowed to warm slowly to
0 °C over 15 min. The orange solution of imine-Ti complex was
recooled to -78 °C, and the alkoxide was added dropwise over 5
min. The resulting dark red solution was slowly warmed to room
temperature over 12 h, and then saturated aqueous NH4Cl
(0.8 mL) was added dropwise. The resulting blue suspension
was stirred for 30 min, filtered, the flask rinsed with EtOAc (2 ꢀ
5 mL), and concentrated. The crude product was purified by
flash column chromatography on silica gel (1/8 EtOAc/hexanes)
to afford homoallylic amine 24 as a colorless oil (252 mg, 92%).
1H NMR (400 MHz, CDCl3) δ 7.32-7.16 (m, 5H), 5.11 (triplet
of septets, J = 7.2, 1.2 Hz, 1H), 3.77 (s, 2H), 2.55 (m, 1H), 2.13
(t, J = 7.2 Hz, 2H), 1.72 (s, 3H), 1.63 (s, 3H), 1.45-1.26 (m,
15H), 0.89 (t, J = 7.2 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ
141.1, 133.6, 128.3, 128.1, 126.7, 121.4, 57.3, 51.4, 34.2, 32.7,
31.9, 29.6, 25.9, 25.8, 22.7, 18.1, 14.1; IR (thin film, NaCl) νmax
3027, 2956, 2926, 2855, 1494, 1454, 1376, 1103, 1028, 729, 697
cm-1; HRMS (EI, H) m/z calcd for C19H32N [M þ H]þ
274.2529, found 274.2554.
General Procedure for the One-Pot Synthesis of γ-Lactam.
Synthesis of (3S*,3aS*)-2-Benyl-3-phenyl-2,3,3a,4,5,6-hexahy-
dro-1H-isoindol-1-one (39). To a solution of imine 14 (74 μL,
78 mg, 0.400 mmol) and ClTi(Oi-Pr)3 (1.0 M in Et2O, 0.500
mmol) in toluene (1.6 mL) at -70 °C was added c-C5H9MgCl
(2.00 M in Et2O, 1.00 mmol) in a dropwise manner via a syringe.
The orange-brown solution was slowly warmed to -40 °C over
30 min and stirred at this temperature for 1.5 h. A solution of
sodium alkoxide, prepared by the deprotonation of alcohol 38
(106 mg, 0.600 mmol) in THF (1.6 mL) at 0 °C with NaH (60%
dispersion in mineral oil, 30 mg, 0.750 mmol), was added
dropwise via cannula to the brown solution of imine-Ti com-
plex at -40 °C. The reaction was allowed to warm to room
temperature and stirred overnight. To the reaction was added
H2O (36 μL, 36 mg, 2.00 mmol), and the resultant mixture was
rapidly stirred for 2 h.
Conclusion
With our focus on the discovery and elaboration of unique
metal-centered [2 þ 2 þ 1] chemistry for convergent C-C
bond formation, we have discovered a series of stereoselec-
tive Ti-mediated reactions for the union of allylic alcohols
with imines. During the course of our study, we have found
that Ti-mediated coupling reactions of allylic alcohols with
imines offers a family of bond constructions that are un-
rivaled by existing chemical methods. Moving beyond the
study of simple allylation, our studies have realized (1) a
highly regioselective allylic alcohol-based coupling reaction,
(2) a general pathway for imine prenylation, (3) a means for
the establishment of anti-homoallylic amines in concert with
the stereoselective generation of (E)- or (Z)-alkenes, and (4)
enantioselective formation of complex homoallylic amines
via single- or double-asymmetric reaction manifolds. Final-
ly, a series of empirical models have been proposed for these
complex bimolecular C-C bond forming processes that are
consistent with the sense of regio- and stereoselection observed.
Due to the low cost of the metal-containing reagents,37 the
ready availability of the coupling partners, benign nature of the
byproducts (TiO2 and Mg(II) salts), and substrate-controlled
selectivity, the current fragment coupling process is anticipated
to be of great utility in chemical synthesis. We look forward to
advances in reaction development and chemical synthesis that
follow from this report.
Experimental Section
General Procedure for the Reductive Cross-Coupling of Aro-
matic Imines with Allylic Alcohols. Synthesis of (()-N-Benzyl-1-
phenylbut-3-en-1-amine (16). To a solution of imine 14 (125 μL,
131 mg, 0.672 mmol) and Ti(Oi-Pr)4 (300 μL, 288 mg, 1.01
mmol) in Et2O (2.5 mL) at -78 °C was added dropwise
c-C5H9MgCl (2.25 M in Et2O, 2.03 mmol) via a syringe. The
mixture was warmed to -40 °C over 30 min and stirred for 1 h at
this temperature. A solution of lithium alkoxide, prepared by
the deprotonation of alcohol 15 (69 μL, 58.9 mg, 1.01 mmol) in
THF (1.0 mL) at -78 °C with n-BuLi (2.56 M in hexanes, 1.08
mmol) followed by warming to 0 °C over 15 min, was added
dropwise to the brown solution of imine-Ti complex at -40 °C
via cannula. The mixture was warmed to 0 °C over 30 min then
stirred at this temperature for 3 h. The reaction was quenched by
addition of H2O (1.0 mL) followed by rapid stirring until the
To the yellow solution of the reaction mixture was added
PdCl2 (1 mg, 0.008 mmol), t-Bu3P (1.0 M intoluene, 0.024mmol),
and Et3N (223 μL, 161 mg, 1.60 mmol). The reaction was
placed under an atmosphere of carbon monoxide using a
balloon, and heated at 70 °C for 12 h. After cooling down to room
temperature, the mixture was diluted with EtOAc (10 mL) and
filtered through a pad of Celite. The filtrate was further diluted
(37) For a discussion in the context of regioselective reductive cross-
coupling reactions of disubstituted alkynes, see ref 17.
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with EtOAc (75 mL) and washed successively with 1.0 N HCl
aqueous solution (75 mL), saturated aqueous NaHCO3 (75 mL),
and brine (100 mL). The organic layer was dried over MgSO4 and
concentrated in vacuo. The crude product was purified by flash
column chromatography on silica gel (1/10f1/5 EtOAc/hexanes)
to afford γ-lactam 39 as a white solid (89 mg, 73%, dr g 20:1). 1H
NMR (400 MHz, CDCl3) δ 7.34-7.22 (m, 3H), 7.18-7.10
(m, 3H), 7.10-7.05 (m, 2H), 6.94-6.86 (m, 2H), 6.54 (dt, J =
3.3, 3.3 Hz, 1H), 5.04 (d, J = 14.4 Hz, 1H), 3.78 (d, J = 7.6 Hz,
1H), 3.50 (d, J = 14.4 Hz, 1H), 2.54-2.40 (m, 1H), 2.28-2.14
(m, 1H), 1.85-1.66 (m, 2H), 1.43-1.26 (m, 1H), 1.16-0.99 (m,
1H); NMR (100 MHz, CDCl3) δ 169.2, 139.3, 136.5, 134.9, 129.0,
128.8, 128.5, 128.3, 127.6, 127.4, 66.7, 45.3, 44.4, 25.1, 24.8, 21.5; IR
(thin film, NaCl) νmax 3026, 2929, 2862, 1688, 1494, 1455, 1393,
1272, 736, 701 cm-1; HRMS (EI, H) m/z calcd for C21H22NO
[M þ H]þ 304.1696, found 304.1666.
(dd, J = 13.6, 12.0 Hz, 1H), 2.75 (m, 1H), 2.70 (dd, J = 14.8, 3.6
Hz, 1H), 2.55(qd, J = 6.4, 2.8Hz, 1H), 2.29 (dd, J = 13.6, 2.8 Hz,
1H), 1.29 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
150.7, 148.6, 137.2, 132.4, 126.4, 126.2, 124.7, 124.2, 120.7, 118.8,
117.8, 108.6, 106.2, 68.1, 62.5, 50.4, 42.2, 41.3, 29.1, 26.0, 14.8; IR
(thin film, NaCl) νmax 3585, 2919, 1660, 1471 cm-1; LRMS (ESI,
H) m/z calcd for C22H25NOS [M þ H]þ 412.2, found 412.5.
General Procedure for the Double Asymmetric Cross-Coupling
of Phenylglycine-Derived Imines with Chiral Allylic Alcohols.
Synthesis of (1R,2R,Z)-N-((R-2-Methoxy-1-phenylethyl)-2-
methyl-1-phenylhex-3-en-1-amine (48). To a solution of imine
44 (239 mg, 1.0 mmol) and Ti(Oi-Pr)4 (444 μL, 426 mg, 1.5 mmol)
in Et2O (4 mL) at -78 °C was added dropwise c-C5H9MgCl
(2.0 M in Et2O, 3.0 mmol) via a syringe. The mixture was warmed
to -30 °C over 30 min and stirred at this temperature for another
3 h. A solution of lithium alkoxide 47 in Et2O (0.5 mL), generated
in situ via deprotonation of the corresponding alcohol (50 mg,
0.5 mmol) with n-BuLi (2.54 M in hexanes, 0.55 mmol) at -78 °C
followed by warming to 0 °C over 20 min, was added dropwise to
the brown solution of imine-Ti complex at -30 °C via cannula.
The resulting mixture was warmed to ambient temperature over-
night. The reaction was quenched with saturated aqueous NaH-
CO3 (5 mL), and the resulting biphasic mixture was rapidly stirred
until the precipitate became white in color. The mixture was further
diluted with saturated aqueous NaHCO3 (10 mL) and extracted
with EtOAc (3 ꢀ 20 mL). The combined organic extracts were
washed with brine, dried over MgSO4, and concentrated in vacuo.
The crude product was purified by flash column chromatography
on silica gel (3% EtOAc/hexanes) to afford homoallylic amine 48
as a pale yellow oil (dr g20:1, Z/E g20:1, 126 mg, 78%). 1H NMR
(400 MHz, CDCl3) δ 7.11-6.96 (m, 10H), 5.45 (app dt, J = 10.8,
7.3 Hz, 1H), 5.13 (dd, J = 10.8, 10.8 Hz, 1H), 3.67 (dd, J = 6.7, 4.7
Hz, 1H), 3.44-3.34 (m, 2H), 3.28 (d, J = 8.5 Hz, 1H), 3.26
(s, 3H), 2.72-2.60 (m, 1H), 2.35 (br, 1H), 2.08-1.97 (m, 2H), 0.90
(t, J = 7.5 Hz, 3H), 0.63 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 143.5, 142.2, 133.3, 133.1, 128.7, 128.0, 127.8, 127.7,
126.8, 126.7, 76.6, 67.5, 61.0, 59.1, 38.8, 21.2, 18.1, 14.6; IR (thin
film, NaCl) νmax 3320, 3063, 2962, 2874, 2823, 1946, 1806, 1602,
1493, 1455, 1194, 1110, 757, 698 cm-1; HRMS (ESI, H) m/z calcd
General Procedure for the Synthesis of Quinolizidines and
Indolizidines. Synthesis of (8S*,11S*,11aS*)-5,11-Dimethyl-
10-methylene-8-(thiophen-2-yl)-5,6,8,9,10,11,11a,12 -octahydro-
indolo[3,2-b]quinolizine (43). To a solution of imine 41 (295 mg,
0.86 mmol) in Et2O (10 mL) was added Ti(Oi-Pr)4 (390 μL,
366 mg, 1.29 mmol). After stirring for 10 min, the solution was
cooled down to -78 °C and c-C5H9MgCl (2.0 M in Et2O,
2.58 mmol) was added via a syringe over 2 min. The solution
turned from yellow to dark brown after stirring at -78 °C for
1.5 h. Next, a solution of lithium alkoxide, prepared by the depro-
tonation of alcohol 40 (201 mg, 1.29 mmol) in THF (2.0 mL) at
-78 °C with n-BuLi (2.5 M in hexanes, 1.37 mmol) followed by
stirring for 10 min, was added dropwise to the brown solution of
imine-Ti complex via cannula. The mixture was slowly warmed to
room temperature, and stirred for 16 h. The reaction was quenched
by sequential addition of Et2O (10 mL) and saturated aqueous
NaHCO3 (5 mL), followed by vigorous stirring for 1 h. The
aqueous phase was extracted with Et2O (2 ꢀ 10 mL). the organic
extracts were combined, dried over MgSO4 and concentrated in
vacuo. The crude product was purified by flash column chroma-
tography on silica gel (1/20 EtOAc/hexanes) to afford homoallylic
amine 42 as a yellow oil (290 mg, 70%).
To a solution of homoallylic amine 42 (56 mg, 0.12 mmol) in
THF (5 mL) was added 1.0 N HCl aqueous solution (0.5 mL,
0.5 mmol). After stirring for 16 h, the reaction was quenched by
addition of pulverized K2CO3 (150 mg, 1.1 mmol). The neutra-
lized mixture was extracted with Et2O (2 ꢀ 10 mL). The organic
extracts were dried over MgSO4 and concentrated in vacuo. The
crude product was purified by flash column chromatography on
silica gel (1/40 EtOAc/hexanes) to afford quinolizidine 43 as a
white solid (26 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 7.38
(d, J = 7.2 Hz, 1H), 7.18 (m, 1H), 7.14 (m, 1H), 6.98 (m, 1H),
6.91 (m, 2H), 6.89 (m, 1H), 4.73 (s, 1H), 4.60 (s, 1H), 3.99
(ABq, J = 14.8 Hz, 1H), 3.61 (dd, J = 11.6, 3.6 Hz, 1H), 3.12
(ABq, J = 14.8 Hz, 1H), 3.04 (dd, J = 12.4, 10.4 Hz, 1H), 2.80
for C22H30NO [M þ H]þ 324.2327, found 324.2317; [R]D þ19.8
20
(c 0.69, CHCl3).
Acknowledgment. We gratefully acknowledge financial
support of this work by the National Institutes of Health
(GM80266 and GM80266-S1).
Supporting Information Available: Experimental proce-
dures, compound characterization, and copies of spectral data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 23, 2010 8059