Aliphatic lmines in titanium-mediated reductive cross-coupling: unique reactivity of Ti(O-i-Pr)-BuLi

Article abstract of DOI:10.1021/ol901870n

A procedure for the coupling of aliphatic lmlnes with allyllc and alienle alkoxldes Is described. The success of these studies was enabled by a unique reactivity profile of TI(IV) IsopropoxIde/n-BuLI compared to well-known TI(IV) IsopropoxIde/RMgX systems

Full text of DOI:10.1021/ol901870n

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4596-4599
Aliphatic Imines in Titanium-Mediated
Reductive Cross-Coupling: Unique
Reactivity of Ti(O-i-Pr)4/n-BuLi
Michael A. Tarselli and Glenn C. Micalizio*
Department of Chemistry, The Scripps Research Institute, Scripps Florida,
Jupiter, Florida 33458
micalizio@scripps.edu
Received August 11, 2009
ABSTRACT
A procedure for the coupling of aliphatic imines with allylic and allenic alkoxides is described. The success of these studies was enabled by
a unique reactivity profile of Ti(IV) isopropoxide/n-BuLi compared to well-known Ti(IV) isopropoxide/RMgX systems.
Nitrogen-containing small molecules have emerged as a
subset of organic structures that display a range of pharma-
ceutically relevant properties.1 As such, chemical methods
that provide new approaches to the stereoselective assembly
of diverse nitrogen-containing small molecules have great
potential to affect the pace of discovery in medicine. Of the
many robust methods available for the convergent synthesis
of such molecules, embracing the reactivity of imines as
electrophiles has proven to be a productive pursuit.2 By a
mechanistically distinct process, the reductive cross-coupling
of imines with alkenes, alkynes, and allenes has great po-
tential to unlock unique and powerful convergent coupling
reactions for the synthesis of stereodefined nitrogen-contain-
ing products. Until recently, many of these bond construc-
tions were ill-defined, with only a handful of processes
available for the regioselective coupling of highly activated
imine-based systems with a small subset of alkynes.3 In
our efforts to discover new cross-coupling reactions capa-
ble of forging C-C bonds between unactivated imines and
unsymmetrical and electronically unactivated alkynes, alk-
enes, and allenes, we have described a series of highly regio-
and stereoselective metal-mediated coupling reactions for the
synthesis of unsaturated 1,5-aminoalcohols,4 allylic amines,5
saturated 1,5-amino alcohols,6 and homoallylic amines7
(1 f 2-5; Figure 1). While these advances demonstrated
(3) (a) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2003, 42,
1364–1367. (b) Kong, J.-R.; Cho, C.-W.; Krische, M. J. J. Am. Chem. Soc.
2005, 127, 11269–11276. (c) Barchuk, A.; Ngai, M.-Y.; Krische, M. J.
J. Am. Chem. Soc. 2007, 129, 8432–8433. (d) Ngai, M.-Y.; Barchuk, A.;
Krische, M. J. J. Am. Chem. Soc. 2007, 129, 12644–12645. (e) Skucas, E.;
Zbieg, J. R.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 7242–7243.
(4) McLaughlin, M.; Takahashi, M.; Micalizio, G. C. Angew. Chem.,
Int. Ed. 2007, 46, 3912–3914.
(1) (a) Analogue-based Drug DiscoVery; Fischer, J., Ganellin, C. R.,
Eds.; John Wiley & Sons: New York, 2006. (b) Four of the top ten best-
selling drugs currently marketed in the US contain nitrogen heterocycles
(Lipitor, Plavix, Prevacid, and Nexium); see Forbes.com.
(5) McLaughlin, M.; Shimp, H. L.; Navarro, R.; Micalizio, G. C. Synlett
2008, 735–738.
(6) Takahashi, M.; Micalizio, G. C. J. Am. Chem. Soc. 2007, 129, 7514–
7416.
(2) (a) Martin, S. F. Pure Appl. Chem. 2009, 81, 195–204. (b) Ferraris,
D. Tetrahedron 2007, 63, 9581–9597. (c) Kobayashi, S.; Ishitani, H. Chem.
ReV. 1999, 99, 1069–1094.
(7) Takahashi, M.; McLaughlin, M.; Micalizio, G. C. Angew. Chem.,
Int. Ed. 2009, 48, 3648–3652.
10.1021/ol901870n CCC: $40.75
Published on Web 09/18/2009
 2009 American Chemical Society

(homocoupling) and addition of the organometallic reducing
agent to the imine, have been observed. In studies aimed at
overcoming these significant limitations, we explored the
titanium-mediated reduction of imine 8. As depicted in
Scheme 1, our preliminary study confirmed the poor reactiv-
Scheme 1
.
Reactivity Differences between RMgX and RLi in
the Reduction of Aliphatic Iminesa
Figure 1. Reductive cross-coupling reactions of imines with
unsaturated alkoxides: a new procedure for the coupling of aliphatic
imines.
a The crude secondary amine was dissolved in CH2Cl2 and treated with
TsCl (1.2 equiv) and 2 M NaOH (see the Supporting Information for details).
ity of the Kulinkovich/Sato system for this process (Ti(Oi-
Pr)4, i-PrMgCl) but demonstrated a significant dependence
of this reaction on the nature of the organometallic reducing
agent employed. In this case, employing n-BuLi as the
reductant11 led to superior results. Aside from the differences
in reactivity of the Ti(Oi-Pr)4/n-BuLi system in the reduction
of aliphatic imine 8, we observed a significant change in
physical properties associated with the reaction media at
elevated concentrations. As depicted in Figure 2, exposure
coupling processes of potential significance in chemical
synthesis, like other contributions in this general area of
reaction methodology (reductive coupling chemistry), they
were uniformly limited to a subset of imines, in this case
aromatic imines. In an effort to increase the significance of
these alkoxide-directed titanium-mediated reductive cross-
coupling reactions of imines, we sought to identify a method
suitable for the functionalization of aliphatic imines. Here,
we describe a useful method for the activation of aliphatic
imines via epititanation (6 f 7) and the application of these
activated complexes in reductive cross-coupling reactions
with allylic- and allenic alcohols.
The reduction of an aromatic imine by formation of an
azametallacyclopropane, and subsequent hydrolysis, is a well-
known process.8 To date, azametallacyclopropane formation
has generally been accomplished in one of two ways: (1) by
exposure of preformed aromatic imines to the combination
of a titanium(IV) alkoxide and a reactive organometallic
reagent (i.e., RMgX) or (2) by a metal-mediated redox
process with suitably functionalized amines.9 For the former
case, it has been documented that aliphatic imines are poor
substrates for the process,10 although the mechanistic details
that lead to their poor behavior remain poorly understood.
Deleterious side reactions, including pinacol-type coupling
Figure 2. Solution characteristics as a function of the nature of the
reducing metal employed.
(8) For a review, see: (a) Guan, H. Curr. Org. Chem. 2008, 12, 1406–
1430. (b) Uchikawa, W.; Matsuno, C.; Okamoto, S. Tetrahedron Lett. 2004,
45, 9037–9045. (c) Fukuhara, K.; Okamoto, S.; Sato, F. Org. Lett. 2003, 5,
2145–2148. (d) Gao, Y.; Yoshida, Y.; Sato, F. Synlett 1997, 1353–1354.
(9) Zr: (a) Buchwald, S. L.; Wannamaker, M. W.; Watson, B. T. J. Am.
Chem. Soc. 1989, 111, 776–777. (b) Buchwald, S. L.; Watson, B. T.;
Wannamaker, M. W.; Dewan, J. C. J. Am. Chem. Soc. 1989, 111, 4486–
4494. (c) Coles, N.; Whitby, R. J.; Blagg, J. Synlett 1990, 27, 1–272. Ca:
(d) Buch, F.; Harder, S. Organometallics 2007, 26, 5132–5135. Ta, Nb:
(e) Castro, A.; Galakhov, M. V.; Gomez, M.; Gomez-Sal, P.; Martin, A.;
Sanchez, F.; Velasco, P. Eur. J. Inorg. Chem. 2000, 204, 7–2054.
(10) Propionaldimine results in a 38% yield under Ti(O-i-Pr)4/i-PrMgCl
conditions: ref.8d A recent example by Cha and co-workers demonstrated
two aliphatic substrates in 40-60% yield using a Ti/RMgX system:
Lysenko, I. L.; Lee, H. G.; Cha, J. K. Org. Lett. 2009, 11, 3132–3134. In
this report, preformation of the presumed Ti-imine complex was not
required for allylation to ensue.
of imine 8 to Ti(Oi-Pr)4/n-BuLi in THF (0.7 M in titanium)
led to the formation of a free-flowing solution. In contrast,
treatment of imine 8 with Ti(Oi-Pr)4/i-PrMgCl in THF (0.5
M in titanium) led to the formation of a gelatinous suspen-
sion. While the unique reactivity of the n-BuLi-based system
is of central interest to the studies presented here, the ability
(11) (a) Eisch, J. J.; Gitua, J. N.; Otieno, P. O.; Shi, X. J. Organomet.
Chem. 2001, 624, 229–238. (b) Eisch, J. J.; Gitua, J. N. Organometallics
2003, 22, 24–26. (c) Eisch, J. J.; Adeosun, A. A.; Birmingham, J. M. Eur.
J. Inorg. Chem. 2007, 3, 9–43.
Org. Lett., Vol. 11, No. 20, 2009
4597

to maintain a free-flowing solution at elevated concentrations
of Ti(O-i-Pr)4 is a notable property of the system.
Moving on to explore C-C bond-forming processes with
aliphatic imines, success in titanium-mediated prenylation
of 8 was similarly dependent on the nature of the reducing
metal used (Table 1).12 While the secondary Grignard
Scheme 2
.
Reductive Cross-Coupling Reactions of Aliphatic
Imines with Allylic Alcohola
Table 1. Differences in Reactivity of Reducing Agents for
Imine Prenylationa
a Reaction conditions: (a) imine (1 equiv), Ti(O-i-Pr)4 (1.5 equiv),
reducing agent (3.0 equiv), alkoxide 12 (1.5 equiv), THF; (b) imine (2
equiv), Ti(O-i-Pr)4 (2.0 equiv), n-BuLi (4.0 equiv), alkoxide 12 (1.0 equiv),
Et2O/THF (6:1).
a Reaction conditions: imine (2.0 equiv), Ti(O-i-Pr)4 (2.0 equiv), n-BuLi
(4.0 equiv), Et2O, -78 °C to rt, 1 h; recool to -78 °C, add Li alkoxide of
allylic alcohol (1.0 equiv) in THF (0.5 mL) -78 °C to rt. b This product
was isolated as an inseparable mixture containing an additional 10% of the
product derived from butyl addition to the imine.
reagents investigated led to little product formation (entries
1 and 2), n-BuMgCl was marginally effective (entry 3).
Interestingly, organolithium reagents were uniformly more
effective for this transformation, with n-BuLi providing the
prenylated product 13 in 59% yield (entry 6). Due to the
enhanced efficiency observed in this preliminary screen, and
the practical advantages of n-BuLi, further study was
dedicated to this reducing metal. Optimization of the
prenylation was relatively straightforward, where simply
employing 2 equiv of aliphatic imine in the coupling reaction
with 12 led to the formation of the homoallylic amine 13 in
80% yield.13
As illustrated in Schemes 2 and 3, this preparatively simple
protocol to produce aliphatic imine-derived azametallacy-
clopropanes is useful for coupling reactions that extend
beyond prenylation. Scheme 2 highlights the compatibility
of this process for the coupling of aliphatic imines with a
variety of allylic alcohols. Equations 1-4 (Scheme 2)
describe coupling reactions of aliphatic imines that bear
R-branching. Finally, aliphatic imines that lack R-branching
are also competent reaction partners for coupling with allylic
alcohols. As demonstrated in eq 5 (Scheme 2), the heptyl-
imine 22 was converted to the prenylation product 23 in 92%
yield.14
The presumed azametallacyclopropanes prepared by ex-
posure of aliphatic imines to the combination of BuLi and
Ti(Oi-Pr)4 are also effective in cross-coupling reactions with
allenic alcohols. As depicted in Scheme 3, mono-, di-, and
trisubstituted allenes are all compatible with the process and
deliver allylic amines containing a valuable 1,3-diene motif.
Consistent with the trends in stereoselectivity observed in
the related coupling reaction of aromatic imines, the present
process was generally E-selective, with highest levels of
stereoselection observed in coupling reactions of allenes
bearing branched terminal substitution (i.e., 24 vs 26; Scheme
3, eqs 1 and 2). Finally isomeric allenes 28 and 30 are viable
partners with imine 8 (Scheme 3, eqs 3 and 4). In these cases,
the production of dienes 29 and 31 occurred in a regiospecific
fashion in 52 and 58% yield.
(12) Amin, S. R.; Crowe, W. E. Tetrahedron Lett. 1997, 38, 7487–7490
(see footnote 15).
In conclusion, it has long been accepted that alkyl imines
are particularly challanging substrates in reductive cross-
(13) (a) No evidence was found for the production of regioisomeric
products (derived from reverse prenylation). (b) This reaction also produced
15% of the product derived from butyl addition to the imine. (c) An
interesting Mg-ion effect was observed in this coupling reaction: When 1
equiv of MgBr2·OEt2 was added to this reaction (coupling of 8 with12 under
the optimized conditions with n-BuLi), the yield of 13 dropped to 47%. (d)
1H NMR spectra of the crude reaction mixtures resulting from attempted
prenylation of imine 8 via procedures employing a secondary alkyl Grignard
reagent and n-BuLi can be found in the Supporting Information.
(14) A limitation of this coupling reaction, compared to our previously
described allylation of aromatic imines, currently includes 2-halo-substituted
allylic alcohols. Employing the reaction conditions used to generate the
homoallylic amines in Scheme 2 for the coupling of 2-bromopropen-1-ol
with imine 12 did not lead to appreciable quantities of the anticipated product
of allyl transfer.
4598
Org. Lett., Vol. 11, No. 20, 2009

reagent typically employed in these processes has been cited
as the root cause of this limitation. In an attempt to overcome
this limitation, we initiated empirical studies to probe the
structure/activity relationships of a range of reducing orga-
nometallic reagents in titanium alkoxide-mediated reduction
of aliphatic imines. Initial studies led to the identification of
n-BuLi as a particularly effective reagent in combination with
Ti(O-i-Pr)4 for the net reduction of aliphatic imines. Subse-
quent to this observation, the reductive cross-coupling of a
variety of aliphatic imines with allylic and allenic alcohols
was accomplished. While the mechanistic underpinnings that
have resulted in empirical success remain undefined, the
current findings greatly impact the potential utility of metal-
mediated reductive cross-coupling reactions for the assembly
of stereodefined nitrogen-containing small molecules. Due
to the significance of such molecules in biology and
medicine, and the potential impact of stereoselective con-
vergent coupling processes well-suited for their synthesis,
we look forward to future developments that emerge from
these findings.
Scheme 3
.
Reductive Cross-Coupling Reactions of Aliphatic
Imines with Allenic Alcohols
Acknowledgment. We gratefully acknowledge financial
support of this work by the American Cancer Society (RSG-
06-117-01), Boehringer Ingelheim, Eli Lilly & Co., and the
National Institutes of Health NIGMS (GM80266).
a Reaction conditions: (a) imine (2.0 equiv), Ti(O-i-Pr)4 (2.0 equiv),
n-BuLi (4.0 equiv), THF, -78 °C to rt, 1 h; recool to -78 °C, add Li
alkoxide of allenyl alcohol (1.0 equiv) in THF, -78 °C to rt (10 min), then
warm to 60 °C; (b) imine (2.0 equiv), Ti(O-i-Pr)4 (2.0 equiv), n-BuLi (4.0
equiv), THF, -78 °C to rt, 1 h; recool to -78 °C and add Li-alkoxide of
allenyl alcohol (1.0 equiv) in THF, -78 °C to rt.
Supporting Information Available: Experimental pro-
cedures and tabulated spectroscopic data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
coupling chemistry. In titanium alkoxide-mediated processes,
alkylation of aliphatic imines with the reducing Grignard
OL901870N
Org. Lett., Vol. 11, No. 20, 2009
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