An alkoxide-directed intermolecular [2+2+1] annulation: A three-component coupling reaction for the synthesis of tetrasubstituted α,β- unsaturated γ-lactams

Article abstract of DOI:10.1002/anie.200605060

(Chemical Equation Presented) In full control: A regio- and stereoselective cross-coupling reaction between internal alkynes and imines that provides selective access to allylic amines and γ-lactams has been developed (see scheme). This intermolecular [2+2+1] process could be described as an alkoxide-directed aza-Pauson-Khand-like annulation. The alkyne can tolerate a wide range of substituents R³.

Full text of DOI:10.1002/anie.200605060

Communications
DOI: 10.1002/anie.200605060
Synthetic Methods
An Alkoxide-Directed Intermolecular [2+2+1] Annulation: A Three-
Component Coupling Reaction for the Synthesis of Tetrasubstituted
a,b-Unsaturated g-Lactams**
Martin McLaughlin, Masayuki Takahashi, and Glenn C. Micalizio*
Metal-mediated [2+2+1] annulations are a powerful class of
reactions for the synthesis of functionalized five-membered
rings.[1] These processes, which proceed by the initial forma-
tion of a metallacyclopentene followed by the insertion of
CO, have been described for a variety of functionalized
p systems (alkyne–alkene,[2] alkyne–ketone, alkene–ketone,[3]
alkene–aldehyde,[3,4] and alkyne–imine[5]), and have been
useful for the preparation of functionalized carbocyclic and
heterocyclic molecules. The vast majority of these annulation
reactions are synthetically useful only in intramolecular
contexts, whereby geometrical constraints imposed by a
tether between the two reacting p systems dictate the site-
ꢀ
selectivity in the C Cbond-forming event. The correspond-
ing bimolecular coupling reaction of unsymmetrically sub-
Scheme 1. Regioisomeric products from bimolecular [2+2+1] annula-
tion reactions. L=ligand.
stituted p systems from metal-mediated [2+2+1] annulations
has proven much less general as a result of the challenges
associated with the control of both reactivity and regioselec-
tivity in the generation of the polysubstituted metallacyclo-
pentene (Scheme 1, 1+2![A–D]!3–6). Here, we describe a
highly regioselective process for the bimolecular [2+2+1]
annulation that provides a convenient and direct route to
tetrasubstituted a,b-unsaturated g-lactams.
Nitrogen-containing heterocycles are ubiquitous struc-
tural motifs in natural products and small molecules of
biomedical relevance. Many methods for the convergent
between the internal alkyne and the imine (alkyne+imine!
azametallacyclopentene).[7] A general means to control the
ꢀ
site- and stereoselective C Cbond formation in these
bimolecular coupling reactions would render such processes
versatile for the synthesis of highly functionalized nitrogen-
containing acyclic and heterocyclic targets. Our recent success
in the development of selective cross-coupling reactions of
unactivated and differentially functionalized p systems
(alkyne–alkyne[8] and alkyne–alkene[9]), in which the unique
reactivity of Group IV metal alkoxides was harnessed, led us
to question whether we could define such a process for
alkyne–imine cross-coupling reactions through the directed
carbometalation of an internal alkyne with an azametallacy-
clopropane.
ꢀ
ꢀ
assembly of such structures target C Cor C N bond
=
formation by nucleophilic addition to C N-based p systems,
condensation, or metal-mediated cross-coupling reactions.[6]
An alternative and potentially more powerful pathway to
functionalized heterocycles is through multicomponent cou-
pling reactions between all-carbon-based p systems, imines,
and CO2 by using [2+2+1] annulation reactions.[5] To date,
these annulation processes have been of limited utility in
organic synthesis because of the poor levels of regioselection
commonly observed in the initial cross-coupling reaction
Our initial results for the regioselective cross-coupling
reaction between internal alkynes and imines are shown in
Table 1. In short, preformation of an azametallacyclopropane
(imine, Ti(OiPr)4, and cyclopentylmagnesium chloride, ꢀ78
to ꢀ408C) was followed by the addition of a homopropargylic
alkoxide, and warming the reaction mixture to 08C. Proto-
nation of the presumed bicyclic azametallacyclopentene then
delivered an unsaturated 1,5-amino alcohol. As illustrated in
entry 1 (Table 1), the coupling of imine 7 with the homopro-
pargylic alkoxide 8 provided the unsaturated 1,5-amino
alcohol 9. Importantly, no evidence was found for the
production of a minor regioisomer or olefin isomer. This
single result represents the first highly regioselective cross-
coupling reaction between an unsymmetrically substituted
internal alkyne and an imine that proceeds without the
requirement of electronic or steric differentiation of the
internal alkyne. Although metal-mediated coupling reactions
between alkynes and imines have been described, these
[*] M. McLaughlin, M. Takahashi, Prof. G. C. Micalizio
Department of Chemistry, Yale University
225 Prospect St., New Haven, CT 06520-8107 (USA)
Fax: (+1)203-432-6144
E-mail: glenn.micalizio@yale.edu
[**] We gratefully acknowledge financial support of this work by the
American Cancer Society, the American Chemical Society (PRF-G),
the Arnold and Mabel Beckman Foundation, Boehringer Ingelheim,
Eli Lilly & Co., the National Institutes of Health—NIGMS
(GM80266), and Yale University.
Supporting information for this article (including the character-
ization of all new compounds) is available on the WWW under
http://www.angewandte.org or from the author.
3912
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Angew. Chem. Int. Ed. 2007, 46, 3912 –3914

Angewandte
Chemie
Table 1: Stereoselective synthesis of unsaturated 1,5-amino alcohols.[a]
Table 2: Stereoselective synthesis of tetrasubstituted a,b-unsaturated
g-lactams.[a]
Entry
1
Imine
Unsaturated alkoxide Yield [%] Major regioisomer
65
Entry
Imine
Unsaturated alkox- Yield [%] Major regioisomer
ide
1
2
3
16
16
16
8; R=Me
10; R=Et
12; R=iPr
66
61
64
17; R=Me
18; R=Et
19; R=iPr
2
3
4
7
7
7
10: R=Et
12: R=iPr
14: R=TMS
60
53
55
11: R=Et
13: R=iPr
15: R=TMS
4
16
49
[a] Reaction conditions: Ti(OiPr)4, cC5H9MgCl, Et2O, ꢀ78 to ꢀ408C, then
unsaturated alkoxide (ꢀ40 to 08C), quenched with sat. aq NH4Cl. TMS=
trimethylsilyl.
coupling reactions proceed in a regioselective manner with
only a small subset of alkynes: terminal, trimethylsilyl (TMS)-
substituted, or conjugated alkynes.[5,7]
5
55
As observed in our alkyne–alkyne and alkene–alkyne
cross-coupling reactions,[8,9] the current process is relatively
insensitive to nonbonded steric interactions imposed by
substitution at the alkyne. For example, as depicted in
entries 2–4 (Table 1), ethyl-, isopropyl-, and TMS-substituted
alkynes were all effective cross-coupling partners, and fur-
nished the unsaturated 1,5-amino alcohols 11, 13, and 15 as
6
7
63
59
ꢀ
single regioisomeric products—in all cases C Cbond for-
mation occurred distal to the homopropargylic alkoxide,
independent of steric considerations. Interestingly, entry 4
(Table 1) demonstrated a complete reversal in regioselectivity
with respect to known cross-coupling reactions of TMS-
[a] Reaction conditions: Ti(OiPr)4, cC5H9MgCl, PhMe, ꢀ78 to ꢀ308C, then
unsaturated alkoxide (ꢀ30 to 08C), then CO2 (20 psi) 908C, 48 h. Bn=
benzyl.
ꢀ
substituted alkynes and imines (C Cbond formation typi-
cally occurred b to the TMS substitutent), hence demonstrat-
ing that the directing effect of the tethered alkoxide
completely overrides the directing effect of the TMS sub-
stituent.[10]
imine 21 with alkoxide 8 proceeded in a diastereoselective
manner and produced the corresponding atropisomeric
lactam 22 in a 4:1 ratio.
This [2+2+1] cross-coupling reaction could also be
performed in a stereoselective manner. As depicted in
Scheme 2, use of a chiral imine 27[12] in the cross-coupling
reaction with alkynes 8 or 12 provided the unsaturated 1,5-
amino alcohol products with regioselectivity greater than
95:5 (major/minor regioisomer) in all cases. Interestingly,
diastereoselectivity in these reactions appears to be a function
of the size of the terminal substituent of the alkyne (90:10 d.r.
when R = Me, 75:25 d.r. when R = iPr).
This diastereoselective cross-coupling reaction could be
extended to [2+2+1] annulation processes. As depicted in
Scheme 2b, coupling of imine 31, alkyne 8, and CO2
proceeded in a regio- and stereoselective manner to provide
the g-lactam 32 in 48% yield (ꢁ 95:5 (major/minor regioiso-
mer); 83:17 d.r.).[13]
With this site-selective alkyne–imine cross-coupling reac-
tion in hand, we focused our attention on developing an
intermolecular aza-Pauson–Khand-like annulation reaction
for the synthesis of tetrasubstituted g-lactams (Table 2).[5c] As
illustrated in entry 1 (Table 2), coupling of the imine 16 and
the methyl-substituted internal alkyne 8, followed by expo-
sure to CO2 (20 psi) and heating to 908C, furnished the
tetrasubstituted g-lactam 17 as a single regioisomer in 66%
yield. This annulation process was similarly effective with
alkyne substrates that possessed more sterically demanding
substituents at the terminus of the alkyne (entries 2–4,
Table 2), and provided access to the ethyl-, isopropyl-, and
TMS-substituted unsaturated g-lactams 18–20 as single
regioisomers. Substituted aromatic imines were also effective
coupling partners in this reaction; the aromatic imines 21, 23,
and 25 with ortho-methyl, meta-bromo, and para-bromo
substitution, respectively, provided the functionalized lactams
22, 24, and 26 in 55–63% yield (entries 5–7, Table 2).[11]
Interestingly, the coupling of the ortho-substituted aromatic
In conclusion, we have developed a highly regioselective
cross-coupling reaction between internal alkynes and imines
that provides convergent access to unsaturated 1,5-amino
alcohols or tetrasubstituted a,b-unsaturated g-lactams.[14] The
regiochemical control in these bimolecular coupling reactions
Angew. Chem. Int. Ed. 2007, 46, 3912 –3914ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3913

Communications
Keywords: alkynes · carbometalation · cross-coupling · imines ·
.
titanium
[1] For reviews, see: a) I. Ojima, M. Tzamarioudaki, Z. Li, R. J.
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azatitanacyclopentene to a g-lactam via exposure to CO2, see:
c) Y. Gao, M. Shirai, F. Sato, Tetrahedron Lett. 1997, 38, 6849 –
6852.
Scheme 2. Stereoselective synthesis of unsaturated 1,5-amino alcohols
and tetrasubstituted a,b-unsaturated g-lactams.
[6] For a recent review of transition-metal-catalyzed reactions in the
synthesis of heterocycles, see: I. Nakamura, Y. Yamamoto,
Chem. Rev. 2004, 104, 2127 – 2198.
[7] Control of regioselectivity in bimolecular metal-mediated cou-
pling reactions between internal alkynes and imines has been
possible in only a small subset of reactions, whereby the origin of
selectivity is derived by steric or electronic effects; for zirco-
nium-mediated coupling, see: a) S. L. Buchwald, B. T. Watson,
M. W. Wannamaker, J. C. Dewan, J. Am. Chem. Soc. 1989, 111,
4486 – 4494; b) R. B. Grossman, W. M. Davis, S. L. Buchwald, J.
Am. Chem. Soc. 1991, 113, 2321 – 2322; for titanium-mediated
coupling, see: c) Y. Gao, K. Harada, F. Sato, Tetrahedron Lett.
1995, 36, 5913 – 5916; d) Y. Gao, Y. Yoshida, F. Sato, Synlett 1997,
1353 – 1354; for nickel-mediated coupling, see: e) S. J. Patel, T. F.
Jamison, Angew. Chem. 2003, 115, 1402 – 1405; Angew. Chem.
Int. Ed. 2003, 42, 1364 – 1367; f) S. J. Patel, T. F. Jamison, Angew.
Chem. 2004, 116, 4031 – 4034; Angew. Chem. Int. Ed. 2004, 43,
3941 – 3944; for rhodium-mediated coupling, see: g) J.-R. Kong,
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11276.
results from alkoxide-directed carbometalation between a
preformed azametallacyclopropane and an internal alkyne.
The selectivity in these processes was independent of the
differential size of substituents around the internal alkyne,
and was completely dictated by the presence of a neighboring
alkoxide group. Finally, we have demonstrated the potential
to employ this coupling reaction in a stereoselective manner
whereby absolute stereochemical control is derived from a
chiral imine. Further studies focused on the control of related
intermolecular [2+2+1] processes are in progress.
Experimental Section
Representative procedure (entry 1, Table 2): Cyclopentylmagnesium
chloride (1.8m in diethyl ether, 2.70 mmol) was added dropwise with a
gas-tight syringe to a Schlenk tube charged with a solution of imine 16
(0.292 g, 1.50 mmol) and Ti(OiPr)4 (0.383 g, 1.35 mmol) in toluene
(5 mL) at ꢀ788C. The yellow solution was slowly warmed to ꢀ308C
over 1 h and the brown solution was stirred at ꢀ308Cfor a further 2 h.
Next, a solution of lithium alkoxide 8, generated from the deproto-
nation of the corresponding alcohol (0.028 g, 0.338 mmol) with nBuLi
(2.5m in hexanes, 0.371 mmol) in toluene (900 mL) at ꢀ788Cthen
warming to 08Cover 20 min, was added dropwise to the brown
solution of imine 16 at ꢀ308C. The reaction was allowed to warm to
08Cover 1 h and stirred at 0 8Cfor 4 h. The reaction was then cooled
to ꢀ308C, evacuated, backfilled with CO2 (20 psi, evacuation and
backfilling repeated 3 times), and heated to 908Cfor 48 h. Next, the
reaction was removed from the oil bath, the CO2 was released, and
the reaction was quenched with 1 mL of H2O. The resulting biphasic
mixture was rapidly stirred until the precipitate became white in
color. The solution was then further diluted with 0.5m HCl (40 mL)
and extracted with diethyl ether. The combined organic phases were
washed with saturated aqueous NaHCO3, brine, dried over MgSO4,
and concentrated in vacuo. The crude material was purified by
column chromatography on silica gel (50%!66% EtOAc/hexanes)
to yield g-lactam 17 as an off-white solid (68 mg, 66%).
[8] J. Ryan, G. C. Micalizio, J. Am. Chem. Soc. 2006, 128, 2764 –
2765.
[9] H. A. Reichard, G. C. Micalizio, Angew. Chem. 2007, 119, 1462 –
1465; Angew. Chem. Int. Ed. 2007, 46, 1440 – 1443.
[10] a) Y. Gao, K. Harada, F. Sato, Tetrahedron Lett. 1995, 36, 5913 –
5916; see also Ref. [9]; for an example of a unique nickel-
ꢂ
catalyzed reductive coupling with TMS-C C-Ph and nPrCHO
that provides similar regioselectivity, see: b) K. M. Miller, W.-S.
Huang, T. F. Jamison, J. Am. Chem. Soc. 2003, 125, 3442 – 3443.
[11] An aromatic heterocycle was tolerated on the imine, yet yields in
the coupling reaction with 2-furylbenzylimine were uniformly
lower (23%) than those between homopropargylic alkoxides
and imines 7, 16, 21, 23 and 25; for details, see the Supporting
Information.
[12] K. Fukuhara, S. Okamoto, F. Sato, Org. Lett. 2003, 5, 2145 – 2148.
[13] In this process, the addition of TMSCl prior to heating the
reaction mixture in the presence of CO2 minimized scrambling
of the g stereocenter.
[14] For an alternative coupling reaction of imines with fumarates in
the synthesis of a,b-unsaturated g-lactams, see: J. Barluenga, F.
Palacios, S. Fustero, V. Gotor, Synthesis 1981, 200 – 201.
Received: December 14, 2006
Revised: February 8, 2007
Published online: April 10, 2007
3914
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Angew. Chem. Int. Ed. 2007, 46, 3912 –3914