Regio- and stereoselective direct cross-coupling of aromatic imines with allenic alcohols

Article abstract of DOI:10.1055/s-2008-1042808

We describe a titanium-mediated reaction for the convergent coupling of allenic alcohols with aromatic imines. Overall, the bond formation occurs at the central carbon of the allene, proceeds with net allylic transposition, and provides substituted 1,3-dienes bearing allylic amine functionality in a regio- and stereoselective fashion. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042808

CLUSTER
735
Regio- and Stereoselective Direct Cross-Coupling of Aromatic Imines with
Allenic Alcohols
C
ross-Coupling of Aro
a
matic Imin
r
e
s
w
ith
A
t
llenic
i
A
lcoho
n
ls McLaughlin, Heidi L. Shimp, Raul Navarro, Glenn C. Micalizio*
Department of Chemistry, Yale University, New Haven, CT 06520, USA
Fax +1(203)4326144; E-mail: glenn.micalizio@yale.edu
Received 13 November 2007
trienes, presumably by a pathway that involves directed
Abstract: We describe a titanium-mediated reaction for the conver-
gent coupling of allenic alcohols with aromatic imines. Overall, the
bond formation occurs at the central carbon of the allene, proceeds
with net allylic transposition, and provides substituted 1,3-dienes
bearing allylic amine functionality in a regio- and stereoselective
fashion.
carbometalation followed by syn elimination.5b
In an effort to explore the utility of this type of control in
bimolecular functionalization of substituted allenes, ef-
forts were directed to the study of an imine–allene cross-
coupling reaction for the synthesis of substituted 1,3-
dienes 3. As depicted in Figure 2, preformation of an aza-
metallacyclopropane from imine 2, followed by addition
of an allenic alkoxide was anticipated to provide a path-
way to stereodefined 1,3-dienes 3 via formation of an in-
termediate metallacycle 4, followed by syn elimination.
As described in our reports of allene–alkyne5b and allylic
alcohol–alkyne6 cross-coupling, such bond construction
may be conceptualized by formal metallo-[3,3] rearrange-
ment by way of boat-like geometry I.
Key words: imines, allenes, cross-coupling, metallacycles, titani-
um
Site- and stereoselective functionalization of substituted
allenes represents a broad class of reactions of great utility
for the synthesis of stereodefined small molecules.1 The
subset of these transformations that proceed in an inter-
molecular fashion, and provide a carbon–carbon bond in
a regio- and stereoselective manner, are particularly pow-
erful in complex molecule synthesis.2 Carbometalation as
a pathway for such functionalization is rather complex
owing to the numerous regio- and stereoisomeric products
possible in the bimolecular bond-forming event (A–H;
Figure 1). Here, we describe an allene–imine cross-
coupling3 reaction that proceeds via site- and stereoselec-
tive union of a preformed azametallacyclopropane4 with
an allenic alcohol, and provides a convenient pathway to
the synthesis of substituted 1,3-dienes.
Formation of the azametallacyclopropane of aromatic
imine 5 [ClTi(Oi-Pr)3, c-C5H9MgCl, Et2O; –78 °C to –40
°C], followed by addition of the lithium alkoxide of allene
6 (as a solution in Et2O) and warming to 0 °C provides, on
aqueous workup, the substituted 1,3-diene 7 in 57% yield
(entry 1; Table 1).7 As demonstrated in entry 2, aromatic
chlorides are well tolerated in this cross-coupling reac-
tion. Reaction of 8 with the simple allene 6 provides the
functionalized diene 9 in 60% yield.
When the allene is substituted at the site distal to the hy-
droxymethyl substituent, one can achieve stereoselectivi-
ty in the cross-coupling reaction. As depicted in entry 3,
the methyl-substituted allenic alcohol 11 can be coupled
with imine 10 to provide the stereodefined 1,3-diene 12
(E/Z = 4:1). When the size of the distal substituent is in-
Recently, we demonstrated that allenes bearing tethered
hydroxy functionality are viable substrates for bimolecu-
lar reactions with preformed metallacyclopropenes.5 In
some cases, these cross-coupling reactions provide a
means to access highly substituted cross-conjugated
R3
R3
M
M
R3
R3
R2
M
M
R1
R1
R1
R1
R3
HN
R3
R2
R2
R2
HO
titanium-mediated
•
N
+
R2
A
B
C
D
R3M
cross-coupling
R1
•
R2
R1
H
R2
R1
H
R1
R1
R3
M
1
2
3
R1
R1
M
R3
M
R2
R3
R2
M
(Oi-Pr)n
R2
R3 R2
(i-PrO)n
Ti
O
R3
N
E
F
G
H
R2
Ti
R3
N
M = metal
O
H
H
H
R1
•
Scheme 1 Initial products possible in bimolecular carbometalation
R1
R2
of substituted allenes
4
I
directed carbometalation
then syn elimination
formal metallo-[3,3]
rearrangement
SYNLETT 2008, No. 5, pp 0735–0738
Advanced online publication: 10.03.2008
x
x.
x
x.
2
0
0
8
DOI: 10.1055/s-2008-1042808; Art ID: Y01407ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Plan for allene–imine cross-coupling

736
M. McLaughlin et al.
CLUSTER
Table 1 Cross-Coupling of Aromatic Imines with Allenic Alcohols
R2
R1
NH
R3
R2
OH
titanium-mediated
cross-coupling
•
N
+
R4
R1
H
R3
R4
Entrya
Imine
N
Allene
Yield (%)
E/Zb
Product
PMB
H
PMB
NH
OH
•
•
1
57
60
50
–
6
5
7
n-Pr
n-Pr
N
NH
OH
OH
Cl
Cl
2
3
–
H
6
8
9
Bn
Bn
NH
N
•
4:1
H
Me
Me
11
13
13
10
12
n-Pr
n-Pr
NH
N
OH
OH
•
Cl
Cl
4
5
63
57
≥ 20:1
≥ 20:1
H
i-Pr
i-Pr
8
14
Ph
Ph
H
NH
N
•
O
O
O
i-Pr
O
i-Pr
15
16
Bn
Bn
N
NH
OH
•
H
6
7
54
51
≥ 20:1
≥ 20:1
Me
O
Me
O
i-Pr
N
N
i-Pr
13
13
Me
Me
17
18
N
N
OH
NH
N
•
H
i-Pr
i-Pr
i-Pr
19
20
OMe
Ph
OH
H
N
•
N
MeO
8
78
≥ 20:1
i-Pr
Ph
Ph
13
22
dr ≥ 13:1c
21
a Typical reaction conditions: imine (1.0 equiv), ClTi(Oi-Pr)3 (1.25 equiv), c-C5H9MgCl (2.5 equiv), Et2O (–78 °C to –40 °C), then add allenyl
alkoxide (3–4 equiv, –40 °C to 0 °C).
b Refers to the establishment of the stereodefined substituted olefin derived from the allene.
c The relative stereochemistry was assigned based on analogy to alkyne–imine cross-coupling with imine 21 (see ref. 4f); this reaction was
warmed from 0 °C to 18 °C over 6 h.8
Synlett 2008, No. 5, 735–738 © Thieme Stuttgart · New York

CLUSTER
Cross-Coupling of Aromatic Imines with Allenic Alcohols
737
(3) For examples of palladium-catalyzed coupling of allenes
with imines, see: (a) Cooper, I. R.; Grigg, R.; MacLachlan,
W. S.; Thornton-Pett, M.; Sridharan, V. Chem. Commun.
2002, 1372. (b) Hopkins, C. D.; Malinakova, H. C. Org.
Lett. 2006, 8, 5971. For examples of cross-coupling
between allenylsulfides and imines, see: (c) Hayashi, Y.;
Shibata, T.; Narasaka, K. Chem. Lett. 1990, 1693.
(d) Narasaka, K.; Shibata, T.; Hayashi, Y. Bull. Chem. Soc.
Jpn. 1992, 65, 1392. For cross-coupling of vinyl allenes
with imines, see: (e) Regás, D.; Afonso, M. M.; Rodríguez,
M. L.; Palenzuela, J. A. J. Org. Chem. 2003, 68, 7845. For
cross-coupling of electron-deficient allenes with imines,
see: (f) Gandhi, R. P.; Ishar, M. P. S.; Wali, A. Tetrahedron
Lett. 1987, 28, 6679. (g) Xu, Z.; Lu, X. Tetrahedron Lett.
1997, 38, 3461. (h) Xu, Z.; Lu, X. J. Org. Chem. 1998, 63,
5031. (i) Ishar, M. P. S.; Kumar, K.; Kaur, S.; Kumar, S.;
Girdhar, N. K.; Sachar, S.; Marwaha, A.; Kapoor, A. Org.
Lett. 2001, 3, 2133. (j) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am.
Chem. Soc. 2003, 125, 4716. (k) Zhao, G.-L.; Huang, J.-W.;
Shi, M. Org. Lett. 2003, 5, 4737. (l) Zhao, G.-L.; Shi, M.
J. Org. Chem. 2005, 70, 9975. For a vanadium-catalyzed
allenol–imine cross-coupling, see: (m) Trost, B. M.;
Jonasson, C. Angew. Chem. Int. Ed. 2003, 42, 2063.
(4) For examples of cross-coupling with
creased, the stereoselection of the cross-coupling reaction
improves significantly. For example, reaction of the chlo-
rinated aromatic imine 8 with the isopropyl-substituted al-
lene 13 provides the stereodefined diene 14 in 63% yield,
with ≥20:1 stereoselection. As illustrated in entries 6 and
7, electron-rich aromatic imines 15 and 17 are equally ef-
fective in this cross-coupling reaction, providing the sub-
stituted 1,3-dienes 16 and 18 in 57% and 54% yield,
respectively.
Simple heterocyclic motifs are compatible with this
stereoselective cross-coupling reaction. As demonstrated
in entry 7, the morpholine-containing imine 19 can be
coupled to allene 13, in this case providing the stereode-
fined diene 20 with ≥20:1 stereoselection.
Finally, this reaction can be performed in a diastereoselec-
tive fashion. For example, coupling of the chiral imine
214e,g with racemic allene 13 provides allylic amine 22 in
78% yield (dr ≥13:1).
In summary, we have developed a new strategy for the
cross-coupling of aromatic imines with substituted al-
lenes. Selectivity is presumed to derive from a reaction
pathway that utilizes an allenic alkoxide as a key organiz-
ing structural motif. We propose a pathway for bimolecu-
lar C–C bond formation by ligand exchange at titanium,
followed by intramolecular carbometalation and syn elim-
ination. Overall, the selectivity of the process is consistent
with an empirical model based on formal metallo-[3,3] re-
arrangement. Studies aimed at exploring the generality of
this new cross-coupling reaction, and applications to the
synthesis of complex heterocycles are under way.
azametallacyclopropanes, see: (a) Buchwald, S. L.; Watson,
B. T.; Wannamaker, M. W.; Dewan, J. C. J. Am. Chem. Soc.
1989, 111, 4486. (b) Jensen, M.; Livinghouse, T. J. Am.
Chem. Soc. 1989, 111, 4495. (c) Brossman, R. B.; Davis, W.
M.; Buchwald, S. L. J. Am. Chem. Soc. 1991, 113, 2321.
(d) Gao, Y.; Harada, K.; Sato, F. Tetrahedron Lett. 1995, 36,
5913. (e) Fukuhara, K.; Okamoto, S.; Sato, F. Org. Lett.
2003, 5, 2145. (f) McLaughlin, M.; Takahashi, M.;
Micalizio, G. C. Angew. Chem. Int. Ed. 2007, 46, 3912.
(g) Takahashi, M.; Micalizio, G. C. J. Am. Chem. Soc. 2007,
129, 7514.
(5) (a) Shimp, H. L.; Micalizio, G. C. Chem. Commun. 2007,
4531. (b) Shimp, H. L.; Hare, A.; McLaughlin, M.;
Micalizio, G. C. Tetrahedron 2008, 64, accepted.
(6) Kolundzic, F.; Micalizio, G. C. J. Am. Chem. Soc. 2007, 129,
15112.
Acknowledgment
We gratefully acknowledge financial support of this work by the
American Cancer Society (RSG-06-117-01), the American Chemi-
cal Society (PRF-45334-G1), the Arnold and Mabel Beckman
Foundation, Boehringer Ingelheim, Eli Lilly & Co., and the Natio-
nal Institutes of Health – NIGMS (GM80266). H.L.S. acknowled-
(7) Experimental Procedure for the Preparation of 7
A solution of imine 5 (0.075 g, 0.333 mmol) in Et2O (2.2
mL) was cooled to –60 °C, and ClTi(Oi-Pr)3 (1.0 M solution
in hexanes, 0.416 mmol) was added dropwise with a gas-
tight syringe. The reaction was then cooled to –70 °C and
c-C5H9MgCl (2.02 M solution in Et2O, 0.832 mmol) was
added dropwise with a gas-tight syringe. During the addition
the solution turned light brown in color. The reaction was
then slowly warmed to –45 °C over 30 min and stirred at
–45 °C for an additional 90 min. Next, a solution of allenyl
alkoxide 6, generated from the deprotonation of the
corresponding alcohol (0.093 g, 1.33 mmol) with n-BuLi
(2.5 M in hexanes, 1.33 mmol), in Et2O (2 mL) at
ges Bristol-Myers Squibb for
a graduate fellowship. R.N.
acknowledges support from the STARS program at Yale Universi-
ty, and the ACS-PRF.
References and Notes
(1) For a recent review, see: Modern Allene Chemistry, Vol. 1
and 2; Krause, N.; Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, 2004.
–78 °C warming to 0 °C over 30 min, was added via Teflon
cannula. The reaction was then warmed to 0 °C over 60 min
and stirred at 0 °C 6 h. The reaction was then quenched at 0
°C with 5 mL of sat. aq NH4Cl and the resulting biphasic
mixture was rapidly stirred overnight at r.t. The reaction
mixture was further diluted with sat. NaHCO3, and extracted
with EtOAc. The combined organic phases were washed
with brine, dried over MgSO4, and concentrated in vacuo.
The crude material was purified by column chromatography
on silica gel (4% → 8% EtOAc–hexanes) to yield amine 7 as
(2) For application of allenes in natural product synthesis, see:
(a) Brummond, K. M.; Chen, H. Allenes in Natural Product
Synthesis, In Modern Allene Chemistry, Vol 2; Krause, N.;
Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004,
1041. (b) Alcaide, B.; Almendros, P. Eur. J. Org. Chem.
2004, 3377. (c) Marshall, J. A. J. Org. Chem. 2007, 72,
8153. (d) Wei, L.; Xiong, H.; Hsung, R. P. Acc. Chem. Res.
2003, 36, 773. (e) Sydnes, L. K. Chem. Rev. 2003, 103,
1133. (f) Krause, N.; Hoffmann-Röder, A.; Canisius, J.
Synthesis 2002, 1759. (g) Zimmer, R. Synthesis 1993, 165.
Synlett 2008, No. 5, 735–738 © Thieme Stuttgart · New York

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M. McLaughlin et al.
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a colorless oil (53 mg, 57%). 1H NMR (500 MHz, CDCl3):
d = 7.42–7.39 (m, 2 H), 7.34–7.30 (m, 2 H), 7.27–7.23 (m, 3
H), 6.88–6.85 (m, 2 H), 6.32 (dd, J = 17.7, 11.3 Hz, 1 H),
6.39 (s, 1 H), 5.31 (s, 1 H), 5.28 (d, J = 17.9 Hz, 1 H), 5.01
(d, J = 11.4 Hz, 1 H), 4.52 (s, 1 H), 3.80 (s, 3 H), 3.68 (dd,
J = 21.8, 12.9 Hz, 2 H), 1.61 (br s, 1 H). 13C NMR (126
MHz, CDCl3): d = 158.9, 147.6, 142.5, 137.1, 132.9, 129.6,
128.5, 127.9, 127.3, 115.9, 114.7, 114.0, 63.2, 55.5, 51.4. IR
(thin film, NaCl): 3004, 2935, 2833, 1512, 1246, 1611 cm–1.
LRMS (EI, H): m/z calcd for C19H22NO: 280.2 [M + H];
found: 280.1 [M + H]+.
(8) Experimental details for this reaction can be obtained on
request from the author.
Synlett 2008, No. 5, 735–738 © Thieme Stuttgart · New York

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