Mn-mediated coupling of alkyl iodides and ketimines: A radical addition route to α,α-disubstituted α-aminoesters

Article abstract of DOI:10.1021/ol800733b

(Chemical Equation Presented) Coupling of primary and secondary alkyl iodides with N-acylhydrazonoesters via Mn-mediated photolysis conditions affords access to tert-alkyl amines.

Full text of DOI:10.1021/ol800733b

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2311-2313
Mn-Mediated Coupling of Alkyl Iodides
and Ketimines: A Radical Addition
Route to r,r-Disubstituted
r-Aminoesters
Gregory K. Friestad* and An Ji
Department of Chemistry, UniVersity of Iowa, Iowa City, Iowa 52242
gregory-friestad@uiowa.edu
Received April 1, 2008
ABSTRACT
Coupling of primary and secondary alkyl iodides with N-acylhydrazonoesters via Mn-mediated photolysis conditions affords access to tert-
alkyl amines.
As a simple and valuable strategy for synthesis of chiral
amines, the carbon-carbon bond disconnection approach
involving additions to imino compounds (Figure 1) has
generated some notable recent accomplishments.1
both coupling components.3 Until now, these Mn-mediated
coupling reactions have been limited to aldehyde-derived
imino acceptors. However, additions to ketone-derived imino
compounds4 are of particular interest as they could provide
a diverse range of tert-alkyl amines not conveniently prepared
by nucleophilic substitution. Here we describe the first
examples of Mn-mediated coupling of diverse alkyl iodides
with ketone-derived hydrazones in a route to R,R-disubsti-
tuted R-amino esters (Figure 2).
Intermolecular radical additions to aldehyde-derived imino
acceptors are attracting increased attention, and a variety of
Figure 1. Carbon-carbon bond disconnection of chiral amines.
(2) Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2001, 123, 9922–9923.
Friestad, G. K.; Qin, J.; Suh, Y.; Marie´, J.-C. J. Org. Chem. 2006, 71, 7016–
7027.
However, a significant obstacle to these additions, when
strongly basic nucleophiles are used (e.g., Grignard reagents),
is a competitive aza-enolization to form metalloenamines.
Furthermore, the presence of other electrophilic functionality
within such organometallic nucleophiles is often quite
limited.
We have addressed this problem by developing Mn-
mediated coupling of alkyl iodides with N-acylhydrazones,2
exploiting conditions of notable versatility with respect to
(3) For applications in total synthesis, see: Friestad, G. K.; Deveau,
A. M.; Marie, J.-C. Org. Lett. 2004, 6, 3249–3252. Korapala, C. S.; Qin,
J.; Friestad, G. K. Org. Lett. 2007, 9, 4243–4246.
(4) (a) Review: Ramon, D. J.; Yus, M. Curr. Org. Chem. 2004, 8, 149–
183. (b) For examples, see: Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc.
1999, 121, 268–269. Davis, F. A.; Lee, S.; Zhang, H.; Fanelli, D. L. J.
Org. Chem. 2000, 65, 8704–8708. Ogawa, C.; Sugiura, M.; Kobayashi, S.
J. Org. Chem. 2002, 67, 5359–5364. Berger, R.; Duff, K.; Leighton, J. L.
J. Am. Chem. Soc. 2004, 126, 5686–5687. Ding, H.; Friestad, G. K. Synthesis
2004, 2216–2221. Dhudshia, B.; Tiburcio, J.; Thadani, A. N. Chem.
Commun. 2005, 5551–5553. Lauzon, C.; Charette, A. B. Org. Lett. 2006,
8, 2743–2745. Wada, R.; Shibuguchi, T.; Makino, S.; Oisaki, K.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 7687–7691. Canales, E.;
Hernandez, E.; Soderquist, J. A. J. Am. Chem. Soc. 2006, 128, 8712–8713.
(1) Review: Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541–
2569.
10.1021/ol800733b CCC: $40.75
Published on Web 05/08/2008
2008 American Chemical Society

was prepared. Condensation of N-benzoyl-N-methylhydrazine
with methyl pyruvate afforded (E)-hydrazone 3 in 83% yield,
with only trace amounts of the (Z)-hydrazone detected by
1H NMR (E/Z > 99:1). With this radical acceptor in hand,
Mn-mediated additions of various iodides to 3 were inspected
(Table 1). Combining 3 with InCl3 (2.2 equiv) in CH2Cl2,
Figure 2. Mn-mediated C-C bond construction approach to R,R-
disubstituted R-amino esters.
Table 1. Mn-Mediated Addition of Alkyl Iodides to
N-Acylhydrazone 3 and N-N Bond Cleavage (Scheme 1)a
conditions may be used to achieve the additions.5 However,
the corresponding additions to ketimine acceptors have not
yet reached their synthetic potential.6,7 In an important
seminal paper, several relevant examples were reported
involving addition of alkyl iodides (15-30 equiv) to ketimine
acceptors in the presence of triethylborane (5.0-7.5 equiv).7
Addition of simple commercial iodides (isopropyl, cyclo-
hexyl, and tert-butyl) was accompanied by ethyl addition,
N,C-dialkylation, and disproportionation side reactions. We
hoped the versatility of our Mn-mediated coupling method
could broaden the scope with respect to the radical precursors
(including primary and difunctional iodides more amenable
to synthetic applications), reduce the amount of iodide
required, and avoid all of the side reactions noted in the
earlier work.7
entry
R
yield of 4 (%)
yield of 5 (%)
1
2
3
4
5
6
7
Et
i-Pr
n-C5H11
n-C12H25
i-Bu
44
69
63
57
5a, 85
5b, 98
5c, 79
5d, 80
5e, 76
5f, 95
5g, 94
38b (51c)
49
TBSO(CH2)2
TBSO(CH2)4
50d (73c)
a Conditions: see text. b Recovered 3: 25%. c Yield in parentheses is
corrected for recovered 3. d Recovered 3: 32%.
introduction of Mn2(CO)10 (1.1 equiv) and the appropriate
iodide (5 equiv), and irradiation (300 nm, Rayonet) led to
the alkyl adducts 4a-4g. The N-H bond is likely formed
by H-atom abstraction from solvent.2 Subsequent treatment
with SmI2/MeOH in THF smoothly cleaved the N-N bonds
of these adducts to provide the corresponding free amines.8
These were isolated as their N-benzoyl derivatives in
76-98% yield.
Scheme 1
Asymmetric induction of this process was next examined.
For this purpose we chose the chiral N-acylhydrazone motif
derived from N-amino-2-oxazolidinones, successfully em-
ployed previously in a variety of reactions,9 including
stereocontrolled Mn-mediated radical additions to aldimine-
type acceptors.2,3 Amination of the potassium salt of com-
mercially available (S)-4-benzyl-2-oxazolidinone (6) with a
solution of monochloramine in methyl tert-butyl ether10 (eq
1) gave a quantitative yield of the N-amino-2-oxazolidinone,
which in turn was condensed with methyl pyruvate (1) to
give hydrazone 7 (E/Z 92:8). After removal of the minor
(Z)-isomer via flash chromatography, the (E)-N-acylhydra-
zone 7 was obtained in 75% yield.
For initial examination of the radical additions to ketone
hydrazones, a simple R-ketoester-derived N-acylhydrazone
(5) (a) Reviews of radical addition to CdN bonds: Friestad, G. K.
Tetrahedron 2001, 57, 5461–5496. Bertrand, M.; Feray, L.; Gastaldi, S.
C. R. Chimie 2002, 5, 623–638. Miyabe, H.; Ueda, M.; Naito, T. Synlett
2004, 1140–1157. (b) For selected recent examples, see: Cho, D. H.; Jang,
D. O. Chem. Commun. 2006, 5045–5047. Clerici, A.; Cannella, R.; Pastori,
N.; Panzeri, W.; Porta, O. Tetrahedron 2006, 62, 5986–5994. Yamada, K.;
Yamamoto, Y.; Maekawa, M.; Akindele, T.; Umeki, H.; Tomioka, K. Org.
Lett. 2006, 8, 87–89. Ueda, M.; Miyabe, H.; Sugino, H.; Miyata, O.; Naito,
T. Angew. Chem., Int. Ed. 2005, 44, 6190–6193. Risberg, E.; Fischer, A.;
Somfai, P. Tetrahedron 2005, 61, 8443–8450. Friestad, G. K.; Draghici,
C.; Soukri, M.; Qin, J. J. Org. Chem. 2005, 70, 6330–6338. McNabb, S. B.;
Ueda, M.; Naito, T. Org. Lett. 2004, 6, 1911–1914. Friestad, G. K.; Shen,
Y.; Ruggles, E. L. Angew. Chem., Int. Ed. 2003, 42, 5061–5063. Ferna´ndez,
M.; Alonso, R. Org. Lett. 2003, 5, 2461–2464.
Addition of ethyl iodide to (E)-7 using the Mn-mediated
photolysis conditions as described above gave 66% yield of
(7) (a) Miyabe, H.; Yamaoka, Y.; Takemoto, Y. J. Org. Chem. 2005,
70, 3324–3327. (b) Reactions reported in ref. 7a required oxygen atmosphere
to minimize competing ethyl addition, and the authors noted significant
hazards associated with that procedure.
(8) (a) Burk, M. J.; Feaster, J. E. J. Am. Chem. Soc. 1992, 114, 6266–
6267. (b) Ding, H.; Friestad, G. K. Org. Lett. 2004, 6, 637–640.
(9) Review: Friestad, G. K. Eur. J. Org. Chem. 2005, 3157–3172.
(6) Torrente, S.; Alonso, R. Org. Lett. 2001, 3, 1985–1987
.
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Org. Lett., Vol. 10, No. 11, 2008

Scheme 2
Table 2. Effects of Lewis Acids on Mn-Mediated Additiona
to the ester functionality of 7 in addition to the two-point
binding of the N-acylhydrazone. In light of this, Lewis acids
of higher coordination number might be expected to offer
anomalous results; thus the inversion of stereocontrol with
lanthanide Lewis acids (entries 5 and 6) is not surprising.
Lastly, the N-N bond cleavage was achieved upon
sequential treatment of isopropyl adduct 8b with n-butyl-
lithium, benzoic anhydride, and SmI2/MeOH (Scheme 2).
This sequence afforded known benzamide (S)-(+)-5b12 in
good yield, confirming the assigned configuration. Although
this N-N bond cleavage employed the benzoyl group for
purposes of chemical correlation of 5b, the more synthetically
useful trifluoroacetyl group can also be effective for N-N
bond activation.8b
The couplings of iodides and N-acylhydrazones described
herein document the first applications of this Mn-mediated
addition methodology to generation of quaternary carbon
stereocenters by addition to ketimine acceptors and offer
access to a variety of R-alkylated alanine analogs. With the
feasibility of these Mn-mediated additions to ketimines now
demonstrated, further studies are warranted. Notably, the
numerous side reactions and large excesses of reagents found
in the earlier work7 can be avoided by use of the Mn-
mediated couplings presented here.
yield of
dr of
8
entry
R
Lewis acid
8 (%)b
1
2
3
4
5
6
7
8
Et
InCl3
In(OTf)3
ZnCl2
Zn(OTf)2
La(OTf)3
Yb(OTf)3
Mg(ClO4)2
none
66
25
<3
53
21 (58)
25 (36)
33 (57)
44 (49)
85
70:30
51:49
n.d.c
63:37
42:58
34:66
56:44
55:45
92:8
9
i-Pr
InCl3 (2.2)d
InCl3 (1.2)d
InCl3 (0.5)d
InCl3 (0.2)d
10
11
12
70
54
50
82:18
80:20
74:26
a Conditions: see text. b Yield in parentheses is corrected for recovered
7. c Not determined. d The amount of InCl3 (equiv) is shown in parentheses.
the ethyl adduct, with diastereomer ratio of 70:30 (Table 2,
entry 1). Screening a variety of Lewis acids (entries 1-7)
showed that InCl3, Zn(OTf)2, La(OTf)3, and Mg(ClO4)2 all
led to similar yields of adduct 8a (after correcting for
recovered 7), but interestingly, La(OTf)3 and Yb(OTf)3
inverted the diastereoselection.
With stereocontrol at modest levels and subject to inver-
sion with different Lewis acids, these observations were
sharply in contrast to prior work involving additions to
aldimines.2,3 Thus it was of interest to gain further insight
into the role of the Lewis acid. Without Lewis acid, 8a
exhibited low selectivity in ethyl addition (entry 8). Isopropyl
addition occurred with much higher selectivity (entry 9); in
this case the indicated configuration of adduct 8b was
determined by crystallography (8a was assigned by anal-
ogy).11 The use of tert-butyl bromide was previously
ineffective in Mn-mediated addition2 and was not attempted
here. The stoichiometry of the Lewis acid was varied (Table
2, entries 9-12), illustrating the importance of at least 2
equiv of Lewis acid for effective stereocontrol. This evidence
suggests the possibility of competitive binding of Lewis acids
These radical additions complement enolate alkylation
methodologies, as they occur under nonbasic conditions and
permit introduction of both primary and secondary alkyl
groups with relative ease. The versatility with respect to the
iodide is a distinguishing feature of the Mn-mediated
coupling that foreshadows application to more complex
targets.
Acknowledgment. We thank NSF for continued support
of our radical addition methodology program (CHE-0096803
and CHE-0749850).
Supporting Information Available: Preparative proce-
dures and characterization data for compounds 3-5, 7, and
8. This material is available free of charge via the Internet
at http://pubs.acs.org.
(10) Hynes, J., Jr.; Doubleday, W. W.; Dyckman, A. J.; Godfrey, J. D.,
Jr.; Grosso, J. A.; Kiau, S.; Leftheris, K. J. Org. Chem. 2004, 69, 1368–
1371.
OL800733B
(11) The configuration of the major diasterereomer is consistent with
radical addition to the (E)-hydrazone according to the proposed chelate
model.2 Preliminary tests show that the pure (Z)-hydrazone leads to the
same diastereomer, suggesting in situ isomerization of the CdN bond. This
point is still under investigation.
(12) Obrecht, D.; Bohdal, U.; Broger, C.; Bur, D.; Lehmann, C.;
Ruffieux, R.; Scho¨nholzer, P.; Spiegler, C.; Mu¨ller, K. HelV. Chim. Acta
1995, 78, 563–580.
Org. Lett., Vol. 10, No. 11, 2008
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