Regioselective copper-catalyzed alkylation of [2.2.2]-acylnitroso cycloadducts: Remarkable effect of the halide of grignard reagents

Article abstract of DOI:10.1021/ol100454c

Ring opening with organometallic reagents of [2.2.2]-acylnitroso cycloadducts, including an enantioselective kinetic resolution of these compounds, has been accomplished for the first time. By the careful choice of reaction conditions, it was possible to obtain new cyclohexenyl hydroxamic acids with complete anti-stereoselectivity and a nice regioalternating control. A remarkable effect of the halogen of the Grignard reagent was observed during ring opening.

Full text of DOI:10.1021/ol100454c

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1828-1830
Regioselective Copper-Catalyzed
Alkylation of [2.2.2]-Acylnitroso
Cycloadducts: Remarkable Effect of the
Halide of Grignard Reagents
Stefano Crotti, Ferruccio Bertolini, Valeria di Bussolo, and Mauro Pineschi*
Dipartimento di Scienze Farmaceutiche, Sede di Chimica Bioorganica e Biofarmacia,
UniVersita` di Pisa, Via Bonanno 33, 56126 Pisa, Italy
pineschi@farm.unipi.it
Received February 23, 2010
ABSTRACT
Ring opening with organometallic reagents of [2.2.2]-acylnitroso cycloadducts, including an enantioselective kinetic resolution of these
compounds, has been accomplished for the first time. By the careful choice of reaction conditions, it was possible to obtain new cyclohexenyl
hydroxamic acids with complete anti-stereoselectivity and a nice regioalternating control. A remarkable effect of the halogen of the Grignard
reagent was observed during ring opening.
The use of heterobicyclic templates to obtain cycloaliphatic
compounds in a regio- and stereoselective way is a valuable
strategy in organic synthesis.1 Recently, many efforts have
been devoted to the nucleophilic ring-opening of hetero-
Diels-Alder [2.2.1]-bicyclic adducts as an efficient strategy
toward the synthesis of functionalized cyclopentenes.2,3
However, little interest can be found in analogous reactions
involving the less strained [2.2.2]-cycloadducts notwithstand-
ing the possibility to access valuable nitrogen-substituted
cyclohexenes by their ring openings. The ring opening of
[2.2.2]-acylnitroso adducts is more often effected by N-O
bond cleavage to give amino alcohols.4 On the other hand,
their nucleophilic ring-opening has been realized so far only
with heteronucleophiles (alcohols, water) in Lewis acid
catalyzed solvolytic conditions and showed a poor regio-
control.5 The C-O bond cleavage is of particular interest
because it allows the generation of a hydroxamic acid moiety,
a key structural element in a wide range of biologically active
compounds.3,5
(1) (a) Chiu, P.; Lautens, M. Top. Curr. Chem. 1997, 190, 1. (b) Hartung,
I. V.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. 2004, 443, 1934.
(2) For reviews on the ring opening of [2.2.1]-bicyclic hydrazines, see:
(a) Bournaud, C.; Chung, F.; Pe´rez Luna, A.; Pasco, M.; Errasti, G.; Lecourt,
T.; Micouin, L. Synthesis 2009, 869. (b) Sajisha, V. S.; Anas, S.; John, J.;
Radhakrishnan, K. V. Synlett 2009, 2885
.
(3) For very recent examples of the ring opening of [2.2.1]-acylnitroso
derivatives, see: (a) Tardibono, L. P. Jr.; Patzner, J.; Cesario, C.; Miller,
M. J. Org. Lett. 2009, 11, 4076. (b) Lin, W.; Virga, K. G.; Kim, K.-H.;
Zajicek, J.; Mendel, D.; Miller, M. J. J. Org. Chem. 2009, 74, 5941. (c)
Cesario, C.; Miller, M. J. J. Org. Chem. 2009, 74, 5730. (d) Yang, B.;
Miller, P. A.; Mo¨llmann, U.; Miller, M. J. Org. Lett. 2009, 11, 2828. (e)
Tardibono, L. P. Jr.; Miller, M. J. Org. Lett. 2009, 11, 1575. (f) Cesario,
C.; Miller, M. J. Org. Lett. 2009, 11, 1293. (g) Machin, B. P.; Howell, J.;
Mandel, J.; Blanchard, N.; Tam, W. Org. Lett. 2009, 11, 2077. (h) Machin,
B. P.; Ballantine, M.; Mandel, J.; Blanchard, N.; Tam, W. J. Org. Chem.
(4) Reductive N-O bond cleavage: (a) Mulvihill, M. J.; Gage, J. L.;
Miller, M. J. J. Org. Chem. 1998, 63, 3357. (b) Cesario, C.; Tardibono,
L. P. Jr.; Miller, M. J. J. Org. Chem. 2009, 74, 448. See also: (c) Yang, B.;
Miller, M. J. Org. Lett. 2010, 12, 392.
(5) (a) Yang, B.; Miller, M. J. Tetrahedron Lett. 2010, 51, 889, and
references therein. (b) Surman, M. D.; Miller, M. J. J. Org. Chem. 2001,
66, 2466.
2009, 74, 7261
.
10.1021/ol100454c  2010 American Chemical Society
Published on Web 03/16/2010

We report here unprecedented ring-openings of [2.2.2]-
acylnitroso cycloadducts with organometallic reagents to give
new substituted cyclohexenyl hydroxamic acids with a
definite stereo- and regiochemistry.
addition products 2b and 3b with a moderate yield but a
good 1,2-regioselectivity (Table 1, entry 1). To our surprise,
these compounds derived from the attack of the methyl
moiety, with only marginal formation (<7%) of the corre-
sponding phenylated adducts. This result deviates from the
normal exclusive or predominant addition of the phenyl
moiety from a reagent of this kind.8 Moreover, and without
any reasonable explanation, when the transmetalation with
PhLi was performed with the more common Et2AlCl or with
MeAlCl2 no addition took place (entry 2). To overcome the
scarce reactivity of Me2Zn with 1a, a solution was found by
the addition of Sc(OTf)3 (10 mol %) as an external Lewis
acid. In this way, we were able to obtain the 1,2-adduct with
complete regio- and anti-stereoselectivity, albeit with a
moderate conversion (entries 3-5 and 7).
The use of racemic phosphoramidite type ligand L2 (12
mol %) gave an improved conversion, together with a
complete regioselectivity (entry 4). The propensity of the
present addition reaction to stop halfway prompted us to
explore a kinetic resolution of acylnitroso cycloadducts 1a,b.
It is worth mentioning that [2.2.2]-acylnitroso cycloadducts
in enantioenriched form have been obtained by means of a
chiral auxiliary approach,9 probably because catalytic enan-
tioselective intermolecular acylnitroso Diels-Alder reactions
are very difficult processes.10 The kinetic resolution of
acylnitroso cycloadducts 1a,b with Me2Zn using (3.0 mol
%) of chiral ligand (R,R,R)-L3 showed modest but significant
levels of enantiomeric enrichment (36% ee for 1a, entry 5)
and (70% ee for 1b, entry 6). Diastereoisomeric phosphora-
midite (S,R,R)-L4 gave an inferior result (14% ee at 38%
conversion, entry 7). A significant increase in the efficiency
of the kinetic resolution (s ) 8.3) was found in the reaction
of Cbz-derivative 1b with 2.0 equiv of AlEt3 using (3.0 mol
%) of (R,R,R)-L3 and carrying out the reaction at -20 °C
(entry 8).11
In our continued interest in the reactivity of small-medium
ring heterocycles with carbon nucleophiles, we examined a
variety of organometallic reagents for the ring-opening of
compounds 1a,b. For this purpose, we examined the use of
organozinc and organoaluminium reagents which were found
to be effective in the related alkylation of the [2.2.1]-bicyclic
system.6 In preliminary experiments, we were disappointed
by the scarce reactivity (<5% conversion) of compounds 1a
and 1b with Et2Zn in the presence of catalytic amounts of
copper- and phosphorus-containing ligands. On the other
hand, the Cu(OTf)2-(()-binap (L1)-catalyzed addition of
organoaluminium reagents (3.0 equiv) to 1a gave a complex
mixture of products with removal of the protecting group,
while the addition to 1b proved to be rather slow (data not
shown in Table 1).7 Aiming to have a clean 1,2-arylation of
the bicyclic framework, we turned our attention to the mixed
organoaluminum reagent obtained from a dialkylaluminum
chloride reagent and PhLi. When we used Me2AlCl with the
Cbz-protected substrate 1b, we obtained the corresponding
Table 1. Copper-Catalyzed Ring Opening of Cycloadducts 1a,b
with Organozinc and Organoaluminium Reagentsa
In order to have a more robust and versatile entry to alkylated
cyclohexenyl hydroxamic acids, we also examined the reactions
of Grignard reagents with [2.2.2]-cycloadducts (Table 2).12 The
addition of 3.0 equiv of ethereal MeMgBr to 1a and 1b in
CH2Cl2 from 0 °C to rt for 18 h gave mixtures of the methylated
adducts with a preference for 1,4-addition adducts and consistent
amounts (22% for 1a and 43% for 1b) of the corresponding
sub
(% ee)
convnb
(%)
ratio
yieldc
(%)
(6) Pineschi, M.; Del Moro, F.; Crotti, P.; Macchia, F. Org. Lett. 2005,
7, 3605.
N
R-M
L
1,2/1,4b
(7) It is known that phosphoramidite ligands readily react with
organoaluminium reagents leading to aminophosphine ligands; see:
Bournaud, C.; Falciola, C.; Lecourt, C.; Rosset, S.; Alexakis, A.; Micouin,
L. Org. Lett. 2006, 8, 3581.
1
2
3
1b (Na)
1b (Na)
1a (Na)
1a (Na)
1a (36)
1b (70)
1a (14)
1b (49)
PhAlMe2
PhAlEt2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
AlEt3
L1
L1
L1
L2
L3
L3
L4
L3
95
<5
45
70
48
75
38
42
85/15
Nd
>98/<2
>98/<2
>98/<2
97/3
55d
Nd
(2a) 35
(2a) 58
(2a) 40
(2b) 50
Nd
e
4e
5e
6
(8) Millet, R.; Bernardez, T.; Palais, L.; Alexakis, A. Tetrahedron Lett.
2009, 50, 3474, and references cited therein.
(9) (a) Kirby, G. W.; Nazeer, M. Tetrahedron Lett. 1988, 29, 6173. (b)
Miller, A.; Paterson, T. Mc. C.; Procter, G. Synlett 1989, 32. (c) Miller,
A.; Procter, G. Tetrahedron Lett. 1990, 31, 1043. (d) Behr, J.-B.; Defoin,
A.; Pires, J.; Streith, J.; Macko, L.; Zehnder, M. Tetrahedron 1996, 52,
3283.
7e
8f
>98/<2
94/6
(4b) 30
a Reaction conditions: 1a or 1b (0.4 mmol), Cu(OTf)2 (0.02 mmol for
(10) For a review, see: (a) Yamamoto, Y.; Yamamoto, H. Eur. J. Org.
Chem. 2006, 2031. For mechanistic insights, see: (b) Howard, J. A. K.;
Ilyashenko, G.; Sparkes, H. A.; Whiting, A.; Wright, A. R. AdV. Synth.
Catal. 2008, 350, 869. For catalytic enantioselective intramolecular acylni-
troso Diels-Alder reactions, see: (c) Chow, C. P.; Shea, K. J J. Am. Chem.
Soc. 2005, 127, 3678.
entries 1-4, 0.006 mmol for entries 5-8), ligand (0.024 mmol for entries
1-3, 0.04 mmol for entry 4, and 0.012 mmol for entries 5-8), RM (1.2
mmol, 3.0 equiv), CH2Cl2 (2.0 mL), from 0 °C to rt for 18 h. b Determined
by H NMR of the crude mixture. c Isolated yields after chromatographic
1
purification of the indicated product. d Inseparable mixture of 2b and 3b.
e Addition of Sc(OTf)3 (10 mol %). f Reaction carried out at -20 °C for
24 h in anhydrous toluene with 2.0 equiv of AlEt3.
(11) Stereoselectivity factor (s) determined by the following equation:
s ) ln[(1 - c)(1 - ee)/ln[(1 - c)(1 + ee)] where c is the conversion of
1a,b and ee is the enantiomeric excess of remaining 1a,b.
Org. Lett., Vol. 12, No. 8, 2010
1829

edge, a regioalternating control of this kind has no precedents
in ring-opening reactions.
Table 2. Ring Opening of Cycloadduct 1a with Grignard
In particular, it was possible to change the native uncata-
lyzed SN2 regioselectivity observed with methyl Grignard
reagents and to obtain with a high regioselectivity the
corresponding 1,2-adducts deriving from a SN2′ pathway.
Probably, the influence of the halide stems from their relative
coordinating potency to copper within the magnesium cuprate
structure (i.e., the RCuMgXY species formed in situ) that is
in competition with the coordination of the phosphine ligand
to copper. Thus, the use of an uncatalyzed Grignard addition
and/or the use of harder chlorine based Grignard reagents
in combination with copper(II) salts preferentially gave 1,4-
adducts (path a, Scheme 1). The decreased acidity of the
Reagentsa
entry temp (°C) Grignard ratio 1,2/1,4b
yieldc (%)
1
0 to rt
-78
MeMgBr
MeMgBr
MeMgCl
MeMgCl
MeMgI
33/67
17/83
15/85
7/93
(2a) 18, (3a) 45
(2a) 10, (3a) 65
Nd
2
3
-78
4d
5
-78
(3a) 75
0 to rt
-78
93/7
(2a) 85
6
EtMgBr
EtMgCl
i-PrMgCl
EtMgI
80/20
33/67
60/40
94/6
(4a) 65
7d
8d
9
-78
(5a) 52
Scheme 1
.
Copper-Catalyzed Position Selective Ring Opening
of 1a with Different Grignard Reagents
-78
(6a) 45, (7a) 26
(4a) 85
-78
10
11
12
0 to rt
-78
EtMgI
PhMgBr
PhMgI
98/2
(4a) 94
30/70
66/34
(8a) 18, (9a) 40
(8a) 45, (9a) 22
0 to rt
a Reaction conditions: 1a (0.4 mmol), Cu(OTf)2 (0.02 mmol), (()-L1
(0.24 mmol), Grignard (1.2 mmol of a 2.0 M solution in Et2O), CH2Cl2
b
1
(2.0 mL) for 18 h, unless stated otherwise. Determined by H NMR of
the crude mixture. c Isolated yields of the indicated product after chromato-
graphic purification. d Anhydrous CuCl2 (0.02 mmmol) was used.
deprotected bicyclic oxazines. Next, our efforts concentrated
on N-Boc derivative 1a because the corresponding alkylated
adducts were separable by chromatographic purification. The
N-deprotection pathway and the presence of minor amounts of
other methylated adducts were suppressed when the reaction
was carried out in the presence of catalytic amounts of Cu(OTf)2
(5 mol %) and (()-binap (L1) (6 mol %) (Table 1, entry 1).
An increase of the 1,4-adducts 3a, deriving from a direct anti-
SN2 cleavage of the C-O bond, was observed when the
alkylation was performed at -78 °C (entries 2 and 3).13 The
maximization of the anti-SN2 addition pathway was realized
by means of chlorine-based Grignard reagents using anhydrous
CuCl2 as the copper salt (entry 4). To our surprise, switching
to the iodo Grignard reagent MeMgI dramatically reversed the
position selectivity of the methyl addition in favor of the 1,2-
adduct 2a that derives from an anti-SN2′ cleavage of the C-O
bond (entry 5). The use of other Grignards showed a predomi-
nant SN2-addition pathway, revealing the complex nature of the
catalytic system (entries 6-8). However, the addition of iodide-
based Grignard was still highly regioselective (entries 9 and
10). Aryl nucleophiles reacted efficiently but displayed poor
regioselectivity (entries 11 and 12).
corresponding magnesium salts, makes it possible for the
softer iodo magnesium cuprates to react with a high
selectivity at the softer site γ-position of the double bond
giving the 1,2-adduct (path b).
In conclusion, we successfully accomplished the ring-
opening by C-O bond cleavage of 1,3-cyclohexadiene-acyl
nitroso cycloadducts with organometallic reagents including
a kinetic resolution of these compounds. The position
selective installation of carbon based nucleophiles can be
tuned by the appropriate choice of reaction conditions, thus
opening a new regio- and stereocontrolled access to a variety
of cyclohexenyl hydroxamic acids.
Acknowledgment. This work was supported by the
Ministero dell’ Istruzione, dell’Universita` e della Ricerca
(MIUR Rome, PRIN 2006), and the University of Pisa.
A critical influence of the halogen of a Grignard reagent
on the regioselectivity of the addition process has been
described elsewhere.14 However, to the best of our knowl-
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(12) For the addition of Grignard reagents to [2.2.1]-acylnitroso
cycloadducts, see: (a) Surman, M. D.; Mulvihill, M. J.; Miller, M. J.
Tetrahedron Lett. 2002, 43, 1131. (b) Surman, M. D.; Mulvihill, M. J.;
Miller, M. J. J. Org. Chem. 2002, 67, 4115.
OL100454C
(13) The regio- and stereochemistry of the 1,2- and 1,4-adducts were
demonstrated by 2D NMR (COSY, HSQC, NOE) and 1D homodecoupling
experiments.
(14) For example, see: Kobayashi, Y.; Nakata, K.; Ainai, T. Org. Lett.
2005, 7, 183.
1830
Org. Lett., Vol. 12, No. 8, 2010