Catalytic enantioselective addition of organometallic reagents to N-formylimines using monodentate phosphoramidite ligands

Article abstract of DOI:10.1021/jo702140f

(Chemical Equation Presented) The asymmetric synthesis of protected amines via the copper/phosphoramidite-catalyzed addition of organozinc and organoaluminum reagents to N-acylimines, generated in situ from aromatic and aliphatic α-amidosulfones, is reported. High yields of optically active N-formyl-protected amines and enantioselectivities up to 99% were obtained. Under the reaction conditions, partial oxidation of the phosphoramidite ligand to the corresponding phosphoric amide was detected. A preliminary study on the origin and the effect on the catalytic addition reaction is presented.

Full text of DOI:10.1021/jo702140f

Catalytic Enantioselective Addition of Organometallic Reagents to
N-Formylimines Using Monodentate Phosphoramidite Ligands
Maria Gabriella Pizzuti, Adriaan J. Minnaard,* and Ben L. Feringa*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute for Chemistry,
UniVersity of Groningen, Nijenborgh 4, 9747, AG Groningen, The Netherlands
a.j.minnaard@rug.nl; b.l.feringa@rug.nl
ReceiVed October 2, 2007
The asymmetric synthesis of protected amines via the copper/phosphoramidite-catalyzed addition of
organozinc and organoaluminum reagents to N-acylimines, generated in situ from aromatic and aliphatic
R-amidosulfones, is reported. High yields of optically active N-formyl-protected amines and enantiose-
lectivities up to 99% were obtained. Under the reaction conditions, partial oxidation of the phosphoramidite
ligand to the corresponding phosphoric amide was detected. A preliminary study on the origin and the
effect on the catalytic addition reaction is presented.
Introduction
electrophilicity of the azomethine carbon makes these substrates
less reactive toward nucleophilic attack; moreover, enolizable
imines show a high tendency to undergo deprotonation, rather
than addition. The control of stereoselectivity in this reaction
is difficult because of the cis-trans isomerization about the
CdN double bond.6 Although many procedures employing
chiral auxiliaries5a-e,7 and stoichiometric chiral ligands5a-c,e,8
are described in the literature, the development of catalytic
versions of this reaction has been hampered by the capability
of the nitrogen of the imine or the product of the nucleophilic
addition to strongly bind the catalyst (for example, Lewis acids),
Enantiomerically pure chiral amines play a prominent role
in the area of fine chemicals and pharmaceuticals comprising
resolving agents,1 chiral auxiliaries,2 and catalysts3 as well as
building blocks for the synthesis of biologically active com-
pounds.4
The asymmetric addition of organometallic reagents to
CdN double bonds is one of the most powerful methods to
form optically active R-chiral amines.5 The development of this
reaction, however, has been limited, in comparison to the
corresponding addition to carbonyl compounds, by several
factors associated with the reactivity of imines. The poor
(5) For reviews on the addition of organometallic reagents to C,N double
bonds, see: (a) Denmark, S. E.; Nicaise, O. J.-C. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: Heidelberg, Germany 1999; Vol. 2, Chapter 26. (b)
Denmark, S. E.; Nicaise, O. J.-C. Chem. Commun. 1996, 999-1004. (c)
Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895-1946.
(d) Bloch, R. Chem. ReV. 1998, 98, 1407-1438. (e) Kobayashi, S.; Ishitani,
H. Chem. ReV. 1999, 99, 1069-1094. (f) Vilaivan, T.; Bhanthumnavin,
W.; Sritana-Anant, Y. Curr. Org. Chem. 2005, 9, 1315-1392. (g) Friestad,
G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541-2569.
(6) Eliel, E. L.; Wilen, S. H.; Mander, L. N. In Stereochemistry of
Organic Compounds; John Wiley & Sons, Inc.: New York, 1994; Chapter
9.
(7) (a) Yuan, Q.; Jian, S.-Z.; Wang, Y.-G. Synlett 2006, 7, 1113-1115.
(b) Boezio, A. A.; Solberghe, G.; Lauzon, C.; Charette, A. B. J. Org. Chem.
2003, 68, 3241-3245. (c) Di Fabio, R.; Alvaro, G.; Bertani, B.; Donati,
D.; Giacobbe, S.; Marchioro, C.; Palma, C.; Lynn, S. M. J. Org. Chem.
2002, 67, 7319-7328.
(8) (a) Andersson, P. G.; Johansson, F.; Tanner, D. Tetrahedron 1998,
54, 11549-11566. (b) Zhang, X.-M.; Zhang, H.-L.; Lin, W.-Q.; Gong, L.-
Z.; Mi, A.-Q.; Cui, X.; Jiang, Y.-Z.; Yu, K.-B. J. Org. Chem. 2003, 68,
4322-4329.
* To whom correspondence should be addressed. Fax: +31 50 363 4296.
Phone: +31 50 363 4278; +31 50 363 4258.
(1) Jacques, J.; Collet, A.; Wilen, S. H. In Enantiomers, Racemates and
Resolution; John Wiley and Sons: New York, 1981.
(2) Whitesell, J. K. Chem. ReV. 1989, 89, 1581-1590.
(3) For examples, see: (a) Shen, Y.-M.; Zhao, M.-X.; Xu, J.; Shi, Y.
Angew. Chem., Int. Ed. 2006, 45, 8005-8008. (b) Sandoval, C. A.; Ohkuma,
T.; Utsumi, N.; Tsutsumi, K.; Murata, K.; Noyori, R. Chem. Asian J. 2006,
1-2, 102-110. (c) Ibrahem, I.; Zou, W.; Engqvist, M.; Xu, Y.; Cordova,
A. Chem. Eur. J. 2005, 11, 7024-7029. (d) Li, H.; Walsh, P. J. J. Am.
Chem. Soc. 2004, 126, 6538-6539. (e) Adamo, M. F. A.; Aggarwal, V.
K.; Sage, M. A. J. Am. Chem. Soc. 2000, 122, 83-17-8318.
(4) For examples, see: (a) Berger, M.; Albrecht, B.; Berces, A.; Ettmayer,
P.; Neruda, W.; Woisetschla¨ger, M. J. Med. Chem. 2001, 44, 3031-3038.
(b) Rutenber, E. E.; De Voss, J. J.; Hoffman, L.; Stroud, R. M.; Lee, K.
H.; Alvarez, J.; McPhee, F.; Craik C.; Ortiz de Montellano P. R. Bioorg.
Med. Chem. 1997, 5, 1311-1320. (c) Cimarelli, C.; Palmieri, G. J. Org.
Chem. 1996, 61, 5557-5563. (d) Occhiato, E.; Bryan, J. J. Tetrahedron
1996, 52, 4199-4214.
10.1021/jo702140f CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/03/2008
940
J. Org. Chem. 2008, 73, 940-947

Addition of Organometallic Reagents to N-Formylimines
SCHEME 1. Addition of Organozinc Reagents to in Situ
Generated Imines
interrupting the cycle. Only recently, highly enantioselective
catalytic methods have appeared in the literature.5e,f,g The highest
enantioselectivities for the addition of dialkylzinc reagents have
been obtained on imine derivatives activated through N-
alkylation,9,10 N-sulfonylation,11,12 N-phosphonylation,13,14 and
N-acylation.15,16
Hoveyda reported the first efficient catalytic method for the
enantioselective addition of dialkylzinc reagents to a variety of
N-o-methoxyphenyl alkyl/aryl-aldimines.9a-c The use of chiral
Zr-dipeptide complexes as Lewis acid activators of the imino
acceptors allows the corresponding o-anisidine amines to be
obtained with enantioselectivities exceeding 98%. The low
yields observed for the aliphatic substrates were improved using
less Lewis acidic Hf-complexes.9d N-Sulfonylimines can also
undergo diethylzinc addition in high yields and with ee values
up to 96% in the presence of Cu(OTf)2 and amidophosphine
ligands, under mild conditions, as described by Tomioka et al.11
The state of the art for the dialkylzinc addition to N-diphe-
nylphosphinoylimines is currently represented by the protocol
developed by Charette group13 in which the use of a catalytic
amount of Cu(OTf)2 in combination with (R,R)-BozPHOS
promotes the alkylation of several aromatic and aliphatic
aldimines as well as aromatic ketimines in high yields and with
high enantioselectivities. Finally, the scope of the addition of
diorganozinc reagents to N-acylimines has been successfully
investigated by Bra¨se15 and Gong16 using respectively [2.2]-
paracyclophane-based N,O-ligands and 3,3′-substituted optically
active BINOLs in combination with racemic and achiral
diimines as effective activators. Although the latter methods
provide access to chiral N-acylamines in high yields and with
high enantioselectivities, they are restricted to the use of
substrates derived from aryl aldehydes. Moreover, laborious
synthesis of the chiral ligand or high catalyst loading is
frequently required. The use of N-formylimines as substrates
for the synthesis of alkylated chiral amines, however, appears
particularly attractive for several reasons. First, the product of
the reaction is a formamide that can be deprotected under mild
hydrolytic conditions and without loss of enantioselectivity.
Moreover, in order to prevent practical problems arising from
the inherent instability of imines, especially those derived from
aliphatic aldehydes, it is possible to generate these N-formyl
substrates in situ, from stable precursors (Scheme 1).
The starting material 1 is an imine adduct substituted on the
R-carbon with a leaving group. Elimination of the leaving group
under basic conditions generates the imine 2, which can undergo
nucleophilic attack to form the N-acylamine 3. Deprotection of
3 under mild conditions affords the free R-chiral amine 4. In
the addition reaction of R2Zn, the nucleophile acts also as a
base generating the N-acylimine together with an equimolar
amount of RH and of the adduct LGZnR. Clearly, it is important
that such a species does not inhibit the catalytic process. Several
leaving groups have been used to form N-acylimines, for
example, benzotriazolates,17 succinimidates,18 and sulfinates.15,16,19
In the addition reaction of diorganozinc reagents, the sulfinate
is often the leaving group of choice because its adduct with
R2Zn does not affect the addition reaction13c and because the
corresponding R-amidosulfones are readily available via a one-
pot condensation of the desired aldehyde with p-toluenesulfinic
acid and an amide or a carbamate.20
(9) (a) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J.
Am. Chem. Soc. 2001, 123, 10409-10410. (b) Porter, J. R.; Traverse, J.
F.; Hoveyda, A. H.; Snapper, M. L. J. Am. Chem. Soc. 2001, 123, 984-
985. (c) Akullian, L. C.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2003, 42, 4244-4247. (d) Akullian, L. C.; Porter, J. R.; Traverse,
J. F.; Snapper, M. L.; Hoveyda, A. H. AdV. Synth. Catal. 2005, 347, 417-
425.
(10) Basra, S.; Fennie, M. W.; Kozlowski, M. C. Org. Lett. 2006, 8,
2659-2662.
We considered these features highly attractive in order to
develop a short and practical catalytic, enantioselective route
to chiral amines, starting from aromatic and aliphatic aldehydes,
formamide, and organometallic reagents, based on the use of
readily available chiral phosphoramidite ligands21 in combination
with Cu(II) salts.
(11) (a) Fujihara, H.; Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000,
122, 12055-12056. (b) Nagai, K.; Fujihara, H.; Kuriyama, M.; Yamada,
K.; Tomioka, K. Chem. Lett. 2002, 8-9. (c) Soeta, T.; Nagai, K.; Fujihara,
H.; Kuriyama, M.; Tomioka, K. J. Org. Chem. 2003, 68, 9723-9727.
(12) (a) Wang, C.-J.; Shi, M. J. Org. Chem. 2003, 68, 6229-6237. (b)
Shi, M.; Zhang, W. Tetrahedron: Asymmetry 2003, 14, 3407-3414. (c) Li,
X.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Tetrahedron: Asymmetry
2003, 14, 3819-3821. (d) Wang, M.-C.; Xu, C.-L.; Zou, Y.-X.; Liu, H.-
M.; Wang, D.-K. Tetrahedron Lett. 2005, 46, 5413-5416.
Results and Discussion
(13) (a) Boezio, A. A.; Charette, A. B. J. Am. Chem. Soc. 2003, 125,
1692-1693. (b) Boezio, A. A.; Pytkowicz, J.; Cote, A.; Charette, A. B. J.
Am. Chem. Soc. 2003, 125, 14260-14261. (c) Coˆte´, A.; Boezio, A. A.;
Charette, A. B. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5405-5410. (d)
Desrosiers, J.-N.; Coˆte´, A.; Charette, A. B. Tetrahedron 2005, 61, 6186-
6192. (e) Coˆte´, A.; Charette, A. B. J. Org. Chem. 2005, 70, 10864-10867.
(f) Charette, A. B.; Boezio, A. A.; Cote, A.; Moreau, E.; Pytkowicz, J.;
Desrosiers, J.-N.; Legault, C. Pure Appl. Chem. 2005, 77, 1259-1267. (g)
Lauzon, C.; Charette, A. B. Org. Lett. 2006, 8, 2743-2745.
(14) (a) Shi, M.; Wang, C.-J. AdV. Synth. Catal. 2003, 345, 971-973.
(b) Beresford, K. J. M. Tetrahedron Lett. 2004, 45, 6041-6044. (c) Zhang,
H.-L.; Jiang, F.; Zhang, X.-M.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang,
Y.-Z.; Wu, Y.-D. Chem.-Eur. J. 2004, 10, 1481-1492. (d) Wang, M.-C.;
Liu, L.-T.; Hua, Y.-Z.; Zhang, J.-S.; Shi, Y.-Y.; Wang, D.-K. Tetrahedron:
Asymmetry 2005, 16, 2531-2534. (e) Shi, M.; Lei, Z-Y.; Xu, Q. AdV. Synth.
Catal. 2006, 348, 2237-2242.
Initially, we investigated the reactivity of the R-amidosulfone
5, derived from the condensation of benzaldehyde, p-toluene-
sulfinic acid, and formamide, in the copper/phosphoramidite-
catalyzed addition of Et2Zn (Scheme 2). For the optimization
of the reaction conditions, 5 mol % of Cu(OTf)2 and 10 mol %
(17) (a) Katritzky, A. R.; Harris, P. A. Tetrahedron: Asymmetry 1992,
3, 437-442. (b) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V.
Chem. ReV. 1998, 98, 409-548. (c) Katritzky, A. R.; Fang, Y.; Silina, A.
J. Org. Chem. 1999, 64, 7622-7624.
(18) Kohn, H.; Sawhney, K. A.; Robertson, D. W.; Leander, J. D. J.
Pharm. Sci. 1994, 83, 689-691.
(19) (a) Petrini, M.; Torregiani, E. Tetrahedron Lett. 2006, 47, 3501-
3503. (b) Lombardo, M.; Mosconi, E.; Pasi, F.; Petrini, M.; Trombini, C.
J. Org. Chem. 2007, 72, 1834-1837. (c) Mecozzi, T.; Petrini, M.
Tetrahedron Lett. 2000, 41, 2709-2712.
(15) (a) Dahmen, S.; Bra¨se, S. J. Am. Chem. Soc. 2002, 124, 5940-
5941. (b) Hermanns, N.; Dahmen, S.; Bolm, C.; Bra¨se, S. Angew. Chem.,
Int. Ed. 2002, 41, 3692-3694.
(16) (a) Zhang, H.-L.; Liu, H.; Cui, X.; Mi, A.-Q.; Jiang, Y.-Z.; Gong,
L.-Z. Synlett 2005, 4, 615-618. (b) Liu, H.; Zhang, H.-L.; Wang, S.-J.;
Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Tetrahedron: Asymmetry 2005, 16,
2901-2907.
(20) (a) Sisko, J.; Mellinger, M.; Sheldrake, P. W.; Baine, N. H.
Tetrahedron Lett. 1999, 37, 8113-8116. (b) Mecozzi, T.; Petrini, M. J.
Org. Chem. 1999, 64, 8970-8972.
(21) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-353.
J. Org. Chem, Vol. 73, No. 3, 2008 941

Pizzuti et al.
SCHEME 2. Screening of Ligands for the Addition of Et2Zn to 5
SCHEME 3. Screening of Protecting Groups
TABLE 1. Addition of Diorganozinc Reagents and
Trimethylaluminum to 5
of the homochiral monodentate phosphoramidite (S,R,R)-L121,22
(2 equiv with respect to Cu) were used. The screening of a
number of solvents (see the Supporting Information, A1) showed
that THF gave the best results, affording, at -50 °C, product
(R)-5a in quantitative yield and with 96% ee. Phosphoramidite
ligands L3-L5 also gave full conversion of 5 to product 5a at
-50 °C in THF, however, with lower enantioselectivity in
comparison to (S,R,R)-L1. Phosphoramidite (R,R,R)-L1, a
diastereoisomer of (S,R,R)-L1, afforded 5a with 20% ee,
indicating a mismatch combination of the binaphthol and chiral
amine moieties. Moreover, the formation of the opposite
enantiomer of 5a, in this experiment, suggests that the binaphthol
part is the dominant feature contributing to the chiral induction.
On the basis of these preliminary studies we concluded that
(S,R,R)-L1 was the ligand of choice.
Further screening of the reaction conditions showed that it is
possible to lower the catalyst loading to 2 mol % and the amount
of diethylzinc to 2.5 equiv without affecting the yield or
enantioselectivity. A decrease of the amount of catalyst to 1
mol % resulted in longer reaction times (full conversion after
36 h). Replacing the amide moiety for a carbamate was
deleterious for both the isolated yield and the enantioselectivity
(Scheme 3, substrates 6 and 7).
Next, the scope of other commercially available organozinc
reagents in the addition to the N-formylimine generated in situ
from 5 was investigated. Using 2 mol % of the chiral
Cu/phosphoramidite catalyst and 2.5 equiv of the organozinc
reagent (Table 1), iPr2Zn and nBu2Zn afforded compound 5b
and 5c in high yield and 91% and 88% enantioselectivity,
respectively (entries 2 and 3).
The introduction of a methyl substituent was not possible at
-50 °C because of the lower reactivity of Me2Zn. At -30 °C,
two products could be observed on TLC: the expected product
5d and benzaldehyde.23 The latter derives from the hydrolysis
of the in situ generated imine during the quenching of the
reaction mixture (aq HCl, 1 M), indicating that, using Me2Zn,
which has low reactivity compared to the other zinc reagents,
the rate-determining step is the addition reaction and not the
formation of the imine. Product 5d could be isolated in
entry
RM
T (°C)
product
yield (%)a
ee (%)
1
2
3
4
5
6
7c
Et2Zn
-50
-50
-50
-50
-30
-10
-30
5a
5b
5c
5d
5d
5d
ent-5d
99
97
92
96-(+)-(R)
91-(+)-(R)
88-(+)-(R)b
iPr2Zn
nBu2Zn
Me2Zn
Me2Zn
Me2Zn
Me3Al
n.d.
99
70
27-(+)-(R)
10-(+)-(R)
86-(-)-(S)
a Isolated yield. b The absolute configuration of 5c was assigned on the
basis of the selectivity observed with the same catalyst (S,R,R)-L1 in the
addition of the other organozinc reagents to 5. c 5 mol % of Cu(acac)2, 10
mol % of (S,R,R)-L1, i-Pr2O.
quantitative yield carrying out the addition reaction at higher
temperature (-10 °C); however, the enantioselectivity was low
(entry 6).
Because the methyl group is ubiquitous in biologically active
compounds and difficulties are frequently encountered in the
transferring of a methyl group in organometallic addition
reactions, we made considerable efforts to achieve high enan-
tioselectivity in the addition of methyl nucleophiles. Toward
this goal, we investigated the use of Me3Al as the methyl source.
Optimization of the solvent, Cu salt, and temperature (see the
Supporting Information, A2) led to the formation of product
5d in 70% yield and 86% ee, using Cu(acac)2 as copper salt in
iPr2O, at -30 °C (entry 7). In contrast to the formation of (+)-
(R)-5d using Me2Zn, the application of Me3Al resulted in the
formation of (-)-(S)-5d using the same enantiomer of the
phosphoramidite ligand (S,R,R)-L1.24
(23) Formation of benzaldehyde was detected by GC-MS as well. The
formation of benzaldehyde in the addition of Me2Zn to the aromatic model
substrate in THF, at -30 °C, was detected by GC-MS. We did not detect
the aldehyde in the addition of the other organozinc reagents or Me3Al,
indicating that in such cases the imine formation is the rate-determining
step. However, considering the lower reactivity of Me2Zn, we believe that
the rate of the addition decreases to a large extent, becoming slower than
the imine formation.
(22) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries, A.
H. M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620-2623.
942 J. Org. Chem., Vol. 73, No. 3, 2008

Addition of Organometallic Reagents to N-Formylimines
TABLE 2. Cu-Catalyzed Addition of Et2Zn to N-Acyl Imines
Generated in Situ from Aromatic and Aliphatic r-Amidosulfones
entry
compd
R
product
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
11a
12a
13a
5
8
9
Ph
4-Cl-Ph
4-Br-Ph
5a
8a
9a
99
94
94
99
90
99
96
99
99
94
81
99
99
96-(+)-(R)
97-(+)-(R)
99-(+)-(R)
97-(+)-(R)
96-(+)-(R)
95-(+)-(R)
95-(+)
10
11
12
13
14
15
16
17
18
19
4-OMe-Ph
4-Me-Ph
3-Me-Ph
3-OMe-Ph
2-OMe-Ph
2-OBn-Ph
2-naphthyl
PhCH2CH2
c-hexyl
10a
11a
12a
13a
14a
15a
16a
17a
18a
19a
47-(-)
45-(-)
80-(+)
66-(+)
45-(+)
n-hexyl
70-(+)
a Reaction conditions: Cu(OAc)2‚H2O (5 mol %), (S,R,R)-L1 (10 mol
%) in iPr2O at -20 °C.
The scope of in situ generated aromatic and aliphatic
N-formylimines for the copper/phosphoramidite-catalyzed ad-
dition of Et2Zn to aromatic R-amidosulfones was investigated
next (Table 2). Electronic effects do not seem to play a major
role: substitution at the para position of the aryl moiety with
electron-donating and electron-withdrawing groups does not
affect the enantioselectivity and the N-formylamines were
isolated with g96% ee and near-quantitative yield (entries 2-5).
High enantioselectivities were obtained with meta-substituted
substrates as well (entries 6 and 7). The introduction of a
substituent in the ortho position resulted in a dramatic decrease
in the ee to less than 50% (entries 8 and 9). We attribute this
depletion of stereocontrol to steric effects of the ortho substitu-
ent. Addition to the 2-naphthyl-substituted sulfone 16 gave
product 16a in 80% ee.
R-Amidosulfones derived from aliphatic aldehydes showed
lower reactivity in the addition reaction than their aromatic
counterparts. Compound 17 was chosen as the model substrate.
No addition reaction was observed in THF, at -50 °C. An
increase of the temperature to -20 °C was necessary to achieve
full conversion of the starting material after overnight reaction
and the enantioselectivity observed was modest. Further screen-
ing of solvents revealed that toluene and Et2O provide better
results compared to THF. Several copper salts were tested to
improve the enantioselectivity of the reaction and, using Cu-
(OAc)2‚H2O, product 17a was obtained with 66% ee.
FIGURE 1. NMR spectra of (S,R,R)-L1 and (S,R,R)-L2: (a) 1H NMR
in CDCl3, 400 MHz; (b) 31P NMR in CDCl3, 400 MHz. (S,R,R)-L1 δ
) 144.7 ppm; (S,R,R)-L2 δ ) 12.3 ppm.
In summary, with use of (S,R,R)-L1, high yields and
enantioselectivities between 45% and 70% were obtained for
the Cu-catalyzed addition of diethylzinc to aliphatic substrates
(entries 11-13).
Studies on in Situ Ligand Oxidation. To investigate the
efficiency of recovery of the chiral phosphoramidite ligand, we
tried to isolate (S,R,R)-L1 after the addition reaction of Et2Zn
to 5 carried out on 1.5 mmol scale, in THF, at -50 °C. Ligand
(S,R,R)-L1 was recovered in 61% yield. It is possible that partial
hydrolysis of the phosphoramidite occurs during the quenching
of the reaction and during column chromatography on silica
gel. Together with (S,R,R)-L1, a second compound containing
phosphorus was isolated as a white foamy solid. The 1H NMR
of this species looked rather similar to that of (S,R,R)-L1 while
the 31P NMR showed one single absorption at 12.3 ppm. The
spectroscopic data as well as HRMS analysis suggest that this
new species is (S,R,R)-L2 (Figure 1a,b).
Further investigations revealed that the formation of the
species (S,R,R)-L2 could be detected after performing the
addition reaction of both Me3Al and Et2Zn to substrate 5 in the
solvents THF, Et2O, iPr2O, EtOAc, and DCM. In contrast, if
the reactions were performed in hexane, at room temperature,
or in toluene, at -30 °C, the only phosphorus compound
recovered was (S,R,R)-L1.
Different phosphoramidite ligands were tested to improve the
enantioselectivity for the addition of Et2Zn to 17 (see the
Supporting Information, A3). Also in this case, however, ligand
(S,R,R)-L1 was proven to be the best one. Variation of the steric
or chiral properties of the amine moiety in ligands L3-L5
determined, invariably, a decrease in the enantioselectivity.
(24) In analogy with organocuprate and zincate chemistry, we suppose
that the organometallic species is involved in the structure of the active
catalytic system. We assume that by switching from an organozinc to an
organoaluminum reagent we probably form two different catalysts, thereby
changing the stereochemical outcome of the reaction. This assumption is
in agreement with what was demonstrated by our group for the copper-
catalyzed 1,4-addition of Grignard reagents. For reference see: (a) Mori,
S.; Nakamura, E. Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-
VCH: New York, 2002. (b) Harutyunyan, S. R.; Lopez, F.; Browne, W.
R.; Correa, A.; Pena, D.; Badorrey, R.; Meetsma, A.; Minnaard, A. J.;
Feringa, B. L. J. Am. Soc. Chem. 2006, 128, 9103.
Modification of phosphoramidite ligands during a reaction
with organometallic reagents has been previously reported in
the literature. Recently, Alexakis and Micouin25 observed that,
in the Cu(OTf)2-catalyzed ring opening of meso bicyclic
J. Org. Chem, Vol. 73, No. 3, 2008 943

Pizzuti et al.
TABLE 3. Effect of Sulfinate on (S,R,R)-L1
SCHEME 4. In Situ Ligand Oxidation
NaSO2Tol
(equiv)
Et2Zn
(equiv)
Cu(OTf)2
(equiv)
entry
L1/L2a
1
2
3
4
0
1
1
1
3
3
0
0
0.05
0
0
100/0
95/5
94/6
hydrazines, the phosphoramidite (R,R,R)-L1 reacts with Me3-
Al, in dichloromethane and toluene, leading to the corresponding
aminophosphine, which is the actual ligand in the reaction. In
our case, even though the chemical shift of the newly formed
species (S,R,R)-L2 in the 31P NMR would be consistent with
the formation of the dimethylaminophosphine, the 1H NMR data
0.05
0/100
a The L1/L2 ratio was determined by 31P NMR of the crude product
after quenching with a saturated aqueous solution of NH4Cl.
1
rule out this possibility. The H NMR, in fact, clearly shows
organoaluminium reagents to N-formylimines generated in situ
from R-amidosulfones, could be due to the substrate itself. The
in situ formation of the imine, in fact, generates 1 equiv of zinc-
sulfinate adduct, which could act as an oxidizing agent. To
confirm this hypothesis, we investigated the effect that the
sulfinate, added as sodium salt, has on ligand (S,R,R)-L1, under
different conditions (Table 3).30 If no sulfinate was present in
the reaction mixture, no oxidation occurred (entry 1); when the
sulfinate was added in a copper-free environment, with or
without Et2Zn, a small percentage (<10%) of (S,R,R)-L1 was
oxidized to (S,R,R)-L2 (entries 2 and 3). On the other hand, if
both the sulfinate and a copper salt were added to the reaction
mixture, than complete oxidation of (S,R,R)-L1 to the phosphoric
amide was observed, after overnight reaction, suggesting that
the copper salt acts as a catalyst for the reaction (entry 4).
that the BINOL moiety is still present in (S,R,R)-L2; moreover
the substitution pattern is very similar to (S,R,R)-L1: only minor
shifts can be observed for the doublet corresponding to the
methyl group and for the signal of the benzylic hydrogen; small
differences are present in the aromatic region. The work of
Charette et al.26 provided inspiration for the elucidation ofthe
(S,R,R)-L2 structure. They found that, in the Cu-catalyzed
addition of diorganozinc reagents to N-phosphonoylimines, an
in situ oxidation of Me-Duphos occurs by Cu(II) salts, to
produce the highly effective monoxide ligand (BozPHOS) and,
in minor extent, the Me-Duphos bisoxide. Redox processes
between phosphorus-based ligand and transition metals had been
previously reported.27 Pd(II) salts, for example, can be reduced
to Pd(0) in the presence of Ph3P, producing Ph3PdO as the
byproduct.28 Much less is known about this type of chemistry
for copper. It has been reported that Cu(II) salts are reduced by
1,2-bis(diphenylphosphino)ethane to produce several phosphine/
phosphine oxide ligands;29 however, to the best of our knowl-
edge, no precedents for the Cu-catalyzed oxidation of phos-
phoramidite ligands are described in the literature. We decided
to investigate the possibility of in situ oxidation of the
phosphoramidite ligand (S,R,R)-L1 to the corresponding phos-
phoric amide (S,R,R)-L2 under the reaction conditions and the
possible role in asymmetric catalysis (Scheme 4).
We were interested to see whether the chiral phosphoric
amide (S,R,R)-L2 was merely a byproduct in the reaction or
actually part of the active catalyst.
We mentioned earlier that no ligand modification was
detectable when the Me3Al or Et2Zn addition to compound 5
was performed in hexane or in toluene. This allowed us to
analyze the activity and enantioselectivity of the species (S,R,R)-
L1 and (S,R,R)-L2, used separately, from a mixture of the two
(that would be inevitably formed in situ, when performing the
reaction in THF, DCM, or ethereal solvents, starting with
(S,R,R)-L1 alone). The addition of Me3Al and Et2Zn to the
R-amidosulfone 5 and the addition of Et2Zn to the aliphatic
R-amidosulfone 17 were carried out in toluene, at -30 °C, using
5 mol % of Cu(OTf)2 and 10 mol % of the ligand (S,R,R)-L1,
(S,R,R)-L2, or their 1/1 mixture. The results are presented in
Table 4. Entries 3, 6, and 9 demonstrate that the phosphoric
amide (S,R,R)-L2 is not an efficient chiral ligand by itself,
affording product 5a in full conversion but in racemic form.
Moreover, low conversions of the starting material (<10%) were
observed for the addition of Et2Zn to compound 17 and the
addition of Me3Al to compound 5. No significant difference in
the enantioselectivity was observed in the addition of diethylzinc
to compound 5 in the presence of only (S,R,R)-L1 or a 1/1
mixture of (S,R,R)-L1 and (S,R,R)-L2 (entries 1 and 2). The
reaction proceeded to full conversion, overnight, and high ee
values of 85% and 86%, respectively, were achieved for the
product 5a. However, the use of a 1/1 mixture of (S,R,R)-L1
and (S,R,R)-L2 led to a slight improvement in the enantiose-
lectivity of the addition of diethylzinc to the aliphatic R-ami-
dosulfone 17 (entries 4 and 5).
The phosphoric amide could be easily synthesized, in
quantitative yield, upon reaction of (S,R,R)-L1 with hydrogen
peroxide. Characterization by 1H NMR, 31P NMR, and HRMS
and elemental analysis of the synthesized phosphoric amide and
the isolated species (S,R,R)-L2 confirmed that the two com-
pounds are identical. We hypothesized that the ligand oxidation,
observed in the Cu-catalyzed addition of diorganozinc and
(25) Bournaud, C.; Falciola, C.; Lecourt, T.; Rosset, S.; Alexakis, A.;
Micouin, L. Org. Lett. 2006, 8, 3581-3584.
(26) Coˆte´, A.; Boezio, A. A.; Charette, A. B. Angew. Chem., Int. Ed.
2004, 43, 6525-6528.
(27) Shimizu, I.; Matsumoto, Y.; Shoji, K.; Ono, T.; Satake, A.;
Yamamoto, A. Tetrahedron Lett. 1996, 37, 7115-7118.
(28) (a) Grushin, V. V. J. Am. Chem. Soc. 1999, 121, 5831-5831. (b)
Ozawa, F.; Kubo, A.; Matsumoto, Y.; Hayashi, T.; Nishioka, E.; Yanagi,
K.; Moriguchi, K. Organometallics 1993, 12, 4188-4196. (c) Amatore,
C.; Carre´, E.; Jutand, A.; M’Barki, M. A. Organometallics 1995, 14, 1818-
1826. (d) Bianchini, C.; Meli, A.; Oberhauser, W. Organometallics 2003,
22, 4281-4285. (e) Amatore, C.; M’Barki, M. A. Organometallics 1992,
11, 3009-3013. (f) Mason, M. R.; Verkade, J. G. Organometallics 1992,
11, 2212-2220. (g) Grushin, V. V.; Bensimon, C.; Alper, H. Inorg. Chem.
1994, 33, 4804-4806. (h) Marshall, W. J.; Grushin, V. V. Organometallics
2003, 22, 555-562. (i) Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lett. 1992,
2177-2188. (j) Amatore, C.; Jutand, A.; Thuilliez, A. Organometallics 2001,
20, 3241-3249.
(29) Berners-Price, S. J.; Johnson, R. K.; Mirabelli, C. K.; Faucette, L.
F.; McCabe, F. L.; Sadler, P. Inorg. Chem. 1987, 26, 3383-3387.
(30) Compound (S,R,R)-L2 is even formed when O2 and H2O are
rigorously excluded.
944 J. Org. Chem., Vol. 73, No. 3, 2008

Addition of Organometallic Reagents to N-Formylimines
TABLE 4. Study on the Effect of (S,R,R)-L2 in Toluene
Conclusions
We show that the copper/phosphoramidite-catalyzed addition
of diorganozinc reagents and trimethylaluminum to N-acylimines
generated in situ from aromatic and aliphatic R-amidosulfones
furnishes optically active R-alkylamides in high yield and
enantiomeric excess up to 99%. Oxidation of the chiral
phosphoramidite ligand (S,R,R)-L1 to the corresponding phos-
phoric amide (S,R,R)-L2, under the reaction conditions, was
observed when performing the organometallic addition in THF,
Et2O, iPr2O, DCM, and EtOAc, but not in hexane and toluene.
A preliminary investigation on the effect of the chiral phosphoric
amide (S,R,R)-L2 shows that, under certain conditions, the
presence of this species in the reaction mixture can improve
the level of the enantioselectivity of the reaction. Further
mechanistic studies are ongoing to clarify the actual role played
by (S,R,R)-L2. The advantage of readily available and stable
starting materials as well as the easy deprotection of the obtained
R-alkylamides make the new methodology a useful alternative
to the existing methods for the formation of optically active
R-chiral amines.
conv
(%)
ee
(%)
entry compd
L
RM
product
1
2
5
5
L1
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Me3Al
Me3Al
Me3Al
Me3Al
5a
5a
5a
17a
17a
17a
5d
5d
5d
5d
5d
100
100
100
100
100
<10
100
100
<10
100
100
85
86
L1 + L2(1/1)
3
5
L2
L1
4
5
6
7
17
17
17
5
38
47
L1 + L2(1/1)
L2
L1
8
5
L1 + L2 (1/1)
52
9
5
5
5
L2
10a
11a
L1 + L2 (1/1)
L1 + HMPA (1/1) Me3Al
60
50
a Cu(acac)2 was used as the copper source.
A striking improvement in the enantioselectivity was reached
using Me3Al in the formation of 5d, that went from 0%, when
(S,R,R)-L1 was used as the only chiral species (entry 7), to 52%,
when both (S,R,R)-L1 and (S,R,R)-L2 were present in the
reaction mixture (entry 8). These preliminary results suggest
that the phosphoric amide (S,R,R)-L2, indeed, can have an effect
on the enantioselectivity of the reaction.
Experimental Section
General Procedure for the Copper/Phosphoramidite-Cata-
lyzed Addition of Dialkylzinc Reagents to Aromatic r-Ami-
dosulfones. Cu(OTf)2 (3.6 mg, 0.010 mmol) and ligand (S,R,R)-
L1 (10.8 mg, 0.020 mmol) were dissolved in anhydrous THF (10
mL) and the solution was stirred for 30 min at rt. The mixture was
cooled to -50 °C and the substrate (0.50 mmol) was added. A
solution of a R2Zn (1.25 mmol) was added dropwise and the
reaction mixture was stirred for 16 h at -50 °C, then quenched
with sat. aq NH4Cl (10 mL) and extracted with EtOAc (3 × 5 mL).
The combined organic extracts were washed with brine, dried (Na2-
SO4), filtered, and concentrated. The crude product was purified
by flash chromatography.
We considered that (S,R,R)-L2 could act as a chiral analogue
of HMPA, whose strong coordinating properties are known to
largely affect the regio- and stereochemical outcome of reactions
involving organometallic species.31 The presence of a metal-
coordinating species might vary the structure of the actual
catalyst, for example, in terms of aggregation level, which is
known to be strongly dependent on several factors, first of all
the solvent.32 This observation prompted us to study the effect
of the addition of HMPA in place of (S,R,R)-L2 (Table 4, entry
11). Having observed a major influence of the phosphoric amide
(S,R,R)-L2 in the addition of Me3Al to compound 5, we decided
to evaluate the effect of HMPA addition in the same reaction.
Cu(acac)2 was used in place of Cu(OTf)2 because, from the
screening of the copper salts for the Me3Al addition (see the
Supplementary Information, Table 7), it was proven to be the
most effective. As shown in Table 4 (entries 10 and 11), HMPA
seems to play a similar role compared to (S,R,R)-L2. With Cu-
(acac)2 as copper source, the use of a 1/1 mixture of (S,R,R)-
L1 and (S,R,R)-L2 afforded the product 5d with 60% ee, while
the use of a 1/1 mixture of (S,R,R)-L1 and HMPA gave 5d
with a slightly lower, but significant, 50% ee, suggesting that
the effect that (S,R,R)-L2 has on the enantioselectivity of the
Me3Al addition to 5 might not be due to its chiral properties
but rather an additional (HMPA type) co-ligand effect. Further
investigations are needed to clarify the exact role of (S,R,R)-
L2 in the Cu-catalyzed addition of organometallic reagents to
N-formylimines generated in situ from R-amidosulfones.
N-(1-Phenylpropyl)formamide, 5a.15a Purification by column
chromatography (SiO2; EtOAc/pentane 1:1) afforded compound 5a
in 99% isolated yield (Rf 0.4) as a colorless oil that slowly solidified,
mp 56.8-58.8 °C. Chiral GC-CP Chiralsil Dex CB, 25 m × 0.25
mm × 0.25 µm; He-flow: 1 mL/min; oven: 60 °C for 10 min, 1
°C/min until 150 °C, then 10 °C/min until 180 °C; Rt(S) ) 95.17
min (minor), Rt(R) ) 95.75 min (major); 96% ee. [R]D +136.1 (c
1
0.99, CHCl3). The H and 13C NMR spectra (CDCl3) show a 4:1
mixture of two rotamers (rotation of the N-formyl group). Major
1
rotamer H NMR (300 MHz, CDCl3) δ 8.18 (s, 1H), 7.36-7.22
(m, 5H), 6.02 (s, br, 1H), 4.96 (q, J ) 7.8 Hz, 1H), 1.92-1.80 (m,
2H), 0.90 (t, J ) 7.4 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3)
δ 162.1, 141.0, 128.6, 127.5, 126.6, 54.2, 28.9, 10.6 ppm. Minor
rotamer 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J ) 12.0 Hz, 1H),
7.36-7.22 (m, 5H, HAr), 6.30 (s, br, 1H), 4.37 (q, J ) 7.2 Hz,
1H), 1.92-1.80 (m, 2H), 0.94 (t, J ) 7.4 Hz, 3H) ppm. 13C NMR
(100 MHz, CDCl3) δ 165.9, 140.8, 128.9, 127.9, 126.2, 59.1, 30.1,
10.5 ppm. HRMS calcd for C10H13NO 163.1004, found 163.0997.
N-[1-(4-Chlorophenyl)propyl]formamide, 8a.15a Purification by
column chromatography (SiO2; EtOAc/pentane 1:1) afforded
compound 8a in 94% isolated yield (Rf ) 0.28) as a colorless oil
which slowly solidified, mp 94.0-94.8 °C. Chiral GC-CP Chiralsil
Dex CB, 25 m × 0.25 mm × 0.25 µm; He-flow: 1 mL/min; oven:
60 °C for 10 min, then 1 °C/min until 180 °C; Rt(S) ) 117.57 min
(minor), Rt(R) ) 118.06 min (major); 97% ee. [R]D +149.5 (c 1.06,
CHCl3). The 1H and 13C NMR spectra (CDCl3) show a 4:1 mixture
of two rotamers (rotation of the N-formyl group). Major rotamer
1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.31-7.25 (m, 2H),
7.19-7.15 (m, 2H), 6.54 (br d, J ) 7.2 Hz, 1H), 4.86 (q, J ) 7.6
Hz, 1H), 1.84-1.71 (m, 2H), 0.92-0.84 (m, 3H) ppm. 13C NMR
(50 MHz, CDCl3) δ 160.8, 140.0, 133.1, 128.7, 127.9, 53.3, 28.9,
10.5 ppm.
(31) (a) Suzuki, M.; Koyama, H.; Noyori, R. Bull. Chem Soc. Jpn. 2004,
77, 259-268. (b) Sikorski, W. H.; Reich, H. J. J. Am. Chem. Soc. 2001,
123, 6527-6535. (c) Ye, S.; Yuan, L.; Huang, Z.-Z.; Tang, Y.; Dai, L.-X.
J. Org. Chem. 2001, 65, 6257-6260. (d) Yamamoto, K.; Ogura, H.; Jukuta,
J.-i.; Inoue, H.; Hamada, K.; Sugiyama, Y.; Yamada, S. J. Org. Chem. 1998,
63, 4449-4458.
(32) (a) Zhang, H.; Gschwind, R. M. Angew. Chem., Int. Ed. 2006, 45,
6391-6394. (b) Zhang, H.; Gschwind, R. M. Chem. Eur. J. 2007, 13, 6691-
6700.
J. Org. Chem, Vol. 73, No. 3, 2008 945

Pizzuti et al.
1
Minor rotamer H NMR (400 MHz, CDCl3) δ 8.04 (d, J ) 11.9
min until 180 °C; Rt ) 89.32 min (major), Rt ) 91.05 min (minor);
85% ee. [R]D -102.3 (c 1.05, CHCl3). The 1H and 13C NMR spectra
(CDCl3) show a 4:1 mixture of two rotamers (rotation of the
Hz, 1H), 7.31-7.25 (m, 2H), 7.19-7.15 (m, 2H), 7.06 (br t, J )
10.0 Hz, 1H), 4.31 (q, J ) 7.6 Hz, 1H), 1.84-1.71 (m, 2H), 0.92-
0.84 (m, 3H) ppm. 13C NMR (50 MHz, CDCl3) δ 164.5, 140.2,
133.5, 129.0, 127.6, 57.7, 30.1, 10.5 ppm. HRMS calcd for C11H12-
ClNO 197.0607, found 197.0604. Anal. Calcd for C11H12ClNO:
C 60.76, H 6.12, N 7.09. Found: C 60.60, H 6.13, N 6.97.
N-[1-(3-Methoxyphenyl)propyl]formamide, 13a.33 Purification
by column chromatography (SiO2; EtOAc/pentane 1:1) afforded
compound 13a in 96% isolated yield (Rf 0.30) as a colorless oil.
Chiral GC-CP Chiralsil Dex CB, 25 m × 0.25 mm × 0.25 µm;
He-flow: 1 mL/min; oven: 60 °C for 10 min, then 1 °C/min until
180 °C; Rt ) 121.75 min (minor), Rt ) 122.98 min (major); 95%
1
N-formyl group). Major rotamer H NMR (400 MHz, CDCl3) δ
8.09 (br s, 1H), 7.37-7.23 (m, 5H), 6.32 (br s, 1H), 5.20-5.13
(m, 1H), 1.48 (d, J ) 6.9 Hz, 3H) ppm. 13C NMR (50 MHz, CDCl3)
δ 160.3, 142.6, 128.6, 127.4, 126.0, 47.5, 21.7 ppm. Minor rotamer
1H NMR (400 MHz, CDCl3) δ 8.12 (br s, 1H), 7.37-7.23 (m, 5H),
6.44 (br s, 1H), 4.69-4.61 (m, 1H), 1.53 (d, J ) 6.9 Hz, 3H) ppm.
13C NMR (50 MHz, CDCl3) δ 164.2, 142.6, 128.8, 127.6, 125.7,
51.6, 23.5 ppm. HRMS calcd for C9H11NO 149.0841, found
149.0847.
General Procedure for the Copper/Phosphoramidite-Cata-
lyzed Addition of Diethylzinc to Aliphatic R-Amido Sulfones.
Cu(OAc)2‚H2O (2.0 mg, 0.010 mmol) and ligand (S,R,R)-L1 (10.8
mg, 0.020 mmol) were dissolved in anhydrous Et2O (10 mL) and
the mixture was stirred for 45 min at rt. The mixture was cooled to
-20 °C and the substrate (0.50 mmol) was added. A 1 M solution
of Et2Zn in hexane (1.25 mmol) was added dropwise and the
reaction mixture was stirred for 16 h at -20 °C, then quenched
with sat. aq NH4Cl (10 mL) and extracted with EtOAc (3 × 5 mL).
The combined organic extracts were washed with brine, dried (Na2-
SO4), filtered, and concentrated. The crude product was purified
by flash chromatography.
ee. [R]D +116.1 (c 1.025, CHCl3). The H and 13C NMR spectra
(CDCl3) show a 4:1 mixture of two rotamers (rotation of the
N-formyl group). Major rotamer H NMR (400 MHz, CDCl3) δ
8.12 (s, 1H), 7.26-7.20 (m, 1H), 6.85-6.76 (m, 3H), 6.44 (br s,
1H), 4.89 (q, J ) 7.7 Hz, 1H), 3.76 (s, 3H), 1.84-1.73 (m, 2H),
0.87 (t, J ) 7.4 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ
160.6, 159.6, 143.2, 129.6, 118.7, 112.4, 112.4, 55.1, 53.6, 29.0,
1
1
1
10.6 ppm. Minor rotamer H NMR (400 MHz, CDCl3) δ 8.08 (d,
J ) 11.9 Hz, 1H), 7.26-7.20 (m, 1H), 6.85-6.76 (m, 3H), 6.44
(br s, 1H), 4.29 (q, J ) 7.6 Hz, 1H), 3.77 (s, 3H), 1.84-1.73 (m,
2H), 0.92 (t, J ) 7.4 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3)
δ 164.6, 159.8, 143.4, 129.8, 118.3, 112.6, 112.0, 58.1, 55.1, 30.1,
10.6 ppm. HRMS calcd for C11H15NO2 193.1103, found 193.1102.
N-[1-(2-Methoxyphenyl)propyl]formamide, 14a. Purification
by column chromatography (SiO2; EtOAc/pentane 1:1) afforded
compound 14a in 99% isolated yield (Rf 0.31) as a white solid.
Mp 122.4-124.2 °C. Chiral GC-CP Chiralsil Dex CB, 25 m ×
0.25 mm × 0.25 µm; He-flow: 1 mL/min; oven: 60 °C for 10
min, 1 °C/min until 150 °C, then 10 °C/min until 180 °C; Rt )
111.15 min (major), Rt ) 112.39 min (minor); 47% ee. [R]D -47.8
N-(1-Ethyl-3-phenylpropyl)formamide, 17a. Purification by
column chromatography (SiO2; EtOAc/pentane 6:4) afforded
compound 17a in 81% isolated yield (Rf 0.44) as a colorless oil
that slowly solidified, mp 46.8-48.1 °C. Chiral GC-CP Chiralsil
Dex CB, 25 m × 0.25 mm × 0.25 µm; He-flow: 1 mL/min; oven:
60 °C for 10 min, 1 °C/min until 150 °C, then 10 °C/min until 180
°C; Rt ) 111.79 min (minor), Rt ) 112.76 min (major); 66% ee.
[R]D +16.5 (c 0.935, CHCl3). The 1H and 13C NMR spectra (CDCl3)
show a 2.2:1 mixture of two rotamers (rotation of the N-formyl
group). Major rotamer 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H),
7.30-7.25 (m, 2H), 7.21-7.14 (m, 3H), 5.83 (d, J ) 7.9 Hz, 1H),
4.03-3.94 (m, 1H), 2.79-2.54 (m, 2H), 1.91-1.79 (m, 1H), 1.76-
1.54 (m, 2H), 1.40-1.38 (m, 1H), 0.91 (t, J ) 7.4 Hz, 3H) ppm.
13C NMR (100 MHz, CDCl3) δ 161.0, 141.6, 128.3, 128.2, 125.8,
(c 0.98, CHCl3). The H and 13C NMR spectra (CDCl3) show a
1
2.5:1 mixture of two rotamers (rotation of the N-formyl group).
Major rotamer 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.26-
7.21 (m, 1H), 7.71-7.11 (m, 1H), 6.93-6.87 (m, 2H), 6.73 (br s,
1H), 5.10 (q, J ) 8.1 Hz, 1H), 3.84 (s, 3H), 1.87-1.78 (m, 2H),
0.85 (t, J ) 7.4 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ
160.3, 156.9, 129.0, 128.8, 128.4, 120.7, 110.9, 55.2, 52.0, 28.2,
1
49.3, 36.4, 32.2, 27.8, 10.0 ppm. Minor rotamer H NMR (400
MHz, CDCl3) δ 7.97 (d, J ) 11.9 Hz, 1H), 7.30-7.25 (m, 2H),
7.21-7.14 (m, 3H), 6.22 (t, J ) 10.9 Hz, 1H), 3.20-3.11 (m, 1H),
2.79-2.54 (m, 2H), 1.91-1.79 (m, 1H), 1.76-1.54 (m, 2H), 1.40-
1.38 (m, 1H), 0.91 (t, J ) 7.4 Hz, 3H) ppm. 13C NMR (100 MHz,
CDCl3) δ 164.5, 140.8, 128.4, 128.3, 126.0, 53.6, 36.8, 31.9, 29.0,
10.2 ppm. HRMS calcd for C12H17NO 191.1310, found 191.1319.
Anal. Calcd for C12H17NO: C 75.35, H 8.96, N 7.32. Found: C
74.88, H 8.93, N 7.20.
1
11.0 ppm. Minor rotamer H NMR (400 MHz, CDCl3) δ 8.12 (d,
J ) 12.0 Hz, 1H), 7.26-7.21 (m, 1H), 7.71-7.11 (m, 1H), 6.93-
6.87 (m, 2H), 6.54 (br s, 1H), 4.45 (q, J ) 8.2 Hz, 1H), 3.82 (s,
3H), 1.87-1.78 (m, 2H), 0.91 (t, J ) 7.4 Hz, 3H) ppm. 13C NMR
(100 MHz, CDCl3) δ 164.1, 156.4, 129.3, 128.7, 127.5, 120.7,
110.8, 55.7, 52.0, 28.6, 11.0 ppm. HRMS calcd for C11H15NO2
193.1103, found 193.1102. Anal. Calcd for C11H15NO2: C 68.37,
H 7.82, N 7.25. Found: C 68.45, H 7.89, N 7.04.
O,O′-(S)-(1,1′-Dinaphthyl-2,2′diyl)-N,N-di-(R,R)-1-phenyleth-
ylphosphoricamide, (S,R,R)-L2. Phosphoramidite (S,R,R)-L1 (770
mg, 1.43 mmol) was dissolved in 25 mL of THF. The solution
was cooled to 0 °C and 5 mL of a solution of H2O2 30% in water
was added. Formation of a white precipitate was observed. The
reaction mixture was warmed to rt and stirred overnight. The
reaction mixture was treated with a saturated aqueous solution of
Na2SO3 (15 mL) and extracted (2 × 10 mL) with EtOAc. The
organic layer was dried over Na2SO4, filtered, and concentrated in
vacuo to afford 788 mg (1.42 mmol) of (S,R,R)-L2 as a white solid,
mp 184.8-185.0 °C. Yield 99%. [R]D +384.1 (c 1.01, CHCl3).1H
NMR (300 MHz, CDCl3) δ 8.03-8.00 (m, 1H), 7.95-7.90 (m,-
3H), 7.53-7.44 (m, 4H), 7.39-7.24 (m, 4H), 7.12 (br s, 10H),
4.65-4.52 (m, 2H), 1.83 (d, J ) 7.1 Hz, 6H). 13C NMR (100 MHz,
CDCl3) δ 155.3, 149.0, 148.9, 146.6, 146.6, 141.2, 141.2, 132.5,
132.3, 131.7, 131.1, 131.0, 130.5, 128.4, 128.1, 128.0, 127.7, 127.4,
127.0, 126.9, 126.4, 126.3, 125.4, 121.7, 121.7, 120.4, 120.3, 54.7,
54.6, 20.3 ppm. 31P NMR (95 MHz, CDCl3) δ 12.34 ppm. HRMS
calcd for C36H30NO3P 555.1963, found 555.1932. Anal. Calcd for
C36H30NO3P: C 77.82, H 5.44, N 2.52. Found: C 77.50, H 5.71,
N 2.55.
Procedure for the Copper/Phosphoramidite-Catalyzed Ad-
dition of Trimethylaluminum to 1. Cu(acac)2 (6.6 mg, 0.025
mmol) and ligand (S,R,R)-L1 (27.0 mg, 0.050 mmol) were dissolved
in anhydrous iPr2O (10 mL) and the mixture was stirred for 45
min at rt. The mixture was cooled to -30 °C and substrate 5 (0.50
mmol) was added. A 1 M solution of Me3Al in heptane (1.25 mmol)
was added dropwise and the reaction mixture was stirred for 16 h
at -30 °C, then quenched with 1 M aq HCl (10 mL) and extracted
with EtOAc (3 × 5 mL). The combined organic extracts were
washed with brine, dried (Na2SO4), filtered, and concentrated. The
crude product was purified by flash chromatography.
N-(1-Phenylethyl)formamide, 5d.34 Purification by column
chromatography (SiO2; EtOAc/pentane 3:2) afforded compound 5d
in 70% isolated yield (Rf 0.37) as a colorless oil. Chiral GC-CP
Chiralsil Dex CB, 25 m × 0.25 mm × 0.25 µm; He-flow: 1 mL/
min; oven: 60 °C for 10 min, 1 °C/min until 150 °C, then 10 °C/
(33) Alesso, E. N.; Tombari, D. G.; Moltrasio, I.; Graciela, Y.; Aguirre,
J. M. Can. J. Chem. 1987, 65, 2568-2574.
(34) Murahashi, S.; Yoshimura, N.; Tsumiyama, T.; Kojima, T. J. Am.
Chem. Soc. 1983, 105, 5002-5011.
946 J. Org. Chem., Vol. 73, No. 3, 2008

Addition of Organometallic Reagents to N-Formylimines
18a, and 19a and the starting materials 5-19, and screening of
solvents, temperatures, and Cu salts for the addition reactions to 5
and 17. This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the University of Groningen
(Ubbo Emmius Scholarship) for financial support. We also thank
T. D. Tiemersma-Wegman and A. Kiewiet for technical
assistance.
Supporting Information Available: Analytical and spectral
characterization data for products 5b, 5c, 6a, 7a, 9a-12a, 15a, 16a,
JO702140F
J. Org. Chem, Vol. 73, No. 3, 2008 947