Stereoselective synthesis of N-heterocycles: application of the asymmetric Cu-catalyzed addition of Et2Zn to functionalized alkyl and aryl imines

Article abstract of DOI:10.1016/j.tet.2009.04.002

The preparation of N-heterocycles from alkyl- and aryl-substituted imines is described. The key step involves a copper-catalyzed addition of diethylzinc to functionalized alkyl-substituted imines that were generated in situ from the sulfinic acid adducts.

Full text of DOI:10.1016/j.tet.2009.04.002

Tetrahedron 65 (2009) 4968–4976
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Stereoselective synthesis of N-heterocycles: application of the asymmetric
Cu-catalyzed addition of Et2Zn to functionalized alkyl and aryl imines
*
´
Isabelle Bonnaventure, Andre B. Charette
Department of Chemistry, Universite´ de Montre´al, PO Box 6128, Station Downtown, Montreal, QC H3C 3J7, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of N-heterocycles from alkyl- and aryl-substituted imines is described. The key step
involves a copper-catalyzed addition of diethylzinc to functionalized alkyl-substituted imines that were
generated in situ from the sulfinic acid adducts. The nucleophilic addition products were then converted
to 2-substituted pyrrolidines and piperidines. Aryl-substituted imines were transformed into enan-
tioenriched 1- and 1,4-substituted tetrahydroisoquinolines.
Received 3 February 2009
Received in revised form 30 March 2009
Accepted 1 April 2009
Available online 9 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
a
-Chiral amines
Asymmetric catalysis
Chemoselectivity
Heterocycles
Functionalized imines
1. Introduction
sensitive to moisture, and thus are prone to facile hydrolysis.7
Furthermore, they exist as an equilibrium between the imine and
The nucleophilic addition to imines is a versatile method to
the enamine form, which can undergo homo-coupling.7e,f To
overcome this, the sulfinic acid adducts were used as stable pre-
cursors, which were compatible with the Cu$Me–DuPHOS(O) sys-
access a
-chiral amines.1 These products are important subunits of
more complex bioactive molecules,2 as well as useful building
blocks for the synthesis of both chiral ligands3 and auxiliaries.4
Recently we reported a copper-catalyzed asymmetric addition
of diorganozinc reagents to aryl-substituted N-phosphinoyl-
tem.8 We were then able to prepare numerous
a-chiral amines from
aliphatic aldehydes in excellent yields (83–98%) and enantiose-
lectivities (89–97% ee) (Scheme 1).9
imines.5 The corresponding N-protected
a-chiral amines were
Herein, we demonstrate the excellent chemoselectivity of the
asymmetric copper-catalyzed diorganozinc addition to imines to
generated in high yields (80–98%) and high enantioselectivities
(90–98% ee), with the diphosphine monoxide, Me-DuPHOS(O) 1
being a very efficient chiral ligand for this reaction (Eq. 1).6
We have also reported that alkyl-substituted imines are also
compatible with this reaction. However, these aldimines are highly
prepare suitably functionalized
a-chiral amines that could be
converted into N-heterocycles after simple synthetic steps.
Et2Zn (2.5 equiv),
Cu(OTf)2 (4.5 mol%),
O
O
R2Zn (2 equiv),
1 (5 mol%),
Cu(OTf)2 (6 mol%),
toluene, -60 °C to rt, 20 h
NHPPh2
NHPPh2
O
O
1 (3 mol%),
toluene, 0 °C, 20 h
P
O
83-98%
Alkyl
Et
Alkyl
Ts
NHPPh2
NPPh2
89-97% ee
(1)
Alkyl = Me, n-Hex, PhCH2CH2, i-Bu,
AcO(CH2)4, i-Pr, c-Hex, c-Pent
80-98%
Aryl
R
Aryl
H
P
90-98% ee
1
EtZn-Et
O
O
H
PPh2
PPh2
-EtZnTs
via
N
N
Alkyl
Ts
Alkyl
H
* Corresponding author. Fax: þ1 514 343 5900.
Scheme 1. Synthesis of N-protected a-chiral alkylamines.
E-mail address: andre.charette@umontreal.ca (A.B. Charette).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.002

I. Bonnaventure, A.B. Charette / Tetrahedron 65 (2009) 4968–4976
4969
2. Results and discussion
coupling compounds (through enamine formation)13a were obtained
after the asymmetric addition step, as determined by 1H NMR.
It was envisioned that N-heterocycles could be obtained from
the corresponding acyclic precursors 2–5. These compounds should
provide access to pyrrolidines, pyrrolidinones, piperidines, piper-
idinones, and tetrahydroisoquinolines.10–12 The challenge was not
only to prepare the imine (or the sulfinic acid imine precursor
adduct), but also to determine the degree of functionality com-
patible with the enantioselective nucleophilic addition (Scheme 2).
O
O
Et2Zn (2.5 equiv),
NHPPh2
NHPPh2
Cu(OTf)2 (4.5 mol%)
Br
Br
( )n
( )n
Ts
Et
1 (5 mol%),
toluene, -20 °C, 20 h
n = 1, 15
n = 1, 8
n = 2, 16
n = 2, 10
t-BuOK, THF,
50 °C, 2-4 h
H
H
( )n
Br
1,2
N
Ph
Ph
N
Ph
Ph
Et
O
P
O
N
PPh2
P
O
4
2
O
n = 1, 17, 61% (99% ee)
n = 2, 18, 55% (98% ee)
R
H
RO
H
1,2
Scheme 4. Application to the synthesis of pyrrolidine 17 and piperidine 18.
N
Ph
Ph
P
O
N
Ph
Ph
P
O
5
3
We next studied the behavior of the sulfinic acid adducts 12 and
14 bearing a methyl ester functional group under the conditions for
the asymmetric addition of Et2Zn (Scheme 5). In the case of 12, we
observed complete conversion to the cyclized compound 19, which
was obtained in 87% yield and excellent enantioselectivities (97%
ee). On the other hand, treatment of 14 under the same reaction
conditions gave rise to a mixture of the uncyclized product 20 and
piperidinone 21 (5.7:1 ratio).
Scheme 2. Potential functionalized imines: access to various important
a-chiral
amines.
Aldehydes containing bromide and ester were treated with
phosphinic amide 6 (1 equiv) and p-toluenesulfinic acid (1.5 equiv)
at rt in Et2O to produce the desired sulfinic acid adducts (Scheme 3).
In all cases, the sulfinic acid adducts precipitated out of the solution
and were isolated by simple filtration as white solids in excellent
yields (83–91%).
Et2Zn (2.5 equiv)
Cu(OTf)2 (4.5 mol%)
1 (5 mol%)
O
NHPPh2
Et
O
N
Ph2P(O)NH2 (6) (1 equiv)
TolSO2H (1.5 equiv)
O
O
O
PPh2
MeO2C
Ts
NHPPh2
toluene, -20 °C, 20 h
12
FG-Alkyl
H
19
87% (97% ee)
Et2O, rt, 24-48 h
FG-Alkyl
Ts
Starting material
Product
O
O
O
NHPPh2
NHPPh2
Br
H
Br
MeO2C
Ts
Et
7
Et2Zn (2.5 equiv)
Cu(OTf)2 (4.5 mol%)
1 (5 mol%)
8, 91%
20 (major)
O
O
O
NHPPh2
+
NHPPh2
MeO2C
Ts
Br
H
Br
Ts
O
NHPPh2
14
toluene, -20 °C, 20 h
9
10, 88%
Et
N
PPh2
O
O
O
MeO2C
MeO2C
H
MeO2C
12, 83%
Ts
21 (minor)
ratio 20:21: 5.7:1
11
O
O
NHPPh2
Scheme 5. Application to the synthesis of pyrrolidinones and piperidinones 20 and 21.
H
MeO2C
Ts
13
14, 88%
To promote the cyclization we tried heating the reaction mix-
ture, but this did not increase the amount of 21 formed. The ad-
dition of Lewis acids (MgBr2, AlMe315) to activate the methyl ester
moiety gave very low conversion toward the cyclized product. We
finally found that the addition of a mixture of Et2Zn–CuCN gave
satisfactory results. Thus, CuCN and Et2Zn were added at the end of
Scheme 3. Synthesis of functionalized sulfinic acid adducts.
With these substrates in hand, we next examined their compati-
bility with the catalytic asymmetric reaction. Alkyl bromide sub-
strates are often incompatible with organometallic species, thereby
leading to extra protection/deprotection steps.13 Moreover, there are
noreportsof theaddition toimines in thepresenceofmethyl esters.14
The brominated sulfinic acid adducts 8 and 10 were subjected to
the conditions for the catalytic asymmetric addition of diethylzinc at
ꢀ20 ꢁC to give compounds 15 and 16, which were not isolated
(Scheme 4). The crude mixture was directly treated with t-BuOK in
THF at 50 ꢁC to yield the desired N-heterocycles 17 and 18 in good
yields (55–61%)and with excellentenantioselectivities (98–99% ee). It
isinterestingtonotethatneithercyclizedproducts17 or18 norhomo-
i. Et2Zn (2.5 equiv)
Cu(OTf)2 (4.5 mol%)
O
1 (5 mol%)
NHPPh2
toluene, -20 °C, 20 h
Et
N
PPh2
21
O
MeO2C
ii. Et2Zn (1.5 equiv)
CuCN (1.5 equiv)
-20 °C to rt, 24 h
O
(2)
Ts
14
68% (96% ee)

4970
I. Bonnaventure, A.B. Charette / Tetrahedron 65 (2009) 4968–4976
the reaction at ꢀ20 ꢁC and the reaction mixture was allowed to stir
at rt for 24 h, yielding the desired compound in 68% yield and high
enantiomeric excesses (96% ee) (Eq. 2).
was treated with PhSH to yield the crude aldehyde 29,20 which in
turn was transformed to sulfinic acid adduct 30 in 94% yield over the
two steps (Scheme 8). The copper-catalyzed asymmetric addition of
diethylzinc was then conducted under usual conditions. The con-
version to the corresponding N-protected amine was high (86%),
though a decrease in enantioselectivity (76%) was observed.
Encouraged by the high functional group compatibility of the
catalytic system, we next turned our attention to the synthesis of a-
chiral allylic amines 24.11 These compounds have been shown to be
extremely useful precursors to pyrroline derivatives 22 through the
use of ring closing metathesis strategies (Scheme 6).16
O
6 (1.5 equiv)
O
NHPPh2
Et2O, rt, 48 h
PhS
H
PhS
Ts
29
30
94%
R
R
N
H
N
PG
23
22
Et2Zn (2.5 equiv)
Cu(OTf)2 (4.5 mol%)
1 (5 mol%)
additive (1 equiv)
toluene, -20 °C, 24 h
O
R
H
NPG
24
O
O
25
1. MCPBA, CH2Cl2
2. DMF, mw, 200 °C
NHPPh2
NHPPh2
Scheme 6. Strategy for the synthesis of
a
-chiral allylic amines.
PhS
Et
Et
28
31
without additive, 86%, 76% ee
with BEt3, 93%, 94% ee
At first, we planned to use a tosyl group as a suitable protecting
group for the olefin,17 the corresponding sulfinic acid adduct 26
would be readily available in one step from acrolein by a double
condensation of p-toluenesulfinic acid. Thus, we submitted acrolein
to the conditions used above but with 3 equiv of p-toluenesulfinic
acid (Scheme 7).
50%
Scheme 8. Addition/elimination sequence to generate allylic amine 28.
We envisioned that sulfur might interfere with the catalyst by
complexing either copper or zinc and induce a competitive non-
enantioselective intramolecular addition.21 To circumvent this,
a Lewis acid was added to the sulfinic acid adduct that would
temporarily block the complexing ability of the sulfur atom during
the course of the reaction. We chose BEt3 as a compatible additive
under our reaction conditions.22 The use of the Lewis acid was ef-
ficient, and the desired amine 31 was obtained with high conver-
sion (93%) and excellent enantioselectivity (94% ee) (Scheme 8).
Finally, the allylic amine 28 was obtained in 50% yield using a two-
step sequence consisting of the oxidation to the sulfoxide and
elimination under microwave conditions. No epimerization oc-
curred under these conditions.23
6 (1 equiv)
TolSO2H (3 equiv)
Et2O, rt, 48 h
97%
O
O
NHPPh2
Ts
H
Ts
26
Et2Zn (2.5 equiv)
Cu(OTf)2 (4.5 mol%)
1 (5 mol%)
toluene, -20 °C, 39 h
O
O
NHPPh2
NHPPh2
X
We next focused on the application of the enantioselective ad-
dition methodology to the preparation of tetrahydroisoquinolines.
Et
Ts
Et
28
27
68% (96% ee)
Scheme 7. Tosyl as a protecting group for a,b-unsaturated system.
NPPh2
O
Et
32
R'
Et
Cyclization
We were pleased to observe that p-toluenesulfinic acid was
adding cleanly to both the 1,2 and 1,4-positions to yield the desired
sulfinic acid adduct 26 in 97% yield. These substrates are generally
difficult to prepare, and only 1,4-addition of p-toluenesulfinic acid is
observed with tosyl amide (TolSO2NH2).18 Compound 26 was then
reacted under the conditions for the asymmetric addition of Et2Zn
NPPh2
O
Me
34 (R' = vinyl)
35 (R' = I)
NPPh2
O
Et
33
(Scheme 7). The corresponding N-protected a-chiral amine 27 was
isolated in 68% yield and in high enantioselectivities (96% ee). Un-
fortunately, all attempts to deprotect the olefin by elimination of the
tosyl group failed to yield 28. We also considered to use a reduction/
oxidation sequence of the sulfone to the corresponding sulfoxide,
whichwould be moreeasilyeliminated. However, the reduction step
requiredharsh conditions that led tothe cleavageof the phosphinoyl
O
NPPh2
Asymmetric
Catalyzed
R'
H
38
Addition of R2Zn
NHPPh2
O
I
group. The a-chiral amine 27 is still an interesting substrate that
O
NPPh2
Et
could lead to 1,3-substituted compounds by nucleophilic displace-
ment of the tosyl group. We then decided to change the olefin pro-
tecting group for a sulfide substituent that would be readily oxidized
to the corresponding sulfoxide, a substituent that should be more
easily eliminated to generate allylic amine.19 Consequently, acrolein
36 (R' = vinyl)
37 (R' = I)
H
39
Scheme 9. Strategy for the synthesis of tetrahydroisoquinolines 32 and 33.

I. Bonnaventure, A.B. Charette / Tetrahedron 65 (2009) 4968–4976
4971
We planned to use the following strategy to access appropriate
substrates (Scheme 9).
generated in situ was mild and tolerated the presence of primary
alkyl bromide and methyl ester substituents for the aliphatic series,
iodine, and vinyl substituents were tolerated for the aromatic
series. This enabled us to synthesize N-heterocycles, such as
pyrrolidine/piperidine, pyrrolidinone/piperidinone as well as tet-
rahydroisoquinolines and allylic amines, which are important
subunits for biologically active compounds.
Functionalized imines 38 (R0¼vinyl) and 39 (R0¼I) were chosen
as substrates for the catalyzed asymmetric addition of dialkylzinc.
After allylation of the corresponding amines 36 and 37, a Heck
coupling reaction or a tandem isomerization/metathesis followed
by hydrogenation would lead to the desired tetrahydroisoquino-
lines 32 and 33.
The N-phosphinoylimines 38 and 39 were synthesized in 54%
and 65% yields, respectively, from 6 and the corresponding alde-
hydes 40 and 41 in the presence of Ti Lewis acids24 (Scheme 10).
The asymmetric addition of diethylzinc was performed at 0 ꢁC and
4. Experimental
4.1. General
the N-protected
a
-chiral amines 36 and 37 were obtained in good
All non-aqueous reactions were carried out in oven-dried
glassware under argon atmosphere. Anhydrous solvents were
obtained either by filtration through drying columns (CH2Cl2, DMF,
PhMe, MeOH), or by distillation over CaH (Et3N), Ba(OH) (DMA).
Analytical thin-layer chromatography (TLC) was performed on
precoated, glass-backed silica gel. Visualization was performed by
UV light or aq KMnO4. Flash column chromatography was per-
formed using 230–400 mesh silica of the indicated solvent system
according to standard technique. Melting points were obtained on
a melting point apparatus and are uncorrected. IR spectra were
taken on an FTIR and are reported in reciprocal centimeters (cmꢀ1).
NMR spectra (1H, 13C, 31P, DEPT 135, COSY, HMQC) were recorded on
an AV 400 spectrometer. Chemical shifts are reported relative to
Me4Si with the solvent resonance as the internal standard (CDCl3 or
C6D6). All spectra were obtained with complete proton decoupling.
Microwave reactions were run using a Biotage apparatus. Tol-
SO2H,28a 6,5c and aldehydes 7,28b 9,28c 11,28d 13,28d 40,28e and 4128f
were synthesized according to literature procedures.
yields (73–90%) and excellent enantioselectivities (92–97% ee). It
was interesting to note that the presence of an ortho substituent did
not affect the reactivity and the level of enantioinduction of the
reaction. Moreover, no product resulting from an iodine–zinc ex-
change was observed.25 Finally, reaction with allyl bromide26
afforded compounds 34 and 35 in 97% and 85% yields, respectively
(Scheme 10).
6 (1 equiv),
R'
R'
O
Ti(IV), DCM
O
NPPh2
For 40, Ti(OEt)4
For 41, TiCl4
H
H
R' = vinyl, 40
R' = I, 41
R' = vinyl, 38, 54%
R' = I, 39, 65%
Et2Zn (2 equiv),
Cu(OTf)2 (6 mol%)
1 (3 mol%),
toluene, 0 °C, 25 h
K2CO3, KOH
H2C=CHCH2Br
NBu4•HSO4
4.2. Experimental procedure
R'
Et
R'
PhMe, rt to 60 °C
NHPPh2
O
4.2.1. General procedure for the synthesis of the sulfinic acid
adducts 8, 10, 12, 14, 26, 30
NPPh2
O
Et
Aldehyde (6.1–20.0 mmol, 1.5 equiv) was mixed with P,P-
diphenylphosphinic amide (6) (4.0–13.3 mmol, 1 equiv) and p-tolu-
enesulfinic acid (6.1–20 mmol, 1.5 equiv) in Et2O (41–140 mL). The
resulting mixture was then stirred at rt for 24–48 h. The white
precipitate was then filtered through a fine sintered funnel and
washed with Et2O to give sulfinic acid adduct as a white solid.
R' = vinyl, 34, 97%
R' = I, 35, 85%
R' = vinyl, 36, 73% (97% ee)
R' = I, 37, 90% (92% ee)
Scheme 10. Synthesis of precursors 34 and 35.
Alkene 34 was then treated sequentially with [RuHCl-
(CO)(PPh3)3]27 to perform the isomerization of the allyl moiety and
Grubbs catalyst (second generation) led to the cyclized product 42
in 93% yield (Scheme 11). Conversely, Heck coupling conditions
were applied to 35 to afford 43 in 60% yield. A final stage of hy-
drogenation on PtO2 gave the desired tetrahydroisoquinolines 32
and 33 in 64% and 75% yields, respectively.
4.2.2. N-{4-Bromo-1-[(4-methylphenyl)sulfonyl]butyl}-P,P-
diphenylphosphinic amide (8)
Yield: 1.8 g (91%); mp 117–118 ꢁC; IR (neat): 3214, 1435, 1290,
1191, 1143, 1116, 1087, 983, 874, 750, 721, 692, 664 cmꢀ1 1H NMR
;
(400 MHz, DMSO-d6):
d
¼7.77–7.63 (m, 2H), 7.63–7.33 (m, 10H), 7.28
(d, J¼8.1 Hz, 2H), 6.42 (t, J¼11.9 Hz, 1H), 4.48 (qd, J¼10.3, 2.7 Hz,
1H), 3.48–3.37 (m, 2H), 2.36 (s, 3H), 2.19–2.05 (m, 1H), 2.00–1.67
1. RuHCl(CO)(PPh3)3
(m, 3H); 13C NMR (100 MHz, DMSO-d6):
d
¼144.3, 134.0 (d, JC–P¼
H2, Pt
64%
2. Grubbs II
NPPh2
O
32
34
124.3 Hz), 133.3, 133.1 (d, JC–P¼127.3 Hz), 131.6 (d, JC–P¼1.9 Hz),
131.4, 131.0 (d, JC–P¼9.3 Hz), 130.8 (d, JC–P¼9.8 Hz, 2 C), 129.5, 129.0,
128.4 (d, JC–P¼12.4 Hz, 2 C), 128.3 (d, JC–P¼12.5 Hz, 2 C), 71.4, 33.9,
93%
Et
42
28.2, 27.5, 21.1; 31P NMR (162 MHz, DMSO-d6):
d
¼23.7; MS (APCI,
70 eV): m/z (%)¼350.1 (100), 352.1 (100) [M]þ; Anal. Calcd for
C23H25BrNO3PS: C, 54.55; H, 4.98; N, 2.77; S, 6.33. Found: C, 54.51;
H, 4.92; N, 2.93; S, 6.52.
Pd2(dba)3
60%
H2, Pt
75%
35
33
NPPh2
O
6:1 dr
Et
43
4.2.3. N-{5-Bromo-1-[(4-methylphenyl)sulfonyl]pentyl}-P,P-
diphenylphosphinic amide (10)
Scheme 11. Tetrahydroisoquinoline formation.
Yield: 3.8 g (88%); mp 121–123 ꢁC; IR (neat): 3206, 2952, 1596,
3. Conclusion
1437, 1289, 1191, 1145, 1124, 1109, 1087, 722, 692, 666 cmꢀ1 1H
;
NMR (400 MHz, DMSO-d6):
d
¼7.70 (dd, J¼11.9, 8.0 Hz, 2H), 7.59 (d,
In conclusion, we have demonstrated the ability to synthesize
sulfinic acid adducts as stable precursors of functionalized alkyl-
imines. The catalyzed asymmetric addition of diethylzinc to imines
J¼8.0 Hz, 2H), 7.56–7.35 (m, 8H), 7.28 (d, J¼8.0 Hz, 2H), 6.35 (t,
J¼12.1 Hz, 1H), 4.45 (qd, J¼10.9, 3.4 Hz, 1H), 3.26 (t, J¼6.7 Hz, 2H),
2.36 (s, 3H), 2.06–1.90 (m, 1H), 1.68 (m, 3H), 1.54–1.41 (m, 1H),

4972
I. Bonnaventure, A.B. Charette / Tetrahedron 65 (2009) 4968–4976
1.35–1.19 (m, 1H); 13C NMR (100 MHz, DMSO-d6):
d
¼144.1, 134.2
12.6 Hz, 2 C),125.8, 71.2, 28.4, 28.3, 21.1; 31P NMR (162 MHz, DMSO-
(d, JC–P¼123.7 Hz), 133.4, 133.4 (d, JC–P¼127.3 Hz), 131.5 (d, JC–P
¼
d6):
d
¼23.5; MS (APCI, 70 eV): m/z (%)¼366.2 (100) [MþH]þ; Anal.
1.9 Hz), 131.3 (d, JC–P¼1.8 Hz), 131.0 (d, JC–P¼10.1 Hz, 2 C), 130.9 (d,
JC–P¼10.4 Hz, 2 C), 129.4, 129.1, 128.2 (d, JC–P¼12.4 Hz, 2 C), 127.9 (d,
JC–P¼12.6 Hz, 2 C), 71.9, 34.2, 31.2, 27.7 (d, JC–P¼1.3 Hz), 23.6, 21.1;
Calcd for C28H28NO3PS2: C, 64.47; H, 5.41; N, 2.69; S, 12.29. Found:
C, 64.19; H, 5.58; N, 2.87; S, 12.18.
31P NMR (162 MHz, DMSO-d6):
d
¼23.6; MS (APCI, 70 eV): m/z
4.2.8. General procedure for the asymmetric catalyzed addition of
diethylzinc to sulfinic acid adducts 8, 10, 12, 14, 26, 30
(%)¼364.1 (100), 366.1 (100) [(MꢀTs)þH]þ; Anal. Calcd for
C24H27BrNO3PS: C, 55.39; H, 5.23; N, 2.69; S, 6.16. Found: C, 55.23;
H, 5.26; N, 2.79; S, 6.23.
The general procedure9a was followed using (R)-1 (4.8–32.2 mg,
0.015–0.1 mmol, 0.05 equiv), Cu(OTf)2 (5–33.0 mg, 0.014–
0.09 mmol, 0.045 equiv), Et2Zn (79–523 mL, 0.75–5 mmol,
4.2.4. Methyl 4-[(diphenylphosphoryl)amino]-4-[(4-methylphenyl)-
sulfonyl]butanoate (12)
2.5 equiv), sulfinic acid adduct (0.3–2.0 mmol) in dry PhMe (2.7–
35 mL) for 19–39 h at ꢀ20 ꢁC. The crude material was purified by
flash chromatography on silica gel to afford the corresponding
amide as a white solid.
Yield: 3.8 g (83%); mp 121–123 ꢁC; IR (neat): 3163, 2953, 1732,
1436, 1290, 1189, 1144, 1121, 1085, 968, 720, 695, 669 cmꢀ1; 1H NMR
(400 MHz, DMSO-d6):
d
¼7.78–7.67 (m, 2H), 7.63–7.45 (m, 6H),
For 17/18. The crude material was dissolved in dry THF (47 mL).
t-BuOK (53.0 mg, 0.47 mmol) was added and the reaction was
heated to 50 ꢁC for 4 h. The resulting mixture was diluted with
EtOAc (10 mL), washed with brine (10 mL), and dried over Na2SO4.
Concentration under vacuum gave the crude material, which was
purified by flash chromatography on silica gel eluting with 100%
EtOAc to afford the desired compound.
7.45–7.30 (m, 6H), 6.36 (t, J¼10.8 Hz, 1H), 4.46 (qd, J¼11.2, 3.1 Hz,
1H), 3.51 (s, 3H), 2.48–2.43 (m, 2H), 2.39 (s, 3H), 2.27–2.14 (m, 1H),
1.93–1.77 (m, 1H); 13C NMR (100 MHz, DMSO-d6):
d
¼172.3, 144.4,
133.4, 133.6 (d, JC–P¼125.9 Hz), 132.5 (d, JC–P¼127.4 Hz), 131.6, 131.4,
131.1 (tapp, JC–P¼9.1 Hz, 2 C), 129.5, 129.0, 128.3 (d, JC–P¼12.4 Hz, 2
C), 128.0 (d, JC–P¼12.6 Hz, 2 C), 71.5, 51.2, 28.8, 24.4, 21.0; 31P NMR
(162 MHz, DMSO-d6):
d
¼23.3; HRMS–ESI: m/z [MþNa]þ calcd for
For 21. After stirring for 26 h at ꢀ20 ꢁC, the reaction was diluted
C24H26NNaO5PS: 494.11615; found: 494.11394.
with dry PhMe (10 mL). CuCN (134 mg, 1.5 mmol) and Et2Zn
(160
m
L, 1.5 mmol) were then added at ꢀ20 ꢁC and the reaction was
4.2.5. Methyl 5-[(diphenylphosphoryl)amino]-5-[(4-methylphenyl)-
sulfonyl]pentanoate (14)
allowed to warm to rt and stirred for 24 h (monitored by MS). The
reaction was quenched with aq satd NH4Cl (20 mL) and the aque-
ous layer was extracted with CH2Cl2 (4ꢂ20 mL). The combined
organic layers were dried over Na2SO4. Concentration under vac-
uum gave the crude material, which was purified by flash chro-
matography on silica gel eluting with 100% EtOAc.
Yield: 3.8 g (88%); mp 119–121 ꢁC; IR (neat): 3200, 2933, 1732,
1437, 1289, 1191, 1148, 1123, 1109, 1087, 751, 723, 694, 665 cmꢀ1; 1H
NMR (400 MHz, DMSO-d6):
d
¼7.68 (dd, J¼12.0, 7.0 Hz, 2H), 7.62–
7.35 (m,10H), 7.27 (d, J¼8.0 Hz, 2H), 6.37 (t, J¼12.0 Hz,1H), 4.46 (qd,
J¼10.9, 3.2 Hz, 1H), 3.52 (s, 3H), 2.36 (s, 3H), 2.27–2.14 (m, 2H),
2.04–1.90 (m, 1H), 1.79–1.56 (m, 2H), 1.52–1.36 (m, 1H); 13C NMR
For 31. BEt3 (290 mL, 2 mmol) was added to 26 and the resulting
heterogeneous mixture was stirred for 5 min at rt prior to the ad-
dition to the catalyst solution at ꢀ20 ꢁC.
(100 MHz, DMSO-d6):
d
¼172.6, 144.1, 134.2 (d, JC–P¼124.0 Hz),
133.4, 133.3 (d, JC–P¼127.3 Hz), 131.5 (d, JC–P¼2.2 Hz), 131.3 (d, JC–P
¼
2.2 Hz),131.0 (d, JC–P¼9.8 Hz, 2 C), 130.9 (d, JC–P¼10.0 Hz, 2 C), 129.4,
129.0, 128.2 (d, JC–P¼12.4 Hz, 2 C), 127.9 (d, JC–P¼12.7 Hz, 2 C), 71.8,
51.2, 32.3, 27.9 (d, JC–P¼1.3 Hz), 21.1, 20.5; 31P NMR (162 MHz,
4.2.9. (2S)-1-(Diphenylphosphoryl)-2-ethylpyrrolidine (17)
Enantiomeric excess (99% ee) was determined by SFC analysis
(Chiralpak) AD, 180 bar, 2 mL/min, 26 ꢁC, modifier 10% i-PrOH:
DMSO-d6):
d
¼23.7; HRMS–ESI: m/z [MþNa]þ calcd for
(major enantiomer) tR¼25.9 min, (minor enantiomer) tR¼29.0 min.
20
C25H28NNaO5PS: 508.53180; found: 508.12985.
Yield: 85 mg (61%); colorless oil; [
a]
ꢀ26.0 (c 1.2, CHCl3); Rf¼0.3
D
(hexanes–EtOAc, 1:4); IR (neat): 2962, 2872, 1437, 1188, 1116, 1071,
4.2.6. N-{1,3-Bis[(4-methylphenyl)sulfonyl]propyl}-P,P-
diphenylphosphinic amide (26)
994, 723, 697 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d¼7.92–7.83 (m,
4H), 7.51–7.39 (m, 6H), 3.26–3.14 (m, 1H), 3.12–2.94 (m, 2H), 1.84–
3 Equiv of sulfinic acid was used. Yield: 7.3 g (97%); mp 124–
126 ꢁC; IR (neat): 3154, 1595, 1437, 1312, 1197, 1147, 1118, 724, 692,
1.67 (m, 2H), 1.66–1.43 (m, 6H), 0.78 (t, J¼7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3):
d
¼132.8 (d, JC–P¼129.2 Hz), 132.3 (d, JC–P¼9.1 Hz,
663 cmꢀ1
;
1H NMR (400 MHz, DMSO-d6):
d¼7.75–7.29 (m, 18H),
2 C), 132.0 (d, JC–P¼9.3 Hz, 2 C), 132.6 (d, JC–P¼128.5 Hz), 131.4 (d,
6.50 (dd, J¼11.3, 9.6 Hz, 1H), 4.57 (qdapp, J¼11.3, 2.9 Hz, 1H), 3.59–
JC–P¼2.6 Hz), 131.3 (d, JC–P¼2.6 Hz), 128.3 (d, JC–P¼12.3 Hz, 2 C),
3.45 (m, 1H), 3.36–3.23 (m, 1H), 2.42 (s, 3H), 2.40 (s, 3H), 2.27–2.16
128.1 (d, JC–P¼12.5 Hz, 2 C), 60.0 (d, JC–P¼1.4 Hz), 47.1 (d, JC–P
¼
¼
(m, 1H), 2.09–1.95 (m, 1H); 13C NMR (100 MHz, DMSO-d6):
d¼144.7,
2.2 Hz), 30.7 (d, JC–P¼4.5 Hz), 28.9 (d, JC–P¼3.4 Hz), 25.3 (d, JC–P
144.5, 135.5, 133.3 (d, JC–P¼126.1 Hz), 133.0, 131.9 (d, JC–P¼127.7 Hz),
5.3 Hz), 10.4; 31P NMR (162 MHz, CDCl3):
d
¼26.6; HRMS-ESI: m/z
131.8 (d, JC–P¼2.0 Hz), 131.4 (d, JC–P¼1.9 Hz), 131.2 (tapp, JC–P
¼
[MþH]þ calcd for C18H23NOP: 300.14990; found: 300.15117.
10.6 Hz, 4 C), 129.9, 129.7, 129.1, 128.4 (d, JC–P¼12.4 Hz, 2 C), 128.0,
128.0 (d, JC–P¼12.6 Hz, 2 C), 127.6, 125.5, 70.4, 51.0, 23.1, 21.1, 21.1;
4.2.10. (2S)-1-(Diphenylphosphoryl)-2-ethylpiperidine (18)
Enantiomeric excess (98% ee) was determined by SFC analysis
(Chiralpak) AS, 180 bar, 2 mL/min, 40 ꢁC, modifier 10% i-PrOH:
31P NMR (162 MHz, DMSO-d6):
d
¼23.5; HRMS–ESI: m/z [MþH]þ
calcd for C29H31NO5PS2: 568.13758; found: 568.13729.
(major enantiomer) tR¼6.6 min, (minor enantiomer) tR¼7.8 min.
20
4.2.7. N[1-[(4-Methylphenyl)sulfonyl]-3-(phenylthio)propyl]-P,P-
diphenylphosphinic amide (30)
Yield: 51.5 mg (55%); mp 110–113 ꢁC; [
a]
ꢀ21.0 (c 1.0, CHCl3);
D
Rf¼0.4 (EtOAc); IR (neat): 3052, 2923, 2847, 1443, 1434, 1203, 1113,
Yield: 6.5 g (94%); mp 134–135 ꢁC; IR (neat): 3117, 2894, 1595,
1437, 1309, 1302, 1190, 1165, 1145, 1125, 967, 736, 723, 661,
1105, 954, 722, 702 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
¼7.92–7.83
(m, 4H), 7.51–7.39 (m, 6H), 3.26–3.14 (m, 1H), 3.12–2.94 (m, 2H),
581 cmꢀ1
;
1H NMR (400 MHz, DMSO-d6):
d
¼7.77 (dd, J¼11.9,
1.84–1.67 (m, 2H),1.66–1.43 (m, 6H), 0.78 (t, J¼7.4 Hz, 3H); 13C NMR
7.0 Hz, 2H), 7.62–7.09 (m, 17H), 6.48 (t, J¼10.9 Hz, 1H), 4.69–4.56
(100 MHz, CDCl3):
d
¼132.5 (d, JC–P¼129.9 Hz), 132.4 (d, JC–P¼
(m, 1H), 3.14–3.02 (m, 1H), 2.96–2.84 (m, 1H), 2.38 (s, 3H), 2.18–1.92
129.7 Hz), 132.3 (d, JC–P¼9.0 Hz, 4 C), 131.4 (tapp, JC–P¼2.2 Hz), 128.4
(m, 2H); 13C NMR (100 MHz, DMSO-d6):
d¼144.4,134.8,133.8 (d, JC–P
¼
(d, JC–P¼12.3 Hz, 2 C), 128.3 (d, JC–P¼12.3 Hz, 2 C), 53.1 (d, JC–P
¼
¼
119.8 Hz),132.5 (d, JC–P¼121.5 Hz),132.2,131.7 (d, JC–P¼2.0 Hz),131.5
0.9 Hz), 39.9 (d, JC–P¼2.1 Hz), 27.7 (d, JC–P¼4.2 Hz), 26.0 (d, JC–P
(d, JC–P¼2.0 Hz), 131.3 (d, JC–P¼4.5 Hz, 2 C), 131.2 (d, JC–P¼4.9 Hz, 2
4.0 Hz), 22.8 (d, JC–P¼3.6 Hz), 18.7, 11.3; 31P NMR (162 MHz, CDCl3):
C), 129.6, 129.0, 128.4, 128.3 (d, JC–P¼12.4 Hz, 2 C), 128.0 (d, JC–P
¼
d
¼28.9; MS (APCI, 70 eV): m/z (%)¼314.2 (100) [MþH]þ; Anal. Calcd

I. Bonnaventure, A.B. Charette / Tetrahedron 65 (2009) 4968–4976
4973
for C19H24NOP: C, 72.82; H, 7.72; N, 4.47. Found: C, 72.65; H, 7.77; N,
4.49.
(hexanes–EtOAc, 1:4); IR (neat): 2968, 1651, 1436, 1392, 1274, 1201,
1122,1098, 755, 728, 692 cmꢀ1; 1H NMR (400 MHz, CDCl3):
7.82 (m, 4H), 7.52–7.36 (m, 6H), 7.31–7.20 (m, 4H), 7.18–7.11 (m, 1H),
3.19–3.05 (br, 1H), 3.07 (ddd, J¼13.0, 9.1, 5.6 Hz, 1H), 2.93 (ddd,
J¼12.9, 9.1, 6.6 Hz, 1H), 2.88–2.76 (br, 1H), 1.91–1.68 (m, 2H), 1.66–
1.50 (m, 2H), 0.87 (t, J¼7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
¼7.94–
4.2.11. (5S)-1-(Diphenylphosphoryl)-5-ethylpyrrolidin-2-one (19)
Enantiomeric excess (97% ee) was determined by HPLC analysis
(Chiralpak) AD-H, 80:20 hexane–i-PrOH, 1.0 mL/min: (major en-
antiomer) tR¼9.3 min, (minor enantiomer) tR¼13.8 min. Yield:
d
¼136.4, 133.4, 133.3, 132.1 (d, JC–P¼9.4 Hz, 2 C), 132.1 (d, JC–P
¼
¼
20
115 mg (87%); mp 166–169 ꢁC; [
a]
þ169.3 (c 1.4, CHCl3); Rf¼0.3
9.3 Hz, 2 C), 131.7 (d, JC–P¼2.6 Hz, 2 C), 128.9, 128.8, 128.4 (d, JC–P
D
(hexanes–EtOAc, 1:4); IR (neat): 2963, 1709, 1689, 1438, 1207, 1120,
12.5 Hz, 2 C),128.4 (d, JC–P¼12.5 Hz, 2 C),125.8, 52.1 (d, JC–P¼1.8 Hz),
964, 757, 725, 695 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
¼7.98–7.88
35.4 (d, JC–P¼5.3 Hz), 30.0, 29.8 (d, JC–P¼4.2 Hz), 9.7; 31P NMR
(m, 2H), 7.77–7.67 (m, 2H), 7.63–7.39 (m, 6H), 4.44–4.29 (m, 1H),
2.68–2.51 (m, 1H), 2.43–2.19 (m, 2H), 2.02–1.85 (m, 2H), 1.67–1.50
(162 MHz, CDCl3):
d
¼22.2; MS (APCI, 70 eV): m/z (%)¼412.2 (100)
[M(O)þH]þ; Anal. Calcd for C23H26NOPS: C, 69.85; H, 6.63; N, 3.54.
(m, 1H), 0.86 (t, J¼7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d¼178.6
Found: C, 69.68; H, 6.52; N, 3.51.
(d, JC–P¼1.9 Hz), 132.4 (d, JC–P¼3.0 Hz), 132.3 (d, JC–P¼3.0 Hz), 131.9
(d, JC–P¼11.2 Hz, 2 C), 131.6 (d, JC–P¼11.3 Hz, 2 C), 131.0 (d, JC–P
¼
4.2.15. N-[(1S)-1-Ethylprop-2-enyl]-P,P-diphenylphosphinic
amide (28)
125.9 Hz), 130.7 (d, JC–P¼126.2 Hz), 128.3 (d, JC–P¼13.8 Hz, 2 C),
128.2 (d, JC–P¼13.9 Hz, 2 C), 60.2 (d, JC–P¼2.7 Hz), 31.6 (d, JC–P
¼
Chiral amine 31 (270 mg, 0.68 mmol) was dissolved in dry
CH2Cl2 (6.8 mL). m-CPBA (141 mg, 0.82 mmol) was added at rt and
the reaction was stirred for 2 h. The reaction was then quenched by
a slow addition of aq satd Na2SO3 (5 mL), extracted with CH2Cl2
(3ꢂ10 mL), and dried over Na2SO4. Concentration under vacuum
gave the crude material, which was purified by flash chromato-
graphy on silica gel eluting with the following gradient: 100% EtOAc
then MeOH–EtOAc (1:19) to afford the corresponding sulfoxide as
a white solid (210 mg, 75%). The sulfoxide (188 mg, 0.46 mmol) was
charged in a microwave vial with dry DMF (4.5 mL). The microwave
was set as the following: 200 ꢁC, high absorption, 20 min. The
resulting brown mixture was diluted with EtOAc (20 mL), washed
with brine (3ꢂ20 mL), and dried over Na2SO4. Concentration under
vacuum gave the crude material, which was purified by flash
chromatography on silica gel eluting with 100% EtOAc to afford 28
as a white solid (85 mg, 66%). Enantiomeric excess (97% ee) was
confirmed by SFC analysis of the corresponding allyl derivative
(Chiralpak) AD, 180 bar, 2 mL/min, 40 ꢁC, modifier 5% i-PrOH: (mi-
5.7 Hz), 28.4, 24.4 (d, JC–P¼6.2 Hz), 9.7; 31P NMR (162 MHz, CDCl3):
d
¼27.5; HRMS–ESI: m/z [MþH]þ calcd for C18H21NO2P: 314.13044;
found: 314.13089.
4.2.12. (6S)-1-(Diphenylphosphoryl)-6-ethylpiperidin-2-one (21)
Enantiomeric excess (96% ee) was determined by HPLC analysis
(Chiralpak) AD-H, 80:20 hexane–i-PrOH, 1.0 mL/min: (major enan-
tiomer) tR¼9.3 min, (minor enantiomer) tR¼12.5 min. Yield: 223 mg
20
(68%); mp 104–106 ꢁC; [
a]
þ131.8 (c 1.5, CHCl3); Rf¼0.4 (hexanes–
D
EtOAc, 1:4); IR (neat): 2968, 1651, 1436, 1392, 1274, 1201, 1122, 1098,
755, 728, 692 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
¼7.99–7.88 (m,
2H), 7.73–7.64 (m, 2H), 7.59–7.36 (m, 6H), 4.54–4.39 (m, 1H), 2.51–
2.26 (m, 2H), 2.11–2.00 (m,1H), 2.00–1.73 (m, 4H),1.65–1.50 (m,1H),
0.88 (t, J¼7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3):
¼174.4, 132.4 (d,
d
JC–P¼11.1 Hz, 2 C), 132.1 (d, JC–P¼128.1 Hz), 132.0 (d, JC–P¼3.0 Hz),
131.8 (d, JC–P¼3.0 Hz), 131.3 (d, JC–P¼11.2 Hz, 2 C), 131.0 (d, JC–P
126.7 Hz), 128.1 (d, JC–P¼13.7 Hz, 2 C), 128.0 (d, JC–P¼13.9 Hz, 2 C),
54.3 (d, JC–P¼1.4 Hz), 32.5 (d, JC–P¼2.9 Hz), 28.2, 24.4 (d, JC–P
¼
¼
nor enantiomer) tR¼8.8 min, (major enantiomer) tR¼10.3 min. Mp
20
3.9 Hz), 15.7, 10.6; 31P NMR (162 MHz, CDCl3):
d
¼32.1; MS (APCI,
122–123 ꢁC; [
a
]
þ11.6 (c 1.1, CHCl3); Rf¼0.4 (EtOAc); IR (neat):
D
70 eV): m/z (%)¼328.2 (100) [MþH]þ; Anal. Calcd for C19H22NO2P: C,
3118, 2967, 2870, 1437, 1198, 1182, 1107, 1069, 1014, 904, 720,
69.71; H, 6.77; N, 4.28. Found: C, 69.37; H, 6.78; N, 4.19.
693 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d¼7.96–7.84 (m, 4H), 7.52–
7.38 (m, 6H), 5.79 (ddd, J¼17.1, 10.3, 6.0 Hz, 1H), 5.14 (dtapp, J¼17.2,
1.4 Hz, 1H), 5.09 (dtapp, J¼10.4, 1.3 Hz, 1H), 3.56 (br, 1H), 2.88 (br,
1H), 1.71 (m, 1H), 1.65–1.53 (m, 1H), 0.88 (t, J¼7.4 Hz, 3H); 13C NMR
4.2.13. N-{(1S)-1-Ethyl-3-[(4-methylphenyl)sulfonyl]propyl}-P,P-
diphenylphosphinic amide (27)
Enantiomeric excess (96% ee) was determined by SFC analysis of
the corresponding allyl derivative (Chiralpak) AD, 200 bar, 2 mL/
min, 60 ꢁC, modifier 20% i-PrOH: (minor enantiomer) tR¼29.3 min,
(100 MHz, CDCl3):
d
¼140.0 (d, JC–P¼6.1 Hz), 133.0 (d, JC–P¼128.7 Hz),
132.3 (d, JC–P¼9.4 Hz, 2 C), 131.9 (d, JC–P¼9.4 Hz, 2 C), 132.5 (d, JC–P
130.7 Hz), 131.7 (tapp, JC–P¼2.3 Hz, 2 C), 128.4 (d, JC–P¼12.5 Hz, 2 C),
128.3 (d, JC–P¼12.6 Hz, 2 C), 114.7, 55.0 (d, JC–P¼1.1 Hz), 30.4 (d, JC–P
¼
(major enantiomer) tR¼33.5 min. Yield: 600 mg (68%); mp 174–
¼
20
176 ꢁC; [
a
]
ꢀ14.6 (c 1.1, CHCl3); Rf¼0.5 (EtOAc); IR (neat): 3215,
4.2 Hz), 9.8; 31P NMR (162 MHz, CDCl3):
d
¼22.5; HRMS-ESI: m/z
D
2927, 1593, 1437,1298, 1273, 1190, 1138, 1122, 1107, 1086,750,
[MþNa]þ calcd for C17H20NNaOP: 308.11747; found: 308.11799.
692 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d¼7.89–7.78 (m, 4H), 7.75 (d,
J¼8.1 Hz, 2H), 7.54–7.36 (m, 6H), 7.33 (d, J¼8.1 Hz, 2H), 3.52–3.41
(m, 1H), 3.13 (m, 1H), 3.08–2.96 (br, 1H), 2.94–2.83 (br, 1H), 2.43 (s,
3H), 2.03–1.90 (m, 1H), 1.85–1.72 (m, 1H), 1.65–1.46 (m, 2H), 0.85 (t,
4.2.16. P,P-Diphenyl-N-[(1Z)-(2-vinylphenyl)methylene]phosphinic
amide (38)
Compound 38 was synthesized according to literature pro-
cedure24c using 2-vinylbenzaldehyde (40) (1.1 g, 8.3 mmol), 6
(1.6 g, 7.6 mmol), and distilled Ti(OEt)4 (3.8 g, 16.6 mmol). Puri-
fication by flash chromatography on silica gel eluting with the
following gradient: EtOAc–hexane (1:1) then (4:1) afforded 38 as
a white solid (1.3 g, 54%). Mp 108–110 ꢁC; Rf¼0.3 (hexanes–
EtOAc, 1:1.5); IR (neat): 3056, 1610, 1588, 1437, 1201, 1122, 1106,
J¼7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3):
¼144.4, 136.1, 132.6 (d,
d
JC–P¼129.0 Hz), 132.2 (d, JC–P¼129.3 Hz, 2 C), 132.1 (d, JC–P¼9.5 Hz, 2
C), 131.8 (d, JC–P¼35.8 Hz), 131.7 (d, JC–P¼9.4 Hz, 2 C), 129.8, 128.4 (d,
JC–P¼12.5 Hz, 2 C), 128.3 (d, JC–P¼12.6 Hz, 2 C), 127.9, 53.1, 51.4 (d, JC–P
¼
1.2 Hz), 30.2 (d, JC–P¼4.6 Hz), 28.6 (d, JC–P¼4.3 Hz), 21.5, 9.7; 31P NMR
(162 MHz, CDCl3):
d
¼22.5; MS (APCI, 70 eV): m/z (%)¼442.2 (100)
[MþH]þ; Anal. Calcd for C24H28NO3PS: C, 65.29; H, 6.39; N, 3.17; S,
837, 747, 723, 691 cmꢀ1
;
1H NMR (400 MHz, C6D6):
d
¼9.88 (d,
7.26. Found: C, 65.05; H, 6.24; N, 3.20; S, 7.30.
JH–P¼32.0 Hz, 1H), 8.22–8.15 (m, 4H), 8.05 (dd, J¼7.7, 1.3 Hz, 1H),
7.13–6.92 (m, 10H), 5.29 (dd, J¼17.3, 1.3 Hz, 1H), 5.04 (dd, J¼11.0,
4.2.14. N-[(1S)-1-Ethyl-3-(phenylthio)propyl]-P,P-
diphenylphosphinic amide (31)
Enantiomeric excess (94% ee) was determined by HPLC analysis
(Chiralpak) AD-H, 80:20 hexane–i-PrOH, 1.0 mL/min: (minor en-
1.3 Hz, 1H); 13C NMR (100 MHz, C6D6):
d
¼172.2 (d, JC–P¼7.4 Hz),
141.4, 134.7 (d, JC–P¼125.8 Hz, 2 C), 133.5, 133.2, 133.0, 132.0 (d,
JC–P¼8.9 Hz, 4 C), 131.6 (d, JC–P¼2.7 Hz), 129.2, 128.7 (d, JC–P
¼
12.3 Hz, 4 C), 128.3, 127.3, 118.9; 31P NMR (162 MHz, C6D6):
antiomer) tR¼11.6 min, (major enantiomer) tR¼13.5 min. Yield:
d
¼23.3; HRMS-ESI: m/z [MþH]þ calcd for C21H19NOP: 332.11988;
20
772 mg (98%); mp 159–162 ꢁC; [
a
]
ꢀ11.5 (c 1.1, CHCl3); Rf¼0.4
found: 332.11934.
D

4974
I. Bonnaventure, A.B. Charette / Tetrahedron 65 (2009) 4968–4976
4.2.17. N-[(1E)-(2-Iodophenyl)methylene]-P,P-diphenylphosphinic
amide (39)
(162 MHz, CDCl3):
d
¼22.8; MS (APCI, 70 eV): m/z (%)¼462.1 (100)
[MþH]þ; Anal. Calcd for C21H21INOP: C, 54.68; H, 4.59; N, 3.04.
Compound 39 was synthesized according to literature proce-
Found: C, 54.53; H, 4.55; N, 3.01.
dure24b using 2-iodobenzaldehyde (41) (920 mg, 4.0 mmol), 6
(869 mg, 4.0 mmol), TiCl4 (242
m
L, 1.7 mmol), and distilled Et3N
4.2.21. General procedure for the allylation reaction
(1.7 mL, 3.0 mmol). Purification by flash chromatography on silica
gel eluting with 70% EtOAc in hexane afforded 39 as a white solid
(1.1 g, 65%). Mp 135–137 ꢁC; Rf¼0.3 (hexanes–EtOAc, 1:1.5); IR
(neat): 1601, 1437, 1266, 1192, 1126, 1105, 1017, 825, 754, 727,
The general procedure26 was followed using chiral amine (0.87–
1.1 mmol), K2CO3 (150–191 mg, 1.1–1.4 mmol), KOH (147–187 mg,
2.6–3.3 mmol), NBu4$HSO4 (30–38 mg, 0.09–0.1 mmol), distilled
allyl bromide (100–120 mL, 1.1–1.4 mmol) in PhMe (11–14 mL) at
60 ꢁC for 5–13 h. The crude material was purified by flash chro-
matography on silica gel to afford the allylic amine.
693 cmꢀ1
;
1H NMR (400 MHz, C6D6):
d
¼9.74 (d, JH–P¼31.0 Hz, 1H),
8.19–8.08 (m, 4H), 8.00 (dd, J¼7.8, 1.7 Hz, 1H), 7.43 (d, J¼7.9 Hz,
1H), 7.11–7.00 (m, 6H), 6.86–6.79 (m, 1H), 6.52–6.45 (m, 1H); 13C
NMR (100 MHz, C6D6):
d
¼176.9 (d, JC–P¼6.3 Hz), 140.5, 136.8 (d, JC–P
¼
4.2.22. N-Allyl-P,P-diphenyl-N-[(1S)-(2-vinylphenyl)-
24.7 Hz), 134.3 (d, JC–P¼125.6 Hz, 2 C), 134.1, 132.1 (d, JC–P¼9.0 Hz,
propyl]phosphinic amide (34)
20
4 C), 131.7 (d, JC–P¼2.5 Hz, 2 C), 130.1, 128.7 (d, JC–P¼12.3 Hz, 4 C),
Yield: 431 mg (97%); colorless oil; [
a]
þ111.0 (c 3.4, PhH);
D
128.2, 103.1; 31P NMR (162 MHz, C6D6):
d
¼25.1; MS (APCI,
Rf¼0.4 (hexanes–EtOAc, 1:1.5); IR (neat): 3057, 2967, 2874, 1736,
1436, 1200, 1118, 1104, 915, 890, 746, 722, 697 cmꢀ1 1H NMR
(400 MHz, C6D6):
70 eV): m/z (%)¼432.0 (100) [MþH]þ; Anal. Calcd for
C19H15INOP: C, 52.92; H, 3.51; N, 3.25. Found: C, 52.88; H, 3.44;
N, 3.18.
;
d
¼7.95–7.85 (m, 2H), 7.83–7.75 (m, 2H), 7.57 (dd,
J¼17.2, 10.9 Hz), 7.52–7.45 (m, 2H), 7.13–6.96 (m, 8H), 5.51 (dd,
J¼17.2, 1.6 Hz, 1H), 5.56–5.44 (m, 1H), 5.29 (qapp, J¼8.0 Hz, 1H), 5.15
(dd, J¼10.9, 1.6 Hz, 1H), 4.66–4.58 (m, 2H), 3.59–3.34 (m, 2H), 2.25
(papp, J¼7.5 Hz, 2H), 0.73 (t, J¼7.3 Hz, 3H); 13C NMR (100 MHz,
4.2.18. Asymmetric addition of diethylzinc to aromatic imines 38
and 39
General procedure was followed using (R)-1 (9.7–22 mg, 0.03–
0.07 mmol, 3 mol %), Cu(OTf)2 (21.7–49.5 mg, 0.06–0.14 mmol,
C6D6):
d
¼138.7 (d, JC–P¼90.1 Hz), 138.2, 137.0 (d, JC–P¼5.1 Hz), 135.8,
134.0 (d, JC–P¼123.9 Hz), 134.6 (d, JC–P¼123.1 Hz), 132.8 (d, JC–P
8.5 Hz, 2 C), 132.7 (d, JC–P¼8.9 Hz, 2 C), 131.5 (d, JC–P¼2.8 Hz), 131.4
(d, JC–P¼2.7 Hz), 128.8, 128.4 (d, JC–P¼12.3 Hz, 2 C), 128.6 (d, JC–P
¼
6 mol %), Et2Zn (210–477 mL, 2.0–4.6 mmol, 2 equiv), and imine
(1.0–2.3 mmol) in PhMe (10–23 mL) for 25 h at 0 ꢁC. The crude
material was purified by flash chromatography on silica gel elut-
ing with 100% EtOAc to afford the desired compound as a white
solid.
¼
12.4 Hz, 2 C) 127.9, 127.5, 126.8, 116.3, 115.4, 57.2 (d, JC–P¼3.3 Hz),
47.5 (d, JC–P¼5.0 Hz), 27.8, 11.7; 31P NMR (162 MHz, C6D6):
¼30.6;
d
HRMS-ESI: m/z [MþNa]þ calcd for C26H29NOP: 402.19813; found:
402.19848.
4.2.19. P,P-Diphenyl-N-[(1S)-(2-vinylphenyl)propyl]phosphinic
amide (36)
4.2.23. N-Allyl-N-[(1S)-1-(2-iodophenyl)propyl]-P,P-
Enantiomeric excess (97% ee) was determined by HPLC analysis
(Chiralpak) AD-H, 90:10 hexane–i-PrOH, 1.0 mL/min: (minor en-
diphenylphosphinic amide (35)
20
Yield: 370 mg (85%); mp 77–79 ꢁC; [
a]
þ56.3 (c 1.3, CHCl3);
D
antiomer) tR¼16.1 min, (major enantiomer) tR¼26.8 min. Yield:
Rf¼0.4 (hexanes–EtOAc, 1:9); IR (neat): 3056, 2968, 1463, 1437,
20
264 mg (73%); mp 117–120 ꢁC; [
a]
þ85.1 (c 2.5, PhH); Rf¼0.3
1199, 1118, 1104, 1009, 922, 749, 723, 696 cmꢀ1; 1H NMR (400 MHz,
D
(EtOAc); IR (neat): 3154, 3057, 2965, 2930, 2873, 1437, 1196, 1182,
CDCl3):
d
¼7.86–7.76 (m, 4H), 7.73–7.66 (m, 2H), 7.54–7.30 (m, 7H),
1108, 899, 751, 720, 694 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
6.92 (td, J¼7.6, 1.6 Hz, 1H), 5.57 (ddt, J¼16.8, 10.5, 6.4 Hz, 1H), 4.91–
4.76 (m, 2H), 4.54 (ddd, J¼10.9, 9.9, 5.7 Hz, 1H), 3.69–3.41 (m, 2H),
2.35–2.06 (m, 2H), 0.75 (t, J¼7.3 Hz, 3H); 13C NMR (100 MHz,
d
¼7.93–7.85 (m, 2H), 7.76–7.68 (m, 2H), 7.55–7.19 (m, 10H), 6.58
(dd, J¼17.2, 10.9 Hz, 1H), 5.41 (dd, J¼17.2, 1.4 Hz, 1H), 5.12 (dd,
J¼10.9, 1.40 Hz, 1H), 4.53–4.40 (m, 1H), 3.43–3.30 (m, 1H), 2.03–
1.75 (m, 2H), 0.82 (t, J¼7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3):
CDCl3):
d
¼143.4 (d, JC–P¼4.0 Hz), 139.7, 136.5, 133.0 (d, JC–P¼
126.4 Hz), 132.9 (d, JC–P¼126.1 Hz), 132.5 (d, JC–P¼10.0 Hz, 2 C),
d
¼141.3 (d, JC–P¼5.4 Hz), 136.3, 134.3, 133.2 (d, JC–P¼127.8 Hz),
132.4 (d, JC–P¼9.8 Hz, 2 C), 131.6 (d, JC–P¼2.4 Hz), 131.5 (d, JC–P¼
132.6 (d, JC–P¼9.7 Hz, 2 C), 131.9 (d, JC–P¼9.6 Hz, 2 C), 131.9 (d, JC–P
¼
2.4 Hz), 130.1, 129.0, 128.2, 128.2 (d, JC–P¼12.6 Hz, 4 C), 116.5, 102.5,
130.9 Hz), 131.8 (d, JC–P¼2.7 Hz), 131.6 (d, JC–P¼2.7 Hz), 128.5 (d,
JC–P¼12.5 Hz, 2 C), 128.3 (d, JC–P¼12.7 Hz, 2 C), 128.1, 127.0, 126.5,
125.8, 116.8, 52.7, 32.8 (d, JC–P¼3.4 Hz), 10.7; 31P NMR (162 MHz,
67.7, 49.5 (d, JC–P¼5.0 Hz), 28.7, 11.5; 31P NMR (162 MHz, CDCl3):
d
¼32.9; MS (APCI, 70 eV): m/z (%)¼502.2 (100) [MþH]þ; Anal. Calcd
for C24H25INOP: C, 57.50; H, 5.03; N, 2.79. Found: C, 57.36; H, 5.05;
N, 2.84.
C6D6):
d
¼22.9; MS (APCI, 70 eV): m/z (%)¼362.2 (100) [MþH]þ;
Anal. Calcd for C23H24NOP: C, 76.43; H, 6.69; N, 3.88. Found: C,
76.10; H, 6.59; N, 3.83.
4.2.24. (1S)-2-(Diphenylphosphoryl)-1-ethyl-1,2-
dihydroisoquinoline (42)
4.2.20. N-[(1S)-1-(2-Iodophenyl)propyl]-P,P-diphenylphosphinic
amide (37)
Enantiomeric excess (92% ee) was determined by HPLC analysis
(Chiralpak) AD-H, 90:10 hexane–i-PrOH, 1.0 mL/min: (minor en-
RuH(CO)(PPh3)3 (10 mg, 0.010 mmol) was added to a solution of
34 (300 mg, 0.75 mmol) in PhMe (38 mL). The resulting mixture
was warmed to 115 ꢁC for 9 h and three other portions of RuH-
(CO)(PPh3)3 (10 mg) were added every 2 h during that time. After
completion of the isomerization (monitored by TLC), Grubbs (II)
catalyst (32 mg, 0.037 mmol) was added in one portion to the same
flask at 115 ꢁC. The reaction was then stirred at 115 ꢁC for 2 h
(monitored by MS). After cooling to rt, the reaction was concen-
trated under vacuum. The crude material was purified by flash
antiomer) tR¼23.0 min, (major enantiomer) tR¼27.0 min. Yield:
20
946 mg (90%); mp 153–155 ꢁC; [
a]
þ51.5 (c 1.2, CHCl3); Rf¼0.4
D
(EtOAc); IR (neat): 3139, 2868, 1452, 1437, 1196, 1180, 1124, 1108,
1058, 1005, 903, 747, 721, 693 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
¼7.92–7.82 (m, 2H), 7.75–7.68 (m, 3H), 7.52–7.26 (m, 8H), 6.91
(ddd, J¼7.9, 6.8, 2.2 Hz, 1H), 4.42–4.32 (m, 1H), 3.55–3.42 (br, 1H),
chromatography on silica gel (dry pack) eluting with 65% EtOAc in
20
1.89–1.73 (m, 2H), 0.93 (t, J¼7.4 Hz, 3H); 13C NMR (100 MHz,
hexane to afford 42 as a colorless oil (251 mg, 93%). [
a
]
þ552.8 (c
D
CDCl3):
d¼146.0, 139.5, 132.7 (d, JC–P¼128.1 Hz), 132.5 (d, JC–P
¼
2.2, PhH); Rf¼0.3 (hexanes–EtOAc, 1:2); IR (neat): 3057, 2964, 2873,
9.7 Hz, 2 C), 131.8 (d, JC–P¼9.8 Hz, 2 C), 131.7, 131.6 (d, JC–P¼1.90 Hz),
131.4 (d, JC–P¼131.0 Hz), 128.5 (d, JC–P¼13.7 Hz, 2 C), 128.4 (d, JC–P
12.8 Hz, 2 C), 128.4, 128.2, 127.4, 98.7, 60.4, 32.3, 10.5; 31P NMR
1618, 1437, 1211, 1120, 1043, 930, 773, 725, 701, 680 cmꢀ1; 1H NMR
¼
(400 MHz, C6D6):
J¼7.40 Hz, 1H), 6.20–6.12 (m, 1H), 5.59 (dd, J¼7.4, 1.8 Hz, 1H), 4.80
d
¼7.94–7.71 (m, 4H), 7.09–6.84 (m, 9H), 6.55 (d,

I. Bonnaventure, A.B. Charette / Tetrahedron 65 (2009) 4968–4976
4975
(qapp, J¼7.1 Hz, 1H), 2.12–1.87 (m, 2H), 0.78 (t, J¼7.5 Hz, 3H); 13C
4.2.28. (1S)-2-(Diphenylphosphoryl)-1-ethyl-4-methyl-1,2,3,4-
tetrahydroisoquinoline (33)
Yield: 32.4 mg (75%), isolated as a 6:1 mixture; elution with
NMR (100 MHz, C6D6):
d
¼132.8 (d, JC–P¼127.0 Hz), 132.8 (d, JC–P¼
9.7 Hz, 2 C), 132.8 (d, JC–P¼9.7 Hz, 2 C), 132.0 (d, JC–P¼2.1 Hz, 2 C),
131.9 (d, JC–P¼124.2 Hz), 131.5, 129.2 (d, JC–P¼5.9 Hz), 128.7 (d, JC–P
¼
EtOAc–hexane (4:1) then (9:1); Rf¼0.36 (hexanes–EtOAc, 1:9). (
*
)
12.5 Hz, 2 C),128.3,127.7,126.6 (d, JC–P¼16.6 Hz, 2 C),124.4,107.4 (d,
stands for the minor isomer; IR (neat): 3056, 2963, 2929, 2873,
JC–P¼8.1 Hz), 58.3 (d, JC–P¼3.3 Hz), 28.5, 10.4; 31P NMR (162 MHz,
2217, 1438, 1197, 1119, 1023, 931, 724, 699 cmꢀ1; 1H NMR (400 MHz,
C6D6):
d
¼25.4; HRMS-ESI: m/z [MþH]þ calcd for C23H23NOP:
CDCl3):
), 7.24–7.15 (m, 2H), 7.11 (td, J¼7.2, 1.7 Hz, 1H), 6.90 (d, J¼7.2 Hz,
1H), 6.86 (d, J¼7.2 Hz, 1H ), 4.26 (m, 1H), 4.14 (m, 1H ), 3.63 (ddd,
J¼12.6, 6.4, 5.1 Hz, 1H), 3.46–3.36 (m, 1H ), 3.13–2.97 (m, 1H, H ),
2.94–2.84 (m, 1H), 2.16–1.88 (m, 1H, H ), 1.88–1.66 (m, 1H, H ), 1.18
), 0.81
¼139.2 (d, J¼1.0 Hz),
d¼7.92–7.78 (m, 4H), 7.55–7.36 (m, 6H), 7.33–7.25 (m, 2 H,
360.15118; found: 360.15264.
H
*
*
*
4.2.25. (1S)-2-(Diphenylphosphoryl)-1-ethyl-4-methylene-1,2,3,4-
tetrahydroisoquinoline (43)
*
*
*
*
Compound 35 (137 mg, 0.27 mmol), Pd2(dba)3 (12.5 mg,
0.014 mmol), (ꢃ)-BINAP (16.8 mg, 0.027 mmol), and K2CO3 (75 mg,
0.54 mmol) were mixed together in dry dimethylacetamide (6 mL).
The mixture was then heated to 90 ꢁC and stirred for 17 h. The
reaction was then allowed to cool to rt, diluted with Et2O (12 mL)
and distilled H2O (12 mL), and HCl (10%) was added. The organic
layer was separated and the aqueous layer was extracted with Et2O
(3ꢂ10 mL). The combined organic layers were washed with brine
(20 mL) and dried over Na2SO4. Concentration under vacuum gave
the crude material, which was purified by flash chromatography on
(d, J¼7.1 Hz, 3H), 1.15 (d, J¼7.1 Hz, 3H
*
), 0.97 (t, J¼7.5 Hz, 3H
*
(t, J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
138.7 (C
*
), 138.2 (d, J¼4.9 Hz, C
*
), 137.1 (d, J¼6.6 Hz), 132.7 (d,
), 132.3 (C ), 131.7 (d,
J¼2.6 Hz), 131.5 (d, J¼2.7 Hz), 132.2 (d, J¼129.9 Hz, C ), 132.1 (d,
J¼129.0 Hz), 131.0, 128.5 (d, J¼12.4 Hz), 128.2 (d, J¼12.6 Hz), 128.4
(d, J¼12.4 Hz, C ), 128.2 (C ), 128.1, 127.5 (C ), 127.0, 126.8, 126.7 (C ),
125.3, 57.5 (d, J¼2.7 Hz), 57.3 (d, J¼2.4 Hz, C ), 45.1 (d, J¼1.8 Hz),
44.7 (d, J¼1.9 Hz, C ), 31.8 (d, J¼5.2 Hz), 31.2 (d, J¼3.3 Hz, C ), 30.6
(d, J¼1.5 Hz), 30.0 (d, J¼2.8 Hz, C
NMR (162 MHz, CDCl3):
J¼9.1 Hz), 132.6 (d, J¼9.3 Hz), 132.4 (C
*
*
*
*
*
*
*
*
*
*
*
), 21.9, 18.6 (C
*
), 11.8 (C P
), 11.6; 31
*
silica gel eluting with 90% EtOAc in hexane to afford 43 as an air
d
¼28.7, 28.3 (P
*
); HRMS-ESI: m/z [MþH]þ
20
sensitive colorless oil (60 mg, 60%). [
a
]
ꢀ69.5 (c 3.4, PhH); Rf¼0.3
calcd for C24H27NOP: 376.18248; found: 376.18217.
D
(hexanes–EtOAc, 1:9); IR (neat): 3057, 2965, 1438, 1203, 1120, 1107,
1058, 754, 724, 699, 630 cmꢀ1; 1H NMR (400 MHz, C6D6):
¼8.05–
7.96 (m, 2H), 7.94–7.86 (m, 2H), 7.53 (d, J¼7.8 Hz, 1H), 7.08–6.90 (m,
8H), 6.55 (dd, J¼7.5, 0.8 Hz, 1H), 5.38 (s, 1H), 4.47 (s, 1H), 4.34 (qapp
d
Acknowledgements
,
This work was supported by the National Science and Engi-
J¼6.5 Hz, 1H), 4.06–3.90 (m, 2H), 1.92 (m, 1H), 1.59–1.44 (m, 1H),
´
neering Research of Canada (NSERC) and the Universite de Mon-
1.02 (t, J¼7.4 Hz, 3H); 13C NMR (100 MHz, C6D6):
d¼139.2 (d, JC–P
¼
¼
tre´al. I.B. thanks the Universite´ de Montre´al for a postgraduate
fellowship.
6.0 Hz),138.3 (d, JC–P¼5.2 Hz),133.4 (d, JC–P¼129.4 Hz),133.1 (d, JC–P
9.2 Hz, 2 C),133.0 (d, JC–P¼9.3 Hz, 2 C),133.2 (d, JC–P¼127.0 Hz),132.0,
131.5 (tapp, JC–P¼2.1 Hz, 2 C), 128.5 (d, JC–P¼12.3 Hz, 2 C), 128.5 (d,
JC–P¼12.3 Hz, 2 C),127.3,127.0,124.5,107.8, 58.4 (d, JC–P¼2.4 Hz), 44.3
(d, JC–P¼3.4 Hz), 28.6 (d, JC–P¼1.5 Hz), 12.0; 31P NMR (162 MHz,
References and notes
1. (a) Volkmann, R. A. Nucleophilic Addition to Imines and Imine Derivatives. In
Comprehensive Organic Synthesis: Additions to C–X p-Bonds; Schreiber, S. L., Ed.;
C6D6):
d
¼26.6; HRMS-ESI: m/z [MþH]þ calcd for C24H25NOP:
Pergamon: Oxford, 1991; Vol. 1, Part 1, pp 355–396; (b) Enders, D.; Reinhold, U.
Tetrahedron: Asymmetry 1997, 8, 1895; (c) Kobayashi, S.; Ishitani, H. Chem. Rev.
1999, 99, 1069; (d) Vilaivan, T.; Bhanthumnavin, W.; Sritana-Anant, Y. Curr. Org.
Chem. 2005, 9, 1315; (e) Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541.
2. Selected examples: Cortistatin A: (a) Aoki, S.; Watanabe, Y.; Sanagawa, M.;
Setiawan, A.; Kotoku, N.; Kobayashi, M. J. Am. Chem. Soc. 2006, 128, 3148 In-
dolizomycin: (b) Yamashita, F.; Hotta, K.; Kurasawa, S.; Okami, Y.; Umezawa, H.
J. Antibiot. 1985, 38, 58 Rivastigmine: (c) Anand, R.; Gharabawi, G.; Enz, A.
J. Drug Dev. Clin. Pract. 1996, 8, 109.
3. For phosphoramidite-type ligands, see: (a) Hua, Z.; Vassar, V. C.; Choi, H.;
Ojima, I. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5411; (b) Imbos, R.; Minnaard, A.
J.; Feringa, B. L. Dalton Trans. 2003, 2017.
4. For oxazolidinone, see: Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica Acta
1997, 30, 3.
374.15955; found: 374.16693.
4.2.26. General procedure for the hydrogenation reaction
Compound 42/43 (118/43 mg, 0.33/0.11 mmol), PtO2 (30/12 mg,
0.4 equiv), and anhydrous AcOH/MeOH (3/1 mL) were mixed. The
reaction was stirred under H2 pressure (400 psi/1 atm) for 24 h at
rt. H2 was then evacuated and the reaction was filtered through
a pad of CeliteÒ. For 32, the filtrate was diluted with CH2Cl2 and
transferred to a separatory funnel. The organic layer was washed
with distilled H2O (10 mL) and dried over Na2SO4. Concentration
under vacuum gave the crude material, which was purified by flash
chromatography on silica gel to afford the tetrahydroisoquinoline
as a colorless oil.
5. (a) Boezio, A. A.; Charette, A. B. J. Am. Chem. Soc. 2003, 125, 1692; (b) Boezio, A.
ˆ ´
A.; Pytkowicz, J.; Cote, A.; Charette, A. B. J. Am. Chem. Soc. 2003, 125, 14260; (c)
Desrosiers, J.-N.; Coˆte´, A.; Boezio, A. A.; Charette, A. B. Org. Synth. 2006, 83, 5.
ˆ ´
6. (a) Cote, A.; Boezio, A. A.; Charette, A. B. Angew. Chem., Int. Ed. 2004, 43, 6525;
(b) Coˆte´, A.; Desrosiers, J.-N.; Boezio, A. A.; Charette, A. B. Org. Synth. 2006, 83, 1;
(c) Me-DuPHOS(O) is now commercially available from Aldrich (CAS 638132-
66-8, no. 678635).
7. (a) Yamada, K.-I.; Harwood, S. J.; Gro¨ger, H.; Shibasaki, M. Angew. Chem., Int. Ed.
1999, 38, 3504; (b) Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc.
2003, 125, 761; (c) Weinreb, S. M.; Orr, R. K. Synthesis 2005, 1205; (d) Yama-
guchi, A.; Matsunaga, S.; Shibasaki, M. Tetrahedron Lett. 2006, 47, 3985; For
imine-enamine tautomerism, see: (e) Raczyn´ ska, E. D.; Kosin´ ska, W.;
4.2.27. (1S)-2-(Diphenylphosphoryl)-1-ethyl-1,2,3,4-
tetrahydroisoquinoline (32)
Yield: 76.3 mg (64%); elution with EtOAc–hexane (1.5:1) then
20
100% EtOAc; [
a
]
D
ꢀ14.6 (c 4.7, MeOH); Rf¼0.3 (EtOAc); IR (neat):
3056, 2929, 2872, 1734, 1437, 1197, 1117, 1104, 1061, 933, 755, 723,
696 cmꢀ1 1H NMR (400 MHz, C6D6):
;
d¼8.05–7.93 (m, 4H), 7.09–
ꢀ
Osmia1owski, B.; Gawinecki, R. Chem. Rev. 2005, 105, 3561; (f) Palacios, F.;
6.86 (m, 9H), 6.59 (d, J¼7.6 Hz, 1H), 4.37–4.26 (m, 1H), 3.36–3.22
(m, 1H), 3.21–3.07 (m, 1H), 2.98–2.84 (m, 1H), 2.15 (dd, J¼16.7,
3.7 Hz, 1H), 1.96–1.82 (m, 1H), 1.62–1.48 (m, 1H), 0.99 (t, J¼7.4 Hz,
´
´
Aparicio, D.; Garcıa, J.; Rodrıguez, E. Eur. J. Org. Chem. 1998, 1413.
8. For benzotriazole adducts, see: (a) Katritzky, A. R.; Manju, K.; Singh, S. K.;
Meher, N. K. Tetrahedron 2005, 61, 2555; For sulfinic acid adducts, see: (b)
Petrini, M.; Torregiani, E. Synthesis 2007, 159; For succinimide adducts, see: (c)
Kohn, H.; Sawhney, K. N.; Robertson, D. W.; Leander, J. D. J. Pharm. Sci. 1994,
83, 689.
3H); 13C NMR (100 MHz, C6D6):
d¼139.2 (d, JC–P¼5.0 Hz), 134.1,
134.0 (d, JC–P¼128.6 Hz), 133.6 (d, JC–P¼127.5 Hz), 133.5 (d, JC–P
¼
9. (a) Coˆte´, A.; Boezio, A. A.; Charette, A. B. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
8.9 Hz, 2 C), 133.3 (d, JC–P¼9.0 Hz, 2 C), 131.9 (d, JC–P¼2.6 Hz), 131.8
ˆ ´
5405; (b) Desrosiers, J.-N.; Cote, A.; Charette, A. B. Tetrahedron 2005, 65, 6186.
(d, JC–P¼2.6 Hz), 129.7, 129.0 (d, JC–P¼12.2 Hz, 2 C), 128.9 (d, JC–P
12.3 Hz, 2 C), 127.2, 126.7, 125.8, 57.1 (d, JC–P¼2.2 Hz), 37.6 (d, JC–P
¼
¼
10. (a) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun. 1998, 633; (b)
Laschat, S.; Dickner, T. Synthesis 2000, 1781; (c) Mitchinson, A.; Nadin, A.
J. Chem. Soc., Perkin Trans. 1 2000, 2862; (d) O’Hagan, D. Nat. Prod. Rep. 2000, 17,
435; (e) Pinder, A. R. Nat. Prod. Rep. 1992, 9, 491; (f) Weintraub, P. M.; Sabol, J. S.;
Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953; (g) Felpin, F.-X.;
Lebreton, J. Eur. J. Org. Chem. 2003, 3693; (h) Buffat, M. G. P. Tetrahedron 2004,
2.3 Hz), 30.4 (d, JC–P¼2.8 Hz), 28.4 (d, JC–P¼3.6 Hz), 12.1; 31P NMR
(162 MHz, C6D6):
d
¼26.3; HRMS-ESI: m/z [MþNa]þ calcd for
C23H24NNaOP: 384.14877; found: 384.14847.

4976
I. Bonnaventure, A.B. Charette / Tetrahedron 65 (2009) 4968–4976
60, 1701; (i) Cossy, J. Chem. Rec. 2005, 5, 70; (j) Escolano, C.; Amat, M.; Bosch, J.
Chem.dEur. J. 2006, 12, 8198; (k) Alcaide, B.; Almendros, P.; Aragoncillo, C.
Chem. Rev. 2007, 107, 4437.
22. This additive has been used by Knochel in the catalytic asymmetric alkyl-
ation of aldehydes: Lutz, C.; Graf, C. D.; Knochel, P. Tetrahedron 1998, 54,
10317.
11. Johannsen, M.; Jorgensen, K. A. Chem. Rev. 1998, 98, 1689.
12. Rozwadowska, M. D. Heterocycles 1994, 39, 903; (b) Chrzanowska, M.; Roz-
wadowska, M. D. Chem. Rev. 2004, 104, 3341.
23. This was checked by SFC analysis of the corresponding allyl derivative ((Chir-
alpak) AD, 180 bar, 2 mL/min, 40 ꢁC, modifier 5% i-PrOH: (minor enantiomer),
tR¼8.8 min (major enantiomer) tR¼10.3 min).
13. (a) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am. Chem. Soc.
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14. One report mentions the use of isopropyl ester: Akullian, L. C.; Porter, J. R.;
Traverse, J. F.; Snapper, M. L.; Hoveyda, A. H. Adv. Synth. Catal. 2005, 347, 417.
15. Petrini, M.; Profeta, R.; Righi, P. J. Org. Chem. 2002, 67, 4530.
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J.; Lindsay, K. B.; Tang, M.; Pyne, S. G. Synlett 2004, 49.
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W. B.; Lovely, C. J. Tetrahedron 1991, 47, 5561; (c) Lee, A.; Ellman, J. A. Org. Lett.
2001, 3, 3707.
25. (a) Kneisel, F. F.; Dochnahl, M.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 1017;
(b) Gong, L.-Z.; Knochel, P. Synlett 2005, 267.
26. Tietze, L. F.; Schimpf, R. Synthesis 1993, 876.
27. (a) van Otterlo, W. A. L.; Pathak, R.; de Koning, C. B. Synlett 2003, 1859; (b)
Schmidt, B. Eur. J. Org. Chem. 2004, 1865; (c) Terada, Y.; Arisawa, M.; Nishida, A.
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gawa, N.; Nishida, A. Chem. Rec. 2007, 7, 238.
´
17. Najera, C.; Yus, M. Tetrahedron 1999, 55, 10547.
18. Chemla, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 75.
19. The same strategy has also been used recently by: Kamimura, A.; Okawa, H.;
Morisaki, Y.; Ishikawa, S.; Uno, H. J. Org. Chem. 2007, 72, 3569.
20. Ono, N.; Matsumoto, K.; Ogawa, T.; Tani, H.; Uno, H. J. Chem. Soc., Perkin Trans. 1
1996, 1905.
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Kelkar, S. V.; Joshi, G. S.; Reddy, G. B.; Kulkanni, G. H. Synth. Commun. 1989, 19,
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