Copper Cyanide-Catalyzed Palladium Coupling of N-tert-Butoxycarbonyl-Protected α-Lithio Amines with Aryl Iodides or Vinyl Iodides

Article abstract of DOI:10.1021/jo970985b

Treatment of (α-aminoalkyl)lithium reagents with aryl iodides in the presence of catalytic amounts of CuCN and PdCl₂(PPh₃)₂ or [(p-MeOC₆H₄)₃P]₄Pd affords 2-aryl substituted amines in modest to good yields. The yields can be improved by use of softer ligands such as AsPh₃ and SbPh₃ or by use of bis(diphenylphosphino)ferrocene (dppf). Coupled products are obtained with electron-rich aryl iodides (XArI, X = Me, OMe), and the reaction fails with electron-poor aryl iodides (XArI, X = NO₂, CO₂Li). Treatment of the (α-aminoalkyl)lithium reagents with vinyl iodides and Pd(0)/dppf/ CuCN afforded the coupling products in low to modest yields.

Full text of DOI:10.1021/jo970985b

7726
J . Org. Chem. 1997, 62, 7726-7735
Cop p er Cya n id e-Ca ta lyzed P a lla d iu m Cou p lin g of
N-ter t-Bu toxyca r bon yl-P r otected r-Lith io Am in es w ith Ar yl
Iod id es or Vin yl Iod id es
R. Karl Dieter* and ShengJ ian Li
Howard L. Hunter Chemistry Laboratory, Clemson University, Clemson, South Carolina 29634-1905
Received J une 3, 1997X
Treatment of (R-aminoalkyl)lithium reagents with aryl iodides in the presence of catalytic amounts
of CuCN and PdCl2(PPh3)2 or [(p-MeOC6H4)3P]4Pd affords 2-aryl substituted amines in modest to
good yields. The yields can be improved by use of softer ligands such as AsPh3 and SbPh3 or by
use of bis(diphenylphosphino)ferrocene (dppf). Coupled products are obtained with electron-rich
aryl iodides (XArI, X ) Me, OMe), and the reaction fails with electron-poor aryl iodides (XArI, X )
NO2, CO2Li). Treatment of the (R-aminoalkyl)lithium reagents with vinyl iodides and Pd(0)/dppf/
CuCN afforded the coupling products in low to modest yields.
In tr od u ction a n d Ba ck gr ou n d
reagents with N,O and/or N,S mixed acetals which are
prepared either by electrochemical oxidation of the
amine8 or via reduction6a of the corresponding lactam.
Reaction of Grignard reagents with chiral 1,3-oxazo-
lidines provides an asymmetric version of the N,O-acetal
protocol.9 R-Arylpyrrolidines and -piperidines have been
prepared by alkylation of R-aryl-R-lithio amines with
dihaloalkanes10 followed by cyclization onto the nitrogen
atom or by intramolecular reaction of the R-lithio amine11
with an alkyl chloride or epoxide functionality. A pal-
ladium-catalyzed12a tandem R-arylation-isomerization of
cyclic enamides has been used to prepare R-arylpyrro-
lidines and -piperidines while the 2-(1-alkenyl) deriva-
tives have been prepared by Pd(0)-catalyzed coupling of
vinyl halides with olefinic sulfonamides.12b
Addition of a suitable R-aminoalkyl organometallic
reagent to a σ-aryl or vinyl palladium(II) complex pro-
vides a potential solution for the direct introduction of
an aryl or vinyl substituent adjacent to a N atom.13
Although an (R-aminoalkyl)(tri-n-butyl)stannane has
been reported to undergo palladium/CuCN-mediated
coupling with acid chlorides,14 the butyl group transferred
competitively with the R-aminoalkyl group consistent
with our own observations. We reported15 the first
successful palladium-promoted coupling of (R-aminoalkyl)-
lithium reagents with aryl iodides and now describe the
full details of our investigation along with efforts to
extend the coupling reaction to vinyl iodides.
The direct R-lithiation of amines is possible when the
nitrogen atom is protected with a dipole stabilizing group
that can participate in complex-induced proximity (CIP)
effects.1 R-Aminoalkyl carbanions are readily accessible
from formamidines2 and carbamates3 as a result of the
pioneering work of Meyers and Beak, respectively.4
These carbanions react with typical carbonyl electro-
philes and with alkyl halides, chlorosilanes, and chlo-
rostannanes. We have extended the range of R-ami-
noalkyl metal chemistry with the development of the
corresponding cuprate and/or copper reagents5 which
react with enones,5a,b, enoates,5e allylic substrates,5f acid
chlorides,5d and cyclic vinyl triflates.5c Although the
organolithium and organocopper reagents react with a
wide range of carbonyl and saturated electrophiles, the
direct introduction of an aryl or vinyl substituent remains
problematic.
R-Arylation of amines has been achieved principally
by reaction of Grignard,6 organocopper,7 or organozinc8
X Abstract published in Advance ACS Abstracts, October 1, 1997.
(1) For a review, see: Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986,
19, 356.
(2) For selected references, see: (a) Meyers, A. I.; Edwards, P. D.;
Rieker, W. F.; Bailey, T. R. J . Am. Chem. Soc. 1984, 106, 3270. (b)
Meyers, A. I.; Edwards, P. D.; Bailey, T. R.; J agdmann, G. E., J r. J .
Org. Chem. 1985, 50, 1019. (c) Meyers, A. I.; Fuentes, L. M.; Kubota,
Y. Tetrahedron 1984, 40, 1361.
(3) For selected references, see: (a) Beak, P.; Lee, W. K. Tetrahedron
Lett. 1989, 30, 1197. (b) Beak, P.; Lee, W. K. J . Org. Chem. 1990, 55,
2578. (c) Kerrick, S. T.; Beak, P. J . Am. Chem. Soc. 1991, 113, 9708.
(d) Beak, P.; Lee, W. K. J . Org. Chem. 1993, 58, 1109.
(8) Brown, D. S.; Charreau, P.; Hannsson, T.; Ley, S. V. Tetrahedron
1991, 47, 1311.
(9) Higashiyama, K.; Inoue, H.; Takahashi, H. Tetrahedron 1994,
50, 1083.
(10) (a) Meyers, A. I.; Marra, J . M. Tetrahedron Lett. 1985, 26, 5863.
(b) Fraser, R. R.; Boussard, G.; Postescu, I. D.; Whiting, J . J .; Wigfield,
Y. Y. Can. J . Chem. 1973, 51, 1109.
(11) Beak, P.; Wu, S.; Yum, E. K.; J un, Y. M. J . Org. Chem. 1994,
59, 276.
(4) For reviews, see: (a) Beak, P.; Reitz, D. B. Chem. Rev. 1978, 78,
275. (b) Beak, P; Zajdel, W. J .; Reitz, D. B. Chem. Rev. 1984, 84, 471.
(c) Meyers, A. I. Aldrichimica Acta 1985, 18, 59. (d) Gawley, R. E.;
Rein, K. In Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon: Oxford, 1991; Vol. 1, Chapter 2.1 and Vol. 3, Chapter 1.2.
(5) (a) Dieter, R. K.; Alexander, C. W. Tetrahedron Lett. 1992, 33,
5693. (b) Dieter, R. K.; Alexander, C. W. Synlett 1993, 407. (c) Dieter,
R. K.; Dieter, J . W.; Alexander, C. W.; Bhinderwala, N. S. J . Org. Chem.
1996, 61, 2930. (d) Dieter, R. K.; Sharma, R. R.; Ryan, W. Tetrahedron
Lett. 1997, 38, 783. (e) Dieter, R. K.; Velu, S. E. J . Org. Chem. 1997,
62, 3798. (f) Dieter, R. K.; Velu, S. E.; Nice, L. E. Synlett, in press.
(6) (a) Gottlieb, L.; Meyers, A. I. Tetrahedron Lett. 1990, 31, 4723.
(b) Naota, T.; Nakato, T.; Murahashi, S.-I. Tetrahedron Lett. 1990, 31,
7475. (c) Meyers, A. I.; Shawe, T. T.; Gottlieb, L. Tetrahedron Lett.
1992, 33, 867.
(7) (a) Dieter, R. K.; Alexander, C. W. Unpublished work. (b) Alkyl
copper reagents undergo substitution reactions with pyrrolidine N,O-
acetal derivatives, and in principle the reaction can be extended to
aryl copper reagents. See: Wistrand, L.-G.; Skrinjar, M. Tetrahedron
1991, 47, 573. Ludwig, C.; Wistrand, L.-G. Acta Chem. Scand. 1990,
44, 707.
(12) (a) Nilsson, K.; Hallberg, A. J . Org. Chem. 1990, 55, 2464. (b)
Larock, R. C.; Yang, H.; Weinreb, S. M.; Herr, R. J . J . Org. Chem.
1994, 59, 4172.
(13) For synthetic applications of organopalladium chemistry, see:
(a) Hegedus, L. S. In Organometallics in Synthesis: A Manual; Wiley:
Chichester, England, 1994; p 383. (b) Tamao, K. In Comprehensive
Organic Synthesis; Trost, B. M., Pattenden, G., Eds.; Pergamon:
Oxford, 1991; Vol. 3, Chapter 2.2, p 435. (c) Mitchell, T. N. Synthesis
1992, 803. (d) Kalinin, V. N. Synthesis 1992, 413. (e) Farina, V. In
Comprehensive Organometallic Chemistry II; Hegedus, L. S., Ed.;
Pergamon: Oxford, 1995; Vol. 12, Chapter 3, Part 4, p 161. (f) Farina,
V.; Krishnamurthy, V.; Scott, W. J . Org. React. 1997, 50, 1.
(14) Ye, J ianhua; Bhatt, R. K.; Falck, J . R. J . Am. Chem. Soc. 1994,
116, 1.
(15) Dieter, R. K.; Li, S. Tetrahedron Lett. 1995, 36, 3613.
S0022-3263(97)00985-7 CCC: $14.00 © 1997 American Chemical Society

Coupling of R-Lithio Amines with Organic Iodides
J . Org. Chem., Vol. 62, No. 22, 1997 7727
Ta ble 1. Effect of P d Ca ta lysts a n d Liga n d s on th e
Cou p lin g Rea ction of
Resu lts
The N-Boc protected amines (1-3) were prepared in
high yields from pyrrolidine, piperidine, and N,N-di-
methylamine [tert-butoxycarbonate anhydride, triethyl-
amine (TEA), (dimethylamino)pyridine (DMAP), CH2Cl2,
rt] and were purified by vacuum distillation. The io-
doalkenes16 and 1-iodohexyne17 were prepared by estab-
lished procedures.
N-(ter t-Bu toxyca r bon yl)-2-lith iop yr r olid in e (1-Li) w ith
P h I To Affor d N-Boc-2-p h en ylp yr r olid in e (eq 1, 5)a
time (h)
(at higher
temp)
Pd
temp
°Cd
yield
(%)e
entry catb ligand equivc
solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
A
A
A
A
A
B
C
D
D
D
D
D
D
D
D
D
D
-78
3
PhMe/Et2O
PhMe/Et2O 54
0
-78 (75)
-78 (75)
-78 (40)
-78 (rt)
-30f (40)
rtf (70)
2 (18)
2.5 (18) PhMe/Et2O 39
2 (24)
8 (64)
4 (12)
3 (24)
Et2O
Et2O
Et2O
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
47
38
26
57
0
38
52
58
71
72
43
46
55
79
-78 to rt 18
PBu3
PPh3
PPh3
AsPh3
SbPh3
dppb
dppp
BNAP
dppf
4
2
4
2
2
1
1
1
1
19
18
17
18
18
13
13
15
13
Initial attempts to couple [(N-Boc-N-methylamino)-
methyl]stannane 4b with iodobenzene in the presence of
bis(dibenzylideneacetone)palladium [Pd(dba)2]18a and PPh3
[PhMe/THF, sealed tube, 140 °C]14 failed to yield any
coupled products. The R-stannyl derivatives 4a 3a and 4b
also failed to afford coupling products when 5 mol % of
several palladium catalysts such as PdCl2(PPh3)2,18b
PdCl2 + 4 Ph3P, and [(p-MeOC6H4)3P]4Pd18a were used.
Transmetalation of 4a [n-BuLi, TMEDA, THF, -78 °C,
1 h]3c,19 into the lithium derivative followed by cannula
transfer into a mixture of PdCl2(Ph3P)2 (5 mol %) and
CuCN (10 mol %)20 containing iodobenzene, with stirring
at -78 °C to room temperature over a period of 10 h,
afforded the coupled product 5 in 29% yield.
a
N-Boc-2-lithiopyrrolidine (1-Li) was generated by deprotona-
tion (TMEDA, s-BuLi, THF, or Et2O, -78 °C, 2 h) of N-Bocpyr-
rolidine (1). A ) [(p-MeOC6H4)3]4Pd (5 mol %)/CuCN (10 mol %).
b
B ) [(p-MeOC6H4)3]4Pd on Celite (5 mol %)/CuCN (10 mol %). C
) PdCl2(PPh3)2 (5 mol %)/CuCN (10 mol %). D ) Pd0 (5 mol %)/
CuCN (10 mol %) prepared by K reduction of PdCl2/CuCN/ligand.
c dppb ) 1,4-bis(diphenylphosphino)butane. dppp ) 1,3-bis(diphen-
ylphosphino)propane. BINAP ) 2,2'-bis(diphenylphosphino)-bi-
d
naphthalene. dppf ) bis(diphenylphosphino)ferrocene. The tem-
perature was held at -78 °C for the indicated period of time and
then at a higher temperature for an additional period of time or
allowed to rise from -78 °C to room temperature and then stirred
at room temperature. e Yields are based upon isolated products
purified by column chromatography. f Allowed to rise from -78
°C to this temperature.
of PdCl2(PPh3)2 (5 mol %)/CuCN (10 mol %) gave 57%
yield (Table 1, entry 7; 20% yield with bromobenzene15)
of 5. In an effort to produce a more reactive palladium
catalyst, a PdCl2/CuCN/P, As, or Sb ligand mixture was
reduced with K metal to afford activated Pd(0).21 This
active Pd(0) catalyst gave no coupled product in the
absence of added phosphine ligands (Table 1, entry 8).
Addition of 4 equiv of PBu3 gave 5 in 38% yield which
could be increased to 52-58% yield by using 2 or 4 equiv
of Ph3P (Table 1, entries 8-11). Slightly lower yields of
5 could be obtained with the bidentate ligands dppb and
dppp, while higher yields could be obtained with softer
ligands20,22 such as AsPh3 and SbPh3 (Table 1, entries
12-15). Modest yields of 5 were obtained with BINAP
as added ligand, while the best results were obtained
with the phosphinyl-substituted ferrocence catalyst
dppf23 (Table 1, entries 16, 17).
Efforts to optimize the yield of 5 were focused on the
reactions of the R-lithio carbamate 1-Li, derived from
pyrrolidine, with iodobenzene in the presence of pal-
ladium and CuCN catalysts (eq 1). The R-lithio carbam-
ate 1-Li was generated by deprotonation of 1 [s-BuLi,
TMEDA (2.2 equiv), THF, -78 °C, 2 h]3a and then
transferred by cannula to a mixture of iodobenzene or,
in one case bromobenzene, and the palladium and CuCN
co-catalyst at -78 °C (Table 1). Initial experiments with
[(p-MeOC6H4)3P]4Pd (5 mol %)/CuCN (10 mol %) revealed
that the coupling process did not occur at -78 °C, but
moderate yields of 5 could be obtained, with variable
results, at temperatures between 25 and 74 °C (Table 1,
entries 1-5). Utilization of [(p-MeOC6H4)3P]4Pd absorbed
on Celite gave a lower yield (Table 1, entry 6), while use
The effect of the Cu(I) salt co-catalyst20 was briefly
examined with 10 mol % of SbPh3 as added ligand (Table
2). The absence of a Cu(I) salt resulted in a low yield of
5, while 2 equiv of CuBr, CuI, or CuSCN per 1 equiv of
palladium catalyst gave 5 in yields between 37 and 58%
(Table 2, entries 2-4). Two equiv of CuCN per 1 equiv
of palladium catalyst proved the most effective, and yields
varied in a nonlinear way as the amount of CuCN was
increased and diminished to zero at 10 equiv and above
per 1 equiv of palladium catalyst (Table 2, entries 9, 10).
(16) (a) Brown, H. C.; Hamaoka, T.; Ravindran, N. J . Am. Chem.
Soc. 1973, 95, 5786. (b) Kamiya, N.; Chikami, Y.; Ishii, Y. Synlett 1990,
675.
(17) Rao, M. L. N.; Periasamy, M. Synth. Commun. 1995, 2295.
(18) (a) Tsuji, J . Organic Synthesis with Palladium Compounds;
Springer-Verlag: Berlin Heidelberg, 1980; pp 2-3. (b) Hartley, F. R.
Organomet. Chem. Rev., Sect. A 1970, 6, 119.
(19) (a) Beak, P.; Kerrick, S. T. J . Am. Chem. Soc. 1991, 113, 9708.
(b) Burchat, A. F.; Chong, J . M.; Park, S. B. Tetrahedron Lett. 1993,
34, 51.
(20) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind,
L. S. J . Org. Chem. 1994, 59, 5905.
(21) (a) Murahashi, S. I.; Yamamura, M.; Yanagisawa, K.-I.; Mita,
N.; Kondo, K. J . Org. Chem. 1979, 44, 2408; and references cited
therein. (b) Rieke, R. D.; Wolf, W. J .; Kujundzic, N.; Kavaliunas, A. V.
J . Am. Chem. Soc. 1977, 99, 4159.
(22) Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113, 9585.
(23) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.;
Hirotsu, K. J . Am. Chem. Soc. 1984, 106, 158.

7728 J . Org. Chem., Vol. 62, No. 22, 1997
Dieter and Li
Ta ble 2. Effect of Co-Ca ta lysts, MX, on th e Cou p lin g
Rea ction of N-Boc-2-lith iop yr r olid in e (1-Li) w ith
Iod oben zen e Ca ta lyzed by P d (0) (5 m ol %)/SbP h 3
(10 m ol %)/MX (m equ ivs) To Affor d 5a
and vinyl iodides (Table 4). The active Pd(0)/CuCN-
catalyzed coupling of 1-Li with iodobenzene occurred with
nearly equal facility when either dppf or SbPh3 were used
as ligands (Table 4, entries 1, 2), while lower yields were
obtained when PdCl2(PPh3)2/CuCN was employed (Table
4, entry 3). It should be noted, however, that 10 mol %
of the organolithium reagent could be consumed in
reducing 5 mol % of the PdCl2(PPh3)2 catalyst precursor
to Pd0 via R2PdL2. The latter catalyst system promoted
the coupling of N-Boc-2-lithiopyrrolidine (1-Li) and N-Boc-
2-lithiopiperidine (2-Li) with 4-iodoanisole (Table 4,
entries 4, 5), o-iodotoluene (Table 4, entries 6, 7), and
p-iodotoluene (Table 4, entries 8, 9) in modest to good
yields. The more electron-rich anisole derivative gave
lower yields of coupling product than did the toluene
derivatives. The PdCl2(PPh3)2/CuCN or [(p-MeOC6H4)3-
P]4Pd catalyst system was completely ineffective in
promoting the coupling of 1-iodonaphthalene, 2-iodo-
thiophene,(E)-1-iodo-1-hexene,and2-iodo-1-hexene. These
aryl iodides could be coupled with 1-Li and 2-Li in
modest yields when the active Pd(0)/CuCN catalyst
system was employed with either dppf, AsPh3, or SbPh3
serving as added ligands (Table 4, entries 10-13). These
conditions also promoted the coupling of 1-Li and 2-Li
to (E)-1-iodo-1-hexene in low to moderate yields (Table
4, entries 14-17), while coupling with 2-iodo-1-hexene
could be achieved only in low yields (Table 4, entries 18,
19). The attempted coupling of 1-Li with either (E)-1-
iodo-1-hexene or 2-iodo-1-hexene gave as the major
product N-Boc-2-hydroxypyrrolidine. The active Pd(0)/
CuCN/SbPh3 catalyst system promoted the coupling of
1-Li and 2-Li to 1-iodohexyne in modest to low yields,
respectively (Table 4, entries 20, 21). Trace amounts of
symmetrical biaryl or 1,3-divinyl coupling products were
observed in the reactions of 1-Li with 1-iodonaphthalene,
2-iodothiophene, and (E)-1-iodo-1-hexene. The acyclic
derivative, 3-Li, was coupled with PhI [Pd0(SbPh3)2 (5
mol %), CuCN (10 mol %), THF, -75 °C to room
temperature, 18 h] to afford N-(tert-butoxycarbonyl)-N-
methylbenzylamine in 49% yield.
In an effort to probe the dynamics of this reaction
process, the thermal stability of N-Boc-2-lithiopyrrolidine
was examined by allowing the reagent to stir at a given
temperature for 30 min, quenching the anion with
chlorotrimethylsilane, and then measuring the yield of
N-Boc-2-(trimethylsilyl)pyrrolidine (23) as an indication
of the amount of 1-Li that did not decompose. The
reagent 1-Li was found to be stable at -78 °C (94% 23),
moderately stable at -50 °C (71.5% 23), and unstable at
0 °C (1.5% 23) or room temperature (1.5% 23).
In a limited study, 1-Li was treated with either MgBr2
or ZnX2 (X ) Br, I) and the putative Grignard or
organozinc reagent was added to a Pd0 (5 mol %)/CuCN
(10 mol %)/ligand (SbPh3 or PPh3, 10 mol %) mixture at
-78 °C and warmed to room temperature. Although
traces of 2-aryl- or 2-vinylpyrrolidines were observed in
a few experiments, these reaction conditions generally
failed to give the desired products and usually resulted
in recovered N-Bocpyrrolidine (1).
entry
m equivb
MXc
time (h)d
yield (%) 5e
1
2
3
4
5
6
7
8
9
none
0.10
0.10
0.10
0.10
0.20
0.25
0.33
0.50
1.10
0.10
1.10
none
CuBr
CuI
18
15
22
18
18
18
18
18
15
18
18
15
15.3
43.7
58
37
72
39.6
37.9
53.8
0
0
0
CuSCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
ZnI2
10
11
12
ZnI2
0
a
TMEDA was present in the reaction mixture from the depro-
b
tonation step (s-BuLi, diamine, THF, -78 °C, 2 h). equiv with
respect to 1 mmol of N-Boc-2-lithiopyrrolidine. c All copper(I) salts
and ZnI2 were purchased from Aldrich and used as received.
After transferring of N-Boc-2-lithiopyrrolidine (1-Li) into the
d
catalysts’ [active Pd(0) and co-catalyst were prepared by K metal
reduction of a PdCl2/SbPh3/CuCN mixture] flask, the mixture was
stirred in the cold bath and then warmed naturally to room
temperature for the time indicated. e Yields are based on isolated
product purified by column chromatography.
Ta ble 3. Effect of th e Dia m in e Liga n d on th e Cou p lin g
Rea ction of N-Boc-2-lith iop yr r olid in e (1-Li) w ith
Iod oben zen e Ca ta lyzed by P d (0) (5 m ol %)/SbP h 3
(10 m ol %)/Cu CN (10 m ol %) To Affor d 5a
entry
amineb
equivc
time (h)d
yield (%) 5e
1
2
3
4
5
6
7
TMEDA
2.2
1.0
2.2
1.0
2.0
1.0
2.2
18
15
15
17
17
14
15
72
46
38.8
25
27.5
0
(-)-sparteine
(-)-sparteine
Proton Sponge
Proton Sponge
DPTMEDA
DPTMEDA
0
a
1 mmol of N-Bocpyrrolidine (1) was used for deprotonation
(s-BuLi, diamine, THF, -78 °C, 2 h); about 1.5 mL of cyclohexane
b
was introduced from s-BuLi. TMEDA ) N,N,N′,N′-tetramethyl-
ethylenediamine. Proton Sponge ) 1,8-bis(dimethylamino)naph-
thalene. DPTMEDA ) N,N,N′,N′-tetramethyl-1,2-diphenylethyl-
enediamine. c Number of equivalents with respect to 1 mmol of
N-Boc-pyrrolidine; 2.2 equiv of TMEDA was always used for
d
deprotonation. After N-Boc-2-lithiopyrrolidine was transferred
into the catalysts’ flask, the mixture was stirred for the time
indicated. e Yields are based upon isolated products purified by
column chromatography.
Attempted use of ZnI2 proved completely ineffective
(Table 2, entries 11, 12).24
The yield of coupled product was also found to depend
upon the diamine utilized to aid in the deprotonation of
the carbamates (Table 3). Utilization of TMEDA afforded
the highest yield of 5, which significantly decreased when
TMEDA was replaced by sparteine or 1,8-bis(dimethyl-
amino)naphthalene (Proton Sponge) (Table 3, entries
1-5). Interestingly, use of 1 equiv of sparteine gave a
higher yield of 5 than did the use of 2 equiv. Use of 1,2-
diphenyl-N,N,N′,N′-tetramethylethylenediamine gave no
coupled product 5 (Table 3, entries 6, 7).
With the optimum conditions established, the scope of
the reaction was examined with a range of aryl iodides
Discu ssion
(24) (a) Negishi, E.-I.; Valente, L. F.; Kobayashi, M. J . Am. Chem.
Soc. 1980, 102, 3298. (b) Tucker, C. E.; Majid, T. N.; Knochel, P. J .
Am. Chem. Soc. 1992, 114, 3983. (c) Piers, E.; Roberge, J . Y.
Tetrahedron Lett. 1992, 33, 6923. (d) Evans, P. A.; Nelson, J . D.;
Stanley, A. L. J . Org. Chem. 1995, 60, 2298; and references cited
therein. (e) Abarbri, M.; Parrain, J .-L.; Duchene, A. Tetrahedron Lett.
1995, 36, 2469.
Crucial mechanistic questions concerning the copper
cyanide-catalyzed palladium-promoted coupling of (R-
aminoalkyl)lithium reagents with aryl iodides are the
following. (1) What is the rate-determining step in the
catalytic cycle? (2) What is the nature of the organome-

Coupling of R-Lithio Amines with Organic Iodides
J . Org. Chem., Vol. 62, No. 22, 1997 7729
Ta ble 4. Effect of P d Ca ta lysts a n d Liga n d s on th e Cou p lin g Rea ction of N-(ter t-bu toxyca r bon yl)-2-lith iop yr r olid in e
(1-Li) a n d th e Cor r esp on d in g P ip er id in e (2-Li) w ith Ar yl, Vin yl, a n d 1-Alk yn yl Iod id es
time (h)g
(higher temp)
compd
no.
entry aminea
RIb
Pd cat.c ligandd equive
temp (°C)f
-78 to rt
product
n
yield (%)h
1
2
3
1
2
2
Pd(0)
Pd(0)
PdCl2
dppf
SbPh3
PPh3
1
2
2
13
18
10 (24)
5
6
6
1
2
2
79
75
55
-78 to rt
4
5
1
2
PdCl2
PdCl2
PPh3
PPh3
2
2
-78 to rt (75)
-78 to rt (40)i
8 (5)
24 (20)
7
8
1
2
34
43
6
7
1
2
PdCl2
PdCl2
PPh3
PPh3
2
2
-78 to -12 (75)
-78 to rt (75)
4.5 (14)
11 (18)
9
10
1
2
64
65
8
9
1
2
PdCl2
PdCl2
PPh3
PPh3
2
2
-78 to -12 (75)
-78 to rt (75)
4.5 (14)
11 (8)
11
12
1
2
67
71
10
11
1
2
Pd(0)
Pd(0)
dppf
SbPh3
1
2
-78 to rt
-78 to rt
13
15
13
14
1
2
39j
42
12
13
1
2
Pd(0)
Pd(0)
AsPh3
SbPh3
2
2
-78 to rt
-78 to rt
18
18
15
16
1
2
36j
42
14
15
16
17
18
19
1
1
1
2
1
2
Pd(0)
Pd(0)
Pd(0)
Pd(0)
Pd(0)
Pd(0)
SbPh3
dppf
AsPh3
SbPh3
SbPh3
SbPh3
2
1
2
2
2
2
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
14
13
13
23
14
23
17
17
17
18
19
20
1
1
1
2
1
2
35k
12j
20j
17
10k
<5l
20
21
1
2
Pd(0)
Pd(0)
SbPh3
SbPh3
2
2
-78 to rt
-78 to rt
20
20
21
22
1
2
34j
<9l
a
b
The carbamate was deprotonated (TMEDA, s-BuLi, -78 °C) in THF unless otherwise noted. 1.2 equiv of the aryl iodide, vinyl iodide,
or 1-alkynyl iodide was used. c The Pd(0) catalyst was prepared by potassium metal reduction of a PdCl2/CuCN/ligand mixture. PdCl2
was employed as a preformed PdCl2(PPh3)2 complex (ref 18b). dppf ) bis(diphenylphosphino)ferrocene. e Equivalents of ligand per
d
equivalent of palladium catalyst. f The temperature range over which the reaction was carried out. The temperature was held at -78
g
°C for the indicated period of time and then at the higher temperature for an additional period of time, or allowed to rise from -78 °C to
h
room temperature and then stirred at room temperature. Yields are based upon isolated products purified by column chromatography.
i
j
k
Et2O was used as solvent. Small amounts of biaryl or 1,3-dienyl homocoupled products were observed. N-Boc-2-hydroxypyrrolidine
was formed in 36% yield. Product yield was estimated from MS-GC analysis.
l
tallic reagent acting as the nucleophile? (3) What is the
role of the Cu(I) salt? (4) What roles does the diamine
play? (5) Why do chemical yields decrease with 1-io-
donaphthalene, 2-iodothiophene, and vinyl iodides? (6)
Why do Grignard and organozinc analogs fail in this
reaction? A perspective on these questions can be
obtained by examining known facts in the context of
current mechanistic proposals for palladium-promoted
coupling of aryl iodides and organometallic reagents.
Pd(0)- and Ni(0)-catalyzed couplings of organometallic
reagents with electrophiles are thought to proceed via a
catalytic cycle involving oxidative addition-transmeta-
lation-reductive elimination.25 Oxidative addition of a
Pd0 species to aryl or vinyl halides affords an aryl or vinyl
PdII halide which can then undergo a transmetalation
reaction with the organometallic reagent giving rise to
either a cis or trans diorganopalladium species (Scheme
1) with the latter being thermodynamically more
stable.25a,26 Reductive elimination from the cis complex
affords the coupled product and regenerates the Pd(0)
or Ni(0) catalyst. Recent studies have suggested that
effective catalytic cycles involve rapid transmetalation
of an initially formed cis organopalladium halide, and
that involvement of the trans complex represents a
slower, less efficient catalytic cycle. These mechanistic
modifications involve tetracoordinate or pentacoordinate
palladium complexes (Scheme 1).26,30
Although the vast range of Pd(0)- and Ni(0)-catalyzed
coupling reactions can be accommodated by this descrip-
tive catalytic cycle, each step is open to kinetic complica-
tions and mechanistic possibilities.26 Any of the three
steps can, depending upon electrophile/organometallic
combination and particular reaction conditions, function
as the rate-determining step.26 The oxidative addition
of zero-valent palladium to aryl iodides is generally rapid
at room temperature,13a,26 and the rate is increased by
electron-withdrawing groups25,27 on the aromatic ring.
The oxidative addition proceeds via a dissociative mech-
anism involving a coordinatively unsaturated palladium
species (i.e., Pd0L2) and is inhibited by increased ligand
(25) For reviews detailing mechanistic aspects of organopalladium
chemistry, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Yamamoto, A. Organotransition Metal ChemistrysFundamental
Concepts and Applications; Wiley: New York, 1986.
(26) Amatore, C.; J utand, A.; Suarez, A. J . Am. Chem. Soc. 1993,
115, 9531 and references cited therein.
(27) (a) Fauvarque, J . F.; Pflu¨ger, F.; Troupel, M. J . Organomet.
Chem. 1981, 208, 419. (b) Ben-David, Y.; Portnoy, M.; Gozin, M.;
Milstein, D. Organometallics 1992, 11, 1995.

7730 J . Org. Chem., Vol. 62, No. 22, 1997
Dieter and Li
Sch em e 1
and reductive elimination steps are slower than the
transmetalation step (e.g., RLi to RPdAr).
Table 1 reveals that ligand effectiveness is in the order
of dppf ≈ AsPh3 ≈ SbPh3 > (p-MeOC6H4)3P ≈ PPh3
≈
BINAP > PBu3 ≈ dppb ≈ dppp. The effect of the
heteroatom ligands (P, As, and Sb) was examined in
conjunction with a more reactive Pd(0) generated by
potassium metal reduction. No coupling product was
observed in the absence of an added phosphine ligand,
and this can be attributed to catalyst decomposition in
the absence of stabilizing ligands.22 The yield of coupled
product increased as the softness of the ligand (SbPh3,
AsPh3 > PPh3 > PBu3) increased (Table 1, entries 8-13).
This trend is also consistently observed in the bisphos-
phine ligands with the diarylalkylphosphines dppb and
dppp giving higher yields than PBu3 but lower yields
than PPh3 and BINAP (Table 1, entries 14, 15 vs 9, 10,
16). Soft ligands (e.g., AsPh3 and SbPh3) and bisphos-
phines with a large bite angle all are relatively effective
in promoting the coupling reaction of 1-Li with PhI. The
soft ligands facilitate, through facile ligand dissociation,
formation of a coordinately unsaturated Pd(0) intermedi-
ate necessary for the oxidative addition, while bisphos-
phines (particularly dppf) may facilitate reductive elimi-
nation,31 relative to â-hydrogen elimination, and prevent
formation of the trans diorganopalladium complex lead-
ing to a nonproductive or a slower and less effective
catalytic cycle (Scheme 1).26 These observations are
consistent with a rate-limiting dissociative process oc-
curring among some or all32 of the steps of the catalytic
cycle. The more tightly bound the heteroatom is to the
Pd intermediate, the slower the ligand dissociation
necessary for the oxidative addition step and perhaps the
transmetalation step and hence the slower the overall
rate of the catalytic cycle.
The Pd-catalyzed coupling of R-aminoalkyl anions with
aryl halides requires the use of a Cu(I) salt as a
co-catalyst in order to achieve good yields. Copper co-
catalysts are frequently used in the Stille coupling of
organostannanes, and a mechanistic study attributed the
resultant increase in reaction rates and product yields
to the ability of Cu(I) to scavenge free phosphine ligand.20
Formation of a copper-phosphine complex facilitates
ligand dissociation from palladium intermediates which
may be necessary for transmetalation to occur. In more
polar solvents, Sn/Cu transmetalation followed by Cu/
Pd transmetalation may also contribute to the observed
rate accelerations. The “copper effect” is not nearly as
dramatic when soft ligands (e.g., AsPh3) are used since
ligand dissociation is not a problem. In contrast, Cu(I)
co-catalysts are required in the R-aminoalkyl anion
couplings regardless of the ligands employed (i.e., PPh3,
AsPh3, or SbPh3). Potassium metal reduction of a
PdCl2(Ph3P)2/CuCN mixture is assumed to afford KCl,
Pd0(PPh3)2 or Pd0(PPh3)2Cl-Li+, and CuCN. Addition of
an R-lithio carbamate to this mixture will rapidly con-
sume the CuCN at -50 °C to afford a cuprate reagent,
removing 20% of the lithium reagent when 10 mol %
CuCN is employed and perhaps more if higher order
cuprate compositions are involved. These cuprate re-
agents are also capable of binding phosphine and nitro-
stoichiometry favoring formation of Pd0L4.25a,26 Difficul-
ties in the reaction are often attributed to the transmeta-
lation step.13a Grignard, organozinc, and organotin re-
agents are the most widely employed,13a while organo-
lithium21a reagents are infrequently used. Transmeta-
lation from copper28 to palladium is generally slow, and
organolithium reagents can form ate complexes (e.g.,
[PdR3L]-Li+ and [PdR4]Li2).29 Reductive elimination
occurs via a nondissociative nonassociative mechanism
for cis diaryl- and divinylpalladium complexes and via a
dissociative mechanism for dialkylpalladium complexes.25a
The dissociative pathway is inhibited by excess phosphine
ligands, and the effect of particular ligands is related to
their binding affinity to palladium (dppe > PEt3
>
PEt2Ph > PMePh2 > PEtPh2 > PPh3);25a the lower the
binding affinity to palladium the greater the rate of
reductive elimination.
The oxidative addition of (dppf)Pd0 to (E)-2-halo-1-(4-
methoxyphenyl)ethene displays the characteristic halide
reactivity pattern of I > Br >> Cl (-70, -40, and >25
°C, respectively),30 while the oxidative addition of
(PPh3)2Pd0 with PhI is instantaneous26 at 20 °C. The
addition of aryl Grignard reagents to the above vinylpal-
ladium halides is rapid at -80 °C, and reductive elimina-
tion is so fast at -80 °C that only the product olefin-
palladium complex can be observed by 31P NMR.
Utilization of benzylmagnesium chloride results in trans-
metalation at -80 °C, but reductive elimination begins
to occur at temperatures > -30 °C with a half-life of 4
min at -15 °C. We have observed that R-aminoalkyl
cuprates are formed from the organolithium reagents at
around -50 °C,5 whereas simple lithium dialkyl or diaryl
cuprates form at lower temperatures (-120 to -78 °C).
It seems plausible, therefore, that all three steps in the
coupling of R-aminoalkyl anions with aryl iodides occur
between -50 and 20 °C and that the oxidative addition
(31) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.;
Hirotsu, K. J . Am. Chem. Soc. 1984, 106, 158.
(32) For descriptions of reductive elimination promoted by ligand
dissociation, see: (a) Tatsumi, K.; Hoffmann, R.; Yamamoto, A.; Stille,
J . K. Bull. Chem. Soc. J pn. 1981, 54, 1720. (b) Ozawa, F.; Kurihara,
K.; Yamamoto, T.; Yamamoto, A. Bull. Chem. Soc. J pn. 1985, 58, 399.
(28) Tsuda, T.; Yoshida, T.; Saegusa, T. J . Org. Chem. 1988, 53, 607;
and references cited therein.
(29) Nakazawa, H.; Ozawa, F.; Yamamoto, A. Organometallics 1983,
2, 241.
(30) Brown, J . M.; Cooley, N. A. Organometallics 1990, 9, 353.

Coupling of R-Lithio Amines with Organic Iodides
J . Org. Chem., Vol. 62, No. 22, 1997 7731
gen ligands33 and could accelerate the R-aminoalkyl anion
couplings in a manner similar to that proposed for the
“copper effect” in Stille couplings.20 In this regard, it
should be remembered that the 2 equiv of diamine used
to facilitate carbamate deprotonation are present in the
reaction medium. Amines form complexes with pal-
ladium species in palladium-promoted amination of aryl
halides,34 and methyllithium readily reacts with PdBr2-
(TMEDA) to form Me2Pd(TMEDA) and eventually Me4Pd-
Li2.29 The effect of the Cu(I) salts (i.e., CuCN > CuI >
CuBr > CuSCN) on product yield could reflect either
cuprate reactivity if they are involved in the transmeta-
lation process or cuprate instability resulting in removal
of the R-aminoalkyl group from the catalytic cycle upon
cuprate decomposition. Increasing the amount of Cu(I)
co-catalyst generally results in diminished product yield,
although 33 mol % CuCN per equivalent of the R-lithio
carbamate provides an anomaly in an otherwise uniform
trend. Utilization of sufficient CuCN to consume all the
R-lithio carbamate and form either R2CuLi‚LiCN or
RCuCNLi (50 and 100 mol %, respectively) results in no
product formation. These results are consistent with
either decomposition of the Pd(0) catalyst with increasing
copper content or the failure of the cuprate reagent to
participate in the transmetalation step. Cuprate reagents
can exist in equilibrium with the organolithium precur-
sors, and the cuprate reagents formed from the CuCN
co-catalyst could return some of the alkyllithium reagent
to the catalytic cycle.35
It is difficult to ascertain the nature of the organome-
tallic reagent undergoing transmetalation to palladium
under these reaction conditions. The 2-lithiopyrrolidine
derivative begins to undergo decomposition at -55 °C and
rapidly decomposes at 0 °C in THF. Our own experience
with the R-aminoalkyl cuprates5 is that the onset of their
thermal decomposition is around -40 °C. It seems
reasonable that Li/Pd transmetalation should be faster
than Cu/Pd transmetalation and that a crucial factor is
the temperature at which Pd(0) undergoes oxidative
addition to the aryl halide. Since cuprate reagents are
in equilibrium with the alkyllithium species from which
they were formed,35 they could be an equilibrium source
of the lithium reagents as the latter are removed by the
catalytic cycle. Since utilization of sufficient CuCN to
convert all of the (R-aminoalkyl)lithium reagent into a
cuprate reagent results in no coupling, it seems reasonable
to assume that the organometallic nucleophile participat-
ing in the transmetalation with a PdII species is an
organolithium reagent.
diamines could influence these coupling reactions through
ion-pairing effects,26 functioning as ligands for palladium
intermediates, promoting stability of the Pd(0) catalysts,
or promoting stability of the organolithium reagent.
Diamine ligands have been used in place of phosphine
ligands in Pd-catalyzed reactions.36 The necessity of
CuCN as a co-catalyst, even with soft ligands such as
SbPh3, is plausibly related to the presence of these
nitrogen ligands in the reaction mixture and the increased
stoichiometry of ligands capable of binding to palladium
species.
The coupling of R-aminoalkyl carbanions with 1-io-
donaphthalene, 2-iodothiophene, and 1-iodo-1-hexene
proceeds in modest yields when soft ligands, such as
AsPh3 or SbPh3, or dppf were employed. A major side
reaction in the vinyl iodide couplings involved halogen
metal exchange affording 2-iodopyrrolidine, which hy-
drolyzed to the hydroxy derivative upon workup. The
lower yields obtained with these substrates can also be
due to a slower rate of reductive elimination. The rate
of reductive elimination is reported to be in the order of
diaryl > aryl(alkyl) > dipropyl > diethyl > dimethyl.25a
The formation of trace amounts of homocoupling products
(Table 4, entries 10, 12, 15, and 16, legend f ) are
consistent with either halogen-metal exchange or de-
creased rate of reductive elimination with resultant
increased formation of the trans diorganopalladium
complex, given the observation26 that stoichiometric
trans-PhPdI(PPh3)2 affords homocoupled product (i.e.,
biphenyl) in the presence of nucleophiles. Given the
thermal instability of the (R-aminoalkyl)lithium and
R-aminoalkyl cuprate reagents above -40 °C, a decrease
in the rate of the catalytic cycle will result in a competi-
tive nonproductive decomposition of the organometallic
nucleophile.
The failure of R-aminoalkyl Grignard and zinc reagents
to participate in these coupling reactions is in marked
contrast to the general superiority of Grignard and
organozinc reagents over organolithium reagents in
palladium-promoted coupling reactions.13a If the R-ami-
noalkyl Grignard and zinc reagents undergo transmeta-
lation to palladium more slowly than the lithium re-
agents, more of the initial cis-ArPdIL2 complex formed
upon oxidative addition may undergo isomerization to the
trans-ArPdIL2 complex resulting in a nonproductive
pathway if the subsequent trans-aryl(R-aminoalkyl)pal-
ladium complexes are significantly more stable than the
corresponding cis isomers. In this regard it is interesting
to note that alkyllithium reagents promote isomerization
of trans-PdR2L2 to the cis isomer.29 These considerations
could account for the failure of R-aminoalkyl Grignard
and zinc reagents to couple with aryl iodides under these
reaction conditions.
The diamine employed to facilitate deprotonation of the
carbamate moiety also effects the observed yield of the
coupling reaction. Both TMEDA and sparteine effec-
tively facilitate deprotonation of the carbamates, and in
the R-aminoalkyl cuprate conjugate addition reactions
use of sparteine afforded higher yields.5b For these
reasons the dependence of coupling yield on diamine does
not appear to reflect deprotonation efficiencies. The
Con clu sion s
In summary, (R-aminoalkyl)lithium reagents can be
coupled with aryl iodides in the presence of palladium
catalysts and CuCN as a co-catalyst. The reaction is
largely limited to phenyl iodides, and diminished yields
are observed with polyaromatic and heteroaromatic
halides. The success of the reaction appears to depend
(33) (a) van Koten, G.; J astrzebski, J . T. B. H. J . Am. Chem. Soc.
1985, 107, 697. (b) Hallnemo, G.; Ullenius, C. Tetrahedron Lett. 1986,
27, 395. (c) Dieter, R. K.; Lagu, B.; Deo, N.; Dieter, J . W. Tetrahedron
Lett. 1990, 31, 4108. (d) Rossiter, B. E.; Eguchi, M.; Miao, G.; Swingle,
N. M.; Hernandez, A. E.; Vickers, D.; Fluckiger, E.; Patterson, R. G.;
Reddy, K. V. Tetrahedron 1993, 49, 965. (e) Alexakis, A.; Mutti, S.;
Normant, J . F. J . Am. Chem. Soc. 1991, 113, 6332.
(34) (a) Louie, J .; Hartwig, J . F. Tetrahedron Lett. 1995, 36, 3609.
(b) Wolfe, J . P.; Wagaw, S.; Buchwald, S. L. J . Am. Chem. Soc. 1996,
118, 7215 and references cited therein.
(35) Lipshutz, B. H.; Kozlowski, J . A.; Breneman, C. M. J . Am.
Chem. Soc. 1995, 107, 3197.
(36) (a) Markies, B. A.; Wijkens, P.; Boersma, J .; Kooijman, H.;
Veldman, N.; Spek, A. L.; van Koten, G. Organometallics 1994, 13,
3244. (b) van Asselt, R.; Elsevier, C. J . Organometallics 1994, 13, 1972.
(c) van Asselt, R.; Elsevier, C. J . Tetrahedron 1994, 50, 323. (d) Wright,
M. E.; Lowe-Ma, C. K. Organometallics 1990, 9, 347.

7732 J . Org. Chem., Vol. 62, No. 22, 1997
Dieter and Li
cooled by a dry ice-acetone bath (-78 °C), and the mixture
was stirred for 10 min. Then s-BuLi (1.2 mmol) was added in
one portion, and the mixture was stirred for an additional 2
or 3 h.
At the same time, the flask containing the Pd(0) species was
cooled in the same cold bath. The R-lithio amine was trans-
ferred into the flask containing the Pd(0) species by cannula.
The mixture was stirred, warmed naturally overnight, and
monitored by TLC (silica gel, 10% Et2O-petroleum ether, v/v)
until no starting material was observed.
The mixture was diluted with 15-20 mL of Et2O, quenched
with 5 mL of H2O, and filtered. The residue was washed with
Et2O (5 mL × 3). The organic layer was separated, and the
aqueous layer was extracted with Et2O (5 mL × 3). The
combined organic extracts were washed with 1 N HCl (5 mL
× 2), NaHCO3 (saturated, 5 mL × 2), and brine (5 mL × 3),
then dried over Na2SO4/K2CO3, and filtered. Upon concentra-
tion in vacuo, the crude material was obtained as a pale yellow
or colorless oil. Pure product was obtained by gravity or flash
column chromatography (silica gel, 200-400 or 60-200 mesh),
MPLC, or preparative TLC.
on a fine balance between the rates of each step of the
oxidative addition-transmetalation-reductive elimina-
tion sequence. Rate reduction of either the oxidative
addition or reductive elimination steps as a result of
substrate structure or ligand composition may result in
competitive decomposition of the organolithium reagent.
Reduction in the rate of the transmetalation step may
result in either catalyst decomposition or pathways that
do not favor eventual coupling. Recent insights (Scheme
1)26,30 into the mechanism of palladium-catalyzed nucleo-
philic substitution, outlined in the discussion, suggest
that mechanistic studies of this reaction may be particu-
larly useful in expanding its scope and synthetic utility.
Exp er im en ta l Section
Ma t er ia ls. House nitrogen gas was passed sequentially
through concentrated sulfuric acid, potassium hydroxide, and
anhydrous calcium chloride before being introduced into the
reaction flask. The reaction flasks were flame-dried and cooled
to room temperature in a dry nitrogen atmosphere before use.
Tetrahydrofuran (THF) and diethyl ether (Et2O) were distilled
from sodium and benzophenone (dark blue-purple color) under
a N2 atmosphere. N,N,N′,N′-Tetramethyl-1,2-diphenylethyl-
enediamine was prepared according to a literature procedure.37
Gen er a l P r oced u r e A: Cou p lin g Rea ction s Em p loyin g
Cu (I) Sa lts a n d P r efor m ed P a lla d iu m Ca ta lysts. Under
a N2 atmosphere, the N-Bocpyrrolidine (1) or N-Bocpiperidine
(2) (1.0 mmol), tetramethylethylenediamine (2.2 mmol), and
THF (2 mL) were put into a flame-dried flask. The contents
cooled to -78 °C (acetone-dry ice), whereupon s-BuLi (1.2
mmol) was added in one portion, and the mixture was stirred
for 2 or 3 h at -78 °C to form the R-lithio amines (1-Li and
2-Li) as yellow-orange solutions.
N-(ter t-Bu toxyca r bon yl)p yr r olid in e (1). Under a N2
atmosphere, pyrrolidine (1, 3.56 g, 50 mmol) was stirred
together with tert-butoxy carbonate anhydride (12.15 g, 55.7
mmol), p-(dimethylamino)pyridine (6.60 g, 50 mmol), and NEt3
(7.5 mL, 50 mmol) in CH2Cl2 (75 mL) for 24 h. The reaction
mixture was diluted with Et2O (120 mL), then washed with
10% HCl, K2CO3 (saturated), and brine, and finally dried over
K2CO3/Na2SO4. Pure 1 (8.27 g, 96.7% yield) was obtained as
a colorless oil (lit.3a,d): bp 70-75 °C (0.05 mmHg); IR 2977 (vs),
1
2876 (s), 1702 (vs), 882 (s), 774 (s) cm-1; H NMR δ 1.46 (s, 9
H), 1.84 (m, 4 H), 3.30 (m, 4 H); 13C NMR δ 25.2, 28.4, 45.6,
78.7, 154.6; mass spectrum m/z (intensity) EI 172 (0.3, M+
+
1), 171 (3, M+), 156 (0.3, M+ - CH3), 114 (16, M+ - C4H9), 98
(28.5, M+ - C4H9O), 57 (100, C4H9).
Under a N2 atmosphere, THF (2.0 mL), the palladium
catalyst (0.05 mmol), CuCN (0.10 mmol), and the aryl iodide
(1.2-2.0 mmol) were placed into another flask. The mixture
was cooled to -78 °C. The R-lithio amine solution was
transferred by cannular into the flask containing the aryl
iodide and catalyst, and the mixture was stirred and warmed
to room temperature naturally (ca. 8 h). The mixture was
heated to reflux (75 °C) until the disappearance of the
N-Bocpyrrolidine (1, Rf ) 0.43) or N-Boc piperidine (2, Rf )
0.35) as indicated by TLC analysis (silica gel, 10% Et2O-
petroleum ether, v/v).
The reaction mixture was cooled to room temperature,
diluted with Et2O (8-15 mL), quenched with aqueous satu-
rated NH4Cl (2 mL), and filtered through Celite or paper. The
organic layer was separated and the aqueous layer was
extracted with Et2O (5 mL × 4). The combined organic phase
was washed with 1 N HCl (15 mL × 2), NaHCO3 (saturated,
15 mL × 2), and brine (15 mL × 2) and dried over K2CO3/
Na2SO4. The crude product was obtained by evaporation of
solvent in vacuo.
N-(ter t-Bu toxyca r bon yl)p ip er id in e (2). The same pro-
cedure used for preparing (1) was employed. From 4.26 g (50
mmol) of piperidine was obtained 8.92 g of pure 2 (bulb-to-
bulb distillation, 79 °C, 0.05 mmHg) in 96.4% yield (lit.3d): IR
2973 (s), 2937 (s), 2859 (s), 1695 (vs), 1423 (vs), 1030 (s) cm-1
;
1H NMR δ 1.46 (s, 10 H), 1.47-1.72 (m, 5 H), 3.36 (t, J ) 5.78
Hz, 4 H); 13C NMR δ 24.4, 25.6, 28.3, 44.5, 78.9, 154.8; mass
spectrum m/z (intensity) EI 187 (0.05, M+ + 2), 186 (0.9, M+
+ 1), 185 (6.4, M+), 170 (0.1, M+ - CH3), 128 (34, M+ - C4H9),
57 (100, C4H9).
N,N-Dim eth yl-N-(ter t-bu toxyca r bon yl)a m in e (3). The
same procedure employed for preparing 1 was used. From 8.18
g (100 mmol) of dimethylamine hydrochloride was obtained
11.95 g (82% yield) of pure 3 (lit.3a): bp 75-80 °C (16-17
mmHg); IR 2981 (s), 2933 (s), 1702 (vs), 1391 (s), 1167 (vs)
cm-1; 1H NMR δ 1.43 (s) and 1.45 (s, 9 H), 2.84 (s) and 2.85 (s,
6 H); 13C NMR δ 28.4, 36.0, 79.1, 156.0; mass spectrum m/z
(intensity) EI 146 (0.4, M+ + 1), 145 (4.6, M+), 130 (1.2, M+
CH3), 90 (34), 88 (3.1), 72 (74.8), 57 (100).
-
N-[(Tr ibu tylsta n n yl)m eth yl]-N-(ter t-bu toxyca r bon yl)-
m eth yla m in e (4b). N-Boc-N,N-dimethylamine (3, 0.7298 g,
5 mmol) was mixed with TMEDA (0.75 mL, 5 mmol) and Et2O
(10 mL) under N2, and the colorless mixture was cooled to -78
°C and reacted with s-BuLi (4.6 mL, 5 mmol) for 1 h. Bu3SnCl
(1.36 mL, 5 mmol) was syringed into the pale-yellow solution.
The mixture was stirred and warmed to room temperature
overnight (white turbid), quenched with saturated aqueous
NH4Cl (5 mL), washed with brine, and dried over K2CO3/
Na2SO4. Concentration in vacuo followed by bulb-to-bulb
distillation after column chromatography (silica gel, 100-200
mesh, 20% Et2O-petroleum ether, v/v) of the crude product
gave 1.44 g of pure 4b in 66% yield as a colorless oil: bp 100
The pure product was isolated by column chromatography
(silica gel, 10% Et2O-petroleum ether, v/v, gravity or flash),
medium-pressure liquid chromatography (MPLC), or prepara-
tive TLC (silica gel).
Gen er a l P r oced u r e B: Cou p lin g Rea ction s Em p loyin g
Cu (I) Sa lts a n d Active P d (0) Gen er a ted in Situ . PdCl2
(5 mol %), the P, As, or Sb ligand (listed in Tables 1 and 4),
CuCN (10 mol %) or other metal salt, and potassium (5 mol
%) were put into one flask. THF (2 mL) was added, and the
flask was vacuum degassed (5 mmHg) and flushed with dry
N2. The mixture was heated in an oil bath (75 °C) for 2 h
(reddish mixture became black slurry) and cooled to room
temperature. The aryl iodide (2 mmol) or vinyl iodide was
added, and the mixture was stirred at room temperature for
1 h.
°C (0.005 mmHg); IR 2924 (s), 1683 (s), 1485 (s), 767 (m) cm-1
;
1H NMR δ 0.88 (m, 14 H), 1.32 (m, 8 H), 1.39-1.68 (br m, 16
H), 2.95 (m, 3 H); 13C NMR δ 8.7, 9.4, 10.2, 13.7, 17.5, 26.8,
27.4, 27.8, 28.5, 28.9, 29.1, 29.2, 32.2, 34.8, 36.3, 37.3, 78.7,
155.4.
N-Bocamine (1 mmol), TMEDA (2.2 mmol) or (-)-sparteine
(1 or 2.2 mmol) or other appropriate tertiary diamines, and
THF (2 mL) were placed into another flask. The flask was
N-(ter t-Bu t oxyca r b on yl)-2-(t r ib u t ylst a n n yl)p yr r oli-
d in e (4a ). The same procedure for preparing 4b was used.
From 0.855 g (5 mmol) of 1 was obtained 1.961 g (colorless
liquid, 85.3% yield) of 4a (lit.3a): IR 2961 (s), 2932 (s), 2875
(37) Mangeney, P.; Tejero, T.; Alexakis, A.; Grosjean, F.; Normant,
J . Synthesis 1988, 255.

Coupling of R-Lithio Amines with Organic Iodides
J . Org. Chem., Vol. 62, No. 22, 1997 7733
(m), 2853 (m), 1683 (s) cm-1; 1H NMR δ 0.65-1.03 (m, 15 H),
1.03-1.38 (m, 8 H), 1.38-1.74 (m, 14 H), 1.74-2.32 (m, 3 H),
3.09-3.79 (m, 3 H); 13C NMR δ 8.2, 9.9, 13.6, 26.9, 27.3, 27.9,
29.1, 30.3, 46.2, 78.2, 154.0.
N-(ter t-Bu toxyca r bon yl)-2-(4-m eth oxyp h en yl)p yr r oli-
d in e (7). General procedure A was employed. PdCl2(PPh3)2
(35 mg, 5 mol %) and CuCN (9 mg, 10 mol %) were used as
catalysts. N-Bocpyrrolidine (1, 0.171 g, 1 mmol) was converted
into N-Boc-R-lithiopyrrolidine (1-Li) which reacted with
p-MeOC6H4I (0.351 g, 1.5 mmol), affording 0.505 g of crude
product (orange oil). Half of the crude material was subjected
to preparative TLC (silica gel, 20 cm × 20 cm × 0.2 cm, 10%
Et2O-petroleum ether, v/v), and 0.0466 g of pure 7 (pale yellow
oil) was obtained (34% yield): IR 3065 (w), 2965 (s), 1698 (vs),
1615 (m), 1516 (s), 1398 (s), 1252 (s), 1170 (m), 1117 (m), 1041
(m), 835 (m), 777 (w) cm-1; 1H NMR δ 1.21 (s, 6 H), 1.47 (br s,
3 H), 1.69-2.06 (m, 3 H), 2.26 (br s, 1 H), 3.42-3.69 (m, 2 H),
3.79 (s, 3 H), 4.73 and 4.80 (2 br s, 1 H, rotamer), 6.84 (d, J )
8.31 Hz, 2 H), 7.08 (d, J ) 8.31 Hz, 2 H); 13C NMR δ 23.2,
28.2, 36.0, 47.0, 55.2, 60.7, 79.1, 113.5, 114.7, 126.5, 133.9,
158.2; mass spectrum, m/z (intensity) EI 278 (21, M+ + 1),
277 (60, M+), 276 (12, M+ - 1), 203 (11, M+ - C4H9OH), 175
(30, M+ - C4H9OCHO). Anal. Calcd for C16H23NO3: C, 69.31;
H, 8.30; N, 5.05. Found: C, 69.13; H, 8.39; N, 5.10.
N-(ter t-Bu t oxyca r b on yl)-2-p h en ylp yr r olid in e
(5).
N-Boc-2-phenylpyrrolidine (5) was obtained as a colorless oil
in three ways: (1) the reduction of 3,4-dihydro-5-phenyl-2H-
pyrrole (2-phenyl-1-pyrroline) and the subsequent protection
of 2-phenylpyrrolidine with the Boc group (64% yield); (2) the
coupling reaction catalyzed by preformed palladium catalyst
(general procedure A, up to 57% yield); and (3) the coupling
reaction catalyzed by CuCN and active Pd(0) generated in situ
(general procedure B, up to 79% yield). 5 (lit.11): IR 3064 (w),
3031 (w), 2983 (s), 2925 (m), 2873 (m), 1698 (vs), 1397 (vs),
1370 (m), 1168 (s), 1120 (m), 753 (m), 708 (s) cm-1; 1H NMR δ
1.17 (s, 6 H), 1.46 (s, 3 H), 1.72-2.03 (m, 3 H), 2.30 (br s, 1 H),
3.62 (br s, 2 H), 4.76 and 4.97 (2 br s, 1 H, rotamer), 7.06-
7.42 (m, 5 H); 13C NMR δ 23.0, 28.0 (28.3), 35.8 (34.8), 46.9,
61.1 (60.4), 78.9, 125.2, 126.3, 128.0, 144.9 (143.6), 154.3; mass
spectrum m/z (intensity) EI 248 (22, M+ + 1), 246 (11, M+
1), 192 (100, M+ - C4H7), 170 (17, M+ - C6H5), 146 (83, M+
tBuCO2).
-
-
N-(ter t-Bu t oxyca r b on yl)-2-(4-m et h oxyp h en yl)p ip er i-
d in e (8). General procedure A was employed. PdCl2(PPh3)2
(35 mg, 0.05 mmol) and CuCN (9 mg, 0.10 mmol) were used
as catalysts. N-Bocpiperidine (2, 0.185 g, 1 mmol) was
converted into R-lithio amine 2-Li which was mixed with
p-methoxyiodobenzene (0.351 g, 1.5 mmol)/catalyst mixture
affording crude product (0.247 g, yellow oil). Pure 8 (pale
yellow oil) was obtained by column chromatography (silica gel,
10% Et2O-petroleum ether, v/v, Rf ) 0.27) in 43% yield. When
the oil was placed in a freezer, it became a white solid: mp
76.9-78 °C; IR 3061 (w), 3018 (w), 2962 (m), 2925 (m), 2882
(m), 2845 (w), 1686 (vs), 1612 (s), 1520 (s), 1471 (m), 1421 (s),
1267 (s), 1163 (s), 1039 (s), 842 (m) cm-1; 1H NMR δ 1.47 (s, 9
H), 1.33-1.67 (m, 4 H), 1.78-1.94 (m, 1 H), 2.26 (d, J ) 13.38
Hz, 1 H), 2.64-2.69 (m, 1 H), 3.80 (s, 3 H), 4.02 (d, J ) 12.10
Hz, 1 H), 5.37 (br s, 1 H,), 6.88 (d, J ) 8.63 Hz, 2 H), 7.14 (d,
J ) 8.81 Hz, 2 H); 13C NMR δ 19.3, 25.5, 28.4, 28.0, 39.9, 52.6,
55.2, 79.4, 113.9, 127.6, 132.3, 155.6, 158.1; mass spectrum,
m/z (intensity) EI 292 (2, M+ + 1), 291 (7, M+), 235 (93), 218
(30), 190 (100, M+ - C4H9 - CO2), 57 (100, C4H9). Anal. Calcd
for C17H25NO3: C, 70.10; H, 8.59; N, 4.81. Found: C, 70.19;
H, 8.25; N, 5.40.
Under a N2 atmosphere, 3,4-dihydro-5-phenyl-2H-pyrrole38
(2.08 mmol), NiCl2 (0.52 g, 4 mmol), and MeOH (anhydrous,
20 mL) were stirred together and cooled to -30 °C. Then
NaBH4 (0.78 g, 20 mmol) was added in one portion, and the
mixture changed color from gold to blue, finally becoming a
black slurry. The mixture was stirred overnight (-30 °C to
rt, 14 h),39 treated with 2 N NaOH (10 mL), and extracted with
Et2O (20 mL × 3). The combined organic phase was washed
with brine (15 mL × 3) and dried over K2CO3. The crude
2-phenylpyrrolidine (yellowish liquid, 0.2426 g, 79% yield)
obtained upon filtration and concentrated in vacuo was used
without further purification.
2-Phenylpyrrolidine (0.2426 g, ca. 1.65 mmol), tert-butoxy
carbonate anhydride (0.72 g, 3.3 mmol), 4-(dimethylamino)py-
ridine (0.22 g, 1.65 mmol), NEt3 (0.25 mL, ca. 1.7 mmol), and
CH2Cl2 (20 mL) were stirred together under a N2 atmosphere
at room temperature for 16 h. The mixture was diluted with
50 mL of Et2O and washed with 1 N HCl (20 mL × 3) and
saturated aqueous NaHCO3 (25 mL × 3). The organic phase
was dried over K2CO3 (yellowish clear solution), filtered, and
concentrated in vacuo to afford 0.458 g of a yellow liquid. Pure
5 (0.260 g colorless oil, 64% yield) was obtained by column
chromatography (silica gel, 200-400 mesh, 20% Et2O-
petroleum ether, v/v, gravity, Rf ) 0.37).
N-(ter t-Bu toxyca r bon yl)-2-p h en ylp ip er id in e (6). Gen-
eral procedure A was employed. PdCl2(PPh3)2 (35 mg, 0.05
mmol) and CuCN (9 mg, 0.10 mmol) were used as catalysts
on a 1 mmol reaction scale. Pure 6 was isolated as a colorless
oil (lit.11) in 55% yield by column chromatography (silica gel,
10% Et2O-petroleum ether, v/v, Rf ) 0.35).
General procedure B was employed. TMEDA (0.33 mL, 2.2
mmol) or (-)-sparteine (0.23 mL, 1 mmol) was used in THF
as solvent. PdCl2 (9 mg, 0.05 mmol), CuCN (9 mg, 0.10 mmol),
SbPh3 (70.6 mg, 0.10 mmol), and K (2 mg, 0.05 mmol) were
used to generate the catalyst mixture. N-Bocpiperidine (2,
0.185 g, 1 mmol) was converted into lithio amine 2-Li which
reacted with PhI (0.16 mL, 2 mmol) to afford crude product
(0.541 g, yellow oil). Pure 6 (0.195 g, 75% yield) was obtained
as colorless oil by preparative TLC (silica gel, 10% Et2O-
petroleum ether, v/v, Rf ) 0.35): (lit.11) IR 3088 (w), 3065 (w),
3015 (w), 2980 (m), 2944 (s), 2870 (m), 1701 (vs), 1499 (m),
1481 (m), 1457 (s), 1420 (vs), 1371 (s), 1279 (s), 1249 (s), 1182
(s), 1163 (vs), 1022 (s), 863 (m), 741(w), 692 (m) cm-1; 1H NMR
δ 1.46 (s, 9 H), 1.36-1.72 (m, 4 H), 1.78-2.03 (m, 1 H), 2.30
(d, J ) 14.02 Hz, 1 H), 2.67-2.86 (m, 1 H), 4.05 (d, J ) 13.45,
1 H), 5.42 (br s, 1 H), 7.08-7.53 (m, 5 H); 13C NMR δ 19.3,
25.4, 28.0, 28.3, 40.0, 53.1, 79.4, 126.2, 126.4, 128.4, 140.3,
155.5; mass spectrum, m/z (intensity) EI 262 (14, M+ + 1),
206 (98), 205 (98, M+ - C4H8), 188 (52, M+ - C4H9O), 160 (100,
M+ - C4H9 - CO2), 77 (63, C6H5).
4-Methoxybenzonitrile was formed as a byproduct present
in up to 26 mol %: IR 2216 cm-1; 1H NMR δ 4.04 (s, 3 H), 7.14
(d, J ) 9 Hz, 2 H), 7.60 (d, J ) 9 Hz, 2 H); 13C NMR δ 55.4,
103.9, 114.7, 119.1, 133.9, 162.8 (calcd δ 56.0, 104.8, 114.8,
116.5, 133.0, 166.3).
N-(ter t-Bu t oxyca r b on yl)-2-(2-m et h ylp h en yl)p yr r oli-
d in e (9). General procedure A was employed. PdCl2(PPh3)2
(35 mg, 5 mol %) and CuCN (9 mg, 10 mol %) were used as
catalysts. N-Bocpyrrolidine (1, 0.171 g, 1 mmol) was converted
into N-Boc-R-lithiopyrrolidine (1-Li) which reacted with
o-MeC6H4I (0.262 g, 1.2 mmol), affording 0.249 g of crude
product (brown liquid) of which 0.169 g was subjected to
column chromatography (silica gel, 10% Et2O-petroleum
ether, v/v, then pure Et2O) to afford 0.113 g of pure 9 (pale
yellow oil, 64% yield): IR 3068 (w), 3026 (w), 2979 (s), 2926
(m), 2878 (m), 1705 (vs), 1486 (m), 1463 (m), 1393 (vs), 1362
(s), 1255 (m), 1160 (vs), 1125 (s), 929 (m), 899 (m), 870 (m),
1
758 (m), 728 (s) cm-1; H NMR δ 1.15 (s, 6 H), 1.46 (s, 3 H),
1.58-1.81 (m, 1 H), 1.81-2.03 (m, 2 H), 2.32 (br s, 4 H), 3.38-
3.78 (m, 2 H), 4.89-5.01 and 5.07-5.17 (2 m, 1 H, rotamers),
6.92-7.22 (m, 4 H); 13C NMR δ 19.2, 23.1, 28.0 (28.5), 34.1,
47.1, 58.0, 79.0, 124.3, 125.8, 126.2, 129.9, 133.8, 143.2, 154.3;
mass spectrum, m/z (intensity) CI 263 (11, M+ + 2), 262 (65,
M+ + 1), 260 (4, M+ - 1), 206 (100, M+ - C4H9), 188 (13, M+
- C4H9O), 162 (31). Anal. Calcd for C16H23NO2: C, 73.56; H,
8.81; N, 5.36. Found: C, 73.45; H, 8.91; N, 5.30.
N -(t er t -Bu t oxyca r b on yl)-2-(2-m e t h ylp h e n yl)p ip e r i-
d in e (10). General procedure A was employed. PdCl2(PPh3)2
(35 mg, 0.05 mmol) and CuCN (9 mg, 0.10 mmol) were used
as catalysts. N-Bocpiperidine (2, 0.185 g, 1 mmol) was
converted into R-lithio amine 2-Li which was reacted with
o-methyliodobenzene (0.3301 g, 1.6 mmol) affording 0.2997 g
of crude product (orange oil). Crude product (0.2747 g) was
(38) Fry, D. F.; Fowler, C. B.; Dieter, R. K. Synlett 1994, 836.
(39) Li, S. J .; J iang, Y.; Mi, A.; Yang, G. Synth. Commun. 1992, 22,
1497.

7734 J . Org. Chem., Vol. 62, No. 22, 1997
Dieter and Li
subjected to preparative TLC (silica gel, 10% Et2O-petroleum
ether, v/v, Rf ) 0.49), and 0.166 g of pure 10 (pale yellow oil)
was obtained in 65% yield: IR 3101 (w), 3060 (w), 2971 (s),
2936 (s), 2870 (s), 1705 (vs), 1681 (vs), 1646 (m), 1479 (s), 1450
(s), 1402 (s), 1360 (s), 1277 (s), 1242 (s), 1182 (s), 1152 (s), 736
- C4H9 - CO2), 168 (30), 127 (10, C10H7), 57 (54, C4H9). Anal.
Calcd for C19H23NO2: C, 76.77; H, 7.74; N, 4.71. Found: C,
76.70; H, 7.80; N, 4.70.
N-(ter t-Bu toxyca r bon yl)-2-(1-n a p h th yl)pip er id in e (14).
General procedure B was employed. (-)-Sparteine (0.23 mL,
1 mmol) was used in THF as solvent. PdCl2 (9 mg, 0.05 mmol),
CuCN (9 mg, 0.10 mmol), SbPh3 (70.6 mg, 0.10 mmol), and K
(2 mg, 0.05 mmol) were used to generate the catalyst mixture.
The lithio amine 2-Li was generated (1 mmol) and was mixed
with 1-iodonaphthalene (0.381 g, 1.5 mmol)/catalyst mixture,
affording 0.684 g of crude product (pink oil). Preparative TLC
(silica gel, 10% Et2O-petroleum ether, v/v, Rf ) 0.13) afforded
0.1308 g of pure 14 (colorless oil, 42% yield): IR 3056 (w), 2977
1
(m), 718 (w) cm-1; H NMR δ 1.27 (s, 9 H), 1.46-1.68 (m, 3
H), 1.68-2.00 (m, 3 H), 2.32 (s, 3 H), 3.11-3.42 (m, 1 H), 4.04
and 4.08 (2 br s, 1 H), 5.22 (t, J ) 5.54 Hz, 1 H), 7.02-7.32
(m, 4 H); 13C NMR δ 18.7, 19.2, 24.4, 28.1, 28.4, 41.2, 52.6,
79.2, 125.3, 125.6, 126.2, 130.6, 134.8, 142.5, 155.6; mass
spectrum, m/z (intensity) CI 275 (5, M+), 220 (93), 202 (14,
M+ - C4H9O), 128 (100, M+ - C4H9OH - C6H4CH3), 57 (22,
C4H9). Anal. Calcd for C17H25NO2: C, 74.18; H, 9.09.
Found: C, 74.08; H, 9.18.
1
(m), 2941 (m), 2862 (w), 1685 (vs), 1157 (m) cm-1; H NMR δ
N-(ter t-Bu t oxyca r b on yl)-2-(4-m et h ylp h en yl)p yr r oli-
d in e (11). General procedure A was employed. PdCl2(PPh3)2
(35 mg, 5 mol %) and CuCN (9 mg, 10 mol %) were used as
catalysts in a 1 mmol scale reaction. p-Iodotoluene (0.262 g,
1.2 mmol) was used. Crude product (0.248 g), (a brown liquid),
was obtained, of which 0.168 g was purified by column
chromatography (silica gel, 10% Et2O-petroleum ether, v/v)
to afford 0.1190 g (67.3% yield) of pure 10 (pale yellow oil).
When the product was placed in a freezer for approximately 2
weeks, it became colorless crystals: mp 62.7-64.2 °C; IR 3061
(w), 3025 (w), 2968 (s), 2874 (m), 1700 (vs), 1677 (vs), 1512
(m), 1459 (m), 1394 (vs), 1359 (s), 1158 (vs), 1123 (s), 822 (m),
1.25 (s, 9 H), 1.39-1.92 (m, 5 H), 1.92-2.25 (m, 2 H), 3.08-
3.36 (m, 1 H), 3.90-4.21 (m, 1 H), 5.94 (t, J ) 4.45 Hz, 1 H),
7.03-8.17 (m, 6 H); 13C NMR δ 19.4, 24.7, 28.2, 29.4, 41.7,
52.1, 79.5, 123.2, 123.5, 124.9, 125.3, 125.8, 127.3, 128.8, 130.9,
134.0, 139.3, 155.7; mass spectrum, m/z (intensity) EI 312 (1.4,
M+
+ 1), 311 (6, M+), 255 (85, M+ - C4H8), 210 (100, M+
-
C4H9 - CO2), 194 (21), 154 (17), 127 (13, C10H7), 57 (38, C4H9).
Anal. Calcd for C20H25NO2: C, 77.17; H, 8.04. Found: C,
77.02; H, 8.14.
2-[N-(ter t-Bu t oxyca r bon yl)-2-p yr r olid in yl]t h iop h en e
(15). General procedure B was employed. PdCl2 (9 mg, 0.05
mmol), CuCN (9 mg, 0.10 mmol), AsPh3 (61.5 mg, 0.10 mmol),
and K (2 mg, 0.05 mmol) were used to generate the catalysts.
N-Bocpyrrolidine (1, 0.171 g, 1 mmol) was converted into
R-lithio amine 1-Li which was mixed with R-iodothiophene
(0.231 g, 1.1 mmol)/catalysts and stirred at -78 °C to room
temperature for 18 h, affording 0.499 g of crude product (brown
cake). Purification by preparative TLC (silica gel, 20 cm ×
20 cm × 0.2 cm, 10% Et2O-petroleum ether, v/v) gave pure
15 (yellow oil) in 36% yield: IR 3068 (w), 2978 (s), 2935 (m),
1
775 (w), 740 (w) cm-1; H NMR δ 1.20 (s, 6 H), 1.46 (s, 3 H),
1.72-1.98 (m, 3 H), 2.30 (br s, 4 H), 3.61 (br s, 2 H), 4.73 and
4.91 (br s, 1 H, rotamer), 7.00-7.14 (m, 4 H); 13C NMR δ 20.9
(20.3), 23.0, 28.1 (28.7), 35.8 (34.7), 46.9, 60.9 (60.0), 79.1,
125.3, 128.6, 135.8, 141.9, 154.6 (rotomers); mass spectrum,
m/z (intensity) CI 263 (5, M+ + 2), 262 (29, M+ + 1), 260 (3,
M+ - 1), 206 (100), 188 (11, M+ - C4H9O), 160 (32, M+ - C4H9
- CO2). Anal. Calcd for C16H23NO2: C, 73.56; H, 8.81; N, 5.36.
Found: C, 73.44; H, 8.91; N, 5.21.
2877 (m), 1696 (vs), 1398 (vs), 1170 (s), 1111 (m), 702 (m) cm-1
;
1H NMR δ 1.37 (br s, 9 H), 1.81-2.14 (m, 3 H), 2.14-2.42 (m,
1 H), 3.19-3.78 (m, 2 H), 5.13 (br s, 1 H), 6.72-7.00 (m, 2 H),
7.13 (d, J ) 6.26 Hz, 1 H); 13C NMR δ 23.3, 28.3, 35.0, 46.2,
56.7, 79.5, 123.0, 123.2, 126.4, 149.0, 154.4; mass spectrum
m/z (intensity) EI 197 (99, M+ - C4H8), 180 (19, M+ - C4H9O),
152 (74, M+ - C4H9 - CO2), 57 (100, C4H9).
2-[N-(ter t-Bu t oxyca r b on yl)-2-p ip er id in yl]t h iop h en e
(16). General procedure B was employed. N-Bocpiperidine
(2, 0.185 g, 1 mmol) was converted into lithio amine 2-Li
N -(t er t -Bu t oxyca r b on yl)-2-(4-m e t h ylp h e n yl)p ip e r i-
d in e (12). General procedure A was employed. PdCl2(PPh3)2
(35 mg, 0.05 mmol) and CuCN (9 mg, 0.10 mmol) were used
as catalysts. N-Bocpiperidine (2, 0.185 g, 1 mmol) was
converted into R-lithio amine 2-Li which was mixed with
p-methyliodobenzene (0.262 g, 1.2 mmol)/catalyst mixture,
affording 0.337 g of crude product (golden oil). Crude product
(0.307 g) was subjected to preparative TLC (silica gel, 15%
Et2O-petroleum ether, v/v, Rf ) 0.26), and 0.178 g of pure 12
was obtained as a colorless oil (71% yield): IR 3089 (w), 3060
(w), 3012 (w), 2977 (m), 2941 (s), 2870 (m), 1699 (vs), 1521
(m), 1485 (m), 1461 (m), 1420 (vs), 1372 (s), 1277 (s), 1248 (s),
1182 (s), 1164 (vs), 1040 (s), 879(m), 825 (m), 778 (w) cm-1; 1H
NMR δ 1.46 (s, 9 H), 1.31-1.69 (m, 4 H), 1.69-1.94 (m, 1 H),
2.08-2.25 (m, 1 H), 2.26 (s, 3 H), 2.61-2.83 (m, 1 H), 4.04
and 4.06 (2 br s, 1 H, rotomers), 5.39 (br s, 1 H), 7.00-7.28
(m, 4 H); 13C NMR δ 19.2, 20.8, 25.4, 27.9, 28.3, 39.9, 52.9,
79.3, 126.3, 129.1, 135.7, 137.1, 155.5; mass spectrum, m/z
(TMEDA, 0.33 mL, 2.2 mmol was used). PdCl2
(9 mg, 0.05
mmol), SbPh3 (0.706 mg, 0.10 mmol), CuCN (10 mg, 0.11
mmol), and K (2 mg, 0.05 mmol) were used to generate the
catalyst. 2-Iodothiophene (0.231 g, 1.1 mmol) was reacted with
the lithio amine and afforded 0.315 g of crude product (brown
cake), which was purified by preparative TLC (silica gel, 10%
Et2
O-petroleum ether, v/v, Rf ) 0.47) to afford 0.1121 g (42.0%
yield) of 16 (pale yellow oil). The product was further purified
by bulb-to-bulb distillation to afford a colorless oil: bp 110-
125 °C (0.05-0.10 mmHg); IR 2969 (w), 2938 (m), 2865 (w),
1695 (vs), 1457 (m), 1415 (m), 1368 (m), 1274 (m), 1165 (m)
(intensity) CI 277 (4, M+ + 2), 276 (32, M+ + 1), 274 (3, M+
-
1), 220 (100), 176 (57), 57 (11). Anal. Calcd for C17H25NO2:
C, 74.18; H, 9.09; N, 5.09. Found: C, 73.93; H, 9.02; N, 4.96.
N-(ter t-Bu toxycar bon yl)-2-(1-n aph th yl)pyr r olidin e (13).
General procedure B was employed. PdCl2 (9 mg, 0.05 mmol),
bppf (27.7 mg, 0.05 mmol), CuCN (9 mg, 0.10 mmol), and K (2
mg, 0.05 mmol) were used to generate the catalyst. N-
Bocpyrrolidine (1, 0.171 g, 1 mmol) was converted into R-lithio
amine 1-Li which reacted with 1-iodonaphthalene (0.381 g,
1.5 mmol) at -78 °C to room temperature for 13 h, affording
0.508 g of crude product (dark-yellow oil). Pure 13 was
obtained in 39% yield as white/colorless crystals after prepara-
tive TLC (silica gel, 20 cm × 20 cm × 0.2 cm, 10% Et2O-
petroleum ether, v/v, Rf ) 0.20): mp 126.1-127.6 °C; IR 3068
(w), 3052 (w), 2978 (m), 2882 (w), 1686 (vs), 1404 (vs), 1175
(s), 1132 (m), 909 (vs), 745 (vs) cm-1; 1H NMR δ 1.10 (s, 6 Η),
1.46 (s, 3 Η), 1.64-1.99 (m, 3 H), 2.25-2.55 (m, 1 H), 3.39-
3.86 (m, 2 H), 5.60 and 5.75 (2 d, J ) 6.56 Hz, J ) 7.94 Hz, 1
H, rotamer), 7.11-8.06 (m, 7 H); 13C NMR δ 22.9 (23.4), 28.0
(28.5), 34.3 (33.2), 46.8 (47.2), 58.1, 79.1, 121.7 (121.3), 122.9
(123.2), 125.2 (125.1), 125.6, 127.0, 128.7, 130.2, 133.7 (134.0),
138.7, 139.8, 154.5; mass spectrum, m/z (intensity) EI 297 (6,
M+), 241 (41, M+ - C4H8), 240 (27, M+ - C4H9), 196 (100, M+
cm-
1; 1H NMR δ 1.49, (s, 9 H), 1.42-1.78 (m, 4 H), 1.78-2.01
(m, 1 H), 2.18 (d, J ) 13.87 Hz, 1 H), 2.64-2.94 (dt, J 1 ) 2.88
Hz, J 2 ) 13.04 Hz, 1 H), 3.99 and 4.04 (2 br s, 1 H), 5.59 (br
s,1 H), 6.82 (d, J ) 2.44 Hz, 1 H), 6.95 (t, J ) 3.60 Hz, 1 H),
7.20 (d, J ) 5.03 Hz, 1 H); 13C NMR δ 19.5, 25.3, 28.4, 29.4,
39.7, 50.7, 79.8, 124.1, 124.2, 126.7, 145.4, 154.9; mass
spectrum, m/z (intensity) EI 211 (100, M+ - C4H8), 194 (12,
M+ - C4H9O), 166 (58), 97 (14), 57 (47, C4H9). Anal. Calcd
for C14H21NO2S: C, 62.92; H, 7.87. Found: C, 63.12; H, 8.04.
N-(ter t-Bu toxyca r bon yl)-2-(1-h exen yl)p yr r olid in e (17).
General procedure B was employed. N-Bocpyrrolidine (1,
0.171 g, 1.0 mmol) was converted into lithio amine 1-Li. PdCl2
(9 mg, 0.05 mmol), SbPh3 (70.6 mg, 0.10 mmol), K (2 mg, 0.05
mmol), and CuCN (9 mg, 0.10 mmol) were used to generate
the catalyst system. 1-Iodohexene (0.315 g, 1.5 mmol) was
reacted with the lithio amine under the influence of the
catalyst, affording 0.382 g of crude product (brown liquid),
which was purified by column chromatography (silica gel, 10%
Et2O-petroleum ether, v/v, Rf ) 0.28), and gave 0.0879 g (35%
yield) of 17 (yellow oil) and 0.0675 g (36% yield) of N-Boc-2-
hydroxypyrrolidine. Product 17 was further purified by bulb-

Coupling of R-Lithio Amines with Organic Iodides
J . Org. Chem., Vol. 62, No. 22, 1997 7735
to-bulb distillation to afford a colorless oil: bp 105-115 °C
(0.05-0.01 mmHg): IR 2961 (s), 2932 (s), 2873 (m), 1701 (vs),
1480 (m), 1455 (m), 1397 (vs), 1366 (s), 1174 (s), 1115 (m), 967
13.9, 22.6, 22.8 (23.2), 28.4, 30.2, 31.4, 32.7, 46.5 (46.8), 61.3,
78.9, 107.2, 150.2 (149.6), 154.6; mass spectrum, m/z (intensity)
EI 253 (0.5, M+), 197 (13, M+ - C4H8), 180 (13, M+ - C4H9O),
154 (18), 114 (100), 83 (1). Anal. Calcd for C15H27NO2: C,
71.15; H, 10.67. Found: C, 70.87; H, 10.69.
1
(w), 879 (w), 775 (w) cm-1; H NMR δ 0.88 (t, J ) 6.9 Hz, 3
H), 1.19-1.54 (m, 5 H), 1.43 (s, 9 H), 1.54-2.10 (m, 5 H), 3.77
(br s, 2 H), 4.08-4.41 (m. 1 H), 5.22-5.58 (m, 2 H); 13C NMR
δ 13.8, 22.0, 22.8 (br), 28.4, 31.4, 31.7, 32.4 (br), 46.0 (br), 58.5,
78.7, 130.2 (2C), 154.6 (br); mass spectrum, m/z (intensity) EI
198 (3.6), 197 (25, M+ - C4H8), 196 (15, M+ - C4H9), 180 (17,
M+ - C4H9O), 152 (6, M+ - C4H9 - CO2). Anal. Calcd for
C15H27NO2: C, 71.15; H, 10.67. Found: C, 70.88; H, 10.60.
N-(ter t-Bu toxyca r bon yl)-2-(h ex-1-en yl)p ip er id in e (18).
General procedure B was employed. N-Bocpiperidine (2, 0.185
g, 1 mmol) was converted into lithio amine 2-Li (TMEDA, 0.33
mL, 2.2 mmol was used). PdCl2 (9 mg, 0.05 mmol), CuCN (9
mg, 0.10 mmol), SbPh3 (0.706 mg, 0.10 mmol), and K (2 mg,
0.05 mmol) were used to generate the catalyst system. 1-Io-
dohexene (0.42 g, 2 mmol) was reacted with the lithio amine
and gave 0.400 g of crude product (reddish oil), which was
subjected to column chromatography (silica gel, 10% Et2O-
petroleum ether, v/v, Rf ) 0.38), and gave 0.0461 g (17% yield)
of pure 18 (colorless oil): bp 65-70 °C (0.01-0.05 mmHg); IR
3014 (w), 2939 (s), 2865 (m), 1701 (vs), 1679 (shoulder), 1426
(s), 1369 (m), 1277 (m), 1243 (m), 1169 (m), 1138 (s), 1020 (w),
N-(ter t-Bu toxyca r bon yl)-2-(1-h exyn yl)p yr r olid in e (21).
General procedure B was employed. N-Bocpyrrolidine (1,
0.171 g, 1.0 mmol) was used to generate the lithio amine [0.35
mL (ca. 1.5 mmol) of (-)-sparteine was used]. PdCl2 (9 mg,
0.05 mmol), SbPh3 (70.6 mg, 0.10 mmol), K (2 mg, 0.05 mmol),
and CuCN (9 mg, 0.10 mmol) were used to generate the
catalyst system. 1-Iodohexyne (0.367 g, ca. 1.6 mmol) was used
as coupling substrate. The crude material (0.749 g, dark
brown oil) was purified by column chromatography (silica gel,
10% Et2O-petroleum ether, v/v, Rf ) 0.33) and gave 0.0863 g
(yellow oil, 34% yield) of 21. The product was further purified
by bulb-to-bulb distillation to give a colorless oil: bp 125 °C
(0.05 mmHg); IR 2982 (m), 2962 (m), 2933 (m), 2875 (w), 1687
1
(vs), 1407 (s), 1375 (m), 1174 (m), 1116 (w) cm-1; H NMR δ
0.61-1.11 (m, 3 H), 1.41 (br s, 14 H), 1.69-2.06 (m, 3 H), 2.10
(t, J ) 6.74 Hz, 2 H), 3.24 (br s, 1 H), 3.38 (br s, 1 H), 4.35 (br
s, 1 H); 13C NMR δ 13.5 (14.0), 18.2, 21.7, 23.7, 28.4 (28.5),
30.8, 33.9, 45.4, 48.2, 79.2, 80.5, 81.7, 154.1; mass spectrum,
m/z (intensity) EI 195 (6, M+ - C4H8), 178 (12), 153 (99), 81
(17), 57 (100).
1
876 (w), 762 (w) cm-1; H NMR δ 0.74-0.88 (m, 3 H), 1.44-
1.77 (m, 10 H), 1.38 (s, 9 H), 1.86-2.17 (m, 1 H), 2.75 (t, J )
12.82 Hz, 1 H), 3.24-3.34 (m, 1 H), 3.85 (d, J ) 12.17 Hz, 1
H), 4.66 (br s, 1 H), 5.22-5.53 (m, 2 H); 13C NMR δ 13.9, 19.5,
22.1, 25.6, 28.5, 29.4, 31.5, 32.1, 39.6, 51.9, 79.1, 128.1, 131.9,
155.4; mass spectrum, m/z (intensity) EI 211 (20, M+ - C4H8),
194 (17, M+ - C4H9O), 166 (21, M+ - C4H9 - CO2), 154 (69),
141 (100), 57 (57, C4H9). Anal. Calcd for C16H29NO2: C, 71.91;
H, 10.86; N, 5.24. Found: C, 72.07; H, 11.03; N, 5.09.
N-(ter t-Bu toxyca r bon yl)-2-(2-h exen yl)p yr r olid in e (19).
General procedure B was employed using 2-iodo-1-hexene
(0.415 g, 1.9 mmol). The crude material (0.452 g, brown liquid)
was purified by column chromatography (silica gel, 10% Et2O-
petroleum ether, v/v, Rf ) 0.26), and 0.0675 g (36% yield) of
N-Boc-2-hydroxypyrrolidine along with 0.0263 g (colorless oil,
10% yield) of pure 19 was obtained: bp 100-115 °C (0.05-
0.01 mmHg); IR 2965 (s), 2934 (s), 2879 (m), 1701 (vs), 1389
(vs), 1366 (s), 1178 (s), 1124 (s), 898 (w), 770 (w) cm-1; 1H NMR
δ 0.91 (t, J ) 7.16 Hz, 3 H), 1.17-1.64 (m, 4 H), 1.41 (s, 9 H),
1.64-2.39 (m, 6 H), 3.30-3.55 (br s, 2 H), 4.19 and 4.27 (2 br
s, 1 H, rotamer), 4.71 (br s, 1 H), 4.75 (br s, 1 H); 13C NMR δ
N-(ter t-Bu toxyca r bon yl)-2-h ydr oxyp yr r olid in e. N-Boc-
2-hydroxypyrrolidine was obtained in two ways: (1) The
reduction of N-Boc-2-pyrrolidinone by DIBALH (2 equiv) at
-78 °C gave an almost quantitative yield of N-(tert-butoxy-
carbonyl)-2-hydroxypyrrolidine; (2) The coupling reaction of
1- or 2-iodo-1-hexene with lithio amine 1-Li (general procedure
B) gave 36% yield of N-(tert-butoxycarbonyl)-2-hydroxy-
pyrrolidine: IR 3448 (br, w), 2973 (s), 2934 (s), 2879 (m), 1704
1
(vs), 1397 (vs) cm-1; H NMR δ 1.47 (s, 9 H), 1.66-2.76 (m, 4
H), 2.92-3.42 (m, 1 H), 3.42-3.66 (m, 1 H), 3.66-4.18 (m, 1
H), 5.39 and 5.48 (2 br s, 1 H, rotamer); 13C NMR δ 22.6 (21.9),
28.3, 32.7 (33.4), 45.8 (45.6), 79.9 (80.2), 81.5 (81.3), 155.0 (153,
rotamers); mass spectrum, m/z (intensity) EI 169 (8, M+
H2O), 113 (39), 96 (28), 68 (41), 57 (100, C4H9).
-
Ack n ow led gm en t. This work was generously sup-
ported by the National Science Foundation (CHE-
9408912).
J O970985B