Asymmetric deprotonation-substitution of N-Pop-benzylamines using [RLi/(-)-sparteine]. Enantioselective sequential reactions and synthesis of N-heterocycles

Article abstract of DOI:10.1021/ol801027p

(Chemical Equation Presented) Pop-directed asymmetric deprotonation of benzylic amines using [n-BuLi/(-)-sparteine] provides an efficient method for the synthesis of chiral NC_α and NC _α,α′ derivatives with total selectivity with respect to competing allylic and ortho lithiation. The method described herein offers a straightforward route of accessing chiral N-Pop-protected nitrogen heterocycles.

Full text of DOI:10.1021/ol801027p

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3195-3198
Asymmetric Deprotonation-Substitution
of N-Pop-benzylamines Using [RLi/
(-)-Sparteine]. Enantioselective
Sequential Reactions and Synthesis of
N-Heterocycles
Pascual On˜a-Burgos,† Ignacio Ferna´ndez,† Laura Roces,‡
Laura Torre-Ferna´ndez,‡ Santiago Garc´ıa-Granda,‡ and Fernando Lo´pez-Ortiz*,†
´
Area de Qu´ımica Orga´nica, UniVersidad de Almer´ıa, Carretera de Sacramento s/n,
04120 Almer´ıa, Spain, and Departamento de Qu´ımica F´ısica y Anal´ıtica, UniVersidad
de OViedo, C/ Julia´n ClaVer´ıa 8, 33006 OViedo, Spain
flortiz@ual.es
Received May 5, 2008
ABSTRACT
Pop-directed asymmetric deprotonation of benzylic amines using [n-BuLi/(-)-sparteine] provides an efficient method for the synthesis of
chiral NCr and NCr,r′ derivatives with total selectivity with respect to competing allylic and ortho lithiation. The method described herein
offers a straightforward route of accessing chiral N-Pop-protected nitrogen heterocycles.
Benzylic lithiation of carbamates mediated by (-)-sparteine
has become a well established method for the enantiocon-
trolled generation of OCR and NCR stereogenic carbon
centers.1 The carbamate moiety contributes to directing the
deprotonation and stabilizing the carbanion formed. After
electrophilic quench, R-substituted oxy2 and amino3 deriva-
tives are obtained with excellent enantioselectivities. This
asymmetric deprotonation-substitution sequence can be
successfully applied to a number of Csp3-heteroatom sys-
tems.4,5
(4) For reviews, see: (a) Basu, A.; Thayumanavan, S. Angew. Chem.,
Int. Ed. 2002, 41, 716. (b) Chinchilla, R.; Na´jera, C.; Yus, M. Tetrahedron
2005, 61, 3139. (c) Wu, G.; Huang, M. Chem. ReV. 2006, 106, 2596. For
some recent references, see: (d) Chedid, R. B.; Bruemmer, M.; Wibbeling,
B.; Froehlich, R.; Hoppe, D. Angew. Chem., Int. Ed. 2007, 46, 3131. (f)
Stymiest, J. L.; Dutheuil, G.; Mahmood, A.; Aggarwal, V. K. Angew. Chem.,
Int. Ed. 2007, 46, 7491. (g) Yousaf, T. I.; Williams, R. L.; Coldham, I.;
Gawley, R. E. Chem. Commun. 2008, 97. (h) Coldham, I.; Patel, J. J.;
Raimbault, S.; Whittaker, D. T. E.; Adams, H.; Fang, G. Y.; Aggarwal,
† Universidad de Almer´ıa.
‡ Universidad de Oviedo.
(1) Clayden, J. Organolithiums: SelectiVity for Synthesis; Pergamon:
Oxford, 2002.
(2) (a) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. 1997, 36, 2282.
(b) Beak, P.; Anderson, D. R.; Curtis, M. D.; Laumer, J. M.; Pipel, D. J.;
Weisenburger, G. A. Acc. Chem. Res. 2000, 33, 715. (c) O’Brien, P.; Bilke,
J. L. Angew. Chem., Int. Ed. 2008, 47, 2734.
V. K. Org. Lett. 2008, 10, 141
.
(5) For applications of (+)-sparteine surrogates see: (a) Hermet, J.-P. R.;
Viterisi, A.; Wright, J. M.; McGrath, M. J.; O’Brien, P.; Whitwood, A. C.;
Gilday, J. Org. Biomol. Chem. 2007, 5, 3614. (b) O’Brien, P. Chem.
(3) (a) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan,
S. Acc. Chem. Res. 1996, 29, 552. (b) Whisler, M. C.; MacNeil, S.; Snieckus,
V.; Beak, P. Angew. Chem., Int. Ed. 2004, 43, 2206.
Commun. 2008, 655, and references cited therein
.
10.1021/ol801027p CCC: $40.75
Published on Web 06/27/2008
2008 American Chemical Society

PdO-assisted benzylic lithiation has been much less
studied, and its usefulness in organic synthesis remains
almost unexploited.6 We are aware of only one example of
asymmetric NCR metalation of an organophosphorus com-
pound. The deprotonation of N-benzylphosphoramidates with
[s-BuLi/L*] (L* ) (-)-sparteine) or chiral lithium amides
affords rearranged R-aminophosphonates in moderate yield
and low enantiomeric excess (Scheme 1).7
First, optimized reaction conditions were established for
the prototypal asymmetric deprotonation-methylation of
phosphinamide 1a (Table 1).11 The best results are obtained
Table 1. Asymmetric NCR Lithiation-methylation Optimization
of 1a in Toluene Using MeI as Eletrophilea, b
entry RLi T (°C): RLi T (°C): MeI 2, convn (%)c
erd
1
2
3
4
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
t-Bu
90
90
50
90f
90g
90
90
90
50
90e
90e
90
90
90
90 (85)
91
90
92
92
80:20
62:38
60:40
60:40
80:20
56:44
Scheme 1. Enantioselective
Phosphoramidate-Aminophosphonate Rearrangement
5
6
56
7h
n-Bu
0i
a Lithiation during 60 min, reaction with the electrophile 5 min. In all
cases, 1.31 mmol of [n-BuLi/L*] and 0.93 mmol of 1a were used. b In
THF, racemic product is formed. In Et2O, very low conversion is observed
due to poor substrate solubility. Phosphinamide 1a is completely insoluble
in hexanes. c Established based on 31P{1H} NMR spectra. Yield in
parentheses. d Determined by chiral HPLC. e The temperature was stabilized
for 60 min before quench. f The temperature was allowed to increase to
-50 °C. g 240 min of lithiation time. h Absence of (-)-sparteine. i Ca. 6%
of products derived from n-BuP(O)Ph2 were observed.
We have developed Pop-directed [Pop ) Ph2P(O)] lithia-
tion of phosphinamides into a versatile method for obtaining
dearomatized compounds8 and NCR-9 and ortho-substituted10
products (Scheme 2). In all cases, asymmetry was introduced
by treating 1a with [n-BuLi/L*] in toluene for 1 h at -90
°C followed by addition of MeI at the same temperature.
After reaction for 5 min, phosphinamide 2a8b is obtained in
90% conversion and with an er of 80:20 (Table 1, entry 1).
Increasing the temperature of either deprotonation or me-
thylation to -50 °C caused a significant decrease in the er
(entries 2-4 and Table S1, Supporting Information).
This implies that at -90 °C the deprotonation of 1a takes
place enantioselectively leading to a benzylic carbanion
configurationally stable in the time scale of electrophilic
quench. Prolonged lithiation of 1a for 4 h produced a
marginal improvement of the conversion without affecting
the er (entry 5). Significantly, products of ortho deprotonation
were not observed. The use of [t-BuLi/L*] affords almost
racemic 2a in low yield (entry 6). In the absence of (-)-
sparteine, 1a is recovered almost unaffected (entry 7 and
Table S1, Supporting Information). Next, we extended the
(-)-sparteine-assisted deprotonation-substitution process to
other phosphinamides and electrophiles (Table 2). The anion
of 1a (R1 ) Me) reacts with alkyl, acyl, and tin halides to
give compounds 2-6 in high yield and with er ranging from
80:20 to 88:12 (entries 1-5).12 Electrophilic quench with
aldehydes proceeds with very high conversion although with
low face selectivity (entries 6 and 7). Interestingly, acrolein
undergoes [1,2] addition exclusively.13 The diastereoisomers
were separated through column chromatography. N-Pop-1,2-
amino alcohols of unlike configuration are formed predomi-
nantly with high er.
Scheme 2
by using chiral starting materials. We report herein the first
examplesoftheefficientasymmetricdeprotonation-substitution
reaction of N-benzyl-N-alkylphosphinamides using the com-
plex [n-BuLi/(-)-sparteine] as a base.
The scope of the methodology is demonstrated through
the application to one-pot double-NCR,R′ dibenzylic enanti-
oselective substitution and to the synthesis of a chiral
tetrahydropyridine.
(6) Phosphoramides: (a) Savignac, P.; Dreux, M. Tetrahedron Lett. 1976,
17, 2025, and references therein. (b) Seebach, D.; Yoshifuji, M. HelV. Chim.
Acta 1981, 64, 643. (c) Seebach, D.; Lohmann, J. J.; Syfrig, M. A.;
Yoshifuji, M. Tetrahedron 1983, 39, 1963. (d) Mu¨ller, J. F. K.; Zehnder,
M.; Barbosa, F.; Spingler, B. HelV. Chim. Acta 1999, 82, 1486, and
references therein. Phosphonamides: (e) Afarinkia, K.; Jones, C. L.; Yu,
H.-W. Synlett 2003, 509. (f) Pedrosa, R.; Maestro, A.; Pe´rez-Encabo, A.;
Raliegos, R. Synlett 2004, 1300. (g) Lo´pez, B.; Maestro, A.; Pedrosa, R.
Synthesis 2006, 817.
(7) Hammerschmidt, F.; Hanbauer, M. J. Org. Chem. 2000, 65, 6121.
(8) Review: (a) Lo´pez-Ortiz, F.; Iglesias, M. J.; Ferna´ndez, I.; Andu´jar-
Sa´hez, C. M.; Ruiz-Go´mez, G. Chem. ReV 2007, 107, 1580. See also: (b)
Ferna´ndez, I.; Ruiz-Go´mez, G.; Alfonso, I.; Iglesias, M. J.; Lo´pez-Ortiz,
F. Chem. Commun. 2005, 5408. (c) Mora´n-Ramallal, A.; Ferna´ndez, I.;
Lo´pez-Ortiz, F.; Gonza´lez, J. Chem. Eur. J. 2005, 11, 3022. (d) Ruiz-Go´mez,
G.; Iglesias, M. J.; Serrano-Ruiz, M.; Garc´ıa-Granda, S.; Francesch, A.;
Lo´pez-Ortiz, F.; Cuevas, C. J. Org. Chem. 2007, 72, 3790. (e) Ruiz-Go´mez,
G.; Iglesias, M. J.; Serrano-Ruiz, M.; Lo´pez-Ortiz, F. J. Org. Chem. 2007,
72, 9704.
(11) Synthesis of 1a and 1b: (a) Ferna´ndez, I.; Lo´pez-Ortiz, F.; Tejerina,
B.; Garc´ıa-Granda, S. Org. Lett. 2001, 3, 1339.
(9) (a) Ferna´ndez, I.; Gonza´lez, J.; Lo´pez-Ortiz, F. J. Am. Chem. Soc.
2004, 126, 12551. (b) Ferna´ndez, I.; Lo´pez-Ortiz, F. Chem. Commun. 2004,
1142. (c) On˜a-Burgos, P.; Ferna´ndez, I.; Iglesias, M. J.; Garc´ıa-Granda, S.;
Lo´pez-Ortiz, F. Org. Lett. 2008, 10, 537.
(12) For analogue NCR-methylations of N-Boc-N-methylbenzylamine,
see: (a) Park, Y. S.; Boys, M. L.; Beak, P. J. Am. Chem. Soc. 1996, 118,
3757. (b) Park, Y. S.; Beak, P. Bull. Kor. Chem. Soc. 1998, 19, 1253.
(13) R-Lithiated N-Boc-N-arylbenzylamine exclusively attacks the CO
group of acrolein: (a) Park, Y. S.; Beak, P. J. Org. Chem. 1997, 62, 1574.
(10) Ferna´ndez, I.; On˜a-Burgos, P.; Ruiz-Go´mez, G.; Bled, C.; Garc´ıa-
Granda, S.; Lo´pez-Ortiz, F. Synlett 2007, 611.
3196
Org. Lett., Vol. 10, No. 15, 2008

Table 2. Asymmetric Deprotonation-Electrophilic Trapping of
N-Benzylphosphinamide 1a and 1ba
Scheme 3
.
Diastereospecific Lithiation of Phosphinamide (S)-2
and (R)-2
entry R1
E+
product convnb (%)
erc
80:20
85:15
84:16
82:18
88:12
1
Me MeI
(R)-2
(R)-3
90 (85)
89 (83)
69 (61)
95 (83)
96 (91)
84 (76)
88 (80)
91 (83)
94 (85)
94 (84)
94 (87)
2
Me PhCH2Br
to react with [n-BuLi/(-)-sparteine] for 1 h and the resulting
anion is quenched with MeOTf, meso-12 is formed as the
only product (Scheme 2). In contrast, the analogous reaction
of (R)-2 leads to a mixture of meso-12 and (R,R)-13 in a
ratio of 1.4:1 (Scheme 3). The above results suggest that
[n-BuLi/(-)-sparteine] removes the pro-R proton of phos-
phinamides 1 enantioselectively and that the configurationally
stable carbanion generated is alkylated with retention with
MeI, MeOTf, PhCH2Br, and MeO2CCH2Br, whereas
MeO2CCl, Me3SnCl, and R2CHO react with inversion.14
Successive application of the asymmetric deprotonation-
substitution method to 1b allowed installation of a different
electrophile in each benzylic arm (Scheme 4). Treating 1b
3
Me MeO2CCH2Br (R)-4
4
5
6
Me MeO2CCl
Me Me3SnCl
(R)-5
(S)-6
Me CH2dCHCHO (R)-7d
92:8;e 88:12
93:7;e 87:13
87:13
7
8
Me PhCHO
Bn MeI
(R)-8d
(R)-9
9
10
11
Bn MeOTf
Bn Me3SnCl
Bn PhCHO
(R)-9
90:10
(S)-10
>99
(R)-11f
98:2;e 95:5
a 60 min of lithiation, 5 min of electrophilic quench. In all cases, 1.31
mmol of [n-BuLi/L*] and 0.93 mmol of 1 were used. b Established based
on 31P{1H} NMR spectra. Yield in parentheses. c Determined by HPLC
using Chiralcel OD-H. d Diastereoisomers in the COH, dr 66:34. e (1S,2R).
f Diastereoisomers in the COH, dr 78:22; er established trough Mosher ester
derivatives.
The performance of the electrophilic quench step improved
notably by increasing the size of the R1 substituent linked
to the nitrogen. Thus, from phophinamide 1b (R1 ) CH2Ph)
NCR-substituted derivatives 9-11 are obtained in excellent
yields and very high enantioselectivities (entries 8-11). It
is worth mentioning that the stannylation reaction leads
almost quantitatively to (S)-10, which may be used for further
transformations without purification.
Scheme 4. NCR,R′ Sequential Asymmetric
Deprotonation-Substitution Method
The absolute configuration of (R)-2 and (R)-9 was assigned
by comparison of retention times (Chiralcel OD-H) with
enantiomerically pure compounds. The sense of electrophile
substitution leading to (R)-3 and (R)-4 is assumed to be the
same. The structure of (R)-5 was correlated with the
corresponding N-deprotected R-amino ester (Supporting
Information). The configuration of (1S,2R)-8, (1S,2R)-11
(Mosher ester derivative), and (S)-10 was established on the
basis of their X-ray crystal structures (Figure 1, Supporting
Information). Indirectly, this allows assigning the absolute
configuration of (S)-6 and (1S,2R)-7.
The stereochemical course of the synthesis of 2-11 could
be ascertained by applying the method to phosphinamides
of known behavior toward lithiation-electrophilic quench
(Scheme 3).
Deprotonation of (S)-2 with t-BuLi in Et2O followed by
addition of MeI affords meso-12 via diastereoespecific
abstraction of the pro-R proton and iodide displacement with
retention of the configuration.9c As expected, under the same
conditions (R)-2 also affords meso-12. When (S)-2 is allowed
with [n-BuLi/L*] at -90 °C in toluene for 1 h followed by
addition of MeOTf and then repeating the procedure by using
Me3SnCl as electrophile provides a mixture of diasteroiso-
mers (S,R)-14 and (R,R)-15 (dr 5:1) in a yield of 74% and
er of 94:6 and 79:21, respectively. Interestingly, the direct
stannylation of (R)-4 via deprotonation with t-BuLi proceeds
without stereoselectivity.9c To the best of our knowledge,
this is the first time that double-asymmetric induction
mediated by (-)-sparteine on two different methylene groups
of an acyclic amine is achieved.15
Pop-directed enantioselective lithiation-substitution can
be readily applied to the asymmetric synthesis of N-
heterocycles, an area of current interest.16
Using phosphinamide 1c as scaffold (Supporting Informa-
tion), lithiation with [n-BuLi/L*] and subsequent allylation
(14) These features are in some cases different to those found in the
analogue reactions of N-Boc-benzylamines: (a) Faibish, N. C.; Park, Y. S.;
Lee, S.; Beak, P. J. Am. Chem. Soc. 1997, 119, 11561. See also ref 13.
Org. Lett., Vol. 10, No. 15, 2008
3197

Figure 1. X-ray crystal structures of compounds (a) (1S,2R)-8, (b) (S)-10, and (c) Mosher ester of (1S,2R)-11.
with allylBr gives the product of benzylic substitution (R)-
16 with total regioselectivity in 88% isolated yield and er of
75:25 (Scheme 5).17 Exposure of (R)-16 to Grubb’s catalyst
(second generation) in dichloromethane at room temperature
for 1 h furnishes tetrahydropyridine (R)-17 quantitatively.
The absolute configuration of (R)-16 is assigned by analogy
with compounds (R)-2 to (R)-4 (Table 1, entries 1-3).
In summary, Pop-directed asymmetric deprotonation of
benzylic amines using [n-BuLi/(-)-sparteine] is an efficient
method for the synthesis of chiral NCR and NCR,R′ derivatives
with total selectivity with respect to competing allylic and
ortho lithiation and provides a straightforward route of
accessing to chiral N-Pop protected nitrogen heterocycles.
Contrary to N-benzylphosphoramidates, products of [1,2]
Scheme 5
.
Enantioselective Lithiation-Allylation of 1c and
Subsequent Ring-Closing Metathesis
rearrangement of the benzylic carbanion are not observed.
Moreover, Pop removal can be readily achieved in a variety
of ways.9c
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia (MEC) (project: CTQ2005-1792BQU) for funding.
I.F. thanks the Ramo´n y Cajal program for financial support.
(15) For a sequential deprotonation-electrophilic trapping of Boc-
pyrrolidine, see: (a) Stead, D.; O’Brien, P.; Sanderson, A. Org. Lett. 2008,
10, 1409.
(16) (a) Wallace, D. J.; Goodman, J. M.; Kennedy, D. J.; Davies, A. J.;
Cowden, C. J.; Ashwood, M. S.; Cottrell, I. F.; Dolling, U.-H.; Reider,
P. J. Org. Lett. 2001, 3, 671. (b) Weihofen, R.; Dahnz, A.; Tverskoy, O.;
Helmchen, G. Chem. Commun. 2005, 3541.
Supporting Information Available: Experimental details,
characterization data, and crystallographic data for (1S,2R)-
8, Mosher ester of (1S,2R)-11, and (S)-10. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) Formation of 16 via competing [1,2] or [2,3] anion rearrangement
reactions has been discarded by trapping the anion formed by treatment of
1c with t-BuLi at -90 °C in Et2O with MeI. Methylation happened
exclusively at the benzylic position.
OL801027P
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Org. Lett., Vol. 10, No. 15, 2008