Practical asymmetric synthesis of α-branched 2- piperazinylbenzylamines by 1,2-additions of organometallic reagents to N-tert-butanesulfinyl imines

Article abstract of DOI:10.1021/jo051514p

2-[4-(tert-Butoxycarbonyl)piperazinyl] benzylidene-tert-butanesulfinamides underwent nucleophilic 1,2-addition with different organometallic reagents to give highly diastereomerically enriched adducts. X-ray crystallography of the resulting α-branched N-B

Full text of DOI:10.1021/jo051514p

Practical Asymmetric Synthesis of r-Branched
2-Piperazinylbenzylamines by 1,2-Additions of Organometallic
Reagents to N-tert-Butanesulfinyl Imines
Wanlong Jiang, Chen Chen, Dragan Marinkovic, Joe A. Tran, Caroline W. Chen,
L. Melissa Arellano, Nicole S. White, and Fabio C. Tucci*
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real,
San Diego, California 92130
ftucci@neurocrine.com
Received July 20, 2005
2-[4-(tert-Butoxycarbonyl)piperazinyl]benzylidene-tert-butanesulfinamides underwent nucleophilic
1,2-addition with different organometallic reagents to give highly diastereomerically enriched
adducts. X-ray crystallography of the resulting R-branched N-Boc-2-piperazinylbenzyl-tert-butane-
sulfinamides confirms different mechanisms depending on the organometallic reagent used.
Differential deprotection of the N-Boc and the tert-butanesulfinamides was investigated, and the
dehydration byproducts have been identified and characterized. To avoid the formation of byproducts
in the acidic deprotection step, the N-tert-butanesulfinamide group was converted to the corre-
sponding N-tert-butanesulfonamide (Bus), which allowed for clean orthogonal deprotection. The
efficient synthesis and deprotection of the N-Boc-2-piperazinylbenzyl-tert-butanesulfinamides herein
described constitutes an attractive method for extensive structure-activity studies in the search
for novel ligands of the human melanocortin 4 receptor.
Introduction
structure-activity relationships (SAR) of this novel class
of molecules, we needed to synthesize R-branched piper-
azinylbenzylamines in asymmetric fashion. The synthetic
method of choice would have to satisfy a few require-
ments, including excellent enantio- or diastereoselectiv-
ity, predictability of the stereochemical outcome of the
reaction, and employment of readily available starting
materials. In addition, it would be desirable to find a
method robust enough to allow for the kilogram prepara-
tion of intermediates during eventual preclinical studies.
Among the existing methods for the preparation of
optically pure benzylamines bearing a stereogenic center
at the R-position, those involving the nucleophilic addi-
tion of an organometallic reagent to a CdN imine bond,
where a stereodirecting group originates on the nitrogen
atom, stood out due to the operational simplicity and the
availability of commercial starting materials.3 The chiral
Benzylamines are ubiquitous structures in organic and
medicinal chemistry. Many benzylamines are present in
molecules that display important pharmacological activi-
ties.1 During the course of a medicinal chemistry program
aimed at discovering small molecule ligands of the
human melanocortin type 4 receptor (MC4R), we found
that various compounds possessing the 2-piperazinyl-
benzylamine core displayed excellent biological activities
at that receptor.2 To better explore and understand the
* Corresponding author. Phone: (858) 617-7677.Fax: (858) 617-
7619.
(1) For a few examples see: (a) Tucci F. C.; Zhu Y.-F.; Struthers R.
S.; Guo Z.; Gross T. D.; Rowbottom M. W.; Acevedo O.; Gao Y.;
Saunders J.; Xie Q.; Reinhart G. J.; Liu X.-J.; Ling N.; Bonneville A.
L. K.; Chen T.-K.; Bozigian H.; Chen C. J. Med. Chem. 2005, 48, 1169-
1178. (b) Ekhato V.; Huang, Y. J. Labelled Compd. Radiopharm. 1997,
39, 1020-1038. (c) Macdonald, S. J. F.; Clarke, G. D. E.; Dowle, M.
D.; Harrison, L. A.; Hodgson, S. T.; Inglis, G. G. A.; Johnson, M. R.;
Shah, P.; Upton, R. J.; Walls, S. B. J. Org. Chem. 1999, 64, 5166-
5175.
(3) For reviews on asymmetric additions of organometallic reagents
to CdN bonds see: (a) Bloch, R. Chem. Rev. 1998, 98, 1407-1438. (b)
Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069-1094. (c)
Giuseppe Alvaro, G.; Savoia, D. Synlett 2002, 651-673. (d) Enders,
D.; Reinhold: U. Tetrahedron: Asymmetry 1997, 8, 1895-1946. (e)
Weinreb, S. M.; Orr, R. K. Synthesis 2005 1205-1227.
(2) Chen, C.; Pontillo, J.; Fleck, B. A.; Gao, Y.; Wen, J.; Tran, J. A.;
Tucci, F. C.; Foster, A. C.; Saunders: J. J. Med. Chem. 2004, 49, 6821-
6830.
10.1021/jo051514p CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/24/2005
8924
J. Org. Chem. 2005, 70, 8924-8931

Synthesis of R-Branched 2-Piperazinylbenzylamines
TABLE 1. Reaction Conditions for the Aromatic
Nucleophlic Substitutions of Fluorobenzaldehydes 1 and
N-Boc-piperazine 2
SCHEME 1
entry reactant product
conditions
yield (%)
1
2
1a
1b
1b
1c
1c
1d
1e
1e
1f
3a
3b
3b
3c
3c
3d
3e
3e
3f
DMF, 130 °C, 18 h
DMF, 110 °C, 21 h
1,4-dioxane, 101 °C, 48 h
DMF, 140 °C, 18 h
DMSO, 80 °C, 20 h
DMF, 110 °C, 24 h
DMF, 130 °C, 2 h
DMSO, 80 °C, 24 h
DMF, 110 °C, 12 h
DMF, 100 °C, 16 h
DMF, 130 °C, 36 h
DMA, 155 °C, 22 h
71a,e
45d
3
75b,e
32c,d
8d
4
5
imine C is readily prepared from a condensation reaction
of a benzaldehyde A and a chiral amine B, and after
organometallic addition, the protected enantiopure ben-
zylamine D is obtained. Depending on the nature of the
stereodirecting group (G), it can also function as a
protecting group for the newly formed benzylamine
(Scheme 1).
Our group chose the addition of organometallic re-
agents to chiral N-sulfinyl imines developed by Davis and
Ellman,4 since it fulfilled all of the requirements men-
tioned earlier. Thus, the benzaldehyde of choice is
condensed with either enantiomer of N-tert-butanesul-
finamide (reagent B, Scheme 1) to yield the correspond-
ing chiral N-sulfinyl aldimine (compound C, Scheme 1).
This, in turn, reacts with an organometallic reagent
(Grignard or alkyllithium) to produce the final compound
(D, Scheme 1).
6
67c,e
92a,e
64d
7
8
9
20a,e
13c,d
20e
10
11
12
1g
1h
1h
3g
3h
3h
61b,d
a Purification was conducted by trituration with hexanes. b Pu-
rification was conducted by crystallization from hexanes or a
mixture of EtOAc and hexanes. c Purification was conducted by
silica gel chromatography. d Two equivalents of N-Boc-piperazine
was used. e One equivalent of N-Boc-piperazine were used.
robenzaldehyde (1b) was heated to 110 °C in the presence
of 2 equiv of N-Boc-piperazine and K2CO3, in DMF, only
45% yield of product was observed, in conjunction with
varying amounts of N,N-dimethylamino displacement of
the fluorine at the 2-position (entry 2, Table 1). Changing
the reaction solvent and temperature to refluxing 1,4-
dioxane (101 °C) not only avoided the occurrence of the
N,N-dimethylamino impurity but it also suppressed the
decomposition of N-Boc-piperazine, allowing it to react
with the substrate, albeit at a slower rate (entry 3, Table
1). The SNAr of 2-fluoro-5-methylbenzaldehyde (1h) was
very sluggish in DMF due to the presence of the deacti-
vating methyl group at the 5-position (entry 11, Table
1). In this case, the reaction had to be conducted in
dimethylacetamide (DMA) in order to allow a higher
reaction temperature (155 °C). In most cases, the prod-
ucts were isolated after a standard workup, followed by
recrystallization of the crude from a mixture of hexanes
and EtOAc.
In this paper, we report our efforts on the application
of the Ellman-Davis method to the asymmetric synthesis
of 2-piperazinylbenzylamines bearing an R-substituent.
Results and Discussion
a. Preparation of 2-Piperazinylbenzaldehydes.
The preparation of the starting materials in our synthetic
sequence, the 2-piperazinylbenzaldehydes, was accom-
plished by the aromatic nucleophilic substitution (SNAr)
reaction between the appropriately substituted 2-fluo-
robenzaldehyde 1a-1h and N-Boc-piperazine 2 (eq 1).5
b. Preparation of the N-Sulfinyl Imines. Benz-
aldehydes 3a-h were then converted to the correspond-
ing N-tert-butanesulfinyl imines by condensation with
either enantiomer of N-tert-butanesulfinamide (eq 2).
The results are summarized in Table 1. Most reactions
were conducted in a similar manner as reported by
Reinhoudt and co-workers, i.e., using DMF as the solvent
and K2CO3 as the base, at high temperatures (110-150
°C).5 For a few substrates, however, the reaction was
sluggish under those conditions, and upon prolonged
heating, in addition to starting materials, several byprod-
ucts resulting from decomposition of N-Boc-piperazine
and DMF were observed. For instance, when 2,3-difluo-
Initially, several conditions were investigated, including
the use of anhydrous MgSO4, as suggested by earlier
studies of Ellman and co-workers.6 In their investiga-
tions, they found that in the case of aromatic aldehydes,
an excess of the former was needed in order to drive the
(4) For reviews on asymmetric additions of organometallic reagents
to N-sulfinyl imines see: (a) Zhou, P.; Chen, B.-C.; Davis, F. A.
Tetrahedron 2004, 60, 8003-8030. (b) Ellman, J. A.; Owens, T. D.;
Tang, T. P. Acc. Chem. Res. 2002, 35, 984-995. (c) Ellman, J. A. Pure
Appl. Chem. 2003, 75, 39-46.
(5) Nijhuis, W. H. N.; Verboom, W.; Reinhoudt, D. N. Synthesis 1987,
641-645. For a review on aromatic nucleophilic substitution see:
Zoltewicz, J. A. Top. Curr. Chem. 1975, 59, 33-64.
(6) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J.
Org. Chem. 1999, 64, 1278-1284 and references therein.
J. Org. Chem, Vol. 70, No. 22, 2005 8925

Jiang et al.
TABLE 2. Reaction between Benzaldehydes 3a-h and N-tert-Butanesulfinamides 4 under Various Conditions (eq 2)
entry
benzaldehyde
n-tert-butanesulfinamide
product
conditions
reagent
yield (%)a
1
2
3a
3b
3b
3b
3c
3c
3d
3e
3e
3e
3e
3f
Ss-4
Ss-4
Rs-4
Ss-4
Ss-4
Rs-4
Ss-4
Ss-4
Ss-4
Ss-4
Ss-4
Ss-4
Rs-4
Ss-4
Ss-4
Ss-4
Ss-5a
Ss-5b
Rs-5b
Ss-5b
Ss-5c
Rs-5c
Ss-5d
Ss-5e
Ss-5e
Ss-5e
Ss-5e
Ss-5f
Rs-5f
Ss-5g
Ss-5h
Ss-5h
THF, rt, 14 h
Ti(OEt)4
Ti(OEt)4
Ti(OEt)4
Cs2CO3
Ti(OEt)4
Ti(OEt)4
Ti(OEt)4
Ti(OEt)4
Cs2CO3
-
MgSO4
Ti(OEt)4
Ti(OEt)4
Ti(OEt)4
Ti(OEt)4
Cs2CO3
73c,d
100b
90c
THF, rt, 16 h
3
THF, rt, 18 h
4
CH2Cl2, reflux, 48 h
THF, rt, 16 h
91c
5
94b
100b
90b
100b
88c
6
THF, rt, 7 h
7
THF, rt, 16 h
8
THF, rt, 16 h
9
CH2Cl2, reflux, 24 h
THF, rt, 24 h
10
11
12
13
14
15
16
-
-
CH2Cl2, rt, 24 h
THF, rt, 24 h
97b
100b
91c,d
99c
3f
THF, rt, 24 h
3g
3h
3h
THF, rt, 16 h
THF, rt, 16 h
CH2Cl2, reflux, 48 h
9e
a Isolated yields of pure products. b Product triturated with hexanes. c Purification was performed by recrystallization from EtOAc or
hexane/EtOAc mixtures. d Purification performed by silica gel chromatography. e Slow conversion. After prolonged heating decomposition
was observed.
reaction to completion when MgSO4 was used as the
dehydrating agent.6 In our efforts to identify an efficient
synthetic route to the desired R-branched benzylamines,
we purposely avoided reaction conditions that relied on
the use of an excess of either reacting partner. In the
absence of any catalyst, no reaction occurred between
benzaldehyde 3e and (S)-N-tert-butanesulfinamide Ss-4
in THF (entry 10, Table 2). When the same benzaldehyde
3e was allowed to react with an equimolar amount of
sulfinamide Ss-4, in CH2Cl2 in the presence of anhydrous
MgSO4 at room temperature, very little product was
observed, even after prolonged reaction times (>24 h)
(entry 11, Table 2). The condensations proved more
efficient by the use of 4 equiv of the powerful Lewis acid
and dehydrating agent Ti(OEt)4.7 Thus, by performing
the reaction in THF at ambient temperature, it was
possible to accomplish the condensation between 3e and
Ss-4 in quantitative yield (entry 8, Table 2). The same
methodology was applied to other benzaldehydes 3a-h
with similar results. Both enantiomers of sulfinamide 4
participated in the condensation with similar efficiency
(entries 3, 6, and 13, Table 2). The reactions were
normally completed within 2 h at ambient temperature,
and the workup consisted of pouring the entire reaction
mixture onto a brine solution. The titanium oxide salts
that formed were promptly removed by filtration through
a pad of Celite, and the product could be obtained by
washing the cake with an organic solvent such as EtOAc
or CH2Cl2. After solvent removal, the resulting N-sulfinyl
imines were of sufficient purity (>95% by HPLC) to be
used in the next step without further purification. In
several cases, however, the resulting imines were recrys-
tallized from hexanes/EtOAc to achieve greater purity.
Despite the fact that Ti(OEt)4 was a powerful catalyst
for the condensation described above, its use in large-
scale reactions generated large amounts of titanium
oxides byproducts and required tedious vacuum filtration
and washing of the cake with copious amounts of
solvents. A recent report by Nakata’s group described the
use of Cs2CO3 as a catalyst for the condensation between
aldehydes and sulfinamides.8 When we applied this
method to our system, we were delighted to find that for
benzaldehydes activated by an electron-withdrawing
group (3b and 3e) the reactions proceeded to give the
desired products in excellent yields (entries 4 and 9, Table
2). The conversions were typically 96% after 24 h of reflux
in CH2Cl2, and the workup was greatly simplified by
decantation of the solid Cs2CO3 and filtration. Upon
concentration, the product was obtained in pure form
after recrystallization from hexanes/EtOAc. Yields were
greater than 85% in both cases. When benzaldehyde 3h,
containing an electron-donating methyl group at the
5-position, was reacted with (S)-N-tert-butanesulfinamide
4a in refluxing CH2Cl2, in the presence of 1.05 equiv of
Cs2CO3, a very slow conversion to the corresponding
imine was observed (entry 16, Table 2). Upon prolonged
heating, thermal decomposition of the imine via syn
elimination to give the corresponding benzonitrile and
the transient sulfenic acid was observed (eq 3). This is
not unprecedented, since similar processes have been
reported, first by Davis9 and later by Ellman.10
The geometry of the N-tert-butanesulfinyl imines syn-
thesized herein was determined by a combination of NMR
spectroscopy and X-ray crystallography. In all cases, only
1
one species was observed by H and 13C NMR spectros-
copy. The X-ray crystal structures of N-sulfinyl imines
Ss-5b, Ss-5e, and Ss-5g are shown in Figure 1 and
confirm the presence of the E geometry only. The enan-
(8) Higashibayashi, S.; Tohmiya, H.; Mori, T.; Hashimoto, K.;
Nakata, M. Synlett. 2004, 457-460.
(9) (a) Davis, F. A.; Friedman, A. J.; Kluger, E. W. J. Am. Chem.
Soc. 1974, 96, 5000-5001. (b) Davis, F. A.; Reddy, R. E.; Szewczyk, J.
M.; Reddy, G. V.; Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R.
T.; Zhou, P.; Carrol, P. J. J. Org. Chem. 1997, 62, 2555-2563.
(10) Mukade, T.; Dragoli, D. R.; Ellman, J. A. J. Comb. Chem. 2003,
5, 590-596.
(7) Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268-
269.
8926 J. Org. Chem., Vol. 70, No. 22, 2005

Synthesis of R-Branched 2-Piperazinylbenzylamines
completely consumed and a mixture of 1:10 of the Rs,R-
7b and Rs,S-7b, respectively, resulted (eq 4). In addition,
FIGURE 1. ORTEP representations of the X-ray structures
of N-tert-butanesulfinyl imines Ss-5b, Ss-5e, and Ss-5g.
tiomeric purities of the products were maintained, ac-
cording to chiral HPLC.
ca. 8% of the reduction product 11b was observed (entry
1, Table 3). Addition of i-BuMgBr under the same
conditions, however, led to the production of 11b as the
major product, with little Rs,S-8b present (entry 2, Table
3). Other solvents were investigated, such as THF,
toluene, and Et2O, but none was able to suppress the
formation of 11b. In fact, in the cases of toluene and Et2O,
the conversions were poor, on the order of 20% or lower
(entries 4 and 5, Table 3). The presence of a Lewis acid,
such as Me3Al, did not lead to any improvement when
the solvent was toluene (entry 6, Table 3). At this point
we turned our attention to alkyllithium reagents in an
attempt to utilize some of the knowledge acquired by
Ellman and co-workers on the use of Lewis acids to
c. Asymmetric Addition of Organometallics across
the CdN Imine Double Bond. The results of our
investigations on the asymmetric additions of organo-
lithium and organomagnesium reagents to N-tert-bu-
tanesulfinyl imines 5a-h are summarized in Table 3. We
started our studies by looking into the addition of
Grignard reagents to N-tert-butanesulfinyl imine Ss-5b.
Grignard reagents are easily prepared from alkyl or aryl
halides or can be purchased from commercial sources. In
contrast, only a few alkyl- and aryllithium reagents are
available commercially, and they are much less trivial
to prepare, especially in larger quantities. When a
solution of EtMgBr was added slowly to compound Rs-
5b, in CH2Cl2 at -40 °C, the starting material was
TABLE 3. Organometallic Additions to N-tert-Butanesulfinyl Imines 5a-h
entry
substrate
reagent
Lewis acid
solvent
product(s)
ratioa
yield (%)b
1
2
Rs-5b
Rs-5b
Rs-5b
Rs-5b
Rs-5b
Rs-5b
Ss-5a
Ss-5a
Ss-5b
Ss-5b
Rs-5b
Ss-5b
Rs-5c
Rs-5d
Ss-5d
Ss-5d
Ss-5e
Ss-5e
Ss-5g
Ss-5h
Ss-5h
Ss-5a
Ss-5a
Ss-5b
Ss-5b
Ss-5b
Ss-5c
Ss-5e
Ss-5e
Ss-5g
Ss-5g
Ss-5h
Rs-5c
Rs-5c
EtMgBr
i-BuMgBr
i-BuMgBr
i-BuMgBr
i-BuMgBr
i-BuMgBr
i-BuLi
i-BuLi
i-BuLi
i-BuLi
i-BuLi
i-BuLi
i-BuLi
i-BuLi
i-BuLi
i-BuLi
i-BuLi
i-BuLi
i-BuLi
i-BuLi
i-BuLi
i-PrLi
-
CH2Cl2
CH2Cl2
THF
PhCH3
Et2O
PhCH3
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Rs,R-7b/Rs,S-7b/11b
Rs,S-8b/11b
1:10:1
1:10
6:5
94c
93c
95c
N/Ad
N/Ad
N/Ad
67c
70c
58c
60e
70c
70c
87c
90c
67c
90c
67c
59c
65c
61c
79c
57e
52e
67e
67e
50e
81c
59e
54e
82c
41c
71c
68c
46c
-
3
-
Rs,S-8b/11b
4
-
Rs,S-8b/11b
1:5
5
-
Rs,S-8b/11b
1:3
6
Me3Al
-
Rs,S-8b/11b
1:5
7
Ss,S-8a/Ss,R-8ag
Ss,S-8a/Ss,R-8ag
Ss,S-8b/Ss,R-8bf
Ss,S-8b/Ss,R-8b
Rs,R-8b/Rs,S-8b
Ss,S-8b/Ss,R-8b
Rs,R-8c/Rs,S-8cg
Rs,R-8d/Rs,S-8dg
Ss,S-8d/Ss,R-8d
Ss,S-8d/Ss,R-8dg
Ss,S-8e/Ss,R-8eg
Ss,S-8e/Ss,R-8eg
Ss,S-8g/Ss,R-8gg
Ss,S-8h/Ss,R-8hg
Ss,S-8h/Ss,R-8hg
Ss,S-9a/Ss,R-9ag
Ss,S-9a/Ss,R-9a
Ss,S-9b/Ss,R-9bf
Ss,S-9b/Ss,R-9b
Ss,S-9b/Ss,R-9b
Ss,S-9c/Ss,R-9cg
Ss,S-9e/Ss,R-9ef
Ss,S-9e/Ss,R-9e
Ss,S-9g/Ss,R-9gg
Ss,S-9g/Ss,R-9g
Ss,S-9h/Ss,R-9hf
Rs,R-10c/Rs,S-10cf
Rs,R-10c/Rs,S-10c
7:1
8
Me3Al
-
6:1
9
7:1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
Me3Al
Et3Al
Oct3Al
Me3Al
Me3Al
-
12:1
5:1
6:1
13:1
10:1
7:1
Me3Al
-
Me3Al
Me3Al
-
Me3Al
-
Me3Al
-
Me3Al
Oct3Al
-
10:1
7:1
18:1
13:1
7:1
12:1
20:1
11:1
12:1
12:1
6:1
i-PrLi
i-PrLi
i-PrLi
i-PrLi
i-PrLi
10:1
30:1
12:1
20:1
10:1
11:1
2:1
i-PrLi
-
Me3Al
-
i-PrLi
i-PrLi
i-PrLi
Me3Al
Me3Al
-
i-PrLi
MeLi
MeLi
Me3Al
1.5:1
a Ratios were determined by reverse phase HPLC/MS. b Yields refer to isolated amounts of the major diastereomer. c Purification
performed by silica gel chromatography. d Conversions for these reactions were usually lower than 20%. e Major diastereomer purified by
crystallization. f Configuration determined by X-ray crystallography. g Configurations were determined by correlation with similar
compounds.
J. Org. Chem, Vol. 70, No. 22, 2005 8927

Jiang et al.
FIGURE 2. ORTEP representations of the X-ray structures
of N-tert-butanesulfinamides Ss,S-8b, Ss,S-9b, Ss,S-9e, and
Ss,S-9h.
improve reactivity and diastereoselectivity of the addi-
tions to N-tert-butanesulfinyl imines.11
Dropwise addition of i-BuLi to a chilled (-72 °C)
solution of Ss-5b in THF, in the absence of any additives,
resulted in the formation of products Ss,S-8b and Ss,R-
8b in 7:1 ratio, respectively. Most importantly, no reduc-
tion product was observed. The major diastereomer Ss,S-
8b was isolated in 58% after silica gel chromatography
(entry 9, Table 3). When the reaction was conducted in
the presence of 2 equiv of Me3Al, the ratio of diastereo-
mers was increased to 12:1, favoring compound Ss,S-8b.
Alternatively to chromatography, the major product could
be isolated in pure form and in good yield (60%) after
recrystallization from hexanes/EtOAc (entry 10, Table 3).
The stereochemical assignment was conducted by X-ray
crystallography of Ss,S-8b (Figure 2). Interestingly, the
stereochemical outcome of the i-BuLi reaction is the
opposite of the i-BuMgBr one. We briefly investigated the
nature of the aluminum Lewis acid. When bulkier Et3Al
and n-Oct3Al were utilized in lieu of Me3Al, the i-BuLi
additions to either Rs-5b or Ss-5b gave approximately
the same diastereomeric ratio (5-6:1), both inferior to
that of Me3Al. The sense of stereochemical induction
followed the Me3Al case, i.e., Ss-5b gave rise to a new
stereocenter of S-configuration, whereas Rs-5b gave rise
to an R-center (entries 11 and 12, Table 3).
Other substrates, when subjected to the Me3Al-medi-
ated additions of i-BuLi, gave good to excellent diaste-
reoselectivities and good overall yields (entries 13, 14,
16, 18, 19 and 21, Table 3). We found that, in all cases,
the diastereoselectivity is dependent on the rate and
temperature at which the organolithium reagent is
introduced. Higher selectivities are obtained when the
internal reaction temperature remains below -70 °C.
Lower selectivities resulted when the reactions were run
in the absence of Me3Al (entries 15, 17, and 20, Table 3).
Marked differences in selectivities were observed when
i-PrLi was utilized instead. For instance, addition of
i-PrLi to sulfinyl imine Ss-5a, in THF at -72 °C, resulted
in an excellent 20:1 mixture of Ss,S-9a and Ss,R-9a,
respectively (entry 22, Table 3). When the same addition
was performed in the presence of 2 equiv of Me3Al, the
same sense of stereochemical induction was observed,
albeit in an inferior 11:1 ratio (entry 23, Table 3). Similar
results were obtained with the remaining substrates Ss-
5b, Ss-5c, Ss-5e, Ss-5g, and Ss-5h (entries 24-32, Table
3). In those cases, the reactions conducted in the absence
FIGURE 3. ORTEP representation of the X-ray structure of
N-tert-butanesulfinamide Rs,S-10c. The unit cell consists of
two molecules of Rs,S-10c hydrogen-bonded through a mol-
ecule of H2O.
of any additives gave excellent diastereoselectivities that
were at least equal to, if not better than, those of the
Me3Al-mediated additions. In all cases examined herein,
where the (S)-N-tert-butanesulfinyl group was utilized
as the chiral auxiliary, the newly created stereocenter
in the major product had S-configuration, as ascertained
by X-ray crystallography of compounds Ss,S-9b, Ss,S-9e,
and Ss,S-9h (Figure 2). The stereochemistry of the other
compounds obtained in this study were assigned by
correlation with similar compounds, based on TLC and
spectroscopic behavior. Similarly to the i-BuLi additions,
use of bulkier n-Oct3Al as the Lewis acid led to a decrease
in diastereoselectivity (entry 26, Table 3).
Finally, addition of MeLi to Rs-5c, in the presence of
Me3Al, gave a nonselective mixture of Rs,R-10c and Rs,S-
10c in a 1.5:1 ratio, respectively (entry 34, Table 3). The
same reaction, when preformed in the absence of Me3Al,
gave essentially the same ratio (entry 33, Table 3). The
stereochemical assignment of the reaction products was
based on the X-ray crystal structure of the minor isomer
(Figure 3). We attribute the lack of selectivity in this
particular reaction to the size of the alkyllithium reagent
used, since the bulkier i-PrLi and i-BuLi, under similar
conditions, gave much greater diastereomeric ratios.
d. Mechanistic Rationale. In view of our results
described above, it is clear that there are two operating
manifolds in the asymmetric addition of organometallics
to the chiral N-tert-butanesulfinyl imines. When Grig-
nard reagents are used, for instance, in the addition to
N-tert-butanesulfinyl imine Rs-5b, a chelation-controlled
model is valid, where Mg coordinates with the oxygen of
the sulfinyl imine, leading to a six-membered transition
state. This is in accordance to the model proposed by
Ellman and co-workers.10 In this case, both the bulky tert-
butyl group and the aryl moiety adopt equatorial posi-
tions, allowing the delivery of the R group from the same
face. The stereodirecting ability of this chelation-con-
trolled model dictates that, when the sulfur configuration
is R (Rs), the newly formed chiral center of the major
product should have the S configuration (Figure 4). Given
(11) Cogan, D. A.; Liu, G.; Ellman, J. A. Tetrahedron 1999, 55,
8883-8904.
8928 J. Org. Chem., Vol. 70, No. 22, 2005

Synthesis of R-Branched 2-Piperazinylbenzylamines
FIGURE 4. Model predictive of the “chelation-controlled”
addition of Grignard reagents to N-tert-butanesulfinyl imines.
FIGURE 6. Model for “uncatalyzed” alkyllithium additions
to N-tert-butanesulfinyl imines.
SCHEME 2a
FIGURE 5. Model predictive of the “Yamamoto-type” addition
of alkyllithium reagents to N-tert-butanesulfinyl imines.
the outcome of these reactions, having a large substitu-
ent, such as the N-Boc-piperazinyl group, ortho to the
imine carbon apparently did not disturb this proposed
transition state conformation.
In the case of addition of alkyllithiums to the N-tert-
butanesulfinyl imines, either mediated by Me3Al or
uncatalyzed, a reversal in stereochemical outcome was
observed. Thus, when Ss-5b was treated with i-BuLi/Me3-
Al in THF, great diastereofacial selection was observed
for the newly formed stereocenter, which had predomi-
nantly the S-configuration. Alternatively, when Rs-5b
was subjected to the same reaction conditions, the major
product had R-configuration. The same trend was ob-
served for all other examples.
The diastereofacial selectivity of the alkylithium ad-
ditions can be rationalized by using a model similar to
the one proposed by Plobeck and Powell,12 where a
nonchelated or “Yamamoto-type” transition state is in-
volved.13 In this model, the Lewis acid (LA) coordinates
with the sulfinyl oxygen, leaving the opposite face of the
complex open for nucleophilic attack. A second equivalent
of LA most likely enhances the reactivity of the imine
nitrogen, facilitating the addition (Figure 5).
In the absence of Me3Al, however, the reaction out-
comes are similar and appear more dependent on the size
of the organolithium used. Thus, when MeLi was utilized,
very little selectivity was observed (2:1). With larger
i-BuLi, which contains one substituent on the R-carbon,
higher de’s were obtained (typically 7:1). When i-PrLi,
containing a doubly-substituted R-position, was used,
excellent degrees of selectivities were seen (>10:1).
Examination of the X-ray strucutures of sulfinyl imines
Ss-5b, Ss-5e, and Ss-5g suggest that the N-Boc-piper-
azinyl group at the ortho-position of the aryl ring may
be shielding the re face of the CdN imine bond, and the
incoming nucleophile would preferentially add to the si
face (Figure 6). Bulkier organolithium reagents would be
expected to yield greater selectivities in this case.
e. Orthogonal Deprotection. One of the attractive
features of the use of N-tert-butanesulfinamide 4 as a
a Key: (a) HCl/dioxane (1.2 equiv), MeOH, rt, 1 h (95%); (b) TFA
(3 equiv), CH2Cl2, rt, 1 h (68%)
chiral auxiliary for the preparation of benzylamines is
the fact that, after formation of the new stereocenter, the
sulfinyl group functions as an amine protecting group,
which can be easily removed under mild acidic condi-
tions.10 Since it was practical to utilize a Boc protecting
group on the arylpiperazine starting materials, it became
paramount to find selective deprotection methods for both
of these acid-labile protecting groups. Thus, when com-
pound Ss,S-9h was treated with 1.2 equiv of HCl in
MeOH at ambient temperature, clean removal of the tert-
butanesulfinyl group was accomplished within 1 h.
Conversely, when Ss,S-9h was exposed to ∼25 equiv of
trifluoroacetic acid in CH2Cl2 at 0.1 M concentration, the
Boc group was selectively removed in 68% isolated yield
to give compound 13h. Approximately 5% of the double
deprotection product 15h was observed, along with 10%
of the sulfenyl imine 14h (Scheme 2). When larger
amounts of TFA were used, more byproducts were
observed. Either lowering the reaction temperature or
reducing the amount of TFA slowed the reaction but did
not avoid the formation of 14h and 15h. Similar results
were obtained for other substrates.
We reasoned that sulfenyl imine 14h is formed due to
the possible presence of trace amounts of trifluoroacetic
anhydride in commercial TFA. To confirm that assump-
tion, Ss,S-9h was exposed to trifluoroacetic anhydride in
CH2Cl2 at low temperature. After approximately 15 min,
the starting material was consumed, leading to the
exclusive formation of 14h. This compound is sufficiently
stable to allow for purification by silica gel chromatog-
raphy and characterization. In addition, exposure of 14h
to methanolic acid led to the smooth conversion to ketone
16h (Scheme 3). The acidic hydrolysis of sulfenyl imines
to the corresponding carbonyl compounds is well-docu-
mented,14 and the synthetic route described in Scheme
3 represents an attractive way to convert amines to
(12) Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303-
310.
(13) (a) Yamamoto, Y.; Komatsu, T.; Maruyama, K. J. Am. Chem.
Soc. 1984, 106, 5031-5033. (b) Yamamoto, Y.; Nishii, S.; Maruyama,
K.; Komatsu, T.; Ito, W. J. Am. Chem. Soc. 1986, 108, 7778-7786. (c)
Davis, F. A.; McCoull, W. J. Org. Chem. 1999, 64, 3396-3397.
J. Org. Chem, Vol. 70, No. 22, 2005 8929

Jiang et al.
SCHEME 3a
crystallography, and models predictive of the stereo-
chemical outcome of the additions have been applied. In
addition, the resulting products can be efficiently depro-
tected selectively to allow for further manipulations.
Experimental Section
a Key: (a) trifluoroacetic anhydride, CH2Cl2, 0 °C (95%); (b) 0.1
N HCl(aq)., EtOH, rt, 1 h (85%)
General Procedure for the Preparation of 2-Piperazi-
nylbenzaldehydes (3a-h, Table 1). A solution containing
the corresponding 2-fluorobenzaldehyde, N-Boc-piperazine,
and K2CO3 in either DMF, DMA, or 1,4-dioxane was heated
to the temperatures and times listed in Table 1. After
consumption of the starting material, the reaction mixture was
cooled to room temperature and filtered, and the solids were
rinsed EtOAc. The filtrate was concentrated in vacuo, and the
residue was diluted with EtOAc and washed with 0.1 N HCl,
saturated aqueous NaHCO3 solution, and brine. The organic
extracts were dried over anhydrous MgSO4 and filtered,
followed by concentration at reduced pressure. The residue was
triturated with hexanes to afford the desired products as
yellow solids, unless stated otherwise.
SCHEME 4a
General Procedure for the Condensation Reaction
between 2-Piperazinylbenzaldehydes 3a-h and N-tert-
Butanesulfinamides 4, using Ti(OEt)4 (Table 2). A solu-
tion containing the corresponding 2-piperazinylbenzaldehyde
3 and N-tert-butanesulfinamide 4 in THF was treated with
Ti(OEt)4 (tech. grade, Ti ∼20%, contains excess ethanol) at
ambient temperature. The resulting homogeneous mixture was
stirred, under N2, for the times indicated in Table 2. The
reaction mixture was cautiously poured onto a saturated NaCl
aqueous solution, with vigorous stirring. The resulting suspen-
sion was filtered through a pad of Celite and rinsed thoroughly
with EtOAc and CH2Cl2, until no more product could be
detected by TLC. The organic layer was separated, dried over
anhydrous MgSO4, and filtered. The solvents were removed
in a rotary evaporator at reduced pressure. The resulting solids
were either triturated or recrystallized from hexanes to give
the final product in analytically pure form, unless otherwise
stated.
General Procedure for the Condensation Reaction
between 2-Piperazinylbenzaldehydes 3a-h and N-tert-
Butanesulfinamides 4, using Cs2CO3 (Table 2). A solution
of the corresponding 2-piperazinylbenzaldehyde 3 and N-tert-
butanesulfinamide 4 in CH2Cl2 was treated with Cs2CO3. The
resulting suspension was heated to reflux and the reaction
progress was monitored by TLC and HPLC/MS. The reactions
were allowed to proceed for the times indicated in Table 2 and
then cooled to ambient temperature. The solids were removed
by filtration, and the filtrate was concentrated in vacuum. The
residue was purified by crystallization from EtOAc.
a Key: (a) mCPBA, CH2Cl2, rt, 1 h (95%); (b) TFA (3 equiv),
CH2Cl2, rt, 1 h (95%); (c) anisole, trifluoromethanesulfonic acid,
CH2Cl2, rt, 3 h (90%)
ketones and aldehydes. We are currently investigating
the generality of this approach.
To avoid the formation of byproducts and to maximize
the yields of the benzylamine deprotections, we decided
to oxidize the N-tert-butylsulfinamide group to the cor-
responding sulfonamide, with the knowledge that the
N-tert-butylsulfonamide (Bus) would tolerate TFA.15
Other groups have also utilized a similar strategy.16
Thus, compound Ss,S-9h was oxidized by mCPBA in CH2-
Cl2, at room temperature, in nearly quantitative yield.
The resulting sulfonamide 17h, when treated with TFA
in CH2Cl2, was smoothly converted to the secondary
amine 18h in 95% yield. Alternatively, the sulfonamide
group in 17h could be selectively removed by treatment
with trifluoromethane sulfonic acid in CH2Cl2, in the
presence of 2 equiv of anisole, to give benzylamine 12h
(Scheme 4).
General Procedure for the Organolithium Additions
to N-tert-Butanesulfinyl Imines 5 (Table 3). A round-
bottom flask equipped with a magnetic stirring bar, thermom-
eter, and an inert gas inlet was flame-dried under N2. Upon
cooling, the flask was charged with the corresponding N-tert-
butanesulfinyl imine 5 and THF. The resulting solution was
cooled to -72 °C (dry ice/acetone bath) and the desired
organolithium reagent was introduced via syringe in a drop-
wise fashion, to keep the internal temperature below -68 °C.
After the addition, the reaction was kept at low temperature
for another hour and then quenched with saturated NH4Cl
aqueous. Upon warming to room temperature, the mixture was
transferred to a separatory funnel and the reaction was
partitioned between EtOAc and H2O. The organic layer was
separated, washed with brine, and dried over anhydrous
MgSO4. Filtration and concentration under vacuum gave a
residue that was purified by silica gel chromatography or
crystallization.
Conclusion
We have demonstrated the practical conversion of
2-fluorobenzaldehydes to protected chiral (arylpiperazi-
nyl)benzylamines, which are key intermediates for the
preparation of MC4R ligands. The synthetic route pre-
sented herein utilizes chiral N-tert-butanesulfinamide as
both an activating agent for the addition or organome-
tallics reagents to the CdN bond and a powerful stereo-
directing group. The diastereoselectivities obtained are
good to excellent, and in many cases the major product
can be isolated in pure form by a simple recrystallization.
The stereochemical assignments were effected via X-ray
(14) Davis, F. A.; Slegeir, W. A. R.; Evans, S.; Schwartz, A.; Goff,
D. L.; Palmer, R. J. Org. Chem. 1973, 38, 2809-2813.
(15) Sun, P.; Weinreb, S. M.; Shang, M. J. Org. Chem. 1997, 62,
8604-8608.
(16) (a) Borg, G.; Chino, M.; Ellman, J. A. Tetrahedron Lett. 2001,
42, 1433-1436. (b) Kells, K. W.; Chong, J. M. J. Am. Chem. Soc. 2004,
126, 15666-15667.
General Procedure for the Me3Al-Mediated Organo-
lithium Additions to N-tert-Butanesulfinyl Imines 5
(Table 3). A three-necked round-bottom flask equipped with
a magnetic stirring bar, thermometer, a dropping funnel, and
8930 J. Org. Chem., Vol. 70, No. 22, 2005

Synthesis of R-Branched 2-Piperazinylbenzylamines
an inert gas inlet was flame-dried under N2. Upon cooling, the
flask was charged with the corresponding N-tert-butanesulfinyl
imine 5 and THF. The flask was cooled to -40 °C and then
Me3Al was introduced slowly. The reaction was stirred at that
temperature for 20 min, and then cooled to -72 °C (dry ice/
acetone bath). The desired organolithium reagent was added
in a dropwise fashion at such a rate to keep the internal
temperature below -68 °C. After the addition, the reaction
was kept at low temperature for another hour and then
quenched with a 5% aqueous HCl solution (60 mL) carefully
at -72 °C. The reaction mixture was brought up slowly to room
temperature to ensure the controlled release of methane gas.
The mixture was transferred to a separatory funnel and the
reaction was partitioned between EtOAc and H2O. The organic
layer was separated, washed with brine, and dried over
anhydrous MgSO4. Filtration and concentration under vacuum
gave a residue that was purified by silica gel chromatography
or crystallization.
Deprotection of Compound Ss,S-9h. Trifluoroacetic acid
(2 mL) was added dropwise to a solution of N-tert-butanesul-
finamide Ss,S-9h (451 mg, 1.00 mmol) in CH2Cl2 (10 mL). The
reaction was monitored by TLC and HPLC/MS. After the
disappearance of the starting material (1 h), the reaction
mixture was slowly poured onto a 1:1 mixture of saturated
NaHCO3 and saturated Na2CO3 solutions (v/v, 20 mL). The
products were extracted with CH2Cl2 (50 mL). The organic
layer was separated, dried over anhydrous MgSO4, and
filtered. Evaporation gave the crude residue as a yellow foam.
According to HPLC/MS, the crude product mixture consisted
of ∼85% of amine 13h, ∼10% of sulfenyl imine 14h, and ∼5%
of doubly deprotected amine 15h. This was purified by silica
gel chromatography, eluting with a 400:50:2 mixture of CHCl3/
MeOH/NH4OH v/v, respectively. Pure 13h was obtained as a
white solid (238 mg, 0.68 mmol, 68%).
4-[2-((S)-1-Amino-2-methylpropyl)-4-methylphenyl]pip-
erazine-1-carboxylic Acid tert-Butyl Ester (12h). To a
methanol (100 mL) solution of Ss,S-9h (10.45 g, 23.13 mmol)
at room temperature was added HCl (6.65 mL of a 4 N solution
in 1,4-dioxane, 26.60 mmol) dropwise, and the mixture was
stirred at room temperature until all starting material disap-
peared (∼80 min). The reaction was monitored by TLC and
HPLC/MS, and no byproducts were found. MeOH and excess
HCl were removed by rotary evaporator in vacuo to give the
hydrochloride salt of amine 12h as a white solid that was used
in the next reaction without further purification. For charac-
terization purposes, an analytically pure sample of this mate-
rial was obtained after silica gel chromatography (5-10%
MeOH/CH2Cl2, v/v) as a white foam.
separated and dried over Na2SO4. Solvents were removed by
rotary evaporation to give crude 14h, which was purified by
silica gel chromatography, eluting with a 20% mixture of
EtOAc in hexanes, v/v. The title compound 14h was obtained
as a white solid (112.0 mg, 89%).
4-(2-Isobutyryl-4-methylphenyl)piperazine-1-carboxy-
lic Acid tert-Butyl Ester (16h). To a methanol (5 mL)
solution of 14h (12.6 mg, 29.1 µmol) at room temperature was
added HCl (8.0 µL of a 4 N solution in 1,4-dioxane, 29.1 µmol)
dropwise and the mixture was stirred at ambient temperature
until all starting material disappeared (∼1 h). The reaction
was monitored by TLC and HPLC/MS. MeOH was removed
in a vacuum, to give ketone 16h as a white solid that was
purified by silica column chromatography (20% EtOAc/hex-
anes, v/v) to give a white foam (9.2 mg, 91%).
4-{4-Methyl-2-[(S)-2-methyl-1-(2-methylpropane-2-sul-
fonylamino)propyl]phenyl}piperazine-1-carboxylic Acid
tert-Butyl Ester (17h). To a CH2Cl2 (5 mL) solution of Ss,S-
9h (70.0 mg, 155 µmol) at room temperature was added
m-CPBA (∼55%, 63.4 mg, 202 µmol) and the mixture was
stirred at room temperature until all starting material disap-
peared (∼45 min). The reaction was monitored by TLC and
HPLC/MS. The mixture was diluted with EtOAc (30 mL) and
washed with an aqueous solution of Na2S2O3 (200 mg) and Na2-
CO3 (2.0 g). The organic solution was dried over Na2SO4.
Solvents were removed by evaporation in a vacuum to give
sulfonamide 17h as a white solid (72.0 mg, 100%).
2-Methylpropane-2-sulfonic Acid [(S)-2-Methyl-1-(5-
methyl-2-piperazin-1-ylphenyl)propyl]amide (18h). To a
CH2Cl2 (2.55 mL) solution of 17h (38.7 mg, 82.8 µmol) at room
temperature was added trifluoroacetic acid (0.45 mL, 6.0
mmol) and the mixture was stirred at room temperature until
all starting material disappeared (∼45 min). The reaction was
monitored by TLC and HPLC/MS. The mixture was basified
with a saturated solution of NaHCO3 (20 mL) extracted with
EtOAc (30 mL). The organic layer was dried over Na2SO4, and
the solvents were removed in vacuo to give amine 18h as white
foam, which was used in the next step without any further
purification. For characterization purposes, an analytical
sample of this material was obtained after silica gel chroma-
tography (5-10% MeOH/CH2Cl2, v/v) as a white foam.
Acknowledgment. We thank Drs. Lev Zegelman,
David Provencal, and Raymond S. Gross, for experi-
mental assistance, and Dr. John Huffman of the Indiana
University Molecular Structure Center, for assistance
with the X-ray structural determinations.
Sulfenyl Imine (14h). To a CH2Cl2 (5 mL) solution of Ss,S-
9h (130.6 mg, 289.1 µmol) at 0 °C, was added trifluoroacetic
anhydride (48.3 µL, 347 µmol). The color of the resulting
solution turned yellow almost immediately. The mixture was
stirred at 0 °C until all starting material disappeared (∼10
min). The reaction was monitored by TLC and HPLC/MS. The
mixture was diluted with 30 mL of EtOAc and washed with a
saturated solution of NaHCO3 (10 mL). The organic layer was
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 13C NMR spectra
for all compounds and X-ray crystallographic parameters (CIF
files) for compounds Ss-5b, Ss-5e, Ss-5g, Ss,S-8b, Ss,S-9b,
Ss,S-9e, Ss,S-9h, and Rs,S-10c. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO051514P
J. Org. Chem, Vol. 70, No. 22, 2005 8931