Click chemistry inspired synthesis of ferrocene amino acids and other derivatives

Article abstract of DOI:10.1016/j.tet.2009.12.011

This work reports the synthesis of a wide range of ferrocenyl-amino acids and other derivatives in excellent yield. Diverse amino acid containing azides were synthesized and ligated to ferrocene employing click reaction to access ferrocenyl amino acids. Chiral alcohols, esters, diols, amines containing azido group were tagged to ferrocene via click reaction to generate ferrocene derived chiral derivatives. A novel strategy for direct incorporation of ferrocene into a peptide and a new route to 1, 1′disubstituted ferrocene amino acid derivative are reported.

Full text of DOI:10.1016/j.tet.2009.12.011

Tetrahedron 66 (2010) 1327–1334
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Click chemistry inspired synthesis of ferrocene amino acids and other derivatives
*
V. Sai Sudhir, N.Y. Phani Kumar, S. Chandrasekaran
Department of Organic Chemistry, Indian Institute of Science, CV Raman Avenue, Bangalored560012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
This work reports the synthesis of a wide range of ferrocenyl-amino acids and other derivatives in ex-
cellent yield. Diverse amino acid containing azides were synthesized and ligated to ferrocene employing
click reaction to access ferrocenyl amino acids. Chiral alcohols, esters, diols, amines containing azido
group were tagged to ferrocene via click reaction to generate ferrocene derived chiral derivatives. A novel
strategy for direct incorporation of ferrocene into a peptide and a new route to 1, 10disubstituted fer-
rocene amino acid derivative are reported.
Received 28 September 2009
Received in revised form 28 November 2009
Accepted 2 December 2009
Available online 6 December 2009
Keywords:
Click chemistry
Ó 2009 Elsevier Ltd. All rights reserved.
Ferrocene amino acids
Ferrocene based chiral derivatives
Cycloaddition
1. Introduction
ferrocene derivatives in this manner since introducing chirality on
achiral ferrocene scaffold is non-trivial and involves the use of ex-
A large number of chiral ferrocenes with a wide range of sub-
stitution and functionality have been finding increasing applications
in asymmetric catalysis,1 material science,1e,f bioorganometallic and
biological chemistry.2 Many ferrocene containing amino acids have
been synthesized employing diverse strategies and some of them
have been incorporated into peptides.3,4 Chiral auxiliaries and
ligands derived form chiral ferrocenes have been shown to be useful
stereochemical controllers in a variety of reactions.1 Recently, novel
triazole containing ligands like clickphine, clickphos and clickferro-
phos, thioclickferrophos have been synthesized by implementation
of click reaction in the synthetic scheme of ligands.5 These ligands
have been shown to be powerful chiral inducers in various organic
transformations exploiting the metal coordination ability of triazoles
and have also been successfully utilized for various palladium cata-
lyzed transformations. Moyano et al. recently published an excellent
account highlighting the known strategies, dead ends and avenues
toward the synthesis of chiral ferrocene derivatives and amino acids.4
In this context, an easy access to diversely substituted ferrocene
amino acids and chiral ferrocenes poses a serious challenge. There is
no general method in the literature to synthesize ferrocene amino
acids and other chiral derivatives since every method is unique for
the specific functionality to be incorporated. Therefore, ligating an
optically pure molecule to ferrocene through a simple method would
definitely be advantageous. It will be easier to synthesize chiral
pensive chiral catalysts and a large number of steps.
2. Results and discussion
In our recent report, we employed click reaction between fer-
rocene derived azides and alkynes with amino acid derived alkynes
and azides, respectively, to access diverse ferrocene amino acids
and peptide conjugates.6 In continuation of our interest in this field,
herein we present a detailed report on the synthesis of ferrocene
amino acids and other chiral derivatives via click reaction
employing ethynyl ferrocene (1) and ferrocene derived azides (2
and 3). Strategically designed chiral azides or alkynes can be sub-
jected to click reaction with ferrocene labels like ethynyl ferrocene
1 and ferrocene derived azides (2 and 3) to access ferrocene amino
acids and other chiral derivatives easily (Scheme 1).
N3
N3
Fe
Fe
Fe
N3
1
2
3
Scheme 1. Ferrocene derivatives employed for labeling.
2.1. Synthesis of ferrocene containing amino acid derivatives
To synthesize ferrocene amino acids, we required amino acids
containing azido group, which could be subjected to click reaction
with ethynyl ferrocene. In order to achieve this, sulfamidates 4 and 5
* Corresponding author. Tel.: þ91 80 2293 2404; fax: þ91 80 2360 2423.
E-mail address: scn@orgchem.iisc.ernet.in (S. Chandrasekaran).
derived from L-serine and sulfamidates 6 and 7 from threonine were
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.12.011

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V. Sai Sudhir et al. / Tetrahedron 66 (2010) 1327–1334
synthesized.7a When they were opened with sodium azide in DMF
the corresponding enantiopure azides (4a–7a) were obtained
(Scheme 2).7b When azides (4a–7a) were treated with ethynyl fer-
rocene 1 in CH3CN with CuI as catalyst and DIPEA as base (rt, 7–8 h)
Treatment of compound 8 with imidozole-1-sulfonyl azide
hydrochloride8a as diazotransfer reagent resulted in the formation
of azide 8a in good yield. When azide 8a was subjected to click
reaction with 1, lysine derived
was obtained in 91% yield. Similarly, azide 9a was synthesized by
diazotransfer of
amino group of compound 9.8a Treatment of
azide 9a with 1 furnished lysine derived ferrocenyl amino acid
a-ferrocene amino acid derivative 8b
the corresponding protected ferrocene
a-amino acid derivatives
(4b–7b) were isolated in excellent yields (Scheme 3, Table 1).
a
R
derivative 9b in excellent yield. To synthesize b-ferrocenyl amino
O
N3
R
1) NaN3, DMF, 80ºC, 5 h
2) citric acid
O
O
acid derivative 10b, the sulfamidate 107c was synthesized from (2R,
3S)-ethyl 2,3-dihydroxy-3-phenylpropanoate employing Burgess
reagent and subjected to ring opening with sodium azide to furnish
S
O
O
N
R'HN
R'
O
O
R= H, R' = Bn (4)
R=H, R'= Cbz (5)
R=Me, R'= Boc (6)
R= Me, R'= Bn (7)
4a-7a
b-amino azide 10a in good yield. When 10a was subjected to click
reaction with ethynyl ferrocene 1, -ferrocenyl amino acid de-
b
rivative 10b was obtained in 85% yield as the only product (Table 1).
Scheme 2. Amino acid derived azides (4aꢀ7a) from serine derived sulfamidates (4 and
5) and threonine derived sulfamidates (6 and 7).
2.2. Synthesis of other chiral ferrocene derivatives
N
N
N
CO2Me
NHR
N3
( )n
To synthesize ferrocene tagged chiral amino derivatives (11b and
12b) two enantiopure azides (11a and 12a) were synthesized from
CuI, DIPEA
Fe
Fe
( )n
+
CH3CN, 7-10 h, rt
RHN
CO2Me
L
-phenylalanine.8b The secondary azide 11a was synthesized by ring
1
4a-10a
4b-10b
opening of sulfamidate derived from L-phenylalanine with sodium
azide. When azides 11a and 12a were subjected to click reaction with
1, ferrocene tagged chiral derivatives 11b and 12b were obtained in
Scheme 3. Synthesis of ferrocene amino acids (4b–10b) from amino acid derived
azides (4a–10a).
Table 1
Synthesis of diverse ferrocene amino acid derivatives (4bꢀ10b) from sulfamidates and lysine derived azides (4aꢀ10a)
Sulfamidate
Amino acid azide
Ferrocene amino acid
N
N3
O
O
N
N
CO2Me
NHBn
S
S
S
O
Fe
Fe
Fe
N
CO2Me
CO2Me
CO2Me
BnHN
CO2Me
Bn
4
4a, 4 h, 95%
4b, 7 h, 88%
N
N
N3
O
N
O
CO2Me
N
O
NHCbz
CbzHN
CO2Me
Cbz
5
5a, 4 h, 90%
5b, 7 h, 90%
N
N
N3
O
CO2Me
O
N
O
NHBoc
N
BocHN
CO2Me
Boc
6
6a, 5 h, 90%
6b, 8 h, 85%
N
N3
N
N
CO2Me
NHBn
O
O
S
Fe
O
BnHN
CO2Me
N
CO2Me
Bn
7
7a, 5 h, 88%
7b, 8 h, 92%
ClH3N
N3
N
N
N
Fe
CbzHN
CO2Me
CbzHN
CO2Me
CbzHN
CO2Me
8b, 8 h, 91%
8a, 10 h, 87%
8
CO2Me
CbzHN
CbzHN
N
N
N
Fe
CO2Me
N3
CO2Me
ClH3N
NHCbz
9
9a, 8 h, 86%
9b, 9 h, 94%
N
N
N
O
O
Ph
EtO2C
NHCO2Me
S
O
NCO2Me
Fe
NHCO2Me
N3
Ph
EtO2C
Ph
EtO2C
10a, 4 h, 92%
10
10b, 10 h, 85%

V. Sai Sudhir et al. / Tetrahedron 66 (2010) 1327–1334
1329
Table 3
very good yields (Table 2). The Boc protected diamine containing
azide 13a derived from lysine was treated with 1 to synthesize fer-
rocene tagged chiral diamino derivative 13b in good yield.
Ferrocene tagged alcohols (14bꢀ17b) and ester 18b from azido alcohols (14aꢀ17a)
and azido ester 18a
Precursor
Azido alcohol
or ester
Ferrocene tagged
alcohol or ester
Table 2
Synthesis of ferrocene tagged chiral amines (11bꢀ13b) from azido amines
N
N
(11aꢀ13a)
N3
OH
H2N
OH
N
Amino azide
Ferrocene tagged amine
Fe
OH
N
N
N
Ph
14a.
Ph
14
Ph
N3
NHCO2Me
11a
14b, 7 h, 80%
Fe
NHCO2Me
Ph
N3
N
N
HO
HO
N3
Ph
11b, 7 h, 85%
N
CO2Me
Fe
ClH3N
CO2Me
CO2Me
CO2Me
15a
N
N
Ph
HO
Ph
15
N
15b, 8 h, 91%
Fe
NHBoc
NHBoc
12a
N
N
HO
N3
HO
12b, 7 h, 87%
N
CO2Me
OH
Fe
CO2Me
16a
NHBoc
ClH3N
NHBoc
16
N
16b, 7 h, 88%
N
N
Fe
N3
BocHN
N
N
BocHN
13a
NH2
N3
13b, 9 h, 80%
N
Fe
OH
OH
Ph
Ph
OH
OH
2.3. Ferrocene tagged chiral alcohols and diols
OH
17
OH
17a
Ph
17b, 12 h, 82%
To synthesize diverse ferrocene containing chiral alcohols (14b–
17b), various precursors were employed to synthesize chiral azido
alcohols (14a–17a), which could be tagged to ferrocene by means of
clickreaction.Diazotransferreactionofaminetoazidewasusedasthe
N
N
N
Ph
Ph
N3
CO2Me
Ph
Fe
ClH3N
CO2Me
CO2Me
18a
key reaction in many cases.8a The amino group of
L-phenylalaninol 14
18
18b, 7 h, 90%
was converted to azide using imidazole-1-sulfonyl azide hydrochlo-
ride to furnish secondary azido alcohol 14a, which when subjected to
click reactionwith 1 furnished ferrocene tagged chiral compound 14b
containing primary alcohol group as the only product (80%). Diazo-
transfer reaction of threonine and serine methyl esters 15 and 16
furnished azides 15a and 16a, respectively. Compounds 15a and 16a
when reacted with 1 furnished ferrocene tagged chiral beta hydroxy
esters 15b and 16b, respectively, in good yield (Table 3). Similarly,
amino diol 17 was converted to 17b via the formation of azide 17a.
Ferrocene tagged chiral ester 18b was synthesized by subjecting
azide 18a to click reaction with 1. Many ferrocene derived chiral 1,2-
diols were used as precursors to synthesize the corresponding
amino alcohols.4,9 In general, these diols were accessed by other
workers using Sharpless asymmetric dihydroxylation of alkenyl
ferrocenes.4,9a,b,10 In the present methodology the azides 19a7e and
20a7d were subjected to click reaction with ethynyl ferrocene 1
followed by acetonide deprotection in AcOH/H2O to obtain the
corresponding ferrocene tagged 1,2-diols 19c and 20c, respectively,
in excellent yields (Table 4).
Table 4
Synthesis of ferrocene 1,2-diols (19c and 20c)
Azide
Protected Ferrocene diol
Ferrocene diol
N
N
N
N
N
N
O
O
O
Fe
Fe
OH
N3
O
OH
O
19b, 8 h, 92%
19a
19c, 1 h, 98%
N
N
N
N
N
N
O
OH
O
O
a
OH
Fe
Fe
N3
20aa
20c, 1 h, 99%
20b, 8 h, 94%
aCompound 20a was synthesized from commercially available isopropylidene
glycerol (99% ee)7d
.
Many applications of chiral auxiliaries and ligands derived from
ferrocenyl amino alcohols in asymmetric synthesis are well docu-
mented.4 To access ferrocenyl amino alcohols, ester functionality in
triazole containing ferrocene amino acid derivatives 5b and 7b
were reduced with Lithium aluminum hydride to furnish 21 and 22
in excellent yields (Scheme 4).
N
N
OH
OH
N
N
N
N
Fe
Fe
NHCbz
NHBn
21, 1 h, 92%
22, 1 h, 95%
Scheme 4. Ferrocenyl amino alcohols 21 and 22 from ferrocene amino acids.
2.4. Direct incorporation of ferrocene into a peptide
To incorporate ferrocene directly into a peptide, a peptide con-
taining azido group is required. For this we synthesized the di-
peptide 23a by ring opening of sulfamidate 237a with sodium azide
(DMF, 6 h, 90%). The azide 23a when reacted with ethynyl ferrocene
1 furnished 23b, a ferrocene tagged dipeptide in excellent yield
(Scheme 5).
To demonstrate the applicability of chiral ferrocene de-
rivatives, we synthesized two ferrocene dipeptides 24a and 25a
under standard peptide bond formation conditions (EDC$HCl,
NMM, HOBt) employing chiral ferrocene ester 18b and N-Boc
amine 12a.

1330
V. Sai Sudhir et al. / Tetrahedron 66 (2010) 1327–1334
O
In these cases 18b and 12a served as N-terminus and C-terminus
labels, respectively, (Scheme 6).
N3
O
O
S
i) NaN3, DMF, 6 h
H
N
O
H
N
O
N
OMe
ii) citric acid, 4 h, 90%
Boc
BocHN
OMe
O
O
23
2.5. Synthesis of 1,10disubstituted ferrocene derivatives
23a
1 equiv of 1
CuI, DIPEA
CH3CN
To access disubstituted, functionalized ferrocene derivatives, fer-
rocene derived azides 2 and 3 were subjected to click reaction with
propargyl alcohol 27. It led to the isolation of monosubstituted ferro-
cenyl alcohol 30 and disubstituted ferrocenyl alcohol 33, respectively.
Similar treatment of 2 and 3 with Boc protected propargyl amine
28 and methyl propiolate 26 furnished mono and disubstituted
ferrocene tagged Boc protected amines 31 and 34 and esters 29 and
32, respectively, in good yield (Table 5). We anticipated that click
reaction could be used to synthesize 1,10-disubstituted amino acid
derivative.12 For this, excess of ferrocene derived bis azide 3 was
treated with Boc protected propargyl amine 28 furnishing com-
pound 35, which when treated with methyl propiolate 26 gave
a novel 1,10- ferrocene amino acid derivative 36 in excellent yield.
Hitherto, similar 1,10- ferrocene amino acid derivatives were
accessed employing different procedures3b,3m (Scheme 7).
10 h, 95%
N
N
N
Fe
O
H
N
BocHN
OMe
O
23b
Scheme 5. Direct incorporation of ferrocene into a dipeptide.
N
Ph
N
N
Ph
O
i) LiOH.H2O, THF/H2O, 1 h
18b
+
+
Fe
Fe
N
H
CO2Me
ii) EDC.HCl, NMM, HOBt
CH3CN, 6 h, 85%
ClH3N
CO2Me
Ph
24a
24
N
Ph
N
N
O
i) TFA, DCM, 1 h
HO2C
NHCO2Et
NHCO2Et
12a
N
H
ii) EDC.HCl, NMM, HOBt
CH3CN, 6 h, 87%
Ph
Ph
25a
25
Scheme 6. Synthesis of ferrocene dipeptides 24a and 25a.
Table 5
Synthesis of mono and bis functionalized ferrocene derivatives
N
N
N
R
R
N
N
CuI, DIPEA
CuI, DIPEA
Fe
N
R
Fe
CH3CN, 6-8 h, rt
CH3CN, 6-9 h, rt
N
N
R
(26-28)
(32-34)
(29-31)
N
Alkyne
Mono functionalized derivative
Bis functionalized derivative
O
N
N
O
N
N
N
OMe
N
CO2Me
26
OMe
Fe
MeO
O
Fe
N
N
29, 6 h, 80%
32, 7 h, 78%
N
N
N
N
N
N
N
N
OH
OH
OH
Fe
HO
Fe
27
N
N
30, 8 h, 85%
33, 9 h, 80%
N
N
N
N
N
N
N
NHBoc
NHBoc
NHBoc
Fe
Fe
BocHN
28
N
N
31, 7 h, 86%
34, 8 h, 82%

V. Sai Sudhir et al. / Tetrahedron 66 (2010) 1327–1334
1331
N
N
N
N3
NHBoc
CuI, DIPEA
NHBoc
Fe
Fe
+
CH3CN
N3
N3
35, 2 h, 95%
(5 eq)
3
28
CuI, DIPEA
CH3CN
CO2Me
26
N
N
N
NHBoc
Fe
MeO
N
N
O
36, 5 h, 95%
N
Scheme 7. Synthesis of 1,10-disubstituted ferrocene amino acid derivative 36.
3. Conclusion
1 (0.21 g, 1 mmol) in acetonitrile (8 ml) DIPEA (0.323 g, 2.5 mmol)
followed by CuI (0.019 g, 0.1 mmol) were added. The reaction
mixture was stirred for 7 h at room temperature (28 ꢁC). Ethyl ac-
etate (30 ml) was added to the reaction mixture, washed with brine
(15 ml) and filtered through anhydrous sodium sulfate. After
evaporating ethyl acetate, the crude product was purified by flash
chromatography on silica gel to yield 4b in 88% yield (0.355 g).
Orange solid; Rf (40% EA:Hexanes, 0.3); mp: 128 ꢁC; 1H NMR
(300 MHz): 7.54 (s, 1H, HTriazole), 7.34–7.25 (m, 5H, Ph), 4.74–4.72
(m, 1H, HCp), 4.70–4.69 (m, 1H, HCp), 4.63 (dd, J1¼13.8 Hz, J2¼5.1 Hz,
1H, CH2Ph), 4.52 (dd, J1¼13.8 Hz, J2¼6.6 Hz, 1H, CH2Ph), 4.29 (t,
0
Diversely substituted ferrocene amino acid derivatives were
accessed from amino acid containing azides and ethynyl ferrocene.
Many functionalized chiral azides were synthesized and tagged to
ferrocene employing click reaction to generate ferrocene contain-
ing alcohols, amines, esters, hydroxyl esters, 1,2 and 1,3-diols and
amino alcohols. In one example, ferrocene was directly in-
corporated into a dipeptide. Two dipeptides were also synthesized
employing ferrocene amine and ester as ferrocene markers. 1,10
Disubsituted ferrocene alcohol, amine, ester and amino acid de-
rivatives were synthesized via click reaction between ferrocene
derived azides and corresponding propargylated derivatives. Syn-
thesis of peptidic constructs and further studies employing triazole
containing ferrocene amino acids are under progress.
J¼1.8 Hz, 3H, HCp
, aCH), 4.06 (s, 5H, HCp ), 3.88–3.67 (m, 5H, OMe,
CHCH2); 13C NMR (75 MHz): 172.3, 146.5, 138.9, 128.5, 128.2, 127.3,
119.9, 75.3, 69.5, 68.5, 66.6, 66.5, 60.3, 52.5, 52.0, 51.9; IR (Neat):
3246, 1737, 1453, 1210, 818 cmꢀ1
; HRMS m/z: Calcd for
23
C23H24FeN4O2 (MþNa): 467.1146, found: 467.1141; [
a
]
ꢀ7.0 (c 1,
D
4. Experimental section
4.1. General methods
CHCl3).
The following compounds were synthesized using the pro-
cedure described above.
All reactions were carried out in oven-dried apparatus using dry
solvents under anhydrous conditions, unless otherwise noted. Re-
action mixtures were stirred magnetically unless otherwise stated.
Commercial grade solvents were distilled and dried according to
literature procedures (‘Purification of laboratory chemicals’, third
ed., D. D. Perrin, W. L. F. Armarego, Pergamon Press, Oxford, 1988).
Analytical TLC was performed on commercial plates coated with
silica gel GF254 (0.25 mm). Silica gel (230–400 mesh) was used for
column chromatography using mixtures of ethyl acetate and hex-
anes as eluents. Yields refer to chromatographically and spectro-
scopically (1H NMR) homogeneous materials, unless otherwise
stated. NMR spectra were recorded on 300 or 400 MHz instruments
and calibrated using residual undeuterated solvent as an internal
reference. The following abbreviations explain the multiplicity
s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet,
br¼broad. IR spectra were recorded on a FTIR spectrometer. High-
resolution mass spectra (HRMS) were recorded on a Q-TOF mass
spectrometer. All the spectra were recorded in CDCl3 unless men-
tioned otherwise. Ethynyl ferrocene was purchased from Sigma
Aldrich and used as such. Azides 2 and 3 were synthesized
according to literature procedure.11
4.2.2. Compound 5b. Yellow solid; Rf (45% EA:Hexanes, 0.3); mp:
133 ꢁC; 1H NMR (300 MHz): 7.38–7.35 (m, 6H, HTriazole, Ph), 5.76 (d,
J¼6.3 Hz,1H, NH), 5.14 (s, 2H, CH2Ph), 4.89–4.76 (m, 3H, aCH, CH2Fc),
0
4.69–4.67 (m, 2H, HCp), 4.29 (t, J¼1.8 Hz, 2H, HCp), 4.05 (s, 5H, HCp ),
3.79 (s, 3H, OMe); 13C NMR (75 MHz): 169.2, 155.7, 146.9, 135.9,
128.6, 128.3, 128.1, 119.9, 74.8, 69.5, 68.7, 67.3, 66.6, 54.1, 53.2, 50.7;
IR (Neat): 3324, 1720, 1519, 1219, 1052, 820 cmꢀ1; HRMS m/z: Calcd
23
for C24H24FeN4O4 (MþNa): 511.1045, found: 511.1046; [
a
]
28.0 (c
D
1, CHCl3).
4.2.3. Compound 6b. Yellow solid; Rf (40% EA:Hexanes, 0.3); mp:
97 ꢁC; 1H NMR (300 MHz): 7.48 (s, 1H, HTriazole), 5.47 (br s, 1H, NH),
5.08 (t, J¼5.4 Hz, 1H, aCH), 4.7 (s, 3H, CHMe, HCp), 4.28 (s, 2H, HCp),
4.07 (s, 5H, HCp), 3.73 (s, 3H, OMe),1.72 (d, J¼6.6 Hz, 3H, CHMe),1.43
(s, 9H, Boc); 13C NMR (75 MHz): 169.5, 154.9, 146.5, 117.6, 80.6, 75.2,
69.5, 68.5, 66.6, 80.6, 75.2, 69.5, 68.5, 66.6, 57.9, 52.8, 28.2, 16.3,
14.1; IR (Neat): 3344, 2980, 1746, 1718, 1509, 1367, 1156, 819 cmꢀ1
HRMS m/z: Calcd for C22H28FeN4O4 (MþNa): 491.1358, found:
491.1356; [
23 36.0 (c 1, CHCl3).
;
a
]
D
4.2.4. Compound 7b. Orange solid; Rf (40% EA:Hexanes, 0.35); mp:
131 ꢁC; 1H NMR (300 MHz): 7.66 (s, 1H, HTriazole), 7.30–7.23 (m, 5H,
Ph), 5.07 (t, J¼5.1 Hz, 1H, aCH), 4.74 (s, 1H, HCp), 4.69 (s, 1H, HCp),
4.29 (s, 2H, HCp), 4.05 (s, 5H, HCp), 3.77–3.68 (m, 5H, OMe, CH2Ph),
3.49 (d, J¼12.9 Hz, 1H, CHMe), 2.15 (br s, 1H, NH), 1.57 (d, J¼6.9 Hz,
3H, CHMe); 13C NMR (75 MHz): 172.6, 146.1, 139.0, 128.4, 128.2,
127.3, 117.9, 75.6, 69.4, 68.5, 66.5, 64.7, 57.9, 52.9, 52.4, 15.7; IR
4.2. Procedure for the synthesis of monosubstituted
ferrocene derivatives (4b–20b, 23b, 29–31)
4.2.1. Representative procedure for the synthesis of 4b. To a well
stirred solution of azide 4a (0.234 g, 1 mmol) and ethynyl ferrocene

1332
V. Sai Sudhir et al. / Tetrahedron 66 (2010) 1327–1334
(Neat): 3437, 3119, 1736, 1446, 816 cmꢀ1; HRMS m/z: Calcd for
1518, 1170, 1023 cmꢀ1; HRMS m/z: Calcd for C28H41FeN5O4 (MþNa):
23
23
C24H26FeN4O2 (MþNa): 481.1303, found: 481.1308; [
a
]
D
20.5 (c 2,
590.2406, found: 590.2420; [
a
]
ꢀ20.0 (c 1, CHCl3).
D
CHCl3).
4.2.11. Compound 14b. Yellow solid; Rf (50% EA:Hexanes, 0.25);
mp: 138 ꢁC; 1H NMR (300 MHz): 7.26–7.15 (m, 3H, Ph), 7.06–7.02
(m, 3H, Ph, HTriazole), 4.66–4.53 (m, 3H, HCp, CHCH2), 4.29–4.17 (m,
4.2.5. Compound 8b. Yellow oil; Rf (50% EA:Hexanes, 0.3); 1H
NMR (300 MHz): 7.43 (s, 1H, HTriazole), 7.34 (s, 5H, Ph), 5.39 (d,
J¼7.8 Hz, 1H, NH), 5.09 (s, 2H, CH2Ph), 4.71 (s, 2H, HCp), 4.41–4.28
0
4H, CH2OH, HCp), 4.13–4.06 (m, 1H, OH), 3.91 (s, 5H, HCp ),
0
(m, 5H, CHCH2, HCp), 4.06 (s, 5H, HCp ), 3.72 (s, 3H, OMe), 2.04–
3.33ꢀ3.18 (m, 2H, CH2Ph); 13C NMR (75 MHz): 145.6, 136.7, 128.9,
1.65 (m, 4H, 2CH2), 1.45–1.28 (m, 2H, CH2); 13C NMR (75 MHz):
172.5, 155.8, 146.7, 136.2, 128.5, 128.1, 128.0, 118.6, 75.5, 69.5,
68.5, 67.0, 66.6, 53.4, 52.4, 49.7, 31.9, 29.5, 22.1; IR (Neat): 3337,
128.7, 126.9, 119.9, 74.8, 69.5, 68.6, 66.6, 65.7, 64.2, 37.8; IR (Neat):
3378, 1590, 1220, 1047, 817, 753 cmꢀ1; HRMS m/z: Calcd for
23
C21H21FeN3O (MþNa): 410.0932, found: 410.0935; [
a
]
ꢀ129.5 (c
D
2951, 1720, 1529, 1213, 820 cmꢀ1
;
HRMS m/z: Calcd for
2, CHCl3).
23
C27H30FeN4O4 (MþNa):553.1514, found: 553.1512; [
a
]
ꢀ1.5 (c 2,
D
CHCl3).
4.2.12. Compound 15b. Yellow solid; Rf (50% EA:Hexanes, 0.25);
mp: 160 ꢁC; 1H NMR (300 MHz): 7.88 (s, 1H, HTriazole), 5.37 (d,
J¼3.3 Hz, 1H, CHN), 4.78–4.75 (m, 3H, CHOH, HCp), 4.31 (t, J¼1.8 Hz,
4.2.6. Compound 9b. Yellow oil; Rf (50% EA:Hexanes, 0.25); 1H
NMR (300 MHz): 7.68 (s, 1H, HTriazole), 7.33 (s, 5H, Ph), 5.34 (dd,
J1¼9.6 Hz, J2¼5.7 Hz, 1H, aCH), 5.09–5.01 (m, 2H, CH2Ph), 4.91 (br s,
1H, NH), 4.78 (s, 1H, HCp), 4.71 (s, 1H, HCp), 4.29 (t, J¼1.8 Hz, 2H,
0
2H, HCp), 4.07 (s, 5H, HCp ), 3.83 (s, 3H, OMe), 2.97 (d, J¼5.1 Hz, 1H,
OH), 1.13 (d, J¼6.6 Hz, 3H, Me); 13C NMR (75 MHz): 168.0, 146.7,
120.4, 75.1, 69.6, 68.7, 67.8, 66.7, 53.1, 19.5; IR (Neat): 3370, 1752,
0
HCp), 4.06 (s, 5H, HCp ), 3.77 (s, 3H, OMe), 3.18–3.11 (m, 2H, CHCH2),
1443, 1209, 819 cmꢀ1; HRMS m/z: Calcd for C17H19FeN3O3 (MþNa):
23
2.31–2.12 (m, 2H, CH2), 1.57–1.42 (m, 2H, CH2), 1.35–1.23 (m, 2H,
CH2); 13C NMR (75 MHz): 169.3, 156.4, 147.1, 136.5, 128.4, 127.9 (2C),
118.0, 75.1, 69.5, 68.6, 66.7, 62.4, 52.9, 40.4, 32.2, 29.1, 22.7; IR
392.0674, found: 392.0658; [
a
]
ꢀ11.0 (c 1, CHCl3).
D
4.2.13. Compound 16b. Yellow oil; Rf (50% EA:Hexanes, 0.25); 1H
NMR (300 MHz): 7.83 (s, 1H, HTriazole), 5.44 (dd, J1¼5.1 Hz,
J2¼3.6 Hz, 1H, aCH), 4.71 (s, 1H, HCp), 4.65 (s, 1H, HCp), 4.56–4.52 (m,
1H, CH2OH), 4.48–4.40 (m,1H, CH2OH), 4.29 (s, 2H, HCp), 4.06 (s, 5H,
(Neat): 3333, 2952, 1748, 1714, 1529, 1455, 1251, 1001, 820 cmꢀ1
;
HRMS m/z: Calcd for C27H30FeN4O4 (MþNa): 553.1514, found:
23
553.1512; [
a]
ꢀ29.5 (c 2, CHCl3).
D
HCp ), 3.79 (s, 3H, OMe); 13C NMR (75 MHz): 167.6,146.6,120.4, 74.8,
0
4.2.7. Compound 10b. Yellow oil; Rf (45% EA:Hexanes, 0.25); 1H
NMR (300 MHz): 7.57 (s,1H, HTriazole), 7.36–7.24 (m, 5H, Ph), 6.26 (d,
J¼9.6 Hz,1H, NH), 5.73 (t, J¼7.5 Hz,1H, CHNH), 5.51 (d, J¼7.2 Hz,1H,
CHN), 4.73 (s, 1H, HCp), 4.69 (s, 1H, HCp), 4.29 (s, 2H, HCp), 4.23–4.09
69.6, 68.7, 66.7, 64.4, 62.3, 53.1; IR (Neat): 3424, 1752, 1220, 1051,
820 cmꢀ1
356.0688; [
;
Calcd for C16H18FeN3O3 (MþH): 356.0697, found:
23
a]
ꢀ16.0 (c 2, CHCl3).
D
0
(m, 2H, CH2CH3), 4.02 (s, 5H, HCp ), 3.61 (s, 3H, CO2Me), 1.13 (t,
4.2.14. Compound 17b. Yellow solid; Rf (70% EA:Hexanes, 0.25);
mp: 156 ꢁC; 1H NMR (300 MHz, DMSO): 8.12 (s,1H, HTriazole), 7.27 (s,
5H, Ph), 5.88 (d, J¼4.2 Hz, 1H, CHOH), 5.13 (t, J¼4.8 Hz, 1H, CH2OH),
5.03 (t, J¼5.1 Hz, 1H, CH2OH), 4.75 (br s, 2H, HCp), 4.29 (s, 2H, HCp),
J¼6.9 Hz, 3H, CH2CH3); 13C NMR (75 MHz): 166.4,156.2, 146.8, 137.1,
128.9, 128.6, 126.7, 119.7, 74.6, 69.7, 68.8, 66.9, 66.7, 66.6, 62.6, 56.9,
52.5, 13.8; IR (Neat): 2110, 1749, 1518, 1259, 1021, 820 cmꢀ1; Calcd
for C25H26FeN4O4 (MþNa): 525.1201, found: 525.1204; [
23 12.0 (c
4.03 (s, 5H, HCp ), 3.81 (t, J¼5.7 Hz, 2H, CHN); 13C NMR (75 MHz):
0
a
]
D
0.25, CHCl3).
144.3, 142.1, 127.9, 127.3, 126.0, 120.1, 76.3, 71.1, 69.2, 68.5, 68.1, 66.1,
61.1; IR (Neat): 3431, 2925, 1657, 816 cmꢀ1; HRMS m/z: Calcd for
23
4.2.8. Compound 11b. Yellow solid; Rf (50% EA:Hexanes, 0.2); mp:
152 ꢁC; 1H NMR (300 MHz): 7.27–7.21 (m, 3H, Ph, HTriazole), 7.02–
7.01 (m, 3H, Ph), 5.17 (br s, 1H, NH), 4.78–4.72 (m, 2H, HCp), 4.50
C21H21FeN3O2 (MþNa): 426.0881, found: 426.0884; [
a
]
104.0 (c
D
0.5, MeOH).
0
(s, 1H, CHCH2), 4.26–4.23 (m, 2H, HCp), 3.97 (s, 5H, HCp ), 3.88–
4.2.15. Compound 18b. Yellow solid; Rf (40% EA:Hexanes, 0.3); mp:
116 ꢁC; 1H NMR (300 MHz): 7.5 (s, 1H, HTriazole), 7.26–7.22 (m, 3H,
Ph), 7.09–7.05 (m, 2H, Ph), 5.58 (dd, J1¼8.7 Hz, J2¼6.3 Hz, 1H, aCH);
4.69 (t, J¼1.8 Hz, 2H, HCp), 4.28 (t, J¼1.8 Hz, 2H, HCp), 4.01 (s, 5H,
3.79 (m, 2H, CH2Ph), 3.64 (s, 3H, OMe), 3.22 (d, J¼7.5 Hz, 2H,
NHCH2); 13C NMR (75 MHz): 156.9, 146.0, 136.4, 128.9, 128.8,
127.1, 119.9, 75.1, 69.5, 68.6, 66.6, 66.4, 63.0, 52.3, 44.8, 39.4; IR
(Neat): 3326, 1715, 1537, 1255, 754 cmꢀ1; HRMS m/z: Calcd for
HCp ), 3.77 (s, 3H, OMe), 3.59–3.45 (m, 2H, CH2Ph); 13C NMR
0
23
C23H24FeN4O2 (MþNa): 467.1146, found: 467.1148; [
a
]
24.0 (c
(75 MHz): 168.7, 146.7, 134.8, 128.9, 128.8, 128.7, 127.5, 118.7, 75.0,
69.5, 68.6, 66.6, 63.8, 52.9, 38.7; IR (Neat): 3092, 1748, 1455, 1213,
D
0.5, CHCl3).
819, 700 cmꢀ1; HRMS m/z: Calcd for C22H21FeN3O2 (MþNa):
23
4.2.9. Compound 12b. Yellow solid; Rf (50% EA:Hexanes, 0.3); mp:
166 ꢁC; 1H NMR (300 MHz): 7.45 (s, 1H, HTriazole), 7.37–7.22 (m, 5H,
Ph), 4.92 (d, J¼6.9 Hz, 1H, NH), 4.71 (s, 2H, HCp), 4.52–4.2 (m, 5H,
438.0881, found: 438.0887; [
a
]
ꢀ32.0 (c 0.5, CHCl3).
D
4.2.16. Compound 19b. Yellow gummy solid; Rf (50% EA:Hexanes,
0.4); 1H NMR (300 MHz): 7.51 (s, 1H, HTriazole), 4.72–4.70 (m, 2H,
HCp), 4.59–4.42 (m, 2H, CH2O), 4.29 (t, J¼1.8 Hz, 2H, HCp), 4.07–4.03
0
CH2N, CHNHBoc, HCp), 4.07 (s, 5H, HCp ), 2.95–2.69 (m, 2H, CH2Ph),
1.4 (s, 9H, Boc); 13C NMR (75 MHz): 155.2, 146.6, 136.7, 129.3, 128.7,
0
126.9, 119.9, 79.9, 75.2, 69.5, 68.6, 66.6, 52.1, 51.7, 38.0, 28.3; IR
(m, 7H, CH2N, HCp ), 3.59–3.53 (m, 1H, CHO), 2.30–2.19 (m, 1H,
(Neat): 3402, 3121, 2977, 1697, 1515, 1364, 1169, 819, 700 cmꢀ1
;
CHCH2), 2.15–2.04 (m, 1H, CHCH2), 1.45 (s, 3H, Me), 1.36 (s, 3H, Me);
13C NMR (75 MHz): 119.3, 109.3, 75.5, 72.7, 69.5, 68.9, 68.6, 66.6
(2C), 47.0, 34.3, 26.9, 25.5; IR (Neat): 3119, 2986, 1587, 1370, 1217,
HRMS m/z: Calcd for C26H30FeN4O2 (MþNa): 509.1616, found:
509.1602; [
a]
23 1.5 (c 2.0, CHCl3).
D
1051, 818 cmꢀ1; HRMS m/z: Calcd for C19H23FeN3O2 (MþNa):
23
4.2.10. Compound 13b. Yellow solid; Rf (60% EA:Hexanes, 0.3); mp:
156 ꢁC; 1H NMR (300 MHz): 7.52 (s, 1H, HTriazole), 5.04 (d, J¼7.2 Hz,
1H, NH), 4.71 (d, J¼9.6 Hz, 2H, HCp), 4.48 (br s, 2H, CH2N), 4.29 (s,
404.1037, found: 404.1039; [
a
]
ꢀ8.0 (c 0.5, CHCl3).
D
4.2.17. Compound 19c. Yellow oil: Rf (80% EA:Hexanes, 0.25); 1H
NMR (300 MHz): 7.55 (s, 1H, HTriazole), 4.68 (br s, 2H, HCp), 4.51 (br s,
0
2H, HCp), 4.06 (s, 5H, HCp ), 3.93 (br s, 1H, CHCH2), 3.09 (br s, 2H,
CH2NHBoc), 1.46–1.43 (br s, 24H, 2Boc, 3CH2); 13C NMR (75 MHz):
156.1, 155.5, 146.5, 119.7, 79.7, 78.9, 75.2, 69.4, 68.5, 66.5, 66.4, 53.0,
50.8, 39.7, 31.3, 29.6, 28.3 (2C), 22.6; IR (Neat): 3391, 2976, 1694,
2H, CH2OH), 4.28 (s, 2H, HCp), 4.05 (s, 5H, HCp ), 3.65–3.62 (m, 2H,
0
CH2N), 3.53–3.49 (m, 1H, CHOH), 2.05 (br s, 2H, CH2CH); 13C NMR
(75 MHz): 146.7, 119.7, 74.9, 69.5, 68.9, 68.7, 66.6, 66.4, 47.0, 33.3; IR

V. Sai Sudhir et al. / Tetrahedron 66 (2010) 1327–1334
1333
(Neat): 3369, 2927, 1597, 1436, 1218, 1105, 818 cmꢀ1; HRMS m/z:
CuI (0.019 g, 0.1 mmol). The reaction mixture was stirred for 7 h
at room temperature (28 ꢁC). Ethyl acetate (40 ml) was added
into the reaction mixture and was washed with brine (15 ml) and
filtered through anhydrous sodium sulfate. After evaporating
ethyl acetate, the crude product was purified by flash chroma-
tography on silica gel to yield 32 (0.180 g, 78%). Yellow gummy
solid; Rf (55% EA:Hexanes, 0.25); 1H NMR (300 MHz): 7.98 (s, 1H,
HTriazole), 5.39 (s, 2H, CH2Cp), 4.35 (s, 2H, HCp), 4.20 (s, 2H, HCp),
3.95 (s, 3H, OMe); 13C NMR (75 MHz): 161.0, 139.8, 126.6, 81.6,
23
Calcd for C16H19FeN3O2 (MþNa):364.0724, found: 364.0726; [
a]
D
ꢀ53.0 (c 1, MeOH).
4.2.18. Compound 20b. Orange solid; Rf (50% EA:Hexanes, 0.4); mp:
157 ꢁC; 1H NMR (300 MHz): 7.59 (s, 1H, HTriazole), 4.76 (s, 1H, CH2O),
4.69 (s, 1H, CH2O), 4.59–4.42 (m, 3H, CHO, HCp), 4.29 (s, 2H, HCp),
0
4.15–4.08 (m, 6H, CH2N, HCp ), 3.76 (dd, J1¼9 Hz, J2¼5.7 Hz, 1H,
CH2N), 1.41 (s, 3H, Me), 1.36 (s, 3H, Me); 13C NMR (75 MHz): 120.2,
110.1, 75.6, 74.1, 69.5, 68.6, 66.7, 66.5, 66.4, 51.9, 26.7, 25.2; IR (Neat):
69.6, 68.9, 52.0, 50.6; IR (Neat): 3115, 1717, 1546, 1220, 808 cmꢀ1
;
3125, 2980, 1372, 1219, 1036, 829 cmꢀ1; HRMS m/z: Calcd for
HRMS m/z: Calcd for C20H20FeN6O4 (MþNa): 487.0793, found:
23
C18H21FeN3O2 (MþNa): 390.0881, found: 390.0885; [
a
]
28.0 (c
D
487.0799.
0.5, CHCl3).
The following compounds were synthesized using the pro-
cedure described above.
4.2.19. Compound 20c. Yellow oil; Rf (75% EA:Hexanes, 0.25); 1H
NMR (300 MHz): 7.56 (s,1H, HTriazole), 4.70–4.47 (m, 3H, CH2N, HCp),
4.3.2. Compound 33. Orange solid; Rf (80% EA:Hexanes, 0.3); mp:
187 ꢁC; 1H NMR (300 MHz, DMSO): 7.92 (s, 1H, HTriazole), 5.29 (s, 2H,
CH2Cp), 5.15 (t, J¼5.7 Hz, 1H, OH), 4.48 (d, J¼5.7 Hz, 2H, CH2OH),
4.35 (s, 2H, HCp), 4.19 (s, 2H, HCp); 13C NMR (75 MHz): 148.0, 122.2,
83.2, 69.6, 69.3, 55.0, 48.5; IR (Neat): 3207, 1221, 1117, 1014, 792,
718 cmꢀ1; HRMS m/z: Calcd for C18H20FeN6O2 (MþNa): 431.0895,
found: 431.0881.
0
4.39–4.30 (m, 3H, CH2N, HCp), 4.19–4.00 (m, 6H, CHOH, HCp ), 3.73–
3.61 (m, 2H, CH2OH); 13C NMR (75 MHz): 146.6, 120.7, 75.2, 70.5,
69.7, 68.9, 66.8, 63.7, 52.8; IR (Neat): 3358, 2924, 2854, 1589, 1105,
1045, 810 cmꢀ1; HRMS m/z: Calcd for C15H17FeN3O2 (MþNa):
23
350.0568, found: 350.0569; [
a
]
ꢀ14.0 (c 0.5, MeOH).
D
4.2.20. Compound 23b. Orange solid; Rf (60% EA:Hexanes, 0.25);
mp: 174 ꢁC; 1H NMR (300 MHz): 7.56 (s, 1H, HTriazole), 6.78 (d,
J¼7.2 Hz, 1H, NH), 5.68 (d, J¼8.1 Hz, 1H, NH), 5.07–5.04 (m, 1H,
CHNHBoc), 4.7–4.67 (m, 2H, HCp), 4.51–4.44 (m, 1H, CHCH2), 4.28 (s,
4.3.3. Compound 34. Yellow gummy solid; Rf (70% EA:Hexanes,
0.25); 1H NMR (300 MHz): 7.51 (s, 1H, HTriazole), 5.27 (s, 2H, CH2Cp),
4.40 (d, J¼6.5 Hz, 2H, HCp), 4.32 (s, 2H, HCp), 4.23 (s, 2H, CH2NH),
1.40 (s, 9H, Boc); 13C NMR (75 MHz): 155.8, 145.3, 121.0, 80.7, 81.0,
69.0, 69.1, 49.9, 36.0, 28.3; IR (Neat): 3338, 2974, 1710, 1515, 1165,
1043, 822 cmꢀ1; HRMS m/z: Calcd for C28H38FeN8O4 (MþNa):
629.2263, found: 629.2266.
0
2H, HCp), 4.08 (s, 5H, HCp ), 3.67 (s, 3H, OMe), 1.86 (s, 2H, CHMe,
CHMeleu), 1.76 (d, J¼6.9 Hz, 3H, CHMe), 1.63–1.43 (m, 11H, Boc,
CH2CHLeu), 0.87–0.84 (m, 6H, 2Meleu); 13C NMR (75 MHz): 172.4,
168.6, 155.3, 146.5, 118.6, 80.9, 75.4, 69.6, 68.6, 66.7, 66.6, 58.1, 52.3,
50.9, 41.1, 28.2, 24.7, 22.7, 21.8, 16.4; IR (Neat): 3305, 3109, 2957,
1744, 1689, 1656, 1522, 1297, 1169, 1002, 736 cmꢀ1; HRMS m/z:
4.4. Characterization of chiral azides
23
Calcd for C28H39FeN5O5 (MþNa): 604.2198, found: 604.2196; [
a]
D
19.0 (c 1, CHCl3).
4.4.1. Compound 7a. Colorless oil; Rf (30% EA:Hexanes, 0.3); 1H
NMR (300 MHz): 7.35–7.22 (m, 5H, Ph), 3.87–3.57 (m, 6H, CH2Ph,
CHCH3, CO2Me), 3.30 (d, J¼5.4 Hz, 1H, CHNH), 2.02 (s, 1H, NH), 1.31
(d, J¼7.2 Hz, 3H, CHCH3); 13C NMR (75 MHz): 173.0, 139.2, 128.3,
128.1, 127.1, 64.6, 58.4, 52.3, 51.9, 15.1; IR (Neat): 3333, 3030, 2953,
2109, 1732, 1454, 1260, 1199, 989, 699 cmꢀ1; Calcd for C12H16N4O2
4.2.21. Compound 29. Orange solid; Rf (40% EA:Hexanes, 0.3); mp:
166 ꢁC; 1H NMR (300 MHz): 7.97 (s, 1H, HTriazole), 5.35 (s, 2H,
0
CH2Cp), 4.29 (s, 2H, HCp), 4.25 (s, 2H, HCp), 4.19 (s, 5H, HCp ), 3.92 (s,
3H, OMe); 13C NMR (75 MHz): 161.1, 139.7, 126.7, 79.7, 69.3, 68.9,
68.8, 52.1, 50.4; IR (Neat): 3113, 1715, 1547, 1224, 811 cmꢀ1; HRMS
m/z: Calcd for C15H15FeN3O2 (MþNa): 348.0411, found: 348.0404.
(MþNa): 271.1171, found: 271.1165; [
a]
23 7.5 (c 2, CHCl3).
D
4.4.2. Compound 8a. Colorless oil; Rf (40% EA:Hexanes, 0.3); 1H
NMR (300 MHz): 7.35 (s, 5H, Ph), 5.42 (d, J¼8.1 Hz, 1H, NH), 5.11 (s,
2H, CH2Ph), 4.39 (dd, J1¼12.9 Hz, J2¼7.8 Hz, 1H, aCH), 3.74 (s, 3H,
OMe), 3.25 (t, J¼6.6 Hz, 2H, CHCH2), 1.92–1.81 (m, 1H, CH2), 1.74–
1.54 (m, 3H, CH2), 1.49–1.37 (m, 2H, CH2); 13C NMR (75 MHz): 172.7,
155.8, 136.2, 128.4, 128.1, 128.0, 66.9, 53.6, 52.3, 50.9, 32.1, 28.3,
4.2.22. Compound 30. Yellow solid; Rf (60% EA:Hexanes, 0.3); mp:
141 ꢁC; 1H NMR (300 MHz): 7.44 (s, 1H, HTriazole), 5.29 (s, 2H,
CH2Cp), 4.74 (s, 2H, CH2OH), 4.28 (s, 2H, HCp), 4.23 (s, 2H, HCp), 4.19
(s, 5H, HCp ), 2.11 (br s, 1H, OH); 13C NMR (100 MHz): 146.0, 120.3,
0
80.5, 68.8, 68.7, 55.3, 49.9; IR (Neat): 3246, 1783, 1332, 1215, 1054,
814 cmꢀ1; HRMS m/z: Calcd for C14H15FeN3O (MþNa): 320.0462,
found: 320.0465.
22.4; IR (Neat): 3342, 2952, 2097, 1728, 1538, 1254, 1058, 740 cmꢀ1
HRMS m/z: Calcd for C15H20N4O4 (MþNa): 343.1382, found:
343.1388; [
23 14.0 (c 2, CHCl3).
;
a]
D
4.2.23. Compound 31. Yellow solid; Rf (50% EA:Hexanes, 0.3); mp:
112 ꢁC; 1H NMR (300 MHz): 7.43 (s, 1H, HTriazole), 5.25 (s, 2H,
CH2Cp), 4.33 (d, J¼6.3 Hz, 2H, CH2NH), 4.26 (t, J¼1.8 Hz, 2H, HCp),
4.4.3. Compound 10a. White solid; Rf (30% EA:Hexanes, 0.35); mp:
57 ꢁC; 1H NMR (300 MHz): 7.41–7.26 (m, 5H, Ph), 5.55 (d, J¼7.5 Hz,
1H, CHNH), 5.35 (d, J¼8.1 Hz, 1H, CHN3), 4.38–4.22 (m, 3H, NH,
CH2CH3), 3.66 (s, 3H, CO2Me), 1.29 (t, J¼6.9 Hz, 3H, CH2CH3); 13C
NMR (75 MHz): 168.0, 156.0, 138.1, 128.8, 128.2, 126.6, 66.6, 62.4,
55.6, 52.5, 14.0; IR (Neat): 3371, 2984, 2114, 1736, 1528, 1261,
4.19 (t, J¼1.8 Hz, 2H, HCp), 4.17 (s, 5H, HCp ), 1.41 (s, 9H, Boc); 13C
0
NMR (75 MHz): 155.7, 145.2, 121.1, 80.8, 79.4, 68.8, 68.7, 68.6, 49.8,
35.9, 28.2; IR (Neat): 3340, 2976, 1707, 1511, 1169, 1048, 820 cmꢀ1
;
HRMS m/z: Calcd for C19H24FeN4O2 (MþNa): 419.1146, found:
419.1156.
700 cmꢀ1; HRMS m/z: Calcd for C13H16N4O4 (MþNa): 315.1069,
23
found: 315.1066; [
a
]
ꢀ35.0 (c 1, CHCl3).
D
4.3. General procedure for the synthesis of disubstituted
ferrocene derivatives (32–34)
4.4.4. Compound 23a. Colorless oil; Rf (35% EA:Hexanes, 0.3); 1H
NMR (300 MHz): 6.47 (d, J¼8.1 Hz, 1H, NH), 5.26 (br s, 1H, aCH),
4.66–4.59 (m, 1H, aCH), 4.17–4.12 (m, 1H, CHN3), 3.74 (s, 3H, OMe),
1.69–1.54 (m, 3H, CHCH2, CHMe), 1.46 (s, 9H, Boc), 1.36 (d, J¼6.6 Hz,
3H, N3CHMe), 0.95 (s, 3H, MeLeu), 0.93 (s, 3H, MeLeu); 13C NMR
(75 MHz): 172.8, 169.1, 155.4, 80.7, 58.4, 57.9, 52.3, 50.9, 41.5, 28.2,
4.3.1. Representative Procedure for the synthesis of 32. To a well
stirred solution of 1,10-ferrocenyl methyl azide
3 (0.148 g,
0.5 mmol) and methyl propiolate 26 (0.084 g, 1 mmol) in aceto-
nitrile (8 mL) DIPEA(0.323 g, 2.5 mmol) was added followed by

1334
V. Sai Sudhir et al. / Tetrahedron 66 (2010) 1327–1334
24.8, 22.7, 21.9, 15.4; IR (Neat): 3315, 2964, 2101, 1740, 1652, 1520,
room temperature (28 ꢁC). Ethyl acetate (30 ml) was added to the
reaction mixture, washed with brine (15 ml) and filtered through
anhydrous sodium sulfate. After evaporating ethyl acetate, the
crude product was purified by flash chromatography on silica gel to
yield 35 (0.428 g, 95%). Treatment of compound 35 with 26 in
a similar manner employed for the synthesis of 4b furnished
compound 36 in 95% yield as yellow solid; Rf (50% EA:Hexanes, 0.3);
mp: 131 ꢁC; 1H NMR (300 MHz): 8.04 (s, 1H, HTriazole), 7.51 (s, 1H,
HTriazole), 5.30 (s, 2H, CH2Fc), 5.25 (s, 2H, CH2Fc), 4.37 (d, J¼5.7 Hz,
2H, CH2NHBoc), 4.27–4.22 (m, 8H, HCp), 3.93 (s, 3H, CO2Me), 1.41 (s,
9H, Boc); 13C NMR (75 MHz): 161.1, 155.8, 145.6, 139.8, 126.9, 121.6,
82.8, 81.3, 79.7, 70.1, 69.8, 69.6, 69.4, 52.1, 49.9, 49.4, 36.2, 28.3; IR
(Neat): 3384, 2977, 1713, 1522, 1366, 1169, 1045 cmꢀ1; HRMS m/z:
C24H29FeN7O4 Calcd for (MþNa): 558.1528, found: 558.1525.
1252, 1168 cmꢀ1; HRMS m/z: C16H29N5O5 Calcd for (MþNa):
394.2066, found: 394.2069; [a]
23 19.0 (c 1, CHCl3).
D
4.5. Synthesis of ferrocenyl amino alcohols 21 and 22
4.5.1. Synthesis of compound 21. To a well stirred solution of fer-
rocene amino acid 5b (0.488 g, 1 mmol) in THF (6 mL) LiAlH4
(0.038 g. 1 mmol) was added at 0 ꢁC and stirred for 2 h. THF was
evaporated and to the resultant slurry EtOAc (10 mL) was added
and filtered through Celite. EtOAc was evaporated to furnish pure
ferrocenyl amino alcohol 21 (0.496 g, 92%). Yellow oil; Rf (50%
EA:Hexanes, 0.35); 1H NMR (300 MHz): 7.55 (s, 1H, HTriazole), 7.29–
7.26 (m, 5H, Ph), 5.99 (d, J¼7.8 Hz, 1H, NH), 5.08 (s, 2H, CH2Ph), 4.69
(s, 2H, HCp), 4.54 (s, 1H, CHCH2), 4.31 (s, 2H, HCp), 4.15–4.04 (m, 7H,
CH2OH, HCp ), 3.65 (br s, 2H, CH2N); 13C NMR (100 MHz): 156.3,
0
Acknowledgements
146.9, 136.1, 128.5, 128.2, 128.0, 120.3, 74.8, 69.6, 68.9, 66.9, 66.7,
61.2, 52.6, 49.9; IR (Neat): 3470, 3404, 1690, 1513, 1215, 696 cmꢀ1
;
VSS thanks CSIR, New Delhi for a senior research fellowship and
SCN thanks DST, New Delhi for the J.C. Bose National Fellowship.
HRMS m/z: C23H24FeN4O3 Calcd for (MþNa): 483.1096, found:
23
483.1099; [
a
]
ꢀ8.0 (c 1, CHCl3).
D
4.5.2. Compound 22. Yellow oil; Rf (50% EA:Hexanes, 0.35); 1H
NMR (300 MHz): 7.55 (s, 1H, HTriazole), 7.33–7.25 (m, 5H, Ph), 4.88–
4.79 (m, 1H, CHMe), 4.70–4.69 (m, 2H, HCp), 4.29 (t, J¼1.8 Hz, 2H,
References and notes
1. (a) Richards, C. J.; Locke, A. J. Tetrahedron: Asymmetry 1998, 9, 2377; (b) Sutcliffe,
O. B.; Bryce, M. R. Tetrahedron: Asymmetry 2003, 14, 2297; (c) Barbaro, P.;
Bianchini, C.; Giambastiani, G.; Parisel, S. L. Coord. Chem. Rev. 2004, 248, 2131;
(d) Arraya´s, R. G.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed. 2006, 45, 7674;
(e) Ferrocenes. Homogeneous Catalysis, Organic Synthesis and Materials Chemis-
try; Togni, A., Hayashi, T., Eds.; VCH: Weinheim, 1995; (f) Ferrocenes. From
Materials and Chemistry to Biology: Ligands, Materials and Biomolecules; Step-
nicka, P., Ed.; Wiley-VCH: Weinheim, 2008; (g) Siemeling, U.; Auch, T.-C. Chem.
Soc. Rev. 2005, 34, 584; (h) Atkinson, R. C. J.; Gibson, V. C.; Long, N. J. Chem. Soc.
Rev. 2004, 33, 313.
2. (a) Metzler-Nolte, N. Angew. Chem., Int. Ed. 2001, 40, 1040; (b) van Staveren,
D. R.; Metzler-Nolte, N. Chem. Rev. 2004, 104, 5931; (c) Fouda, M. R. F.; Abd-
Elhazer, M. M.; Abdelsamaia, R. A.; Labib, A. A. Appl. Organomet. Chem. 2007,
21, 613.
3. Schlo¨gl, K. Monatsh. Chem. 1957, 88, 601; (b) Heinze, K.; Schlenker, M. Eur. J.
Inorg. Chem. 2004, 2974; (c) Semencic, M. C.; Barisic, L.; Rapic, R. Tetrahedron:
Asymmetry 2007, 18, 2125; (d) Tharamani, C. N.; Mahmoud, K. A.; Vasantha-
kumar, G. R.; Kraatz, H.-B. Sens. Actuators, B 2009, 253; (e) Jackson, R. F. W.;
Turner, D.; Block, M. H. Synlett 1996, 862; (f) Brunner, H.; Ko¨nig, W.; Nuber, B.
Tetrahedron: Asymmetry 1993, 4, 699; (g) Maricic, S.; Berg, U.; Frejd, T. Tetra-
hedron 2002, 58, 3085; (h) Adamczyc, M.; Reddy, R. E.; Rege, S. D. Synth.
Commun. 2000, 30, 1389; (i) Dialer, H.; Steglich, W.; Beck, W. Tetrahedron 2001,
57, 4855; (j) Moreno, R. M.; Catasus, M.; Lopez, C.; Moyano, A. Eur. J. Org. Chem.
2008, 2388; (k) Tebben, L.; Bussmann, K.; Hegemann, M.; Kehr, G.; Frohlich, R.;
Erker, G. Organometallics 2008, 17, 4269; (l) Hunold, A.; Neundorf, I.; James, P.;
Neudorfl, J.; Schmalz, H.-G. Eur. J. Org. Chem. 2009, 26, 4429; (m) Okamura, T.;
Sakauye, K.; Ueyama, N.; Nakamura, A. Inorg. Chem. 1998, 37, 6731.
4. Moyano, A.; Rios, R. Synlett 2009 and references therein.
5. (a) Fukuzawa, S.-I.; Oki, H. Org. Lett. 2008, 10, 1747; (b) Detz, R. J.; Heras, S. A.; de
Gelder, R.; van Leeuwen, P. W. N. M.; Hiemstra, H.; Reek, J. N. H.; van Maar-
seveen, J. H. Org. Lett. 2006, 15, 3227; (c) Kato, M.; Nakamura, T.; Ogata, K.;
Fukuzawa, S.-I. Eur. J. Org. Chem. 2009, 30, 5232; (d) Fukuzawa, S.-I.; Oki, H.;
Hosaka, M.; Sugasawa, J.; Kikuchi, S. Org. Lett. 2007, 9, 5557; (e) Kato, M.; Oki,
H.; Ogata, K.; Fukuzawa, S.-I. Synlett 2009, 1299; (f) Liu, D.; Gao, W.; Dai, Q.;
Zhang, X. Org. Lett. 2005, 7, 4907.
0
HCp), 4.04 (s, 5H, HCp ), 3.87 (d, J¼13.2 Hz, 1H, CH2Ph), 3.75 (d,
J¼13.2 Hz, 1H, CH2Ph), 3.67 (dd, J1¼11.4 Hz, J2¼3.9 Hz, 1H, CH2OH),
3.29–3.18 (m, 3H, CH2OH, NH), 2.99–2.96 (m, 1H, CHNH), 1.67 (d,
J¼6.9 Hz, 3H, Me); 13C NMR (100 MHz): 146.4, 139.7, 128.5, 128.2,
127.3, 118.3, 75.2, 69.5, 68.6, 66.6, 62.5, 59.4, 57.3, 51.7, 16.8; IR
(Neat): 3647, 3293, 2922, 1651, 1455, 1024, 819 cmꢀ1; HRMS m/z:
23
C23H26FeN4O Calcd for (MþNa): 453.1354, found: 453.1358; [
a]
D
ꢀ16.0 (c 1, CHCl3).
4.5.3. Dipeptide 24a. Yellow solid; Rf (50% EA:Hexanes, 0.3); mp:
124 ꢁC; 1H NMR (300 MHz): 7.37 (s, 1H, HTriazole), 7.26–7.17 (m, 6H,
Ph), 7.05–6.87 (m, 4H, Ph), 6.79 (d, J¼4.8 Hz, 1H, NH), 5.28 (dd,
J1¼9.9 Hz, J2¼5.4 Hz, 1H, aCH), 4.87–4.80 (m, 1H, aCH), 4.69–4.66
0
(m, 2H, HCp), 4.29 (s, 2H, HCp), 3.98 (s, 5H, HCp ), 3.68 (s, 3H, OMe),
3.49 (dd, J1¼14.4 Hz, J2¼6 Hz, 1H, CH2Ph), 3.34 (dd, J1¼14.4 Hz,
J2¼10.5 Hz, 1H, CH2Ph), 3.16 (dd, J1¼13.8 Hz, J2¼5.4 Hz, 1H, CH2Ph),
2.98 (dd, J1¼14.1 Hz, J2¼7.5 Hz, 1H, CH2Ph); 13C NMR (75 MHz):
170.9, 167.1, 147.0, 135.3, 135.2, 129.1, 128.8, 128.7, 128.6, 127.3,
127.2, 119.1, 74.6, 69.5, 68.7, 66.6, 65.8, 53.5, 52.4, 38.8, 37.6; IR
´
´
(Neat): 3316, 3029, 1743, 1681, 1532, 1215, 700 cmꢀ1; HRMS m/z:
23
Calcd for C31H30FeN4O3 (MþNa): 585.1565, found: 585.1580; [
a]
D
14.0 (c 0.5, CHCl3).
4.5.4. Dipeptide 25a. Yellow solid; Rf (40% EA:Hexanes, 0.25); mp:
131 ꢁC; 1H NMR (300 MHz): 7.29–7.15 (m, 11H, 2ꢂPh, HTriazole),
6.63 (d, J¼6.9 Hz, 1H, NH), 5.75 (d, J¼6.6 Hz, 1H, NH), 5.09 (br s, 1H,
aCH), 4.73 (s, 1H, HCp), 4.69 (s, 1H, HCp), 4.59 (s, 1H, aCH), 4.51–4.36
(m, 2H, CH2N), 4.30 (s, 2H, HCp), 4.06–3.98 (m, 7H, CH2CH3, HCp),
2.89–2.73 (m, 2H, CH2Ph), 1.18 (t, J¼6.6 Hz, 3H, Me); 13C NMR
(75 MHz): 170.1, 155.8, 146.7, 137.4, 136.5, 129.2, 129.2, 128.8, 128.6,
128.5, 127.0, 120.1, 75.1, 69.5, 68.7, 66.7, 61.4, 59.2, 51.6, 51.2, 37.2,
6. Sai Sudhir, V.; Venkateswarlu, C.; Muhammed Musthafa, O. T.; Sampath, S.;
Chandrasekaran, S. Eur. J. Org. Chem. 2009, 13, 2120.
7. (a) Nasir baig, R. B.; Kanimozhi, C. K.; Sai Sudhir, V.; Chandrasekaran, S. Synlett
2009, 1227; (b) White, G. J.; Garst, M. E. J. Org. Chem. 1991, 56, 3178; (c) Nic-
olaou, K. C.; Huang, X.; Snyder, S. A.; Rao, P. B.; Bella, M.; Reddy, M. V. Angew.
Chem., Int. Ed. 2002, 41, 834; (d) Losey, E. A.; Smith, M. D.; Meng, M.; Best, M. D.
Bioconjugate Chem. 2009, 20, 376; (e) Saito, S.; Yokoyama, H.; Ishikawa, T.; Niwa,
N.; Moriwake, T. Tetrahedron Lett. 1991, 32, 663.
14.4; IR (Neat): 3294, 1690, 1661, 1537, 1253, 1053, 699 cmꢀ1
HRMS m/z: Calcd for C32H33FeN5O3 (MþNa): 614.1831, found:
614.1836; [
23 32.5 (c 2, CHCl3).
;
8. (a) Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797; (b) Li, R.; Jansen,
D. J.; Datta, A. Org. Biomol. Chem. 2009, 7, 1921.
a
]
D
9. (a) Catasu´ s, M.; Bueno, A.; Moyano, A.; Maestro, M. A.; Mahı´a, J. J. Organomet.
Chem. 2002, 642, 212; (b) Bueno, A.; Moreno, R. M.; Moyano, A. Tetrahedron:
Asymmetry 2005, 16, 1763; (c) Moreno, R. M.; Bueno, A.; Moyano, A. J. Org. Chem.
2006, 71, 2528; (d) Moreno, R. M.; Rosol, M.; Moyano, A. Tetrahedron: Asym-
metry 2006, 17, 1089.
10. Jary, W. G.; Baumgartner, J. Tetrahedron: Asymmetry 1998, 9, 2081.
11. Casas-Solvas, J. M.; Vargas-Berenguel, A.; Capitan-Vallvey, L. F.; Santoyo-Gon-
zalez, F. Org. Lett. 2004, 6, 3687.
4.6. Synthesis of 1,10 ferrocene amino acid derivative 36
To a well stirred solution of azide 3 (1.48 g, 5 mmol) and Boc
protected propargyl amine 28 (0.155 g, 1 mmol) in acetonitrile
(8 ml) DIPEA (0.323 g, 2.5 mmol) followed by CuI (0.019 g,
0.1 mmol) were added. The reaction mixture was stirred for 4 h at
12. Ziegler, T.; Hermann, C. Tetrahedron Lett. 2008, 49, 2166.