Key words
ferrocene - 1,1′-disubstitution - carboxamide - remote functionalization - functional
group manipulation
The discovery of ferrocene in 1952 has profoundly changed the organometallic chemistry
landscape and this sandwich compound remains one of the most important organometallic
scaffolds.[1] Among the various substitution patterns explored in ferrocene chemistry, the most
popular is the 1,1′-disubstitution, with applications in catalysis,[2] material science,[3] and bio-inorganic chemistry.[3a]
[4]
1,1′-Disubstituted ferrocenes with the same substituents can easily be obtained by
two complementary approaches: (1) the ferrocene core assembly from the corresponding
monosubstituted cyclopentadienes[5] and (2) the double deprotometalation-electrophilic trapping sequence from ferrocene.[6] However, while 1′-substituted iodoferrocenes represent an important family of precursors
to unsymmetrical compounds,[7] they cannot be directly prepared by one of the above mentioned approaches. Therefore,
the most popular synthetic routes currently rely on the halogen/Li or Sn/Li mono-exchange
of such 1,1′-disubstituted ferrocenes. Buttler initially reported the mono I/Li exchange
from 1,1′-diiodoferrocene using nBuLi, followed by an electrophilic trapping step (Scheme [1], approach a, R = CO2H, SnBu3).[8] However, low yields were obtained (28–32%), linked with the highly sensitive nature
of the reaction as expressed in a footnote. Similar low yields were recorded by Christmann,
Sarkar, and Heretsch using tosyl azide as the electrophile[9] while Lentz and later Nijhuis, both using tributyltin chloride, managed to isolate
1-iodo-1′-tributylstannylferrocene in good yields (77 and 84%, respectively).[10] The concentration was proposed as being an important reaction parameter in such
reactions,[11] and the development of a flow-based approach partially solved this issue.[9] From 1,1′-bis(tributylstannyl)ferrocene, Wright reported a controlled Sn/Li mono-exchange
by using nBuLi before interception with an electrophile.[12] However, iodine cannot be introduced this way due to a competitive Sn/I exchange
leading to mixtures of products. Therefore, another substituent needs to be introduced
first, before performing the final Sn/I exchange using iodine. Such approach was illustrated
with success during the synthesis of 1′-iodoferrocenecarboxaldehyde (Scheme [1], approach b, R = CHO).[13] Finally, Dong developed a mono Li/Br exchange-electrophilic trapping sequence from
1,1′-dibromoferrocene;[14] this was used by Ilyashenko as the key step in the synthesis of 1-bromo-1′-iodoferrocene
(78% yield; Scheme [1], approach c, R = Br).[11]
Scheme 1 Reported approaches toward 1′-substituted iodoferrocenes. Reagents and conditions: a) i. nBuLi, ii. CO2 or nBu3SnCl; b) i. nBuLi; ii. Me2NCHO, iii. I2; c) i. nBuLi; ii. I2; d) PhN(Me)CHO, POCl3; e) i. N-methylpiperazine Li salt, ii. tBuLi, iii. I2; f) i. nBuLi; ii. I2.
The other strategies toward 1′-substituted iodoferrocene start from monosubstituted
ferrocenes and rely on functionalizations at the unsubstituted cyclopentadienyl (Cp)
ring, remote from the substituent. The regioselective aromatic electrophilic substitution
of iodoferrocene using acetyl chloride in the presence of iron trichloride was first
attempted by Richards.[15] However, the expected 1,1′-disubstituted product was not obtained due to competitive
deiodination observed under the reaction conditions. However, by using N-methylformanilide in the presence of phosphorus oxychloride, Yuan managed to isolate
the corresponding 1′-iodoferrocenecarboxaldehyde in a moderate 61% yield (Scheme [1], approach d, R = CHO).[16]
The use of directing groups able to reroute the classical ortho-deprotometalation to the unsubstituted Cp ring represents the second approach in
the remote functionalization strategy. Balavoine and Manoury reported the reaction
of the lithium salt of N-methylpiperazine with ferrocenecarboxaldehyde, followed by a deprotolithiation-electrophilic
trapping sequence toward 1′-iodoferrocenecarboxaldehyde in a moderate 50% yield (Scheme
[1], approach e, R = CHO).[17] The N-methylpiperazine acts as a protecting group for the aldehyde (temporary formation
of the hemiaminal salt) and as the directing group with methylated nitrogen atom.
More recently, Chong revealed a similar behavior for N-Boc protected α-methylated aminomethylferrocene in deprotolithiation and managed
to obtain the corresponding iodinated derivative in a 71% yield [Scheme [1], approach f, R = CH(Me)NHBoc].[18]
A few other catalytic desymmetrizations of 1,1′-diiodoferrocene have been reported,
based on Stille,[10a]
[19] Sonogashira,[20] Suzuki–Miyaura,[21] and Ulmann[22] cross-couplings and by aminocarbonylation.[23] However, the selectivity is often an issue in such transformations, leading to mixtures
of products.
In the frame of ongoing studies dedicated to the synthesis of original ferrocene derivatives,[24] we required an access to different 1′-substituted iodoferrocene derivatives. We
initially focused our work on the mono-exchange of 1,1′-diiodoferrocene by using nBuLi, as this approach has the potential to easily deliver many derivatives by varying
the electrophile.[8] However, regardless of the reaction conditions, only traces of the desired products
were invariably obtained while 1,1′-bis-functionalized derivatives and mixtures of
1,1′-diiodoferrocene, iodoferrocene, and ferrocene were mainly obtained. We briefly
evaluated the Manoury approach,[17] but failed to obtain significant amounts of the title products by using iodine as
the electrophile. Moderate success was encountered in our attempts to achieve a mono
Sn/Li exchange from 1,1′-bis(tributylstannyl)ferrocene[12] by using nBuLi and either methyl chloroformate or dimethylformamide as the electrophile (22
or 25% yield, respectively). However, as we recognized that the synthesis of the targeted
compounds would require the manipulation of large quantities of toxic stannylated
products, the need for another original approach emerged.
In his seminal paper on the enantioselective deprotometalation of N,N-diisopropylferrocenecarboxamide,[25] Snieckus reported that the introduction of a trimethylsilyl group at position 2
was able to reroute a further deprotometalation to the unsubstituted Cp ring. While
a similar behavior was also noticed by Richards on ferrocene oxazolines,[26] this remote functionalization has never been considered as a valuable synthetic
tool. Therefore, our plan was to use a silyl group to temporarily protect the position
next to the carboxamide and favor the remote deprotometalation to introduce iodine
onto the unsubstituted ring. Final deprotection of the silyl group would afford the
targeted 1,1′-disubstituted ferrocenes.
We first deprotolithiated N,N-diisopropylferrocenecarboxamide (1)[27] by using the nBuLi·TMEDA (TMEDA: N,N,N′,N′-tetramethylethylenediamine) chelate before intercepting the lithiated intermediate
with trimethylsilyl chloride toward the ferrocene rac-2, isolated in a 92% yield (Scheme [2]). To reach the iodinated derivative rac-3, we initially applied the Snieckus reaction conditions by using sBuLi (1.2 equiv) in THF at cryogenic temperature (–80 to –78 °C) before addition of
iodine as the electrophile.[25] However, the title product was isolated in a disappointing 50% yield together with
recovered starting material. While recourse to the more reactive sBuLi·TMEDA chelate improved the conversion to 95%, formation of inseparable by-products
was noticed. However, the use of 2 equivalents of sBuLi at cryogenic temperature (–80 to –78 °C) led to a complete conversion and the
ferrocene rac-3 was isolated in a 95% yield on a 1 mmol scale. Pleasingly, the yield remained constant
upon scaling up (97% yield on a 26 mmol scale). Although the trimethylsilyl group
is usually removed upon treatment with fluorides,[28] we found that rac-3 was reluctant to desilylation under smooth reaction conditions (2 equivalents of
tetrabutylammonium fluoride at room temperature) and that decomposition occurred upon
heating. However, the use of a stoichiometric amount of potassium tert-butoxide in dimethyl sulfoxide afforded 4 in a promising 70% yield after only 5 minutes.[29] Evaluation of other reaction conditions revealed a complete conversion with increased
amount of potassium tert-butoxide, reaction time, and concentration, delivering 4 in an 80% yield on a 1 mmol scale. Furthermore, it was possible to scale-up the reaction
up to 25 mmol with a slightly better yield (88%, 10 g of product 4 made in a single batch).
Scheme 2 Remote functionalization strategy toward the 1,1′-disubstituted ferrocene 4
Clues about the origin of this remote functionalization can be found in the solid-state
structure of compound rac-2. Indeed, to release the steric pressure generated between the diisopropyl and trimethysilyl
moieties, the C=O bond of the carboxamide needs to be almost perpendicular to the
Cp ring (Figure [1], right and S.I.). As shown by a variable temperature 1H NMR study (see S.I.), rotation of the C=O to reach the conformation favorable to
the ortho-deprotometalation (C=O parallel with the Cp ring, Figure [1], left), is too energetic. Therefore, the only reaction observed is the remote deprotometalation,
probably favored by the C=O bound pointing toward the unsubstituted Cp ring to guide
the approach of the lithiated base (Figure [1], right).
Figure 1 Rationalization of the origin of the remote deprotometalation
With a reliable protocol toward 4 in hands, we next focused our attention onto the carboxamide transformation. While
the borane-mediated reduction of similar substrates is well known,[25]
[30] transformation of the resulting diisopropylamine moiety did not receive much attention[31] until we recently documented the substitution of this bulky amine for an acetate.[32] Consequently, the carboxamide 4 was reduced by an excess of borane (generated in situ from sodium borohydride and
iodine) in refluxing tetrahydrofuran to deliver 5 in a 95% yield (Scheme [3]). The substitution step then occurred smoothly in neat acetic anhydride at 160 °C
for 1 hour and 6 was isolated in a 88% yield on a 20 mmol scale (6.7 g of compound in a single batch).
During the reduction of 4 to 5, traces of a by-product, tentatively assigned to be 1-iodo-1′-methylferrocene (7), were noticed. To validate its structure, we engaged the acetate in another borane
reduction and indeed isolated 7 in a 92% yield.
Scheme 3 Functional group manipulation toward the methylated derivative 7
Saponification of the acetate 6 with sodium hydroxide in a tetrahydrofuran/water mixture at 80 °C led to the isolation
of the alcohol 8 in a 90% yield (Scheme [4]). It should be noted that the use of methanol/water mixtures in such reaction should
be avoided as variable amounts of the methyl ether 9 can be formed as a side-product. However, it is possible to obtain 9 in an almost quantitative yield by the deprotonation of the alcohol using sodium
hydride followed by the interception of the alkoxide with methyl iodide. The known
aldehyde 10 then was prepared by a ruthenium-mediated oxidation in the presence of N-methylmorpholine oxide initially described by Sharpless.[33] Addition of phenylmagnesium bromide to the aldehyde afforded the alcohol 11 in a 97% yield, which was finally converted into the known ketone 12 in a 96% yield by following the same ruthenium-mediated oxidation protocol.
Scheme 4 Functional group manipulation toward the ketone 12 (NMO: N-methylmorpholine oxide)
While condensation of the aldehyde 10 with hydroxylamine followed by dehydration led to 1′-iodoferrocenecarbonitrile (13) in 91% yield (Scheme [5]),[34] it is known that such substrates are difficult to oxidize under classical conditions.[35] However, reaction of 10 with iodine in the presence of potassium hydroxide[36] in methanol led to the ester 14 in a very good 97% yield. The acid 15 was easily made by saponification in 96% yield and it was further reacted with diphenylphosphoryl
azide by following our recently developed protocol[37] toward the acyl azide 16, isolated in an 85% yield. Curtius rearrangement at 110 °C in the presence of tert-butyl alcohol to intercept the intermediate isocyanate allowed the isolation of the
Boc-protected aminoferrocene 17 (85% yield). Removal of the protecting group was easily done by using an ethereal
solution of HCl at room temperature toward 18, isolated in a 74% yield as its HCl salt. Although salts of aminoferrocene derivatives
are known to be more stable when compared to the free base, storage of 18 in a closed vessel without specific protection led to decomposition. A double reductive
amination[38] with paraformaldehyde in the presence of an excess of sodium cyanoborohydride was
finally performed toward the sensitive dimethylaminoferrocene 19, isolated in a 40% yield.
Scheme 5 Functional group manipulation toward the dimethylaminoferrocene derivative 19
In conclusion, we have reported a new route toward 1′-substituted iodoferrocenes based
on a remote deprotometalation observed more than 20 years ago and never exploited.
By following this methodology, grams of our key substrate, 1′-iodo-N,N-diisopropylferrocenecarboxamide, were prepared and further functionalized towards
fifteen 1,1′-disubstituted ferrocenes, most of them being fully described for the
first time.
Unless otherwise stated, all the reactions were performed under an argon atmosphere
with anhydrous solvents using Schlenk technics. THF and Et2O were distilled over Na-benzophenone, DMSO and toluene were distilled over CaH2, and acetone and MeOH were dried by prolonged contact over activated 3Å molecular
sieves.[39] Unless otherwise stated, all reagents were used without prior purification. All
organolithiated reagents were titrated before use.[40] tBuOK (99.99% quality) was purchased from Sigma-Aldrich and used without further purification.
Column chromatography separations were achieved on silica gel (40–63 μm). All TLC
analyses were performed on aluminum backed plates pre-coated with silica gel (Merck,
Silica Gel 60 F254). They were visualized by exposure to UV light. Melting points
were measured on a Kofler bench. IR spectra were taken on a PerkinElmer Spectrum 100
spectrometer. 1H and 13C NMR spectra were recorded either (i) on a Bruker Avance III spectrometer at 300
MHz and 75.4 MHz, respectively, or (ii) on a Bruker Avance III at 400 MHz and 100
MHz, respectively or (iii) on a Bruker Avance III HD at 500 MHz and 126 MHz, respectively.
1H chemical shifts (δ) are given in ppm relative to the solvent residual peak and 13C chemical shifts are relative to the central peak of the solvent signal. Cp refers
to the unsubstituted cyclopentadienyl ring of ferrocene.
N,N-Diisopropyl-2-trimethylsilylferrocenecarboxamide (rac-2) [CAS Reg. No. 173910-99-1]
N,N-Diisopropyl-2-trimethylsilylferrocenecarboxamide (rac-2) [CAS Reg. No. 173910-99-1]
TMEDA (4.50 mL, 3.49 g, 30.0 mmol, 1.50 equiv, freshly distilled over CaCl2 and stored over KOH pellets) and anhyd Et2O (90.0 mL) were introduced into a flame-dried round-bottom flask under argon. The
reaction mixture was cooled between –80 and –78 °C (external temperature) in an acetone/liquid
N2 bath. nBuLi (1.4 M, 21.4 mL, 30.0 mmol, 1.50 equiv) was then introduced dropwise by syringe.
After addition, the reaction mixture was stirred at the same temperature for 15 min.
Compound 1 (6.26 g, 20.0 mmol, 1.00 equiv) was introduced into a separate flame-dried round-bottom
flask, which was subjected to three cycles of vacuum/argon. Anhyd Et2O (90.0 mL) was added and the solution was stirred until dissolution of all solids.
The solution of 1 was transferred into the nBuLi·TMEDA chelate solution dropwise by cannula keeping the temperature between –80
and –78 °C. The flask was washed with anhyd Et2O (10 mL), also transferred by cannula. After addition, the reaction mixture was stirred
at the same temperature for 1 h. Me3SiCl (5.10 mL, 4.34 g, 40.0 mmol, 2.00 equiv) was added dropwise by syringe keeping
the temperature between –80 and –78 °C. The mixture was then allowed to warm to –15
°C, keeping the flask into the bath. At –15 °C, the cooling bath was removed and the
mixture was warmed to rt. H2O (100 mL) was added and the layers were separated. The aqueous layer was extracted
with EtOAc (2 × 75 mL). The combined organic layers were washed with brine, dried
(MgSO4), filtered over cotton wool, and concentrated under vacuum using a rotary evaporator
to give the crude product. This was purified by column chromatography, using PE/EtOAc
(80:20) to give the title product rac-2 as an orange solid; yield: 7.12 g (92%); mp 108–110 °C.
Analytical data analogous to those reported previously.[25]
IR (film): 2966, 1628, 1441, 1368, 1328, 1278, 1243, 1148, 1035, 833, 807, 753 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.34 (dd, J = 1.2, 2.3 Hz, 1 H, H5), 4.29 (t, J = 2.3 Hz, 1 H, H4), 4.27 (s, 5 H, Cp), 4.13 (dd, J = 1.2, 2.3 Hz, 1 H, H3), 4.11 (br s, 1 H, CH), 3.39 (br s, 1 H, CH), 1.45 (br s,
6 H, 2 × CH3), 1.11 (br s, 6 H, 2 × CH3), 0.27 [s, 9 H, Si(CH3)3].
13C NMR (126 MHz, CDCl3): δ = 168.9 (C=O), 92.3 (C1), 73.7 (C2), 73.5 (C3), 69.9 (Cp + C5), 69.4 (C4), 50.1
(CH), 45.9 (CH), 21.1 (2 × CH3), 20.9 (2 × CH3), 0.7 [Si(CH3)3].
rac-2 was also characterized by X-ray structural data.[41]
1′-Iodo-N,N-diisopropyl-2-trimethylsilylferrocenecarboxamide (rac-3)
1′-Iodo-N,N-diisopropyl-2-trimethylsilylferrocenecarboxamide (rac-3)
sBuLi (1.2 M, 43.3 mL, 52.0 mmol, 2.00 equiv) was added dropwise to a solution of rac-2 (10.0 g, 26.0 mmol, 1.00 equiv) in anhyd Et2O (300 mL) between –80 and –78 °C. The reaction mixture was stirred at the same temperature
for 1 h after addition. I2 (19.8 g, 78.0 mmol, 3.00 equiv) was introduced in a separate flame-dried round-bottomed
flask under argon and was dissolved in anhyd Et2O (300 mL). The I2 solution was transferred by cannula into the reaction mixture. The flask was washed
with anhyd Et2O (10 mL), also transferred by cannula. After addition, the reaction mixture was stirred
at the same temperature for 30 min before being warmed to rt. A sat. aq solution of
Na2S2O3 (100 mL) was added to the reaction mixture and the layers were separated. The aqueous
layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed
with brine, dried (MgSO4), filtered over cotton wool, and concentrated under vacuum using a rotary evaporator
to give the crude product. This was purified by column chromatography, using PE/EtOAc
(99:1) to give the title product rac-3 as an orange oil; yield: 12.9 g (97%).
IR (film): 2961, 2866, 1626, 1442, 1368, 1326, 1274, 1244, 1150, 1034, 830, 809, 756
cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.51 (s, 1 H, FcH), 4.40 (s, 1 H, FcH), 4.38 (s, 1 H, FcH), 4.29 (s, 1 H, H5),
4.28 (s, 1 H, FcH), 4.25 (s, 1 H, H4), 4.08 (s, 1 H, H3), 3.98 (br s, 1 H, CH), 3.38
(br s, 1 H, CH), 1.46 (br s, 6 H, 2 × CH3), 1.07 (br s, 6 H, 2 × CH3), 0.26 [s, 9 H, Si(CH3)3].
13C NMR (126 MHz, CDCl3): δ = 168.2 (C=O), 93.5 (C1), 77.4 (C3), 76.7 (FcCH), 75.6 (C2), 75.3 (FcCH), 73.9
(C4), 73.6 (C5), 72.1 (FcCH), 71.6 (FcCH), 50.3 (CH), 45.8 (CH), 40.4 (C1′), 21.2
(2 × CH3), 20.8 (2 × CH3), 0.7 [Si(CH3)3].
MS: m/z = 511 [M], 496 [M – CH3].
1′-Iodo-N,N-diisopropylferrocenecarboxamide (4) [CAS Reg. No. 2407448-99-9]
1′-Iodo-N,N-diisopropylferrocenecarboxamide (4) [CAS Reg. No. 2407448-99-9]
tBuOK (5.72 g, 51.0 mmol, 2.00 equiv) was added to a solution of rac-3 (13.0 g, 25.5 mmol, 1.00 equiv) in DMSO (76.5 mL) and the reaction mixture was stirred
for 10 min at rt. Cold H2O (200 mL) was added to the reaction mixture, which was extracted with EtOAc (4 ×
70 mL). The combined organic layers were washed with brine (4 × 50 mL), dried (MgSO4), filtered over cotton wool, and concentrated under vacuum using a rotary evaporator
to give the crude product. This was purified by column chromatography using PE/EtOAc
(85:15) to give the title product 4 as an orange solid; yield: 9.92 g (88%); mp 58–60 °C.
IR (film): 2964, 1615, 1459, 1368, 1315, 1201, 1043, 1029, 862, 825, 804, 762 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.49 (t, J = 1.9 Hz, 2 H, H2, H5), 4.46 (br s, 1 H, CH), 4.41 (t, J = 1.9 Hz, 2 H, H2′, H5′), 4.26–4.24 (m, 4 H, H3, H4, H3′, H4′), 3.41 (br s, 1 H,
CH), 1.47 (br s, 6 H, 2 × CH3), 1.21 (br s, 6 H, 2 × CH3).
13C NMR (75 MHz, CDCl3): δ = 168.5 (C=O), 83.5 (C1), 76.5 (C2′, C5′), 73.1 (C2, C5), 72.2 (C3, C4), 71.3
(C3′, C4′), 49.8 (CH), 46.4 (CH), 40.1 (C1′), 21.3 (4 × CH3).
MS: m/z = 439 [M], 339 [M – NiPr2].
1-(N,N-Diisopropylaminomethyl)-1′-iodoferrocene (5)
1-(N,N-Diisopropylaminomethyl)-1′-iodoferrocene (5)
NaBH4 (2.84 g, 75.0 mmol, 5.00 equiv) was introduced into a flame-dried round-bottom flask
equipped with a bubbler, and THF (75.0 mL) was added before the reaction mixture was
cooled to 0 °C. I2 (9.14 g, 36.0 mmol, 2.40 equiv) was introduced into a separate flame-dried round-bottom
flask under argon and was dissolved into anhyd THF (30.0 mL). The I2 solution was transferred into the NaBH4 suspension dropwise by cannula. Remark: vigorous evolution of H2 occurred during the addition. After addition, the reaction mixture was allowed to
warm to rt out of the cooling bath and was stirred for 1 h, giving a colorless solution
of BH3·THF. Compound 4 (6.60 g, 15.0 mmol, 1.00 equiv) was then added portionwise to the BH3·THF solution, which was then stirred overnight at reflux Remark: the use of PTFE sleeve is strongly recommended to avoid blockage of the ground glass
joints. The reaction mixture was cooled to 0 °C and a solution of aq NaOH (10%, 75
mL) was added dropwise. Caution: as a vigorous evolution of gas was noticed, the first drops of NaOH solution should
be added slowly. After addition, the reaction mixture was stirred at reflux for 1
h. The mixture was cooled to rt and the layers were separated. The aqueous layer was
further extracted with EtOAc (2 × 50 mL). The combined organic layers were extracted
with aq 1 M HCl (3 × 50 mL). The combined aqueous layers were washed with Et2O (2 × 50 mL) and basified with solid K2CO3 until pH 8 was reached. The mixture was extracted with EtOAc (2 × 60 mL) and the
combined organic layers were dried (MgSO4), filtered on Celite (washed with EtOAc until the filtrate was colorless), and concentrated
under vacuum using a rotary evaporator to give the pure product 5 as an orange oil; yield: 6.08 g (95%).
IR (film): 3090, 2961, 1684, 1461, 1380, 1360, 1200, 1164, 1136, 1115, 1018, 861,
823, 807 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.31 (t, J = 1.6 Hz, 2 H, H2′, H5′), 4.15 (t, J = 1.6 Hz, 2 H, H2, H5), 4.10 (d, J = 1.6 Hz, 2 H, H3′, H4′), 4.09 (d, J = 1.6 Hz, 2 H, H3, H4), 3.47 (s, 2 H, CH2), 3.04 (sept, J = 6.7 Hz, 2 H, 2 × CH), 1.02 (d, J = 6.7 Hz, 12 H, 4 × CH3).
13C NMR (75 MHz, CDCl3): δ = 90.4 (C1), 75.1 (C2′, C5′), 72.9 (C2, C5), 70.6 (C3, C4), 69.4 (C3′, C4′),
47.7 (2 × CH), 43.4 (CH2), 41.0 (C1′), 21.0 (4 × CH3).
MS: m/z = 439 [M], 339 [M – NiPr2].
1-(Acetoxymethyl)-1′-iodoferrocene (6)
1-(Acetoxymethyl)-1′-iodoferrocene (6)
Compound 5 (8.53 g, 20.0 mmol, 1.00 equiv) was dissolved into Ac2O (76.2 mL, 82.3 g, 800 mmol, 40.0 equiv) at rt and the resulting solution was stirred
at 160 °C in a pre-heated bath for 1 h. The reaction mixture was cooled to 0 °C and
EtOAc (150 mL) was added before pouring the mixture onto ice (200 mL). Solid K2CO3 was added under stirring until pH 8 was reached. Caution: small portions of K2CO3 should be added each time as vigorous evolution of gas occurred. The layers were
separated and the aqueous layer was extracted with EtOAc (75 mL). The combined organic
layers were washed with H2O (75 mL), brine (50 mL), dried (MgSO4), filtered over cotton wool, and concentrated under vacuum using a rotary evaporator
to give the crude product. This was purified by column chromatography over SiO2, using PE/EtOAc (95:5) to give the title product 6 as an orange solid; yield: 6.75 g (88%); mp 54–56 °C.
IR (film): 3090, 2961, 1684, 1461, 1380, 1360, 1200, 1164, 1136, 1115, 1018, 861,
823, 807 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.91 (s, 2 H, CH2), 4.39 (t, J = 1.7 Hz, 2 H, H2′, H5′), 4.22 (m, 2 H, H3, H4), 4.21 (m, 2 H, H2, H5), 4.15 (t,
J = 1.7 Hz, 2 H, H3′, H4′), 2.05 (s, 3 H, CH3).
13C NMR (126 MHz, CDCl3): δ = 170.9 (C=O), 82.9 (C1), 75.3 (C2′, C5′), 72.6 (C3, C4), 72.0 (C2, C5), 69.5
(C3′, C4′), 62.2 (CH2), 39.9 (C1′), 21.1 (CH3).
MS: m/z = 439 [M], 339 [M – NiPr2].
1-Iodo-1′-methylferrocene (7) [CAS Reg. No. 31833-00-8]
1-Iodo-1′-methylferrocene (7) [CAS Reg. No. 31833-00-8]
Compound 6 (384 mg, 1.00 mmol, 1.00 equiv) was added portionwise to a solution of BH3 in THF (1.0 M, 5.00 mL, 5.00 mmol, 5.00 equiv) at rt before the reaction mixture
was heated at reflux overnight. Remark: the use of PTFE sleeve is strongly recommended to avoid blockage of the ground glass
joints. The reaction mixture was cooled to 0 °C and a solution of aq NaOH (10%, 10
mL) was added dropwise. Caution: as a vigorous evolution of gas occurs, the first drops of NaOH solution should be
added slowly. After addition, the reaction mixture was stirred at reflux for 1 h.
The reaction mixture was cooled to rt and the layers were separated. The aqueous layer
was extracted with EtOAc (10 mL). The combined organic layers were washed with H2O (10 mL), brine (10 mL), dried (MgSO4), filtered over cotton wool, and concentrated under vacuum using a rotary evaporator
to give the crude product. This was purified by column chromatography over SiO2, using PE/EtOAc (95:5) to give the title product 7 as an orange oil; yield: 300 mg (92%).
IR (film): 3087, 2918, 1476, 1453, 1403, 1382, 1368, 1342, 1227, 1144, 1039, 1022,
860, 822, 804 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.31 (t, J = 1.6 Hz, 2 H, H2, H5), 4.11 (t, J = 1.6 Hz, 2 H, H3, H4), 4.09 (t, J = 1.7 Hz, 2 H, H3′, H4′), 4.04 (t, J = 1.7 Hz, 2 H, H2′, H5′), 2.01 (s, 3 H, CH3).
13C NMR (126 MHz, CDCl3): δ = 85.7 (C1′), 75.2 (C2, C5), 72.4 (C2′, C5′), 70.3 (C3′, C4′), 69.5 (C3, C4),
40.9 (C1), 14.2 (CH3).
MS: m/z = 326 [M].
1′-Iodoferrocenemethanol (8) [CAS Reg. No. 224456-53-5]
1′-Iodoferrocenemethanol (8) [CAS Reg. No. 224456-53-5]
NaOH (2.04 g, 51.0 mmol, 3.00 equiv) was dissolved in H2O (55.0 mL) and a solution of compound 6 (6.50 g, 17.0 mmol, 1.00 equiv) in THF (30.0 mL) was added at rt. The reaction mixture
was heated at 80 °C for 2 h in a pre-heated bath. The mixture was cooled to rt and
the layers were separated. The aqueous layer was extracted with EtOAc (2 × 20 mL).
The combined organic layers were dried (MgSO4), filtered over cotton wool, and concentrated under vacuum using a rotary evaporator
to give the crude product. This was purified by column chromatography over SiO2, using PE/EtOAc (95:5) to give the title product 8 as an orange solid; yield: 5.23 g (90%); mp 58–60 °C.
Analytical data analogous to those reported previously.[13]
IR (film): 3325, 3097, 2925, 2863, 1402, 1379, 1343, 1235, 1143, 1040, 996, 922, 862,
825, 738 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.40–4.39 (m, 4 H, H2′, H5′, CH2), 4.19 (s, 4 H, H2, H3, H4, H5), 4.16 (t, J = 1.8 Hz, 2 H, H3′, H4′), 1.78 (br s, 1 H, OH).
13C NMR (126 MHz, CDCl3): δ = 89.6 (C1), 75.0 (C2′, C5′), 71.4 (C2, C5 or C3, C4), 70.9 (C2, C5 or C3, C4),
69.3 (C3′, C4′), 60.3 (CH2), 40.1 (C1′).
MS: m/z = 342 [M], 264.
1-Iodo-1′-(methoxymethyl)ferrocene (9)
1-Iodo-1′-(methoxymethyl)ferrocene (9)
NaH (60% dispersion in oil, 120 mg, 3.00 mmol, 3.00 equiv) was added portionwise to
a solution of compound 8 (342 mg, 1.00 mmol, 1.00 equiv) in THF (5.00 mL) at 0 °C. After addition, the cooling
bath was removed and the reaction mixture was stirred for 1 h at rt. The mixture was
cooled to 0 °C and MeI (250 μL, 568 mg, 4.00 mmol, 4.00 equiv) was added dropwise.
After addition, the cooling bath was removed and the mixture was stirred for 1 h at
rt. The mixture was cooled to 0 °C and sat. aq NH4Cl (10 mL) was added dropwise. EtOAc (10 mL) was added and the layers were separated.
The aqueous layer was extracted with EtOAc (10 mL) and the combined organic layers
were dried (MgSO4), filtered over cotton wool, and concentrated under vacuum using a rotary evaporator
to give the crude product. This was purified by column chromatography over SiO2, using PE/EtOAc (80:20) to give the title product 9 as an orange oil; yield: 346 mg (97%).
IR (film): 3089, 2920, 2887, 2813, 1447, 1402, 1379, 1344, 1234, 1187, 1175, 1085,
1038, 1021, 899, 862, 824, 809 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.36 (s, 2 H, H2, H5), 4.25 (s, 2 H, CH2), 4.19 (s, 4 H, H2′, H3′, H4′, H5′), 4.13 (s, 2 H, H3, H4), 3.34 (s, 3 H, CH3).
13C NMR (126 MHz, CDCl3): δ = 84.8 (C1′), 75.1 (C2, C5), 72.4 (C2′, C5′ or C3′, C4′), 71.7 (C2′, C5′or C3′,
C4′), 70.2 (CH2), 69.4 (C3, C4), 57.9 (CH3), 40.1 (C1).
MS: m/z = 356 [M].
1′-Iodoferrocenecarboxaldehyde (10) [CAS Reg. No. 176100-20-2]
1′-Iodoferrocenecarboxaldehyde (10) [CAS Reg. No. 176100-20-2]
NMO (5.04 g, 43.0 mmol, 3.50 equiv) was placed in a Schlenk tube, which was heated
at 90 °C under high vacuum for 3 h before being cooled to rt. In a separate Schlenk
tube, compound 8 (4.22 g, 12.3 mmol, 1.00 equiv) was dissolved in acetone (120 mL) and this solution
was cannulated onto NMO. RuCl2(PPh3)3 (589 mg, 0.61 mmol, 0.05 equiv) was added in one portion and the reaction mixture
was stirred at rt for 1 h, shielded from light. The mixture was concentrated under
vacuum using a rotary evaporator. Aq 1 M HCl (40 mL) was added and the mixture was
extracted with EtOAc (3 × 30 mL). The combined organic layers were dried (MgSO4), filtered over cotton wool, and concentrated under vacuum using a rotary evaporator
to give the crude product. This was purified by column chromatography over SiO2 using PE/EtOAc (80:20) with 1% of NEt3 to give the title product 10 as a red solid; yield: 3.57 g (85%); mp 31–33 °C.
Analytical data analogous to those reported previously.[13]
IR (film): 3096, 2801, 2761, 1673, 1658, 1455, 1368, 1343, 1242, 1026, 824, 740 cm–1.
1H NMR (500 MHz, CDCl3): δ = 10.00 (s, 1 H, CHO), 4.77 (t, J = 2.0 Hz, 2 H, H2, H5), 4.59 (t, J = 2.0 Hz, 2 H, H3, H4), 4.50 (t, J = 1.9 Hz, 2 H, H2′, H5′), 4.26 (t, J = 1.9 Hz, 2 H, H3′, H4′).
13C NMR (125 MHz, CDCl3): δ = 193.4 (CHO), 80.6 (C1), 76.4 (C3, C4), 76.3 (C2′, C5′), 72.4 (C2, C5), 70.6
(C3′, C4′), 39.4 (C1′).
1-[Hydroxy(phenyl)methyl]-1′-iodoferrocene (11)
1-[Hydroxy(phenyl)methyl]-1′-iodoferrocene (11)
A solution of phenylmagnesium bromide in THF (0.90 M, 2.10 mL, 1.90 mmol, 0.95 equiv)
was added dropwise to a solution of compound 10 (680 mg, 2.00 mmol, 1.00 equiv) in THF (20.0 mL) at –78 °C. Keeping the flask in
the cooling bath, the reaction mixture was allowed to warm slowly to –40 °C and the
progress of the reaction was monitored by TLC. After consumption of the starting material,
sat. aq NH4Cl (20 mL) was added and the mixture was warmed to rt before being extracted with
EtOAc (2 × 20 mL). The combined organic layers were dried (MgSO4), filtered over cotton wool, and concentrated under vacuum using a rotary evaporator
to give the crude product. This was purified by column chromatography over SiO2, using PE/EtOAc (80:20) to give the title product 11 as a red solid; yield: 812 mg (97%); mp 76–78 °C.
Splitting of some ferrocene peaks was noticed in both 1H and 13C NMR spectrum as previously observed in chiral ferrocenemethanol derivatives.[42]
IR (film): 3470, 1490, 1449, 1377, 1179, 1047, 1018, 806, 716 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.40–7.28 (m, 2 H, H2′′, H6′′), 7.35–7.32 (m, 2 H, H3′′, H5′′), 7.28–7.26 (m,
1 H, H4′′), 5.59 (d, J = 3.2 Hz, 1 H, CH), 4.46 (m, 1 H, H2′ or H5′), 4.45 (m, 1 H, H2′ or H5′), 4.27 (dd,
J = 1.8, 3.3 Hz, 1 H, H2 or H5), 4.21 (m, 2 H, H3, H4), 4.19 (m, 2 H, H3′, H4′), 4.14
(dd, J = 1.8, 3.3 Hz, 1 H, H2 or H5), 2.44 (d, J = 3.3 Hz, 1 H, OH).
1H NMR (500 MHz, DMSO-d
6): δ = 7.38 (d, J = 7.7 Hz, 2 H, H2′′, H6′′), 7.31 (t, J = 7.7 Hz, 2 H, H3′′, H5′′), 7.22 (t, J = 7.7 Hz, 1 H, H4′′), 5.50–5.48 (m, 2 H, OH + CH), 4.44 (m, 1 H, FcCH), 4.40 (m,
1 H, FcCH), 4.27 (m, 1 H, FcCH), 4.18 (m, 2 H, FcCH), 4.08 (m, 1 H, FcCH), 4.06 (m,
1 H, FcCH), 3.94 (m, 1 H, FcCH).
13C NMR (126 MHz, CDCl3): δ = 143.4 (C1′′), 128.4 (C3′′, C5′′), 127.7 (C4′′), 126.4 (C2′′, C6′′), 95.2 (C1),
75.3 (C2′ or C5′), 75.2 (C2′ or C5′), 71.9 (CH), 71.5 (C3 or C4), 71.3 (C3 or C4),
70.3 (C2 or C5), 69.6 (C3′ or C4′), 69.5 (C3′ or C4′), 68.9 (C2 or C5), 40.1 (C1′).
1-Benzoyl-1′-iodoferrocene (12) [CAS Reg. No. 1884149-19-2]
1-Benzoyl-1′-iodoferrocene (12) [CAS Reg. No. 1884149-19-2]
NMO (351 mg, 3.00 mmol, 3.00 equiv) was placed in a Schlenk tube, which was heated
at 90 °C under high vacuum for 3 h before cooling to rt. In a separate Schlenk tube,
compound 11 (418 mg, 1.00 mmol, 1.00 equiv) was dissolved in acetone (10.0 mL) and this solution
was cannulated onto NMO. RuCl2(PPh3)3 (47.9 mg, 50.0 μmol, 0.05 equiv) was added in one portion and the reaction mixture
was stirred at rt for 1 h, shielded from light. Volatiles were removed under vacuum
using a rotary evaporator. Aq 1 M HCl (20 mL) was added and the mixture was extracted
with EtOAc (2 × 20 mL). The combined organic layers were dried (MgSO4), filtered over cotton wool, and concentrated under vacuum using a rotary evaporator
to give the crude product. This was purified by column chromatography over SiO2, using PE/EtOAc (80:20) with 1% of NEt3 to give the title product 12 as a red oil; yield: 400 mg (96%).
Analytical data analogous to those reported previously.[10b]
IR (film): 1635, 1447, 1438, 1374, 1282, 1168, 1048, 1024, 852, 828, 797, 724 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.88 (d, J = 7.2 Hz, 2 H, H2′′, H6′′), 7.55 (t, J = 7.2 Hz, 1 H, H4′′), 7.47 (t, J = 7.6 Hz, 2 H, H3′′, H5′′), 4.90 (t, J = 1.9 Hz, 2 H, H2, H5), 4.55 (t, J = 1.9 Hz, 2 H, H3, H4), 4.41 (t, J = 1.8 Hz, 2 H, H2′, H5′), 4.19 (t, J = 1.8 Hz, 2 H, H3′, H4′).
13C NMR (126 MHz, CDCl3): δ = 198.2 (C=O), 139.6 (C1′′), 131.8 (C4′′), 128.4 (C3′′, C5′′), 128.3 (C2′′, C6′′),
79.7 (C1), 76.6 (C2′, C5′), 76.1 (C3, C4), 74.0 (C2, C5), 71.4 (C3′, C4′), 40.0 (C1′).
1′-Iodoferrocenecarbonitrile (13) [CAS Reg. No. 32876-20-3]
1′-Iodoferrocenecarbonitrile (13) [CAS Reg. No. 32876-20-3]
Compound 10 (0.68 g, 2.00 mmol, 1.00 equiv), NH2OH·HCl (181 mg, 2.60 mmol, 1.30 equiv), KI (0.53 g, 2.00 mmol, 1.00 equiv), and ZnO
(0.16 mg, 2.00 mmol, 1.00 equiv) were introduced in a Schlenk tube, which was subjected
to three cycles of vacuum/argon. MeCN (10.0 mL) was added and the reaction mixture
was stirred at 80 °C for 2 h. The mixture was cooled to rt and 5% aq Na2S2O3 (2.00 mL) was added and stirring was continued for 5 min. The mixture was filtered
and the resulting solids were washed with EtOAc (10 mL). H2O (10 mL) was added to the combined filtrates, which were extracted with EtOAc (3
× 15 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered over cotton wool, and concentrated under vacuum using a rotary evaporator
to give the crude product. This was purified by column chromatography, using PE/EtOAc
(90:10) to give the title product 13 as a dark red solid; yield: 0.61 g (91%); mp 39–41 °C.
IR (film): 3101, 3087, 2224, 1406, 1381, 1346, 1233, 1023, 865, 845, 812 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.62 (t, J = 1.9 Hz, 2 H, H2, H5), 4.55 (t, J = 1.9 Hz, 2 H, H2′, H5′), 4.39 (t, J = 1.9 Hz, 2 H, H3, H4), 4.34 (t, J = 1.9 Hz, 2 H, H3′, H4′).
13C NMR (126 MHz, CDCl3): δ = 119.2 (C≡N), 77.0 (C2′, C5′), 74.4 (C2, C5), 74.2 (C3, C4), 71.7 (C3′, C4′),
54.1 (C1), 39.8 (C1′).
MS: m/z = 337 [M], 210 [M – I], 183.
Methyl 1′-Iodoferrocenecarboxylate (14) [CAS Reg. No. 31869-23-5]
Methyl 1′-Iodoferrocenecarboxylate (14) [CAS Reg. No. 31869-23-5]
KOH (2.53 g, 45.0 mmol, 6.00 equiv) was added to a solution of compound 10 (2.51 g, 7.50 mmol, 1.00 equiv) in MeOH (98.0 mL) at 0 °C. I2 (5.71 g, 22.5 mmol, 3.00 equiv) was added to the reaction mixture, which was warmed
to rt and stirred for 1 h. Volatiles were removed under vacuum, aq 1 M HCl (30 mL)
was added, and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic
layers were washed with sat. aq Na2S2O3 (20 mL), H2O (10 mL), brine (10 mL), dried (MgSO4), filtered over cotton wool, and concentrated under vacuum using a rotary evaporator
to give the crude product. This was purified by column chromatography over SiO2, using PE/EtOAc (90:10) to give the title product 14 as an orange solid; yield: 2.69 g (97%); mp 75–77 °C.
IR (film): 2942, 1706, 1465, 1375, 1344, 1273, 1191, 1139, 1030, 696, 865, 843, 819,
773 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.78 (t, J = 1.9 Hz, 2 H, H2, H5), 4.41 (t, J = 1.7 Hz, 2 H, H2′, H5′), 4.38 (t, J = 1.9 Hz, 2 H, H3, H4), 4.17 (t, J = 1.7 Hz, 2 H, H3′, H4′), 3.82 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 171.0 (C=O), 76.2 (C2′, C5′), 74.4 (C3, C4), 73.5 (C1), 72.7 (C2, C5), 70.7
(C3′, C4′), 51.8 (CH3), 40.4 (C1′).
MS: m/z = 370 [M].
1′-Iodoferrocenecarboxylic Acid (15) [CAS Reg. No. 31832-98-1]
1′-Iodoferrocenecarboxylic Acid (15) [CAS Reg. No. 31832-98-1]
NaOH (1.40 g, 35.0 mmol, 5.00 equiv) dissolved in H2O (42.0 mL) was added to a solution of compound 14 (2.60 g, 7.00 mmol, 1.00 equiv) in MeOH (35.0 mL) at rt and the reaction mixture
was heated at 80 °C in a pre-heated bath for 75 min. The mixture was cooled to rt
and MeOH was removed under vacuum using a rotary evaporator. The resulting solution
was cooled to 0 °C and HCl (35% aq) was added dropwise until pH 1 was reached. The
resulting solid was filtered and washed with cold (0 °C) H2O (2 × 5 mL) and pentane (10 mL). Drying the solid under high vacuum with a P2O5 trap afforded the title product 15 as a dark red solid; yield: 2.39 g (96%); mp 153–155 °C.
IR (film): 3108, 2857 (br), 2636, 2562, 1667, 1482, 1296, 1166, 1025, 840, 745 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.86 (s, 2 H, H2, H5), 4.48 (s, 2 H, H2′, H5′), 4.47 (s, 2 H, H3, H4), 4.28
(s, 2 H, H3′, H4′). Acid proton missing.
13C NMR (126 MHz, CDCl3): δ = 176.9 (C=O), 76.5 (C2′, C5′), 75.4 (C3, C4), 73.2 (C2, C5), 72.1 (C1), 71.2
(C3′, C4′), 40.3 (C1′).
1′-Iodoferrocenoyl Azide (16)
1′-Iodoferrocenoyl Azide (16)
Et3N (4.32 mL, 3.14 g, 31.0 mmol, 5.00 equiv) was added to a solution of compound 15 (2.20 g, 6.20 mmol, 1.00 equiv) in CH2Cl2 (12.0 mL) at 40 °C. Diphenylphosphoryl azide (1.47 mL, 1.88 g, 6.82 mmol, 1.10 equiv)
was added dropwise to the reaction mixture, which was then kept at the same temperature
for 10 min. The mixture was cooled to rt and aq 1 M HCl (30 mL) was added. The mixture
was extracted with Et2O (2 × 30 mL) and the combined organic layers were dried (MgSO4), filtered over cotton wool, and concentrated under vacuum using a rotary evaporator
to give the crude product. This was purified by column chromatography over SiO2 using pentane/Et2O (90:10) to give the title product 16 as a red solid; yield: 2.02 g (85%); mp 102–104 °C.
IR (film): 2146, 1673, 1452, 1372, 1261, 1191, 1052, 989, 829, 818 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.81 (t, J = 1.9 Hz, 2 H, H2, H5), 4.49 (t, J = 1.9 Hz, 2 H, H3, H4), 4.47 (t, J = 1.8 Hz, 2 H, H2′, H5′), 4.24 (t, J = 1.8 Hz, 2 H, H3′, H4′).
13C NMR (126 MHz, CDCl3): δ = 176.0 (C=O), 76.6 (C2′, C5′), 75.7 (C3, C4), 74.5 (C1), 72.8 (C2, C5), 71.1
(C3′, C4′), 40.7 (C1′).
1-(tert-Butoxycarbonyl)amino-1′-iodoferrocene (17)
1-(tert-Butoxycarbonyl)amino-1′-iodoferrocene (17)
tert-BuOH (2.40 mL, 1.85 g, 25.0 mmol, 5.00 equiv) was added to a solution of compound
16 (1.85 g, 5.00 mmol, 1.00 equiv) in toluene (31.0 mL) at rt and the reaction mixture
was heated at 100 °C for 1 h in a pre-heated oil bath. The mixture was cooled to rt
and volatiles were removed under vacuum to give the crude product. This was purified
by column chromatography, using PE/EtOAc (90:10) to give the title product 17 as an orange solid; yield: 1.81 g (85%); mp 100–102 °C.
IR (film): 3354, 2147, 1697, 1550, 1389, 1366, 1252, 1157, 1073, 1028, 867, 808 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.86 (br s, 1 H, NH), 4.42 (br s, 2 H, H2, H5), 4.38 (s, 2 H, H2′, H5′), 4.13
(s, 2 H, H3′, H4′), 3.98 (s, 2 H, H3, H4), 1.51 [s, 9 H, C(CH3)3].
13C NMR (126 MHz, CDCl3): δ = 153.3 (C=O), 97.5 (C1), 80.3 [C(CH3)3], 75.6 (C2′, C5′), 69.7 (C3′, C4′), 67.1 (C3, C4), 62.9 (C2, C5), 42.6 (C1′), 28.5
[C(CH3)3].
1′-Iodoferrocenamine Hydrochloride (18)
1′-Iodoferrocenamine Hydrochloride (18)
A solution of HCl in Et2O (≈ 5.00 M, 24.0 mL, 120 mmol, 40.0 equiv) was added to a solution of compound 17 (1.28 g, 3.00 mmol, 1.00 equiv) in Et2O (30.0 mL) and the reaction mixture was stirred at rt for 2 h. The resulting solid
was quickly filtered and washed with Et2O (2 × 10 mL) and pentane (10 mL), and dried under high vacuum to give the title product
18 as an orange solid; yield: 800 mg (74%); mp 146–148 °C.
IR (film): 2802, 2601, 2569, 1672, 1608, 1521, 1469, 1375, 1143, 1023, 855, 833, 818
cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.84 (br s, 3 H, NH3
+), 4.61 (s, 2 H, H2′, H5′), 4.43 (s, 2 H, H2, H5), 4.39 (s, 2 H, H3′, H4′), 4.13 (s,
2 H, H3, H4).
13C NMR (126 MHz, CDCl3): δ = 89.2 (C1), 75.7 (C2′, C5′), 71.1 (C3′, C4′), 70.1 (C3, C4), 65.7 (C2, C5),
39.0 (C1′).
1-(Dimethylamino)-1′-iodoferrocene (19)
1-(Dimethylamino)-1′-iodoferrocene (19)
NaBH3CN (754 mg, 12.0 mmol, 6.00 equiv) was added portionwise to a solution of compound
18 (727 mg, 2.00 mmol, 1.00 equiv) and paraformaldehyde (720 mg, 24.0 mmol, 12.0 equiv)
in glacial AcOH (6.00 mL) at rt. The reaction mixture was stirred for 4 h before additional
portions of paraformaldehyde (120 mg, 4.00 mmol, 2.00 equiv) and NaBH3CN (120 mg, 2.00 mmol, 1.00 equiv) were added to the mixture, which was stirred at
rt overnight. EtOAc (20 mL) was added, followed by solid K2CO3 until pH 8 was reached. The layers were separated and the aqueous layer was extracted
with EtOAc (2 × 10 mL). The combined organic layers were dried (MgSO4), filtered over cotton wool, and concentrated under vacuum using a rotary evaporator
to give the crude product. This was purified by column chromatography over SiO2 using PE/EtOAc (80:20 to 70:30) to give the title product 19 as an orange solid; yield: 284 mg (40%); mp 52–54 °C.
IR (film): 3094, 2922, 1628, 1598, 1487, 1445, 1422, 1367, 1354, 1333, 1293, 1052,
1028, 1008, 814, 792, 726, 700 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.52 (s, 2 H, H2′, H5′), 4.24 (s, 2 H, H3′, H4′), 3.97 (s, 2 H, H3, H4), 3.71
(s, 2 H, H2, H5), 2.66 (br s, 6 H, 2 × CH3).
13C NMR (126 MHz, CDCl3): δ = 117.2 (C1), 73.1 (C2′, C5′), 67.8 (C3′, C4′), 66.9 (C3, C4), 58.1 (C2, C5),
42.4 (2 × CH3), 40.6 (C1′).
