Solubilizing influence of 2,7-bis(trimethylsilyl) substitution on the Fmoc residue

Full text of DOI:10.1021/jo001150v

9238
J . Org. Chem. 2000, 65, 9238-9240
Ta ble 1. Tim e for Com p lete Deblock in g of Su bstitu ted
Solu bilizin g In flu en ce of
Ur eth a n es (U-P CA) by Va r iou s Am in esa
2,7-Bis(tr im eth ylsilyl) Su bstitu tion on th e
F m oc Resid u e†
deblocking time
base
U ) Fmoc
Bts-Fmoc
Dtb-Fmoc
piperidineb
ethanolamine
morpholineb
tert-butylamine
<3 min
45 min
75 min
5 h
<3 min
90 min
190 min
4.5 h
12 min
4 h
10 h
20 h
Louis A. Carpino* and An-Chuu Wu
Department of Chemistry, Box 34510,
University of Massachusetts,
Amherst, Massachusetts 01003-4510
a
A mixture of urethane (0.05 mmol) in a solution prepared from
an equal volume of base (2.5 mmol, 50 equiv) and dichloromethane
was stirred at room temperature. The course of the reaction was
monitored by TLC with an eluant consisting of Skelly B-ether
carpino@chem.umass.edu
Received J uly 28, 2000
b
(3:1) For these amines, a significant amount of the amine-
dibenzofulvene adduct had formed during the periods indicated.
Recently Nowick and co-workers1 described the syn-
thesis of the 2,6-di-tert-butyl-9-fluorenemethyloxycarb-
onyl group (Fmoc* or Dtb-Fmoc) as a substitute for the
Fmoc function2 in cases where the latter led to highly
insoluble derivatives. It was shown for some systems that
such substitution enhanced solubilities by 1-2 orders of
magnitude.3
Faced with a similar problem, we also examined the
Dtb-Fmoc group with analogous results. In addition, we
investigated the related 2,7-bis(trimethylsilyl) (Bts) sys-
tems and found some Bts-substituted carbanilates to be
about 3 times more soluble than the Dtb analogues. The
synthesis of key alcohol 5 is outlined in Scheme 1.
Solubilities were examined for the p-chlorophenyl
carbanilates derived from 5 and the Fmoc and Dtb-Fmoc
analogues 6. For 6a -c solubilities per 100 mL of DCM
were 3.34, 6.74, and 22.3 g, respectively. While the Dtb-
Fmoc group was more sluggishly deblocked than the
Fmoc function, presumably due to a combination of
inductive and steric factors, the Bts-Fmoc and Fmoc
groups were nearly balanced, perhaps because steric
factors were opposed by anionic stabilization4 provided
by the silicon residues. Comparisons are given in Table
1.
The Bts-Fmoc function was also subject to deblocking
under conditions of catalytic hydrogenolysis as previously
reported5 for the Fmoc function. Although stable toward
acetic acid, the Bts-Fmoc function was converted, as
expected,6 to the Fmoc function itself, upon treatment
with trifluoroacetic acid.
In summary, substitution of the 2,7-di-tert-butyl- and
especially the 2,7-bis(trimethylsilyl)-Fmoc functions for
the Fmoc group itself is shown to significantly enhance
the solubility in a solvent such as methylene dichloride.
In addition, in the Bts-Fmoc case the rate of deblocking
by piperidine followed closely that of the Fmoc group,
whereas deblocking of the Dtb-Fmoc was somewhat
slower. These properties could be of practical importance
in the manipulation of highly insoluble Fmoc derivatives,
as already shown by Nowick1 for the Dtb-Fmoc function.
Exp er im en ta l Section
2,7-Di-ter t-bu tyl-9-flu or en em eth yl p-Ch lor oca r ba n ila te
(Dtb-F m oc-P CA), 6b. A mixture of 0.916 g of 2,7-di-tert-butyl-
9-fluorenemethanol7 and 0.456 g of p-chlorophenyl isocyanate
in 4.0 mL of dry benzene was treated as described for the silyl
analogues. Workup gave, after recrystallization from Skelly
B/acetone (4:1), 1.08 g (81.2%) of the pure carbanilate as white
crystals, mp 193-4 °C. IR (KBr): 3400 (NH), 1735 (CdO) cm-1
.
1H NMR (CDCl3): δ 1.37 (s, 18), 4.22 (t, 1), 4.60 (d, 2), 6.63 (b,
1), 7.18-7.55 (m, 10). Anal. Calcd for C29H32NO2Cl: C, 75.39,
H, 6.98; N, 3.03. Found: C, 75.36, H, 6.87; N, 3.01.
P ip er id in e Clea va ge of 2,7-Di-ter t-b u t yl-9-flu or en e-
m eth yl p-Ch lor oca r ba n ila te, 6b. A solution of 0.3 g of Dtb-
Fmoc-PCA in 6.5 mL of piperidine was stirred at room temper-
ature for 30 min and poured into 50 mL of cold water. The
suspended mixture was stirred for 20 min and the precipitate
was removed by filtration, rinsed with water (2 × 5 mL), and
dried in air to give 0.24 g (98.0%) of the crude N-(2,7-d i-ter t-
† Abbreviations used: Bts-Fmoc ) 2, 7-bis(trimethylsilyl)-9-fluo-
renemethyloxycarbonyl; DCM ) dichloromethane; Dtb-Fmoc ) Fmoc*
) 2, 7- di-tert-butyl-9-fluorenemethyloxycarbonyl; Fmoc ) 9- fluoren-
emethyloxycarbonyl; NBS ) N-bromosuccinimide; PCA ) p-chloro-
aniline; Skelly B ) saturated hydrocarbon solvent, bp range 60-70 °C;
Skelly F ) saturated hydrocarbon solvent, bp range 30-60 °C; TFA )
trifluoroacetic acid.
(5) (a) Carpino, L. A.; Tunga, A. J . Org. Chem. 1986, 51, 1930. (b)
Martinez, J .; Tolle, J . C.; Bodanszky, M. J . Org. Chem. 1979, 44, 3596.
(c) Atherton, E.; Bury, C.; Sheppard, R. C.; Williams, B. J . Tetrahedron
Lett. 1979, 20, 3041.
(6) (a) Chan, T. H.; Fleming, I. Synthesis, 1979, 761. (b) Eaborn, C.
J . Organomet. Chem. 1975, 100, 43.; (c) Gilman, H.; Marshall, F. J . J .
Am. Chem. Soc. 1949, 71, 2066. (d) Gilman, H.; Nobis, J . F. J . Am.
Chem. Soc. 1950, 72, 2629.; (e) Ha¨bich, D.; Ettenberger, F. Synthesis
1978, 755.
(1) Stigers, K. D.; Koutroulis, M. R.; Chung, D, M.; Nowick, J . S. J .
Org. Chem. 2000, 65, 3858.
(2) Carpino, L. A.; Han, G. Y. J . Org. Chem. 1972, 37, 3404.
(3) In addition to the examples cited by Nowick and co-workers, the
2,7-di-tert-butyl substitution pattern was found effective in solubility
enhancement in connection with thioxanthenes. See: Carpino, L. A.;
Gao, H.-S.; Ti, G.-S.; Segev, D. J . Org. Chem. 1989, 54, 5887.
(4) (a) Gornowicz, G. A.; West, R. J . Am. Chem. Soc. 1968, 90, 4478.
(b) Eaborn, C.; Eidenschink, R.; J ackson, P. M.; Walton, D. R. M. J .
Organomet. Chem. 1975, 101, C40. (c) Zhang, S.; Zhang, X.-M.;
Bordwell, F. G. J . Am. Chem. Soc. 1995, 117, 602.
(7) In contrast to Nowick’s method, our synthesis of 2,7-di-tert-butyl-
9-fluorenemethanol involved modification of our earlier method8 by
substitution of KH for NaH and in situ reduction of the crude aldehyde
by NaBH4. The properties of the two samples were in agreement. For
the fluorene precursor our method was the same as Nowick’s, except
that CH2Cl2 was used as solvent in place of CS2 and the crude product
was passed through a short column of alumina to remove inorganic
byproducts prior to recrystallization.
(8) Carpino, L. A. J . Org. Chem. 1980, 45, 4250.
10.1021/jo001150v CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/30/2000

Notes
J . Org. Chem., Vol. 65, No. 26, 2000 9239
Sch em e 1
bu tyl-9-flu or en em eth yl)p ip er id in e9 as an off-white solid.
Recrystallization from methanol/chloroform (2:1) afforded 0.20
g (82.01%) of the pure amine as colorless needles, mp. 159-160
°C. 1H NMR (CDCl3): δ 1.42 (s, 18), 1.50-1.82 (m, 6), 2.55-
2.70 (m, 6), 4.02 (t, 1), 7.34-7.82 (m, 6). Anal. Calcd for
of dry ether was added dropwise 18 mL of 1.3 M n-butyllithium
at 0 °C. The mixture was stirred at room temperature for 30
min and cooled in an ice bath. Gaseous formaldehyde, generated
by heating 2.5 g of dried paraformaldehyde at 170 °C, was passed
through a wide tube (8 mm) into the reaction mixture with the
aid of a slow stream of nitrogen until the black color had
disappeared. The mixture was washed with half-saturated NH4-
Cl (50 mL) and water (50 mL). The pooled aqueous layer was
extracted with ether (2 × 50 mL) and the combined organic
extracts were dried over MgSO4. After removal of the solvent
under reduced pressure, the residue was chromatographed on
silica gel (230-400 mesh, 5 × 60 cm packed column) with an
eluant consisting of Skelly B/ether (3:1), to afford 3.73 g (56.7%)
of the alcohol as a white solid. Recrystallization from Skelly B
gave 3.30 g (50.16%) of the pure alcohol as colorless crystals,
mp 112.5-113 °C. IR (KBr): 3250 cm-1 (br, OH). 1H NMR
(CDCl3): δ 0.32 (s, 18), 1.57 (br s, 1), 4.03-4.17 (m, 3), 7.20-
7.90 (m, 6). Anal. Calcd for C20H28Si2O: C, 70.53; H, 8.29.
Found: C, 70.44; H, 8.26.
C
27H37N: C, 86.34; H, 9.93. Found: C, 86.57; H, 9.84.
2,7-Dibr om o-9,9-bis(tr im eth ylsilyl)flu or en e, 2. To a sus-
pension of 4.0 g of 9,9-bis(trimethylsilyl)fluorene10 and 5.0 g of
N-bromosuccinimide in 90 mL of glacial acetic acid was added
1 mL of 48% hydrobromic acid over a period of 3 min. The
reactants dissolved as a new solid separated. After 6 h, 200 mL
of water was added slowly and the solid was filtered, rinsed with
water, and dried in air to afford 6.04 g (99.6%) of the crude
dibromide as a yellowish solid. Recrystallization from acetone
gave 4.51 g (74.4%) of 2,7-dibromo-9,9-bis(trimethylsilyl)fluorene
as white needles, mp 201-202 °C. 1H NMR (CDCl3): δ -0.07
(s, 18), 7.25-7.93 (m, 6). Anal. Calcd for C19H24Br2Si2: C, 48.75;
H, 5.16. Found: C, 49.12; H, 5.27.
2,7,9,9-Tetr a k is(tr im eth ylsilyl)flu or en e, 3. A mixture of
4.0 g of 2,7-dibromo-9,9-bis(trimethylsilyl)fluorene and 4.0 mL
of freshly distilled chlorotrimethylsilane in 70 mL of toluene was
added slowly to molten sodium (1 g of finely cut sodium in 40
mL of boiling toluene). The mixture was refluxed for 12 h and
cooled in an ice bath. Ice chips were added slowly to destroy the
excess sodium. The mixture was then washed with water (2 ×
70 mL) and the pooled aqueous layer was extracted with ether
(2 × 100 mL). The combined organic extracts were dried over
anhydrous MgSO4, and the solvent was evaporated in vacuo to
give 3.63 g (93.6%) of the crude tetrasilane as an off-white solid.
Recrystallization form methanol afforded 2.75 g (70.9%) of the
pure silane derivative as white needles, mp 141-142 °C. 1H
NMR (CDCl3): δ -0.10 (s, 18), 0.32 (s, 18), 7.20-8.00 (m, 6).
Anal. Calcd for C25H42Si4: C, 66.00; H, 9.31. Found: C, 66.04;
H, 9.21.
2,7-Bis(tr im eth ylsilyl)flu or en e, 4. To a suspension of 0.5
g of 2,7,9,9-tetrakis(trimethylsilyl)fluorene in 15 mL of 95%
ethanol was added 1.5 mL of 10% KOH. The mixture was
refluxed for 2 h and cooled in an ice bath for 1 h. The precipitated
crystals were removed by filtration, rinsed with water (2 × 5
mL), dried in air, and recrystallized from methanol to give 0.32
g (93.8%) of the pure fluorene derivative as colorless crystals,
mp 117-118 °C. 1H NMR (CDCl3): δ 0.31 (s, 18), 3.90 (s, 2),
7.20-7.90 (m, 6). Anal. Calcd for C19H26Si2: C, 73.48; H, 8.44.
Found: C, 73.23; H, 8.43.
2,7-Bis(tr im eth ylsilyl)-9-flu or en em eth yl p-Ch lor oca r b-
a n ila te (Bts-F m oc-P CA), 6c. A mixture of 2.5 g of 2,7-bis-
(trimethylsilyl)fluorenemethanol and 1.13 g of p-chlorophenyl
isocyanate in 20 mL of dry benzene was heated in an oil bath at
80 °C for 4 h. The mixture was cooled to room temperature,
treated with 60 mL of Skelly B, and stirred for another 30 min.
The precipitate was removed by filtration to give 3.60 g (99.3%)
of the crude urethane as a white solid. Recrystallization from
Skelly B gave 3.14 g (86.3%) of the carbanilate as white crystals,
mp 162.5-163 °C. IR (KBr): 3240 (NH), 1710 (CdO) cm-1 1H
.
NMR (CDCl3): δ 0.30 (s, 18), 4.28 (t, 1), 4.58 (d, 2), 6.60 (b, 1),
7.15-7.90 (m, 10). Anal.Calcd for C27H32NO2Si2Cl: C, 65.62; H,
6.53; N, 2.83. Found: C, 65.80; H, 6.66; N, 2.80.
2,7-Bis(tr im eth ylsilyl)-9-flu or en em eth yl Car ban ilate (Bts-
F m oc-a n ilin e), 6c, Cl-p ) H. A mixture of 0.71 g of 2,7-bis-
(trimethylsilyl)fluorene-9-methanol and 0.22 mL of phenyl
isocyanate in 4 mL of dry benzene was treated as described for
the p-chloro analogue. Workup gave 0.81 g (87.13%) of the
urethane as white crystals, mp 178-179 °C. IR (KBr): 3240
(NH), 1710 (CdO) cm-1 1H NMR (CDCl3): δ 1.31 (s, 18), 4.30
.
(t, 1), 4.58 (d, 2), 6.61 (b,1), 6.90-7.90 (m, 11). Anal. Calcd for
C27H33NO2Si2: C, 70.54; H, 7.24; N, 3.05. Found: C, 70.40; H,
7.01; N, 2.92.
P ip er id in e Clea va ge of 2,7-Bis(tr im eth ylsilyl)-9-flu o-
r en em eth yl p-Ch lor oca r ba n ila te, 6c. A solution of 0.4 g of
Bts-Fmoc-PCA in 7.6 mL of piperidine was stirred at room
temperature for 30 min and poured into 125 mL of cold water.
The precipitate was removed by filtration and the filtrate was
extracted with ether (3 × 50 mL). The combined organic extracts
were dried over anhydrous MgSO4, and the solvent was evapo-
2,7-Bis(tr im eth ylsilyl)flu or en e-9-m eth a n ol, 5. To an ice-
cold solution of 6.0 g of 2,7-bis(trimethylsilyl)fluorene in 100 mL
(9) Nowick and co-workers inferred the presence of this byproduct
of the deblocking process but did not isolate and purify the material.
(10) Eaborn, C.; Shaw, R. A. J . Chem. Soc. 1955, 1420.

9240 J . Org. Chem., Vol. 65, No. 26, 2000
Notes
rated under reduced pressure to give 0.10 g (96.9%) of yellow
solid, identified by NMR spectroscopy as p-chloroaniline. The
solid (0.31 g, 94.0%, mp 105-108 °C) precipitated from the
original solution by the addition of water was recrystallized from
methanol to give 0.25 g (75.8%) of N-[2,7-bis(tr im eth ylsilyl)-
9-flu or en em eth yl]p ip er id in e, mp 107-108 °C. 1H NMR
(CDCl3): δ 0.32 (s, 18), 1.47-1.80 (m, 6), 2.50-2.68 (m, 6), 4.05
(t, 1), 7.43-7.96 (m, 6). Anal. Calcd for C25H37NSi2: C, 73.64,
H, 9.15; N, 3.44. Found: C, 73.38; H, 8.94, N, 3.35.
EtOAc-Skelly B (2:1) gave 0.16 g (75.3%) of the pure Fmoc-
PCA as colorless needles, mp 184-185 °C (lit.11 mp 183.5-185
°C), identified by mixture melting point and IR and NMR
spectral comparisons with an authentic sample.
2,7-Bis(tr im eth ylsilyl)-9-flu or en em eth yl Ch lor ofor m a te,
5, H ) COCl. To a stirred solution of 1 mL of liquid phosgene,
condensed at -78 °C, in 10 mL of dry THF was added dropwise
a solution of 2.0 g of 2,7-bis(trimethylsilyl)-9-fluorenemethanol
in 20 mL of dry THF at 0 °C over a period of 30 min. The mixture
was stirred for another hour at 0 °C. Excess phosgene along with
the solvent was removed by a water aspirator in a hood to afford
an oil which was triturated with Skelly F to give 2.3 g (97.1%)
of the crude choroformate as white crystals. Recrystallization
from Skelly F gave 2.02 g (85.23%) of the pure chloroformate as
colorless crystals, mp 64-66 °C. IR (KBr): 1770 cm-1 (CdO).
1H NMR (CDCl3): δ 0.37 (s, 18), 4.32 (t, 1), 4.57 (d, 2), 7.50-
7.90 (m, 6). Anal. Calcd for C21H27O2Si2Cl: C, 62.58; H, 6.75.
Found: C, 62.79; H, 6.74.
H yd r ogen olysis of 2,7-Bis(t r im et h ylsilyl)-9-flu or en e-
m eth yl Ca r ba n ila te, 6c, Cl-p ) H. To a solution of 0.2 g of
2,7-bis(trimethylsilyl)-9-fluorenemethyl carbanilate in 15 mL of
100% ethanol and 15 mL of EtOAc was added 20 mg of 10%
palladium on charcoal at 0 °C. The heterogeneous mixture was
stirred under a hydrogen atmosphere (1 atm) for 20 h. The
catalyst was filtered and rinsed with EtOAc (2 × 5 mL). The
combined filtrate was washed with saturated NH4Cl (2 × 20 mL)
and water (20 mL) and dried over anhydrous MgSO4. After
evaporating the solvent in vacuo, the residue (0.14 g) was
recrystallized from 95% ethanol to afford 0.11 g (78.0%) of 2,7-
bis(tr im eth ylsilyl)-9-m eth ylflu or en e as white needles, mp
Ack n ow led gm en t. We are indebted to the National
Science Foundation (NSF CHE-9003192) and the Na-
tional Institutes of Health (GM-09706) for support of
this work. The National Science Foundation is also
thanked for grants used to purchase the high-field NMR
spectrometers used in this research. We also thank
Messrs. J .-H. Tien, H. Shroff, and C. S. Onu for
preliminary work on the synthesis of the Novick alcohol.
1
106.5-108 °C. H NMR (CDCl3): δ 0.34 (s, 18), 1.58 (d, 3), 3.96
(q, 1), 7.4-7.0 (m, 6). Anal. Calcd for C20H28Si2: C, 74.00; H,
8.69. Found: C, 73.91; H, 8.51.
P r oton olysis of 2,7-Bis(tr im eth ylsilyl)-9-flu or en em eth yl
p-Ch lor oca r ba n ila te, 6c, in Tr iflu or a cetic Acid . To a solu-
tion of 0.3 g of Bts-Fmoc-PCA in 8 mL of CH2Cl2 was added
dropwise a solution of 0.5 mL (10.7 equiv) of trifluoroacetic acid
in 3.0 mL of methylene chloride over a period of 10 min. The
mixture was stirred at room temperature for 12 h, washed with
water (2 × 10 mL), and neutralized with saturated NaHCO3 (2
× 10 mL). The organic layer was dried over MgSO4 and the
solvent was evaporated in vacuo to give 0.19 g (89.5%) of crude
9-fluorenemethyl p-chlorocarbanilate, 6a . Recrystallization from
J O001150V
(11) Carpino, L. A.; Mansour, E. M. E.; Cheng, C. H.; Williams, J .
R.; Macdonald, R.; Knapczyk, J .; Carman, M.; Lopusinski, A. J . Org.
Chem. 1983, 48, 661.