Efficient routes toward 4-[(2-aminoethoxy)methyl]benzophenone

Article abstract of DOI:10.1080/00397910500383121

The novel benzophenone derivative 4-[(2-aminoethoxy)methyl]benzophenone (4) was synthesized via two pathways, commencing from 4-(bromomethyl)-benzophenone (1) and methyl 4-(bromomethyl)benzoate (7) respectively. All new compounds were characterized by

Full text of DOI:10.1080/00397910500383121

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Efficient Routes Toward
4‐[(2‐Aminoethoxy)methyl]benzophenone
Rui‐ren Tang a , Jin‐juan Zhu a & Yi‐ming Luo a
a School of Chemistry and Chemical Engineering , Central South University ,
Changsha, China
Published online: 19 Aug 2006.
To cite this article: Rui‐ren Tang , Jin‐juan Zhu & Yi‐ming Luo (2006) Efficient Routes Toward
4‐[(2‐Aminoethoxy)methyl]benzophenone, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 36:4, 421-427, DOI: 10.1080/00397910500383121
To link to this article: http://dx.doi.org/10.1080/00397910500383121
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Synthetic Communicationsw, 36: 421–427, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500383121
Efficient Routes Toward
4-[(2-Aminoethoxy)methyl]benzophenone
Rui-ren Tang, Jin-juan Zhu, and Yi-ming Luo
School of Chemistry and Chemical Engineering, Central South
University, Changsha, China
Abstract: The novel benzophenone derivative 4-[(2-aminoethoxy)methyl]benzo-
phenone (4) was synthesized via two pathways, commencing from 4-(bromomethyl)-
benzophenone (1) and methyl 4-(bromomethyl)benzoate (7) respectively. All new
compounds were characterized by 1H NMR, MS, IR, and EA.
Keywords: 4-[(2-Aminoethoxy)methyl]benzophenone, photophobes, synthesis
Recently, benzophenone photoprobes[1,2] have been extensively used to study
nucleotide, receptor, and enzyme binding sites; equipped with chemically
reactive groups, the benzophenone-containing reagents have also been
employed as cross-linkers to investigate intramolecular as well as protein–
protein interactions.[3–5] The benzophenone photoprobes are superior to
other photoactivatable groups in that the benzophenone group is chemically
more stable and can be photoactivated at 350–360 nm, avoiding protein-
damaging in shorter wavelengths. With the aim of developing new and
more efficient benzophenone photoprobes, we designed three routes toward
a novel benzophenone derivative, 4-[(2-aminoethoxy)methyl]benzophenone
(4), as shown in Schemes 1–3.
Received in Japan June 16, 2005
Address correspondence to Rui-ren Tang, School of Chemistry and Chemical
Engineering, Central South University, Changsha 410083, China. E-mail: trr@mail.
csu.edu.cn
421

422
R. Tang, J. Zhu, and Y. Luo
Scheme 1.
To date, there have been no reported syntheses of compounds 6, 8, and 9.
Oatis et al.[2] have reported the synthesis of 4-(hydroxymethyl)benzophenone
(2) by hydrolysis of 1 with potassium carbonate in refluxing in water for 48 h.
We improved upon this reaction by employing benzyltriethylammonium
chloride as a phase-transfer catalyst and stirring the reaction for 5 h at room
temperature to give 2 in 77% yield (Scheme 1). The benzyl alcohol 2 was
successfully converted to its metal salt by treatment with either sodium hydride
or t-BuOK and was subsequently exposed to methyl (2-chloroethyl)carbamate
(ClCH2CH2NHCOOCH3) under standard Williamson conditions in different
solvents (THF, dioxane). Surprisingly, the expected etherification reaction
failed to take place; no trace of the desired product 3 was detected by GC-
MS and the major compound isolated by purification was unreacted 2. This
revealed that the chloride leaving group of the carbamate is not reactive
enough to be displaced by the anion of 2. It was expected that the target 4
could be formed from 3 by base-mediated removal of the acetyl group.
Yibo Zhou et al.[6] have reported the synthesis of aminoethoxy-containing
compounds from chlor-pyridazinones and salts of ethanolamine (e.g.,
NaOCH2CH2NH2). Based on this literature precedent, we envisaged that 4
could be prepared by treatment of 1 with NaOCH2CH2NH2. Experimentally,
Scheme 2.

4-[(2-Aminoethoxy)methyl]benzophenone
423
Scheme 3.
this resulted in the formation of many by-products, including the Schiff
base obtained by reaction of the carbonyl group of 1 with the amino group
of ethanolamine. Fortunately, after the amino functionality was protected[7]
as the t-butoxycarbonyl (Boc) group with Boc anhydride, the ether 4 could
be conveniently prepared in high yield by treatment of bromide 1 with
NaOCH2CH2NHBoc, followed by basic hydrolysis (Scheme 2). Our original
intention was to convert 1 to 4 via Boc-protected 5, but unexpectedly
the acid 6 formed by partial hydrolysis, rather than 5, was obtained as the inter-
mediate. Treatment of 6 with base completed the very facile synthesis of 4.
Another route for the synthesis of 4 was investigated, commencing from
methyl 4-(bromomethyl)benzoate 7. This was initially treated with NaOCH2-
CH2NHBoc in THF to yield 8. After the ester 8 was converted to the acid
chloride 9 in three high-yielding steps, a classical Friedel–Crafts reaction
was employed to prepare the Boc-protected amine 5. Benzene was treated
with 9 and catalytic aluminium trichloride, yielding 4 after acidic hydrolysis
of the Boc group of 5.
In summary, we have presented two facile routes for the preparation of
4-[(2-aminoethoxy)methyl]benzophenone (4), commencing from either
4-(bromomethyl)benzophenone (1) or methyl 4-(bromomethyl)benzoate (7),
and Boc-protected ethanolamine.
EXPERIMENTAL
General
All reactions were monitored by TLC on silica-gel F-254 plates (Merck)
with detection under UV light. Uncorrected melting points were determined
1
using a XRC-1 apparatus. All H NMR spectra were recorded at 297 K on a
400 MHz apparatus as samples in CDCl3. Chemical shifts are reported as

424
R. Tang, J. Zhu, and Y. Luo
1
d (ppm) relative to CHCl3, fixed at 7.26 ppm for H NMR. Infrared spectra
were measured on a Perkin-Elmer 1600 FTIR spectrophotometer as KBr
pellets. GC-MS data were measured with a HP 5988 instrument.
Compound 1 was synthesized by the method of Houlihan and Nadelson.[8]
4-(Hydroxymethyl)benzophenone (2)
A mixture of 1 (11.0 g, 40 mmol), K2CO3 (15.2 g, 120 mmol), and benzyl-
triethylammonium chloride (1.0 g) in water (100 mL) was stirred at room
temperature for 8 h. The product was extracted into ethyl acetate
(2 ꢀ 100 mL), and the organic extracts were dried over Na2SO4. The
solvent was removed by evaporation to give a yellow solid (7.8 g), which
was crystallized from propanol to give 3 (6.5 g, 77.0%), mp 98–1008C
1
(lit.[2] 59–618C). H NMR: d 7.77–7.61 (m, 5H, Ar-H), 7.50–7.46 (dd, 4H,
J ¼ 7.6 Hz), 4.79 (s, 2H, CH2). MS (m/e): 212 (Mþ), 135, 105.
4-([(2-Carboxyamino)ethoxy]methyl)benzophenone (6)
t-Butoxycarbonyl anhydride (7.3 g, 32 mmol) was dropwise added to a
solution of ethanolamine (2.0 g, 32 mmol) in THF (20 mL) with the tempera-
ture kept below 08C using an ice–salt bath. After the addition was complete,
the reaction mixture was stirred at room temperature for about 30 min. The
reaction mixture was concentrated, and the crude product was diluted with
ethyl acetate, washed with water, and dried over Na2SO4. Evaporation
of the solvent yielded crude HOCH2CH2NHBoc as an oily residue (5.2 g).
Na (0.23 g, 10 mmol) was added to a solution of HOCH2CH2NHBoc
(1.61 g, 10 mmol) in anhydrous THF (20 mL) and the reaction mixture was
stirred until no Na remained. Having generated NaOCH2CH2NHBoc in situ,
a solution of 1 (2.5 g, 9 mmol) in THF (10 mL) was added, and the reaction
was refluxed for about 5 h. The mixture was cooled, the solvent was evapor-
ated, and the residue was diluted with ethyl acetate (20 mL). HCl (3 N) was
added dropwise until pH 5 was reached, and the aqueous phase was
extracted with ethyl acetate (2 ꢀ 10 mL). The combined organic extracts
were washed with saturated NaHCO3 solution (20 mL), and water (20 mL)
and dried over Na2SO4. After the solvent was evaporated, the crude product
was purified by crystallization from ethanol to give 6 (2.3 g, 87%), mp
1
63–648C. H NMR: d 7.81–7.79 (dd, 4H, J ¼ 7.5 Hz, Ar–H), 7.62–7.58
(t, 1H, J ¼ 7.2 Hz, Ar–H), 7.51–7.50 (t, 2H, J ¼ 7.8 Hz, Ar–H), 7.42–7.40
(d, 2H, J ¼ 8.0 Hz, Ar–H), 4.52 (s, 2H, Ar–CH2), 4.35 (t, 2H, J ¼ 8.0 Hz,
–OCH2), 3.48 (t, 2H, J ¼ 8.0 Hz, –CH2–). MS (m/e): 281 (Mþ–H2O),
255, 204, 176, 105. IR (KBr): 3447, 2985, 2898, 1734, 1651, 1596, 1575,
1521 cm21. Elemental analysis calcd. for C17H17NO4: C, 68.23; H, 5.69; N,
4.68. Found: C, 68.71; H, 5.62; N, 4.66.

4-[(2-Aminoethoxy)methyl]benzophenone
425
4-[(2-Aminoethoxy)methyl]benzophenone (4) from Acid 6
To a solution of 6 (1 g, 3.3 mmol) in 95% ethanol (10 mL) was added 30%
NaOH (10 mmol). After stirring for 5 h at room temperature, the reaction
mixture was concentrated and the crude product was obtained as a yellow
oil. Purification by flash chromatography gave 4 (0.81 g, 97%) as a yellow
oil. 1H NMR: d 7.80–7.77 (m, 4H, Ar–H), 7.61–7.57 (m, 1H, Ar–H),
7.50–7.43 (m, 4H, Ar–H), 3.90 (s, 2H, ArCH2), 3.71–3.68 (t, 2H, OCH2),
2.84–2.82 (t, 2H, CH2N), 2.22 (s, 2H, NH2); MS (m/e): 254 (Mþ 2 1),
224, 195, 167, 105. IR (KBr): 3304, 2950, 2837, 1654, 1606, 1557, 1176,
1051, 841, 701 cm21. Elemental analysis calcd. for C16H17NO2: C, 75.29;
H, 6.67; N, 5.49. Found: C, 75.71; H, 6.52; N, 5.46.
Methyl 4-[(2-[(t-butoxycarbonyl)amino]ethoxy)methyl]benzoate (8)
Na (2.3 g, 100 mmol) was added to a solution of HOCH2CH2NHBoc (16.1 g,
100 mmol) in THF (150 mL), and the reaction was stirred for 8 h until no
Na remained. Compound 7 (19.1 g, 90 mmol) was added to this solution of
the sodium salt in anhydrous THF (100 mL), and the reaction was refluxed
for about 5 h. The reaction mixture was concentrated, and the residue
was diluted with CHCl3 (100 mL). HCl (5%) was added dropwise until
pH 5 was reached, and the aqueous phase was extracted with CHCl3
(2 ꢀ 30 mL). The combined organic extracts were washed with saturated
NaHCO3 solution (80 mL) and water (80 mL) and dried over Na2SO4. After
the solvent was evaporated, the crude product was purified by crystallization
1
from ethyl acetate to give 6 (24.5 g, 87%), mp 56–588C. H NMR: d 8.00
(s, 1H, NH), 7.89 (d, 2H, J ¼ 7.4 Hz, Ar-H), 7.31 (d, 2H, J ¼ 7.5 Hz,
Ar–H), 4.68 (s, 2H, Ar–CH2), 4.13 (t, 2H, J ¼ 7.8 Hz, –OCH2), 4.01
(s, 3H, OCH3), 3.87 (t, 2H, J ¼ 8.0 Hz, –CH2N–), 1.40 (s, 9H, –C(CH3)3).
MS (m/e): 294 (Mþ–CH3), 252(M–C4H9). Elemental analysis calcd. for
C16H23NO5: C, 62.14; H, 7.44; N, 4.53. Found: C, 62.58; H, 7.52; N, 4.59.
4-[(2-[(t-Butoxycarbonyl)amino]ethoxy)methyl]benzoyl Chloride (9)
To a solution of 8 (11.7 g, 40 mmol) in methanol (100 mL) was added 30%
NaOH (30 mL), and the reaction was stirred at room temperature for 24 h.
The reaction mixture was concentrated and acidified to pH 5 with 5% HCl.
The product was extracted into ethyl acetate (3 ꢀ 50 mL), and the
combined organic extracts were washed with saturated NaCl solution
(80 mL) and dried over Na2SO4. After the solvent was evaporated, SOCl2
(25 mL, 343 mmol) was added to the residue, and the reaction was heated at
reflux under N2 for 4 h. The excess SOCl2 was removed under reduced
pressure, and the crude solid obtained was purified by crystallization from

426
R. Tang, J. Zhu, and Y. Luo
1
benzene to give 9 (9.9 g, 79%), mp 52–548C. H NMR: d 8.05 (s, 1H, NH),
7.98 (d, 2H, J ¼ 7.2 Hz, Ar–H), 7.31 (d, 2H, J ¼ 7.1 Hz, Ar–H), 4.57
(s, 2H, Ar–CH2), 4.09 (t, 2H, J ¼ 7.8 Hz, –OCH2), 3.84 (t, 2H, J ¼ 8.0 Hz,
–CH2N–), 1.36 [s, 9H, –C(CH3)3]. MS (m/e): 313(Mþ), 315 (Mþ þ 2),
283 (Mþ–2CH3), 256 (M–C4H9). Elemental analysis calculated for
C15H20ClNO4: C, 57.42; H, 6.38; N, 4.47. Found: C, 56.95; H, 6.35; N, 4.46.
4-[(2-[(t-Butoxycarbonyl)amino]ethoxy)methyl]benzophenone (5)
A solution of 9 (2.5 g, 9 mmol) in THF (20 mL) was dropwise added to a sus-
pension of anhydrous AlCl3 (2.7 g, 20 mmol) in benzene (50 mL) and the
mixture was refluxed for 2 h. The reaction was cooled to room temperature
and poured into a mixture of 36% HCl (10 mL) and ice. The aqueous layer
was extracted with benzene (2 ꢀ 10 mL), and the organic extracts were
washed with saturated NaHCO3 solution (20 mL) and water (20 mL) and
dried over Na2SO4. After the solvent was evaporated, the crude product was
purified by crystallization from ethanol to give 5 (2.6 g, 81%), mp
1
47–498C. H NMR: d 7.86–7.81 (dd, 4H, J ¼ 7.2 Hz, Ar-H), 7.63–7.40
(m, 5H, Ar–H), 4.58 (s, 2H, Ar–CH2), 4.45 (t, 2H, J ¼ 8.0 Hz, –OCH2),
3.38 (t, 2H, J ¼ 8.0 Hz, –CH2–), 1.48 [s, 9H, –C(CH3)3]. MS (m/e): 325
(Mþ–2CH3), 298 (M–C4H9), 254, 224, 195. Elemental analysis calcd. for
C21H25NO4: C, 70.99; H, 7.04; N, 3.94. Found: C, 71.32; H, 7.22; N, 4.01.
4-[(2-Aminoethoxy)methyl]benzophenone (4) from Boc Derivative 5
The Boc group of 5 was removed with CF3COOH (1.1 eq) in CH2Cl2 via the
method of Ref. 9, giving 4 (yield, 97%).
ACKNOWLEDGMENTS
This work was supported by the Scientific Research Foundation for the
returned Overseas Chinese Scholars (State Education Ministry).
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