Alternative route to the diisocyanate building block 1,4-Diisocyanato-4- Methylpentane (DIMP)

Article abstract of DOI:10.1080/00397910903097278

The synthesis of 1,4-diisocyanato-4-methylpentane was accomplished starting from isobutyronitrile in six steps with 53% overall yield. The two isocyanates were installed by a double Curtius rearrangement. The product reacts with alcohol in a regioselective manner. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903097278

Synthetic Communications1, 40: 1437–1444, 2010
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903097278
ALTERNATIVE ROUTE TO THE DIISOCYANATE
BUILDING BLOCK 1,4-DIISOCYANATO-4-
METHYLPENTANE (DIMP)
Matthew C. Davis and Lawrence C. Baldwin
Chemistry and Materials Division, Michelson Laboratory, Naval Air
Warfare Center, China Lake, California, USA
The synthesis of 1,4-diisocyanato-4-methylpentane was accomplished starting from
isobutyronitrile in six steps with 53% overall yield. The two isocyanates were installed by
a double Curtius rearrangement. The product reacts with alcohol in a regioselective manner.
Keywords: Curtius reaction; dicarboxylic acid; diisocyanate; dinitrile
Van Benthem and colleagues recently reported that 1,4-diisocyanato-4-
methylpentane (1, DIMP) could be used as a ‘‘double-sided molecular adhesive
tape.’’[1] The molecule was first prepared by Heitka¨mper at Bayer AG in three steps
shown in Scheme 1.[2] Detailed conditions for reduction of the nitrocyano inter-
mediate were not disclosed, and it appeared that this step might be difficult. Also,
avoiding the final step of phosgenation of the diamine was desirable. Therefore, an
alternative method for the preparation of 1 was sought.
Nowatari et al. were able to convert 2,2-dimethyladipic acid (4) into
Heitka¨mper’s penultimate diamine using the Schmidt reaction.[3,4] Using the related
Curtius rearrangement,[5] it was conceived that 4 could be converted into 1 in the
final steps of the synthesis. Diacid 4 has been synthesized previously by nitric acid
oxidation of 2,2-dimethylcyclohexanone, but the latter is not convenient to pre-
pare.[6–8] Thus, the preparation of 4 described by Singer and Ja¨ger was followed
(Scheme 2).[9] First, lithioisobutyronitrile[10] was alkylated with 1-bromo-3-
chloropropane to give the chloronitrile 2.[11–14] Nucleophilic substitution of 2 with
sodium or potassium cyanide in hot N,N-dimethylformamide gave the dinitrile 3.
Refluxing 3 in a mixture of hydrochloric acid and ethanol gave only incomplete
hydrolysis after 24 hours. Complete hydrolysis of 3 to 4 was achieved after 18 hours
of reflux in a mixture of acetic and concentrated hydrochloric acids.[15,16] The diacid
dichloride 5 was readily made by reaction of 4 in thionyl chloride at room tempera-
ture. The intermediate diacyl diazide 6 was made from 5 in a mixture of
Received March 23, 2009.
This article is not subject to U.S. copyright law.
Address correspondence to Matthew C. Davis, Chemistry and Materials Division, Michelson
Laboratory, Naval Air Warfare Center, China Lake, CA 93555, USA. E-mail: matthew.davis@navy.mil
1437

1438
M. C. DAVIS AND L. C. BALDWIN
Scheme 1. Original synthesis of 1. Reagents and conditions: a) base; b) reduction; c) COCl2, PhCl.
1,2-dichloroethane=water=sodium azide and was not isolated. This reaction was
monitored by proton nuclear magnetic resonance (1H NMR) spectroscopy for com-
pletion. The solvent was dried and then refluxed to bring about the Curtius
1
rearrangement while observing the reaction with H NMR. When the peaks corre-
sponding to 6 disappeared [2.35 ppm, a-CH2, and 1.18 ppm, a-C(CH3)2], the solvent
was evaporated, and 1 was distilled. Additional chemical shifts for intermediates in
the synthesis are collected in Table 1.
To confirm the selectivity of 1 found by Van Benthem et al.,[1] 1 was reacted
with the alcohol N-ethyl-N-(2-hydroxyethyl)aniline (7) using their conditions
(Scheme 3).[1] Adding 1 wt% zirconium(IV) tetra(acetylacetonate) to a neat, room-
temperature, equimolar mixture of 1 and 7 was followed by a brief exotherm. After
1 hour, 1H NMR showed complete consumption of the primary isocyanate group to
Scheme 2. Synthesis of diisocyanate (1). Reagents and conditions: a) LDA, THF, Br(CH2)3Cl; b) KCN,
DMF, 60 ꢀC; c) HOAc, conc. HCl, reflux; d) SOCl2; e) NaN3, DCE; f) heat, DCE.

ALTERNATIVE ROUTE TO DIMP
1439
Table 1. Characteristic NMR chemical shifts (ppm) for compounds 1 and 3–6
1H, 300 MHz, CDCl3
a-(CH3)2 a-CH2
13C, 75 MHz, CDCl3
C-X
C1
C6
CN (3)
1.38
1.22
1.33
1.18
1.37
2.45
2.37
2.95
2.35
3.36
124.22
184.97
179.83
185.56
122.82
118.91
180.30
173.43
180.19
122.29
CO2H (4)
COCl (5)
CON3 (6)
NCO (1)
Scheme 3. Selective reaction of 1 with primary alcohol 7. Reagents and conditions: a) neat or neat,
=
Zr[CH3COCH C(O-)CH3]4.
give 8 (Fig. 1). A broadened triplet associated with the NH of carbamate (ꢁ4.7 ppm)
appeared, most likely due to rotamers. The a-methylene group of the alcohol in 7
(ꢁ3.8 ppm) underwent a downfield shift of ꢁ0.5 ppm, and its multiplicity changed
from a quartet to a triplet (loss of OH coupling). The a-methylene of the primary
isocyanate in 1 (ꢁ3.3 ppm) underwent an upfield shift of ꢁ0.2 ppm, and its
Figure 1. Proton NMR spectra of reaction between 1 and 7 catalyzed by zirconium salt (CDCl3, 300 MHz).

1440
M. C. DAVIS AND L. C. BALDWIN
Figure 2. 1H-1H COSY experiment on 8 in CDCl3.
multiplicity changed from triplet to quartet (gain of NH coupling). The integration
of the broad triplet NH region and the a-methylene to the oxygen atom show a
nearly 1:1 ratio. A proton–proton coupled, two-dimensional NMR correlation spec-
troscopy (COSY) experiment was performed on pure 8 (Fig. 2). The cross peak
between the NH of the carbamate (ꢁ4.8 ppm) and the adjacent methylene group
(ꢁ3.2 ppm) confirms that reaction took place at the primary isocyanate of 1. When
this reaction was scaled up, it was discovered that the zirconium catalyst was not
required; apparently the basic nitrogen of 7 catalyzed the carbamate formation.
In conclusion, preparation of the regioselective diisocyanate 1 starting from
isobutyronitrile has been accomplished in six steps and 53% overall yield.
EXPERIMENTAL
The melting point was collected on an electrothermal capillary melting-point
apparatus and is not corrected. All NMR data were collected on a Bruker Avance
II 300-MHz spectrometer (1H at 300 MHz, 13C at 75 MHz) using deuterochloroform
(CDCl3) as a solvent. NMR data (free induction decays) were processed using NUTS
software from Acorn NMR (Livermore, CA). All spectra are referenced to CDCl3 or

ALTERNATIVE ROUTE TO DIMP
1441
tetramethylsilane (TMS), and the data are given in parts per million (ppm). Anhy-
drous tetrahydrofuran (THF, 99%, inhibited with 250 ppm 2,6-di-tert-butyl-4-
methylphenol), 2-(N-ethyl-anilino)ethanol (7, 99%), diisopropylamine (redistilled,
99.5%), sodium azide (NaN3, 99%), 1,2-dichloroethane (DCE, 99%), hexyllithium
(2.3 M in hexanes), isobutyronitrile (99%), 1-bromo-3-chloropropane (99%), potass-
ium cyanide (KCN, 97%), N,N-dimethylformamide (DMF, anhydrous, 99.8%),
thionyl chloride (SOCl2, 99%), and zirconium (IV) tetra(acetylacetonate) [Zr(acac)4,
98%] were purchased from Sigma-Aldrich Chemical Co. (Milwaukee). All other
solvents or reagents were obtained commercially and used as received. Elemental
analyses were made by Atlantic Microlab, Inc. (Norcross, GA).
2,2-Dimethyl-5-chlorovaleronitrile (2)
A 1-L, round-bottomed flask equipped with a magnetic stirbar, an N2 bubbler,
and an addition funnel was charged with 200 mL anhydrous THF and 63.7 mL di-
isopropylamine (0.46 mol). The mixture was cooled in an ice bath while 200 mL
2.3 M hexyllithium in hexanes (0.46 mol) were added in a gentle stream over
30 min. After stirring 20 min further, the mixture was then cooled to ꢂ78 ꢀC. A
new addition funnel was attached and filled with 32 g isobutyronitrile (0.463 mol),
which was added to the mixture over 20 min. The mixture was stirred at ꢂ78 ꢀC
for a further 20 min.
Meanwhile, a separated 1-L flask equipped with magnetic stirbar and
addition funnel was charged with 200 mL anhydrous THF and 120 g 1-bromo-3-
chloropropane (0.76 mol, 1.64 equiv). The solution was cooled in an ice bath before
the solution of the a-lithioisobutyronitrile solution was charged into the addition
funnel and then added in a steady stream over 20 min. The mixture became warm
as the reaction took place. The cooling bath was removed, and the mixture was stir-
red at rt overnight. Most of the THF was rotary evaporated, and the remaining resi-
due was partitioned between H2O and Et2O. After further extractions of the H2O
layer, the extracts were collected and washed once with H2O followed by brine. After
drying over anhydrous MgSO4, the solvent was rotary evaporated, leaving an oil.
The crude product was distilled at reduced pressure (0.1 torr), removing the excess
1-bromo-3-chloropropane, to give 56.76 g of product 2 as a colorless oil (83%).
dH: 3.59 (t, J ¼ 7.6 Hz, 2H), 2.03–1.91 (m, 2H), 1.74–1.65 (m, 2H), 1.37 (s, 6H);
dC: 124.60, 44.48, 38.34, 31.97, 28.44, 26.62. Elemental analysis calculated for
C7H12ClN: C, 57.73; H, 8.31; N, 9.62. Found: C, 57.95; H, 8.54; N, 9.64. A small
amount of colorless needles of 2,6-dimethyl-2,6-heptanedinitrile was left in the distil-
lation pot. Mp 108–110 ꢀC (lit.[17] 117 ꢀC). dH: 1.7–1.5 (m, 6H), 1.35 (s, 12H); dC:
124.99, 40.99, 32.46, 26.82, 21.33. Elemental analysis calculated for C11H18N2: C,
74.11; H, 10.18. Found: C, 73.81; H, 10.22.
2,2-Dimethyladiponitrile (3)
A 500-mL, round-bottomed flask equipped with magnetic stirbar was charged
with 56.76 g 2 (0.357 mol), 35 g KCN (0.54 mol, 1.5 equiv), and 100 mL DMF. The
mixture was heated to 100 ꢀC for 3 h. The mixture was cooled to rt and poured into
500 mL H2O. After several extractions with Et2O, the extracts were collected and

1442
M. C. DAVIS AND L. C. BALDWIN
washed with 200 mL brine. After drying over anhydrous MgSO4, the solvent was
evaporated, leaving a crude yellowish oil. Reduced pressure distillation (0.1 torr)
gave 45.14 g of product 3 as a colorless liquid (84%). dH: 2.45 (t, J ¼ 6.8 Hz, 2H),
1.92–1.79 (m, 2H), 1.72–1.64 (m, 2H), 1.38 (s, 6H); dC: 124.22, 118.91, 39.61,
31.92, 26.41, 21.35, 16.99. Elemental analysis calculated for C8H12N2: C, 70.55; H,
8.88; N, 20.57. Found: C, 70.79; H, 9.05; N, 20.53.
2,2-Dimethyladipic Acid (4)
A mixture of 17 g 3 (0.125 mol), 100 mL conc. HCl, and 50 mL glacial HOAc
was refluxed for 18 h. After cooling to rt, the mixture was extracted three times with
250-mL portions of Et2O. The extracts were collected, washed with 250 mL brine,
and then dried over anhydrous MgSO4. The solvent was evaporated, leaving a crude
crystalline solid (18.68 g, 86%). Product 4 was obtained as colorless crystals by
recrystallization from toluene. Mp 83–85 ꢀC (lit.[16] 87–88.5 ꢀC). dH: 12.04 (bs,
2 CO2H), 2.37 (t, J ¼ 6.4 Hz, 2H), 1.72–1.55 (m, 4H), 1.22 (s, 6H); dC: 184.97,
180.30, 42.28, 39.80, 34.56, 25.05, 20.39. Elemental analysis calculated for
C8H14O4: C, 55.17; H, 8.05. Found: C, 55.29; H, 8.08.
2,2-Dimethyladipoyl Dichloride (5)
To a 100-mL, round-bottomed flask equipped with magnetic stirbar, 12.29 g 4
(0.07 mol) was suspended in 20 mL SOCl2. The mixture was stirred at rt overnight,
and all the solids dissolved, forming a colorless solution. The SOCl2 was evaporated,
and the remaining liquid was distilled to give 14.22 g of product 5 as a colorless
liquid (96%). dH: 2.95 (m, 2H), 1.75–1.68 (m, 4H), 1.33 (s, 6H); dC: 179.83, 173.43,
52.73, 47.08, 38.92, 25.22, 20.56. Elemental analysis calculated for C8H12Cl2O2: C,
45.52; H, 5.73. Found: C, 45.48; H, 5.87.
1,4-Diisocyanato-4-methylpentane (1)
A 500-mL, round-bottomed flask equipped with magnetic stirbar was charged
with 14.22 g 5 (0.067 mol) and 200 mL DCE. The mixture was cooled in an ice bath
and vigorously stirred while a solution of 13 g NaN3 (0.2 mol, 3 equiv) in 50 mL H2O
was added dropwise over 15 min. After stirring 20 min further, the reaction was com-
1
plete according to H NMR, and a solution of 2,2-dimethyladipoyl diazide (6) [dH:
2.35 (t, J ¼ 6.7 Hz, 2H), 1.66–1.49 (m, 4H), 1.18 (s, 6H); dC: 185.56, 180.19, 44.34,
39.43, 37.09, 24.86, 20.24] was formed. For the next steps, the solution of 6 was kept
at less than 10 ꢀC by having an ice bath available. The reaction mixture was poured
into a 500-mL separatory funnel, and the organic layer was washed in sequence with
50 mL ice water followed by 50 mL cold saturated aqueous NaHCO3 and finally
50 mL cold brine. The organic phase was dried over anhydrous MgSO4 and filtered
into a 500-mL round-bottomed flask equipped with magnetic stirbar. The solution
1
was refluxed, and after 1 h the reaction was complete by H NMR. The DCE was
evaporated at the rotovap (30 ꢀC, 10 torr). The remaining liquid was distilled at
reduced pressure (0.2 torr) to give 10.4 g of product 1 as a colorless liquid (92%).
dH: 3.36 (t, J ¼ 6.3 Hz, 2H), 1.78–1.65 (m, 2H), 1.63–1.54 (m, 2H), 1.37 (s, 6H);

ALTERNATIVE ROUTE TO DIMP
1443
dC: 122.82, 122.29, 57.96, 43.14, 40.85, 30.31, 26.61, 24.93. Elemental analysis calcu-
lated for C8H12N2O2: C, 57.13; H, 7.19; N, 16.66. Found: C, 57.26; H, 7.33; N, 16.40.
2-(Ethyl(phenyl)amino)ethyl 4-isocyanato-4-methylpentylcarbamate
(8)
A two-necked, round-bottomed flask equipped with a magnetic stirbar and
thermometer for internal temperature measurement was charged with 7.08 g 1
(0.04 mol). In one portion, 6.95 g 7 (0.04 mol, 1 equiv) was added. As the alcohol dis-
solved, a mild endotherm ensued to ꢁ15 ꢀC, and then the temperature began a gentle
climb and peaked at 37 ꢀC. After stirring at rt for 18 h, the mixture was diluted with
10% EtOAc=hexanes and filtered through a small plug of SiO2 to remove some color
introduced by the alcohol. The filtrate was rotary evaporated, leaving a colorless oil
of product 8 that required no further purification. dH: 7.20 (t, J ¼ 7.6 Hz, 2H), 6.72
(d, J ¼ 8.3 Hz, 2H), 6.66 (t, J ¼ 7.2 Hz, 1H), 4.83 (t, J ¼ 6.1 Hz, NH), 4.19 (t,
J ¼ 6.4 Hz, 2H), 3.52 (t, J ¼ 6.4 Hz, 2H), 3.38 (q, J ¼ 7.2 Hz, 2H), 3.16 (q, J ¼ 6.4 Hz,
2H), 1.64–1.41 (m, 4H), 1.31 (s, 6H), 1.15 (t, J ¼ 7.2 Hz); dC: 156.57 (NCO2), 147.88
[(CH2)2NC], 129.41 (Cmeta, 2C), 122.65 (NCO), 116.20 (Cpara), 112.09 (Cortho, 2C),
62.14 (CH2O), 58.08 (OCH2CH2N), 49.28 (CH2CH3), 45.17 (CH2CH2NH), 41.08
(CNCO), 40.88 (CH2CH2NH), 30.25 [(CH3)2, 2C], 25.41 (CH2CH2CH2NH), 12.29
(CH2CH3). Elemental analysis calculated for C18H27N3O3: C, 64.84; H, 8.16; N,
12.60. Found: C, 64.56; H, 8.16; N, 12.37.
ACKNOWLEDGMENTS
The generous financial support from the Army Research Laboratory is grate-
fully acknowledged. Thanks to Ann M. Moorehead of the Technical Library for
obtaining Ref. 1.
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copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
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