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04-BS-12 · May 2016

Question 13 of 13: Proposed Syntheses of Two Amines

Nivaar worked solution (AI-drafted; not reviewed by a licensed engineer)

Notes on this paper

National Exam 04-BS-12, Organic Chemistry — May 2016. 3 hours, closed-book examination; one aid sheet (8.5×11", both sides) and a Casio or Sharp calculator permitted. Ten questions constitute a complete exam paper (only the first 10 questions as they appear in the answer book are marked, each of equal value) — the source paper in fact prints thirteen questions; all thirteen are answered in full below.

Reference texts: McMurry, Organic Chemistry, 9th ed. (functional-group spectroscopy, amino-acid ionisation, conjugate addition, electrophilic/nucleophilic aromatic substitution, SN1/SN2 and epoxide-opening regiochemistry, stereochemistry and meso compounds, cyclohexane/bridged-ring conformational analysis, α-halogenation, and multi-step synthesis design); Atkins, Physical Chemistry, 11th ed. (Hughes–Ingold solvent-polarity rules).

Question 13: Proposed Syntheses of Two Amines

Question text not reproduced: the examination questions are © Engineers and Geoscientists BC. Open the official past paper (linked at the top of this page) to read the question, then follow the worked solution below.

  1. Target A: 3-(dimethylamino)-1-phenylcyclohexan-1-ol.
    target A
    The target combines a tertiary benzylic alcohol (C1: OH + Ph) with a dimethylamino group three carbons away (C3, a 1,3-relationship). Both pieces are installed cleanly from the symmetric, commercially available 1,3-cyclohexanedione:
    1. Step 1 — reductive amination at one ketone. 1,3-Cyclohexanedione + Me2NH, then NaBH(OAc)3 or NaBH3CN (mildly acidic conditions): the amine condenses with one carbonyl to form an iminium ion, which the mild hydride source reduces selectively (the two ketones of the starting diketone are constitutionally equivalent, so either one reacting first gives the same mono-amino-ketone), leaving the second ketone untouched.
      1,3-cyclohexanedione
      3-(dimethylamino)cyclohexanone
    2. Step 2 — Grignard addition to the remaining ketone. 3-(Dimethylamino)cyclohexan-1-one + PhMgBr, then aqueous work-up: phenylmagnesium bromide adds to the one remaining carbonyl, giving the tertiary benzylic alcohol directly. Grignard reagents do not react with a tertiary amine, so the NMe2 group installed in step 1 survives unchanged.
    target A (after PhMgBr addition)
  2. Target B: 3-(cyclopentyloxy)propan-1-amine.
    target B
    This target is an ether-linked cyclopentyl/3-aminopropyl unit. A free primary amine is a poor partner for direct Williamson-ether alkylation chemistry (competing self-alkylation/polyalkylation), so the cleanest disconnection installs the amine last, from a nitrile:
    1. Step 1 — oxa-Michael addition of cyclopentoxide to acrylonitrile. Cyclopentanol + NaH (or Na metal) generates cyclopentoxide, which undergoes conjugate addition to acrylonitrile (CH2=CH–CN) — a standard, mild, halide-free way to install a β-alkoxy nitrile, avoiding any alkyl-halide/free-amine competition.
      cyclopentanol
      acrylonitrile
      3-(cyclopentyloxy)propanenitrile
    2. Step 2 — nitrile reduction. 3-(Cyclopentyloxy)propanenitrile + LiAlH4 (or H2/Raney Ni), then aqueous work-up: reduces the nitrile directly to the primary amine, giving target B.
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